Restrictions on the use of valproate in female patients of reproductive age: the updated recommendations based on recent clinical data

For more than half a century, valproic acid (VA) has been a first-line drug to control seizures in various forms of epilepsy and status epilepticus; VA is also used in bipolar disorders. However, the accumulated clinical evidence indicates negative outcomes of pregnancies in women receiving valproate. Thus, babies born to mothers receiving VA for their epilepsy or bipolar disorder had an increased risk of serious congenital malformations. In addition, VA was found to affect the development of the CNS in a fetus that may result in attention-deficit hyperactivity syndrome (ADHD), autism spectrum disorder (ASD), childhood autism, and other diseases. The data on teratogenic effects of VA have led the regulatory authorities and the manufacturer to adopt restrictive recommendations regarding the use of VA in female patients of reproductive age. The Russian League Against Epilepsy (RLAE) presents this article to inform the medical community about the consequences of using valproic acid in pregnancy and also recommends a number of preventive measures. The article elaborates on the evidence of teratogenic risks associated with VA and reviews documents from the regulatory authorities (EMA, MHRA, Roszdravnadzor of the Russian Federation), which specify the measures needed to prevent the adverse effects of VA during pregnancy. According to these documents, medications containing VA should no longer be used in female patients of childbearing potential, except in cases where other treatments for epilepsy are ineffective or contraindicated. The changes made by the manufacturer in the official instructions for using the reference drug, and the unified instructions of the RF regulatory bodies on the reproduced (generic) drugs containing VA are also presented. The Pregnancy Prevention Program is proposed to minimize individual risks for women using VA. The article also addresses the international clinical practice on the prevention of VA-associated adverse effects during pregnancy and the recommendations of RLAE on alternative anti-epileptic therapy using minimally teratogenic drugs: lamotrigine, levetiracetam, and oxcarbazepine.