BACKGROUND: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. This included assessment of patients’ potential to become pregnant, pregnancy testing, contraceptive use and annual review of ongoing treatment.
OBJECTIVES: To investigate the effectiveness of the 2018 RMMs on valproate utilisation in five European countries/regions.
METHODS: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures.
RESULTS: There were 69,533 valproate users out of 9,699,371 females of childbearing age from the five participating centres (median follow-up 3.5-10.0 years, mean age at baseline ≥30 years). A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low ( <25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post intervention 12%). Pregnancy testing was insufficiently captured to analyse. There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in none of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07).
CONCLUSIONS: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe.
