Reliability of a short diet and vitamin supplement questionnaire for retrospective collection of maternal nutrient intake.

Background: Gestational nutrition can protect against adverse neurodevelopmental outcomes. Objectives: We developed a short tool for collecting maternal nutritional intake during pregnancy to facilitate research in this area and compared its retrospective use to prospectively-collected food frequency questionnaires (FFQ). Methods: Maternal nutritional intake was retrospectively assessed using three versions (full interview, full self-administered online, and shortened interview) of the Early Life Exposure Assessment Tool (ELEAT) among participants of the MARBLES pregnancy cohort study of younger siblings of autistic children. Retrospective responses were compared with responses to supplement questions and the validated 2005 Block FFQ prospectively collected in MARBLES during pregnancies 2-7 years prior. ELEAT nutrient values were calculated using reported food intake frequencies and nutrient values from the USDA nutrient database. Correlations between retrospectively- and prospectively-reported intake were evaluated using Kappa coefficients, Youden's J, and Spearman Rank Correlation Coefficients (rs). Results: MARBLES FFQ dietary intakes were compared among 54 women who completed the ELEAT full form including 12 online, and among 23 who completed the ELEAT short form. Correlations across most foods were fair to moderate. Most ELEAT quantified nutrient values were moderately correlated (rs = 0.3-0.6) with those on the Block FFQ. Supplement questions in both MARBLES and the ELEAT were completed by 114 women. Kappas were moderate for whether or not supplements were taken, but modest for timing. Correlations varied by version and child diagnosis or concerns, and were higher when mothers completed the ELEAT when their child was 4 years old or younger. Conclusions: With recall up to several years, ELEAT dietary and supplement module responses were modestly to moderately reliable and produced nutrient values moderately correlated with prospectively-collected measures. The ELEAT dietary and vitamin supplements modules can be used to rank participants in terms of intake of several nutrients relevant for neurodevelopment.

Ex vivo exposure to polybrominated diphenyl ether (PBDE) selectively affects the immune response in autistic children.

Children on the autism spectrum have been shown to have immune dysregulation that often correlates with behavioral deficits. The role of the post-natal environment in this dysregulation is an area of active investigation. We examined the association between plasma levels of polybrominated diphenyl ether (PBDE) and immune cell function in age-matched autistic children and non-autistic controls. Plasma from children on the autism spectrum (n = 38) and typically developing controls (TD; n = 60) were analyzed for 14 major PBDE congeners. Cytokine/chemokine production was measured in peripheral blood mononuclear cell (PBMC) supernatants with and without ex vivo BDE-49 exposure. Total plasma concentration (∑PBDE14) and individual congener levels were also correlated with T cell function. ∑PBDE14 did not differ between diagnostic groups but correlated with reduced immune function in children on the autism spectrum. In autistic children, IL-2 and IFN-γ production was reduced in association with several individual BDE congeners, especially BDE-49 (p = 0.001). Furthermore, when PBMCs were exposed ex vivo to BDE-49, cells from autistic children produced elevated levels of IL-6, TNF-α, IL-1ß, MIP-1α and MCP-1 (p < 0.05). Therefore, despite similar plasma levels of PBDE, these data suggest that PBMC function was differentially impacted in the context of several PBDE congeners in autistic children relative to TD children where increased body burden of PBDE significantly correlated with a suppressed immune response in autistic children but not TD controls. Further, acute ex vivo exposure of PBMCs to BDE-49 stimulates an elevated cytokine response in AU cases versus a depressed response in TD controls. These data suggest that exposure to the toxicant BDE-49 differentially impacts immune cell function in autistic children relative to TD children providing evidence for an underlying association between susceptibility to PBDE exposure and immune anomalies in children on the autism spectrum.

Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using 1H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk.

Reductions in particulate matter concentrations resulting from air filtration: A randomized sham-controlled crossover study.

One-hundred seventy-two households were recruited from regions with high outdoor air pollution (Fresno and Riverside, CA) to participate in a randomized, sham-controlled, cross-over study to determine the effectiveness of high-efficiency air filtration to reduce indoor particle exposures. In 129 households, stand-alone HEPA air cleaners were placed in a bedroom and in the main living area. In 43 households, high-efficiency MERV 16 filters were installed in central forced-air heating and cooling systems and the participating households were asked to run the system on a clean-air cycle for 15 min per hour. Participating households that completed the study received true air filtration for a year and sham air filtration for a year. Air pollution samples were collected at approximately 6-month intervals, with two measurements in each of the sham and true filtration periods. One week indoor and outdoor time-integrated samples were collected for measurement of PM2.5 , PM10 , and ultrafine particulate matter (UFP) measured as PM0.2 . Reflectance measurements were also made on the PM2.5 filters to estimate black carbon. True filtration significantly improved indoor air quality, with a 48% reduction in the geometric mean indoor PM0.2 and PM2.5 concentrations, and a 31% reduction in PM10 . Geometric mean concentrations of indoor/outdoor reflectance values, indicating fraction of particles of outdoor origin remaining indoors, decreased by 77%. Improvements in particle concentrations were greater with continuously operating stand-alone air cleaners than with intermittent central system filtration. Keeping windows closed and increased utilization of the filtration systems further improved indoor air quality.

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.

Comparison of maternal beliefs about causes of autism spectrum disorder and association with utilization of services and treatments.

BACKGROUND: This study aimed to describe parental perceptions of the causes of autism spectrum disorder (ASD) in an ethnically diverse sample and explore whether these perceptions relate to treatment choices. METHODS: The sample consisted of White (n = 224), Hispanic (n = 85), and Asian (n = 21) mothers of a child with ASD. A mixed methods approach was used in this secondary analysis focusing on parental perceptions about the causes of ASD and the relationship of these to utilization of services and treatment. RESULTS: Environmental and genetic factors were most often believed to be the cause or one of the causes of ASD by mothers across all ethnic groups studied. Asian mothers were more likely to cite multiple causes. Environmental causes were associated with receiving 20 or more hours of autism-related services per week, whereas belief in environmental exposures and vaccines and medications as causes were associated with complementary-alternative medicine (CAM) use. CONCLUSION: Our findings suggest that ethnic differences in autism causal beliefs and treatment choices may exist. Future research should be conducted to specifically confirm the findings, to understand parental motivation behind their service and treatment choices, and to gain more insight into the types, usage, and sources of CAM treatments. Clinicians can use parental autism causal beliefs in discussions about treatment recommendations.

Understanding environmental contributions to autism: Causal concepts and the state of science.

The complexity of neurodevelopment, the rapidity of early neurogenesis, and over 100 years of research identifying environmental influences on neurodevelopment serve as backdrop to understanding factors that influence risk and severity of autism spectrum disorder (ASD). This Keynote Lecture, delivered at the May 2016 annual meeting of the International Society for Autism Research, describes concepts of causation, outlines the trajectory of research on nongenetic factors beginning in the 1960s, and briefly reviews the current state of this science. Causal concepts are introduced, including root causes; pitfalls in interpreting time trends as clues to etiologic factors; susceptible time windows for exposure; and implications of a multi-factorial model of ASD. An historical background presents early research into the origins of ASD. The epidemiologic literature from the last fifteen years is briefly but critically reviewed for potential roles of, for example, air pollution, pesticides, plastics, prenatal vitamins, lifestyle and family factors, and maternal obstetric and metabolic conditions during her pregnancy. Three examples from the case-control CHildhood Autism Risks from Genes and the Environment Study are probed to illustrate methodological approaches to central challenges in observational studies: capturing environmental exposure; causal inference when a randomized controlled clinical trial is either unethical or infeasible; and the integration of genetic, epigenetic, and environmental influences on development. We conclude with reflections on future directions, including exposomics, new technologies, the microbiome, gene-by-environment interaction in the era of -omics, and epigenetics as the interface of those two. As the environment is malleable, this research advances the goal of a productive and fulfilling life for all children, teen-agers and adults. Autism Res 2018, 11: 554-586. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This Keynote Lecture, delivered at the 2016 meeting of the International Society for Autism Research, discusses evidence from human epidemiologic studies of prenatal factors contributing to autism, such as pesticides, maternal nutrition and her health. There is no single cause for autism. Examples highlight the features of a high-quality epidemiology study, and what comprises a compelling case for causation. Emergent research directions hold promise for identifying potential interventions to reduce disabilities, enhance giftedness, and improve lives of those with ASD.

Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that can be reliably diagnosed at age 24 months. Immunological phenomena, including skewed cytokine production, have been observed among children with ASD. Little is known about whether immune dysregulation is present before diagnosis of ASD. METHODS: We examined neonatal blood spots from 214 children with ASD (141 severe, 73 mild/moderate), 62 children with typical development, and 27 children with developmental delay as control subjects who participated in the Childhood Autism Risks from Genetics and the Environment study, a population-based case-control study. Levels of 17 cytokines and chemokines were compared across groups and in relation to developmental and behavioral domains. RESULTS: Interleukin (IL)-1ß and IL-4 were independently associated with ASD compared with typical development, although these relationships varied by ASD symptom intensity. Elevated IL-4 was associated with increased odds of severe ASD (odds ratio [OR] = 1.40, 95% confidence interval [CI], 1.03, 1.91), whereas IL-1ß was associated with increased odds of mild/moderate ASD (OR = 3.02, 95% CI, 1.43, 6.38). Additionally, IL-4 was associated with a higher likelihood of severe ASD versus mild/moderate ASD (OR = 1.35, 95% CI, 1.04, 1.75). In male subjects with ASD, IL-4 was negatively associated with nonverbal cognitive ability (ß = -3.63, SE = 1.33, p = .04). CONCLUSIONS: This study is part of a growing effort to identify early biological markers for ASD. We demonstrate that peripheral cytokine profiles at birth are associated with ASD later in childhood and that cytokine profiles vary depending on ASD severity. Cytokines have complex roles in neurodevelopment, and dysregulated levels may be indicative of genetic differences and environmental exposures or their interactions that relate to ASD.

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.

Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder.

This study investigates whether sociodemographic factors are associated with utilization of intervention services for children with autism spectrum disorder (ASD) enrolled in the Childhood Autism Risks from Genetics and the Environment Study. Maternal ethnicity, insurance status, and education for 696 families of children with ASD were available. Children of Black mothers entered intervention earlier compared to White mothers (2 vs. 2.6 years; p = 0.001). Having public insurance was associated with receiving <15 h/week of individual services, while having a Bachelor degree was associated with receiving <15 h/week of classroom-based services. These differences suggest that SES may be a factor in utilization of services. Efforts should be made to ensure that interventions offered are culturally and linguistically accessible.

Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study.

BACKGROUND: The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions. METHODS: mtDNA copy number and deletions, and p53 gene copy ratios were evaluated in peripheral blood monocytic cells from children aged 2-5 years with AU (n = 66), race-, gender-, and age-matched typically neurodeveloping children (n = 46), and both parents from each diagnostic group, recruited by the Childhood Autism Risk from Genes and Environment study at the University of California, Davis. RESULTS: mtDNA deletions and higher p53 gene copy ratios were more common in children with AU and their fathers. The incidence of mtDNA deletions in fathers of children with AU was increased 1.9-fold over fathers of typically neurodeveloping children, suggesting a role for deficient DNA repair capacity not driven by paternal age. Deletions in mtDNA and altered p53 gene copy ratios seem to result from genetics (children with severity scores ≥8) and/or act in concert with environmental factors (children with 6-7 severity scores). CONCLUSIONS: Given pro- and antioxidant activities of p53, and associations of genomic instability with disorders other than AU, our study suggests a link between DNA repair capacity, genomic instability in the 17p13.1 region influenced by environmental triggers, and AU diagnosis.

Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma.

Inflammation and asthma have both been reported in some children with autism spectrum disorder (ASD). To further assess this connection, peripheral immune cells isolated from young children with ASD and typically developing (TD) controls and the production of cytokines IL-17, -13, and -4 assessed following ex vivo mitogen stimulation. Notably, IL-17 production was significantly higher following stimulation in ASD children compared to controls. Moreover, IL-17 was increased in ASD children with co-morbid asthma compared to controls with the same condition. In conclusion, children with ASD exhibited a differential response to T cell stimulation with elevated IL-17 production compared to controls.

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.

BACKGROUND: Phthalates are endocrine-disrupting chemicals that influence thyroid hormones and sex steroids, both critical for brain development. AIM: We studied phthalate concentrations in house dust in relation to the risks of developing autism spectrum disorder (ASD) or developmental delay (DD). METHODS: Participants 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. RESULTS: None 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 CONCLUSION: House 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.

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.

IMPORTANCE: 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. OBJECTIVE: To determine whether preeclampsia is associated with ASD and/or DD. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Preeclampsia and placental insufficiency were self-reported and abstracted from medical records. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.

Utilization patterns of conventional and complementary/alternative treatments in children with autism spectrum disorders and developmental disabilities in a population-based study.

OBJECTIVE: To compare the utilization of conventional treatments and utilization of complementary and alternative medicine in preschoolers with autism spectrum disorders (ASD) and other developmental disabilities (DD). METHODS: Participants were 578 children who were part of an ongoing population-based, case-control study of 2- to 5-year olds with ASD, DD, and the general population. Parents completed an interview on past and current services. RESULTS: Four hundred fifty-three children with ASD and 125 DD children were included. ASD families received more hours of conventional services compared with DD families (17.8 vs 11; p < .001). The use of psychotropic medications was low in both groups (approximately 3%). Overall, complementary and alternative medicine (CAM) use was not significantly different in ASD (39%) versus DD (30%). Hispanic families in both groups used CAM less often than non-Hispanic families. Variables such as level of function, immunization status, and the presence of an identified neurogenetic disorder were not predictive of CAM use. A higher level of parental education was associated with an increased CAM use in ASD and DD. Families who used >20 hours per week of conventional services were more likely to use CAM, including potentially unsafe or disproven CAM. Underimmunized children were marginally more likely to use CAM but not more likely to have received potentially unsafe or disproven CAM. CONCLUSION: Use of CAM is common in families of young children with neurodevelopmental disorders, and it is predicted by higher parental education and non-Hispanic ethnicity but not developmental characteristics. Further research should address how health care providers can support families in making decisions about CAM use.

Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.

Minor physical anomalies in children with autism spectrum disorders.

OBJECTIVE: There is clinical heterogeneity among the autism spectrum disorders (ASD). The presence of dysmorphology (minor physical anomalies; MPAs) is one possible tool for defining a clinically relevant subset in ASD. This study employs an adaptation of Miles and Hillman's (2000) classifications by using photographs to identify a subgroup with significant dysmorphology among children with ASD, typical development (TYP), and developmental delay (DD). METHOD: Children with ASD, DD, and TYP between 2 and 5 years old were part of the CHARGE Study. Pediatric specialists blinded to diagnostic group classified photographs based on the number of MPAs present: 'dysmorphic' if >3 and 'nondysmorphic' if <3 MPAs. RESULTS: Photographs for 324 children were included. Significantly more children with ASD were classified as dysmorphic compared to TYP children (p = .007). In children with ASD, seizures were more prevalent in those rated dysmorphic (p = .005). Frequencies were similar between ASD versus DD (p = .19) after removing those with known syndromes. CONCLUSION: Photographic assessment can be used to detect generalized dysmorphology in children who are often difficult to examine. This has clinical relevance, as children with multiple MPAs can be identified through the use of photographs and prioritized for investigation of brain abnormalities and underlying genetic disorders.

Polybrominated diphenyl ethers in relation to autism and developmental delay: a case-control study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely and in increasing amounts in the U.S. over the last few decades. PBDEs and their metabolites cross the placenta and studies in rodents demonstrate neurodevelopmental toxicity from prenatal exposures. PBDE exposures occur both via breastfeeding and hand-to-mouth activities in small children. METHODS: Participants were 100 children from the CHARGE (CHildhood Autism Risk from Genetics and the Environment) Study, a case-control epidemiologic investigation of children with autism/autism spectrum disorder, with developmental delay and from the general population. Diagnoses of autism were confirmed by the Autism Diagnostic Observation Schedule and Autism Diagnostic Inventory-Revised, and of developmental delay using the Mullen's Scales of Early Learning and the Vineland Adaptive Behavior Scales. Typically developing controls were those with no evidence of delay, autism, or autism spectrum disorder. Eleven PBDE congeners were measured by gas chromatography/mass spectrometry from serum specimens collected after children were assessed. Logistic regression was used to evaluate the association between plasma PBDEs and autism. RESULTS: Children with autism/autism spectrum disorder and developmental delay were similar to typically developing controls for all PBDE congeners, but levels were high for all three groups. CONCLUSIONS: Plasma samples collected post-diagnosis in this study may not represent early life exposures due to changes in diet and introduction of new household products containing PBDEs. Studies with direct measurements of prenatal or infant exposures are needed to assess the possible causal role for these compounds in autism spectrum disorders.