Autism and Folic Acid in Pregnancy

Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children

William T. Basco, Jr., 

May 07, 2013

JAMA. 2013;309:570-577

Folic Acid in Pregnancy

Although the use of folic acid among childbearing women and specifically during pregnancy has been shown to reduce neural tube defects, fewer studies have evaluated the association between folic acid supplementation and other neurodevelopmental problems. Small, intriguing studies have suggested that maternal intake of folic acid before pregnancy is associated with lower risk for autism spectrum disorders (ASDs) in children, but this is the first large cohort study to evaluate this potential association.

Study Methods

This Norwegian cohort enrolled 109,000 children born from 2002 to 2008. The mothers were recruited during pregnancy at approximately 18 weeks' gestation. The rate of diagnosis of ASDs in their children was obtained through questionnaires, referrals, and national registries. Cases of ASD were categorized as autism; Asperger syndrome; or pervasive developmental disorder, not otherwise specified (PDD-NOS).

Maternal intake of dietary supplements was determined by survey at the 18-week gestation visit, and a dietary questionnaire at 22 weeks determined dietary folic acid intake. The time window of interest for folic acid intake was from 4 weeks before conception until 8 weeks after conception. The investigators accounted for parental education, parental age, whether the pregnancy was planned, smoking during pregnancy, maternal body mass index, weight gain during the pregnancy, parity, and year of birth. The investigators also collected data on maternal use of fish oil supplements and analyzed the association between fish oil supplementation and ASDs in offspring.

Study Findings

The final sample included more than 85,000 children, with an age range of 3.3-10.2 years at the conclusion of the study. Of this cohort, 270 (0.32%) children were diagnosed with ASD.

When folic acid use in the first interval (before pregnancy to 8 weeks gestation) was examined, 33% of mothers were taking folic acid, increasing to 71% in weeks 9-12. By weeks 13-16, only 46% of the mothers were taking folic acid. The factors associated with the use of folic acid in the first interval were higher levels of education, planned pregnancy, being a nonsmoker, and being a first-time mother. Folic acid use increased from 43.2% to 83.7% over the study period.

In regression analyses, there was an inverse association between folic acid supplementation and the risk for ASD. ASD was diagnosed in 0.1% of the infants whose mothers took folic acid compared with 0.21% of infants whose mothers did not take folic acid. The adjusted odds ratio (OR) was 0.61 (95% confidence interval [CI], 0.41-0.90). Fish oil supplementation was associated with the same demographic factors (maternal education, planned pregnancy, etc.) as folic acid use, and the use of fish oil also increased over the study time window. However, there was no difference in the rate of diagnosis of ASD in children of mothers who took fish oil supplement compared with the children of mothers who did not. Mid-pregnancy use of folate was not associated with risk for being diagnosed with ASD. The adjusted OR for Asperger syndrome was 0.65; however, the 95% CI was 0.36-1.16, failing to reach statistical significance. The adjusted OR for prevention of PDD-NOS was 1.04.

The investigators concluded that maternal use of folic acid from 4 weeks before conception through 8 weeks after conception was associated with a lower odds of the offspring being diagnosed with ASD.