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

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.

Figure 1.. Proportion of Vitamin Supplement Dispensations Before Childbirth

Dispensations of folic acid and/or multivitamin vitamin supplements, folic acid supplements, and multivitamin supplements before childbirth.

Figure 2.. Adjusted Relative Risk of Autism Spectrum Disorder in Offspring to Mothers Exposed to Folic Acid (FA) and/or Multivitamin Supplements, FA Supplements, or Multivitamin Supplements in the Periods Before and During Pregnancy

The solid boxes represent the estimated relative risk adjusted for the study covariates, and the lines represent the corresponding 95% CI. For each exposure, the reference group was children whose mothers had no exposure in each corresponding interval.