Impact of regulatory safety notices on valproate prescribing and pregnancy outcome among women of child-bearing potential in Scotland: a population-based cohort study

OBJECTIVE: To examine the impact of Medicines and Healthcare products Regulatory Agency (MHRA) safety alerts on valproate prescribing among women aged 14–45 years in Scotland and examine trends in pregnancies exposed to valproate. DESIGN: Population-based cohort study. PARTICIPANTS: 21 983 women of all ages who received valproate between January 2011 and December 2019. METHODS: All valproate prescriptions issued to women in Scotland between January 2011 and December 2019 were identified and prevalence/incidence rates per 10 000 population derived. The impact of regulatory safety alerts on prescribing was analysed using Joinpoint models. Linked pregnancy records for January 2011 to September 2019 were identified and annual rates of pregnancy per 1000 valproate-treated women aged 14–45 years were calculated for each pregnancy outcome: live birth, stillbirth, miscarriage and termination. RESULTS: Annual prevalent and incident rates of valproate prescribing declined in women aged 14–45 years between 2011 and 2019 from 40.5 to 18.3 per 10 000 population (54.8% reduction) and 7.9 to 1.3 per 10 000 population (83.5% reduction), respectively. Statistically significant changes occurred around the times of the MHRA safety alerts. The number of valproate-exposed pregnancies conceived each year fell from 70 in 2011 to 20 in 2018, a 71.4% reduction, and the number of live births fell from 52 to 14, a 73.0% reduction. Expressed as a rate this was a 46.4% decrease from 15.3 to 8.2 per 1000 valproate-treated women aged 14–45 years in 2011 and 2018, respectively. Live birth was the most common pregnancy outcome. CONCLUSION: This study demonstrates, for the first time, the capabilities of national data sets to identify drug exposure and derive pregnancy outcome at scale across Scotland. Building on this as part of an evolving national/UK surveillance capability will continue efforts to minimise in-utero exposure to valproate; enabling ongoing surveillance to understand better long-term outcomes, and to inform better provision of health and wider support services.