INTRODUCTION: Due to the established teratogenic effects of valproates [1], the European risk minimisation measures (RMMs) for valproates were updated in March 2018 [2]. This included assessment of patients’ potential to become pregnant, pregnancy testing, contraceptive use and annual review of ongoing treatment.
OBJECTIVE: To investigate the effectiveness of the 2018 RMMs in five European countries/regions.
METHODS: An observational pharmacoepidemiological times-series study of females of childbearing age (12–55 years) was conducted using electronic healthcare databases from five countries/regions (Jan. 2010–Dec. 2020): Denmark (DNR), Italy (ARS Tuscany), the Netherlands (PHARMO), Spain (BIFAP), and the UK (CPRD). Clinical and demographic information from each source was transformed to the ConcePTION common data model [3], quality checks were conducted and a distributed analysis was performed using common analysis scripts. Incidence and prevalence rates of valproate use, proportion of valproate discontinuers and switchers to alternative medicine, frequency of pregnancy testing and contraception prior to and after 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 mentioned outcome measures.
RESULTS: There were 69,533 valproate users out of 9,699,371 female subjects of childbearing age from the five participating centres (median follow-up 3.5–10.0 years, mean age at baseline ≥ 30 years). We observed a statistically significant decline in prevalent use of valproates in all countries/regions, but no significant decreasing trend 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 (ranged between 0.5–25%), without an increasing trend after the 2018 RMMs across the studied databases. Pregnancy testing was insufficiently captured to analyse. The only significant increase in trend in switching rates from valproates to alternative medicine after the 2018 RMMs was observed in ARS Tuscany. There was a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in ARS Tuscany (0.70 per 1000 valproate users pre- and 0.27 post-intervention), BIFAP (0.48 and 0.13) and PHARMO (0.34 and 0.00), and an increasing rate in CPRD (1.13 and 5.07).
CONCLUSION: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. Despite the declining rates of concurrent pregnancies with valproate use after the 2018 intervention, the occurrence of a substantial number of such events warrants a careful monitoring of the existing policies and regulations on valproate use in Europe.
