{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T05:54:57Z","timestamp":1793253297648,"version":"4.5.0"},"reference-count":30,"publisher":"BMJ","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["DNR 4-2979\/2020"],"award-info":[{"award-number":["DNR 4-2979\/2020"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ALF Medicine","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2025,11,27]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Regulatory authorities have raised concerns about potential teratogenic and neurodevelopmental disorders (NDDs) risks associated with paternal valproate use during spermatogenesis, leading to restrictions. We aimed to investigate the association between paternal valproate exposure during spermatogenesis and the risk of NDDs in offspring in Sweden and Norway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a population-based cohort study of two nationwide cohorts from Sweden and Norway, including all singleton live births (\u226522 gestational weeks) from 2007 to 2020. Paternal monotherapy exposure to valproate, lamotrigine or levetiracetam was defined as \u22651 prescription filled for only one of these medications during the 3 months prior to conception. NDDs were identified from health registers from age 1 through 2022. Cox proportional hazards models were used to estimate adjusted HRs (aHRs), accounting for relevant confounders. A random-effects meta-analysis combined results from both countries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The Swedish cohort included 1588 children with paternal valproate and 3093 with lamotrigine\/levetiracetam monotherapy, while the Norwegian cohort included 463 and 1109, respectively. Compared with paternal lamotrigine\/levetiracetam monotherapy, paternal valproate exposure was not associated with increased pooled risk of any NDD (aHR, 1.06; 95%\u2009CI 0.81 to 1.22), including autism spectrum disorder (aHR, 1.29; 95%\u2009CI 0.89 to 1.85), attention-deficit\/hyperactivity disorder (aHR, 0.98; 95%\u2009CI 0.76 to 1.25), intellectual disability (aHR, 1.20; 95%\u2009CI 0.65 to 2.21; Sweden only) or psychological development disorders (aHR, 1.28; 95%\u2009CI 0.84 to 1.97). Findings remained consistent in dose\u2013response analyses and when restricted to fathers with epilepsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this large Nordic study, paternal valproate use during spermatogenesis was not associated with increased risk of NDDs in offspring, suggesting current regulatory restrictions may warrant re-evaluation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2025-337441","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:20:29Z","timestamp":1772648429000},"page":"jnnp-2025-337441","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1273-0110","authenticated-orcid":false,"given":"Neda","family":"Razaz","sequence":"first","affiliation":[{"name":"Division of Clinical Epidemiology, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Soderling","sequence":"additional","affiliation":[{"name":"Division of Clinical Epidemiology, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0554-5352","authenticated-orcid":false,"given":"Torbj\u00f6rn","family":"Tomson","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Werenberg Dreier","sequence":"additional","affiliation":[{"name":"Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark"},{"name":"National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Department of Neurology, Aarhus University Hospital, Affiliated Member of Epi-CARE, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marte-Helene","family":"Bj\u00f8rk","sequence":"additional","affiliation":[{"name":"Department of Neurology, Haukeland University Hospital, Bergen, Norway"},{"name":"Department of Clinical Medicine, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2289-0978","authenticated-orcid":false,"given":"Jannicke","family":"Igland","sequence":"additional","affiliation":[{"name":"Department of Neurology, Haukeland University Hospital, Bergen, Norway"},{"name":"Global Public Health and Primary Care, University of Bergen Faculty of Medicine and Dentistry, Bergen, Norway"},{"name":"Department of Health and Caring Sciences, Western Norway University of Applied Sciences, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"2026030410202065000_jnnp-2025-337441v1.1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2024-334547"},{"key":"2026030410202065000_jnnp-2025-337441v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60461-9"},{"key":"2026030410202065000_jnnp-2025-337441v1.3","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0140-6736(21)00246-4","article-title":"The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial","volume":"397","author":"Marson","year":"2021","journal-title":"The Lancet"},{"key":"2026030410202065000_jnnp-2025-337441v1.4","doi-asserted-by":"crossref","first-page":"100624","DOI":"10.1016\/j.ebr.2023.100624","article-title":"Management of epilepsy in pregnancy: What we still need to learn","volume":"24","author":"Tomson","year":"2023","journal-title":"Epilepsy & Behavior Reports"},{"key":"2026030410202065000_jnnp-2025-337441v1.5","unstructured":"European Medicines Agency . PRAC recommends strengthening the restrictions on the use of valproate in women and girls. 2014. Available: https:\/\/www.ema.europa.eu\/en\/documents\/referral\/valproate-and-related-substances-article-31-referral-cmdh-agrees-strengthen-warnings-use-valproate-medicines-women-and-girls_en.pdf"},{"key":"2026030410202065000_jnnp-2025-337441v1.6","unstructured":"European Medicines Agency . New measures to avoid valproate exposure in pregnancy endorsed. 2018. Available: https:\/\/www.ema.europa.eu\/en\/documents\/referral\/valproate-article-31-referral-new-measures-avoid-valproate-exposure-pregnancy-endorsed_en.pdf-0"},{"key":"2026030410202065000_jnnp-2025-337441v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2019.106837"},{"key":"2026030410202065000_jnnp-2025-337441v1.8","unstructured":"Agency. UMaHPR . Valproate: review of safety data and expert advice on management of risks. 2023. 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Global database on body mass index: BMI classification. Available: http:\/\/appswhoint\/bmi\/indexjsp?introPage=intro_3html [Accessed 19 Feb 2016]."},{"key":"2026030410202065000_jnnp-2025-337441v1.23","unstructured":"IQVIA . A post-authorisation safety study (pass) to evaluate the paternal exposure to valproate and the risk of neurodevelopmental disorders including autism spectrum disorder as well as congenital abnormalities in offspring. 2023. 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