Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics

Abstract

Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons. Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine- and ethosuximide-treated mothers. This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasized. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.