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Title High Dose Folic Acid during Pregnancy and the Risk of Autism - The Birth Order Bias: A Nested Case-Control Study
Authors Sarah Sharman Moser*, Michael Davidovich, Ran S Rotem, Gabriel Chodick, Varda Shalev and Gideon Koren

Background: There has been a dramatic increase in the prevalence of autism worldwide, concurring with growing use of folic acid for the prevention of neural tube defects. A recent study suggested increased risk of autism at high gestational dose levels of folic acid, raising public anxiety and fears of using folic acid. Our objective was to examine whether gestational use of folic acid is associated with increased risk of autism, with focus on high doses. Methods: This was a nested case- control study in a large health fund insuring 2 million citizens. Among 504,028 children born into Maccabi from 2000 to 2010 (inclusive) singleton children with autism (n=2009) were matched with up to 10 non autistic controls (n=19,886). The main dependent outcome measure was the diagnosis of autism, and the independent variable was the mean gestational dose of folic acid compared between cases of autism and controls after appropriate matching. Results: Significantly more autistic children were first born, and birth order effect was independently and significantly associated with folic acid use; Mothers purchased significantly more folic acid during the first pregnancy than during later pregnancies (P<0.001). In multivariate analysis, accounting for birth order and other confounders, folic acid use was not associated with increased autistic risk, and no dose -response trends were observed. Compared with mothers of the lowest average daily folate dose, the odds ratio for autism among mothers of highest daily dose (3 mg) was 0.99 (95% confidence interval: 0.59-1.67). The lack of association was further confirmed in sensitivity analysis restricted to first-born children only. Conclusions: Folic acid supplementation is not associated with a risk for autism even at high doses. A new type of bias, the birth order bias, has to be recognized and accounted for. The results are of public health importance given that folic acid is needed to prevent neural tube defects, sometime at high doses.