Health Care for Autistic Children: A Public Health Perspective
Autism has been the subject of large-scale public health investment. These investments are increasingly shifting toward mitigating the lifelong disability and impairment associated with autism. Key efforts include bolstering screening schedules, accelerating the path to diagnosis and early entry into evidence-based therapies, and providing preventive management of common co-occurring conditions. Enhancing their implementation will necessitate addressing neurodiversity and health equity. Pediatric primary care teams continue to be important stewards in population-level initiatives to promote autistic health. To thrive in this role, these providers will benefit from specific educational and logistical supports from the health care system.
Authors: Ames, Jennifer L;Davignon, Meghan N;Hayes, Elizabeth A;Croen, Lisa A
Pediatr Clin North Am. 2024 Apr;71(2):111-125. Epub 2024-02-02.
Gestational thyroid hormones and autism-related traits in the EARLI and HOME studies
Thyroid hormones are essential for neurodevelopment. Few studies have considered associations with quantitatively measured autism spectrum disorder (ASD)-related traits, which may help elucidate associations for a broader population. Participants were drawn from two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI), enrolling pregnant women who already had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study, following pregnant women from the greater Cincinnati, OH area. Gestational thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in mid-pregnancy 16 (±3) weeks gestation serum samples. ASD-related traits were measured using the Social Responsiveness Scale (SRS) at ages 3-8 years. The association was examined using quantile regression, adjusting for maternal and sociodemographic factors. 278 participants (132 from EARLI, 146 from HOME) were included. TSH distributions were similar across cohorts, while FT4 levels were higher in EARLI compared to HOME. In pooled analyses, particularly for those in the highest SRS quantile (95th percentile), higher FT4 levels were associated with increasing SRS scores (β = 5.21, 95% CI = 0.93, 9.48), and higher TSH levels were associated with decreasing SRS scores (β = -6.94, 95% CI = -11.04, -2.83). The association between TSH and SRS remained significant in HOME for the 95% percentile of SRS scores (β = -6.48, 95% CI = -12.16, -0.80), but not EARLI. Results for FT4 were attenuated when examined in the individual cohorts. Our results add to evidence that gestational thyroid hormones may be associated with ASD-related outcomes by suggesting that relationships may differ across the distribution of ASD-related traits and by familial likelihood of ASD.
Authors: Zhong, Caichen;Croen, Lisa A;Lyall, Kristen;et al.
Autism Res. 2024 Apr;17(4):716-727. Epub 2024-03-04.
Barriers to Healthcare for Latinx Autistic Children and Adolescents
To understand the ways in which autistic Latinx children experience disparities in diagnosis, healthcare, and receipt of specialty services. 417 individuals who identified as Latinx caregivers of autistic children who were members of the same integrated healthcare system in Northern California were surveyed. Responses were analyzed using the child’s insurance coverage (Government or Commercial) and caregiver’s primary language (Spanish or English). Compared to the commercially-insured, government-insured participants accessed several services at a higher rate and were less likely to cite the high cost of co-pays as a barrier. There were no significant differences in service access by language status, but Spanish speakers were more likely to cite health literacy as a barrier to receiving care.
Authors: Grosvenor, Luke P;Cohen, Ryan J;Gordon, Nancy P;Massolo, Maria L;Cerros, Hilda J;Yoshida, Cathleen K;Ames, Jennifer L;Croen, Lisa A
J Autism Dev Disord. 2024 Jan 17.
Reproductive Health Care in Adolescents with Autism and Other Developmental Disabilities
Adults with developmental disabilities often have less access to reproductive health services than adults without these disabilities. However, little is known about how adolescents with developmental disabilities, including autism, access reproductive health care. We aimed to characterize the utilization of reproductive health care services among autistic adolescents and adolescents with other developmental disabilities in comparison with typically developing adolescents. We conducted a cohort study of a sample of adolescents who were continuously enrolled members of Kaiser Permanente Northern California, an integrated healthcare system, from ages 14 to 18. The final analytic sample included 700 autistic adolescents, 836 adolescents with other developmental disabilities, and 2187 typically developing adolescents who sought care between 2000 and 2017. Using electronic health records, we obtained information on menstrual conditions, use of obstetric/gynecological care, and prescriptions of hormonal contraception. We compared utilization between groups using chi-squared tests and covariate-adjusted risk ratios estimated with modified Poisson regression. Autistic adolescents and adolescents with other developmental disabilities were significantly more likely to have diagnoses of menstrual disorders, polycystic ovary syndrome, and premenstrual syndrome than typically developing adolescents. These two groups also were less likely than typically developing peers to visit the OB/GYN or to use any form of hormonal contraception, including oral contraception, hormonal implants, and intrauterine devices. Adolescents in all three groups accessed hormonal contraception most frequently through their primary care provider, followed by an OB/GYN provider. Autistic adolescents and adolescents with other developmental disabilities are less likely than their typically developing peers to visit the OB/GYN and use hormonal contraception, suggesting possible care disparities that may persist into adulthood. Efforts to improve access to reproductive healthcare in these populations should target care delivered in both pediatric and OB/GYN settings.
Authors: Ames, Jennifer L;Anderson, Meredith C;Cronbach, Emily;Lee, Catherine;Giwa Onaiwu, Morénike;Vallerie, Amy M;Croen, Lisa A
Am J Obstet Gynecol. 2024 Jan 11.
Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders
Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood. We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD (n = 311) and DDs (n = 1291) compared with children from the general population (n = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship. Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD. Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.
Authors: Croen, Lisa A;Ames, Jennifer L;Qian, Yinge;Alexeeff, Stacey;Ashwood, Paul;Gunderson, Erica P;Wu, Yvonne W;Boghossian, Andrew S;Yolken, Robert;Van de Water, Judy;Weiss, Lauren A
Biol Psychiatry Glob Open Sci. 2024 Jan;4(1):39-50. Epub 2023-10-11.
A mixture of urinary phthalate metabolite concentrations during pregnancy and offspring Social Responsiveness Scale (SRS) scores
Phthalates are a group of chemicals with ubiquitous exposure worldwide. Exposures to phthalates during pregnancy may play a role in autism spectrum disorder (ASD) etiology by disrupting hormone levels or directly impacting fetal neurodevelopment. However, there is little research quantifying the aggregate effect of phthalates on child ASD-related behaviors. We used data from two prospective pregnancy and birth cohorts-the Health Outcomes and Measures of the Environment (HOME) and the Early Autism Risk Longitudinal Investigation (EARLI). HOME is a general population cohort while participants in EARLI were at higher familial risk for ASD. Using quantile g-computation and linear regression models, we assessed the joint and individual associations of a mixture of six phthalate metabolites during pregnancy with child ASD-related traits measured by Social Responsiveness Scale (SRS) scores at ages 3-8 years. Our analyses included 271 participants from HOME and 166 participants from EARLI. There were imprecise associations between the phthalate mixture and SRS total raw scores in HOME (difference in SRS scores per decile increase in every phthalate = 1.3; 95% confidence interval [CI] = -0.2, 2.8) and EARLI (difference in SRS scores per decile increase in every phthalate = -0.9; 95% CI = -3.5, 1.7). The cohort-specific effect sizes of the pthalates-SRS associations were small and CIs were imprecise. These results suggest that if there are associations between phthalate metabolites during pregnancy and child SRS scores, they may differ across populations with different familial liabilities. Further studies with larger sample sizes are warranted.
Authors: Yu, Emma X;Braun, Joseph M;Lyall, Kristen;Hertz-Picciotto, Irva;Fallin, M Daniele;Croen, Lisa A;Chen, Aimin;Xu, Yingying;Yolton, Kimberly;Newschaffer, Craig J;Hamra, Ghassan B
Epidemiology. 2024 Jan 01;35(1):84-93. Epub 2023-10-11.
Mixture of air pollution, brominated flame retardants, polychlorinated biphenyls, per- and polyfluoroalkyl substances, and organochlorine pesticides in relation to vitamin D concentrations in pregnancy
Over two-thirds of pregnant women in the U.S. have insufficient 25(OH)D (Vitamin D) concentrations, which can adversely impact fetal health. Several pollutants have been associated with 25(OH)D, but have not been considered in the context of chemical co-exposures. We aimed to determine associations between a broad mixture of prenatal environmental chemical exposures and 25(OH)D concentrations in mid-pregnancy. Stored mid-pregnancy serum samples were assayed from 421 women delivering live births in Southern California in 2000-2003. 25(OH)D, six BFRs, eleven polychlorinated biphenyls (PCBs), six per- and polyfluoroalkyl substances, and two organochlorine pesticides were detected in ≥60% of specimens. Gestational exposures to airborne particulate matter ≤ 10 μm (PM10) and ≤ 2.5 μm (PM2.5), nitrogen monoxide (NO), nitrogen dioxide (NO2), and ozone concentrations were derived from monitoring station data. Bayesian Hierarchical Modeling (BHM) and Bayesian Kernel Machine Regression (BKMR) analyses estimated overall mixture and individual chemical associations accounting for co-exposures and covariates with mean 25(OH)D levels, and BHM was used to estimate associations with insufficient (<75 nMol/L) 25(OH)D levels. Non-mixture associations for each chemical were estimated with linear and logistic models. PM10 [BHM estimate: -0.133 nmol/l 95% Credible Interval (-0.240, -0.026)] was associated with lower 25(OH)D in BHM and BKMR. Higher quantiles of combined exposures were associated with lower 25(OH)D, though with wide credible intervals. In non-mixture models, PM10, PM2.5, NO, and NO2 were associated with lower concentrations, while O3 and PBDE153 were associated with higher 25(OH)D and/or lower insufficiency. While some chemicals were associated with increased and others with decreased 25(OH)D concentrations, the overall mixture was associated with lower concentrations. Mixture analyses differed from non-mixture regressions, highlighting the importance of mixtures approaches for estimating real-world associations.
Authors: Berger, Kimberly;Ames, Jenn;Croen, Lisa A;Pearl, Michelle;et al.
Environ Pollut. 2024 Jan 01;340(Pt 2):122808. Epub 2023-11-03.
Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program
Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results. We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex. We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as log2-transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex. Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in >85% of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling=1.07; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect=1.25; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age z-scores (β for detect vs. nondetect=0.04-0.07); other chemicals showed null associations. In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.
Authors: Oh, Jiwon;Ames, Jennifer L;Croen, Lisa A;Ferrara, Assiamira;Zhu, Yeyi;program collaborators for Environmental influences on Child Health Outcomes,;et al.
Environ Health Perspect. 2024 Jan;132(1):17004. Epub 2024-01-24.
Association between maternal prenatal cannabis use and missed child preventive care visits in an integrated health care delivery system in Northern California
The periodicity of well-child visits recommended by the American Academy of Pediatrics emphasizes the importance of continuity of care in health management. Exposure to cannabis in utero has been associated with adverse development, and adherence to well-child visits is critical for earlier detection and intervention. To assess whether maternal prenatal cannabis use was associated with missed well-child visits in the first three years after birth we conducted a longitudinal cohort study in Kaiser Permanente Northern California of pregnant individuals and their children born between January 1, 2011 and December 31, 2018. Maternal prenatal cannabis use was defined as any self-reported cannabis use since becoming pregnant and/or a positive urine toxicology test for cannabis during pregnancy. Well-child visits were defined as an encounter for a well-child visit or physical exam and categorized into seven time periods from birth to 36 months. Modified Poisson regression models were conducted. Of the 168,589 eligible pregnancies, 3.4% screened positive for maternal prenatal cannabis use. Compared to no use, maternal prenatal cannabis use was associated with more missed well-child visits at every time period; (missed 12-month visit: adjusted relative risk (aRR): 1.43, 95%CI: 1.32-1.54; missed 3-year visit: aRR: 1.15, 95%CI: 1.11-1.20). Maternal prenatal cannabis use was also associated with missing two or more well-child visits through 36 months of age (35.8% among cannabis users vs. 23.0% among non-users, Χ2p < .001). Educating pregnant individuals who use cannabis on the importance of well-child visits may benefit children's health and development.
Authors: Avalos, Lyndsay A;Oberman, Nina;Alexeeff, Stacey E;Croen, Lisa A;Adams, Sara R;Davignon, Meghan;Young-Wolff, Kelly C
Prev Med. 2023 Oct;175:107716. Epub 2023-09-28.
Latent Class Analysis of Prenatal Substance Exposure and Child Behavioral Outcomes
To predict behavioral disruptions in middle childhood, we identified latent classes of prenatal substance use. As part of the Environmental influences on Child Health Outcomes Program, we harmonized prenatal substance use data and child behavior outcomes from 2195 women and their 6- to 11-year-old children across 10 cohorts in the US and used latent class-adjusted regression models to predict parent-rated child behavior. Three latent classes fit the data: low use (90.5%; n = 1986), primarily using no substances; licit use (6.6%; n = 145), mainly using nicotine with a moderate likelihood of using alcohol and marijuana; and illicit use (2.9%; n = 64), predominantly using illicit substances along with a moderate likelihood of using licit substances. Children exposed to primarily licit substances in utero had greater levels of externalizing behavior than children exposed to low or no substances (P = .001, d = .64). Children exposed to illicit substances in utero showed small but significant elevations in internalizing behavior than children exposed to low or no substances (P < .001, d = .16). The differences in prenatal polysubstance use may increase risk for specific childhood problem behaviors; however, child outcomes appeared comparably adverse for both licit and illicit polysubstance exposure. We highlight the need for similar multicohort, large-scale studies to examine childhood outcomes based on prenatal substance use profiles.
Authors: Maylott, Sarah E;Aschner, Judy;Avalos, Lyndsay A;program collaborators for Environmental influences on Child Health Outcomes (ECHO),;et al.
J Pediatr. 2023 Sep;260:113468. Epub 2023-05-13.
Prenatal depression and risk of child autism-related traits among participants in the Environmental influences on Child Health Outcomes program
This study evaluated the association between prenatal depression and offspring autism-related traits. The sample comprised 33 prenatal/pediatric cohorts participating in the Environmental influences on Child Health Outcomes program who contributed information on prenatal depression and autism-related traits. Autism-related traits were assessed continuously and at the diagnostic cut-off using the Social Responsiveness Scale for children up to 12 years of age. Main analyses included 3994 parent-child pairs with prenatal depression diagnoses data; secondary analyses included 1730 parent-child pairs with depression severity data. After confounder adjustment, we observed an increase in autism-related traits among children of individuals with prenatal depression compared to those without (adjusted β = 1.31 95% CI: 0.65, 1.98). Analyses stratified by child sex documented a similar significant association among boys (aβ = 1.34 95%CI: 0.36, 2.32) and girls (aβ = 1.26 95% CI: 0.37, 2.15). Prenatal depression was also associated with increased odds of moderate to severe autism-related traits (adjusted odds ratio: 1.64, 95%CI: 1.09, 2.46), the screening threshold considered high risk of autism spectrum disorder (ASD) diagnosis. Findings highlight the importance of prenatal depression screening and preventive interventions for children of pregnant individuals with depression to support healthy development. Future research is needed to clarify whether these findings reflect overlap in genetic risk for depression and ASD-related traits or another mechanism.
Authors: Avalos, Lyndsay A;Gao, Xingyu;Cioffi, Camille C;Goldson, Brandon;Wright, Rosalind J;Zhu, Yeyi;Program Collaborators for Environmental influences on Child Health Outcomes,;et al.
Autism Res. 2023 Sep;16(9):1825-1835. Epub 2023-08-01.
Short report: Recommendations for education, clinical practice, research, and policy on promoting well-being in autistic youth and adults through a positive focus on sexuality and gender diversity
In this article, we propose recommendations on what we can do to promote that autistic people can enjoy their sexuality and gender identity, because that contributes to overall well-being.First, we briefly summarize the existing research on sexuality and gender diversity in autistic individuals.Next, we propose recommendations for how to promote sexual and gender diversity-related health and well-being. Based on what is known about sexuality, gender diversity, and relationships in autistic adolescents and adults, we convened an international group of autistic and non-autistic researchers, advocates, parents, and professionals to develop recommendations to promote sexual and gender health in autistic people.The resulting recommendations were checked through an online survey distributed to autistic people across the world. The online participants endorsed the importance of eight final recommendations related to:1. Providing education and information on sexuality, relationships, and gender diversity to autistic individuals and their families;2. Improving expertise in and accessibility to healthcare for sexuality, relationships, and gender-related questions, with specific attention to prevention of and support after sexual victimization; and3. Meaningfully including the autism community in future research that addresses well-being relating to sexuality, relationships, and gender diversity.These community-driven recommendations aim to promote sexual health and well-being in autistic individuals internationally.
Authors: Dewinter, Jeroen;Crehan, Eileen T;van der Miesen, Anna Ir;et al.
Autism. 2023 Aug 02:13623613231188349.
Sociodemographic Differences in COVID-19 Pandemic Experiences Among Families in the United States
Few population-based studies in the US collected individual-level data from families during the COVID-19 pandemic. To examine differences in COVID-19 pandemic-related experiences in a large sociodemographically diverse sample of children and caregivers. The Environmental influences on Child Health Outcomes (ECHO) multi-cohort consortium is an ongoing study that brings together 64 individual cohorts with participants (24 757 children and 31 700 caregivers in this study) in all 50 US states and Puerto Rico. Participants who completed the ECHO COVID-19 survey between April 2020 and March 2022 were included in this cross-sectional analysis. Data were analyzed from July 2021 to September 2022. Exposures of interest were caregiver education level, child life stage (infant, preschool, middle childhood, and adolescent), and urban or rural (population <50 000) residence. Dependent variables included COVID-19 infection status and testing; disruptions to school, child care, and health care; financial hardships; and remote work. Outcomes were examined separately in logistic regression models mutually adjusted for exposures of interest and race, ethnicity, US Census division, sex, and survey administration date. Analyses included 14 646 children (mean [SD] age, 7.1 [4.4] years; 7120 [49%] female) and 13 644 caregivers (mean [SD] age, 37.6 [7.2] years; 13 381 [98%] female). Caregivers were racially (3% Asian; 16% Black; 12% multiple race; 63% White) and ethnically (19% Hispanic) diverse and comparable with the US population. Less than high school education (vs master's degree or more) was associated with more challenges accessing COVID-19 tests (adjusted odds ratio [aOR], 1.88; 95% CI, 1.06-1.58), lower odds of working remotely (aOR, 0.04; 95% CI, 0.03-0.07), and more food access concerns (aOR, 4.14; 95% CI, 3.20-5.36). Compared with other age groups, young children (age 1 to 5 years) were least likely to receive support from schools during school closures, and their caregivers were most likely to have challenges arranging childcare and concerns about work impacts. Rural caregivers were less likely to rank health concerns (aOR, 0.77; 95% CI, 0.69-0.86) and social distancing (aOR, 0.82; 95% CI, 0.73-0.91) as top stressors compared with urban caregivers. Findings in this cohort study of US families highlighted pandemic-related burdens faced by families with lower socioeconomic status and young children. Populations more vulnerable to public health crises should be prioritized in recovery efforts and future planning.
Authors: LeWinn, Kaja Z;Dunlop, Anne L;Porucznik, Christina A;Environmental influences on Child Health Outcomes Consortium,;et al.
JAMA Netw Open. 2023 Aug 01;6(8):e2330495. Epub 2023-08-01.
Examining Prenatal Dietary Factors in Association with Child Autism-Related Traits Using a Bayesian Mixture Approach: Results from 2 United States Cohorts
Prior work has suggested relationships between prenatal intake of certain nutrients and autism. We examined a broad set of prenatal nutrients and foods using a Bayesian modeling approach. Participants were drawn from the Early Autism Risks Longitudinal Investigation (n = 127), a cohort following women with a child with autism through a subsequent pregnancy. Participants were also drawn from the Nurses’ Health Study II (NHSII, n = 713), a cohort of United States female nurses, for comparison analyses. In both studies, information on prospectively reported prenatal diet was drawn from food frequency questionnaires, and child autism-related traits were measured by the Social Responsiveness Scale (SRS). Bayesian kernel machine regression was used to examine the combined effects of several nutrients with neurodevelopmental relevance, including polyunsaturated fatty acids (PUFAs), iron, zinc, vitamin D, folate, and other methyl donors, and separately, key food sources of these, in association with child SRS scores in crude and adjusted models. In adjusted analyses, the overall mixture effects of nutrients in Early Autism Risks Longitudinal Investigation and foods in both cohorts on SRS scores were not observed, though there was some suggestion of decreasing SRS scores with increasing overall nutrient mixture in NHSII. No associations were observed with folate within the context of this mixture, but holding other nutrients fixed, n-6 PUFAs were associated with lower SRS scores in NHSII. In both cohorts, lower SRS scores were observed with higher intake of some groupings of vegetables, though for differing types of vegetables across cohorts, and some vegetable groups were associated with higher SRS scores in NHSII. Our work extends prior research and suggests the need to further consider prenatal dietary factors from a combined effects perspective. In addition, findings here point to potential differences in nutrient associations based on a family history of autism, which suggests the need to consider gene interactions in future work.
Authors: Lyall, Kristen;Weisskopf, Marc G;Newschaffer, Craig J;et al.
Curr Dev Nutr. 2023 Aug;7(8):101978. Epub 2023-07-25.
Prenatal ultrasound use and risk of autism spectrum disorder: Findings from the case-control Study to Explore Early Development
Studies evaluating the association between prenatal ultrasounds and autism spectrum disorder (ASD) have largely produced negative results. Concern remains due to the rising identification of children with ASD and ultrasound use. To evaluate the association between prenatal ultrasound use and ASD. We used data from the Study to Explore Early Development, a multisite case-control study of preschool-aged children with ASD implemented during 2007-2012. We recruited cases from children receiving developmental disability services and randomly selected population controls from birth records. ASD case status was based on in-person standardised assessments. We stratified analyses by pre-existing maternal medical conditions and pregnancy complications associated with increased ultrasound use (ultrasound indications) and used logistic regression to model case status by increasing ultrasound counts. For pregnancies with medical record data on ultrasound timing, we conducted supplementary tests to model associations by trimester of exposure. Among 1524 singleton pregnancies, ultrasound indications were more common for ASD cases than controls; respectively, for each group, no indications were reported for 45.1% and 54.2% of pregnancies, while ≥2 indications were reported for 26.1% and 18.4% of pregnancies. The percentage of pregnancies with multiple ultrasounds varied by case status and the presence of ultrasound indications. However, stratified regression models showed no association between increasing ultrasound counts and case status, either for pregnancies without (aOR 1.01, 95% CI 0.92, 1.11) or with ultrasound indications (aOR 1.01, 95% CI 0.95, 1.08). Trimester-specific analyses using medical record data showed no association in any individual trimester. We found no evidence that prenatal ultrasound use increases ASD risk. Study strengths included gold-standard assessments for ASD case classification, comparison of cases with controls, and a stratified sample to account for conditions associated both with increased prenatal ultrasound use and ASD.
Authors: Christensen, Deborah;Alexander, Aimee A;Shapira, Stuart K;et al.
Paediatr Perinat Epidemiol. 2023 Aug;37(6):527-535. Epub 2023-07-23.
Updates to the Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda
Autistic individuals, now representing one in 36 individuals in the U.S., experience disproportionate physical health challenges relative to non-autistic individuals. The Health Resources and Services Administration’s (HRSA) Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multi-center Research Network that aims to increase the health, well-being, and quality of life of autistic individuals. The current paper builds on the initial AIR-P Research Agenda (proposed in Year 1) and provides an updated vision for the Network. Updates to the Research Agenda were made via the administration of a Qualtrics survey, and disseminated widely to all AIR-P entities, including the Research Node Leaders, Steering Committee, Autistic Researcher Review Board, and collaborating academic and non-academic entities. Network members were tasked with evaluating the Year 1 Research Agenda and proposing additional priorities. Within each Research Node, all Year 1 priorities were endorsed as continued priorities for research on autism and physical health. Specific topics, including co-occurring conditions and self-determination, advocacy, and decision-making, were particularly endorsed. Opportunities for exploratory studies and intervention research were identified across Research Nodes. Qualitative responses providing feedback on additional research priorities were collected. The updated AIR-P Research Agenda represents an important step toward enacting large-scale health promotion efforts for autistic individuals across the lifespan. This updated agenda builds on efforts to catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health promotion.
Authors: Hotez, Emily;Croen, Lisa A;Kuo, Alice;et al.
Cureus. 2023 Aug;15(8):e44388. Epub 2023-08-30.
A Comparative Analysis of the Full and Short Versions of the Social Responsiveness Scale in Estimating an Established Autism Risk Factor Association in ECHO: Do we Get the Same Estimates?
Prior work developed a shortened 16-item version of the Social Responsiveness Scale (SRS), a quantitative measure of social communication and autism spectrum disorder (ASD)-related traits. However, its properties for use in risk factor estimation have not been fully tested compared to the full SRS. We compared the associations between gestational age (previously established risk factor for ASD) and the 65-item “full” and 16-item “short” versions of the SRS to test the shortened version’s ability to capture associations in epidemiologic analyses of ASD risk factors. We used data from participants in the Environmental influences on Child Health Outcomes (ECHO) Program (n = 2,760). SRS scores were collected via maternal/caregiver report when children were aged 2.5-18 years. We compared estimates of associations between gestational age and preterm birth between the full and short SRS using multivariable linear regression, quantile regression, and prediction methods. Overall, associations based on full and short SRS scores were highly comparable. For example, we observed positive associations between preterm birth with both full ([Formula: see text]=2.8; 95% CI [1.7, 4.0]) and short ([Formula: see text]=2.9; 95% CI [1.6, 4.3]) SRS scores. Quantile regression analyses indicated similar direction and magnitude of associations across the distribution of SRS scores between gestational age with both short and full SRS scores. The comparability in estimates obtained for full and short SRS scores with an “established” ASD risk factor suggests ability of the shortened SRS in assessing associations with potential ASD-related risk factors and has implications for large-scale research studies seeking to reduce participant burden.
Authors: Patti, Marisa A;Hosseini, Mina;Lyall, Kristen;et al.
J Autism Dev Disord. 2023 Jul 22.
The influence of loss to follow-up in autism screening research: Taking stock and moving forward
How best to improve the early detection of autism spectrum disorder (ASD) is the subject of significant controversy. Some argue that universal ASD screeners are highly accurate, whereas others argue that evidence for this claim is insufficient. Relatedly, there is no clear consensus as to the optimal role of screening for making referral decisions for evaluation and treatment. Published screening research can meaningfully inform these questions-but only through careful consideration of children who do not complete diagnostic follow-up. We developed two simulation models that re-analyze the results of a large-scale validation study of the M-CHAT-R/F by Robins et al. (2014, Pediatrics, 133, 37). Model #1 re-analyzes screener accuracy across six scenarios, each reflecting different assumptions regarding loss to follow-up. Model #2 builds on this by closely examining differential attrition at each point of the multi-step detection process. Estimates of sensitivity ranged from 40% to 94% across scenarios, demonstrating that estimates of accuracy depend on assumptions regarding the diagnostic status of children who were lost to follow-up. Across a range of plausible assumptions, data also suggest that children with undiagnosed ASD may be more likely to complete follow-up than children without ASD, highlighting the role of clinicians and caregivers in the detection process. Using simulation modeling as a quantitative method to examine potential bias in screening studies, analyses suggest that ASD screening tools may be less accurate than is often reported. Models also demonstrate the critical importance of every step in a detection process-including steps that determine whether children should complete an additional evaluation. We conclude that parent and clinician decision-making regarding follow-up may contribute more to detection than is widely assumed.
Authors: Sheldrick, R Christopher;Hooker, Jessica L;Carter, Alice S;Feinberg, Emily;Croen, Lisa A;Kuhn, Jocelyn;Slate, Elizabeth;Wetherby, Amy M
J Child Psychol Psychiatry. 2023 Jul 19.
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 Jul 15;229:115978. Epub 2023-04-26.
Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort
Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a “high” exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.
Authors: Martenies, Sheena E;Cowell, Whitney;Program Collaborators for Environmental Influences on Child Health Outcomes,;et al.
Int J Environ Res Public Health. 2023 Jul 10;20(14). Epub 2023-07-10.
Neonatal immune signatures differ by sex regardless of neurodevelopmental disorder status: Macrophage migration inhibitory factor (MIF) alone reveals a sex by diagnosis interaction effect
Immune dysregulation, including aberrant peripheral cytokine/chemokine levels, is implicated in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD). While the diagnosis of ASD is more common in males compared to females, sex effects in immune dysregulation related to neurodevelopment remain understudied. The aim of this exploratory study was to determine whether there are sex-specific effects in neonatal immune dysregulation with respect to an ASD or delayed development (DD) diagnosis. We utilized the data from the Early Markers for Autism study, a population based case-control study of prenatal and neonatal biomarkers of ASD. The immune profile of newborns later diagnosed with ASD (n = 482, 91 females), DD (n = 140, 61 females) and sex-matched general population controls (GP; n = 378, 67 females) were analyzed using neonatal bloodspots (NBS) via 42-plex multiplex assay. Multiple linear regression analysis was performed to identify whether sex was associated with differences in cytokine/chemokine levels of children with ASD, DD, and GP. A sex by diagnosis interaction effect was observed only for the chemokine macrophage migration inhibitory factor (MIF), with males displaying higher levels of NBS MIF than females in the GP control group (p = 0.02), but not in ASD (p = 0.52) or DD (p = 0.29) groups. We found that regardless of child diagnosis, newborn bloodspot eluates from females had a significantly higher concentration than males with the same diagnosis of the chemokines granulocyte chemotactic protein 2 (GCP-2; p < 0.0001), macrophage inflammatory protein 2-alpha (GROβ; p = 0.002), interferon-inducible t-cell alpha chemoattractant (I-TAC; p < 0.0001), stromal cell-derived factor 1 alpha and beta (SDF-1α-β; p = 0.03), innate inflammatory chemokines interferon-gamma induced protein 10 (IP-10; p = 0.02), macrophage inflammatory protein 1-alpha (MIP-1α; p = 0.02), and Th1-related pro-inflammatory cytokine interleukin-12 active heterodimer (IL-12p70; p = 0.002). In contrast, males had a higher concentration than females of secondary lymphoid-tissue chemokine (6CKINE; p = 0.02), monocyte chemotactic protein 1 (MCP-1; p = 0.005) and myeloid progenitor inhibitory factor 1 (MPIF-1; p = 0.03). Results were similar when analyses were restricted to NBS from DD and ASD further classified as ASD with intellectual disability (ID), ASD without ID, and DD (GCP-2, p = 0.007; I-TAC, p = 0.001; IP-10, p = 0.005; IL-12p70, p = 0.03 higher in females; MPIF-1, p = 0.03 higher in male). This study is the first to examine sex differences in neonatal cytokine/chemokine concentrations, and whether these differences are associated with neurodevelopmental outcomes. Results highlight the importance of considering sex as a critical factor in understanding the immune system as it relates to child development.
Authors: Kim, Danielle H J;Iosif, Ana-Maria;Ramirez-Celis, Alexandra;Ashwood, Paul;Ames, Jennifer L;Lyall, Kristen;Berger, Kimberly;Croen, Lisa A;Van de Water, Judy
Brain Behav Immun. 2023 Jul;111:328-333. Epub 2023-05-08.
Health conditions in autism: Defining the trajectory from adolescence to early adulthood
Autistic adults, as compared to non-autistic adults, have increased rates of nearly all medical and psychiatric conditions. Many of these conditions begin in childhood, although few longitudinal studies have been conducted to examine prevalence rates of these conditions from adolescence into early adulthood. In this study, we analyze the longitudinal trajectory of health conditions in autistic youth, compared to age and sex-matched non-autistic youth, transitioning from adolescence into early adulthood in a large integrated health care delivery system. The percent and modeled prevalence of common medical and psychiatric conditions increased from age 14 to 22 years, with autistic youth having a higher prevalence of most conditions than non-autistic youth. The most prevalent conditions in autistic youth at all ages were obesity, neurological disorders, anxiety, and ADHD. The prevalence of obesity and dyslipidemia rose at a faster rate in autistic youth compared to non-autistic youth. By age 22, autistic females showed a higher prevalence of all medical and psychiatric conditions compared to autistic males. Our findings emphasize the importance of screening for medical and psychiatric conditions in autistic youth, coupled with health education targeted at this population, to mitigate the development of adverse health outcomes in autistic adults.
Authors: Malow, Beth A;Qian, Yinge;Ames, Jennifer L;Alexeeff, Stacey;Croen, Lisa A
Autism Res. 2023 Jul;16(7):1437-1449. Epub 2023-06-28.
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.
Prepregnancy BMI, gestational weight gain, and susceptibility to autism-related traits: the EARLI and HOME studies
Excessive gestational weight gain (GWG) has been associated with autism spectrum disorder (ASD). This study sought to examine whether familial susceptibility for autism, intensity of ASD-related behaviors, or prepregnancy BMI influences the association of GWG with ASD-related behaviors. Using data from the Early Autism Risk Longitudinal Investigation (EARLI) study (n = 136), a familial enriched cohort of mothers who had a previous child with ASD, and the Health Outcomes and Measures of the Environment (HOME) study (n = 253), a general population cohort, gestational age and prepregnancy BMI category-specific GWG z scores were calculated. Caregivers completed the Social Responsiveness Scale (SRS) to assess the presence and severity of ASD-related traits in children aged 3 to 8 years. Using quantile regression, the association between GWG z scores and ASD-related behaviors in children was estimated. In HOME, among mothers who had overweight or obesity prepregnancy BMI values, GWG z scores and SRS scores were positively associated in children with more ASD-related traits (higher SRS scores), but not in children with fewer ASD-related traits. Similar patterns were observed in EARLI among mothers with prepregnancy obesity. GWG may be associated with autism-related behaviors among children who have a greater predisposition to these behaviors and who have mothers with prepregnancy overweight or obesity.
Authors: Patti, Marisa A;Croen, Lisa A;Chen, Aimin;Fallin, M Daniele;Khoury, Jane;Lyall, Kristen;Newschaffer, Craig;Hertz-Picciotto, Irva;Schmidt, Rebecca J;Yolton, Kimberly;Braun, Joseph M
Obesity (Silver Spring). 2023 May;31(5):1415-1424.
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.
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;Conradt, Elisabeth;Program Collaborators for Environmental influences on Child Health Outcomes,;et al.
JAMA Netw Open. 2023 Apr 03;6(4):e2310059. Epub 2023-04-03.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Safety of measles and pertussis-containing vaccines in children with autism spectrum disorders
To determine whether children aged 4-7 years with a diagnosis of autism spectrum disorders (ASD) were at increased risk of fever, febrile seizures, or emergency department (ED) visits following measles- or pertussis-containing vaccines compared with children without ASD. The study included children born between 1995-2012, aged 4-7 years at vaccination, and members of six healthcare delivery systems within Vaccine Safety Datalink. We conducted self-controlled risk interval analyses comparing rates of outcomes in risk and control intervals within each group defined by ASD status, and then compared outcome rates between children with and without ASD, in risk and control intervals, by estimating difference-in-differences using logistic regressions. The study included 14,947 children with ASD and 1,650,041 children without ASD. After measles- or pertussis-containing vaccination, there were no differences in association between children with and without ASD for fever (ratio of rate ratio for measles-containing vaccine = 1.07, 95% CI 0.58-1.96; for pertussis-containing vaccine = 1.16, 95% CI 0.63-2.15) or ED visits (ratio of rate ratio for measles-containing vaccine = 1.11, 95% CI 0.80-1.54; for pertussis-containing vaccine = 0.87, 95% CI 0.59-1.28). Febrile seizures were rare. Pertussis-containing vaccines were associated with small increased risk of febrile seizures in children without ASD. Children with ASD were not at increased risk for fever or ED visits compared with children without ASD following measles- or pertussis-containing vaccines. These results may provide further reassurance that these vaccines are safe for all children, including those with ASD.
Authors: Zerbo, Ousseny; Fireman, Bruce; Klein, Nicola P; et al.
Vaccine. 2022 04 20;40(18):2568-2573. Epub 2022-03-18.
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).
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).
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. https://doi.org/10.1289/EHP1830.
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.
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.
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.
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.
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.
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.
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.
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.
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. https://doi.org/10.1289/EHP1079.
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.
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.
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; https://dx.doi.org/10.1289/EHP277.
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.
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.
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.
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.
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.
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.
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.
The Changing Epidemiology of Autism Spectrum Disorders
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction.Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications. Expected final online publication date for the Annual Review of Public Health Volume 38 is March 20, 2017. Please see https://www.annualreviews.org/page/journal/pubdates for revised estimates.
Authors: Lyall K; Croen L; Daniels J; Fallin MD; Ladd-Acosta C; Lee BK; Park BY; Snyder NW; Schendel D; Volk HE; Windham GC; Newschaffer C
Annu Rev Public Health. 2016 Dec 21.
Pleiotropic Mechanisms Indicated for Sex Differences in Autism
Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.
Authors: Mitra I; Croen LA; Weiss LA; et al.
PLoS Genet. 2016 11;12(11):e1006425. Epub 2016-11-15.
Maternal Exposure to Occupational Asthmagens During Pregnancy and Autism Spectrum Disorder in the Study to Explore Early Development
Maternal immune activity has been linked to children with autism spectrum disorder (ASD). We examined maternal occupational exposure to asthma-causing agents during pregnancy in relation to ASD risk. Our sample included 463 ASD cases and 710 general population controls from the Study to Explore Early Development whose mothers reported at least one job during pregnancy. Asthmagen exposure was estimated from a published job-exposure matrix. The adjusted odds ratio for ASD comparing asthmagen-exposed to unexposed was 1.39 (95 % CI 0.96-2.02). Maternal workplace asthmagen exposure was not associated with ASD risk in this study, but this result does not exclude some involvement of maternal exposure to asthma-causing agents in ASD.
Authors: Singer AB; Windham GC; Croen LA; Daniels JL; Lee BK; Qian Y; Schendel DE; Fallin MD; Burstyn I
J Autism Dev Disord. 2016 Nov;46(11):3458-3468.
Risk of Autism Associated With Hyperbilirubinemia and Phototherapy
Whether neonatal hyperbilirubinemia and/or phototherapy increase the risk of autism spectrum disorder (ASD) is unclear. We sought to quantify the risk of ASD associated with elevated total serum bilirubin (TSB) levels and with phototherapy. In a retrospective cohort study of 525?409 infants born at ?35 weeks’ gestation in 15 Kaiser Permanente Northern California (KPNC) hospitals, 1995-2011, we obtained all TSB levels and determined which infants received phototherapy. From the KPNC Autism Registry, we identified patients with ASD diagnosed at a KPNC Autism Center, by a clinical specialist, or by a pediatrician. We calculated Cox proportional hazard ratios (HRs) for time to diagnosis of ASD, adjusting for confounding factors. Among infants in the birth cohort, 2% had at least 1 TSB level ?20 mg/dL, and 8% received phototherapy. The rate of ASD was 13 per 1000 births. Crude analyses revealed an association between TSB ?20 and ASD (relative risk: 1.4; 95% confidence interval [CI]: 1.1-1.6), and between phototherapy and ASD (relative risk: 1.7; 95% CI: 1.5-1.8). After adjusting for confounders, TSB ?20 (HR: 1.09; 95% CI: 0.89-1.35) and phototherapy (HR: 1.10; 95% CI: 0.98-1.24) were no longer significantly associated with ASD. Independent risk factors for ASD included maternal and paternal age; maternal and paternal higher education; male sex; birth weight <2500 g or ?4200 g; and later year of birth. After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.
Authors: Wu YW; Kuzniewicz MW; Croen L; Walsh EM; McCulloch CE; Newman TB
Pediatrics. 2016 Oct;138(4).
Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder
The Study to Explore Early Development (SEED) is designed to enhance knowledge of autism spectrum disorder characteristics and etiologies. This paper describes the demographic profile of enrolled families and examines sociodemographic differences between children with autism spectrum disorder and children with other developmental problems or who are typically developing. This multi-site case-control study used health, education, and birth certificate records to identify and enroll children aged 2-5 years into one of three groups: 1) cases (children with autism spectrum disorder), 2) developmental delay or disorder controls, or 3) general population controls. Study group classification was based on sampling source, prior diagnoses, and study screening tests and developmental evaluations. The child’s primary caregiver provided demographic characteristics through a telephone (or occasionally face-to-face) interview. Groups were compared using ANOVA, chi-squared test, or multinomial logistic regression as appropriate. Of 2768 study children, sizeable proportions were born to mothers of non-White race (31.7%), Hispanic ethnicity (11.4%), and foreign birth (17.6%); 33.0% of households had incomes below the US median. The autism spectrum disorder and population control groups differed significantly on nearly all sociodemographic parameters. In contrast, the autism spectrum disorder and developmental delay or disorder groups had generally similar sociodemographic characteristics. SEED enrolled a sociodemographically diverse sample, which will allow further, in-depth exploration of sociodemographic differences between study groups and provide novel opportunities to explore sociodemographic influences on etiologic risk factor associations with autism spectrum disorder and phenotypic subtypes.
Authors: DiGuiseppi CG; Croen LA; Schendel DE; et al.
Disabil Health J. 2016 Jul;9(3):544-51. Epub 2016-01-29.
Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study
Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.
Authors: Zerbo O; Croen LA; et al.
Transl Psychiatry. 2016 Apr 19;6:e783. Epub 2016-04-19.
Health Services Utilization Among Children With and Without Autism Spectrum Disorders
Using data from multiple health systems (2009-2010) and the largest sample to date, this study compares health services use among youth with and without an autism spectrum disorder (ASD)-including preventive services not previously studied. To examine these differences, we estimated logistic and count data models, controlling for demographic characteristics, comorbid physical health, and mental health conditions. Results indicated that youth with an ASD had greater health care use in many categories, but were less likely to receive important preventive services including flu shots and other vaccinations. An improved understanding of the overall patterns of health care use among this population could enable health systems to facilitate the receipt of appropriate and effective health care.
Authors: Cummings JR; Croen LA; et al.
J Autism Dev Disord. 2016 Mar;46(3):910-20.
Peripheral Blood Leukocyte Production of BDNF following Mitogen Stimulation in Early Onset and Regressive Autism
Brain-derived neurotrophic factor (BDNF) is critical for neuronal differentiation and synaptic development. BDNF is also implicated in the development of psychological disorders including depression, bipolar disorder and schizophrenia. Previously, elevated BDNF levels were observed in neonatal blood samples from infants who were later diagnosed with autism when compared with children who developed normally, suggesting that BDNF may be involved in the development of autism. BDNF is produced by activated brain microglial cells, a cellular phenotype that shares several features with peripheral macrophages, suggesting an important role for the immune system in BDNF production. We hypothesized that under mitogenic stimulation, peripheral blood mononuclear cells obtained from children with autism may have altered BDNF production compared with age-matched typically developing control subjects. In addition, we examined the differences between the production of BDNF in classic/early-onset autism and children who had a regressive form of autism. We show here that plasma levels of BDNF levels are increased in children with autism, especially in early onset autism subjects. Furthermore, under mitogenic stimulation with PHA and LPS, BDNF production is significantly increased in children with autism compared with typically developing subjects. However, stimulation with tetanus toxoid results in a decreased response in children with autism. This data suggest that immune cell-derived production of BDNF could be an important source for the increased BDNF that is detected in some subjects with autism. As a neurotrophic factor produced by immune cells, BDNF could help elucidate the role of the immune system in neurodevelopment and neuronal maintenance, which may be dysregulated in autism.
Authors: Enstrom A; Onore C; Tarver A; Hertz-Picciotto I; Hansen R; Croen L; Van de Water J; Ashwood P
Am J Biochem Biotechnol. 2008;4(2):121-129.
Prenatal and Newborn Immunoglobulin Levels from Mother-Child Pairs and Risk of Autism Spectrum Disorders
An etiological role for immune factors operating during early brain development in children with autism spectrum disorders (ASD) has not yet been established. A major obstacle has been the lack of early biologic specimens that can be linked to later diagnosis. In a prior study, we found lower risk of ASD associated with higher levels of maternally-derived total IgG and Toxoplasmosis gondii (Toxo) IgG in newborn blood spot specimens from children later diagnosed with ASD compared to population controls. We obtained maternal mid-gestational serum specimens and newborn screening blood spots from the California Genetics Disease Screening Program (GDSP) for linked mother-baby pairs for 84 children with ASD and 49 children with developmental delay but not ASD (DD) identified from California Department of Developmental Services records and for 159 population controls sampled from birth certificates.Immunoglobulin levels in maternal and newborn specimens were measured by solid phase immunoassays and analyzed in logistic regression models for total IgG, total IgM, and Toxo IgG, and, for maternal specimens only, Toxo IgM. Correlations between maternal and newborn ranked values were evaluated. In both maternal and newborn specimens, we found significantly lower risk of ASD associated with higher levels of Toxo IgG. In addition, point estimates for all comparisons were < 1.0 suggesting an overall pattern of lower immunoglobulin levels associated with higher ASD risk but most did not reach statistical significance. We did not find differences in maternal or newborn specimens comparing children with DD to controls. These results are consistent with evidence from our prior study and other published reports indicating that immune factors during early neurodevelopment may be etiologically relevant to ASD. Lowered immunoglobulin levels may represent suboptimal function of the maternal immune system or reduced maternal exposure to common infectious agents. Patterns seen in these selected immunoglobulins may provide clues to mechanisms of early abnormalities in neurodevelopment contributing to ASD. We recommend further study of immunoglobulin profiles in larger samples of linked mother-baby pairs to evaluate possible etiologic relevance.
Authors: Grether JK; Ashwood P; Van de Water J; Yolken RH; Anderson MC; Torres AR; Westover JB; Sweeten T; Hansen RL; Kharrazi M; Croen LA
Front Neurosci. 2016;10:218. Epub 2016-05-18.
Maternal Infection During Pregnancy and Autism Spectrum Disorders
We conducted a nested case-control study including 407 cases and 2,075 frequency matched controls to investigate the association between maternal infections during pregnancy and risk of autism spectrum disorders (ASD). Cases, controls, and maternal infections were ascertained from Kaiser Permanente Northern California clinical databases. No overall association between diagnoses of any maternal infection during pregnancy and ASD was observed [adjusted odds ratio (ORadj) = 1.15, 95 % confidence interval (CI) 0.92-1.43]. However, women with infections diagnosed during a hospital admission (ORadj = 1.48, 95 % CI 1.07-2.04), particularly bacterial infections (ORadj = 1.58, 95 % CI 1.06-2.37), were at increased risk of delivering a child with ASD. Multiple infections during pregnancy were associated with ASD (ORadj = 1.36, 95 % CI 1.05-1.78).
Authors: Zerbo O; Qian Y; Yoshida C; Grether JK; Van de Water J; Croen LA
J Autism Dev Disord. 2015 Dec;45(12):4015-25.
A Study of Physician Knowledge and Experience with Autism in Adults in a Large Integrated Healthcare System
We conducted an online survey of adult health care providers at Kaiser Permanente Northern California and semi-structured interviews with a subset of physicians. The survey assessed providers’ ability to recognize autism spectrum disorder (ASD), asked them to rate their autism knowledge, comfort level in treating affected patients, and evaluated training and resource needs. 922 providers completed the survey (response rate 25.3 %), and 9 were interviewed by telephone regarding their autism training and experiences caring for patients with autism. Most providers reported lacking skills and tools to care for this adult patient population. A high proportion of adult providers were not aware that they had patients with ASD. These findings underscore the need to educate physicians caring for adults with ASD.
Authors: Zerbo O; Massolo ML; Qian Y; Croen LA
J Autism Dev Disord. 2015 Dec;45(12):4002-14.
The health status of adults on the autism spectrum
Compared to the general pediatric population, children with autism have higher rates of co-occurring medical and psychiatric illnesses, yet very little is known about the general health status of adults with autism. The objective of this study was to describe the frequency of psychiatric and medical conditions among a large, diverse, insured population of adults with autism in the United States. Participants were adult members of Kaiser Permanente Northern California enrolled from 2008 to 2012. Autism spectrum disorder cases (N = 1507) were adults with autism spectrum disorder diagnoses (International Classification of Diseases-9-Clinical Modification codes 299.0, 299.8, 299.9) recorded in medical records on at least two separate occasions. Controls (N = 15,070) were adults without any autism spectrum disorder diagnoses sampled at a 10:1 ratio and frequency matched to cases on sex and age. Adults with autism had significantly increased rates of all major psychiatric disorders including depression, anxiety, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and suicide attempts. Nearly all medical conditions were significantly more common in adults with autism, including immune conditions, gastrointestinal and sleep disorders, seizure, obesity, dyslipidemia, hypertension, and diabetes. Rarer conditions, such as stroke and Parkinson’s disease, were also significantly more common among adults with autism. Future research is needed to understand the social, healthcare access, and biological factors underlying these observations.
Authors: Croen, Lisa A; Zerbo, Ousseny; Qian, Yinge; Massolo, Maria L; Rich, Steve; Sidney, Stephen; Kripke, Clarissa
Autism. 2015 Oct;19(7):814-23. Epub 2015-04-24.
Autism Spectrum Disorder Symptoms Among Children Enrolled in the Study to Explore Early Development (SEED)
This study examined the phenotypic profiles of children aged 30-68 months in the Study to Explore Early Development (SEED). Children classified as autism spectrum disorder (ASD), developmental delay (DD) with ASD symptoms, DD without ASD symptoms, and population comparison (POP) differed significantly from each other on cognitive, adaptive, behavioral, and social functioning and the presence of parent-reported conditions. Children with ASD and DD with ASD symptoms had mild to severe ASD risk on several measures compared to children with other DD and POP who had little ASD risk across measures. We conclude that children in SEED have varying degrees of ASD impairment and associated deficits. SEED thus provides a valuable sample to explore ASD phenotypes and inform risk factor analyses.
Authors: Wiggins LD; Croen LA; Schendel D; et al.
J Autism Dev Disord. 2015 Oct;45(10):3183-94.
Prevalence and Predictors of Complementary and Alternative Medicine Use in a Large Insured Sample of Children with Autism Spectrum Disorders
The purpose of the present study was to examine the prevalence and predictors of complementary and alternative medicine (CAM) use as well as parental perceptions of CAM efficacy in a large, geographically diverse sample of children with Autism Spectrum Disorders (ASD). Data were obtained from a web-based survey administered to parents of children with ASD at four sites participating in the Mental Health Research Network (MHRN). The web survey obtained information about services and treatments received by children with ASD as well as the caregivers’ experiences with having a child with ASD. Approximately 88% of the sample had either used CAM in the past or had recently used some type of CAM. The following characteristics were associated with CAM use: greater parental education, younger child age, a mix of regular and special classroom settings and prescription drug use in the past three months. The use of CAM was very prevalent in this large, geographically diverse sample of children with ASD. It is critical that providers be prepared to discuss the advantages and potential side effects with families to help them make well-informed health care decisions and prevent possible CAM-drug interactions.
Authors: Owen-Smith AA; Bent S; Lynch FL; Coleman KJ; Yau VM; Pearson KA; Massolo ML; Quinn V; Croen LA
Res Autism Spectr Disord. 2015 Sep 01;17:40-51.
Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort
Epigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features. Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children. We examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (?485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available. Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)] <0.05 associated with performance on the Autism Observational Scale for Infants (AOSI) at 12 months of age in offspring. The DMRs clustered near genes involved in developmental processes, including many genes in the SNORD family, within the Prader-Willi syndrome gene cluster. These results were consistent among the 75 probes on the Illumina 450K array that cover AOSI-associated DMRs from CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent differences in the cerebellums of autistic individuals compared with controls. These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring, and provide evidence that directionally consistent, potentially related epigenetic mechanisms may be operating in the cerebellum of individuals with autism.
Authors: Feinberg JI; Bakulski KM; Jaffe AE; Tryggvadottir R; Brown SC; Goldman LR; Croen LA; Hertz-Picciotto I; Newschaffer CJ; Fallin MD; Feinberg AP
Int J Epidemiol. 2015 Aug;44(4):1199-210. Epub 2015-04-14.
Validation of Autism Spectrum Disorder Diagnoses in Large Healthcare Systems with Electronic Medical Records
To identify factors associated with valid Autism Spectrum Disorder (ASD) diagnoses from electronic sources in large healthcare systems. We examined 1,272 charts from ASD diagnosed youth <18 years old. Expert reviewers classified diagnoses as confirmed, probable, possible, ruled out, or not enough information. A total of 845 were classified with 81% as a confirmed, probable, or possible ASD diagnosis. The predictors of valid ASD diagnoses were >2 diagnoses in the medical record (OR 2.94; 95% CI 2.03-4.25; p < 0.001) and being male (OR 1.51; 95% CI 1.05-2.17; p = 0.03). In large integrated healthcare settings, at least two diagnoses can be used to identify ASD patients for population-based research.
Authors: Coleman KJ; Croen LA; et al.
J Autism Dev Disord. 2015 Jul;45(7):1989-96.
Immune mediated conditions in autism spectrum disorders
We conducted a case-control study among members of Kaiser Permanente Northern California (KPNC) born between 1980 and 2003 to determine the prevalence of immune-mediated conditions in individuals with autism, investigate whether these conditions occur more often than expected, and explore the timing of onset relative to autism diagnosis. Cases were children and young adults with at least two autism diagnoses recorded in outpatient records (n=5565). Controls were children without autism randomly sampled at a ratio of 5 to 1, matched to cases on birth year, sex, and length of KPNC membership (n=27,825). The main outcomes – asthma, allergies, and autoimmune diseases – were identified from KPNC inpatient and outpatient databases. Chi-square tests were used to evaluate case-control differences. Allergies and autoimmune diseases were diagnosed significantly more often among children with autism than among controls (allergy: 20.6% vs. 17.7%, Crude odds ratio (OR)=1.22, 95% confidence interval (CI) 1.13-1.31; autoimmune disease: 1% vs. 0.76%, OR=1.36, 95% CI 1.01-1.83), and asthma was diagnosed significantly less often (13.7% vs. 15.9%; OR=0.83, 95% CI 0.76-0.90). Psoriasis occurred more than twice as often in cases than in controls (0.34% vs. 0.15%; OR=2.35, 95% CI 1.36-4.08). Our results support previous observations that children with autism have elevated prevalence of specific immune-related comorbidities.
Authors: Zerbo O; Leong A; Barcellos L; Bernal P; Fireman B; Croen LA
Brain Behav Immun. 2015 May;46:232-6. Epub 2015-02-11.
Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders
Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay (n = 45), and general population controls (GP) (n = 149). Samples were retrieved from prenatal and newborn screening specimen archives. Adjusted logistic regression models showed inverse associations between ASD and log transformed TSH levels in maternal serum samples (ASD vs. GP: OR [95 % CI] 0.33 [0.12-0.91], Early Onset ASD vs. GP: 0.31 [0.10-0.98]). Results for thyroid levels in newborn blood samples were similar though not significant (ASD vs. GP: 0.61 [0.18-2.04]).
Authors: Yau VM; Lutsky M; Yoshida CK; Lasley B; Kharrazi M; Windham G; Gee N; Croen LA
J Autism Dev Disord. 2015 Mar;45(3):719-30.
Increased female autosomal burden of rare copy number variants in human populations and in autism families
Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10(-5)) and gene content (P=4.1 × 10(-3)). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.
Authors: Desachy G; Croen LA; Torres AR; Kharrazi M; Delorenze GN; Windham GC; Yoshida CK; Weiss LA
Mol Psychiatry. 2015 Feb;20(2):170-5. Epub 2015-01-13.
Familial Recurrence of Autism Spectrum Disorder: Evaluating Genetic and Environmental Contributions
This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth. The authors linked California Department of Developmental Services records with state birth certificates to identify all siblings and half siblings of individuals affected with ASD born between 1990 and 2003. A total of 6,616 full siblings, 644 maternal half siblings, and 299 paternal half siblings born after ASD index cases were used to calculate recurrence risks. Control families, identified through matching to cases, were included for comparison (a total of 29,384 siblings). The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls. The recurrence risk in second-born children was higher (11.5%) than in later-born siblings (7.3%); a similar pattern was observed for maternal half siblings (6.5% for second-born compared with 3.0% for later-born siblings; 4.8% overall). The recurrence risk was significantly higher for siblings who immediately followed the index case in birth order compared with those later in birth order. The recurrence risk for paternal half siblings (2.3%) was half the overall recurrence risk for maternal half siblings but was similar to that for later-born maternal half siblings. An exponential effect of short interbirth interval was observed, with the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more. An identical phenomenon was observed in maternal half siblings. The results support genetic susceptibility in the familial recurrence of ASD along with factors related to timing of birth.
Authors: Risch N; Hoffmann TJ; Anderson M; Croen LA; Grether JK; Windham GC
Am J Psychiatry. 2014 Nov 1;171(11):1206-13.
Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder: A Large, Population-Based Cohort Study
Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD). To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of ASD. Individuals with ASD born from January 1, 1990, through December 31, 2003, were identified in the California Department of Developmental Services records, which were then linked to state birth certificates to identify full sibs and half-sibs and to obtain information on birth order and demographics. A total of 19,710 case families in which the first birth occurred within the study period was identified. These families included 39,361 individuals (sibs and half-sibs). Control individuals were randomly sampled from birth certificates and matched 2:1 to cases by sex, birth year, and maternal age, self-reported race/ethnicity, and county of birth after removal of children receiving services from the California Department of Developmental Services. Using similar linkage methods as for case families, 36,215 pure control families (including 75,724 total individuals) were identified that had no individuals with an ASD diagnosis. History of affected children. Stoppage was investigated by comparing the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child using a survival analysis framework for time to next birth and adjusting for demographic variables. For the first few years after the birth of a child with ASD, the parents’ reproductive behavior was similar to that of control parents. However, birth rates differed in subsequent years; overall, families whose first child had ASD had a second child at a rate of 0.668 (95% CI, 0.635-0.701) that of control families, adjusted for birth year, birth weight, maternal age, and self-reported maternal race/ethnicity. Results were similar when a later-born child was the first affected child in the family. Reproductive curtailment was slightly stronger among women who changed partners (relative rate for second-born children, 0.553 [95% CI, 0.498-0.614]). These results provide the first quantitative assessment and convincing statistical evidence of reproductive stoppage related to ASD. These findings have implications for recurrence risk estimation and genetic counseling.
Authors: Hoffmann TJ; Windham GC; Anderson M; Croen LA; Grether JK; Risch N
JAMA Psychiatry. 2014 Aug;71(8):943-51.
Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders
Prenatal and early-life exposures to mercury have been hypothesized to be associated with increased risk of autism spectrum disorders (ASDs). This study investigated the association between ASDs and levels of total mercury measured in maternal serum from mid-pregnancy and infant blood shortly after birth. The study sample was drawn from the Early Markers for Autism (EMA) Study. Three groups of children who were born in Orange County, CA in 2000-2001 were identified: children with ASD (n=84), children with intellectual disability or developmental delay (DD) (n=49), and general population controls (GP) (n=159). Maternal serum specimens and newborn bloodspots were retrieved from the California Department of Public Health prenatal and newborn screening specimen archives. Blood mercury levels were measured in maternal serum samples using mass spectrometer and in infant bloodspots with a 213 nm laser. Maternal serum and infant blood mercury levels were significantly correlated among all study groups (all correlations >0.38, p<0.01). Adjusted logistic regression models showed no significant associations between ASD and log transformed mercury levels in maternal serum samples (ASD vs. GP: OR [95% CI]=0.96 [0.49-1.90]; ASD vs. DD: OR [95% CI]=2.56 [0.89-7.39]). Results for mercury levels in newborn blood samples were similar (ASD vs. GP: OR [95% CI]=1.18 [0.71-1.95]; ASD vs. DD: OR [95% CI]=1.96 [0.75-5.14]). Results indicate that levels of total mercury in serum collected from mothers during mid-pregnancy and from newborn bloodspots were not significantly associated with risk of ASD, though additional studies with greater sample size and covariate measurement are needed.
Authors: Yau VM; Green PG; Alaimo CP; Yoshida CK; Lutsky M; Windham GC; Delorenze G; Kharrazi M; Grether JK; Croen LA
Environ Res. 2014 Aug;133:294-303. Epub 2014-06-28.
Prenatal and perinatal risk factors in a twin study of autism spectrum disorders
Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently. Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed. Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74). Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.
Authors: Froehlich-Santino W; Croen LA; Hallmayer J; et al.
J Psychiatr Res. 2014 Jul;54:100-8. Epub 2014-03-29.
Determining Source Strength of Semivolatile Organic Compounds using Measured Concentrations in Indoor Dust
Consumer products and building materials emit a number of semivolatile organic compounds (SVOCs) in the indoor environment. Because indoor SVOCs accumulate in dust, we explore the use of dust to determine source strength and report here on analysis of dust samples collected in 30 US homes for six phthalates, four personal care product ingredients, and five flame retardants. We then use a fugacity-based indoor mass balance model to estimate the whole-house emission rates of SVOCs that would account for the measured dust concentrations. Di-2-ethylhexyl phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were the most abundant compounds in these dust samples. On the other hand, the estimated emission rate of diethyl phthalate is the largest among phthalates, although its dust concentration is over two orders of magnitude smaller than DEHP and DiNP. The magnitude of the estimated emission rate that corresponds to the measured dust concentration is found to be inversely correlated with the vapor pressure of the compound, indicating that dust concentrations alone cannot be used to determine which compounds have the greatest emission rates. The combined dust-assay modeling approach shows promise for estimating indoor emission rates for SVOCs. The combined dust-assay modeling approach in this study can be used to predict the source strength of indoor released compounds, integrating emissions from consumer products, building materials, and other home furnishings. Our findings show that estimated emission rates are closely related to not only the level of compounds on dust, but also the vapor pressure of the compound. Thus, a fugacity-based indoor mass balance model and measured dust concentrations can be used to estimate the whole-house emission rates from all sources in actual indoor settings, when individual sources of emissions are unknown.
Authors: Shin HM; McKone TE; Nishioka MG; Fallin MD; Croen LA; Hertz-Picciotto I; Newschaffer CJ; Bennett DH
Indoor Air. 2014 Jun;24(3):260-71. Epub 2013-10-31.
Adaptation of the ‘ten questions’ to screen for autism and other neuro-developmental disorders in Uganda
Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for ?1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.
Authors: Kakooza-Mwesige A; Ssebyala K; Karamagi C; Kiguli S; Smith K; Anderson MC; Croen LA; Trevathan E; Hansen R; Smith D; Grether JK
Autism. 2014 May;18(4):447-57. Epub 2013-03-27.
Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study
Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles. To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism. We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n?=?84), or developmental delay but not ASD (DD, n?=?49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n?=?159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening. Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1?) and RANTES were decreased in children with DD compared to GP controls. Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.
Authors: Zerbo O; Yoshida C; Grether JK; Van de Water J; Ashwood P; Delorenze GN; Hansen RL; Kharrazi M; Croen LA
J Neuroinflammation. 2014;11:113. Epub 2014-06-20.
Prevalence and Neonatal Factors Associated with Autism Spectrum Disorders in Preterm Infants
To determine the prevalence of autism spectrum disorders (ASD) across gestational age, examine the risk of ASD by gestational age controlling for other risk factors, and identify potential risk factors in the neonatal intensive care unit. A retrospective cohort of infants born at ? 24 weeks between January 1, 2000, and December 31, 2007 at 11 Kaiser Permanente Northern California hospitals (n = 195,021). ASD cases were defined by a diagnosis made at a Kaiser Permanente ASD evaluation center, by a clinical specialist, or by a pediatrician. Cox proportional hazards regression models were used to evaluate the association between gestational age and ASD as well as potential risk factors in the neonatal intensive care unit and ASD. The prevalence of ASD in infants <37 weeks was 1.78% compared with 1.22% in infants born ? 37 weeks (P < .001). Compared with term infants, infants born at 24-26 weeks had an adjusted hazard ratio (HR) for a diagnosis of ASD of 2.7 (95% CI 1.5-5.0). Infants born at 27-33 weeks (adjusted HR 1.4, 95% CI 1.1-1.8) and 34-36 weeks (adjusted HR 1.3, 95% CI 1.1-1.4) were also at increased risk. High frequency ventilation and intracranial hemorrhage were associated with ASD in infants < 34 weeks. ASD was ~ 3 times more prevalent in infants <27 weeks compared with term infants. Each week of shorter gestation was associated with an increased risk of ASD. High frequency ventilation and intracranial hemorrhage were associated with ASD among infants <34 weeks.
Authors: Kuzniewicz MW; Wi S; Qian Y; Walsh EM; Armstrong MA; Croen LA
J Pediatr. 2014 Jan;164(1):20-5. Epub 2013-10-22.
Cognitive enhancement therapy for adults with autism spectrum disorder: results of an 18-month feasibility study
Adults with autism experience significant impairments in social and non-social information processing for which few treatments have been developed. This study conducted an 18-month uncontrolled trial of Cognitive Enhancement Therapy (CET), a comprehensive cognitive rehabilitation intervention, in 14 verbal adults with autism spectrum disorder to investigate its feasibility, acceptability, and initial efficacy in treating these impairments. Results indicated that CET was satisfying to participants, with high treatment attendance and retention. Effects on cognitive deficits and social behavior were also large (d = 1.40-2.29) and statistically significant (all p < .001). These findings suggest that CET is a feasible, acceptable, and potentially effective intervention for remediating the social and non-social cognitive impairments in verbal adults with autism.
Authors: Eack SM; Greenwald DP; Hogarty SS; Bahorik AL; Litschge MY; Mazefsky CA; Minshew NJ
J Autism Dev Disord. 2013 Dec;43(12):2866-77. doi: 10.1007/s10803-013-1834-7.
Brief report: Is cognitive rehabilitation needed in verbal adults with autism? Insights from initial enrollment in a trial of cognitive enhancement therapy
Cognitive rehabilitation is an emerging set of potentially effective interventions for the treatment of autism spectrum disorder, yet the applicability of these approaches for "high functioning" adults who have normative levels of intelligence remains unexplored. This study examined the initial cognitive performance characteristics of 40 verbal adults with autism enrolled in a pilot trial of Cognitive Enhancement Therapy to investigate the need for cognitive rehabilitation in this population. Results revealed marked and broad deficits across neurocognitive and social-cognitive domains, despite above-average IQ. Areas of greatest impairment included processing speed, cognitive flexibility, and emotion perception and management. These findings indicate the need for comprehensive interventions designed to enhance cognition among verbal adults with autism who have intact intellectual functioning.
Authors: Eack SM; Bahorik AL; Hogarty SS; Greenwald DP; Litschge MY; Mazefsky CA; Minshew NJ
J Autism Dev Disord. 2013 Sep;43(9):2233-7. doi: 10.1007/s10803-013-1774-2.
Head Circumferences in Twins With and Without Autism Spectrum Disorders
To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20 % of males and 27 % of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16 % of males and 22 % of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.
Authors: Froehlich W; Croen LA; Hallmayer J; et al.
J Autism Dev Disord. 2013 Sep;43(9):2026-37.
Commonalities in social and non-social cognitive impairments in adults with autism spectrum disorder and schizophrenia
Autism spectrum disorder (ASD) and schizophrenia are both conditions that are characterized by impairments in social and non-social cognition, yet commonalities in the magnitude and domains of cognitive deficits across these two conditions remain unclear. This study examined neurocognitive and social-cognitive functioning in 47 outpatients with schizophrenia, 43 verbal adults with ASD, and 24 healthy volunteers. A comprehensive neuropsychological battery assessing processing speed, attention, memory, and problem-solving domains was administered along with a social-cognitive battery of emotion processing. Results demonstrated large and significant impairments in emotion processing and neurocognition relative to healthy individuals in participants with autism (d=-.97 and -1.71, respectively) and schizophrenia (d=-.65 and -1.48, respectively). No significant differences were observed between those with ASD and schizophrenia on any cognitive domain assessed, and the areas of greatest impairment were identical across both disorders and included slowness in speed of processing and an inability to understand emotions. These findings indicate a high degree of similarity in the cognitive challenges experienced by verbal adults with autism and schizophrenia, and the potential need for trans-diagnostic remediation approaches to enhance cognition in these conditions.
Authors: Eack SM; Bahorik AL; McKnight SA; Hogarty SS; Greenwald DP; Newhill CE; Phillips ML; Keshavan MS; Minshew NJ
Schizophr Res. 2013 Aug;148(1-3):24-8. doi: 10.1016/j.schres.2013.05.013. Epub 2013 Jun 13.
Is Infertility Associated with Childhood Autism?
Concerns persist about a possible link between infertility and risk of autism spectrum disorders (ASD). Interpretation of existing studies is limited by racial/ethnic homogeneity of study populations and other factors. Using a case-control design, we evaluated infertility history and treatment documented in medical records of members of Kaiser Permanente Northern California. Among singletons (349 cases, 1,847 controls), we found no evidence to support an increase in risk of ASD associated with infertility. Among multiple births (21 cases, 54 controls), we found an increased risk associated with infertility history and with infertility evaluations and treatment around the time of index pregnancy conception; however, small sample size and lack of detailed data on treatments preclude firm interpretation of results for multiple births.
Authors: Grether JK; Qian Y; Croughan MS; Wu YW; Schembri M; Camarano L; Croen LA
J Autism Dev Disord. 2013 Mar;43(3):663-72.
Use of Birth Certificates to Examine Maternal Occupational Exposures and Autism Spectrum Disorders in Offspring
The continuing rise in the prevalence of autism spectrum disorders has led to heightened interest in the role of nongenetic factors, including exogenous exposures, but little research has been conducted. To explore a possible role in autism etiology, we used data available from our prior studies to examine potential occupational exposures, as these may occur at higher levels than environmental exposures. Parental occupation was obtained from birth certificates for 284 children with autism and 659 controls, born in 1994 in the San Francisco Bay Area. Self-reported occupation and industry were coded into eight exposure/chemical groups based on potential neurotoxicity or reprotoxicity by a board-certified physician in occupational medicine and an industrial hygienist blinded to case-control status. Mothers of autistic children were twice as likely to work in occupations considered exposed (14.4%) as mothers of controls (7.2%) (adjusted odds ratio [AOR] 2.3 [95% confidence interval {CI} 1.3-4.2]). The exposure categories of the greatest frequency among case mothers were exhaust and combustion products (AOR = 12.0 [95% CI 1.4-104.6]) and disinfectants (AOR = 4.0 [95% CI 1.4-12.0]). Paternal occupational exposure was not associated with autism, potentially consistent with a direct in-utero exposure effect. There are several limitations of this hypothesis-generating study, including lack of detail on workplace and job duties, leading to possible misclassification and low proportion exposed. However, this misclassification would not be biased by case-control status and is unlikely to explain the associations we did find, suggesting that further research on exogenous exposures may yield useful etiologic clues.
Authors: Windham GC; Sumner A; Li SX; Anderson M; Katz E; Croen LA; Grether JK
Autism Res. 2013 Feb;6(1):57-63. Epub 2013 Jan 29.
Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study
We analyzed data from case groups of 538 children with autism spectrum disorders (ASD) and 163 with developmental delays (DD), and from 421 typically developing controls to assess associations with maternal influenza or fever during pregnancy. Exposure information was obtained by telephone interviews, and outcomes were clinically confirmed. Though neither ASD nor DD was associated with influenza, both were associated with maternal fever during pregnancy: OR’s (odds ratios) were 2.12 (95 % CI 1.17, 3.84) and 2.50 (95 % CI 1.20, 5.20) respectively. However, the fever-associated ASD risk was attenuated among mothers who reported taking antipyretic medications (OR = 1.30, 95 % CI 0.59, 2.84), but remained elevated for those who did not (OR = 2.55, 95 % CI 1.30, 4.99).
Authors: Zerbo O; Iosif AM; Walker C; Ozonoff S; Hansen RL; Hertz-Picciotto I;
J Autism Dev Disord. 2013 Jan;43(1):25-33. doi: 10.1007/s10803-012-1540-x.
A genome-wide survey of transgenerational genetic effects in autism
Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4)) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.
Authors: Tsang KM; Croen LA; Torres AR; Kharrazi M; Delorenze GN; Windham GC; Yoshida CK; Zerbo O; Weiss LA
PLoS ONE. 2013;8(10):e76978. Epub 2013-10-24.
Sequencing of the IL6 gene in a case–control study of cerebral palsy in children
Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein levels in amniotic fluid and cord plasma and within brain lesions. This SNP has been associated with other neurological, vascular, and malignant processes as well, often as part of a haplotype block. To refine the regional genetic association with CP, we sequenced (Sanger) the IL6 gene and part of the promoter region in 250 infants with CP and 305 controls. We identified a haplotype of 7 SNPs that includes rs1800795. In a recessive model of inheritance, the variant haplotype conferred greater risk (OR?=?4.3, CI?=?[2.0-10.1], p?=?0.00007) than did the lone variant at rs1800795 (OR?=?2.5, CI?=?[1.4-4.6], p?=?0.002). The risk haplotype contains one SNP (rs2069845, CI?=?[1.2-4.3], OR?=?2.3, p?=?0.009) that disrupts a methylation site. The risk haplotype identified in this study overlaps with previously identified haplotypes that include additional promoter SNPs. A risk haplotype at the IL6 gene likely confers risk to CP, and perhaps other diseases, via a multi-factorial mechanism.
Authors: Khankhanian P; Baranzini SE; Johnson BA; Madireddy L; Nickles D; Croen LA; Wu YW
BMC Med Genet. 2013;14:126. Epub 2013-12-07.
The Study to Explore Early Development (SEED): A Multisite Epidemiologic Study of Autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network
The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case-control design with population-based ascertainment of children aged 2-5 years with an autism spectrum disorder (ASD) and children in two control groups-one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes.
Authors: Schendel DE; Croen LA; Yeargin-Allsopp M; et al.
J Autism Dev Disord. 2012 Oct;42(10):2121-40.
Evaluating Changes in the Prevalence of the Autism Spectrum Disorders (ASDs)
Autism spectrum disorders (ASDs) are estimated to occur among about one percent of children in the United States. This estimate is in line with estimates from other industrialized countries. However, the identified prevalence of ASDs has increased significantly in a short time period based on data from multiple studies including the U.S. Centers for Disease Control and Prevention’s (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network. Whether increases in ASD prevalence are partly attributable to a true increase in the risk of developing ASD or solely to changes in community awareness and identification patterns is not known. It is clear that more children are identified with an ASD now than in the past and the impact on individuals, families, and communities is significant. However, disentangling the many potential reasons for ASD prevalence increases has been challenging. Understanding the relative contribution of multiple factors such as variation in study methods, changes in diagnostic and community identification, and potential changes in risk factors is an important priority for the ADDM Network and for CDC. This article summarizes the discussion from a workshop that was co-sponsored by CDC and Autism Speaks as a forum for sharing knowledge and opinions of a diverse range of stakeholders about changes in ASD prevalence. Panelists discussed recommendations for building on existing infrastructure and developing new initiatives to better understand ASD trends. The information, research, and opinions shared during this workshop add to the knowledge base about ASD prevalence in an effort to stimulate further work to understand the multiple reasons behind increasing ASD prevalence.
Authors: Rice CE; Rosanoff M; Dawson G; Durkin MS; Croen LA; Singer A; Yeargin-Allsopp M
Public Health Rev. 2012;34(2):1-22.
Infant siblings and the investigation of autism risk factors
ABSTRACT: Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
Authors: Newschaffer CJ; Croen LA; Shedd-Wise KM; et al.
J Neurodev Disord. 2012 Apr 18;4(1):7.
Candidate Genes and Risk for Cerebral Palsy: a Population-Based Study
Studies suggest that genetic polymorphisms may increase an individual’s susceptibility to CP. Most findings have yet to be corroborated in an independent cohort. This case-control study is nested within all 334,333 infants >/=36 wk gestation born at Kaiser Permanente Medical Care Program, 1991-2002. We included only non-Hispanic whites who had a neonatal blood sample available. Case patients (n = 138) were identified from medical records to have spastic or dyskinetic CP. Controls (n = 165) were randomly selected from the population. We genotyped polymorphisms previously associated with CP: inducible NOS (iNOS)-231, apolipoprotein E (apoE) epsilon2 and epsilon4 alleles, TNF-alpha-308, IL-8 -251, lymphotoxin 60, endothelial NOS -922, endothelial protein C receptor 219, mannose-binding lectin 54 and 52, factor V Leiden, methyltetrahydrofolate reductase 1298 and 667, prothrombin 20210, and platelet activator inhibitor 11053. Similar to previous reports, the iNOS-231 T allele (25.7 versus 18.9%, p = 0.04) and the apoE epsilon4 allele (19.3 versus 13.2%, p = 0.04) were more common in patients with CP than in controls. However, there was no statistically significant association between any genetic polymorphism and CP after correction for multiple comparisons.
Authors: Wu YW; Croen LA; Vanderwerf A; Gelfand AA; Torres AR
Pediatr Res. 2011 Dec;70(6):642-6.
Prenatal exposure to beta2-adrenergic receptor agonists and risk of autism spectrum disorders
This study aims to investigate the association between prenatal exposure to terbutaline and other beta2 adrenergic receptor (B2AR) agonists and autism spectrum disorders (ASDs). The methodology used is a case-control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 291) were children with an ASD diagnosis; controls (n = 284) were children without ASDs, randomly sampled and frequency-matched to cases on sex, birth year, and delivery hospital. Exposure to B2AR agonists during 30 days prior to conception and each trimester of pregnancy was ascertained from prenatal medical records and health plan databases. The frequency of exposure to any B2AR agonist during pregnancy was similar for mothers of children with ASD and mothers of controls (18.9% vs. 14.8%, P = 0.19). Exposure to B2AR agonists other than terbutaline was not associated with an increased risk for ASDs. However, terbutaline exposure for >2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (OR(adj) = 4.4; 95% confidence interval, 0.8-24.6). This analysis does not offer evidence linking B2AR exposure in pregnancy with autism risk. However, exposure to terbutaline during the third trimester for >2 days may be associated with an increased risk of autism. Should this result be confirmed in larger samples, it would point to late pregnancy as an etiologic window of interest in autism risk factor research.
Authors: Croen LA; Connors SL; Matevia M; Qian Y; Newschaffer C; Zimmerman AW
J Neurodev Disord. 2011 Dec;3(4):307-15. Epub 2011 Aug 27.
Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism
CONTEXT: Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. OBJECTIVE: To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. Design, Setting, and PARTICIPANTS: Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services. MAIN OUTCOME MEASURES: Structured diagnostic assessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD). RESULTS: For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD). CONCLUSION: Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.
Authors: Hallmayer J; Croen LA; Risch N; et al.
Arch Gen Psychiatry. 2011 Nov;68(11):1095-102. Epub 2011 Jul 4.
Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders
CONTEXT: The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD. OBJECTIVE: To systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD. DESIGN: Population-based case-control study. Medical records were used to ascertain case children and control children and to derive prospectively recorded information on mothers’ use of antidepressant medications, mental health history of mothers, and demographic and medical covariates. SETTING: The Kaiser Permanente Medical Care Program in Northern California. PARTICIPANTS: A total of 298 case children with ASD (and their mothers) and 1507 randomly selected control children (and their mothers) drawn from the membership of the Kaiser Permanente Medical Care Program in Northern California. MAIN OUTCOME MEASURES: ASDs. RESULTS: Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors. CONCLUSION: Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.
Authors: Croen LA; Grether JK; Yoshida CK; Odouli R; Hendrick V
Arch Gen Psychiatry. 2011 Nov;68(11):1104-12. Epub 2011 Jul 4.
Birth Prevalence of Autism Spectrum Disorders in the San Francisco Bay Area by Demographic and Ascertainment Source Characteristics
Using standardized methods for multi-source surveillance, we calculated the prevalence of autism spectrum disorders (ASD) among children born in a racially diverse region in 1994 or 1996 as 4.7/1000 live births. Children with ASD before age 9 were identified through chart abstraction at health-related sources; three-quarters were being served by the state-wide Department of Developmental Services. In adjusted models, we found a male:female ratio of 6:1, a doubling of ASD prevalence among children of older mothers (40+), and lower prevalence with lower paternal education. Children of Black or Hispanic mothers had lower prevalence than those of White, non-Hispanic mothers, but these differences were attenuated after adjustment. Prevalence in children of Asian mothers was similar to Whites. Potential under-counting is discussed.
Authors: Windham GC; Anderson MC; Croen LA; Smith KS; Collins J; Grether JK
J Autism Dev Disord. 2011 Oct;41(10):1362-72.
Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: A case-control study
ABSTRACT: BACKGROUND: Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. METHODS: Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. RESULTS: Elevated concentrations of IFN-gamma, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. CONCLUSION: The profile of elevated serum IFN-gamma, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.
Authors: Goines PE; Croen LA; Braunschweig D; Yoshida CK; Grether J; Hansen R; Kharrazi M; Ashwood P; Van de Water J
Mol Autism. 2011 Aug 2;2:13.
Month of conception and risk of autism
BACKGROUND:Studies of season of birth or season of conception can provide clues about etiology. We investigated whether certain months or seasons of conception are associated with increased risk of autism spectrum disorders, for which etiology is particularly obscure.METHODS:The study population comprises 6,604,975 children born from 1990 to 2002 in California. Autism cases (n = 19,238) were identified from 1990 through 2008 in databases of the California Department of Developmental Services, which coordinates services for people with developmental disorders. The outcome in this analysis was autism diagnosed before the child’s sixth birth date. The main independent variables were month of conception and season of conception (winter, spring, summer, and fall). Multivariate logistic regression models were used to estimate odds ratios (ORs) with their 95% confidence intervals (CIs) for autism by month of conception.RESULTS:Children conceived in December (OR = 1.09 [95% CI = 1.02-1.17]), January (1.08 [1.00-1.17]), February (1.12 [1.04-1.20]), or March (1.16 [1.08-1.24]) had higher risk of developing autism compared with those conceived in July. Conception in the winter season (December, January, and February) was associated with a 6% (OR = 1.06, 95% CI = 1.02-1.10) increased risk compared with summer.CONCLUSIONS:Higher risks for autism among those conceived in winter months suggest the presence of environmental causes of autism that vary by season.
Authors: Zerbo O; Iosif AM; Delwiche L; Walker C; Hertz-Picciotto I;
Epidemiology. 2011 Jul;22(4):469-75. doi: 10.1097/EDE.0b013e31821d0b53.
Jaundice-autism link unconvincing
Authors: Newman TB; Croen LA
Pediatrics. 2011 Mar;127(3):e858-9.
Neonatally measured immunoglobulins and risk of autism
Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.
Authors: Grether JK; Croen LA; Anderson MC; Nelson KB; Yolken RH
Autism Res. 2010 Dec;3(6):323-32. Epub 2010 Dec 9.
Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism
OBJECTIVE: Exposure to thimerosal, a mercury-containing preservative that is used in vaccines and immunoglobulin preparations, has been hypothesized to be associated with increased risk of autism spectrum disorder (ASD). This study was designed to examine relationships between prenatal and infant ethylmercury exposure from thimerosal-containing vaccines and/or immunoglobulin preparations and ASD and 2 ASD subcategories: autistic disorder (AD) and ASD with regression. METHODS: A case-control study was conducted in 3 managed care organizations (MCOs) of 256 children with ASD and 752 controls matched by birth year, gender, and MCO. ASD diagnoses were validated through standardized in-person evaluations. Exposure to thimerosal in vaccines and immunoglobulin preparations was determined from electronic immunization registries, medical charts, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We used conditional logistic regression to assess associations between ASD, AD, and ASD with regression and exposure to ethylmercury during prenatal, birth-to-1 month, birth-to-7-month, and birth-to-20-month periods. RESULTS: There were no findings of increased risk for any of the 3 ASD outcomes. The adjusted odds ratios (95% confidence intervals) for ASD associated with a 2-SD increase in ethylmercury exposure were 1.12 (0.83-1.51) for prenatal exposure, 0.88 (0.62-1.26) for exposure from birth to 1 month, 0.60 (0.36-0.99) for exposure from birth to 7 months, and 0.60 (0.32-0.97) for exposure from birth to 20 months. CONCLUSIONS: In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs.
Authors: Price CS; Croen LA; DeStefano F; et al.
Pediatrics. 2010 Oct;126(4):656-64. Epub 2010 Sep 13.
Antenatal ultrasound and risk of autism spectrum disorders
We evaluated antenatal ultrasound (U/S) exposure as a risk factor for autism spectrum disorders (ASD), comparing affected singleton children and control children born 1995-1999 and enrolled in the Kaiser Permanente health care system. Among children with ASD (n = 362) and controls (n = 393), 13% had no antenatal exposure to U/S examinations; case-control differences in number of exposures during the entire gestation or by trimester were small and not statistically significant. In analyses adjusted for covariates, cases were generally similar to controls with regard to the number of U/S scans throughout gestation and during each trimester. This study indicates that antenatal U/S is unlikely to increase the risk of ASD, although studies examining ASD subgroups remain to be conducted.
Authors: Grether JK; Li SX; Yoshida CK; Croen LA
J Autism Dev Disord. 2010 Feb;40(2):238-45. Epub 2009 Sep 1.
Risk of autism and increasing maternal and paternal age in a large north American population
Previous studies are inconsistent regarding whether there are independent effects of maternal and paternal age on the risk of autism. Different biologic mechanisms are suggested by maternal and paternal age effects. The study population included all California singletons born in 1989-2002 (n = 7,550,026). Children with autism (n = 23,311) were identified through the California Department of Developmental Services and compared with the remainder of the study population, with parental ages and covariates obtained from birth certificates. Adjusted odds ratios and 95% confidence intervals were used to evaluate the risk of autism associated with increasing maternal and paternal age. In adjusted models that included age of the other parent and demographic covariates, a 10-year increase in maternal age was associated with a 38% increase in the odds ratio for autism (odds ratio = 1.38, 95% confidence interval: 1.32, 1.44), and a 10-year increase in paternal age was associated with a 22% increase (odds ratio = 1.22, 95% confidence interval: 1.18, 1.26). Maternal and paternal age effects were seen in subgroups defined by race/ethnicity and other covariates and were of greater magnitude among first-born compared with later-born children. Further studies are needed to help clarify the biologic mechanisms involved in the independent association of autism risk with increasing maternal and paternal age.
Authors: Grether JK; Anderson MC; Croen LA; Smith D; Windham GC
Am J Epidemiol. 2009 Nov 1;170(9):1118-26. Epub 2009 Sep 25.
Investigation of shifts in autism reporting in the California Department of Developmental Services
We investigated if shifts in the coding of qualifying conditions in the California Department of Developmental Services (DDS) have contributed to the increase in California children with autism observed in recent years. Qualifying condition codes for mental retardation (MR) and autism in DDS electronic files were compared to hard-copy records for samples of children born 1987, 1990, 1994, and 1997. Contrary to expectations, we did not find evidence of a coding shift from ‘MR only’ to ‘both MR and autism’ or an increase in the proportion of children with coded autism who lacked supportive diagnostic documentation in records (possible ‘misclassifications’). These results indicate that changes in DDS coding practices are unlikely to explain the increase in DDS clients with autism.
Authors: Grether JK; Rosen NJ; Smith KS; Croen LA
J Autism Dev Disord. 2009 Oct;39(10):1412-9. Epub 2009 May 29.
Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGF beta 1) because of its role in controlling immune responses. Plasma levels of active TGF beta 1 were evaluated in 75 children with ASD compared with 68 controls. Children with ASD had significantly lower plasma TGF beta 1 levels compared with typically developing controls (p=0.0017) and compared with children with developmental disabilities other than ASD (p=0.0037), after adjusting for age and gender. In addition, there were significant correlations between psychological measures and TGF beta 1 levels, such that lower TGF beta 1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGF beta 1. Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.
Authors: Ashwood P; Enstrom A; Krakowiak P; Hertz-Picciotto I; Hansen RL; Croen LA; Ozonoff S; Pessah IN; Van de Water J
J Neuroimmunol. 2008 Nov 15;204(1-2):149-53.
Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study
BACKGROUND: Immune dysfunction has been associated with autism, yet whether maternal immune status during pregnancy plays a causal role remains to be clarified. METHODS: We conducted a population-based case-control study nested within the cohort of infants born July 2000-September 2001 to women who participated in the prenatal screening program in Orange County, California. Cases (AU; n = 84) were children receiving services for autism at the Regional Center of Orange County. Two control groups were included: children with mental retardation or developmental delay (MR; n = 49) receiving services at the same regional center; and children not receiving services for developmental disabilities, randomly sampled from the California birth certificate files (GP; n = 160). Maternal autoantibody reactivity to fetal brain protein was measured by Western blot in archived mid-pregnancy blood specimens drawn during routine prenatal screening. Presence of specific bands and band patterns were compared between the three study groups. RESULTS: The pattern of maternal mid-gestation antibody reactivity to human fetal brain protein varied by study group and by autism onset type, although most differences did not reach statistical significance. Reactivity to a band at 39 kDa was more common among mothers of children with autism (7%) compared with mothers of MR (0%; p = .09) and GP control subjects (2%; p = .07), and simultaneous reactivity to bands at 39 kDa and 73 kDa was found only in mothers of children with early onset autism (n = 3). CONCLUSIONS: Our findings indicate that further studies of prenatal immune markers might be a productive area for etiologic and biologic marker discovery for autism.
Authors: Croen LA; Braunschweig D; Haapanen L; Yoshida CK; Fireman B; Grether JK; Kharrazi M; Hansen RL; Ashwood P; Van de Water J
Biol Psychiatry. 2008 Oct 1;64(7):583-8. Epub 2008 Jun 20.
Maternal Rh D status, anti-D immune globulin exposure during pregnancy, and risk of autism spectrum disorders
OBJECTIVE: The objective of the study was to investigate the association between maternal Rh D status, prenatal exposure to anti-D immune globulin, and the risk of autism in the offspring. STUDY DESIGN: Case-control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 400) were children with an autism diagnosis; controls (n = 410) were children without autism, randomly sampled and frequency matched to cases on sex, birth year, and birth hospital. Maternal Rh D status and anti-D immune globulin exposure were ascertained from prenatal medical records. RESULTS: No case-control differences were observed for maternal Rh negative status (11.5% vs 10.0%, P = .5) or prenatal anti-D immune globulin exposure (10.0% vs. 9.3%, P = .7). Risk of autism remained unassociated with maternal Rh status or prenatal exposure to anti-D immune globulins after adjustment for covariates. CONCLUSION: These data support previous findings that prenatal exposure to thimerosal-containing anti-D immune globulins does not increase the risk of autism.
Authors: Croen LA; Matevia M; Yoshida CK; Grether JK
Am J Obstet Gynecol. 2008 Sep;199(3):234.e1-6. Epub 2008 Jun 13.
Detection of IL-17 and IL-23 in plasma samples of children with autism
Interleukin-23 (IL-23) is a survival factor for a newly described population of T lymphocytes, namely Th-17 cells, that secrete IL-17, tumor necrosis factor- alpha (TNF?) and IL-6. It has been shown that Th-17 cells are a pathogenic T cell subset involved in autoimmune and chronic inflammatory diseases. Based on the increasing evidence of immune dysfunction in autism, including possible autoimmune and inflammatory processes, we hypothesized that Th-17 cells, a T cell lineage that has not been previously examined in this disorder, may be altered in autism. To assess the potential role, if any, of Th-17 cells in autism, we analyzed plasma samples obtained from children ranging in age from 2-5 years with a diagnosis of autism and age-matched typically developing controls for the presence of IL-17 and IL-23 cytokines. Plasma samples from 40 children with autism including 20 children with a regressive form of autism, 20 with early onset and no regression and 20 typically developing age-matched control children were analyzed for IL-17 and IL-23, under the hypothesis that altered number and function of Th-17 cells would directly correlate with altered levels of IL-17 and IL-23 in the plasma. In this study, we were able to demonstrate that IL-23 cytokine levels were significantly different in children with autism compared with age-matched controls, a finding primarily driven by children with early onset autism. In contrast, there were no statistical differences in IL-17 levels autism compared with age-matched typically developing controls. This is the first study to report altered IL-23 production in autism. The decreased plasma IL-23 production observed in children with autism warrants further research as to its affect on the generation and survival of Th-17 cells, a subset important in neuroinflammatory conditions that may include autism.
Authors: Enstrom A; Onore C; Hertz-Piccioto I; Hansen R; Croen L; Van de Water J; Ashwood P
Am J Biochem Biotechnology. 2008 Jun;4(2):114-20.
Peripheral blood leukocyte production of BDNF following mitogen stimulation in early onset and regressive autism
Brain-derived neurotrophic factor (BDNF) is critical for neuronal differentiation and synaptic development. BDNF is also implicated in the development of psychological disorders including depression, bipolar disorder and schizophrenia. Previously, elevated BDNF levels were observed in neonatal blood samples from infants who were later diagnosed with autism when compared with children who developed normally, suggesting that BDNF may be involved in the development of autism. BDNF is produced by activated brain microglial cells, a cellular phenotype that shares several features with peripheral macrophages, suggesting an important role for the immune system in BDNF production. We hypothesized that under mitogenic stimulation, peripheral blood mononuclear cells obtained from children with autism may have altered BDNF production compared with age-matched typically developing control subjects. In addition, we examined the differences between the production of BDNF in classic/early-onset autism and children who had a regressive form of autism. We show here that plasma levels of BDNF levels are increased in children with autism, especially in early onset autism subjects. Furthermore, under mitogenic stimulation with PHA and LPS, BDNF production is significantly increased in children with autism compared with typically developing subjects. However, stimulation with tetanus toxoid results in a decreased response in children with autism. This data suggest that immune cell-derived production of BDNF could be an important source for the increased BDNF that is detected in some subjects with autism. As a neurotrophic factor produced by immune cells, BDNF could help elucidate the role of the immune system in neurodevelopment and neuronal maintenance, which may be dysregulated in autism.
Authors: Enstrom A; Onore C; Tarver A; Hertz-Picciotto I; Hansen R; Croen L; Van de Water J; Ashwood P
Am J Biochem Biotechnology. 2008 Jun;4(2):121-9.
Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study
This study compared parent-reported sleep characteristics in 2- to 5-year-old children with autism spectrum disorders (ASD) to children with other developmental delays (DD) and typical development (TD). We included 529 children (303 ASD [167 males], 63 DD [46 males], and 163 TD [134 males]) enrolled in the CHARGE study, an ongoing population-based case-control study. The mean age of participants was 3.6 years (standard deviation, 0.8 years). ASD diagnosis was confirmed with Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedules (ADOS). Cognitive and adaptive functioning was assessed using Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS), respectively. Demographic, medical and sleep history information were ascertained from California birth records, telephone interview, medical assessments at clinic visit, and parent-administered questionnaires. Fifty-three percent of children with ASD had at least one frequent sleep problem, followed by 46% of children with DD, and 32% of the TD group (P < 0.0001). Exploratory factor analyses of sleep history data yielded two factors: sleep onset problems and night waking. Children with ASD had marginally higher sleep onset factor scores and significantly higher night waking factor scores compared with the TD group. Factor scores for children with DD were intermediate between the ASD and TD groups. Cognitive or adaptive development did not predict severity of sleep problems in the ASD group.
Authors: Krakowiak P; Goodlin-Jones B; Hertz-Picciotto I; Croen LA; Hansen RL
J Sleep Res. 2008 Jun;17(2):197-206.
Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study
To investigate levels of brain-derived neurotrophic factor (BDNF) in mid-pregnancy and neonatal blood specimens as early biologic markers for autism, we conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, CA. Cases (n=84) were all children receiving services for autism at the Regional Center of Orange County. Two comparison groups from the same study population were included: children with mental retardation or developmental delay (n=49) receiving services at the same regional center, and children not receiving services for developmental disabilities, randomly sampled from the California birth certificate files (n=159), and frequency matched to autism cases on sex, birth year, and birth month. BDNF concentrations were measured in archived mid-pregnancy and neonatal blood specimens drawn during routine prenatal and newborn screening using a highly sensitive bead-based assay (Luminex, Biosource Human BDNF Antibody Bead Kit, Invitrogen-Biosource, Carlsbad, CA). The concentration of BDNF in maternal mid-pregnancy and neonatal specimens was similar across all three study groups. These data do not support previous findings of an association between BDNF and autism and suggest that the concentration of BDNF during critical periods of early neurodevelopment is not likely to be a useful biomarker for autism susceptibility.
Authors: Croen LA; Goines P; Braunschweig D; Yolken R; Yoshida CK; Grether JK; Fireman B; Kharrazi M; Hansen RL; Van de Water J
Autism Res. 2008 Apr;1(2):130-7.
Autism: maternally derived antibodies specific for fetal brain proteins
Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies. To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09-15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.
Authors: Braunschweig D; Ashwood P; Krakowiak P; Hertz-Picciotto I; Hansen R; Croen LA; Pessah IN; Van de Water J
Neurotoxicology. 2008 Mar;29(2):226-31. Epub 2007 Nov 6.
Detection of IL-17 and IL-23 in plasma samples of children with autism
Interleukin-23 (IL-23) is a survival factor for a newly described population of T lymphocytes, namely Th-17 cells, that secrete IL-17, tumor necrosis factor- alpha (TNF?) and IL-6. It has been shown that Th-17 cells are a pathogenic T cell subset involved in autoimmune and chronic inflammatory diseases. Based on the increasing evidence of immune dysfunction in autism, including possible autoimmune and inflammatory processes, we hypothesized that Th-17 cells, a T cell lineage that has not been previously examined in this disorder, may be altered in autism. To assess the potential role, if any, of Th-17 cells in autism, we analyzed plasma samples obtained from children ranging in age from 2-5 years with a diagnosis of autism and age-matched typically developing controls for the presence of IL-17 and IL-23 cytokines. Plasma samples from 40 children with autism including 20 children with a regressive form of autism, 20 with early onset and no regression and 20 typically developing age-matched control children were analyzed for IL-17 and IL-23, under the hypothesis that altered number and function of Th-17 cells would directly correlate with altered levels of IL-17 and IL-23 in the plasma. In this study, we were able to demonstrate that IL-23 cytokine levels were significantly different in children with autism compared with age-matched controls, a finding primarily driven by children with early onset autism. In contrast, there were no statistical differences in IL-17 levels autism compared with age-matched typically developing controls. This is the first study to report altered IL-23 production in autism. The decreased plasma IL-23 production observed in children with autism warrants further research as to its affect on the generation and survival of Th-17 cells, a subset important in neuroinflammatory conditions that may include autism.
Authors: Enstrom A; Onore C; Hertz-Piccioto I; Hansen R; Croen L; Van de Water J; Ashwood P
Am J Biochem Biotechnology. 2008 Jun;4(2):114-20.
Regression in autism: prevalence and associated factors in the CHARGE Study
OBJECTIVE: The aim of this study was to examine the prevalence of regressive autism and associated demographic, medical, and developmental factors by using 2 different definitions of regression based on the Autism Diagnostic Interview, Revised. METHODS: Subjects were aged 2 to 5 years, with autism (AU) or autism spectrum disorder (ASD) confirmed by standardized measures. Children with regression, defined as a) loss of both language and social skills or b) loss of either language or social skills, were compared with each other and to children with AU or ASD with no reported loss of skills on developmental and adaptive functioning. Parents reported on seizure, gastrointestinal, and sleep concerns. RESULTS: Fifteen percent (50/333) of the combined AU-ASD group lost both language and social skills; 41% (138/333) lost either language or social skills. No differences were found between the 2 samples of children with regression. Few developmental, demographic, or medical differences were found between the combined regression group and children without loss of skills, in both the larger AU-ASD sample and the more homogeneous AU-only sample. Children with regression had significantly lower communication scores than children without regression. CONCLUSIONS: The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes.
Authors: Hansen RL; Ozonoff S; Krakowiak P; Angkustsiri K; Jones C; Deprey LJ; Le DN; Croen LA; Hertz-Picciotto I
Ambul Pediatr. 2008 Jan-Feb;8(1):25-31.
Gene expression changes in children with autism
The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP (n=55 genes), for A-E versus GP (n=140 genes), for A-R versus GP (n=20 genes), and for A-R versus A-E (n=494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A-E, and A-R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway (p=0.02). A subset of these genes (n=7) was tested with qRT-PCR and all genes were found to be differentially expressed (p<0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder.
Authors: Gregg JP; Lit L; Baron CA; Hertz-Picciotto I; Walker W; Davis RA; Croen LA; Ozonoff S; Hansen R; Pessah IN; Sharp FR
Genomics. 2008 Jan;91(1):22-9. Epub 2007 Nov 14.
Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype?
There is evidence of both immune dysregulation and autoimmune phenomena in children with autism spectrum disorders (ASD). We examined the hormone/cytokine leptin in 70 children diagnosed with autism (including 37 with regression) compared with 99 age-matched controls including 50 typically developing (TD) controls, 26 siblings without autism, and 23 children with developmental disabilities (DD). Children with autism had significantly higher plasma leptin levels compared with TD controls (p<.006). When further sub-classified into regression or early onset autism, children with early onset autism had significantly higher plasma leptin levels compared with children with regressive autism (p<.042), TD controls (p<.0015), and DD controls (p<.004). We demonstrated an increase in leptin levels in autism, a finding driven by the early onset group.
Authors: Ashwood P; Kwong C; Hansen R; Hertz-Picciotto I; Croen L; Krakowiak P; Walker W; Pessah IN; Van de Water J
J Autism Dev Disord. 2008 Jan;38(1):169-75. Epub 2007 Mar 9.
Maternal and paternal age and risk of autism spectrum disorders
OBJECTIVE: To explore the association between maternal and paternal age and risk of autism spectrum disorders (ASDs) in offspring. DESIGN: Historical birth cohort study. SETTING: Kaiser Permanente (KP) in Northern California. PARTICIPANTS: All singleton children born at KP from January 1, 1995, to December 31, 1999, were included in the study. We identified 593 children who had ASD diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification, code 299.0 or 299.8) recorded 2 or more times in KP outpatient databases before May 2005. These children were compared with all 132,251 remaining singleton KP births. Main Exposures Maternal and paternal age at birth of offspring. MAIN OUTCOME MEASURES: Relative risks (RRs) estimated from proportional hazards regression models. Risk of ASDs evaluated in relation to maternal and paternal age, adjusted for each other and for the sex, birth date, and birth order of the child, maternal and paternal educational level, and maternal and paternal race/ethnicity. RESULTS: Risk of ASDs increased significantly with each 10-year increase in maternal age (adjusted RR, 1.31; 95% confidence interval [CI], 1.07-1.62) and paternal age (RR, 1.28; 95% CI, 1.09-1.51). Adjusted RRs for both maternal and paternal age were elevated for children with autistic disorder (maternal age: RR, 1.18; 95% CI, 0.87-1.60; paternal age: RR, 1.34; 95% CI, 1.06-1.69) and children with Asperger disorder or pervasive developmental disorder not otherwise specified (maternal age: RR, 1.45; 95% CI, 1.09-1.93; paternal age: RR, 1.24; 95% CI, 0.99-1.55). Associations with parental age were somewhat stronger for girls than for boys, although sex differences were not statistically significant. CONCLUSION: Advanced maternal and paternal ages are independently associated with ASD risk.
Authors: Croen LA; Najjar DV; Fireman B; Grether JK
Arch Pediatr Adolesc Med. 2007 Apr;161(4):334-40.
The epidemiology of autism spectrum disorders
Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.
Authors: Newschaffer CJ; Croen LA; Windham GC; et al.
Annu Rev Public Health. 2007;28:235-58.
Infection in the first 2 years of life and autism spectrum disorders
OBJECTIVE: The purpose of this work was to investigate the association between infections in the first 2 years and subsequent diagnosis of autism spectrum disorders. METHODS: We conducted a case-control study among children born at Kaiser Permanente Northern California from 1995 to 1999. Case subjects (n = 403) were children with an autism diagnosis recorded in Kaiser Permanente databases. Control subjects (n = 2100) were randomly sampled from the remaining children without autism and frequency matched to case subjects on gender, birth year, and birth hospital. Information on infections and covariates were obtained from Kaiser Permanente and birth certificate databases. RESULTS: Overall, infection diagnoses in the first 2 years of life were recorded slightly less often for children with autism than control children (95.0% vs 97.5%). Among specific diagnoses, upper respiratory infections were significantly less frequently diagnosed and genitourinary infections more frequently diagnosed in children with autism. In the first 30 days of life, the frequency of having an infection was slightly higher among children with autism (22.6% vs 18.7%). CONCLUSIONS: Children with subsequent diagnoses of autism do not have more overall infections in the first 2 years of life than children without autism. Data suggest that children with autism may have modestly elevated rates of infection in the first 30 days and that, during the first 2 years, children with autism may be at higher risk for certain types of infections and lower risk for others. Additional studies that explore the associations between prenatal and early childhood infections and autism may help clarify the role of infection and the immune system in the etiology of autism spectrum disorder.
Authors: Rosen NJ; Yoshida CK; Croen LA
Pediatrics. 2007 Jan;119(1):e61-9.
A comparison of health care utilization and costs of children with and without autism spectrum disorders in a large group-model health plan
OBJECTIVE: Data on the current costs of medical services for children with autism spectrum disorders are lacking. Our purpose for this study was to compare health care utilization and costs of children with and without autism spectrum disorders in the same health plan. PATIENTS AND METHODS: Participants included all 2- to 18-year-old children with autism spectrum disorders (n = 3053) and a random sample of children without autism spectrum disorders (n = 30529) who were continuously enrolled in the Kaiser Permanente Medical Care Program in northern California between July 1, 2003, and June 30, 2004. Data on health care utilization and costs were derived from health plan administrative databases. MAIN OUTCOME MEASURES: Outcome measures included mean annual utilization and costs of health services per child. RESULTS: Children with autism spectrum disorders had a higher annual mean number of total clinic (5.6 vs 2.8), pediatric (2.3 vs 1.6), and psychiatric (2.2 vs 0.3) outpatient visits. A higher percentage of children with autism spectrum disorders experienced inpatient (3% vs 1%) and outpatient (5% vs 2%) hospitalizations. Children with autism spectrum disorders were nearly 9 times more likely to use psychotherapeutic medications and twice as likely to use gastrointestinal agents than children without autism spectrum disorders. Mean annual member costs for hospitalizations (550 dollars vs 208 dollars), clinic visits (1373 dollars vs 540 dollars), and prescription medications (724 dollars vs 96 dollars) were more than double for children with autism spectrum disorders compared with children without autism spectrum disorders. The mean annual age- and gender-adjusted total cost per member was more than threefold higher for children with autism spectrum disorders (2757 dollars vs 892 dollars). Among the subgroup of children with other psychiatric conditions, total mean annual costs were 45% higher for children with autism spectrum disorders compared with children without autism spectrum disorders; excess costs were largely explained by the increased use of psychotherapeutic medications. CONCLUSIONS: The utilization and costs of health care are substantially higher for children with autism spectrum disorders compared with children without autism spectrum disorders. Research is needed to evaluate the impact of improvements in the management of children with autism spectrum disorders on health care utilization and costs.
Authors: Croen LA; Najjar DV; Ray GT; Lotspeich L; Bernal P
Pediatrics. 2006 Oct;118(4):e1203-11.
Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area
OBJECTIVE: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. METHODS: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. RESULTS: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.
Authors: Windham GC; Zhang L; Gunier R; Croen LA; Grether JK
Environ Health Perspect. 2006 Sep;114(9):1438-44.
The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism
Causes and contributing factors for autism are poorly understood. Evidence suggests that prevalence is rising, but the extent to which diagnostic changes and improvements in ascertainment contribute to this increase is unclear. Both genetic and environmental factors are likely to contribute etiologically. Evidence from twin, family, and genetic studies supports a role for an inherited predisposition to the development of autism. Nonetheless, clinical, neuroanatomic, neurophysiologic, and epidemiologic studies suggest that gene penetrance and expression may be influenced, in some cases strongly, by the prenatal and early postnatal environmental milieu. Sporadic studies link autism to xenobiotic chemicals and/or viruses, but few methodologically rigorous investigations have been undertaken. In light of major gaps in understanding of autism, a large case-control investigation of underlying environmental and genetic causes for autism and triggers of regression has been launched. The CHARGE (Childhood Autism Risks from Genetics and Environment) study will address a wide spectrum of chemical and biologic exposures, susceptibility factors, and their interactions. Phenotypic variation among children with autism will be explored, as will similarities and differences with developmental delay. The CHARGE study infrastructure includes detailed developmental assessments, medical information, questionnaire data, and biologic specimens. The CHARGE study is linked to University of California-Davis Center for Children’s Environmental Health laboratories in immunology, xenobiotic measurement, cell signaling, genomics, and proteomics. The goals, study design, and data collection protocols are described, as well as preliminary demographic data on study participants and on diagnoses of those recruited through the California Department of Developmental Services Regional Center System.
Authors: Hertz-Picciotto I; Croen LA; Hansen R; Jones CR; van de Water J; Pessah IN
Environ Health Perspect. 2006 Jul;114(7):1119-25.
Congenital anomalies associated with autism spectrum disorders
This study examined whether major congenital structural anomalies identified in infancy occurred more frequently in children later diagnosed with autism spectrum disorders (ASD; n=417; 341 males, 76 females) than in comparison children (n=2,067; 1,681 males, 386 females). Participants were sampled from infants born at Kaiser Permanente Northern California facilities between 1995 and 1999 who remained health plan members for at least 2 years (n=88,163). Comparison children were frequency-matched to children with ASD according to sex, birth year, and birth hospital. Congenital anomalies were diagnosed in 10.8% of children with ASD and 6.2% of comparison children (crude odds ratio [ORc] 1.8, 95% confidence interval [CI] 1.3-2.6). This association remained significant after adjustment for key maternal and infant covariates (adjusted OR [ORa] 1.7, 95% CI 1.1-2.4). Almost all organ-system anomaly categories were more prevalent in children with ASD, however only gastrointestinal anomalies were significantly associated with ASD in adjusted analyses (1.9 vs 0.4%, ORa 5.1, 95% CI 1.8-14.1).
Authors: Wier ML; Yoshida CK; Odouli R; Grether JK; Croen LA
Dev Med Child Neurol. 2006 Jun;48(6):500-7.
Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study
OBJECTIVE: To investigate the association between physician-documented diagnoses of maternal autoimmune diseases, allergies, and asthma around the time of pregnancy and subsequent diagnoses of autism in children. DESIGN: A case-control study nested within a cohort of infants born between January 1995 and June 1999. SETTING: Northern California Kaiser Permanente Medical Care Program. PARTICIPANTS: Cases (n = 420) were children with at least 1 diagnosis of an autism spectrum disorder (ASD) recorded in Kaiser Permanente outpatient clinical databases. Controls (n = 2100) were children without an ASD diagnosis who were frequency matched to cases on sex, birth year, and hospital of birth. MAIN OUTCOME MEASURES: Frequencies of maternal immunologic disorders were compared between cases and controls with a chi2 statistic, and relative risks were estimated by crude and adjusted odds ratios and 95% confidence intervals using logistic regression. RESULTS: The final study population included 407 cases and 2095 controls. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease in the 4-year period surrounding pregnancy (10.3% vs 8.2%, P = .15). After adjustment for maternal factors, only 1 autoimmune condition, psoriasis, was significantly associated with ASDs (adjusted odds ratio, 2.7; 95% confidence interval, 1.3-5.8). A greater than 2-fold elevated risk of ASD was observed for maternal asthma and allergy diagnoses recorded during the second trimester of pregnancy. CONCLUSIONS: These findings suggest that maternal autoimmune disorders present in women around the time of pregnancy are unlikely to contribute significantly to autism risk. Further etiologic investigations are needed to confirm these results and should include objective documentation of diagnoses and consider a larger set of maternal immune-related conditions, including asthma and allergies.
Authors: Croen LA; Grether JK; Yoshida CK; Odouli R; Van de Water J
Arch Pediatr Adolesc Med. 2005 Feb;159(2):151-7.
Neonatal hyperbilirubinemia and risk of autism spectrum disorders
OBJECTIVE: To investigate the association between neonatal hyperbilirubinemia and autism spectrum disorders (ASD). METHODS: We conducted a large case-control study nested within the cohort of singleton term infants born between 1995 and 1998 at a northern California Kaiser Permanente hospital. Case subjects (n = 338) were children with an ASD diagnosis recorded in Kaiser Permanente outpatient databases; control subjects (n = 1817) were children without an ASD diagnosis, who were randomly sampled and frequency-matched to case subjects according to gender, birth year, and birth hospital. RESULTS: Approximately 28% of case and control subjects received > or =1 bilirubin test in the first 30 days of life. No case-control differences were observed for maximal bilirubin levels of > or =15 mg/dL (10.1% vs 12.1%), > or =20 mg/dL (2.1% vs 2.5%), or > or =25 mg/dL (0.3% vs 0.2%). Compared with children whose maximal neonatal bilirubin levels were <15 mg/dL or not measured, children with any degree of bilirubin level elevation were not at increased risk of ASD, after adjustment for gender, birth facility, maternal age, maternal race/ethnicity, maternal education, and gestational age (for bilirubin levels of 15-19.9 mg/dL: odds ratio: 0.7; 95% confidence interval: 0.5-1.2; for bilirubin levels of 20-24.9 mg/dL: odds ratio: 0.7; 95% confidence interval: 0.3-1.6; for bilirubin levels of > or =25 mg/dL: odds ratio: 1.1; 95% confidence interval: 0.1-11.2). CONCLUSION: These data suggest that neonatal hyperbilirubinemia is not a risk factor for ASD.
Authors: Croen LA; Yoshida CK; Odouli R; Newman TB
Pediatrics. 2005 Feb;115(2):e135-8.
Identifying environmental contributions to autism: provocative clues and false leads
The potential role of environmental factors in autism spectrum disorders (ASD) is an area of emerging interest within the public and scientific communities. The high degree of heritability of ASD suggests that environmental influences are likely to operate through their interaction with genetic susceptibility during vulnerable periods of development. Evaluation of the plausibility of specific neurotoxicants as etiological agents in ASD should be guided by toxicological principles, including dose-effect dependency and pharmacokinetic parameters. Clinical and epidemiological investigations require the use of sufficiently powered study designs with appropriate control groups and unbiased case ascertainment and exposure assessment. Although much of the existing data that have been used to implicate environmental agents in ASD are limited by methodological shortcomings, a number of efforts are underway that will allow more rigorous evaluation of the role of environmental exposures in the etiology and/or phenotypic expression of the disorder. Surveillance systems are now in place that will provide reliable prevalence estimates going forward in time. Anticipated discoveries in genetics, brain pathology, and the molecular/cellular basis of functional impairment in ASD are likely to provide new opportunities to explore environmental aspects of this disorder.
Authors: Lawler CP; Croen LA; Grether JK; van de Water J
Ment Retard Dev Disabil Res Rev. 2004;10(4):292-302.
On the twin risk in autism
Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies (Greenberg et al. 2001; Betancur et al. 2002) suggested that the twinning process itself is an important risk factor in the development of autism. If true, this would have major consequences for the interpretation of twin studies. Both studies compared the number of affected twin pairs among affected sib pairs to expected values in two separate samples of multiplex families and reported a substantial and significant excess of twin pairs. Using data from our epidemiological study in Western Australia, we investigated the possibility of an increased rate of autism in twins. All children born between 1980 and 1995 with autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) were ascertained. Of the 465 children with a diagnosis, 14 were twin births (rate 30.0/1,000) compared to 9,640 children of multiple births out of a total of 386,637 births in Western Australia between 1980 and 1995 (twin rate weighted to number of children with autism or PDD per year 26.3/1,000). These data clearly do not support twinning as a substantial risk factor in the etiology of autism. We demonstrate that the high proportion of twins found in affected-sib-pair studies can be adequately explained by the high ratio of concordance rates in monozygotic (MZ) twins versus siblings and the distribution of family size in the population studied. Our results are in agreement with those of two similar studies by Croen et al. (2002) in California and Hultman et al. (2002) in Sweden.
Authors: Hallmayer J; Glasson EJ; Bower C; Petterson B; Croen L; Grether J; Risch N
Am J Hum Genet. 2002 Oct;71(4):941-6. Epub 2002 Sep 12.
The changing prevalence of autism in California
We conducted a population-based study of eight successive California births cohorts to examine the degree to which improvements in detection and changes in diagnosis contribute to the observed increase in autism prevalence. Children born in 1987-1994 who had autism were identified from the statewide agency responsible for coordinating services for individuals with developmental disabilities. To evaluate the role of diagnostic substitution, trends in prevalence of mental retardation without autism were also investigated. A total of 5038 children with full syndrome autism were identified from 4,590,333 California births, a prevalence of 11.0 per 10,000. During the study period, prevalence increased from 5.8 to 14.9 per 10,000, for an absolute change of 9.1 per 10,000. The pattern of increase was not influenced by maternal age, race/ethnicity, education, child gender, or plurality. During the same period, the prevalence of mental retardation without autism decreased from 28.8 to 19.5 per 10,000, for an absolute change of 9.3 per 10,000. These data suggest that improvements in detection and changes in diagnosis account for the observed increase in autism; whether there has also been a true increase in incidence is not known.
Authors: Croen LA; Grether JK; Hoogstrate J; Selvin S
J Autism Dev Disord. 2002 Jun;32(3):207-15.
Descriptive epidemiology of autism in a California population: who is at risk?
We investigated the association between selected infant and maternal characteristics and autism risk. Children with autism born in California in 1989-1994 were identified through service agency records and compared with the total population of California live births for selected characteristics recorded on the birth certificate. Multivariate models were used to generate adjusted risk estimates. From a live birth population of more than 3.5 million, 4381 children with autism were identified. Increased risks were observed for males, multiple births, and children born to black mothers. Risk increased as maternal age and maternal education increased. Children born to immigrant mothers had similar or decreased risk compared with California-born mothers. Environmental factors associated with these demographic characteristics may interact with genetic vulnerability to increase the risk of autism.
Authors: Croen LA; Grether JK; Selvin S
J Autism Dev Disord. 2002 Jun;32(3):217-24.
Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation
There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.
Authors: Nelson KB; Grether JK; Croen LA; Dambrosia JM; Dickens BF; Jelliffe LL; Hansen RL; Phillips TM
Ann Neurol. 2001 May;49(5):597-606.
Maternal exposure to nitrate from drinking water and diet and risk for neural tube defects
In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.
Authors: Croen LA; Todoroff K; Shaw GM
Am J Epidemiol. 2001 Feb 15;153(4):325-31.
