Folic acid antagonists during pregnancy and the risk of birth defects

N Engl J Med. 2000 Nov 30;343(22):1608-14. doi: 10.1056/NEJM200011303432204.


Background: Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations.

Methods: We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use.

Results: The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs.

Conclusions: Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.

Publication types

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

MeSH terms

  • Abnormalities, Drug-Induced / etiology*
  • Abnormalities, Drug-Induced / prevention & control
  • Anticonvulsants / adverse effects*
  • Case-Control Studies
  • Cleft Lip / chemically induced
  • Dietary Supplements
  • Female
  • Folic Acid / therapeutic use
  • Folic Acid Antagonists / adverse effects*
  • Heart Defects, Congenital / chemically induced
  • Humans
  • Logistic Models
  • Pregnancy
  • Urinary Tract / abnormalities
  • Vitamins / therapeutic use


  • Anticonvulsants
  • Folic Acid Antagonists
  • Vitamins
  • Folic Acid