Introduction from Dr Markus Reuber, editor-in-chief of Seizure
It has been recognized for several decades that the use of antiepileptic drugs during pregnancy can harm foetal development. Several antiepileptic drugs (AEDs) have been linked to diverse major congenital malformations including cardiac abnormalities, spina bifida and other skeletal abnormalities. In addition, over the last fifteen years, it has become increasingly clear that exposure to AEDs in utero can have a detrimental effect on the intellectual development of babies born to mothers with epilepsy (1). Valproate, one of the most widely used antiepileptic drugs, has been shown to put babies at particularly high risk of suboptimal cognitive development. Early reports of adverse effects on verbal IQ have been confirmed by further studies and meta-analyses (2-3). It is now clear that children exposed to valproate in the womb have a lower IQ than those born to untreated women with epilepsy, or those exposed to carbamazepine, lamotrigine, levetiracetam, topiramate or phenytoin in pregnancy. Valproate has been shown to affect cognitive development in terms of attention, memory, executive functioning, adaptive behavior, social skills and motor functions. Increased rates of developmental disorders including autistic spectrum disorders have been reported (1).
My editor’s choice article from the current volume of Seizure, an interrupted time series analysis of valproate prescriptions issued by the public health service in Lithuania by Kristijonas Puteikis, Irma Medziausaite and Ruta Mamensikiene, shows how these scientific discoveries and the regulatory responses which they prompted have led to change in the use of an antiepileptic drug, which continues to be the most effective drug for genetic generalized epilepsies (4).
We learn that valproate use began to decline gradually in women and girls even before the first interventions from European regulators in 2013. The first intervention by regulators in 2013/14 did not significantly accelerate the overall trend – except in girls below the age of 15 – a relevant group, but arguably not the most important target population. In contrast the regulatory tightening of the valproate prescription procedures in 2017/18 had a much more dramatic effect on the use of valproate in female patients of all age groups.
The fact that the drop in valproate prescriptions to women above the age of fifty was as great as that in younger women suggests indicates that the new prescription guidelines may be a fairly blunt tool. Perhaps the guidelines have caused clinicians to review the prescription or continuation of inappropriate medication. However, it is also possible that women who are not at risk of having children who could be harmed by valproate exposure are now inappropriately deprived of a highly effective antiepileptic drug.
- Bromley RL and Baker G. Fetal antiepileptic drug exposure and cognitive outcomes. Seizure 2017;44:225-231.
- Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75: 1575-83
- Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 2014;10:Cd010236
- Puteikis K, Medziausaite I, Mamensikiene R. Valproate untilisation trends among girls and women from 2013 to 2018. Seizure 2019; 70: 77-81.