Kristen Lyall

Perinatal Air Pollutant Exposures and Autism Spectrum Disorder in the Children of Nurses’ Health Study II Participants

Objective: Air pollution contains many toxicants known to affect neurological function and to have effects on the fetus in utero. Recent studies have reported associations between perinatal exposure to air pollutants and autism spectrum disorder (ASD) in children. We tested the hypothesis that perinatal exposure to air pollutants is associated with ASD, focusing on pollutants associated with ASD in prior studies. Methods: We estimated associations between U.S. Environmental Protection Agency–modeled levels of hazardous air pollutants at the time and place of birth and ASD in the children of participants in the Nurses’ Health Study II (325 cases, 22,101 controls). Our analyses focused on pollutants associated with ASD in prior research. We accounted for possible confounding and ascertainment bias by adjusting for family-level socioeconomic status (maternal grandparents’ education) and census tract–level socioeconomic measures (e.g., tract median income and percent college educated), as well as maternal age at birth and year of birth. We also examined possible differences in the relationship between ASD and pollutant exposures by child’s sex. Results: Perinatal exposures to the highest versus lowest quintile of diesel, lead, manganese, mercury, methylene chloride, and an overall measure of metals were significantly associated with ASD, with odds ratios ranging from 1.5 (for overall metals measure) to 2.0 (for diesel and mercury). In addition, linear trends were positive and statistically significant for these exposures (p < .05 for each). For most pollutants, associations were stronger for boys (279 cases) than for girls (46 cases) and significantly different according to sex. Conclusions: Perinatal exposure to air pollutants may increase risk for ASD. Additionally, future studies should consider sex-specific biological pathways connecting perinatal exposure to pollutants with ASD.

Maternal lifestyle and environmental risk factors for autism spectrum disorders

BACKGROUND Over the past 10 years, research into environmental risk factors for autism has grown dramatically, bringing evidence that an array of non-genetic factors acting during the prenatal period may influence neurodevelopment. METHODS This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated, in some studies, with autism spectrum disorder (ASD), including nutrition, substance use and exposure to environmental agents. This review is restricted to human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade and focusing on maternal lifestyle or environmental chemicals. RESULTS Higher maternal intake of certain nutrients and supplements has been associated with reduction in ASD risk, with the strongest evidence for periconceptional folic acid supplements. Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD, more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically. CONCLUSIONS More work is needed to examine fats, vitamins and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental deficits. The field can be advanced by large-scale epidemiological studies, attention to critical aetiological windows and how these vary by exposure, and use of biomarkers and other means to understand underlying mechanisms.

Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses' Health Study II Cohort.

Background Autism spectrum disorder (ASD) is a developmental disorder with increasing prevalence worldwide, yet has unclear etiology. Objective We explored the association between maternal exposure to particulate matter (PM) air pollution and odds of ASD in her child. Methods We conducted a nested case–control study of participants in the Nurses’ Health Study II (NHS II), a prospective cohort of 116,430 U.S. female nurses recruited in 1989, followed by biennial mailed questionnaires. Subjects were NHS II participants’ children born 1990–2002 with ASD (n = 245), and children without ASD (n = 1,522) randomly selected using frequency matching for birth years. Diagnosis of ASD was based on maternal report, which was validated against the Autism Diagnostic Interview-Revised in a subset. Monthly averages of PM with diameters ≤ 2.5 μm (PM2.5) and 2.5–10 μm (PM10–2.5) were predicted from a spatiotemporal model for the continental United States and linked to residential addresses. Results PM2.5 exposure during pregnancy was associated with increased odds of ASD, with an adjusted odds ratio (OR) for ASD per interquartile range (IQR) higher PM2.5 (4.42 μg/m3) of 1.57 (95% CI: 1.22, 2.03) among women with the same address before and after pregnancy (160 cases, 986 controls). Associations with PM2.5 exposure 9 months before or after the pregnancy were weaker in independent models and null when all three time periods were included, whereas the association with the 9 months of pregnancy remained (OR = 1.63; 95% CI: 1.08, 2.47). The association between ASD and PM2.5 was stronger for exposure during the third trimester (OR = 1.42 per IQR increase in PM2.5; 95% CI: 1.09, 1.86) than during the first two trimesters (ORs = 1.06 and 1.00) when mutually adjusted. There was little association between PM10–2.5 and ASD. Conclusions Higher maternal exposure to PM2.5 during pregnancy, particularly the third trimester, was associated with greater odds of a child having ASD. Citation Raz R, Roberts AL, Lyall K, Hart JE, Just AC, Laden F, Weisskopf MG. 2015. Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case–control analysis within the Nurses’ Health Study II cohort. Environ Health Perspect 123:264–270; http://dx.doi.org/10.1289/ehp.1408133

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.

Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability

Background: Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are neurodevelopmental toxicants, but few studies have examined associations with autism spectrum disorder (ASD). Objectives: We aimed to determine whether prenatal exposure to PCBs and OCPs influences offspring risk of ASD and intellectual disability without autism (ID). Methods: 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. Results: 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. Conclusions: 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; http://dx.doi.org/10.1289/EHP277

Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study.

Immune aberrations are often noted in children with autism spectrum disorder (ASD), but whether asthma and allergy are related to ASD is not well defined. This study examined asthma and allergies in association with ASD and phenotypic subsets. Participants were 560 children with confirmed ASD and 391 typically developing children from the CHildhood Autism Risks from Genetics and the Environment study. Maternally reported child asthma and allergy was compared between cases and controls, and in association with cognitive and behavioral test scores. Prevalence of asthma and overall allergies did not differ between cases and controls, but overall allergy in children with ASD was associated with higher stereotypy scores as measured by the Aberrant Behavior Checklist. In addition, reported food allergies were significantly associated with ASD (adjusted odds ratio = 2.23, 95% confidence interval 1.28, 3.89). Our results suggest food allergies and sensitivities may be more common in children with ASD, and that these issues may correlate with other behaviors. Autism Res 2015, 8: 567–574.

RLS in middle aged women and attention deficit/hyperactivity disorder in their offspring.

BACKGROUND Previous studies have suggested that attention deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS) could share some common genetic backgrounds, but the effect of these genetic components could be modest. To test this hypothesis, we conducted a large-scaled cross-sectional study to examine whether women with a child with ADHD had a higher risk of having RLS than women of unaffected children. METHODS We included 65,554 women free of diabetes, arthritis, and pregnancy in the current analyses. Information on RLS was assessed using a set of standardized questions. Participants were considered to have RLS if they met four RLS diagnostic criteria recommended by the International RLS Study Group and had restless legs ≥5 times/month. Information on ADHD in offspring was collected via questionnaire. RESULTS We observed a significant association between presence of ADHD in the offspring and risk of having RLS; the multivariate-adjusted OR for RLS was 1.27 (95% CI: 1.15, 1.41; P<0.0001), after adjusting for age, body mass index, number of deliveries during life time and other covariates. CONCLUSION We found that mothers of children with ADHD had an increased risk of having RLS. Further studies are warranted to explore biological mechanisms underling this association.

Maternal exposure to intimate partner abuse before birth is associated with autism spectrum disorder in offspring

We sought to determine whether maternal (a) physical harm from intimate partner abuse during pregnancy or (b) sexual, emotional, or physical abuse before birth increased risk of autism spectrum disorder. We calculated risk ratios for autism spectrum disorder associated with abuse in a population-based cohort of women and their children (54,512 controls, 451 cases). Physical harm from abuse during pregnancy was not associated with autism spectrum disorder. However, autism spectrum disorder risk was increased in children of women who reported fear of partner or sexual, emotional, or physical abuse in the 2 years before the birth year (abuse in the year before the birth year: risk ratio = 1.58, 95% confidence interval = 1.04, 2.40; abuse in both of the 2 years before the birth year: risk ratio = 2.16, 95% confidence interval = 1.33, 3.50). Within-family results were similar, although did not reach statistical significance. Association of intimate partner abuse before the child’s birth year with autism spectrum disorder in the child was not accounted for by gestation length, birth weight, maternal smoking or alcohol consumption during pregnancy, gestational diabetes, preeclampsia, or history of induced abortion.

Prevalence of Autism Spectrum Disorders with and without Intellectual Disability by Gestational Age at Birth in the Stockholm Youth Cohort: a Register Linkage Study

BACKGROUND Preterm birth has been linked to increased risk of autism spectrum disorders (ASD), but how this risk changes with gestational age at birth has not been well characterised, especially with regard to co-occurring intellectual disability (ID). METHODS Register-based cohort study of singleton births in 1984-2007 in Stockholm County, Sweden (N total: 480 728; n ASD: 10 025). We assessed overall and sex-specific, gestational week-specific prevalence estimates and risk ratios of ASD with and without ID. RESULTS Preterm and postterm births were associated with elevated risk of ASD, and the relationship between gestational age at birth and ASD with and without ID differed in males and females. Risk of ASD without ID was higher in preterm births among both sexes and decreased continuously with increasing length of gestation. Risk of ASD with ID was higher in both preterm and postterm births among both sexes, with postterm birth in females being more highly associated with ASD with ID than that in males. CONCLUSIONS The relationship between gestational age at birth and ASD differs by the presence/absence of co-occurring ID and fetal sex. Both preterm and postterm birth are associated with increased risk of ASD. Risk of ASD is not constant within conventionally defined gestational age at birth periods. Further research on mechanism underlying these associations is needed.

Independent Maternal and Fetal Genetic Effects on Midgestational 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.