Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

ImportanceNeural tube defects are among the most common birth defects in the US. ObjectiveTo review new evidence on the benefits and harms of folic acid supplementation for the prevention of neural tube defects to inform the US Preventive Services Task Force. Evidence ReviewSources included PubMed, Cochrane Library, Embase, and trial registries from July 1, 2015, through July 2, 2021; references; and experts, with surveillance through February 10, 2023. Two investigators independently reviewed English-language randomized studies and nonrandomized cohort studies in very highly developed countries that focused on the use of folic acid supplementation for the prevention of neural tube defect-affected pregnancies; methodological quality was dually and independently assessed. FindingsTwelve observational studies (reported in 13 publications) were eligible for this limited update (N=1244072). Of these, 3 studies (n=990372) reported on the effect of folic acid supplementation on neural tube defects. For harms, 9 studies were eligible: 1 randomized clinical trial (n=431) reported on variations in twin delivery, 7 observational studies (n=761125) reported on the incidence of autism spectrum disorder, and 1 observational study (n=429004) reported on maternal cancer. Two cohort studies and 1 case-control study newly identified in this update reported on the association between folic acid supplementation and neural tube defects (n=990372). One cohort study reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR], 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]), but this association occurred for only the later of 2 periods studied (2006-2013 and not 1999-2005). No other statistically significant benefits were reported overall. No study reported statistically significant harms (multiple gestation, autism, and maternal cancer) associated with pregnancy-related folic acid exposure. Conclusions and RelevanceNew evidence from observational studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects and no evidence of harms related to multiple gestation, autism, or maternal cancer. The new evidence was consistent with previously reviewed evidence on benefits and harms. This systematic review to support the 2023 US Preventive Services Task Force Recommendation Statement on folic acid supplementation to prevent neural tube defects summarizes published evidence on the benefits and harms of folic acid supplementation for persons who are planning to or could become pregnant.