Pregnant women are advised to take folic acid to reduce the risk of having an infant with a neural-tube defect. Now researchers have found that folic acid may be necessary to prevent other congenital defects, by showing an increased risk of defects in infants whose mothers took folic acid antagonists during pregnancy.

Folic acid antagonists include dihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim) and antiepileptic drugs (carbamazepine, phenytoin, primidone, and phenobarbital) that interfere with folate metabolism.

The retrospective study revealed that the use of dihydrofolate reductase inhibitors during early pregnancy increased the risk of having an infant with a cardiovascular defect or an oral cleft by 3.4-fold and 2.6-fold, respectively. Exposure to any of the antiepileptic drugs increased the risk of cardiovascular defects by 2.2-fold, that of oral clefts by 2.5-fold, and that of urinary tract defects by 2.5-fold. The risk of defects was elevated to a lesser extent in women taking dihydrofolate reductase inhibitors plus concomitant folic acid supplementation, but such supplementation did not modify the risk of defects among the ones taking antiepileptic drugs.

Hernandez-Diaz S, et al. N Engl J Med 2000;343(22):1608-14.