Folic acid antagonists during pregnancy and the risk of birth defects

Background: Multivitamin supplementation in pregnant women may reduce the r isks of cardiovascular defects, oral clefts, and urinary tract defects in t heir infants. We evaluated whether the folic acid component of multivitamin s is responsible for the reduction in risk by examining the associations be tween maternal use of folic acid antagonists and these congenital malformat ions. Methods: We assessed exposure to folic acid antagonists that act as dihydro folate reductase inhibitors and to certain antiepileptic drugs in 3870 infa nts with cardiovascular defects, 1962 infants with oral clefts, and 1100 in fants with urinary tract defects and also in 8387 control infants with malf ormations the risk of which is not reduced after vitamin supplementation. M others were interviewed within six months after delivery about their medica tion use during pregnancy. Results: The relative risks of cardiovascular defects and oral clefts in in fants whose mothers were exposed to dihydrofolate reductase inhibitors duri ng the second or third month after the last menstrual period, as compared w ith infants whose mothers had no such exposure, were 3.4 (95 percent confid ence 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 clef ts, and urinary tract defects after maternal exposure to antiepileptic drug s were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent co nfidence 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 a cid diminished the adverse effects of dihydrofolate reductase inhibitors, b ut not that of antiepileptic drugs. Conclusions: Folic acid antagonists, which include such common drugs as tri methoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primid one, may increase the risk not only of neural-tube defects, but also of car diovascular 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.) (C) 2000, Massachusetts Medical Society.