Significant Change in Valproate Prescribing Patterns Identified Following 2016 EMA Recommendations

Elisabeth Polard, MD

Two cross-section studies carried out in 2013 and 2016—before and after the European Medicines Agency (EMA) reinforced its warnings regarding the use of valproate (VPA) among women of childbearing age—showed significant changes in practice, with fewer women exposed to the antiseizure medication during pregnancy and before pregnancy.¹

Among pregnant women with epilepsy (2607 pregnancies), the proportion exposed to VPA during pregnancy decreased from 26.4% to 9.3% between 2013 and 2016. Among pregnant women with bipolar disorder (4278 pregnancies), the proportion of women exposed during pregnancy decreased from 3.7% in 2013 to 1.9% in 2016, without any switch to alternative drugs. In both populations, less than one-third had consulted a specialist before pregnancy.

Sodium VPA, an anticonvulsant shown to be effective for several epileptic syndromes and in the management of bipolar disorder, has also been shown to elevate the risk of major congenital malformations and neurodevelopmental disorders in children exposed in-utero.² As a result, in 2014, the EMA recommended that VPA should not be prescribed to adolescent girls, women of childbearing age, or pregnant women.

According to senior investigator Elisabeth Polard, MD, clinical pharmacologist, Centre Hospitalier Universitaire de Rennes, and colleagues, this was the first study to assess the impact of these recommendations on VPA use before, during, and after pregnancy in the setting of both epilepsy and bipolar disorder. Using the French National Health Insurance Database, a cross-sectional study was conducted in 2013 and in 2016 that included women who became pregnant and had at least 1 reimbursement claim for VPA in the 2 years prior to pregnancy or during pregnancy.¹

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The study included 6704 pregnant women (6885 pregnancies), of whom 2542 had epilepsy and 4162 had bipolar disorder. In these pregnancies, 96.7% had their first claim for VPA in the 2 years prior to pregnancy and 20.8% in the year prior to pregnancy. Only 3.3% had their first claim during pregnancy, 2.1% of these in the first trimester.

Prior to EMA recommendations, exposure to VPA decreased mainly during pregnancy, from 36% in the first trimester (T1) to 23% in the last trimester (T3) of pregnancy. Additionally, 16% of the women not exposed in T3 were exposed post partum (T+1). In 2016, after the recommendations, exposure to VPA decreased in the year prior to pregnancyfrom 59.9% to 29.1%.

Notably, 50.9% of women exposed in T-1 remained so in T1, which the study investigators suggested that "measures need to be reinforced to encourage pregnancy planning, aiming at the right targets," expressing particular importance for general practitioners, pharmacists, neurologists, psychiatrists, and patients.

Exposure to VPA also decreased during pregnancy, from 20.2% in T1 to 6.3% in T3, and 10.6% of the women not exposed in T3 were exposed post partum. These changes were parallel to an increase in the proportion of women exposed to therapeutic alternatives such as lamotrigine and levetiracetam. Between 2013 and 2016, there was an 8.6% increase for lamotrigine, a 9.4% increase for levetiracetam, and a 3.9% increase for benzodiazepines, while exposure to other antiseizure medications remained fairly stable.

Prior to the recommendations, among women with epilepsy for whom pregnancies ended in T3, 74.5% received a folic acid issue in the trimester preceding pregnancy (T-1) and 77% in the first trimester of pregnancy. In the year prior to pregnancy, 33.7% of the women saw a hospitalist, 28.4% saw a neurologist, and 12.7% saw a gynecologist/obstetrician. Over the study period, the proportions evolved very little for folic acid (+1.5 points in T1 in 2016 compared with 2013).

In 2013, in the course of pregnancy (T1, T2, or T3), the majority of VPA prescribers for epilepsy were GPs (64.1%), with neurologists making up a small portion (10.6%). Over the study period, the proportion of specialist doctors increased (+14% points for hospital doctors; +4% points for neurologists) whereas the proportion of GPs decreased (–15% points).

REFERENCES
1. Degremont A, Kerbat S, Balusson F, et al. Prescribing trends for valproate among pregnant women: a cross-sectional study in 2013 and 2016 using the French Health Insurance Database. Neurology. Published online April 4, 2022. doi:10.1212/WNL.000000000000200260

2. Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016;11(11):CD010224.