Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers

Abstract

The pharmacokinetics of valproic acid (VPA) and several metabolites were measured in 11 epileptic mothers and their 12 newborns. VPA was found in higher concentrations in cord serum than in maternal serum [(factor 1.7 +/- 0.6; (n = 6)]. VPA was excreted in the neonates with a mean half-life of 47 +/- 15 hr (n = 8) which is approximately 4 times the mean value found in adult epileptics. Maternal comedication (primidone and phenytoin) resulted in slightly reduced half-lives. The transplacental kinetics of the two main VPA metabolites in blood were similar to those of VPA. The very low levels of VPA in mother's milk (3% of maternal serum concentrations) suggest apparent safety of breast feeding. The [13C]aminopyrine breath test indicated neonatal hepatic enzyme activities which were slightly above those of unexposed neonates, but much below those of neonates which had been exposed to primidone and phenytoin in utero. Six of eight neonates exposed to VPA-monotherapy, but only one exposed to primidone or phenytoin comedication, developed an icterus neonatorum. A number of minor anomalies (four to eight per child) were observed, particularly hernias, diastasis of musculus rectus abdominis and weak abdominal walls. Two children were microcephalic and in another four children the head circumferences were below the 10th percentile. Significant withdrawal symptoms were not observed. Also hypoplasia of the nails and phalanges and facial dysmorphism associated with the "fetal hydantoin syndrome" did not occur in VPA-exposed children except in one case in which primidone had been administered as comedication.