Drug utilisation of valproate-containing medicinal products in women of childbearing potential in 5 European countries: a population-based network cohort study part of DARWIN EU®

Background: Valproic acid/valproate-containing medicines (VPA) are first-line treatment for epilepsy. VPA is a teratogen posing a risk of neurodevelopmental impairment and congenital malformations in the child. Therefore, its use in women of childbearing age is restricted in the European Union to prevent VPA exposure during conception and pregnancy.

Objectives: To estimate the incidence and prevalence of VPA use and to characterise patient-level VPA use in women aged ≥12 to ≤55 years from 2010 to 2022.

Methods: Study design: Population-based cohort and new user cohort study. EU PAS register number: EUPAS50789
Setting: Data was included from primary care records (IPCI (NL), SIDIAP (ES), CPRD (UK)) and ambulatory specialist data (IQVIA DA Germany, IQVIA LPD Belgium) mapped to the OMOP common data model.
Source population: All women present in the databases and aged ≥12 years and ≤55 years on 1st of January of each year in the period 2010-2022 (or latest available), with at least 365 days of data availability before.
Outcomes: Any use of a VPA containing medicine for prevalence, and first use for incidence and patient level utilisation.
Statistical analysis: Period prevalence was estimated, as of the 1st January for each year 2010-2022. Initial dose/strength and treatment duration were estimated for the first VPA prescription for each person. All analyses were stratified by age.

Results: The incidence of use of VPA decreased between 2010 and 2021 in all contributing datasets, from a maximum of 250 new users per 100,000 person years in 2010 to less than 89 in 2021. Similarly, the prevalence of VPA use decreased over time, steadily during the whole study period in BE, DE and the UK; but only after 2015/2016 in ES, and NL. This decrease was more marked for the younger age groups ( < 45), and use was also more prevalent in older age groups than in younger throughout the study period.
6416, 1241, 10398, 945, and 4002 eligible women initiated VPA in CPRD GOLD, IPCI, SIDIAP, LPD BE and DA Germany, respectively. Initial daily doses/strength for VPA were on average between 500 mg/day and 875 mg/day. While initial dose did not change over the course of the study, cumulative annual use decreased in SIDIAP, but remained stable in all other databases.

Conclusions: The incidence and prevalence of use of VPA among women of childbearing age have declined in BE, DE, ES, NL, and the UK. Although initial dose did not change over time, cumulative annual use decreased in ES (but not in any of the other countries).