Developmental effects of anticonvulsants.

In a series of experiments, prenatal administration of phenytoin to rats at non-embryotoxic and non-teratogenic doses produced offspring exhibiting large and enduring abnormalities in behavior. Plasma drug concentrations on the last day of exposure in the dams were within the human therapeutic range for anticonvulsant efficacy. The behavioral abnormalities in the offspring were hyperactivity on tests of locomotion (increased pivoting behavior and figure-8 ambulation), but decreased figure-8 rearing. As adults, the phenytoin rats exhibited no impairment in swimming ability in a straight channel, but when placed in a complex water maze showed large increases in errors compared to controls. The effects of prenatal phenytoin on these behaviors were highly replicable, dose-dependent and stage-dependent. The stage of greatest vulnerability was during organogenesis. The data demonstrate that phenytoin is a potent behavioral teratogen in rats. The data also support clinical descriptions implicating CNS dysfunction as a major feature of the fetal hydantoin syndrome.