Childhood Autism Risks From Genetics And The Environment Research Articles

Newborn Dried Blood Spot Folate in Relation to Maternal Self-reported Folic Acid Intake, Autism Spectrum Disorder, and Developmental Delay.

Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined. We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes. Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08). Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.

Selecting External Controls for Internal Cases Using Stratification Score Matching Methods.

Rare-disease registries can be useful for studying the associations between environmental exposures and disease severity, but often require the addition of a healthy comparison control group. Defining a surrogate control group, matched and balanced on potentially confounding variables, would allow for the comparison of exposure distributions with cases from a registry. In the present study, we assess whether controls selected externally, using stratification score (SS) matching, can serve as effective proxies for internal controls. In addition, we use methyl paraben (MEPB) to compare the estimated associations between an externally matched sample and case–control frequencies in a cohort with internally matched controls. We started with 225 eligible cases of autism spectrum disorder (ASD) from Childhood Autism Risks from Genetics and the Environment (CHARGE), 241 internal controls from CHARGE, and 265 external controls from the National Health and Nutrition Examination Survey (NHANES) cycles 2005–2016. We calculated the SSs using demographic covariates and matched 1:1 using a caliper method without a replacement. The distribution of the covariates and the mean squared error of the paired differences (MSEpaired) in the SSs between the internal and external group were similar (MSEpaired = 0.007 and 0.011, respectively). The association between MEPB and ASD compared to the controls was similar between the externally matched SS pairs and the original frequency matched cohort. Controls selected externally, via SS matching, can provide a comparable bias reduction to that provided by the internal controls, and therefore may be a useful strategy in situations when the internal controls are not available.

Neonatal chemokine markers predict subsequent diagnosis of autism spectrum disorder and delayed development

Immune dysregulation has been found to be related to a diagnosis of autism spectrum disorder (ASD). However, investigations in very early childhood examining immunological abnormalities such as altered neonatal cytokine/chemokine profiles in association with an aberrant developmental trajectory, are sparse. We assessed neonatal blood spots from 398 children, including 171 with ASD, which were subdivided according to severity (121 severe, 50 mild/moderate) and cognitive/adaptive levels (144 low-functioning, 27 typical to high-functioning). The remainder were 69 children with developmental delay (DD), and 158 with typical development (TD), who served as controls in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. Exploratory analysis suggested that, in comparisons with TD and DD, CTACK (CCL27) and MPIF-1 (CCL23), respectively, were independently associated with ASD. Higher neonatal levels of CTACK were associated with decreased odds of ASD compared to TD (odds ratio [OR] = 0.40, 95% confidence interval [Cl] 0.21, 0.77), whereas higher levels of MPIF-1 were associated with increased odds of ASD (OR = 2.38, 95% Cl 1.42, 3.98) compared to DD but not to TD. MPIF-1 was positively associated with better scores in several developmental domains. Dysregulation of chemokine levels in early life can impede normal immune and neurobehavioral development, which can lead to diagnosis of ASD or DD. This study collectively suggests that certain peripheral chemokines at birth are associated with ASD progression during childhood and that children with ASD and DD have distinct neonatal chemokine profiles that can differentiate their diagnoses.

Organophosphate Exposures, Financial Hardship and Child Neurodevelopmental Outcomes in the CHARGE study

OPS 55: Pesticides and neurological outcomes, Room 412, Floor 4, August 26, 2019, 1:30 PM - 3:00 PM In-utero exposure to organophosphate pesticides has been associated with neurodevelopmental delay. This study examined whether maternal report of inability to pay for basic needs (food, housing, medical care and heating) modified the relationship between prenatal pesticide exposure and autism spectrum disorder (ASD). Methods: We studied 488 children with ASD and 329 typically-developing controls aged 2-5 years enrolled between 2003 and 2008 in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation. Diagnoses were confirmed by standardized assessments and information regarding maternal factors was determined from a structured interview with the mother. Residential proximity to agricultural application of organophosphate pesticides, based on California Department of Pesticide Regulation data, was determined by spatial analysis of maternal residence before and during pregnancy. Multiple logistic regression was used to examine the association between exposure during several time points during the pregnancy, and effect modification by the experience of financial hardship. Results: 213 (26%) CHARGE study mothers lived within 1.5 km of agricultural application of organophosphate compounds during their pregnancies. ASD odds were elevated in those exposed to pesticides between the 3 months prior to conception up through delivery (adjusted odds ratio (aOR) 2.44; 95% CI [1.05, 5.63]). Odds for mothers with 2nd trimester organophosphate exposure was higher for women with financial hardship compared to those without, 3.01; 95% CI [1.34, 6.75] vs 1.92; 95% CI [1.35, 2.76], respectively. This disparity was particularly pronounced for chlorpyrifos exposure, where those with financial hardship exhibited odds ratios ranging from 5 to 15 at all pregnancy timepoints. Conclusions: This study identified financial hardship as an amplifier of the association between organophosphate pesticide exposures during pregnancy and offspring ASD. It adds to the existing evidence highlighting the importance of studying the co-exposure of social and environmental factors affecting children at early developmental stages.

Effects of Neighborhood- and Individual-Level Economic and Mental Health Stressors as Susceptibility Factors for Environmental Exposures on Child ASD

PDS 73: Neurological effects, Johan Friso Foyer, Floor 1, August 26, 2019, 10:30 AM - 12:00 PM This study examined the effects of both mental health and socioeconomic status (SES) as susceptibility factors for the influences of prenatal environmental exposures on neurodevelopment. Methods: Children aged 2 to 5 years (488 with ASD and 329 controls) were enrolled between 2003 and 2012 into the CHARGE (Childhood Autism Risks from Genetics and the Environment) population-based, case-control investigation. Children’s diagnoses were confirmed using standardized assessments. Neighborhood level factors were obtained from the California Communities Environmental Health Screening Tool (CalEnviroScreen), which ranks census tracts based on environmental exposures, socioeconomic factors, and prevalence of certain health conditions. Principal component (PC) analysis was used to visualize the data, and derive composite variables. Odd ratios (OR’s) for financial hardship, maternal mood disorders and PC’s were calculated with multivariate logistic regression models. Results: The air quality PC included measures of diesel particulate matter (PM), traffic density, toxic releases and PM2.5, and was significantly associated with ASD risk in unadjusted and adjusted logistic regression, with increased odds of ASD among children whose mothers reported financial hardship (OR = 1.5; 95% CI [1.1, 1.9]). Worsening air quality was associated with increased risk of ASD (OR = 1.1; 95% CI [1.01, 1.3]). Children whose mothers reported mood disorders exhibited higher risk of ASD (OR = 1.9; 95% CI [1.5, 2.3]). There was also evidence of increasing risk with worsening air quality (OR = 1.2; 95% CI [1.05, 1.3]) when controlling for maternal mental health. We found increasing odds ratios at increasing levels of air quality when adjusting for maternal mood disorders, and significant persistent risk when adjusting for financial hardship. Conclusions: Findings are consistent with studies linking prenatal exposures to air-pollutants, and SES with ASD. There is a critical need for action to reduce air pollution, with a focus on those communities with greatest exposures and socioeconomic vulnerabilities.

Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.

Background:Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals.Objective:We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD).Methods:Participants were California children born from 2000–2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case–control study at age 2–5 y, were clinically confirmed to have ASD () or typical development (), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003–2011. High vs. low daily FA intake was dichotomized at (median). Mothers’ addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure.Results:High FA intake () during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with and any indoor pesticide exposure {adjusted odds ratio [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [ (95% CI: 0.7, 2.2)] or indoor pesticides [ (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure () to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models.Conclusions:In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604

Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions.

Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of autoantibodies to fetal brain proteins that have been detected in only 1% of mothers of typically developing children. The biological mechanisms underlying the development of ASD-specific maternal autoantibodies are poorly understood. We sought to determine whether ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation. Participants were 227 mothers of 2-5 year old children with confirmed ASD, enrolled in CHARGE (Childhood Autism Risk from Genetics and the Environment) between January 2003 and April 2008, and from whom blood samples were collected and analyzed for anti-fetal brain autoantibodies (Ab+). MCs included diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews. Log-linear regression models were performed to estimate prevalence ratios and 95% confidence intervals (CI) based on robust standard errors. Fifty-six (25%) mothers were Ab+. Ab+ prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant. In a subset of 145 mothers whose children exhibited severe ASD (31 Ab+), those diagnosed with type 2 or gestational diabetes were 2.7-fold more likely to be Ab+ (95% CI 1.1, 6.6), controlling for delivery payer and smoking. Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence (95% CI 1.2, 8.6). In this exploratory study, mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2-5 years later. Autism Res 2017, 10: 89-98. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Prenatal mercury exposure, autism, and developmental delay, using pharmacokinetic combination of newborn blood concentrations and questionnaire data: a case control study.

BackgroundMethylmercury (MeHg), known for well over a century as a neurotoxin in adults, has more recently been studied for potential detrimental effects during early brain development. While several studies have estimated mercury exposure, they usually rely on either a single biomarker or questionnaire data, each of which has limitations. The goal of this paper was to develop a toxicokinetic model that incorporates both biomarker and questionnaire data to estimate the cumulative exposure to MeHg through seafood consumption using data collected from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study.MethodsWe utilized a previously described discrete-time model that estimates blood MeHg concentration given a piecewise-constant ingestion rate and single-compartment pharmacokinetics. We measured newborn bloodspot Hg concentrations and obtained information pertaining to maternal fish consumption using a questionnaire. Using MeHg concentration estimates from the toxicokinetic model, cumulative MeHg exposure was estimated in children with autism, children with developmental delay, and typically developing children. Median estimated cumulative MeHg was compared among diagnostic groups using the Kruskal-Wallis Test. Multinomial logistic regression models were constructed to assess the association between cumulative MeHg concentration and the risk of autism and developmental delay (vs. typical development).ResultsThe estimated average MeHg concentration of for all fish species consumed by mothers was 42 ppb. Median cumulative MeHg over gestation was similar across diagnostic groups (p-values raged from 0.91 to 0.98). After adjusting for potential confounding, we found no association between cumulative MeHg exposure and the risk of autism (OR = 0.95, 95 % CI: 0.95, 1.12) or developmental delay (OR = 1.00, 95 % CI: 0.89, 1.13).ConclusionsThe toxicokinetic model described in this paper yielded fish MeHg concentration estimates that are consistent with fish species containing lower levels of MeHg. Overall, cumulative MeHg exposure does not appear to detectably elevate the risk of autism or developmental delay. Based on the regression standard error for the association between ASD and TD, we would have reported statistical significance for an adjusted odds ratio of 1.09 or larger. This method can easily be extended to other epidemiologic studies in which there is a biomarker measurement and questionnaire data regarding exposure.

Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study.

BackgroundPhthalates are endocrine-disrupting chemicals that influence thyroid hormones and sex steroids, both critical for brain development.AimWe studied phthalate concentrations in house dust in relation to the risks of developing autism spectrum disorder (ASD) or developmental delay (DD).MethodsParticipants were a subset of children from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) case–control study. ASD and DD cases were identified through the California Department of Developmental Services system or referrals; general population controls were randomly sampled from state birth files and frequency-matched on age, sex, and broad geographic region to ASD cases. All children (50 ASD, 27 DD, 68 typically developing (TD)) were assessed with Mullen Scales of Early Learning, Vineland Adaptive Behavior Scales (VABS) and Aberrant Behavior Checklist. We measured 5 phthalates in dust collected in the child’s home using a high volume small surface sampler.ResultsNone of the phthalates measured in dust was associated with ASD. After adjustment, we observed greater di(2-ethylhexyl) phthalate (DEHP) and butylbenzyl phthalate (BBzP) concentrations in indoor dust from homes of DD children: Odds ratios (OR) were 2.10 (95 % confidence interval (CI); 1.10; 4.09) and 1.40 (95 % CI; 0.97; 2.04) for a one-unit increase in the ln-transformed DEHP and BBzP concentrations, respectively. Among TD children, VABS communication, daily living, and adaptive composite standard scores were lower, in association with increased diethyl phthalate (DEP) concentrations in dust. Participants with higher dibutyl phthalate (DBP) concentrations in house dust also trended toward reduced performance on these subscales. Among ASD and DD boys, higher indoor dust concentrations of DEP and DBP were associated with greater hyperactivity-impulsivity and inattention.Discussion and conclusionHouse dust levels of phthalates were not associated with ASD. The inability to distinguish past from recent exposures in house dust and the fact that house dust does not capture exposure from all sources, limit the interpretation of both positive and null findings and further work is needed. However, the associations observed for DEP and DBP with impairments in several adaptive functions and greater hyperactivity, along with evidence for increased risk of DD raise concerns that these chemicals may affect neurodevelopment in children.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-015-0024-9) contains supplementary material, which is available to authorized users.

Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study.

To assess validity of maternally-reported diabetes and hypertensive disorders, and reliability of BMI measurements during periconception and pregnancy compared with medical records when mothers are interviewed 2-5 years after delivery. To investigate whether reporting accuracy differed by child's case status (autism, delays, typical development). Participants were mothers of 2-5 year old children with and without neurodevelopmental disorders from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) Study who had both prenatal/delivery records and telephone interviews. Sensitivity and specificity of self-report in telephone interview was assessed by comparison with medical records; agreement was evaluated by kappa statistics. Deviations in reported BMI were evaluated with Bland-Altman plots and concordance correlation coefficient (CCC). Mothers of children with neurodevelopmental disorders (autism or developmental delay) reported metabolic conditions slightly more accurately than control mothers. For diabetes, sensitivity ranged from 73 to 87% and specificity was ≥98% across groups. For hypertensive disorders, sensitivity ranged from 57 to 77% and specificity from 93 to 98%. Reliability of BMI was high (CCC = 0.930); when grouped into BMI categories, a higher proportion of mothers of delayed children were correctly classified (κ(wt) = 0.93) compared with the autism group and controls (κ(wt) = 0.85 and κ(wt) = 0.84, respectively; P = 0.05). Multiparity was associated with higher discrepancies in BMI and misreporting of hypertensive disorders. For purposes of etiologic studies, self-reported diabetes and hypertensive disorders during periconception and pregnancy show high validity among mothers irrespective of child's case status. Recall of pre-pregnancy BMI is reliable compared with self-reported values in medical records.

Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay.

Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms. To determine whether preeclampsia is associated with ASD and/or DD. The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n = 350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status. Preeclampsia and placental insufficiency were self-reported and abstracted from medical records. The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection. Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P = .02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64). Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

Maternal intake of supplemental iron and risk of autism spectrum disorder.

Iron deficiency affects 40%-50% of pregnancies. Iron is critical for early neurodevelopmental processes that are dysregulated in autism spectrum disorder (ASD). We examined maternal iron intake in relation to ASD risk in California-born children enrolled in a population-based case-control study (the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study) from 2003 to 2009 with a diagnosis of ASD (n = 520) or typical development (n = 346) that was clinically confirmed using standardized assessments. Mean maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews. Mothers of cases were less likely to report taking iron-specific supplements during the index period (adjusted odds ratio = 0.63, 95% confidence interval: 0.44, 0.91), and they had a lower mean daily iron intake (51.7 (standard deviation, 34.0) mg/day) than mothers of controls (57.1 (standard deviation, 36.6) mg/day; P = 0.03). The highest quintile of iron intake during the index period was associated with reduced ASD risk compared with the lowest (adjusted odds ratio = 0.49, 95% confidence interval: 0.29, 0.82), especially during breastfeeding. Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk. Further studies of this link between maternal supplemental iron and ASD are needed to inform ASD prevention strategies.

Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay

To examine associations between prenatal use of selective serotonin reuptake inhibitors (SSRIs) and the odds of autism spectrum disorders (ASDs) and other developmental delays (DDs). A total of 966 mother-child pairs were evaluated (492 ASD, 154 DD, 320 typical development [TD]) from the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study, a population-based case-control study. Standardized measures confirmed developmental status. Interviews with biological mothers ascertained prenatal SSRI use, maternal mental health history, and sociodemographic information. Overall, prevalence of prenatal SSRI exposure was lowest in TD children (3.4%) but did not differ significantly from ASD (5.9%) or DD (5.2%) children. Among boys, prenatal SSRI exposure was nearly 3 times as likely in children with ASD relative to TD (adjusted odds ratio [OR]: 2.91; 95% confidence interval [CI]: 1.07-7.93); the strongest association occurred with first-trimester exposure (OR: 3.22; 95% CI: 1.17-8.84). Exposure was also elevated among boys with DD (OR: 3.39; 95% CI: 0.98-11.75) and was strongest in the third trimester (OR: 4.98; 95% CI: 1.20-20.62). Findings were similar among mothers with an anxiety or mood disorder history. In boys, prenatal exposure to SSRIs may increase susceptibility to ASD or DD. Findings from published studies on SSRIs and ASD continues to be inconsistent. Potential recall bias and residual confounding by indication are concerns. Larger samples are needed to replicate DD results. Because maternal depression itself carries risks for the fetus, the benefits of prenatal SSRI use should be carefully weighed against potential harms.

Maternal Immune-Mediated Conditions, Autism Spectrum Disorders, and Developmental Delay

The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study. Results from conditional logistic regression demonstrated few significant associations overall. Maternal autoimmune disease was significantly associated with a modest increase in odds of developmental disorders (combined ASD + DD; OR = 1.46, 95% CI 1.01, 2.09) but not of ASD alone. Associations with certain allergens and onset periods were also suggested. These findings suggest maternal autoimmune disease may modestly influence childhood developmental disorders (ASD + DD).

Infertility and its treatments in association with autism spectrum disorders: a review and results from the CHARGE study.

Previous findings on relationships between infertility, infertility therapies, and autism spectrum disorders (ASD) have been inconsistent. The goals of this study are first, to briefly review this evidence and second, to examine infertility and its treatments in association with having a child with ASD in newly analyzed data. In review, we identified 14 studies published as of May 2013 investigating infertility and/or its treatments and ASD. Overall, prior results showed little support for a strong association, though some increases in risk with specific treatments were found; many limitations were noted. In new analyses of the CHildhood Autism Risk from Genetics and the Environment (CHARGE) population-based study, cases with autism spectrum disorder (ASD, n = 513) and controls confirmed to have typical development (n = 388) were compared with regard to frequencies of infertility diagnoses and treatments overall and by type. Infertility diagnoses and treatments were also grouped to explore potential underlying pathways. Logistic regression was used to obtain crude and adjusted odds ratios overall and, in secondary analyses, stratified by maternal age (≥35 years) and diagnostic subgroups. No differences in infertility, infertility treatments, or hypothesized underlying pathways were found between cases and controls in crude or adjusted analyses. Numbers were small for rarer therapies and in subgroup analyses; thus the potential for modest associations in specific subsets cannot be ruled out. However, converging evidence from this and other studies suggests that assisted reproductive technology is not a strong independent risk factor for ASD. Recommendations for future studies of this topic are provided.

Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders

We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in specific domains of development in the offspring. Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children's diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother. All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10-2.37; odds ratio: 2.35 [95% confidence interval: 1.43-3.88], respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite). Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.

Autism spectrum disorders in Hispanics and non-Hispanics

To compare differences in autism between Hispanic and non-Hispanics. We also examined the relationship between multiple language exposure and language function and scores of children. The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is an ongoing population-based case-control study with children sampled (n=1061) from three strata: those with autism (AU) or autism spectrum disorder (ASD); developmental delay (DD); or the general population (GP). Non-Hispanic cases demonstrated higher cognitive composite scores for the Mullen Scales of Early Learning (MSEL). There were significant associations between multiple language exposure and MSEL subscales for receptive language and expressive language, in both cases (AU/ASD) and TD controls, but not DD controls. Results of multivariate regression analyses suggest several predictors to be associated with lower Mullen expressive language scores including: diagnosis of ASD/AU, speaking to the child in a second language 25-50% of the time and Hispanic ethnicity; while maternal college education was associated with higher scores. Overall, the CHARGE Hispanic group displayed more similarities than differences compared to non-Hispanics in terms of autistic phenotypes and maladaptive & adaptive scores for cases. The relationship between multiple language use and cognitive scores warrants a closer look.

TRAFFIC RELATED AIR POLLUTION AND REGIONAL AIR QUALITY ARE ASSOCIATED WITH AUTISM

Background and Aims: Autism is a developmental disorder with rising prevalence. Examination of regional pollutants has suggested the importance of air toxics in autism etiology, yet little research has examined local level air pollution exposure beyond measures of roadway proximity. In this study we investigate the relationship between traffic related air pollution (TRP), regional air quality, and autism. Methods: This study analyzed data on 303 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. Autism diagnosis was confirmed from evaluations conducted at the M.I.N.D. Institute. The mother’s address from the birth certificate and addresses from a residential history questionnaire were geo-coded and used to determine residential location for the first year of life and each trimester of pregnancy. TRP estimates were assigned to each location using the CALINE4 line-source air-quality dispersion model. Regional air pollutant measures were assigned using the EPA’s Air Quality System data. Logistic regression models were fit comparing estimated first year pollutant levels for autism cases vs. typically developing controls. Results: Cases were more likely to live at residences with the highest quartile of TRP exposure as compared to controls (OR 2.02, 95%CI 1.25-3.28). Measures of regional PM2.5 and PM10 also increased autism risk (2.10, 1.18-3.76 per 8.8 µg/m3 PM2.5 and 2.15, 1.22-3.84 per 12.4 µg/m3 PM10). Results were relatively unchanged after including covariates. Conclusions: Exposure to both regional and local air pollutants was associated with autism risk. Further examination of specific air pollution measures is needed to better understand this association.

INTERACTION EFFECTS BETWEEN MATERNAL PRENATAL VITAMIN INTAKE AND PYRETHROID PESTICIDE EXPOSURE IN RELATION TO AUTISM SPECTRUM DISORDERS IN THE CHARGE CASE-CONTROL STUDY

Background and Aims: Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder affecting 1:110 children in the United States (CDC, 2009). Evidence supports large heritable contributions to the etiology of ASD, though environmental factors are likely to modify both the development and the course of ASD. Prenatal nutrient-environment interactions are unstudied in relation to autism etiology and risk. The objective of this study is to examine interaction effects between maternal supplemental nutrient intake and pyrethroid pesticides in relation to ASD. Methods: Northern California families were enrolled from 2003-2009 in the population-based case-control CHARGE (Childhood Autism Risks from Genetics and the Environment) Study. Children aged 24-60 months were evaluated and confirmed to have autism (n=288), autism spectrum disorder (n=141), or typical development (n=278) at the M.I.N.D. Institute using standardized clinical assessments. Maternal prenatal vitamin intake before and during pregnancy and use of products containing pyrethroid pesticides were retrospectively collected through telephone interviews. Adjusted odds ratios (OR) were estimated for associations between ASD and combinations of prenatal vitamin and pyrethroid pesticide exposure. Results: Estimated risk for having a child with autism when mothers did not take a prenatal vitamin and were exposed to pyrethroid pesticides during pregnancy (OR=5.4, 95% CI: 2.4-11.9) was over twice what was expected for that combination by either an additive (OR=2.2) or multiplicative model (OR=2.6). Though still significantly elevated, the observed risk for having a child with ASD associated with pyrethroid exposure during pregnancy was much lower if the mother reported taking a prenatal vitamin during the period around conception (OR=1.7, 95% CI: 1.0-2.8). Conclusions: These findings suggest that vitamin supplements taken before or early in pregnancy could potentially reduce the risk of ASD associated with pyrethroid pesticides. Further studies are warranted.

MAOA, DBH, and SLC6A4 variants in CHARGE: a case-control study of autism spectrum disorders.

Genetic factors are established to contribute to the development of autism. We examined three loci, serotonin transporter (SLC6A4), dopamine β-hydroxylase (DBH), and the variable number of tandem repeat promoter of the monoamine oxidase A (MAOA) for association with autism in participants from the Childhood Autism Risks from Genetics and the Environment (CHARGE ) Study, the first large-scale population-based case-control investigation of both environmental and genetic contributions to autism risk. Among male children enrolled in the CHARGE study we tested associations between each of the three polymorphisms and autism (AU) (n = 119), or a combined group of autism and other autism spectrum disorders (AU+ASD, which includes an additional n = 53) as compared with typically developing controls (TD, n = 137). The case-control association analysis showed neither SLC6A4 nor DBH to be statistically significantly associated with AU or ASD. However, the male children carrying 4 tandem repeats in the promoter region of the MAOA gene showed a two-fold higher risk of AU (or AU+ASD) than those carrying allele 3, adjusted for confounders (OR = 2.02, 95% CI = 1.12, 3.65, P = 0.02 for AU vs. TD, and OR = 2.05, 95% CI = 1.19, 3.53, P = 0.01 for ASD vs. TD). In addition, children of mothers homozygous for the 4 tandem repeat allele showed at least a three-fold higher risk of AU (or AU+ASD) than those with mothers homozygous for allele 3 (OR = 3.07, 95% CI = 1.19, 7.91, P = 0.02 for AU vs. TD, and OR = 3.26, 95% CI = 1.35, 7.89, P = 0.009 for AU+ASD vs. TD). These results suggest a potential role of the functional MAOA promoter alleles in the male child, the mother, or both in ASD.