Sobre Vivir

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

FOLIC ACID ANTAGONISTS DURING PREGNANCY AND THE RISK OF BIRTH DEFECTS
SONIA HERNÁNDEZ-DÍAZ, M.D., DR.P.H., MARTHA M. WERLER, SC.D., ALEXANDER M. WALKER, M.D., DR.P.H., AND ALLEN A. MITCHELL, M.D.

ABSTRACT
Background Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinarytract 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 infantswith 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 ininfants 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 defectsafter 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 Folicacid 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. (N Engl J Med 2000;343:1608-14.)
©2000,Massachusetts Medical Society.

id.1,2 Periconceptional supplementation with multivitamins containing folic acid may also reduce the risk of congenital malformations other than neural-tube defects, such as cardiovascular defects,3-6 oral clefts,6-9 urinary tract defects,4,6,9-11 and limb-reduction defects.3,4,9 However, it is not clear whether folic acid or some other component in the multivitamins isresponsible for these reductions in risk, since most multivitamins contain more than 15 vitamins and minerals. One way to assess the role of the folic acid component of multivitamins in decreasing the prevalence of birth defects is to determine whether folic acid antagonists are associated with an increased risk of such defects. There are two general groups of folic acid antagonists. One groupconsists of the dihydrofolate reductase inhibitors, including aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim, which displace folate from the enzyme and thereby block the conversion of folate to its more active metabolites.12 The second group of folic acid antagonists may affect various other enzymes in folate metabolism, impair the absorption of folate, or increasethe degradation of folate. These folic acid antagonists, which are primarily antiepileptic drugs, include carbamazepine, phenytoin, primidone, and phenobarbital. Postulating that folic acid antagonists might counteract the effect of folic acid, we used data from a large, multicenter, case–control program of surveillance for birth defects to assess whether folic acid antagonists might increase...