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Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and encephalocele) with data from a control group of 6,660 infants with malformations not related to vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional folic acid supplementation, maternal age, weight, education, and infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs. Am J Epidemiol 2001;153:961-8. [ABSTRACT FROM AUTHOR]

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. (N Engl J Med 2000;343:1608-14.) [ABSTRACT FROM AUTHOR]