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.

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.

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.

Demographic, Reproductive, and Dietary Determinants of Perfluorooctane Sulfonic (PFOS) and Perfluorooctanoic Acid (PFOA) Concentrations in Human Colostrum.

To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography-mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: -56 to -17%) and 40% lower PFOA (95% CI: -54 to -23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children.

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.

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.

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 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.

Comparison of organochlorine compound concentrations in colostrum and mature milk.

Human breast milk represents the best choice for the nutrition of infants. It is often used for monitoring human exposures to environmental chemicals. Uniquely suited to meet human biological needs, breast milk composition, especially fat content, changes significantly with time from delivery. With the aim to compare the concentration of organochlorine compounds (OCs) in colostrum versus mature milk, we obtained samples of fourth-fifth day postpartum milk (colostrum) and day-14 postpartum milk (mature milk) from 12 women enrolled in the project "Early Childhood Development and PCB Exposure in Slovakia". The concentrations of selected organochlorine pesticides and congeners of polychlorinated biphenyls (PCBs) were measured using gas chromatography with electron capture detection and reported on lipid adjusted basis. No significant differences were found between organochlorine levels in colostrum and those in mature milk samples. A very close correlation was found between the concentrations of organochlorine compounds in colostrum and mature milk (Spearman correlation coefficient r=0.94-0.98 for PCBs, and r=0.85-0.99 for organochlorine pesticides, p<0.001 for all compounds). The present study concludes that the use of colostrum samples provides a close estimate of the child's exposure to OCs in the early neonatal period and demonstrates that, despite the lower fat content, colostrum specimens are adequate to conduct OC analyses.

Choice of exposure scores for categorical regression in meta-analysis: a case study of a common problem.

OBJECTIVE: Reporting categorical relative risk estimates for a series of exposure levels versus a common reference category is a widespread practice. In meta-analysis, categorical regression estimates a dose-response trend from such results. This method requires the assignment of a single score to each exposure category. We examined how closely meta-analytical categorical regression approximates the results of analysis based on the individual-level continuous exposure. METHODS: The analysis included five studies on tea intake and outcomes related to colorectal cancer. In addition, we derived categorical mean and median values from published distributions of tea consumption in similar populations to assign scores to the categories of tea intake when possible. We examined whether these derived mean and median values well approximate the individual-level results. RESULTS: In meta-analytical categorical regression, using the midrange scores approximated the individual-level continuous analyses reasonably well, if the value assigned to the uppermost, open-ended category was at least as high as the lower bound plus the width of the second-highest category. Categorical mean values derived from the published distributions of regular tea (in the US) and green tea (in Japan) well approximated the slope obtained from individual-level analysis. CONCLUSION: Publication of both the categorical and the continuous estimates of effect in primary studies, with their standard errors, can enhance the quality of meta-analysis, as well as providing intrinsically valuable information on dose-response.

Calcium intake during pregnancy among white and African-American pregnant women in the United States.

OBJECTIVE: To characterize the calcium intake in a racially mixed cohort of pregnant women, including the contribution of supplementation and antacids. METHODS: A cohort of women was interviewed twice during their pregnancies. The interviews included a food frequency questionnaire and questions on calcium supplementation and antacid intake. Pregnant women seeking prenatal care at a Pittsburgh hospital in the first trimester were enrolled. 454 women were enrolled and did not miscarry; 385 completed two interviews and were of white or African-American race. RESULTS: Mean and median intakes of calcium were 1671 mg/day and 1482 mg/day. 36% of the women were under the former RDA level (1200 mg/day) for calcium, while 26% were under the current AI (1000 mg/day). Six percent were taking in less than 600 mg/day, and 15% over 2500 mg/day, the tolerable upper limit. Young women were particularly likely to have low intakes (12% of those less than 21 years of age had less than 600 mg/day). Black women were slightly overrepresented among those with low intake (8% vs. 5% of whites), but, overall, their intake was quite similar to whites. Milk and cheese provided more calcium than other food items. Many women took antacids, especially during the second half of pregnancy, and these were a major source of calcium for some members of the cohort. CONCLUSIONS: Although mean and median calcium intake in the cohort were above the AI, many women had calcium intakes that were too high or low. Dairy products provided the most calcium for most pregnant women, and antacids were an important source for many.