Use of Sodium Valproate and Other Anti-Seizure Medications in England and Wales During the COVID-19 Pandemic: A Population-Level Analysis of 60 Million Individuals

Background: Key policy statements in 2018 on the use of sodium valproate (SV), an evidence-based treatment for idiopathic generalised epilepsy (IGE), which also has teratogenic effects, were followed by the onset of the COVID-19 pandemic. We investigated the use of SV in England and Wales, the impact of policy implementation and the pandemic. Methods: Prevalent (current) and incident (new) uses of SV and other anti-seizure medications (ASMs) before and during the COVID-19 pandemic (2019-2021) were identified in England and Wales (n=60 million), stratifying use by age-bands, sex, geography, ethnic group, deprivation and disease indication. We assessed pregnancy rates and examine the timing and dose of ASMs dispensed during pregnancy. Using multivariate logistic regression we investigated factors associated with SV use during pregnancy and trends in epilepsy-related deaths between 2015 to 2021 using time series analysis. Findings: Use of SV in women of CBP decreased whilst use of other ASMs increased between 2019 and 2021. New initiation of SV per 100,000 women fell from 13 to 8 in women aged 30-39, 10 to 6 in women aged 20-29 and 7 to 5 in women aged 15-19 between 2019 and 2021, while pregnancy rates fell from 5.9 to 5.1 per 1000 women of CBP dispensed SV. The number of pregnant women with evidence of a SV dispense during the pregnancy period fell from 112 in 2019 to 67 in 2021. Epilepsy was the most common indication, followed by bipolar disorder (678 and 190 per 1,000 women of CBP dispensed SV respectively). There was no clear evidence that epilepsy-related deaths increased in women and men aged 15-49 during the period 2018-2021.Interpretation: Rates of use of SV by women, including during pregnancy, fell before and continued to decline during the COVID-19 pandemic. Further research using linked health data is needed to investigate how policy changes impact on seizure control and mortality in men and women of CBP and on harms to children exposed in utero. Our approach could be used to investigate medicines safety more broadly in pregnancy and demonstrate how linked routinely-collected electronic health record data can be used to inform policy.Funding: This work was carried out with the support of the BHF Data Science Centre led by HDR UK (BHF Grant no. SP/19/3/34678).Declaration of Interest: The views represented in this manuscript are entirely those of the authors, and do not represent the views of any organisations they represent. MP has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co- funded by MRC and Roche, UCB, Eli Lilly and Novartis). He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www.ardat.org) and Chair of the Commission on Human Medicines (CHM). RS is a member of the Pharmacovigilance Expert Advisory Group, a sub-committee of the CHM. CT has received funding paid to University College London from GlaxoSmithKline (GSK), outside of the scope of the submitted work. AGM has received funding paid to University of Liverpool from UCB Pharma, Sanofi, Eiasi and GSK. He is a member of the MHRA valproate implementation group, chief investigator of the SANAD trials and senior author of the Cochrane reviews assessing the teratogenic effects of anti-seizure medications.Ethical Approval: The North East - Newcastle and North Tyneside 2 research ethics committee provided ethical approval for the CVD-COVID-UK/COVID-IMPACT research programme (REC No 20/NE/0161) to access, within secure trusted research environments, unconsented, whole-population, de-identified data from electronic health records collected as part of patients’ routine healthcare.