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Women’s and Children’s Health - Women’s and Children’s Health Publications

Novel approaches to examining weight changes in pregnancies affected by obesity

Current gestational weight change (GWC) recommendations for obese individuals were established with limited evidence of the pattern and timing of weight change across pregnancy. Similarly, the recommendation of 5-9 kg does not differentiate by the severity of obesity. We sought to describe GWC trajectory classes by obesity grade and associated infant outcomes among a large, diverse cohort. The study population included 22,355 individuals with singleton pregnancies, obesity (BMI ≥30.0 kg/m2), and normal glucose tolerance who delivered at Kaiser Permanente Northern California between 2008 and 2013. Obesity grade-specific GWC trajectories were modeled at 38 wk using flexible latent class mixed modeling (package lcmm) in R. Multivariable Poisson or linear regression models estimated the associations between the GWC trajectory class and infant outcomes (size-for-gestational age and preterm birth) by obesity grade. Five GWC trajectory classes were identified for each obesity grade, each with a distinct pattern of weight change before 15 wk (including loss, stability, and gain) followed by weight gain thereafter (low, moderate, and high). Two classes with high overall gain were associated with an increased risk for large for gestational age (LGA) in obesity grade 1 (IRR = 1.27; 95% CI: 1.10, 1.46; IRR = 1.47; 95% CI: 1.24, 1.74). Both high (IRR = 2.02; 95% CI: 1.61, 2.52; IRR = 1.98; 95% CI: 1.52, 2.58) and 2 moderate-gain classes (IRR = 1.40; 95% CI 1.14, 1.71; IRR = 1.51; 95% CI: 1.20, 1.90) were associated with LGA in grade 2, and only early loss/late moderate-gain class 3 (IRR = 1.30; 95% CI: 1.04, 1.62) was associated in grade 3. This class was also associated with preterm birth in grade 2. No associations were detected between GWC and small for gestational age (SGA). Among the pregnancies affected by obesity, GWC was not linear or uniform. Different patterns of high gain were associated with an increased risk for LGA with the greatest magnitude in obesity grade 2, whereas GWC patterns were not associated with SGA.

Authors: Nichols, Amy R; Burns, Natalie; Xu, Fei; Foster, Saralyn F; Rickman, Rachel; Hedderson, Monique M; Widen, Elizabeth M

Am J Clin Nutr. 2023 May;117(5):1026-1034. Epub 2023-03-05.

PubMed abstract

Prenatal exposure to per- and polyfluoroalkyl substances and childhood autism-related outcomes

Epidemiologic evidence linking prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with altered neurodevelopment is inconclusive, and few large studies have focused on autism-related outcomes. We investigated whether blood concentrations of PFAS in pregnancy are associated with child autism-related outcomes. We included 10 cohorts from the National Institutes of Health (NIH)-funded Environmental influences on Child Health Outcomes (ECHO) program (n = 1,429). We measured 14 PFAS analytes in maternal blood collected during pregnancy; eight analytes met detection criteria for analysis. We assessed quantitative autism-related traits in children via parent report on the Social Responsiveness Scale (SRS). In multivariable linear models, we examined relationships of each PFAS (natural log-transformed) with SRS scores. We further modeled PFAS as a complex mixture using Bayesian methods and examined modification of these relationships by child sex. Most PFAS in maternal blood were not associated with child SRS T-scores. Perfluorononanoic acid (PFNA) showed the strongest and most consistent association: each 1-unit increase in ln-transformed PFNA was associated with greater autism-related traits (adjusted β [95% confidence interval (CI)] = 1.5 [-0.1, 3.0]). The summed mixture, which included six PFAS detected in >70% of participants, was not associated with SRS T-scores (adjusted β [95% highest posterior density interval] = 0.7 [-1.4, 3.0]). We did not observe consistent evidence of sex differences. Prenatal blood concentrations of PFNA may be associated with modest increases in child autism-related traits. Future work should continue to examine the relationship between exposures to both legacy and emerging PFAS and additional dimensional, quantitative measures of childhood autism-related outcomes.

Authors: Ames, Jennifer L; Avalos, Lyndsay A; Croen, Lisa A; Ferrara, Assiamira; Hedderson, Monique M; Zhu, Yeyi; program collaborators for Environmental influences on Child Health Outcomes,; et al.

Epidemiology. 2023 May 01;34(3):450-459. Epub 2023-04-03.

PubMed abstract

Prepregnancy Body Mass Index and Risk of Childhood Asthma

Growing evidence suggests that maternal obesity may affect the intrauterine environment and increase a child’s risk of developing asthma. We aim to investigate the relationship between prepregnancy obesity and childhood asthma risk. Cohorts of children enrolled in Kaiser Permanente Northern California integrated healthcare system were followed from birth (2005-2014) to age 4 (n = 104,467), 6 (n = 63,084), or 8 (n = 31,006) using electronic medical records. Child’s asthma was defined using ICD codes and asthma-related prescription medication dispensing. Risk ratios (RR) and 95% confidence intervals (95% CIs) for child’s asthma were estimated using Poisson regression with robust error variance for (1) prepregnancy BMI categories (underweight [<18.5], normal [18.5-24.9], overweight [25-29.9], obese 1 [30-34.9], and obese 2/3 [≥35]) and (2) continuous prepregnancy BMI modeled using cubic splines with knots at BMI category boundaries. Models were adjusted for maternal age, education, race, asthma, allergies, smoking, gestational weight gain, child's birth year, parity, infant sex, gestational age, and child's BMI. Relative to normal BMI, RRs (95%CIs) for asthma at ages 4, 6, and 8 were 0.91 (0.75, 1.11), 0.95 (0.78, 1.16), and 0.97 (0.75, 1.27) for underweight, 1.06 (0.99, 1.14), 1.08 (1.01, 1.16), and 1.03 (0.94, 1.14) for overweight, 1.09 (1.00, 1.19), 1.12 (1.03, 1.23), 1.03 (0.91, 1.17) for obese 1, and 1.10 (0.99, 1.21), 1.13 (1.02, 1.25), 1.14 (0.99, 1.31) for obese 2/3. When continuous prepregnancy BMI was modeled with splines, child's asthma risk generally increased linearly with increasing prepregnancy BMI. Higher prepregnancy BMI is associated with modestly increased childhood asthma risk.

Authors: Rosenquist, Natalie A; Richards, Megan; Ferber, Jeannette R; Li, De-Kun; Ryu, So Young; Burkin, Heather; Strickland, Matthew J; Darrow, Lyndsey A

Allergy. 2023 May;78(5):1234-1244. Epub 2022-12-11.

PubMed abstract

Opportunities for Inclusion and Engagement in the Transition of Autistic Youth from Pediatric to Adult Healthcare: A Qualitative Study

Transitioning autistic youth from pediatric to adult healthcare requires coordination of multiple stakeholders, including youth, caregivers, and pediatric and adult care providers, whose interests at times overlap but often differ. To understand barriers and facilitators to inclusive transition experiences, we conducted thematic analysis of interviews with 39 stakeholders from the same large, integrated healthcare system. We identified three major themes: (1) Navigating the healthcare transition without guidance, (2) Health consequences of a passive healthcare transition, and (3) Strategies for inclusion and continuous engagement. Facilitators included gradual transition planning, a warm handoff between providers, and support of shared healthcare decision-making. Providers also sought clinical tools and logistical supports such as care coordinators and longer transition-specific visit types to enhance patient-centered care.

Authors: Ames, Jennifer L; Mahajan, Arjun; Davignon, Meghan N; Massolo, Maria L; Croen, Lisa A

J Autism Dev Disord. 2023 May;53(5):1850-1861. Epub 2022-03-09.

PubMed abstract

Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort

There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.

Authors: Feinberg, Jason I; Schrott, Rose; Ladd-Acosta, Christine; Newschaffer, Craig J; Hertz-Picciotto, Irva; Croen, Lisa A; Daniele Fallin, M; Feinberg, Andrew P; Volk, Heather E

Mol Psychiatry. 2023 Apr 27.

PubMed abstract

Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study

Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (β = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p’-DDE was associated with lower social deficits (β = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (β = 5.68, 95% CI: 0.18, 11.17; β = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p’-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. We observed independent effects of PCB180, PCB187, PBDE47, and p,p’ DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

Authors: Song, Ashley Y; Kauffman, Elizabeth M; Hamra, Ghassan B; Dickerson, Aisha S; Croen, Lisa A; Hertz-Picciotto, Irva; Schmidt, Rebecca J; Newschaffer, Craig J; Fallin, M Daniele; Lyall, Kristen; Volk, Heather E

Environ Res. 2023 Apr 26:115978.

PubMed abstract

Health Care Utilization During the COVID-19 Pandemic Among Individuals Born Preterm

Limited data exist on pediatric health care utilization during the COVID-19 pandemic among children and young adults born preterm. To investigate differences in health care use related to COVID-19 concerns during the pandemic among children and young adults born preterm vs those born at term. In this cohort study, questionnaires regarding COVID-19 and health care utilization were completed by 1691 mother-offspring pairs from 42 pediatric cohorts in the National Institutes of Health Environmental Influences on Child Health Outcomes Program. Children and young adults (ages 1-18 years) in these analyses were born between 2003 and 2021. Data were recorded by the August 31, 2021, data-lock date and were analyzed between October 2021 and October 2022. Premature birth (<37 weeks' gestation). The main outcome was health care utilization related to COVID-19 concerns (hospitalization, in-person clinic or emergency department visit, phone or telehealth evaluations). Individuals born preterm vs term (≥37 weeks' gestation) and differences among preterm subgroups of individuals (<28 weeks', 28-36 weeks' vs ≥37 weeks' gestation) were assessed. Generalized estimating equations assessed population odds for health care used and related symptoms, controlling for maternal age, education, and psychiatric disorder; offspring history of bronchopulmonary dysplasia (BPD) or asthma; and timing and age at COVID-19 questionnaire completion. Data from 1691 children and young adults were analyzed; among 270 individuals born preterm, the mean (SD) age at survey completion was 8.8 (4.4) years, 151 (55.9%) were male, and 193 (71.5%) had a history of BPD or asthma diagnosis. Among 1421 comparison individuals with term birth, the mean (SD) age at survey completion was 8.4 (2.4) years, 749 (52.7%) were male, and 233 (16.4%) had a history of BPD or asthma. Preterm subgroups included 159 individuals (58.5%) born at less than 28 weeks' gestation. In adjusted analyses, individuals born preterm had a significantly higher odds of health care utilization related to COVID-19 concerns (adjusted odds ratio [aOR], 1.70; 95% CI, 1.21-2.38) compared with term-born individuals; similar differences were also seen for the subgroup of individuals born at less than 28 weeks' gestation (aOR, 2.15; 95% CI, 1.40-3.29). Maternal history of a psychiatric disorder was a significant covariate associated with health care utilization for all individuals (aOR, 1.44; 95% CI, 1.17-1.78). These findings suggest that during the COVID-19 pandemic, children and young adults born preterm were more likely to have used health care related to COVID-19 concerns compared with their term-born peers, independent of a history of BPD or asthma. Further exploration of factors associated with COVID-19-related health care use may facilitate refinement of care models.

Authors: McGowan, Elisabeth C; Ferrara, Assiamira M; program collaborators for Environmental Influences on Child Health Outcomes (ECHO),; et al.

JAMA Netw Open. 2023 Apr 03;6(4):e2310696. Epub 2023-04-03.

PubMed abstract

Assessment of Psychosocial and Neonatal Risk Factors for Trajectories of Behavioral Dysregulation Among Young Children From 18 to 72 Months of Age

Emotional and behavioral dysregulation during early childhood are associated with severe psychiatric, behavioral, and cognitive disorders through adulthood. Identifying the earliest antecedents of persisting emotional and behavioral dysregulation can inform risk detection practices and targeted interventions to promote adaptive developmental trajectories among at-risk children. To characterize children’s emotional and behavioral regulation trajectories and examine risk factors associated with persisting dysregulation across early childhood. This cohort study examined data from 20 United States cohorts participating in Environmental influences on Child Health Outcomes, which included 3934 mother-child pairs (singleton births) from 1990 to 2019. Statistical analysis was performed from January to August 2022. Standardized self-reports and medical data ascertained maternal, child, and environmental characteristics, including prenatal substance exposures, preterm birth, and multiple psychosocial adversities. Child Behavior Checklist caregiver reports at 18 to 72 months of age, with Dysregulation Profile (CBCL-DP = sum of anxiety/depression, attention, and aggression). The sample included 3934 mother-child pairs studied at 18 to 72 months. Among the mothers, 718 (18.7%) were Hispanic, 275 (7.2%) were non-Hispanic Asian, 1220 (31.8%) were non-Hispanic Black, 1412 (36.9%) were non-Hispanic White; 3501 (89.7%) were at least 21 years of age at delivery. Among the children, 2093 (53.2%) were male, 1178 of 2143 with Psychosocial Adversity Index [PAI] data (55.0%) experienced multiple psychosocial adversities, 1148 (29.2%) were exposed prenatally to at least 1 psychoactive substance, and 3066 (80.2%) were term-born (≥37 weeks’ gestation). Growth mixture modeling characterized a 3-class CBCL-DP trajectory model: high and increasing (2.3% [n = 89]), borderline and stable (12.3% [n = 479]), and low and decreasing (85.6% [n = 3366]). Children in high and borderline dysregulation trajectories had more prevalent maternal psychological challenges (29.4%-50.0%). Multinomial logistic regression analyses indicated that children born preterm were more likely to be in the high dysregulation trajectory (adjusted odds ratio [aOR], 2.76; 95% CI, 2.08-3.65; P < .001) or borderline dysregulation trajectory (aOR, 1.36; 95% CI, 1.06-1.76; P = .02) vs low dysregulation trajectory. High vs low dysregulation trajectories were less prevalent for girls compared with boys (aOR, 0.60; 95% CI, 0.36-1.01; P = .05) and children with lower PAI (aOR, 1.94; 95% CI, 1.51-2.49; P < .001). Combined increases in PAI and prenatal substance exposures were associated with increased odds of high vs borderline dysregulation (aOR, 1.28; 95% CI, 1.08-1.53; P = .006) and decreased odds of low vs high dysregulation (aOR, 0.77; 95% CI, 0.64-0.92; P = .005). In this cohort study of behavioral dysregulation trajectories, associations were found with early risk factors. These findings may inform screening and diagnostic practices for addressing observed precursors of persisting dysregulation as they emerge among at-risk children.

Authors: Hofheimer, Julie A; Croen, Lisa A; Program Collaborators for Environmental influences on Child Health Outcomes,; et al.

JAMA Netw Open. 2023 Apr 03;6(4):e2310059. Epub 2023-04-03.

PubMed abstract

The prospective association of hyperandrogenism, oligomenorrhea and polycystic ovary syndrome with incident gestational diabetes: The coronary artery risk development in young adults women’s study

In this 28-year prospective study of 455 women (mean age: 26 years), polycystic ovary syndrome (PCOS) was associated with a 2.6-fold elevated risk of gestational diabetes (GDM). However, hyperandrogenism or oligomenorrhea in the absence of PCOS was not associated with GDM.

Authors: Appiah, Duke; Hedderson, Monique M; Kim, Catherine; Sidney, Stephen; Sternfeld, Barbara; Quesenberry, Charles P; Wellons, Melissa F; Gunderson, Erica P

Diabetes Res Clin Pract. 2023 Apr;198:110593. Epub 2023-03-02.

PubMed abstract

NICU Versus Mother/Baby Unit Admission for Low-Acuity Infants Born at 35 Weeks’ Gestation

To estimate the effect of NICU admission of low-acuity infants born at 35 weeks’ gestation versus care in a mother/baby unit, on inpatient and outpatient medical outcomes. This retrospective cohort study included 5929 low-acuity infants born at 350/7 to 356/7 weeks’ gestation at 13 Kaiser Permanente Northern California hospitals with level II or level III NICUs between January 1, 2011, and December 31, 2021. Exclusion criteria included congenital anomalies and early respiratory support or antibiotics. We used multivariable regression and regression discontinuity analyses to control for confounding variables. Infants admitted to the NICU within 2 hours of birth (n = 862, 14.5%) had a 58 hour adjusted (98-hour unadjusted) longer length of stay. NICU admission was associated with an increased probability of a length of stay ≥96 hours (67% vs 21%; adjusted odds ratio [aOR], 4.94; 95% confidence interval [CI], 3.96-6.16). Regression discontinuity results suggested a similar (57 hour) increase in length of stay. Readmission risk, primarily for jaundice, was lower for those admitted to the NICU (3% vs 6%; aOR, 0.43; 95% CI, 0.27-0.69). Infants admitted to the NICU were slightly less likely to be receiving exclusive breast milk at 6-month follow-up (15% vs 25%; aOR, 0.73; 95% CI, 0.55-0.97; adjusted marginal risk difference -5%). Admitting low-acuity infants born at 35 weeks’ gestation to the NICU was associated with decreased readmission, but with longer length of stay and decreased exclusive breast milk feeding at 6 months. Routine NICU admission may be unnecessary for low-acuity infants born at 35 weeks’ gestation.

Authors: Wickremasinghe, Andrea C; Kuzniewicz, Michael W; Walsh, Eileen M; Li, Sherian; Newman, Thomas B

Pediatrics. 2023 Apr 01;151(4).

PubMed abstract

Changes in Body Mass Index Among School-Aged Youths Following Implementation of the Healthy, Hunger-Free Kids Act of 2010

The prevalence of obesity among youths 2 to 19 years of age in the US from 2017 to 2018 was 19.3%; previous studies suggested that school lunch consumption was associated with increased obesity. The Healthy, Hunger-Free Kids Act of 2010 (HHFKA) strengthened nutritional standards of school-based meals. To evaluate the association between the HHFKA and youth body mass index (BMI). This cohort study was conducted using data from the Environmental Influences on Child Health Outcomes program, a nationwide consortium of child cohort studies, between January 2005 and March 2020. Cohorts in the US of youths aged 5 to 18 years with reported height and weight measurements were included. Full implementation of the HHFKA. The main outcome was annual BMI z-score (BMIz) trends before (January 2005 to August 2016) and after (September 2016 to March 2020) implementation of the HHFKA, adjusted for self-reported race, ethnicity, maternal education, and cohort group. An interrupted time-series analysis design was used to fit generalized estimating equation regression models. A total of 14 121 school-aged youths (7237 [51.3%] male; mean [SD] age at first measurement, 8.8 [3.6] years) contributing 26 205 BMI measurements were included in the study. Overall, a significant decrease was observed in the annual BMIz in the period following implementation of the HHFKA compared with prior to implementation (-0.041; 95% CI, -0.066 to -0.016). In interaction models to evaluate subgroup associations, similar trends were observed among youths 12 to 18 years of age (-0.045; 95% CI, -0.071 to -0.018) and among youths living in households with a lower annual income (-0.038; 95% CI, -0.063 to -0.013). In this cohort study, HHFKA implementation was associated with a significant decrease in BMIz among school-aged youths in the US. The findings suggest that school meal programs represent a key opportunity for interventions to combat the childhood obesity epidemic given the high rates of program participation and the proportion of total calories consumed through school-based meals.

Authors: Chandran, Aruna; Ferrara, Assiamira; Hedderson, Monique; Knapp, Emily; et al.

JAMA Pediatr. 2023 Apr 01;177(4):401-409.

PubMed abstract

In utero metabolomic signatures of refined grains intake and risk of gestational diabetes: A metabolome-wide association study

Epidemiologic evidence has linked refined grain intake to a higher risk of gestational diabetes (GDM), but the biological underpinnings remain unclear. We aimed to identify and validate refined grain-related metabolomic biomarkers for GDM risk. In a metabolome-wide association study of 91 cases with GDM and 180 matched controls without GDM (discovery set) nested in the prospective Pregnancy Environment and Lifestyle Study (PETALS), refined grain intake during preconception and early pregnancy and serum untargeted metabolomics were assessed at gestational weeks 10-13. We identified refined grain-related metabolites using multivariable linear regression and examined their prospective associations with GDM risk using conditional logistic regression. We further examined the predictivity of refined grain-related metabolites selected by least absolute shrinkage and selection operator regression in the discovery set and validation set (a random PETALS subsample of 38 individuals with and 336 without GDM). Among 821 annotated serum (87.4% fasting) metabolites, 42 were associated with refined grain intake, of which 17 (70.6% in glycerolipids, glycerophospholipids, and sphingolipids clusters) were associated with subsequent GDM risk (all false discovery rate-adjusted P values <0.05). Adding 7 of 17 metabolites to a conventional risk factor-based prediction model increased the C-statistic for GDM risk in the discovery set from 0.71 (95% CI: 0.64, 0.77) to 0.77 (95% CI: 0.71, 0.83) and in the validation set from 0.77 (95% CI: 0.69, 0.86) to 0.81 (95% CI: 0.74, 0.89), both with P-for-difference <0.05. Clusters of glycerolipids, glycerophospholipids, and sphingolipids may be implicated in the association between refined grain intake and GDM risk, as demonstrated by the significant associations of these metabolites with both refined grains and GDM risk and the incremental predictive value of these metabolites for GDM risk beyond the conventional risk factors. These findings provide evidence on the potential biological underpinnings linking refined grain intake to the risk of GDM and help identify novel disease-related dietary biomarkers to inform diet-related preventive strategies for GDM.

Authors: Chehab, Rana F; Ferrara, Assiamira; Zheng, Siwen; Barupal, Dinesh K; Ngo, Amanda L; Chen, Liwei; Fiehn, Oliver; Zhu, Yeyi

Am J Clin Nutr. 2023 Apr;117(4):731-740. Epub 2023-02-11.

PubMed abstract

Incidence Rates of Medically Attended COVID-19 in Infants Less Than 6 Months of Age

Studies suggest infants may be at increased risk of severe coronavirus disease 2019 (COVID-19) relative to older children, but few data exist regarding the incidence of COVID-19 episodes and associated risk factors. We estimate incidence rates and describe characteristics associated with medically attended COVID-19 episodes among infants younger than 6 months of age. We analyzed electronic medical record data from a cohort of infants born March 1, 2020-February 28, 2021. Data from 3 health care delivery systems included demographic characteristics, maternal and infant outpatient visit and hospitalization diagnoses and severe acute respiratory syndrome coronavirus syndrome 2 (SARS-CoV-2) test results. Medically attended COVID-19 episodes were defined by positive SARS-CoV-2 clinical tests and/or COVID-19 diagnosis codes during medical care visits. Unadjusted and site-adjusted incidence rates by infant month of age, low and high SARS-CoV-2 circulation periods and maternal COVID-19 diagnosis were calculated. Among 18,192 infants <6 months of age whose mothers received prenatal care within the 3 systems, 173 (1.0%) had medically attended COVID-19 episodes. Incidence rates were highest among infants under 1 month of age (2.0 per 1000 person-weeks) and 1 month (2.0 per 1000 person-weeks) compared with older infants. Incidence rates were also higher for infants born to women with postpartum COVID-19 compared with women without known COVID-19 and women diagnosed with COVID-19 during pregnancy. Infants of women with postpartum COVID-19 had a higher risk of medically attended COVID-19 than infants born to mothers who were diagnosed during pregnancy or never diagnosed underscoring the importance of COVID-19 prevention measures for their household members and caregivers to prevent infections in infants.

Authors: Griffin, Isabel; Li, De-Kun; Munoz, Flor M; et al.

Pediatr Infect Dis J. 2023 Apr 01;42(4):315-320. Epub 2023-01-05.

PubMed abstract

Prenatal Antidepressant Exposures and Autism Spectrum Disorder or Traits: A Retrospective, Multi-Cohort Study

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Authors: Brennan, Patricia A; Croen, Lisa A; Avalos, Lyndsay A; Paneth, Nigel; et al.

Res Child Adolesc Psychopathol. 2023 Apr;51(4):513-527. Epub 2022-11-22.

PubMed abstract

Racial-Ethnic Differences in Treatment Initiation for New Diagnoses of Perinatal Depression

The adverse consequences of untreated perinatal depression highlight the need to identify populations to target in order to increase treatment rates. The authors sought to evaluate treatment initiation for a new diagnosis of depression during pregnancy or postpartum and to describe racial-ethnic differences in initiation and type (psychotherapy, antidepressants) of treatment in a large health care system with universal perinatal depression screening. This retrospective cohort study included women who delivered a live birth in the Kaiser Permanente Northern California system between October 2012 and May 2017. Black, Latina, Asian, and White women ages ≥15 years were eligible. New depression diagnoses were defined by using ICD-9 and ICD-10 codes from electronic health records. Treatment initiation was defined as receiving at least one antidepressant medication dispensation or psychotherapy visit up to 90 days after the diagnosis. Modified Poisson regression was used to estimate the risk for initiating treatment and the type of treatment initiated. In total, 13,637 women with a new depression diagnosis (prenatal: N=7,041, 51.6%; postpartum: N=6,596, 48.4%) were identified. Of the pregnant women, 31.4% initiated treatment, and of the postpartum women, 73.1% initiated treatment. Latina and Asian women were less likely than White women to initiate treatment postpartum. During pregnancy and postpartum, non-White women were more likely to initiate psychotherapy. White women were more likely to initiate antidepressant medication during pregnancy and postpartum or a combination of antidepressant medication and psychotherapy during the postpartum period. Research is warranted to identify patient-, provider-, and system-level barriers that contribute to racial-ethnic disparities in perinatal mental health care.

Authors: Avalos, Lyndsay A; Nance, Nerissa; Iturralde, Esti; Badon, Sylvia E; Quesenberry, Charles P; Sterling, Stacy; Li, De-Kun; Flanagan, Tracy

Psychiatr Serv. 2023 Apr 01;74(4):341-348. Epub 2022-10-13.

PubMed abstract

Incidence Rates of Childhood Asthma with Recurrent Exacerbations in the U.S. Environmental influences on Child Health Outcomes (ECHO) Program

Descriptive epidemiological data on incidence rates (IRs) of asthma with recurrent exacerbations (ARE) are sparse. We hypothesized that IRs for ARE would vary by time, geography, age, race and ethnicity, irrespective of parental asthma history. We leveraged data from 17246 children born after 1990 enrolled in 59 U.S. and one Puerto Rican cohort in the Environmental Influences on Child Health Outcomes consortium to estimate IRs for AREs. The overall crude IR for ARE was 6.07/1000 person-years (95% confidence intervals (CI) 5.63, 6.51) and was highest for children age 2-4 years, for Hispanic and non-Hispanic Black children and for those with a parental history of asthma. ARE IRs were higher for 2-4 year olds in each race and ethnicity category and for both sexes. Multi-variable analysis confirmed higher adjusted ARE IRs (aIRR) for children born 2000-2009 compared to 1990-1999 and 2010-2017, 2-4 versus 10-19 years old (aIRR=15.36; CI 12.09, 2.99), and for males versus females (aIRR=1.34; CI 1.16, 1.55). Black children (non-Hispanic and Hispanic) had higher rates than non-Hispanic White children (aIRR=2.51; CI 2.10, 2.99 and aIRR=2.04; CI 1.22, 3.39, respectively). Children born in the Midwest, Northeast and South had higher rates than the West (p<0.01 for each comparison). Children with a parental history of asthma had rates nearly three times higher than those without such history (aIRR=2.90; CI 2.43-3.46). Factors associated with time, geography, age, race and ethnicity, sex and parental history appear to influence the inception of ARE among children and adolescents.

Authors: Miller, Rachel L; Ferrara, Assiamira; program collaborators for Environmental influences on Child Health Outcomes,; et al.

J Allergy Clin Immunol. 2023 Mar 25.

PubMed abstract

The Environmental influences on Child Health Outcomes (ECHO)-wide Cohort

The Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children’s health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-wide Cohort data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in five main outcome areas: pre-, peri-, and post-natal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include place- (e.g., air pollution, neighborhood socioeconomic status), family- (e.g., parental mental health), and individual-level (e.g., diet, genomics) factors.

Authors: Knapp, Emily A; Croen, Lisa; Ferrara, Assiamira; Environmental Influences On Child Health Outcomes, On Behalf Of Program Collaborators For; et al.

Am J Epidemiol. 2023 Mar 24.

PubMed abstract

Modifying the social responsiveness scale for adaptive administration

The social responsiveness scale (SRS) is frequently used to quantify the autism-related phenotype and is gaining use in health outcomes research. However, it has a high respondent burden (65 items) for large-scale studies. Further, most evaluations of it have focused on the school-age form, not the preschool form. More validity evidence of shortened forms is necessary in the general population to support the broader health outcomes context of use. We evaluated the psychometrics of the SRS in 7030 individuals from multiple predominantly neurotypical samples in order to shorten it based on non-autistic sample metrics. Analyses included item factor analysis, differential item functioning (DIF), and multiple-group item response theory (IRT) to place the SRS items on a comparable scale, which was then simulated via computer adaptive testing (CAT) administration. The SRS was broadly unidimensional with few methodological residual dependencies. On average, males had more autistic characteristics than females, and preschoolers had fewer characteristics than school-age children. The final IRT calibration included 45 items equated across forms, and each form had 11 with significant wording discrepancies and 9 items with near-identical wording that exhibited form-related DIF. The CAT simulation suggested a median of 14 items was sufficient to reach a reliable score, demonstrating its feasibility across the range of impairments. IRT allows practitioners the ability to get highly reliable scores with fewer items than the full-length SRS. This supports the future application of the SRS in a computer adaptive testing mode in both neurotypical and ASD samples.

Authors: Kaat, Aaron J; Croen, Lisa A; Constantino, John; Newshaffer, Craig J; Lyall, Kristen

Qual Life Res. 2023 Mar 21.

PubMed abstract

A framework for measuring the cost to families of caring for children’s health: the design, methodology, and study population of the r-Kids study

All families experience financial and time costs related to caring for their children’s health. Understanding the economic burden faced by families of children with chronic health conditions (CHC) is crucial for designing effective policies to support families. In this prospective study we used electronic health records to identify children between 3 and 17 years old with autism spectrum disorder (ASD), asthma, or neither (control) from three Kaiser Permanente regions and several community health centers in the OCHIN network. We oversampled children from racial and ethnic minority groups. Parent/guardian respondents completed surveys three times, approximately four months apart. The surveys included the Family Economic Impact Inventory (measuring financial, time, and employment costs of caring for a child’s health), and standardized measures of children’s quality of life, behavioral problems, and symptom severity for children with ASD or asthma. We also assessed parenting stress and parent physical and mental health. All materials were provided in English and Spanish. Of the 1,461 families that enrolled (564 ASD, 468 asthma, 429 control), children were predominantly male (79%), with a mean age of 9.0 years, and racially and ethnically diverse (43% non-Hispanic white; 22% Hispanic; 35% Asian, Black, Native Hawaiian, or another race/ethnicity). The majority of survey respondents were female (86%), had a college degree (62%), and were married/partnered (79%). ASD group respondents were less likely to be employed (73%) than those in the asthma or control groups (both 80%; p = .023). Only 32% of the control group reported a household income ≤ $4,000/month compared with 41% of asthma and 38% of ASD families (p = .006). Utilizing a novel measure assessing family economic burden, we successfully collected survey responses from a large and diverse sample of families. Drawing upon the conceptual framework, survey measures, and self-report data described herein we will conduct future analyses to examine the economic burdens related to CHC and the incremental differences in these burdens between health groups. This information will help policy makers to design more equitable health and social policies that could reduce the burden on families.

Authors: Bulkley, Joanna E; Croen, Lisa A; Lynch, Frances L; et al.

BMC Pediatr. 2023 Mar 20;23(1):128. Epub 2023-03-20.

PubMed abstract

Rates of malignancies among patients with moderate to severe atopic dermatitis: a retrospective cohort study

Patients with atopic dermatitis (AD), also known as eczema, may be at an increased risk for malignancies compared with patients without AD; however, incidence rates (IRs) of malignancies in patients with moderate to severe AD are largely unknown. The objective of this study was to evaluate and compare IRs of malignancies in adults with moderate to severe AD (aged ≥18 years). Retrospective cohort study using data from a Kaiser Permanente Northern California (KPNC) cohort. AD severity classification was adjudicated with medical chart review. Covariates and stratification variables included age, sex and smoking status. Data were obtained from the KPNC healthcare delivery system in northern California, USA. Cases of AD were defined by outpatient dermatologist-rendered codes and prescriptions of topical therapy or phototherapy (moderate) or systemic treatment (severe). KPNC health plan members with moderate or severe AD (2007-2018). Malignancy IRs and 95% CIs per 1000 person-years were calculated. 7050 KPNC health plan members with moderate and severe AD met eligibility criteria for inclusion. IRs (95% CI) were highest for non-melanoma skin cancer (NMSC) in patients with moderate and severe AD (4.6 (95% CI 3.9 to 5.5) and 5.9 (95% CI 3.8 to 9.2), respectively) and breast cancer (2.2 (95% CI 1.6 to 3.0) and 0.5 (95% CI 0.1 to 3.9), respectively). Except for breast cancer, which was only evaluated in women, malignancies were higher (with non-overlapping CIs) in patients with moderate and moderate to severe AD in men versus women for basal cell carcinoma and NMSC and in former versus never smokers for NMSC and squamous cell carcinoma. This study estimated IRs of malignancies in patients with moderate and severe AD and provides valuable information for dermatology clinicians and ongoing clinical trials in these populations.

Authors: Hedderson, Monique M; Asgari, Maryam M; Xu, Fei; Quesenberry, Charles P; Sridhar, Sneha; Geier, Jamie; Lemeshow, Adina R

BMJ Open. 2023 Mar 10;13(3):e071172. Epub 2023-03-10.

PubMed abstract

Impact of sedentary behavior and emotional support on prenatal psychological distress and birth outcomes during the COVID-19 pandemic

Abstract. Studies have reported mixed findings regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women and birth outcomes. This study used a quasi-experimental design to account for potential confounding by sociodemographic characteristics. Data were drawn from 16 prenatal cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) program. Women exposed to the pandemic (delivered between 12 March 2020 and 30 May 2021) (n = 501) were propensity-score matched on maternal age, race and ethnicity, and child assigned sex at birth with 501 women who delivered before 11 March 2020. Participants reported on perceived stress, depressive symptoms, sedentary behavior, and emotional support during pregnancy. Infant gestational age (GA) at birth and birthweight were gathered from medical record abstraction or maternal report. After adjusting for propensity matching and covariates (maternal education, public assistance, employment status, prepregnancy body mass index), results showed a small effect of pandemic exposure on shorter GA at birth, but no effect on birthweight adjusted for GA. Women who were pregnant during the pandemic reported higher levels of prenatal stress and depressive symptoms, but neither mediated the association between pandemic exposure and GA. Sedentary behavior and emotional support were each associated with prenatal stress and depressive symptoms in opposite directions, but no moderation effects were revealed. There was no strong evidence for an association between pandemic exposure and adverse birth outcomes. Furthermore, results highlight the importance of reducing maternal sedentary behavior and encouraging emotional support for optimizing maternal health regardless of pandemic conditions.

Authors: Hipwell, Alison E; Ferrera, Assiamira; program collaborators for Environmental influences on Child Health Outcomes,; et al.

Psychol Med. 2023 Mar 08:1-14.

PubMed abstract

Using Peer Support to Prevent Diabetes: Results of a Pragmatic RCT

High-contact structured diabetes prevention programs are effective in lowering weight and HbA1cs, yet their intensity level can create barriers to participation. Peer support programs improve clinical outcomes among adults with Type 2 diabetes, but their effectiveness in diabetes prevention is unknown. This study examined whether a low-intensity peer support program improved outcomes more than enhanced usual care in a diverse population with prediabetes. The intervention was tested in a pragmatic 2-arm RCT. Participants were adults with prediabetes at 3 healthcare centers. Participants randomized to the enhanced usual care arm received educational materials. Participants in the Using Peer Support to Aid in Prevention and Treatment in Prediabetes arm were matched with a peer supporter: another patient who had made healthy lifestyle changes and was trained in autonomy-supportive action planning. Peer supporters were instructed to provide weekly telephone support to their peers on specific action steps toward behavioral goals for 6 months, then monthly support for 6 months. Changes in primary outcomes of weight and HbA1c and secondary outcomes of enrollment in formal diabetes prevention programs, self-reported diet, physical activity, health-specific social support, self-efficacy, motivation, and activation at 6 and 12 months were examined. Data collection occurred from October 2018 to March 2022, with analyses completed in September 2022. Among 355 randomized patients, in intention-to-treat analyses, there were no between-group differences in HbA1c or weight changes at 6 and 12 months. Using Peer Support to Aid in Prevention and Treatment in Prediabetes participants were more likely to enroll in structured programs at 6 (AOR=2.45, p=0.009) and 12 (AOR=2.21, p=0.016) months and to report eating whole grains at 6 (4.49, p=0.026) and 12 (4.22, p=0.034) months. They reported greater improvements in perceived social support for diabetes prevention behaviors at 6 (6.39, p<0.001) and 12 (5.48, p<0.001) months, with no differences in other measures. A stand-alone, low-intensity peer support program improved social support and participation in formal diabetes prevention programs but not weight or HbA1c. It will be important to examine whether peer support could effectively complement higher-intensity, structured diabetes prevention programs. This trial is registered at, NCT03689530. Full protocol available at

Authors: Heisler, Michele; Dyer, Wendy T; Finertie, Holly; Stoll, Shelley C; Wiley, Deanne; Turner, Cassie D; Sedgwick, Tali; Kullgren, Jeffrey; Richardson, Caroline R; Hedderson, Monique; Schmittdiel, Julie A

Am J Prev Med. 2023 Mar 08.

PubMed abstract

Associations between antidepressant use patterns during pregnancy and birth outcomes among periconception antidepressant users

Little is known about antidepressant medication use patterns during pregnancy among periconception (before and immediately following conception) users. Additionally, the associations between these patterns and birth outcomes is unclear, after taking into account underlying depression severity. This study describes patterns of antidepressant use among periconception users and examines associations between usage patterns and birth outcomes. This retrospective cohort study included pregnant Kaiser Permanente Northern California (KPNC) members with a live birth between 2014 and 2017 and an antidepressant medication fill that overlapped the 8th week of pregnancy. Outcomes were preterm birth and neonatal intensive care unit (NICU) admission. Data were extracted from KPNC’s electronic health records. Modified Poisson regression was conducted. Of the 3637 pregnancies meeting inclusion criteria, 33% (n = 1204) continued antidepressant use throughout the pregnancy (refilled throughout pregnancy), 47% (n = 1721) discontinued use (no refills), and 20% (n = 712) stopped and reinitiated use (refill after 30+ day gap in supply). Women who continued use had 1.86 (95% confidence interval (CI) 1.53, 2.27) times the risk of preterm birth and 1.76 (95% CI: 1.42, 2.19) times the risk of NICU admission, compared to women who discontinued use during pregnancy. Similarly, women with continued use had 1.66 (95% CI: 1.27, 2.18) times the risk of preterm birth and 1.85 (95% CI: 1.39, 2.46) times the risk of NICU admission, compared to women who stopped and reinitiated use. This relationship held when examining continuous exposure; the relationship between continuous exposure and preterm delivery was stronger in later trimesters. Periconception antidepressant users who continue use during pregnancy, particularly into the second and third trimesters, may be at higher risk of adverse birth outcomes. This evidence should be considered alongside the risks associated with depression relapse.

Authors: Nance, Nerissa; Badon, Sylvia E; Ridout, Kathryn; Ahern, Jennifer; Li, De-Kun; Quesenberry, Charles; Avalos, Lyndsay A

Pharmacotherapy. 2023 Mar 05.

PubMed abstract

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program

Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of β=-0.15 [95% confidence interval (CI): -0.27, -0.03], β=-0.14 (95% CI: -0.28, -0.002), β=-0.22 (95% CI: -0.23, -0.10), β=-0.06 (95% CI: -0.18, 0.06), and β=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans.

Authors: Padula, Amy M; Ferrara, Assiamira; Zhu, Yeyi; program collaborators for Environmental influences on Child Health Outcomes,; et al.

Environ Health Perspect. 2023 Mar;131(3):37006. Epub 2023-03-15.

PubMed abstract

Perinatal Outcomes After Bariatric Surgery Compared With a Matched Control Group

To evaluate perinatal outcomes associated with pregnancy after bariatric surgery within a large integrated health care system using propensity score matching. We conducted a retrospective cohort study that evaluated perinatal outcomes in pregnant patients after bariatric surgery from January 2012 through December 2018. History of bariatric surgery was identified by using International Classification of Diseases codes and a clinical database. Primary outcomes were preterm birth (PTB), gestational hypertension, preeclampsia, impaired glucose tolerance or gestational diabetes, a large-for-gestational-age (LGA) or small-for-gestational-age (SGA) neonates, and cesarean birth. Propensity scores were estimated by using logistic regression that accounted for age at delivery, prepregnancy body mass index, year of delivery, parity, neighborhood deprivation index, race and ethnicity, insurance status, initiation of prenatal visit in the first trimester, smoking during pregnancy, chronic hypertension, and preexisting diabetes. Five patients in the control group were matched to each patient in the case group on linear propensity score, and modified Poisson regression was used to adjust for covariates. Sensitivity analyses by timing and type of surgery were performed. We identified a case cohort of 1,591 pregnancies in patients after bariatric surgery and a matched cohort of 7,955 pregnancies in patients who had not undergone bariatric surgery. Demographic characteristics were similar in both groups. In multivariate models, pregnancy after bariatric surgery was associated with a decreased risk of preeclampsia (7.5% vs 10.2%, adjusted relative risk [aRR] 0.72, 95% CI 0.60-0.86), gestational diabetes or impaired fasting glucose (23.5% vs 35.0%, aRR 0.73, 95% CI 0.66-0.80), and LGA (10.6% vs 19.9%, aRR 0.56, 95% CI 0.48-0.65) and an increased risk of SGA (10.9% vs 6.6%, aRR 1.51, 95% CI 1.28-1.78). No significant differences were observed in PTB, gestational hypertension and cesarean delivery. Pregnancy after bariatric surgery in a racially and ethnically diverse cohort of patients is associated with decreased risk of preeclampsia, gestational diabetes or impaired fasting glucose, and LGA neonates; it is also associated with an increased risk of SGA neonates compared with pregnant patients in a matched control group.

Authors: Boller, Marie J; Xu, Fei; Lee, Catherine; Sridhar, Sneha; Greenberg, Mara B; Hedderson, Monique M

Obstet Gynecol. 2023 Mar 01;141(3):583-591. Epub 2023-02-02.

PubMed abstract

Metabolomic biomarkers of the mediterranean diet in pregnant individuals: A prospective study

Metabolomic profiling is a systematic approach to identifying biomarkers for dietary patterns. Yet, metabolomic markers for dietary patterns in pregnant individuals have not been investigated. The aim of this study was to identify plasma metabolomic markers and metabolite panels that are associated with the Mediterranean diet in pregnant individuals. This is a prospective study of 186 pregnant individuals who had both dietary intake and metabolomic profiles measured from the Fetal Growth Studies-Singletons cohort. Dietary intakes during the peri-conception/1st trimester and the second trimester were accessed at 8-13 and 16-22 weeks of gestation, respectively. Adherence to the Mediterranean diet was measured by the alternate Mediterranean Diet (aMED) score. Fasting plasma samples were collected at 16-22 weeks and untargeted metabolomics profiling was performed using the mass spectrometry-based platforms. Metabolites individually or jointly associated with aMED scores were identified using linear regression and least absolute shrinkage and selection operator (LASSO) regression models with adjustment for potential confounders, respectively. Among 459 annotated metabolites, 64 and 41 were individually associated with the aMED scores of the diet during the peri-conception/1st trimester and during the second trimester, respectively. Fourteen metabolites were associated with the Mediterranean diet in both time windows. Most Mediterranean diet-related metabolites were lipids (e.g., acylcarnitine, cholesteryl esters (CEs), linoleic acid, long-chain triglycerides (TGs), and phosphatidylcholines (PCs), amino acids, and sugar alcohols. LASSO regressions also identified a 10 metabolite-panel that were jointly associated with aMED score of the diet during the peri-conception/1st trimester (AUC: 0.74; 95% CI: 0.57, 0.91) and a 3 metabolites-panel in the 2nd trimester (AUC: 0.68; 95% CI: 0.50, 0.86). We identified plasma metabolomic markers for the Mediterranean diet among pregnant individuals. Some of them have also been reported in previous studies among non-pregnant populations, whereas others are novel. The results from our study warrant replication in pregnant individuals by future studies. This study was registered at

Authors: Chen, Liwei; Zhu, Yeyi; Zhang, Cuilin; et al.

Clin Nutr. 2023 Mar;42(3):384-393. Epub 2023-01-14.

PubMed abstract

Intergenerational transmission of the effects of maternal exposure to childhood maltreatment in the USA: a retrospective cohort study

Childhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring. We conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively. Our sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship. Our findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity. Environmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health.

Authors: Moog, Nora K; Ferrara, Assiamira; ECHO collaborators,; et al.

Lancet Public Health. 2023 Mar;8(3):e226-e237.

PubMed abstract

The impact of autism spectrum disorder on parent employment: Results from the r-Kids study

Parents of children with autism spectrum disorder (ASD) and other chronic health conditions often face exceptional caregiving demands that can lead to challenges related to maintaining and succeeding in employment. Detailed information on the specific ways in which these health conditions impact parent employment could aid in designing equitable, effective policies to support families. The r-Kids study used electronic health records to identify three groups of children: those with ASD, asthma, or neither condition (control), from several health care systems. We oversampled racial and ethnic minorities and matched the asthma and control groups to the age and sex distribution of the ASD group. Parents completed three online surveys over the course of a year to measure annual employment outcomes. Surveys included the Family Economic Impact Inventory (measuring employment impacts) and measures of quality of life and symptom severity. All materials were provided in English and Spanish. The study enrolled 1461 families (564 ASD, 468 asthma, 429 control). Youth were 3-16.5 years old and predominantly male (79%). The sample was diverse (43% non-Hispanic White; 35% non-Hispanic Asian, Black, Native Hawaiian, or Other; and 21% Hispanic ethnicity). Parents of children with ASD were significantly less likely to be employed than parents of youth with asthma and control combined (OR: 14.2, p < 0.001), and were more likely to have other difficulties with employment and productivity while at work. Public and employer policies to help mitigate these impacts could aid families in managing care for youth with ASD.

Authors: Lynch, Frances L; Bulkley, Joanna E; Varga, Alexandra; Crawford, Phillip; Croen, Lisa A; Daida, Yihe G; Fombonne, Eric; Hatch, Brigit; Massolo, Maria; Dickerson, John F

Autism Res. 2023 Mar;16(3):642-652. Epub 2022-12-22.

PubMed abstract

Accuracy of diagnostic codes for prenatal opioid exposure and neonatal opioid withdrawal syndrome

Determine the accuracy of diagnostic codes in identifying Prenatal Opioid Exposure (POE) and Neonatal Opioid Withdrawal Syndrome (NOWS). A cross-sectional study of 374,222 mother-infant dyads with delivery from 01/01/2010 to 12/31/2019. We ascertained maternal diagnostic codes for opioid use during pregnancy and infant diagnostic codes for drug exposure and withdrawal. We assessed sensitivity and positive predictive value (PPV) for POE and NOWS, defined using laboratory, pharmacy, and clinical data. Maternal codes had low sensitivity (36.4%) and PPV (34.7%) for POE. Infant codes for drug exposure were neither sensitive for POE (14%) nor NOWS (31.6%) and had low PPV. Codes for newborn withdrawal had low sensitivity (31.6%) for detecting NOWS, but high PPV (85%). Sensitivity improved (95.1%) for NOWS requiring pharmacologic treatment. Diagnostic codes identify POE and NOWS poorly. Improved case identification would include pharmacy and laboratory results, and clearly defined criteria for evidence of withdrawal.

Authors: Kuzniewicz, Michael W; Campbell, Cynthia I; Li, Sherian; Walsh, Eileen M; Croen, Lisa A; Comer, Sandra D; Pimentel, Samuel D; Hedderson, Monique; Sun, Lena S

J Perinatol. 2023 Mar;43(3):293-299. Epub 2022-09-21.

PubMed abstract

Maternal and neonatal outcomes associated with treating hypertension in pregnancy at different thresholds

In the United States, there has been controversy over whether treatment of mild-to-moderate hypertension during pregnancy conveys more benefit than risk. The objective of the study was to compare risks and benefits of treatment of mild-to-moderate hypertension during pregnancy. This retrospective cohort study included 11,871 pregnant women with mild-to-moderate hypertension as defined by blood pressure (BP) values from three Kaiser Permanente regions between 2005 and 2014. Data were extracted from electronic health records. Dynamic marginal structural models with inverse probability weighting and informative censoring were used to compare risks of adverse outcomes when beginning antihypertensive medication treatment at four BP thresholds (≥155/105, ≥150/100, ≥145/95, ≥140/90 mm Hg) compared with the recommended threshold in the United States at that time, ≥160/110 mm Hg. Outcomes included preeclampsia, preterm birth, small-for-gestational-age (SGA), Neonatal Intensive Care Unit (NICU) care, and stillbirth. Primary analyses allowed 2 weeks for medication initiation after an elevated BP. Several sensitivity and subgroup (i.e., race/ethnicity and pre-pregnancy body mass index) analyses were also conducted. In primary analyses, medication initiation at lower BP thresholds was associated with greater risk of most outcomes. Comparing the lowest (≥140/90 mm Hg) to the highest BP threshold (≥160/110 mm Hg), we found an excess risk of preeclampsia (adjusted Risk Difference (aRD) 38.6 per 100 births, 95% Confidence Interval (CI): 30.6, 46.6), SGA (aRD: 10.2 per 100 births, 95% CI: 2.6, 17.8), NICU admission (aRD: 20.2 per 100 births, 95% CI: 12.6, 27.9), and stillbirth (1.18 per 100 births, 95% CI: 0.27, 2.09). The findings did not reach statistical significance for preterm birth (aRD: 2.5 per 100 births, 95% CI: -0.4, 5.3). These relationships were attenuated and did not always reach statistically significance when comparing higher BP treatment thresholds to the highest threshold (i.e., ≥160/110 mm Hg). Sensitivity and subgroup analyses produced similar results. Initiation of antihypertensive medication at mild-to-moderate BP thresholds (140-155/90-105 mm Hg; with the largest risk consistently associated with treatment at 140/90 mm Hg) may be associated with adverse maternal and neonatal outcomes. Limitations include inability to measure medication adherence.

Authors: Avalos, Lyndsay A; Neugebauer, Romain S; Nance, Nerissa; Badon, Sylvia E; Cheetham, T Craig; Easterling, Thomas R; Reynolds, Kristi; Idu, Abisola; Bider-Canfield, Zoe; Holt, Victoria L; Dublin, Sascha

Pharmacotherapy. 2023 Feb 13.

PubMed abstract

Perinatal Outcomes During vs. Prior to the COVID-19 Pandemic and the Role of Maternal Depression and Perceived Stress: A Report from the ECHO Program

We sought to evaluate the impact of the COVID-19 pandemic on perinatal outcomes while accounting for maternal depression or perceived stress and to describe COVID-specific stressors, including changes in prenatal care, across specific time periods of the pandemic. Data dyads from 41 cohorts from the National Institutes of Health Environmental influences on Child Health Outcomes Program (N=2983) were used to compare birth outcomes before and during the pandemic (n= 2355), and a partially overlapping sample (n=1490) responded to a COVID-19 questionnaire. Psychosocial stress was defined using prenatal screening for depression and perceived stress. Propensity-score matching and general estimating equations with robust variance estimation were used to estimate the pandemic’s effect on birth outcomes. Symptoms of depression and perceived stress during pregnancy were similar prior to and during the pandemic, with nearly 40% of participants reporting mild to severe stress, and 24% reporting mild depression to severe depression. Gestations were shorter during the pandemic (B=-0.33 weeks, p=0.025), and depression was significantly associated with shortened gestation (B=-0.02 weeks, p=0.015) after adjustment. Birth weights were similar (B=-28.14 g, p=0.568), but infants born during the pandemic had slightly larger birth weights for gestational age at delivery than those born before the pandemic (B=0.15 z-score units, p=0.041). More women who gave birth early in the pandemic reported being moderately or extremely distressed about changes to their prenatal care and delivery (45%) compared with those who delivered later in the pandemic. A majority (72%) reported somewhat to extremely negative views of COVID-19 on their life. In this national cohort, we detected no effect of COVID-19 on prenatal depression or perceived stress. However, experiencing the COVID-19 pandemic in pregnancy was associated with decreases in gestational age at birth as well as distress about changes in prenatal care early in the pandemic.

Authors: McKee, Kimberly S; Ferrara, Assiamira; Comstock, Sarah S; et al.

Am J Perinatol. 2023 Feb 13.

PubMed abstract

SARS-CoV-2 testing and detection during peripartum hospitalizations among a multi-center cohort of pregnant persons, March 2020-February 2021

Identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections during peripartum hospitalizations is important to guide care, implement prevention measures, and understand infection burden. This cross-sectional analysis used electronic health record data from hospitalizations during which pregnancies ended (peripartum hospitalizations) among a cohort of pregnant persons at 3 US integrated healthcare networks (sites 1-3). Maternal demographic, medical encounter, SARS-CoV-2 testing, and pregnancy and neonatal outcome information was extracted for persons with estimated delivery and pregnancy end dates during March 2020-February 2021 and ≥1 antenatal care record. Site-stratified multivariable logistic regression was used to identify factors associated with testing and compare pregnancy and neonatal outcomes among persons tested. Among 17 858 pregnant persons, 10 863 (60.8%) had peripartum SARS-CoV-2 testing; 222/10 683 (2.0%) had positive results. Testing prevalence varied by site and was lower during March-May 2020. Factors associated with higher peripartum SARS-CoV-2 testing odds were Asian race (adjusted odds ratio [aOR]: 1.36; 95% confidence interval [CI]: 1.03-1.79; referent: White) (site 1), Hispanic or Latino ethnicity (aOR: 1.33; 95% CI: 1.08-1.64) (site 2), peripartum Medicaid coverage (aOR: 1.33; 95% CI: 1.06-1.66) (site 1), and preterm hospitalization (aOR: 1.69; 95% CI: 1.19-2.39 [site 1]; aOR: 1.39; 95% CI: 1.03-1.88 [site 2]). Findings highlight potential disparities in SARS-CoV-2 peripartum testing by demographic and pregnancy characteristics. Testing practice variations should be considered when interpreting studies relying on convenience samples of pregnant persons testing positive for SARS-CoV-2. Efforts to address testing differences between groups could improve equitable testing practices and care for pregnant persons with SARS-CoV-2 infections.

Authors: Delahoy, Miranda J; Li, De Kun; Greenberg, Mara; Naleway, Allison L; et al.

Clin Infect Dis. 2023 Feb 08;76(3):e51-e59.

PubMed abstract

Dietary Quality Indices in Early Pregnancy and Rate of Gestational Weight Gain among a Prospective Multi-Racial and Ethnic Cohort

Meeting the Institute of Medicine (IOM) gestational weight gain (GWG) guidelines is associated with a reduced risk of adverse perinatal outcomes. Overall diet quality comprehensively assesses dietary components and accounts for interactions between them. While GWG is influenced by maternal diet, its association with overall diet quality-measured by various dietary quality indices-is not well-defined. We prospectively estimated the relationship between four established dietary quality indices and the risk of GWG rate above (excessive) or below (inadequate) IOM guidelines in a multi-racial and ethnic cohort of 2914 pregnant people from the Pregnancy Environment and Lifestyle Study (2014-2019). We assessed diet quality using the Healthy Eating Index 2010 (HEI-2010), alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Empirical Dietary Inflammatory Index (EDIP). Following the first trimester, 56% of the cohort had excessive GWG, and 14% had inadequate GWG. Poor diet quality (below the 75th percentile), measured by HEI-2010, was associated with a higher risk of excessive GWG in the second and third trimesters [RR = 1.03 (1.00, 1.06)]. Effect modification of this relationship by race and ethnicity and pre-pregnancy BMI was assessed. We found poor diet quality to be associated with elevated risk of excessive GWG among Black participants [RR = 1.14 (1.02, 1.28)] and White participants [RR 1.07 (1.01, 1.12)]. This was also the case for participants with pre-pregnancy BMI < 25.0 [RR 1.05 (1.00, 1.10)]. These results suggest that diet quality measured by the HEI-2010 is associated with excessive GWG, and the associations appear to be stronger among pregnant people without overweight or obesity and pregnant people who identify as Black or White race and ethnicity.

Authors: Liu, Emily F; Zhu, Yeyi; Ferrara, Assiamira; Hedderson, Monique M

Nutrients. 2023 Feb 06;15(4). Epub 2023-02-06.

PubMed abstract

Association of the COVID-19 Pandemic With Unstable and/or Unsafe Living Situations and Intimate Partner Violence Among Pregnant Individuals

The social, behavioral, and economic consequences of the COVID-19 pandemic may be associated with unstable and/or unsafe living situations and intimate partner violence (IPV) among pregnant individuals. To investigate trends in unstable and/or unsafe living situations and IPV among pregnant individuals prior to and during the COVID-19 pandemic. A cross-sectional population-based interrupted time-series analysis was conducted among Kaiser Permanente Northern California members who were pregnant and screened for unstable and/or unsafe living situation and IPV as part of standard prenatal care between January 1, 2019, and December 31, 2020. COVID-19 pandemic (prepandemic period: January 1, 2019, to March 31, 2020; during pandemic period: April 1 to December 31, 2020). The 2 outcomes were unstable and/or unsafe living situations and IPV. Data were extracted from electronic health records. Interrupted time-series models were fit and adjusted for age and race and ethnicity. The study sample included 77 310 pregnancies (74 663 individuals); 27.4% of the individuals were Asian or Pacific Islander, 6.5% were Black, 29.0% were Hispanic, 32.3% were non-Hispanic White, and 4.8% were other/unknown/multiracial, with a mean (SD) age of 30.9 (5.3) years. Across the 24-month study period there was an increasing trend in the standardized rate of unsafe and/or unstable living situations (2.2%; rate ratio [RR], 1.022; 95% CI, 1.016-1.029 per month) and IPV (4.9%; RR, 1.049; 95% CI, 1.021-1.078 per month). The ITS model indicated a 38% increase (RR, 1.38; 95% CI, 1.13-1.69) in the first month of the pandemic for unsafe and/or unstable living situation, with a return to the overall trend afterward for the study period. For IPV, the interrupted time-series model suggested an increase of 101% (RR, 2.01; 95% CI, 1.20-3.37) in the first 2 months of the pandemic. This cross-sectional study noted an overall increase in unstable and/or unsafe living situations and IPV over the 24-month period, with a temporary increase associated with the COVID-19 pandemic. It may be useful for emergency response plans to include IPV safeguards for future pandemics. These findings suggest the need for prenatal screening for unsafe and/or unstable living situations and IPV coupled with referral to appropriate support services and preventive interventions.

Authors: Avalos, Lyndsay A; Ray, G Thomas; Alexeeff, Stacey E; Adams, Sara R; Does, Monique B; Watson, Carey; Young-Wolff, Kelly C

JAMA Netw Open. 2023 Feb 01;6(2):e230172. Epub 2023-02-01.

PubMed abstract

Trends in Screen Time Use Among Children During the COVID-19 Pandemic, July 2019 Through August 2021

The COVID-19 pandemic led to widespread lockdowns and school closures that may have affected screen time among children. Although restrictions were strongest early in the pandemic, it is unclear how screen time changed as the pandemic progressed. To evaluate change in children’s screen time from before the pandemic to during the pandemic, from July 2019 through August 2021. This is a longitudinal cohort study with repeated measures of screen time collected before the pandemic and during 2 pandemic periods. Children aged 4 to 12 years and their parent were enrolled in 3 pediatric cohorts across 3 states in the US participating in the Environmental Influences of Child Health Outcomes (ECHO) Program. Data analysis was performed from November 2021 to July 2022. COVID-19 pandemic period: prepandemic (July 2019 to March 2020), pandemic period 1 (December 2020 to April 2021), and pandemic period 2 (May 2021 to August 2021). The primary outcomes were total, educational (not including remote school), and recreational screen time assessed via the ECHO Child Media Use questionnaire. Linear mixed-effects models were used for screen time adjusted for child’s age, number of siblings, sex, race, ethnicity, and maternal education. The cohort included 228 children (prepandemic mean [SD] age, 7.0 [2.7] years; 100 female [43.9%]) with screen time measured during the prepandemic period and at least once during the pandemic period. Prepandemic mean (SD) total screen time was 4.4 (3.9) hours per day and increased 1.75 hours per day (95% CI, 1.18-2.31 hours per day) in the first pandemic period and 1.11 hours per day (95% CI, 0.49-1.72 hours per day) in the second pandemic period, in adjusted models. Prepandemic mean (SD) recreational screen time was 4.0 (3.5) hours per day and increased 0.89 hours per day (95% CI, 0.39-1.39 hours per day) in the first pandemic period and 0.70 hours per day (95% CI, 0.16-1.25 hours per day) in the second pandemic period. Prepandemic mean (SD) educational screen time was 0.5 (1.2) hours per day (median [IQR], 0.0 [0.0-0.4] hours per day) and increased 0.93 hours per day (95% CI, 0.67-1.19 hours per day) in the first pandemic period and 0.46 hours per day (95% CI, 0.18-0.74 hours per day) in the second pandemic period. These findings suggest that screen time among children increased during the COVID-19 pandemic and remained elevated even after many public health precautions were lifted. The long-term association of increased screen time during the COVID-19 pandemic with children’s health needs to be determined.

Authors: Hedderson, Monique M; Zhu, Yeyi; Ferrara, Assiamira; Environmental Influences on Child Health Outcomes Program,; et al.

JAMA Netw Open. 2023 Feb 01;6(2):e2256157. Epub 2023-02-01.

PubMed abstract

Daytime napping and nighttime sleep in pregnant individuals with insomnia disorder

Examine bidirectional associations between daytime napping and nighttime sleep among pregnant individuals with insomnia disorder. We used baseline data from a randomized controlled trial of insomnia treatment during pregnancy (n = 116). Participants in their second or third trimester of pregnancy self-reported daytime napping and nighttime sleep parameters using a sleep diary and wore an Actiwatch-2 during the same 7-day period. Linear regression models, accounting for intraindividual correlation, were used to estimate associations between daytime napping and nighttime sleep parameters (duration, efficiency, quality, awakenings). Models were also stratified by trimester of pregnancy. Sixty-three percent of participants reported napping on at least 1 day. Among participants in the second trimester (65%), napping 15-59 minutes was associated with 6.3% greater self-reported sleep efficiency (95% confidence interval: 2.3, 10.2) and 0.5 units greater self-reported sleep quality (95% confidence interval: 0.0, 0.9) that night; napping 60+ minutes was associated with 0.6 hours shorter actigraphy-measured sleep duration (95% confidence interval: -1.0, -0.2). Napping was not associated with nighttime sleep overall or during the third trimester. Nighttime sleep parameters were not associated with napping duration the following day. Among pregnant individuals with insomnia in the second trimester, short napping duration was associated with higher self-reported sleep efficiency and quality; long napping duration was associated with shorter actigraphy-measured sleep duration. Additional research is needed to examine the interaction between nap duration and nap timing. In the future, these results may lead to more nuanced recommendations for daytime napping among pregnant individuals with insomnia disorder. Registry:; Name: Treatment for Insomnia during Pregnancy; URL:; Identifier: NCT01846585. Badon SE, Dietch R, Simpson N, Lyell DJ, Manber R. Daytime napping and nighttime sleep in pregnant individuals with insomnia disorder. J Clin Sleep Med. 2023;19(2):371-377.

Authors: Badon, Sylvia E; Dietch, Jessica R; Simpson, Norah; Lyell, Deirdre J; Manber, Rachel

J Clin Sleep Med. 2023 Feb 01;19(2):371-377.

PubMed abstract

Association of cannabis use during pregnancy with severe acute respiratory syndrome coronavirus 2 infection: a retrospective cohort study

Cannabis use is increasingly common among pregnant individuals and might be a risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to test whether prenatal cannabis use is associated with increased risk of SARS-CoV-2 infection during pregnancy. This is a retrospective cohort study. The study was conducted in California, USA. A total of 58?114 pregnancies (with outcomes from 5 March 2020 to 30 September 2021) among 57?287 unique pregnant women aged 14-54?years who were screened for prenatal substance use, enrolled in Kaiser Permanente Northern California (KPNC) (a health-care system) and had not tested positive for COVID-19 prior to pregnancy onset. We utilized data from the KPNC electronic health record. Cannabis use status (current, recently quit and non-user) was based on universal screenings during prenatal care (including urine toxicology testing and self-reported use on a self-administered questionnaire). SARS-CoV-2 infection [based on polymerase chain reaction (PCR) tests] was estimated in time-to-event analyses using Cox proportional hazard regression models adjusting for covariates. Secondary analyses examined differences in (a) SARS-CoV-2 testing rates and (b) SARS-CoV-2 infection rates among those tested. We observed 348?810 person-months of follow-up time in our cohort with 41?064 SARS-CoV-2 PCR tests and 6% (n?=?2414) of tests being positive. At the start of follow-up, 7% of pregnant individuals had current use, 12% had recently quit and 81% did not use cannabis. Adjusting for covariates, current use was associated with lower rates of SARS-CoV-2 infection [adjusted hazard ratio (aHR)?=?0.60, 95% confidence interval (CI)?=?0.49-0.74 than non-use. Those who had recently quit did not differ from non-cannabis users in infection rates (aHR?=?0.96, 95% CI?=?0.86-1.08). Sensitivity analyses among patients who received a SARS-CoV-2 test also found lower odds of infection associated with current versus no cannabis use (aOR?=?0.76, CI?=?0.61-0.93). Current cannabis use appears to be associated with a reduced risk of SARS-CoV-2 infection among pregnant individuals.

Authors: Young-Wolff, Kelly C; Ray, G Thomas; Alexeeff, Stacey E; Benowitz, Neal; Adams, Sara R; Does, Monique B; Goler, Nancy; Ansley, Deborah; Conway, Amy; Avalos, Lyndsay A

Addiction. 2023 Feb;118(2):317-326. Epub 2022-10-12.

PubMed abstract

Impact of the COVID-19 pandemic on children’s sleep habits: an ECHO study

Sleep in childhood is affected by behavioral, environmental, and parental factors. We propose that these factors were altered during the COVID-19 pandemic. This study investigates sleep habit changes during the pandemic in 528 children 4-12 years old in the US, leveraging data from the Environmental Influences on Child Health Outcomes (ECHO) Program. Data collection occurred in July 2019-March 2020 (pre-pandemic) and two pandemic periods: December 2020-April 2021 and May-August 2021. Qualitative interviews were performed in 38 participants. We found no changes in sleep duration, but a shift to later sleep midpoint during the pandemic periods. There was an increase in latency at the first pandemic collection period but no increase in the frequency of bedtime resistance, and a reduced frequency of naps during the pandemic. Qualitative interviews revealed that parents prioritized routines to maintain sleep duration but were more flexible regarding timing. Children from racial/ethnic minoritized communities slept less at night, had later sleep midpoint, and napped more frequently across all collection periods, warranting in-depth investigation to examine and address root causes. The COVID-19 pandemic significantly impacted children sleep, but parental knowledge of the importance of sleep might have played a significant protective role. During the COVID-19 pandemic, US children changed their sleep habits, going to bed and waking up later, but their sleep duration did not change. Sleep latency was longer. Parental knowledge of sleep importance might have played a protective role. Regardless of data collection periods, children from racial/ethnic minoritized communities slept less and went to bed later. This is one of the first study on this topic in the US, including prospective pre-pandemic qualitative and quantitative data on sleep habits. Our findings highlight the pandemic long-term impact on childhood sleep. Results warrants further investigations on implications for overall childhood health.

Authors: Lucchini, Maristella; Ferrara, Assiamira; Hedderson, Monique; Environmental influences on Child Health Outcomes,; et al.

Pediatr Res. 2023 Feb;93(3):586-594. Epub 2022-10-04.

PubMed abstract

Placental Histopathologic Findings of a Large Cohort of Patients With SARS-CoV-2 Infection During Pregnancy

Pregnant individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at a higher risk for adverse pregnancy outcomes. Previous small cohort studies have shown increased frequency of placental lesions associated with maternal vascular malperfusion, fetal vascular malperfusion, and inflammation among patients with SARS-CoV-2, without controlling for cardiometabolic risk factors among many such patients. We aimed to evaluate whether SARS-CoV-2 infection during pregnancy is independently associated with placental abnormalities when controlling for risk factors that could affect placental histopathology. Retrospective cohort study of placentas from singleton pregnancies in Kaiser Permanente Northern California from March to December 2020. Pathologic findings were compared among those with confirmed cases of SARS-CoV-2 during pregnancy and those without. We examined the association between SARS-CoV-2 infection and categorical placental pathologies, controlling for maternal age, gestational age, prepregnancy body mass index, gestational hypertension, preeclampsia/eclampsia, preexisting diabetes, history of thrombosis, and stillbirth. A total of 2,989 singleton gestation placentas were analyzed, 416 (13%) from pregnancies with SARS-CoV-2 infection and 2,573 (86%) from those without infection. Among placentas from pregnancies with SARS-CoV-2, 54.8% had evidence of inflammation, 27.1% maternal malperfusion abnormality, 20.7% massive perivillous fibrin or chronic villitis, 17.3% villous capillary abnormality, and 15.1% fetal malperfusion. After controlling for risks factors and stratifying interval time between SARS-CoV-2 infection and delivery, no association was found between placental abnormalities and SARS-CoV-2 infection during pregnancy. SARS-CoV-2 infection was not associated with an increased risk of placentally mediated adverse outcomes during pregnancy, compared with placentas sent for other indications, in this large diverse cohort.

Authors: Lin, Ruby; Forquer, Heather; Cviko-Pajt, Aida; Schauer, Galen M; Abellar, Rosanna G; Hedderson, Monique; Kuzniewicz, Michael W; Greenberg, Mara B

Int J Gynecol Pathol. 2023 Jan 25.

PubMed abstract

Ambient air pollutants are associated with morning serum cortisol in overweight and obese Latino youth in Los Angeles.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA)-axis dysfunction has been associated with a variety of mental health and cardio-metabolic disorders. While causal models of HPA-axis dysregulation have been largely focused on either pre-existing health conditions or psychosocial stress factors, recent evidence suggests a possible role for central nervous system activation via air pollutants, such as nitrogen dioxide (NO2), ozone (O3) and particulate matter (PM). Therefore, in an observational study of Latino youth, we investigated if monthly ambient NO2, O3, and PM with aerodynamic diameter

Authors: Toledo-Corral, C M; Alderete, T L; Herting, M M; Habre, R; Peterson, A K; Lurmann, F; Goran, M I; Weigensberg, M J; Gilliland, F D

Environ Health. 2021 Apr 8;20(1):39. doi: 10.1186/s12940-021-00713-2.

PubMed abstract

Prenatal Maternal Cortisol Levels and Infant Birth Weight in a Predominately Low-Income Hispanic Cohort.

Infant birth weight influences numerous health outcomes throughout the life course including childhood obesity and metabolic morbidities. Maternal experience of stress, both before and during pregnancy, has been hypothesized to influence fetal growth and birth outcomes. However, these associations currently are not fully understood, due to conflicting results in the published literature. Salivary cortisol is often used as a biological biomarker to assess the diurnal pattern of the hypothalamic-pituitary-adrenal axis (HPA-axis) functioning. Cortisol metrics include both the total cortisol concentration secreted during waking hours, reflected by the area under the curve (AUC), and cortisol dynamics, which include the diurnal cortisol slope (DCS) and the cortisol awakening response (CAR). This study examined the association of these cortisol metrics measured during the third trimester of pregnancy and infant birth weight among 240 mother-infant dyads participating in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort study, which is predominately comprised of Hispanic low-income women. There were no significant associations with the maternal biological stress response and infant birth weight in this study. More research is needed in larger studies to better understand how the biological stress response influences birth weight in populations facing health disparities.

Authors: Peterson, Alicia K; Toledo-Corral, Claudia M.; Chavez, Thomas A; Naya, Christine H; Johnson, Mark; Eckel, Sandrah P; Lerner, Deborah; Grubbs, Brendan H; Farzan, Shohreh F; Dunton, Genevieve F; Bastain, Theresa M; Breton, Carrie V

Int J Environ Res Public Health. 2020 Sep 21;17(18). pii: ijerph17186896. doi: 10.3390/ijerph17186896.

PubMed abstract

Third trimester cortisol is positively associated with gestational weight gain in pregnant women with class one obesity.

BACKGROUND/OBJECTIVE: Prevalence of pre-pregnancy obesity and excessive gestational weight gain (GWG) are higher among women of color with low SES. Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and its end-product, cortisol, during pregnancy is hypothesized to be associated with excessive GWG. However, past studies have produced inconsistent findings and often did not include health disparities populations. This study examined the association between pre-pregnancy body mass index (BMI), third trimester diurnal cortisol, and GWG in low-income, predominantly Hispanic women. SUBJECTS/METHODS: The MADRES study is an ongoing prospective cohort study of primarily Hispanic, low-income pregnant women and their children in Los Angeles, California. Data from 176 participants were included in this study. Total cortisol secretion (area under the curve, AUC) was quantified using four salivary cortisol samples (awakening, 30 min after awakening, afternoon, and bedtime) that were collected at home on one day during the third trimester of pregnancy. Moderation of the association between total cortisol and GWG by pre-pregnancy BMI was tested using multiple linear regression with a multiplicative interaction term. RESULTS: There was no association between total cortisol secretion and GWG overall (p = 0.82), but the association between total cortisol and GWG was stronger for women with class 1 pre-pregnancy obesity compared to women with normal pre-pregnancy BMI (interaction term p = 0.04). CONCLUSIONS: Results suggest that obesity status before pregnancy may be exacerbating the physiological impact of cortisol on GWG.

Authors: Naya, Christine H; Toledo-Corral, Claudia M; Chavez, Thomas; Lerner, Deborah; Lurvey, Nathana; Eckel, Sandrah P; Peterson, Alicia K; Grubbs, Brendan H; Dunton, Genevieve F; Breton, Carrie V; Bastain, Theresa M

Int J Obes (Lond). 2022 Feb;46(2):366-373. doi: 10.1038/s41366-021-01009-8. Epub 2021 Oct 30.

PubMed abstract

Effects of COVID-19 Financial and Social Hardships on Infants’ and Toddlers’ Development in the ECHO Program

The financial hardships and social isolation experienced during the COVID-19 pandemic have been found to adversely affect children’s developmental outcomes. While many studies thus far have focused on school-aged children and the pandemic-related impacts on their academic skills and behavior problems, relatively less is known about pandemic hardships and associations with children’s development during their early years. Using a racially and economically diverse sample, we examined whether hardships experienced during the pandemic were associated with children’s development with a particular focus on communication and socioemotional development. Participants from eight cohorts of the Environmental influences on Child Health Outcomes program provided data on pandemic-related financial and social hardships as well as child developmental outcomes. Financial hardship was defined as at least one parent experiencing job loss or change, and social hardship was defined as families’ quarantining from household members or extended family and friends. The development of children under 4 was assessed longitudinally, before and during the pandemic (N = 684), using the Ages and Stages Questionnaire (ASQ). The Generalized Estimating Equations, which accounted for within-child correlation, were used for analysis. Families from minority backgrounds and low socioeconomic status disproportionately experienced pandemic-related hardships. Male children had higher odds of experiencing negative changes in communication and personal social skills from pre- to during-pandemic visits (ORs ranged between 2.24 and 3.03 in analysis with binary ASQ outcomes and ranged from -0.34-0.36 in analyses with ASQ z-scores, ps = 0.000). Pandemic-related hardships in the social and financial areas did not explain within-individual changes in children’s developmental outcomes. Negative developmental changes from pre- to during-pandemic were found in boys, yet we did not find any associations between increased experience of pandemic-related hardships and children’s development. E how pandemic hardships affect development using a larger sample size and with longer follow-up is warranted.

Authors: Nozadi, Sara S; Croen, Lisa A; Ferrara, Assiamira; Lewis, Johnnye L; et al.

Int J Environ Res Public Health. 2023 Jan 05;20(2). Epub 2023-01-05.

PubMed abstract

Indoor and outdoor air pollution and couple fecundability: a systematic review

Air pollution is both a sensory blight and a threat to human health. Inhaled environmental pollutants can be naturally occurring or human-made, and include traffic-related air pollution (TRAP), ozone, particulate matter (PM) and volatile organic compounds, among other substances, including those from secondhand smoking. Studies of air pollution on reproductive and endocrine systems have reported associations of TRAP, secondhand smoke (SHS), organic solvents and biomass fueled-cooking with adverse birth outcomes. While some evidence suggests that air pollution contributes to infertility, the extant literature is mixed, and varying effects of pollutants have been reported. Although some reviews have studied the association between common outdoor air pollutants and time to pregnancy (TTP), there are no comprehensive reviews that also include exposure to indoor inhaled pollutants, such as airborne occupational toxicants and SHS. The current systematic review summarizes the strength of evidence for associations of outdoor air pollution, SHS and indoor inhaled air pollution with couple fecundability and identifies gaps and limitations in the literature to inform policy decisions and future research. We performed an electronic search of six databases for original research articles in English published since 1990 on TTP or fecundability and a number of chemicals in the context of air pollution, inhalation and aerosolization. Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of both air pollution and fecundability studies. The search returned 5200 articles, 4994 of which were excluded at the level of title and abstract screening. After full-text screening, 35 papers remained for data extraction and synthesis. An additional 3 papers were identified independently that fit criteria, and 5 papers involving multiple routes of exposure were removed, yielding 33 articles from 28 studies for analysis. There were 8 papers that examined outdoor air quality, while 6 papers examined SHS exposure and 19 papers examined indoor air quality. The results indicated an association between outdoor air pollution and reduced fecundability, including TRAP and specifically nitrogen oxides and PM with a diameter of ?2.5?�m, as well as exposure to SHS and formaldehyde. However, exposure windows differed greatly between studies as did the method of exposure assessment. There was little evidence that exposure to volatile solvents is associated with reduced fecundability. The evidence suggests that exposure to outdoor air pollutants, SHS and some occupational inhaled pollutants may reduce fecundability. Future studies of SHS should use indoor air monitors and biomarkers to improve exposure assessment. Air monitors that capture real-time exposure can provide valuable insight about the role of indoor air pollution and are helpful in assessing the short-term acute effects of pollutants on TTP.

Authors: Siegel, Eva L; Zhu, Yeyi; Kahn, Linda G; et al.

Hum Reprod Update. 2023 Jan 05;29(1):45-70.

PubMed abstract

Pregnancy post-bariatric surgery: Improved outcomes with telephonic nutritional management program

Pregnancies post-bariatric surgery are increasingly common. It is important to understand how to manage prenatal care in this high-risk population to optimize perinatal outcomes. To determine among pregnancies post-bariatric surgery whether participation in a telephonic nutritional management program was associated with improved perinatal outcomes and nutritional adequacy. Retrospective cohort study of pregnancies post-bariatric surgery from 2012 to 2018. Participation in a telephonic management program with nutritional counseling, monitoring and nutritional supplement adjustment. Modified Poisson Regression estimated the relative risk using propensity score methods to account for baseline differences between the patients who participated in the program and patients who did not. 1575 pregnancies occurred post-bariatric surgery, of which 1142 (72.5 % of pregnancies) participated in the telephonic nutritional management program. Participants in the program were less likely than non-participants to have a preterm birth (aRR 0.48, 95 % CI 0.35-0.67), preeclampsia (aRR 0.43, 95 % CI (0.27-0.69)), gestational hypertension (aRR 0.62, 95 % CI 0.41-0.93), and to have neonates admitted to a Level 2 or 3 (aRR 0.61, 95 % CI0.39-0.94; aRR 0.66, 95 % CI 0.45-0.97, respectively), after adjusting for the propensity score to account for baseline differences. Risk of cesarean delivery, gestational weight gain, glucose intolerance and birthweight did not differ by participation. Among 593 pregnancies with nutritional labs available, participants in the telephonic program were less likely to have nutritional inadequacy in late pregnancy (aRR 0.91, 95 % CI 0.88-0.94). Participation in a telephonic nutritional management program post-bariatric surgery was associated with improved perinatal outcomes and nutritional adequacy.

Authors: Hedderson, Monique M; Boller, Marie; Xu, Fei; Lee, Catherine; Sridhar, Sneha; Greenberg, Mara

Obes Res Clin Pract. 2023 Mar-Apr;17(2):144-150. Epub 2023-03-10.

PubMed abstract

Prenatal Opioid Exposure and Neurodevelopmental Outcomes

The opioid epidemic in the United States has resulted in a significant increase in opioid use disorder among pregnant women and a concomitant increase in the incidence of neonatal opioid withdrawal syndrome. The long-term consequences of prenatal opioid exposure on neurodevelopmental outcomes are not fully understood. Animal studies indicate increased neuronal apoptosis and decreased neuronal proliferation and myelination with opioid exposure in-utero. Meta-analyses of human studies suggest decreased cognition and psychomotor performance in infancy and deficits in cognition and language in preschool. However, current studies have primarily focused on heroin or methadone exposure and have been limited by small sample size, inadequate comparison groups, and the inability to account for additional risk factors and exposures such as polysubstance abuse, poor prenatal care, neonatal withdrawal and treatment with opioids, and unsupportive home environment. Future studies should aim to better understand the potential impact of these confounding factors on the neurodevelopmental trajectory of exposed infants. This review discusses the up-to-date literature, current gaps in knowledge, and considerations for future studies in the arena of prenatal opioid exposure and neurodevelopmental outcomes.

Authors: Lee, Jennifer J; Saraiya, Neeta; Kuzniewicz, Michael W

J Neurosurg Anesthesiol. 2023 Jan 01;35(1):142-146. Epub 2022-12-06.

PubMed abstract

Perinatal Anesthesia Exposure and Autism Spectrum Disorders

Epidural analgesia is frequently used during labor among pregnant people in the United States. Different factors have been associated with the development of autism spectrum disorder in the epidemiological literature: maternal health, infectious and pharmacological etiologies, social factors, and environmental exposures. Current data indicates no clear association between the use of epidural labor analgesia and the development of autism spectrum disorder in the offspring. This review presents the public health perspective on the postulated association between perinatal anesthesia exposure and autism spectrum disorders.

Authors: Houck, Philipp; Naus, Claire; Croen, Lisa; Sun, Lena S

J Neurosurg Anesthesiol. 2023 Jan 01;35(1):127-129. Epub 2022-12-06.

PubMed abstract

Changes in COVID-19 Vaccine Intent Among a Diverse Population of Older Adults, June 2021-February 2022

Introduction COVID-19 vaccination rates remain suboptimal in the United States. Clinicians and policymakers need to better understand how likely vaccine-hesitant individuals are to ultimately accept vaccination and what is associated with such changes. This study’s aims were to 1) describe changes between vaccine intentions and actual uptake from June 2021 through February 2022, and 2) identify modifiable factors associated with vaccine uptake among those with initial hesitancy. Methods This cohort study included a stratified random sample of adults aged 65 years and older in an integrated health care system. The survey, conducted June through August 2021, elicited intent and perceptions regarding COVID-19 vaccination. Subsequent vaccine uptake through February 2022 was analyzed using electronic health records. Results Of 1195 individuals surveyed, 66% responded; 213 reported not yet having received a COVID-19 vaccine and were further analyzed. At baseline, most individuals said they would definitely not (42%) or probably not (5%) get the COVID-19 vaccine or were not sure (26%). During follow-up, 61 individuals (29%) were vaccinated, including 19% of those who initially said they would definitely not be vaccinated. Among vaccine-hesitant individuals, the rate of vaccination was highest for those who initially considered COVID-19 less dangerous than the vaccine (46%) or named short-term side effects (36%) as their most important concern. Conclusions COVID-19 vaccine intent among older adults was malleable during the pandemic’s second year, even among those who initially said they would definitely not be vaccinated. Vaccine uptake could be enhanced by increasing awareness of COVID-19 risks and by addressing vaccine side effects.

Authors: Durojaiye, Cimone; Prausnitz, Stephanie; Elkin, Eric P; Escobar, Patricia; Finn, Lucy; Chen, Yi-Fen Irene; Lieu, Tracy A

Perm J. 2022 Dec 19;26(4):78-84. Epub 2022-10-31.

PubMed abstract

Habitual coffee consumption and subsequent risk of type 2 diabetes in individuals with a history of gestational diabetes – a prospective study

Females with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes mellitus (T2D) later in life. This study prospectively examined whether greater habitual coffee consumption was related to a lower risk of T2D among females with a history of GDM. We followed 4522 participants with a history of GDM in the NHS II for incident T2D between 1991 and 2017. Demographic, lifestyle factors including diet, and disease outcomes were updated every 2-4 y. Participants reported consumption of caffeinated and decaffeinated coffee on validated FFQs. Fasting blood samples were collected in 2012-2014 from a subset of participants free of diabetes to measure glucose metabolism biomarkers (HbA1c, insulin, C-peptide; n = 518). We used multivariable Cox regression models to calculate adjusted HRs and 95% CIs for the risk of T2D. We estimated the least squares mean of glucose metabolic biomarkers according to coffee consumption. A total of 979 participants developed T2D. Caffeinated coffee consumption was inversely associated with the risk of T2D. Adjusted HR (95% CI) for ≤1 (nonzero), 2-3, and 4+ cups/d compared with 0 cup/d (reference) was 0.91 (0.78, 1.06), 0.83 (0.69, 1.01), and 0.46 (0.28, 0.76), respectively (P-trend = 0.004). Replacement of 1 serving/d of sugar-sweetened beverage and artificially sweetened beverage with 1 cup/d of caffeinated coffee was associated with a 17% (risk ratio [RR] = 0.83, 95% CI: 0.75, 0.93) and 9% (RR = 0.91, 95% CI: 0.84, 0.99) lower risk of T2D, respectively. Greater caffeinated coffee consumption was associated with lower fasting insulin and C-peptide concentrations (all P-trend <0.05). Decaffeinated coffee intake was not significantly related to T2D but was inversely associated with C-peptide concentrations (P-trend = 0.003). Among predominantly Caucasian females with a history of GDM, greater consumption of caffeinated coffee was associated with a lower risk of T2D and a more favorable metabolic profile.

Authors: Yang, Jiaxi; Zhu, Yeyi; Zhang, Cuilin; et al.

Am J Clin Nutr. 2022 Dec 19;116(6):1693-1703.

PubMed abstract

Physical activity and individual plasma phospholipid saturated fatty acids in pregnancy, a longitudinal study among a multiracial/multiethnic cohort in the United States

Circulating individual SFAs in pregnant females are critical for maternal and fetal health. However, research on identifying their modifiable factors is limited. We aimed to examine the associations of total physical activity (PA) and types of PA with circulating individual SFAs during pregnancy in a multiracial/multiethnic cohort of pregnant females in the United States. The study included participants in a nested case-control study (n = 321) from the Eunice Kennedy Shriver NICHD Fetal Growth Studies-Singleton Cohort. Sampling weights were applied, so the results represented the entire Fetal Growth Cohort. Plasma phospholipid SFAs were measured at 4 visits [10-14 (visit 1), 15-26 (visit 2), 23-31 (visit 3), and 33-39 (visit 4) weeks of gestation] throughout pregnancy. PA of the previous year at visit 1 and since the previous visit at the subsequent visits was assessed using the validated Pregnancy PA Questionnaire. Time-specific and longitudinal associations were examined using multivariable linear and generalized estimating equation models. Total PA (metabolic equivalent of task-h/wk) was positively associated with circulating heptadecanoic acid (17:0) at visit 1 (β × 103: 0.07; 95% CI: 0.02, 0.11) and pentadecanoic acid (15:0) at visit 3 (β × 103: 0.09; 95% CI: 0.03, 0.14) independent of sociodemographic, reproductive, pregnancy, and dietary factors. Across the 4 visits, the positive associations with total PA were consistent for pentadecanoic acid (β × 103: 0.06; 95% CI: 0.02, 0.10) and heptadecanoic acid (β × 103: 0.10; 95% CI: 0.06, 0.14). Out of the 4 PA types (i.e., sports/exercise, household/caregiving, transportation, and occupational PA) considered, the magnitude of positive associations was the largest for sports/exercise PA. Our findings suggest that maternal PA is positively associated with circulating pentadecanoic and heptadecanoic acids. The findings warrant confirmation by future studies.This trial was registered at as NCT00912132.

Authors: Liu, Xinyue; Zhu, Yeyi; Zhang, Cuilin; et al.

Am J Clin Nutr. 2022 Dec 19;116(6):1729-1737.

PubMed abstract

Examining shortened versions of the Social Responsiveness Scale for use in autism spectrum disorder prediction and as a quantitative trait measure: Results from a validation study of 3-5 year old children

The Social Responsiveness Scale (SRS) is a 65-item measure yielding a continuous score capturing autism-related traits. Scores based on SRS item subsets have been analytically examined but administration of shortened versions has not been evaluated prospectively. The goal of this study was to compare psychometric properties of two shortened versions of the SRS to the full 65-item SRS, in young children from both a clinical and general population setting. Study participants (aged 3-5 years) were drawn from the AJ Drexel Autism Institute clinic (n = 154) and Kaiser Permanente Northern California (n = 201) and block randomized to receive either the 16-item short SRS, a newly developed computer adaptive testing-SRS, or the published full-length SRS. Total scores across the three SRS administration methods were scaled to facilitate comparisons. Scores were plotted to assess distributional properties, while Receiver Operating Characteristic analysis was used to estimate Area Under the Curve (AUC) and address predictive ability. Overall, distributional properties of the three administration methods were highly comparable, with shortened measures demonstrating similar ability to capture the range of the distribution and case non-case separation as the full SRS. In addition, AUC values were high (0.91-0.97) and comparable across the administration methods, though there was evidence of difference in predictive ability across measures for females (AUC for full SRS = 0.99 vs. 0.84 for short). Within individual comparisons of short versus full scores (available only for participants at the general population site) suggested underestimation of actual full SRS scores with the CAT-SRS. Our findings broadly support the construct validity and performance of shortened SRS versions examined here, though the full measure may be needed to more accurately assess traits consistent with ASD diagnosis in females. This work suggests opportunities for collection of ASD-related phenotype in settings where participant burden or feasibility considerations may have otherwise prohibited such measurement.

Authors: Lyall, Kristen; Croen, Lisa A; program collaborators for Environmental influences on Child Health Outcomes,; et al.

JCPP Adv. 2022 Dec;2(4):e12106. Epub 2022-10-05.

PubMed abstract

Racial/Ethnic Differences in Psychiatric and Medical Diagnoses Among Autistic Adults

Racial/ethnic disparities in access to diagnostic services are pervasive for autistic children. However, a few studies have examined racial/ethnic health disparities among autistic adults, who commonly experience higher rates of health conditions than non-autistic adults. We aimed at examining the intersection of autism and race/ethnicity in association with psychiatric and medical diagnoses. The study population included adult members of Kaiser Permanente Northern California enrolled from 2008 to 2012. We ascertained 1507 adults who had an autism diagnosis documented in their electronic medical records. We sampled a matched control group of adults without an autism diagnosis (N = 15,070) at a 10:1 ratio. Our sample was 46% White, 17% Hispanic, 16% Asian, 7% Black, and 14% other race/ethnicity. We compared health diagnoses (a) between autistic and non-autistic adults within strata of race/ethnicity and (b) across race/ethnicity within strata of autistic and non-autistic adults. Lastly, we examined the interaction between autism and race/ethnicity on both multiplicative and additive scales. Autistic adults were more likely to be diagnosed with most medical and psychiatric conditions compared with their non-autistic counterparts of the same race/ethnicity. Among autistic adults, Black, Hispanic, and Asian adults were less likely to be diagnosed with psychiatric conditions and Black and Hispanic autistic adults were more likely to be diagnosed with obesity than their White counterparts. In interaction models, we found that adults who were Black and autistic were disproportionately less likely to be diagnosed with psychiatric conditions and autoimmune disease and more likely to be diagnosed with hypertension than expected. Health vulnerabilities may be compounded at the intersection of autism and race/ethnicity. Future research should continue to apply an intersectional lens toward understanding and addressing these disparities. Our findings likely underestimate the health disparities that exist in uninsured autistic adults and those living in other parts of the United States. Very few studies have looked at how the combination of a person’s autistic and racial/ethnic identities affects their health in adulthood. Dual experiences of ableism and structural racism may have a larger negative effect on the health of autistic people of color than either one experience alone. It is important to identify potential health disparities so that they can be addressed. We wanted to understand whether autistic adults of color were more likely to be diagnosed with medical and psychiatric conditions than non-autistic and/or White peers. We studied a diverse group of 1507 autistic adults and 15,070 non-autistic adults who all received health care from the same large, health plan in California. We examined electronic health records to determine whether diagnoses of health conditions differed by autism status and race/ethnicity. We then looked at whether autistic people of color were disproportionately diagnosed with these conditions compared with other groups. Within every racial/ethnic group, autistic adults were more likely than non-autistic adults to be diagnosed with most medical and psychiatric conditions. Among the autistic group, Black, Hispanic, and Asian adults were less likely to be diagnosed with psychiatric conditions compared with White adults. We saw similar differences in psychiatric diagnoses by race/ethnicity among non-autistic adults. Further, the diagnostic patterns among adults who were autistic and Black suggested that this group may experience unique difficulties receiving mental health and autoimmune diagnoses. They also may be at a higher risk of hypertension. Previous studies have found racial/ethnic disparities in both mental health and access to health care among autistic children. This study suggests that racial/ethnic disparities, especially in mental health care, may also exist among autistic adults. As a broad social label, race/ethnicity does not tell us much about people’s lived experiences. Future studies should replace race/ethnicity with more useful measures of our social environment, including economic opportunity and experiences of structural racism. In addition, health records may imperfectly represent the actual occurrence of health conditions. For example, we cannot tell from this study whether autistic people of color actually experience fewer psychiatric problems, are less likely to visit the doctor, or are more likely to have their problems missed by doctors. Lastly, because our findings are from an insured population, we have likely underestimated the health disparities that exist among autistic adults who do not have consistent insurance coverage or health care access. We hope this study highlights the need for greater attention to the unique health risks at the intersection of autism and race/ethnicity in adults. Through more research and advocacy, we can increase awareness and understanding of these potential health disparities. This will lead to changes that promote more equal access to health care and greater well-being among autistic people of color.

Authors: Ames, Jennifer L; Morgan, Elizabeth H; Onaiwu, Morénike Giwa; Qian, Yinge; Massolo, Maria L; Croen, Lisa A

Autism Adulthood. 2022 Dec 01;4(4):290-305. Epub 2022-12-13.

PubMed abstract

Associations of Neighborhood Opportunity and Social Vulnerability With Trajectories of Childhood Body Mass Index and Obesity Among US Children

Physical and social neighborhood attributes may have implications for children’s growth and development patterns. The extent to which these attributes are associated with body mass index (BMI) trajectories and obesity risk from childhood to adolescence remains understudied. To examine associations of neighborhood-level measures of opportunity and social vulnerability with trajectories of BMI and obesity risk from birth to adolescence. This cohort study used data from 54 cohorts (20 677 children) participating in the Environmental Influences on Child Health Outcomes (ECHO) program from January 1, 1995, to January 1, 2022. Participant inclusion required at least 1 geocoded residential address and anthropometric measure (taken at the same time or after the address date) from birth through adolescence. Data were analyzed from February 1 to June 30, 2022. Census tract-level Child Opportunity Index (COI) and Social Vulnerability Index (SVI) linked to geocoded residential addresses at birth and in infancy (age range, 0.5-1.5 years), early childhood (age range, 2.0-4.8 years), and mid-childhood (age range, 5.0-9.8 years). BMI (calculated as weight in kilograms divided by length [if aged <2 years] or height in meters squared) and obesity (age- and sex-specific BMI ≥95th percentile). Based on nationwide distributions of the COI and SVI, Census tract rankings were grouped into 5 categories: very low (<20th percentile), low (20th percentile to <40th percentile), moderate (40th percentile to <60th percentile), high (60th percentile to <80th percentile), or very high (≥80th percentile) opportunity (COI) or vulnerability (SVI). Among 20 677 children, 10 747 (52.0%) were male; 12 463 of 20 105 (62.0%) were White, and 16 036 of 20 333 (78.9%) were non-Hispanic. (Some data for race and ethnicity were missing.) Overall, 29.9% of children in the ECHO program resided in areas with the most advantageous characteristics. For example, at birth, 26.7% of children lived in areas with very high COI, and 25.3% lived in areas with very low SVI; in mid-childhood, 30.6% lived in areas with very high COI and 28.4% lived in areas with very low SVI. Linear mixed-effects models revealed that at every life stage, children who resided in areas with higher COI (vs very low COI) had lower mean BMI trajectories and lower risk of obesity from childhood to adolescence, independent of family sociodemographic and prenatal characteristics. For example, among children with obesity at age 10 years, the risk ratio was 0.21 (95% CI, 0.12-0.34) for very high COI at birth, 0.31 (95% CI, 0.20-0.51) for high COI at birth, 0.46 (95% CI, 0.28-0.74) for moderate COI at birth, and 0.53 (95% CI, 0.32-0.86) for low COI at birth. Similar patterns of findings were observed for children who resided in areas with lower SVI (vs very high SVI). For example, among children with obesity at age 10 years, the risk ratio was 0.17 (95% CI, 0.10-0.30) for very low SVI at birth, 0.20 (95% CI, 0.11-0.35) for low SVI at birth, 0.42 (95% CI, 0.24-0.75) for moderate SVI at birth, and 0.43 (95% CI, 0.24-0.76) for high SVI at birth. For both indices, effect estimates for mean BMI difference and obesity risk were larger at an older age of outcome measurement. In addition, exposure to COI or SVI at birth was associated with the most substantial difference in subsequent mean BMI and risk of obesity compared with exposure at later life stages. In this cohort study, residing in higher-opportunity and lower-vulnerability neighborhoods in early life, especially at birth, was associated with a lower mean BMI trajectory and a lower risk of obesity from childhood to adolescence. Future research should clarify whether initiatives or policies that alter specific components of neighborhood environment would be beneficial in preventing excess weight in children.

Authors: Aris, Izzuddin M; Ferrara, Assiamira; Zhu, Yeyi; Program Collaborators for Environmental Influences on Child Health Outcomes,; et al.

JAMA Netw Open. 2022 Dec 01;5(12):e2247957. Epub 2022-12-01.

PubMed abstract

COVID-19 Pandemic Experiences and Symptoms of Pandemic-Associated Traumatic Stress Among Mothers in the US

The primary outcomes of the COVID-19 pandemic on the mental health of women with children remain largely unknown. To identify and describe clusters of mothers of children participating in the Environmental influences on Child Health Outcomes (ECHO) Program that characterize pandemic-associated hardships, coping mechanisms, and behaviors, and to evaluate associations between pandemic-associated hardships, coping strategies, and behavior changes with pandemic-associated traumatic stress symptoms. This multicenter cohort study investigated experiences during the COVID-19 pandemic between April 2020 and August 2021 among maternal caregivers of children participating in the ECHO Program. Data from self-identified mothers of ECHO-enrolled children from 62 US cohorts were included in analyses. Data were analyzed from November 2021 to July 2022. The primary exposures were pandemic-associated changes in mothers’ health, health care utilization, work and finances, coping strategies, and health-associated behaviors. Exposures were assessed via a self-reported questionnaire designed by ECHO investigators. The primary outcome was the total symptoms score of pandemic-associated traumatic stress (PTS), defined as the number of items endorsed at least sometimes or more frequently, from a 10-item self-report measure. The study surveyed 11 473 mothers (mean [SD] age, 37.8 [7.4] years; 342 American Indian [2.98%], 378 Asian [3.29%], 1701 Black [14.83%], and 7195 White [62.71%]; 2184 with Hispanic/Latina ethnicity [19.04%]) and identified 2 clusters that best characterized their COVID-19 pandemic experiences-one characterized by higher life disruptions (eg, to work and health care), higher social isolation, more coping behaviors to mitigate the outcomes of the pandemic, and more changes to their health behavior routines (high change [1031 mothers]) and the other characterized by lower changes (low change [3061 mothers]). The high change cluster was more socioeconomically advantaged and reported higher PTS (mean [SD] number of symptoms, 3.72 [2.44] vs 2.51 [2.47]). Across both clusters, higher pandemic-associated hardships, coping mechanisms, and behavior changes were associated with higher PTS, and these associations were greater in the low change cluster. In this study of more than 11 000 US mothers, associations between socioeconomic factors, stressful life events, and mental health sequelae were complex. Accordingly, programs, policies, and practices targeting mental health during public health crises such as the COVID-19 pandemic should consider the range and configuration of hardships in designing the most effective interventions to mitigate long-term outcomes.

Authors: Bastain, Theresa M; Avalos, Lyndsay A; Environmental Influences on Child Health Outcomes Program Collaborators,; et al.

JAMA Netw Open. 2022 Dec 01;5(12):e2247330. Epub 2022-12-01.

PubMed abstract

Changes in 24-Hour Movement Behaviors From Early to Late Pregnancy in Individuals With Prepregnancy Overweight or Obesity

Understanding how sleep, sedentary behavior (SED), and physical activity (PA) (24-h movement profile) changes across pregnancy in individuals with prepregnancy overweight or obesity and how parity (previous births) impacts these changes can help inform interventions. In 155 participants, movement was measured using wrist-worn accelerometers, and sleep was self-reported in early (8-15 wk) and late (29-38 wk) pregnancy. The 24-hour movement profiles were analyzed using compositional analyses. Nulliparous participants (no previous births) spent 33.95%, 38.14%, 25.32%, and 2.58% of the 24-hour day in early pregnancy in sleep, SED, light-intensity PA, and moderate/vigorous-intensity PA, respectively. Multiparous participants (≥1 previous birth) spent 2.50 percentage points less in SED (mean log-ratio difference = -0.068; 95% confidence interval [CI], -0.129 to -0.009) and 2.73 percentage points more in light-intensity PA (mean log-ratio difference = 0.102; 95% CI, 0.035 to 0.180). From early to late pregnancy, participants decreased the proportion of the 24-hour day spent asleep by 1.67 percentage points (mean log-ratio difference = -0.050; 95% CI, -0.092 to -0.011) and increased light-intensity PA by 1.56 percentage points (mean log-ratio difference = 0.057; 95% CI, 0.003 to 0.108), with no change in other behaviors. Nulliparous and multiparous individuals with prepregnancy overweight or obesity both had high levels of SED, with no change across pregnancy, and may require interventions to reduce  SED.

Authors: Badon, Sylvia E; Ferrara, Assiamira; Gabriel, Kelley Pettee; Avalos, Lyndsay A; Hedderson, Monique M

J Phys Act Health. 2022 Dec 01;19(12):842-846. Epub 2022-11-12.

PubMed abstract

Fibroids and vitamin D: another piece of the puzzle

Authors: Mitro, Susanna D; Waetjen, L Elaine; Hedderson, Monique M

Fertil Steril. 2022 Dec;118(6):1137-1138. Epub 2022-11-04.

PubMed abstract

Plasma Phospholipids Monounsaturated Fatty Acids and Gestational Diabetes Mellitus: a Longitudinal Study in the NICHD Fetal Growth Studies-Singleton Cohort

Fatty acids (FAs) have been implicated in the development of gestational diabetes mellitus (GDM), but the role of monounsaturated FAs (MUFAs) remains understudied. We investigated the associations of plasma phospholipid MUFAs in early to mid-pregnancy with cardiometabolic biomarkers and GDM risk. From the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort (2009-2013), we identified 107 women with GDM according to Carpenter and Coustan criteria and 214 control participants without GDM matched (2:1) on age, race/ethnicity, and gestational week (GW) of blood collection. MUFAs were measured at 10-14, 15-26, 23-31, and 33-39 GWs by gas chromatography mass spectrometry. We found that the concentration of total 18:1 MUFAs was significantly lower among women with GDM than those without GDM at 15-26 GWs. Each SD increment in the level of total 18:1 MUFAs was associated with a 40% lower risk of GDM at 15-26 GWs. Moreover, each SD increment in vaccenic acid (18:1n-7) levels at 10-14 and 15-26 GWs were associated with a 36% and 45% lower risk of GDM, respectively. Our extensive assessments of MUFAs advance our understanding of the unique associations of FA composition with GDM risk, suggesting the potentially beneficial role of MUFAs in GDM pathophysiology.

Authors: Tsoi, Kit Ying; Zhu, Yeyi; Wu, Jing; Sun, Qi; Hinkle, Stefanie N; Li, Ling-Jun; Chen, Zhen; Weir, Natalie L; Tsai, Michael Y; Ma, Ronald Cw; Zhang, Cuilin

Diabetes. 2022 Dec 01;71(12):2707-2715.

PubMed abstract

The effect of the COVID-19 pandemic on prenatal cannabis use by pre-conception depression and anxiety status

Authors: Avalos, Lyndsay A; Ray, G Thomas; Alexeeff, Stacey E; Adams, Sara R; Does, Monique; Ansley, Deborah; Tucker, Lue-Yen; Conway, Amy; Ettenger, Allison; Goler, Nancy; Young-Wolff, Kelly C

J Affect Disord Rep. 2022 Dec;10:100432. Epub 2022-11-11.

PubMed abstract

Associations between accelerated parental biologic age, autism spectrum disorder, social traits, and developmental and cognitive outcomes in their children

Parental age is a known risk factor for autism spectrum disorder (ASD), however, studies to identify the biologic changes underpinning this association are limited. In recent years, “epigenetic clock” algorithms have been developed to estimate biologic age and to evaluate how the epigenetic aging impacts health and disease. In this study, we examined the relationship between parental epigenetic aging and their child’s prospective risk of ASD and autism related quantitative traits in the Early Autism Risk Longitudinal Investigation study. Estimates of epigenetic age were computed using three robust clock algorithms and DNA methylation measures from the Infinium HumanMethylation450k platform for maternal blood and paternal blood specimens collected during pregnancy. Epigenetic age acceleration was defined as the residual of regressing chronological age on epigenetic age while accounting for cell type proportions. Multinomial logistic regression and linear regression models were completed adjusting for potential confounders for both maternal epigenetic age acceleration (n = 163) and paternal epigenetic age acceleration (n = 80). We found accelerated epigenetic aging in mothers estimated by Hannum’s clock was significantly associated with lower cognitive ability and function in offspring at 12 months, as measured by Mullen Scales of Early Learning scores (β = -1.66, 95% CI: -3.28, -0.04 for a one-unit increase). We also observed a marginal association between accelerated maternal epigenetic aging by Horvath’s clock and increased odds of ASD in offspring at 36 months of age (aOR = 1.12, 95% CI: 0.99, 1.26). By contrast, fathers accelerated aging was marginally associated with decreased ASD risk in their offspring (aOR = 0.83, 95% CI: 0.68, 1.01). Our findings suggest epigenetic aging could play a role in parental age risks on child brain development.

Authors: Song, Ashley Y; Croen, Lisa A; Ladd-Acosta, Christine; et al.

Autism Res. 2022 Dec;15(12):2359-2370. Epub 2022-10-03.

PubMed abstract

Urinary Phenols in Early to Mid-Pregnancy and Risk of Gestational Diabetes: A Longitudinal Study in a Multiracial Cohort

Environmental phenols are ubiquitous endocrine disruptors and putatively diabetogenic. However, data during pregnancy are scant. We investigated the prospective associations between pregnancy phenol concentrations and gestational diabetes mellitus (GDM) risk. In a nested matched case-control study of 111 individuals with GDM and 222 individuals without GDM within the prospective PETALS cohort, urinary bisphenol A (BPA), BPA substitutes (bisphenol F and bisphenol S [BPS]), benzophenone-3, and triclosan were quantified during the first and second trimesters. Cumulative concentrations across the two times were calculated using the area under the curve (AUC). Multivariable conditional logistic regression examined the association of individual phenols with GDM risk. We conducted mixture analysis using Bayesian kernel machine regression. We a priori examined effect modification by Asian/Pacific Islander (A/PI) race/ethnicity resulting from the case-control matching and highest GDM prevalence among A/PIs. Overall, first-trimester urinary BPS was positively associated with increased risk of GDM (adjusted odds ratio comparing highest vs. lowest tertile [aORT3 vs. T1] 2.12 [95% CI 1.00-4.50]). We identified associations among non-A/Ps, who had higher phenol concentrations than A/PIs. Among non-A/PIs, first-trimester BPA, BPS, and triclosan were positively associated with GDM risk (aORT3 vs. T1 2.91 [95% CI 1.05-8.02], 4.60 [1.55-13.70], and 2.88 [1.11-7.45], respectively). Triclosan in the second trimester and AUC were positively associated with GDM risk among non-A/PIs (P < 0.05). In mixture analysis, triclosan was significantly associated with GDM risk. Urinary BPS among all and BPA, BPS, and triclosan among non-A/PIs were associated with GDM risk. Pregnant individuals should be aware of these phenols' potential adverse health effects.

Authors: Zhu, Yeyi; Hedderson, Monique M; Calafat, Antonia M; Alexeeff, Stacey E; Feng, Juanran; Quesenberry, Charles P; Ferrara, Assiamira

Diabetes. 2022 Dec 01;71(12):2539-2551.

PubMed abstract

The clinical burden of extremely preterm birth in a large medical records database in the United States: complications, medication use, and healthcare resource utilization

Approximately 5% of global preterm births are extremely premature (EP), defined as occurring at less than 28?weeks gestational age. Advances in care have led to an increase in the survival of EP infants during the neonatal period. However, EP infants have a higher risk of developing complications such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP). BPD and other respiratory morbidities are particularly prevalent among this population. To understand the healthcare resource utilization (HRU) of EP infants in the United States, the clinical and economic burden of extreme prematurity was examined in this retrospective study of data extracted from electronic medical records in the Kaiser Permanente Northern California (KPNC) health system. The analysis included data from EP infants live-born between January 1997 and December 2016, and focused on complications and HRU up to 3?years corrected age (CA), covering the period up to December 2018. Stillbirths, infants born at <22?weeks gestational age, and infants with major congenital malformations were excluded. Complications of interest (BPD, IVH, and ROP) and medication use were compared by age group (?1?year, >1?year and ?2?years, and >2?years and ?3?years CA). Analysis of HRU included hospital readmissions, ambulatory visits, and emergency room (ER) visits. A total of 2154 EP births (0.32% of total live births and 4.0% of preterm births that met the inclusion/exclusion criteria) were analyzed. The prevalence of EP birth showed a declining trend over time. ROP was the most commonly recorded complication during the birth hospitalization (37.1% any stage; 2.9% Stages 3 and 4). BPD was recorded in 34.3% of EP infants. IVH (any grade) was recorded in 22.7% of EP infants (6.4% Grades III and IV). A majority (78.7%) of EP infants were diagnosed with at least one respiratory condition during the first year CA, the most common being pneumonia (68.9%); the prevalence of respiratory conditions decreased over the second and third years CA. During the first 3?years CA, the most common medications prescribed to children born EP were inhaled bronchodilators (approximately 30% of children); at least 15% of children received systemic corticosteroids and inhaled steroids during this period. During the first 3?years CA, at least one hospital readmission was recorded for 16.4% of children born EP; 57.1% of these readmissions were related to respiratory conditions. At least one ER visit was recorded for 33.8% of children born EP, for which 53.1% were due to a respiratory condition. Ambulatory visits were recorded for 54.2% of EP children, for which 82.9% were due to a respiratory condition. The short- and long-term clinical burden of EP birth was high. The onset of BPD, IVH, and ROP was common during the birth hospitalization for EP infants. Medication use, hospital readmission, and clinic visits (ER and ambulatory) occurred frequently in these children during the first 3?years CA, and were commonly due to respiratory conditions. Strategies prioritizing the reduction of risk and severity of respiratory conditions may alleviate the clinical burden of EP birth over the long term.

Authors: Siffel, Csaba; Hirst, Andrew K; Sarda, Sujata P; Chen, Hong; Ferber, Jeannette; Kuzniewicz, Michael W; Li, De-Kun

J Matern Fetal Neonatal Med. 2022 Dec;35(26):10271-10278. Epub 2022-09-28.

PubMed abstract

Efficacious lifestyle interventions for appropriate gestational weight gain in women with overweight or obesity set in the health care system: a scoping review

Purpose: Health care systems offer opportunities to scale up interventions for appropriate gestational weight gain (GWG); however, GWG interventions in the health care setting remain largely unavailable to women with overweight or obesity. To inform the translation of efficacious lifestyle interventions to health care delivery systems, this scoping review aimed to systematically identify randomized controlled trials for appropriate GWG in women with overweight or obesity that were set in a health care system.Methods: A scoping review allows for the systematic synthesis of knowledge on an exploratory research question aimed at mapping key concepts (e.g. time, location, source, and evidence) and gaps in a specific area of study. The Colquhoun et al. (2014) framework to conducting scoping reviews was used to develop the research question, identify relevant studies, select studies, extract data, and synthesize data. Specifically, two reviewers searched publication databases for English-language articles published from January 2009 to May 2020 using specific keywords/MeSH terms.Results: Eight peer-reviewed journal articles were identified; six trials were based in Europe and two in the U.S. Only four included lifestyle interventions that were efficacious in reducing GWG. Three trials with efficacious interventions were among women with obesity only and encouraged them to gain at or below the lower limit for total GWG (i.e. ≤5 kg) of the Institute of Medicine (IOM) guidelines. The fourth was among women with overweight or obesity and encouraged women to gain within the IOM guidelines with a telehealth behavioral intervention. Efficacious interventions were initiated in the first half of pregnancy and included frequent contact delivered through multiple modalities (i.e. in-person visits, telephone calls, text messages, email) by trained intervention staff (i.e. dietitian, lifestyle coach, and/or physiotherapist). Only one efficacious intervention trial briefly mentioned theoretical components for health promotion (e.g. self-monitoring); likewise, only one included cost-effectiveness analyses.Conclusions: This review systematically identified randomized controlled trials of efficacious lifestyle interventions (i.e. consisting of diet and physical activity components) for appropriate GWG in women with overweight or obesity that were set in the health care system and delivered by non-clinicians. Translation efforts could draw upon aspects of the efficacious lifestyle interventions described in this review. Future studies should examine theory-based telehealth interventions and cost-effectiveness.

Authors: Barroso, Cristina S; Yockey, Andrew; Degon, Emoni; Gautam Poudel, Pragya; Brown, Susan D; Hedderson, Monique M; Moreno-Hunt, Carey; Ehrlich, Samantha F

J Matern Fetal Neonatal Med. 2022 Dec;35(25):6411-6424. Epub 2021-05-25.

PubMed abstract

Antepartum and intrapartum stillbirth rates across gestation: a cross-sectional study using the revised foetal death reporting system in the U.S

There is a renewed call to address preventable foetal deaths in high-income countries, especially where progress has been slow. The Centers for Disease Control and Prevention released publicly, for the first time, the initiating cause and estimated timing of foetal deaths in 2014. The objective of this study is to describe risk and characteristics of antepartum versus intrapartum stillbirths in the U.S., and frequency of pathological examination to determine cause. We conducted a cross-sectional study of singleton births (24-43 weeks) using 2014 U.S. Fetal Death and Natality data available from the National Center for Health Statistics. The primary outcome was timing of death (antepartum (n = 6200), intrapartum (n = 453), and unknown (n = 5403)). Risk factors of interest included maternal sociodemographic, behavioural, medical and obstetric factors, along with foetal sex. We estimated gestational week-specific stillbirth hazard, risk factors for intrapartum versus antepartum stillbirth using multivariable log-binomial regression models, conditional probabilities of intrapartum and antepartum stillbirth at each gestational week, and frequency of pathological examination by timing of death. The gestational age-specific stillbirth hazard was approximately 2 per 10,000 foetus-weeks among preterm gestations and > 3 per 10,000 foetus-weeks among term gestations. Both antepartum and intrapartum stillbirth risk increased in late-term and post-term gestations. The risk of intrapartum versus antepartum stillbirth was higher among those without a prior live birth, relative to those with at least one prior live birth (RR 1.32; 95% CI 1.08-1.61) and those with gestational hypertension, relative to those with no report of gestational hypertension (RR 1.47; 95% CI 1.09-1.96), and lower among Black, relative to white, individuals (RR 0.70; 95% CI 0.55-0.89). Pathological examination was not performed/planned in 25% of known antepartum stillbirths and 29% of known intrapartum stillbirths. These findings suggest greater stillbirth risk in the late-term and post-term periods. Primiparous mothers had greater risk of intrapartum than antepartum still birth, suggesting the need for intrapartum interventions for primiparous mothers in this phase of pregnancy to prevent some intrapartum foetal deaths. Efforts are needed to improve understanding, prevention and investigation of foetal deaths as well as improve stillbirth data quality and completeness in the United States.

Authors: Ncube, Collette N; McCormick, Sarah M; Badon, Sylvia E; Riley, Taylor; Souter, Vivienne L

BMC Pregnancy Childbirth. 2022 Nov 29;22(1):885. Epub 2022-11-29.

PubMed abstract

Association between Quality of Maternal Prenatal Food Source and Preparation and Breastfeeding Duration in the Environmental Influences on Child Health Outcome (ECHO) Program

This study examined the relationship between maternal food source and preparation during pregnancy and the duration of breastfeeding among 751 mother-child dyads in the United States. The data collected from the Environmental influences on Child Health Outcomes (ECHO) Program included twelve cohorts of mothers (age ≥ 18) who delivered infant(s). Three categories of maternal food source and preparation including, High, Moderate, or Low Food Source Quality were derived from the mother report. The mean duration of breastfeeding differed strongly across the three categories. The High Food Source Quality group breastfed an average of 41 weeks, while shorter durations were observed for the Moderate (26 weeks) and Low (16 weeks) Food Source Quality groups. Cox proportional hazards models were used to estimate the relative hazard of time to breastfeeding cessation for each participant characteristic. The full model adjusted for clustering/cohort effect for all participant characteristics, while the final model adjusted for the subset of characteristics identified from variable reduction modeling. The hazard of breastfeeding cessation for those in the High Food Source Quality group was 24% less than the Moderate group (RH = 0.76; 95% CI, 0.63-0.92). Pregnant women in the High Food Source Quality group breastfed longer than the Moderate and Low groups. We encourage more detailed studies in the future to examine this relationship longitudinally.

Authors: Zimmerman, Emily; Zhu, Yeyi; On Behalf Of Program Collaborators For Environmental Influences On Child Health Outcomes,; et al.

Nutrients. 2022 Nov 21;14(22). Epub 2022-11-21.

PubMed abstract

Association of serum folate levels during pregnancy and prenatal depression

To evaluate the association between serum folate levels during pregnancy and prenatal depression and the extent to which obesity may modify this relationship. This secondary data analysis leveraged data from a previous study of pregnant Kaiser Permanente Northern California participants who completed a survey and provided a serum sample between 2011 and 2013. Serum folate was assessed using the Center for Disease Control’s Total Folate Serum/Whole Blood Microbiological Assay Method. A score of 15 or greater on the Center for Epidemiologic Studies Depression Scale was defined as prenatal depression. We used Poisson regression to estimate risk of prenatal depression given prenatal serum folate status (low/medium tertiles vs. high tertile) in the full sample and in subsamples of women with pre-pregnancy body mass index in the (a) normal range and (b) overweight/obese range. Of the sample, 13% had prenatal depression. Combined low/medium folate tertiles was associated with prenatal depression (adjusted relative risk [aRR]?=?1.97, 95% confidence interval [CI]: 0.93-4.18), although results did not reach statistical significance. This relationship was stronger among women with overweight/obesity than women with normal weight (aRR: 2.61, 95% CI: 1.01-6.71 and aRR: 1.50, 95% CI: 0.34-6.66, respectively). Results suggest an association between lower pregnancy folate levels and prenatal depression that may be stronger among women with overweight or obesity. Future studies need to clarify the temporal sequence of these associations.

Authors: Avalos, Lyndsay A; Nance, Nerissa; Caan, Bette; Sujan, Ayesha C; Uriu-Adams, Janet Y; Li, De-Kun; Quesenberry, Charles P; Hedderson, Monique M

J Matern Fetal Neonatal Med. 2023 Dec;36(1):1-4. Epub 2022-11-17.

PubMed abstract

Medically Attended Influenza During Pregnancy in the 2019-2020 and 2020-2021 Influenza Seasons

Influenza testing and case-confirmation rates in pregnant populations have not been reported during the coronavirus disease 2019 (COVID-19) pandemic. Using electronic medical record data from a cohort of nearly 20,000 pregnancies in the United States, this retrospective cohort study examines the frequency of acute respiratory or febrile illness encounters, influenza testing, and influenza positivity during the 2020-2021 influenza season, which occurred during the COVID-19 pandemic, compared with the 2019-2020 influenza season, which largely did not. The ratios of influenza tests to acute respiratory or febrile illness visits were similar in the 2019-2020 and 2020-2021 influenza seasons (approximately 1:8 and 1:9, respectively) but were low and varied by study site. Although influenza testing in pregnant patients continued in the 2020-2021 season, when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) circulation was widespread in the United States, no cases of influenza were identified in our study cohort.

Authors: Irving, Stephanie A; Li, De-Kun; Naleway, Allison L; et al.

Obstet Gynecol. 2022 11 01;140(5):874-877. Epub 2022-10-05.

PubMed abstract

Geographic Accessibility of Retail Cannabis in Northern California and Prenatal Cannabis Use During the COVID-19 Pandemic

Prenatal cannabis use is associated with health risks for mothers and their children. Prior research suggests that rates of prenatal cannabis use in Northern California increased during the COVID-19 pandemic, but it is unknown whether increases varied with the local cannabis retail and policy environment. To test whether pandemic-related increases in prenatal cannabis use were greater among pregnant individuals with greater retail availability of cannabis around their homes or among those living in jurisdictions that allowed storefront retailers. A cross-sectional, population-based time series study used data from pregnancies in the Kaiser Permanente Northern California health care system screened for cannabis use before (January 1, 2019, to March 31, 2020) and during (April 1 to December 31, 2020) the early COVID-19 pandemic. Proximity to the nearest retailer and number of retailers within a 15-minute drive from one’s home and local cannabis storefront retailer policy (banned vs permitted) were calculated. Interrupted time series models were fit using multiplicative and additive Poisson regression, adjusting for age and race and ethnicity. The COVID-19 pandemic. Prenatal cannabis use based on universal urine toxicology tests conducted during early pregnancy at entrance to prenatal care. The sample (n = 99 127 pregnancies) included 26.2% Asian or Pacific Islander, 6.8% Black, 27.6% Hispanic, 34.4% non-Hispanic White, and 4.9% other, unknown, or multiracial individuals, with a mean (SD) age of 30.8 (5.3) years. Prenatal cannabis use before (6.8%) and during (8.2%) the pandemic was associated with closer proximity to a retailer, greater retailer density, and residing in a jurisdiction that permitted vs banned retailers. There was a greater absolute increase in cannabis use from before to during the pandemic among those within a 10-minute drive (<10 minutes: adjusted rate difference [aRD], 0.93 cases/100 patients; 95% CI, 0.56-1.29 cases/100 patients; ≥10 minutes: aRD, 0.40 cases/100 patients; 95% CI, 0.12-0.68 cases/100 patients; interaction P = .02). Otherwise, relative and absolute rates increased similarly across categories of cannabis retailer proximity/density and local policy (interaction P > .05). Prenatal cannabis use was more common among individuals living in areas with greater retail availability of cannabis. Although relative rates increased similarly during the pandemic regardless of local cannabis retail and policy environment, there was a larger absolute increase associated with living closer to a storefront cannabis retailer. Continued monitoring of local cannabis policy, the retail environment, and prenatal cannabis use is needed.

Authors: Young-Wolff, Kelly C; Alexeeff, Stacey E; Campbell, Cynthia I; Avalos, Lyndsay A; et al.

JAMA Netw Open. 2022 Nov 01;5(11):e2244086. Epub 2022-11-01.

PubMed abstract

Time to positivity of blood cultures in neonatal late-onset bacteraemia

To determine the time to positivity (TTP) of blood cultures among infants with late-onset bacteraemia and predictors of TTP >36 hours. Retrospective cohort study. 16 birth centres in two healthcare systems. Infants with positive blood cultures obtained >72 hours after birth. The main outcome was TTP, defined as the time interval from specimen collection to when a neonatal provider was notified of culture growth. TTP analysis was restricted to the first positive culture per infant. Patient-specific and infection-specific factors were analysed for association with TTP >36 hours. Of 10 235 blood cultures obtained from 3808 infants, 1082 (10.6%) were positive. Restricting to bacterial pathogens and the first positive culture, the median TTP (25th-75th percentile) for 428 cultures was 23.5 hours (18.4-29.9); 364 (85.0%) resulted in 36 hours. Excluding coagulase-negative staphylococci (CoNS), 275 of 294 (93.5%) cultures were flagged positive by 36 hours. In a multivariable model, CoNS isolation and antibiotic pretreatment were significantly associated with increased odds of TTP >36 hours. Projecting a 36-hour empiric duration at one site and assuming that all negative evaluations were associated with an empiric course of antibiotics, we estimated that 1164 doses of antibiotics would be avoided in 629 infants over 10 years, while delaying a subsequent antibiotic dose in 13 infants with bacteraemia. Empiric antibiotic administration in late-onset infection evaluations (not targeting CoNS) can be stopped at 36 hours. Longer durations (48 hours) should be considered when there is pretreatment or antibiotic therapy is directed at CoNS.

Authors: Mukhopadhyay, Sagori; Briker, Sara M; Flannery, Dustin D; Dhudasia, Miren B; Coggins, Sarah A; Woodford, Emily; Walsh, Eileen M; Li, Sherian; Puopolo, Karen M; Kuzniewicz, Michael W

Arch Dis Child Fetal Neonatal Ed. 2022 Nov;107(6):583-588. Epub 2022-03-10.

PubMed abstract

Peri-Pregnancy Cannabis Use and Autism Spectrum Disorder in the Offspring: Findings from the Study to Explore Early Development

The association of autism spectrum disorder (ASD) with self-reported maternal cannabis use from 3 months pre-conception to delivery (“peri-pregnancy”) was assessed in children aged 30-68 months, born 2003 to 2011. Children with ASD (N = 1428) were compared to children with other developmental delays/disorders (DD, N = 1198) and population controls (POP, N = 1628). Peri-pregnancy cannabis use was reported for 5.2% of ASD, 3.2% of DD and 4.4% of POP children. Adjusted odds of peri-pregnancy cannabis use did not differ significantly between ASD cases and DD or POP controls. Results were similar for any use during pregnancy. However, given potential risks suggested by underlying neurobiology and animal models, further studies in more recent cohorts, in which cannabis use and perception may have changed, are needed.

Authors: DiGuiseppi, Carolyn; Daniels, Julie L; Robinson Rosenberg, Cordelia; et al.

J Autism Dev Disord. 2022 Nov;52(11):5064-5071. Epub 2021-11-12.

PubMed abstract

Patterns of Substance Use During Early Pregnancy and Associations With Behavioral Health Characteristics

The aims of the study are to identify patterns of early pregnancy substance use and to examine how these patterns relate to behavioral health conditions measured in early pregnancy. We conducted a retrospective observational study (N= 265,274 pregnancies) screened for alcohol, cannabis, nicotine, pharmaceutical opioids, and stimulants during the first trimester via self-report and urine toxicology tests in Kaiser Permanente Northern California from January 1, 2012, to December 31, 2019. To identify patterns of prenatal substance use, we conducted latent class analysis. We then calculated the prevalence of depression, anxiety, intimate partner violence, and family drug use history for each prenatal substance use group and compared the prevalences by estimating prevalence ratios using modified Poisson regression, adjusting for sociodemographic characteristics. We identified the following 4 latent groups with different patterns of substance use: (a) predominantly alcohol and no other substances (9.30%), (b) predominantly cannabis and no other substances (4.88%), (c) predominantly nicotine and some pharmaceutical opioids (1.09%), and (d) high-polysubstance (alcohol, cannabis, nicotine, and stimulants; 0.36%); these pregnancies were compared with (e) no prenatal substance use (84.37%). The prevalence of all behavioral health conditions was elevated in all prenatal substance use groups compared with the no substance use group. Furthermore, the prevalence of depressive and anxiety disorders, intimate partner violence and family drug use history were greater in the high-polysubstance cluster than the alcohol and cannabis clusters. Results highlight the importance of screening and interventions for all types of substance use during early pregnancy and suggest a particularly high need to prioritize targeting early interventions to pregnant and reproductive age individuals with polysubstance use.

Authors: Sujan, Ayesha C; Alexeeff, Stacey E; Slama, Natalie; Avalos, Lyndsay A; Adams, Sara R; Conway, Amy; Ansley, Deborah; Young-Wolff, Kelly C

J Addict Med. 2022 Oct 18.

PubMed abstract

Reconciling Between Medication Orders and Medication Fills for Lupus in Pregnancy

Most studies consider either medications ordered or filled, but not both. Medication underuse based on filling data cannot necessarily be ascribed to patient nonadherence. Using both data sources, we quantified primary medication adherence in a cohort of prevalent systemic lupus erythematosus (SLE) pregnancies. We identified 419 pregnancies in Kaiser Permanente Northern California in patients with prevalent SLE from 2011 to 2020. We calculated the number of physician-initiated orders or pharmacy-initiated reorders during pregnancy and a comparable 9-month window the year before (prepregnancy) and the proportion of orders ever filled and filled within 30 days for hydroxychloroquine (HCQ), azathioprine, and corticosteroids. For pregnancies without an order or reorder, we identified the proportion with previous prescription fills overlapping into the respective study period. New orders for lupus medications were usually filled. HCQ was prescribed most often (45.8% pregnancies) and usually filled (89.7% in prepregnancy, 93.2% during pregnancy). The majority filled within 30 days (80.5% prepregnancy, 83.3% pregnancy). Some pregnancies without new HCQ orders had continuous refills from prior orders; 53% of 2011-2015 pregnancies either had a new order or fill coverage from a previous period, compared to 63.2% of pregnancies delivering in 2016-2019. Corticosteroid fill frequencies were 90.6% in prepregnancy and 83.6% during pregnancy. Fewer patients used azathioprine; however, most new orders were filled (94.3% prepregnancy, 91.7% pregnancy). For azathioprine and corticosteroids, fill rates were modestly higher in prepregnancy compared to pregnancy. We observed that patients have high adherence to filling new orders for lupus medications, such as HCQ and azathioprine, in pregnancy.

Authors: Simard, Julia F; Liu, Emily F; Chakravarty, Eliza; Rector, Amadeia; Cantu, Miranda; Kuo, Daniel Z; Shaw, Gary M; Druzin, Maurice; Weisman, Michael H; Hedderson, Monique M

ACR Open Rheumatol. 2022 Oct 17.

PubMed abstract

Gestational diabetes mellitus, prenatal maternal depression, and risk for postpartum depression: an Environmental influences on Child Health Outcomes (ECHO) Study

Prior research has demonstrated bidirectional associations between gestational diabetes mellitus (GDM) and perinatal maternal depression. However, the association between GDM, prenatal depression, and postpartum depression (PPD) has not been examined in a prospective cohort longitudinally. Participants in the current analysis included 5,822 women from the National Institutes of Health’s Environmental influences on Child Health Outcomes (ECHO) Research Program: N = 4,606 with Neither GDM nor Prenatal Maternal Depression (Reference Category); N = 416 with GDM only; N = 689 with Prenatal Maternal Depression only; and N = 111 with Comorbid GDM and Prenatal Maternal Depression. The PROMIS-D scale was used to measure prenatal and postnatal maternal depressive symptoms. Primary analyses consisted of linear regression models to estimate the independent and joint effects of GDM and prenatal maternal depression on maternal postpartum depressive symptoms. A higher proportion of women with GDM were classified as having prenatal depression (N = 111; 21%) compared to the proportion of women without GDM who were classified as having prenatal depression (N = 689; 13%), however this finding was not significant after adjustment for covariates. Women with Comorbid GDM and Prenatal Maternal Depression had significantly increased postpartum depressive symptoms measured by PROMIS-D T-scores compared to women with Neither GDM nor Prenatal Maternal Depression (mean difference 7.02, 95% CI 5.00, 9.05). Comorbid GDM and Prenatal Maternal Depression was associated with an increased likelihood of PPD (OR 7.38, 95% CI 4.05, 12.94). However, women with GDM only did not have increased postpartum PROMIS-D T-scores or increased rates of PPD. Our findings underscore the importance of universal depression screening during pregnancy and in the first postpartum year. Due to the joint association of GDM and prenatal maternal depression on risk of PPD, future studies should examine potential mechanisms underlying this relation.

Authors: Shuffrey, Lauren C; Hedderson, Monique M; Zhu, Yeyi; program collaborators for Environmental influences on Child Health Outcomes,; et al.

BMC Pregnancy Childbirth. 2022 Oct 08;22(1):758. Epub 2022-10-08.

PubMed abstract

Development and validation of prediction models for gestational diabetes treatment modality using supervised machine learning: a population-based cohort study

Gestational diabetes (GDM) is prevalent and benefits from timely and effective treatment, given the short window to impact glycemic control. Clinicians face major barriers to choosing effectively among treatment modalities [medical nutrition therapy (MNT) with or without pharmacologic treatment (antidiabetic oral agents and/or insulin)]. We investigated whether clinical data at varied stages of pregnancy can predict GDM treatment modality. Among a population-based cohort of 30,474 pregnancies with GDM delivered at Kaiser Permanente Northern California in 2007-2017, we selected those in 2007-2016 as the discovery set and 2017 as the temporal/future validation set. Potential predictors were extracted from electronic health records at different timepoints (levels 1-4): (1) 1-year preconception to the last menstrual period, (2) the last menstrual period to GDM diagnosis, (3) at GDM diagnosis, and (4) 1 week after GDM diagnosis. We compared transparent and ensemble machine learning prediction methods, including least absolute shrinkage and selection operator (LASSO) regression and super learner, containing classification and regression tree, LASSO regression, random forest, and extreme gradient boosting algorithms, to predict risks for pharmacologic treatment beyond MNT. The super learner using levels 1-4 predictors had higher predictability [tenfold cross-validated C-statistic in discovery/validation set: 0.934 (95% CI: 0.931-0.936)/0.815 (0.800-0.829)], compared to levels 1, 1-2, and 1-3 (discovery/validation set C-statistic: 0.683-0.869/0.634-0.754). A simpler, more interpretable model, including timing of GDM diagnosis, diagnostic fasting glucose value, and the status and frequency of glycemic control at fasting during one-week post diagnosis, was developed using tenfold cross-validated logistic regression based on super learner-selected predictors. This model compared to the super learner had only a modest reduction in predictability [discovery/validation set C-statistic: 0.825 (0.820-0.830)/0.798 (95% CI: 0.783-0.813)]. Clinical data demonstrated reasonably high predictability for GDM treatment modality at the time of GDM diagnosis and high predictability at 1-week post GDM diagnosis. These population-based, clinically oriented models may support algorithm-based risk-stratification for treatment modality, inform timely treatment, and catalyze more effective management of GDM.

Authors: Liao, Lauren D; Ferrara, Assiamira; Greenberg, Mara B; Ngo, Amanda L; Feng, Juanran; Zhang, Zhenhua; Bradshaw, Patrick T; Hubbard, Alan E; Zhu, Yeyi

BMC Med. 2022 09 15;20(1):307. Epub 2022-09-15.

PubMed abstract

Strategies Facilitating Video Visit Implementation by a Medical Group Serving a Diverse Population

IntroductionVideo visits have created new opportunities to enhance access to care, but limited information exists on strategies medical groups can employ to facilitate video visit use by higher-risk patients. Our objective was to identify generalizable strategies to facilitate successful delivery of video visits by systems serving highly diverse patient populations. MethodsThe authors conducted a qualitative study of physicians and staff members in a large group practice with 4.5 million patients with diverse race and ethnicity and socioeconomic status. Semi-structured interviews were conducted between January 2021 and April 2021, with key informants identified via purposive and snowball sampling. Video-recorded interviews were transcribed and analyzed using thematic analysis to identify major themes and subthemes. ResultsThe 42 key informants included regional and medical center leaders, primary care physicians, service managers, and medical assistants. Participants described clinical leadership in technology and multidisciplinary collaboration as crucial to sustained video care adoption. Strategies to facilitate real-time learning included local innovation, rapid communication channels, and psychological safety. The organization offered broad access to frequently updated data reports to help managers and practitioners understand processes, measure performance, and share best practices. Medical assistants and physicians developed new approaches to empathize, tailor interactions with patients, and overcome psychological and technical barriers to connecting via video. ConclusionsKey strategies for sustained video care adoption included clinical leadership articulating its purpose, multidisciplinary collaboration, local innovation, effective data use, empathy, and personalized care. These findings provide a model for how health care systems can foster robust adoption of technologies to serve diverse populations.

Authors: Lieu, Tracy A; Altschuler, Andrea; Hsueh, Loretta; Warton, E Margaret; Levan, Christine; Dixon, Matthew; San, Karen; Awsare, Sameer; Chen, Yi-Fen Irene; Lee, Edward R; Reed, Mary E

Perm J. 2022 Sep 14;26(3):20-29. Epub 2022-07-20.

PubMed abstract

Racial/ethnic disparities in subjective sleep duration, sleep quality, and sleep disturbances during pregnancy: an ECHO study

In the United States, racial/ethnic minoritized groups experience worse sleep than non-Hispanic Whites (nHW), but less is known about pregnant people. This is a key consideration since poor sleep during pregnancy is common and associated with increased risk of adverse perinatal outcomes. This study reports the prevalence of subjective sleep measures in a multi-racial/ethnic pregnant population from the Environmental influences on Child Health Outcomes (ECHO) program. Participants’ self-reported race and ethnicity were grouped into: nHW, non-Hispanic Black/African American (nHB/AA), Hispanic, non-Hispanic Asian (nHA). Analyses examined trimester-specific (first (T1), second (T2), third (T3)) nocturnal sleep duration, quality, and disturbances (Pittsburgh Sleep Quality Index and ECHO maternal sleep health questionnaire). Linear or multinomial regressions estimated the associations between race/ethnicity and each sleep domain by trimester, controlling for body mass index and age, with nHW as reference group. We repeated analyses within maternal education strata. nHB/AA participants reported shorter sleep duration (T2: β = -0.55 [-0.80,-0.31]; T3: β = -0.65 [-0.99,-0.31]) and more sleep disturbances (T2: β = 1.92 [1.09,2.75]; T3: β = 1.41 [0.09,2.74]). Hispanic participants reported longer sleep duration (T1: β = 0.22 [0.00004,0.44]; T2: β = 0.61 [0.47,0.76]; T3: β = 0.46 [0.22,0.70]), better sleep quality (Reference group: Very good. Fairly good T1: OR = 0.48 [0.32,0.73], T2: OR = 0.36 [0.26,0.48], T3: OR = 0.31 [0.18,0.52]. Fairly bad T1: OR = 0.27 [0.16,0.44], T2: OR = 0.46 [0.31, 0.67], T3: OR = 0.31 [0.17,0.55]), and fewer sleep disturbances (T2: β = -0.5 [-1.0,-0.12]; T3: β = -1.21 [-2.07,-0.35]). Differences persisted within the high-SES subsample. Given the stark racial/ethnic disparities in perinatal outcomes and their associations with sleep health, further research is warranted to investigate the determinants of these disparities.

Authors: Lucchini, Maristella; Wright, Rosalind J; Environmental influences on Child Health Outcomes; et al.

Sleep. 2022 Sep 08;45(9).

PubMed abstract

Glycemic Control Trajectories and Risk of Perinatal Complications Among Individuals With Gestational Diabetes

Glycemic control is the cornerstone of gestational diabetes management. Glycemic control trajectories account for differences in longitudinal patterns throughout pregnancy; however, studies on glycemic control trajectories are scarce. To examine whether glycemic control trajectories from gestational diabetes diagnosis to delivery were associated with differential risk of perinatal complications. This population-based cohort study included individuals with gestational diabetes with longitudinal electronic health record data from preconception to delivery who received prenatal care at Kaiser Permanente Northern California (KPNC) and were enrolled in KPNC’s telemedicine-based gestational diabetes care program between January 2007 and December 2017. Data analysis was conducted from September 2021 to January 2022. Glycemic control trajectories were derived using latent class modeling based on the American Diabetes Association’s recommended self-monitoring of blood glucose measurements. Optimal glycemic control was defined as at least 80% of all measurements meeting the targets at KPNC clinical settings. Multivariable Poisson regression models were used to estimate the associations of glycemic control trajectories with cesarean delivery, preterm birth, shoulder dystocia, large- and small-for-gestational-age, and neonatal intensive care unit admission and stay of 7 days or longer. Among a total of 26 774 individuals (mean [SD] age, 32.9 [5.0] years; 11 196 Asian or Pacific Islander individuals [41.8%], 1083 Black individuals [4.0%], 7500 Hispanic individuals [28.0%], and 6049 White individuals [22.6%]), 4 glycemic control trajectories were identified: stably optimal (10 528 individuals [39.3%]), rapidly improving to optimal (9151 individuals [34.2%]), slowly improving to near-optimal (4161 individuals [15.5%]), and slowly improving to suboptimal (2934 individuals [11.0%]). In multivariable models with the rapidly improving to optimal trajectory group as the reference group, glycemic control trajectories were associated with perinatal complications with a gradient across stably optimal to slowly improving to suboptimal. For individuals in the stably optimal trajectory group, there were lower risks of cesarean delivery (adjusted relative risk [aRR], 0.93 [95% CI, 0.89-0.96]), shoulder dystocia (aRR, 0.75 [95% CI, 0.61-0.92]), large-for-gestational age (aRR, 0.74 [95% CI, 0.69-0.80]), and neonatal intensive care unit admission (aRR, 0.90 [95% CI, 0.83-0.97]), while for patients in the slowly improving to suboptimal glycemic control trajectory group, risks were higher for cesarean delivery (aRR, 1.18 [95% CI, 1.12-1.24]; (P for trend < .001), shoulder dystocia (aRR, 1.41 [95% CI, 1.12-1.78]; P for trend < .001), large-for-gestational-age (aRR, 1.42 [95% CI, 1.31-1.53]; P for trend < .001), and neonatal intensive care unit admission (aRR, 1.33 [95% CI, 1.20-1.47]; P for trend < .001). The risk of small-for-gestational-age was higher in patients in the stably optimal group (aRR, 1.10 [95% CI, 1.02-1.20]) and lower in the slowly improving to suboptimal group (aRR, 0.63 [95% CI, 0.53-0.75]). These findings suggest that slowly improving to near-optimal and slowly improving to suboptimal glycemic control trajectories were associated with increased risk of perinatal complications. Future interventions should help individuals achieve glycemic control early after gestational diabetes diagnosis and throughout pregnancy to decrease the risk of perinatal complications.

Authors: Chehab, Rana F; Ferrara, Assiamira; Greenberg, Mara B; Ngo, Amanda L; Feng, Juanran; Zhu, Yeyi

JAMA Netw Open. 2022 Sep 01;5(9):e2233955. Epub 2022-09-01.

PubMed abstract

Predicting the Need for Phototherapy After Discharge: Update for 2022 Phototherapy Guidelines

Authors: Kuzniewicz, Michael W; Li, Sherian Xu; McCulloch, Charles E; Newman, Thomas B

Pediatrics. 2022 09 01;150(3).

PubMed abstract

Changes in BMI During the COVID-19 Pandemic

Experts hypothesized increased weight gain in children associated with the coronavirus disease 2019 (COVID-19) pandemic. Our objective was to evaluate whether the rate of change of child body mass index (BMI) increased during the COVID-19 pandemic compared with prepandemic years. The study population of 1996 children ages 2 to 19 years with at least 1 BMI measure before and during the COVID-19 pandemic was drawn from 38 pediatric cohorts across the United States participating in the Environmental Influences on Child Health Outcomes-wide cohort study. We modeled change in BMI using linear mixed models, adjusting for age, sex, race, ethnicity, maternal education, income, baseline BMI category, and type of BMI measure. Data collection and analysis were approved by the local institutional review board of each institution or by the central Environmental Influences on Child Health Outcomes institutional review board. BMI increased during the COVID-19 pandemic compared with previous years (0.24 higher annual gain in BMI during the pandemic compared with previous years, 95% confidence interval 0.02 to 0.45). Children with BMI in the obese range compared with the healthy weight range were at higher risk for excess BMI gain during the pandemic, whereas children in higher-income households were at decreased risk of BMI gain. One effect of the COVID-19 pandemic is an increase in annual BMI gain during the COVID-19 pandemic compared with the 3 previous years among children in our national cohort. This increased risk among US children may worsen a critical threat to public health and health equity.

Authors: Knapp, Emily A; Hedderson, Monique; Bekelman, Traci A; Chandran, Aruna; et al.

Pediatrics. 2022 09 01;150(3).

PubMed abstract

Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX, and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to >999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child’s needs.

Authors: Ramirez-Celis, Alexandra; Croen, Lisa A; Yoshida, Cathleen K; Alexeeff, Stacey E; Schauer, Joseph; Yolken, Robert H; Ashwood, Paul; Van de Water, Judy

Mol Psychiatry. 2022 Sep;27(9):3760-3767. Epub 2022-05-26.

PubMed abstract

Ovarian Cystadenomas: Growth Rate and Reliability of Imaging Measurements

To evaluate the growth rate of benign ovarian cystadenomas and the degree of variability in ultrasound measurements. Two independent retrospective cohorts of women found to have benign cystadenomas at surgery were identified. To assess growth rate, ultrasounds on women in a community-based health system were reviewed and the growth rate was determined based on the maximum reported size dimension using a mixed effect model. To assess measurement variability, two radiologists independently measured presurgical adnexal imaging findings for women in a tertiary care referral setting. Interobserver, intra-observer, and intermodality (cine clip versus still images) variability in measurements was determined using correlation coefficients (CC) and Bland-Altman analysis, with the proportion of measurements varying by more than 1 cm calculated. For growth rate assessment, 405 women with 1412 ultrasound examinations were identified. The median growth rate was 0.65 cm/year with mucinous cystadenomas growing faster at 0.83 cm/year compared to 0.51 cm/year for serous cystadenomas (median test P < .0001). To evaluate measurement variability, 75 women were identified with 176 ultrasound studies. The within-subject standard deviations for ultrasound measurements were 0.74 cm for cine clip images and 0.41 cm for static images, with 11% of measurements overall differing by more than 1 cm. Cystadenomas grow on average 0.65 cm/year, which is similar in magnitude to the inherent error observed in measurement on ultrasound, suggesting that repeat ultrasound at intervals of longer than a year will often be needed to accurately assess growth if a cyst represents a benign cystadenoma.

Authors: Suh-Burgmann, Elizabeth; Nakhaei, Masoud; Gupta, Sonia; Brook, Alexander; Hecht, Jonathan; Hung, Yun-Yi; Levine, Deborah

J Ultrasound Med. 2022 Sep;41(9):2157-2167. Epub 2021-11-30.

PubMed abstract

Adverse short- and long-term outcomes among infants with mild neonatal encephalopathy

Studies in newborns with mild neonatal encephalopathy (mNE) demonstrated normal outcomes, but recent literature suggests otherwise. This retrospective cohort study examined inborn infants between 2014 and 2017. Biochemical and clinical characteristics determined the presence of NE and an encephalopathy score categorized infants as Definite or Possible mNE. An Unexposed control group consisted of newborns not meeting the inclusion criteria. Long-term outcomes assessed included cerebral palsy, seizures, developmental disorder, and motor and speech delay. The association of mNE with seizure disorder by 3 years of age was assessed with logistic regression and developmental disorders with Cox proportional hazards models. Of the 156,501 births, we identified 130 with Definite mNE and 445 with Possible mNE (0.8 and 2.8 per 1000 births, respectively). Both groups had significantly higher rates of any developmental disorder and motor and speech delay when compared to the Unexposed (p < 0.05, except for p = 0.07 for motor delay in the Possible NE group). The Definite mNE group had higher rates of developmental disorder and motor and speech delay when compared to the Unexposed with hazard ratios (95% CI) 2.0 (1.2-3.2), 3.7 (1.5-8.8), and 2.1 (1.3-3.5), respectively. An estimate of short- and long-term consequences of mNE suggests that there may be a higher risk of adverse outcome. Infants with mild NE are at significant risk for adverse short- and long-term outcomes. The risk of having an abnormal long-term outcome at 3 years of age were doubled in the mild NE group compared to the Unexposed group. Randomized clinical trials are needed as neuroprotective strategies may mitigate these.

Authors: Akula, Vishnu-Priya; Sriram, Achyuth; Xu, Sherian; Walsh, Eileen; Van Meurs, Krisa; Cranshaw, Matthew; Kuzniwiecz, Michael

Pediatr Res. 2022 Aug 23.

PubMed abstract

Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts

Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies. In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI -1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value < 0.01 (EARLI cord nCpGs = 4068, EARLI placenta nCpGs = 3647, MARBLES cord nCpGs = 4068, MARBLES placenta nCpGs = 9563) were consistently enriched in neuronal developmental pathways. Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.

Authors: Dou, John F; Hertz-Picciotto, Irva; Bakulski, Kelly M; et al.

Epigenetics Chromatin. 2022 Aug 02;15(1):28. Epub 2022-08-02.

PubMed abstract

In-utero cannabis exposure and long-term psychiatric and neurodevelopmental outcomes: The limitations of existing literature and recommendations for future research

Given increases in cannabis use in pregnancy and animal model research showing effects of in-utero cannabis exposure, high-quality information on long-term consequences of in-utero cannabis exposure in humans is needed. While reviews have summarized findings from observational studies with humans, reviews have not focused on limitations of these studies and recommendations for future research. Therefore, we critically reviewed observational research on in-utero cannabis exposure and psychiatric and neurodevelopmental outcomes measured at or after age 3 and provided recommendations for future research. We used Web of Science, Google Scholar, and work cited from relevant identified publications to identify 46 papers to include in our review. Our review includes two main sections. The first section highlights the extensive limitations of the existing research, which include small and nongeneralizable samples, reliance on self-reported data, lack of detail on timing and amount of exposure, inclusion of older exposure data only, not accounting for important confounders, inclusion of potential mediators as covariates, not including outcome severity measures, and not assessing for offspring sex differences. The second section provides recommendations for future research regarding exposure and outcome measures, sample selection, confounder adjustment, and other methodological considerations. For example, with regard to exposure definition, we recommend that studies quantify the amount of cannabis exposure, evaluate the influence of timing of exposure, and incorporate biological measures (e.g., urine toxicology measures). Given that high-quality information on long-term consequences of in-utero cannabis exposure in humans does not yet exit, it is crucial for future research to address the limitations we have identified.

Authors: Sujan, Ayesha C; Young-Wolff, Kelly C; Avalos, Lyndsay A

Birth Defects Res. 2022 08 01;114(13):689-713. Epub 2022-06-16.

PubMed abstract

The clinical burden of extremely preterm birth in a large medical records database in the United States: Mortality and survival associated with selected complications

Preterm birth is a leading cause of infant mortality, particularly for those born extremely prematurely (EP; <28 weeks' gestational age [GA]). Survivors are predisposed to complications such as bronchopulmonary dysplasia (BPD), chronic lung disease (CLD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP). To examine the epidemiology, complications, and mortality/survival among EP infants. Retrospective analysis of electronic medical records from the Kaiser Permanente Northern California database. EP infants live-born between 22 and <28 weeks' GA from 1997 to 2016. Cumulative all-cause mortality/survival were analyzed and stratified by GA (22 to <24, 24 to <26, 26 to <28 weeks), complications (BPD/CLD, IVH, ROP), and birth period (1997 to 2003, 2004 to 2009, 2010 to 2016). Cox proportional hazard models were constructed to assess the mortality risk associated with BPD/CLD or IVH. 2154 EP infants were identified; of these, 916 deaths were recorded. Mortality was highest during the first 3 months (41.7 % cumulative mortality), and few were reported after 2 years (42.5 % cumulative mortality). Mortality decreased with higher GA and over more recent birth periods. BPD/CLD and IVH grade 3/4 were associated with increased mortality risk versus no complications (adjusted hazard ratios 1.41 and 1.78, respectively). The risk of mortality is high during the first few months of life for EP infants, and is even higher for those with BPD and IVH. Despite an overall trend toward increased survival for EP infants, strategies targeting survival of EP infants with these complications are needed.

Authors: Siffel, Csaba; Hirst, Andrew K; Sarda, Sujata P; Kuzniewicz, Michael W; Li, De-Kun

Early Hum Dev. 2022 08;171:105613. Epub 2022-06-22.

PubMed abstract

Predictive Metabolomic Markers in Early to Mid-Pregnancy for Gestational Diabetes: A Prospective Test and Validation Study

Gestational diabetes mellitus (GDM) predisposes pregnant individuals to perinatal complications and long-term diabetes and cardiovascular diseases. We developed and validated metabolomic markers for GDM in a prospective test-validation study. In a case-control sample within the PETALS cohort (GDM n = 91 and non-GDM n = 180; discovery set), a random PETALS subsample (GDM n = 42 and non-GDM n = 372; validation set 1), and a case-control sample within the GLOW trial (GDM n = 35 and non-GDM n = 70; validation set 2), fasting serum untargeted metabolomics were measured by gas chromatography/time-of-flight mass spectrometry. Multivariate enrichment analysis examined associations between metabolites and GDM. Ten-fold cross-validated LASSO regression identified predictive metabolomic markers at gestational weeks (GW) 10-13 and 16-19 for GDM. Purinone metabolites at GW 10-13 and 16-19 and amino acids, amino alcohols, hexoses, indoles, and pyrimidine metabolites at GW 16-19 were positively associated with GDM risk (false discovery rate <0.05). A 17-metabolite panel at GW 10-13 outperformed the model using conventional risk factors, including fasting glycemia (area under the curve: discovery 0.871 vs. 0.742, validation 1 0.869 vs. 0.731, and validation 2 0.972 vs. 0.742; P < 0.01). Similar results were observed with a 13-metabolite panel at GW 17-19. Dysmetabolism is present early in pregnancy among individuals progressing to GDM. Multimetabolite panels in early pregnancy can predict GDM risk beyond conventional risk factors.

Authors: Zhu, Yeyi; Barupal, Dinesh K; Ngo, Amanda L; Quesenberry, Charles P; Feng, Juanran; Fiehn, Oliver; Ferrara, Assiamira

Diabetes. 2022 08 01;71(8):1807-1817.

PubMed abstract

Health Behavior Changes during the COVID-19 Pandemic: A Longitudinal Analysis among Children

This longitudinal study compared children’s health behaviors before the COVID-19 pandemic versus during the pandemic. This analysis examined the association between individual-level characteristics and health behavior change. Four prospective cohort studies in the Environmental influences on Child Health Outcomes (ECHO) Program contributed data. Children aged 4-12 years and their caregivers were recruited in California, Colorado, North Dakota, and New Hampshire. Dietary intake, physical activity, screen time, and sleep duration were assessed with questionnaires pre-pandemic and during the pandemic. The final sample included 347 children: 47% female and 62% non-Hispanic White. Compared with pre-pandemic, weekday screen time duration was higher during the pandemic (3.0 vs. 4.5 h, p < 0.001). Unadjusted increases in screen time duration differed by race and ethnicity: 1.3 h/day for non-Hispanic White children, 2.3 h/day for Hispanic children, and 5.3 h/day for non-Hispanic Black children. Overall, no changes occurred in sugar-sweetened beverage (SSB) intake (p = 0.26), discretionary food intake (p = 0.93), and physical activity (p = 0.15). Sleep duration increased by 30 min among children who did not meet sleep recommendations pre-pandemic. Child sex and maternal education level were not associated with health behavior change. The pandemic may have exacerbated disparities in some health behaviors. Families may need support to re-establish healthy routines.

Authors: Bekelman, Traci A; Friesen, Kaylyn; Hockett, Christine W; Program Collaborators for Environmental influences on Child Health Outcomes (ECHO),; et al.

Int J Environ Res Public Health. 2022 Jul 28;19(15). Epub 2022-07-28.

PubMed abstract

Cardiometabolic Pregnancy Complications in Association with Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (β = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (β = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

Authors: Lyall, Kristen; Avalos, Lyndsay A; Croen, Lisa A; Ferrara, Assiamira; Environmental Influences On Child Health Outcomes, On Behalf Of Program Collaborators For; et al.

Am J Epidemiol. 2022 Jul 23;191(8):1407-1419.

PubMed abstract

Sociodemographic Variation in Children’s Health Behaviors During the COVID-19 Pandemic

Background: Societal changes during the COVID-19 pandemic may affect children’s health behaviors and exacerbate disparities. This study aimed to describe children’s health behaviors during the COVID-19 pandemic, how they vary by sociodemographic characteristics, and the extent to which parent coping strategies mitigate the impact of pandemic-related financial strain on these behaviors. Methods: This study used pooled data from 50 cohorts in the Environmental influences on Child Health Outcomes Program. Children or parent proxies reported sociodemographic characteristics, health behaviors, and parent coping strategies. Results: Of 3315 children aged 3-17 years, 49% were female and 57% were non-Hispanic white. Children of parents who reported food access as a source of stress were 35% less likely to engage in a higher level of physical activity. Children of parents who changed their work schedule to care for their children had 82 fewer min/day of screen time and 13 more min/day of sleep compared with children of parents who maintained their schedule. Parents changing their work schedule were also associated with a 31% lower odds of the child consuming sugar-sweetened beverages. Conclusions: Parents experiencing pandemic-related financial strain may need additional support to promote healthy behaviors. Understanding how changes in parent work schedules support shorter screen time and longer sleep duration can inform future interventions.

Authors: Bekelman, Traci A; Ferrara, Assiamira; Hedderson, Monique M; program collaborators for Environmental influences on Child Health Outcomes (ECHO),; et al.

Child Obes. 2022 Jul 19.

PubMed abstract

Reach, acceptability, and perceived success of a telehealth diabetes prevention program among racially and ethnically diverse patients with gestational diabetes: the GEM cluster-randomized trial

Patients with gestational diabetes mellitus and from racial/ethnic minority groups face disproportionate risk for type 2 diabetes. Lifestyle interventions, if accessible and acceptable to diverse patients, could advance diabetes prevention and mitigate racial/ethnic disparities. Here we describe overall and race/ethnicity-specific reach, acceptability, and perceived success from an effective telehealth diabetes prevention lifestyle program for patients with gestational diabetes mellitus, implemented in the Gestational Diabetes Effects on Moms (GEM) cluster-randomized controlled trial. GEM tested a program of 13 telephone sessions and behavior change techniques (BCTs, e.g., goal setting) in a healthcare system. We evaluated participation (completing ≥1 session), acceptability of BCTs, and perceived success reaching program goals. Among 1,087 patients (75.2% from minority groups), 50.3% participated. Participation rates were 61.7% among Black, 56.4% among Hispanic, 55.6% among multiracial/other, 53.0% among White, and 43.7% among Asian/Pacific Islander patients. Evaluation survey respondents (n = 433/547; 79.2%) largely rated BCTs as very helpful (range 40.9%-58.4%) or moderately helpful (27.3%-34.9%). Respondents from minority groups largely rated goal setting for weight management as very or moderately helpful, with fewer minority respondents rating it as only a little/not at all helpful than White respondents (p = .02). Black and White respondents reported more limited success reaching a healthy weight than Asian/Pacific Islander, Hispanic, and multiracial/other women (p = .005). A telehealth diabetes prevention lifestyle program demonstrated reach and acceptability across racial/ethnic groups. While perceived success can be improved among Black and White participants, such programs could promote access to preventive care and help mitigate disparities in diabetes risk.

Authors: Brown, Susan D; Hedderson, Monique M; Gordon, Nancy; Albright, Cheryl L; Tsai, Ai-Lin; Quesenberry, Charles P; Ferrara, Assiamira

Transl Behav Med. 2022 Jul 18;12(7):793-799.

PubMed abstract

Coping strategies for COVID-19 pandemic-related stress and mental health during pregnancy

Increased stress has likely contributed to the observed high prevalence of depression and anxiety in pregnant individuals during the COVID-19 pandemic. The objective of this study was to assess the prevalence of coping strategies for COVID-19 pandemic-related stress and associations of these coping strategies with depression and anxiety symptoms during pregnancy. 8320 members of Kaiser Permanente Northern California who were pregnant between June 22, 2020 and May 10, 2021 completed an online survey including questions about coping strategies since the start of the COVID-19 pandemic and current depression and anxiety symptoms. We used weighted regression to estimate prevalence ratios for moderate/severe depression and anxiety symptom severity associated with coping strategies. The most common coping strategies for COVID-19 pandemic-related stress were talking with friends and family (77%), outdoor physical activity (54%), and increasing screen time activities (52%). Exercising using online programs or videos, outdoor physical activity, talking with friends and family, and engaging in more family activities were associated with 29% to 38% lower prevalence of moderate/severe depression symptom severity and 16% to 34% lower prevalence of moderate/severe anxiety symptom severity. We are unable to rule out reverse temporality as an explanation for the observed results because of the cross-sectional design; depression or anxiety symptom severity may influence use of specific coping strategies. Our results suggest that physical activity and connecting with others are coping strategies for COVID-19 pandemic-related stress that may be associated with better mental health in pregnant individuals.

Authors: Badon, Sylvia E; Croen, Lisa A; Ferrara, Assiamira; Ames, Jennifer L; Hedderson, Monique M; Young-Wolff, Kelly C; Zhu, Yeyi; Avalos, Lyndsay A

J Affect Disord. 2022 Jul 15;309:309-313. Epub 2022-04-28.

PubMed abstract

Multi-Chain Semi-Markov Analysis of Intrapartum Cardiotocography

Visual assessment of the evolution of fetal heart rate (FHR) and uterine pressure (UP) patterns is the standard of care in the intrapartum period. Unfortunately, this assessment has high levels of intra- and inter-observer variability. This study processed and analyzed FHR and UP patterns using computerized pattern recognition tools. The goal was to evaluate differences in FHR and UP patterns between fetuses with normal outcomes and those who developed hypoxic-ischemic encephalopathy (HIE). For this purpose, we modeled the sequence of FHR patterns and uterine contractions using Multi-Chain Semi-Markov models (MCSMMs). These models estimate the probability of transitioning between FHR or UP patterns and the dwell time of each pattern. Our results showed that in comparison to the control group, the HIE group had: (1) more frequent uterine contractions during the last 12 hours before birth; (2) more frequent FHR decelerations during the last 12 hours before birth; (3) longer decelerations during the last eight hours before birth; and (4) shorter baseline durations during the last five hours before birth. These results demonstrate that the fetuses in the HIE group were subject to a more stressful environment than those in the normal group. Clinical Relevance- Our results revealed statistically significant differences in FHR/UP patterns between the normal and HIE groups in the hours before birth. This indicates that features derived using MCSMMs may be useful in a machine learning framework to detect infants at increased risk of developing HIE allowing preventive interventions.

Authors: Vargas-Calixto, Johann; Wu, Yvonne; Kuzniewicz, Michael; Cornet, Marie-Coralie; Forquer, Heather; Gerstley, Lawrence; Hamilton, Emily; Warrick, Philip A; Kearney, Robert E

Annu Int Conf IEEE Eng Med Biol Soc. 2022 Jul;2022:1948-1952.

PubMed abstract

Associations between combined exposure to environmental hazards and social stressors at the neighborhood level and individual perinatal outcomes in the ECHO-wide cohort

Limited studies examine how prenatal environmental and social exposures jointly impact perinatal health. Here we investigated relationships between a neighborhood-level combined exposure (CE) index assessed during pregnancy and perinatal outcomes, including birthweight, gestational age, and preterm birth. Across all participants, higher CE index scores were associated with small decreases in birthweight and gestational age. We also observed effect modification by race; infants born to Black pregnant people had a greater risk of preterm birth for higher CE values compared to White infants. Overall, our results suggest that neighborhood social and environmental exposures have a small but measurable joint effect on neonatal indicators of health.

Authors: Martenies, Sheena E; Croen, Lisa A; program collaborators for Environmental influences on Child Health Outcomes,; et al.

Health Place. 2022 07;76:102858. Epub 2022-07-21.

PubMed abstract

Association Between Prenatal Cannabis Use and Psychotropic Medication Use in Pregnant Patients With Depression and Anxiety

This cross-sectional study examined associations between prenatal cannabis use and prescribed psychotropic medication use among pregnant patients with depression or anxiety in a large, integrated healthcare system. Study patients had a confirmed pregnancy and a depressive or anxiety disorder defined by International Classification of Diseases codes between 2012 and 2018 at Kaiser Permanente Northern California. Patients were screened for prenatal substance use via a self-reported questionnaire and urine toxicology test as part of standard prenatal care. Generalized estimating equation models tested for associations between prenatal cannabis use and any dispensation of antidepressants, benzodiazepines, and hypnotics during gestation. Models were stratified by diagnosis (depression or anxiety) and depression symptom severity. This study included 35,047 pregnancies (32,278 patients; 17.6% aged <25 years, 48.1% non-Hispanic White). Adjusting for patient age, income, race/ethnicity, and depression symptom severity, the 12.6% of patients who screened positive for prenatal cannabis use demonstrated higher odds of prenatal benzodiazepine (adjusted odds ratios [aOR] = 1.40; 95% confidence interval [CI] = 1.20-1.62) and hypnotic (aOR = 1.28; 95% CI = 1.11-1.48), but not antidepressants (aOR = 1.05, 95% CI = 0.96-1.14) use. This pattern persisted when diagnostic groups were examined separately. The odds of prenatal benzodiazepine and hypnotic use associated with prenatal cannabis use were higher among pregnancies with severe depression symptom severity (31.8% of the sample). Among pregnant patients with depression or anxiety, prenatal cannabis use was associated with higher odds of prenatal benzodiazepine and hypnotic use. As patients may be using cannabis to address depression and anxiety, prescribers should remain vigilant for under- or untreated psychiatric symptoms among pregnant patients and provide evidence-based treatments.

Authors: Hirschtritt, Matthew E; Avalos, Lyndsay A; Sarovar, Varada; Ridout, Kathryn K; Goler, Nancy C; Ansley, Deborah R; Satre, Derek D; Young-Wolff, Kelly C

J Addict Med. 2022 Jul-Aug 01;16(4):e269-e273. Epub 2022-01-22.

PubMed abstract

Maternal Dietary Patterns during Pregnancy and Child Autism-Related Traits: Results from Two US Cohorts

We examined the relationship between maternal intake of established dietary patterns and child autism-related outcomes in two prospective cohorts in the United States. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI, n = 154) and the Nurses’ Health Study II (NHSII, n = 727). Dietary information was collected via food frequency questionnaires (FFQs) and used to calculate the empirical dietary inflammatory pattern (EDIP), Alternative Healthy Eating Index (AHEI), Western and Prudent dietary patterns, and the alternative Mediterranean Diet (aMED) score. Primary analyses examined associations with continuous autism-related traits as measured by the Social Responsiveness Scale (SRS), and secondary analyses with autism spectrum disorder (ASD) diagnosis. We used crude and multivariable quantile regression fixed at the 50th percentile to examine associations between quartiles of dietary patterns and SRS scores, and logistic regression to examine associations with ASD diagnosis. There was suggestion of a positive association with the Western diet (Q4 vs. Q1, ß = 11.19, 95% CI: 3.30, 19.90) in EARLI, though the association was attenuated with adjustment for total energy intake, and no clear associations were observed with other dietary patterns and ASD diagnosis or SRS scores. Further work is needed to better understand the role of maternal dietary patterns in ASD and related outcomes.

Authors: Vecchione, Rachel; Wang, Siwen; Rando, Juliette; Chavarro, Jorge E; Croen, Lisa A; Fallin, M Daniele; Hertz-Picciotto, Irva; Newschaffer, Craig J; Schmidt, Rebecca J; Lyall, Kristen

Nutrients. 2022 Jun 30;14(13). Epub 2022-06-30.

PubMed abstract

Placental morphology in association with autism-related traits in the EARLI study

In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

Authors: Zhong, Caichen; Croen, Lisa A; Lyall, Kristen; et al.

BMC Pregnancy Childbirth. 2022 Jun 28;22(1):525. Epub 2022-06-28.

PubMed abstract

Impaired fasting glucose in pregnancy: improved perinatal outcomes with active glycemic management

To assess the association between active glycemic management and large for gestational age (LGA) neonates and cesarean delivery (CD) among pregnant women with impaired fasting glucose (IFG). Retrospective cohort study using electronic health record data of women with IFG who delivered at Kaiser Permanente Northern California from 2012-2017. IFG was defined as isolated fasting glucose ≥95 mg/dL. Women with gestational diabetes (GDM) or in whom GDM could not be ruled out were excluded. Baseline and treatment characteristics, and pregnancy outcomes were compared among women with IFG who participated in telephonic home glucose monitoring and glycemic management through a centralized standardized program (participants) with those who did not participate (non-participants). The relative risks (RR) of perinatal complications associated with participation versus non-participation were estimated with Poisson regression models. We identified 1,584 women meeting inclusion criteria, of whom 1,151 (72.7%) were participants and 433 (27.3%) were non-participants. There were no differences between groups in baseline characteristics or comorbidities, except for higher mean levels of fasting glucose (FG) at the time of IFG diagnosis in participants than in non-participants (98.9 mg/dL vs 98.0 mg/dL, p=0.01). Participants received hypoglycemic medications more frequently than non-participants (68.2% vs 0.9%, p<0.01). The rate of LGA was significantly lower in participants compared with non-participants (19.1% vs 25.0%, p=0.01). After adjusting for age, race/ethnicity, education, body mass index, and level of FG impairment, the RR for LGA for participants compared with non-participants was 0.68, 95% CI: 0.55-0.84. The risk of cesarean delivery did not differ significantly by participation status, in unadjusted or adjusted analyses. Active standardized glycemic management was associated with a decreased risk of LGA for women with IFG. This finding supports an active glycemic management strategy for patients with IFG during pregnancy to reduce the risk of LGA, similar to GDM management.

Authors: Berglin, Mendy; Anderson, Meredith; Ritterman Weintraub, Miranda; Navalta, Stephanie; Hedderson, Monique; Ferrara, Assiamira; Greenberg, Mara

Am J Perinatol. 2022 Jun 24.

PubMed abstract

A Web-Based mHealth Intervention With Telephone Support to Increase Physical Activity Among Pregnant Patients With Overweight or Obesity: Feasibility Randomized Controlled Trial

Pregnant patients with overweight or obesity are at high risk for perinatal complications. Excess gestational weight gain (GWG) further exacerbates this risk. Mobile health (mHealth) lifestyle interventions that leverage technology to facilitate self-monitoring and provide just-in-time feedback may motivate behavior change to reduce excess GWG, reduce intervention costs, and increase scalability by improving access. This study aimed to test the acceptability and feasibility of a pilot mHealth lifestyle intervention for pregnant patients with overweight or obesity to promote moderate intensity physical activity (PA), encourage guideline-concordant GWG, and inform the design of a larger pragmatic cluster randomized controlled trial. We conducted a mixed methods acceptability and feasibility randomized controlled trial among pregnant patients with a prepregnancy BMI of 25 to 40 kg/m2. Patients with singletons at 8 to 15 weeks of gestation who were aged ≥21 years and had Wi-Fi access were recruited via email from 2 clinics within Kaiser Permanente Northern California and randomized to receive usual prenatal care or an mHealth lifestyle intervention. Participants in the intervention arm received wireless scales, access to an intervention website, activity trackers to receive automated feedback on weight gain and activity goals, and monthly calls from a lifestyle coach. Surveys and focus groups with intervention participants assessed intervention satisfaction and ways to improve the intervention. PA outcomes were self-assessed using the Pregnancy Physical Activity Questionnaire, and GWG was assessed using electronic health record data for both arms. Overall, 33 patients were randomly assigned to the intervention arm, and 35 patients were randomly assigned to the usual care arm. All participants in the intervention arm weighed themselves at least once a week, compared with 20% (7/35) of the participants in the usual care arm. Participants in the intervention arm wore the activity tracker 6.4 days per week and weighed themselves 5.3 times per week, and 88% (29/33) of them rated the program “good to excellent.” Focus groups found that participants desired more nutrition-related support to help them manage GWG and would have preferred an app instead of a website. Participants in the intervention arm had a 23.46 metabolic equivalent of task hours greater change in total PA per week and a 247.2-minute greater change in moderate intensity PA per week in unadjusted models, but these effects were attenuated in adjusted models (change in total PA: 15.55 metabolic equivalent of task hours per week; change in moderate intensity PA: 199.6 minutes per week). We found no difference in total GWG (mean difference 1.14 kg) compared with usual care. The pilot mHealth lifestyle intervention was feasible, highly acceptable, and promoted self-monitoring. Refined interventions are needed to effectively affect PA and GWG among pregnant patients with overweight or obesity. NCT03936283;

Authors: Thomas, Tainayah; Xu, Fei; Sridhar, Sneha; Sedgwick, Tali; Nkemere, Linda; Badon, Sylvia E; Quesenberry, Charles; Ferrara, Assiamira; Mandel, Sarah; Brown, Susan D; Hedderson, Monique

JMIR Form Res. 2022 Jun 22;6(6):e33929. Epub 2022-06-22.

PubMed abstract

Examining associations between prenatal biomarkers of oxidative stress and ASD-related outcomes using quantile regression

We examined associations between prenatal oxidative stress (OS) and child autism-related outcomes. Women with an autistic child were followed through a subsequent pregnancy and that younger sibling’s childhood. Associations between glutathione (GSH), glutathione disulfide (GSSG), 8-oxo-deoxyguanine (8-OHdG), and nitrotyrosine and younger sibling Social Responsiveness Scale (SRS) scores were examined using quantile regression. Increasing GSH:GSSG (suggesting decreasing OS) was associated with minor increases in SRS scores (50th percentile β: 1.78, 95% CI: 0.67, 3.06); no other associations were observed. Results from this cohort with increased risk for autism do not support a strong relationship between OS in late pregnancy and autism-related outcomes. Results may be specific to those with enriched autism risk; future work should consider other timepoints and biomarkers.

Authors: Carey, Meghan E; Croen, Lisa A; Lyall, Kristen; et al.

J Autism Dev Disord. 2022 Jun 09.

PubMed abstract

Associations between antenatal corticosteroid exposure and neurodevelopment in infants

It has been well recognized that antenatal administration of dexamethasone to pregnant women at risk of preterm delivery may significantly accelerate fetal maturation and reduce the risk of adverse perinatal outcomes in their preterm infants, particularly for births before 34 weeks of gestation. Since 2015, antenatal corticosteroid administration has been extended beyond 34 weeks of gestation by clinical guidelines, as it might have beneficial effects on fetal maturation and perinatal outcomes. However, concerns regarding the potential influence of antenatal corticosteroid treatment on offspring neurodevelopment have been raised. This study aimed to investigate whether maternal antenatal corticosteroid administration was associated with neurodevelopment in infants at 1 year of age. In this prospective and longitudinal birth cohort study, women were followed up throughout gestation, and their infants underwent a Bayley Scales of Infant and Toddler Development, third edition, screening test at 1 year of age between December 2018 and September 2020. Finally, 1609 pregnant women and 1759 infants were included in the current study. Using a generalized linear mixed model, we examined the association between antenatal corticosteroid exposure and infant neurodevelopment in cognitive, receptive communication, expressive communication, fine motor, and gross motor functions. Of the 1759 infants eligible for this study, 1453 (82.6%) were singletons. A total of 710 infants were exposed to antenatal corticosteroids, among whom 415 were dexamethasone-exposed and 483 were prednisone-exposed. Dexamethasone was prescribed most often in late pregnancy while prednisone was often used before 8 weeks of gestation among women who conceived through assisted reproductive technology. Compared with those who had no exposure, antenatal corticosteroid exposure was associated with an increased risk of infants being noncompetent in the cognitive development domain after adjusting for conventional risk factors (adjusted risk ratio, 1.53; 95% confidence interval, 1.08-2.18; P=.017). For medication-specific exposure, those exposed versus not exposed to antenatal dexamethasone were 1.62-fold (95% confidence interval, 1.10-2.38; P=.014) more likely to be noncompetent in the cognitive development domain at 1 year. The association did not vary significantly between preterm and term infants, singletons and twins, or assisted-reproductive-technology- and spontaneously conceived infants (all P >.05 for heterogeneity). In contrast, a null association was observed for the risk of being noncompetent in any domain of neurodevelopment with antenatal prednisone exposure at early pregnancy. In this cohort study, antenatal corticosteroid, particularly dexamethasone exposure, was significantly associated with an increased risk of infants being noncompetent in the cognitive development domain at 1 year of age. These findings may provide new information when weighing the benefits and potential risks of maternal antenatal corticosteroid administration.

Authors: Tao, Shiyao; Zhu, Yeyi; CNBC Study Group,; et al.

Am J Obstet Gynecol. 2022 Jun 03.

PubMed abstract

Uptake of guideline-recommended postpartum diabetes screening among diverse women with gestational diabetes: associations with patient factors in an integrated health system in USA

Clinical guidelines urge timely postpartum screening for diabetes among women with gestational diabetes mellitus (GDM), yet patient factors associated with screening uptake remain unclear. We aimed to identify patient factors associated with completed postpartum diabetes screening (2-hour oral glucose tolerance test within 4-12 weeks postpartum), as recommended by the American Diabetes Association (ADA). Within the context of Gestational Diabetes’ Effects on Moms (GEM), a pragmatic cluster randomized trial (2011-2012), we examined survey and electronic health record data to assess clinical and sociodemographic factors associated with uptake of ADA-recommended postpartum screening. Participants included 1642 women (76% racial/ethnic minorities) identified with GDM according to the Carpenter and Coustan criteria in a health system that deploys population-level strategies to promote screening. To contextualize these analyses, screening rates derived from the GEM trial were compared with those in the health system overall using registry data from a concurrent 10-year period (2007-2016, n=21 974). Overall 52% (n=857) completed recommended postpartum screening in the analytic sample, comparable to 45.7% (n=10 040) in the registry. Screening in the analytic sample was less likely among women at elevated risk for type 2 diabetes, assessed using items from an ADA risk test (vs non-elevated; adjusted rate ratio (aRR)=0.86 (95% CI 0.75 to 0.98)); perinatal depression (0.88 (0.79 to 0.98)); preterm delivery (0.84 (0.72 to 0.98)); parity ≥2 children (vs 0; 0.80 (0.69 to 0.93)); or less than college education (0.79 (0.72 to 0.86)). Screening was more likely among Chinese Americans (vs White; 1.31 (1.15 to 1.49)); women who attended a routine postpartum visit (5.28 (2.99 to 9.32)); or women who recalled receiving healthcare provider advice about screening (1.31 (1.03 to 1.67)). Guideline-recommended postpartum diabetes screening varied by patient clinical and sociodemographic factors. Findings have implications for developing future strategies to improve postpartum care.

Authors: Brown, Susan D; Hedderson, Monique M; Zhu, Yeyi; Tsai, Ai-Lin; Feng, Juanran; Quesenberry, Charles P; Ferrara, Assiamira

BMJ Open Diabetes Res Care. 2022 06;10(3).

PubMed abstract

Effect of Electronic and Mail Outreach From Primary Care Physicians for COVID-19 Vaccination of Black and Latino Older Adults: A Randomized Clinical Trial

COVID-19 morbidity is highest in Black and Latino older adults. These racial and ethnic groups initially had lower vaccination uptake than others, and rates in Black adults continue to lag. To evaluate the effect of outreach via electronic secure messages and mailings from primary care physicians (PCPs) on COVID-19 vaccination uptake among Black and Latino older adults and to compare the effects of culturally tailored and standard PCP messages. This randomized clinical trial was conducted from March 29 to May 20, 2021, with follow-up surveys through July 31, 2021. Latino and Black individuals aged 65 years and older from 4 Kaiser Permanente Northern California (KPNC) service areas were included. Data were analyzed from May 27, 2021, to September 28, 2021. Individuals who had not received COVID-19 vaccination after previous outreach were randomized to electronic secure message and/or mail outreach from their PCP, similar outreach with additional culturally tailored content, or usual care. Outreach groups were sent a secure message or letter in their PCP’s name, followed by a postcard to those still unvaccinated after 4 weeks. The primary outcome was time to receipt of COVID-19 vaccination during the 8 weeks after initial study outreach. KPNC data were supplemented with state data from external sources. Intervention effects were evaluated via proportional hazards regression. Of 8287 included individuals (mean [SD] age, 72.6 [7.0] years; 4665 [56.3%] women), 2434 (29.4%) were Black, 3782 (45.6%) were Latino and preferred English-language communications, and 2071 (25.0%) were Latino and preferred Spanish-language communications; 2847 participants (34.4%) had a neighborhood deprivation index at the 75th percentile or higher. A total of 2767 participants were randomized to culturally tailored PCP outreach, 2747 participants were randomized to standard PCP outreach, and 2773 participants were randomized to usual care. Culturally tailored PCP outreach led to higher COVID-19 vaccination rates during follow-up compared with usual care (664 participants [24.0%] vs 603 participants [21.7%]; adjusted hazard ratio (aHR), 1.22; 95% CI, 1.09-1.37), as did standard PCP outreach (635 participants [23.1%]; aHR, 1.17; 95% CI, 1.04-1.31). Individuals who were Black (aHR, 1.19; 95% CI, 1.06-1.33), had high neighborhood deprivation (aHR, 1.17; 95% CI, 1.03-1.33), and had medium to high comorbidity scores (aHR, 1.19; 95% CI, 1.09-1.31) were more likely to be vaccinated during follow-up. This randomized clinical trial found that PCP outreach using electronic and mailed messages increased COVID-19 vaccination rates among Black and Latino older adults. Identifier: NCT05096026.

Authors: Lieu, Tracy A; Klein, Nicola P; Quesenberry, Charles P; Chen, Yi-Fen Irene; et al.

JAMA Netw Open. 2022 Jun 01;5(6):e2217004. Epub 2022-06-01.

PubMed abstract

Association of Medical Assistant-Supported Virtual Rooming With Successful Video Visit Connections

Authors: Lieu, Tracy A; Warton, E Margaret; Levan, Christine; San, Karen; Hsueh, Loretta; Awsare, Sameer; Reed, Mary E

JAMA Intern Med. 2022 06 01;182(6):680-682.

PubMed abstract

What do we know about in-utero antidepressant exposure, and are these medications safe to use during pregnancy?

Authors: Sujan, Ayesha C

Acta Psychiatr Scand. 2022 06;145(6):541-543. Epub 2022-04-20.

PubMed abstract

Perspectives on Postpartum Diabetes Screening among Patients with Gestational Diabetes in an Integrated Healthcare System

Authors: Glaser, Katherine; Ferrara, Assiamira; Ritchie, Jenna L; Tsai, Ai-Lin; Greenberg, Mara; Quesenberry, Charles P; Brown, Susan D

Am J Obstet Gynecol. 2022 06;226(6):857-859.e1. Epub 2022-02-12.

PubMed abstract

The Association of Prenatal Vitamins and Folic Acid Supplement Intake with Odds of Autism Spectrum Disorder in a High-Risk Sibling Cohort, the Early Autism Risk Longitudinal Investigation (EARLI)

We examined maternal prenatal vitamin use or supplemental folic acid intake during month one of pregnancy for association with autism spectrum disorder (ASD) in the Early Autism Risk Longitudinal Investigation, an enriched-risk pregnancy cohort. Total folic acid intake was calculated from monthly prenatal vitamins, multivitamins, and other supplement reports. Clinical assessments through age 3 years classified children as ASD (n = 38) or non-ASD (n = 153). In pregnancy month one, prenatal vitamin use (59.7%) was not significantly associated with odds of ASD (OR = 0.70, 95%CI 0.32, 1.53). Sample size was limited and residual confounding was possible. Given the estimated effect sizes in this and previous work, prenatal vitamin intake during early pregnancy could be a clinically useful preventative measure for ASD.

Authors: Brieger, Katharine K; Bakulski, Kelly M; Pearce, Celeste L; Baylin, Ana; Dou, John F; Feinberg, Jason I; Croen, Lisa A; Hertz-Picciotto, Irva; Newschaffer, Craig J; Fallin, M Daniele; Schmidt, Rebecca J

J Autism Dev Disord. 2022 Jun;52(6):2801-2811. Epub 2021-06-10.

PubMed abstract

Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children

To evaluate whether children born to women who use serotonergic antidepressants during pregnancy have higher risk of neonatal seizures and epilepsy. We used Swedish register-based data to examine associations between maternal-reported use of selective-serotonin reuptake inhibitor (SSRI) and selective serotonin-norepinephrine reuptake inhibitors (SNRI) in pregnancy and diagnosis of neonatal seizures and/or epilepsy in over 1.2 million children. To account for systematic differences between exposed and unexposed children we adjusted for a wide range of measured confounders. After first evaluating the role of maternal indication for SSRI/SNRI use (i.e., depression and anxiety) and parental epilepsy, we adjusted for remaining parental background factors (e.g., age, co-morbidities, education, and family socioeconomic indices) and pregnancy-specific characteristics (e.g., maternal use of other psychotropic medications and tobacco smoking in early pregnancy). Compared with all other children, children of women that reported use of SSRI/SNRI in pregnancy had an elevated risk of neonatal seizures and epilepsy (risk ratio [RR]=1.41, 95% confidence interval [CI]=1.03-1.94; hazard ratio [HR]=1.21, 95% CI=1.03-1.43 respectively). The estimates of association were attenuated by adjustment for maternal indications for SSRI/SNRI use (RR=1.30, 95% CI=0.94-1.79; HR = 1.13, 95% CI = 0.95-1.33), but not by additional adjustment for parental history of epilepsy. Full adjustment for all measured parental and pregnancy-specific factors resulted in substantial attenuation of the remaining associations (RR = 1.10, 95% CI = 0.79-1.53; HR = 0.96, 95% CI = 0.81-1.14). The present study found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children’s risk for neonatal seizures or epilepsy. This study provides Class II evidence that exposure to SSRI/SNRI’s in the first trimester of pregnancy is not associated with an increased incidence of neo-natal seizures/epilepsy.

Authors: Wiggs, Kelsey Kathleen; Sujan, Ayehsa C; Rickert, Martin E; Quinn, Patrick D; Larsson, Henrik; Lichtenstein, Paul; D'Onofrio, Brian M; Oberg, A Sara

Neurology. 2022 May 11.

PubMed abstract

The Effect of Readmission for Phototherapy on Early Breast Milk Feeding

To estimate the effect of readmission for inpatient phototherapy on parent-reported exclusive and any breast milk feeding at 2-month well-child visits. We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥35 weeks’ gestation with outpatient total serum bilirubin levels ranging from 1 mg/dL below to 2.9 mg/dL above the American Academy of Pediatrics phototherapy threshold at <15 days of age. We compared breast milk feeding at 2-month well-child visits among those readmitted and not readmitted to the hospital for phototherapy, adjusting for bilirubin and other confounding variables. Approximately one-quarter (26.5%) of the cohort (n = 7729) were readmitted for phototherapy. Almost half (48.5%) of the infants who were not readmitted for phototherapy received exclusively breast milk at the 2-month visit compared with slightly fewer infants who were readmitted (42.9%). In both groups of infants, most (82.2% not readmitted and 81.2% readmitted) received any breast milk. Readmission for phototherapy was associated with a lower adjusted risk of exclusive breast milk feeding (adjusted risk ratio 0.90; 95% confidence interval [CI], 0.84 to 0.96), corresponding to a marginal absolute reduction in exclusive breast milk feeding of 5.0% (95% CI, -7.9% to -2.1%). It was not associated with a reduction in any breast milk feeding (adjusted risk ratio, 1.00; 95% CI, 0.97 to 1.02). Infants readmitted for phototherapy were more likely to receive any formula, but no less likely to receive any breast milk at 2-month well-child visits.

Authors: Digitale, Jean C; Chang, Pearl W; Li, Sherian X; Kuzniewicz, Michael W; Newman, Thomas B

Hosp Pediatr. 2022 05 01;12(5):e146-e153.

PubMed abstract

Prenatal exposure to pesticide residues in the diet in association with child autism-related traits: Results from the EARLI study

Prior work has suggested associations between prenatal exposure to several classes of pesticides and child autism spectrum disorder (ASD). We examined a previously developed pesticide residue burden score (PRBS) and intake of high pesticide residue foods in association with ASD-related traits. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 256), a cohort following mothers who previously had a child with ASD through a subsequent pregnancy and that child’s development. ASD-related traits were captured according to total Social Responsiveness Scale (SRS) scores at age 3 (mean raw total SRS score = 35.8). Dietary intake was assessed through a food frequency questionnaire collected during pregnancy. We also incorporated organic intake and fatty foods in modified versions of the PRBS. Associations between high-residue fruit and vegetable intake, the overall PRBS and modified versions of it, and SRS scores were assessed using multivariable linear regression. Overall, we did not observe associations between pesticide residues in foods and ASD-related outcomes, and modified versions of the PRBS yielded similar findings. However, reductions in ASD-related traits were observed with higher overall fruit and vegetable intake (adjusted estimates for Q4 vs. Q1: β -12.76, 95%CI -27.8, 2.3). Thus, findings from this high familial probability cohort did not suggest relationships between pesticide residues in the diet according to the PRBS and ASD-related traits. Beneficial effects of fruit and vegetable intake may influence these relationships. Future work should consider fruit and vegetable intake in association with ASD-related outcomes. LAY SUMMARY: Diet is the main source of exposure to most pesticides in use today. In this study, we examined the relationship between pesticide exposure from residues in the diet during pregnancy and child autism-related traits. We found that these pesticide residues from the diet were not related to child autism-related outcomes at age three. However, higher prenatal fruit and vegetable intake was associated with reductions in child autism-related traits.

Authors: Joyce, Emily E; Chavarro, Jorge E; Rando, Juliette; Song, Ashley Y; Croen, Lisa A; Fallin, M Daniele; Hertz-Picciotto, Irva; Schmidt, Rebecca J; Volk, Heather; Newschaffer, Craig J; Lyall, Kristen

Autism Res. 2022 05;15(5):957-970. Epub 2022-03-08.

PubMed abstract

Contribution of Maternal Cardiometabolic Risk Factors to Racial-Ethnicity Disparities in Preterm Birth Subtypes

There are recognized racial-ethnic disparities in preterm birth and in maternal cardiometabolic risk factors likely linked to systemic racism. However, it is unclear the extent to which cardiometabolic risk factors contribute to the higher rates of preterm birth among minoritized populations. This study aimed to evaluate racial-ethnic disparities in preterm birth subtypes and the role of maternal cardiometabolic risk factors as mediators of the association between maternal race-ethnicity and preterm birth subtypes. This was a retrospective cohort study of 295,210 singleton live births from 2011 to 2018. Preterm birth subtypes were defined as medically indicated and spontaneous preterm birth. Poisson regression with robust standard errors were used to provide estimates of the relative risks and 95% confidence intervals for preterm birth subtypes. Causal mediation analysis used logistic regression models to estimate the natural direct and natural indirect (mediated) effects of maternal cardiometabolic risk factors. Compared with White individuals, Black, Asian, and Hispanic individuals were at increased risk for having both medically indicated preterm birth (1.45, 1.30-1.61; 1.21, 1.12-1.31; and 1.13, 1.05-1.22, respectively) (risk ratios, 95% confidence intervals, respectively) and spontaneous preterm birth (1.20, 1.08-1.34; 1.34, 1.26-1.43; and 1.16, (1.08-1.23), independent of established risk factors. The extent to which cardiometabolic risk factors mediated the associations between race-ethnicity (each group vs White in separate analyses) and preterm birth subtypes varied by race-ethnicity. Hypertensive disorders mediated 30.1% of the association between Black race-ethnicity and medically indicated preterm birth, but it did not mediate the association for other racial-ethnic groups or for spontaneous preterm birth. Any glucose disorder in pregnancy was a mediator of medically indicated preterm birth and spontaneous preterm birth for Asian (65.8% and 13.9%, respectively) and Hispanic (17.3% and 11.9%) race-ethnicity but not for Black race-ethnicity. Overweight or obesity mediated the association between race-ethnicity and medically indicated preterm birth (15.5% among Black individuals and 25.1% among Hispanic individuals) and spontaneous preterm birth (10.7% among Hispanic individuals) but was not a mediator among Asian individuals. Black, Asian, and Hispanic individuals are at increased risk for preterm birth. Maternal cardiometabolic risk factors partially mediate the associations between race-ethnicity and preterm birth subtypes but the extent varies by race-ethnicity. These findings suggest that strategies that improve and diminish differences in cardiometabolic health between race-ethnicity populations may diminish disparities in preterm birth.

Authors: Hedderson, Monique M; Xu, Fei; Dayo, Olumayowa M; Liu, Emily; Sridhar, Sneha; Lee, Catherine; Greenberg, Mara

Am J Obstet Gynecol MFM. 2022 05;4(3):100608. Epub 2022-03-04.

PubMed abstract

Perinatal Complications in Individuals in California With or Without SARS-CoV-2 Infection During Pregnancy

Additional research from population-based studies is needed to inform the treatment of SARS-CoV-2 infection during pregnancy and to provide health risk information to pregnant individuals. To assess the risk of perinatal complications associated with SARS-CoV-2 infection and to describe factors associated with hospitalizations. This population-based cohort study included 43 886 pregnant individuals with longitudinal electronic health record data from preconception to delivery who delivered at Kaiser Permanente Northern California between March 1, 2020, and March 16, 2021. Individuals with diagnostic codes for COVID-19 that did not have a confirmatory polymerase chain reaction test for SARS-CoV-2 were excluded. SARS-CoV-2 infection detected by polymerase chain reaction test (from 30 days before conception to 7 days after delivery) as a time varying exposure. Severe maternal morbidity including 21 conditions (eg, acute myocardial infarction, acute renal failure, acute respiratory distress syndrome, and sepsis) that occurred at any time during pregnancy or delivery; preterm birth; pregnancy hypertensive disorders; gestational diabetes; venous thromboembolism (VTE); stillbirth; cesarean delivery; and newborn birth weight and respiratory conditions. Standardized mean differences between individuals with and without SARS-CoV-2 were calculated. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for the association between SARS-CoV-2 infection and perinatal complications and hospitalization and to consider the timing of SARS-CoV-2 infection relative to outcomes. In this study of 43 886 pregnant individuals (mean [SD] age, 30.7 [5.2] years), individuals with a SARS-CoV-2 infection (1332 [3.0%]) were more likely to be younger, Hispanic, multiparous individuals with a higher neighborhood deprivation index and obesity or chronic hypertension. After adjusting for demographic characteristics, comorbidities, and smoking status, individuals with SARS-CoV-2 infection had higher risk for severe maternal morbidity (HR, 2.45; 95% CI, 1.91-3.13), preterm birth (<37 weeks; HR, 2.08; 95% CI, 1.75-2.47), and VTE (HR, 3.08; 95% CI, 1.09-8.74) than individuals without SARS-CoV-2. SARS-CoV-2 infection was also associated with increased risk of medically indicated preterm birth (HR, 2.56; 95% CI, 2.06-3.19); spontaneous preterm birth (HR, 1.61; 95% CI, 1.22-2.13); and early (HR, 2.52; 95% CI, 1.49-4.24), moderate (HR, 2.18; 95% CI, 1.25-3.80), and late (HR, 1.95; 95% CI, 1.61-2.37) preterm birth. Among individuals with SARS-CoV-2 infection, 76 (5.7%) had a hospitalization; pregestational diabetes (HR, 7.03; 95% CI, 2.22-22.2) and Asian or Pacific Islander (HR, 2.33; 95% CI, 1.06-5.11) and Black (HR, 3.14; 95% CI, 1.24-7.93) race and ethnicity were associated with an increased risk of hospitalization. In this cohort study, SARS-CoV-2 infection was associated with increased risk of severe maternal morbidity, preterm birth, and VTE. The study findings inform clinicians and patients about the risk of perinatal complications associated with SARS-CoV-2 infection in pregnancy and support vaccination of pregnant individuals and those planning conception.

Authors: Ferrara, Assiamira; Hedderson, Monique M; Zhu, Yeyi; Avalos, Lyndsay A; Kuzniewicz, Michael W; Myers, Laura C; Ngo, Amanda L; Gunderson, Erica P; Ritchie, Jenna L; Quesenberry, Charles P; Greenberg, Mara

JAMA Intern Med. 2022 05 01;182(5):503-512.

PubMed abstract

The Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda

In the United States, autistic individuals experience disproportionate physical and mental health challenges relative to non-autistic individuals, including higher rates of co-occurring and chronic conditions and lower physical, social, and psychological health-related quality of life. The Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multicenter research network for scientific collaboration and infrastructure that aims to increase the life expectancy and quality of life for autistic individuals, with a focus on underserved or vulnerable populations. The current paper describes the development of the AIR-P Research Agenda. Development of the research agenda involved an iterative and collaborative process between the AIR-P Advisory Board, Steering Committee, and Autistic Researcher Review Board. The methodology consisted of 3 phases: (1) ideation and design, (2) literature review and synthesis; and (3) network engagement. Six core research priorities related to the health of autistic individuals were identified: (1) primary care services and quality, (2) community-based lifestyle interventions, (3) health systems and services, (4) gender, sexuality, and reproductive health, (5) neurology, and (6) genetics. Specific topics within each of these priorities were identified. Four cross-cutting research priorities were also identified: (1) neurodiversity-oriented care, (2) facilitating developmental transitions, (3) methodologically rigorous intervention studies, and (4) addressing health disparities. The AIR-P Research Agenda represents an important step forward for enacting large-scale health-promotion efforts for autistic individuals across the lifespan. This agenda will catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health-promotion.

Authors: Kuo AA; Croen LA; Kogan MD; et al.

Pediatrics. 2022 Apr 01;149(Suppl 4).

PubMed abstract

The Autism Intervention Research Network on Physical Health (AIR-P) Charter

Authors: Kuo, Alice A; Croen, Lisa A; Kogan, Michael D; et al.

Pediatrics. 2022 Apr 01;149(Suppl 4).

PubMed abstract

Improving the Sexual and Reproductive Health and Health Care of Autistic People

Authors: Graham Holmes L; Ames JL; Massolo ML; Nunez DM; Croen LA

Pediatrics. 2022 Apr 01;149(Suppl 4).

PubMed abstract

Youth Well-being During the COVID-19 Pandemic

The family stress model proposes economic hardship results in caregiver distress and relational problems, which negatively impact youth outcomes. We extend this model to evaluate the impact of coronavirus disease 2019 pandemic-related family hardships on caregiver and youth stress, and, in turn, youth’s psychological well-being. We also investigate how social supports moderate this relationship. We used 2 samples of cross-sectional survey data collected between May 2020 and May 2021: children aged 2 to 12 years (n = 977) and adolescents aged 11 to 17 years (n = 669). Variables included pandemic-related family hardships, stress, social support, and youth life satisfaction. Data were analyzed using structural equation modeling. Experiencing more pandemic-related family hardships was associated with increased caregiver and youth stress (b = 0.04 to 0.21, SE = 0.01-0.02) and, in turn, decreased youth life satisfaction (b = -0.36 to -0.38, SE = 0.04-0.07). Social connectedness (b^ = 0.11-0.17, SE = 0.04) and family engagement (b^ = 0.12-0.18, SE = 0.05-0.06) had direct positive associations with life satisfaction; for children aged 2 to 12 years, greater family engagement was associated with decreased effect of child stress on life satisfaction (b^ = 0.15, SE = 0.05). For adolescents, females had higher levels of stress compared with males (b^ = 0.40, SE = 0.6), and having anxiety and/or depression was associated with decreased life satisfaction (b^ = -0.24, SE = 0.11). Caregivers and youth who experienced more coronavirus disease 2019 pandemic hardships had higher levels of stress, particularly adolescent females. Although stress negatively impacted life satisfaction across all ages, family engagement was a protective factor for children aged 2 to 12 years, whereas having anxiety and/or depression was a risk factor for adolescents. For all youth, however, being more socially connected and engaged with family promoted life satisfaction.

Authors: Blackwell, Courtney K; Deoni, Sean; Fry, Rebecca C; Wright, Rosalind J; et al.

Pediatrics. 2022 04 01;149(4).

PubMed abstract

Emotional and Behavioral Problems in Youth with Autism: High Prevalence and Impact on Functioning

Emotional and behavioral problems (EBPs) may co-occur with autism spectrum disorder (ASD) and impair children’s functioning beyond autism symptomatology. We compared the prevalence of EBPs in youths with or without ASD and evaluated their unique contribution to impairment in ASD. We surveyed 1267 children (79.4% boys, mean age: 9.2 years, range: 3-17) recruited at 3 sites in Kaiser Permanente and OCHIN primary care clinical networks, with confirmed International Classification of Diseases-10th ed. diagnosis of ASD (N = 564), asthma (N = 468), or neither (N = 429). Children from the 2 comparison groups were age-matched and sex-matched to the ASD group. EBPs and impairment were measured by the Strengths and Difficulties Questionnaire and autism symptomatology by the Social Responsiveness Scale in the ASD group only. EBPs and impairment mean scores were significantly (p < 0.001) higher in participants with ASD compared with children from the 2 comparison groups, across sexes and age groups, with no significant difference between the asthma and control groups. Among children with ASD, both EBPs and autistic symptoms were significantly correlated with impairment (r = 0.64 and r = 0.65, respectively) and explained a significant proportion of impairment variance (R2 = 0.525; p < 0.001) in multiple linear regression. In the relative importance analysis, EBPs and autistic symptoms explained comparable proportions of impairment variance (46% and 52%, respectively) with no significant difference between their relative weights (mean difference: 0.03; 95% confidence interval: -0.049 to 0.114). Among youth with ASD, high levels of EBPs impair daily functioning as much as autistic symptoms. Systematic detection and management of EBPs may improve functioning and outcomes in youth with ASD.

Authors: Fombonne, Eric; Croen, Lisa A; Bulkley, Joanna E; Varga, Alexandra M; Daida, Yihe G; Hatch, Brigit A; Dickerson, John F; Lynch, Frances L

J Dev Behav Pediatr. 2022 04 01;43(3):140-148. Epub 2021-10-21.

PubMed abstract

Intrapartum antibiotics and childhood asthma and allergic rhinitis: a retrospective cohort study

This study aimed to evaluate the association between intrapartum antibiotics (IABX) and asthma and allergic rhinitis among children by ages 6, 8 and 10 years. Retrospective cohort. Data were collected though Kaiser Permanente Northern California’s (KPNC) integrated healthcare system. Children were eligible if they were born in a KPNC hospital between 1997 and 2012 and stayed enrolled through age 6. Modified Poisson regressions with robust error variances were used to estimate risk ratios for IABX and each outcome at each follow-up age during two separate time periods: 1997-2004 (n = 91 739) and 2005-2012 (n = 108 314). Asthma and allergic rhinitis by ages 6, 8 and 10. The proportion of women receiving IABX increased drastically over the study period (from 4% in 1997 to 49% in 2011), while the incidence of asthma (8%) and allergic rhinitis (6%) stayed relatively stable. In adjusted models, risk ratios for the association between IABX and asthma and allergic rhinitis were largely compatible with the null, with some slightly elevated risk ratios observed. For births from 1997 to 2004, risk ratios for asthma were 1.08 (95% CI 1.00-1.17) at age 6, 1.05 (95% CI 0.97-1.15) at age 8, and 1.08 (95% CI 0.99-1.18) at age 10. For births from 2005 to 2012, risk ratios were 1.00 (95% CI 0.95-1.04) at age 6, 1.07 (95% CI 1.01-1.12) at age 8, and 1.11 (95% CI 1.03-1.20) at age 10. Exposure to intrapartum antibiotics is not a strong predictor of childhood asthma or allergic rhinitis risk. Exposure to intrapartum antibiotics is not a strong predictor of childhood asthma or allergic rhinitis risk.

Authors: Richards, M; Ferber, J; Swor, E; Frescholtz, T; Li, D-K; Darrow, L A

BJOG. 2022 Apr;129(5):722-730. Epub 2021-11-08.

PubMed abstract

Associations between infant growth and pubertal onset timing in a multiethnic prospective cohort of girls

Early puberty increases risk of adverse health conditions throughout the life course. US girls are experiencing earlier puberty without clear reasons. Studies suggest early life factors, such as infant growth, may influence pubertal timing. We assessed the associations between infant growth and onset of breast development (thelarche), pubic hair development (pubarche), and menarche in girls. A prospective cohort of girls born at a Kaiser Permanente Northern California medical facility in 2005-11 was used. Weight-for-age z-scores were calculated at birth and 24 months. Difference in z-scores greater than 0.67 represent rapid “catch-up” growth, less than -0.67 represent delayed “catch-down” growth, and between -0.67 and 0.67 represent “normal” growth. Pubertal onset was measured using clinician-assessed sexual maturity ratings (SMRs) and defined as the age at transition from SMR 1 to SMR 2 + for both thelarche and pubarche. SMR data was collected through June 2020. Menarche was analyzed as a secondary outcome. Weibull and modified Poisson regression models were used. Models were adjusted for potential confounders. There were 15,196 girls included in the study. Approximately 30.2% experienced catch-up growth, 25.8% experienced catch-down growth, and 44% had normal growth. Girls with catch-up growth had increased risk of earlier thelarche (hazard ratio = 1.26, 95% confidence interval (CI): 1.18, 1.35), pubarche (1.38, 95% CI: 1.28, 1.48), and menarche (< 12y, relative risk = 1.52, 95% CI: 1.36, 1.69) compared to those with normal growth, after adjusting for covariates. These associations were partially mediated by childhood body mass index. Catch-down growth was associated with later pubertal onset. Girls who experience infant catch-up growth have higher risk of earlier pubertal development compared to girls with normal growth and the associations are partially explained by childhood obesity. This information may help clinicians to monitor girls who are at high risk of developing earlier.

Authors: Aghaee, Sara; Quesenberry, Charles P; Deardorff, Julianna; Kushi, Lawrence H; Greenspan, Louise C; Ferrara, Assiamira; Kubo, Ai

BMC Pediatr. 2022 Mar 31;22(1):171. Epub 2022-03-31.

PubMed abstract

A retrospective, observational study on medication for opioid use disorder during pregnancy and risk for neonatal abstinence syndrome

The prevalence of opioid use disorder (OUD) among pregnant women is increasing. Research consistently demonstrates the efficacy of medications for OUD (MOUD); however, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of two commonly used MOUD medications-methadone and buprenorphine. This study aimed to evaluate the consequences of MOUD exposure during pregnancy on risk for neonatal abstinence syndrome (NAS). In a clinical sample of infants born to women with OUD, we evaluated the risk of NAS among those exposed to (i) methadone and (ii) buprenorphine compared with those unexposed to MOUD, as well as the risk of NAS among those exposed to (i) methadone compared with those exposed to (ii) buprenorphine. Compared with buprenorphine-exposed infants (n = 37), methadone-exposed infants (n = 27) were at increased risk for NAS (odds ratio [OR] = 4.67, 95% confidence interval [CI]: 1.03, 21.17). Compared with unexposed infants (n = 43), buprenorphine-exposed infants were at decreased risk for NAS (OR = 0.45, 95% CI: 0.14, 1.39) and methadone-exposed infants were at increased risk for NAS (OR = 2.64, 95% CI: 0.79, 8.76), though these associations were not statistically significant. Our study suggests that when methadone and buprenorphine are equally appropriate options for the treatment of OUD in pregnant women, buprenorphine may add the additional benefit of reduced risk of newborn NAS. Medications for opioid use disorder (MOUD), such as buprenorphine and methadone, are effective in reducing the significant harms associated with untreated opioid use disorder (OUD) in nonpregnant and pregnant adults. While previous research clearly documents that the risks of MOUD in pregnancy are less than the risks of untreated OUD in pregnancy, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of methadone and buprenorphine. In a clinical sample of infants born to women with OUD, we showed that buprenorphine-exposed infants were at significantly reduced risk for neonatal abstinence syndrome compared with methadone-exposed infants. Our study adds to the growing body of evidence supporting the use of buprenorphine over methadone for the treatment of OUD among pregnant women.

Authors: Sujan, Ayesha; Cleary, Emma; Douglas, Edie; Aujla, Rubin; Boyars, Lisa; Smith, Claire; Guille, Constance

Fam Pract. 2022 03 24;39(2):311-315.

PubMed abstract

Association of Glyburide and Subcutaneous Insulin With Perinatal Complications Among Women With Gestational Diabetes

Nearly 30% of individuals with gestational diabetes (GDM) do not achieve glycemic control with lifestyle modification alone and require medication treatment. Oral agents, such as glyburide, have several advantages over insulin for the treatment of GDM, including greater patient acceptance; however, the effectiveness of glyburide for the treatment of GDM remains controversial. To compare the perinatal and neonatal outcomes associated with glyburide vs insulin using causal inference methods in a clinical setting with information on glycemic control. The population-based cohort study included patients with GDM who required medication treatment from 2007 to 2017 in Kaiser Permanente Northern California. Machine learning and rigorous casual inference methods with time-varying exposures were used to evaluate associations of exposure to glyburide vs insulin with perinatal outcomes. Data analysis was conducted from March 2018 to July 2017. Time-varying exposure to glyburide vs insulin during pregnancy. Outcomes evaluated separately included neonatal hypoglycemia, jaundice, shoulder dystocia, respiratory distress syndrome (RDS), neonatal intensive care unit (NICU) admission, size-for-gestational age, and cesarean delivery. Inverse probability weighting (IPW) estimation was used to separately compare perinatal outcomes between those initiating glyburide and insulin. This approach was combined with Super Learning for propensity score estimation to account for both baseline and time-dependent confounding in both per-protocol (primary) and intention-to-treat (secondary) analyses to evaluate sustained exposure to the same therapy. From 2007 to 2017, 11 321 patients with GDM (mean [SD] age, 32.9 [4.9] years) initiated glyburide or insulin during pregnancy. In multivariate models, the risk of neonatal respiratory distress was 2.03 (95% CI, 0.13-3.92) per 100 births lower and the risk of NICU admission was 3.32 (95% CI, 0.20-6.45) per 100 births lower after continuous exposure to glyburide compared with insulin. There were no statistically significant differences in glyburide vs insulin initiation in risk for neonatal hypoglycemia (0.85 [95% CI, -1.17 to 2.86] per 100 births), jaundice (0.02 [95% CI, -1.46 to 1.51] per 100 births), shoulder dystocia (-1.05 [95% CI, -2.71 to 0.62] per 100 births), or large-for-gestational age categories (-2.75 [95% CI, -6.31 to 0.80] per 100 births). Using data from a clinical setting and contemporary causal inference methods, our findings do not provide evidence of a difference in the outcomes examined between patients with GDM initiating glyburide compared with those initiating insulin.

Authors: Hedderson, Monique M; Badon, Sylvia E; Pimentel, Noel; Xu, Fei; Regenstein, Anne; Ferrara, Assiamira; Neugebauer, Romain

JAMA Netw Open. 2022 03 01;5(3):e225026. Epub 2022-03-01.

PubMed abstract

Maternal tobacco smoking and offspring autism spectrum disorder or traits in ECHO cohorts

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child’s risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Authors: Hertz-Picciotto, Irva; Dabelea, Dana; program collaborators for Environmental influences on Child Health Outcomes (ECHO),; et al.

Autism Res. 2022 03;15(3):551-569. Epub 2022-02-24.

PubMed abstract

Closing Evidence Gaps in Clinical Prevention: A Report From the National Academies of Sciences, Engineering, and Medicine

Authors: Lieu, Tracy A; Wojtowicz, Alexis; Stratton, Kathleen

JAMA. 2022 03 01;327(9):815-816.

PubMed abstract

Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.

Authors: Aung, Max T; Croen, Lisa A; Fallin, M Daniele; et al.

Epigenetics. 2022 03;17(3):253-268. Epub 2021-04-02.

PubMed abstract

Prenatal Cannabis Use Before and During the COVID-19 Pandemic-Reply

Authors: Young-Wolff, Kelly C; Ansley, Deborah; Avalos, Lyndsay A

JAMA. 2022 02 08;327(6):587-588.

PubMed abstract

Cumulative Lactation and Clinical Metabolic Outcomes at Mid-Life among Women with a History of Gestational Diabetes

Lactation is associated with a lower risk of subsequent cardiometabolic disease among parous women; however, the underlying mechanisms are unknown. Further, the potential protective effects of lactation on cardiometabolic risk markers at mid-life among high-risk women with past gestational diabetes (GDM) are not established. Using data from the Diabetes & Women’s Health Study (2012-2014; n = 577), a longitudinal cohort of women with past GDM from the Danish National Birth Cohort (1996-2002), we assessed associations of cumulative lactation duration (none, <6 months, 6-12 months, ≥12-24 months, and ≥24 months) with clinical metabolic outcomes (including type 2 diabetes [T2D], prediabetes, and obesity) and cardiometabolic biomarkers (including biomarkers of glucose/insulin metabolism, fasting lipids, inflammation, and anthropometrics) 9-16 years after enrollment when women were at mid-life. At follow-up, women were 43.9 years old (SD 4.6) with a BMI of 28.7 kg/m2 (IQR 24.6, 33.0); 28.6% of participants had T2D, 39.7% had prediabetes, and 41.2% had obesity. Relative risks (95% CI) of T2D for 0-6, 6-12, 12-24, and ≥24 months of cumulative lactation duration compared to none were 0.94 (0.62,1.44), 0.88 (0.59,1.32), 0.73 (0.46,1.17), and 0.71 (0.40,1.27), respectively. Cumulative lactation duration was not significantly associated with any other clinical outcome or continuous biomarker. In this high-risk cohort of middle-aged women with past GDM, T2D, prediabetes, and obesity were common at follow-up, but not associated with history of cumulative lactation duration 9-16 years after the index pregnancy. Further studies in diverse populations among women at mid-age are needed to understand associations of breastfeeding with T2D.

Authors: Wander, Pandora L; Zhu, Yeyi; Zhang, Cuilin; et al.

Nutrients. 2022 Feb 03;14(3). Epub 2022-02-03.

PubMed abstract

Longitudinal Associations of Plasma Phospholipid Fatty Acids in Pregnancy with Neonatal Anthropometry: Results from the NICHD Fetal Growth Studies-Singleton Cohort

Despite increasing interest in the health effects of polyunsaturated FAs (PUFAs), their roles in fetal and neonatal growth remain understudied. Within the NICHD Fetal Growth Studies-Singleton Cohort, we prospectively investigated the associations of individual and subclasses of plasma phospholipid PUFAs at gestational weeks (GW) 10-14, 15-26, 23-31, and 33-39 with neonatal anthropometric measures as surrogates for fetal growth among 107 women with gestational diabetes mellitus (GDM) and 214 non-GDM controls. Multivariable weighted linear regression models estimated the associations between plasma phospholipid PUFAs and neonatal anthropometric measures. Adjusted beta coefficients for phospholipid docosahexaenoic acid (DHA) per standard deviation (SD) increase at GW 23-31 in association with birthweight z-score, neonatal length, and neonatal fat mass were 0.25 (95% CI: 0.08-0.41), 0.57 (0.11-1.03) cm, and 54.99 (23.57-86.42) g, respectively; all false discovery rates (FDRs) < 0.05. Estimated Δ5-desaturase activity per SD increase at GW 33-39 but not at other time points was positively associated with birthweight z-score: 0.29 (95% CI: 0.08-0.33); neonatal length: 0.61 (0.29-0.94) cm; and neonatal fat mass: 32.59 (8.21-56.96) g; all FDRs < 0.05. Longitudinal analysis showed consistent results. Our findings suggest that mid-to-late pregnancy presented as critical windows for primarily diet-derived DHA and Δ5-desaturase activity in relation to neonatal anthropometric measures.

Authors: Wang E; Zhu Y; Chehab RF; Wu J; Hinkle SN; Weir NL; Bremer AA; Yang J; Chen Z; Tsai MY; Zhang C

Nutrients. 2022 Jan 29;14(3). Epub 2022-01-29.

PubMed abstract

Respiratory Viral Infections and Infection Prevention Practices among Women with Acute Respiratory Illness during Delivery Hospitalizations during the 2019-2020 Influenza Season

We conducted a cross-sectional study of pregnant women with acute respiratory illness during delivery hospitalizations during influenza season to describe clinical testing for respiratory viruses and infection prevention practices. Women had nasal swabs tested for influenza and other respiratory viruses. Among 91 enrolled women, 22 (24%) had clinical testing for influenza. Based on clinical and study testing combined, 41 of 91 (45%) women had samples positive for respiratory viruses. The most common virus was influenza (17 of 91, 19%); 53% (9 of 17) of influenza virus infections were identified through study testing alone. Only 16% of women were on droplet precautions. Peripartum respiratory infections may be underrecognized.

Authors: Dawood, Fatimah S; Li, De-Kun; Campbell, Angela P; et al.

J Infect Dis. 2022 01 05;225(1):50-54.

PubMed abstract

Identifying hypertensive disorders of pregnancy, a comparison of two epidemiologic definitions

Studies of hypertension in pregnancy that use electronic health care data generally identify hypertension using hospital diagnosis codes alone. We sought to compare results from this approach to an approach that included diagnosis codes, antihypertensive medications and blood pressure (BP) values. We conducted a retrospective cohort study of 1,45,739 pregnancies from 2009 to 2014 within an integrated healthcare system. Hypertensive pregnancies were identified using the “BP-Inclusive Definition” if at least one of three criteria were met: (1) two elevated outpatient BPs, (2) antihypertensive medication fill plus an outpatient hypertension diagnosis, or (3) hospital discharge diagnosis for preeclampsia or eclampsia. The “Traditional Definition” considered only delivery hospitalization discharge diagnoses. Outcome event analyses compared rates of preterm delivery and small for gestational age (SGA) between the two definitions. The BP-Inclusive Definition identified 14,225 (9.8%) hypertensive pregnancies while the Traditional Definition identified 13,637 (9.4%); 10,809 women met both definitions. Preterm delivery occurred in 20.9% of BP-Inclusive Definition pregnancies, 21.8% of Traditional Definition pregnancies and 6.6% of non-hypertensive pregnancies; for SGA the numbers were 15.6, 16.3, and 8.6%, respectively (p < 0.001 for all events compared to non-hypertensive pregnancies). Analyses in women meeting only one hypertension definition (21-24% of positive cases) found much lower rates of both preterm delivery and SGA. Prevalence of hypertension in pregnancy was similar between the two study definitions. However, a substantial number of women met only one of the study definitions. Women who met only one of the hypertension definitions had much lower rates of adverse neonatal events than women meeting both definitions.

Authors: Cheetham, T Craig; Avalos, Lyndsay A; Neugebauer, Romain S; Dublin, Sascha; et al.

Front Cardiovasc Med. 2022;9:1006104. Epub 2022-11-23.

PubMed abstract

Maternal and neonatal outcomes of antihypertensive treatment in pregnancy: A retrospective cohort study

To compare maternal and infant outcomes with different antihypertensive medications in pregnancy. Retrospective cohort study. Kaiser Permanente, a large healthcare system in the United States. Women aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension. We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding. Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks. Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication. Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.

Authors: Dublin, Sascha; Avalos, Lyndsay A; Neugebauer, Romain S; Badon, Sylvia E; Shortreed, Susan M; et al.

PLoS One. 2022;17(5):e0268284. Epub 2022-05-16.

PubMed abstract

A longitudinal study on associations of moderate-to-vigorous physical activity with plasma monounsaturated fatty acids in pregnancy

Physical activity (PA) during pregnancy influences women and offspring’s health via fatty acids metabolism. However, studies on associations of PA with plasma monounsaturated fatty acids (MUFAs) across pregnancy are sparse. Thus, our study aimed to examine associations of PA with individual plasma phospholipid MUFAs throughout pregnancy in a prospective and longitudinal study in the United States (US). The study included 318 pregnant women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons cohort. PA was measured four times: PA reported at 10-14 gestational weeks (GWs) representing PA in the past year, and at 15-26 GWs, 23-31 GWs, and 33-39 GWs representing PA since the last visit. Plasma phospholipid MUFAs were measured at the same four visits as the measurement of PA. Associations between moderate-to-vigorous PA (MVPA) and the total MUFAs and seven individual plasma phospholipid MUFAs (i.e., palmitoleic acid, 18:1n6-9 trans, 18:1n6c, cis-vaccenic acid, oleic acid, eicosenoic acid, and nervonic acid) were assessed at each visit using multivariable linear regression models adjusting for confounders. MVPA (hours/week) reported at 15-26 GWs representing MVPA since the last visit was positively associated with total MUFAs (% of total fatty acids) [adjusted β*102 (standard error (SE)*102) = 10.41 (3.19), P = 0.001] at 15-26 GWs. For individual MUFAs, MVPA reported at 15-26 GWs representing MVPA since the last visit was positively associated with oleic acid [adjusted β*102 (SE*102) = 8.56 (2.65), P = 0.001] and eicosenoic acid [adjusted β*102 (SE*102) = 0.55 (0.20), P = 0.01] at 15-26 GWs. MVPA reported at 23-31 GWs representing MVPA since the last visit was positively associated with palmitoleic acid [adjusted β*102 (SE*102) = 2.24 (0.64), P = 0.001] at 23-31 GWs. MVPA reported at 10-14 GWs and 33-39 GWs was not associated with total or individual MUFAs. We found novel positive associations of MVPA with individual MUFAs, such as oleic acid, eicosenoic acid, and palmitoleic acid, during middle-to-late pregnancy. These findings suggest that MVPA represents a potentially modifiable factor for plasma individual MUFA levels during pregnancy.

Authors: Xia, Tong; Chen, Liwei; Fei, Zhe; Liu, Xinyue; Dai, Jin; Hinkle, Stefanie N; Zhu, Yeyi; Wu, Jing; Weir, Natalie L; Tsai, Michael Y; Zhang, Cuilin

Front Nutr. 2022;9:983418. Epub 2022-10-24.

PubMed abstract

Rates of cardiovascular events among patients with moderate-to-severe atopic dermatitis in an integrated health care system: A retrospective cohort study

Patients with versus without atopic dermatitis may have a greater risk of cardiovascular events, and the risk increases with severity of atopic dermatitis. The incidence of cardiovascular events in the population of patients with moderate-to-severe atopic dermatitis is largely unknown. This retrospective study evaluates incidence rates of cardiovascular events in patients aged ≥12 years with moderate-to-severe atopic dermatitis in a cohort of Kaiser Permanente Northern California health care system members without recognized risk factors for adverse events. Patients with moderate-to-severe atopic dermatitis, as defined by dermatologist-rendered code and prescription history between 2007 and 2018, were included. Major adverse cardiovascular events, venous thrombotic events, deep vein thrombosis, and pulmonary embolisms were identified via International Classification of Diseases codes. Stratification variables included age, sex, race, smoking history, and diabetes. Incidence rates per 1000 person-years were calculated by the number of patients with an incident event divided by the total person-years of observation. Among 8197 patients with moderate-to-severe atopic dermatitis, incidence rates per 1000 person-years (95% confidence interval) for major adverse cardiovascular events, venous thrombotic events, deep vein thrombosis, and pulmonary embolism were: 2.6 (2.1-3.2), 2.0 (1.5-2.5), 1.6 (1.2-2.1), and 0.7 (0.5-1.0), respectively. Incidence rates for all events were higher for older versus younger patients, patients with versus without diabetes, former smokers versus patients who had never smoked, and men versus women, except for pulmonary embolisms, which were higher in women. This study estimated the incidence of cardiovascular events in patients with moderate-to-severe atopic dermatitis and provides valuable information for clinicians.

Authors: Hedderson, Monique M; Asgari, Maryam M; Xu, Fei; Quesenberry, Charles P; Sridhar, Sneha; Geier, Jamie; Lemeshow, Adina R

PLoS One. 2022;17(11):e0277469. Epub 2022-11-17.

PubMed abstract

Prenatal Exposure to Ambient Air Pollution and Epigenetic Aging at Birth in Newborns

In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue-Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (β = -0.62, 95% CI: -1.17, -0.06; β = -0.32, 95% CI: -0.63, -0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.

Authors: Song, Ashley Y; Feinberg, Jason I; Bakulski, Kelly M; Croen, Lisa A; Fallin, M Daniele; Newschaffer, Craig J; Hertz-Picciotto, Irva; Schmidt, Rebecca J; Ladd-Acosta, Christine; Volk, Heather E

Front Genet. 2022;13:929416. Epub 2022-06-28.

PubMed abstract

Associations of COVID-19-Related Health, Healthcare and Economic Factors With Prenatal Depression and Anxiety

Objective: This study evaluated whether COVID-19 pandemic-related health, healthcare and economic factors during pregnancy are associated with prenatal depression and anxiety. Methods: We conducted a cross-sectional study of 6,628 pregnant members of Kaiser Permanente Northern California who responded to a survey between 22 June and 30 September 2020. The survey included questions about depression (Patient Health Questionnaire) and anxiety (Generalized Anxiety Disorder) symptoms and COVID-19-related health and healthcare (e.g., had COVID-19) and economic (e.g., food insecurity) factors. Results: Over one third of individuals reported depression (25% mild, 8% moderate, 3% severe) or anxiety (22% mild, 8% moderate, 5% severe) symptoms. In multivariable analyses, COVID-19 during pregnancy, employment with greater risk of COVID-19, distress over changes in prenatal care, job loss, changes in childcare and food insecurity were associated with greater odds of prenatal depression or anxiety. Conclusion: Findings suggest the COVID-19 pandemic may have severe mental health repercussions for pregnant individuals. Support services for pregnant individuals experiencing these COVID-19-related factors and monitoring of those who had moderate/severe prenatal depression and anxiety symptoms during the COVID-19 pandemic is warranted.

Authors: Avalos, Lyndsay A; Nance, Nerissa; Badon, Sylvia E; Young-Wolff, Kelly; Ames, Jennifer; Zhu, Yeyi; Hedderson, Monique M; Ferrara, Assiamira; Zerbo, Ousseny; Greenberg, Mara; Croen, Lisa A

Int J Public Health. 2022;67:1604433. Epub 2022-05-04.

PubMed abstract

Contributions of COVID-19 Pandemic-Related Stressors to Racial and Ethnic Disparities in Mental Health During Pregnancy

This study aimed to identify racial and ethnic disparities in prenatal mental health and identify COVID-19 pandemic-related health/healthcare and economic contributors to these disparities, using an established framework for disparity investigation. This cross-sectional study includes 10,930 pregnant people at Kaiser Permanente Northern California who completed an online survey between June 22, 2020 and April 28, 2021 on COVID-19 pandemic-related health/healthcare and economic stressors, depression, and anxiety. Self-reported race and ethnicity were extracted from electronic health records. Weighted analyses were used to evaluate the association between racial and ethnic category and prenatal depression and anxiety; the prevalence of each stressor by race and ethnicity; and the relationship between each stressor and prenatal depression and anxiety in each racial and ethnic category. The sample was 22% Asian, 3% Black, 20% Hispanic, 5% Other/Multiracial/Unknown, and 49% White. Compared to White people, Black and Hispanic people had a higher prevalence of prenatal depression (aPR: 1.85, 95% CI: 1.45, 2.35 and aPR: 1.17, 95% CI: 1.00, 1.37, respectively) and anxiety (aPR: 1.71, 95% CI: 1.34, 2.18 and aPR: 1.10, 95% CI: 0.94, 1.29, respectively). Compared to White people, Black and Hispanic people had a higher prevalence of moderate/severe distress due to changes in prenatal care (24 vs. 34 and 31%), and food insecurity (9 vs. 31 and 24%). Among Black and Hispanic people, distress due to changes in prenatal care was associated with a greater prevalence of prenatal depression (aPR: 2.27, 95% CI: 1.41, 3.64 and aPR: 2.76, 95% CI: 2.12, 3.58, respectively) and prenatal anxiety (aPR: 3.00, 95% CI: 1.85, 4.84 and aPR: 2.82, 95% CI: 2.15, 3.71, respectively). Additionally, among Hispanic people, high-risk employment and food insecurity were associated with a greater prevalence of prenatal depression and anxiety. This study identified racial and ethnic disparities in mental health for pregnant Black and Hispanic people. Distress due to prenatal care changes contributed to the observed disparities in prenatal depression and anxiety for Black and Hispanic people and food insecurity additionally contributed to the observed disparities for Hispanic people. Addressing distress due to changes to prenatal care and food insecurity specifically in Black and Hispanic people may help reduce the high burden of poor mental health and reduce observed disparities in these communities.

Authors: Avalos, Lyndsay A; Nance, Nerissa; Zhu, Yeyi; Croen, Lisa A; Young-Wolff, Kelly C; Zerbo, Ousseny; Hedderson, Monique M; Ferrara, Assiamira; Ames, Jennifer L; Badon, Sylvia E

Front Psychiatry. 2022;13:837659. Epub 2022-03-14.

PubMed abstract

Considering Toxic Chemicals in the Etiology of Autism

Authors: Volk, Heather E; Ames, Jennifer L; Chen, Aimin; Fallin, M Daniele; Hertz-Picciotto, Irva; Halladay, Alycia; Hirtz, Deborah; Lavin, Arthur; Ritz, Beate; Zoeller, Tom; Swanson, Maureen

Pediatrics. 2022 01 01;149(1).

PubMed abstract

A Nation-Wide Swedish Cohort Study on Early Maternal Age at First Childbirth and Risk for Offspring Deaths, Accidents, and Suicide Attempts

In a sample of over one million Swedish first-born offspring, we examined associations between early maternal age at first childbirth (MAFC; i.e., < 20 and 20-24 vs 25-29 years) and offspring non-accidental deaths, accidental deaths, deaths by suicide, non-fatal accidents, and suicide attempts. We included year of birth and several maternal and paternal characteristics as covariates and conducted maternal cousin comparisons to adjust for unmeasured confounding. Early MAFC (e.g., teenage childbearing) was associated with all outcomes, with the most pronounced risk elevation for accidental deaths [Hazard Ratio (HR) < 20 2.50, 95% confidence interval (CI) 2.23, 2.80], suicides (HR < 20 2.08, 95% CI 1.79, 2.41), and suicide attempts (HR < 20 2.85, 95% CI 2.71, 3.00). Adjusting for covariates and comparing cousins greatly attenuated associations (e.g., accidental deaths HR < 20 1.61, 95% CI 1.22, 2.11; suicides HR < 20 1.01, 95% CI 0.69, 1.47; and suicide attempts HR < 20 1.35, 95% CI 1.19, 1.52). A similar pattern emerged for non-accidental deaths and non-fatal accidents. Therefore, results indicated maternal background factors may be largely responsible for observed associations.

Authors: Sujan, Ayesha C; O'Reilly, Lauren M; Rickert, Martin E; Larsson, Henrik; Lichtenstein, Paul; Oberg, A Sara; D'Onofrio, Brian M

Behav Genet. 2022 01;52(1):38-47. Epub 2021-11-11.

PubMed abstract

The Role of Childhood Asthma in Obesity Development: A Nationwide U.S. Multi-cohort Study

Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset. To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association. We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years). We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23). This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Authors: Stratakis, Nikos; Ferrara, Assiamira; Zhu, Yeyi; program collaborators for Environmental influences on Child Health Outcomes,; et al.

Epidemiology. 2022 01 01;33(1):131-140.

PubMed abstract

Plasma Acylcarnitines during Pregnancy and Neonatal Anthropometry: A Longitudinal Study in a Multiracial Cohort

As surrogate readouts reflecting mitochondrial dysfunction, elevated levels of plasma acylcarnitines have been associated with cardiometabolic disorders, such as obesity, gestational diabetes, and type 2 diabetes. This study aimed to examine prospective associations of acylcarnitine profiles across gestation with neonatal anthropometry, including birthweight, birthweight z score, body length, sum of skinfolds, and sum of body circumferences. We quantified 28 acylcarnitines using electrospray ionization tandem mass spectrometry in plasma collected at gestational weeks 10-14, 15-26, 23-31, and 33-39 among 321 pregnant women from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons. A latent-class trajectory approach was applied to identify trajectories of acylcarnitines across gestation. We examined the associations of individual acylcarnitines and distinct trajectory groups with neonatal anthropometry using weighted generalized linear models adjusting for maternal age, race/ethnicity, education, parity, gestational age at blood collection, and pre-pregnancy body mass index (BMI). We identified three distinct trajectory groups in C2, C3, and C4 and two trajectory groups in C5, C10, C5-DC, C8:1, C10:1, and C12, respectively. Women with nonlinear decreasing C12 levels across gestation (5.7%) had offspring with significantly lower birthweight (-475 g; 95% CI, -942, -6.79), birthweight z score (-0.39, -0.71, -0.06), and birth length (-1.38 cm, -2.49, -0.27) than those with persistently stable C12 levels (94.3%) (all nominal p value < 0.05). Women with consistently higher levels of C10 (6.1%) had offspring with thicker sum of skinfolds (4.91 mm, 0.85, 8.98) than did women with lower levels (93.9%) during pregnancy, whereas women with lower C10:1 levels (12.6%) had offspring with thicker sum of skinfolds (3.23 mm, 0.19, 6.27) than did women with abruptly increasing levels (87.4%) (p < 0.05). In conclusion, this study suggests that distinctive trajectories of C10, C10:1, and C12 acylcarnitine levels throughout pregnancy were significantly associated with neonatal anthropometry.

Authors: Song, Yiqing; Zhu, Yeyi; Zhang, Cuilin; et al.

Metabolites. 2021 Dec 17;11(12). Epub 2021-12-17.

PubMed abstract

Are you what you eat? Through the lens of prepregnancy plant-based diets and risk of gestational diabetes

Authors: Zhu, Yeyi

Am J Clin Nutr. 2021 12 01;114(6):1892-1893.

PubMed abstract

Regional and sociodemographic differences in average BMI among US children in the ECHO program

The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region. This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome. The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β = -0.12, 95% CI: -0.19 to -0.05) and West (β = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (β = -0.12, 95% CI: -0.16 to -0.08) and West (β = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight. Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

Authors: Bekelman, Traci A; Ferrara, Assiamira; Program collaborators for Environmental influences on Child Health Outcomes (ECHO),; et al.

Obesity (Silver Spring). 2021 12;29(12):2089-2099. Epub 2021-08-31.

PubMed abstract

Tooth biomarkers to characterize the temporal dynamics of the fetal and early-life exposome

Teeth have unique histology that make this biomatrix a time-capsule for retrospective exposure analysis of fetal and early life. However, most analytic methods require pulverizing the whole tooth, which eliminates exposure timing information. Further, the range of chemicals and endogenous exposures that can be measured in teeth has yet to be fully characterized. We performed untargeted metabolomics on micro-dissected layers from naturally shed deciduous teeth. Using four liquid-chromatography high-resolution mass spectrometry analytical modes, we profiled small molecules (<1000 Da) from prenatal and postnatal tooth fractions. In addition, we employed linear regression on the tooth fraction pairs from 31 children to identify metabolites that discriminate between prenatal and postnatal exposures. Of over 10,000 features measured in teeth dentin, 390 unique compounds were annotated from 62 chemical classes. The class with the largest number of compounds was carboxylic acids and their derivatives (36%). Of the annotated exogenous metabolites (phthalates, parabens, perfluoroalkyl compounds, and cotinine) and endogenous metabolites (fatty acids, steroids, carnitines, amino acids, and others), 91 are linked to 256 health conditions through published literature. Differential analysis revealed 267 metabolites significantly different between the prenatal and the postnatal tooth fractions (adj. p-value < 0.05, Bonferroni correction), and 21 metabolites exclusive to the prenatal fraction. The prenatal and early postnatal exposome revealed from dental biomarkers represents a broad range of endogenous and exogenous metabolites for a comprehensive characterization in environmental health research. Most importantly, this technology provides a direct window into fetal exposures that is not possible by maternal biomarkers. Indeed, we identified several metabolites exclusively in the prenatal fraction, suggesting unique fetal exposures that are markedly different to postnatal exposures. Expansion of databases that include tooth matrix metabolites will strengthen biological interpretation and shed light on exposures during gestation and early life that may be causally linked with later health conditions.

Authors: Yu, Miao; Croen, Lisa; Petrick, Lauren M; et al.

Environ Int. 2021 12;157:106849. Epub 2021-09-02.

PubMed abstract

Changes of Plasma Phospholipid Fatty Acids Profiles in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes Mellitus

Plasma phospholipid fatty acids (FAs) in early and mid-pregnancy have been prospectively related to gestational diabetes mellitus (GDM) risk. Yet, changes of FAs following GDM diagnosis and treatment and their implications for glucose metabolism and control remain understudied. From the Eunice Kennedy Shriver National Institute Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2802 pregnant women, we ascertained 85 GDM cases using the Carpenter and Coustan criteria and 85 non-GDM controls after exclusion. Using plasma collected before (23-31 weeks) and after GDM diagnosis (33-39 weeks), we quantified 25 saturated, poly- and monounsaturated FAs levels. We estimated the fold change of FAs before and after GDM diagnosis, using multiple linear mixed models adjusting for confounders. Eight FAs showed significant fold changes from the baseline values (23-31 weeks) among GDM cases as compared to women without GDM. Five FAs showed reduced fold changes [myristic acid (14:0): β: -0.22 (95% CI: -0.30, -0.14), palmitic acid (16:0): β: -0.02 (95% CI: -0.04, -0.01), cis-palmitoleic acid (16:1n7): β: -0.15 (95% CI: -0.24, -0.05), alpha-linolenic acid (18:3n3): β: -0.19 (95% CI: -0.31, -0.07], and dihomo-gamma-linoleic acid (20:3n6): β:-0.16; 95% CI: -0.21, -0.11)], whereas 3 showed increases [heptadecanoic acid (17:0): β: 0.17 (95% CI: 0.11, 0.22), cis-vaccenic acid (18:1n7): β: 0.06 (95% CI: 0.03, 0.10), and arachidonic acid (20:4n6): β: 0.10 (95% CI: 0.06, 0.13)]. Our study identified 8 FAs with unique patterns of change before and after GDM diagnosis that differed significantly between women with and without GDM. Our findings may shed light on the role of FA metabolism in the pathophysiology and disease management and progression of GDM. NCT00912132.

Authors: Li, Lingjun; Zhu, Yeyi; Wu, Jing; Hinkle, Stefanie N; Tobias, Deirdre K; Ma, Ronald C W; Weir, Natalie L; Tsai, Michael Y; Zhang, Cuilin

Clin Chem. 2021 Nov 26;67(12):1660-1675.

PubMed abstract

Disparities in Risks of Inadequate and Excessive Intake of Micronutrients during Pregnancy

Inadequate or excessive intake of micronutrients in pregnancy has potential to negatively impact maternal/offspring health outcomes. The aim was to compare risks of inadequate or excessive micronutrient intake in diverse females with singleton pregnancies by strata of maternal age, race/ethnicity, education, and prepregnancy BMI. Fifteen observational cohorts in the US Environmental influences on Child Health Outcomes (ECHO) Consortium assessed participant dietary intake with 24-h dietary recalls (n = 1910) or food-frequency questionnaires (n = 7891) from 1999-2019. We compared the distributions of usual intake of 19 micronutrients from food alone (15 cohorts; n = 9801) and food plus dietary supplements (10 cohorts with supplement data; n = 7082) to estimate the proportion with usual daily intakes below their age-specific daily Estimated Average Requirement (EAR), above their Adequate Intake (AI), and above their Tolerable Upper Intake Level (UL), overall and within sociodemographic and anthropometric subgroups. Risk of inadequate intake from food alone ranged from 0% to 87%, depending on the micronutrient and assessment methodology. When dietary supplements were included, some women were below the EAR for vitamin D (20-38%), vitamin E (17-22%), and magnesium (39-41%); some women were above the AI for vitamin K (63-75%), choline (7%), and potassium (37-53%); and some were above the UL for folic acid (32-51%), iron (39-40%), and zinc (19-20%). Highest risks for inadequate intakes were observed among participants with age 14-18 y (6 nutrients), non-White race or Hispanic ethnicity (10 nutrients), less than a high school education (9 nutrients), or obesity (9 nutrients). Improved diet quality is needed for most pregnant females. Even with dietary supplement use, >20% of participants were at risk of inadequate intake of ≥1 micronutrients, especially in some population subgroups. Pregnancy may be a window of opportunity to address disparities in micronutrient intake that could contribute to intergenerational health inequalities.

Authors: Sauder, Katherine A; Avalos, Lyndsay A; Zhu, Yeyi; Breton, Carrie V; Program Collaborators for Environmental influences on Child Health Outcomes (ECHO),; et al.

J Nutr. 2021 11 02;151(11):3555-3569.

PubMed abstract

Rates of Prenatal Cannabis Use Among Pregnant Women Before and During the COVID-19 Pandemic

Authors: Young-Wolff, Kelly C; Ray, G Thomas; Alexeeff, Stacey E; Adams, Sara R; Does, Monique B; Ansley, Deborah; Avalos, Lyndsay A

JAMA. 2021 11 02;326(17):1745-1747.

PubMed abstract

Update on Phototherapy and Childhood Cancer in a Northern California Cohort

We aimed to reassess the relationship between phototherapy and cancer in an extended version of a previous cohort and to replicate a report from Quebec of increased cancer risk after phototherapy beginning at age 4 years. This cohort study included 139 100 children born at ≥35 weeks’ gestation from 1995 to 2017, followed through March 16, 2019, in Kaiser Permanente Northern California hospitals who had a qualifying bilirubin level from -3 mg/dL to +4.9 mg/dL from the American Academy of Pediatrics phototherapy threshold; an additional 40 780 children and 5 years of follow-up from our previous report. The exposure was inpatient phototherapy (yes or no), and the outcomes were various types of childhood cancer. We used Cox proportional hazard models, controlling for propensity-score quintiles, and allowed for time-dependent exposure effects to assess for the risk of cancer after a latent period. Over a mean (SD) follow-up of 8.2 (5.7) years, the crude incidence of cancer per 100 000 person-years was 25.1 among those exposed to phototherapy and 19.2 among those not exposed (233 cases of cancer). After propensity adjustment, phototherapy was not associated with any cancer (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.83-1.54), hematopoietic cancer (HR: 1.17, 95% CI: 0.74-1.83), or solid tumors (HR: 1.01, 95% CI: 0.65-1.58). We also found no association with cancer diagnoses at age ≥4 years. We did not confirm previous, concerning associations between phototherapy and adjusted risk of any cancer, nonlymphocytic leukemia, or brain and/or central nervous systems tumors in later childhood.

Authors: Digitale, Jean C; Kim, Mi-Ok; Kuzniewicz, Michael W; Newman, Thomas B

Pediatrics. 2021 11;148(5). Epub 2021-10-29.

PubMed abstract

Prevalence of prescription opioid use during pregnancy in 8 U.S. health plans during 2001-2014

To estimate prevalence of prescription opioid use during pregnancy in eight US health plans during 2001-2014. We conducted a cohort study of singleton live birth deliveries. Maternal characteristics were ascertained from health plan and/or birth certificate data and opioids dispensed during pregnancy from health plan pharmacy records. Prevalence of prescription opioid use during pregnancy was calculated for any use, cumulative days of use, and number of dispensings. We examined prevalence of prescription opioid use during pregnancy in each health plan. Tennessee Medicaid had appreciably greater prevalence of use compared to the seven other health plans. Thus, results for the two groups were reported separately. In the seven health plans (n = 587 093 deliveries), prevalence of use during pregnancy was relatively stable at 9%-11% throughout 2001-2014. In Tennessee Medicaid (n = 256 724 deliveries), prevalence increased from 29% in 2001 to a peak of 36%-37% in 2004-2010, and then declined to 28% in 2014. Use for ≥30 days during pregnancy was stable at 1% in the seven health plans and increased from 2% to 7% in Tennessee Medicaid during 2001-2014. Receipt of ≥5 opioid dispensings during pregnancy increased in the seven health plans (0.3%-0.6%) and Tennessee Medicaid (3%-5%) during 2001-2014. During 2001-2014, prescription opioid use during pregnancy was more common in Tennessee Medicaid (peak prevalence in late 2000s) compared to the seven health plans (relatively stable prevalence). Although a small percentage of women had opioid use during pregnancy for ≥30 days or ≥ 5 dispensings, they represent thousands of women during 2001-2014.

Authors: Pocobelli, Gaia; Li, De-Kun; Boudreau, Denise M; et al.

Pharmacoepidemiol Drug Saf. 2021 11;30(11):1541-1550. Epub 2021-07-07.

PubMed abstract

The effect of hospital phototherapy on early breastmilk feeding

The effect of phototherapy on breastmilk feeding is unclear. To estimate the effect of inpatient phototherapy on breastmilk feeding at 2-month well-child visits. We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥ 35 weeks’ gestation with total serum bilirubin levels close to the American Academy of Pediatrics 2004 phototherapy threshold during their birth hospitalisation. We compared self-reported breastmilk feeding at 2-month well-child visits among those who had and had not received birth hospitalisation phototherapy, adjusting for bilirubin levels and other confounding variables. We used multiple imputation (K = 200) to address missing data. Approximately a quarter of infants in the cohort (24.5%) received phototherapy during their birth hospitalisation. At the 2-month visit, exclusive breastmilk feeding was less common (RR 0.91, 95% interval [CI] 0.88, 0.95) among those who received phototherapy (41.3%) than those who did not (45.2%). However, no association remained after adjusting for potential confounders (RR 0.99, 95% CI 0.95, 1.04; average treatment effect on the treated [ATET] -0.2%, 95% CI -2.0%, 1.5%). In contrast, any breastmilk feeding was similar between infants who did (76.8%) and did not get phototherapy (77.9%). After adjusting for confounders, phototherapy had a slightly positive association with any breastmilk feeding at 2 months (RR 1.02, 95% CI 1.00, 1.04). Among infants who received phototherapy, the proportion being fed any breastmilk at the 2-month visit was an estimated 1.6 percentage points higher than it would have been if they had not received phototherapy (ATET 1.6%, 95% CI 0.1%, 3.1%). Multiple imputation results were similar. Birth hospitalisation phototherapy can be delivered in a way that does not adversely affect breastmilk feeding at 2 months.

Authors: Digitale, Jean C; Chang, Pearl W; Li, Sherian X; Kuzniewicz, Michael W; Newman, Thomas B

Paediatr Perinat Epidemiol. 2021 11;35(6):717-725. Epub 2021-06-29.

PubMed abstract

Gastrointestinal Symptoms in 2- to 5-Year-Old Children in the Study to Explore Early Development

Gastrointestinal symptoms (GIS) are commonly reported in children with autism spectrum disorder (ASD). This multi-site study evaluated the prevalence of GIS in preschool-aged children with ASD/(n = 672), with other developmental delays (DD)/(n = 938), and children in the general population (POP)/(n = 851). After adjusting for covariates, children in the ASD group were over 3 times more likely to have parent-reported GIS than the POP group, and almost 2 times more likely than the DD group. Children with GIS from all groups had more behavioral and sleep problems. Within the ASD group, children with developmental regression had more GIS than those without; however, there were no differences in autism severity scores between children with and without GIS. These findings have implications for clinical management.

Authors: Reynolds, Ann M; Croen, Lisa A; Levy, Susan E; et al.

J Autism Dev Disord. 2021 Nov;51(11):3806-3817. Epub 2021-01-04.

PubMed abstract

Maternal Proinflammatory Adipokines Throughout Pregnancy and Neonatal Size and Body Composition: A Prospective Study

Increased maternal adiposity and inflammation have impacts on fetal growth. The purpose of this prospective study was to investigate the associations of 3 proinflammatory adipokines in pregnancy with neonatal anthropometry. In a sample of 321 US pregnant women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (NCT00912132), plasma IL-6, fatty acid binding protein-4 (FABP4), and chemerin were measured in plasma samples collected at 10-14, 15-26, 23-31, and 33-39 weeks of gestation. Generalized linear models were used to estimate associations of adipokines with neonatal weight, thigh, and crown-heel length, and skinfolds at birth. Models adjusted for age, race/ethnicity, education, nulliparity, prepregnancy BMI, and weeks of gestation at blood collection. At each time point, higher IL-6 was associated with lower neonatal birthweight and thigh length. At 15-26 weeks of gestation, a 1 SD pg/mL increase in IL-6 was associated with -84.46 g lower neonatal birthweight (95% CI: -150.70, -18.22), -0.17 cm shorter thigh length (95% CI: -0.27, -0.07), -0.43 cm shorter crown-heel length (95% CI: -0.75, -0.10), and -0.75 mm smaller sum of skinfolds (95% CI: -1.19, -0.31), with similar associations at 23-31 and 33-39 weeks of gestation. There were no associations of FABP4 and chemerin with neonatal anthropometry. Starting as early as 15 weeks of gestation, higher maternal IL-6 concentrations in pregnancy were associated with lower neonatal birthweight, thigh and crown-heel length, and skinfolds. These data provide insight into the relevance of maternal inflammatory markers with neonatal anthropometry.

Authors: Francis, Ellen C; Li, Mengying; Hinkle, Stefanie N; Chen, Jinbo; Wu, Jing; Zhu, Yeyi; Cao, Haiming; Tsai, Michael Y; Chen, Liwei; Zhang, Cuilin

Curr Dev Nutr. 2021 Oct;5(10):nzab113. Epub 2021-09-07.

PubMed abstract

Methods-Motivational Interviewing Approach for Enhanced Retention and Attendance

Suboptimal and differential participant engagement in randomized trials-including retention at primary outcome assessments and attendance at intervention sessions-undermines rigor, internal validity, and trial conclusions. First, this study describes Methods-Motivational Interviewing approach and strategies for implementation. This approach engages potential participants before randomization through interactive, prerequisite orientation sessions that illustrate the scientific rationale behind trial methods in accessible language and use motivational interviewing to diffuse ambivalence about participation. Then, this study examines the potential improvements in retention (proportion of participants assessed at follow-up visits) and attendance (e.g., mean percentage of intervention sessions attended, percentage of participants who attended 0 sessions) in 3 randomized weight-management trials that quickly added prerequisite orientations to their protocols following early signs of suboptimal or differential participant engagement (Supporting Health by Integrating Nutrition and Exercise [2009-2013, n=194]; Get Social [2016-2020, n=217]; GestationaL Weight Gain and Optimal Wellness [2014-2018, n=389]). Using a pre-post analytical design, adjusted estimates from regression models controlling for condition and assessment timepoint (analyses from 2020) are reported. After adding prerequisite orientations, all 3 trials attained higher participant engagement. Retention at assessments was 11.4% and 17.3% higher (Get Social and Supporting Health by Integrating Nutrition and Exercise, respectively). Mean percentage of attendance at intervention sessions was 8.8% higher (GestationaL Weight Gain and Optimal Wellness), and 10.1% fewer participants attended 0 intervention sessions (Get Social). Descriptively, all the remaining retention and attendance outcomes were consistently higher but were nonsignificant. Across the trials, adding prerequisite orientations did not impact the proportion of eligible participants enrolled or the baseline demographics. The Methods-Motivational Interviewing approach shows promise for increasing the rigor of randomized trials and is readily adaptable to in-person, webinar, and conference call formats. All 3 trials are registered at (Supporting Health by Integrating Nutrition and Exercise: NCT00960414; Get Social: NCT02646618; and GestationaL Weight Gain and Optimal Wellness: NCT02130232).

Authors: Jake-Schoffman, Danielle E; Brown, Susan D; Ferrara, Assiamira; Hedderson, Monique M; Kiernan, Michaela; et al.

Am J Prev Med. 2021 10;61(4):606-617.

PubMed abstract

Ultrasound characteristics of early stage high-grade serous ovarian cancer

Survival from ovarian cancer is strongly dependent on the stage at diagnosis. Therefore, when confronted with a woman with an isolated adnexal mass, clinicians worry about missing the opportunity to detect cancer at an early stage. High-grade serous ovarian cancers account for 80% of ovarian cancer deaths, largely because of their tendency to be diagnosed at a late stage. Among adnexal masses, large size and the presence of solid areas on ultrasound examination have been found to be associated with cancer, but it is unclear whether these characteristics identify early-stage cases. This study aimed to evaluate the ultrasound findings associated with clinically detected early-stage high-grade serous ovarian cancer. This was a retrospective cohort study of women diagnosed with stage I or II high-grade serous ovarian or fallopian tube cancer measuring at least 1 cm at pathology from 2007 to 2017. Preoperative ultrasound examinations were independently reviewed by 3 radiologists. Adnexal masses were scored for size and volume; overall appearance; presence, thickness, and vascularity of septations; morphology and vascularity of other solid components; and degree of ascites. Characteristics were compared between masses of <5 cm and larger masses and between stage I and stage II cases. Interobserver variability was assessed. Among 111 women identified, 4 had bilateral ovarian involvement, for a total of 115 adnexal masses characterized by ultrasound examination. The mean age at diagnosis was 61.8 years (range, 42-91 years). The median mass size was 9.6 cm (range, 2.2-23.6 cm) with 87% of cases having a mass size of ≥5 cm. A mixed cystic and solid appearance was most common (77.4%), but a completely solid appearance was more frequently seen for tumors of <5 cm compared with larger tumors (26.7% vs 13.0%). Solid components other than septations were seen in 97.4% of cases. The characteristics of stage I and II cases were similar other than ascites, which was more commonly seen in stage II cases (18.0% vs 3.1%, respectively). Interobserver concordance was high for size and volume measurements (correlation coefficients, 0.96-0.99), with moderate agreement observed across the other ultrasound characteristics (Fleiss kappa, 0.45-0.58). In this community-based cohort, early-stage high-grade serous cancers rarely presented as masses of <5 cm or masses without solid components other than septations. Our findings provide additional support for the observation of small masses without solid areas on ultrasound examination.

Authors: Suh-Burgmann, Elizabeth; Brasic, Natasha; Jha, Priyanka; Hung, Yun-Yi; Goldstein, Ruth B

Am J Obstet Gynecol. 2021 10;225(4):409.e1-409.e8. Epub 2021-05-13.

PubMed abstract

Associations of household food insufficiency with childhood depression and anxiety: a nationwide cross-sectional study in the USA

Household food insufficiency (HFIS) is a major public health threat to children. Children may be particularly vulnerable to HFIS as a psychological stressor due to their rapid growth and accelerated behavioural and cognitive states, whereas data focusing on HFIS and childhood mental disorders are as-yet sparse. We aimed to examine the associations of HFIS with depression and anxiety in US children. Cross-sectional study. The 2016-2018 National Survey of Children’s Health, a nationally-representative study. Primary caregivers of 102 341 children in the USA. Physician diagnosed depression and anxiety were assessed by questionnaires administered to primary caregivers of 102 341 children. Multivariable logistic regression models estimated adjusted OR (aOR) for current depression or anxiety associated with HFIS measured through a validated single-item instrument. Among children aged 3-17 years, 3.2% and 7.4% had parent-reported physician-diagnosed current depression and anxiety, respectively. Compared with children without HFIS, children with HFIS had approximately twofold higher weighted prevalence of anxiety or depression. After adjusting for covariates, children with versus without HFIS had a 1.53-fold (95% CI 1.15 to 2.03) and 1.48-fold (95% CI 1.20 to 1.82) increased odds of current depression and anxiety, respectively. Associations were slightly more pronounced among girls (aOR (95% CI): depression 1.69 (1.16 to 2.48); anxiety 1.78 (1.33 to 2.38)) than boys (1.42 (0.98 to 2.08); 1.32 (1.00 to 1.73); both P-for-interaction <0.01). The associations did not vary by children's age or race/ethnicity. HFIS was independently associated with depression and anxiety among US children. Girls presented slightly greater vulnerability to HFIS in terms of impaired mental health. Children identified as food-insufficient may warrant mental health assessment and possible intervention. Assessment of HFIS among children with impaired mental health is also warranted. Our findings also highlight the importance of promptly addressing HFIS with referral to appropriate resources and inform its potential to alleviate childhood mental health issues.

Authors: Zheng, Siwen; Ngo, Amanda L; Forman, Michele R; Barcellos, Anna L; Liao, Lauren; Ferrara, Assiamira; Zhu, Yeyi

BMJ Open. 2021 09 07;11(9):e054263. Epub 2021-09-07.

PubMed abstract

Longitudinal Plasma Metabolomics Profile in Pregnancy-A Study in an Ethnically Diverse U.S. Pregnancy Cohort

Amino acids, fatty acids, and acylcarnitine metabolites play a pivotal role in maternal and fetal health, but profiles of these metabolites over pregnancy are not completely established. We described longitudinal trajectories of targeted amino acids, fatty acids, and acylcarnitines in pregnancy. We quantified 102 metabolites and combinations (37 fatty acids, 37 amino acids, and 28 acylcarnitines) in plasma samples from pregnant women in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort (n = 214 women at 10-14 and 15-26 weeks, 107 at 26-31 weeks, and 103 at 33-39 weeks). We used linear mixed models to estimate metabolite trajectories and examined variation by body mass index (BMI), race/ethnicity, and fetal sex. After excluding largely undetected metabolites, we analyzed 77 metabolites and combinations. Levels of 13 of 15 acylcarnitines, 7 of 25 amino acids, and 18 of 37 fatty acids significantly declined over gestation, while 8 of 25 amino acids and 10 of 37 fatty acids significantly increased. Several trajectories appeared to differ by BMI, race/ethnicity, and fetal sex although no tests for interactions remained significant after multiple testing correction. Future studies merit longitudinal measurements to capture metabolite changes in pregnancy, and larger samples to examine modifying effects of maternal and fetal characteristics.

Authors: Mitro, Susanna D; Zhu, Yeyi; Zhang, Cuilin; et al.

Nutrients. 2021 Sep 01;13(9). Epub 2021-09-01.

PubMed abstract

Association of Habitual Alcohol Consumption With Long-term Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes

Women with gestational diabetes are at high risk for type 2 diabetes. Identifying modifiable dietary and lifestyle factors, such as alcohol intake, that can be useful in delaying or preventing progression to overt type 2 diabetes is of particular interest. To evaluate the association between alcohol consumption and risk for type 2 diabetes among women with a history of gestational diabetes. This cohort study included women from the Nurses’ Health Study II cohort who reported a history of gestational diabetes and were followed up from January 1, 1991, to December 31, 2017, as part of the Diabetes & Women’s Health Study. Data analysis was performed from 2020 to 2021. Dietary intakes, including alcohol, were assessed every 4 years using validated food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for the association of alcohol intake with risk for incident type 2 diabetes after a pregnancy during which gestational diabetes was diagnosed. A total of 4740 women were included in the study; the mean (SD) age at baseline was 38.2 (5.0) years, and the median follow-up time was 24 years (interquartile range, 18-28 years), resulting in 78 328 person-years of follow-up. During this period, 897 incident cases of type 2 diabetes were reported. After adjustment for major dietary and lifestyle factors, compared with women who did not consume any alcohol, only alcohol consumption of 5.0 to 14.9 g/d was associated with decreased risk for incident type 2 diabetes (HR, 0.45; 95% CI, 0.33-0.61); there was no association of alcohol consumption of 0.1 to 4.9 g/d or 15.0 g/d or more (maximum, 74.2 g/d) with risk of type 2 diabetes (0.1 to 4.9 g/d: HR, 0.87 [95% CI, 0.73-1.03]; ≥15.0 g/d: HR, 0.62 [95% CI, 0.37-1.04]). After additional adjustment for body mass index, women who reported alcohol consumption of 5.0 to 14.9 g/d had a 41% lower risk for developing incident type 2 diabetes (HR, 0.59; 95% CI, 0.42-0.81); consumption of 0.1 to 4.9 g/d and consumption of 15.0 g/d or more were still not associated with risk of type 2 diabetes, but the results were attenuated (0.1-4.9 g/d: HR, 1.02 [95% CI, 0.85-1.23]; ≥15.0 g/d: HR, 0.75 [95% CI, 0.42-1.33]). In this cohort study, among women with a history of gestational diabetes, usual alcohol intake of 5.0 to 14.9 g/d (approximately 0.5-1 drinks per day) was associated with a lower risk for type 2 diabetes. These findings should be interpreted in the context of other known risks and benefits of alcohol consumption when considering clinical recommendations for individual women with a history of gestational diabetes.

Authors: Hinkle, Stefanie N; Zhu, Yeyi; Zhang, Cuilin; et al.

JAMA Netw Open. 2021 09 01;4(9):e2124669. Epub 2021-09-01.

PubMed abstract

Steps per Day and All-Cause Mortality in Middle-aged Adults in the Coronary Artery Risk Development in Young Adults Study

Steps per day is a meaningful metric for physical activity promotion in clinical and population settings. To guide promotion strategies of step goals, it is important to understand the association of steps with clinical end points, including mortality. To estimate the association of steps per day with premature (age 41-65 years) all-cause mortality among Black and White men and women. This prospective cohort study was part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were aged 38 to 50 years and wore an accelerometer from 2005 to 2006. Participants were followed for a mean (SD) of 10.8 (0.9) years. Data were analyzed in 2020 and 2021. Daily steps volume, classified as low (<7000 steps/d), moderate (7000-9999 steps/d), and high (≥10 000 steps/d) and stepping intensity, classified as peak 30-minute stepping rate and time spent at 100 steps/min or more. All-cause mortality. A total of 2110 participants from the CARDIA study were included, with a mean (SD) age of 45.2 (3.6) years, 1205 (57.1%) women, 888 (42.1%) Black participants, and a median (interquartile range [IQR]) of 9146 (7307-11 162) steps/d. During 22 845 person years of follow-up, 72 participants (3.4%) died. Using multivariable adjusted Cox proportional hazards models, compared with participants in the low step group, there was significantly lower risk of mortality in the moderate (hazard ratio [HR], 0.28 [95% CI, 0.15-0.54]; risk difference [RD], 53 [95% CI, 27-78] events per 1000 people) and high (HR, 0.45 [95% CI, 0.25-0.81]; RD, 41 [95% CI, 15-68] events per 1000 people) step groups. Compared with the low step group, moderate/high step rate was associated with reduced risk of mortality in Black participants (HR, 0.30 [95% CI, 0.14-0.63]) and in White participants (HR, 0.37 [95% CI, 0.17-0.81]). Similarly, compared with the low step group, moderate/high step rate was associated with reduce risk of mortality in women (HR, 0.28 [95% CI, 0.12-0.63]) and men (HR, 0.42 [95% CI, 0.20-0.88]). There was no significant association between peak 30-minute intensity (lowest vs highest tertile: HR, 0.98 [95% CI, 0.54-1.77]) or time at 100 steps/min or more (lowest vs highest tertile: HR, 1.38 [95% CI, 0.73-2.61]) with risk of mortality. This cohort study found that among Black and White men and women in middle adulthood, participants who took approximately 7000 steps/d or more experienced lower mortality rates compared with participants taking fewer than 7000 steps/d. There was no association of step intensity with mortality.

Authors: Paluch, Amanda E; Gabriel, Kelley Pettee; Fulton, Janet E; Lewis, Cora E; Schreiner, Pamela J; Sternfeld, Barbara; Sidney, Stephen; Siddique, Juned; Whitaker, Kara M; Carnethon, Mercedes R

JAMA Netw Open. 2021 09 01;4(9):e2124516. Epub 2021-09-01.

PubMed abstract

Maternal prepregnancy weight and gestational weight gain in association with autism and developmental disorders in offspring

Maternal prepregnancy BMI and gestational weight gain (GWG) are examined in relation to autism spectrum disorder (ASD) and other developmental disorders (DD) in offspring in a multisite case-control study. Maternal prepregnancy BMI, obtained from medical records or self-report, was categorized as underweight, normal weight, overweight, obesity Class 1, or obesity Class 2/3. GWG was standardized for gestational age (GWG z score), and the rate (pounds/week) was categorized per adherence with clinical recommendations. Logistic regression models, adjusting for demographic factors, were used to assess associations with ASD (n = 1,159) and DD (n = 1,617), versus control children (n = 1,633). Maternal obesity Class 2/3 was associated with ASD (adjusted odds ratio [AOR] = 1.87, 95% CI: 1.40-2.51) and DD (AOR = 1.61, 95% CI: 1.22-2.13). GWG z score was not associated with DD (AOR = 1.14, 95% CI: 0.95-1.36), but the GWG z score highest tertile was associated with higher odds of ASD, particularly among male children (AOR = 1.47, 95% CI: 1.15-1.88). Results indicate that maternal prepregnancy severe obesity increases risk of ASD and DD in children and suggest high gestational-age-adjusted GWG is a risk factor for ASD in male children. Because maternal BMI and GWG are routinely measured and potentially modifiable, these findings could inform early interventions for high-risk mother-child dyads.

Authors: Matias, Susana L; Pearl, Michelle; Lyall, Kristen; Croen, Lisa A; Kral, Tanja V E; Fallin, Daniele; Lee, Li-Ching; Bradley, Chyrise B; Schieve, Laura A; Windham, Gayle C

Obesity (Silver Spring). 2021 09;29(9):1554-1564. Epub 2021-08-04.

PubMed abstract

Use of Complete Blood Cell Count Components to Screen for Hereditary Spherocytosis in Neonates

The neonatal hereditary spherocytosis (HS) index, defined as the mean corpuscular hemoglobin concentration divided by the mean corpuscular volume, has been proposed as a screening tool for HS in neonates. In a population of mostly white infants, an HS Index >0.36 was 97% sensitive and >99% specific. We evaluated the utility of the HS Index among a more racially and ethnically diverse population and determined if its discrimination varies with total serum bilirubin (TSB) levels. Infants born at ≥35 weeks’ gestation at 15 Kaiser Permanente Northern California hospitals from 1995 to 2015 were eligible (N = 670 272). Erythrocyte indices from the first complete blood count drawn at ≤7 days and TSB levels drawn at ≤30 days were obtained. Diagnoses of HS were confirmed via chart review. HS was confirmed in 79 infants, 1.2 per 10 000. HS was more common among infants of white and “other” race or ethnicity and among those with higher peak TSB levels. The area under the receiver operating characteristic curve for the HS Index was 0.84 (95% confidence interval 0.78-0.90). Likelihood ratios ranged from 10.1 for an HS Index ≥0.380 to 0.1 for an HS Index <0.310. Dichotomized at 0.36, the HS Index was 56% sensitive and 93% specific. Discrimination of the HS Index appeared best among infants with TSB levels <10 mg/dL. The HS Index, when obtained from a CBC drawn within the first week after birth, had only modest ability to alter the probability of HS.

Authors: Weiss, Nicole M; Kuzniewicz, Michael W; Shimano, Kristin A; Walsh, Eileen M; Newman, Thomas B

Pediatrics. 2021 09;148(3). Epub 2021-08-10.

PubMed abstract

Longitudinal bidirectional associations of physical activity and depressive symptoms: The CARDIA study

Depression affects many aspects of health and may be attenuated through increases in physical activity. While bidirectional associations between physical activity (PA) and depressive symptoms have been examined, few studies have examined these associations using both self-reported and accelerometer-estimated measures. Using data from Years 20 (2005-06, age 38-50) and 30 of the Coronary Artery Risk Development in Young Adults (CARDIA) study (N = 2,871), the bidirectional associations between moderate to vigorous intensity physical activity (MVPA) and depressive symptoms were examined using a cross-lagged panel model. Differences in the observed associations by physical activity assessment method were also examined. An inverse bidirectional association between self-reported MVPA and depressive symptoms was found. In subsequent analyses stratified by intensity category, higher levels of vigorous intensity physical activity at baseline, but not moderate intensity physical activity were associated with lower levels of depressive symptoms at the 10-year follow-up (ϕ = -0.04, p < 0.01; ϕ = -0.03, p = 0.15, respectively). A 10-year increase in self-reported MVPA was associated with a 10-year decrease in depressive symptoms. No associations were observed between accelerometer MVPA estimates and depressive symptoms. These findings may support the notion that each assessment method captures related, but also unique, aspects of physical activity behavior. When possible, future studies should explore measures of association by each physical activity assessment method to gain a better understanding of the complex relationship between physical activity and health.

Authors: Zhang, Dong; Pettee Gabriel, Kelley; Sidney, Stephen; Sternfeld, Barbara; Jacobs, David; Whitaker, Kara M

Prev Med Rep. 2021 Sep;23:101489. Epub 2021-07-12.

PubMed abstract

Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes

It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes. Two cohorts were analysed including 771 diabetic participants, 30-70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20-45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays. GADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay. Detection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.

Authors: Gu, Yong; Ferrara, Assiamira; Action LADA consortium and the Diabetes in Young Adults (DiYA) Study Group,; et al.

Diabetologia. 2021 09;64(9):2052-2060. Epub 2021-07-16.

PubMed abstract

Associations of accelerometer-determined sedentary behavior and physical activity with physical performance outcomes by race/ethnicity in older women

To determine the cross-sectional associations of accelerometer-measured time spent in physical activity intensity categories (sedentary, low and high light intensity, or moderate to vigorous intensity physical activity (MVPA) with physical performance outcomes [stair climb ascent, 40 foot walk test, and short physical performance battery (SPPB)] in older women and examine differences by race/ethnicity. Data were from 1,256 Study of Women’s Health Across the Nation (SWAN) participants [aged 64.9 (2.7) years at Visit 15 (2015-16); 54.1% non-White]. Three sets of adjusted multivariable linear or logistic regression models were built to test the study objectives using the backward elimination approach to identify relevant covariates. In the full analytic sample, a 10 min increment in MVPA was related to faster performance on the stair climb [β = -0.023 (95% CI: -0.04, -0.005) seconds] and 40 foot walk test [β = -0.066 (95% CI: -0.133, -0.038) seconds], and a 9% lower odds [OR: 0.91; 95% CI: 0.87, 0.96; p = 0.004] of limitations based on the SPPB. Statistically significant differences by race/ethnicity were found for the stair climb ascent time as MVPA was associated with better performance for White, Chinese, and Japanese participants while high light intensity physical activity, but not MVPA, was deemed beneficial in Black women. Findings from the isotemporal substitution models were consistent. Findings further support the importance of MVPA on physical performance outcomes in older women. Further research is needed to examine the complex associations between physical (in)activity and physical performance outcomes by race/ethnicity to provide more targeted recommendations.

Authors: Pettee Gabriel, Kelley; Karvonen-Gutierrez, Carrie A; Colvin, Alicia B; Ylitalo, Kelly R; Whitaker, Kara M; Lange-Maia, Brittney S; Lucas, Alexander R; Dugan, Sheila A; Derby, Carol; Cauley, Jane A; Sternfeld, Barbara

Prev Med Rep. 2021 Sep;23:101408. Epub 2021-05-19.

PubMed abstract

Lifestyle-related education and counseling resource utilization and cardiovascular biomarkers in midlife women with low physical activity

Health plan-based resources are promising avenues for decreasing cardiovascular disease risk. This study examined associations of lifestyle-related resource utilization within a healthcare delivery system and cardiovascular biomarkers among midlife women with low physical activity. Midlife women (45-55 years old) with <10 min/week of reported physical activity at a primary care visit within a large integrated healthcare delivery system in Northern California in 2015 (n = 55,393) were identified. Within this cohort, subsequent lifestyle-related health education and individual coaching resource utilization, and the next recorded physical activity, weight, systolic blood pressure, plasma glucose, HDL and LDL cholesterol measures up to 2 years after the index primary care visit were identified from electronic health records. We used a multilevel linear model to estimate associations. About 3% (n = 1587) of our cohort had ≥1 lifestyle-related resource encounter; 0.3% (n = 178) had ≥ 4 encounters. Participation in ≥4 lifestyle-related resource encounters (compared to none) was associated with 51 more minutes/week of physical activity (95% CI: 33,69) at the next clinical measurement in all women, 6.2 kg lower weight (95% CI: -7.0,-5.5) at the next measurement in women with obesity, and 8-10 mg/dL lower plasma glucose (95% CI: -30,14 and -23,2, respectively) at the next measurement in women with diabetes or prediabetes. Our results support the sustained utilization of health plan-based lifestyle-related resources for improving physical activity, weight, and plasma glucose in high-risk midlife women. Given the observed low utilization, health system-wide efforts may be warranted to increase utilization of lifestyle-related resources in this population.

Authors: Badon, Sylvia E; Nance, Nerissa; Fogelberg, Renee; Quesenberry, Charles; Hedderson, Monique M; Avalos, Lyndsay A

Prev Med Rep. 2021 Sep;23:101401. Epub 2021-05-17.

PubMed abstract

Cardiovascular risk and functional burden at midlife: Prospective associations of isotemporal reallocations of accelerometer-measured physical activity and sedentary time in the CARDIA study

Cardiovascular risk and functional burden, or the accumulation of cardiovascular risk factors coupled with functional decline, may be an important risk state analogy to multimorbidity. We investigated prospective associations of sedentary time (ST), light intensity physical activity (LPA), and moderate to vigorous intensity physical activity (MVPA) with cardiovascular risk and functional burden at midlife. Participants were 1648 adults (mean ± SD age = 45 ± 4 years, 61% female, 39% Black) from Coronary Artery Risk Development in Young Adults (CARDIA) who wore accelerometers in 2005-2006 and 2015-2016. Cardiovascular risk and functional burden was defined as ≥2 cardiovascular risk factors (untreated/uncontrolled hypertension and hypercholesterolemia, type 2 diabetes, reduced kidney function) and/or functional decline conditions (reduced physical functioning and depressive symptoms). Prospective logistic regression models tested single activity, partition, and isotemporal substitution associations of accelerometer-measured ST, LPA, and MVPA with cardiovascular risk and functional burden 10 years later. In isotemporal models of baseline activity, reallocating 24 min of ST to MVPA was associated with 15% lower odds of cardiovascular risk and functional burden (OR: 0.85; CI: 0.75, 0.96). Reallocating 24 min of LPA to MVPA was associated with a 14% lower odds of cardiovascular risk and functional burden (OR: 0.86; CI: 0.75, 0.99). In longitudinal isotemporal models, similar beneficial associations were observed when 10-year increases in MVPA replaced time in ST or LPA. Findings suggest that maintaining an MVPA dose reflecting daily physical activity recommendations in early midlife is associated with lower odds of cardiovascular risk and functional burden later in midlife.

Authors: Full, Kelsie M; Whitaker, Kara M; Pettee Gabriel, Kelley; Lewis, Cora E; Sternfeld, Barbara; Sidney, Stephen; Reis, Jared P; Jacobs, David R; Gibbs, Bethany Barone; Schreiner, Pamela J

Prev Med. 2021 09;150:106626. Epub 2021-05-19.

PubMed abstract

Maternal Psychiatric Conditions, Treatment With Selective Serotonin Reuptake Inhibitors, and Neurodevelopmental Disorders

This study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitor (SSRI) use during preconception and pregnancy with risk of neurodevelopmental disorders in offspring. We used data from the Study to Explore Early Development, a multisite case-control study conducted in the United States among children born between 2003 and 2011. Final study group classifications of autism spectrum disorder (ASD) (n = 1367), developmental delays or disorders (DDs) (n = 1750), and general population controls (n = 1671) were determined by an in-person standardized developmental assessment. Maternal psychiatric conditions and SSRI use during pregnancy were ascertained from both self-report and medical records. We used logistic regression to evaluate associations of ASD and DDs (vs. population controls) with maternal psychiatric conditions and SSRI treatment in pregnancy. To reduce confounding by indication, we also examined SSRI associations in analyses restricted to mothers with psychiatric conditions during pregnancy. Psychiatric conditions and SSRI use during pregnancy were significantly more common among mothers of children with either ASD or DDs than among population controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio 1.81, 95% confidence interval 1.44-2.27) as in mothers who did use SSRIs (adjusted odds ratio 2.05, 95% confidence interval 1.50-2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (adjusted odds ratio 1.14, 95% confidence interval 0.80-1.62). Primary findings for DDs exhibited similar relationships to those observed with ASD. Maternal psychiatric conditions but not use of SSRIs during pregnancy were associated with increased risk of neurodevelopmental disorders in offspring.

Authors: Ames, Jennifer L; Croen, Lisa A; et al.

Biol Psychiatry. 2021 08 15;90(4):253-262. Epub 2021-04-14.

PubMed abstract

Associations between longitudinal trajectories of insomnia symptoms and sleep duration with objective physical function in postmenopausal women: the Study of Women’s Health Across the Nation

Examine the association between trajectories of self-reported insomnia symptoms and sleep duration over 13 years with objective physical function. We utilized data from 1,627 Study of Women’s Health Across the Nation participants, aged 61.9 ± 2.7 years at the end of the 13-year follow-up. Latent class growth models identified trajectories of insomnia symptoms (trouble falling asleep, frequent night-time awakenings, and/or early morning awakening) and sleep duration over 13 years. Physical function tests were performed at the end of the 13-year period: 40-ft walk, 4-m walk, repeated chair stand, grip strength, and balance. Multivariable regression analyses examined each physical function measure according to the insomnia symptom or sleep duration trajectory group. Five insomnia symptom trajectories and two sleep duration trajectories were identified. Women with a consistently high likelihood of insomnia symptoms and women with a decreased likelihood of insomnia symptoms (i.e. improving) had slower gait speed (3.5% slower 40-ft walk [consistently high], 3.7% slower 4-m walk [improving]; each p ≤ .05) than those with a consistently low likelihood of insomnia symptoms. In contrast, women with a steep increase in the likelihood of insomnia symptoms over time and women with persistent insufficient sleep duration had lower odds of having a balance problem (odds ratio [OR] = 0.36 and OR = 0.61, respectively; each p < .02) compared to those with a consistently low likelihood of insomnia symptoms and those with persistent sufficient sleep duration, respectively. These results suggest that women's sleep during midlife has important implications for maintaining physical function during the transition into older adulthood.

Authors: Kline, Christopher E; Colvin, Alicia B; Pettee Gabriel, Kelley; Karvonen-Gutierrez, Carrie A; Cauley, Jane A; Hall, Martica H; Matthews, Karen A; Ruppert, Kristine M; Neal-Perry, Genevieve S; Strotmeyer, Elsa S; Sternfeld, Barbara

Sleep. 2021 08 13;44(8).

PubMed abstract

Healthy preconception and early-pregnancy lifestyle and risk of preterm birth: a prospective cohort study

Preterm birth (PTB) remains a leading cause of neonatal mortality and long-term morbidity. Individual factors have been linked to PTB risk. The impact of a healthy lifestyle, with multiple modifiable prenatal factors, remains unknown. We aimed to examine the associations of preconceptional and early-pregnancy low-risk modifiable factors (individually and in combination) with PTB risk. This prospective cohort study included 2449 women with singleton pregnancies in the Pregnancy Environment and Lifestyle Study. PTB was defined as ultrasound-confirmed obstetric estimate-based gestational age at delivery <37 wk. A set of low-risk modifiable factors were identified: healthy weight (prepregnancy BMI: 18.5-24.9 kg/m2) based on clinical measurements and high-quality diet (Alternate Healthy Eating Index-Pregnancy score ≥75th percentile) and low-to-moderate stress during early pregnancy (Perceived Stress Scale score <75th percentile) assessed at gestational weeks 10-13. Poisson regression estimated adjusted relative risk (aRR) of PTB in association with individual and combined low-risk modifiable prenatal factors, adjusting for sociodemographic, clinical, and other prenatal factors. One hundred and sixty women (6.5%) delivered preterm. Risk of PTB was lower among women who had a healthy weight (aRR: 0.58; 95% CI: 0.39, 0.86), high-quality diet (aRR: 0.68; 95% CI: 0.39, 0.99), and low-to-moderate stress (aRR: 0.60; 95% CI: 0.41, 0.88). Women with 1, 2, or 3 low-risk modifiable prenatal factors compared with none had a 38% (aRR: 0.72; 95% CI: 0.45, 1.16), 51% (aRR: 0.49; 95% CI: 0.29, 0.84), or 70% (aRR: 0.30; 95% CI: 0.13, 0.70) lower PTB risk, respectively. Associations of having ≥1 low-risk factor with PTB risk were more pronounced for medically indicated than for spontaneous PTB and for late than for early or moderate PTB. Associations also varied by race or ethnicity, although with overlapping 95% CIs. A healthy prenatal lifestyle with multiple low-risk modifiable factors was associated with lower risk of PTB. Our findings may inform multicomponent preconceptional or early-pregnancy prevention strategies to mitigate PTB risk.

Authors: Zhu, Yeyi; Hedderson, Monique M; Brown, Susan D; Badon, Sylvia E; Feng, Juanran; Quesenberry, Charles P; Ferrara, Assiamira

Am J Clin Nutr. 2021 08 02;114(2):813-821.

PubMed abstract

A longitudinal study of plasma acylcarnitines throughout pregnancy and associations with risk of gestational diabetes mellitus

Prospective and longitudinal data on the association between acylcarnitines and gestational diabetes (GDM) are lacking. This study aims to prospectively investigate 28 acylcarnitines in relation to subsequent GDM risk. Within the NICHD Fetal Growth Studies-Singleton Cohort, plasma levels of acylcarnitines and cardiometabolic biomarkers were measured at gestational week (GW) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases and 214 controls. At GW 10-14, per standard deviation (SD) increased level of C14:1-OH was associated with a 55% increased risk of GDM after adjusting for major risk factors for GDM [OR (95% CI): 1.55 (1.05-2.29)]. At GW 15-26, C4, C8:1 and C16:1-OH were associated with an increased risk of GDM [OR (95% CI) for per SD increase: 1.42 (1.01-2.00), 1.41 (1.02-1.96), and 1.77 (1.10-2.84), respectively]. Whereas increased C10 and C18 were related to lower risk of GDM [OR (95% CI) for per SD increase: 0.74 (0.55-1.00), and 0.69 (0.49-0.97), respectively]. Moreover, we observed correlations of individual acylcarnitine with multiple clinical markers implicated in glucose homeostasis and cardiometabolic function among non-GDM women. Our results demonstrate that several plasma acylcarnitine species are differentially associated with GDM risk by chain length. Future studies are warranted to investigate the distinct roles of individual acylcarnitine in glucose homeostasis in pregnancy.

Authors: Lin, Yuan; Wu, Jing; Zhu, Yeyi; Hinkle, Stefanie N; Rawal, Shristi; Liang, Liming; Weir, Natalie L; Tsai, Michael Y; Zhang, Cuilin

Clin Nutr. 2021 08;40(8):4863-4870. Epub 2021-07-10.

PubMed abstract

Cardiovascular risk and midlife cognitive decline in the Study of Women’s Health Across the Nation

Cardiovascular risk factors in midlife have been linked to late life risk for Alzheimer’s disease and related dementias (ADRD). The relation of vascular risk factors on cognitive decline within midlife has been less studied. Using data from the Study of Women’s Health Across the Nation, we examined associations of midlife hypertension, elevated lipid levels, diabetes, fasting glucose, central adiposity, and Framingham heart age with rates of cognitive decline in women who completed multiple cognitive assessments of processing speed, and working and verbal memory during midlife. Diabetes, elevated fasting glucose, central obesity, and heart age greater than chronological age were associated with rate of decline in processing speed during midlife. Vascular risk factors were not related to rate of decline in working or verbal memory. Midlife may be a critical period for intervening on cardiovascular risk factors to prevent or delay later life cognitive impairment and ADRD.

Authors: Derby, Carol A; Hutchins, Franya; Greendale, Gail A; Matthews, Karen A; Sternfeld, Barbara; Everson-Rose, Susan A; Kazlauskaite, Rasa; Whitmer, Rachel A; Brooks, Maria M

Alzheimers Dement. 2021 08;17(8):1342-1352. Epub 2021-03-12.

PubMed abstract

Relative-Intensity Physical Activity and Its Association With Cardiometabolic Disease

Authors: Siddique, Juned; Welch, Whitney A; Aaby, David; Sternfeld, Barbara; Pettee Gabriel, Kelley; Carnethon, Mercedes R; Rana, Jamal S; Sidney, Stephen

J Am Heart Assoc. 2021 07 20;10(14):e019174. Epub 2021-07-14.

PubMed abstract

Engagement in perinatal depression treatment: a qualitative study of barriers across and within racial/ethnic groups

To better understand previously observed racial/ethnic disparities in perinatal depression treatment rates we examined care engagement factors across and within race/ethnicity. Obstetric patients and women’s health clinician experts from a large healthcare system participated in this qualitative study. We conducted focus groups with 30 pregnant or postpartum women of Asian, Black, Latina, and White race/ethnicity with positive depression screens. Nine clinician experts in perinatal depression (obstetric, mental health, and primary care providers) were interviewed. A semi-structured format elicited treatment barriers, cultural factors, and helpful strategies. Discussion transcripts were coded using a general inductive approach with themes mapped to the Capability-Opportunity-Motivation-Behavior (COM-B) theoretical framework. Treatment barriers included social stigma, difficulties recognizing one’s own depression, low understanding of treatment options, and lack of time for treatment. Distinct factors emerged for non-White women including culturally specific messages discouraging treatment, low social support, trauma history, and difficulty taking time off from work for treatment. Clinician factors included knowledge and skill handling perinatal depression, cultural competencies, and language barriers. Participants recommended better integration of mental health treatment with obstetric care, greater treatment convenience (e.g., telemedicine), and programmatic attention to cultural factors and social determinants of health. Women from diverse backgrounds with perinatal depression encounter individual-level, social, and clinician-related barriers to treatment engagement, necessitating care strategies that reduce stigma, offer convenience, and attend to cultural and economic factors. Our findings suggest the importance of intervention and policy approaches effecting change at multiple levels to increase perinatal depression treatment engagement.

Authors: Iturralde, Esti; Hsiao, Crystal A; Nkemere, Linda; Kubo, Ai; Sterling, Stacy A; Flanagan, Tracy; Avalos, Lyndsay A

BMC Pregnancy Childbirth. 2021 Jul 16;21(1):512. Epub 2021-07-16.

PubMed abstract

Perceived Barriers and Motivators for Physical Activity in Women With Perinatal Depression

Physical activity (PA) can help reduce depression symptom severity in women with perinatal depression. However, PA is low, and barriers and motivators for PA among women with perinatal depression are not well understood. An ethnically diverse sample of women with perinatal depression was identified using a universal perinatal depression screening program. The authors conducted 8 focus groups (4 in pregnant women [n = 15] and 4 in postpartum women [n = 20]). Depression symptoms were measured using the Patient Health Questionnaire-8 at recruitment. Focus groups were analyzed using an inductive approach. Pregnant participants were 27 weeks gestation, and postpartum participants were 11.5 months postpartum, on average. Depression symptoms were moderately severe (mean Patient Health Questionnaire-8 score: 16). Women identified practical barriers and motivators for PA common to perinatal women (physical health, parental responsibilities, PA tracking tools, and environmental factors) and described emotional and social factors influencing PA. Motivators included using PA to improve mood, relieve stress, boost self-image, and spend time with others. Bad mood, fear of social judgment, and feeling discouraged made it difficult to be active. PA interventions in women with perinatal depression should include components addressing emotional and social barriers to PA in addition to addressing additional common practical barriers to PA.

Authors: Badon, Sylvia E; Iturralde, Esti; Nkemere, Linda; Nance, Nerissa; Avalos, Lyndsay A

J Phys Act Health. 2021 07 01;18(7):801-810. Epub 2021-05-12.

PubMed abstract

Mediating Effects of Cardiometabolic Risk Factors on the Association Between Maternal Race-Ethnicity and Cesarean Delivery Among Low-Risk Women

Background: While racial-ethnic disparities in cesarean delivery rates among nulliparous women delivering a term singleton in the vertex position (NTSV) exist, it remains unclear the extent to which potentially modifiable maternal cardiometabolic risk factors (obesity, maternal hyperglycemia and hypertensive disorders) underlie these disparities. We examined race-ethnicity and risk of NTSV cesarean deliveries and whether the associations were mediated by maternal cardiometabolic risk factors. Materials and Methods: A cohort study of 62,048 NTSV deliveries in Kaiser Permanente Northern California. The outcome was cesarean delivery. Results: Black, Asian, and Hispanic women were at increased risk of having a NTSV cesarean delivery compared with White women (relative risks and 95% confidence intervals: 1.37 [1.28-1.45]; 1.11 [1.07-1.16]; 1.12 [1.07-1.16], respectively), independent of established risk factors and prenatal care utilization. The extent to which cardiometabolic risk factors mediated the associations between race-ethnicity (each group vs. White, in separate analyses) and NTSV cesarean delivery varied by race-ethnicity. Maternal overweight/obesity (body mass index ≥25.0) mediated the association between Black and Hispanic race-ethnicity and NTSV cesarean delivery (21.1% [15.8-26.4] and 24.7% [14.6-34.8, respectively), but not for Asian race. Maternal hyperglycemia (gestational diabetes mellitus or preexisting diabetes) mediated the association between Asian and Hispanic race and NTSV cesarean delivery (18.5% [9.8-27.2] and 9.8% [5.0-14.7], respectively), but not for Black race. Hypertensive disorders mediated 3.2% (0.70-5.8) of the association between Black race and cesarean delivery, but not for other race-ethnicities. Conclusion: Black, Asian, and Hispanic women are at increased risk for NTSV cesarean deliveries. Maternal cardiometabolic risk factors only partially mediate the associations between race-ethnicity and NSTV cesarean deliveries.

Authors: Hedderson, Monique M; Xu, Fei; Liu, Emily; Sridhar, Sneha B; Quesenberry, Charles P; Flanagan, Tracy A

J Womens Health (Larchmt). 2021 07;30(7):1028-1037. Epub 2021-02-11.

PubMed abstract

Distributional Properties and Criterion Validity of a Shortened Version of the Social Responsiveness Scale: Results from the ECHO Program and Implications for Social Communication Research

Prior work proposed a shortened version of the Social Responsiveness Scale (SRS), a commonly used quantitative measure of social communication traits. We used data from 3031 participants (including 190 ASD cases) from the Environmental Influences on Child Health Outcomes (ECHO) Program to compare distributional properties and criterion validity of 16-item “short” to 65-item “full” SRS scores. Results demonstrated highly overlapping distributions of short and full scores. Both scores separated case from non-case individuals by approximately two standard deviations. ASD prediction was nearly identical for short and full scores (area under the curve values of 0.87, 0.86 respectively). Findings support comparability of shortened and full scores, suggesting opportunities to increase efficiency. Future work should confirm additional psychometric properties of short scores.

Authors: Lyall, Kristen; Croen, Lisa A; program collaborators for Environmental influences on Child Health Outcomes,; et al.

J Autism Dev Disord. 2021 Jul;51(7):2241-2253.

PubMed abstract

Exploring the evidence for epigenetic regulation of environmental influences on child health across generations

Environmental exposures, psychosocial stressors and nutrition are all potentially important influences that may impact health outcomes directly or via interactions with the genome or epigenome over generations. While there have been clear successes in large-scale human genetic studies in recent decades, there is still a substantial amount of missing heritability to be elucidated for complex childhood disorders. Mounting evidence, primarily in animals, suggests environmental exposures may generate or perpetuate altered health outcomes across one or more generations. One putative mechanism for these environmental health effects is via altered epigenetic regulation. This review highlights the current epidemiologic literature and supporting animal studies that describe intergenerational and transgenerational health effects of environmental exposures. Both maternal and paternal exposures and transmission patterns are considered, with attention paid to the attendant ethical, legal and social implications.

Authors: Breton, Carrie V; Fry, Rebecca; Fry, Rebecca; et al.

Commun Biol. 2021 06 22;4(1):769. Epub 2021-06-22.

PubMed abstract

Pharmacists’ knowledge, perspectives, and experiences with mifepristone dispensing for medication abortion

The U.S. Food and Drug Administration (FDA) restricts dispensing of mifepristone for medication abortion to certified health care providers at clinical facilities, thus prohibiting pharmacist dispensing. Allowing mifepristone dispensing by pharmacists could improve access to medication abortion. To assess the feasibility of pharmacists dispensing mifepristone to patients who have undergone evaluation for eligibility and counseling for medication abortion by a clinician. Before providing a study training on medication abortion, we administered baseline surveys to pharmacists who participated in a multisite mifepristone-dispensing intervention. The survey assessed medication abortion knowledge-using a 15-item score-and perceptions about the benefits and challenges of the model. We administered follow-up surveys in the study’s final month that also assessed the pharmacists’ satisfaction and experiences with mifepristone dispensing. To investigate the association of the study intervention with the pharmacists’ knowledge, perceptions, and experiences dispensing mifepristone, we conducted multivariable linear regression analyses using generalized estimating equation models, accounting for clustering by individual. Among the 72 pharmacists invited from 6 pharmacies, 47 (65%) completed the baseline surveys, and 56 (78%) received training. At the study’s end (mean 18 months later), 43 of the 56 pharmacists who received training (77%) completed the follow-up surveys. At follow-up, 36 (83%) respondents were very or somewhat satisfied with mifepristone dispensing, and 24 (56%) reported experiencing no challenges dispensing mifepristone. Four (6%) of the 72 pharmacists invited objected to participating in mifepristone dispensing. In regression analyses, average knowledge scores, perceived ease of implementation, and level of support for the pharmacist-dispensing model were higher at follow-up (P < 0.001). Most pharmacists were willing to be trained, dispensed mifepristone with few challenges when given the opportunity, were satisfied with the model, and had higher knowledge levels at follow-up. Our findings support removal of FDA's restriction on pharmacist dispensing of mifepristone.

Authors: Kaller S; Raine-Bennett TR; Grossman D; et al.

J Am Pharm Assoc (2003). 2021 Jun 18.

PubMed abstract

Genetic and Epigenetic Variations of HPV52 in Cervical Precancer

The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.

Authors: Bee KJ; Gradissimo A; Chen Z; Harari A; Schiffman M; Raine-Bennett T; Castle PE; Clarke M; Wentzensen N; Burk RD

Int J Mol Sci. 2021 Jun 16;22(12). Epub 2021-06-16.

PubMed abstract

Bidirectional associations of accelerometer-derived physical activity and stationary behavior with self-reported mental and physical health during midlife

Moderate-to-vigorous intensity physical activity (MVPA) is associated with favorable self-rated mental and physical health. Conversely, poor self-rated health in these domains could precede unfavorable shifts in activity. We evaluated bidirectional associations of accelerometer-estimated time spent in stationary behavior (SB), light intensity physical activity (LPA), and MVPA with self-rated health over 10 years in in the CARDIA longitudinal cohort study. Participants (n = 894, age: 45.1 ± 3.5; 63% female; 38% black) with valid accelerometry wear and self-rated health at baseline (2005-6) and 10-year follow-up (2015-6) were included. Accelerometry data were harmonized between exams and measured mean total activity and duration (min/day) in SB, LPA, and MVPA; duration (min/day) in long-bout and short-bout SB (≥30 min vs. < 30 min) and MVPA (≥10 min vs. < 10 min) were also quantified. The Short-Form 12 Questionnaire measured both a mental component score (MCS) and physical component score (PCS) of self-rated health (points). Multivariable linear regression associated baseline accelerometry variables with 10-year changes in MCS and PCS. Similar models associated baseline MCS and PCS with 10-year changes in accelerometry measures. Over 10-years, average (SD) MCS increased 1.05 (9.07) points, PCS decreased by 1.54 (7.30) points, and activity shifted toward greater SB and less mean total activity, LPA, and MVPA (all p < 0.001). Only baseline short-bout MVPA was associated with greater 10-year increases in MCS (+ 0.92 points, p = 0.021), while baseline mean total activity, MVPA, and long-bout MVPA were associated with greater 10-year changes in PCS (+ 0.53 to + 1.47 points, all p < 0.005). In the reverse direction, higher baseline MCS and PCS were associated with favorable 10-year changes in mean total activity (+ 9.75 cpm, p = 0.040, and + 15.66 cpm, p < 0.001, respectively) and other accelerometry measures; for example, higher baseline MCS was associated with - 13.57 min/day of long-bout SB (p < 0.001) and higher baseline PCS was associated with + 2.83 min/day of MVPA (p < 0.001) in fully adjusted models. The presence of bidirectional associations between SB and activity with self-rated health suggests that individuals with low overall activity levels and poor self-rated health are at high risk for further declines and supports intervention programming that aims to dually increase activity levels and improve self-rated health.

Authors: Barone Gibbs, Bethany; Sternfeld, Barbara; Whitaker, Kara M; Brach, Jennifer S; Hergenroeder, Andrea L; Jacobs, David R; Reis, Jared P; Sidney, Stephen; White, Daniel; Pettee Gabriel, Kelley

Int J Behav Nutr Phys Act. 2021 06 06;18(1):74. Epub 2021-06-06.

PubMed abstract

A prognostic information system for real-time personalized care: Lessons for embedded researchers

Embedded researchers could play a central role in developing tools to personalize care using electronic medical records (EMRs). However, few studies have described the steps involved in developing such tools, or evaluated the key factors in success and failure. This case study describes how we used an EMR-derived data warehouse to develop a prototype informatics tool to help oncologists counsel patients with pancreatic cancer about their prognosis. The tool generated real-time prognostic information based on tumor type and stage, age, comorbidity status and lab tests. Our multidisciplinary team included embedded researchers, application developers, user experience experts, and an oncologist leader.This prototype succeeded in establishing proof of principle, but did not reach adoption into actual practice. In pilot testing, oncologists succeeded in generating prognostic information in real time. A few found it helpful in patient encounters, but all identified critical areas for further development before implementation. Generalizable lessons included the need to (1) include a wide range of potential use cases and stakeholders when selecting use cases for such tools; (2) develop talking points for clinicians to explain results from predictive tools to patients; (3) develop ways to reduce lag time between events and data availability; and (4) keep the options presented in the user interface very simple. This case demonstrates that embedded researchers can lead collaborations using EMR-derived data to create systems for real-time personalized patient counseling, and highlights challenges that such teams can anticipate.

Authors: Lieu, Tracy A; Neugebauer, Romain; Van Den Eeden, Stephen K; Baer, David M; et al.

Healthc (Amst). 2021 Jun;8 Suppl 1:100486. Epub 2021-06-23.

PubMed abstract

Bidirectional associations of accelerometer measured sedentary behavior and physical activity with knee pain, stiffness, and physical function: The CARDIA study

The objective was to examine bidirectional associations of accelerometer estimated sedentary time and physical activity with reported knee symptoms. Participants were 2,034 adults (mean age 45.3 ± 3.6 years, 58.7% female) from CARDIA. Generalized estimating equations for logistic regression and linear mixed regression models examined associations of accelerometer estimated sedentary time, light-intensity physical activity (LPA), and moderate-to-vigorous intensity physical activity (MVPA) at baseline (2005-06) with knee discomfort, pain, stiffness, and physical function (yes/no and continuous scores from short-form WOMAC function scale) at the 5- and 10-year follow-up exams. Linear regression models examined associations between knee symptoms at the 5-year follow-up with accelerometer estimates at the 10-year follow-up. Models were adjusted for confounders; individuals with comorbidities were excluded in sensitivity analyses. A 30 min/day increment in sedentary time at baseline was associated with lower odds of knee symptoms at the 5- and 10-year follow-up (OR: 0.95, 95% CI range: 0.92-0.98), while LPA and MVPA were associated with greater odds of knee symptoms (LPA OR range: 1.04-1.05, 95% CI range: 1.01-1.09; MVPA OR range: 1.17-1.19, 95% CI range: 1.06-1.32). Report of knee symptoms at the 5-year follow-up was associated with 13.52-17.51 (95% CI range: -29.90, -0.56) fewer minutes/day of sedentary time and 14.58-17.51 (95% CI range: 2.48, 29.38) more minutes/day of LPA at the 10-year follow-up, compared to those reporting no symptoms. Many associations were no longer statistically significant when excluding individuals with comorbidities. Findings support a bidirectional association of accelerometer estimated sedentary time and physical activity with knee symptoms across midlife.

Authors: Whitaker, Kara M; Pettee Gabriel, Kelley; Laddu, Deepika; White, Daniel K; Sidney, Stephen; Sternfeld, Barbara; Lewis, Cora E; Jacobs, David R

Prev Med Rep. 2021 Jun;22:101348. Epub 2021-03-09.

PubMed abstract

Design of the Association of Uterine Perforation and Expulsion of IUD (APEX-IUD) Study: A Multisite Retrospective Cohort Study

Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device-related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion. We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up. APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights. The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74-177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m2, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record. Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.

Authors: Anthony, Mary S; Getahun, Darios; Asiimwe, Alex; et al.

Am J Obstet Gynecol. 2021 06;224(6):599.e1-599.e18. Epub 2021-01-15.

PubMed abstract

Predicting the Need for Phototherapy After Discharge

Bilirubin screening before discharge is performed to identify neonates at risk for future hyperbilirubinemia. The American Academy of Pediatrics recommends using a graph of bilirubin levels by age (the Bhutani Nomogram) to guide follow-up and a different graph to determine phototherapy recommendations. Our objective was to evaluate predictive models that incorporate the difference between the last total serum bilirubin (TSB) before discharge and the American Academy of Pediatrics phototherapy threshold (Δ-TSB) to predict a postdischarge TSB above the phototherapy threshold by using a single graph. We studied 148 162 infants born at ≥35 weeks’ gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017 whose TSB did not exceed phototherapy levels and who did not receive phototherapy during the birth hospitalization. We compared 3 logistic models (Δ-TSB; Δ-TSB-Plus, which included additional variables; and the Bhutani Nomogram) by using the area under the receiver operating characteristic curve (AUC) in a 20% validation subset. A total of 2623 infants (1.8%) exceeded the phototherapy threshold postdischarge. The predicted probability of exceeding the phototherapy threshold after discharge ranged from 56% for a predischarge Δ-TSB 0 to 1 mg/dL below the threshold to 0.008% for Δ-TSB >7 mg/dL below the threshold. Discrimination was better for the Δ-TSB model (AUC 0.93) and the Δ-TSB-Plus model (AUC 0.95) than for the Bhutani Nomogram (AUC 0.88). The use of Δ-TSB models had excellent ability to predict postdischarge TSB above phototherapy thresholds and may be simpler to use than the Bhutani Nomogram.

Authors: Kuzniewicz, Michael W; Park, Jina; Niki, Hamid; Walsh, Eileen M; McCulloch, Charles E; Newman, Thomas B

Pediatrics. 2021 05;147(5).

PubMed abstract


DISCLOSURES: No funding was received for the writing of this letter. All authors were members of the National Academies study committee to which this letter refers, with Shortliffe as the chair. All committee members who contributed to the report were themselves vetted for potential conflicts of interest, as is described in the recently published version of the report. Lieu is an employee of Kaiser Permanente and the content does not represent the official views of Kaiser Permanente. The other authors have nothing to disclose.

Authors: Watanabe, Jonathan H; Lieu, Tracy; Shortliffe, Edward H

J Manag Care Spec Pharm. 2021 May;27(5):689-690.

PubMed abstract

Evaluation of sex differences in preschool children with and without autism spectrum disorder enrolled in the study to explore early development

Research in school-aged children, adolescents, and adults with autism spectrum disorder (ASD) has found sex-based differences in behavioral, developmental, and diagnostic outcomes. These findings have not been consistently replicated in preschool-aged children. We examined sex-based differences in a large sample of 2-5-year-old children with ASD symptoms in a multi-site community-based study. Based on a comprehensive evaluation, children were classified as having ASD (n = 1480, 81.55 % male) or subthreshold ASD characteristics (n = 593, 70.15 % male). Outcomes were behavior problems, developmental abilities, performance on ASD screening and diagnostic tests, and parent-reported developmental conditions diagnosed before study enrollment. We found no statistically significant sex differences in behavioral functioning, developmental functioning, performance on an ASD screening test, and developmental conditions diagnosed before study enrollment among children with ASD or subthreshold ASD characteristics. Males in both study groups had more parent reported restricted interests and repetitive behaviors than females, but these differences were small in magnitude and not clinically meaningful. Preschool males and females who showed risk for ASD were more similar than different in the outcomes assessed in our study. Future research could examine sex-based differences in ASD phenotypes as children age.

Authors: Wiggins, Lisa D; Croen, Lisa; Schieve, Laura; et al.

Res Dev Disabil. 2021 May;112:103897. Epub 2021-02-17.

PubMed abstract

Prenatal Air Pollution Exposure and Neurodevelopment: A Review and Blueprint for a Harmonized Approach within ECHO

Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children’s health.

Authors: Volk, Heather E; Eskenazi, Brenda; Environmental influences on Child Health Outcomes,; et al.

Environ Res. 2021 05;196:110320. Epub 2020-10-22.

PubMed abstract

Physician Stress During Electronic Health Record Inbox Work: In Situ Measurement With Wearable Sensors

Increased work through electronic health record (EHR) messaging is frequently cited as a factor of physician burnout. However, studies to date have relied on anecdotal or self-reported measures, which limit the ability to match EHR use patterns with continuous stress patterns throughout the day. The aim of this study is to collect EHR use and physiologic stress data through unobtrusive means that provide objective and continuous measures, cluster distinct patterns of EHR inbox work, identify physicians’ daily physiologic stress patterns, and evaluate the association between EHR inbox work patterns and physician physiologic stress. Physicians were recruited from 5 medical centers. Participants (N=47) were given wrist-worn devices (Garmin Vivosmart 3) with heart rate sensors to wear for 7 days. The devices measured physiological stress throughout the day based on heart rate variability (HRV). Perceived stress was also measured with self-reports through experience sampling and a one-time survey. From the EHR system logs, the time attributed to different activities was quantified. By using a clustering algorithm, distinct inbox work patterns were identified and their associated stress measures were compared. The effects of EHR use on physician stress were examined using a generalized linear mixed effects model. Physicians spent an average of 1.08 hours doing EHR inbox work out of an average total EHR time of 3.5 hours. Patient messages accounted for most of the inbox work time (mean 37%, SD 11%). A total of 3 patterns of inbox work emerged: inbox work mostly outside work hours, inbox work mostly during work hours, and inbox work extending after hours that were mostly contiguous to work hours. Across these 3 groups, physiologic stress patterns showed 3 periods in which stress increased: in the first hour of work, early in the afternoon, and in the evening. Physicians in group 1 had the longest average stress duration during work hours (80 out of 243 min of valid HRV data; P=.02), as measured by physiological sensors. Inbox work duration, the rate of EHR window switching (moving from one screen to another), the proportion of inbox work done outside of work hours, inbox work batching, and the day of the week were each independently associated with daily stress duration (marginal R2=15%). Individual-level random effects were significant and explained most of the variation in stress (conditional R2=98%). This study is among the first to demonstrate associations between electronic inbox work and physiological stress. We identified 3 potentially modifiable factors associated with stress: EHR window switching, inbox work duration, and inbox work outside work hours. Organizations seeking to reduce physician stress may consider system-based changes to reduce EHR window switching or inbox work duration or the incorporation of inbox management time into work hours.

Authors: Akbar F; Mark G; Prausnitz S; Warton EM; East JA; Moeller MF; Reed ME; Lieu TA

JMIR Med Inform. 2021 Apr 28;9(4):e24014. Epub 2021-04-28.

PubMed abstract

Physicians’ electronic inbox work patterns and factors associated with high inbox work duration

Electronic health record systems are increasingly used to send messages to physicians, but research on physicians’ inbox use patterns is limited. This study’s aims were to (1) quantify the time primary care physicians (PCPs) spend managing inboxes; (2) describe daily patterns of inbox use; (3) investigate which types of messages consume the most time; and (4) identify factors associated with inbox work duration. We analyzed 1 month of electronic inbox data for 1275 PCPs in a large medical group and linked these data with physicians’ demographic data. PCPs spent an average of 52 minutes on inbox management on workdays, including 19 minutes (37%) outside work hours. Temporal patterns of electronic inbox use differed from other EHR functions such as charting. Patient-initiated messages (28%) and results (29%) accounted for the most inbox work time. PCPs with higher inbox work duration were more likely to be female (P < .001), have more patient encounters (P < .001), have older patients (P < .001), spend proportionally more time on patient messages (P < .001), and spend more time per message (P < .001). Compared with PCPs with the lowest duration of time on inbox work, PCPs with the highest duration had more message views per workday (200 vs 109; P < .001) and spent more time on the inbox outside work hours (30 minutes vs 9.7 minutes; P < .001). Electronic inbox work by PCPs requires roughly an hour per workday, much of which occurs outside scheduled work hours. Interventions to assist PCPs in handling patient-initiated messages and results may help alleviate inbox workload.

Authors: Akbar, Fatema; Mark, Gloria; Warton, E Margaret; Reed, Mary E; Prausnitz, Stephanie; East, Jeffrey A; Moeller, Mark F; Lieu, Tracy A

J Am Med Inform Assoc. 2021 04 23;28(5):923-930.

PubMed abstract

Development and psychometric testing of the AASPIRE Adult Autism Healthcare Provider Self-Efficacy Scale

The adult healthcare system is ill-prepared to provide high-quality care to autistic adults. Lack of provider training may contribute to the problem, but there are few previously tested survey instruments to guide provider training efforts. Our objective was to develop and test a measure of healthcare providers’ confidence (or “self-efficacy”) in providing healthcare to autistic adults and to use it to better understand their training needs. We used a community-based participatory research (CBPR) approach, in partnership with academic researchers, autistic adults, supporters, and healthcare providers, throughout the project. We developed a one-page questionnaire and surveyed 143 primary care providers from eight primary care clinics in Oregon and California, United States. Preliminary testing of the AASPIRE Adult Autism Healthcare Provider Self-Efficacy Scale suggests that the measure is reliable and valid. Using this scale, we found only a minority of providers reported high confidence in communicating with patients (25%); performing physical exams or procedures (43%); accurately diagnosing and treating other medical issues (40%); helping patients stay calm and comfortable during visits (38%); identifying accommodation needs (14%); and making necessary accommodations (16%). While providers need training across all aspects of care related to autism in adulthood, interventions should pay particular attention to helping providers communicate with patients, and identify and make necessary accommodations. Future research is needed to further validate this scale and to understand how to meet providers’ training needs most effectively.

Authors: Nicolaidis, Christina; Schnider, Gavin; Lee, Junghee; Raymaker, Dora M; Kapp, Steven K; Croen, Lisa A; Urbanowicz, Anna; Maslak, Joelle

Autism. 2021 04;25(3):767-773. Epub 2020-08-28.

PubMed abstract

Dual trajectories of physical activity and blood lipids in midlife women: The Study of Women’s Health Across the Nation

Physical activity (PA) has the potential to attenuate cardiovascular disease risk in midlife women through multiple pathways, including improving lipid profiles. Longitudinal patterns of PA and blood lipid levels have not been studied in midlife women. Our study identified trajectories of PA and blood lipids across midlife and characterized the associations between these trajectories. We evaluated 2,789 participants from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study with follow-up over the menopause transition. Women reported PA using the Kaiser Physical Activity Survey at seven study visits across 17 years of follow-up. Serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at eight study visits across the same 17-year follow-up period. We used group-based trajectory models to characterize trajectories of PA and blood lipids over midlife and dual trajectory models to determine the association between PA and blood lipid trajectories adjusted for race/ethnicity, body mass index category, smoking, and lipid-lowering medication use. Women were 46 years old, on average, at study entry. Forty-nine percent were non-Hispanic white; 32 % were Black; 10 % were Japanese; and 9 % were Chinese. We identified four PA trajectories, three HDL cholesterol trajectories, four LDL cholesterol trajectories, and two triglyceride trajectories. The most frequently occurring trajectories were the consistently low PA trajectory (69 % of women), the low HDL cholesterol trajectory (43 % of women), the consistently moderate LDL cholesterol trajectory (45 % of women), and the consistently low triglycerides trajectory (90 % of women). In dual trajectory analyses, no clear associations were observed between PA trajectories and HDL cholesterol, LDL cholesterol, or triglycerides trajectories. The most frequently observed trajectories across midlife were characterized by low physical activity, low HDL cholesterol, moderate LDL cholesterol, and low triglycerides. Despite the absence of an association between long-term trajectories of PA and blood lipids in this study, a large body of evidence has established the importance of clinical and public health messaging and interventions targeted at midlife women to promote regular and sustained PA during midlife to achieve other cardiovascular and metabolic benefits.

Authors: Badon, Sylvia E; Gabriel, Kelley Pettee; Karvonen-Gutierrez, Carrie; Sternfeld, Barbara; Gold, Ellen B; Waetjen, L Elaine; Lee, Catherine; Avalos, Lyndsay A; El Khoudary, Samar R; Hedderson, Monique M

Maturitas. 2021 Apr;146:49-56. Epub 2021-02-06.

PubMed abstract

Household mold, pesticide use, and childhood asthma: A nationwide study in the U.S

To investigate the associations of household mold and pesticide use with risk of childhood asthma and examine the potential effect modification by child’s sex at a national level in the U.S. Nationally representative data were drawn from the cross-sectional 2017 and 2018 National Surveys of Children’s Health. Household mold and pesticide exposures during the past 12 months and physician-diagnosed childhood asthma were assessed by standard questionnaires administered to primary caregivers. Multivariable logistic regression models were used to calculate adjusted odds ratios (aOR) for current asthma, adjusting for child, caregiver, and household covariates. We also examined potential effect modification by child’s sex. Sampling weights accounted for the complex survey design. Among 41,423 U.S. children in 2017-2018, the weighted prevalence of current asthma was 10.8% in household mold-exposed children, compared with 7.2% in non-exposed children (P < 0.001). After adjusting for covariates including child's obesity, children with household mold exposure compared to those with no household mold exposure had a 1.41-fold (95% CI: 1.07, 1.87) higher odds of current asthma. Associations between household mold and current asthma were pronounced among boys (aOR 1.57; 95% CI: 1.03-2.38) but not girls (aOR 1.28; 0.90-1.83; P for interaction <0.001). No significant associations were observed between household pesticide use and current asthma, after adjusting for covariates. Our findings suggest that household mold is associated with current asthma among children, independent of other major risk factors including child's obesity status. Our findings may inform strategies targeting mitigation of household mold as an important indoor environment factor to address childhood asthma.

Authors: Xiao, Siyuan; Ngo, Amanda L; Mendola, Pauline; Bates, Michael N; Barcellos, Anna L; Ferrara, Assiamira; Zhu, Yeyi

Int J Hyg Environ Health. 2021 04;233:113694. Epub 2021-02-06.

PubMed abstract

Psychometric testing of a set of patient-reported instruments to assess healthcare interventions for autistic adults

Interventions to improve healthcare for autistic adults are greatly needed. To evaluate such interventions, researchers often use surveys to collect data from autistic adults (or sometimes, their supporters), but few survey measures have been tested for use with autistic adults. Our objective was to create and test a set of patient- or proxy-reported survey measures for use in studies that evaluate healthcare interventions. We used a community-based participatory research (CBPR) approach, in partnership with autistic adults, healthcare providers, and supporters. We worked together to create or adapt survey measures. Three survey measures focus on things that interventions may try to change directly: (1) how prepared patients are for visits; (2) how confident they feel in managing their health and healthcare; and (3) how well the healthcare system is making the accommodations patients feel they need. The other measures focus on the outcomes that interventions may hope to achieve: (4) improved patient-provider communication; (5) reduced barriers to care; and (6) reduced unmet healthcare needs. We then tested these measures in a survey of 244 autistic adults recruited from 12 primary care clinics in Oregon and California, USA (with 194 participating directly and 50 participating via a proxy reporter). Community partners made sure items were easy to understand and captured what was important about the underlying idea. We found the survey measures worked well in this sample. These measures may help researchers evaluate new healthcare interventions. Future research needs to assess whether interventions improve healthcare outcomes in autistic adults.

Authors: Nicolaidis, Christina; Zhen, Kelly Y; Lee, Junghee; Raymaker, Dora M; Kapp, Steven K; Croen, Lisa A; Urbanowicz, Anna; Maslak, Joelle; Scharer, Mirah

Autism. 2021 04;25(3):786-799. Epub 2020-10-25.

PubMed abstract

Healthcare service utilization and cost among transition-age youth with autism spectrum disorder and other special healthcare needs

Youth with autism spectrum disorder often have complex medical needs. Disruptions of healthcare during the transition from pediatric to adult healthcare may put youth with autism spectrum disorder at higher risk of medical emergencies and high medical costs. To understand healthcare utilization during the transition years, we conducted a study among transition-age youth (14-25 years old) receiving healthcare at Kaiser Permanente Northern California during 2014-2015. We examined differences in healthcare utilization and costs among youth with autism spectrum disorder (n = 4123), attention deficit and hyperactivity disorder (n = 20,6015), diabetes mellitus (n = 2156), and general population controls (n = 20,615). Analyses were also stratified by age and sex. Youth with autism spectrum disorder had the highest utilization of outpatient primary care, mental health, and psychotropic medications and the lowest utilization of obstetrics/gynecology and urgent care. Costs for youth with autism spectrum disorder were higher than those for attention deficit and hyperactivity disorder and general population peers and lower than for diabetes mellitus. Healthcare utilization patterns varied by age. Transition-age youth with autism spectrum disorder generally used healthcare at higher rates relative to attention deficit and hyperactivity disorder and general population peers but at similar or lower rates than diabetes mellitus peers, indicating this group’s complex combination of psychiatric and medical healthcare needs. The relatively high utilization of psychiatric services and low utilization of women’s health services in transition-age youth with autism spectrum disorder may have implications for long-term health and warrants additional research.

Authors: Ames JL; Massolo ML; Davignon MN; Qian Y; Croen LA

Autism. 2021 04;25(3):705-718. Epub 2020-06-25.

PubMed abstract

Transitioning youth with autism spectrum disorders and other special health care needs into adult primary care: A provider survey

The transition from pediatric to adult care is a critical inflection point for the long-term health of youth with autism spectrum disorders and other special health care needs. However, for many patients, their caregivers, and providers, the transition lacks coordination. This survey study demonstrates that pediatric and adult providers struggle to implement many components of transition best practices for youth with autism and other chronic conditions, highlighting the urgent need for enhanced medical coordination and additional transition training and resources.

Authors: Ames JL; Massolo ML; Davignon MN; Qian Y; Cerros HJ; Croen LA

Autism. 2021 04;25(3):731-743. Epub 2020-06-18.

PubMed abstract

Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study

Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring. This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period). The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11]. Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Authors: Kodesh, Arad; Croen, Lisa; Janecka, Magdalena; et al.

Psychol Med. 2021 Mar 26:1-9.

PubMed abstract

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California

The Early Markers for Autism (EMA) study is a population-based case-control study designed to learn more about early biologic processes involved in ASD. Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Authors: Lyall, Kristen; Ames, Jennifer L; Croen, Lisa A; et al.

Mol Autism. 2021 03 18;12(1):24. Epub 2021-03-18.

PubMed abstract

mHealth Mindfulness Intervention for Women with Moderate-to-Moderately-Severe Antenatal Depressive Symptoms: a Pilot Study Within an Integrated Health Care System

Traditional mindfulness-based interventions have been shown to reduce depression symptoms in pregnant women, although in-person classes may pose significant accessibility barriers, particularly during the COVID-19 pandemic. Mobile technology offers greater convenience, but little is known regarding the efficacy of self-paced, mobile-delivered (mHealth) mindfulness interventions in this population. This study tested the feasibility and acceptability of offering such an intervention for pregnant women with moderate-to-moderately-severe depression symptoms. We conducted a single-arm trial within Kaiser Permanente Northern California (KPNC). Participants were identified through KPNC’s universal perinatal depression screening program. Eligible participants included English-speaking pregnant women (<28 weeks of gestation) with moderate-to-moderately-severe depressive symptoms without a regular (<3 times/week) mindfulness/meditation practice. Participants were asked to follow a self-paced, 6-week mindfulness meditation program using a mobile app, Headspace™, 10-20 min/day. Outcome measures included feasibility, acceptability, and patient-reported outcomes (e.g., depression symptoms). Of the 27 women enrolled, 20 (74%) completed the study. Over half (55%) of participants used the app ≥50% of the days during the 6-week intervention. Responses to the semi-structured interviews indicated that women appreciated the convenience of the intervention and the ability to engage without having to attend classes or arrange childcare. We observed significant improvements in pre-postintervention scores for depression symptoms, perceived stress, sleep disturbance, and mindfulness. Our study demonstrates the feasibility and acceptability of an mHealth mindfulness intervention for women with moderate-to-moderately-severe antenatal depression symptoms. The preliminary data further suggest that an efficacy trial is warranted.

Authors: Kubo, Ai; Aghaee, Sara; Kurtovich, Elaine M; Nkemere, Linda; Quesenberry, Charles P; McGinnis, MegAnn K; Avalos, Lyndsay A

Mindfulness (N Y). 2021 Mar 11:1-11.

PubMed abstract

Editorial Expression of Concern: Exposure to Magnetic Field Non-Ionizing Radiation and the Risk of Miscarriage: A Prospective Cohort Study

Authors: Li DK; Chen H; Ferber JR; Odouli R; Quesenberry C

Sci Rep. 2021 03 10;11(1):6021. Epub 2021-03-10.

PubMed abstract

Association of Cannabis Retailer Proximity and Density With Cannabis Use Among Pregnant Women in Northern California After Legalization of Cannabis for Recreational Use

Authors: Young-Wolff, Kelly C; Adams, Sara R; Padon, Alisa; Silver, Lynn D; Alexeeff, Stacey E; Van Den Eeden, Stephen K; Avalos, Lyndsay A

JAMA Netw Open. 2021 03 01;4(3):e210694. Epub 2021-03-01.

PubMed abstract

Plasma lipidomics profile in pregnancy and gestational diabetes risk: a prospective study in a multiracial/ethnic cohort

Disruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms. This study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10-14 weeks) and visit 1 (15-26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson’s partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits. Lipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR) <0.05). Among individual lipids, 58 metabolites at visit 0 and 96 metabolites at visit 1 (40 metabolites at both time points) significantly differed between women who developed GDM and who did not (FDR <0.05). Furthermore, GDM-related lipid networks and individual lipids showed consistent correlations with maternal glycemic markers particularly in early pregnancy at visit 0. Plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk in race/ethnically diverse US women. Future research is warranted to assess lipid metabolites as etiologic markers of GDM.

Authors: Rahman, Mohammad L; Feng, Yen-Chen A; Fiehn, Oliver; Albert, Paul S; Tsai, Michael Y; Zhu, Yeyi; Wang, Xiaobin; Tekola-Ayele, Fasil; Liang, Liming; Zhang, Cuilin

BMJ Open Diabetes Res Care. 2021 03;9(1).

PubMed abstract

Gestational weight gain and adverse pregnancy outcomes by pre-pregnancy BMI category in women with chronic hypertension: A cohort study

It is important to understand relationships of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension, given their high baseline risk of adverse outcomes. We assessed associations of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension by pre-pregnancy body mass index categories. We identified 14,369 women with chronic hypertension using electronic health records from 3 integrated health care delivery systems (2005-2014). Gestational weight gain-for-gestational age charts were used to calculate gestational weight gain z-scores, which account for gestational age. Modified Poisson regression models using generalized estimating equations were used to calculate relative risks and 95% confidence intervals, adjusted for sociodemographic and medical characteristics. Preeclampsia, preterm delivery, cesarean delivery, neonatal intensive care unit admission, birthweight (extracted from the electronic health record). In women with normal weight or overweight, low gestational weight gain (z-score < -1) was associated with 27-28% greater risk of preterm delivery and 48-82% greater risk of small-for-gestational age birthweight, while high gestational weight gain (z-score > 1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of large-for-gestational age birthweight. In women with obesity, low gestational weight gain was associated with 27-54% lower risk of several adverse pregnancy outcomes, including preeclampsia and cesarean delivery. In women with chronic hypertension and normal weight or overweight, moderate gestational weight gain may confer the lowest risk of adverse outcomes. In women with chronic hypertension and obesity, low gestational weight gain may be necessary for the lowest risk of adverse pregnancy outcomes.

Authors: Badon, Sylvia E; Dublin, Sascha; Nance, Nerissa; Hedderson, Monique M; Neugebauer, Romain; Easterling, Thomas; Cheetham, T Craig; Chen, Lu; Holt, Victoria L; Avalos, Lyndsay A

Pregnancy Hypertens. 2021 Mar;23:27-33. Epub 2020-10-24.

PubMed abstract

Reinventing Pediatrics Through Video Care First

Authors: Lieu, Tracy A; Gizzi, Elio; Lee, Edward R

JAMA Pediatr. 2021 03 01;175(3):232-234.

PubMed abstract

Persistent organic pollutants and couple fecundability: a systematic review

Despite increasing regulation, exposure to persistent organic pollutants (POPs) remains a serious public health concern due to their accumulation in the environment and ability to biomagnify up the food chain. POPs are associated with endocrine-disrupting effects including adverse reproductive outcomes that could affect fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). Results of epidemiologic studies that examine the impact of various chemical classes of POPs on TTP have not been synthesised. We undertook a systematic review to summarise the strength of evidence for associations of four common groups of POPs with couple fecundability and to identify gaps and limitations in the literature in order to inform policy decisions and future research. We performed an electronic search of literature published between 1 January 2007 and 6 August 2019 in MEDLINE,, Global Health, DART/TOXLINE and POPLINE. We included empirical research papers that examined human exposure to organochlorine (OC) pesticides, brominated flame retardants, polychlorinated organic compounds and/or per- and polyfluoroalkyl substances (PFAS) and considered TTP or fecundability as an outcome. Standardised forms for screening, data extraction and study quality were developed using DistillerSR software, and all reviews were completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. The search returned 4573 articles, and 28 papers from 19 different studies met inclusion criteria. Among them, four studies measured TTP prospectively, three had data on participants’ prenatal exposure, three examined associations in both male and female partners and one focused exclusively on males. Analyses varied widely in terms of exposure characterisation, precluding a meta-analytic approach. Evidence was strongest for adverse associations of female exposure to polychlorinated biphenyls with TTP, with some additional support for associations of female exposure to polybrominated diphenyl ethers and PFAS with longer TTP. Our review provided little or no support for associations between female exposure to OC pesticides or male exposure to any of the POP groups and TTP. Evidence suggests that female exposure to at least some POPs may reduce fecundability. Although many of these chemicals are no longer in production, they are still detectable in human biosamples because of their persistence in the environment. Replacement chemicals that are being introduced as older ones are restricted may have similar reproductive consequences. Future studies should examine these newer POPs, assess interactions between POPs and other chemical and non-chemical exposures, investigate how POPs are distributed in and metabolised by the human body and focus on populations that may be disproportionately exposed.

Authors: Kahn, Linda G; Harley, Kim G; Siegel, Eva L; Zhu, Yeyi; Factor-Litvak, Pam; Porucznik, Christina A; Klein-Fedyshin, Michele; Hipwell, Alison E; program collaborators for Environmental Influences on Child Health Outcomes Program,

Hum Reprod Update. 2021 02 19;27(2):339-366.

PubMed abstract

Prenatal Exposure to Mixtures of Phthalates, Parabens, and Other Phenols and Obesity in Five-Year-Olds in the CHAMACOS Cohort

Exposures to phthalates, parabens, and other phenols are often correlated due to their ubiquitous use in personal care products and plastics. Examining these compounds as a complex mixture may clarify inconsistent relationships between individual chemicals and childhood adiposity. Using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal cohort of children in Salinas Valley, California (n = 309), we examined biomarkers of 11 phthalate metabolites and 9 phenols, including several parabens and bisphenol A, measured in maternal urine at two time points during pregnancy. We measured child height and weight at age five to calculate the body mass index (BMI) z-scores and overweight/obesity status. The association between prenatal urinary concentrations of biomarkers with the childhood BMI z-score and overweight/obesity status was analyzed using single-pollutant models and two mixture methods: Bayesian hierarchical modeling (BMH) and Bayesian kernel machine regression (BKMR). Urinary concentrations of monoethyl phthalate, monocarboxy-isononly phthalate (metabolites of diethyl phthalate and di-isodecyl phthalate, respectively), and propylparaben were consistently associated with an increased BMI z-score and overweight/obesity status across all modeling approaches. Higher prenatal exposures to the cumulative biomarker mixture also trended with greater childhood adiposity. These results, robust across two methods that control for co-pollutant confounding, suggest that prenatal exposure to certain phthalates and parabens may increase the risk for obesity in early childhood.

Authors: Berger, Kimberly; Hyland, Carly; Ames, Jennifer L; Mora, Ana M; Huen, Karen; Eskenazi, Brenda; Holland, Nina; Harley, Kim G

Int J Environ Res Public Health. 2021 02 12;18(4). Epub 2021-02-12.

PubMed abstract

Bayesian Weighted Sums: A Flexible Approach to Estimate Summed Mixture Effects

Methods exist to study exposure mixtures, but each is distinct in the research question it aims to address. We propose a new approach focused on estimating both the summed effect and individual weights of one or multiple exposure mixtures: Bayesian Weighted Sums (BWS). We applied BWS to simulated and real datasets with correlated exposures. The analytic context in our real-world example is an estimation of the association between polybrominated diphenyl ether (PBDE) congeners (28, 47, 99, 100, and 153) and Autism Spectrum Disorder (ASD) diagnosis and Social Responsiveness Scores (SRS). Simulations demonstrate that BWS performs reliably. In adjusted models using Early Autism Risk Longitudinal Investigation (EARLI) data, the odds of ASD for a 1-unit increase in the weighted sum of PBDEs were 1.41 (95% highest posterior density 0.82, 2.50) times the odds of ASD for the unexposed and the change in z-score standardized SRS per 1 unit increase in the weighted sum of PBDEs is 0.15 (95% highest posterior density -0.08, 0.38). BWS provides a means of estimating the summed effect and weights for individual components of a mixture. This approach is distinct from other exposure mixture tools. BWS may be more flexible than existing approaches and can be specified to allow multiple exposure groups based on a priori knowledge from epidemiology or toxicology.

Authors: Hamra, Ghassan B; Maclehose, Richard F; Croen, Lisa; Kauffman, Elizabeth M; Newschaffer, Craig

Int J Environ Res Public Health. 2021 02 03;18(4). Epub 2021-02-03.

PubMed abstract

Longitudinal Associations of Midlife Accelerometer Determined Sedentary Behavior and Physical Activity With Cognitive Function: The CARDIA Study

Background To determine if accelerometer measured sedentary behavior (SED), light-intensity physical activity (LPA), and moderate-to-vigorous-intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function. Methods and Results Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38-50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01-0.14), SD 0.09 (95% CI, 0.02-0.17), and SD -0.11 (95% CI, -0.19 to -0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD -0.05 (95% CI, -0.06 to -0.03), SD -0.03 (95% CI, -0.05 to -0.01), and SD 0.05 (95% CI, 0.03- 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women. Conclusions Our findings support the idea that for men, higher-intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.

Authors: Whitaker, Kara M; Zhang, Dong; Pettee Gabriel, Kelley; Ahrens, Monica; Sternfeld, Barbara; Sidney, Stephen; Jacobs, David R; Palta, Priya; Yaffe, Kristine

J Am Heart Assoc. 2021 02 02;10(3):e018350. Epub 2021-01-20.

PubMed abstract

Notice of Retraction and Replacement. Li et al. Association Between Maternal Exposure to Magnetic Field Nonionizing Radiation During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring in a Longitudinal Birth Cohort. JAMA Netw Open. 2020;3(3):e201417

Authors: Li DK

JAMA Netw Open. 2021 Feb 01;4(2):e2033605. Epub 2021-02-01.

PubMed abstract

Exercise During the First Trimester of Pregnancy and the Risks of Abnormal Screening and Gestational Diabetes Mellitus

To estimate the effects of exercise during the first trimester on the risks of abnormal screening and gestational diabetes mellitus (GDM). Data come from PETALS, a prospectively followed pregnancy cohort (n = 2,246, 79% minorities) receiving care at Kaiser Permanente Northern California. A Pregnancy Physical Activity Questionnaire was used to assess exercise. Glucose testing results for screening and diagnostic tests were obtained from electronic health records. Inverse probability of treatment weighting and targeted maximum likelihood with data-adaptive estimation (machine learning) of propensity scores and outcome regressions were used to obtain causal risk differences adjusted for potential confounders, including prepregnancy BMI, exercise before pregnancy, and gestational weight gain. Exercise was dichotomized at 1) the cohort’s 75th percentile for moderate- to vigorous-intensity exercise (≥13.2 MET-h per week or ≥264 min per week of moderate exercise), 2) current recommendations (≥7.5 MET-h per week or ≥150 min per week of moderate exercise), and 3) any vigorous exercise. Overall, 24.3% and 6.5% had abnormal screening and GDM, respectively. Exercise meeting or exceeding the 75th percentile decreased the risks of abnormal screening and GDM by 4.8 (95% CI 1.1, 8.5) and 2.1 (0.2, 4.1) fewer cases per 100, respectively, in adjusted analyses. Exercise reduces the risks of abnormal screening and GDM, but the amount needed to achieve these risk reductions is likely higher than current recommendations. Future interventions may consider promoting ≥38 min per day of moderate-intensity exercise to prevent GDM.

Authors: Ehrlich, Samantha F; Ferrara, Assiamira; Hedderson, Monique M; Feng, Juanran; Neugebauer, Romain

Diabetes Care. 2021 02;44(2):425-432. Epub 2020-12-21.

PubMed abstract

The Association Between Maternal Prenatal Fish Intake and Child Autism-Related Traits in the EARLI and HOME Studies

We examined the association between prenatal fish intake and child autism-related traits according to Social Responsiveness Scale (SRS) and cognitive development scores in two US prospective pregnancy cohorts. In adjusted linear regression analyses, higher maternal fish intake in the second half of pregnancy was associated with increased child autism traits (higher raw SRS scores; ß = 5.60, 95%CI 1.76, 12.97). Differences by fish type were suggested; shellfish and large fish species were associated with increases, and salmon with decreases, in child SRS scores. Clear patterns with cognitive scores in the two cohorts were not observed. Future work should further evaluate potential critical windows of prenatal fish intake, and the role of different fish types in association with child autism-related outcomes.

Authors: Vecchione R; Croen LA; Lyall K; et al.

J Autism Dev Disord. 2021 Feb;51(2):487-500.

PubMed abstract

Gestational Exposure to Phthalates and Social Responsiveness Scores in Children Using Quantile Regression: The EARLI and HOME Studies

Linear regression is often used to estimate associations between chemical exposures and neurodevelopment at the mean of the outcome. However, the potential effect of chemicals may be greater among individuals at the ‘tails’ of outcome distributions. Here, we investigated distributional effects on the associations between gestational phthalate exposure and child Autism Spectrum Disorder (ASD)-related behaviors using quantile regression. We harmonized data from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 140) Study, an enriched-risk cohort of mothers who had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study (n = 276), a general population cohort. We measured concentrations of 9 phthalate metabolites in urine samples collected twice during pregnancy. Caregivers reported children’s ASD-related behaviors using the Social Responsiveness Scale (SRS) at age 3-8 years; higher scores indicate more ASD-related behaviors. In EARLI, associations between phthalate concentrations and SRS scores were predominately inverse or null across SRS score quantiles. In HOME, positive associations of mono-n-butyl phthalate, monobenzyl phthalate, mono-isobutyl phthalate, and di-2-ethylhexyl phthalate concentrations with SRS scores increased in strength from the median to 95th percentile of SRS scores. These results suggest associations between phthalate concentrations and SRS scores may be stronger in individuals with higher SRS scores.

Authors: Patti, Marisa A; Croen, Lisa A; Braun, Joseph M; et al.

Int J Environ Res Public Health. 2021 01 30;18(3). Epub 2021-01-30.

PubMed abstract

Associations of diet, physical activity and polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults Women’s Study

Current evidence supports the adoption of healthy diet and physical activity (PA) behaviors in patients with polycystic ovary syndrome (PCOS), given the positive effects of those behaviors on physical well-being. An improved understanding of the associations between diet and PA with PCOS is needed to ascertain whether tailored dietary and PA recommendations are needed for this population. Thus, we investigated the associations of diet and PA with PCOS and its isolated features. Cross-sectional study. Of the 748 women who were included in this study from the Coronary Artery Risk Development in Young Adults (CARDIA) Women’s Study, 40 were classified as having PCOS, 104 had isolated hyperandrogenism (HA) and 75 had isolated oligomenorrhea (OA). Dietary intake was measured using the CARDIA diet history questionnaire and diet quality was scored using the Alternative Healthy Eating Index 2010; a higher score indicated a better quality diet. Self-reported PA was measured using a validated interviewer-administered questionnaire. Polytomous logistic regression analyses examined the associations between diet and PA with PCOS, HA, and OA status (outcomes), adjusting for age, race, total energy intake, education, and/or body mass index. The threshold for statistical significance was set at p < 0.05. Mean age of the participants was 25.4 years (SD 3.6) and 46.8% of participants were Black women. There was little to no association of total energy intake, nutrients, diet quality, and PA with PCOS, HA or OA status. Energy intake, nutrient composition, diet quality, and PA were not associated with PCOS, supporting recent PCOS guidelines of using national recommendations for the general population to encourage health-promoting behaviors among women with PCOS. However, longitudinal studies evaluating changes in diet and physical activity in relation to the development and/or the progression of PCOS are needed to establish a causal association.

Authors: Lin, Annie W; Sternfeld, Barbara; Lujan, Marla E; et al.

BMC Public Health. 2021 01 06;21(1):35. Epub 2021-01-06.

PubMed abstract

Evaluation of Attention Switching and Duration of Electronic Inbox Work Among Primary Care Physicians

Primary care physicians (PCPs) report multitasking during workdays while processing electronic inbox messages, but scant systematic information exists on attention switching and its correlates in the health care setting. To describe PCPs’ frequency of attention switching associated with electronic inbox work, identify potentially modifiable factors associated with attention switching and inbox work duration, and compare the relative association of attention switching and other factors with inbox work duration. This cross-sectional study of the work of 1275 PCPs in an integrated group serving 4.5 million patients used electronic health record (EHR) access logs from March 1 to 31, 2018, to evaluate PCPs’ frequency of attention switching. Statistical analysis was performed from October 15, 2018, to August 28, 2020. Attention switching was defined as switching between the electronic inbox, other EHR work, and non-EHR periods. Inbox work duration included minutes spent on electronic inbox message views and related EHR tasks. Multivariable models controlled for the exposures. The 1275 PCPs studied (721 women [56.5%]; mean [SD] age, 45.9 [8.5] years) had a mean (SD) of 9.0 (7.6) years of experience with the medical group and received a mean (SD) of 332.6 (148.3) (interquartile range, 252-418) new inbox messages weekly. On workdays, PCPs made a mean (SD) of 79.4 (21.8) attention switches associated with inbox work and did a mean (SD) 64.2 (18.7) minutes of inbox work over the course of 24 hours on workdays. In the model for attention switching, each additional patient secure message beyond the reference value was associated with 0.289 (95% CI, 0.217-0.362) additional switches, each additional results message was associated with 0.203 (95% CI, 0.127-0.278) additional switches, each additional request message was associated with 0.190 (95% CI, 0.124-0.257) additional switches, and each additional administrative message was associated with 0.262 (95% CI, 0.166-0.358) additional switches. Having a panel (a list of patients assigned to a primary care team) with more elderly patients (0.144 switches per percentage increase [95% CI, 0.009-0.278]) and higher inbox work duration (0.468 switches per additional minute of inbox work [95% CI, 0.411-0.524]) were also associated with higher attention switching involving the inbox. In the model for inbox work duration, each additional patient secure message beyond the reference value was associated with 0.151 (95% CI, 0.085-0.217) additional minutes, each additional results message was associated with 0.338 (95% CI, 0.272-0.404) additional minutes, each additional request message was associated with 0.101 (95% CI, 0.041-0.161) additional minutes, and each additional administrative message was associated with 0.179 (95% CI, 0.093-0.265) additional minutes. A higher percentage of the panel’s patients initiating messages (0.386 minutes per percentage increase [95% CI, 0.026-0.745]) and attention switches (0.373 minutes per switch [95% CI, 0.328-0.419]) were also associated with higher inbox work duration. In addition, working at a medical center where all PCPs had high inbox work duration was independently associated with high or low inbox work duration. This study suggests that PCPs make frequent attention switches during workdays while processing electronic inbox messages. Message quantity was associated with both attention switching and inbox work duration. Physician and patient panel characteristics had less association with attention switching and inbox work duration. Assisting PCPs with message quantity might help modulate both attention switching and inbox work duration.

Authors: Lieu, Tracy A; Warton, E Margaret; East, Jeffrey A; Moeller, Mark F; Prausnitz, Stephanie; Ballesca, Manuel; Mark, Gloria; Akbar, Fatema; Awsare, Sameer; Chen, Yi-Fen Irene; Reed, Mary E

JAMA Netw Open. 2021 01 04;4(1):e2031856. Epub 2021-01-04.

PubMed abstract

Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci. Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes. Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database. Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10-29, maternal blood early pregnancy P = 6.1 × 10-27, maternal blood late pregnancy P = 2.8 × 10-16, maternal placenta P = 5.6 × 10-15, fetal placenta P = 1.3 × 10-20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes. Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

Authors: Bakulski, Kelly M; Croen, Lisa A; Fallin, Margaret D; et al.

Front Mol Neurosci. 2021;14:775390. Epub 2021-11-25.

PubMed abstract

Development and Validation of an Obstetric Comorbidity Risk Score for Clinical Use

Background: A comorbidity summary score may support early and systematic identification of women at high risk for adverse obstetric outcomes. The objective of this study was to conduct the initial development and validation of an obstetrics comorbidity risk score for automated implementation in the electronic health record (EHR) for clinical use. Methods: The score was developed and validated using EHR data for a retrospective cohort of pregnancies with delivery between 2010 and 2018 at Kaiser Permanente Northern California, an integrated health care system. The outcome used for model development consisted of adverse obstetric events from delivery hospitalization (e.g., eclampsia, hemorrhage, death). Candidate predictors included maternal age, parity, multiple gestation, and any maternal diagnoses assigned in health care encounters in the 12 months before admission for delivery. We used penalized regression for variable selection, logistic regression to fit the model, and internal validation for model evaluation. We also evaluated prenatal model performance at 18 weeks of pregnancy. Results: The development cohort (n = 227,405 pregnancies) had an outcome rate of 3.8% and the validation cohort (n = 41,683) had an outcome rate of 2.9%. Of 276 candidate predictors, 37 were included in the final model. The final model had a validation c-statistic of 0.72 (95% confidence interval [CI] 0.70-0.73). When evaluated at 18 weeks of pregnancy, discrimination was modestly diminished (c-statistic 0.68 [95% CI 0.67-0.70]). Conclusions: The obstetric comorbidity score demonstrated good discrimination for adverse obstetric outcomes. After additional appropriate validation, the score can be automated in the EHR to support early identification of high-risk women and assist efforts to ensure risk-appropriate maternal care.

Authors: Ruppel, Halley; Liu, Vincent X; Kipnis, Patricia; Hedderson, Monique M; Greenberg, Mara; Forquer, Heather; Lawson, Brian; Escobar, Gabriel J

Womens Health Rep (New Rochelle). 2021;2(1):507-515. Epub 2021-11-02.

PubMed abstract

COVID-19 prevalence, symptoms, and sociodemographic disparities in infection among insured pregnant women in Northern California

Research on COVID-19 during pregnancy has mainly focused on women hospitalized for COVID-19 or other reasons during their pregnancy. Little is known about COVID-19 in the general population of pregnant women. To describe the prevalence of COVID-19, symptoms, consequent healthcare use, and possible sources of COVID-19 exposure among a population-based sample of pregnant women residing in Northern California. We analyzed data from 19,458 members of Kaiser Permanente Northern California who were pregnant between January 2020 and April 2021 and responded to an online survey about COVID-19 testing, diagnosis, symptoms, and their experiences during the COVID-19 pandemic. Medical diagnosis of COVID-19 during pregnancy was defined separately by self-report and by documentation in electronic health records (EHR). We examined relationships of COVID-19 with sociodemographic factors, underlying comorbidities, and survey measures of COVID-19-like symptoms, consequent healthcare utilization, and possible COVID-19 exposures. Among 19,458 respondents, the crude prevalence of COVID-19 was 2.5% (n = 494) according to self-report and 1.4% (n = 276) according to EHR. After adjustment, the prevalence of self-reported COVID-19 was higher among women aged <25 years compared with women aged ≥35 years (prevalence ratio [PR], 1.75, 95% CI: 1.23, 2.49) and among Hispanic women compared with White women (PR, 1.91, 95% CI: 1.53, 2.37). Prevalence of self-reported COVID-19 was higher among women affected by personal or partner job loss during the pandemic (PR, 1.23, 95% CI: 1.02, 1.47) and among women living in areas of high vs. low neighborhood deprivation (PR, 1.74, 95% CI: 1.33, 2.27). We did not observe differences in self-reported COVID-19 between women with and without underlying comorbidities. Results were similar for EHR-documented COVID-19. Loss of smell or taste was a unique and common symptom reported among women with COVID-19 (42.3% in self-reported; 54.0% in EHR-documented). Among women with symptomatic COVID-19, approximately 2% were hospitalized, 71% had a telehealth visit, and 75% quarantined at home. Over a third of women with COVID-19 reported no known exposure to someone with COVID-19. Observed COVID-19 prevalence differences by sociodemographic and socioeconomic factors underscore social and health inequities among reproductive-aged women. Women with COVID-19 reported unique symptoms and low frequency of hospitalization. Many were not aware of an exposure to someone with COVID-19.

Authors: Ames, Jennifer L; Ferrara, Assiamira; Avalos, Lyndsay A; Badon, Sylvia E; Greenberg, Mara B; Hedderson, Monique M; Kuzniewicz, Michael W; Young-Wolff, Kelly C; Zerbo, Ousseny; Zhu, Yeyi; Croen, Lisa A; et al.

PLoS One. 2021;16(9):e0256891. Epub 2021-09-03.

PubMed abstract

Racial and geographic variation in effects of maternal education and neighborhood-level measures of socioeconomic status on gestational age at birth: Findings from the ECHO cohorts

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate’s degree, vocational or technical training [reference category]; bachelor’s degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor’s degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor’s degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Authors: Dunlop, Anne L; Alvalos, Lyndsay; Hedderson, Monique M; program collaborators for Environmental Influences on Child Health Outcomes,; et al.

PLoS One. 2021;16(1):e0245064. Epub 2021-01-08.

PubMed abstract

Association between self-reported caffeine intake during pregnancy and social responsiveness scores in childhood: The EARLI and HOME studies

Maternal nutrition during gestation has been investigated for its role in child neurodevelopment. However, little is known about the potential impact of gestational caffeine exposure on child autistic behaviors. Here, we assess the relation between maternal caffeine intake during pregnancy and children’s behavioral traits related to Autism Spectrum Disorder (ASD). We harmonized data from two pregnancy cohorts, Early Autism Risk Longitudinal Investigation (EARLI) (n = 120), an enriched-risk cohort of mothers who previously had a child with ASD, from Pennsylvania, Maryland, and Northern California (2009-2012), and the Health Outcomes and Measures of the Environment (HOME) Study (n = 269), a general population cohort from Cincinnati, Ohio (2003-2006). Mothers self-reported caffeine intake twice during pregnancy. Caregivers reported child behavioral traits related to ASD using the Social Responsiveness Scale (SRS) when children were aged 3-8 years. Higher scores indicate more ASD-related behaviors. We estimated covariate-adjusted differences in continuous SRS T-scores per interquartile range increase in caffeine intake. Self-reported caffeine intake during pregnancy was positively associated with SRS T-scores among children in EARLI (β: 2.0; 95% CI -0.1, 4.0), but to a lesser extent in HOME (β: 0.6; 95% CI -0.5, 1.6). In HOME, pre-pregnancy body mass index (BMI) modified the association between caffeine intake and SRS T-scores, where more positive associations were observed among women with higher BMIs. Our findings suggest gestational caffeine intake may represent a marker of vulnerability to childhood ASD-related behaviors. Additional studies are warranted to extend these findings.

Authors: Patti, Marisa A; Braun, Joseph M; Braun, Joseph M; et al.

PLoS One. 2021;16(1):e0245079. Epub 2021-01-15.

PubMed abstract

Incidence and predictors of type 1 diabetes among younger adults aged 20-45 years: The diabetes in young adults (DiYA) study

To estimate incidence of type 1 diabetes (T1D) and to develop a T1D prediction model among young adults. Adults 20-45 years newly-diagnosed with diabetes in 2017 were identified within Kaiser Permanente’s healthcare systems in California and invited for diabetes autoantibody (DAA) testing. Multiple imputation was conducted to assign missing DAA status. The primary outcome for incidence rates (IR) and the prediction model was T1D defined by ≥1 positive DAA. Among 2,347,989 persons at risk, 7862 developed diabetes, 2063 had DAA measured, and 166 (8.0%) had ≥1 positive DAA. T1D IR (95% CI) per 100,000 person-years was 15.2 (10.2-20.1) for ages 20-29 and 38.2 (28.6-47.8) for ages 30-44 years. The age-standardized IRs were 32.5 (22.2-42.8) for men and 27.2 (21.0-34.5) for women. The age/sex-standardized IRs were 30.1 (23.5-36.8) overall; 41.4 (25.3-57.5) for Hispanics, 37.0 (11.6-62.4) for Blacks, 21.4 (14.3-28.6) for non-Hispanic Whites, and 19.4 (8.5-30.2) for Asians. Predictors of T1D among cases included female sex, younger age, lower BMI, insulin use and having T1D based on diagnostic codes. T1D may account for up to 8% of incident diabetes cases among young adults. Follow-up is needed to establish the clinical course of patients with one DAA at diagnosis.

Authors: Lawrence, Jean M; Quesenberry, Charles; Ferrara, Assiamira; et al.

Diabetes Res Clin Pract. 2021 Jan;171:108624. Epub 2020-12-15.

PubMed abstract

Maternal immune response and air pollution exposure during pregnancy: insights from the Early Markers for Autism (EMA) study

Perinatal exposure to air pollution and immune system dysregulation are two factors consistently associated with autism spectrum disorders (ASD) and other neurodevelopmental outcomes. However, little is known about how air pollution may influence maternal immune function during pregnancy. To assess the relationship between mid-gestational circulating levels of maternal cytokines/chemokines and previous month air pollution exposure across neurodevelopmental groups, and to assess whether cytokines/chemokines mediate the relationship between air pollution exposures and risk of ASD and/or intellectual disability (ID) in the Early Markers for Autism (EMA) study. EMA is a population-based, nested case-control study which linked archived maternal serum samples collected during weeks 15-19 of gestation for routine prenatal screening, birth records, and Department of Developmental Services (DDS) records. Children receiving DDS services for ASD without intellectual disability (ASD without ID; n = 199), ASD with ID (ASD with ID; n = 180), ID without ASD (ID; n = 164), and children from the general population (GP; n = 414) with no DDS services were included in this analysis. Serum samples were quantified for 22 cytokines/chemokines using Luminex multiplex analysis technology. Air pollution exposure for the month prior to maternal serum collection was assigned based on the Environmental Protection Agency’s Air Quality System data using the maternal residential address reported during the prenatal screening visit. Previous month air pollution exposure and mid-gestational maternal cytokine and chemokine levels were significantly correlated, though weak in magnitude (ranging from - 0.16 to 0.13). Ten pairs of mid-pregnancy immune markers and previous month air pollutants were significantly associated within one of the child neurodevelopmental groups, adjusted for covariates (p < 0.001). Mid-pregnancy air pollution was not associated with any neurodevelopmental outcome. IL-6 remained associated with ASD with ID even after adjusting for air pollution exposure. This study suggests that maternal immune activation is associated with risk for neurodevelopmental disorders. Furthermore, that prenatal air pollution exposure is associated with small, but perhaps biologically relevant, effects on maternal immune system function during pregnancy. Additional studies are needed to better evaluate how prenatal exposure to air pollution affects the trajectory of maternal immune activation during pregnancy, if windows of heightened susceptibility can be identified, and how these factors influence neurodevelopment of the offspring.

Authors: Volk, Heather E; Alexeeff, Stacey E; Croen, Lisa A; et al.

J Neurodev Disord. 2020 12 16;12(1):42. Epub 2020-12-16.

PubMed abstract

Prenatal Multivitamin Use and MTHFR Genotype Are Associated with Newborn Cord Blood DNA Methylation

Fetal development involves cellular differentiation and epigenetic changes-complex processes that are sensitive to environmental factors. Maternal nutrient levels during pregnancy affect development, and methylene tetrahydrofolate reductase (MTHFR) is important for processing the nutrient folate. We hypothesize that supplement intake before pregnancy and maternal genotype are associated with DNA methylation in newborns. In the pregnancy cohort, Early Autism Risk Longitudinal Investigation (EARLI), health history, and genotype information was obtained (n = 249 families). Cord blood DNA methylation (n = 130) was measured using the Illumina HumanMethylation450k array and global DNA methylation levels were computed over 455,698 sites. Supplement use preconception and during pregnancy were surveyed at visits during pregnancy. We evaluated associations between maternal preconception supplement intake and global DNA methylation or DNA methylation density distributions of newborn cord blood, stratified by the presence of a variant maternal MTHFR C677T allele. Maternal preconceptional multivitamin intake was associated with cord blood methylation, dependent on maternal MTHFR genotype (interaction term p = 0.013). For mothers without the MTHFR variant allele, multivitamin intake was associated with 0.96% (95% CI: 0.09, 1.83) higher global cord blood methylation (p = 0.04) and was also associated with the cumulative density distribution of methylation (p = 0.03). For mothers with at least one variant allele, multivitamin intake had a null -0.06% (95% CI: -0.45, 0.33) association with global cord blood DNA methylation, and was not associated with the cumulative density distribution (p = 0.37). We observed that cord blood DNA methylation was associated with maternal supplement exposure preconception and maternal genotype. Genetic context should be considered when assessing DNA methylation effects of modifiable risk factors around the time of pregnancy.

Authors: Bakulski, Kelly M; Dou, John F; Feinberg, Jason I; Brieger, Katharine K; Croen, Lisa A; Hertz-Picciotto, Irva; Newschaffer, Craig J; Schmidt, Rebecca J; Fallin, M Daniele

Int J Environ Res Public Health. 2020 12 09;17(24). Epub 2020-12-09.

PubMed abstract

Rethinking ethical oversight in the era of the learning health system

Opportunities to advance science increasingly arise through investigations embedded within routine clinical practice in the form of learning health systems. Such activities challenge conventional approaches to research regulation that have not caught up with those opportunities, often imposing burdens generalized from riskier research. We analyze the rules and conventions in the US, demonstrating how even those rules are compatible with a much more flexible approach to participant risk, institutional oversight, participant consent, and disclosure for low-risk learning activities in all jurisdictions.

Authors: Asch, David A; Joffe, Steven; Bierer, Barbara E; Greene, Sarah M; Lieu, Tracy A; Platt, Jodyn E; Whicher, Danielle; Ahmed, Mahnoor; Platt, Richard

Healthc (Amst). 2020 Dec;8(4):100462. Epub 2020-08-25.

PubMed abstract

Maternal Vitamin D Levels During Pregnancy in Association With Autism Spectrum Disorders (ASD) or Intellectual Disability (ID) in Offspring; Exploring Non-linear Patterns and Demographic Sub-groups

Increasing vitamin D deficiency and evidence for vitamin D’s role in brain and immune function have recently led to studies of neurodevelopment; however, few are specific to autism spectrum disorder (ASD) and vitamin D in pregnancy, a likely susceptibility period. We examined this in a case-control study of 2000-2003 Southern Californian births; ASD and intellectual disability (ID) were identified through the Department of Developmental Services and controls from birth certificates (N = 534, 181, and 421, respectively, in this analysis). Total 25-Hydroxyvitamin D (25(OH)D) was measured in mid-pregnancy serum, categorized as deficient (<50 nmol/L), insufficient (50-74 nmol/L), or sufficient (≥75 nmol/L, referent category), and examined continuously (per 25 nmol/L). Crude and adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) were calculated. Non-linearity was examined with cubic splines. AORs (95% CI) for ASD were 0.79 (0.49-1.3) for maternal deficiency (9.5%), 0.93 (0.68-1.3) for insufficiency (25.6%), and 0.95 (0.86, 1.05) for linear continuous 25(OH)D. Results were similarly null for ASD with or without ID, and ID only. Interactions were observed; non-Hispanic whites (NHW) (AOR = 0.82, 95% CI = 0.69-0.98) and males (AOR = 0.89, 95% CI = 0.80-0.99) had protective associations for ASD with continuous 25(OH)D. A positive association with ASD was observed in females (AOR = 1.40, 95% CI = 1.06-1.85). With splines, a non-linear inverted j-shaped pattern was seen overall (P = 0.009 for non-linearity), with the peak around 100 nmol/L; a non-linear pattern was not observed among NHW, females, nor for ID. Our findings from a large study of ASD and prenatal vitamin D levels indicate that further research is needed to investigate non-linear patterns and potentially vulnerable sub-groups. LAY SUMMARY: We studied whether mothers' vitamin D levels during pregnancy were related to their children having autism (or low IQ) later. Low vitamin D levels were not related to greater risk of autism or low IQ in children overall. With higher levels of mothers' vitamin D, risk of autism went down in boys, but went up in girls. Risk of autism also went down in children of non-Hispanic white mothers with higher vitamin D levels, but we did not find a relation in other race/ethnic groups.

Authors: Windham, Gayle C; Pearl, Michelle; Poon, Victor; Berger, Kimberly; Soriano, Jasmine W; Eyles, Darryl; Lyall, Kristen; Kharrazi, Martin; Croen, Lisa A

Autism Res. 2020 12;13(12):2216-2229. Epub 2020-11-02.

PubMed abstract

Antibiotic stewardship for early-onset sepsis

Antibiotics are administered to the vast majority of preterm newborns and to a substantial proportion of term infants in the hours after birth due to risk for early-onset sepsis. The approaches taken to determine which newborns should be evaluated for early-onset sepsis, and what type and duration of antibiotics are administered, are important elements of neonatal antibiotic stewardship. The use of multivariate prediction models for sepsis risk assessment among infants born ≥35 weeks’ gestation can safely reduce the use of empiric antibiotic therapy. Approaches incorporating serial physical examination may also contribute to decreasing empiric antibiotic exposure among such infants. Among infants born <35 weeks' gestation, delivery characteristics can be used to identify preterm infants at low enough risk of early infection that empiric therapies are not required. Data informing the epidemiology, microbiology and antibiotic susceptibility patterns of early-onset sepsis pathogens can be used to optimize antibiotic choice for empiric and targeted antibiotic therapy to ensure that effective therapies are administered, while decreasing the risks associated with broad-spectrum antibiotic exposure. Optimal use of blood culture and time to positivity data can also contribute to decreasing the risks associated with prolonged antibiotic administration in the face of sterile cultures.

Authors: Kuzniewicz, Michael W; Puopolo, Karen M

Semin Perinatol. 2020 Dec;44(8):151325. Epub 2020-10-12.

PubMed abstract

Impact of nulliparity, hypertensive disorders of pregnancy, and gestational diabetes on vasomotor symptoms in midlife women

To determine whether women with a history of nulliparity, hypertensive disorders of pregnancy (HDP), or gestational diabetes mellitus (GDM) have a higher odds of reporting vasomotor symptoms (VMS) at midlife. A longitudinal analysis was performed with 2,249 women with pregnancy history data in the Study of Women’s Health Across the Nation. Women were classified as nulliparous, no HDP/GDM, or a history of HDP/GDM. VMS (hot flashes, night sweats) were assessed separately at baseline and at each follow-up visit. VMS was recorded as any versus none; 0 , 1-5 , 6+ days in past 2 weeks. Pregnancy history was examined in relation to each VMS (hot flashes, night sweats) using generalized estimating equations adjusting for age (time-varying), site, race/ethnicity, education, financial strain, smoking, and body mass index. Models excluded women with hysterectomy/bilateral oophorectomy and observations with hormone therapy use. Women in the HDP/GDM group (n = 208, 9%) were more likely to be Black, financially strained, and overweight. Compared to women with no HDP/GDM, women with HDP/GDM had greater odds of reporting any hot flashes (OR:1.27; 95% CI:1.05-1.53). Nulliparous women had lower odds of any hot flashes (OR:0.64; 95% CI:0.51-0.80) and night sweats (OR:0.73; 95% CI:0.58-0.93) in age-adjusted models. Similar patterns were observed for frequency of hot flashes and night sweats; associations were attenuated to nonsignificance after adjusting for covariates. History of HDP/GDM may be associated with more VMS and nulliparity with fewer VMS, but not independently of sociodemographic factors. Our findings underscore the importance of social and economic disparities in both reproductive outcomes and VMS. VIDEO SUMMARY::

Authors: Cortés, Yamnia I; Conant, Rhoda; Catov, Janet M; Matthews, Karen A; Crawford, Sybil L; Hedderson, Monique M; Thurston, Rebecca C

Menopause. 2020 12;27(12):1363-1370.

PubMed abstract

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort

Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS. Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium. This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

Authors: Terloyeva, Dina; Croen, Lisa A; Snyder, Nathaniel W; et al.

Mol Autism. 2020 11 23;11(1):93. Epub 2020-11-23.

PubMed abstract

Plasma Phospholipid n-3/n-6 Polyunsaturated Fatty Acids and Desaturase Activities in Relation to Moderate-to-Vigorous Physical Activity through Pregnancy: A Longitudinal Study within the NICHD Fetal Growth Studies

Maternal plasma phospholipid polyunsaturated fatty acids (PUFAs) play critical roles in maternal health and fetal development. Beyond dietary factors, maternal moderate-to-vigorous physical activity (MVPA) has been linked to multiple health benefits for both the mother and offspring, but studies investigating the influence of maternal MVPA on maternal PUFA profile are scarce. The objective of present study was to examine the time-specific and prospective associations of MVPA with plasma PUFA profile among pregnant women. This study included 321 participants from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort. Maternal plasma phospholipid PUFAs and MPVA were measured at four visits during pregnancy (10-14, 15-26, 23-31, and 33-39 gestational weeks (GW)). Associations of maternal MVPA with individual plasma PUFAs and desaturase activity were examined using generalized linear models. Maternal MVPA was associated inversely with plasma phospholipid linoleic acid, gamma-linolenic acid, and Δ6-desaturase in late pregnancy (23-31 or 33-39 GW), independent of maternal age, race, education, parity, pre-pregnancy body mass index, and dietary factors. Findings from this longitudinal study indicate that maternal habitual MVPA may play a role on PUFAs metabolism, particular by alerting plasma n-6 subclass and desaturase activity in late pregnancy. These associations are novel and merit confirmation in future studies.

Authors: Chen, Liwei; Zhu, Yeyi; Zhang, Cuilin; et al.

Nutrients. 2020 Nov 19;12(11). Epub 2020-11-19.

PubMed abstract

A Mobile Health Mindfulness Intervention for Women With Moderate to Moderately Severe Postpartum Depressive Symptoms: Feasibility Study

Approximately 20% of women suffer from postpartum depression (PPD). Due to barriers such as limited access to care, half of the women with PPD do not receive treatment. Therefore, it is critical to identify effective and scalable interventions. Traditional mindfulness programs have been effective in reducing depressive symptoms, however access remains a barrier. A self-paced mobile health (mHealth) mindfulness program may fit the lifestyle of busy mothers who are unable to attend in-person classes. However, little is known regarding the feasibility or efficacy of mHealth mindfulness interventions in postpartum women with depressive symptoms. This study aims to assess the feasibility, acceptability, and preliminary efficacy of an mHealth mindfulness intervention for postpartum women with moderate to moderately severe depressive symptoms. We conducted a single-arm feasibility trial of an mHealth mindfulness intervention within Kaiser Permanente Northern California (KPNC), a large integrated health care system. Participants were identified through clinician referral and electronic health records via KPNC’s universal perinatal depression screening program and recruited by the study team. Inclusion criteria included the following: English-speaking, up to 6 months postpartum with a Patient Health Questionnaire (PHQ-8) score of 10 to 19, and no regular mindfulness/meditation practice. Participants were asked to use a mindfulness app, Headspace, 10 to 20 min/day for 6 weeks. Baseline and postintervention surveys captured data on patient-reported outcomes (depression and stress symptoms, sleep quality, and mindfulness). Semistructured interviews captured acceptability. Retention and adherence were used to assess feasibility. Of the 115 women who were contacted and met the eligibility criteria or declined participation before eligibility assessment, 27 (23%) were enrolled. In addition, 70% (19/27) completed the study. The mean age of participants was 31 years (SD 5.2), 30% (8/27) were non-Hispanic White, and, on average, participants were 12.3 weeks postpartum (SD 5.7). Of the women who completed the study, 100% (19/19) used the Headspace app at least once, and nearly half (9/19, 47%) used the app on ≥50% of the days during the 6-week intervention period. Of the 16 participants who completed the postintervention interview, 69% (11/16) reported that they were very or extremely satisfied with the app. Interviews indicated that women appreciated the variety of meditations and felt that the program led to reduced anxiety and improved sleep. Significant improvements in pre- and postintervention scores were observed for depressive symptoms (PHQ-8: -3.8, P=.004), perceived stress (10-item Perceived Stress Scale: -6.0, P=.005), and sleep quality (Pittsburgh Sleep Quality Index: -2.1, P=.02, indicating less sleep disturbance). Improvements in mindfulness were also significant (Five Facet Mindfulness Questionnaire-Short Form: 10.9, P=.01). An mHealth mindfulness intervention for postpartum women with moderate to moderately severe depressive symptoms is feasible and acceptable. An efficacy trial is warranted.

Authors: Avalos, Lyndsay A; Aghaee, Sara; Kurtovich, Elaine; Quesenberry, Charles; Nkemere, Linda; McGinnis, MegAnn K; Kubo, Ai

JMIR Ment Health. 2020 Nov 12;7(11):e17405. Epub 2020-11-12.

PubMed abstract

Translating Research on Diabetes and Obesity in Pregnancy Into Prevention: The 2019 Norbert Freinkel Award Lecture

Epidemiological studies on the intergenerational transmission of hyperglycemia and obesity via in utero exposure have established the scientific foundation for the vicious cycle of diabetes and obesity. The findings compel us to address an urgent public health question: how do we break this vicious cycle and implement upstream prevention strategies that are feasible for patients and health care delivery systems? To address this question, it is necessary to work across a continuum of translational research from basic science, epidemiology, and efficacy trials to pragmatic trials, which, along with evaluations of health programs, may lead to implementation of positive changes in clinical care. Three strategies for translating research on diabetes and obesity in pregnancy into prevention are discussed: 1) identifying diagnostic criteria of gestational diabetes mellitus (GDM) practicable in clinical settings to implement treatment and prevention, 2) examining trends in the prevalence of diabetes in pregnancy and related complications across racial/ethnic groups to plan prevention efforts, and 3) developing and evaluating scalable upstream diabetes and obesity prevention interventions. Upstream preventive interventions aimed at breaking the vicious cycle are discussed. Areas of future research needed to break the vicious cycle are identified. Evaluating the effectiveness of programs for the management of pregnancy hyperglycemia is necessary to reduce complications. Understanding racial/ethnic differences in the pathophysiology of GDM and its complications will be important for risk stratification. Pragmatic trials in real-world clinical settings for upstream prevention are needed to break the vicious cycle at the population level. Finally, leveraging basic science with intergenerational studies will inform targeted interventions.

Authors: Ferrara, Assiamira

Diabetes Care. 2020 11;43(11):2635-2642.

PubMed abstract

Validity of diagnosis and procedure codes for identifying neural tube defects in infants

The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants’ medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

Authors: Cheetham, T Craig; Li, De-Kun; Boudreau, Denise M; et al.

Pharmacoepidemiol Drug Saf. 2020 11;29(11):1489-1493. Epub 2020-09-15.

PubMed abstract

Understanding Racial/Ethnic Disparities in Physical Performance in Mid-Life Women: Findings from SWAN (Study of Women’s Health Across the Nation)

Evaluate degree to which racial/ethnic differences in physical performance are mediated by sociodemographic, health, behavioral, and psychosocial factors. Physical performance was evaluated using a decile score derived from grip strength, timed 4 m walk, and timed repeat chair stand in 1,855 African American, Caucasian, Chinese, Hispanic, and Japanese women, mean age = 61.8 (SD = 2.7) in the Study of Women’s Health Across the Nation. Mediators included education, financial strain, comorbidities, pain, body mass index (BMI), physical activity, and perceived stress. Structural equation models provided estimates of the total difference in physical performance between Caucasians and each race/ethnic groups and differences due to direct effects of race/ethnicity and indirect effects through mediators. The mean decile score for Caucasian women was 16.9 (SD = 5.6), 1.8, 2.6, and 2.1 points higher than the model-estimated scores in African Americans, Hispanics and Chinese, respectively, and 1.3 points lower than the Japanese. Differences between Caucasians and the Chinese and Japanese were direct effects of race/ethnicity whereas in African Americans and Hispanics 75% or more of that disparity was through mediators, particularly education, financial strain, BMI, physical activity, and pain. Addressing issues of poverty, racial inequality, pain, and obesity could reduce some racial/ethnic disparity in functional limitations as women age.

Authors: Sternfeld B; Colvin A; Stewart A; Appelhans BM; Cauley JA; Dugan SA; El Khoudary SR; Greendale GA; Strotmeyer E; Karvonen-Gutierrez C

J Gerontol B Psychol Sci Soc Sci. 2020 10 16;75(9):1961-1971.

PubMed abstract

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

Authors: Mordaunt, Charles E; Newschaffer, Craig J; LaSalle, Janine M; et al.

Genome Med. 2020 10 14;12(1):88. Epub 2020-10-14.

PubMed abstract

Gestational weight gain, birthweight and early-childhood obesity: between- and within-family comparisons

Associations of excessive gestational weight gain (GWG) with greater birthweight and childhood obesity may be confounded by shared familial environment or genetics. Sibling comparisons can minimize variation in these confounders because siblings grow up in similar environments and share the same genetic predisposition for weight gain. We identified 96 289 women with live births in 2008-2014 at Kaiser Permanente Northern California. Fifteen percent of women (N = 14 417) had at least two births during the study period for sibling analyses. We assessed associations of GWG according to the Institute of Medicine (IOM) recommendations with birthweight and obesity at age 3 years, using conventional analyses comparing outcomes between mothers and sibling analyses comparing outcomes within mothers, which control for stable within-family unmeasured confounders such as familial environment and genetics. We used generalized estimating-equations and fixed-effects models. In conventional analyses, GWG above the IOM recommendations was associated with 88% greater odds of large-for-gestational age birthweight [95% confidence interval (CI): 1.80, 1.97] and 30% greater odds of obesity at 3 years old (95% CI: 1.24, 1.37) compared with GWG within the IOM recommendations. In sibling analyses, GWG above the IOM recommendations was also associated with greater odds of large-for-gestational age [odds ratio (OR): 1.36; 95% CI: 1.20, 1.54], but was not associated with obesity at 3 years old (OR = 0.98; 95% CI: 0.84, 1.15). GWG likely has a direct impact on birthweight; however, shared environmental and lifestyle factors within families may play a larger role in determining early-childhood weight status and obesity risk than GWG.

Authors: Badon, Sylvia E; Quesenberry, Charles P; Xu, Fei; Avalos, Lyndsay A; Hedderson, Monique M

Int J Epidemiol. 2020 10 01;49(5):1682-1690.

PubMed abstract

Feasibility of Measuring Preferences for Chemotherapy Among Early-Stage Breast Cancer Survivors Using a Direct Rank Ordering Multicriteria Decision Analysis Versus a Time Trade-Off

Chemotherapy is increasingly a preference-based choice among women diagnosed with early-stage breast cancer. Multicriteria decision analysis (MCDA) is a promising but underutilized method to facilitate shared decision making. We explored the feasibility of conducting an MCDA using direct rank ordering versus a time trade-off (TTO) to assess chemotherapy choice in a large population-based sample. We surveyed 904 early-stage breast cancer survivors who were within 5 years of diagnosis and reported to the Western Washington State Cancer System and Kaiser Permanente Northern California registries. Direct rank ordering of 11 criteria and TTO surveys were conducted from September 2015 to July 2016; clinical data were obtained from registries or medical records. Multivariable regressions estimated post hoc associations between the MCDA, TTO, and self-reported chemotherapy receipt, considering covariates. Survivors ranged in age from 25 to 74 years and 73.9% had stage I tumors. The response rate for the rank ordering was 81.0%; TTO score was 94.2%. A one-standard deviation increase in the difference between the chemotherapy and no chemotherapy MCDA scores was associated with a 75.1% (95% confidence interval 43.9-109.7%; p < 0.001) increase in the adjusted odds of having received chemotherapy; no association was found between the TTO score and chemotherapy receipt. A rank-order-based MCDA was feasible and was associated with chemotherapy choice. Future research should consider developing and testing this MCDA for use in clinical encounters. Additional research is required to develop a TTO-based model and test its properties against a pragmatic MCDA to inform future shared decision-making tools.

Authors: Panattoni L; Phelps CE; Lieu TA; Alexeeff S; O'Neill S; Mandelblatt JS; Ramsey SD

Patient. 2020 10;13(5):557-566.

PubMed abstract

Cesarean Delivery and the Risk of Allergic Rhinitis in Children

Cesarean delivery (C-section) may influence the infant microbiome and affect immune system development and subsequent risk for allergic rhinitis (AR). To investigate the association between C-section and AR at ages 6, 8, and 10 years. Data were collected prospectively through Kaiser Permanente Northern Californias (KPNC) integrated healthcare system. Children were eligible if they were born in a KPNC hospital and remained in the KPNC system for minimum 6 years (n = 117,768 age 6; n = 75,115 age 8; n = 40,332 age 10). Risk ratios (RR) for C-section and AR were estimated at each follow-up age and adjusted for important covariates, including intrapartum antibiotics, pre-pregnancy body mass index, maternal allergic morbidities, and breastfeeding. Subanalyses considered information on C-section indication, labor, and membrane rupture. After adjusting for confounders, we did not observe an association between C-section and AR at follow-up ages 6, 8, or 10 years (RR [CI]: 6 years, 0.98 [0.91, 1.04]; 8 years, 1.00 [0.95, 1.07]; 10 years, 1.03 [0.96, 1.10]). In stratified analyses, there was limited evidence that C-section increases the risk of AR in certain subgroups (eg, children of non-atopic mothers, second or higher birth order children), but most estimated risk ratios were consistent with no association. Estimated associations were unaffected by participant attrition, missing data, or intrapartum antibiotics. C-section delivery was not associated with AR at follow-up ages of 6, 8, or 10 years in a large contemporary US cohort.

Authors: Richards M; Ferber J; Li DK; Darrow LA

Ann Allergy Asthma Immunol. 2020 09;125(3):280-286.e5. Epub 2020-05-06.

PubMed abstract

Nut Consumption and Renal Function Among Women With a History of Gestational Diabetes

Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations between nut intake and renal function among women with previous gestational diabetes mellitus (GDM), a population with an increased risk for renal dysfunction. This study included 607 women with a history of GDM who participated in the Diabetes & Women’s Health Study (2012-2014) follow-up clinical examination in Denmark. At the clinic, biospecimens were collected, and habitual intake of nuts (9 types) in the past year was assessed using a food frequency questionnaire. A total of 330 women free of major chronic diseases were included in the analysis. Total nut intake was classified as none (≤1 serving/month), monthly (2-3 servings/month), weekly (1-6 servings/week), and daily (≥1 serving/day). One serving was defined as 28 g. Renal function markers included estimated glomerular rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), calculated based on plasma creatinine (mg/dL), and urinary albumin (mg/L), and creatinine (mg/dL) measurements, respectively. We estimated percent differences with 95% confidence intervals for each outcome by nut intake, adjusted for current body mass index, age, physical activity, energy intake, alcohol consumption, and vegetables intake. We observed a nonlinear association between total nut intake and UACR with lowest UACR values among women with weekly intake. Compared to women with weekly intake (n = 222), the adjusted UACR values were higher by 86% [95% confidence interval: 15%, 202%], 24% [-1%, 54%], and 117% [22%, 288%] among women with no (n = 13), monthly (n = 86), and daily (n = 9) intake, respectively. Compared to weekly consumers, daily nut consumers also had 9% [0%, 19%] significantly higher eGFR values, but eGFR values were similar among women with no and monthly intake. Moderate nut consumption may be beneficial to kidney health among women with prior GDM.

Authors: Ajjarapu AS; Zhu Y; Zhang C; et al.

J Ren Nutr. 2020 09;30(5):415-422. Epub 2020-01-17.

PubMed abstract

Body mass index versus bioelectrical impedance analysis for classifying physical function impairment in a racially diverse cohort of midlife women: the Study of Women’s Health Across the Nation (SWAN)

Body composition strongly influences physical function in older adults. Bioelectrical impedance analysis (BIA) differentiates fat mass from skeletal muscle mass, and may be more useful than body mass index (BMI) for classifying women on their likelihood of physical function impairment. This study tested whether BIA-derived estimates of percentage body fat (%BF) and height-normalized skeletal muscle mass (skeletal muscle mass index; SMI) enhance classification of physical function impairment relative to BMI. Black, White, Chinese, and Japanese midlife women (N = 1482) in the Study of Women’s Health Across the Nation (SWAN) completed performance-based measures of physical function. BMI (kg/m2) was calculated. %BF and SMI were derived through BIA. Receiver-operating characteristic (ROC) curve analysis, conducted in the overall sample and stratified by racial group, evaluated optimal cutpoints of BMI, %BF, and SMI for classifying women on moderate-severe physical function impairment. In the overall sample, a BMI cutpoint of ≥ 30.1 kg/m2 correctly classified 71.1% of women on physical function impairment, and optimal cutpoints for %BF (≥ 43.4%) and SMI (≥ 8.1 kg/m2) correctly classified 69% and 62% of women, respectively. SMI did not meaningfully enhanced classification relative to BMI (change in area under the ROC curve = 0.002; net reclassification improvement = 0.021; integrated discrimination improvement = - 0.003). Optimal cutpoints for BMI, %BF, and SMI varied substantially across race. Among Black women, a %BF cutpoint of 43.9% performed somewhat better than BMI (change in area under the ROC curve = 0.017; sensitivity = 0.69, specificity = 0.64). Some race-specific BMI and %BF cutpoints have moderate utility for identifying impaired physical function among midlife women.

Authors: Appelhans BM; Lange-Maia BS; Pettee Gabriel K; Karvonen-Gutierrez C; Karavolos K; Dugan SA; Greendale GA; Avery EF; Sternfeld B; Janssen I; Kravitz HM

Aging Clin Exp Res. 2020 Sep;32(9):1739-1747. Epub 2019-10-04.

PubMed abstract

Study protocol: Using peer support to aid in prevention and treatment in prediabetes (UPSTART)

There is an urgent need to develop and evaluate effective and scalable interventions to prevent or delay the onset of type 2 diabetes mellitus (T2DM). In this randomized controlled pragmatic trial, 296 adults with prediabetes will be randomized to either a peer support arm or enhanced usual care. Participants in the peer support arm meet face-to-face initially with a trained peer coach who also is a patient at the same health center to receive information on locally available wellness and diabetes prevention programs, discuss behavioral goals related to diabetes prevention, and develop an action plan for the next week to meet their goals. Over six months, peer coaches call their assigned participants weekly to provide support for weekly action steps. In the final 6 months, coaches call participants at least once monthly. Participants in the enhanced usual care arm receive information on local resources and periodic updates on available diabetes prevention programs and resources. Changes in A1c, weight, waist circumference and other patient-centered outcomes and mediators and moderators of intervention effects will be assessed. At least 296 participants and approximately 75 peer supporters will be enrolled. Despite evidence that healthy lifestyle interventions can improve health behaviors and reduce risk for T2DM, engagement in recommended behavior change is low. This is especially true among racial and ethnic minority and low-income adults. Regular outreach and ongoing support from a peer coach may help participants to initiate and sustain healthy behavior changes to reduce their risk of diabetes. The registration number is NCT03689530.

Authors: Heisler M; Adams A; Hedderson M; Schmittdiel JA; et al.

Contemp Clin Trials. 2020 08;95:106048. Epub 2020-06-01.

PubMed abstract

Adipokines in early and mid-pregnancy and subsequent risk of gestational diabetes: a longitudinal study in a multiracial cohort

Several adipokines are implicated in the pathophysiology of gestational diabetes mellitus (GDM), however, longitudinal data in early pregnancy on many adipokines are lacking. We prospectively investigated the association of a panel of adipokines in early and mid-pregnancy with GDM risk. Within the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort (n=2802), a panel of 10 adipokines (plasma fatty acid binding protein-4 (FABP4), chemerin, interleukin-6 (IL-6), leptin, soluble leptin receptor (sOB-R), adiponectin, omentin-1, vaspin, and retinol binding protein-4) were measured at gestational weeks (GWs) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used to estimate ORs of each adipokine and GDM, controlling for known GDM risk factors including pre-pregnancy body mass index. Throughout pregnancy changes in chemerin, sOB-R, adiponectin, and high-molecular-weight adiponectin (HMW-adiponectin) concentrations from 10-14 to 15-26 GWs were significantly different among GDM cases compared with non-GDM controls. In early and mid-pregnancy, FABP4, chemerin, IL-6 and leptin were positively associated with increased GDM risk. For instance, at 10-14 GWs, the OR comparing the highest versus lowest quartile (ORQ4-Q1) of FABP4 was 3.79 (95% CI 1.63 to 8.85). In contrast, in both early and mid-pregnancy adiponectin (eg, ORQ4-Q1 0.14 (0.05, 0.34) during 10-14 GWs) and sOB-R (ORQ4-Q1 0.23 (0.11, 0.50) during 10-14 GWs) were inversely related to GDM risk. At 10-14 GWs a model that included conventional GDM risk factors and FABP4, chemerin, sOB-R, and HMW-adiponectin improved the estimated prediction (area under the curve) from 0.71 (95% CI 0.66 to 0.77) to 0.77 (95% CI 0.72 to 0.82). A panel of understudied adipokines including FABP4, chemerin, and sOB-R may be implicated in the pathogenesis of GDM with significant associations detected approximately 10-18 weeks before typical GDM screening.

Authors: Francis, Ellen C; Zhu, Yeyi; Zhang, Cuilin; et al.

BMJ Open Diabetes Res Care. 2020 07;8(1).

PubMed abstract

Time to Positivity of Neonatal Blood Cultures for Early-onset Sepsis

In newborns at risk for early-onset sepsis, empiric antibiotics are often initiated while awaiting the results of blood cultures. The duration of empiric therapy can be guided by the time to positivity (TTP) of blood cultures. The objective of the study was to determine the TTP of neonatal blood cultures for early-onset sepsis and the factors which may impact TTP. Observational study of blood cultures growing pathogenic species obtained within 72 hours of birth from infants born at 23-42 weeks gestation, at 19 hospitals in Northern California, Boston, and Philadelphia. TTP was defined as the time from blood culture collection to the time organism growth was reported by the microbiology laboratory. A total of 594 blood cultures growing pathogenic bacteria were identified. Group B Streptococcus and Escherichia coli accounted for 74% of blood culture isolates. Median TTP was 21.0 hours (interquartile range, 17.1-25.3 hours). Blood cultures were identified as positive by 24 hours after they were obtained in 68% of cases; by 36 hours in 94% of cases; and by 48 hours in 97% of cases. Neither the administration of maternal intrapartum antibiotic prophylaxis, gestational age <35 weeks, nor blood culture system impacted median TTP. Pathogens are isolated by 36 hours after blood culture collection in 94% of neonatal early blood cultures, regardless of maternal antibiotic administration. TTP information can inform decisions regarding the duration of empiric neonatal antibiotic therapies.

Authors: Kuzniewicz MW; Mukhopadhyay S; Li S; Walsh EM; Puopolo KM

Pediatr Infect Dis J. 2020 07;39(7):634-640.

PubMed abstract

Cesarean Delivery and the Risk of Atopic Dermatitis in Children

Caesarean delivery (C-section) may disrupt maternal-infant microbial transfer and alter immune system development and subsequent risk for atopic dermatitis. Investigate the association between C-section and atopic dermatitis by age four and examine potential sources of bias in the relationship in a large cohort study. Maternal and child information was collected through Kaiser Permanente Northern California’s (KPNC) integrated healthcare system. Data sources included electronic medical records, pharmacy databases, state birth records, and prospectively collected breastfeeding surveys. Children were eligible if they were born in a KPNC or contracting hospital between 2005 and 2014 and had continuous enrolment in the KPNC system for at least four years (n = 173 105). Modified Poisson regression with robust variance estimation was used to estimate the association between C-section and atopic dermatitis overall and when stratified by demographic and labour and delivery characteristics. Although unadjusted analyses showed a positive association between C-section and atopic dermatitis [RR(95%CI): 1.06(1.03, 1.10)], this effect was attenuated towards the null after adjustment [aRR(95%CI): 1.02(0.99, 1.05)]. In stratified analyses, there was evidence that C-section increased atopic dermatitis risk among certain subgroups (eg firstborns, overweight/obese pre-pregnancy BMI), but associations were weak. C-section delivery conditions indicative of the least exposure to maternal microbiome (ie no labour, short interval between membrane rupture and delivery) showed no evidence of association with atopic dermatitis. Estimated associations were not strongly influenced by intrapartum antibiotics, breastfeeding, missing data, or familial factors. Caesarean delivery was not associated with atopic dermatitis by age four in this large US cohort. This association did not appear to be biased by intrapartum antibiotics, breastfeeding behaviour, C-section indication, missing covariates, or familial factors.

Authors: Richards M; Ferber J; Chen H; Swor E; Quesenberry CP; Li DK; Darrow LA

Clin Exp Allergy. 2020 07;50(7):805-814. Epub 2020-06-11.

PubMed abstract

Breast cancer risk after hysterectomy with and without salpingo-oophorectomy for benign indications

Breast cancer risk has been extensively studied in women with genetic predisposition, i.e. BRCA1/2. Though there are guidelines for performing bilateral salpingo-oophorectomies in individuals with specific genetic risks, oophorectomies are also performed in many average-risk women. The risk of breast cancer in average risk women who undergo hysterectomy with bilateral salpingo-oophorectomy for benign indications is less clear. We aim to estimate breast cancer risk following hysterectomy with and without concomitant bilateral salpingo-oophorectomy for benign indications. From 2001 to 2015, women aged 18 and older from Kaiser Permanente Northern California who underwent hysterectomy alone and hysterectomy with bilateral salpingo-oophorectomy were identified using ICD-9 procedure and CPT codes. Women with a BRCA mutation and prior history of breast or gynecologic cancer were excluded. Descriptive and bivariate analyses were used to describe and compare demographic and clinical characteristics. Breast cancer incidence rates were calculated per 100,000 person-years. Survival analysis and Cox proportional hazard models were conducted to compare risk of developing breast cancer. Of 49,215 women who underwent hysterectomy, 19,826 had hysterectomy with bilateral salpingo-oophorectomy. Whites comprised 51.2%, Hispanics 20.3%, Blacks 12.7%, Asians 10.4%, and other/unknown 5.3% of the study population. The average age of women with hysterectomy only was 45.5 compared to 50.8 with hysterectomy with bilateral salpingo-oophorectomy. During the study period, 915 women were diagnosed with breast cancer. Age-specific breast cancer incidence rates were higher in women over 60 with oophorectomy compared with hysterectomy alone (471.2 [95% CI 386.2-556.2] vs. 463.0 [95% CI 349.6-576.5], respectively). After controlling for age, race, income, and Charlson comorbidity index, women with bilateral salpingo-oophorectomy had a 14% lower risk of breast cancer compared with women with hysterectomy only (HR=0.86, 95% CI 0.75-0.98). All-cause mortality was higher with oophorectomy versus hysterectomy only (64.4% vs. 35.6%, p

Authors: Chow S; Raine-Bennett T; Samant ND; Postlethwaite DA; Holzapfel M

Am J Obstet Gynecol. 2020 Jun 22.

PubMed abstract

Prenatal bisphenol A exposure, fetal thyroid hormones and neurobehavioral development in children at 2 and 4 years: A prospective cohort study

Findings about the association between prenatal Bisphenol A (BPA) exposure and neurobehavioral development in children are still inconsistent. In addition, whether fetal thyroid hormones (THs) mediate the reported association remains unclear. The present study aimed to examine the association between prenatal BPA exposure and risks of child behavioral problems at 2 and 4 years of age and whether the association could be explained by alteration of fetal THs as measured in cord plasma. Using the Shanghai-Minhang Birth Cohort Study (S-MBCS), BPA concentration was measured in maternal urine samples collected at 12-16 weeks of gestation. Children’s neurobehavioral development was assessed using the Child Behavior Checklist/1.5-5 (CBCL), at 2 and 4 years of age. Using generalized estimating equation (GEE) models, 745 mother-pairs were included to examine associations of BPA with CBCL scores, Using multiple linear regression models, 348 mother-pairs were included to evaluate the association between maternal BPA and THs in cord plasma. A mediation analysis was conducted to explore the potential mediating role of THs. After adjusting for potential confounders, prenatal BPA level was associated with increased risks of Emotionally Reactive problem, Anxious/Depressed problem, having Somatic Complaints, exhibiting Aggressive Behavior, and Internalizing and Externalizing Problems: compared to the lowest tertile, the risks in the highest tertile and middle tertile, ranged between 1.55-fold (95% CI: 1.09, 2.21) and 2.59-fold (95% CI: 1.52, 4.42). The association was more pronounced among boys. None of the associations reached statistical significance among girls. An inverse association between prenatal BPA and fetal TH level was also observed. However, the observed neurotoxic effects of prenatal BPA exposure did not appear to be mediated by THs levels. The current findings suggest that prenatal exposure to BPA may disrupt fetal THs levels and may induce long-lasting behavioral alterations, especially in boys.

Authors: Li F; Yang F; Li DK; Tian Y; Miao M; Zhang Y; Ji H; Yuan W; Liang H

Sci Total Environ. 2020 Jun 20;722:137887. Epub 2020-03-12.

PubMed abstract

Alternative Wear-time Estimation Methods Compared to Traditional Diary Logs for Wrist-Worn ActiGraph Accelerometers in Pregnant Women

This study sought to compare three sensor-based wear-time estimation methods to conventional diaries for ActiGraph wGT3X-BT accelerometers worn on the non-dominant wrist in early pregnancy. Pregnant women (n= 108) wore ActiGraph wGT3X-BT accelerometers for 7 days and recorded their device on and off times in a diary (criterion). Average daily wear-time estimates from the Troiano and Choi algorithms and the wGT3X-BT accelerometer wear sensor were compared against the diary. The Hibbing 2-regression model was used to estimate time spent in activity (during periods of device wear) for each method. Wear-time and time spent in activity were compared with multiple repeated measures ANOVAs. Bland Altman plots assessed agreement between methods. Compared to the diary [825.5 minutes (795.1, 856.0)], the Choi [843.0 (95% CI 812.6, 873.5)] and Troiano [839.1 (808.7, 869.6)] algorithms slightly overestimated wear-time, whereas the sensor [774.4 (743.9, 804.9)] underestimated it, although only the sensor differed significantly from the diary (P < .0001). Upon adjustment for average daily wear-time, there were no statistically significant differences between the wear-time methods in regards to minutes per day of moderate to vigorous physical activity (MVPA), vigorous PA, and moderate PA. Bland Altman plots indicated the Troiano and Choi algorithms were similar to the diary and within ≤ 0.5% of each other for wear-time and MVPA. The Choi or Troiano algorithms offer a valid and efficient alternative to diaries for the estimation daily wear-time in larger-scale studies of MVPA during pregnancy, and reduce burden for study participants and research staff.

Authors: Ehrlich, Samantha F; Casteel, Amanda J; Crouter, Scott E; Hibbing, Paul R; Hedderson, Monique M; Brown, Susan D; Galarce, Maren; Coe, Dawn P; Bassett, David R; Ferrara, Assiamira

J Meas Phys Behav. 2020 Jun;3(2):110-117.

PubMed abstract

Behavioural and psychosocial factors associated with 5-year weight trajectories within the PORTAL Overweight/Obesity Cohort

The purpose of this study was to model weight trajectories over a 5-year time period (2012-2016) and their association with behavioural and psychosocial characteristics and health care-related experiences using data from the Patient Outcomes Research to Advance Learning (PORTAL) overweight/obesity cohort. Weight trajectories for each eligible patient in the PORTAL overweight/obesity cohort (n = 2864) were identified first using growth modelling; trajectories were then grouped using a hierarchical cluster analysis. Weight trajectory clusters that emerged were compared on demographics, and predictors of cluster membership were examined. Clusters were also compared on responses to a survey assessing health behaviours, quality of life, and health care experience completed in 2015 by 49% of the total sample (n = 1391). Seven distinct weight trajectory clusters were identified: (a) significant weight loss then maintenance; (b) higher stable weight; (c) moderate stable weight; (d) steady weight loss then relapse; (e) weight gain then weight loss; (f) steady weight gain then maintenance; and (g) lower stable weight. Age, sex, race/ethnicity, and body mass index at baseline predicted patient’s weight trajectory (P < .001). Over two thirds of patients maintained their weight over the 5-year period. Significant weight loss then maintenance, weight gain then weight loss, and higher stable weight patients were more likely to report receiving weight counselling from their provider. Patients in the significant weight loss then maintenance and lower stable weight clusters were more likely to be physically active than the other clusters. Findings suggest variability in patterns of weight change among adults with overweight or obesity who have access to health care and that these patterns differ on demographic, behavioural and psychosocial factors, and health care experience.

Authors: Fitzpatrick SL; Rosales AG; Brown SD; Arterburn DE; Daley MF; Horberg M; Koebnick C; Oshiro C; Young DR

Obes Sci Pract. 2020 Jun;6(3):272-281. Epub 2020-02-27.

PubMed abstract

A telehealth lifestyle intervention to reduce excess gestational weight gain in pregnant women with overweight or obesity (GLOW): a randomised, parallel-group, controlled trial

Excess gestational weight gain (GWG) among women with overweight or obesity synergistically increases their already elevated risk of having gestational diabetes, a caesarean delivery, a large for gestational age infant, and post-partum weight retention, and increases their child’s risk of obesity. We investigated whether a primarily telehealth lifestyle intervention reduced excess GWG among women with overweight or obesity. We did a randomised controlled trial in five antenatal clinics of Kaiser Permanente; Oakland, San Leandro, Walnut Creek, Fremont, and Santa Clara, CA, USA. Women at 8-15 weeks’ gestation with singletons, pre-pregnancy BMI 25·0-40·0 kg/m2, and aged 18 years or older were randomly assigned (1:1) to receive the telehealth lifestyle intervention or usual antenatal care. Randomisation was adaptively balanced for age, BMI, and race and ethnicity. Data collectors and investigators were masked to group assignments. The core lifestyle intervention consisted of two in-person and 11 telephone sessions on behavioural strategies to improve weight, diet, and physical activity, and stress management to help women meet a trial goal of gaining at the lower limit of the Institute of Medicine (IOM) guidelines range for total GWG: 7 kg for women with overweight and 5 kg for women with obesity. Usual antenatal care included an antenatal visit at 7-10 weeks’ gestation, an additional seven antenatal visits, on average, and periodic health education newsletters, including the IOM GWG guidelines and information on healthy eating and physical activity in pregnancy. The primary outcome was weekly rate of GWG expressed as excess GWG, per Institute of Medicine guidelines and mean assessed in the intention-to-treat population. The trial is registered at, NCT02130232. Between March 24, 2014, and Sept 26, 2017, 5329 women were assessed for eligibility and 200 were randomly assigned to the lifestyle intervention group and 198 to the usual care group. Analyses included 199 women in the lifestyle intervention group (one lost to follow-up) and 195 in the usual care group (three lost to follow-up). 96 (48%) women in the lifestyle intervention group and 134 (69%) women in the usual care group exceeded Institute of Medicine guidelines for rate of GWG per week (relative risk 0·70, 95% CI 0·59 to 0·83). Compared with usual care, women in the lifestyle intervention had reduced weekly rate of GWG (mean 0·26 kg per week [SD 0·15] vs 0·32 kg per week [0·13]; mean between-group difference -0·07 kg per week, 95% CI -0·09 to -0·04). No between-group differences in perinatal complications were observed. Our evidence-based programme showed that health-care delivery systems could further adapt to meet the needs of their clinical settings to prevent excess GWG and improve healthy behaviours and markers of insulin resistance among women with overweight or obesity by using telehealth lifestyle interventions. US National Institutes of Health.

Authors: Ferrara A; Hedderson MM; Brown SD; Ehrlich SF; Tsai AL; Feng J; Galarce M; Marcovina S; Catalano P; Quesenberry CP

Lancet Diabetes Endocrinol. 2020 06;8(6):490-500.

PubMed abstract

Association between Objective Activity Intensity and Heart Rate Variability: Cardiovascular Disease Risk Factor Mediation (CARDIA)

We evaluated the associations between accelerometer-estimated physical activity (PA) intensity and heart rate variability (HRV) and examined mediation of these associations by glycemic control indices and other cardiovascular disease risk factors. Data were from 1668 participants (X[Combining Overline]age = 45.9 ± 3.5 yr, 58.0% female, 39.9% black) who participated in year 20 (2005-2006) of the Coronary Artery Risk Development in Young Adults Fitness Study. The ActiGraph 7164 estimated participants’ mean minutes per day of vigorous-intensity PA (VPA), moderate-intensity PA (MPA), and light-intensity PA (LPA) over 7 d. Three sequential 10-s 12-lead ECG strips were used to derive standard deviation of all normal RR intervals (SDNN) and root mean square of all successive RR intervals (rMSSD) HRV. Mediators representing glycemic control indices included fasting glucose, fasting insulin, and 2-h oral glucose tolerance, with other mediators being traditional cardiovascular disease risk factors. Multiple linear regression assessed independent associations of PA intensity with HRV per 1-SD. Mediation analyses computed the proportion of the PA-HRV association attributable to physiological mediators. Participants averaged 2.7 ± 6.2 min·d, 33.0 ± 22.0 min·d, and 360.2 ± 83.8 min·d of VPA, MPA, and LPA, respectively, with mean values for SDNN (32.6 ± 22.4 ms) and rMSSD (34.0 ± 24.8 ms) similar. After adjustment for demographic and lifestyle behaviors, VPA was associated with both HRV metrics (SDNN: std beta = 0.06 [0.03, 0.10]; rMSSD: std beta = 0.08 [0.05, 0.12]) and LPA with rMSSD only (std beta = 0.05 [0.01, 0.08]). Fasting insulin and glucose mediated 11.6% to 20.7% of the association of VPA and LPA with HRV, with triglycerides also potentially mediating these associations (range, 9.6%-13.4%). Accelerometer-estimated VPA was associated with higher (i.e., improved) HRV. Light-intensity PA also demonstrated a positive association. Mediation analyses suggested these associations may be most attributable to glucose-insulin dynamics.

Authors: Pope ZC; Gabriel KP; Whitaker KM; Chen LY; Schreiner PJ; Jacobs DR; Sternfeld B; Carr JJ; Lloyd-Jones DM; Pereira MA

Med Sci Sports Exerc. 2020 06;52(6):1314-1321.

PubMed abstract

Prenatal Depression and Diet Quality During Pregnancy

Maternal nutrition during pregnancy has a significant effect on the health of the offspring and mother, highlighting the need for identifying factors that may affect diet during pregnancy. Research in nonpregnant and pregnant populations suggest depression may play a role. To investigate the relationship between prenatal depression and diet quality during pregnancy overall and by race/ethnicity and to explore the relationships between prenatal depression and the 12 Healthy Eating Index 2010 dietary components. A cross-sectional secondary analysis of a cohort study of Kaiser Permanente Northern California women entering prenatal care between October 2011 and April 2013. Participants included 1,160 adult pregnant women. Poor diet quality was defined as a Healthy Eating Index 2010 score in the lowest quartile. Logistic regression was used to assess the relationship between prenatal depression (defined as a depression diagnosis, Patient Health Questionnaire score of 10 or greater or antidepressant medication dispensing between the last menstrual period and completion of the food frequency questionnaire) and poor diet quality overall and by race/ethnicity. Relationships between prenatal depression and each of the 12 Healthy Eating Index 2010 dietary components were assessed using t-tests and linear regression analyses. One hundred fifty-nine (14%) participants had prenatal depression. Women with prenatal depression had nearly two times the odds of poor diet quality (odds ratio 1.80, 95% CI 1.23 to 2.60) compared with women without prenatal depression, after adjusting for potential confounders. Differences emerged by race/ethnicity; after adjusting for potential confounders the adjusted odds of poor diet quality were significant only among Hispanic women. Hispanic women with prenatal depression had an increased odds of poor diet quality compared with Hispanic women without prenatal depression (odds ratio 2.66, 95% CI 1.15 to 6.06). Women with prenatal depression had a higher consumption of empty calories (from solid fats, alcohol, and added sugars; threshold for counting alcohol >13 g/1,000 kcal) (P=0.01) and lower consumption of greens and beans (P<0.05), total fruit (P<0.01), and whole fruit (P<0.01), compared with women without prenatal depression. Except for empty calories, these findings remained after adjusting for potential confounders. Study findings suggest that women with prenatal depression are at a higher risk of poor diet quality compared with women without prenatal depression, and the relationship is stronger among Hispanic women. Nutrition counseling interventions for women with depression should consider the use of culturally sensitive materials and target limiting empty calories from solid fats, alcohol, and added sugars and encourage eating more greens, beans, and fruit.

Authors: Avalos LA; Caan B; Nance N; Zhu Y; Li DK; Quesenberry C; Hyde RJ; Hedderson MM

J Acad Nutr Diet. 2020 06;120(6):972-984. Epub 2020-02-13.

PubMed abstract

Comparative Effectiveness of 2 Diabetes Prevention Lifestyle Programs in the Workplace: The City and County of San Francisco Diabetes Prevention Trial

Data on the comparative effectiveness of Diabetes Prevention Programs (DPPs) in the workplace are limited. Between September 2015 and July 2016, employees of the City and County of San Francisco who were at risk for type 2 diabetes (N = 158) were randomly assigned to one of 2 DPP-derived programs recognized by the Centers for Disease Control and Prevention: an in-person YMCA-DPP (n = 78) or an online virtual lifestyle management DPP (VLM-DPP) offered through Canary Health (n = 80). The primary outcome was change in body weight assessed at 6 and 12 months. Follow-up ended in August 2017. Both the YMCA-DPP and VLM-DPP yielded a significant reduction in percentage body weight at 6 months. For the YMCA-DPP, mean percentage change at 6 months was -2.70% (95% confidence interval [CI], -3.91% to -1.48%) and at 12 months was -2.46% (95% CI, -4.24% to -0.68%). For the VLM-DPP, mean percentage change at 6 months was -2.41% (95% CI, -4.07% to -0.77%) and at 12 months was -1.59% (95% CI, -3.51% to 0.33%). The mean between-condition difference at 6 months was -0.25% (95% CI, -2.04% to 1.55%) and at 12 months was -0.84% (95% CI, -3.03% to 1.34%). No significant differences were observed between conditions. The YMCA-DPP had a slightly higher reduction in waist circumference than VLM-DDP at 6 months (mean between-condition difference -2.00 cm [95% CI, -4.24 to 0.25 cm]). Participant engagement, expressed as mean number of completed core program sessions, was significantly higher for the YMCA-DPP than the VLM-DPP. Participants of the YMCA-DPP completed an average of 10.2 sessions (95% CI, 9.0 to 11.4), and participants of the VLM-DPP completed an average of 5.9 sessions (95% CI, 4.7 to 7.1). The adjusted mean between-condition difference was 4.2 sessions (95% CI, 2.54 to 5.99). Both the YMCA-DPP and VLM-DPP yielded weight loss at 6 months, which was maintained at 12 months in the YMCA-DPP. The workplace may be an effective setting to offer DPPs.

Authors: Ferrara A; McDonald JC; Brown SD; Alexander JG; Christian-Herman JL; Fisher S; Quesenberry CP

Prev Chronic Dis. 2020 May 28;17:E38. Epub 2020-05-28.

PubMed abstract

Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P 

Authors: Pinheiro M; Raine-Bennett T; Mirabello L; et al.

Int J Cancer. 2020 May 04.

PubMed abstract

Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study

Leukocyte telomere length, a marker of immune system function, is sensitive to exposures such as psychosocial stressors and health-maintaining behaviors. Past research has determined that stress experienced in adulthood is associated with shorter telomere length, but is limited to mostly cross-sectional reports. We test whether repeated reports of chronic psychosocial and financial burden is associated with telomere length change over a 5-year period (years 15 and 20) from 969 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, population-based cohort, ages 18-30 at time of recruitment in 1985. We further examine whether multisystem resiliency, comprised of social connections, health-maintaining behaviors, and psychological resources, mitigates the effects of repeated burden on telomere attrition over 5 years. Our results indicate that adults with high chronic burden do not show decreased telomere length over the 5-year period. However, these effects do vary by level of resiliency, as regression results revealed a significant interaction between chronic burden and multisystem resiliency. For individuals with high repeated chronic burden and low multisystem resiliency (1 SD below the mean), there was a significant 5-year shortening in telomere length, whereas no significant relationships between chronic burden and attrition were evident for those at moderate and higher levels of resiliency. These effects apply similarly across the three components of resiliency. Results imply that interventions should focus on establishing strong social connections, psychological resources, and health-maintaining behaviors when attempting to ameliorate stress-related decline in telomere length among at-risk individuals.

Authors: Cabeza de Baca T; Prather AA; Lin J; Sternfeld B; Adler N; Epel ES; Puterman E

Mol Psychiatry. 2020 05;25(5):1141-1153. Epub 2019-08-27.

PubMed abstract

A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs

HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30-65 yielding 14,158 type-specific infections. Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks

Authors: Demarco M; Raine-Bennett TR; Schiffman M; et al.

EClinicalMedicine. 2020 May;22:100293. Epub 2020-04-25.

PubMed abstract

The Association Between Parental Age and Autism-Related Outcomes in Children at High Familial Risk for Autism

Advanced parental age is a well-replicated risk factor for autism spectrum disorder (ASD), a neurodevelopmental condition with a complex and not well-defined etiology. We sought to determine parental age associations with ASD-related outcomes in subjects at high familial risk for ASD. A total of 397 younger siblings of a child with ASD, drawn from existing prospective high familial risk cohorts, were included in these analyses. Overall, we did not observe significant associations of advanced parental age with clinical ASD diagnosis, Social Responsiveness Scale, or Vineland Adaptive Behavior Scales scores. Instead, increased odds of ASD were found with paternal age 

Authors: Lyall K; Croen LA; Volk HE; et al.

Autism Res. 2020 Apr 21.

PubMed abstract

Reservations Regarding O-RADS Recommendations

Authors: Suh-Burgmann E; Flanagan T; Brasic N

Radiology. 2020 04;295(1):248-249. Epub 2020-02-25.

PubMed abstract

A Study of Partial Human Papillomavirus Genotyping in Support of the 2019 ASCCP Risk-Based Management Consensus Guidelines

The 2019 ASCCP Risk-Based Management Consensus Guidelines include recommendations for partial human papillomavirus (HPV) genotyping in management of abnormal cervical cancer screening results. The guidelines are based on matching estimates of cervical intraepithelial neoplasia (CIN) 3+ risk to consensus clinical action thresholds. In support of the guidelines, this analysis addresses the risks predicted by individual identification of HPV 16 and HPV 18. Risk estimates were drawn from a subset of women in the Kaiser Permanente Northern California screening program, whose residual cervical specimens were HPV typed as part of the HPV Persistence and Progression study. We calculated risk of CIN 3+ to assess how identification of HPV 16, HPV 18, or 12 other "high-risk" HPV types would influence recommended clinical management of new abnormal screening results, taking into account current cytologic results and recent screening history. Immediate and/or 5-year risks of CIN 3+ were matched to clinical actions identified in the guidelines. Identification of HPV 16 at the first visit including HPV testing elevated immediate risk of diagnosing CIN 3+ sufficiently to mandate colposcopic referral even when cytology was Negative for Intraepithelial Lesions or Malignancy and to support a preference for treatment of cytologic high-grade squamous intraepithelial lesion. HPV 18 less clearly elevated CIN 3+ risk. Identification of HPV 16 clearly mandated consideration in clinical management of new abnormal screening results. HPV 18 positivity must be considered as a special situation because of established disproportionate risk of invasive cancer. More detailed genotyping and use beyond initial management will be considered in guideline updates.

Authors: Demarco M; Raine-Bennett TR; Schiffman M; et al.

J Low Genit Tract Dis. 2020 Apr;24(2):144-147.

PubMed abstract

Genetic Contributions to Maternal and Neonatal Vitamin D Levels

Vitamin D is essential for several physiological functions and biological processes. Increasing levels of maternal vitamin D are required throughout pregnancy as a unique source of vitamin D for the fetus, and consequently maternal vitamin D deficiency may result in several adverse outcomes in newborns. However, the genetic regulation of vitamin D in pregnancy and at birth is not yet well understood. We performed genome-wide association studies of maternal midgestational serum-derived and neonatal blood-spot-derived total 25-hydroxyvitamin D from a case-control study of autism spectrum disorder (ASD). We identified one fetal locus (rs4588) significantly associated with neonatal vitamin D levels in the GC gene, encoding the binding protein for the transport and function of vitamin D. We also found suggestive cross-associated loci for neonatal and maternal vitamin D near immune genes, such as CXCL6-IL8 and ACKR1 We found no interactions with ASD. However, when including a set of cases with intellectual disability but not ASD (N = 179), we observed a suggestive interaction between decreased levels of neonatal vitamin D and a specific maternal genotype near the PKN2 gene. Our results suggest that genetic variation influences total vitamin D levels during pregnancy and at birth via proteins in the vitamin D pathway, but also potentially via distinct mechanisms involving loci with known roles in immune function that might be involved in vitamin D pathophysiology in pregnancy.

Authors: Traglia M; Windham GC; Pearl M; Poon V; Eyles D; Jones KL; Lyall K; Kharrazi M; Croen LA; Weiss LA

Genetics. 2020 04;214(4):1091-1102. Epub 2020-02-11.

PubMed abstract

Maternal infection and antibiotic use in pregnancy and the risk of childhood obesity in offspring: a birth cohort study

The reported association between maternal antibiotic use and childhood obesity, if true, could change obstetric practice. However, it is unclear whether the reported association was due to antibiotics, or underlying infection or both. To examine the independent contributions of maternal infection and antibiotic use separately, we conducted a birth cohort study among Kaiser Permanente Northern California (KPNC) members. The study consisted of 145,393 mother-child dyads. The KPNC electronic medical records provided data on maternal infections, antibiotic use during pregnancy, and longitudinal anthropometric measurements throughout childhood. Obesity was defined by BMI using CDC criteria. Mixed effects logistic regression for repeated measurements was used to analyze multiple BMI measurements per child (five measurements per child on average). After controlling for confounders using propensity score methodology, there was no increased risk associated with maternal antibiotic use during pregnancy once underlying infection was controlled for: OR = 0.97 (95% CI: 0.92-1.01). There was also no association with timing of use or use of broad-spectrum antibiotics, nor a dose-response relationship. In contrast, maternal untreated infection (without antibiotic use) during pregnancy was associated with a statistically significant risk of childhood obesity compared with mothers without infection: odds ratio (OR) = 1.09 (95% confidence interval (CI): 1.03-1.16). The association was stronger for GBS positive infection (OR = 1.16) than GBS negative infections (OR = 1.08). These results were further confirmed by a discordant sibling study. This discordant sibling study allowed additional control of unmeasured confounders including genetic, maternal intrauterine, and familiar factors. The consistent findings from this sibling study enhances the reproducibility of our findings. It is maternal infection, NOT antibiotic use, during pregnancy that is associated with increased risk of childhood obesity. While use of antibiotics should always be judicious, in the context of preventing childhood obesity, the focus should be on reducing maternal infections during pregnancy.

Authors: Li DK; Chen H; Ferber J; Odouli R

Int J Obes (Lond). 2020 04;44(4):771-780. Epub 2019-12-05.

PubMed abstract

Food insecurity and the extremes of childhood weight: defining windows of vulnerability

Weight extremes and food insecurity (FIS) represent public-health challenges, yet their associations in childhood remain unclear. We aimed to investigate the longitudinal time-specific relationship between FIS and risk of overweight/obesity and underweight in kindergarten through 8th grade. In the prospective Early Childhood Longitudinal Study-Kindergarten Cohort (1998-2007) of 6368 children, household FIS was assessed by the validated US Household Food Security Survey Module in kindergarten, 3rd, 5th and 8th grades. Multivariable linear-regression and Poisson-regression models were computed. Compared with children experiencing food security (FS), children exposed to FIS in 5th grade had 0.19 [95% confidence interval (CI): 0.07-0.30] and 0.17 (0.06-0.27) higher body mass index z-score (BMIZ) in the 5th and 8th grades, respectively, whereas FIS in the 8th grade was associated with a 0.29 (0.19-0.40) higher BMIZ at the same wave, after adjusting for covariates and FIS at earlier waves. Children with FIS vs FS had 27% (relative risk: 1.27, 95% CI: 1.07-1.51), 21% (1.21, 1.08-1.35) and 28% (1.28, 1.07-1.53) higher risk of overweight/obesity in the 3rd, 5th and 8th grades, respectively, adjusting for covariates and FIS at prior wave(s). Children with FIS vs FS in kindergarten had a 2.76-fold (1.22-6.25) higher risk of underweight in the 8th grade. Proximal exposure to household FIS was associated with a higher risk of overweight/obesity in the 3rd, 5th and 8th grades. FIS in kindergarten was associated with a risk of underweight in the 8th grade. Thus, FIS coexists in weight extremes during vulnerable early-life windows in the USA, similarly to the global burden of FIS.

Authors: Zhu Y; Mangini LD; Hayward MD; Forman MR

Int J Epidemiol. 2020 04 01;49(2):519-527.

PubMed abstract

The impact of breast cancer on physical activity from midlife to early older adulthood and predictors of change post-diagnosis

To examine physical activity (PA) patterns from pre- to post-diagnosis, and compare these changes to women without breast cancer. To determine pre-diagnosis predictors of PA change, post-diagnosis, in breast cancer survivors (BCS). Data were from 2314 Study of Women’s Health Across the Nation (SWAN) participants, average age of 46.4 ± 2.7 years at baseline (1996-1997). In Pink SWAN, 151 women who reported an incident breast cancer diagnosis over 20 years were classified as BCS; the remaining 2163 women were controls. LOESS plots and linear mixed models were used to illustrate and compare PA changes (sports/exercise [primary measure] and total PA) from pre- to post-diagnosis (or corresponding period) in BCS versus controls. Adjusted linear regression models were used to determine pre-diagnosis predictors of at-risk post-diagnosis PA change patterns (consistently low and decreased PA). No differences in pre- to post-diagnosis PA (or corresponding period) were observed in BCS versus controls. Among BCS, the odds of at-risk post-diagnosis PA change patterns was 2.50 (95% CI 0.96-6.48) times higher for those who reported sleep problems at ≥ 50% (compared to 0%) of pre-diagnosis visits and 3.49 (95% CI 1.26-9.65) times higher for those who were overweight or obese at all (compared to no) pre-diagnosis visits. No other statistically significant predictors were noted. Age-related declines in PA were not amplified by a breast cancer diagnosis. Given the beneficial role of PA across the cancer control continuum, efforts to increase or maintain adequate PA, post-diagnosis, should be continued. While age-related physical activity declines were not amplified breast cancer diagnosis, efforts to identify breast cancer survivors at increased risk for post-diagnosis physical activity declines (or maintenance of low activity) may be a high-yield strategy to improve prognosis and quality of life.

Authors: Pettee Gabriel K; Sternfeld B; Colvin AB; Lucas AR; Karvonen-Gutierrez CA; Gold EB; Crawford S; Greendale GA; Avis NE

J Cancer Surviv. 2020 Mar 30.

PubMed abstract

Association Between Maternal Exposure to Magnetic Field Nonionizing Radiation During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring in a Longitudinal Birth Cohort

An association between maternal exposure to magnetic field (MF) nonionizing radiation during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) has been reported in both animal and human studies. To determine whether maternal exposure to high levels of MF nonionizing radiation is associated with an increased risk of ADHD in offspring by using more accurate measurements of MF nonionizing radiation levels and physician-diagnosed ADHD, rather than self-reports, and to determine whether the association differs for the subtypes of ADHD with or without immune-related comorbidities. A longitudinal birth cohort study was conducted at Kaiser Permanente Northern California among 1482 mother-child pairs whose mothers were participants of an existing birth cohort and whose level of exposure to MF nonionizing radiation was captured during pregnancy in 2 studies conducted from October 1, 1996, to October 31, 1998, and from May 1, 2006, to February 29, 2012. The offspring were followed up from May 1, 1997, to December 31, 2017. All participating women wore a monitoring meter for 24 hours during pregnancy to capture the level of exposure to MF nonionizing radiation from any sources. Physician-diagnosed ADHD and immune-related comorbidities of asthma or atopic dermatitis up to 20 years of age in offspring captured in the Kaiser Permanente Northern California electronic medical record from May 1, 1997, to December 31, 2017. Confounders were ascertained during in-person interviews during pregnancy. Among the 1454 mother-child pairs (548 white [37.7%], 110 African American [7.6%], 325 Hispanic [22.4%], 376 Asian or Pacific Islander [25.9%], and 95 other or unknown [6.5%]; mean [SD] maternal age, 31.4 [5.4] years]), 61 children (4.2%) had physician-diagnosed ADHD. Using Cox proportional hazards regression to account for follow-up time and confounders, compared with children whose mothers had a low level of exposure to MF nonionizing radiation during pregnancy, children whose mothers were exposed to higher levels of MF nonionizing radiation had more than twice the risk of ADHD (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.06-3.81). The association was stronger for ADHD that persisted into adolescence (≥12 years of age), with an aHR of 3.38 (95% CI, 1.43-8.02). When the subtypes of ADHD were examined, the association existed primarily for ADHD with immune-related comorbidities (asthma or atopic dermatitis), with an aHR of 4.57 (95% CI, 1.61-12.99) for all ADHD cases and an aHR of 8.27 (95% CI, 1.96-34.79) for persistent cases of ADHD. Consistent with the emerging literature, this study suggests that in utero exposure to high levels of MF nonionizing radiation was associated with an increased risk of ADHD, especially ADHD with immune-related comorbidity. The findings should spur more research to examine the biological association of in utero MF exposure with risk of ADHD in offspring, given that almost everyone is exposed to it.

Authors: Li DK; Chen H; Ferber JR; Hirst AK; Odouli R

JAMA Netw Open. 2020 03 02;3(3):e201417. Epub 2020-03-02.

PubMed abstract

Cytological sampling of fallopian tubes using a hysteroscopic catheter: A multi-center study

To assess the feasibility of a novel hysteroscopic catheter to collect fallopian tube cytologic samples and to correlate cytologic findings with histopathology. This was a prospective, multicenter, single-arm pilot study. Women undergoing salpingo-oophorectomy for a pelvic mass suspicious for malignancy or for prevention of cancer for BRCA mutation carriers were recruited from 3 gynecologic oncology centers (October 2016-August 2017). Cytologic samples were collected from the fallopian tube using a novel FDA-cleared hysteroscopic catheter and evaluated by a pathologist blinded to surgical or pathologic findings. The correlation between cytologic results and final surgical pathology was assessed. Of the 50 patients enrolled, 42 were eligible. Hysteroscopies were completed in 40 patients with 78 fallopian tubes, of which 65 ostia (83%) were identified. Of these, 61 (72%) were successfully catheterized resulting in 44 (68%) cytology samples adequate for further evaluation: 5 were classified as positive (3 neoplastic and 2 malignant) and 39 as negative (34 benign and 5 reactive/atypical). A comparison of cytology results with fallopian tube histopathology showed a concordance rate of 95% (42/44). Of the two samples with discordant results, both had positive cytology but negative tubal pathology, and both were stage I ovarian cancers with malignant ovary histology. Deployment of the device yielded an evaluable cytologic sample in 68% of cases with a high rate of concordance with histopathology. Further evaluation of the device’s ability to detect malignancy in high risk populations is warranted.

Authors: Powell CB; Littell RD; Landen CN; Pramanik S; Hamilton IC; Suh-Burgmann EJ

Gynecol Oncol. 2020 03;156(3):636-640. Epub 2020-01-07.

PubMed abstract

Neonatal Thyroid Stimulating Hormone and Subsequent Diagnosis of Autism Spectrum Disorders and Intellectual Disability

Hypothyroid conditions in early life, if left untreated, are associated with adverse neurodevelopmental outcomes, including intellectual disability (ID). However, evidence addressing the role of neonatal thyroid hormone insufficiencies in the altered neurobiology underlying autism spectrum disorders (ASD), particularly among its subphenotypes, is limited. We conducted a population-based, case-control study among a sample of children born during 2000-2003 in Southern California. We examined neonatal thyroid-stimulating hormone (TSH) measured during routine newborn screening among children later diagnosed with ASD (n = 518) or ID (n = 145) and general population (GP) controls (n = 399). TSH was further analyzed in relation to ASD subgroups of intellectual ability and onset type (early-onset ASD vs. ASD with regression) ascertained by expert review of developmental services records. Odds ratios (ORs) of the differences in TSH between groups were obtained from multivariate logistic regression. We examined neonatal TSH as continuous (ln-transformed) and as quartiles. We found no association between continuous neonatal TSH levels and ASD (adj-OR: 1.00, 95% CI: 0.79-1.26) nor ID (adj-OR = 1.01, 95% CI: 0.73-1.40). Among ASD subphenotypes, we observed a suggestive inverse trend between ASD with regression and TSH, though the association only reached statistical significance in the highest TSH quartile (adj-OR: 0.50, 95% CI: 0.26-0.98). While there was little evidence that neonatal TSH is related to overall ASD risk, more work is needed to understand the influence of thyroid hormones on ASD subphenotypes. Autism Res 2020, 13: 444-455. © 2019 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Low levels of thyroid hormone at birth can negatively impact brain development. We studied whether newborn levels of thyroid stimulating hormone (TSH) were associated with autism spectrum disorder (ASD) and its subtypes in a sample of children born in California. Newborn TSH was not related to the overall risk of ASD or intellectual disability. However, the relationships of thyroid hormone levels at birth and specific subtypes of ASD, particularly ASD with developmental regression, may need more research.

Authors: Ames JL; Windham GC; Lyall K; Pearl M; Kharrazi M; Yoshida CK; Van de Water J; Ashwood P; Croen LA

Autism Res. 2020 03;13(3):444-455. Epub 2019-12-10.

PubMed abstract

Understanding childhood obesity in the US: the NIH environmental influences on child health outcomes (ECHO) program

Few resources exist for prospective, longitudinal analysis of the relationships between early life environment and later obesity in large diverse samples of children in the United States (US). In 2016, the National Institutes of Health launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate influences of environmental exposures on child health and development. We describe demographics and overweight and obesity prevalence in ECHO, and ECHO’s potential as a resource for understanding how early life environmental factors affect obesity risk. In this cross-sectional study of 70 extant US and Puerto Rico cohorts, 2003-2017, we examined age, race/ethnicity, and sex in children with body mass index (BMI) data, including 28,507 full-term post-birth to <2 years and 38,332 aged 2-18 years. Main outcomes included high BMI for age <2 years, and at 2-18 years overweight (BMI 85th to <95th percentile), obesity (BMI???95th percentile), and severe obesity (BMI???120% of 95th percentile). The study population had diverse race/ethnicity and maternal demographics. Each outcome was more common with increasing age and varied with race/ethnicity. High BMI prevalence (95% CI) was 4.7% (3.5, 6.0) <1 year, and 10.6% (7.4, 13.7) for 1 to <2 years; overweight prevalence increased from 13.9% (12.4, 15.9) at 2-3 years to 19.9% (11.7, 28.2) at 12 to <18 years. ECHO has the statistical power to detect relative risks for 'high' BMI ranging from 1.2 to 2.2 for a wide range of exposure prevalences (1-50%) within each age group. ECHO is a powerful resource for understanding influences of chemical, biological, social, natural, and built environments on onset and trajectories of obesity in US children. The large sample size of ECHO cohorts adopting a standardized protocol for new data collection of varied exposures along with longitudinal assessments will allow refined analyses to identify drivers of childhood obesity.

Authors: Tylavsky FA; Ferrara A; Hedderson MM; Zhu Y; Trasande L; et al.

Int J Obes (Lond). 2020 03;44(3):617-627. Epub 2019-10-24.

PubMed abstract

Trivalent inactivated influenza vaccine (IIV3) during pregnancy and six-month infant development

Despite recommendations by professional organizations that all pregnant women receive inactivated influenza vaccine, safety concerns remain a barrier. Our objective was to assess the effect of trivalent influenza vaccines (IIV3) during pregnancy on parent report 6-month infant development. We conducted a multi-site prospective birth cohort study during the 2010-2011 influenza season and followed pregnant women and their newborns through 6 months of age. Information on IIV3 during pregnancy was ascertained from the EHR and self-report. The Ages and Stages Questionnaire-3 (ASQ-3) was completed by the mother to assess 6-month infant neurodevelopment in five domains (communication, gross motor, fine motor, problem-solving, and personal adaptive skills). Scores for each domain above the cut-off point indicating typical development were categorized as “on schedule” while scores in the zones indicating the need for either monitoring or further assessment were categorized as “not on schedule”. Multivariable logistic regression was conducted. Of the 1225 infant-mother pairs, 65% received IIV3 during pregnancy. In bivariate analysis, infants of women who received IIV3 during pregnancy were moderately-less likely to need monitoring or further assessment in the personal social domain compared with infants of unvaccinated women (10.0% vs. 14.1%, p = 0.033; crude OR (cOR): 0.68(95%CI:0.48,0.97)). However, after controlling for potential confounders, the findings were no longer statistically significant (aOR:0.72,95%CI: 0.49,1.06,p = 0.46). No significant unadjusted or adjusted associations emerged in any other ASQ-3 domain. There was no significant association between IIV3 exposure during pregnancy and 6-month infant development. Studies of IIV3 during pregnancy to assess longer-term developmental outcomes are indicated.

Authors: Avalos LA; Zerbo O; Li DK; et al.

Vaccine. 2020 02 28;38(10):2326-2332. Epub 2020-02-05.

PubMed abstract

Exercise During the First Trimester and Infant Size at Birth: Targeted Maximum Likelihood Estimation of the Causal Risk Difference

This cohort study sought to estimate the differences in risk of delivering infants who were small or large for gestational age (SGA or LGA, respectively) according to exercise during the first trimester of pregnancy (vs. no exercise) among 2,286 women receiving care at Kaiser Permanente Northern California in 2013-2017. Exercise was assessed by questionnaire. SGA and LGA were determined by the sex- and gestational-age-specific birthweight distributions of the 2017 US Natality file. Risk differences were estimated by targeted maximum likelihood estimation, with and without data-adaptive prediction (machine learning). Analyses were also stratified by prepregnancy weight status. Overall, exercise at the cohort-specific 75th percentile was associated with an increased risk of SGA of 4.5 (95% CI: 2.1, 6.8) per 100 births, and decreased risk of LGA of 2.8 (95% CI: 0.5, 5.1) per 100 births; similar findings were observed among the underweight and normal-weight women, but no associations were found among those with overweight or obesity. Meeting Physical Activity Guidelines was associated with increased risk of SGA and decreased risk of LGA but only among underweight and normal-weight women. Any vigorous exercise reduced the risk of LGA in underweight and normal-weight women only and was not associated with SGA risk.

Authors: Ehrlich SF; Neugebauer RS; Feng J; Hedderson MM; Ferrara A

Am J Epidemiol. 2020 02 28;189(2):133-145.

PubMed abstract

Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher’s exact test, P = 6.2 x 10-14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.

Authors: Zhu B; Raine-Bennett T; Mirabello L; et al.

Nat Commun. 2020 Feb 14;11(1):886. Epub 2020-02-14.

PubMed abstract

Association of Depression, Anxiety, and Trauma With Cannabis Use During Pregnancy

Authors: Young-Wolff KC; Sarovar V; Tucker LY; Goler NC; Alexeeff SE; Ridout KK; Avalos LA

JAMA Netw Open. 2020 02 05;3(2):e1921333. Epub 2020-02-05.

PubMed abstract

The Effect of Gestational Weight Gain Across Reproductive History on Maternal Body Mass Index in Midlife: The Study of Women’s Health Across the Nation

Background: Excessive weight gain during pregnancy is common and has been shown to be associated with increased long-term maternal weight. However, less is known on whether there is a cumulative effect of excessive gestational weight gain (GWG) over multiple pregnancies. Methods: Data from the Study of Women’s Health Across the Nation were used, restricted to parous women with no history of stillbirth or premature birth. The effect of the number of excessive GWG pregnancies on body mass index (BMI) in midlife (age 42-53) was analyzed using multivariable linear regression. Fully adjusted models included parity, inadequate GWG, demographic, and behavioral characteristics. Results: The 1181 women included in this analysis reported a total of 2693 births. Overall, 466 (39.5%) were categorized as having at least one pregnancy with excessive GWG. The median BMI at midlife was 26.0 kg/m2 (interquartile range 22.5-31.1). In fully adjusted models, each additional pregnancy with excessive GWG was associated with 0.021 higher estimated log BMI (p = 0.031). Among women with 1-3 births, adjusted mean (95% confidence interval) BMI for those with 0, 1, 2, and 3 excessive GWG pregnancies was 25.4 (24.9-25.9), 26.8 (26.1-27.5), 27.5 (26.6-28.4), and 28.8 (27.3-30.5), respectively. Conclusions: In this multiethnic study of women with a history of term live births, the number of pregnancies with excessive GWG was associated with increased maternal BMI in midlife. Our findings suggest that prevention of excessive GWG at any point in a woman’s reproductive history can have an impact on long-term maternal health.

Authors: Hutchins F; Abrams B; Brooks M; Colvin A; Moore Simas T; Rosal M; Sternfeld B; Crawford S

J Womens Health (Larchmt). 2020 02;29(2):148-157. Epub 2019-11-27.

PubMed abstract

Sexual function, menopausal symptoms, depression and cancer worry in women with BRCA mutations

Assess sexual function, menopausal symptoms, and depression in women with BRCA mutations associated with oophorectomy and menopause status. Women age 40 and older with BRCA mutations completed a questionnaire with validated measures of sexual activity, menopausal symptoms, depression, and cancer worry. These measures were compared between those with intact ovaries and those who had undergone pre- or post-menopausal risk-reducing salpingo-oophorectomy (RRSO). Of the 244 women, 21 had intact ovaries and 223 had undergone RRSO. Women with intact ovaries had less menopausal symptoms (Menopausal Symptom Checklist (MSCL) score 14 versus 23, P = .01) but more cancer worry than women who had undergone RRSO (median Cancer Worry Scale (CWS) score 5 versus 4, P < .0001) with no significant difference in sexual activity or function. Compared with women with postmenopausal RRSO, women with premenopausal RRSO were more likely to be sexually active (56.3% versus 42.0%, P =.04) but had similar sexual functioning, including frequency, pleasure and discomfort. Women with premenopausal RRSO were also more likely to report menopausal symptoms (MSCL score 26 versus 19, P = .04) and depression (PHQ-8 score 4 versus 2, P < .001). Factors associated with sexual activity included younger age, lower BMI, living with a partner, and lower depression scores. Higher current depression score was associated with history of depression and more menopausal symptoms. Risk-reducing surgery decreases cancer risk and worry in women with BRCA mutations. Among women undergoing oophorectomy, factors such as age and history of depression were related to reduced sexual activity and increased depression, but menopausal status was not related.

Authors: Powell CB; Alabaster A; Le A; Stoller N; Armstrong MA; Raine-Bennett T

Psychooncology. 2020 02;29(2):331-338. Epub 2019-11-22.

PubMed abstract

Individualized Relative Intensity Physical Activity Accelerometer Cut-points

Physical activity (PA) intensity is expressed as either absolute or relative intensity. Absolute intensity refers to the energy required to perform an activity. Relative intensity refers to a level of effort that takes into account how hard an individual is working relative to their maximum capacity. We sought to develop methods for obtaining individualized relative-intensity accelerometer cut points using data from a maximal graded exercise treadmill test (GXT) so that each individual has their own cut point. A total of 2363 men and women 38 to 50 yr old from the CARDIA fitness study wore ActiGraph 7164 accelerometers during a maximal GXT and for seven consecutive days in 2005-2006. Using mixed-effects regression models, we regressed accelerometer counts on heart rate as a percentage of maximum (%HRmax) and on RPE. Based on these two models, we obtained a moderate-intensity (%HRmax = 64% or RPE = 12) count cut point that is specific to each participant. We applied these subject-specific cut points to the available CARDIA accelerometer data. Using RPE, the mean moderate-intensity accelerometer cut point was 4004 (SD = 1120) counts per minute. On average, cut points were higher for men (4189 counts per minute) versus women (3865 counts per minute) and were higher for Whites (4088 counts per minute) versus African Americans (3896 counts per minute). Cut points were correlated with body mass index (rho = -0.11) and GXT duration (rho = 0.33). Mean daily minutes of absolute- and relative-intensity moderate to vigorous PA were 34.1 (SD = 31.1) min·d and 9.1 (SD = 18.2) min·d, respectively. RPE cut points were higher than those based on %HRmax. This is likely due to some participants ending the GXT before achieving their HRmax. Accelerometer-based relative-intensity PA may be a useful measure of intensity relative to maximal capacity.

Authors: Siddique J; Sternfeld B; Freedson P; et al.

Med Sci Sports Exerc. 2020 02;52(2):398-407.

PubMed abstract

Neonatal jaundice in association with autism spectrum disorder and developmental disorder

To examine the association between neonatal jaundice and autism spectrum disorder (ASD) and non-ASD developmental disorder (DD). We analyzed data from the Study to Explore Early Development, a US multisite, case-control study conducted from 2007 to 2011. Developmental assessment classified children aged 2-5 years into: ASD (n = 636), DD (n = 777), or controls (POP; n = 926). Neonatal jaundice (n = 1054) was identified from medical records and maternal interviews. We examined associations between neonatal jaundice and ASD and DD using regression models to obtain adjusted odds ratios (aOR). Our results showed interaction between gestational age and neonatal jaundice. Neonatal jaundice was associated with ASD at 35-37 weeks (aOR = 1.83, 95%CI 1.05, 3.19), but not ≥38 weeks gestation (aOR = 0.97, 95%CI 0.76, 1.24). Similar results were observed with DD. Further exploration of timing and severity of neonatal jaundice and ASD/DD is warranted.

Authors: Cordero C; Schieve LA; Croen LA; Engel SM; Maria Siega-Riz A; Herring AH; Vladutiu CJ; Seashore CJ; Daniels JL

J Perinatol. 2020 02;40(2):219-225. Epub 2019-08-06.

PubMed abstract

Association Between Objective Activity Intensity & Heart Rate Variability: CVD Risk Factor Mediation (CARDIA)

We evaluated the associations between accelerometer-estimated physical activity (PA) intensity and heart rate variability (HRV) and examined mediation of these associations by glycemic control indices and other cardiovascular disease (CVD) risk factors. Data were from 1,668 participants (X[Combining Overline]age=45.9±3.5 years, 58.0% female, 39.9% black) who participated in Year 20 (2005-06) of the Coronary Artery Risk Development in Young Adults (CARDIA) Fitness Study. The ActiGraph 7164 estimated participants’ mean min/day of vigorous-intensity PA (VPA), moderate-intensity PA (MPA), and light-intensity PA (LPA) over seven days. Three sequential 10-sec 12-lead ECG strips were used to derive standard deviation of all normal RR intervals (SDNN) and root mean square of all successive RR intervals (rMSSD) HRV. Mediators representing glycemic control indices included fasting glucose, fasting insulin, and 2-hour oral glucose tolerance, with other mediators being traditional CVD risk factors. Multiple linear regression assessed independent associations of PA intensity with HRV per 1-SD. Mediation analyses computed the proportion of the PA-HRV association attributable to physiological mediators. Participants averaged 2.7±6.2, 33.0±22.0, and 360.2±83.8 min/day of VPA, MPA, and LPA, respectively, with mean values for SDNN (32.6±22.4 ms) and rMSSD (34.0±24.8 ms) similar. After adjustment for demographic and lifestyle behaviors, VPA was associated with both HRV metrics (SDNN: std beta=0.06 [0.03, 0.10]; rMSSD: std beta=0.08, [0.05, 0.12]) and LPA with rMSSD only (std beta=0.05, [0.01, 0.08]). Fasting insulin and glucose mediated 11.6%-20.7% of the association of VPA and LPA with HRV, with triglycerides also potentially mediating these associations (range: 9.6%-13.4%). Accelerometer-estimated VPA was associated with higher (i.e., improved) HRV. LPA also demonstrated a positive association. Mediation analyses suggested these associations may be most attributable to glucose-insulin dynamics.

Authors: Pope ZC; Gabriel KP; Whitaker KM; Chen LY; Schreiner PJ; Jacobs DR; Sternfeld B; Carr JJ; Lloyd-Jones DM; Pereira MA

Med Sci Sports Exerc. 2020 Jan 06.

PubMed abstract

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis

This study investigated the prospective associations of circulating levels of sex hormone-binding globulin (SHBG) levels with cardiometabolic biomarkers and risk of gestational diabetes (GDM) during pregnancy. It also examines the longitudinal trajectory of SHBG in women with and without GDM. We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort. The cohort enrolled non-obese and obese women aged 18-40 years with a singleton pregnancy between 8 and 13 weeks of gestation from 2009 to 2013. GDM was ascertained via medical records review. Blood samples were drawn four times at gestational weeks 10-14, 15-26, 23-31, and 33-39. The prospective associations between SHBG levels and cardiometabolic biomarkers were examined using the Spearman partial correlation among the controls. The longitudinal trajectories of SHBG levels were examined among the cases and the controls. Meta-analysis of prospective studies were performed to examine the association between SHBG levels and GDM risk. SHBG levels at gestational weeks 10-14 were significantly inversely associated with fasting insulin (r = -0.17, P = 0.01) and insulin resistance as measured by HOMA-IR (r = -0.17, P = 0.01) at gestational week 15-26. SHBG at gestational weeks 10-14 and 15-26 was lower in cases than controls (mean ± standard deviation: (204.0 ± 97.6) vs. (220.9 ± 102.5) nmol/L, P = 0.16 and (305.6 ± 124.3) vs. (322.7 ± 105.1) nmol/L, P = 0.14, respectively), yet the differences were not significant. In the meta-analysis, SHBG was 41.5 nmol/L (95% confidence interval: 23.9, 59.1, P < 0.01) significantly lower among women with GDM than without, and each 50 nmol/L increase in SHBG was significantly associated with an odds ratio of 0.85 (95% confidence interval: 0.76-0.95, P = 0.01) for GDM. Lower SHBG levels in early pregnancy were prospectively associated with higher high insulin levels and insulin resistance in mid-pregnancy and subsequent risk of GDM, independent of adiposity. SHBG may serve as a marker for the identification of high-risk pregnancies during early pregnancy.

Authors: Li, Meng-Ying; Rawal, Shristi; Hinkle, Stefanie N; Zhu, Ye-Yi; Tekola-Ayele, Fasil; Tsai, Michael Y; Liu, Si-Min; Zhang, Cui-Lin

Matern Fetal Med. 2020 Jan;2(1):2-9. Epub 2020-01-24.

PubMed abstract

Factors Influencing Participation in Biospecimen Research among Parents of Youth with Mental Health Conditions

Biospecimens are tools that have the potential to improve early identification and treatment for autism spectrum disorders (ASD) and bipolar disorders (BPD). Unfortunately, most biobanks lack racial/ethnic diversity. One challenge to including a diverse sample of youth is recruiting and engaging families. We sought to better understand facilitators and barriers to participation in biospecimen research among a diverse group of parents of youth with ASD and BPD. The current study involved 3 Mental Health Research Network sites. At each site, parents participated in an interview that explored attitudes and beliefs about genetic research. Interviews were audio-recorded, and audio files were transcribed and coded using content analysis. A total of 58 interviews were conducted. Four challenges emerged: (1) contacting and engaging potential research participants, (2) motivating potential participants to read recruitment and consent materials, (3) motivating participation in research, in general, and (4) motivating participation in research involving biospecimen donation, specifically. Participants were eager to participate as long as the research process involved trust, clarity, and flexibility. Future research involving youth with mental health conditions would benefit from implementing multimodal strategies for recruitment and data collection and sharing knowledge gained by the research with study participants.

Authors: Owen-Smith AA; Sesay MM; Lynch FL; Massolo M; Cerros H; Croen LA

Public Health Genomics. 2020;23(3-4):122-132. Epub 2020-07-22.

PubMed abstract

Family Environment, Neurodevelopmental Risk, and the Environmental Influences on Child Health Outcomes (ECHO) Initiative: Looking Back and Moving Forward

The family environment, with all its complexity and diverse components, plays a critical role in shaping neurodevelopmental outcomes in children. Herein we review several domains of the family environment (family socioeconomic status, family composition and home environment, parenting behaviors and interaction styles, parental mental health and functioning, and parental substance use) and discuss how these domains influence neurodevelopment, with particular emphasis on mental health outcomes. We also highlight a new initiative launched by the National Institutes of Health, the Environmental influences on Child Health Outcomes (ECHO) program. We discuss the role that ECHO will play in advancing our understanding of the impact of the family environment on children’s risk for psychiatric outcomes. Lastly, we conclude with important unanswered questions and controversies in this area of research, highlighting how ECHO will contribute to resolving these gaps in our understanding, clarifying relationships between the family environment and children’s mental health.

Authors: Bush NR; Avalos LA; Posner J; et al.

Front Psychiatry. 2020;11:547. Epub 2020-06-19.

PubMed abstract

Leisure Time Physical Activity, Sedentary Time in Pregnancy, and Infant Weight at Approximately 12 Months

Background: Maternal leisure time physical activity (LTPA) and sedentary time during pregnancy may influence programming of infant growth in a sex-specific manner. Materials and Methods: Participants (N = 35,212) from the Danish National Birth Cohort reported moderate/vigorous LTPA (hours/week) in early (conception to mean 16 weeks of gestation) and late pregnancy (mean 31 weeks of gestation to delivery) during interviews at 16 weeks of gestation and 6 months postpartum. Participants reported screen time at work and time spent watching television/videos (hours/day) in early pregnancy. Infant weight at 12 months of age was reported by mothers. Weight-for-length was categorized using sex-specific international standards. Results:Participants reported on average 1 hour per week of early pregnancy moderate/vigorous LTPA, 0.5 hour per week of late pregnancy LTPA, and 3 hours per day of early pregnancy sedentary time. Early pregnancy LTPA category was not associated with infant weight (p for trend = 0.62). There were suggested associations of early pregnancy sedentary time above the first quartile with greater odds of infant underweight (odds ratio = 1.15-1.27; p for trend = 0.27). Associations were similar in male and female infants. Conclusions: There is no clear relationship between early or late pregnancy LTPA and infant weight at 12 months in our study. Maternal early pregnancy sedentary time may be associated with infant underweight at 12 months.

Authors: Badon SE; Littman AJ; Chan KCG; Williams MA; Kirkegaard H; Nohr EA; Enquobahrie DA

Womens Health Rep (New Rochelle). 2020;1(1):123-131. Epub 2020-05-12.

PubMed abstract

Plasma Prolactin and Progesterone Levels and the Risk of Gestational Diabetes: A Prospective and Longitudinal Study in a Multiracial Cohort

Objective: Prolactin and progesterone are implicated in glucose homeostasis in and outside of pregnancy. However, their associations with gestational diabetes (GDM) risk were not well-understood. This study investigates this question in a prospective and longitudinal cohort. Methods: This is a nested case-control study of 107 incident GDM cases and 214 matched non-GDM controls within the NICHD Fetal Growth Studies-Singleton Cohort. Blood samples were collected at gestational weeks 10-14, 15-26, 23-31, and 33-39. The odds ratios (OR) of GDM were estimated using conditional logistic regression. The longitudinal changes in prolactin and progesterone were estimated using linear mixed-effects models. Results: Compared to controls, cases have significantly higher prolactin levels at weeks 10-14 (median: 50.4 vs. 42.1 ng/mL), and significantly lower progesterone levels at weeks 10-14 (median: 109.4 vs. 126.5 nmol/L). Prolactin levels at weeks 10-14 were significantly and positively associated with GDM risk; the adjusted ORs across increasing quartiles were 1.00, 1.13, 1.80, 2.33 (p-trend = 0.02). A similar but slightly attenuated association was observed at weeks 15-26 (p-trend = 0.05). Progesterone was not associated with GDM risk at either time points. Longitudinal changes in prolactin and progesterone between the first two visits were not associated with GDM risk. In addition, prolactin was significantly and positively associated with insulin and C-peptide levels at weeks 10-14, and significantly and inversely associated with C-peptide levels at weeks 15-26; progesterone was significantly and inversely associated with glucose and insulin levels. Conclusions: This study provided the first prospective evidence of a positive association between prolactin levels in early pregnancy and GDM risk.

Authors: Li M; Song Y; Rawal S; Hinkle SN; Zhu Y; Tekola-Ayele F; Ferrara A; Tsai MY; Zhang C

Front Endocrinol (Lausanne). 2020;11:83. Epub 2020-02-27.

PubMed abstract

Identifying hypertension in pregnancy using electronic medical records: The importance of blood pressure values

To incorporate blood pressure (BP), diagnoses codes, and medication fills from electronic medical records (EMR) to identify pregnant women with hypertension. A retrospective cohort study of singleton pregnancies at three US integrated health delivery systems during 2005-2014. Women were considered hypertensive if they had any of the following: (1) ≥2 high BPs (≥140/90 mmHg) within 30 days during pregnancy (High BP); (2) an antihypertensive medication fill in the 120 days before pregnancy and a hypertension diagnosis from 1 year prior to pregnancy through 20 weeks gestation (Treated Chronic Hypertension); or (3) a high BP, a hypertension diagnosis, and a prescription fill within 7 days during pregnancy (Rapid Treatment). We described characteristics of these pregnancies and conducted medical record review to understand hypertension presence and severity. Of 566,624 pregnancies, 27,049 (4.8%) met our hypertension case definition: 24,140 (89.2%) with High BP, 5,409 (20.0%) with Treated Chronic Hypertension, and 5,363 (19.8%) with Rapid Treatment (not mutually exclusive). Of hypertensive pregnancies, 19,298 (71.3%) received a diagnosis, 9,762 (36.1%) received treatment and 11,226 (41.5%) had a BP ≥ 160/110. In a random sample (n = 55) of the 7,559 pregnancies meeting the High BP criterion with no hypertension diagnosis, clinical statements about hypertension were found in medical records for 58% of them. Incorporating EMR BP identified many pregnant women with hypertension who would have been missed by using diagnosis codes alone. Future studies should seek to incorporate BP to study treatment and outcomes of hypertension in pregnancy.

Authors: Chen L; Avalos LA; Neugebauer R; Badon SE; Dublin S; et al.

Pregnancy Hypertens. 2020 Jan;19:112-118. Epub 2020-01-03.

PubMed abstract

Early Life Exposure to Air Pollution and Autism Spectrum Disorder: Findings from a Multisite Case-Control Study

Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. We examined associations between early life exposure to particulate matter ≤2.5 µm in diameter (PM2.5) and ozone in association with ASD across multiple US regions. Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case-control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. The air pollution-ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM2.5 exposure during the first year of life (OR = 1.3 [95% CI: 1.0, 1.6] per 1.6 µg/m increase in PM2.5). Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.

Authors: McGuinn LA; Croen LA; Daniels JL; et al.

Epidemiology. 2020 01;31(1):103-114.

PubMed abstract

Primary Care Physicians’ Experiences With and Strategies for Managing Electronic Messages

The increasing use of electronic communications has enhanced access to physicians for patients and clinical staff. Primary care physicians (PCPs) have anecdotally identified electronic inbox management as a new source of work-related stress. To describe PCPs’ experiences managing their electronic inboxes and to characterize the array of management strategies developed by individual physicians and practice groups. This qualitative study was conducted in 8 medical centers of a large group practice with more than 4 million patients in diverse settings and a mature electronic health record. The group encourages patients to use portal secure messaging to enhance access to their physicians and the care experience. Semistructured interviews were conducted with 24 internists and family medicine physicians identified via snowball sampling. Interviews were conducted July through November 2018. Data analysis was conducted between November 2018 and April 2019. Audio recorded interviews were transcribed and analyzed using thematic analysis to identify major themes and subthemes. The 24 participants (12 women [50.0%]; mean [SD] age, 45.5 [6.5] years), including 9 department chiefs and 15 PCPs, had a mean (SD) of 16.8 (7.8) years since medical school graduation. Participants described substantial changes in medical practice due to electronic communication, including perceived patient expectations to receive rapid responses to portal secure messages. They described portal secure messaging as useful for building relationships with patients, but also reported that electronic message management has created new stressors, including erosion of work-life boundaries and anxiety associated with unlimited inbox volume. Individual PCPs used a diverse array of strategies, including multitasking during and outside work and delegating to medical assistants. Chiefs described group-level strategies, including reserving clinic time for inbox management, coverage systems for vacation and sick days, physician-to-physician training, and interdisciplinary teams to share messaging work. Individual physicians and local practice groups have developed a wide array of strategies for electronic inbox management. The volume of electronic messages and PCPs’ perceptions that patients expect rapid responses have created new stressors in primary care practice. Medical groups and health systems can support PCPs by facilitating knowledge transfer among physicians about inbox management strategies and further developing team structures for inbox coverage.

Authors: Lieu TA; Altschuler A; Weiner JZ; East JA; Moeller MF; Prausnitz S; Reed ME; Warton EM; Goler N; Awsare S

JAMA Netw Open. 2019 12 02;2(12):e1918287. Epub 2019-12-02.

PubMed abstract

Racial Disparities in Route of Hysterectomy for Benign Indications Within an Integrated Health Care System

Authors: Zaritsky E; Ojo A; Tucker LY; Raine-Bennett TR

JAMA Netw Open. 2019 Dec 02;2(12):e1917004. Epub 2019-12-02.

PubMed abstract

Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research

The National Institutes of Health’s Environmental influences on Child Health Outcomes (ECHO) initiative aims to understand the impact of environmental factors on childhood disease. Over 40,000 chemicals are approved for commercial use. The challenge is to prioritize chemicals for biomonitoring that may present health risk concerns. Our aim was to prioritize chemicals that may elicit child health effects of interest to ECHO but that have not been biomonitored nationwide and to identify gaps needing additional research. We searched databases and the literature for chemicals in environmental media and in consumer products that were potentially toxic. We selected chemicals that were not measured in the National Health and Nutrition Examination Survey. From over 700 chemicals, we chose 155 chemicals and created eight chemical panels. For each chemical, we compiled biomonitoring and toxicity data, U.S. Environmental Protection Agency exposure predictions, and annual production usage. We also applied predictive modeling to estimate toxicity. Using these data, we recommended chemicals either for biomonitoring, to be deferred pending additional data, or as low priority for biomonitoring. For the 155 chemicals, 97 were measured in food or water, 67 in air or house dust, and 52 in biospecimens. We found in vivo endocrine, developmental, reproductive, and neurotoxic effects for 61, 74, 47, and 32 chemicals, respectively. Eighty-six had data from high-throughput in vitro assays. Positive results for endocrine, developmental, neurotoxicity, and obesity were observed for 32, 11, 35, and 60 chemicals, respectively. Predictive modeling results suggested 90% are toxicants. Biomarkers were reported for 76 chemicals. Thirty-six were recommended for biomonitoring, 108 deferred pending additional research, and 11 as low priority for biomonitoring. The 108 deferred chemicals included those lacking biomonitoring methods or toxicity data, representing an opportunity for future research. Our evaluation was, in general, limited by the large number of unmeasured or untested chemicals.

Authors: Pellizzari ED; Woodruff TJ; Boyles RR; Kannan K; Beamer PI; Buckley JP; Wang A; Zhu Y; Bennett DH; (Environmental influences on Child Health Outcomes)

Environ Health Perspect. 2019 12;127(12):126001. Epub 2019-12-18.

PubMed abstract

Racial/Ethnic Disparities in the Prevalence of Diabetes and Prediabetes by BMI: Patient Outcomes Research To Advance Learning (PORTAL) Multisite Cohort of Adults in the U.S

To examine racial/ethnic disparities in the prevalence of diabetes and prediabetes by BMI category. In a consortium of three U.S. integrated health care systems, 4,906,238 individuals aged ≥20 years during 2012-2013 were included. Diabetes and prediabetes were ascertained by diagnosis and laboratory results; antihyperglycemic medications were also included for diabetes ascertainment. The age-standardized diabetes and prediabetes prevalence estimates were 15.9% and 33.4%, respectively. Diabetes but not prediabetes prevalence increased across BMI categories among all racial/ethnic groups (P for trend < 0.001). Racial/ethnic minorities reached a given diabetes prevalence at lower BMIs than whites; Hawaiians/Pacific Islanders and Asians had a diabetes prevalence of 24.6% (95% CI 24.1-25.2%) in overweight and 26.5% (26.3-26.8%) in obese class 1, whereas whites had a prevalence of 23.7% (23.5-23.8%) in obese class 2. The age-standardized prediabetes prevalence estimates in overweight among Hispanics (35.6% [35.4-35.7%]), Asians (38.1% [38.0-38.3%]), and Hawaiians/Pacific Islanders (37.5% [36.9-38.2%]) were similar to those in obese class 4 among whites (35.3% [34.5-36.0%]), blacks (36.8% [35.5-38.2%]), and American Indians/Alaskan Natives (34.2% [29.6-38.8%]). In adjusted models, the strength of association between BMI and diabetes was highest among whites (relative risk comparing obese class 4 with normal weight 7.64 [95% CI 7.50-7.79]) and lowest among blacks (3.16 [3.05-3.27]). The association between BMI and prediabetes was less pronounced. Racial/ethnic minorities had a higher burden of diabetes and prediabetes at lower BMIs than whites, suggesting the role of factors other than obesity in racial/ethnic disparities in diabetes and prediabetes risk and highlighting the need for tailored screening and prevention strategies.

Authors: Zhu Y; Ferrara A; et al.

Diabetes Care. 2019 12;42(12):2211-2219. Epub 2019-09-19.

PubMed abstract

Detection of early stage ovarian cancer in a large community cohort

Although detecting ovarian cancer at early stage is a highly meaningful clinical goal, no studies have evaluated early stage disease presentation in a large community-based population and how it differs from that of late stage disease. Electronic medical records were evaluated for women diagnosed with ovarian or fallopian tube cancer in 2016 and 2017 to identify the first imaging study to detect disease. Women being followed prior to diagnosis for known genetic risk from BRCA or other mutation were excluded. The visit in which the imaging test was ordered and related encounters were reviewed to determine the indication for imaging. Patient characteristics, presenting symptoms and duration, and modality of first abnormal imaging were compared for early vs late stage ovarian cancer and by provider specialty. Of 540 women with ovarian cancer, 190 (35%) were diagnosed with early stage disease, of whom 141 (74%) were symptomatic, with 45% of women presenting to internists, 33% to gynecologists, and 20% to emergency medicine physicians. Pelvic ultrasonography detected only 23% of late stage cases whereas pelvic ultrasonography and abdominal pelvic computed tomography (CT) each detected 47% of early stage cases. While abdominal pain and bloating were common to both women with early and late stage cancer, women with early stage disease were younger (58 vs 64 years, P < .0001), more likely to present to gynecologists (33% vs 15%, P < .001) and complained more often of a palpable mass (17% vs 6%, P < .0001) or postmenopausal bleeding (11% vs 5%, P < .001). Excluding women with genetic predisposition to ovarian cancer known prior to diagnosis, approximately three out of four cases of early stage ovarian cancer are detected as the result of evaluation of symptoms and one in four cases are detected incidentally. Abdominal pelvic CT and pelvic ultrasonography each detect an equal proportion of early stage cases. In contrast to late stage presentation, women diagnosed with early stage disease present more often with complaints of a palpable mass or postmenopausal bleeding, particularly to gynecologists.

Authors: Suh-Burgmann EJ; Alavi M

Cancer Med. 2019 11;8(16):7133-7140. Epub 2019-09-30.

PubMed abstract

A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort

Short telomere length (TL), an indicator of cellular aging and oxidative stress, has been implicated in glucose homeostasis. Additionally, studies have illustrated that the association of TL with health outcomes may vary by age. Yet, data on the association between TL and gestational diabetes mellitus (GDM) are sparse and the potential effect modification by age remains unknown. We prospectively investigated TL in early pregnancy in relation to the subsequent GDM risk in a case-control study of 93 women with GDM and 186 randomly selected controls matched on age, race/ethnicity, and gestational weeks at blood collection. TL was measured using blood samples collected at 10-14 gestational weeks and reported as the T/S ratio, a ratio of telomere repeat length T to copy number of a single copy gene S. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for major risk factors. Overall, TL was not significantly associated with GDM risk. The TL-GDM association was significantly modified by age (Pinteraction = 0.02). Shorter TL in early pregnancy was associated with an increased GDM risk among women <30 years old (adjusted OR comparing the shortest vs. longest tertile: 3.1, 95% CI = 1.2, 8.1), but not associated with GDM risk among women ≥30 years. Our findings suggest that TL in early pregnancy may be implicated in GDM development, particularly among younger women.

Authors: Lin Y; Zhu Y; Wu J; Hinkle SN; Rawal S; Han J; Weir NL; Tsai MY; Zhang C

Epidemiology. 2019 11;30 Suppl 2:S10-S16.

PubMed abstract

Community-based service use in preschool children with autism spectrum disorder and associations with insurance status

ASD-related services can improve outcomes for children, but less is known about service outside of school settings during preschool age. We aimed to describe amount and category of community-based service use among 3-5-year-old children with ASD and examine differences by health insurance. We used cross-sectional data on 792 children with ASD diagnoses in the Study to Explore Early Development, a community-based study of neurodevelopment with enrollment between 2012-2016. Mothers reported current child service use and insurance status at study entry. We used log-Poisson and logistic regression to compare service use by insurance group. Nearly 40% of children were not receiving community-based services at study entry. Children with public insurance had fewer total services than children with private or both insurances. After adjustment for sociodemographic confounders, insurance status was not associated with types of different categories of community-based services. However, children with public insurance alone were least likely to receive community-based behavioral therapy and most likely to receive psychotropic medication compared to other insurances. Many preschool-aged children do not receive community-based services, with receipt associated with insurance type. Increasing access and availability for evidence-based service, especially for beneficiaries of public insurance, may improve service use and outcomes.

Authors: Rubenstein, Eric; Croen, Lisa; Lee, Li-Ching; Moody, Eric; Schieve, Laura A; Soke, Gnakub N; Thomas, Kathleen; Wiggins, Lisa; Daniels, Julie

Res Autism Spectr Disord. 2019 Oct;66. Epub 2019-06-15.

PubMed abstract

Air pollution, neighborhood deprivation, and autism spectrum disorder in the Study to Explore Early Development

To examine whether neighborhood deprivation modifies the association between early life air pollution exposure and autism spectrum disorder (ASD), we used resources from a multisite case-control study, the Study to Explore Early Development. Cases were 674 children with confirmed ASD born in 2003-2006; controls were 855 randomly sampled children born during the same time period and residents of the same geographic areas as cases. Air pollution was assessed by roadway proximity and particulate matter <2.5 μm (PM2.5) exposure during pregnancy and first year of life. To characterize neighborhood deprivation, an index was created based on eight census tract-level socioeconomic status-related parameters. The continuous index was categorized into tertiles, representing low, moderate, and high deprivation. Logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Neighborhood deprivation modified (Pfor interaction = 0.08) the association between PM2.5 exposure during the first year of life and ASD, with a stronger association for those living in high (OR = 2.42, 95% CI = 1.20, 4.86) rather than moderate (OR=1.21, 95% CI = 0.67, 2.17) or low (OR=1.46, 95% CI = 0.80, 2.65) deprivation neighborhoods. Departure from additivity or multiplicativity was not observed for roadway proximity or exposures during pregnancy. These results provide suggestive evidence of interaction between neighborhood deprivation and PM2.5 exposure during the first year of life in association with ASD.

Authors: McGuinn LA; Croen LA; Daniels JL; et al.

Environ Epidemiol. 2019 Oct;3(5).

PubMed abstract

Infection and Fever in Pregnancy and Autism Spectrum Disorders: Findings from the Study to Explore Early Development

Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.

Authors: Croen LA; Zerbo O; Ames JL; et al.

Autism Res. 2019 10;12(10):1551-1561. Epub 2019-07-17.

PubMed abstract

Simple Adnexal Cysts: SRU Consensus Conference Update on Follow-up and Reporting.

This multidisciplinary consensus update aligns prior Society of Radiologists in Ultrasound (SRU) guidelines on simple adnexal cysts with recent large studies showing exceptionally low risk of cancer associated with simple adnexal cysts. Most small simple cysts do not require follow-up. For larger simple cysts or less well-characterized cysts, follow-up or second opinion US help to ensure that solid elements are not missed and are also useful for assessing growth of benign tumors. In postmenopausal women, reporting of simple cysts greater than 1 cm should be done to document their presence in the medical record, but such findings are common and follow-up is recommended only for simple cysts greater than 3-5 cm, with the higher 5-cm threshold reserved for simple cysts with excellent imaging characterization and documentation. For simple cysts in premenopausal women, these thresholds are 3 cm for reporting and greater than 5-7 cm for follow-up imaging. If a cyst is at least 10%-15% smaller at any time, then further follow-up is unnecessary. Stable simple cysts at initial follow-up may benefit from a follow-up at 2 years due to measurement variability that could mask growth. Simple cysts that grow are likely cystadenomas. If a previously suspected simple cyst demonstrates papillary projections or solid areas at follow-up, then the cyst should be described by using standardized terminology. These updated SRU consensus recommendations apply to asymptomatic patients and to those whose symptoms are not clearly attributable to the cyst. These recommendations can reassure physicians and patients regarding the benign nature of simple adnexal cysts after a diagnostic-quality US examination that allows for confident diagnosis of a simple cyst. Patients will benefit from less costly follow-up, less anxiety related to these simple cysts, and less surgery for benign lesions.

Authors: Levine D; Suh-Burgmann EJ; Brown DL; et al.

Radiology. 2019 Nov;293(2):359-371. doi: 10.1148/radiol.2019191354. Epub 2019 Sep 24.

PubMed abstract

Walking for health during pregnancy: A literature review and considerations for future research

Walking is the most commonly chosen type of physical activity (PA) during pregnancy and provides several health benefits to both mother and child. National initiatives have promoted the importance of walking in general, but little emphasis is directed toward pregnant women, the majority of whom are insufficiently active. Pregnant women face a variety of dynamic barriers to a physically active lifestyle, some of which are more commonly experienced during specific times throughout the pregnancy experience. Walking is unique in that it appears resistant to a number of these barriers that limit other types of PA participation, and it can be meaningfully integrated into some transportation and occupational activities when leisure-time options are unavailable. Preliminary intervention work suggests that walking programs can be effectively adopted into a typical pregnancy lifestyle. However, a great deal of work remains to administer successful pregnancy walking interventions, including developing and using validated methods of PA and walking assessment. This narrative review discusses the unique advantages of walking during pregnancy, provides recommendations for future intervention work, and outlines the need for pregnancy-focused community walking initiatives. Standard search procedures were followed to determine sources from the literature specific to walking during pregnancy for use in each section of this review.

Authors: Connolly CP; Conger SA; Montoye AHK; Marshall MR; Schlaff RA; Badon SE; Pivarnik JM

J Sport Health Sci. 2019 Sep;8(5):401-411. Epub 2018-11-17.

PubMed abstract

Plasma phospholipid n-3 and n-6 polyunsaturated fatty acids in relation to cardiometabolic markers and gestational diabetes: A longitudinal study within the prospective NICHD Fetal Growth Studies

Despite dietary recommendations of polyunsaturated fatty acids (PUFAs) for cardiometabolic health, n-3 and n-6 PUFAs and their interplay in relation to diabetes risk remain debated. Importantly, data among pregnant women are scarce. We investigated individual plasma phospholipid n-3 and n-6 PUFAs in early to midpregnancy in relation to subsequent risk of gestational diabetes mellitus (GDM). Within the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (n = 2,802), individual plasma phospholipid n-3 and n-6 PUFAs levels were measured at gestational weeks (GWs) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used, adjusting for major risk factors for GDM. After adjusting for covariates, individual n-3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were inversely correlated with insulin-resistance markers, whereas individual n-6 dihomo-gamma-linolenic acid (DGLA) was positively correlated with insulin-resistance markers. At GW 15-26, a standard deviation (SD) increase in total n-3 PUFAs and individual n-3 DPA was associated with a 36% (adjusted odds ratio 0.64; 95% CI 0.42-0.96; P = 0.042) and 33% (0.67; 95% CI 0.45-0.99; P = 0.047) lower risk of GDM, respectively; however, the significance did not persist after post hoc false-discovery rate (FDR) correction (FDR-corrected P values > 0.05). Associations between total n-6 PUFAs and GDM were null, whereas associations with individual n-6 PUFAs were differential. Per SD increase, gamma-linolenic acid (GLA) at GWs 10-14 and DGLA at GWs 10-14 and 15-26 were significantly associated with a 1.40- to 1.95-fold higher risk of GDM, whereas docosatetraenoic acid (DTA) at GW 15-26 was associated with a 45% (0.55; 95% CI 0.37-0.83) lower risk of GDM (all FDR-corrected P values < 0.05). Null associations were observed for linoleic acid (LA) in either gestational window in relation to risk of GDM. Women with high (≥median) n-3 PUFAs and low (

Authors: Zhu Y; Li M; Rahman ML; Hinkle SN; Wu J; Weir NL; Lin Y; Yang H; Tsai MY; Ferrara A; Zhang C

PLoS Med. 2019 09;16(9):e1002910. Epub 2019-09-13.

PubMed abstract

Enhanced Recovery After Surgery to Change Process Measures and Reduce Opioid Use After Cesarean Delivery: A Quality Improvement Initiative

To evaluate implementation of an enhanced recovery after surgery (ERAS) program for patients undergoing elective cesarean delivery by comparing opioid exposure, multimodal analgesia use, and other process and outcome measures before and after implementation. An ERAS program was implemented among patients undergoing elective cesarean delivery in a large integrated health care delivery system. We conducted a pre-post study of ERAS implementation to compare changes in process and outcome measures during the 12 months before and 12 months after implementation. The study included 4,689 patients who underwent an elective cesarean delivery in the 12 months before (pilot sites: March 1, 2015-February 29, 2016, all other sites: October 1, 2015-September 30, 2016), and 4,624 patients in the 12 months after (pilot sites: April 1, 2016-March 31, 2017, all other sites: November 1, 2016-October 31, 2017) ERAS program implementation. After ERAS implementation mean inpatient opioid exposure (average daily morphine equivalents) decreased from 10.7 equivalents (95% CI 10.2-11.3) to 5.4 equivalents (95% CI 4.8-5.9) controlling for age, race-ethnicity, prepregnancy body mass index, patient reported pain score, and medical center. The use of multimodal analgesia (ie, acetaminophen and neuraxial anesthesia) increased from 9.7% to 88.8%, the adjusted risk ratio (RR) for meeting multimodal analgesic goals was 9.13 (RR comparing post-ERAS with pre-ERAS; 95% CI 8.35-10.0) and the proportion of time patients reported acceptable pain scores increased from 82.1% to 86.4% (P<.001). Outpatient opioids dispensed at hospital discharge decreased from 85.9% to 82.2% post-ERAS (P<.001) and the average number of dispensed pills decreased from 38 to 26 (P<.001). The hours to first postsurgical ambulation decreased by 2.7 hours (95% CI -3.1 to -2.4) and the hours to first postsurgical solid intake decreased by 11.1 hours (95% CI -11.5 to -10.7). There were no significant changes in hospital length of stay, surgical site infections, hospital readmissions, or breastfeeding rates. Implementation of an ERAS program in patients undergoing elective cesarean delivery was associated with a reduction in opioid inpatient and outpatient exposure and with changes in surgical process measures of care without worsened surgical outcomes.

Authors: Hedderson M; Campbell C; Quesenberry C; Liu V; et al.

Obstet Gynecol. 2019 09;134(3):511-519.

PubMed abstract

Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.

Authors: Conradt E; Croen LA; Hedderson MM; Lester BM; et al.

Pediatrics. 2019 Sep;144(3).

PubMed abstract

Pre- and Early Pregnancy Onset Depression and Subsequent Rate of Gestational Weight Gain

Background:Depression is associated with weight change outside of pregnancy. We assessed associations of prepregnancy or early pregnancy onset depression with gestational weight gain (GWG) rate overall and according to Institute of Medicine (IOM) recommendations. Materials and Methods:Depression from 6 months prepregnancy through 20 weeks gestation was identified in a health care system in northern California with perinatal depression screening (2011-2016; n = 87,600). GWG rate (lbs/week) was calculated using weight at delivery and at diagnosis or depression screening ≤20 weeks. Results:Compared to women without prepregnancy or early pregnancy depression, women with prepregnancy onset depression had 11% greater risk of GWG rate IOM recommendations (95% CI: 1.01-1.05), with a stronger association for >IOM in normal weight women. Early pregnancy onset depression was associated with 0.04 lbs/week greater GWG rate (95% CI: 0.02-0.07) and 4% greater risk of GWG rate >IOM recommendations (95% CI: 1.02-1.07) compared to no prepregnancy or early pregnancy depression, with stronger associations in obese women. Conclusions:Women with prepregnancy onset depression may be at higher risk for GWG both below and above recommendations. Women with early onset prenatal depression may be at slightly higher risk for GWG rate above recommendations. Our results suggest that the relationship between depression and GWG may vary based on timing of depression onset, prepregnancy body mass index category, and antidepressant use. Additional research should identify factors that predict how a woman’s lifestyle behaviors and weight change after depression diagnosis.

Authors: Badon SE; Hedderson MM; Hyde RJ; Quesenberry CP; Avalos LA

J Womens Health (Larchmt). 2019 09;28(9):1237-1245. Epub 2019-05-07.

PubMed abstract

Bidirectional 10-year associations of accelerometer-measured sedentary behavior and activity categories with weight among middle-aged adults

Although higher sedentary behavior (SB) with low light intensity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) are thought to increase risk for obesity, other data suggest excess weight may precede these behaviors in the causal pathway. We aimed to investigate 10-year bidirectional associations between SB and activity with weight. Analysis included 886 CARDIA participants (aged 38-50 years, 62% female, 38% black) with weight and accelerometry ( ≥ 4 days with ≥ 10 h/day) collected in 2005-6 (ActiGraph 7164) and 2015-6 (ActiGraph wGT3X-BT). Accelerometer data were calibrated, harmonized, and expressed as counts per minute (cpm) and time-dependent intensity categories (min/day of SB, LPA, and MVPA; SB and MVPA were also separated into long-bout and short-bout categories). Linear regression models were constructed to estimate adjusted associations of baseline activity with 10-year change in weight and vice versa. When activity categories were the independent variables, standardized regression coefficients (βstd.) estimated associations of replacing SB with a one SD increase in other categories, adjusted for accelerometer wear time. Over 10-years, weight increased by a mean 2.55 ± 8.05 kg and mean total activity decreased by 50 ± 153 cpm. In adjusted models, one SD higher baseline mean total activity (βstd. = -1.4 kg, p 

Authors: Barone Gibbs B; Aaby D; Siddique J; Reis JP; Sternfeld B; Whitaker K; Pettee Gabriel K

Int J Obes (Lond). 2019 Aug 28.

PubMed abstract

A Seat at the Table: Strategic Engagement in Service Activities for Early Career Faculty From Underrepresented Groups in the Academy

Many academic institutions strive to promote more diverse and inclusive campuses for faculty, staff, and students. As part of this effort, these institutions seek to include individuals from historically underrepresented groups (URGs)-such as women, people from racial/ethnic minority populations, persons with disabilities-on committees and in other service activities. However, given the low number of faculty members from URGs at many institutions, these faculty members tend to receive more requests to provide service to the institution or department (e.g., serving on committees, mentoring) than their counterparts from majority groups. Faculty members from URGs, especially early-career faculty, thus risk becoming overburdened with providing service at the expense of working on other scholarly activities required for promotion and tenure (i.e., conducting research, publishing). Although many scholars and others have written about this “minority tax” and its implications for early-career faculty from underrepresented racial/ethnic minority groups, fewer have published about how this tax extends beyond racial/ethnic minorities to women and persons with disabilities. Further, the literature provides scant practical advice on how to avoid overburdening early-career faculty from URGs. Here, a group of multidisciplinary early- and mid-career faculty members from URGs seek to provide their peers from URGs with practical strategies for both evaluating the appropriateness of service requests and declining those that are not a good fit. The authors also provide institutional leaders with actionable recommendations to prevent early-career faculty from URGs from becoming overburdened with service.

Authors: Carson TL; Aguilera A; Brown SD; Peña J; Butler A; Dulin A; Jonassaint CR; Riley I; Vanderbom K; Molina KM; Cené CW

Acad Med. 2019 08;94(8):1089-1093.

PubMed abstract

Unbounded-Parent-Physician Communication in the Era of Portal Messaging

Authors: Lieu TA; Freed GL

JAMA Pediatr. 2019 Jul 29.

PubMed abstract

Scientific abstracts: Featured research at the 2019 Society of Family Planning Annual Meeting

Authors: Teal S; Haider S; Harris L; Hubacher D; Raine-Bennett T

Contraception. 2019 Jul 23.

PubMed abstract

An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study

The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.

Authors: Heuer LS; Croen LA; Jones KL; Yoshida CK; Hansen RL; Yolken R; Zerbo O; DeLorenze G; Kharrazi M; Ashwood P; Van de Water J

Biol Psychiatry. 2019 May 15.

PubMed abstract

Viral coinfection analysis using a MinHash toolkit

Human papillomavirus (HPV) is a common sexually transmitted infection associated with cervical cancer that frequently occurs as a coinfection of types and subtypes. Highly similar sublineages that show over 100-fold differences in cancer risk are not distinguishable in coinfections with current typing methods. We describe an efficient set of computational tools, rkmh, for analyzing complex mixed infections of related viruses based on sequence data. rkmh makes extensive use of MinHash similarity measures, and includes utilities for removing host DNA and classifying reads by type, lineage, and sublineage. We show that rkmh is capable of assigning reads to their HPV type as well as HPV16 lineage and sublineages. Accurate read classification enables estimates of percent composition when there are multiple infecting lineages or sublineages. While we demonstrate rkmh for HPV with multiple sequencing technologies, it is also applicable to other mixtures of related sequences.

Authors: Dawson ET; Raine-Bennett T; Durbin R; et al.

BMC Bioinformatics. 2019 Jul 12;20(1):389. Epub 2019-07-12.

PubMed abstract

A prospective study of artificially sweetened beverage intake and cardiometabolic health among women at high risk

Artificially sweetened beverages (ASBs) are commonly consumed and recommended for individuals at high risk for cardiometabolic diseases; however, the health effects of ASBs remain contradictory. Given that cross-sectional analyses are subject to reverse causation, prospective studies with long-term follow-up are needed to evaluate associations between ASBs and cardiometabolic health, especially among high-risk individuals. The aim of this study was to examine associations of ASB intake and cardiometabolic health among high-risk women with prior gestational diabetes mellitus (GDM). We included 607 women with GDM from the Danish National Birth Cohort (DNBC; 1996-2002) who completed a clinical exam 9-16 y after the DNBC pregnancy for the Diabetes & Women’s Health (DWH) Study (2012-2014). We assessed ASB intake using FFQs completed during the DNBC pregnancy and at the DWH Study clinical exam. We examined cardiometabolic outcomes at the DWH clinical exam. We estimated percentage differences in continuous cardiometabolic markers and RRs for clinical endpoints in association with ASB intake both during pregnancy and at follow-up adjusted for prepregnancy BMI, diet, and lifestyle factors. Sensitivity analyses to account for reverse causation were performed. In pregnancy and at follow-up, 30.4% and 36.4% of women regularly (≥2 servings/wk) consumed ASB, respectively. Consumption of ASBs, both during pregnancy and at follow-up, was associated with higher glycated hemoglobin (HbA1c), insulin, HOMA-IR, triglycerides, liver fat, and adiposity and with lower HDL at follow-up. After adjustment for covariates, particularly prepregnancy BMI, the majority of associations between ASB intake in pregnancy and outcomes at follow-up became null with the exception of HbA1c. ASB intake at follow-up (≥1 serving/d compared with <1 serving/mo) was associated with higher HbA1c (6.5%; 95% CI: 1.9, 11.3; P-trend = 0.007); however, associations were not upheld in sensitivity analyses for reverse causation. Among Danish women with a history of GDM, ASB intake was not significantly associated with cardiometabolic profiles.

Authors: Hinkle SN; Zhu Y; Zhang C; et al.

Am J Clin Nutr. 2019 07 01;110(1):221-232.

PubMed abstract

A Randomized Study of Values Affirmation to Promote Interest in Diabetes Prevention Among Women With a History of Gestational Diabetes

The objective of this study was to test whether 2 interventions promote interest in diabetes prevention among women with a history of gestational diabetes mellitus, who face high lifetime risk for diabetes. We designed an email outreach message promoting an existing preventive lifestyle program. The message incorporated values affirmation, a theory-based intervention that can improve openness to health information but typically relies on a writing exercise less practical in health care settings. In a 3-arm randomized study, 237 women with elevated body mass index and a history of gestational diabetes mellitus were randomized to read an outreach message containing either no affirmation (control) or 1 of 2 affirmations, streamlined to remove the typical writing exercise: either a values affirmation prompting reflection on any personal value, or a parenting affirmation prompting reflection on caregiving-related values. Outcomes included demonstrating interest in the lifestyle program (seeking information about it or intending to join) and seeking publicly-available health information about diabetes prevention. Compared with control, participants randomized to the values affirmation more frequently demonstrated interest in the lifestyle program (59.0% vs. 74.4%; adjusted relative risk: 1.31; 95% confidence interval: 1.04-1.66) and sought information about diabetes prevention (59.0% vs. 73.4%; adjusted relative risk: 1.22; 95% confidence interval: 0.97-1.54). The parenting affirmation yielded no significant differences in either outcome. A streamlined values affirmation, designed for feasibility in a health care setting, can promote interest in diabetes prevention among women at high risk. Research is needed to evaluate its effects on diabetes prevention program enrollment and clinical outcomes.

Authors: Brown SD; Fotuhi O; Grijalva CS; Tsai AL; Quesenberry CP; Ritchie JL; Cohen GL; Ferrara A

Med Care. 2019 07;57(7):528-535.

PubMed abstract

Understanding periviable birth: A microeconomic alternative to the dysregulation narrative

Periviable infants (i.e., those born in the 20th through 26th weeks of gestation) suffer much morbidity and approximately half die in the first year of life. Attempts to explain and predict these births disproportionately invoke a “dysregulation” narrative. Research inspired by this narrative has not led to efficacious interventions. The clinical community has, therefore, urged novel approaches to the problem. We aim to provoke debate by offering the theory, inferred from microeconomics, that risk tolerant women carry, without cognitive involvement, high risk fetuses farther into pregnancy than do other women. These extended high-risk pregnancies historically ended in stillbirth but modern obstetric practices now convert a fraction to periviable births. We argue that this theory deserves testing because it suggests inexpensive and noninvasive screening for pregnancies that might benefit from the costly and invasive interventions clinical research will likely devise.

Authors: Catalano R; Bruckner T; Avalos LA; Stewart H; Karasek D; Kariv S; Gemmill A; Saxton K; Casey J

Soc Sci Med. 2019 07;233:281-284. Epub 2017-12-12.

PubMed abstract

Risk factors for low birth weight among rural and urban Malaysian women

Low birth weight prevalence in Malaysia remains high. Socioeconomic background may lead to differences in physical activity and maternal nutritional status, which may play an important role in birth outcomes. This prospective cross-sectional study aimed to identify rural-urban differences in risk factors for low birth weight among women in Malaysia. Pregnant women at ≥20 weeks of gestation in urban and rural Malaysia (n = 437) completed questionnaires on sociodemographic characteristics and physical activity. Weight and middle-upper arm circumference were measured. Infant birth outcomes were extracted from medical records. The overall prevalence of low birth weight infants was 6.38%. Rural women had more low birth weight infants than urban women (9.8% vs 2.0%, p = 0.03). Findings showed rural women were less sedentary (p = 0.003) and participated in more household/caregiving activities (p = 0.036), sports activities (p = 0.01) and less occupational activity (p < 0.001) than urban women. Logistic regression revealed that older age (OR = 1.395, 95% Cl = 1.053 to 1.846), low parity (OR = 0.256, 95% Cl = 0.088-0.747) and low middle-upper arm circumference (OR = 0.738, 95% Cl = 0.552 to 0.987) increased the risk of low birth weight infants in rural, but not in urban women. We observed differences in risk factors for low birth weight between urban and rural pregnant women. Age, malnutrition and low parity were risk factors for low birth weight among rural pregnant women. Our findings suggest that rural pregnant women with low nutritional status should be encouraged to monitor their middle-upper arm circumference consistently throughout pregnancy. Improving nutritional status in rural pregnant women may reduce the risk of low birth weight infants in this population.

Authors: Kaur S; Ng CM; Badon SE; Jalil RA; Maykanathan D; Yim HS; Jan Mohamed HJ

BMC Public Health. 2019 Jun 13;19(Suppl 4):539. Epub 2019-06-13.

PubMed abstract

Lack of Standardized Terminology in Ultrasound Reports for Ovarian Cysts

Authors: Suh-Burgmann E; Herrinton L

JAMA Intern Med. 2019 06 01;179(6):847-848.

PubMed abstract

Associations of pre-pregnancy body mass index, middle-upper arm circumference, and gestational weight gain

An optimal gestational weight gain is essential for maternal health and to reduce adverse birth outcomes. Current guidelines to monitor gestational weight gain are based on pre-pregnancy body mass index (BMI). However, middle-upper arm circumference (MUAC) is increasingly used as an alternative nutritional status measure for pregnant women. Hence, this study aimed to determine associations of MUAC and pre-pregnancy BMI with gestational weight gain rate among Malaysian pregnant women. A cross-sectional study was conducted among 444 pregnant women (≥20 weeks gestation). Women completed questionnaires on sociodemographic data, maternal characteristics and pre-pregnancy weight. Height, current weight and MUAC were measured at study visit (from 1st February 2016 to 31st January 2017). About a third (34.24%) of pregnant women were overweight or obese prior to pregnancy. MUAC was inversely associated with an inadequate rate of gestational weight gain (OR = 0.77; 95% CI: 0.68, 0.87) as compared to normal gestational weight gain. In contrast, a higher MUAC was associated with a higher odds ratio (OR = 1.28; 95% CI: 1.11, 1.49) of having excessive rate of gestational weight. No associations were found for pre-pregnancy BMI categories for gestational weight gain rate. Our findings revealed that women with low MUAC were more likely to have an inadequate gestational weight gain rate during pregnancy whereas higher MUAC was associated with an excessive gestational weight gain rate. MUAC may be a useful indicator of nutritional status associated with GWG. Routine measurement of MUAC in pregnant women may help health professionals, particularly in middle-income countries, to counsel women about gestational weight gain.

Authors: Ng CM; Badon SE; Dhivyalosini M; Hamid JJM; Rohana AJ; Teoh AN; Satvinder K

Sex Reprod Healthc. 2019 Jun;20:60-65. Epub 2019-03-19.

PubMed abstract

Perceived and objective characteristics of the neighborhood environment are associated with accelerometer-measured sedentary time and physical activity, the CARDIA Study

We investigated cross-sectional and longitudinal associations of neighborhood environment characteristics with accelerometer-measured sedentary time (SED), light-intensity physical activity (LPA), and moderate-to-vigorous intensity physical activity (MVPA). Participants were 2120 men and women in the year 20 (2005-2006) and year 30 CARDIA exams (2015-2016). Year 20 neighborhood characteristics included neighborhood cohesion, resources for physical activity, poverty, and racial residential segregation. Physical activity was measured by accelerometer at years 20 and 30. Multivariable linear regression models examined associations of standardized neighborhood measures at year 20 with SED, LPA, and MVPA assessed that year, and with 10-year changes in SED, LPA, and MVPA. Cross-sectionally, a one standard deviation (SD) increase in cohesion was associated with 4.06 less SED min/day (95% CI: -7.98, -0.15), and 4.46 more LPA min/day (95% CI: 0.88, 8.03). Each one SD increase in resources was associated with 1.19 more MVPA min/day (95% CI: 0.06, 2.31). A one SD increase in poverty was associated with 11.18 less SED min/day (95% CI: -21.16, -1.18) and 10.60 more LPA min/day (95% CI: 1.79, 19.41) among black men. No neighborhood characteristic was associated with 10-year changes in physical activity in the full sample; however, a one SD increase in cohesion was associated with a 10-year decrease of 25.44 SED min/day (95% CI: -46.73, -4.14) and an increase of 19.0 LPA min/day (95% CI, 1.89, 36.10) in black men. Characteristics of the neighborhood environment are associated with accelerometer-measured physical activity. Differences were observed by race and sex, with more robust findings observed in black men.

Authors: Whitaker KM; Xiao Q; Pettee Gabriel K; Gordon Larsen P; Jacobs DR; Sidney S; Reis JP; Barone Gibbs B; Sternfeld B; Kershaw K

Prev Med. 2019 06;123:242-249. Epub 2019-03-30.

PubMed abstract

Maternal diabetes and hypertensive disorders in association with autism spectrum disorder

Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community-based sample. The Study to Explore Early Development (SEED), a US multisite case-control study, enrolled children born in 2003-2006 at 2-5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non-ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self-report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967-975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied if common complications in pregnancy are associated with autism spectrum disorder (ASD) in a large sample of mothers and children. Our results show an association between conditions marked by high blood pressure and ASD, but no association with conditions marked by high blood sugar and ASD. Associations were similar for children who had a developmental disorder that was not ASD, suggesting that this relationship may not be specific to ASD.

Authors: Cordero C; Windham GC; Schieve LA; Fallin MD; Croen LA; Siega-Riz AM; Engel SM; Herring AH; Stuebe AM; Vladutiu CJ; Daniels JL

Autism Res. 2019 06;12(6):967-975. Epub 2019-04-10.

PubMed abstract

Newborn vitamin D levels in relation to autism spectrum disorders and intellectual disability: A case-control study in california

Vitamin D deficiency has been increasing concurrently with prevalence of autism spectrum disorders (ASD), and emerging evidence suggests vitamin D is involved in brain development. Most prior studies of ASD examined vitamin D levels in children already diagnosed, but a few examined levels during perinatal development, the more likely susceptibility period. Therefore, we examined newborn vitamin D levels in a case-control study conducted among births in 2000-2003 in southern California. Children with ASD (N?=?563) or intellectual disability (ID) (N?=?190) were identified from the Department of Developmental Services and compared to population controls (N?=?436) identified from birth certificates. 25-hydroxyvitamin D (25(OH)D) was measured in archived newborn dried blood spots by a sensitive assay and corrected to sera equivalents. We categorized 25(OH) D levels as deficient (<50?nmol/L), insufficient (50-74?nmol/L), and sufficient (?75?nmol/L), and also examined continuous levels, using logistic regression. The adjusted odds ratios (AOR) and 95% confidence intervals for ASD were 0.96 (0.64-1.4) for 25(OH)D deficiency (14% of newborns) and 1.2 (0.86-1.6) for insufficiency (26% of newborns). The AORs for continuous 25(OH)D (per 25?nmol/L) were 1.0 (0.91-1.09) for ASD and 1.14 (1.0-1.30) for ID. Thus, in this relatively large study of measured newborn vitamin D levels, our results do not support the hypothesis of lower 25(OH)D being associated with higher risk of ASD (or ID), although we observed suggestion of interactions with sex and race/ethnicity. 25(OH)D levels were relatively high (median 84?nmol/L in controls), so results may differ in populations with higher prevalence of low vitamin D levels. Autism Res 2019, 12: 989-998. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied whether vitamin D levels measured at birth were related to whether a child later developed autism (or low IQ). Our results did not show that children with autism, or low IQ, overall had lower vitamin D levels at birth than children without autism. Vitamin D levels were fairly high, on average, in these children born in Southern California.

Authors: Windham GC; Pearl M; Anderson MC; Poon V; Eyles D; Jones KL; Lyall K; Kharrazi M; Croen LA

Autism Res. 2019 06;12(6):989-998. Epub 2019-03-18.

PubMed abstract

Strategies for Building Delivery Science in an Integrated Health Care System

Health systems today have increasing opportunities and imperatives to conduct delivery science, which is applied research that evaluates clinical or organizational practices that systems can implement or encourage. Examples include research on eliminating racial/ethnic disparities in hypertension management and on identifying the types of patients who can successfully use video visits. Clinical leaders and researchers often face barriers to delivery science, including limited funding, insufficient leadership support, lack of engagement between operational and research leaders, limited pools of research expertise, and lack of pathways to identify and develop ideas. We describe five key strategies we employed to address these barriers and develop a portfolio of delivery science programs in Kaiser Permanente Northern California. This portfolio now includes small and medium-sized grant programs, training programs for postdoctoral research fellows and experienced physician researchers, and a dedicated team that partners with clinicians to develop high-priority ideas and conduct small projects. Most of our approaches are consistent with frameworks used to develop delivery science by other health systems; some are innovative. Most of these strategies are adaptable by other health systems prepared to make long-range organizational commitments to mechanisms that foster partnerships between clinical leaders and researchers.

Authors: Lieu TA; Madvig PR

J Gen Intern Med. 2019 06;34(6):1043-1047. Epub 2019-01-25.

PubMed abstract

Factors associated with recruitment, surveillance participation, and retention in an observational study of pregnant women and influenza

This report describes the results of recruitment efforts and the subsequent participation of pregnant women in study activities in a 2010-2012 observational study focused on influenza illness and vaccination in California and Oregon, USA. Socio-demographic and health characteristics extracted from electronic medical records were compared among pregnant women who enrolled in the study, refused to participate, or were never reached for study invitation. These characteristics plus additional self-reported information were compared between women who enrolled in two study tracks: a prospective cohort vs. women enrolled following an acute respiratory illness (ARI) medical encounter. The characteristics of women who participated in weekly ARI surveillance (cohort enrollees, year one) and a 6-month follow-up interview (all enrollees) were also examined. In year one, we reached 51% (6938/13,655) of the potential participants we tried to contact by telephone, and 20% (1374/6938) of the women we invited agreed to join the prospective cohort. Women with chronic medical conditions, pregnancy complications, and medical encounters for ARI (prior to pregnancy or during the study period) were more likely to be reached for recruitment and more likely to enroll in the cohort. Twenty percent of cohort enrollees never started weekly surveillance reports; among those who did, reports were completed for 55% of the surveillance weeks. Receipt of the influenza vaccine was higher among women who joined the cohort (76%) than those who refused (56%) or were never reached (54%). In contrast, vaccine uptake among medical enrollees in year one (54%; 53/98) and two (52%; 79/151) was similar to other pregnant women in those years. Study site, white race, non-Hispanic ethnicity, and not having a child aged < 13 years at home were most consistently associated with joining as a cohort or medical enrollee and completing study activities after joining. We observed systematic differences in socio-demographic and health characteristics across different levels of participant engagement and between cohort and medical enrollees. More methodological research and innovation in conducting prospective observational studies in this population are needed, especially when extended participant engagement and ongoing surveillance are required.

Authors: Thompson MG; Li DK; Bozeman S; et al.

BMC Pregnancy Childbirth. 2019 May 08;19(1):161. Epub 2019-05-08.

PubMed abstract

Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health

Prenatal air pollution exposure has been linked to many adverse health conditions in the offspring. However, little is known about the mechanisms underlying these associations. Epigenetics may be one plausible biologic link. Here, we sought to identify site-specific and global DNA methylation (DNAm) changes, in developmentally relevant tissues, associated with prenatal exposure to nitrogen dioxide (NO2) and ozone (O3). Additionally, we assessed whether sex-specific changes in methylation exist and whether DNAm changes are consistently observed across tissues. Genome-scale DNAm measurements were obtained using the Infinium HumanMethylation450k platform for 133 placenta and 175 cord blood specimens from Early Autism Risk Longitudinal Investigation (EARLI) neonates. Ambient NO2 and O3 exposure levels were based on prenatal address locations of EARLI mothers and the Environmental Protection Agency’s AirNOW monitoring network using inverse distance weighting. We computed sample-level aggregate methylation measures for each of 5 types of genomic regions including genome-wide, open sea, shelf, shore, and island regions. Linear regression was performed for each genomic region; per-sample aggregate methylation measures were modeled as a function of quantitative exposure level with covariate adjustment. In addition, bumphunting was performed to identify differentially methylated regions (DMRs) associated with prenatal O3 and NO2 exposures in each tissue and by sex, with adjustment for technical and biological sources of variation. We identified global and locus-specific changes in DNA methylation related to prenatal exposure to NO2 and O3 in 2 developmentally relevant tissues. Neonates with increased prenatal O3 exposure had lower aggregate levels of DNAm at CpGs located in open sea and shelf regions of the genome. We identified 6 DMRs associated with prenatal NO2 exposure, including 3 sex-specific. An additional 3 sex-specific DMRs were associated with prenatal O3 exposure levels. DMRs initially detected in cord blood samples (n = 4) showed consistent exposure-related changes in DNAm in placenta. However, the DMRs initially detected in placenta (n = 5) did not show DNAm differences in cord blood and, thus, they appear to be tissue-specific. We observed global, locus, and sex-specific methylation changes associated with prenatal NO2 and O3 exposures. Our findings support DNAm is a biologic target of prenatal air pollutant exposures and highlight epigenetic involvement in sex-specific differential susceptibility to environmental exposure effects in 2 developmentally relevant tissues.

Authors: Ladd-Acosta C; Feinberg JI; Brown SC; Lurmann FW; Croen LA; Hertz-Picciotto I; Newschaffer CJ; Feinberg AP; Fallin MD; Volk HE

Environ Int. 2019 05;126:363-376. Epub 2019-02-28.

PubMed abstract

Prenatal exposure to endocrine disrupting chemicals in relation to autism spectrum disorder and intellectual disability

Exposure to endocrine disruptors is unavoidable. Many such compounds are suspected to impact neurologic development of children, but most studies conducted have considered effects of individual chemicals in isolation. Because exposures co-occur, it is important to consider their health impacts in a single regression framework. We applied Bayesian statistical tools (including shared mean and mixture priors for 25 unique chemicals) to study independent associations of endocrine disruptor biomarkers with autism spectrum disorder (ASD) (n = 491) and intellectual disability (n = 155), compared with 373 general population controls, in the Early Markers for Autism study. We measured biomarkers in maternal serum collected and stored from midpregnancy and considered them individually or as a class (i.e., summed polychlorinated biphenyls). We adjusted all models for original matching factors (child sex and month and year of birth), maternal age, maternal race/ethnicity, parity, and maternal education at the time samples were collected. We estimated the change in the odds of ASD or intellectual disability per 1 SD increase in the z-score of measured biomarker concentration for each chemical. Odds of ASD and intellectual disability did not change with increasing concentration for any specific endocrine disruptor. The effect estimates for each chemical were centered on or near an odds ratio of 1.00 in both models where we applied a shared mean or a mixture prior. Our mixtures analyses do not suggest an independent relationship with ASD or intellectual disability with any of the 25 chemicals examined together in this mixtures analysis.

Authors: Hamra GB; Lyall K; Windham GC; Calafat AM; Sjödin A; Volk H; Croen LA

Epidemiology. 2019 05;30(3):418-426.

PubMed abstract

Iodinated Contrast Agents and Risk of Hypothyroidism in Young Children in the United States

Although it is generally acknowledged that exposure to iodine contrast agents can interfere with thyroid function, little is known about the incidence of iodine-induced hypothyroidism in young children (younger than the age of 4 years). This was a retrospective cohort study to estimate the incidence rate of detected hypothyroidism in a US-based general population of pediatric patients exposed to an iodinated contrast agent. The study was conducted in Kaiser Permanente Northern California, an integrated health care delivery system. This study included 2320 pediatric patients younger than 4 years of age who had a diagnostic procedure with an iodinated contrast agent during years 2008 to 2016. Among 2320 young children who met our study criteria, we identified 34 who met the initial criteria to be a case of hypothyroidism. The incidence density ratio for all hypothyroidism in iodine contrast agent-exposed patients was 1.33 per 1000 person months (95% confidence interval, 0.9-1.8). Most cases appeared to have subclinical hypothyroidism. The rate was higher for the probably iodine-induced cases (0.90 per 1000 person months) compared with cases with a possible alternate etiology (0.43 per 1000 person months), for males compared with females, and among children who had a heart catheterization compared with those with a computed tomography scan. It was also highest among the youngest children (younger than 3 months old), and decreased with increasing age. Our finding of hypothyroidism in young children exposed to iodine contrast agents (1.33 per 1000 person months [95% confidence interval, 0.9-1.8]) is broadly consistent with the sparse literature on this outcome.

Authors: Jick SS; Hedderson M; Xu F; Cheng Y; Palkowitsch P; Michel A

Issues Ment Health Nurs. 2019 Nov;40(11):988-989. Epub 2019-08-05.

PubMed abstract

Gestational weight gain and optimal wellness (GLOW): rationale and methods for a randomized controlled trial of a lifestyle intervention among pregnant women with overweight or obesity

Excess gestational weight gain (GWG) is common among women with overweight or obesity, increasing their risks for pregnancy complications, delivering a large infant, and postpartum weight retention. To date, only intensive interventions have had success and few interventions have been designed for implementation in healthcare settings. We describe the development, rationale, and methods of GLOW (GestationaL Weight Gain and Optimal Wellness), a randomized controlled trial evaluating the efficacy of a lifestyle intervention to prevent excess GWG among racially/ethnically diverse women with overweight or obesity in an integrated healthcare delivery system. Participants in Kaiser Permanente Northern California will be randomized, within 2 weeks of completing a study baseline clinic visit at 10 weeks’ gestation, to either usual medical care or a multi-component pregnancy lifestyle intervention adapted from the Diabetes Prevention Program (target N = 400). Informed by focus groups with patients and designed to be feasible in a clinical setting, the intervention will include 13 weekly individual sessions (11 delivered by telephone) focused on behavior change for weight management, healthy eating, physical activity, and stress management. Outcomes will be assessed in women and their infants from randomization to 12 months postpartum. The primary outcome is GWG. Secondary outcomes include changes in diet and physical activity during pregnancy and infant birthweight. Exploratory outcomes include cardiometabolic profile assessed via pregnancy blood samples and cord blood samples; and postpartum weight retention and infant anthropometrics up to 12 months of age. The trial includes systematic approaches to enhance intervention fidelity, intervention adherence, and participant retention in trial assessments. GLOW is among few trials targeting excess GWG among diverse women with overweight or obesity in a healthcare setting, with long-term maternal and infant outcomes assessed up to 12 months after delivery. This evaluation of a multi-component intervention is designed to produce generalizable results to inform potential adoption of the intervention in clinical settings. ( NCT02130232 ): submitted April 30, 2014; posted May 5, 2014.

Authors: Brown SD; Hedderson MM; Ehrlich SF; Galarce MN; Tsai AL; Quesenberry CP; Ferrara A

BMC Pregnancy Childbirth. 2019 Apr 30;19(1):145. Epub 2019-04-30.

PubMed abstract

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Authors: Küpers LK; Croen LA; Felix JF; et al.

Nat Commun. 2019 04 23;10(1):1893. Epub 2019-04-23.

PubMed abstract

Preventing Perinatal Depression to Improve Maternal and Child Health-a Health Care Imperative

Authors: Avalos LA; Flanagan T; Li DK

JAMA Pediatr. 2019 04 01;173(4):313-314.

PubMed abstract

Poor diet quality in pregnancy is associated with increased risk of excess fetal growth: a prospective multi-racial/ethnic cohort study

Nutritional perturbations during pregnancy may impact fetal and long-term childhood growth, although there are limited data on overall diet quality. We investigated whether diet quality, measured by the Healthy Eating Index-2010 (HEI-2010), during pregnancy was related to birthweight z-score (BWZ) and the clinically relevant birth outcomes of large- and small-for-gestational age (LGA and SGA). In a prospective cohort of 2269 multi-racial/ethnic women from the Pregnancy Environment and Lifestyle Study (2014-2017), dietary intake was assessed by a food frequency questionnaire during early pregnancy. Offspring BWZ and LGA or SGA were derived based on gestational age-, sex-, and racial/ethnic-specific birthweight distributions. Multivariable linear and Poisson regression with robust standard errors were used. About 80% of women did not achieve good diet quality (HEI-2010?

Authors: Zhu Y; Hedderson MM; Sridhar S; Xu F; Feng J; Ferrara A

Int J Gynaecol Obstet. 2020 Jan;148 Suppl 1:42-58.

PubMed abstract

Developing a Prognostic Information System for Personalized Care in Real Time

Electronic medical records hold promise to transform clinical practice. However, technological and other barriers may preclude using them to guide care in real time. We used the Virtual Data Warehouse (VDW) to develop a tool that enables physicians to generate real-time, personalized prognostic information about survival after cancer. Patients with cancer often ask their oncologists, “Have you ever seen a patient like me?” To help oncologists answer this question, we developed a prototype Prognostic Information System (PRISM), a web-based tool that gathers data about the index patient from Kaiser Permanente’s clinical information systems, selects a historical cohort of similar patients, and displays the survival curve of the similar patients relative to key points in their treatment course. The prototype was developed by a multidisciplinary team with expertise in oncology, research, and technology. We have completed two rounds of user testing and refinement. Successful development rested on: (1) executive support and a clinical champion; (2) collaboration among experts from multiple disciplines; (3) starting with simple cases rather than ambitious ones; (4) extensive research experience with the Virtual Data Warehouse, related databases, and an existing query tool; and (5) following agile software development principles, especially iterative user testing. Clinical data stored in health care systems’ electronic medical records can be used to personalize clinical care in real time. Development of prognostic information systems can be accelerated by collaborations among researchers, technology specialists, and clinicians and by use of existing technology like the Virtual Data Warehouse.

Authors: Lieu TA; Neugebauer R; Van Den Eeden SK; Baer DM; et al.

EGEMS (Wash DC). 2019 Mar 25;7(1):2. Epub 2019-03-25.

PubMed abstract

Maternal Gestational Weight Gain, Obesity, and the Timing of Pubertal Onset in Daughters

Early puberty is associated with adverse health outcomes, but little is known regarding early life determinants influencing pubertal timing. We examined the associations between maternal gestational weight gain (GWG) and the timing of the onset of breast development (thelarche) and pubic hair development (pubarche) in a cohort of 2,070 girls born in a Kaiser Permanente Northern California facility between 2005-06. Using Weibull regression models accommodating interval censoring, and adjusting for important confounders, we found that excessive GWG was associated with increased risk of early thelarche (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.26-1.78) and early pubarche (HR: 1.35; 95% CI: 1.10-1.66). Inadequate GWG was associated with early thelarche (HR: 1.36; 95% CI: 1.08-1.71). The associations between excess or inadequate GWG and risk of earlier thelarche were stronger if mothers were obese before or at the beginning of pregnancy (body mass index ≥30) (HR: 2.01; 95% CI: 1.53-2.63; HR: 2.08; 95% CI: 1.45-2.98, respectively]. Similar associations were found for pubarche outcome. Inclusion of girls’ prepubertal body mass index slightly attenuated these associations, but they remained significant. Monitoring of maternal weight before and throughout pregnancy may help prevent early pubertal onset and subsequent negative health outcomes.

Authors: Aghaee S; Laurent CA; Deardorff J; Ferrara A; Greenspan LC; Quesenberry CP; Kushi LH; Kubo A

Am J Epidemiol. 2019 Mar 15.

PubMed abstract

Changes in body composition and weight during the menopause transition

The relation between the menopause transition (MT) and changes in body composition or weight remains uncertain. We hypothesized that, independent of chronological aging, the MT would have a detrimental influence on body composition. Participants were from the longitudinal Study of Women’s Health Across the Nation (SWAN) cohort. We assessed body composition by dual energy x-ray absorptiometry. Multivariable mixed effects regressions fitted piece-wise linear models to repeated measures of outcomes as a function of time before or after the final menstrual period (FMP). Covariates were age at FMP, race, study site, and hormone therapy. Fat and lean mass increased prior to the MT. At the start of the MT, rate of fat gain doubled, and lean mass declined; gains and losses continued until 2 years after the FMP. After that, the trajectories of fat and lean mass decelerated to zero slope. Weight climbed linearly during premenopause without acceleration at the MT. Its trajectory became flat after the MT. Accelerated gains in fat mass and losses of lean mass are MT-related phenomena. The rate of increase in the sum of fat mass and lean mass does not differ between premenopause and the MT; thus, there is no discernable change in rate of weight gain at the start of the MT. NIH, Department of Health and Human Services (DHHS), through the National Institute on Aging, National Institute of Nursing Research, and NIH Office of Research on Women’s Health (U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495).

Authors: Greendale GA; Sternfeld B; Huang M; Han W; Karvonen-Gutierrez C; Ruppert K; Cauley JA; Finkelstein JS; Jiang SF; Karlamangla AS

JCI Insight. 2019 03 07;4(5). Epub 2019-03-07.

PubMed abstract

Health Care Service Utilization and Cost Among Adults with Autism Spectrum Disorders in a U.S. Integrated Health Care System

To compare health care utilization patterns and cost among insured adults with autism spectrum disorder (ASD), adults with attention-deficit and hyperactivity disorder (ADHD), and adults with neither condition (general population [GP] controls). We conducted a case-control study among adults (≥18 years) who were members of Kaiser Permanente Northern California (KPNC) for at least 9 months each year from 2008 to 2012. Cases (N = 1507) were adults with an ASD diagnosis (ICD-9-CM 299.0-299.8) recorded in the electronic medical record on at least two separate occasions by December 31, 2012. Two control groups, adults with ADHD (N = 9042) defined by ICD-9-CM code 314 and GP (N = 15,070), were randomly selected and frequency matched to cases on gender and age. Health care utilization and cost data were obtained from KPNC databases for the year 2012. Compared with adults with ADHD, adults with ASD had significantly higher utilization of outpatient visits for primary care (74.2% vs. 66.6%), mental health (43.3% vs. 33.2%), and laboratory services (60.9% vs. 54.4%). Hospitalizations for ambulatory care sensitive diagnoses (5.4% vs. 2.3%) were less frequent overall but more common among adults with ASD than with ADHD. Group differences were larger comparing adults with ASD with GP controls. Gynecology visits and screening for cervical cancer were significantly less common among women with ASD than among women with ADHD (35% vs. 50%) or GP (35% vs. 49%). Total annual mean healthcare costs for adults with ASD were 20% higher than costs for adults with ADHD and double costs for GP. Adults with ASD had significantly higher rates of utilization across most health care service areas compared with adults with ADHD or GP; however, women with ASD were significantly less likely to have gynecology visits and have screening for cervical cancer. We conducted a study among adults (≥18 years) who were members of Kaiser Permanente Northern California (KPNC) from 2008 to 2012. We compared how often people attended different types of health care and costs of health care among adults with autism spectrum disorder (ASD), adults with attention-deficit and hyperactivity disorder (ADHD), and adults with neither condition (general population [GP] controls). The study included 1507 adults with ASD, 9042 with ADHD but not ASD, and 15,070 GP controls with no ASD or ADHD. Health care and cost data were obtained from KPNC databases for the year 2012. The study found that adults with ASD used more outpatient visits for primary care, mental health, and laboratory services than adults with ADHD. Gynecology visits and screening for cervical cancer were less common among women with ASD than among women with ADHD or GP. Health care costs for adults with ASD were higher than costs for adults with ADHD and costs for GP. In conclusion, adults with ASD had higher rates of use of most health care service areas than adults with ADHD or GP; however, women with ASD were less likely to have gynecology visits and have screening for cervical cancer.

Authors: Zerbo, Ousseny; Qian, Yinge; Ray, Thomas; Sidney, Steve; Rich, Steve; Massolo, Maria; Croen, Lisa A

Autism Adulthood. 2019 Mar 01;1(1):27-36. Epub 2019-03-11.

PubMed abstract

Trends in marijuana use among pregnant women with and without nausea and vomiting in pregnancy, 2009-2016

Cross-sectional studies indicate an elevated prevalence of prenatal marijuana use in women with nausea and vomiting in pregnancy (NVP). However, it is unknown whether differences in marijuana use by NVP status have persisted over time as marijuana becomes more acceptable and accessible and prenatal use increases overall. We compared trends in prenatal marijuana use by NVP status in the first trimester of pregnancy using data from Kaiser Permanente Northern California’s (KPNC) large healthcare system. The sample comprised KPNC pregnant women aged ≥12 who completed a self-administered questionnaire on marijuana use and a urine toxicology test for cannabis during standard prenatal care from 2009 to 2016. The annual prevalence of marijuana use via self-report or toxicology by NVP status was estimated using Poisson regression with a log link function, adjusting for sociodemographics and parity. We tested for linear trends and differences in trends by NVP. Of 220,510 pregnancies, 38,831 (17.6%) had an NVP diagnosis. Prenatal marijuana use was elevated each year among women with NVP. The adjusted prevalence of use increased significantly from 2009 to 2016 at an annual rate of 1.086 (95%CI = 1.069-1.104) among women with NVP, from 6.5% (95%CI = 5.7%-7.2%) to 11.1% (95%CI = 0.2%-12.0%), and 1.069 (95%CI = 1.059-1.080) among women without NVP, from 3.4% (95%CI = 3.2%-3.7%) to 5.8% (95%CI = 5.5%-6.1%). Trends did not vary by NVP status. The prevalence of prenatal marijuana use has remained elevated over time among women with NVP. Clinicians should ask pregnant patients about their reasons for marijuana use and treat NVP with evidence-based interventions.

Authors: Young-Wolff KC; Sarovar V; Tucker LY; Avalos LA; Alexeeff S; Conway A; Armstrong MA; Weisner C; Campbell CI; Goler N

Drug Alcohol Depend. 2019 03 01;196:66-70. Epub 2019-01-18.

PubMed abstract

Timing of household food insecurity exposures and asthma in a cohort of US school-aged children

Food insecurity is positively associated with asthma, the most common chronic childhood disease, yet directionality is unclear. The objective was to determine the association between exposure to food insecurity in early childhood and the odds of asthma later in childhood. Data from four waves of the Early Childhood Longitudinal Study-Kindergarten (ECLS-K) cohort, a prospective, dual-frame, multistage probability cluster sampling study of school-aged US children were entered in multivariate logistic regression models, adjusted for covariates. Exposures to food insecurity were based on parental responses to the validated USDA 18-item module at each wave. Public and private primary and secondary schools between 1998 and 2007. At its inception (1999), the ECLS-K had 20 578 kindergarteners; by the spring of eighth grade (2007), the cohort dropped to 9725 due to attrition. Children missing an exposure, outcome or confounding variable were excluded, final n=6731. Child’s diagnosis of asthma by a healthcare professional as reported by the parent. Household food insecurity (vs food security) in the year before kindergarten and in second grade had a higher odds of asthma by 18% (95% CI 1.17 to 1.20) and 55% (95% CI 1.51 to 1.55). After removing asthmatics before third grade from the model, food insecurity in second grade was associated with higher odds of asthma at fifth or eighth grades (OR 1.55; 95% CI 1.53 to 1.58), whereas food insecurity in the year before kindergarten had a lower odds at fifth or eighth grades. Food insecurity in the year before kindergarten and in second grade were associated with a higher odds of asthma in third grade. Food insecurity in second grade retained the signal for increased odds of asthma after third and through eighth grades. Additional research is needed to explore childhood windows of vulnerability to asthma.

Authors: Mangini LD; Hayward MD; Zhu Y; Dong Y; Forman MR

BMJ Open. 2019 02 22;8(11):e021683. Epub 2019-02-22.

PubMed abstract

Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women

Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk. A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage. Logistic regression was used to estimate region-stratified country-adjusted odds ratios (OR) and 95%CI. A1 was the most globally widespread sub-lineage, with others showing stronger regional specificity (A3 and A4 for East Asia, B1-4 and C1-4 for Africa, D2 for the Americas, B4, C4 and D4 for North Africa). Increased cancer risks versus A1 were seen for A3, A4 and D (sub)lineages in regions where they were common: A3 in East Asia (OR=2.2, 95%CI:1.0-4.7); A4 in East Asia (6.6, 3.1-14.1) and North America (3.8, 1.7-8.3); and D in North (6.2, 4.1-9.3) and South/Central America (2.2, 0.8-5.7), where D lineages were also more frequent in ADC than SCC (3.2, 1.5-6.5; 12.1, 5.7-25.6, respectively). HPV16 genetic variation can strongly influence cervical cancer risk. However, burden of cervical cancer attributable to different sub-lineages worldwide is largely driven by historical HPV16 sub-lineage dispersal.

Authors: Clifford GM; Raine-Bennett T; Mirabello L; et al.

Papillomavirus Res. 2019 Feb 06;7:67-74. Epub 2019-02-06.

PubMed abstract

Maternal Pre-pregnancy Body Mass Index and Gestational Weight Gain in Relation to Autism Spectrum Disorder and other Developmental Disorders in Offspring

Most prior studies examining maternal pre-pregnancy body mass index (BMI) in relation to offspring autism spectrum disorders (ASD) have reported an association, though findings are not uniform and few have also examined gestational weight gain (GWG). Therefore, we examined both in the Study to Explore Early Development, a multi-site case-control study of children born in 2003-2006. Children identified from clinics, schools, and birth certificates were enrolled at ages 2-5 year and using standardized developmental evaluations, classified as: ASD, other developmental delays (DD), or population-based controls. Maternal height, weight, and GWG were self-reported during the telephone interview. Three primary weight risk factors were examined: (a) Pre-pregnancy BMI, classified as underweight to obese, (b) GWG continuous and categorized as quintiles, and (c) Institute of Medicine clinical weight-gain recommendations. Odds ratios adjusted (AOR) for sociodemographic and prenatal factors were calculated among term singletons, comparing the ASD (n = 540) or DD (n = 720) groups to the control group (n = 776). The AOR of ASD and maternal obesity was 1.37 (95%CI 0.98-1.92). Associations with higher GWG were stronger (Quintile5 vs. Quintile3 AOR = 1.58, 95%CI 1.08-2.31), and particularly so among overweight/obese women (AOR = 1.90, 95%CI 0.98-3.68). DD was associated with maternal overweight and obesity (obesity AOR = 1.48, 95%CI 1.08-2.02), but not with total GWG or clinical recommendations. High maternal BMI and GWG are risk factors for other pregnancy and child outcomes, and our results suggest they may also represent modifiable risk factors for neurodevelopmental outcomes. Autism Res 2019, 12: 316-327 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In a large, national study, we found that children with autism were more likely than unaffected children to have mothers with higher weight gain during pregnancy; risk of autism may be even stronger if mothers were also overweight before pregnancy. Children with other developmental delays were more likely to have mothers who were overweight or obese before pregnancy, but not who gained more weight during pregnancy. Overweight and weight gain may represent factors that could be modified.

Authors: Windham GC; Anderson M; Lyall K; Daniels JL; Kral TVE; Croen LA; Levy SE; Bradley CB; Cordero C; Young L; Schieve LA

Behav Ther. 2019 03;50(2):446-458. Epub 2018-08-16.

PubMed abstract

Pregnancy-Associated Cancer: A U.S. Population-Based Study

The incidence of pregnancy-associated cancer (PAC) is expected to increase as more women delay childbearing until later ages. However, information on frequency and incidence of PAC is scarce in the United States. We identified pregnancies among women aged 10-54 years during 2001-2013 from five U.S. health plans participating in the Cancer Research Network (CRN) and the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). We extracted information from the health plans’ administrative claims and electronic health record databases, tumor registries, and infants’ birth certificate files to estimate the frequency and incidence of PAC, defined as cancer diagnosed during pregnancy and up to 1 year postpartum. We identified 846 PAC events among 775,709 pregnancies from 2001 to 2013. The overall incidence estimate was 109.1 (95% confidence interval [CI]?=?101.8-116.7) per 100,000 pregnancies. There was an increase in the incidence between 2002 and 2012 (the period during which complete data were available), from 75.0 (95% CI?=?54.9-100.0) per 100,000 pregnancies in 2002 to 138.5 (95% CI?=?109.1-173.3) per 100,000 pregnancies in 2012. The most common invasive cancers diagnosed were breast (n?=?208, 24.6%), thyroid (n?=?168, 19.9%), melanoma (n?=?93, 11.0%), hematologic (n?=?87, 10.3%), and cervix/uterus (n?=?74, 8.7%). Our study provides contemporary incidence estimates of PAC from a population-based cohort of U.S. women. These estimates provide the data needed to help develop clinical and public health policies aimed at diagnosing PAC at an early stage and initiating appropriate therapeutic interventions in a timely manner.

Authors: Cottreau CM; Dashevsky I; Andrade SE; Li DK; Nekhlyudov L; Raebel MA; Ritzwoller DP; Partridge AH; Pawloski PA; Toh S

J Womens Health (Larchmt). 2019 02;28(2):250-257. Epub 2018-10-10.

PubMed abstract

Dietary Quality and Glycemic Control Among Women with Gestational Diabetes Mellitus

Poor dietary quality, measured by the Healthy Eating Index 2010 (HEI-2010), is associated with risk of gestational diabetes mellitus (GDM) and type 2 diabetes. The aim was to investigate the association between dietary quality and glycemic control in women with GDM. The study included 1220 women with GDM. Dietary quality was calculated by HEI-2010 score from a Food Frequency Questionnaire administered shortly after GDM diagnosis; higher scores indicate higher dietary quality. Subsequent glycemic control was defined as ?80% of all capillary glucose measurements meeting recommended clinical targets below 95?mg/dL for fasting, and below 140?mg/dL 1-hour glucose after meals. As compared with Quartile 1 of HEI-2010 score, Quartiles 2, 3, and 4 showed increased adjusted odds of overall optimal glycemic control (odds ratio [95% confidence interval] 1.90 [1.34-2.70], 1.77 [1.25-2.52], and 1.55 [1.09-2.20], respectively). Increased odds of glycemic control were observed in Quartiles 2, 3, and 4 as compared with Quartile 1 of HEI-2010 score for 1-hour postbreakfast and 1-hour postdinner. Mean capillary glucose was lower in Quartiles 2, 3, and 4 of HEI-2010 score when compared with Quartile 1 for 1-hour postdinner (p?=?0.03). Clinicians should be aware that even a small improvement in diet quality may be beneficial for the achievement of improved glycemic control in women with GDM. Clinical number, NCT01344278.

Authors: Gadgil MD; Ehrlich SF; Zhu Y; Brown SD; Hedderson MM; Crites Y; Ferrara A

J Womens Health (Larchmt). 2019 02;28(2):178-184. Epub 2018-10-30.

PubMed abstract

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Authors: Kilpeläinen TO; Sternfeld B; Loos RJF; et al.

Nat Commun. 2019 01 22;10(1):376. Epub 2019-01-22.

PubMed abstract

Prenatal exposure to extremely low frequency magnetic field and its impact on fetal growth

Studies on the effect of prenatal exposure to magnetic field (MF) on fetal growth is inconclusive and subject to some methodological limitations, particularly in measurement of MF exposure. The present study aimed to examine the association between maternal extremely low frequency MF (ELF-MF) exposure during pregnancy and fetal growth in offspring. A total of 128 pregnant women were recruited at their 3rd trimester and asked to wear an EMDEX Lite meter for 24 h to capture daily ELF-MF exposure. Time-weighted average (TWA), P50, and P75 of personal 24-h measurements were used to evaluate prenatal ELF-MF exposure. The medians of these measurements were used as cut-off points of high and low prenatal ELF-MF exposure. Fetal growth was measured by infant’s birth weight, skinfold thickness of triceps, abdomen, and back, and circumference of head, upper arm, and abdomen. These measures were conducted within 24-h after birth. Generalized Linear Model was used to examine the association between maternal ELF-MF level and fetal growth indices after potential confounders were adjusted for. Compared with girls with lower prenatal ELF-MF exposure, girls with higher exposure had a lower birth weight, thinner skinfold of triceps, abdomen and back, and smaller circumference of head, upper arm and abdomen in all three ELF-MF matrices. The differences were statistically significant for birth weight and most other growth measurements (P < 0.05). These measures had no significant difference between higher and lower prenatal ELF-MF exposure in boys except back skinfold thickness. Prenatal exposure to higher ELF-MF levels was associated with decreased fetal growth in girls, but not in boys.

Authors: Ren Y; Chen J; Miao M; Li DK; Liang H; Wang Z; Yang F; Sun X; Yuan W

Environ Health. 2019 01 11;18(1):6. Epub 2019-01-11.

PubMed abstract

Bisphenol A Exposure and Sperm ACHE Hydroxymethylation in Men

Exposure to bisphenol A (BPA) has been shown to impact human sperm quality. The epigenetic mechanisms underlying the effect remain unknown. The acetylcholinesterase (ACHE) gene is a sperm-expressed gene encoding the acetylcholine hydrolyzing enzyme acetylcholinesterase and participates in the apoptosis of cells, including sperm. This study aimed to examine whether BPA exposure is associated with the hydroxymethylation level of the sperm ACHE gene. A total of 157 male factory workers were studied, among whom 74 had BPA exposure in the workplace (BPA exposure group) and 83 had no BPA exposure in the workplace (control group). Urine samples were collected for BPA measurement and semen samples were collected to assay for ACHE hydroxymethylation. Sperm ACHE hydroxymethylation level was higher in the BPA exposure group (p = 0.041) compared to the control group. When subjects were categorized according to tertiles of detected BPA level, higher ACHE hydroxymethylation levels were observed for the lowest, middle, and top tertiles compared to those with BPA below the limit of detection (LOD). In a linear regression analysis adjusted for confounders, a positive linear association between urine BPA concentration and 5-hydroxymethylcytosine (5hmC) rate of the sperm ACHE gene was observed, although the association did not reach statistical significance in all categories after being stratified by the BPA tertile. In conclusion, 5hmC of the sperm ACHE gene was positively associated with BPA exposure, which may provide supportive evidence for BPA’s effects on male fertility or other health endpoints.

Authors: Song X; Miao M; Zhou X; Li D; Tian Y; Liang H; Li R; Yuan W

Int J Epidemiol. 2019 04 01;48(2):423-432.

PubMed abstract

Associations of Accelerometer-Measured Sedentary Time and Physical Activity With Prospectively Assessed Cardiometabolic Risk Factors: The CARDIA Study

Background Isotemporal substitution examines the effect on health outcomes of replacing sedentary time with light-intensity physical activity or moderate-to-vigorous intensity physical activity; however, existing studies are limited by cross-sectional study designs. Methods and Results Participants were 1922 adults from the CARDIA (Coronary Artery Risk Development in Young Adults) study. Linear regression examined the associations of sedentary, light-intensity physical activity, and moderate-to-vigorous intensity physical activity at year 20 (2005-2006) with waist circumference, blood pressure, glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and a composite risk score at year 30 (2015-2016). Models then examined change in activity with change in cardiometabolic risk over the same 10-year period. Replacing 30 min/day of sedentary time with 30 min/day of light-intensity physical activity at year 20 was associated with a lower composite risk score (-0.01 SD [95% CI, -0.02, -0.00]) at year 30, characterized by lower waist circumference (0.15 cm [95% CI, -0.27, 0.02]), insulin (0.20 ?U/mL [95% CI, -0.35, -0.04]), and higher high-density lipoprotein cholesterol (0.20 mg/dL [95% CI, 0.00, 0.40]; all P<0.05). An increase of 30 min/day in MVPA from year 20 to year 30, when replacing an equivalent increase in sedentary time, was associated with a decrease in the composite risk score (-0.08 [95% CI, -0.13, -0.04]) over the same 10 years, characterized by a decrease in waist circumference (1.52 cm [95% CI, -2.21, -0.84]), insulin (-1.13 ?U/mL [95% CI, -1.95, -0.31]), triglycerides (-6.92 mg/dL [95% CI, -11.69, -2.15]), and an increase in high-density lipoprotein cholesterol (1.59 mg/dL [95% CI, 0.45, 2.73]; all P<0.05). Conclusions Replacement of sedentary time with light-intensity physical activity or moderate-to-vigorous intensity physical activity is associated with improved cardiometabolic health 10 years later.

Authors: Whitaker KM; Pettee Gabriel K; Buman MP; Pereira MA; Jacobs DR; Reis JP; Gibbs BB; Carnethon MR; Staudenmayer J; Sidney S; Sternfeld B

J Am Heart Assoc. 2019 02 19;8(4):e010586.

PubMed abstract

Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes.

Authors: Croen LA; Qian Y; Ashwood P; Daniels JL; Fallin D; Schendel D; Schieve LA; Singer AB; Zerbo O

Autism Res. 2019 01;12(1):123-135. Epub 2018-08-10.

PubMed abstract

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children. Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36?months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis. While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change)?>?0.1, p?

Authors: Mordaunt CE; Croen LA; Fallin MD; et al.

Mol Autism. 2019;10:36. Epub 2019-10-24.

PubMed abstract

Identification and validation of uterine perforation, intrauterine device expulsion, and breastfeeding in four health care systems with electronic health records

To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion. Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum. The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled. Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.

Authors: Anthony MS; Getahun D; Schoendorf J; et al.

Clin Epidemiol. 2019;11:635-643. Epub 2019-07-23.

PubMed abstract

Incremental Cost of Prematurity by Week of Gestational Age

Objective  This study was aimed to compare health care costs and utilization at birth through 1 year, between preterm and term infants, by week of gestation. Methods  A cross-sectional study of infants born at ≥ 23 weeks of gestational age (GA) at Kaiser Permanente Northern California facilities between 2000 and 2011, using outcomes data from an internal neonatal registry and cost estimates from an internal cost management database. Adjusted models yielded estimates for cost differences for each GA group. Results  Infants born at 25 to 37 weeks incur significantly higher birth hospitalization costs and experience significantly more health care utilization during the initial year of life, increasing progressively for each decreasing week of gestation, when compared with term infants. Among all very preterm infants (≤ 32 weeks), each 1-week decrease in GA is associated with incrementally higher rates of mortality and major morbidities. Conclusion  We provide estimates of potential cost savings that could be attributable to interventions that delay or prevent preterm delivery. Cost differences were most extreme at the lower range of gestation (≤ 30 weeks); however, infants born moderately preterm (31-36 weeks) also contribute substantially to the burden, as they represent a higher proportion of total births.

Authors: Walsh EM; Li SX; Black LK; Kuzniewicz M

AJP Rep. 2019 Jan;9(1):e76-e83. Epub 2019-03-19.

PubMed abstract

Diagnostic thresholds for pregnancy hyperglycemia, maternal weight status and the risk of childhood obesity in a diverse Northern California cohort using health care delivery system data

To estimate the risk of childhood obesity associated with the various criteria proposed for diagnosis of gestational diabetes (GDM), and the joint effects with maternal BMI. Cohort study of 46,396 women delivering at the Kaiser Permanente Northern California health care delivery system in 1995-2004 and their offspring, followed through 5-7 years of age. Pregnancy hyperglycemia was categorized according to the screening and oral glucose tolerance test values proposed for the diagnosis of GDM by the International Association of the Diabetes and Pregnancy Study Group (IADPSG), Carpenter Coustan (CC), and the National Diabetes Data Group (NDDG). Childhood obesity was defined by the International Obesity Task Force’s age and sex-specific BMI cut-offs. Poisson regression models estimated the risks of childhood obesity associated with each category of pregnancy glycemia compared to normal screening, and the joint effects of maternal BMI category and GDM by the CC and the IADPSG criteria. Compared with normal screening, increased risks of childhood obesity were observed for abnormal screening [RR (95% CI): 1.30 (1.22, 1.38)], 1+ abnormal values by the IADPSG or CC [1.47 (1.36, 1.59) and 1.48 (1.37, 1.59), respectively], and 2+ values by CC or NDDG [1.52 (1.39, 1.67) and 1.60 (1.43, 1.78), respectively]. Compared to obese women without GDM, obese women with GDM defined by the CC criteria had significantly increased risk of childhood obesity [1.20 (1.07, 1.34)], which was also observed for GDM by the IADSPG [1.18 (1.07, 1.30)], though GDM did not significantly increase the risk of childhood obesity among normal weight or overweight women. The risk of childhood obesity starts to increase at levels of pregnancy glycemia below those used to diagnose GDM and the effect of GDM on childhood obesity risk appears more pronounced in women with obesity. Interventions to reduce obesity and pregnancy hyperglycemia are warranted.

Authors: Ehrlich SF; Hedderson MM; Xu F; Ferrara A

PLoS One. 2019;14(5):e0216897. Epub 2019-05-10.

PubMed abstract

A Randomized Controlled Trial of mHealth Mindfulness Intervention for Cancer Patients and Informal Cancer Caregivers: A Feasibility Study Within an Integrated Health Care Delivery System

To assess feasibility and preliminary efficacy of a mobile/online-based (mHealth) mindfulness intervention for cancer patients and their caregivers to reduce distress and improve quality of life (QoL). Two-arm randomized controlled trial within Kaiser Permanente Northern California targeting cancer patients who received chemotherapy and their informal caregivers. The intervention group received a commercially available mindfulness program for 8 weeks. The wait-list control group received usual care. We assessed feasibility using retention and adherence rates and obtained participant-reported data on distress, QoL, sleep, mindfulness, and posttraumatic growth before and immediately after the intervention. Ninety-seven patients (median age 59 years; female 69%; 65% whites) and 31 caregivers (median age 63 years; female 58%; 77% whites) were randomized. Among randomized participants, 74% of the patients and 84% of the caregivers completed the study. Among those in the intervention arm who initiated the mindfulness program, 65% practiced at least 50% of the days during the intervention period. We observed significantly greater improvement in QoL among patients in the intervention arm compared with controls. Caregivers in the intervention group experienced increased mindfulness compared with controls. Participants appreciated the convenience of the intervention and the mindfulness skills they obtained from the program. We demonstrated the feasibility of conducting a randomized trial of an mHealth mindfulness intervention for cancer patients and their informal caregivers. Results from fully powered efficacy trials would inform the potential for clinicians to use this scalable intervention to help improve QoL of those affected by cancer and their caregivers.

Authors: Kubo A; Kurtovich E; McGinnis M; Aghaee S; Altschuler A; Quesenberry C; Kolevska T; Avins AL

Integr Cancer Ther. 2019 Jan-Dec;18:1534735419850634.

PubMed abstract

Links between age at menarche, antral follicle count, and body mass index in African American and European American women

To examine the relationships between age at menarche, antral follicle count (AFC), and body mass index (BMI) in a multi-ethnic population of women. Community-based, cross-sectional study. Academic setting. A total of 245 African American women and 273 European American women, aged 25-45 years, with regular menstrual cycles and no reproductive disorders. The ethnicity of these women was self-reported and genetically validated. The AFCs were measured by transvaginal ultrasound during the early follicular phase. Anthropometric measurements were taken, and age at menarche was gathered by questionnaire. Determination of the associations between age of menarche and adult AFC and BMI. Earlier age of menarche was associated with both higher BMIs and higher AFCs in adulthood, with control for female age. The antral follicle difference between early (<12 years) vs. late (?15 years) initiation of menarche in both white and black women was +3.81 and +3.34 follicles, respectively, which is equivalent to an approximately 20% difference in AFC. This study provides the first evidence that timing of menarche may influence AFC. Because of limited studies on African American women, this work provides additional needed data and may enhance our ability to prospectively screen and better treat various diseases associated with the female reproductive lifespan.

Authors: Schuh SM; Kadie J; Rosen MP; Sternfeld B; Reijo Pera RA; Cedars MI

Fertil Steril. 2019 04;111(4):629-640.

PubMed abstract

Infections in children with autism spectrum disorder: Study to Explore Early Development (SEED)

Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days (“neonatal,” from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Research 2019, 12: 136-146. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life.

Authors: Sabourin KR; Reynolds A; Schendel D; Rosenberg S; Croen LA; Pinto-Martin JA; Schieve LA; Newschaffer C; Lee LC; DiGuiseppi C

Autism Res. 2019 01;12(1):136-146. Epub 2018-11-26.

PubMed abstract

The impact of gene expression profile testing on confidence in chemotherapy decisions and prognostic expectations

Little is known about whether gene expression profile (GEP) testing and specific recurrence scores (e.g., medium risk) improve women’s confidence in their chemotherapy decision or perceived recurrence risk. We evaluate the relationship between these outcomes and GEP testing. We surveyed women eligible for GEP testing (stage I or II, Gr1-2, ER+, HER2-) identified through the Surveillance, Epidemiology, and End Results (SEER) Registry of Washington or Kaiser Permanente Northern California from 2012 to 2016, approximately 0-4 years from diagnosis (N?=?904, RR?=?45.4%). Confidence in chemotherapy was measured as confident (Very, completely) versus Not Confident (Somewhat, A little, Not At All); perceived risk recurrence was recorded numerically (0-100%). Women reported their GEP test receipt (Yes, No, Unknown) and risk recurrence score (High, Intermediate, Low, Unknown). In our analytic sample (N?=?833), we propensity score weighted the three test receipt cohorts and used propensity weighted multivariable regressions to examine associations between the outcomes and the three test receipt cohorts, with receipt stratified by score. 29.5% reported an unknown GEP test receipt; 86% being confident. Compared to no test receipt, an intermediate score (aOR 0.34; 95% CI 0.20-0.58), unknown score (aOR 0.09; 95% CI 0.05-0.18), and unknown test receipt (aOR 0.37; 95% CI 0.24-0.57) were less likely to report confidence. Most women greatly overestimated their recurrence risk regardless of their test receipt or score. GEP testing was not associated with greater confidence in chemotherapy decisions. Better communication about GEP testing and the implications for recurrence risk may improve women’s decisional confidence.

Authors: Panattoni L; Lieu TA; Jayasekera J; O'Neill S; Mandelblatt JS; Etzioni R; Phelps CE; Ramsey SD

Breast Cancer Res Treat. 2019 Jan;173(2):417-427. Epub 2018-10-10.

PubMed abstract

Weight estimation among multi-racial/ethnic infants and children aged 0-5·9 years in the USA: simple tools for a critical measure

In resource-constrained facilities or during resuscitation, immediate paediatric weight estimation remains a fundamental challenge. We aimed to develop and validate weight estimation models based on ulna length and forearm width and circumference measured by simple and portable tools; and to compare them against previous methods (advanced paediatric life support (APLS), Theron and Traub-Johnson formulas). Cross-sectional analysis of anthropometric measurements. Four ulna- and forearm-based weight estimation models were developed in the training set (n 1016). Assessment of bias, precision and accuracy was examined in the validation set (n 457). National Children’s Study-Formative Research in Anthropometry (2011-2012). Multi-racial/ethnic infants and children aged <6 years (n 1473). Developed Models 1-4 had high predictive precision (R 2=0·91-0·97). Mean percentage errors between predicted and measured weight were significantly smaller across the developed models (0·1-0·7 %) v. the APLS, Theron and Traub-Johnson formulas (-1·7, 9·2 and -4·9 %, respectively). Root-mean-squared percentage error was overall smaller among Models 1-4 v. the three existing methods (range=7·5-8·7 v. 9·8-13·3 %). Further, Models 1-4 were within 10 and 20 % of actual weight in 72-87 and 95-99 % of the weight estimations, respectively, which outperformed any of the three existing methods. Ulna length, forearm width and forearm circumference by simple and portable tools could serve as valid and reliable surrogate measures of weight among infants and children aged <6 years with improved precision over the existing age- or length-based methods. Further validation of these models in physically impaired or non-ambulatory children is warranted.

Authors: Zhu Y; Hernandez LM; Dong Y; Himes JH; Caulfield LE; Kerver JM; Arab L; Voss P; Hirschfeld S; Forman MR

Public Health Nutr. 2019 01;22(1):147-156. Epub 2018-10-18.

PubMed abstract

Bisphenol A and pubertal height growth in school-aged children

Bisphenol A (BPA) is an environmental endocrine disruptor and is found in many consumer products. Studies suggest that BPA may perturb pubertal development, although evidence on BPA-influenced pubertal height growth is scarce. A total of 754 children aged 9-18 years from three schools (one elementary, one middle, and one high school) in Shanghai were included in this longitudinal study. Height was measured at enrolment (visit 1) and, subsequently, at 19 months after enrolment (visit 2). Age- and sex-specific Z scores for height were calculated (height Z score?=?[participant’s height-sex- and age-specific population height mean]/sex- and age-specific population height standard deviation). Urine samples were collected at enrolment to measure BPA concentrations. We used multiple linear regression models or general estimating equation models (GEE) to estimate associations between urine BPA level and height Z score. The geometric mean of urine BPA concentrations was 1.6??g/L (95%CI: 1.4, 1.8) or 1.2??g/g creatinine (95%CI: 1.0, 1.3). An inverse association between urine BPA level and height was observed in boys. After adjustment for potential confounders, height Z score at enrolment in boys decreased by 0.49 for the highest exposure level (above 10.9??g/g creatinine as the 90th percentile), compared with the lowest BPA exposure (below 0.2??g/g creatinine as the 25th percentile) (95%CI: -0.96, -0.01; p-trend?=?0.024). The inverse association remained between BPA exposure and height Z score at visit 2. The GEE model showed that a 1-unit increase in log10-transformed BPA concentrations was associated with a 0.15-point decrease in height Z score over the follow-up (95%CI: -0.30, -0.01). BPA was not associated with height growth in girls. Our findings indicate an inverse association between urine BPA level and height growth in boys. These findings need to be confirmed in further studies.

Authors: Wang Z; Liang H; Tu X; Yuan W; Zhou Z; Jin L; Miao M; Li DK

J Expo Sci Environ Epidemiol. 2019 01;29(1):109-117. Epub 2018-09-05.

PubMed abstract

Brief Report: Maternal Opioid Prescription from Preconception Through Pregnancy and the Odds of Autism Spectrum Disorder and Autism Features in Children

Opioid use during pregnancy is associated with suboptimal pregnancy outcomes. Little is known about child neurodevelopmental outcomes. We examined associations between maternal opioid prescriptions preconception to delivery (peri-pregnancy) and child’s risk of ASD, developmental delay/disorder (DD) with no ASD features, or ASD/DD with autism features in the Study to Explore Early Development, a case-control study of neurodevelopment. Preconception opioid prescription was associated with 2.43 times the odds of ASD [95% confidence interval (CI) 0.99, 6.02] and 2.64 times the odds of ASD/DD with autism features (95% CI 1.10, 6.31) compared to mothers without prescriptions. Odds for ASD and ASD/DD were non-significantly elevated for first trimester prescriptions. Work exploring mechanisms and timing between peri-pregnancy opioid use and child neurodevelopment is needed.

Authors: Rubenstein E; Young JC; Croen LA; DiGuiseppi C; Dowling NF; Lee LC; Schieve L; Wiggins LD; Daniels J

J Autism Dev Disord. 2019 Jan;49(1):376-382.

PubMed abstract

Brief Report: Low Rates of Herpesvirus Detection in Blood of Individuals with Autism Spectrum Disorder and Controls

Previous research indicates that infection, especially from viruses in the family Herpesviridae, may play a role in the etiology of some cases of autism spectrum disorder (ASD). Using a case-control design and the polymerase chain reaction with site-specific primers, we screened newborn and childhood blood samples for the presence of eight human herpesviruses. Herpesvirus DNA was detected in 4 of 225 ASD individuals and 2 of 235 controls, with the most frequently detected virus being HHV-6B. Although this study does not detect a significant ASD-Herpesviridae association, it is limited by the use of site-specific primers. We suggest that new techniques using bioinformatics to search next-generation sequencing databases will be more revealing of possible ASD-virus associations.

Authors: Sweeten TL; Croen LA; Windham GC; Odell JD; Stubbs EG; Torres AR

J Autism Dev Disord. 2019 Jan;49(1):410-414.

PubMed abstract

Healthy Lifestyle During the Midlife Is Prospectively Associated With Less Subclinical Carotid Atherosclerosis: The Study of Women’s Health Across the Nation

Background Measures of subclinical atherosclerosis are predictors of future cardiovascular outcomes as well as of physical and cognitive functioning. The menopausal transition is associated with accelerated progression of atherosclerosis in women. The prospective association between a healthy lifestyle during the midlife and subclinical atherosclerosis is unclear. Methods and Results Self-reported data on smoking, diet, and physical activity from 1143 women in the Study of Women’s Health Across the Nation were used to construct a 10-year average Healthy Lifestyle Score ( HLS ) during the midlife. Markers of subclinical atherosclerosis were measured 14 years after baseline and included common carotid artery intima-media thickness ( CCA – IMT ), adventitial diameter ( CCA – AD ), and carotid plaque. The associations of average HLS with CCA – IMT and CCA – AD were estimated using linear models; the association of average HLS with carotid plaque was estimated using cumulative logit models. Average HLS was associated with smaller CCA – IMT and CCA – AD in the fully adjusted models ( P=0.0031 and <0.001, respectively). Compared with participants in the lowest HLS level, those in the highest level had 0.024 mm smaller CCA - IMT (95% confidence interval: -0.048, 0.000), which equals 17% of the SD of CCA - IMT , and 0.16 mm smaller CCA - AD (95% confidence interval: -0.27, -0.04), which equals 24% of the SD of CCA - AD . Among the 3 components of the HLS , abstinence from smoking had the strongest association with subclinical atherosclerosis. Conclusions Healthy lifestyle during the menopausal transition is associated with less subclinical atherosclerosis, highlighting the growing recognition that the midlife is a critical window for cardiovascular prevention in women.

Authors: Wang D; Sternfeld B; Baylin A; et al.

J Am Heart Assoc. 2018 12 04;7(23):e010405.

PubMed abstract

Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort

To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort. In a retrospective cohort study of 44 572 singleton infants ?36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of??5 or a base excess of ?-15?mmol/L. Neonatal acidemia was defined as a base excess of ?-12?mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression. There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk [RR], 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of??35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE. A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.

Authors: Parker SJ; Kuzniewicz M; Niki H; Wu YW

J Pediatr. 2018 12;203:163-169. Epub 2018-09-27.

PubMed abstract

Risk of cardiovascular disease in women with BRCA1 and BRCA2 mutations

Estimate the prevalence of cardiovascular disease risk factors and endpoints in women with BRCA mutations. Women, age 40 and older, with BRCA mutations identified in Kaiser Permanente Northern California completed a questionnaire and underwent a lipid and fasting glucose panel. Bivariable analysis of clinical and demographic factors was performed. The Atherosclerotic Cardiovascular Disease (ASCVD) calculator was used to predict 10-year risk of a cardiovascular event. Of the 233 women, 19 women had intact ovaries (median age 56.0) and 214 had undergone risk-reducing salpingo-oophorectomy (RRSO). Among the 108 women with RRSO under age 50 (median age 51.0), compared to the 106 women who had RRSO at or over age 50 (median age 63.5) 6.5% vs 10.4% reported diabetes (p = 0.30), 23.2% versus 28.3% had elevated fasting blood glucose (p = 0.39), 21.3% versus 34.0% reported hypertension (p = 0.04) with median systolic blood pressure of 118 mmHg versus 125.5 mmHg (p < 0.009), 25% versus 32% reported hyperlipidemia (p = 0.40), and 42% versus 49% had any abnormal lipid test (p = 0.28). An elevated 10-year ASCVD risk of over 10% was seen in 6.1% versus 24.8% respectively (p = 0.0001). Women who underwent RRSO at age of 50 and over, had higher ASCVD 10-year risk than women who underwent RRSO at younger ages most likely owing to older age at study entry. The ASCVD risks for women with BRCA mutation who had RRSO did not suggest increased risk associated with being a BRCA mutation carrier.

Authors: Powell CB; Alabaster A; Armstrong MA; Stoller N; Raine-Bennett T

Gynecol Oncol. 2018 12;151(3):489-493. Epub 2018-10-10.

PubMed abstract

Maternal exposure to bisphenol A and anogenital distance throughout infancy: A longitudinal study from Shanghai, China

Bisphenol A (BPA) is one of the most common endocrine-disrupting compounds (EDCs) with a ubiquitous presence. Both animal and human studies have reported the association between maternal exposure to BPA and anogenital distance (AGD) in offspring. However, the results are conflicting and the longitudinal effect is unknown. We aimed to examine the effect of maternal exposure to BPA on AGD in offspring in a longitudinal birth cohort from birth to 1?year of age. BPA was assayed using urine samples collected at 12-16 gestational weeks from 982 pregnant participants who later delivered infants. Infants’ AGDs (AGDap [anus-penis] and AGDas [anus-scrotum] for boys, AGDac [anus-clitoris] and AGDaf [anus-fourchette] for girls) were measured at birth, and at 6 and 12?months of age. Multiple linear regression analysis was conducted to examine the associations between maternal exposure to BPA and offspring’s AGDs. Then generalized estimating equation (GEE) model was applied to make use of the repeated measurements of AGDs and examine the overall effect of maternal exposure to BPA. Compared to boys with undetected maternal BPA, those with detected BPA were more likely to have shorter AGDap and AGDas at 6 and 12?months. However, the differences were statistically significant for AGDap and AGDas only at 12?months (2.87 and 4.12?mm shorter, respectively). In GEE models, similar patterns were observed. Boys in the higher quartiles were more likely to have shorter AGDap and AGDas than those in the first quartile. However, statistically significant differences were only observed in boys in the third quartile. For girls, these associations were not observed regardless of the timing of measurements (at birth, 6?months and 12?months). Maternal exposure to BPA was associated with shortened AGDap and AGDas in boys at age 12?months but not in girls, which suggests a gender specific effect of BPA exposure on offspring’s development.

Authors: Sun X; Li D; Liang H; Miao M; Song X; Wang Z; Zhou Z; Yuan W

Environ Int. 2018 12;121(Pt 1):269-275. Epub 2018-09-14.

PubMed abstract

Central Obesity Increases the Risk of Gestational Diabetes Partially Through Increasing Insulin Resistance

This study examined the associations of central obesity measures, waist to hip ratio (WHR) and waist circumference (WC), in early pregnancy with subsequent risk of gestational diabetes mellitus (GDM) and evaluated the potential mediating role of insulin resistance markers. Within the prospective Pregnancy Environment and Lifestyle Study cohort of 1,750 women, WC and hip circumference were measured at gestational weeks 10 to 13. In a nested case-control study within the cohort, 115 GDM cases and 230 controls had fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and adiponectin measurements at gestational weeks 16 to 19. Poisson and conditional logistic regression models were used, adjusting for established risk factors for GDM, including prepregnancy overweight or obesity. For women with WHR 

Authors: Zhu Y; Hedderson MM; Quesenberry CP; Feng J; Ferrara A

Obesity (Silver Spring). 2018 Nov 21.

PubMed abstract

Longitudinal Maternal Vitamin D Status during Pregnancy Is Associated with Neonatal Anthropometric Measures

Findings on maternal 25-hydroxyvitamin D (25[OH]D) and neonatal anthropometry are inconsistent, and may at least be partly due to variations in gestational week (GW) of 25(OH)D measurement and the lack of longitudinal 25(OH)D measurements across gestation. The aim of the current study was to examine the associations of longitudinal measures of maternal 25(OH)D and neonatal anthropometry at birth. This study included 321 mother⁻offspring pairs enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies⁻Singletons. This study was a prospective cohort design without supplementation and without data on dietary supplementation. Nevertheless, measurement of plasma 25(OH)D reflects vitamin D from different sources, including supplementation. Maternal concentrations of total 25(OH)D were measured at 10⁻14, 15⁻26, 23⁻31, and 33⁻39 GW and categorized as 75 nmol/L. Generalized linear models were used to examine associations of 25(OH)D at each time-point with neonate birthweight z-score, length, and sum of skinfolds at birth. At 10⁻14 GW, 16.8% and 49.2% of women had 25(OH)D

Authors: Francis EC; Hinkle SN; Song Y; Rawal S; Donnelly SR; Zhu Y; Chen L; Zhang C

Nutrients. 2018 Nov 02;10(11). Epub 2018-11-02.

PubMed abstract

Prospective Validation of a Standardized Ultrasonography-Based Ovarian Cancer Risk Assessment System

To evaluate the performance of a system that standardizes ovarian cancer risk assessment and reporting on ultrasonography. We conducted a prospective community-based cohort study of average-risk women undergoing ultrasonography in 2016 using a reporting system that requires adnexal masses to be categorized as 1, 2, 3, or X based on standardized ultrasound criteria including size, presence of solid components, and vascularity assessed by Doppler. With a median follow-up of 18 months, the risk of ovarian cancer or borderline tumor diagnosis for each category was determined. Among 43,606 women undergoing ultrasonography, 6,838 (16%) had an abnormal adnexal mass reported: 70% were category 1, 21% category 2, 3.7% category 3, and 5.4% category X. Among these women, 89 (1.3%) were subsequently diagnosed with ovarian cancer and 59 (0.9%) with borderline tumors. The risks of ovarian cancer diagnosis associated with masses reported as categories 1, 2, 3, and X were 0.2% (95% CI 0.05-0.3%), 1.3% (95% CI 0.7-1.9%), 6.0% (95% CI 3.0-8.9%), and 13.0% (95% CI 9.5-16.4%), respectively; risks of either ovarian cancer or borderline tumor were 0.4% (95% CI 0.2-0.6%), 2.3% (95% CI 1.6-3.1%), 10.4% (95% CI 6.6-14.1%), and 18.9% (95% CI 14.9-23.0%) respectively. Among 36,768 (84%) women with normal or benign adnexal findings reported, 38 women were diagnosed with ovarian cancer, for a risk of 0.1% (95% CI 0.07-0.14%). In a community-based setting with low ovarian cancer prevalence, our standardized reporting system differentiated adnexal masses into four categories with distinct levels of risk with 9-10% of women having higher risk masses and 70% of women having masses associated with a risk of cancer similar to that of normal ultrasound findings. The system supports risk-based management by providing clinicians a more consistent assessment of risk based on ultrasound characteristics.

Authors: Suh-Burgmann E; Flanagan T; Osinski T; Alavi M; Herrinton L

Obstet Gynecol. 2018 11;132(5):1101-1111.

PubMed abstract

Long-term postmenopausal estrogen therapy may be associated with increased risk of breast cancer: a cohort study

Reports of a role of postmenopausal estrogen replacement therapy in the development of breast cancer have been inconsistent. Although many epidemiologic studies have failed to show an association between short-term use of estrogen and breast cancer, there are indications that long-term use may present an increased risk. We undertook a long-term, retrospective cohort study of the incidence of breast cancer in women who had taken long-term estrogen (average 17.2 years), compared to women who had not taken estrogen. Subjects were 454 women born between 1900 and 1915, who were members of a large health maintenance organization in northern California. By the end of 1995, 26 (11.2%) of estrogen users developed breast cancer, as did 9 (4.1%) of the nonusers; the relative risk (RR) for estrogen use was 2.8 [95% confidence interval (95% CI) 1.3-5.9]. Adjustment for age and multiple breast cancer risk factors, including breast cancer surveillance, reduced the RR for estrogen to 2.0 (95% CI 0.9-4.5). We conclude that long-term estrogen use is associated with a substantially increased risk of breast cancer.

Authors: Ettinger B; Quesenberry C; Schroeder DA; Friedman G

Menopause. 2018 11;25(11):1191-1194.

PubMed abstract

Continuation of postmenopausal hormone replacement therapy: comparison of cyclic versus continuous combined schedules

Discontinuation of hormone replacement therapy (HRT) is much more common than what is reported in randomized, double-blind clinical trials. Our purpose in this retrospective study, using a prescription database, was to compare the continuation rate among women who took cyclic combination therapy adding progesterone to estrogen (CYC-PERT) or continuous combined estrogen progestin therapy (CC-PERT). The study subjects were 1,532 women, ≥45 years old, who initially filled index prescriptions for 0.625 mg conjugated estrogens. They were divided into two groups (CYC-PERT = 644, CC-PERT = 888) on the basis of coprescribed medroxyprogesterone. We found that for all women initiating therapy, 35-40% did not return for a refill and 76-81% stopped therapy within 3 years. Those prescribed CC-PERT initially were more likely to stop than those prescribed CYC-PERT (rate ratio [RR] = 1.20; 95% confidence interval [CI] = 1.06-1.35). Adjustments for age, year of starting medication, cost of medication, and prescriber specialty did not affect the difference in discontinuation between the two regimens (RR 1.18, 95% CI = 1.04-1.34). We conclude that the likelihood of women continuing HRT beyond 3 years of initiation is low. Furthermore, compared with CYC-PERT users, those receiving CC-PERT have a slightly higher probability of discontinuation. Efforts should be made to understand why three quarters of women beginning HRT will stop it long before it can provide major long-term benefit.

Authors: Ettinger B; Li DK; Klein R

Menopause. 2018 11;25(11):1187-1190.

PubMed abstract

The Utility and Cross-Validation of a Composite Physical Activity Score in Relation to Cardiovascular Health Indicators: Coronary Artery Risk Development in Young Adults

Single-method assessment of physical activity (PA) has limitations. The utility and cross-validation of a composite PA score that includes reported and accelerometer-derived PA data has not been evaluated. Participants attending the Year 20 exam were randomly assigned to the derivation (two-thirds) or validation (one-third) data set. Principal components analysis was used to create a composite score reflecting Year 20 combined reported and accelerometer PA data. Generalized linear regression models were constructed to estimate the variability explained (R2) by each PA assessment strategy (self-report only, accelerometer only, composite score, or self-report plus accelerometer) with cardiovascular health indicators. This process was repeated in the validation set to determine cross-validation. At Year 20, 3549 participants (45.2 [3.6] y, 56.7% female, and 53.5% black) attended the clinic exam and 2540 agreed to wear the accelerometer. Higher R2 values were obtained when combined assessment strategies were used; however, the approach yielding the highest R2 value varied by cardiovascular health outcome. Findings from the cross-validation also supported internal study validity. Findings support continued refinement of methodological approaches to combine data from multiple sources to create a more robust estimate that reflects the complexities of PA behavior.

Authors: Pettee Gabriel K; Pérez A; Jacobs DR; Lee J; Kohl HW; Sternfeld B

J Phys Act Health. 2018 11 01;15(11):847-856. Epub 2018-10-19.

PubMed abstract

Omega 3 polyunsaturated fatty acids and healthy ageing

Authors: Zhu Y; Ferrara A; Forman MR

BMJ. 2018 10 17;363:k4263. Epub 2018-10-17.

PubMed abstract

A Pre-Pregnancy Biomarker Risk Score Improves Prediction of Future Gestational Diabetes

Previous studies have not examined the ability of multiple preconception biomarkers, considered together, to improve prediction of gestational diabetes mellitus (GDM). To develop a preconception biomarker risk score and assess its association with subsequent GDM. A nested case-control study among a cohort of women with serum collected as part of a health examination (1984 to 1996) and subsequent pregnancy (1984 to 2009). Biomarkers associated with GDM were dichotomized into high/low risk. Integrated health care system. Two controls were matched to each GDM case (n = 256 cases) on year and age at examination, age at pregnancy, and number of pregnancies between examination and index pregnancy. GDM. High-risk levels of sex hormone-binding globulin (SHBG; <44.2 nM), glucose (>90 mg/dL), total adiponectin (<7.2 μg/mL), and homeostasis model assessment-estimated insulin resistance (>3.9) were independently associated with 2.34 [95% confidence interval (CI): 1.50, 3.63], 2.03 (95% CI: 1.29, 3.19), 1.83 (95% CI: 1.16, 2.90), and 1.67 (95% CI: 1.07, 2.62) times the odds of GDM and included in the biomarker risk score. For each unit increase in the biomarker risk score, odds of GDM were 1.94 times greater (95% CI: 1.59, 2.36). A biomarker risk score including only SHBG and glucose was sufficient to improve prediction beyond established risk factors (age, race/ethnicity, body mass index, family history of diabetes, previous GDM; area under the curve = 0.73 vs 0.67, P = 0.002). The improved, predictive ability of the biomarker risk score beyond established risk factors suggests clinical use of the biomarker risk score in identifying women at risk for GDM before conception for targeted prevention strategies.

Authors: Badon SE; Zhu Y; Sridhar SB; Xu F; Lee C; Ehrlich SF; Quesenberry CP; Hedderson MM

J Endocr Soc. 2018 Oct 01;2(10):1158-1169. Epub 2018-09-13.

PubMed abstract

Hyperbilirubinemia, Phototherapy, and Childhood Asthma

Our aim was to quantify the associations of both hyperbilirubinemia and phototherapy with childhood asthma using a population-based cohort with total serum bilirubin (TSB) levels. Retrospective cohort study of infants born at ?35 weeks’ gestation in the Kaiser Permanente Northern California health system (n = 109?212) from 2010 to 2014. Cox models were used to estimate hazard ratios (HRs) for a diagnosis of asthma. In the study, 16.7% of infants had a maximum TSB level of ?15 mg/dL, 4.5% of infants had a maximum TSB level of ?18 mg/dL, and 11.5% of infants received phototherapy. Compared with children with a maximum TSB level of 3 to 5.9 mg/L, children with a TSB level of 9 to 11.9 mg/dL, 12 to 14.9 mg/dL, and 15 to 17.9 mg/dL were at an increased risk for asthma (HR: 1.22 [95% confidence interval (CI): 1.11-1.3], HR: 1.18 [95% CI: 1.08-1.29], and HR: 1.30 [95% CI: 1.18-1.43], respectively). Children with a TSB level of ?18 mg/dL were not at an increased risk for asthma (HR: 1.04; 95% CI: 0.90-1.20). In propensity-adjusted analyses, phototherapy was not associated with asthma (HR: 1.07; 95% CI: 0.96-1.20). Modest levels of hyperbilirubinemia were associated with an increased risk of asthma, but an association was not seen at higher levels. No dose-response relationship was seen. Using phototherapy to prevent infants from reaching these modest TSB levels is unlikely to be protective against asthma.

Authors: Kuzniewicz MW; Niki H; Walsh EM; McCulloch CE; Newman TB

Pediatrics. 2018 10;142(4). Epub 2018-09-12.

PubMed abstract

Childhood Seizures After Phototherapy

: media-1vid110.1542/5804915133001PEDS-VA_2018-0648Video Abstract BACKGROUND AND OBJECTIVES: In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort. From 499?642 infants born at ?35 weeks’ gestation in 1995-2011 followed for ?60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at <60 days. We ascertained phototherapy, covariates, and outcomes from electronic records and existing databases. Our primary outcome was ?1 encounter with a seizure diagnosis plus ?1 prescription for an antiepileptic drug. We used Cox and Poisson models to adjust for bilirubin levels and other confounding variables. A total of 37?683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10-year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: -1.7 to 3.2) in girls. Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys.

Authors: Newman TB; Wu YW; Kuzniewicz MW; Grimes BA; McCulloch CE

Pediatrics. 2018 10;142(4).

PubMed abstract

Contraception after Abortion and Risk of Repeated Unintended Pregnancy among Health Plan Members

Optimizing access to effective contraception at the time of abortion can reduce repeated unintended pregnancies. To assess contraception initiation and repeated unintended pregnancies among women receiving abortions in Kaiser Permanente Northern California (KPNC) facilities and through outside contracted facilities. A retrospective cohort study was conducted using a randomized proportional sample of women aged 15 to 44 years having abortions in KPNC, to determine contraception initiation within 90 days. Demographic and clinical characteristics (age, race/ethnicity, gravidity, parity, contraceptive method initiated, and pregnancies within 12 months) were collected from electronic health records. Descriptive statistics, χ2 tests, t-tests, and logistic regression models assessed predictors of long-acting reversible contraception (LARC) initiation and having another unintended pregnancy within 12 months of abortion. Women having abortions from contracted facilities were significantly less likely to initiate LARC within 90 days compared with those receiving abortions in KPNC facilities (11.99% vs 19.10%, p = 0.012). Significant factors associated with 90-day LARC initiation included abortions in KPNC facilities (adjusted odds ratio [aOR] = 1.87, p = 0.007) and gravidity of 3 or more. Women initiating short-acting or no contraception were significantly more likely to have an unintended pregnancy within 12 months of the abortion than those initiating LARC (aOR = 3.66, p = 0.005; no contraception vs LARC, aOR = 3.75, p = 0.005). In response to this study, KPNC now provides reimbursement for LARC in all outside abortion contracts, internalized more abortions in KPNC facilities, and strengthened clinical recommendations for immediate, effective postabortion contraception, especially LARC.

Authors: Postlethwaite D; Merchant M; Alabaster A; Raine-Bennett T

Perm J. 2018 Sep 10;22. Epub 2018-09-10.

PubMed abstract

The Seveso accident: A look at 40 years of health research and beyond.

A 1976 chemical factory explosion near Seveso, Italy exposed residents to high levels of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD or dioxin). Dioxin is a known human carcinogen and potent endocrine disruptor. It is highly lipophilic and has a long half-life in humans. Much of what we know and can learn about the risks of dioxin exposure on human health arose from the tragic circumstances of Seveso. This review aims to describe the Seveso accident, summarize the results of 40 years of research on the health of the Seveso population since the accident, and discuss next-stage research on the health of Seveso residents, their children, and grandchildren.

Authors: Eskenazi, Brenda B; Warner, Marcella M; Brambilla, Paolo P; Signorini, Stefano S; Ames, Jennifer J; Mocarelli, Paolo P

Environment international. 2018 Sep 01;121(Pt 1):71-84. Epub 2018-09-01.

PubMed abstract

Data Enclaves for Sharing Information Derived From Clinical and Administrative Data

Authors: Platt R; Lieu T

JAMA. 2018 08 28;320(8):753-754.

PubMed abstract

Placental gross shape differences in a high autism risk cohort and the general population

A growing body of evidence suggests that prenatal environment is important in Autism Spectrum Disorder (ASD) etiology. In this study, we compare placental shape features in younger siblings of children with ASD, who themselves are at high ASD risk, to a sample of low risk peers. Digital photographs of the fetal placenta surface and of the sliced placental disk from 129 high ASD risk newborns and from 267 newborns in the National Children’s Study Vanguard pilot were analysed to extract comparable measures of placental chorionic surface shape, umbilical cord displacement and disk thickness. Placental thickness measures were moderately higher in siblings of ASD cases. The placentas of ASD-case siblings were also rounder and more regular in perimeter than general population placentas. After stratification by sex, these across-group differences persisted for both sexes but were more pronounced in females. No significant differences were observed in cord insertion measures. Variations in placental shape features are generally considered to reflect flexibility in placental growth in response to changes in intrauterine environment as the placenta establishes and matures. Reduced placental shape variability observed in high ASD risk siblings compared to low-risk controls may indicate restricted ability to compensate for intrauterine changes.

Authors: Park BY; Misra DP; Moye J; Miller RK; Croen L; Fallin MD; Walker C; Newschaffer CJ; Salafia CM; National Children’s Study Consortium

PLoS ONE. 2018;13(8):e0191276. Epub 2018-08-22.

PubMed abstract

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy

The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.

Authors: Traglia M; Croen LA; Jones KL; Heuer LS; Yolken R; Kharrazi M; DeLorenze GN; Ashwood P; Van de Water J; Weiss LA

Genome Med. 2018 08 22;10(1):67. Epub 2018-08-22.

PubMed abstract

Association of Nausea and Vomiting in Pregnancy With Prenatal Marijuana Use

Use of marijuana, an antiemetic, is increasing among pregnant women,1,2 and data from 2 small surveys3,4 indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP). To date, only 1 epidemiologic study5 has examined whether women with NVP are at elevated risk of using marijuana. The study of 4735 pregnant women in Hawaii5 from 2009 through 2011 found that self-reported prenatal marijuana use was more prevalent among those with (3.7%) vs without (2.3%) self-reported severe nausea during pregnancy. We used data from a large California health care system with standard universal screening for prenatal marijuana use via self-report and urine toxicologic tests from January 1, 2009, through December 31, 2016, to test whether prenatal marijuana use is elevated among females with a diagnosis of NVP. Methods:Kaiser Permanente Northern California (KPNC) is a multispecialty health care system serving more than 4 million members representative of the Northern California area. The sample consisted of pregnant females 12 years or older in KPNC who completed a self-reported substance use questionnaire and urine toxicologic test in the first trimester (at approximately?8 weeks gestation) during standard prenatal care. All positive toxicologic test findings were confirmed with a laboratory test result. The institutional review board of KPNC approved this study and waived the need for informed consent. Nausea and vomiting during the first trimester of pregnancy (90 days from last menstrual period) was based on International Classification of Disease, Ninth Revision, Clinical Modification, and Tenth Revision, Clinical Modification, diagnostic codes in the electronic health record and categorized as severe (hyperemesis gravidarum [codes 643.00, 643.03, 643.10, 643.13, O21.0, and O21.1]), mild (other NVP diagnoses [codes 536.2, 643.80, 643.90, 643.93, 787.01, 787.02, 787.03, G43.A0, O21.9, R11.0, R11.10, R11.11, and R11.2]), or none. We estimated the adjusted odds of prenatal marijuana use among females with NVP using multilevel logistic regression, controlling for age, race/ethnicity, median neighborhood household income, year, and self-reported marijuana use in the year before pregnancy from the universal screening questionnaire for prenatal substance use. We used in the PROC GLIMMIX procedure in SAS software (version 9.3; SAS Institute, Inc) for all analyses, and 2-sided P?

Authors: Young-Wolff KC; Sarovar V; Tucker LY; Avalos LA; Conway A; Armstrong MA; Goler N

JAMA Intern Med. 2018 Aug 20.

PubMed abstract

Association of Bisphenol A Exposure with LINE-1 Hydroxymethylation in Human Semen

Bisphenol A (BPA), an exogenous endocrine-disrupting chemical, has been shown to alter DNA methylation. However, little information is available about the effect of BPA exposure on DNA hydroxymethylation in humans. The objective of the present study was to examine whether BPA exposure was associated with DNA hydroxymethylation in human semen samples. We measured urine BPA levels and LINE-1 hydroxymethylation in 158 male factory workers selected from an occupational cohort study conducted in China between 2004 and 2008. Among them, there were 72 male workers with occupational BPA exposure (BPA-exposed group) and 86 male workers without occupational BPA exposure (unexposed group). Multivariate linear regression models were used to examine the association of exposure to BPA with LINE-1 hydroxymethylation. LINE-1 was more highly hydroxymethylated in the BPA-exposed group than in the unexposed group (median 12.97% vs. 9.68%, respectively; p < 0.05), after adjusting for the potential confounders. The medians of 5-hydroxymethylcytosine (5hmC) generally increased with increasing urine BPA levels: 8.79%, 12.16%, 11.53%, and 13.45%, for undetected BPA and corresponding tertiles for the detected BPA, respectively. After analysis using data at individual level, our findings indicated that BPA exposure was associated with alterations of sperm LINE-1 hydroxymethylation, which might have implications for understanding the mechanisms underlying BPA-induced adverse effects on male reproductive function.

Authors: Tian Y; Zhou X; Miao M; Li DK; Wang Z; Li R; Liang H; Yuan W

Int J Environ Res Public Health. 2018 Aug 17;15(8). Epub 2018-08-17.

PubMed abstract

AHR gene-dioxin interactions and birthweight in the Seveso Second Generation Health Study.

Background: 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is proposed to interfere with fetal growth via altered activity of the aryl hydrocarbon receptor (protein: AHR; gene: AHR) pathway which regulates diverse biological and developmental processes including xenobiotic metabolism. Genetic variation in AHR is an important driver of susceptibility to low birthweight in children exposed to prenatal smoking, but less is known about these genetic interactions with TCDD, AHR’s most potent xenobiotic ligand.Methods: The Seveso Women’s Health Study (SWHS), initiated in 1996, is a cohort of 981 Italian women exposed to TCDD from an industrial explosion in July 1976. We measured TCDD concentrations in maternal serum collected close to the time of the accident. In 2008 and 2014, we followed up the SWHS cohort and collected data on birth outcomes of SWHS women with post-accident pregnancies. We genotyped 19 single nucleotide polymorphisms (SNPs) in AHR among the 574 SWHS mothers. Results: Among 901 singleton births, neither SNPs nor TCDD exposure alone were significantly associated with birthweight. However, we found six individual SNPs in AHR which adversely modified the association between maternal TCDD and birthweight, implicating gene-environment interaction. We saw an even stronger susceptibility to TCDD due to interaction when we examined the joint contribution of these SNPs in a risk allele score. These SNPs were all located in noncoding regions of AHR, particularly in proximity to the promoter. Conclusions: This is the first study to demonstrate that genetic variation across the maternal AHR gene may shape fetal susceptibilities to TCDD exposure.

Authors: Ames, Jennifer J; Warner, Marcella M; Mocarelli, Paolo P; Brambilla, Paolo P; Signorini, Stefano S; Siracusa, Claudia C; Huen, Karen K; Holland, Nina N; Eskenazi, Brenda B

International journal of epidemiology. 2018 Aug 14;162(Pt 1):55-62. Epub 2018-08-14.

PubMed abstract

Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.

Authors: Wexler DJ; Ferrara A; Catalano PM; et al.

Obstet Gynecol. 2018 08;132(2):496-505.

PubMed abstract

Breastfeeding and growth during infancy among offspring of mothers with gestational diabetes mellitus: a prospective cohort study

Breastfeeding (BF) may protect against obesity and type 2 diabetes mellitus in children exposed to maternal diabetes in utero, but its effects on infant growth among this high-risk group have rarely been evaluated. The objective of this study was to evaluate BF intensity and duration in relation to infant growth from birth through 12 months among offspring of mothers with gestational diabetes mellitus (GDM). Prospective cohort of 464 GDM mother-infant dyads (28% White, 36% Hispanic, 26% Asian, 8% Black, 2% other). Weight and length measured at birth, 6-9 weeks, 6 months and 12 months. Categorized as intensive BF or formula feeding (FF) groups at 6-9 weeks (study baseline), and intensity from birth through 12 months as Group 1: consistent exclusive/mostly FF, Group 2: transition from BF to FF within 3-9 months and Group 3: consistent exclusive/mostly BF. Multivariable mixed linear regression models estimated adjusted mean (95% confidence interval) change in z-scores; weight-for-length (WLZ), weight-for-age and length-for-age. Compared with intensive BF at 6-9 weeks, FF showed greater increases in WLZ-scores from 6 to 9 weeks to 6 months [+0.38 (0.13 to 0.62) vs. +0.02 (-0.15 to 0.19); p = 0.02] and birth to 12 months [+1.11 (0.87 to 1.34) vs. +0.53 (0.37 to 0.69); p < 0.001]. For 12-month intensity and duration, Groups 2 and 3 had smaller WLZ-score increases than Group 1 from 6 to 9 weeks to 6 months [-0.05 (-0.27 to 0.18) and +0.07 (-0.19 to 0.23) vs. +0.40 (0.15 to 0.64); p = 0.01 and 0.07], and birth to 12 months [+0.60 (0.39 to 0.82) and +0.59 (0.33 to 0.85) vs. +0.97 (0.75 to 1.19); p < 0.05]. Among offspring of mothers with GDM, high intensity BF from birth through 1 year is associated with slower infant ponderal growth and lower weight gain.

Authors: Gunderson EP; Greenspan LC; Faith MS; Hurston SR; Quesenberry CP; SWIFT Offspring Study Investigators

Pediatr Obes. 2018 08;13(8):492-504. Epub 2018-04-24.

PubMed abstract

Health Care Utilization in the First Month after Birth and Its Relationship to Newborn Weight Loss and Method of Feeding

Guidelines recommend closer outpatient follow-up for exclusively breastfed newborns, especially those with pronounced weight loss, because of increased risk of hyperbilirubinemia and dehydration that might require readmission. Our objective was to determine how feeding method and weight loss are associated with neonatal health care utilization. A retrospective cohort study conducted at Northern California Kaiser Permanente hospitals in 2009-2013 assessed 143,889 neonates to study the inpatient method of feeding as well as inpatient and outpatient weights. The main outcome measures were inpatient and outpatient health care utilization in the 30 days after birth. Newborn weight loss and feeding method were both associated with utilization. Exclusively breastfed newborns had higher readmission rates than those exclusively formula fed for both vaginal (4.3% compared to 2.1%) (P < .001) and cesarean deliveries (2.1% compared to 1.5%) (P = .025). Those exclusively breastfed also had more neonatal outpatient visits compared to those exclusively formula fed for both vaginal (means of 3.0 and 2.3, P < .001) and cesarean deliveries (means of 2.8 and 2.2, P < .001). Among vaginally delivered newborns of all feeding types, newborns with weight loss >10% at discharge had a relative risk of readmission of 1.10 (95% confidence interval [CI],1.00, 1.20) compared to those with <8% weight loss at discharge; among the subset weighed as inpatients or outpatients between 48 and 72 hours, those with >10% weight loss between 48-72 hours had a relative risk of readmission of 2.11 (95% CI, 1.95, 2.26) compared to those with <8% weight loss at 48-72 hours. Exclusive breastfeeding and weight loss are associated with increased neonatal health care utilization. Improving clinical management of exclusively breastfed neonates with pronounced weight loss might reduce health care utilization.

Authors: Flaherman V; Schaefer EW; Kuzniewicz MW; Li SX; Walsh EM; Paul IM

Acad Pediatr. 2018 08;18(6):677-684. Epub 2017-12-02.

PubMed abstract

Scientific abstracts featured research at the 2018 North American Forum on Family Planning

The Society of Family Planning (SFP), Planned Parenthood Federation of America (PPFA), and the Association of Reproductive Health Professionals (ARHP) are delighted to host the eighth annual North American Forum on Family Planning (the Forum) in New Orleans, LA, from October 20� 22, 2018. This dynamic multidisciplinary meeting is a stimulating opportunity for investigators in the areas of contraception, abortion, and sexual and reproductive health to gather to share research, learn, and develop new ideas. The Forum features presentations of unpublished research, clinical practice updates and thought-provoking breakout sessions that help us stay engaged with the most current evidence and give us the tools to make a difference in the medically, socially, and politically complex sphere of family planning. A record total of 312 scientific abstracts were submitted this year, and reviewed by a panel of 59 family planning experts. The Forum’s Scientific Committee accepted 105 abstracts for poster presentation. The Committee selected 20 of the top-ranked abstracts for oral presentation, and is proud to present four outstanding abstracts in a plenary session for all attendees. These abstracts, described briefly below, detail research from diverse investigators using a spectrum of investigative methodologies, from basic laboratory science to n tionwide integrated knowledge translation.

Authors: Teal S; Borrero S; Hubacher D; Madden T; Raine-Bennett T

Contraception. 2018 Jul 19.

PubMed abstract

Comparison of Collaborative Versus Single-Site Quality Improvement to Reduce NICU Length of Stay

There is unexplained variation in length of stay (LOS) across NICUs, suggesting that there may be practices that can optimize LOS. Three groups of NICUs in the California Perinatal Quality Care Collaborative were followed: (1) collaborative centers participating in an 18-month collaborative quality improvement project to optimize LOS for preterm infants; (2) individual centers aiming to optimize LOS; and (3) nonparticipants. Our aim in the collaborative project was to decrease postmenstrual age (PMA) at discharge for infants born between 27 + 0 and <32 weeks' gestational age by 3 days. A secondary outcome was "early discharge," the proportion of infants discharged from the hospital before 36 + 5 weeks' PMA. The balancing measure of readmissions within 72 hours was tracked for the collaborative group. From 2013 to 2015, 8917 infants were cared for in 20 collaborative NICUs, 19 individual project NICUs, and 71 nonparticipants. In the collaborative group, the PMA at discharge decreased from 37.8 to 37.5 weeks (P = .02), and early discharge increased from 31.6% to 41.9% (P = .006). The individual project group had no significant change. Nonparticipants had a decrease in PMA from 37.5 to 37.3 weeks (P = .01) but no significant change in early discharge (39.8% to 43.6%; P = .24). There was no significant change in readmissions over time in the collaborative group. A structured collaborative project that was focused on optimizing LOS led to a 3-day decrease in LOS and was more effective than individualized quality improvement efforts.

Authors: Lee HC; Kuzniewicz M; Sharek PJ; et al.

Pediatrics. 2018 07;142(1). Epub 2018-06-13.

PubMed abstract

The Relationship Between Prescription Copayments and Contraceptive Adherence in a New-user Cohort

Contraceptive nonadherence is an important contributor to unintended pregnancy in the United States. While the elimination of patient cost sharing has been cited as means to improve contraceptive access, little is known about the relationship between cost sharing and ongoing adherence and continuation of chosen methods. The purpose of this study was to examine the relationship between copayment amount and adherence to pharmacy-dispensed contraception in young women. We conducted a retrospective cohort study of 39,142 women ages 19-29 with a new prescription for the contraceptive pill, patch, or ring at Kaiser Permanente Northern California during 2011-2014. We examined 12-month nonadherence as measured by timely prescription refills and used multivariable Cox proportional hazards models to assess the association between copayment amount and the risk of nonadherence. Ninety-four percent of women used the pill, and 6% used the patch or ring. Forty percent of patients had no copayment and 25% had a copayment of ≥$30. Nearly 75% of women were nonadherent during the study period. In 2013 and 2014, women with a copayment had a 9% increased risk of nonadherence (adjusted hazard ratio, 1.09; 95% confidence interval, 1.04, 1.14) compared with women with no copayment. Prescription copayments may serve as a barrier to adherence of pharmacy-dispensed contraception. Given recent changes to Affordable Care Act contraceptive coverage requirement, these findings can be used to support state-level and health system-level policies for no-cost contraception, and to determine the potential public health impact of this policy change.

Authors: Marshall C; Schmittdiel J; Chandra M; Calhoun A; Raine-Bennett T

Med Care. 2018 07;56(7):577-582.

PubMed abstract

Gestational Diabetes Mellitus and Renal Function: A Prospective Study With 9- to 16-Year Follow-up After Pregnancy

To examine whether gestational diabetes mellitus (GDM), independent of subsequent diabetes, is an early risk factor for renal impairment long term after the index pregnancy. In the Diabetes & Women’s Health (DWH) study (2012-2016), we examined the independent and joint associations of GDM and subsequent diabetes with long-term renal function among 607 women with and 619 women without GDM in the Danish National Birth Cohort (DNBC) index pregnancy (1996-2002). At median follow-up of 13 years after the index pregnancy, serum creatinine (mg/dL) and urinary albumin (mg/L) and creatinine (mg/dL) were measured, from which estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) and urinary albumin-to-creatinine ratio (UACR) (mg/g) were derived. Compared with women without GDM or subsequent diabetes, women with a GDM history had significantly higher eGFR even if they had not subsequently developed diabetes (adjusted β-coefficient [95% CI] = 3.3 [1.7, 5.0]). Women who had a GDM history and later developed diabetes (n = 183) also had significantly higher UACR [exponent β = 1.3 [95% CI 1.1, 1.6]) and an increased risk of elevated UACR (≥20 mg/g) [adjusted relative risk [95% CI] = 2.3 [1.1, 5.9]) compared with women with neither. After adjusting for potential confounders including prepregnancy BMI and hypertension, GDM without subsequent diabetes was not related to UACR. Women who develop GDM in pregnancy were more likely to show increased eGFR levels 9-16 years postpartum, which could indicate early stages of glomerular hyperfiltration and renal damage. However, only those who subsequently developed diabetes showed overt renal damage as evidenced by elevated UACR.

Authors: Rawal S; Zhu Y; Zhang C; et al.

Diabetes Care. 2018 07;41(7):1378-1384. Epub 2018-05-04.

PubMed abstract

Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 × 10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 × 10-8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (P = 1.78 × 10-6) and increased fasted circulating glucose (P = 5.73 × 10-6). Furthermore, rare variants in STAT3 associated with worse metformin response (q <0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D.

Authors: Rotroff DM; Hedderson MM; ACCORD/ACCORDion Investigators; et al.

Diabetes. 2018 07;67(7):1428-1440. Epub 2018-04-12.

PubMed abstract

A Tailored Letter Based on Electronic Health Record Data Improves Gestational Weight Gain Among Women With Gestational Diabetes: The Gestational Diabetes’ Effects on Moms (GEM) Cluster-Randomized Controlled Trial

Evaluate whether a tailored letter improved gestational weight gain (GWG) and whether GWG mediated a multicomponent intervention’s effect on postpartum weight retention among women with gestational diabetes mellitus (GDM). A cluster-randomized controlled trial of 44 medical facilities (n = 2,014 women) randomized to usual care or a multicomponent lifestyle intervention delivered during pregnancy (tailored letter) and postpartum (13 telephone sessions) to reduce postpartum weight retention. The tailored letter, using electronic health record (EHR) data, recommended an end-of-pregnancy weight goal tailored to prepregnancy BMI and GWG trajectory at GDM diagnosis: total GWG at the lower limit of the IOM range if BMI ≥18.5 kg/m2 or the midpoint if <18.5 kg/m2 and weight maintenance if women had exceeded this. The outcomes for this study were the proportion of women meeting the Institute of Medicine (IOM) guidelines for weekly rate of GWG from GDM diagnosis to delivery and meeting the end-of-pregnancy weight goal. The tailored letter significantly increased the proportion of women meeting the IOM guidelines (72.6% vs. 67.1%; relative risk 1.08 [95% CI 1.01-1.17]); results were similar among women with BMI <25.0 kg/m2 (1.07 [1.00-1.15]) and ≥25.0 kg/m2 (1.08 [0.98-1.18]). Thirty-six percent in the intervention vs. 33.0% in usual care met the end-of-pregnancy weight goal (1.08 [0.99-1.18]); the difference was statistically significant among women with BMI <25.0 kg/m2 (1.28 [1.05-1.57]) but not ≥25.0 kg/m2 (0.99 [0.87-1.13]). Meeting the IOM guidelines mediated the effect of the multicomponent intervention in reducing postpartum weight retention by 24.6% (11.3-37.8%). A tailored EHR-based letter improved GWG, which mediated the effect of a multicomponent intervention in reducing postpartum weight retention.

Authors: Hedderson MM; Brown SD; Ehrlich SF; Tsai AL; Zhu Y; Quesenberry CP; Crites Y; Ferrara A

Diabetes Care. 2018 07;41(7):1370-1377. Epub 2018-04-18.

PubMed abstract

Associations Between Maternal Obesity and Pregnancy Hyperglycemia and Timing of Pubertal Onset in Adolescent Girls: A Population-Based Study

Early puberty is associated with adverse health outcomes. We investigated whether in utero exposure to maternal obesity is associated with daughters’ pubertal timing using 15,267 racially/ethnically diverse Kaiser Permanente Northern California members aged 6-11 years with pediatrician-assessed Tanner staging (2003-2017). We calculated maternal body mass index (BMI; weight (kg)/height (m)2) during pregnancy from the electronic health record data. Using a proportional hazards model with interval censoring, we examined the associations between maternal obesity and girls’ pubertal timing, as well as effect modification by race/ethnicity and mediation by prepubertal BMI. Maternal obesity (BMI ≥30) and overweight (BMI 25-29.9) were associated with earlier onset of breast development in girls (hazard ratio (HR) = 1.39 (95% confidence interval (CI): 1.30, 1.49) and HR = 1.21 (95% CI: 1.13, 1.29), respectively), after adjustment for girl’s race/ethnicity, maternal age, education, parity, and smoking during pregnancy. There was interaction by race/ethnicity for associations between maternal obesity and girls’ pubic hair onset: Associations were strongest among Asian and non-Hispanic white girls (HR = 1.53 (95% CI: 1.24, 1.90) and HR = 1.34 (95% CI: 1.18, 1.52), respectively) and absent for African-American girls. Adjustment for girl’s prepubertal BMI only slightly attenuated associations. Our results suggest the importance of maternal metabolic factors during pregnancy in the timing of girls’ puberty and potential differences in the associations by race/ethnicity.

Authors: Kubo A; Deardorff J; Laurent CA; Ferrara A; Greenspan LC; Quesenberry CP; Kushi LH

Am J Epidemiol. 2018 07 01;187(7):1362-1369.

PubMed abstract

Associations Between the 2nd to 4th Digit Ratio and Autism Spectrum Disorder in Population-Based Samples of Boys and Girls: Findings from the Study to Explore Early Development

The ratio of the index (2nd) finger to ring (4th) finger lengths (2D:4D) is a proxy for fetal testosterone and estradiol. Studies suggesting 2D:4D is inversely associated with autism spectrum disorder (ASD) in males were limited by lack of confounder and subgroup assessments. Studies of females are sparse. We examined associations between ASD and 2D:4D among children in the Study to Explore Early Development; we considered case subgroups and numerous potential demographic and maternal-perinatal health confounders. We observed a modest inverse association between ASD and right-hand 2D:4D in males; subgroup analyses indicated associations were limited to ASD cases with birth defects/genetic syndromes or dysmorphic features. We observed a positive association between ASD and left-hand 2D:4D in females, overall and within most case subgroups.

Authors: Schieve LA; Tian L; Dowling N; Croen L; Hoover-Fong J; Alexander A; Shapira SK

J Autism Dev Disord. 2018 07;48(7):2379-2395.

PubMed abstract

Maternal sedentary behavior during pre-pregnancy and early pregnancy and mean offspring birth size: a cohort study

Sedentary behavior is associated with adverse health outcomes in the general population. Whether sedentary behavior during pregnancy is associated with newborn outcomes, such as birth size, is not established, and previous studies have been inconsistent. While previous research suggests that male and female fetuses respond differently to maternal behaviors, such as physical activity, the role of infant sex in sedentary behavior-birth size associations has not been examined. Participants in the Omega study, a cohort in Washington State (1996-2008), reported leisure time sedentary behavior (non-work time spent sitting), light intensity physical activity, and moderate/vigorous leisure time physical activity duration in the year before pregnancy (N = 1373) and in early pregnancy (N = 1535, mean 15 weeks). Offspring birth size was abstracted from delivery records. Non-parametric calibration weighting was used to assign adjustment weight (matching the distribution of sociodemographic and medical characteristics of the full cohort (N = 4128)) to participants with available sedentary behavior data. Weighted linear regression models were used to estimate mean differences in offspring birthweight, head circumference, and ponderal index (birthweight/length3) associated with leisure time sedentary behavior. Regression models were run overall and stratified by offspring sex. Isotemporal substitution modeling was used to determine mean differences in birthweight associated with replacing sedentary behavior with light or moderate/vigorous physical activity. On average, women spent 2.3 and 2.6 h/day in leisure time sedentary behavior during pre- and early pregnancy, respectively. There were no associations of pre-pregnancy leisure time sedentary behavior with mean birthweight, head circumference, or ponderal index (adjusted β = - 12, 95% CI: -28, 4.1; β = 0.0, 95% CI: -0.04, 0.1; and β = 0.1, 95% CI: -0.2, 0.4, respectively). Early pregnancy sedentary behavior was not associated with mean birth size. Associations of sedentary behavior with mean birth size did not differ by offspring sex. Replacing sedentary time with light or moderate/vigorous physical activity was not associated with mean birthweight. We did not observe associations of maternal sedentary behavior during pre- or early pregnancy with mean offspring birth size. Pre-pregnancy and early pregnancy sedentary behavior may have important adverse effects on maternal health, but our results do not support associations with mean offspring birth size.

Authors: Badon SE; Littman AJ; Chan KCG; Williams MA; Enquobahrie DA

BMC Pregnancy Childbirth. 2018 Jun 27;18(1):267. Epub 2018-06-27.

PubMed abstract

A Longitudinal Study of Thyroid Markers across Pregnancy and the Risk of Gestational Diabetes

Triiodothyronine (T3) is the biologically-active thyroid hormone involved in glucose metabolism. fT3:fT4 ratio, a marker indicating conversion of free thyroxine (fT4) to free T3 (fT3), is also implicated in glucose homeostasis. To examine associations of fT3 and fT3:fT4 ratio with gestational diabetes (GDM). In a case-control study, thyroid markers (fT3, fT4, TSH) were measured and fT3:fT4 ratio was derived across four visits in pregnancy, including first (gestational weeks 10-14) and second (weeks 15-26) trimester. Conditional logistic regression adjusting for thyroid autoimmunity status and major GDM risk factors estimated trimester-specific associations of thyroid markers with subsequent GDM risk. 12 U.S. clinical centers. 107 GDM cases and 214 non-GDM controls from a multiracial pregnancy cohort of 2,802 women. GDM diagnosis ascertained from medical records. Both fT3 and fT3:fT4 ratio were positively associated with GDM; aOR (95% CI) comparing the highest vs. lowest fT3 quartile was 4.25 (1.67,10.80) at first and 3.89 (1.50, 10.10) at second trimester. Similarly, the corresponding risk estimates for fT3:fT4 ratio were 8.63 (2.87, 26.00) and 13.60 (3.97, 46.30) at first and second trimester, respectively. Neither TSH nor fT4 was significantly associated with GDM. Isolated hypothyroxinemia in the second, but not first trimester, was significantly related to increased GDM risk; aOR (95% CI) comparing hypothyroxinemic women to euthyroid was 2.97 (1.07,8.24). Higher fT3 levels, potentially resulting from de novo synthesis or increased fT4 to fT3 conversion, may be an indicator of GDM risk starting early in pregnancy.

Authors: Rawal S; Zhu Y; Zhang C; et al.

J Clin Endocrinol Metab. 2018 Jun 07.

PubMed abstract

A prospective and longitudinal study of plasma phospholipid saturated fatty acid profile in relation to cardiometabolic biomarkers and the risk of gestational diabetes

Data on saturated fatty acids (SFAs) in relation to metabolic function and glucose homeostasis remain controversial. Such data are lacking among pregnant women. We prospectively investigated objectively measured individual and subclasses of plasma phospholipid SFAs throughout pregnancy in relation to cardiometabolic markers and gestational diabetes mellitus (GDM) risk. Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2802 singleton pregnancies, 107 GDM cases were ascertained via medical record review and matched to 214 non-GDM controls on age, race/ethnicity, and gestational week (GW) at blood collection. Individual plasma phospholipid SFA concentrations were repeatedly measured throughout pregnancy at GWs 10-14, 15-26, 23-31, and 33-39 and also grouped into subclasses of even- or odd-chain SFAs. From GW 10, even-chain SFA concentrations were significantly higher among women who later developed GDM, whereas odd-chain SFAs were significantly lower among GDM cases compared with controls. At GWs 10-14, the SFA palmitic acid (16:0) was positively associated with impaired insulin resistance and cardiometabolic markers and the risk of GDM [adjusted OR comparing the highest with the lowest quartile (aORQ4-Q1): 4.76; 95% CI: 1.72, 13.10; P-trend = 0.001]. In contrast, odd-chain SFAs were inversely related to the previously mentioned markers and GDM risk [aORQ4-Q1 for pentadecanoic acid (15:0): 0.32; 95% CI: 0.11, 0.92; P-trend = 0.025; for heptadecanoic acid (17:0): 0.20; 95% CI: 0.07, 0.58; P-trend = 0.003]. Women with high (median or greater) even-chain SFA concentrations and low (less than median) odd-chain SFAs had a 9.43-fold (95%: CI 3.26-, 27.30-fold) increased risk compared with women with low even-chain and high odd-chain SFA concentrations. Similar results were observed at GWs 15-26. The study provided one of the first lines of evidence suggesting that circulating concentrations of SFAs varying by SFA chain length, as early as GWs 10-14, were significantly and differentially associated with subsequent risk of GDM. Our findings highlight the importance of assessing objectively measured, individual, and subclasses of SFAs to investigate their distinct biological and pathophysiologic roles in glucose homeostasis and cardiometabolic outcomes. This study was registered at as NCT00912132.

Authors: Zhu Y; Tsai MY; Sun Q; Hinkle SN; Rawal S; Mendola P; Ferrara A; Albert PS; Zhang C

Am J Clin Nutr. 2018 Jun 01;107(6):1017-1026.

PubMed abstract

Comparison of Two Generations of ActiGraph Accelerometers: The CARDIA Study

This study aimed to examine the comparability of the ActiGraph 7164 and wGT3X-BT wear time, count-based estimates, and average time per day in physical activity of different intensities. We studied 87 Coronary Artery Risk Development in Young Adults (CARDIA) participants 48-60 yr of age who simultaneously wore the 7164 and wGT3X-BT accelerometers at the waist in 2015-2016, with wear time of ≥4 of 7 d, ≥10 h·d for both monitors. Freedson cutpoints (counts per minute) were used to define sedentary (<100), light (100-1951), moderate (1952-5724), and vigorous activity (≥5725). Agreement was evaluated using paired-difference tests, intraclass correlation coefficients, and Bland-Altman plots. Given systematic differences in count-based estimates between monitors, a calibration formula applied to the wGT3X-BT values was obtained by linear regression. Total detected wear time minutes per day was nearly identical between the 7164 and the wGT3X-BT (881.5 ± 70.9 vs 880.3 ± 78.1, P = 0.72). The wGT3X-BT values were calibrated to the 7164 values by dividing counts by 1.088. After calibration, no differences were observed between the 7164 and the wGT3X-BT in total counts per day (310,184 ± 129,189 vs 307,085 ± 135,362, P = 0.48), average counts per min per day (349.5 ± 139.5 vs 346.5 ± 147.2, P = 0.54), sedentary (513.2 ± 93.6 vs 509.6 ± 98.6, P = 0.23), light (335.3 ± 81.5 vs 338.7 ± 81.1, P = 0.22), moderate (31.0 ± 21.9 vs 30.3 ± 23.4, P = 0.31), or moderate-to-vigorous minutes per day (33.1 ± 24.6 vs 32.0 ± 26.0, P = 0.13). A significant difference was observed for vigorous minutes per day (0.2 ± 1.0 vs 0.0 ± 0.3, P < 0.01); however, the absolute difference was marginal. Intraclass correlation coefficients showed excellent agreement for all measures (0.95-0.99). After applying a calibration formula, the 7164 and wGT3X-BT were comparable for total wear time, count-based estimates, and average minutes per day in sedentary, light, moderate, and moderate-to-vigorous activity. Findings illustrate a novel methodological approach to facilitate accelerometer data harmonization.

Authors: Whitaker KM; Pettee Gabriel K; Jacobs DR; Sidney S; Sternfeld B

Med Sci Sports Exerc. 2018 06;50(6):1333-1340.

PubMed abstract

Plasma concentrations of lipids during pregnancy and the risk of gestational diabetes mellitus: A longitudinal study

Abnormal lipid profiles have been associated with gestational diabetes mellitus (GDM), but studies with longitudinal measures of lipids throughout pregnancy are sparse. The aim of the present study was to characterize longitudinal changes in lipid profiles throughout pregnancy and prospectively examine the associations of plasma lipid concentrations with risk of GDM. This study was a nested case-control study including 107 GDM cases and 214 matched non-GDM controls from participants in the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies – Singleton cohort. Blood samples were collected longitudinally at Gestational Weeks (GW) 10-14, 15-26 (fasting sample), 23-31, and 33-39. Plasma concentrations of triglycerides, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured by enzymatic assays. Low-density lipoprotein cholesterol (LDL-C) was calculated using Friedewald’s formula. Plasma triglycerides, total cholesterol, and LDL-C increased as pregnancy progressed. At GW 10-14, the adjusted odds ratios (aORs) of GDM comparing the highest versus lowest quartile were 3.15 (95% confidence interval [CI] 1.38-7.15; P trend  = 0.002) for triglycerides and 0.44 (95% CI 0.18-1.09; P trend  = 0.045) for HDL-C. At GW 15-26, the aORs were 6.57 (95% CI 2.25-19.17; P trend  = 0.001) for triglycerides and 0.23 (95% CI 0.08-0.63; P trend  = 0.005) for HDL-C. No significant associations were observed for total cholesterol and LDL-C concentrations with risk of GDM. Higher plasma triglyceride and lower HDL-C concentrations in early and mid-pregnancy were significantly associated with a greater risk of GDM. Total cholesterol and LDL-C concentrations during pregnancy were not significantly associated with GDM risk.

Authors: Bao W; Dar S; Zhu Y; Wu J; Rawal S; Li S; Weir NL; Tsai MY; Zhang C

J Diabetes. 2018 Jun;10(6):487-495. Epub 2017-09-29.

PubMed abstract

Large-Scale Implementation of Structured Reporting of Adnexal Masses on Ultrasound

The aim of this article is to describe the development and implementation of structured reporting of adnexal mass findings on pelvic ultrasound in a large integrated health care delivery system. A structured reporting system that includes standardized terminology for describing adnexal masses on ultrasound was developed by a multidisciplinary team of radiologists, gynecologists, and gynecologic oncologists on the basis of literature review and internal data. The system uses a reporting template that requires radiologists to assign abnormal adnexal masses to one of five possible categories on the basis of standardized criteria: category 0, 1, 2, or 3 for masses <10 cm, to reflect increasing concern for malignancy, and category X for masses >10 cm. Unique predefined hashtags were linked to each category to enable electronic data extraction, and a hard stop feature was installed that prevents reports from being finalized without a category designation. In 2014, after a 3-month pilot study, large-scale implementation was supported by an educational campaign consisting of web-based conferences, e-mail announcements, and local presentations. Clinical management recommendations on the basis of category and other clinical factors were provided in a separate practice resource for clinicians. Analysis of adherence revealed that 93% of the approximately 12,000 reports describing abnormal adnexal masses in 2016 included category designations. Feedback from referring providers via an anonymous survey indicated high levels of satisfaction with reports. Multidisciplinary collaboration and leveraging of technology enabled large-scale implementation of structured reporting with high levels of adherence among radiologists and improved satisfaction among referring providers.

Authors: Suh-Burgmann EJ; Flanagan T; Lee N; Osinski T; Sweet C; Lynch M; Caponigro M; Mehta J; Alavi M; Herrinton LJ

J Am Coll Radiol. 2018 May;15(5):755-761. Epub 2018-03-20.

PubMed abstract

Recent Intrauterine device use and the risk of precancerous cervical lesions and cervical cancer

Understanding the effect of contraceptives on the development of precancerous lesions of the cervix and cervical cancer may provide information that is valuable to women in contraceptive decision-making. The purpose of this study was to evaluate the association between recent intrauterine device (IUD) use (by type) and cervical intraepithelial neoplasia 2, 3, adenocarcinoma in situ or cancer (CIN2+ or CIN3+). Case-control study of 17,559 women age 18-49 with incident CIN2+ cases and 5:1 age-matched, incidence-density selected controls (N=87,378) who were members of Kaiser Permanente Northern California Healthcare System from 1996-2014. Recent IUD use, within 18 months prior to index, was the exposure of interest. We identified 1,657 IUD users among the cases and 7,925 IUD users among controls. After adjusting for sexually transmitted infection testing, smoking, HPV vaccination, hormonal contraceptive use, parity, race and number of outpatient healthcare system visits, IUD use was associated with an increased rate of CIN2+ [rate ratio (RR) 1.12, 95% confidence interval (1.05-1.18), p

Authors: Averbach S; Silverberg MJ; Leyden W; Smith-McCune K; Raine-Bennett T; Sawaya GF

Contraception. 2018 Apr 16.

PubMed abstract

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology

State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions. To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided. Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001). High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.

Authors: Yu K; Raine-Bennett TR; Schiffman M; et al.

J Natl Cancer Inst. 2018 Apr 11.

PubMed abstract

Psychiatric and Medical Conditions in Transition-Aged Individuals With ASD

Children with autism spectrum disorder (ASD) have a variety of medical and psychiatric conditions and an increased use of health care services. There is limited information about the prevalence of psychiatric and medical conditions in adolescents and young adults with ASD. Our objective was to describe the frequency of medical and psychiatric conditions in a large population of diverse, insured transition-aged individuals with ASD. Participants included Kaiser Permanente Northern California members who were enrolled from 2013 to 2015 and who were 14 to 25 years old. Individuals with ASD (n = 4123) were compared with peers with attention-deficit/hyperactivity disorder (n = 20 615), diabetes mellitus (n = 2156), and typical controls with neither condition (n = 20 615). Over one-third (34%) of individuals with ASD had a co-occurring psychiatric condition; the most commonly reported medical conditions included infections (42%), obesity (25%), neurologic conditions (18%), allergy and/or immunologic conditions (16%), musculoskeletal conditions (15%), and gastrointestinal (11%) conditions. After controlling for sex, age, race, and duration of Kaiser Permanente Northern California membership, most psychiatric conditions were significantly more common in the ASD group than in each comparison group, and most medical conditions were significantly more common in the ASD group than in the attention-deficit/hyperactivity disorder and typical control groups but were similar to or significantly less common than the diabetes mellitus group. Although more research is needed to identify factors contributing to this excess burden of disease, there is a pressing need for all clinicians to approach ASD as a chronic health condition requiring regular follow-up and routine screening and treatment of medical and psychiatric issues.

Authors: Davignon MN; Qian Y; Massolo M; Croen LA

Pediatrics. 2018 04;141(Suppl 4):S335-S345.

PubMed abstract

Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy

Treatment of jaundiced newborns with subthreshold phototherapy (phototherapy given to newborns with bilirubin levels below those recommended in American Academy of Pediatrics [AAP] guidelines) is common. However, the use of subthreshold phototherapy may have risks and increase costs, and, to date, it has not been systematically studied in newborns. To estimate the efficacy of subthreshold phototherapy for newborns with total serum bilirubin (TSB) levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold during the birth hospitalization in preventing readmissions for phototherapy, and to identify predictors of readmission for phototherapy. Retrospective cohort study of 25 895 newborns born at 35 or more weeks’ gestation, born in 1 of 16 Kaiser Permanente Northern California hospitals from January 1, 2010, through December 31, 2014, with at least 1 TSB level from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold and not exceeding the threshold during the birth hospitalization. Data were analyzed from November 1, 2015, to November 28, 2017. Subthreshold phototherapy during the birth hospitalization. Readmission for phototherapy. Among 25 895 newborns with qualifying TSB levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold, 4956 (19.1%) received subthreshold phototherapy and 241 of these (4.9%) were readmitted for phototherapy compared with 2690 of 20 939 untreated newborns (12.8%) (unadjusted odds ratio [OR], 0.35; 95% CI, 0.30-0.40). In a logistic regression model, adjustment for confounding variables, including gestational age, race/ethnicity, formula feedings per day, and the difference between the TSB level and the phototherapy threshold, strengthened the association (OR, 0.28; 95% CI, 0.19-0.40). Estimated numbers needed to treat ranged from 60.8 in the lowest quintile of predicted risk to 6.3 in the highest quintile. Newborns who received formula feedings had lower adjusted odds of readmission for phototherapy compared with exclusively breastfed newborns (OR, 0.58; 95% CI, 0.47-0.72 for >0 to <2 formula feedings per day; OR, 0.24; 95% CI, 0.21-0.27 for ≥6 formula feedings per day). Subthreshold phototherapy was associated with a 22-hour longer length of stay (95% CI, 16-28 hours). Subthreshold phototherapy during the birth hospitalization is effective in preventing readmissions for phototherapy; however, for each readmission prevented, many newborns require phototherapy who would otherwise not need it.

Authors: Wickremasinghe AC; Kuzniewicz MW; McCulloch CE; Newman TB

JAMA Pediatr. 2018 04 01;172(4):378-385.

PubMed abstract

Association between paternal alcohol consumption before conception and anogenital distance of offspring

There are limited studies on the effects of paternal alcohol consumption, before conception, on the reproductive development of offspring. Anogenital distance (AGD), the distance from the center of the anus to the genitals, is a sensitive biomarker of reproductive hormone abnormalities during the critical developmental window. The relationship between paternal alcohol consumption and AGD of human offspring has not been studied yet. This cohort study included 1,292 pregnant women recruited in Shanghai. An in-person interview was conducted to collect information on demographic characteristics of couples, and husbands’ lifestyles, including drinking habits. AGD (boys, AGD-AP [anus-penis], AGD-AS [anus-scrotum]; girls, AGD-AC [anus-clitoris], AGD-AF [anus-fourchette]) measurements were performed at birth, and at 6 and 12 months of age. Multiple linear regression analysis was conducted to determine the association between paternal alcohol consumption before conception, and the AGDs of offspring. Data included AGD measurements of infants at birth (N = 980), at 6 months (N = 592, 60.4%), and at 12 months (N = 543, 55.4%). Boys in the paternal alcohol-exposed group had shorter AGDs, irrespective of the areas measured (AGD-AP and AGD-AS) and time of measurements, than those in the unexposed group. However, only the differences in AGD-AP at birth and AGD-AS at 6 months were statistically significant. For girls, the associations were similar at birth; however, the AGD-AC and AGD-AF were longer in the paternal alcohol-exposed group than the unexposed group at 12 months. Our findings provide first, but preliminary evidence, that paternal alcohol consumption within 3 months before conception may be associated with shorter AGD in the offspring, especially in boys, which indicates that paternal alcohol drinking may have an adverse effect on their reproductive development. Further studies should be conducted to validate these results.

Authors: Xia R; Jin L; Li D; Liang H; Yang F; Chen J; Yuan W; Miao M

Alcohol Clin Exp Res. 2018 Apr;42(4):735-742. Epub 2018-02-14.

PubMed abstract

Racial disparities in family-provider interactions for pediatric asthma care

Black and Latino children experience significantly worse asthma morbidity than their white peers for multifactorial reasons. This study investigated differences in family-provider interactions for pediatric asthma, based on race/ethnicity. This was a cross-sectional study of parent surveys of asthmatic children within the Population-Based Effectiveness in Asthma and Lung Diseases Network. Our study population comprised 647 parents with survey response data. Data on self-reported race/ethnicity of the child were collected from parents of the children with asthma. Outcomes studied were responses to the questions about family-provider interactions in the previous 12 months: (1) number of visits with asthma provider; (2) number of times provider reviewed asthma medications with patient/family; (3) review of a written asthma treatment plan with provider; and (4) preferences about making asthma decisions. In multivariate adjusted analyses controlling for asthma control and other co-morbidities, black children had fewer visits in the previous 12 months for asthma than white children: OR 0.63 (95% CI 0.40, 0.99). Additionally, black children were less likely to have a written asthma treatment plan given/reviewed by a provider than their white peers, OR 0.44 (95% CI 0.26, 0.75). There were no significant differences by race in preferences about asthma decision-making nor in the frequency of asthma medication review. Black children with asthma have fewer visits with their providers and are less likely to have a written asthma treatment plan than white children. Asthma providers could focus on improving these specific family-provider interactions in minority children.

Authors: Trivedi M; Fung V; Kharbanda EO; Larkin EK; Butler MG; Horan K; Lieu TA; Wu AC

J Asthma. 2018 04;55(4):424-429. Epub 2017-07-14.

PubMed abstract

A Pilot Mobile-based Mindfulness Intervention for Cancer Patients and their Informal Caregivers

Authors: Kubo A; Altschuler A; Kurtovich E; Hendlish S; Laurent CA; Kolevska T; Li Y; Avins A

Mindfulness (N Y). 2018 Dec;9(6):1885-1894. Epub 2018-03-24.

PubMed abstract

Associations of overweight/obesity and socioeconomic status with hypertension prevalence across racial and ethnic groups

Racial/ethnic disparities in the prevalence of diagnosed hypertension are persistent but may be partially explained by racial/ethnic differences in weight category and neighborhood socioeconomic status. The authors compared hypertension prevalence rates among 4 060 585 adults with overweight or obesity across 10 healthcare systems by weight category and neighborhood education level in geographically and racially diverse individuals. Data were obtained from electronic health records. Hypertension was defined as at least two outpatient visits or one inpatient hospitalization with a coded diagnosis. Logistic regression, adjusted for age, sex, and site, with two-way interactions between race/ethnicity and weight category or neighborhood education, was used to examine the association between hypertension and race/ethnicity, with whites as the reference. Results documented that odds ratios for hypertension prevalence were greater for blacks, American Indians/Alaskan Natives, Asians, and Native Hawaiians/other Pacific Islanders compared with whites and lower for Hispanics in similar weight categories and neighborhood education levels. Although two-way interactions were statistically significant, the magnitude of the odds of hypertension compared with whites did not substantially vary across weight or neighborhood education. Hypertension odds were almost double relative to whites for blacks and Native Hawaiians/other Pacific Islanders across most weight categories and all neighborhood education levels. Odds of hypertension were about 50% greater for Asians relative to whites across weight categories. Results suggest that other factors might be associated with racial/ethnic disparities in hypertension. More research is needed to understand the many factors that may contribute to variation in diagnosed hypertension across racial/ethnic groups with overweight or obesity.

Authors: Young DR; Ferrara A; Yamamoto A; et al.

J Clin Hypertens (Greenwich). 2018 03;20(3):532-540. Epub 2018-02-12.

PubMed abstract

Bone loss in women with BRCA1 and BRCA2 mutations

Estimate the prevalence and identify risk factors for bone loss in women with BRCA mutations. Women, age 40 and older, with BRCA mutations identified from the Breast Cancer Surveillance database at Kaiser Permanente Northern California were invited to participate and undergo a dual-energy x-ray absorptiometry scan to assess for bone loss (osteopenia or osteoporosis). Multivariable logistic regression analysis was performed to assess clinical factors associated with bone loss. Of the 238 women in the final cohort, 20 women had intact ovaries (median age 54.5years) and 218 had undergone risk reducing salpingo-oophorectomy (RRSO) (median age 57). The prevalence of bone loss was 55% in the no RRSO group and 72.5% in the RRSO group (P=0.10). In multivariable analysis, only higher body mass index (OR 0.6 per 5kg/m2, 95% CI: 0.4-0.7) and nonwhite race compared to white (OR 0.5, 95% CI: 0.2-0.9) were protective for bone loss while older age (OR 1.5 per 10years, 95% CI: 1.1-2.1) and selective estrogen receptor modulator use (3.1, 95% CI: 1.2-10.1) were associated with increased odds of bone loss. Among women with RRSO, bone loss was more frequent in women who had postmenopausal (n=106) compared to women who had premenopausal RRSO (n=112), (82.1% and 63.4% respectively, P=0.002). In multivariable analysis, only BMI was protective of bone loss (OR 0.5, 95%, CI: 0.4-0.7) but neither age nor menopausal status at RRSO were associated with bone loss. Bone loss is common in women with BRCA mutations who undergo RRSO.

Authors: Powell CB; Alabaster A; Stoller N; Armstrong MA; Salyer C; Hamilton I; Raine-Bennett T

Gynecol Oncol. 2018 03;148(3):535-539.

PubMed abstract

Acute Associations between Outdoor Temperature and Premature Rupture of Membranes

Extreme ambient temperatures have been linked to preterm birth. Preterm premature rupture of membranes is a common precursor to preterm birth but is rarely studied in relation to temperature. We linked 15,381 singleton pregnancies with premature rupture of membranes from a nationwide US obstetrics cohort (2002-2008) to local temperature. Case-crossover analyses compared daily temperature during the week preceding delivery and the day of delivery to 2 control periods, before and after the case period. Conditional logistic regression models calculated the odds ratio (OR) and 95% confidence intervals (CIs) of preterm and term premature rupture of membranes for a 1°C increase in temperature during the warm (May-September) and cold (October-April) season separately after adjusting for humidity, barometric pressure, ozone, and particulate matter. During the warm season, 1°C increase during the week before delivery was associated with a 5% (95% CI, 3%, 6%) increased preterm premature rupture of membranes risk, and a 4% (95% CI, 3%, 5%) increased term premature rupture of membranes risk. During the cold season, 1°C increase was associated with a 2% decreased risk for both preterm (95% CI, 1%, 3%) and term premature rupture of membranes (95% CI, 1%, 3%). The day-specific associations for the week before delivery were similar, but somewhat stronger for days closer to delivery. Relatively small ambient temperature changes were associated with the risk of both preterm and term premature of membranes. Given the adverse consequences of premature rupture of membranes and concerns over global climate change, these findings merit further investigation. See video abstract at,

Authors: Ha S; Liu D; Zhu Y; Sherman S; Mendola P

Epidemiology. 2018 03;29(2):175-182.

PubMed abstract

Validation of an HPV DNA cervical screening test that provides expanded HPV typing

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity™ (Becton Dickinson Diagnostics, Sparks MD), a nine-channel HPV test recently approved by FDA, by assessing: 1) the association of Onclarity type/channels with precancer/cancer; 2) HPV type/channel agreement between Onclarity and cobas™ (Roche Molecular Systems, Pleasanton CA), another FDA-approved test; and 3) Onclarity typing for all types/channels compared to typing results from a research assay (Linear Array™, LA, Roche).Methods.We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n=9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2, Qiagen, Germantown MD). A subset had already been tested by cobas and LA (n=1,965). Cervical histopathology was ascertained from electronic health records.Results.Hierarchical Onclarity channels showed a significant linear association with histologic severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other twelve types as a pool (sample-weighted kappa: 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and group of types identified by LA (kappas from 0.80 for HPV39/68/35 to 0.97 for HPV16).DiscussionOnclarity typing results corresponded well to histopathology and to an already-validated HPV DNA test, and could provide additional clinical typing if such discrimination is determined to be clinically desirable.

Authors: Demarco M; Fetterman B; Lorey T; Poitras N; Raine-Bennett TR; Schiffman M; et al.

J Clin Microbiol. 2018 Feb 28.

PubMed abstract

Cost Effectiveness of Gene Expression Profile Testing in Community Practice

Purpose Gene expression profile (GEP) testing can support chemotherapy decision making for patients with early-stage, estrogen receptor-positive, human epidermal growth factor 2-negative breast cancers. This study evaluated the cost effectiveness of one GEP test, Onco type DX (Genomic Health, Redwood City, CA), in community practice with test-eligible patients age 40 to 79 years. Methods A simulation model compared 25-year societal incremental costs and quality-adjusted life-years (QALYs) of community Onco type DX use from 2005 to 2012 versus usual care in the pretesting era (2000 to 2004). Inputs included Onco type DX and chemotherapy data from an integrated health care system and national and published data on Onco type DX accuracy, chemotherapy effectiveness, utilities, survival and recurrence, and Medicare and patient costs. Sensitivity analyses varied individual parameters; results were also estimated for ideal conditions (ie, 100% testing and adherence to test-suggested treatment, perfect test accuracy, considering test effects on reassurance or worry, and lowest costs). Results Twenty-four percent of test-eligible patients had Onco type DX testing. Testing was higher in younger patients and patients with stage I disease ( v stage IIA), and 75.3% and 10.2% of patients with high and low recurrence risk scores received chemotherapy, respectively. The cost-effectiveness ratio for testing ( v usual care) was $188,125 per QALY. Considering test effects on worry versus reassurance decreased the cost-effectiveness ratio to $58,431 per QALY. With perfect test accuracy, the cost-effectiveness ratio was $28,947 per QALY, and under ideal conditions, it was $39,496 per QALY. Conclusion GEP testing is likely to have a high cost-effectiveness ratio on the basis of community practice patterns. However, realistic variations in assumptions about key variables could result in GEP testing having cost-effectiveness ratios in the range of other accepted interventions. The differences in cost-effectiveness ratios on the basis of community versus ideal conditions underscore the importance of considering real-world implementation when assessing the new technology.

Authors: Chandler Y; Schechter CB; Jayasekera J; Near A; O'Neill SC; Isaacs C; Phelps CE; Ray GT; Lieu TA; Ramsey S; Mandelblatt JS

J Clin Oncol. 2018 02 20;36(6):554-562. Epub 2018-01-08.

PubMed abstract

Human Papillomavirus DNA methylation as a biomarker for cervical precancer: Consistency across 12 genotypes and potential impact on management of HPV-positive women

Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV-positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. In this nested case-control study, we tested up to 30 cases of precancer (CIN3/AIS) and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, odds ratios, and areas under the curve (AUC). Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden’s index (0.46), compared with cytology (0.31) and a 5-type methylation assay including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared to cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology- or HPV16/18-positives. HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multi-type methylation assay may serve as a triage test for HPV-positive women.

Authors: Clarke MA; Gradíssimo A; Schiffman M; Lam J; Sollecito CC; Fetterman B; Lorey T; Poitras NE; Raine-Bennett T; Castle PE; Wentzensen N; Burk RD

Clin Cancer Res. 2018 Feb 02.

PubMed abstract

Impact of Copayment Changes on Children’s Albuterol Inhaler Use and Costs after the Clean Air Act Chlorofluorocarbon Ban

To examine changes in children’s albuterol use and out-of-pocket (OOP) costs in response to increased copayments after the Food and Drug Administration banned inhalers with chlorofluorocarbon (CFC) propellants. Four health maintenance organizations (HMOs), two that increased copayments for albuterol inhalers that went from generic CFC-containing to branded CFC-free versions, and two that retained generic copayments for CFC-free inhalers (controls). We included children with asthma aged 4-17 years with commercial coverage from 2007 to 2010. Interrupted time series with comparison series. We obtained enrollee and plan characteristics from enrollment files, and utilization data from pharmacy and medical claims; OOP expenditures were extracted from pharmacy claims for two HMOs with cost data available. There were no significant differences in albuterol use between the group with increased cost-sharing and controls with respect to changes after the policy change. There was a postpolicy increase of $6.11 OOP per month per child using albuterol among those with increased cost-sharing versus $0.36 in controls; the difference between groups was significant (p < .01). Increased copayments for brand-name CFC-free albuterol after the CFC ban did not lead to a decrease in children's albuterol use, but it led to a modest increase in OOP costs.

Authors: Galbraith AA; Fung V; Li L; Butler MG; Nordin JD; Hsu J; Smith D; Vollmer WM; Lieu TA; Soumerai SB; Wu AC

Health Serv Res. 2018 02;53(1):156-174. Epub 2016-11-20.

PubMed abstract

Prenatal Maternal Serum Concentrations of Per- and Polyfluoroalkyl Substances in Association with Autism Spectrum Disorder and Intellectual Disability

Emerging work has examined neurodevelopmental outcomes following prenatal exposure to per- and polyfluoroalkyl substances (PFAS), but few studies have assessed associations with autism spectrum disorder (ASD). Our objective was to estimate associations of maternal prenatal PFAS concentrations with ASD and intellectual disability (ID) in children. Participants were from a population-based nested case-control study of children born from 2000 to 2003 in southern California, including children diagnosed with ASD (n=553), ID without autism (n=189), and general population (GP) controls (n=433). Concentrations of eight PFAS from stored maternal sera collected at 15-19 wk gestational age were quantified and compared among study groups. We used logistic regression to obtain adjusted odds ratios for the association between prenatal PFAS concentrations (parameterized continuously and as quartiles) and ASD versus GP controls, and separately for ID versus GP controls. Geometric mean concentrations of most PFAS were lower in ASD and ID groups relative to GP controls. ASD was not significantly associated with prenatal concentrations of most PFAS, though significant inverse associations were found for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) [adjusted ORs for the highest vs. lowest quartiles 0.62 (95% CI: 0.41, 0.93) and 0.64 (95% CI: 0.43, 0.97), respectively]. Results for ID were similar. Results from this large case-control study with prospectively collected prenatal measurements do not support the hypothesis that prenatal exposure to PFAS is positively associated with ASD or ID.

Authors: Lyall K; Yau VM; Hansen R; Kharrazi M; Yoshida CK; Calafat AM; Windham G; Croen LA

Environ Health Perspect. 2018 01 02;126(1):017001. Epub 2018-01-02.

PubMed abstract

Liver Enzymes in Early to Mid-pregnancy, Insulin Resistance, and Gestational Diabetes Risk: A Longitudinal Analysis

Background: Liver enzymes may be implicated in glucose homeostasis; liver enzymes progressively change during pregnancy but longitudinal data during pregnancy in relation to insulin resistance and gestational diabetes (GDM) risk are lacking. We investigated longitudinal associations of γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT) with insulin secretion and resistance markers across early to mid-pregnancy and subsequent GDM risk. Methods: Within the prospective Pregnancy Environment and Lifestyle Study cohort, 117 GDM cases were ascertained and matched to 232 non-GDM controls in a nested case-control study. Fasting blood samples were collected at two clinic visits (CV1, gestational weeks 10-13; CV2, gestational weeks 16-19). Linear mixed model and conditional logistic regression were used, adjusting for major risk factors for GDM. Results: In repeated measure analysis, after adjusting for confounders including body mass index and waist-to-hip ratio, GGT per standard deviation increment was associated with elevated fasting glucose and HOMA-IR (% change = 1.51%, 95% CI 0.56-2.46% and 7.43%, 95% CI 1.76-13.11%, respectively) and decreased adiponectin (% change = -2.86%, 95% CI-5.53 to -0.20%) from CV1 to CV2. At CV1 and CV2, GGT levels comparing the highest versus lowest quartile were associated with 3.01-fold (95% CI 1.32-6.85) and 3.51-fold (95% CI 1.37-8.97) increased risk of GDM, respectively. Progressively increased (

Authors: Zhu Y; Hedderson MM; Quesenberry CP; Feng J; Ferrara A

Front Endocrinol (Lausanne). 2018;9:581. Epub 2018-10-02.

PubMed abstract

Case-control meta-analysis of blood DNA methylation and autism spectrum disorder

Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10- 7. Seven CpGs showed differences at p < 1 × 10- 5 and 48 at 1 × 10- 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

Authors: Andrews SV; Croen LA; Ladd-Acosta C; et al.

Mol Autism. 2018;9:40. Epub 2018-06-28.

PubMed abstract

A cohort study of maternal cardiometabolic risk factors and primary cesarean delivery in an integrated health system

Maternal cardiometabolic risk factors (i.e., hyperglycemia, pre-existing hypertension and high body mass index) impact fetal growth and risk of having a cesarean delivery. However, the independent and joint contribution of maternal cardiometabolic risk factors to primary cesarean section is unclear. We aimed to elucidate the degree to which maternal cardiometabolic risk factors contribute to primary cesarean deliveries and whether associations vary by infant size at birth in an integrated health system. A cohort study of 185,045 singleton livebirths from 2001 to 2010. Poisson regression with robust standard errors provided crude and adjusted relative risks (RR) and 95% confidence intervals (CIs) for cesarean delivery risk associated with risk factors. We then estimated the proportion of cesarean sections that could be prevented if the cardiometabolic risk factor in pregnant women were eliminated (the population-attributable risk [PAR]). In a single multivariable model, maternal cardiometabolic risk factors were independently associated with cesarean delivery: RR (95% CI) abnormal glucose screening 1.04 (1.01-1.08); gestational diabetes 1.18 (1.11-1.18) and pre-existing diabetes 1.60 (1.49-1.71); pre-existing hypertension 1.16 (1.10-1.23); overweight 1.27 (1.24-1.30); obese class I 1.46 (1.42-1.51); obese class II 1.73 (1.67-1.80); and obese class III 1.97 (1.88-2.07); adjusting for established risk factors, medical facility and year. The associations between maternal cardiometabolic risk factors and primary cesarean delivery remained among infants with appropriate weights for gestational age. The PARs were 17.4% for overweight/obesity, 7.0% for maternal hyperglycemia, 2.0% for pre-existing hypertension and 20.5% for any cardiometabolic risk factor. Maternal cardiometabolic risk factors were independently associated with risk of primary cesarean delivery, even among women delivering infants born at an appropriate size for gestational age. Effective strategies to increase the proportion of women entering pregnancy at an optimal weight with normal blood pressure and glucose before pregnancy could potentially eliminate up to 20% of cesarean deliveries.

Authors: Hedderson MM; Xu F; Sridhar SB; Han ES; Quesenberry CP; Crites Y

PLoS ONE. 2018;13(7):e0199932. Epub 2018-07-03.

PubMed abstract

Cord blood buffy coat DNA methylation is comparable to whole cord blood methylation

Cord blood DNA methylation is associated with numerous health outcomes and environmental exposures. Whole cord blood DNA reflects all nucleated blood cell types, while centrifuging whole blood separates red blood cells, generating a white blood cell buffy coat. Both sample types are used in DNA methylation studies. Cell types have unique methylation patterns and processing can impact cell distributions, which may influence comparability. We evaluated differences in cell composition and DNA methylation between cord blood buffy coat and whole cord blood samples. Cord blood DNA methylation was measured with the Infinium EPIC BeadChip (Illumina) in eight individuals, each contributing buffy coat and whole blood samples. We analyzed principal components (PC) of methylation, performed hierarchical clustering, and computed correlations of mean-centered methylation between pairs. We conducted moderated t-tests on single sites and estimated cell composition. DNA methylation PCs were associated with individual (PPC1 = 1.4 × 10-9; PPC2 = 2.9 × 10-5; PPC3 = 3.8 × 10-5; PPC4 = 4.2 × 10-6; PPC5 = 9.9 × 10-13, PPC6 = 1.3 × 10-11) and not with sample type (PPC1-6>0.7). Samples hierarchically clustered by individual. Pearson correlations of mean-centered methylation between paired samples ranged from r = 0.66 to r = 0.87. No individual site significantly differed between buffy coat and whole cord blood when adjusting for multiple comparisons (five sites had unadjusted P<10-5). Estimated cell type proportions did not differ by sample type (P = 0.46), and estimated proportions were highly correlated between paired samples (r = 0.99). Differences in methylation and cell composition between buffy coat and whole cord blood are much lower than inter-individual variation, demonstrating that both sample preparation types can be analytically combined and compared.

Authors: Dou J; Schmidt RJ; Benke KS; Newschaffer C; Hertz-Picciotto I; Croen LA; Iosif AM; LaSalle JM; Fallin MD; Bakulski KM

Epigenetics. 2018;13(1):108-116. Epub 2018-02-16.

PubMed abstract

Autism spectrum disorder and birth spacing: Findings from the study to explore early development (SEED)

Previous studies of autism spectrum disorder (ASD) and birth spacing had limitations; few examined phenotypic case subtypes or explored underlying mechanisms for associations and none assessed whether other (non-ASD) developmental disabilities (DDs) were associated with birth spacing. We assessed associations between inter-pregnancy interval (IPI) and both ASD and other DDs using data from the Study to Explore Early Development, a multi-site case-control study with rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history. Our sample included 356 ASD cases, 627 DD cases, and 524 population (POP) controls born in second or later births. ASD and DD cases were further sub-divided according to whether the child had intellectual disability (ID). ASD cases were also sub-divided by ASD symptom severity, and DD cases were subdivided by presence of some ASD symptoms (indicated on an autism screener). Odds ratios, adjusted for maternal-child sociodemographic factors, (aORs) and 95% confidence intervals were derived from logistic regression models. Among term births, ASD was associated with both IPI <18 months (aOR 1.5 [1.1-2.2]) and ≥60 months (1.5 [0.99-2.4]). Both short and long IPI associations were stronger among ASD cases with high severity scores (aORs 2.0 [1.3-3.3] and 1.8 [0.99-3.2], respectively). Associations were unchanged after adding several factors potentially related to the causal pathway to regression models. DD was not associated with either short or long IPI-overall, among term births, or in any subgroup examined. These findings extend those from previous studies and further inform recommendations on optimal pregnancy spacing. Autism Res 2018, 11: 81-94. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. We investigated whether the amount of time between pregnancies was associated autism spectrum disorder (ASD) or other developmental disabilities (DD) in children. ASD was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth. Other DDs were not associated with birth spacing.

Authors: Schieve LA; Tian LH; Drews-Botsch C; Windham GC; Newschaffer C; Daniels JL; Lee LC; Croen LA; Danielle Fallin M

Autism Res. 2018 01;11(1):81-94. Epub 2017-11-22.

PubMed abstract

Neurocognitive and physical functioning in the Seveso Women’s Health Study.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is neurotoxic in animals but few studies have investigated its effects on the human brain. Related dioxin-like compounds have been linked to poorer cognitive and motor function in older adults, with effects more pronounced in women, perhaps due to the loss of neuro-protective estrogen in menopause. On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in one of the highest known residential exposures to TCDD. In 1996, we initiated the Seveso Women’s Health Study, a retrospective cohort study of the health of the women who were newborn to 40 years old in 1976. Here, we investigate whether TCDD exposure is associated with physical functioning and working memory more than 20 years later. Individual TCDD concentration (ppt) was measured in archived serum collected soon after the explosion. In 1996 and 2008, we measured physical functioning (n=154) and working memory (n=459), respectively. We examined associations between serum TCDD and motor and cognitive outcomes with multivariate linear regression and semi-parametric estimators. A 10-fold increase in serum TCDD was not associated with walking speed (adjusted β=0.0006ft/s, 95% Confidence Interval (CI): -0.13, 0.13), upper body mobility (adjusted β=-0.06, 95% CI: -0.36, 0.23), or manual dexterity (adjusted β=0.34, 95% CI: -0.65, 1.33). We observed an inverted U-shaped association in grip strength, with poorer strength in the lowest and highest TCDD exposure levels. There was no association between TCDD and the Wechsler digit and spatial span tests. Neither menopause status at assessment nor developmental timing of exposure modified associations between TCDD and working memory. Our findings, in one of the only studies of TCDD’s effects on neuropsychological and physical functioning in women, do not indicate an adverse effect on these domains, with the exception of a U-shaped relationship with grip strength. Given the limited assessment and relative youth of the women at this follow-up, future work examining additional neuropsychological outcomes is warranted.

Authors: Ames, Jennifer J; Warner, Marcella M; Brambilla, Paolo P; Mocarelli, Paolo P; Satariano, William A WA; Eskenazi, Brenda B

Environmental research. 2018 Apr 01;162(Pt 1):55-62. Epub 2017-12-26.

PubMed abstract

Exposure to Magnetic Field Non-Ionizing Radiation and the Risk of Miscarriage: A Prospective Cohort Study

Magnetic field (MF) non-ionizing radiation is widespread and everyone is exposed to some degree. This prospective cohort study of 913 pregnant women examined the association between high MF exposure and miscarriage risk. Cox (proportional hazards) regression was used to examine the association. After controlling for multiple other factors, women who were exposed to higher MF levels had 2.72 times the risk of miscarriage (hazard ratio = 2.72, 95% CI: 1.42-5.19) than those with lower MF exposure. The increased risk of miscarriage associated with high MF was consistently observed regardless of the sources of high MF. The association was much stronger if MF was measured on a typical day of participants’ pregnancies. The finding also demonstrated that accurate measurement of MF exposure is vital for examining MF health effects. This study provides fresh evidence, directly from a human population, that MF non-ionizing radiation could have adverse biological impacts on human health.

Authors: Li DK; Chen H; Ferber JR; Odouli R; Quesenberry C

Sci Rep. 2017 12 13;7(1):17541. Epub 2017-12-13.

PubMed abstract

Autism risk classification using placental chorionic surface vascular network features

Autism Spectrum Disorder (ASD) is one of the fastest-growing developmental disorders in the United States. It was hypothesized that variations in the placental chorionic surface vascular network (PCSVN) structure may reflect both the overall effects of genetic and environmentally regulated variations in branching morphogenesis within the conceptus and the fetus’ vital organs. This paper provides sound evidences to support the study of ASD risks with PCSVN through a combination of feature-selection and classification algorithms. Twenty eight arterial and 8 shape-based PCSVN attributes from a high-risk ASD cohort of 89 placentas and a population-based cohort of 201 placentas were examined for ranked relevance using a modified version of the random forest algorithm, called the Boruta method. Principal component analysis (PCA) was applied to isolate principal effects of arterial growth on the fetal surface of the placenta. Linear discriminant analysis (LDA) with a 10-fold cross validation was performed to establish error statistics. The Boruta method selected 15 arterial attributes as relevant, implying the difference in high and low ASD risk can be explained by the arterial features alone. The five principal features obtained through PCA, which accounted for about 88% of the data variability, indicated that PCSVNs associated with placentas of high-risk ASD pregnancies generally had fewer branch points, thicker and less tortuous arteries, better extension to the surface boundary, and smaller branch angles than their population-based counterparts. We developed a set of methods to explain major PCSVN differences between placentas associated with high risk ASD pregnancies and those selected from the general population. The research paradigm presented can be generalized to study connections between PCSVN features and other maternal and fetal outcomes such as gestational diabetes and hypertension.

Authors: Chang JM; Croen L; et al.

BMC Med Inform Decis Mak. 2017 Dec 06;17(1):162. Epub 2017-12-06.

PubMed abstract

Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.

Authors: Andrews SV; Ellis SE; Bakulski KM; Sheppard B; Croen LA; Hertz-Picciotto I; Newschaffer CJ; Feinberg AP; Arking DE; Ladd-Acosta C; Fallin MD

Nat Commun. 2017 10 24;8(1):1011. Epub 2017-10-24.

PubMed abstract

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Authors: Sharp GC; Falahi F; Relton CL; et al.

Hum Mol Genet. 2017 10 15;26(20):4067-4085.

PubMed abstract

Scaling of the surface vasculature on the human placenta

The networks of veins and arteries on the chorionic plate of the human placenta are analyzed in terms of Voronoi cells derived from these networks. Two groups of placentas from the United States are studied: a population cohort with no prescreening, and a cohort from newborns with an elevated risk of developing autistic spectrum disorder. Scaled distributions of the Voronoi cell areas in the two cohorts collapse onto a single distribution, indicating common mechanisms for the formation of the complete vasculatures, but which have different levels of activity in the two cohorts.

Authors: Leonard AS; Lee J; Schubert D; Croen LA; Fallin MD; Newschaffer CJ; Walker CK; Salafia CM; Morgan SP; Vvedensky DD

Phys Rev E. 2017 Oct;96(4-1):040401. Epub 2017-10-02.

PubMed abstract

Offspring risk of obesity in childhood, adolescence and adulthood in relation to gestational diabetes mellitus: a sex-specific association

Animal data suggest sexually dimorphic programming of obesity in response to altered intrauterine environment, but the longitudinal impact of gestational diabetes mellitus (GDM) on sex-specific risk of offspring obesity in humans is unclear. We conducted a prospective analysis of 15 009 US individuals (7946 female and 7063 male) from the Growing-Up Today Study, who were followed from 1996 (ages 9-14 years) through 2010. Height and weight from validated questionnaires were used to derive body mass index (BMI) at different ages. Obesity during childhood (< 18 years) and adulthood (≥ 18 years) were defined using the International Obesity Task Force and the World Health Organization criteria. GDM exposure was identified through self-reported questionnaires from mothers. Relative risks were estimated using multivariable log-binomial regression models with generalized estimating equations accounting for clustering within the same family. Male offspring born from pregnancies complicated by GDM had higher BMI compared with non-GDM offspring and had increased risk of obesity; the adjusted relative risk [RR, 95% confidence interval (CI)] was 1.47 (1.11-1.95) for all age groups, 1.59 (1.05-2.41) for late childhood, 1.48 (1.06-2.06) for adolescence and 1.39 (1.00-1.94) for early adulthood. No significant association between obesity and maternal GDM was observed among female participants (RR = 0.97, 95% CI: 0.71-1.33). The association of GDM with offspring obesity from late childhood through early adulthood may differ by sex; a significant association was observed among male but not female offspring.

Authors: Li S; Zhu Y; Yeung E; Chavarro JE; Yuan C; Field AE; Missmer SA; Mills JL; Hu FB; Zhang C

Int J Epidemiol. 2017 10 01;46(5):1533-1541.

PubMed abstract

Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: Trends and survival outcomes

To assess recent trends of administering adjuvant gemcitabine-docetaxel (GD) chemotherapy for Stage I uterine leiomyosarcoma, and to compare disease-free and overall survival between women who received and did not receive adjuvant GD chemotherapy. All patients diagnosed with Stage I uterine leiomyosarcoma in a California-Colorado population-based health plan inclusive of 2006-2013 were included in a retrospective cohort. Adjuvant GD chemotherapy rates, clinico-pathologic characteristics and survival estimates were assessed. Of 111 women with Stage I uterine leiomyosarcoma, 33 received adjuvant GD (median 4cycles), 77 received no chemotherapy, and 1 patient excluded for non-GD chemotherapy. GD-chemotherapy and no-chemotherapy groups were similar with respect to age, stage (IA/IB), uterine weight, mitotic index, body mass index, and Charlson comorbidity score. Non-Hispanic white women were twice as likely to receive adjuvant chemotherapy as non-white or Hispanic women (37.7 vs. 17.1%, P=0.02). The proportion of women receiving adjuvant GD chemotherapy increased from 6.5% in 2006-2008 to 46.9% in 2009-2013 (P<0.001). There was no significance difference in unadjusted Kaplan-Meyer estimated disease-free (P=0.95) or overall survival (P=0.43) between GD-chemotherapy and no-chemotherapy cohorts. Corresponding adjusted Cox proportional hazard ratios for adjuvant GD chemotherapy compared to no chemotherapy were 1.01 (95% confidence interval [CI] 0.57-1.80, P=0.97) for recurrence and 1.28 (95% CI 0.69-2.36, P-0.48) for mortality. Use of adjuvant GD chemotherapy for Stage I uterine leiomyosarcoma has increased significantly in the last decade, despite unclear benefit. Compared to no chemotherapy, 4-6cycles of adjuvant GD chemotherapy does not appear to alter survival outcomes.

Authors: Littell RD; Tucker LY; Raine-Bennett T; Palen TE; Zaritsky E; Neugebauer R; Embry-Schubert J; Lentz SE

Gynecol Oncol. 2017 10;147(1):11-17. Epub 2017-07-24.

PubMed abstract

Urine leakage during sexual activity among ethnically diverse, community-dwelling middle-aged and older women

Urinary incontinence is associated with decreased female sexual function, but little is known about the prevalence, predictors, and impact of urine leakage during sexual activity among women in the community. The purpose of this study was to evaluate the prevalence and impact of urine leakage during sex in ethnically diverse, community-dwelling midlife and older women. Urinary incontinence and sexual function were assessed by structured questionnaire in a multiethnic, community-based cohort of women enrolled in Kaiser Permanente Northern California, an integrated healthcare delivery system in California. All women were aged 40-80 years and sampled from 1 of 4 racial/ethnic groups (20% black, 20% Latina, 20% Asian, and 40% non-Latina white). Differences in frequency, bother, and fear of urine leakage during sexual activity were examined among women with monthly, weekly, and daily urinary incontinence and across different types of urinary incontinence (stress, urgency, mixed, and other type urinary incontinence), with the use of chi-square tests. Independent risk factors for urine leakage during sexual activity were identified through multivariable logistic regression. Of the 509 women who reported being sexually active and having at least monthly urinary incontinence, 127 of them (25%) reported experiencing any urine leakage during sex during the past 3 months. Nineteen percent of the women reported being subjectively bothered by leakage during sex, and 16% of them reported restricting sexual activity because of fear of leakage. Women with more frequent underlying urinary incontinence were more likely to report experiencing or being bothered by leakage during sex and restricting sexual activity because of fear of leakage (P<.001 for all). Participants with predominantly stress or mixed type urinary incontinence were more likely to report experiencing leakage during sex and being subjectively bothered by this leakage (P<.002 for all). Factors independently associated with leakage during sex were depression (odds ratio,1.96; 95% confidence interval, 1.20-3.20), symptomatic pelvic organ prolapse (odds ratio, 2.10; 95% confidence interval, 1.11-3.98), mixed vs urgency type urinary incontinence (odds ratio, 3.16; 95% confidence interval, 1.70-5.88), stress vs urgency type urinary incontinence (odds ratio, 1.94; 95% confidence interval, 1.01-3.70), and frequency of sexual activity (odds ratio, 1.6395% confidence interval, 1.05-2.55), but not age or race/ethnicity. Up to a quarter of women with at least monthly urinary incontinence in the community may experience urine leakage during sexual activity. Many incontinent women who leak urine during sex remain sexually active, which indicates that the preservation of sexual function should still be a priority in this population. Among incontinent women, depression, pelvic organ prolapse, and stress mixed-type urinary incontinence may be associated with urine leakage during sexual activity.

Authors: Munaganuru N; Van Den Eeden SK; Creasman J; Subak LL; Strano-Paul L; Huang AJ

Am J Obstet Gynecol. 2017 10;217(4):439.e1-439.e8. Epub 2017-06-08.

PubMed abstract

Spontaneous and indicated preterm delivery risk is increased among overweight and obese women without prepregnancy chronic disease

To investigate the independent impact of prepregnancy obesity on preterm delivery among women without chronic diseases by gestational age, preterm category and parity. A retrospective cohort study. Data from the Consortium on Safe Labor (CSL) in the USA (2002-08). Singleton deliveries at ≥23 weeks of gestation in the CSL (43 200 nulliparas and 63 129 multiparas) with a prepregnancy body mass index (BMI) ≥18.5 kg/m2 and without chronic diseases. Association of prepregnancy BMI and the risk of preterm delivery was examined using Poisson regression with normal weight as reference. Preterm deliveries were categorised by gestational age (extremely, very, moderate to late) and category (spontaneous, indicated, no recorded indication). Relative risk of spontaneous preterm delivery was increased for extremely preterm among obese nulliparas (1.26, 95% CI: 0.94-1.70 for overweight; 1.88, 95% CI: 1.30-2.71 for obese class I; 1.99, 95% CI: 1.32-3.01 for obese class II/III) and decreased for moderate to late preterm delivery among overweight and obese multiparas (0.90, 95% CI: 0.83-0.97 for overweight; 0.87, 95% CI: 0.78-0.97 for obese class I; 0.79, 95% CI: 0.69-0.90 for obese class II/III). Indicated preterm delivery risk was increased with prepregnancy BMI in a dose-response manner for extremely preterm and moderate to late preterm among nulliparas, as it was for moderate to late preterm delivery among multiparas. Prepregnancy BMI was associated with increased risk of preterm delivery even in the absence of chronic diseases, but the association was heterogeneous by preterm categories, gestational age and parity. Obese nulliparas without chronic disease had higher risk for spontaneous delivery <28 weeks of gestation.

Authors: Kim SS; Mendola P; Zhu Y; Hwang BS; Grantz KL

BJOG. 2017 Oct;124(11):1708-1716. Epub 2017-04-01.

PubMed abstract

Intimate Partner Violence, Smoking, and Pregnancy: What Can We Do to Help?

Authors: Young-Wolff KC; McCaw B; Avalos LA

J Womens Health (Larchmt). 2017 Sep 22.

PubMed abstract

Maternal and Paternal Infertility Disorders and Treatments and Autism Spectrum Disorder: Findings from the Study to Explore Early Development

Previous studies of associations between ASD and conception using assisted reproductive technology (ART) are inconsistent and few studies have examined associations with other infertility treatments or infertility disorders. We examined associations between ASD and maternal/paternal infertility disorders and numerous maternal treatments among 1538 mother-child pairs in the Study to Explore Early Development, a population-based case-control study. ASD was associated with any female infertility diagnosis and several specific diagnoses: blocked tubes, endometriosis, uterine-factor infertility, and polycystic ovarian syndrome. Stratified analyses suggested associations were limited to/much stronger among second or later births. The findings were not explained by sociodemographic factors such as maternal age or education or multiple or preterm birth. ASD was not associated with ART or non-ART infertility treatments.

Authors: Schieve LA; Drews-Botsch C; Harris S; Newschaffer C; Daniels J; DiGuiseppi C; Croen LA; Windham GC

J Autism Dev Disord. 2017 Sep 12.

PubMed abstract

Prenatal Alcohol Exposure in Relation to Autism Spectrum Disorder: Findings from the Study to Explore Early Development (SEED)

Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD). We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report. Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk. These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment.

Authors: Singer AB; DiGuiseppi C; Daniels JL; et al.

Paediatr Perinat Epidemiol. 2017 Sep 07.

PubMed abstract

HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

Although most cervical human papillomavirus type�16 (HPV16) infections become undetectable within 1-2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected�case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.

Authors: Mirabello L; Yeager M; Yu K; Clifford GM; Xiao Y; Zhu B; Cullen M; Boland JF; Wentzensen N; Nelson CW; Raine-Bennett T; Chen Z; Bass S; Song L; Yang Q; Steinberg M; Burdett L; Dean M; Roberson D; Mitchell J; Lorey T; Franceschi S; Castle PE; Walker J; Zuna R; Kreimer AR; Beachler DC; Hildesheim A; Gonzalez P; Porras C; Burk RD; Schiffman M

Cell. 2017 Sep 07;170(6):1164-1174.e6.

PubMed abstract

Validation of Self-Reported Diagnosis of Gestational Diabetes at Six Weeks Postpartum

Self-report is often used in identifying gestational diabetes events in epidemiologic studies; however, validity data are limited, with little to no data on self-reported severity or treatment. We aimed to assess the validity of self-reported gestational diabetes diagnosis and evaluate the accuracy of glucose diagnosis results and gestational diabetes treatment self-reported at 6-week postpartum. Data were from 82 and 83 women with and without gestational diabetes, respectively, within the prospective National Institute Child Health and Human Development Fetal Growth Studies-Singletons (2009-2013). Medical record data were considered the gold standard. Sensitivity was 95% (95% confidence interval [CI] = 88, 98), and specificity was 100% (95% CI = 96, 100); four women with gestational diabetes incorrectly reported not having the disease, and none of the women without gestational diabetes reported having gestational diabetes. Sensitivity did not vary substantially across maternal characteristics including race/ethnicity. For women who attempted to recall their values (84/159 women), self-reported glucose challenge test results did not differ from the medical records (median difference: 0; interquartile range: 0-0 mg/dl). Medical records indicated that 42 (54%) of 78 women with confirmed gestational diabetes were treated by diet only and 33 (42%) were treated by medication. All 42 women with diet-treated gestational diabetes correctly reported having had diet and lifestyle modification, and 28 (85%) of 33 women with medication-treated gestational diabetes indicated postpartum that they had medication treatment. At 6-week postpartum, regardless of race/ethnicity or socioeconomic status, women accurately recalled whether they had gestational diabetes and, as applicable, their treatment method.

Authors: Hinkle SN; Rawal S; Zhu Y; Grewal J; Albert PS; Zhang C

Epidemiology. 2017 Sep;28(5):747-752.

PubMed abstract

Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case-Control Study in California

Prior studies suggest neurodevelopmental impacts of polybrominated diphenyl ethers (PBDEs), but few have examined diagnosed developmental disorders. Our aim was to determine whether prenatal exposure to brominated flame retardants (BFRs) is associated with autism spectrum disorder (ASD) or intellectual disability without autism (ID). We conducted a population-based case-control study including children with ASD (n=545) and ID (n=181) identified from the California Department of Developmental Services and general population (GP) controls (n=418) from state birth certificates. ASD cases were matched to controls by sex, birth month, and birth year. Concentrations of 10 BFRs were measured in maternal second trimester serum samples stored from routine screening. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses. Geometric mean concentrations of five of the six congeners with ≥55% of samples above the limit of detection were lower in mothers of children with ASD or ID than in controls. In adjusted analyses, inverse associations with several congeners were found for ASD relative to GP (e.g., quartile 4 vs. 1, BDE-153: AOR=0.56, 95% CI: 0.38, 0.84). When stratified by child sex (including 99 females with ASD, 77 with ID, and 73 with GP), estimates were consistent with overall analyses in boys, but in the opposite direction among girls, particularly for BDE-28 and -47 (AOR=2.58, 95% CI: 0.86, 7.79 and AOR=2.64, 95% CI: 0.97, 7.19, respectively). Similar patterns overall and by sex were observed for ID. Contrary to expectation, higher PBDE concentrations were associated with decreased odds of ASD and ID, though not in girls. These findings require confirmation but suggest potential sexual dimorphism in associations with prenatal exposure to BFRs.

Authors: Lyall K; Croen LA; Weiss LA; Kharrazi M; Traglia M; Delorenze GN; Windham GC

Environ Health Perspect. 2017 Aug 30;125(8):087023. Epub 2017-08-30.

PubMed abstract

Rates and Predictors of Vaccinations Among Inflammatory Bowel Disease Patients Receiving Anti-Tumor Necrosis Factor Agents

As an important quality measure, the rates of recommended immunizations among immunocompromised inflammatory bowel disease (IBD) patients in community practice have not been well studied. This study sought to investigate the rates and predictors of recommended immunizations and screening tests among IBD patients receiving anti-tumor necrosis factor (TNF) therapy in a large integrated healthcare organization. We conducted a retrospective cohort study of 1401 IBD patients on anti-TNF therapy between 2010 and 2013 within the Kaiser Permanente Northern California healthcare system. The rates of vaccinations and screening tests were quantified, and the associated predictors were investigated. Vaccination rates for influenza and pneumococcus were 43.5 and 24.1%, respectively. The majority of patients (73.7%) received hepatitis B screening and/or vaccine. Patients receiving infliximab had higher rates of pneumococcal vaccine (P = 0.002), hepatitis B screening (P < 0.001), and tuberculin skin test (P < 0.001) compared with patients receiving adalimumab. Older patient age (≥50 years) was associated with higher likelihood of having HBsAg test (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0, P = 0.002), influenza vaccine (OR 2.6 [2.1-3.4], P < 0.001), and pneumococcal vaccine (OR 4.0 [3.0-5.3], P < 0.001). In contrast, older providers (≥50 years) were associated with significantly lower likelihood of their patients' having hepatitis A and B screening tests, and pneumococcal vaccination. The rates of immunizations for IBD patients receiving anti-TNF treatment were lower than recommended. Structured reminders for vaccinations and education for both patients and providers (older physicians in particular) may prove beneficial in improving immunization rates among immunocompromised IBD patients.

Authors: Pham HV; Hasan I; Udaltsova N; Pham K; Abramson O; Armstrong MA; Postlethwaite D; Li D

Dig Dis Sci. 2017 Aug 23.

PubMed abstract

Healthy Lifestyle During Early Pregnancy and Risk of Gestational Diabetes Mellitus

Previous studies have found associations between individual healthy behaviors and reduced risk of gestational diabetes mellitus (GDM); however, the association of composite healthy lifestyle during pregnancy with GDM has not been examined. Participants in the Omega Study (n = 3,005), a pregnancy cohort study conducted in Washington State (1996-2008), reported information on diet, physical activity, smoking, and stress during early pregnancy. Lifestyle components were dichotomized into healthy/unhealthy and then combined into a total lifestyle score (range, 0-4). Regression models were used to determine relative risk of GDM (n = 140 cases) in relation to healthy lifestyle. Twenty percent of participants had a healthy diet, 66% were physically active, 95% were nonsmokers, and 55% had low stress. Each 1-point increase in lifestyle score was associated with a 21% lower risk of GDM (95% confidence interval: 0.65, 0.96) after adjustment for age, race, and nulliparity. Adjustment for prepregnancy body mass index, prepregnancy physical activity, and prepregnancy smoking attenuated the associations slightly. Associations were similar in normal-weight and overweight/obese women. In this study, a composite measure of healthy lifestyle during early pregnancy was associated with substantially lower GDM risk. Public health messaging and interventions promoting multiple aspects of a healthy lifestyle during early pregnancy should be considered for GDM prevention.

Authors: Badon SE; Enquobahrie DA; Wartko PD; Miller RS; Qiu C; Gelaye B; Sorensen TK; Williams MA

Am J Epidemiol. 2017 Aug 1;186(3):326-333. doi: 10.1093/aje/kwx095.

PubMed abstract

Scientific abstracts featured research at the 2017 North American Forum on Family Planning

Authors: Espey E; Teal S; Borrero S; Raine-Bennett T; Finer L

Contraception. 2017 Aug 01.

PubMed abstract

Peripubertal dietary flavonol and lignan intake and age at menarche in a longitudinal cohort of girls

BackgroundDietary phytoestrogens may alter hormonal activity in childhood. Flavonols and lignans are the most prevalent phytoestrogens in the Western diet. We examined whether higher intake of flavonols and lignans was associated with later age at menarche in a prospective study of young girls.MethodsIn all, 1,044 girls aged 6-8 years (mean 7.3 years) with two to four 24-h dietary recalls during their baseline year were followed up for 11 years until the attainment of menarche in the Breast Cancer and Environment Research Project (BCERP). Associations of age at menarche with quintiles of phytoestrogens were assessed using hazard ratios (HR) and 95% confidence intervals (CIs) from Cox proportional hazards models, controlling for body mass index and other covariates.ResultsThe highest quintile of flavonol intake was associated with a later age at menarche, compared with the lowest quintile (adjusted HR: 0.80, 95% CI: (0.66-1.00). For lignans, there was a later age in overweight girls (HR: 0.56, 95% CI=0.40-0.80).ConclusionThese dietary bioactives may reflect a healthy diet, and foods high in phytoestrogens may influence the timing of menarche.

Authors: Mervish NA; Teitelbaum SL; Pajak A; Windham GC; Pinney SM; Kushi LH; Biro FM; Wolff MS

Pediatr Res. 2017 Aug;82(2):201-208. Epub 2017-06-14.

PubMed abstract

Urinary bisphenol A and pubertal development in Chinese school-aged girls: a cross-sectional study

Animal studies suggest that bisphenol A (BPA) may perturb pubertal development in females. However, evidence from human studies is limited. This was a cross-sectional study to investigate the association between BPA exposure and pubertal development in school-aged girls. A total of 655 girls aged 9-18 years were selected from three schools in Shanghai, from May to June 2011. We collected one single spot urine sample from each girl. Urine BPA concentrations were measured by modified high-performance liquid chromatography and categorized according to LOD and the median of those above LOD. Pubertal development status was assessed by using Tanner staging, and age at menarche was collected as a milestone for mid-puberty. Modified Poisson regression was used to estimate adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs). After adjustment for potential confounders, girls with detected BPA were more likely to have delayed menarche, a mid-puberty event, compared with girls with undetectable BPA; the prevalence ratios (PR) were 0.73 (0.56, 0.95) for those with moderate BPA(LOD-median) and 0.72 (0.52, 0.99) for those with high BPA(>median), respectively. Girls aged 9-12 years with detected BPA were more likely to have reached pubic hair stage 2, the indicator of pubarche; while among girls aged >15 years, those with detected BPA were less likely to have reached pubic hair stage 5, the late stage of pubic hair development. BPA exposure was associated with alterations in the timing of pubertal development. Results in the present study should be interpreted with caution because of its cross-sectional nature and the limited sample size in each age group.

Authors: Miao M; Wang Z; Liu X; Liang H; Zhou Z; Tan H; Yuan W; Li DK

Environ Health. 2017 07 27;16(1):80. Epub 2017-07-27.

PubMed abstract

Demographic and Clinical Characteristics Associated with Engagement in Behavioral Health Treatment Among Children with Autism Spectrum Disorders

This study investigates demographic and clinical factors associated with initiation, continuation, and adherence to behavioral health treatment (BHT) among children with autism spectrum disorder. Among 293 insured children referred for applied behavior analysis (ABA) based BHT, 23% never initiated treatment. Among those initiating treatment, 31% discontinued treatment within 1 year of treatment initiation, and only 15% received 80% or more of recommended treatment hours. Younger age at referral to treatment, private health insurance, and receiving more than 10 h/week of BHT were associated with treatment engagement. Co-occurring psychiatric and medical conditions were related to treatment discontinuation among children 5 years or older. These findings suggest specific subgroups that may benefit from additional support with engaging in recommended behavioral health treatment.

Authors: Croen LA; Shankute N; Davignon M; Massolo ML; Yoshida C

J Autism Dev Disord. 2017 Jul 26.

PubMed abstract

Chronic and Acute Ozone Exposure in the Week Prior to Delivery Is Associated with the Risk of Stillbirth

Chronic and acute air pollution has been studied in relation to stillbirth with inconsistent findings. We examined stillbirth risk in a retrospective cohort of 223,375 singleton deliveries from 12 clinical sites across the United States. Average criteria air pollutant exposure was calculated using modified Community Multiscale Air Quality models for the day of delivery and each of the seven days prior, whole pregnancy, and first trimester. Poisson regression models using generalized estimating equations estimated the relative risk (RR) of stillbirth and 95% confidence intervals (CI) in relation to an interquartile range increase in pollutant with adjustment for temperature, clinical, and demographic factors. Ozone (O₃) was associated with a 13-22% increased risk of stillbirth on days 2, 3, and 5-7 prior to delivery in single pollutant models, and these findings persisted in multi-pollutant models for days 5 (RR = 1.22, CI = 1.07-1.38) and 6 (RR = 1.18, CI = 1.04-1.33). Whole pregnancy and first trimester O₃ increased risk 18-39% in single pollutant models. Maternal asthma increased stillbirth risk associated with chronic PM2.5 and carbon monoxide exposures. Both chronic and acute O₃ exposure consistently increased stillbirth risk, while the role of other pollutants varied. Approximately 8000 stillbirths per year in the US may be attributable to O₃ exposure.

Authors: Mendola P; Ha S; Pollack AZ; Zhu Y; Seeni I; Kim SS; Sherman S; Liu D

Int J Environ Res Public Health. 2017 07 06;14(7). Epub 2017-07-06.

PubMed abstract

Leveraging EHRs for patient engagement: perspectives on tailored program outreach

Electronic health records (EHRs) present healthcare delivery systems with scalable, cost-effective opportunities to promote lifestyle programs among patients at high risk for type 2 diabetes, yet little consensus exists on strategies to enhance patient engagement. We explored patient perspectives on program outreach messages containing content tailored to EHR-derived diabetes risk factors-a theory-driven strategy to increase the persuasiveness of health communications. Convergent mixed methods. Within an integrated healthcare delivery system, women with a history of gestational diabetes participated in 1 of 6 ethnic-specific focus groups to elicit diverse perspectives and a survey yielding quantitative data to contextualize qualitative responses. The sample included 35 participants (80% racial/ethnic minorities; mean age = 36 years). Themes regarding tailored messages centered on diabetes risk communication (opposing attitudes about whether to feature diabetes risk factors), privacy (how and whether patient data should be accessed), authenticity (perceiving messages as personalized vs generically computer generated), and preferences for messages sent by one’s personal physician. Trust in the medical profession and perceived risk for diabetes were similar to levels reported in comparable samples. Patient reactions highlight the challenges of leveraging EHRs for tailored messages. Some viewed messages as caring reminders to take preventive action and others raised concerns over intrusiveness. Optimal lifestyle program outreach to improve quality of care for women at high risk for diabetes may require communication from personal physicians, careful development to mitigate concerns over privacy and authenticity, and techniques to counteract the threatening nature of personalized risk communication.

Authors: Brown SD; Grijalva CS; Ferrara A

Am J Manag Care. 2017 Jul 01;23(7):e223-e230. Epub 2017-07-01.

PubMed abstract

Maternal dietary intakes of refined grains during pregnancy and growth through the first 7 y of life among children born to women with gestational diabetes

Background: Refined grains, a major source of dietary carbohydrates, have been related to impaired glucose homeostasis and obesity. Emerging animal data suggest that in utero exposure to dietary refined carbohydrates may predispose offspring to an obese phenotype, indicating a potential role for nutritional programming in the early origins of obesity, but intergenerational human data are lacking.Objective:We prospectively investigated refined-grain intake during pregnancy in association with offspring growth through age 7 y among high-risk children born to women with gestational diabetes mellitus (GDM).Design:The analysis included 918 mother-singleton child dyads from the Danish National Birth Cohort. Offspring body mass indexzscores (BMIZs) were calculated by using weight and length or height measured at birth, 5 and 12 mo, and 7 y. Overweight or obesity was defined by WHO cutoffs. Linear and Poisson regressions were used, with adjustment for maternal demographic, lifestyle, and dietary factors.Results:Refined-grain intake during pregnancy was positively associated with offspring BMIZ (adjusted β per serving increase per day: 0.09; 95% CI: 0.02, 0.15) and risk of overweight or obesity at age 7 y [adjusted RR (aRR) comparing the highest with the lowest quartile: 1.80; 95% CI: 1.09, 2.98;P-trend = 0.032]. The association appeared to be more pronounced among children who were breastfed <6 mo. The substitution of 1 serving refined grains/d with an equal serving of whole grains during pregnancy was related to a 10% reduced risk of offspring overweight or obesity at 7 y of age (aRR: 0.90; 95% CI: 0.82, 0.98). No associations were observed between refined-grain intake and infant growth.Conclusions:Higher maternal refined-grain intake during pregnancy was significantly related to a greater BMIZ and a higher risk of overweight or obesity at age 7 y among children born after pregnancies complicated by GDM. The findings highlight pregnancy as a potential window of susceptibility associated with offspring growth and obesity risk among this high-risk population. Data with longer follow-up are warranted.

Authors: Zhu Y; Zhang C; et al.

Am J Clin Nutr. 2017 Jul;106(1):96-104. Epub 2017-06-07.

PubMed abstract

Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children

This study examines medical conditions diagnosed prior to the diagnosis of autism spectrum disorder (ASD). Using a matched case control design with 3911 ASD cases and 38,609 controls, we found that 38 out of 79 medical conditions were associated with increased ASD risk. Developmental delay, mental health, and neurology conditions had the strongest associations (ORs 2.0-23.3). Moderately strong associations were observed for nutrition, genetic, ear nose and throat, and sleep conditions (ORs 2.1-3.2). Using machine learning methods, we clustered children based on their medical conditions prior to ASD diagnosis and demonstrated ASD risk stratification. Our findings provide new evidence indicating that children with ASD have a disproportionate burden of certain medical conditions preceding ASD diagnosis.

Authors: Alexeeff SE; Yau V; Qian Y; Davignon M; Lynch F; Crawford P; Davis R; Croen LA

J Autism Dev Disord. 2017 Jul;47(7):2067-2079.

PubMed abstract

Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study

Artificial sweeteners are widely replacing caloric sweeteners. Data on long-term impact of artificially sweetened beverage (ASB) consumption during pregnancy on offspring obesity risk are lacking. We prospectively investigated intake of ASBs and sugar-sweetened beverages (SSBs) during pregnancy in relation to offspring growth through age 7 years among high-risk children born to women with gestational diabetes. In a prospective study of 918 mother-singleton child dyads from the Danish National Birth Cohort, maternal dietary intake was assessed by a food frequency questionnaire during pregnancy. Offspring body mass index z-scores (BMIZ) and overweight/obesity status were derived using weight and length/height at birth, 5 and 12 months and 7 years. Linear regression and Poisson regression with robust standard errors were used, adjusting for major risk factors. Approximately half of women reported consuming ASBs during pregnancy and 9% consumed daily. Compared to never consumption, daily ASB intake during pregnancy was positively associated with offspring large-for-gestational age [adjusted relative risk (aRR) 1.57; 95% CI: 1.05, 2.35 at birth], BMIZ (adjusted β 0.59; 95% CI: 0.23, 0.96) and overweight/obesity (aRR 1.93; 95% CI; 1.24, 3.01) at 7 years. Per-serving-per-day substitution of ASBs with water during pregnancy was related to a lower overweight/obesity risk at 7 years (aRR 0.83; 95% CI: 0.76, 0.91), whereas SSB substitution with ASBs was not related to a lower risk (aRR 1.14; 95% CI: 1.00, 1.31). Our findings illustrated positive associations between intrauterine exposure to ASBs and birth size and risk of overweight/obesity at 7 years. Data with longer follow-up are warranted.

Authors: Zhu Y; Zhang C; et al.

Int J Epidemiol. 2017 Jun 06.

PubMed abstract

Variants in Pharmacokinetic Transporters and Glycaemic Response to Metformin: A MetGen Meta-Analysis

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Authors: Dujic T; van der Heijden AA; Pearson ER; et al.

Clin Pharmacol Ther. 2017 Jun;101(6):763-772. Epub 2017-02-03.

PubMed abstract

Minimally Invasive Hysterectomy and Power Morcellation Trends in a West Coast Integrated Health System

To examine trends in minimally invasive hysterectomy and power morcellation use over time and associated clinical characteristics. We conducted a trend analysis and retrospective cohort study of all women 18 years of age and older undergoing hysterectomy for benign conditions at Kaiser Permanente Northern California collected from electronic health records. Generalized estimating equations and Cochran-Armitage testing were used to assess the primary outcomes, hysterectomy incidence, and proportion of hysterectomies by surgical route and power morcellation. Logistic regression analysis was used to assess secondary outcomes, clinical characteristics, and complications associated with surgical route. There were 31,971 hysterectomies from 2008 to 2015; the incidence decreased slightly from 2.86 (95% confidence interval [CI] 2.85-2.87) to 2.60 (95% CI 2.59-2.61) per 1,000 women (P<.001). Minimally invasive hysterectomies increased from 39.8% to 93.1%, almost replacing abdominal hysterectomies entirely (P<.001). Vaginal hysterectomies decreased slightly from 26.6% to 23.4% (P<.001). The proportion of nonrobotic laparoscopic hysterectomies with power morcellation increased steadily from 3.7% in 2008 to a peak of 11.4% in 2013 and decreased to 0.02% in 2015 (P<.001). Robot-assisted laparoscopic hysterectomies remained a small proportion of all hysterectomies comprising 7.8% of hysterectomies in 2015. Women with large uteri (greater than 1,000 g) were more likely to receive abdominal hysterectomies than minimally invasive hysterectomy (adjusted relative risk 11.62, 95% CI 9.89-13.66) and laparoscopic hysterectomy with power morcellation than without power morcellation (adjusted relative risk 5.74, 95% CI 4.12-8.00). Laparoscopic supracervical hysterectomy was strongly associated with power morcellation use (adjusted relative risk 43.89, 95% CI 37.55-51.31). A high minimally invasive hysterectomy rate is primarily associated with uterine size and can be maintained without power morcellation.

Authors: Zaritsky E; Tucker LY; Neugebauer R; Chou T; Flanagan T; Walter AJ; Raine-Bennett T

Obstet Gynecol. 2017 Jun;129(6):996-1005.

PubMed abstract

​Ambient air pollution and risk of gestational hypertension

​Air pollution has been linked to hypertension in the general population, but data on gestational hypertension (GH) are limited. We investigated air pollutants and toxics during preconception and early gestation in relation to GH risk in the Consortium on Safe Labor/Air Quality and Reproductive Health Study (2002-2008). Modified Community Multiscale Air Quality models estimated air pollution exposures among 6,074 singleton pregnancies with GH and 199,980 normotensives. Generalized estimating equations estimated relative risks per interquartile-range increment for pollutants and high exposure (≥75th percentile) for toxics, after adjustment for major risk factors. For an interquartile-range increment, GH risk was significantly increased by 18% for sulfur dioxide during the three months preconception; and 17% for nitrogen oxides, 10% for particulate matter <2.5 μm, 7% for particulate matter <10 μm, and 22% for sulfur dioxide during gestational weeks 1-20. High exposures to several polycyclic aromatic hydrocarbons both during preconception and the first trimester were significantly associated with 8%-20% higher GH risk. Further, preconceptional exposures to several volatile organic compounds were significantly associated with 11%-19% higher risk. Our findings suggest early exposures to criteria air pollutants, particularly from transport emissions, and high exposure to several air toxics during preconception may increase GH risk.

Authors: Zhu Y; Zhang C; Liu D; Ha S; Kim SS; Pollack A; Mendola P;

​Am J Epidemiol. 2017 May 4. doi: 10.1093/aje/kwx097. [Epub ahead of print]

PubMed abstract

Are Health Plan Design and Prior Use of Long-Acting Reversible Contraception Associated with Pregnancy Intention?

In 2007, high-deductible plans were added to the primarily nondeductible Kaiser Permanente Northern California (KPNC) integrated health plan, which had covered 100% of device and procedure costs of long-acting reversible contraception (LARC) for members regardless of prescription/visit copay amount. We hypothesized that nondeductible plans and prior LARC use decreased unintended pregnancy. The purpose of this study was to determine if health plan design (nondeductible vs. deductible) and LARC use before pregnancy were associated with pregnancy intention. In this retrospective cohort study, women aged 15-44 as of the index date of June 30, 2010 were followed from January 1, 2010 to December 31, 2012 for evidence of pregnancy (n = 65,989). Health plan design, copays, contraceptive method used most recently before the pregnancy, and self-reported pregnancy intention status (intended, mistimed, unwanted) were obtained from electronic medical records. Logistic regression models were developed to determine if various health plan designs, copays, or prior LARC use were associated with pregnancy intention, controlling for potential confounders such as age, race/ethnicity, marital status, education/income, parity, and comorbidities. In all models, LARC use before pregnancy versus non-LARC use was significantly related to intended pregnancies (all models: odds ratio [OR] = 2.26, 95% confidence interval [CI] 2.06-2.48). Women with deductible plans with healthcare spending accounts (HSA) were more likely to report intended pregnancies versus women with nondeductible plans (all models: OR = 1.2, 95% CI 1.04-1.30). In stratified analyses, high income/high education was a significant predictor of intended pregnancy regardless of race/ethnicity. LARC use before pregnancy and having an HSA were associated with intended pregnancy.

Authors: Armstrong MA; Postlethwaite DA; Darbinian JA; McCoy M; Law A

J Womens Health (Larchmt). 2017 May;26(5):450-460. Epub 2016-10-18.

PubMed abstract

Predictors of Breastfeeding Initiation and Maintenance in an Integrated Healthcare Setting

The American Academy of Pediatrics recommends exclusive breastfeeding to age 6 months. Although breastfeeding rates in the United States have been increasing over time, further improvements are needed to meet Healthy People 2020 targets. Research aim: This study examined predictors of breastfeeding initiation and maintenance among a population of insured pregnant women. Participants were 1,149 pregnant women enrolled in the Pregnancy and Influenza Project in two Kaiser Permanente regions in 2010-2011. Data were collected through interviews at enrollment and 1 month and 6 months postpartum and through participants’ electronic medical records. Nearly all (99%) women reported initiating breastfeeding. Rates of exclusive breastfeeding were 70% and 54% at 1 month and 6 months, respectively; an additional 22% and 23% of women reported supplementing breastfeeding with formula. Of the women who supplemented, the mean ( SD) infant age at formula introduction was 53 (62) days. Of those who had stopped breastfeeding, the mean ( SD) infant age at cessation was 85 (59) days. Higher maternal education level, better maternal self-rated health, prenatal folic acid use, absence of chronic medical conditions, and infant full-term birth were significantly associated with breastfeeding maintenance. Although rates of breastfeeding in this population were higher than national rates, a significant number of women stopped breastfeeding or introduced formula earlier than recommended. Two to 3 months postpartum may be a critical period warranting additional encouragement or intervention by healthcare providers. Mothers’ education attainment, maternal health factors, and gestational age at delivery may predict likelihood of breastfeeding maintenance.

Authors: Henninger ML; Avalos LA; Pregnancy and Influenza Project Workgroup; et al.

J Hum Lact. 2017 May;33(2):256-266. Epub 2017-03-23.

PubMed abstract

The Pregnancy Environment and Lifestyle Study (PETALS): a population-based longitudinal multi-racial birth cohort

Increasing recognition has been received regarding the proven and suggested links between multi-level environmental exposures on a broad scale (e.g., chemical, clinical, behavioral, physical and social) and health deficits originated from the critical window of development. However, such prospective human data are limited. In 2016, the National Institutes of Health funded 35 centers comprising 84 extant cohorts for the Environmental Influences on Child Health Outcomes (ECHO) pediatric cohorts program. The Pregnancy Environment and Lifestyle Study (PETALS) is one of the cohorts at the participating centers of Kaiser Permanente Northern California (KPNC). PETALS was originally funded by the National Institute of Environmental Health Sciences to establish a longitudinal birth cohort of 3,350 mother-infant pairs and conduct a nested case-control study of 300 women with gestational diabetes (GDM) and 600 matched controls to investigate the associations between phenol exposures in first and second trimesters and GDM risk and the related outcome of infant macrosomia. This paper describes the prospective cohort design of PETALS, current research activities, and cohort profile of enrolled women who delivered as of February 2016. Women are enrolled from the KPNC membership. Fasting blood draw, urine collection, anthropometric measurements, and questionnaires on health history and lifestyle are completed at baseline and follow-up clinic visits with targeted windows of 10-13 and 16-19 weeks of gestation, respectively. Further, women’s clinical and health assessments before and after the index pregnancy in addition to their children’s birth outcomes and health information can be abstracted from electronic health records, allowing future follow-up. Study data could also be linked and extended to a myriad of additional observational data including environmental and area-level databases and census data. In this racially- and ethnically-diverse pregnancy cohort, the generated biospecimen and data repository will establish a comprehensive framework which may provide unique opportunities to address a multitude of research questions on the intrauterine environment and adverse pregnancy and birth outcomes in a representative multi-racial/ethnic population with generalizable findings.

Authors: Zhu Y; Hedderson MM; Feng J; Mevi AA; Ferrara A

BMC Pregnancy Childbirth. 2017 04 17;17(1):122. Epub 2017-04-17.

PubMed abstract

Maternal healthy lifestyle during early pregnancy and offspring birthweight: differences by offspring sex

PURPOSE: Individual maternal lifestyle factors during pregnancy have been associated with offspring birthweight; however, associations of combined lifestyle factors with birthweight and potential differences by offspring sex have not been examined.

MATERIALS AND METHODS: Participants (N = 2924) were identified from a pregnancy cohort in Washington state. Lifestyle factors during early pregnancy were dichotomized based on Alternate Healthy Eating Index score ≥62, leisure time physical activity (LTPA) ≥ 150 min/week, not smoking during pregnancy and Perceived Stress Scale score ≤3, then combined into a lifestyle score (0-4). Regression models were run overall and stratified by offspring sex, prepregnancy overweight/obese (BMI ≥25 kg/m2) and prepregnancy LTPA.

RESULTS: Overall, 20% of participants had healthy diet, 95% were nonsmokers, 55% had low stress levels, and 66% were physically active. Lifestyle score was not associated with birthweight (β = 3.3 g; 95% CI: -14.5, 21.0); however, associations differed by offspring sex (p = .009). For each unit increase in lifestyle score, there was a suggested 22.4 g higher birthweight (95% CI: -2.7, 47.6) among males and 14.6 g lower birthweight (95% CI: -39.9, 10.7) among females. Prepregnancy BMI and LTPA did not modify associations.

CONCLUSIONS: Healthy lifestyle score in early pregnancy may be associated with greater birthweight among male offspring, but lower birthweight among female offspring.

Authors: Badon SE; Miller RS; Qiu C; Sorensen TK; Williams MA; Enquobahrie DA

J Matern Fetal Neonatal Med. 2017 Apr 3:1-7. doi: 10.1080/14767058.2017.1309383.

PubMed abstract

Outcomes of Admissions for Preterm Labor

Objective  This study aims to quantitate the incidence of preterm labor (PTL) admissions and determine the frequency and predictors of preterm delivery (PTD) during these admissions. Study Design  Retrospective cohort of singleton pregnancies within Kaiser Permanente Northern California, 2001 to 2011. PTL admissions were defined as inpatient encounters > 24 hours with an International Classification of Diseases, 9th Revision code for PTL. Results  Total study population was 365,897 with PTL admission rate 11%. PTD occurred in 85% of pregnancies with PTL admission. Delivery occurred within 48 hours of admission in 96% ≥34 weeks, 67% 31 to 33 weeks, and 51.9% <31 weeks. Predictors of delivery during PTL admission included gestational age 34 to 36 weeks (adjusted odds ratio [aOR], 6.90), chorioamnionitis (aOR, 105.58), and preterm rupture of membranes (aOR 19.29). Conclusion  We demonstrate a high rate of PTD per PTL admission in a highly integrated health care system. More work is needed to determine optimal practices for hospitalization and treatment of women diagnosed with PTL.

Authors: Kuzniewicz MW; Black L; Walsh EM; Li SX; Greenberg M

AJP Rep. 2017 Apr;7(2):e106-e113. Epub 2017-06-22.

PubMed abstract

A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis

Current algorithms for management of neonatal early-onset sepsis (EOS) result in medical intervention for large numbers of uninfected infants. We developed multivariable prediction models for estimating the risk of EOS among late preterm and term infants based on objective data available at birth and the newborn’s clinical status. To examine the effect of neonatal EOS risk prediction models on sepsis evaluations and antibiotic use and assess their safety in a large integrated health care system. The study cohort includes 204 485 infants born at 35 weeks’ gestation or later at a Kaiser Permanente Northern California hospital from January 1, 2010, through December 31, 2015. The study compared 3 periods when EOS management was based on (1) national recommended guidelines (baseline period [January 1, 2010, through November 31, 2012]), (2) multivariable estimates of sepsis risk at birth (learning period [December 1, 2012, through June 30, 2014]), and (3) the multivariable risk estimate combined with the infant’s clinical condition in the first 24 hours after birth (EOS calculator period [July 1, 2014, through December 31, 2015]). The primary outcome was antibiotic administration in the first 24 hours. Secondary outcomes included blood culture use, antibiotic administration between 24 and 72 hours, clinical outcomes, and readmissions for EOS. The study cohort included 204 485 infants born at 35 weeks’ gestation or later: 95 343 in the baseline period (mean [SD] age, 39.4 [1.3] weeks; 46 651 male [51.0%]; 37 007 white, non-Hispanic [38.8%]), 52 881 in the learning period (mean [SD] age, 39.3 [1.3] weeks; 27 067 male [51.2%]; 20 175 white, non-Hispanic [38.2%]), and 56 261 in the EOS calculator period (mean [SD] age, 39.4 [1.3] weeks; 28 575 male [50.8%]; 20 484 white, non-Hispanic [36.4%]). In a comparison of the baseline period with the EOS calculator period, blood culture use decreased from 14.5% to 4.9% (adjusted difference, -7.7%; 95% CI, -13.1% to -2.4%). Empirical antibiotic administration in the first 24 hours decreased from 5.0% to 2.6% (adjusted difference, -1.8; 95% CI, -2.4% to -1.3%). No increase in antibiotic use occurred between 24 and 72 hours after birth; use decreased from 0.5% to 0.4% (adjusted difference, 0.0%; 95% CI, -0.1% to 0.2%). The incidence of culture-confirmed EOS was similar during the 3 periods (0.03% in the baseline period, 0.03% in the learning period, and 0.02% in the EOS calculator period). Readmissions for EOS (within 7 days of birth) were rare in all periods (5.2 per 100 000 births in the baseline period, 1.9 per 100 000 births in the learning period, and 5.3 per 100 000 births in the EOS calculator period) and did not differ statistically (P = .70). Incidence of adverse clinical outcomes, including need for inotropes, mechanical ventilation, meningitis, and death, was unchanged after introduction of the EOS calculator. Clinical care algorithms based on individual infant estimates of EOS risk derived from a multivariable risk prediction model reduced the proportion of newborns undergoing laboratory testing and receiving empirical antibiotic treatment without apparent adverse effects.

Authors: Kuzniewicz MW; Puopolo KM; Fischer A; Walsh EM; Li S; Newman TB; Kipnis P; Escobar GJ

JAMA Pediatr. 2017 Apr 01;171(4):365-371.

PubMed abstract

Cardiometabolic Risk Factors Among 1.3 Million Adults With Overweight or Obesity, but Not Diabetes, in 10 Geographically Diverse Regions of the United States, 2012-2013

Various phenotypes of overweight and obesity pose various health risks. The objective of this study was to determine the prevalence of 4 commonly measured cardiometabolic risk factors (CRFs) among adults with overweight or obesity, but not diabetes, at the time of the study. We analyzed data for 1,294,174 adults (aged ≥20 y) who were members of one of 4 integrated health systems. Each cohort member had a body mass index in 2012 or 2013 that indicated overweight or obesity. We determined the presence of 4 CRFs within 1 year of the first BMI measurement: elevated blood pressure (systolic ≥130 mm Hg or diastolic >85 mm Hg or ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] diagnosis code 401.0-405.9); elevated triglycerides (≥150 mg/dL or ICD-9-CM 272.1); low high-density lipoprotein cholesterol (<40 mg/dL for men or <50 mg/dL for women or ICD-9-CM 272.5); and prediabetes (fasting glucose 100-125 mg/dL or HbA1c 5.7%-6.4% or ICD-9-CM 790.2x). We tested the risk of having 1 or more CRFs after adjusting for obesity class and demographic characteristics with multivariable logistic regression. Among participants with overweight (52.5% of the sample), 18.6% had none of the 4 CRFs. Among the 47.5% of participants with obesity, 9.6% had none; among participants with morbid obesity, 5.8% had none. Age was strongly associated with CRFs in multivariable analysis. Almost 10% of participants with obesity had no CRFs. Overweight or obesity increases cardiometabolic risk, but the number and type of CRFs varied substantially by age, even among participants with morbid obesity.

Authors: Nichols GA; Horberg M; Koebnick C; Young DR; Waitzfelder B; Sherwood NE; Daley MF; Ferrara A

Prev Chronic Dis. 2017 Mar 09;14:E22. Epub 2017-03-09.

PubMed abstract

Over-the-Counter Access to Oral Contraceptives for Adolescents

Oral contraceptives (OCs) are used by millions of women in the U.S. The requirement to obtain OCs by prescription from a clinician may serve as a barrier to contraceptive initiation and continuation for women, in particular adolescents. Over-the-counter (OTC) availability would reduce this barrier and could further reduce unintended pregnancy rates. This review explores the scientific issues and regulatory processes involved in switching OCs to OTC status for minor adolescents. We review: (1) the regulatory criteria for switching a drug to OTC status; (2) risk of pregnancy and safety during use of OCs including combined oral contraceptives and progestin-only pills for adolescents; (3) the ability of adolescents to use OCs consistently and correctly; (4) OTC access to OCs and potential effect on sexual risk behaviors; and (5) the potential for reduced opportunities for clinicians to counsel and provide recommended reproductive health care to adolescents. We find strong scientific rationale for including adolescents in any regulatory change to switch OCs to OTC status. OCs are safe and highly effective among adolescents; contraindications are rarer among adolescents compared to adult women. Ready access to OCs, condoms, and emergency contraception increases their use without increasing sexual risk behaviors.

Authors: Upadhya KK; Santelli JS; Raine-Bennett TR; Kottke MJ; Grossman D

J Adolesc Health. 2017 Mar 06.

PubMed abstract

A Clinical Prediction Rule for Rebound Hyperbilirubinemia Following Inpatient Phototherapy

The American Academy of Pediatrics provides little guidance on when to discontinue phototherapy in newborns treated for hyperbilirubinemia. We sought to develop a prediction rule to estimate the probability of rebound hyperbilirubinemia after inpatient phototherapy. Subjects for this retrospective cohort study were infants born in 2012 to 2014 at ≥35 weeks’ gestation at 16 Kaiser Permanente Northern California hospitals who received inpatient phototherapy before age 14 days. We defined rebound as the return of total serum bilirubin (TSB) to phototherapy threshold within 72 hours of phototherapy termination. We used stepwise logistic regression to select predictors of rebound hyperbilirubinemia and devised and validated a prediction score by using split sample validation. Of the 7048 infants treated with inpatient phototherapy, 4.6% had rebound hyperbilirubinemia. Our prediction score consisted of 3 variables: gestational age <38 weeks (adjusted odds ratio [aOR] 4.7; 95% confidence interval [CI], 3.0-7.3), younger age at phototherapy initiation (aOR 0.51 per day; 95% CI, 0.38-0.68), and TSB relative to the treatment threshold at phototherapy termination (aOR 1.5 per mg/dL; 95% CI, 1.4-1.7). The model performed well with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.86-0.91) in the derivation data set and 0.88 (95% CI, 0.86-0.90) in the validation data set. Approximately 70% of infants had scores <20, which correspond to a <4% probability of rebound hyperbilirubinemia. The risk of rebound hyperbilirubinemia can be quantified according to an infant's gestational age, age at phototherapy initiation, and TSB relative to the treatment threshold at phototherapy termination.

Authors: Chang PW; Kuzniewicz MW; McCulloch CE; Newman TB

Pediatrics. 2017 Mar;139(3). Epub 2017-02-14.

PubMed abstract

Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are neurodevelopmental toxicants, but few studies have examined associations with autism spectrum disorder (ASD). We aimed to determine whether prenatal exposure to PCBs and OCPs influences offspring risk of ASD and intellectual disability without autism (ID). We conducted a population-based case-control study among Southern California births, including children with ASD (n = 545) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV-TR) criteria and ID (n = 181), as well as general population (GP) controls (n = 418). Concentrations of 11 PCB congeners and 2 OCPs measured in banked second-trimester serum samples were compared between the diagnostic groups. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses. Geometric mean levels of several PCB congeners were higher in the ASD group than in the ID and GP groups. ASD risk was elevated for a number of PCB congeners, particularly for the highest vs. lowest quartile of PCB138/158 (AOR = 1.79; 95% CI: 1.10, 2.71) and PCB153 (AOR = 1.82; 95% CI: 1.10, 3.02), and for highest deciles of other congeners in secondary analyses. PCB138/158 was also associated with increased ID (AOR = 2.41; 95% CI: 1.18, 4.91), though no trend was suggested. OCPs were not associated with increased risk of ASD in primary analyses, whereas nonmonotonic increases in risk of ID were found with p,p´-DDE. Our results suggest higher levels of some organochlorine compounds during pregnancy are associated with ASD and ID. Citation: Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M, Windham GC. 2017. Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal mid-pregnancy serum samples: association with autism spectrum disorder and intellectual disability. Environ Health Perspect 125:474-480;

Authors: Lyall K; Croen LA; Sjödin A; Yoshida CK; Zerbo O; Kharrazi M; Windham GC

Environ Health Perspect. 2017 Mar;125(3):474-480. Epub 2016-08-23.

PubMed abstract

Parents’ Perspectives on How to Improve the Childhood Vaccination Process

Few national studies have asked parents how to improve the childhood vaccination process. We surveyed a nationally representative online panel of parents on how to improve this process, rationales for nonstandard approaches, and alternatives to the standard schedule. Twelve percent of the 1222 respondents reported using nonstandard approaches: 3.2% used a specific schedule, 6.0% had no specific schedule, and 2.5% declined all vaccinations. The most common rationales were that too many vaccines are given at once, and discomfort with vaccine ingredients. Regarding how to improve the process, parents using the standard schedule most often said nothing could be improved (51%), or better vaccine information (22%). Those using nonstandard approaches most often would have liked more choice (40%) or better vaccine information (26%). Parents’ experiences with the vaccination process could be improved by offering information prior to visits, giving more information about side effects, and allowing more flexibility about vaccine scheduling.

Authors: Lieu TA; Zikmund-Fisher BJ; Chou C; Ray GT; Wittenberg E

Clin Pediatr (Phila). 2017 Mar;56(3):238-246. Epub 2016-07-20.

PubMed abstract

Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants

Maternal exposure to environmental pollutants could affect fetal brain development and increase autism spectrum disorder (ASD) risk in conjunction with differential genetic susceptibility. Organohalogen congeners measured in maternal midpregnancy blood samples have recently shown significant, but negative associations with offspring ASD outcome. We report the first large-scale maternal and fetal genetic study of the midpregnancy serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children collected in California by the Early Markers for Autism (EMA) Project. Levels of PCB (polychlorinated biphenyl) and PBDE (polybrominated diphenyl ether) congeners showed high maternal and fetal estimated SNP-based heritability (h2g) accounting for 39-99% of the total variance. Genome-wide association analyses identified significant maternal loci for p,p’-DDE (P = 7.8 × 10-11) in the CYP2B6 gene and for BDE-28 (P = 3.2 × 10-8) near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism. Fetal genetic loci contributed to the levels of BDE-100 (P = 4.6 × 10-8) and PCB187 (P = 2.8 × 10-8), near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment. Negative associations were observed for BDE-100, BDE153, and the sum of PBDEs with ASD, partly explained by genome-wide additive genetic effects that predicted PBDE levels. Our results support genetic control of midgestational biomarkers for environmental exposures by nonoverlapping maternal and fetal genetic determinants, suggesting that future studies of environmental risk factors should take genetic variation into consideration. The independent influence of fetal genetics supports previous hypotheses that fetal genotypes expressed in placenta can influence maternal physiology and the transplacental transfer of organohalogens.

Authors: Traglia M; Croen LA; Lyall K; Windham GC; Kharrazi M; DeLorenze GN; Torres AR; Weiss LA

G3 (Bethesda). 2017 Feb 24.

PubMed abstract

Moderate intensity sports and exercise is associated with glycaemic control in women with gestational diabetes

To assess the association of regular, unsupervised sports and exercise during pregnancy, by intensity level, with glycaemic control in women with gestational diabetes (GDM). Prospective cohort study of 971 women who, shortly after being diagnosed with GDM, completed a Pregnancy Physical Activity Questionnaire assessing moderate and vigorous intensity sports and exercise in the past 3 months. Self-monitored capillary glucose values were obtained for the 6-week period following the questionnaire, with optimal glycaemic control defined≥80% values meeting the targets<5.3mmol/L for fasting and <7.8mmol/L 1-hour after meals. Logistic regression estimated the odds of achieving optimal control; linear regression estimated activity level-specific least square mean glucose, as well as between-level mean glucose differences. For volume of moderate intensity sports and exercise ([MET×hours]/week), the highest quartile, compared to the lowest, had significantly increased odds of optimal control (OR=1.82 [95% CI: 1.06-3.14] P=0.03). There were significant trends for decreasing mean 1-hour post breakfast, lunch and dinner glycaemia with increasing quartile of moderate activity (all P<0.05). Any participation in vigorous intensity sports and exercise was associated with decreased mean 1-hour post breakfast and lunch glycaemia (both P<0.05). No associations were observed for fasting. Higher volumes of moderate intensity sports and exercise, reported shortly after GDM diagnosis, were significantly associated with increased odds of achieving glycaemic control. Clinicians should be aware that unsupervised moderate intensity sports and exercise performed in mid-pregnancy aids in subsequent glycaemic control among women with GDM.

Authors: Ehrlich SF; Hedderson MM; Brown SD; Sternfeld B; Chasan-Taber L; Feng J; Adams J; Ching J; Crites Y; Quesenberry CP; Ferrara A

Diabetes Metab. 2017 Feb 23.

PubMed abstract

The impact of preterm birth <37 weeks on parents and families: a cross-sectional study in the 2 years after discharge from the neonatal intensive care unit

Little is known about the quality of life of parents and families of preterm infants after discharge from the neonatal intensive care unit (NICU). Our aims were (1) to describe the impact of preterm birth on parents and families and (2) and to identify potentially modifiable determinants of parent and family impact. We surveyed 196 parents of preterm infants <24 months corrected age in 3 specialty clinics (82% response rate). Primary outcomes were: (1) the Impact on Family Scale total score; and (2) the Infant Toddler Quality of Life parent emotion and (3) time limitations scores. Potentially modifiable factors were use of community-based services, financial burdens, and health-related social problems. We estimated associations of potentially modifiable factors with outcomes, adjusting for socio-demographic and infant characteristics using linear regression. Median (inter-quartile range) infant gestational age was 28 (26-31) weeks. Higher Impact on Family scores (indicating worse effects on family functioning) were associated with taking ≥3 unpaid hours/week off from work, increased debt, financial worry, unsafe home environment and social isolation. Lower parent emotion scores (indicating greater impact on the parent) were also associated with social isolation and unpaid time off from work. Lower parent time limitations scores were associated with social isolation, unpaid time off from work, financial worry, and an unsafe home environment. In contrast, higher parent time limitations scores (indicating less impact) were associated with enrollment in early intervention and Medicaid. Interventions to reduce social isolation, lessen financial burden, improve home safety, and increase enrollment in early intervention and Medicaid all have the potential to lessen the impact of preterm birth on parents and families.

Authors: Lakshmanan A; Agni M; Lieu T; Fleegler E; Kipke M; Friedlich PS; McCormick MC; Belfort MB

Health Qual Life Outcomes. 2017 Feb 16;15(1):38. Epub 2017-02-16.

PubMed abstract

Trends and racial and ethnic disparities in the prevalence of pregestational type 1 and type 2 diabetes in Northern California: 1996-2014

Despite concern for adverse perinatal outcomes in women with diabetes mellitus before pregnancy, recent data on the prevalence of pregestational type 1 and type 2 diabetes mellitus in the United States are lacking. The purpose of this study was to estimate changes in the prevalence of overall pregestational diabetes mellitus (all types) and pregestational type 1 and type 2 diabetes mellitus and to estimate whether changes varied by race-ethnicity from 1996-2014. We conducted a cohort study among 655,428 pregnancies at a Northern California integrated health delivery system from 1996-2014. Logistic regression analyses provided estimates of prevalence and trends. The age-adjusted prevalence (per 100 deliveries) of overall pregestational diabetes mellitus increased from 1996-1999 to 2012-2014 (from 0.58 [95% confidence interval, 0.54-0.63] to 1.06 [95% confidence interval, 1.00-1.12]; Ptrend <.0001). Significant increases occurred in all racial-ethnic groups; the largest relative increase was among Hispanic women (121.8% [95% confidence interval, 84.4-166.7]); the smallest relative increase was among non-Hispanic white women (49.6% [95% confidence interval, 27.5-75.4]). The age-adjusted prevalence of pregestational type 1 and type 2 diabetes mellitus increased from 0.14 (95% confidence interval, 0.12-0.16) to 0.23 (95% confidence interval, 0.21-0.27; Ptrend <.0001) and from 0.42 (95% confidence interval, 0.38-0.46) to 0.78 (95% confidence interval, 0.73-0.83; Ptrend <.0001), respectively. The greatest relative increase in the prevalence of type 1 diabetes mellitus was in non-Hispanic white women (118.4% [95% confidence interval, 70.0-180.5]), who had the lowest increases in the prevalence of type 2 diabetes mellitus (13.6% [95% confidence interval, -8.0 to 40.1]). The greatest relative increase in the prevalence of type 2 diabetes mellitus was in Hispanic women (125.2% [95% confidence interval, 84.8-174.4]), followed by African American women (102.0% [95% confidence interval, 38.3-194.3]) and Asian women (93.3% [95% confidence interval, 48.9-150.9]). The prevalence of overall pregestational diabetes mellitus and pregestational type 1 and type 2 diabetes mellitus increased from 1996-1999 to 2012-2014 and racial-ethnic disparities were observed, possibly because of differing prevalence of maternal obesity. Targeted prevention efforts, preconception care, and disease management strategies are needed to reduce the burden of diabetes mellitus and its sequelae.

Authors: Peng TY; Ehrlich SF; Crites Y; Kitzmiller JL; Kuzniewicz MW; Hedderson MM; Ferrara A

Am J Obstet Gynecol. 2017 Feb;216(2):177.e1-177.e8. Epub 2016-10-15.

PubMed abstract

The impact of high apparent temperature on spontaneous preterm delivery: a case-crossover study

The impact of high apparent temperature on spontaneous preterm delivery: a case-crossover studyBACKGROUND: Despite the prediction that temperatures are expected to increase in the future, little is known about the health effects of increasing temperatures on pregnant women. The objective of this study was to investigate the impact of apparent temperature on spontaneous preterm delivery (PTD).METHODS: A case-crossover study of 14,466 singleton spontaneous preterm deliveries occurring between January 1, 1995 and December 31, 2009 among Kaiser Permanente Northern California (KPNC) members was conducted. Preterm deliveries were identified through KPNC’s Electronic Health Records (EHR) data. Data on gestational age at delivery, infant sex, and maternal address were also extracted from KPNC’s EHR and linked to meteorologic and air pollution monitoring data based on residential zip code.RESULTS: An 11.6% (95% CI: 4.1, 19.7) increase in spontaneous PTD was associated with a 10 °F (5.6 °C) increase in weekly average (lag06) apparent temperature, during the warm season. During the cold season, increases in apparent temperature did not significantly impact the overall effect of spontaneous PTD (6.2%, (95% CI: -3.0, 16.2) per 10 °F (5.6 °C) increase in weekly average (lag06) apparent temperature). Significant differences in the relationship between apparent temperature and spontaneous PTD emerged for region, gestational age and infant sex, during the cold season. No significant differences emerged for air pollutants.CONCLUSIONS: Our findings provide evidence for an increase in the odds of spontaneous PTD associated with increases in apparent temperature, especially during the warm season.

Authors: Avalos LA; Chen H; Li DK; Basu R

Environ Health. 2017 Feb 01;16(1):5. Epub 2017-02-01.

PubMed abstract

Newborn Weight Loss During Birth Hospitalization and Breastfeeding Outcomes Through Age 1 Month

Weight loss is universal for exclusively breastfed newborns in the first few days after birth. Many newborns exclusively breastfed during birth hospitalization receive formula in the first month after discharge and thus cease exclusive breastfeeding. However, the relationship between early weight loss and subsequent cessation of breastfeeding and exclusive breastfeeding is unknown. Research aim: This study aimed to determine the relationship between newborn weight loss and duration and exclusivity of breastfeeding among newborns breastfed exclusively during the birth hospitalization. Retrospective cohort study at Kaiser Permanente Northern California hospitals between 2009 and 2013. The main predictor variable was weight loss during birth hospitalization. The main outcomes were cessation of breastfeeding and cessation of exclusive breastfeeding in the first 25 days after discharge. Among our sample, 83,344 were exclusively breastfed during birth hospitalization. At 25 days after discharge, 15.6%, 95% confidence interval (CI) [14.6%, 16.6%], of those delivered vaginally and 17.6%, 95% CI [14.5%, 20.6%], of those delivered by cesarean section were estimated to have completely ceased breastfeeding; 57.0%, 95% CI [55.5%, 58.4%], and 57.9%, 95% CI [53.6%, 61.8%], respectively, had ceased exclusive breastfeeding. Survival curves depicting rates of breastfeeding cessation through 1 month did not differ by degree of weight loss or by weight loss trajectory. However, curves depicting rates of exclusive breastfeeding demonstrated significantly more formula use among those with more weight loss at discharge. Among those exclusively breastfed during birth hospitalization, weight loss nomograms may help identify newborns at higher risk of cessation of exclusive breastfeeding. Lactation support targeted to those with exacerbated weight loss trajectories may improve duration of exclusive breastfeeding.

Authors: Flaherman VJ; Schaefer EW; Kuzniewicz MK; Li S; Walsh E; Paul IM

J Hum Lact. 2017 Feb;33(1):225-230. Epub 2017-01-20.

PubMed abstract

Patient perceptions of a decision support tool to assist with young women’s contraceptive choice

Contraceptive decision support tools (DSTs) have been suggested as a way to provide patient-centered contraceptive care, but little is known about the role they play in women’s decision-making. The aim of this study is to understand patients’ perceptions of the value of a contraceptive DST. We conducted 21 semi-structured interviews with unmarried women aged 18-29 from an integrated health care system who viewed the DST. Thematic analysis was conducted to identify common themes in the participants’ experience. Four themes were identified: Informative; Narrowing down options; Tool vs. doctor; and Preparation for a clinical visit. In general, participants felt the tool was valuable because it provided them relevant information and facilitated their decision-making process by narrowing down contraceptive options. Participants felt the tool could prepare them for a visit with their health care provider by helping them identify questions for their provider, but also saw distinctions between the DST and what their provider could offer. Contraceptive DSTs are valuable to their users when they include information on contraceptive attributes women deem important and allow for user-driven tailoring. Contraceptive DSTs may address patient informational needs and can serve as a complement to provider counseling.

Authors: Marshall C; Nuru-Jeter A; Guendelman S; Mauldon J; Raine-Bennett T

Patient Educ Couns. 2017 Feb;100(2):343-348. Epub 2016-08-24.

PubMed abstract

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

Authors: Jones KL; Croen LA; Yoshida CK; Heuer L; Hansen R; Zerbo O; DeLorenze GN; Kharrazi M; Yolken R; Ashwood P; Van de Water J

Mol Psychiatry. 2017 Feb;22(2):273-279. Epub 2016-05-24.

PubMed abstract

The impact of maternal factors on the association between temperature and preterm delivery

Few studies have examined maternal modifiers of temperature and adverse birth outcomes because of lack of data. We assessed the relationship between apparent temperature, preterm delivery (PTD) and maternal demographics, medical and mental health conditions, and behaviors. A time-stratified case-crossover analysis was conducted using 14,466 women who had a PTD (20 to less than 37 gestational weeks) from 1995 to 2009 using medical records from a large health maintenance organization in Northern California. Effect modifiers considered by stratification included several maternal factors: age, race/ethnicity, depression, hypertension, diabetes, smoking, alcohol use, pre-pregnancy body mass index, and Medicaid status. Apparent temperature data for women who had a monitor located within 20km of their residential zip codes were included. All analyses were stratified by warm (May 1 through October 31) and cold (November 1 through April 30) seasons. For every 10 F (5.6 C) increase in average cumulative weekly apparent temperature (lag06), a greater risk was observed for births occurring during the warm season (11.63%; 95% CI: 4.08, 19.72%) compared to the cold season (6.18%; -2.96, 16.18%), especially for mothers who were younger, Black, Hispanic, underweight, smoked or consumed alcohol during pregnancy, or had pre-existing /gestational hypertension, diabetes, or pre-eclampsia. Our findings suggest that warmer apparent temperatures exacerbate the risk of PTD, particularly for subgroups of more vulnerable women.

Authors: Basu R; Chen H; Li DK; Avalos LA

Environ Res. 2017 Jan 02;154:109-114. Epub 2017-01-02.

PubMed abstract

Urine bisphenol A and pubertal development in boys

Bisphenol A (BPA) is an environmental endocrine disruptor and is found in many consumer products. Animal studies suggest that BPA may perturb pubertal development in males, although studies in humans are limited. This study investigated the association between BPA exposure and pubertal onset and progression among school-aged boys in Shanghai, China. A total of 671 boys aged 9-18 years from three schools (one elementary, one middle, and one high school) in Shanghai were enrolled in a cross-sectional study. Tanner stages for genital and pubic hair development and testicular volume were assessed by a specifically trained physician. Information concerning spermarche was self-reported. Urine samples were collected to examine peripubertal BPA exposure levels. Associations between BPA exposure and pubertal development, as indicated by the presence of different milestones in early puberty, mid-puberty and late puberty, were assessed using Poisson multivariate regression to derive adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs). Earlier onset of genital and pubic hair development was observed in boys with moderate BPA exposure compared with those exposed to the least BPA; the adjusted PRs were 1.31 (95%CI:1.03, 1.68) and 1.28 (95%CI:1.02, 1.60) for onset of genital maturation and pubic hair development, respectively. A similar trend was seen for onset of testicular development, although the association was not statistically significant. Conversely, compared with the lowest level of BPA exposure, moderate BPA exposure was associated with delayed presence of the late stage of genital development, with an adjusted PR of 0.78 (95%CI: 0.65, 0.92). A suggestive inverse association was also observed between BPA exposure and late progression of testicular development. Our findings indicate an association between peripubertal BPA exposure and earlier pubertal onset, but delayed pubertal progression, in boys. Longitudinal studies of male pubertal development with periodic follow-up are needed to verify these results.

Authors: Wang Z; Li D; Miao M; Liang H; Chen J; Zhou Z; Wu C; Yuan W

Int J Hyg Environ Health. 2017 Jan;220(1):43-50. Epub 2016-10-15.

PubMed abstract

Risk of Type 2 Diabetes Mellitus following Gestational Diabetes Pregnancy in Women with Polycystic Ovary Syndrome

This study examines gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) and the risk of type 2 diabetes mellitus (DM) following GDM pregnancy. A cohort of 988 pregnant women with PCOS who delivered during 2002-2005 was examined to determine the prevalence and predictors of GDM, with follow-up through 2010 among those with GDM to estimate the risk of DM. Of the 988 pregnant women with PCOS, 192 (19%) developed GDM. Multivariable predictors of GDM included older age, Asian race, prepregnancy obesity, family history of DM, preconception metformin use, and multiple gestation. Among women with PCOS and GDM pregnancy, the incidence of DM was 2.8 (95% confidence interval (CI) 1.9-4.2) per 100 person-years and substantially higher for those who received pharmacologic treatment for GDM (6.6 versus 1.5 per 100 person-years, p < 0.01). The multivariable adjusted risk of DM was fourfold higher in women who received pharmacologic treatment for GDM (adjusted hazard ratio 4.1, 95% CI 1.8-9.6). The five-year incidence of DM was 13.1% overall and also higher in the pharmacologic treatment subgroup (27.0% versus 7.1%, p < 0.01). The strongest predictors of GDM among women with PCOS included Asian race and prepregnancy obesity. Pharmacologic treatment of GDM is associated with fourfold higher risk of subsequent DM.

Authors: Lo JC; Yang J; Gunderson EP; Hararah MK; Gonzalez JR; Ferrara A

J Diabetes Res. 2017;2017:5250162. Epub 2017-12-20.

PubMed abstract

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality.

Authors: Zheng H; Zhou X; Li DK; Yang F; Pan H; Li T; Miao M; Li R; Yuan W

PLoS ONE. 2017;12(6):e0178535. Epub 2017-06-05.

PubMed abstract

A Survey of Parents with Children on the Autism Spectrum: Experience with Services and Treatments

Autism spectrum disorders (ASD) are lifelong neurodevelopmental disorders, and little is known about how parents address the health and psychosocial consequences of ASD. Few studies have examined use of various treatments and services in a large, diverse sample of children with ASD and their families. This paper presents methods to create an autism research resource across multiple large health delivery systems and describes services and treatments used by children with ASD and their families. Four study sites conducted a Web survey of parents of children and adolescents with ASD who were members of Kaiser Permanente. We tabulated data distributions of survey responses and calculated χ2 statistics for differences between responders and nonresponders. The children of the 1155 respondents were racially and ethnically diverse (55% white, 6% black, 5% Asian, 9% multiracial, 24% Hispanic) and representative of the total population invited to participate with respect to child sex (83% male), child age (57% < 10 years), and ASD diagnosis (64% autistic disorder). The most frequently used services and treatments were Individualized Education Programs (85%), family physician visits (78%), and occupational and speech therapy (55% and 60%, respectively). Home-based programs frequently included implementation of social skills training (44%) and behavior management (42%). Prescription medication use was high (48%). Caregivers reported disruption of personal and family routines because of problem behaviors. These survey data help to elucidate parents' experiences with health services for their children with ASD and serve as a potential resource for future research.

Authors: Becerra TA; Massolo ML; Yau VM; Owen-Smith AA; Lynch FL; Crawford PM; Pearson KA; Pomichowski ME; Quinn VP; Yoshida CK; Croen LA

Perm J. 2017;21.

PubMed abstract

Perceived psychosocial stress and gestational weight gain among women with gestational diabetes

Growing evidence links perceived stress-a potentially modifiable psychosocial risk factor-with health behaviors and obesity. Yet little is known about the relationship between stress during pregnancy and gestational weight gain, particularly among women with pregnancy complications. We conducted a cross-sectional analysis to examine associations between psychosocial stress during pregnancy and gestational weight gain among women with gestational diabetes. We used baseline data from the Gestational Diabetes’s Effects on Moms (GEM) study: 1,353 women with gestational diabetes who delivered a term singleton within Kaiser Permanente Northern California were included. Perceived stress near the time of gestational diabetes diagnosis was measured using the validated Perceived Stress Scale (PSS10). Gestational weight gain was categorized according to the 2009 Institute of Medicine recommendations. Binomial regression analyses adjusted for gestational age and maternal age at the time of gestational diabetes diagnosis, and race/ethnicity and estimated rate ratios (RR) and their 95% confidence interval (CI). Among women with a normal pregravid Body Mass Index (BMI 18.5-24.9 kg/m2), there was a significant association between high (Q4) PSS score and risk of both exceeding and gaining below the Institute of Medicine recommendations compared to those with lower stress (Q1) [adjusted RR = 2.16 95% CI 1.45-3.21; RR = 1.39 95% CI 1.01-1.91, respectively.] Among women with pregravid overweight/obesity (BMI≥25 kg/m2), there was no association. Although the temporal relationship could not be established from this study, there may be a complex interplay between psychosocial stress and gestational weight gain among women with gestational diabetes. Further studies examining stress earlier in pregnancy, risk of developing gestational diabetes and excess/inadequate gestational weight gain are warranted to clarify these complex relationships.

Authors: Kubo A; Ferrara A; Brown SD; Ehrlich SF; Tsai AL; Quesenberry CP; Crites Y; Hedderson MM

PLoS ONE. 2017;12(3):e0174290. Epub 2017-03-28.

PubMed abstract

Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study

Autism spectrum disorder (ASD) affects more than 1% of children in the USA. The male-to-female prevalence ratio of roughly 4:1 in ASD is a well-recognized but poorly understood phenomenon. An explicit focus on potential etiologic pathways consistent with this sex difference, such as those involving prenatal androgen exposure, may help elucidate causes of ASD. Furthermore, the multi-threshold liability model suggests that the genetic mechanisms in females with ASD may be distinct and may modulate ASD risk in families with female ASD in the pedigree. We examined umbilical cord blood from 137 children in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is an ASD-enriched risk cohort with all children having an older sibling already diagnosed with ASD. Fetal testosterone (T), androstenedione (A4), and dehyroepiandrosterone (DHEA) levels were measured in cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Robust linear regression models were used to determine associations between cord blood androgen levels and 12-month Autism Observation Scales for Infants (AOSI) scores and 36-month Social Responsiveness Scale (SRS) scores adjusting for potential confounders. Increasing androgens were not associated with increasing 12-month AOSI score or 36-month total SRS score in either boys or girls. However, the association between T and autistic traits among subjects with a female older affected sibling was greater at 12 months (test of interaction, P = 0.008) and deficits in reciprocal social behavior at 36 months were also greater (test of interaction, P = 0.006) than in subjects whose older affected sibling was male. While increased prenatal testosterone levels were not associated with autistic traits at 12 or 36 months, our findings of a positive association in infants whose older ASD-affected siblings were female suggests an androgen-related mechanism that may be dependent on, or related to, genetic liability factors present more often in families containing female ASD cases. However, this initial finding, based on a small subgroup of our sample, should be interpreted with considerable caution.

Authors: Park BY; Lee BK; Burstyn I; Tabb LP; Keelan JA; Whitehouse AJO; Croen LA; Fallin MD; Hertz-Picciotto I; Montgomery O; Newschaffer CJ

Mol Autism. 2017;8:3. Epub 2017-01-31.

PubMed abstract

Psychotropic Medication Use among Insured Children with Autism Spectrum Disorder

This study examined psychotropic medication use among 7901 children aged 1-17 with autism spectrum disorder (ASD) in five health systems, comparing to matched cohorts with no ASD. Nearly half (48.5 %) of children with ASD received psychotropics in the year observed; the most common classes were stimulants, alpha-agonists, or atomoxetine (30.2 %), antipsychotics (20.5 %), and antidepressants (17.8 %). Psychotropic treatment was far more prevalent among children with ASD, as compared to children with no ASD (7.7 % overall), even within strata defined by the presence or absence of other psychiatric diagnoses. The widespread use of psychotropics we observed, particularly given weak evidence supporting the effectiveness of these medications for most children with ASD, highlights challenges in ASD treatment and the need for greater investment in its evaluation.

Authors: Madden JM; Lakoma MD; Lynch FL; Rusinak D; Owen-Smith AA; Coleman KJ; Quinn VP; Yau VM; Qian YX; Croen LA

J Autism Dev Disord. 2017 Jan;47(1):144-154.

PubMed abstract

Infection and antibiotic use in infancy and risk of childhood obesity: a longitudinal birth cohort study

Data from previous studies have suggested a possible association between antibiotic use in infancy and risk of childhood obesity, with implications for health-care delivery and obesity prevention strategies. However, whether the observed association was due to antibiotic use or underlying infection, or both, is unclear. We aimed to disentangle the effect of antibiotic use in infancy from that of underlying infection on the risk of childhood obesity. In this longitudinal birth cohort study, we included infants in the Kaiser Permanente Northern California population born between Jan 1, 1997, and March 31, 2013. We used electronic medical records to ascertain data for antibiotic use, infection diagnosis, and anthropometric measurements (and thus BMI and obesity status) from birth up to age 18 years. We used standard mixed-effects logistic regression for repeated measurements to analyse multiple BMI measurements per child (median five measurements) and to obtain odds ratios (ORs) and 95% CIs for obesity risk. We also did a substudy in 547 same-sex twin pairs with discordant exposure status to substantiate our findings. 260 556 individuals were included in our analysis. After controlling for maternal age, race or ethnic origin, pre-pregnancy BMI, preterm delivery, low birthweight, maternal antibiotic use, and infection during pregnancy, infection without antibiotic use in infancy was associated with an increased risk of childhood obesity compared with controls without infection (OR 1·25, 95% CI 1·20-1·29). A clear dose-response relation was seen between infection episodes and risk of childhood obesity (ptrend <0·0001). By contrast, compared with infants with untreated infection, antibiotic use during infancy was not associated with risk of childhood obesity (1·01, 0·98-1·04). Neither broad-spectrum nor narrow-spectrum antibiotics were associated with risk of childhood obesity. These findings were supported by the results of the twin set analysis. Infection, but not antibiotic use, during infancy is associated with risk of childhood obesity. This finding will need to be replicated in future studies. Although our results do not rule out a potential effect of antibiotics on microbiome composition and the use of antibiotics should always be judicious, they suggest that treatment of common infections with antibiotics in infancy is unlikely to be a main contributor to childhood obesity. Kaiser Permanente Center for Effectiveness & Safety Research.

Authors: Li DK; Chen H; Ferber J; Odouli R

Lancet Diabetes Endocrinol. 2017 Jan;5(1):18-25. Epub 2016-11-01.

PubMed abstract

The autism symptom interview, school-age: A brief telephone interview to identify autism spectrum disorders in 5-to-12-year-old children

This study reports on the initial validation of the Autism Symptom Interview (ASI), School-Age, a brief (15-20 min) phone interview derived from questions from the Autism Diagnostic Interview-Revised (ADI-R). The ASI, School-Age was administered by interviewers with minimal training to parents of children ages 5 to 12 who had all been previously identified with (or referred for assessment of) ASD or another neurodevelopmental disorder. Children then underwent a comprehensive assessment to determine a best-estimate clinical diagnosis of ASD (n = 159) or non-ASD (e.g. language disorder, intellectual disability, ADHD; n = 130). Clinicians who conducted the assessments were blind to ASI results. ROC analyses compared ASI scores to clinical diagnosis. Due to the small number of participants with non-ASD diagnoses who were classified as nonverbal (i.e. not yet using phrases on a daily basis), it was not possible to assess sensitivity and specificity of the nonverbal algorithm in this sample. The verbal algorithm yielded a sensitivity of 0.87 (95% CI = 0.81-0.92) and a specificity of 0.62 (95% CI = 0.53-0.70). When used in conjunction with the Autism Diagnostic Observation Schedule (ADOS), sensitivity and specificity were 0.82 (95% CI = 0.74-0.88) and 0.92 (95% CI = 0.86-0.96), respectively. Internal consistency and test-retest reliability were both excellent. Particularly for verbal school age children, the ASI may serve as a useful tool to more quickly ascertain or classify children with ASD for research or clinical triaging purposes. Additional data collection is underway to determine the utility of the ASI in children who are younger and/or nonverbal. Autism Res 2017, 10: 78-88. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Authors: Bishop SL; Huerta M; Gotham K; Alexandra Havdahl K; Pickles A; Duncan A; Hus Bal V; Croen L; Lord C

Autism Res. 2017 Jan;10(1):78-88. Epub 2016-06-10.

PubMed abstract

Placental genetic variations in vitamin D metabolism and birthweight

INTRODUCTION: Vitamin D has pleiotropic functions that regulate fetal growth and development. We investigated associations of common placental genetic variations in vitamin D metabolism with birthweight.

METHODS: The study was conducted among participants (506 maternal-infant pairs) of a pregnancy cohort study. Data were collected using interviewer-administered questionnaires and post-delivery medical record