Folic Acid Supplementation to Prevent Recurrent Neural Tube Defects: 4 Milligrams Is Too Much

Fetal Diagn Ther. 2018;44(3):161-165. doi: 10.1159/000491786. Epub 2018 Aug 22.


Some medical practices have been ingrained in custom for decades, long after "proof" that they were effective was established. It is necessary to periodically reevaluate these practices, as newer theories and research may challenge the evidence upon which they were based. An example is the decades' old practice of recommending a 4-mg (4,000-µg) supplement of folic acid to women who are at risk for recurrent neural tube defect (NTD) during pregnancy. This recommendation was based on findings from a randomized clinical trial in 1991. Since then, multiple studies have confirmed the utility of 400-800 µg of folic acid in lowering both primary and recurrent risks of NTDs, but no studies have established any further reduction in risk with doses over 1 mg. Current understanding of folic acid metabolism during pregnancy suggests that at higher doses, above ∼1 mg, there is not increased absorption. Recent evidence suggests that 4 mg folic acid supplementation may not be any more effective than lower doses for the prevention of recurrent NTDs. Thus, we recommend that it is time for clinicians to reexamine their reliance on this outdated recommendation and consider using current recommendations of 400-800 µg per day for all patients in conjunction with assessment of maternal folate status.

Keywords: Folate; Folic acid; Fortification; Neural tube defects; Nutrition; Pregnancy; Supplementation.

Publication types

  • Review

MeSH terms

  • Dietary Supplements*
  • Female
  • Folic Acid / administration & dosage*
  • Humans
  • Neural Tube Defects / prevention & control*
  • Pregnancy
  • Secondary Prevention


  • Folic Acid