Investigators assert there is still room for improvement to further minimize exposure, as the treatment was used in a relevant number of pregnancies in 2016.
Analyses of health claims data from the German Pharmacoepidemiological Research Database (GePaRD) show the proportion of women with epilepsy using valproate during pregnancy has declined, but the treatment was still used during a relevant number of pregnancies in 2016.
A total of 2068 pregnancies logged in the GePaRD met inclusion criteria, of which 454 pregnancies in 430 women who recorded at least 1 dispensation of valproate either before or during pregnancy were included in the analysis. Of these, 89% ended in live births and 8% ended in induced abortions—the remaining 3% of included pregnancies ended in ectopic pregnancy, stillbirth, or spontaneous abortion. The mean age at time of pregnancy outcome was 31.1 years.
Valproate was dispensed before pregnancy in 357 of these pregnancies (79%) and dispensed during pregnancy in 97 pregnancies (21%). Seventy-five of those pregnancies who had valproate dispensed during pregnancy (77%) had it occur in the first trimester. From 2014 to 2016, the proportion with a valproate dispensation during pregnancy declined from 25%-19%, also decreasing for dispensation during the first trimesters, from 20% in 2014, to 17% in 2015, and 12% in 2016. Investigators also noted that the proportion of pregnancies ending in induced abortion increased from 5% in 2014, to 8% in 2015, and 13% in 2016.
For pregnancies exposed to valproate, 48% (n = 36) had no other antiepileptic drug (AED) dispensed during the observation time or before pregnancy, with this proportion lower for pregnancies beginning in 2016 (33%), as compared with those beginning in 2014 (53%) and 2015 (50%).
“A key element of the PRAC [Pharmacovigilance Risk Assessment Committee of the European Medicines Agency] recommendations from 2014 is that valproate should not be used to treat epilepsy in women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated. In other words, it is recommended that other treatments are tested before valproate is used in these women,” study coauthors Nadine Wentzell, MSc, research fellow, department of clinical epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, in Bremen, Germany; and Ulrike Haug, PhD, professor of clinical epidemiology and pharmacoepidemiology, University of Bremen; and head, department clinical epidemiology, Leibniz Institute for Prevention Research and Epidemiology, wrote.
“Still, our study showed that even in 2016, one-third of pregnant women with epilepsy treated with valproate in the first trimester, were not treated with another AED within the entire observation period before pregnancy beginning. Of note, our estimate of the proportion not using other AEDs before pregnancy may even be an underestimate as we did not distinguish whether other AEDs were used before valproate or in combination with valproate. Of course, we cannot rule out that other treatments were tested before the start of the (on average) 10-year pre-observation period. However, we hypothesize that several physicians may have started treatment with valproate as first-line treatment before the PRAC recommendations were issued and did not reconsider the treatment decision in light of the new recommendations,” Wentzell and Haug added.
The study was limited due to underrepresentation of pregnancies ending in a spontaneous abortion in the GePaRD, as with other claims databases, and investigators’ “conservative approach,” which missed abortions that did not require the patient seeking medical care. With results pulled from the claims database, information was also lacking on the severity of epilepsy, prescribed dose, and physicians’ risk-benefit assessment, limiting investigators’ ability to assess whether valproate-exposed pregnancies beginning in 2016 were medically justified or if providers had prescribed the lowest possible dose.
Additional study of the use of valproate before and during pregnancy is necessary, according to investigators, specifically due to further risk minimization measures that the PRAC recommended in 2018. The increase in the proportion of pregnancies exposed to valproate that ended in abortion should also be further investigated and evaluated.