Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding
The placental transfer of primidone and its metabolites phenobarbital, phenylethylmalondiamide (PEMA) and p-hydroxyphenobarbital (free and conjugated) has been investigated at birth in 14 epileptic women who had been treated with primidone throughout pregnancy. All drugs studied were found in similar concentrations in maternal and cord blood. In seven of the newborns the pharmacokinetics of these drugs were studied during the first postnatal weeks. Primidone and phenobarbital were eliminated with mean half-lives of 23±10 h and 113±40 h, respectively, PEMA with 35±6 h. In some neonates the serum concentrations of phenobarbital and PEMA increased during the first few days due to their formation by neonatal primidone metabolism. Some babies showed a biphasic elimination pattern with elimination rates increasing after a few days. Although half-lives varied greatly, they corresponded well with renal clearance values and aminopyrine demethylase activities as measured by13CO2-exhalation from13C-labelled aminopyrine. Two newborns whose mothers had been treated with phenytoin in addition to primidone, showed half-lives, renal clearance values and aminopyrine demethylase activities well within the corresponding ranges for adults, thus demonstrating prenatal induction. Newborns whose mothers had been treated with valproate as comedication, did not exhibit elevated excretion rates as compared to newborns of mothers who were treated with primidone alone. Withdrawal symptoms developed in two newborns at times when primidone had been essentially excreted, and in spite of the presence of elevated phenobarbital and PEMA levels. All drugs studied were also present in mothers' milk. During breast feeding, drugs ingested with the milk contributed to the neonate's blood levels, particularly in the case of phenobarbital.