Folic Acid and the Prevention of Birth Defects: 30 Years of Opportunity and Controversies

Annu Rev Nutr. 2022 Aug 22:42:423-452. doi: 10.1146/annurev-nutr-043020-091647.


For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify (n = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B12 as well as expanded biomarker testing.

Keywords: folic acid; fortification; meta-analysis; neural tube defects; vB12.

Publication types

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

MeSH terms

  • Dietary Supplements
  • Female
  • Folic Acid*
  • Food, Fortified
  • Humans
  • Neural Tube Defects* / prevention & control
  • Pregnancy
  • Vitamin B 12


  • Folic Acid
  • Vitamin B 12