RESEARCH - Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects

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New England Journal of Medicine

November 30, 2000

Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects

ABSTRACT

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 assessed exposure to folic acid antagonists that act as

dihydrofolate reductase inhibitors and to certain antiepileptic drugs in

3870 infants with cardiovascular defects, 1962 infants with oral clefts, and

1100 infants with urinary tract defects and also in 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 during pregnancy.

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.

http://content.nejm.org/cgi/content/short/343/22/1608

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