{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:01:54Z","timestamp":1792101714564,"version":"4.4.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Information available on the risks of neurodevelopmental disorders (NDs) associated with in utero exposure to valproate (VPA) and to other antiepileptic drugs (AEDs) is limited. A nationwide population-based cohort study was conducted based on comprehensive data of the French National Health Data System (SNDS). Liveborn infants without brain malformation, born between January 2011 and December 2014, were followed from birth up to December 2016. NDs were identified based on diagnoses of mental or behavioural disorders and utilization of speech therapy, orthoptic or psychiatric services. The risk of NDs was compared between children exposed in utero to AED monotherapy and unexposed children, using Cox proportional hazard models adjusted for maternal and neonatal characteristics. The cohort included 1,721,990 children, 8848 of whom were exposed in utero to AED monotherapy. During a mean follow-up of 3.6\u00a0years, 15,458 children had a diagnosis of mental or behavioural disorder. In utero exposure to VPA was associated with an increased risk of NDs overall (aHR: 3.7; 95% CI 2.8\u20134.9) and among children born to a mother without mental illness (aHR 5.1; 95% CI 3.6\u20137.3). A dose\u2013response relationship was demonstrated and the risk of NDs was more particularly increased for an exposure to VPA during the second or third trimesters of pregnancy. Among the other AEDs, only pregabalin was consistently associated with an increased risk of NDs (aHR: 1.5; 95% CI 1.0\u20132.1). This study confirms a four to fivefold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.<\/jats:p>","DOI":"10.1038\/s41598-020-74409-x","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T12:02:48Z","timestamp":1603368168000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France"],"prefix":"10.1038","volume":"10","author":[{"given":"Jo\u00ebl","family":"Coste","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Olivier","family":"Blotiere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Mikaeloff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Peyre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Ramus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Zureik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Weill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7646-3667","authenticated-orcid":false,"given":"Rosemary","family":"Dray-Spira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,22]]},"reference":[{"key":"74409_CR1","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1111\/j.1528-1157.1993.tb02586.x","volume":"34","author":"WA Hauser","year":"1993","unstructured":"Hauser, W. A., Annegers, J. F. & Kurland, L. T. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935\u20131984. Epilepsia 34, 453\u2013468 (1993).","journal-title":"Epilepsia"},{"key":"74409_CR2","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/brain\/123.4.665","volume":"123","author":"BK MacDonald","year":"2000","unstructured":"MacDonald, B. K., Cockerell, O. C., Sander, J. W. & Shorvon, S. D. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 123, 665\u2013676 (2000).","journal-title":"Brain"},{"key":"74409_CR3","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1016\/S0140-6736(15)00045-8","volume":"386","author":"L Viale","year":"2015","unstructured":"Viale, L. et al. Epilepsy in pregnancy and reproductive outcomes: A systematic review and meta-analysis. Lancet 386, 1845\u20131852 (2015).","journal-title":"Lancet"},{"key":"74409_CR4","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/S1474-4422(18)30107-8","volume":"17","author":"T Tomson","year":"2018","unstructured":"Tomson, T. et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 17, 530\u2013538 (2018).","journal-title":"Lancet Neurol."},{"issue":"2","key":"74409_CR5","doi-asserted-by":"publisher","first-page":"e167","DOI":"10.1212\/WNL.0000000000007696","volume":"93","author":"PO Bloti\u00e8re","year":"2019","unstructured":"Bloti\u00e8re, P. O. et al. Risks of 23 specific malformations associated with prenatal exposure to ten antiepileptic drugs. Neurology 93(2), e167\u2013e180 (2019).","journal-title":"Neurology"},{"key":"74409_CR6","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1136\/jnnp.70.1.15","volume":"70","author":"N Adab","year":"2001","unstructured":"Adab, N., Jacoby, A., Smith, D. & Chadwick, D. Additional educational needs in children born to a mother with epilepsy. J. Neurol. Neurosurg. Psychiatry 70, 15\u201321 (2001).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"74409_CR7","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1136\/jnnp-2017-317515","volume":"89","author":"AS Lacey","year":"2018","unstructured":"Lacey, A. S. et al. Educational attainment of children born to a mother with epilepsy. J. Neurol. Neurosurg. Psychiatry 89, 736\u2013740 (2018).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"74409_CR8","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1001\/jamaneurol.2017.5035","volume":"75","author":"LS Elkj\u00e6r","year":"2018","unstructured":"Elkj\u00e6r, L. S., Bech, B. H., Sun, Y., Laursen, T. M. & Christensen, J. Association between prenatal valproate exposure and performance on standardized language and mathematics tests in school-aged children. JAMA Neurol. 75, 663\u2013671 (2018).","journal-title":"JAMA Neurol."},{"key":"74409_CR9","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1212\/WNL.0000000000001182","volume":"84","author":"GA Baker","year":"2015","unstructured":"Baker, G. A. et al. IQ at 6 years after in utero exposure to antiepileptic drugs: A controlled cohort study. Neurology 84, 382\u2013390 (2015).","journal-title":"Neurology"},{"key":"74409_CR10","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/S1474-4422(12)70323-X","volume":"12","author":"KJ Meador","year":"2013","unstructured":"Meador, K. J. et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): A prospective observational study. Lancet Neurol. 12, 244\u2013252 (2013).","journal-title":"Lancet Neurol."},{"key":"74409_CR11","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1212\/WNL.0b013e31820d62c7","volume":"76","author":"C Nadebaum","year":"2011","unstructured":"Nadebaum, C. et al. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology 76, 719\u2013726 (2011).","journal-title":"Neurology"},{"key":"74409_CR12","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1136\/jmg.39.4.251","volume":"39","author":"JCS Dean","year":"2002","unstructured":"Dean, J. C. S. et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J. Med. Genet. 39, 251\u2013259 (2002).","journal-title":"J. Med. Genet."},{"key":"74409_CR13","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1111\/epi.12226","volume":"54","author":"G Veiby","year":"2013","unstructured":"Veiby, G. et al. Exposure to antiepileptic drugs in utero and child development: A prospective population-based study. Epilepsia 54, 1462\u20131472 (2013).","journal-title":"Epilepsia"},{"key":"74409_CR14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ntt.2016.01.001","volume":"54","author":"U Deshmukh","year":"2016","unstructured":"Deshmukh, U. et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicol Teratol 54, 5\u201314 (2016).","journal-title":"Neurotoxicol Teratol"},{"key":"74409_CR15","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.yebeh.2011.06.014","volume":"22","author":"MJ Cohen","year":"2011","unstructured":"Cohen, M. J. et al. Fetal antiepileptic drug exposure: motor, adaptive, and emotional\/behavioral functioning at age 3 years. Epilepsy Behav. 22, 240\u2013246 (2011).","journal-title":"Epilepsy Behav."},{"key":"74409_CR16","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1136\/jnnp-2012-304270","volume":"84","author":"RL Bromley","year":"2013","unstructured":"Bromley, R. L. et al. Liverpool and Manchester Neurodevelopment Group. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 84, 637\u2013643 (2013).","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"74409_CR17","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.yebeh.2008.10.011","volume":"14","author":"J Vinten","year":"2009","unstructured":"Vinten, J. et al. Liverpool and Manchester Neurodevelopment Group. The behavioral consequences of exposure to antiepileptic drugs in utero. Epilepsy Behav. 14, 197\u2013201 (2009).","journal-title":"Epilepsy Behav."},{"key":"74409_CR18","doi-asserted-by":"publisher","first-page":"e017248","DOI":"10.1136\/bmjopen-2017-017248","volume":"7","author":"AA Veroniki","year":"2017","unstructured":"Veroniki, A. A. et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breastfeeding: A systematic review and network meta-analysis. BMJ Open 7, e017248 (2017).","journal-title":"BMJ Open"},{"key":"74409_CR19","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1017\/S0012162205001076","volume":"47","author":"A Rasalam","year":"2005","unstructured":"Rasalam, A. et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev. Med. Child Neurol. 47, 551\u2013555 (2005).","journal-title":"Dev. Med. Child Neurol."},{"key":"74409_CR20","first-page":"10236","volume":"10","author":"RL Bromley","year":"2014","unstructured":"Bromley, R. L. et al. Treatment for epilepsy in pregnancy: Neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 10, 10236 (2014).","journal-title":"Cochrane Database Syst Rev"},{"key":"74409_CR21","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.seizure.2016.10.006","volume":"44","author":"RL Bromley","year":"2017","unstructured":"Bromley, R. L. & Baker, G. A. Fetal antiepileptic drug exposure and cognitive outcomes. Seizure 44, 225\u2013231 (2017).","journal-title":"Seizure"},{"issue":"Suppl 4","key":"74409_CR22","doi-asserted-by":"publisher","first-page":"S149","DOI":"10.1016\/j.respe.2017.05.004","volume":"65","author":"P Tuppin","year":"2017","unstructured":"Tuppin, P. et al. Value of a national administrative database to guide public decisions: From the syst\u00e8me national d\u2019information interr\u00e9gimes de l\u2019Assurance Maladie (SNIIRAM) to the syst\u00e8me national des donn\u00e9es de sant\u00e9 (SNDS) in France. Rev Epidemiol Sante Publique 65(Suppl 4), S149\u2013S167 (2017).","journal-title":"Rev Epidemiol Sante Publique"},{"key":"74409_CR23","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1212\/01.wnl.0000339399.64213.1a","volume":"71","author":"RL Bromley","year":"2008","unstructured":"Bromley, R. L., Mawer, G., Clayton-Smith, J. & Baker, G. A. Liverpool and Manchester Neurodevelopment Group Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 71, 1923\u20131924 (2008).","journal-title":"Neurology"},{"key":"74409_CR24","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1136\/adc.2009.176990","volume":"96","author":"C Cummings","year":"2011","unstructured":"Cummings, C., Stewart, M., Stevenson, M., Morrow, J. & Nelson, J. Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch. Dis. Child 96, 643\u2013647 (2011).","journal-title":"Arch. Dis. Child"},{"key":"74409_CR25","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1001\/jama.2013.2270","volume":"309","author":"J Christensen","year":"2013","unstructured":"Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309, 1696\u20131703 (2013).","journal-title":"JAMA"},{"key":"74409_CR26","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1111\/j.1528-1167.2007.01056.x","volume":"48","author":"J-B Manent","year":"2007","unstructured":"Manent, J.-B. et al. Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias. Epilepsia 48, 684\u2013693 (2007).","journal-title":"Epilepsia"},{"key":"74409_CR27","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1001\/jama.1995.03530190032031","volume":"274","author":"JM Reinisch","year":"1995","unstructured":"Reinisch, J. M., Sanders, W. A., Mortensen, E. L. & Rubin, D. B. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 274, 1518\u20131525 (1995).","journal-title":"JAMA"},{"key":"74409_CR28","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.yebeh.2007.08.009","volume":"11","author":"KJ Meador","year":"2007","unstructured":"Meador, K. J., Baker, G., Cohen, M. J., Gaily, E. & Westerveld, M. Cognitive\/behavioral teratogenetic effects of antiepileptic drugs. Epilepsy Behav. 11, 292\u2013302 (2007).","journal-title":"Epilepsy Behav."},{"key":"74409_CR29","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1111\/j.1528-1167.2009.02129.x","volume":"50","author":"CL Harden","year":"2009","unstructured":"Harden, C. L. et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 50, 1237\u20131246 (2009).","journal-title":"Epilepsia"},{"key":"74409_CR30","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.reprotox.2013.06.001","volume":"41","author":"T Rihtman","year":"2013","unstructured":"Rihtman, T., Parush, S. & Ornoy, A. Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: Cognitive, motor, sensory and behavioral function. Reprod Toxicol 41, 115\u2013125 (2013).","journal-title":"Reprod Toxicol"},{"key":"74409_CR31","doi-asserted-by":"publisher","first-page":"2058","DOI":"10.1111\/j.1528-1167.2010.02668.x","volume":"51","author":"RL Bromley","year":"2010","unstructured":"Bromley, R. L. et al. Liverpool and Manchester Neurodevelopment Group Early cognitive development in children born to women with epilepsy: A prospective report. Epilepsia 51, 2058\u20132065 (2010).","journal-title":"Epilepsia"},{"key":"74409_CR32","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.eplepsyres.2007.10.014","volume":"78","author":"J-B Manent","year":"2008","unstructured":"Manent, J.-B. et al. Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats. Epilepsy Res 78, 131\u2013139 (2008).","journal-title":"Epilepsy Res"},{"key":"74409_CR33","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1111\/j.1651-2227.2000.tb00333.x","volume":"89","author":"AB Dessens","year":"2000","unstructured":"Dessens, A. B. et al. Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr 89, 533\u2013541 (2000).","journal-title":"Acta Paediatr"},{"key":"74409_CR34","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.reprotox.2012.05.038","volume":"34","author":"T Rihtman","year":"2012","unstructured":"Rihtman, T., Parush, S. & Ornoy, A. Preliminary findings of the developmental effects of in utero exposure to topiramate. Reprod Toxicol 34, 308\u2013311 (2012).","journal-title":"Reprod Toxicol"},{"key":"74409_CR35","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.eplepsyres.2015.09.003","volume":"117","author":"N Gopinath","year":"2015","unstructured":"Gopinath, N., Muneer, A. K., Unnikrishnan, S., Varma, R. P. & Thomas, S. V. Children (10\u201312 years age) of women with epilepsy have lower intelligence, attention and memory: observations from a prospective cohort case control study. Epilepsy Res 117, 58\u201362 (2015).","journal-title":"Epilepsy Res"},{"key":"74409_CR36","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1212\/WNL.62.1.28","volume":"62","author":"E Gaily","year":"2004","unstructured":"Gaily, E. et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 62, 28\u201332 (2004).","journal-title":"Neurology"},{"key":"74409_CR37","doi-asserted-by":"crossref","unstructured":"Thorup AAE, Laursen TM, Munk-Olsen T et al, Incidence of child and adolescent mental disorders in children aged 0\u201317 with familial high risk for severe mental illness\u2014A Danish register study. Schizophr Res 2017;pii:S0920\u20139964(17)30686\u20132.","DOI":"10.1016\/j.schres.2017.11.009"},{"key":"74409_CR38","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1001\/jama.2011.1433","volume":"306","author":"C Roth","year":"2011","unstructured":"Roth, C. et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA 306, 1566\u20131573 (2011).","journal-title":"JAMA"},{"key":"74409_CR39","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1017\/S1368980012000067","volume":"15","author":"L Chatzi","year":"2012","unstructured":"Chatzi, L. et al. Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: The mother\u2013child cohort \u2018Rhea\u2019 study in Crete, Greece. Public Health Nutrition 15, 1728\u20131736 (2012).","journal-title":"Public Health Nutrition"},{"key":"74409_CR40","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1001\/jamaneurol.2017.3897","volume":"75","author":"M Bj\u00f8rk","year":"2018","unstructured":"Bj\u00f8rk, M. et al. Association of folic acid supplementation during pregnancy with the risk of autistic traits in children exposed to antiepileptic drugs in utero. JAMA Neurol. 75, 160\u2013168 (2018).","journal-title":"JAMA Neurol."},{"key":"74409_CR41","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1001\/jamapsychiatry.2017.4050","volume":"75","author":"SZ Levine","year":"2018","unstructured":"Levine, S. Z. et al. Association of maternal use of folic acid and multivitamin supplements in the periods before and during pregnancy with the risk of autism spectrum disorder in offspring. JAMA Psychiatry 75, 176\u2013184 (2018).","journal-title":"JAMA Psychiatry"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74409-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74409-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74409-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T16:29:57Z","timestamp":1670344197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74409-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,22]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["74409"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-74409-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,22]]},"assertion":[{"value":"17 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17362"}}