Periconceptional folic acid exposure and risk of occurrent neural tube defects

JAMA. 1993 Mar 10;269(10):1257-61.


Objectives: A recent controlled trial has established that use of a 4-mg folic acid supplement before and during early pregnancy reduces the risk of recurrent neural tube defects (NTDs) by 72%. The present study was designed to determine whether folic acid also reduces the risk of first (occurrent) NTDs.

Design: Case-control study.

Setting: Tertiary and birth hospitals in metropolitan areas of Boston, Mass, Philadelphia, Pa, and Toronto, Ontario.

Participants: Mothers of 436 occurrent cases with NTDs and mothers of 2615 controls with other major malformations.

Main outcome measures: The prevalence of use of multivitamins containing folic acid was compared between mothers of cases and controls.

Results: The mothers of 17% of cases and 3% of controls reported knowledge of the folic acid-NTD hypothesis and were excluded from further analysis. For daily use of a multivitamins containing folic acid in the periconceptional period (28 days before through 28 days after the last menstrual period), the relative risk (RR) (and 95% confidence interval) was 0.4 (0.2 to 0.6). The most commonly used dose of folic acid was 0.4 mg, and the RR estimate was 0.3 (95% confidence interval, 0.1 to 0.6). For dietary folate, there was a dose-related decline in risk according to the quintile of intake (P for trend = .02).

Conclusion: These findings suggest that daily periconceptional intake of 0.4 mg of folic acid (the dose most commonly contained in over-the-counter multivitamin preparations) reduces the risk of occurrent NTDs by approximately 60%. A relatively high dietary intake of folate may also reduce the risk.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Case-Control Studies
  • Diet
  • Female
  • Folic Acid* / administration & dosage
  • Humans
  • Infant, Newborn
  • Neural Tube Defects / epidemiology
  • Neural Tube Defects / prevention & control*
  • Preconception Care*
  • Pregnancy
  • Pregnancy Outcome
  • Prenatal Care*
  • Risk Factors
  • Vitamins


  • Vitamins
  • Folic Acid