Use of folic acid supplementation during pregnancy is associated with reduced risk of neural tube defects (NTDs) and likely other neurodevelopmental disorders in children, including autism spectrum disorders. This cohort study was undertaken to investigate the association between the use of maternal folic acid before and in early pregnancy and the risk of autistic disorder, Asperger syndrome, and pervasive developmental disorder—not otherwise specified (PDD-NOS) in offspring.
The cohort included 109,000 children born during 1999–2009. All women attempting to become pregnant were advised to take one 400-μg folic acid supplement per day from 1 month before conception through the first trimester. Cases of autism spectrum disorders were identified through questionnaire screening of mothers at offspring aged 36 months, 5 years, and 7 years. Detailed information was obtained through maternal questionnaire reports at week 18 of gestation and a food frequency questionnaire at week 22. The primary analyses assessed the interval from 4 weeks before to 8 weeks after the start of pregnancy. Odds ratios with 95% confidence intervals (CIs) for the association between folic acid use and risk of each autism spectrum disorder were estimated from logistic regression models. Exploratory analyses for the autistic disorder subtype were done, seeking clues to interactions that could be tested in future studies.
The final sample included 85,176 children, with a mean age at the end of follow-up of 6.4 years (range, 3.3–10.2 years). Of 270 children (0.32%) diagnosed with autism spectrum disorders, 114 (0.13%) had autistic disorder, 56 (0.07%) had Asperger syndrome, and 100 (0.12%) had PDD-NOS. During weeks 4 to 1 before the start of pregnancy, 32.9% of mothers took folic acid. This rate increased to 70.7% in weeks 9 to 12 and declined to 45.8% in weeks 13 to 16. Women who used folic acid were more likely to have university-level education, to have planned the pregnancy, to be nonsmokers, to have prepregnancy body mass index less than 25 kg/m2, and to be first-time mothers. Between 2002 and 2008, folic acid use increased from 43.2% to 83.7%. The questionnaire response rate was 62% in folic acid users and 55% in nonusers. For the youngest children, born in 2005–2008, the respective response rates were 61% and 50%. An inverse association was found between folic acid use and subsequent risk of autistic disorder. For users and nonusers, autistic disorder was present in 0.10% (64/61,042) and 0.21% (50/24,134) of children, respectively. The adjusted odds ratio (aOR) of autistic disorder was 0.61 (95% CI, 0.41–0.90) in children of folic acid users. No association was found between use of fish oil supplements and risk of autistic disorder. The aOR of autistic disorder was 1.29 (95% CI, 0.88–1.89) in children of mothers who used fish oil supplements. In midpregnancy, the aOR for autistic disorder was 0.96 (95% CI, 0.60–1.55) for mothers taking folic acid (≥400 μg/d) in week 22 and 1.02 (95% CI, 0.62–1.67) for those taking less than 400 μg/d. For Asperger syndrome, the proportion of diagnosed cases was 0.12% (21/17,218) in children of users and 0.21% (27/12,899) in children of nonusers (aOR, 0.65; 95% CI, 0.36–1.16). For PDD-NOS, the proportion in users and nonusers was 0.15% (58/39,543) and 0.17% (33/19,649), respectively (aOR, 1.04; 95% CI, 0.66–1.63). The use of other vitamins and minerals along with folic acid did not affect risk of autistic disorder.
Maternal use of supplemental folic acid before conception and early in pregnancy was associated with a lower risk of autism spectrum disorders in children. This finding does not establish a causal relation between folic acid use and autistic disorder. The analyses should be performed in other cohorts, and genetic factors and biologic mechanisms should be investigated further to explain the inverse association.
Norwegian Institute of Public Health (P.S., M.H., K.K.L., P.M., T.R.-K., A.-S.Ø., C.S., C.R., S.S.), Oslo, Norway; Centre for Paediatric Epidemiology and Biostatistics (P.S.), UCL Institute of Child Health, London, UK; Mailman School of Public Health (M.B., M.H., W.I.L., E.S., C.R.), Columbia University, New York, NY; New York State Psychiatric Institute (M.B., E.S.), New York, NY; National Institute of Neurological Disorders and Stroke (D.H.), Bethesda, MD; Institute of Psychiatry (T.R.-K.), University of Oslo, Oslo, Norway; MRC Centre for Causal Analysis in Translational Epidemiology (G.D.S.), University of Bristol, Bristol, UK; Nic Waals Institute (A.-S.Ä.), Lovisenberg Hospital, Oslo, Norway; and Department of Public Health and Primary Health Care (C.S.), University of Bergen, Bergen, Norway