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Original Investigation
January 3, 2018

Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring

Author Affiliations
  • 1Department of Community Mental Health, University of Haifa, Haifa, Israel
  • 2Department of Mental Health, Meuhedet Health Services, Tel Aviv, Israel
  • 3The Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York
  • 4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
  • 5Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 6Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
JAMA Psychiatry. Published online January 3, 2018. doi:10.1001/jamapsychiatry.2017.4050
Key Points

Question  Does maternal folic acid and/or multivitamin supplement use before and/or during pregnancy increase the risk of autism spectrum disorder in offspring?

Findings  In this case-control cohort study of 45 300 offspring, statistically significant associations between maternal vitamin supplement use before and/or during pregnancy and reduced risk of autism spectrum disorder in offspring were observed.

Meaning  A reduced risk of autism spectrum disorder in children born to women who used the specified vitamin supplements before and during pregnancy has important public health implications; possible mechanisms include epigenetic modifications.

Abstract

Importance  The association of maternal use of folic acid and multivitamin supplements before and during pregnancy with the risk of autism spectrum disorder (ASD) in offspring is unclear.

Objective  To examine the associations between the use of maternal folic acid and multivitamin supplements before and during pregnancy and the risk of ASD in offspring.

Design, Setting, and Participants  A case-control cohort study of 45 300 Israeli children born between January 1, 2003, and December 31, 2007, were followed up from birth to January 26, 2015, for the risk of ASD. The cases were all children diagnosed with ASD and the controls were a random sample of 33% of all live-born children.

Exposures  Maternal vitamin supplements were classified for folic acid (vitamin B9), multivitamin supplements (Anatomical Therapeutic Chemical A11 codes vitamins A, B, C, and D), and any combination thereof exposed in the intervals before and during pregnancy.

Main Outcomes and Measures  The association between maternal vitamin supplementation and the risk of ASD in offspring was quantified with relative risks (RRs) and their 95% CIs fitting Cox proportional hazards regression models adjusted for confounders. Sensitivity analyses were performed to test the robustness of the results.

Results  Of the 45 300 children in the study (22 090 girls and 23 210 boys; mean [SD] age, 10.0 [1.4] years at the end of follow-up), 572 (1.3%) received a diagnosis of ASD. Maternal exposure to folic acid and/or multivitamin supplements before pregnancy was statistically significantly associated with a lower likelihood of ASD in the offspring compared with no exposure before pregnancy (RR, 0.39; 95% CI, 0.30-0.50; P < .001). Maternal exposure to folic acid and/or multivitamin supplements during pregnancy was statistically significantly associated with a lower likelihood of ASD in offspring compared with no exposure during pregnancy (RR, 0.27; 95% CI, 0.22-0.33; P < .001). Corresponding RRs were estimated for maternal exposure to folic acid before pregnancy (RR, 0.56; 95% CI, 0.42-0.74; P = .001), maternal exposure to folic acid during pregnancy (RR, 0.32; 95% CI, 0.26-0.41; P < .001), maternal exposure to multivitamin supplements before pregnancy (RR, 0.36; 95% CI, 0.24-0.52; P < .001), and maternal exposure to multivitamin supplements during pregnancy (RR, 0.35; 95% CI, 0.28-0.44; P < .001). The results generally remained statistically significant across sensitivity analyses.

Conclusions and Relevance  Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD in the offspring compared with the offspring of mothers without such exposure.

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