High dose folic acid during pregnancy and the risk of autism; The birth order bias: A nested case-control study

Objective: To examine whether there is an association between the cumulative dose of folic acid (FA) purchased by mothers, and risk of autistic spectrum disorders (ASD) in their progeny. Methods: We identified 2009 singletons who received an ASD diagnosis from a cohort of 480,526 children born in a large health organization in Israel from 2000 through 2013. ASD patients were individually matched to ASD-free children (n = 19,886). Median cumulative daily doses of supplemented FA during the 12-month period prior to the end of pregnancy (from dispensing records) were compared using conditional logistic regression models. Results: Children with ASD were more likely to be first-born, and birth-order was significantly associated with FA use. In multivariable analysis, there were no statistically significant differences in the cumulative dose of FA between the groups. Conclusion: Birth order effects need to be accounted for in analyses aiming to decipher the associations between gestational FA use and developmental outcomes.