Purpose: To conduct a limited update of new evidence of the benefits and harms of folic acid supplementation for the prevention of neural tube defects (NTDs) in persons capable of becoming pregnant for the U.S. Preventive Services Task Force (USPSTF) to update its 2017 recommendation.
Data Sources: PubMed/MEDLINE, the Cochrane Library, Embase, and trial registries for publications from July 1, 2015, through July 2, 2021; reference lists of retrieved articles, with surveillance of the literature through February 10, 2023.
Study Selection: Two investigators independently screened studies from the update search using a priori inclusion and exclusion criteria. We included English-language randomized studies and nonrandomized cohort studies with comparisons that focused on the use of folic acid supplementation (by itself or in multivitamin) for the prevention of NTD-affected pregnancies in persons capable of getting pregnant. We also evaluated studies investigating potential harms of folic acid supplementation such as maternal cancer and autism spectrum disorder.
We excluded poor-quality studies, studies not conducted in very highly developed countries, and studies focusing solely on persons on antiseizure medications, persons with a history of NTDs in previous pregnancies, or persons not capable of getting pregnant.
Data Extraction and Analysis: One investigator extracted data and a second checked accuracy. Two reviewers independently rated the methodological quality of the included studies based on predefined criteria.
Results: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N=1,244,072 [from nonoverlapping cohorts]). Of these, three studies (N=990,372) reported on the effect of folic acid supplementation on NTDs. No studies reported on differences by race or ethnicity. For harms, nine studies were eligible; one randomized, controlled trial (N=431) reported on variations in twin delivery, seven observational studies (N=761,125) reported on the incidence of autism spectrum disorder, and one observational study (N=429,004) reported on maternal cancer.
Regarding benefits of folic acid supplementation, two cohort studies and one case-control study in this update reported on the association between folic acid supplementation and NTDs (N=990,372). One cohort study reported a statistically significant reduced risk of NTDs associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR]: 0.54 [95% confidence interval {CI}, 0.31 to 0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39 to 0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29 to 0.83]), but for only the later of two periods studied (2006 to 2013 and not 1999 to 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.
Limitations: Interventions evaluated by included studies were restricted to folic acid supplementation and did not include interventions such as food fortification, counseling to increase dietary intake, or screening for NTDs. We did not evaluate the association between red blood cell folate concentrations and NTDs. We found limited information on differences in benefits and risks of folic acid supplementation by dose and timing. We found no information about variation in outcomes by duration of use or by race or ethnicity.
Our review was designed to identify evidence that could result in a change in the 2017 USPSTF A recommendation; therefore, it focused only on studies published since 2015 and did not include the previously reviewed evidence. Ethical and logistical issues constrain the conduct of new randomized, controlled trials of folate supplementation versus placebo. All newly available evidence is observational and offers limited ability to control for confounding (including from mandatory food fortification), selection bias, recall bias, and attrition. As a result, included studies have inherent uncertainty regarding case ascertainment (for NTDs and harms) and degree of exposure (dose, timing, and duration) to folic acid supplementation.
Conclusions: New evidence from observational studies provides continued evidence of benefit of folic acid supplementation for preventing NTDs and no evidence of harms related to multiple gestation, autism, or maternal cancer and is consistent with the previously reviewed evidence on this topic. The 2017 USPSTF recommendation supporting folic acid supplementation in pregnancy was based on previously reviewed evidence from a randomized, controlled trial and observational studies reporting reduced NTDs with supplementation and no consistent evidence of harms for multiple gestations, maternal adverse effects, or child respiratory illness.