The prescription of valproate: risk of harm
Authors: Fergus Rugg-Gunn, David Hunt
Journal: The Lancet Neurology (2024)

In the UK, the Independent Medicines and Medical Devices Safety Review criticised the entire health-care system for its slowness to identify the emerging reproductive risks of valproate and the resulting delay in providing patients with accurate information. The report found that whole-system inertia was a contributing factor to birth defects in an estimated 20 000 children, many of whom experienced avoidable lifelong harm.1Independent Medicines and Medical Devices Safety ReviewFirst do no harm.https://www.immdsreview.org.uk/downloads/IMMDSReview_Web.pdfDate: 2020Date accessed: April 4, 2024Google Scholar Your Editorial described the reproductive risks of valproate for women of childbearing potential in surprisingly mild terms, referring only to an increased risk of major congenital malformations.2The Lancet NeurologyReducing the uses of valproate: a controversial decision.Lancet Neurol. 2024; 23: 123Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Valproate exposure during pregnancy risks congenital disorders in 11% of individuals exposed in utero and neurodevelopmental disorders in up to 30–40% of individuals exposed in utero.3UK Medicines and Healthcare Products Regulatory AgencyValproate: review of safety data and expert advice on management of risks.https://assets.publishing.service.gov.uk/media/65660310312f400013e5d508/Valproate-report-review-and-expert-advice.pdfDate: 2023Date accessed: April 8, 2024Google Scholar In addition to these serious risks, evidence of further reproductive toxicities due to valproate are emerging, leading to continued erosion of the benefit–risk profile of the drug. Specifically, preclinical and clinical reports of intergenerational harms4Martin M Hill C Bewley S MacLennan AH Braillon A Transgenerational adverse effects of valproate? A patient report from 90 affected families.Birth Defects Res. 2022; 114: 13-16Crossref PubMed Scopus (0) Google Scholar and male reproductive toxicities5European Medicines AgencyPrecautionary measures to address potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines.https://www.ema.europa.eu/en/news/precautionary-measures-address-potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicinesDate: 2024Date accessed: April 4, 2024Google Scholar of valproate are of substantial concern. Preclinical studies of valproate have consistently identified human reproductive toxicities before human drug-safety studies.1Independent Medicines and Medical Devices Safety ReviewFirst do no harm.https://www.immdsreview.org.uk/downloads/IMMDSReview_Web.pdfDate: 2020Date accessed: April 4, 2024Google Scholar The European Medicines Agency, which commissioned a major international safety study of the risks of paternal valproate exposure in 2018,5European Medicines AgencyPrecautionary measures to address potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines.https://www.ema.europa.eu/en/news/precautionary-measures-address-potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicinesDate: 2024Date accessed: April 4, 2024Google Scholar reported an increased risk of neurodevelopmental disorders in children born to men taking valproate in the 3 months before conception, compared with fathers similarly exposed to lamotrigine or levetiracetam.5European Medicines AgencyPrecautionary measures to address potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines.https://www.ema.europa.eu/en/news/precautionary-measures-address-potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicinesDate: 2024Date accessed: April 4, 2024Google Scholar Although definitive conclusions cannot yet be made, the results are concordant with preclinical studies published in the past 5 years.6Sakai K Hara K Tanemura K Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation.PLoS One. 2023; 18e0282898 Crossref Scopus (1) Google Scholar, 7Ibi D Fujiki Y Koide N Nakasai G Takaba R Hiramatsu M Paternal valproic acid exposure in mice triggers behavioral alterations in offspring.Neurotoxicol Teratol. 2019; 76106837 Crossref Scopus (15) Google Scholar The drug mechanisms underlying reproductive toxicities require urgent clarification, particularly as a histone deacetylase inhibitor. The UK has a high number of prescriptions of valproate,1Independent Medicines and Medical Devices Safety ReviewFirst do no harm.https://www.immdsreview.org.uk/downloads/IMMDSReview_Web.pdfDate: 2020Date accessed: April 4, 2024Google Scholar but it is not the only country to strengthen regulatory measures surrounding valproate prescribing. At the time of writing on April 4, 2024, other international regulators have also introduced new risk-mitigation measures.5European Medicines AgencyPrecautionary measures to address potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines.https://www.ema.europa.eu/en/news/precautionary-measures-address-potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicinesDate: 2024Date accessed: April 4, 2024Google Scholar, 8New Zealand Medicines and Medical Devices Safety AuthoritySodium valproate (epilim) use in people who can father children: important new safety information.https://www.medsafe.govt.nz/safety/Alerts/Sodium_valproate_Epilim_use_in_people_who_can_father_childrenOLD.aspDate: 2023Date accessed: April 4, 2024Google Scholar These measures include contraception for men, offering alternative treatment options, and mandating increased specialist supervision. Further advice in the UK is imminent and we encourage all involved in the care of people with neurological conditions to be aware of regulatory guidance about valproate in the coming months. DH is a member of the Commission for Human Medicines; is chair of the Neurology, Pain, and Psychiatry Expert Advisory Group of this commission; and is funded by the Wellcome Trust. FR-G is a member of the Neurology, Pain, and Psychiatry Expert Advisory Group. Reducing the uses of valproate: a controversial decisionIn most countries, valproate is primarily used as an anti-seizure drug but it is also approved for the treatment of bipolar disorder. Use of the drug during pregnancy is associated with an increased risk of major congenital malformations, and so valproate is not licensed for first-line treatment of these disorders in women of childbearing potential and is contraindicated in pregnancy, unless no effective alternative is available. In a drastic move that no other country has taken yet, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has introduced new stringent guidelines for valproate use. Full-Text PDF The prescription of valproate: risk of harmYour Editorial1 on the new prescribing measures for valproate (ie, all sodium valproate, valproic acid, and semisodium valproate products) in the UK seriously underplayed the harms of this drug when taken during pregnancy and omitted key evidence. Full-Text PDF