Diphenylhydantoin and Selected Congenital Malformations

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Abstract
In a cohort of 50,897 pregnancies, frequencies of malformations, selected on the basis of reports in the literature, were compared between four groups of children born to epileptic mothers and those born to nonepileptic mothers. The highest malformation rate (61 per 1000) was observed in 98 children exposed during the early months of pregnancy to daily diphenylhydantoin (phenytoin) use. The rate was lowest in 50,591 children born to nonepileptic women (25 per 1000). It was intermediate in children of epileptic mothers exposed before delivery to sporadic or late use of diphenylhydantoin, and in children of such mothers who were not exposed to the drug. Among epileptic women with varying or no exposure to diphenylhydantoin, the malformation rates did not differ significantly. The difference in the malformation rates between children exposed regularly to diphenylhydantoin during early gestation and children born to nonepileptic mothers could reflect the teratogenic effect of the drug, of epilepsy itself or of both factors. (N Engl J Med 289:1049–1052, 1973)