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

Abstract

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.

FIGURE 1.

Mean (±SEM) maternal folic acid intake by pregnancy month for mothers of typically developing children and mothers of children with autism spectrum disorder or developmental delay. Maternal folic acid intake (μg/d) represents total intake reported from vitamins, supplements, and cereal. *Two-sided P < 0.01, Wilcoxon 2-sample test. B, month before pregnancy; P, month of pregnancy.

FIGURE 2.

ORs (95% CIs) for associations between mean maternal daily folic acid intake (≥600 μg compared with <600 μg) during the first month of pregnancy and autism spectrum disorder by maternal and child MTHFR genotype. ORs were adjusted for maternal educational level and child's birth year. Categories of folic acid intake were created on the basis of the recommended intake during pregnancy (600 μg/d). Analyses were based on 272 children with autism spectrum disorder and 275 of their mothers, and 154 children with typical development and 163 of their mothers with MTHFR 677 genotype and folic acid intake data. The frequencies of participants in each category of folic acid intake and MTHFR 677 genotype are presented in Supplemental Table 1 under “Supplemental data” in the online issue.