gms | German Medical Science

Background: Many oral antiepileptic drugs (AED), and valproate in particular, have an increased risk of teratogenicity. The use of valproate during pregnancy can lead to a high rate of malformations and to developmental disorders in children. Recently, the issue has received increasing attention through the risk assessment procedures of the European Medicines Agency (EMA) in 2014 and 2018 [1], [2] and the resulting regulatory actions: A pregnancy prevention program was introduced in Germany, two Red-Hand-Letters were sent, and new or updated educational materials for physicians and patients were commissioned to better inform about the risks of using valproate during pregnancy. The aim of this project was to examine the development of the prescription frequency of valproate in women in general as well as in women of childbearing age and to analyze the prescription patterns of first time valproate users (13-49 years) before, during and after the European risk assessment processes. In addition, a secondary aim was to investigate the development of prescribing behavior with regard to other oral AED to determine to what extent other oral AED where prescribed instead of valproate in women of childbearing age and to investigate the frequency of valproate/AED prescriptions during pregnancy.

Materials and Methods: Routine data of the statutory health insurance in Germany between 2010 and 2020 was used for this study. The data was retrieved from the database for “Integrated Analyses” (IntegAna) of the Scientific Institute of the AOK (WIdO), which contains the billing data of all AOKs in Germany (~ 26 million insured persons). The study population comprised all women who were continuously insured with the AOK in the respective observation year and the previous year (~ between 11.1 and 11.8 million women; ~ between 4.3 and 4.7 million women of childbearing age (13-49 years); and ~ between 5.8 and 6.0 million insured women over 50 per observation year).

Results: Overall, between 2010 and 2020, the prescription prevalence and incidence of valproate declined, especially among women of childbearing age. At the same time, prescribing patterns in terms of daily doses prescribed per capita remained unchanged. The prescription frequency of oral AED among women between 13 and 49 years of age remained almost stable, while it increased among all women and especially among women aged 50 years or older. Besides that, for other oral AED with an increased embryotoxic risk, the prescription prevalence among women (13-49 years) decreased. However, an increase in prescription frequency for newer oral AED was observed. Furthermore, the proportion of valproate recipients with prescriptions during pregnancy decreased, especially since 2014. The proportion of oral AED recipients with prescription in pregnancy (ages 13-49) increased slightly. However, for some of the most common oral AED, the proportion of women receiving these agents during pregnancy decreased between 2014 and 2018. At the same time, there has been a slight increase in the proportion with prescription and pregnancy for those agents considered safer to take during pregnancy.

Conclusion: The results of this study underline a change in the prescribing behavior of valproate in women of childbearing age after the first and during the second European risk assessment process; both valproate and other oral AED with known teratogenicity were prescribed less in this patient group. Analyses of the years 2019 and 2020 indicate that the additional regulatory measures led to a further decrease in valproate prescriptions since 2018.

Acknowledgement: The project was funded by the BfArM.