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

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

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

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

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

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

Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings.

Importance: Maternal use of folic acid supplements has been inconsistently associated with reduced risk for autism spectrum disorder (ASD) in the child. No study to date has examined this association in the context of ASD recurrence in high-risk families. Objective: To examine the association between maternal prenatal vitamin use and ASD recurrence risk in younger siblings of children with ASD. Design, Setting, and Participants: This prospective cohort study analyzed data from a sample of children (n = 332) and their mothers (n = 305) enrolled in the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study. Participants in the MARBLES study were recruited at the MIND Institute of the University of California, Davis and were primarily from families receiving services for children with ASD in the California Department of Developmental Services. In this sample, the younger siblings at high risk for ASD were born between December 1, 2006, and June 30, 2015, and completed a final clinical assessment within 6 months of their third birthday. Prenatal vitamin use during pregnancy was reported by mothers during telephone interviews. Data analysis for this study was conducted from January 1, 2017, to December 3, 2018. Main Outcomes and Measures: Autism spectrum disorder, other nontypical development (non-TD), and typical development (TD) were algorithmically defined according to Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning subscale scores. Results: After exclusions, the final sample comprised 241 younger siblings, of which 140 (58.1%) were male and 101 (41.9%) were female, with a mean (SD) age of 36.5 (1.6) months. Most mothers (231 [95.9%]) reported taking prenatal vitamins during pregnancy, but only 87 mothers (36.1%) met the recommendations to take prenatal vitamins in the 6 months before pregnancy. The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time. Children whose mothers reported taking prenatal vitamins during the first month of pregnancy were less likely to receive an ASD diagnosis (adjusted relative risk [RR], 0.50; 95% CI, 0.30-0.81) but not a non-TD 36-month outcome (adjusted RR, 1.14; 95% CI, 0.75-1.75) compared with children whose mothers reported not taking prenatal vitamins. Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity (adjusted estimated difference, -0.60; 95% CI, -0.97 to -0.23) and higher cognitive scores (adjusted estimated difference, 7.1; 95% CI, 1.2-13.1). Conclusions and Relevance: Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD recurrence in siblings of children with ASD in high-risk families. Additional research is needed to confirm these results; to investigate dose thresholds, contributing nutrients, and biologic mechanisms of prenatal vitamins; and to inform public health recommendations for ASD prevention in affected families.

Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder.

Independent studies report that periconceptional folic acid (FA) may decrease the risk of autism spectrum disorder (ASD) while exposure to air pollution may increase ASD risk. We examined the joint effects of gestational FA and air pollution exposures in association with ASD. We studied 346 ASD cases and 260 typically developing controls from the CHARGE case-control study. Self-reported FA intake for each month of pregnancy was quantified. Estimates of exposure to near roadway air pollution (NRP) and criteria air pollutant measures were assigned based on maternal residential history. Among mothers with high FA intake (>800 µg) in the first pregnancy month, exposure to increasing levels of all air pollutants, except ozone, during the first trimester was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low FA intake (≤800 µg). This difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04). Mothers exposed to higher levels (≥ median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake were at a higher ASD risk compared to mothers exposed to lower levels of that air pollutant and who reported high first month FA intake. Joint effects showed significant (alpha < 0.10) departures from expected interaction for NRP and NO2 . Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure. Further study is needed to replicate these findings in larger sample sizes and to understand mechanisms of this potential relationship.. Autism Res 2018, 11: 69-80. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined interactions between periconceptional folic acid (FA) and air pollution exposure on risk of ASD. Mothers exposed to higher levels of air pollution during the first trimester of pregnancy and who reported low supplemental FA intake during the first pregnancy month were at a higher ASD risk compared to mothers exposed to lower levels of air pollution and who reported high first month FA intake. Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure.

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 (n=296) or typical development (n=220), 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 800µg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. RESULTS: High FA intake (≥800µg) 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 <800µg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) 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.

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.

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.

Environment and Autism: Current State of the Science.

Research into environmental risk factors for autism has grown dramatically over the past 10 years, providing evidence that non-genetic factors acting during the prenatal period may influence the underlying neurodevelopmental processes. This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated with autism spectrum disorder (ASD), including only 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. Consistent results have been reported for an association of higher maternal intake of certain nutrients and supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements. 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. A few studies suggest a link with organophosphate pesticides. More rigorous ascertainment of exposure is needed for studies of substance use; most investigations adjusting for potential confounders, but relying on self-reported use, have shown no links between maternal smoking or alcohol consumption and ASD. Little research has assessed other persistent and non-persistent organic chemical pollutants, such as are found in common household or personal care products, in association with ASD specifically. 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 outcomes. In addition, the field could be advanced by the use of large-scale epidemiologic studies, attention to critical etiologic windows and how these vary by exposure, interactions with genetic susceptibility, and a focus on underlying mechanisms.

Maternal caffeine consumption and risk of congenital limb deficiencies.

BACKGROUND: Animal studies have shown that high doses of caffeine might cause congenital limb deficiencies (LDs); however, no epidemiologic studies have explored this relation. METHODS: This case-control study assessed associations between maternal dietary caffeine and congenital LDs using data from the National Birth Defects Prevention Study (NBDPS), with 844 LD cases and 8069 controls from 1997 to 2007. Caffeine intakes from beverages (coffee, tea, and soda) and chocolate combined and by beverage type were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for subtypes of isolated LDs (no additional major anomalies) and LDs with other major anomalies separately, comparing the odds of 10 to <100, 100 to <200, 200 to <300, and 300+ mg/day total caffeine intake to 0 to <10 mg/day. RESULTS: All total dietary caffeine intake categories of 10 mg/day and above were marginally associated with odds of all isolated LDs combined (aOR, 1.4-1.7), isolated longitudinal LDs (aOR, 1.2-1.6), and isolated transverse LDs (aOR, 1.3-1.8) compared to the lowest intake category. A dose-response pattern for total dietary caffeine intake was not observed. CONCLUSIONS: A weak increased risk of congenital LDs associated with maternal dietary caffeine consumption was observed in this study; however, risk did not vary by amount of caffeine consumed.

Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

BACKGROUND: Periconceptional folate is essential for proper neurodevelopment. OBJECTIVE: Maternal folic acid intake was examined in relation to the risk of autism spectrum disorder (ASD) and developmental delay (DD). DESIGN: Families enrolled in the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study from 2003 to 2009 were included if their child had a diagnosis of ASD (n = 429), DD (n = 130), or typical development (TD; n = 278) confirmed at the University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute by using standardized clinical assessments. Average daily folic acid was quantified for each mother on the basis of dose, brands, and intake frequency of vitamins, supplements, and breakfast cereals reported through structured telephone interviews. RESULTS: Mean (±SEM) folic acid intake was significantly greater for mothers of TD children than for mothers of children with ASD in the first month of pregnancy (P1; 779.0 ± 36.1 and 655.0 ± 28.7 µg, respectively; P < 0.01). A mean daily folic acid intake of ≥600 µg (compared with <600 µg) during P1 was associated with reduced ASD risk (adjusted OR: 0.62; 95% CI: 0.42, 0.92; P = 0.02), and risk estimates decreased with increased folic acid (P-trend = 0.001). The association between folic acid and reduced ASD risk was strongest for mothers and children with MTHFR 677 C>T variant genotypes. A trend toward an association between lower maternal folic acid intake during the 3 mo before pregnancy and DD was observed, but not after adjustment for confounders. CONCLUSIONS: Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted.