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

JAMA. 2023 Aug 1;330(5):460-466. doi: 10.1001/jama.2023.9864.


Importance: Neural tube defects are among the most common birth defects in the US.

Objective: To 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 review: Sources 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.

Findings: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N = 1 244 072). Of these, 3 studies (n = 990 372) 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 = 761 125) reported on the incidence of autism spectrum disorder, and 1 observational study (n = 429 004) 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 = 990 372). 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 relevance: New 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Systematic Review

MeSH terms

  • Autism Spectrum Disorder / chemically induced
  • Dietary Supplements* / adverse effects
  • Female
  • Folic Acid* / administration & dosage
  • Folic Acid* / adverse effects
  • Folic Acid* / therapeutic use
  • Humans
  • Neural Tube Defects* / etiology
  • Neural Tube Defects* / prevention & control
  • Preconception Care
  • Pregnancy
  • Pregnancy Complications* / etiology
  • Pregnancy Complications* / prevention & control
  • Prenatal Care
  • Randomized Controlled Trials as Topic
  • Risk


  • Folic Acid