Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development

“…Despite numerous arguments for avoiding treatment with VPA during pregnancy, there are circumstances when VPA cannot be excluded, as in cases of increased seizure occurrence after therapy replacement [18]. To reduce risk to the fetus, application of the lowest possible daily dose of VPA has been suggested, since a positive dose-response correlation between VPA and fetal anomalies has been observed [18].…”

“…To reduce risk to the fetus, application of the lowest possible daily dose of VPA has been suggested, since a positive dose-response correlation between VPA and fetal anomalies has been observed [18]. The risk of major congenital malformations increases significantly at VPA doses of 600-700 mg/day, with the largest attributable risk observed at doses exceeding 1000 mg/day, which causes defects in 15-30% of children [1,2,18].…”

“…Neural tube defects (NTDs) have been reported as the hallmark of VPA-induced teratogenicity in humans [18,19].…”

Update on management of epilepsy in women for the non-neurologist

“…Overall, the highest malformation rates were seen for valproate (4.7%–10%) and the lowest for lamotrigine (2%–3.4%) (table 2). 23 Valproate doses over 700 mg/day are currently regarded as highly teratogenic, as shown by a number of studies 24. Lamotrigine has been associated with low teratogenic risks, but higher risks of seizures as loss of seizure control can occur in up to 58% of pregnant women 25.…”

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“…1 The major metabolic pathways of VPA comprise glucuronidation, β-oxidation and ω-oxidation. 6,7 The former reaches up to 50% of the total metabolism of the initial dose.…”