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Folic Acid Antagonists
Folic Acid Antagonists During Pregnancy and the Risk of Birth Defects. Hernandez-Diaz S, Werler MM, Walker AM, et al. New Engl J Med 2000; 343: 1608-14.
Multivitamin supplementation in pregnant women may reduce cardiovascular defects, oral clefts and urinary tract defects in their infants. This study examined 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. The authors assessed exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors (DRI) (like trimethoprim, triamterene, sulfasalazine) and to certain anti-epileptic drugs (AED) that interfere with folic acid metabolism (like phenobarbital, carbamazepine, and phenytoin) 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. The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to DRIs during the second and third month of pregnancy compared to mothers who had no such exposure were 3.4 and 2.6 respectively. The relative risks of cardiovascular defects, oral clefts and urinary tract defects after maternal exposure to AEDs were 2.2, 2.5 and 2.5 respectively. The use of multivitamin supplements containing folic acid diminished the adverse effects of DRIs but not that of AEDs.
Comment. As neonatologists, we occasionally encounter babies whose mothers received AEDs or DRIs during early pregnancy. While it has been widely accepted that folic acid supplementation during pregnancy reduces the risk of having an infant with a neural tube defect, we now have strong evidence that folic acid is important in preventing a wide variety of congenital defects, and that drugs that interfere with folic acid metabolism may contribute to the production of these defects.
Andrew B. Kairalla MD