{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:13:31Z","timestamp":1789384411725,"version":"build-2803163510"},"reference-count":72,"publisher":"Cambridge University Press (CUP)","issue":"6","license":[{"start":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T00:00:00Z","timestamp":1735257600000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CNS Spectr."],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec id=\"S1092852924002311_sec1\"><jats:title>Background<\/jats:title><jats:p>Recent guidance from UK health authorities strongly cautions against the use of valproic acid (VPA) in persons under 55 because of reevaluated risk of teratogenicity.<\/jats:p><\/jats:sec><jats:sec id=\"S1092852924002311_sec2\"><jats:title>Objective<\/jats:title><jats:p>To summarize the extant literature documenting VPA-associated anatomical, behavioral, and cognitive teratogenicity.<\/jats:p><\/jats:sec><jats:sec id=\"S1092852924002311_sec3\" sec-type=\"methods\"><jats:title>Method<\/jats:title><jats:p>Pubmed, Medline, Cochrane Library, PsychInfo, Embase, Scopus, Web of Science, and Google Scholar were searched in accordance with PRISMA guidelines. Collected data covered study design, participant characteristics, anatomical, behavioral, or cognitive effects, and folic acid outcomes.<\/jats:p><\/jats:sec><jats:sec id=\"S1092852924002311_sec4\" sec-type=\"results\"><jats:title>Results<\/jats:title><jats:p>122 studies were identified meeting inclusion comprised of studies evaluating anatomical (<jats:italic>n<\/jats:italic>\u00a0=\u00a067), behavioral (<jats:italic>n<\/jats:italic>\u00a0=\u00a028), and cognitive (<jats:italic>n<\/jats:italic>\u00a0=\u00a047) teratogenicity. Twenty studies were identified reporting on the risk mitigation effects of folic acid supplementation. Prenatal VPA exposure is associated with anatomical teratogenicity including major congenital malformations (odds ratio [OR] 2.47\u20139.30; p\u00a0&lt;\u00a00.005). Behavioral teratogenicity including autism (OR 1.70\u20134.38), impaired motor development (OR 7.0), and ADHD (OR 1.39) are also significantly associated with VPA exposure. VPA was associated with intellectual disability and low IQ (hazard ratio [HR] 2.4\u20134.48, verbal intelligence: Spearman\u2019s <jats:italic>\u03c1<\/jats:italic>\u00a0=\u00a0\u22120.436, respectively). Teratogenic effects were dose-dependent across all domains and were significant when compared with controls and other antiepileptic drugs (eg, carbamazepine, lamotrigine, and levetiracetam). Folic acid supplementation does not significantly reduce the hazard associated with VPA.<\/jats:p><\/jats:sec><jats:sec id=\"S1092852924002311_sec5\" sec-type=\"conclusions\"><jats:title>Conclusions<\/jats:title><jats:p>VPA is significantly associated with anatomical, behavioral, and cognitive teratogenicity. Folic acid supplementation does not abrogate the risk of teratogenicity associated with VPA exposure. Available evidence supports recommendations to reduce VPA exposure in women of reproductive age.<\/jats:p><\/jats:sec>","DOI":"10.1017\/s1092852924002311","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T11:56:31Z","timestamp":1735300591000},"page":"604-610","source":"Crossref","is-referenced-by-count":16,"title":["Anatomical, behavioral, and cognitive teratogenicity associated with valproic acid: a systematic review"],"prefix":"10.1017","volume":"29","author":[{"given":"Kyle","family":"Valentino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla M.","family":"Teopiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela T.H.","family":"Kwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gia Han","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Rosenblat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3968-3297","authenticated-orcid":false,"given":"Rodrigo B.","family":"Mansur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi K.Y.","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-2523","authenticated-orcid":false,"given":"Roger S.","family":"McIntyre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"S1092852924002311_r57","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70323-X"},{"key":"S1092852924002311_r69","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2021.1993781"},{"key":"S1092852924002311_r65","doi-asserted-by":"publisher","DOI":"10.1016\/S0967-5868(03)00158-9"},{"key":"S1092852924002311_r60","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2023.107292"},{"key":"S1092852924002311_r34","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200831060-00008"},{"key":"S1092852924002311_r47","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006073"},{"key":"S1092852924002311_r33","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182a43e81"},{"key":"S1092852924002311_r12","unstructured":"12. World Health Organization. Standards for Maternal and Neonatal Care. 2007. https:\/\/www.who.int\/publications\/i\/item\/standards-for-maternal-and-neonatal-care."},{"key":"S1092852924002311_r20","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2068"},{"key":"S1092852924002311_r71","doi-asserted-by":"publisher","DOI":"10.1192\/bjb.2018.48"},{"key":"S1092852924002311_r44","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-034829"},{"key":"S1092852924002311_r49","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2004.067421"},{"key":"S1092852924002311_r13","unstructured":"13. Centers for Disease Control and Prevention. Folic Acid Safety, Interactions, and Health Outcomes. 2024. https:\/\/www.cdc.gov\/folic-acid\/about\/safety.html"},{"key":"S1092852924002311_r25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2004.05.003"},{"key":"S1092852924002311_r61","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000201529"},{"key":"S1092852924002311_r53","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617710001359"},{"key":"S1092852924002311_r26","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30107-8"},{"key":"S1092852924002311_r48","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14140"},{"key":"S1092852924002311_r5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007696"},{"key":"S1092852924002311_r54","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2018.12.031"},{"key":"S1092852924002311_r23","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.029268"},{"key":"S1092852924002311_r59","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617710001359"},{"key":"S1092852924002311_r17","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16827"},{"key":"S1092852924002311_r9","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.5035"},{"key":"S1092852924002311_r24","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2024.0258"},{"key":"S1092852924002311_r36","doi-asserted-by":"publisher","DOI":"10.1002\/pds.900"},{"key":"S1092852924002311_r39","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12226"},{"key":"S1092852924002311_r70","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2020.07.078"},{"key":"S1092852924002311_r45","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2013.08.001"},{"key":"S1092852924002311_r51","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-020-09764-w"},{"key":"S1092852924002311_r40","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.1269"},{"key":"S1092852924002311_r29","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16505"},{"key":"S1092852924002311_r1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31544-0"},{"key":"S1092852924002311_r42","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2008.01.010"},{"key":"S1092852924002311_r46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2016.01.001"},{"key":"S1092852924002311_r50","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001182"},{"key":"S1092852924002311_r56","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq352"},{"key":"S1092852924002311_r72","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2017-020450"},{"key":"S1092852924002311_r11","unstructured":"11. Folic acid supplementation to prevent neural tube defects: Preventive medication. U.S Preventive Services Task Force. August 1, 2023. https:\/\/www.uspreventiveservicestaskforce.org\/uspstf\/recommendation\/folic-acid-for-the-prevention-of-neural-tube-defects-preventive-medication"},{"key":"S1092852924002311_r6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2270"},{"key":"S1092852924002311_r64","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0131130"},{"key":"S1092852924002311_r43","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2011.06.014"},{"key":"S1092852924002311_r62","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.0674"},{"key":"S1092852924002311_r2","unstructured":"2. Medicines and Healthcare products Regulatory Agency. Valproate: Review of safety Data and Expert Advice on Management of Risks. 2023. https:\/\/assets.publishing.service.gov.uk\/media\/65660310312f400013e5d508\/Valproate-report-review-and-expert-advice.pdf."},{"key":"S1092852924002311_r55","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000465"},{"key":"S1092852924002311_r35","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2012.05.010"},{"key":"S1092852924002311_r67","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.3897"},{"key":"S1092852924002311_r10","unstructured":"10. Center for Drug Evaluation and Research. Valproate Anti-Seizure Products Contraindicated for Migraine Preven\u2026 U.S. Food and Drug Administration. 2016. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-drug-safety-communication-valproate-anti-seizure-products-contraindicated-migraine-prevention"},{"key":"S1092852924002311_r27","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(98)00084-9"},{"key":"S1092852924002311_r52","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2016.10.014"},{"key":"S1092852924002311_r32","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.12.006"},{"key":"S1092852924002311_r63","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1195003"},{"key":"S1092852924002311_r38","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.6606"},{"key":"S1092852924002311_r8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31820d62c7"},{"key":"S1092852924002311_r16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907328"},{"key":"S1092852924002311_r14","doi-asserted-by":"publisher","DOI":"10.1007\/s10309-023-00602-3"},{"key":"S1092852924002311_r21","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7239-x"},{"key":"S1092852924002311_r58","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2013.06.001"},{"key":"S1092852924002311_r30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2018.07.035"},{"key":"S1092852924002311_r31","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-306318"},{"key":"S1092852924002311_r19","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"S1092852924002311_r3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(82)90908-4"},{"key":"S1092852924002311_r37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309359"},{"key":"S1092852924002311_r66","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.12.006"},{"key":"S1092852924002311_r68","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2005.074203"},{"key":"S1092852924002311_r7","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.25570"},{"key":"S1092852924002311_r18","doi-asserted-by":"publisher","DOI":"10.1007\/s11920-017-0809-3"},{"key":"S1092852924002311_r22","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2009.11.008"},{"key":"S1092852924002311_r41","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000030"},{"key":"S1092852924002311_r15","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.2977"},{"key":"S1092852924002311_r4","first-page":"111","article-title":"Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs","volume":"42","author":"Lindhout","year":"1992","journal-title":"Neurology"},{"key":"S1092852924002311_r28","doi-asserted-by":"publisher","DOI":"10.9758\/cpn.2017.15.1.19"}],"container-title":["CNS Spectrums"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S1092852924002311","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T13:39:17Z","timestamp":1739972357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S1092852924002311\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":72,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["S1092852924002311"],"URL":"https:\/\/doi.org\/10.1017\/s1092852924002311","relation":{},"ISSN":["1092-8529","2165-6509"],"issn-type":[{"value":"1092-8529","type":"print"},{"value":"2165-6509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]}}}