Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Abstract

Introduction 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. Objectives To investigate the effectiveness of the 2018 EU 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 the 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 We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. 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%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any 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). Conclusion 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, to see if there is any need for additional measures in the future. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-023-01314-3.

Identification of misclassified pregnancy episodes in women of childbearing potential exposed to drugs with known teratogenic potential in the CPRD GOLD Pregnancy Register

“…All other countries showed a decline in pregnancies in the post-implementation period. 6 Similar trends were observed in another ongoing study, with an unexpectedly high number of pregnancies in the post-implementation period. After careful data investigation and quality checks, it was discovered that many pregnancy episodes recorded during the postimplementation period in the CPRD Pregnancy Register shared similar features: (1) Unknown outcome; (2) Mostly of 28 days duration; and…”

“…Going forward, CPRD will supply to researchers the relevant pregnancy code list and advice (i.e., Campbell et al 5 ) when releasing the CPRD Pregnancy Register to support informed decision making on uncertain pregnancies. CPRD will also review whether these advice codes should be excluded from the antenatal code list used to identify pregnancies and continue to consider how the validity of the data can be optimised, including incorporating data from Hospital Episode Statistics and ways of flagging pregnancy episodes according to level of uncertainty such as that proposed by Abtahi et al 6 More generally, although many pregnancies based on single antenatal codes will be valid pregnancies, researchers may wish to carefully review the clinical events that occurred close to the time of the pregnancy episode and design appropriate sensitivity analyses for such pregnancies, particularly in view of the lack of certainty resulting from imputing of pregnancy dates.…”