The disposition of valproate and its metabolites in the late first trimester and early second trimester of pregnancy in maternal serum, urine, and amniotic fluid: Effect of dose, co-medication, and the presence of spina bifida

We have studied 52 pregnancies in epileptic women taking long-term valproate and have measured the concentrations of the parent compound and 13 of its metabolites by gas chromatography-mass spectrometry in amniotic fluid, maternal serum, and 24 h maternal urine samples. All metabolites of valproate present in the serum could also be detected in the amniotic fluid, although at much lower concentrations. Amniotic fluid concentrations of valproate and several of its metabolites ((E)Δ²-valproate, (2E,3′E)Δ^2,3'-valproate, and 3-keto-valproate) correlated with total valproate concentrations as well as with unbound valproate concentrations in maternal serum. We suggest that the amniotic fluid acts as a deep compartment, with slow appearance and disappearance of valproate and its main metabolites. The data further suggest that during the first and early second trimesters of pregnancy the β-oxidation of valproate decreases. In pregnancies associated with fetal neural tube defects (n = 5) significantly higher daily doses of valproate were used compared with normal pregnancies (n = 47). This resulted in higher concentrations of valproate in maternal serum. However, the metabolite patterns in maternal serum, 24 h urine samples, and amniotic fluid did not show any significant differences in pregnancies with neural tube defects.