{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:44:44Z","timestamp":1793108684217,"version":"4.5.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,8,10]],"date-time":"2015-08-10T00:00:00Z","timestamp":1439164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:p>Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta\u2010analyses of cohort studies to determine the time profiles of signal emergence of VPA\u2010associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty\u2010nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10\u201320 years even before large\u2010scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and\/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA\u2010associated CMs are 2\u20137\u2010fold higher than other common antiepileptic drugs. VPA should not be used as a first\u2010line therapy in women of childbearing age unless it is the only option for the patient.<\/jats:p>","DOI":"10.1002\/cpt.158","type":"journal-article","created":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T08:31:20Z","timestamp":1433493080000},"page":"417-441","source":"Crossref","is-referenced-by-count":73,"title":["Risks of congenital malformations in offspring exposed to valproic acid <i>in utero<\/i>: A systematic review and cumulative meta\u2010analysis"],"prefix":"10.1111","volume":"98","author":[{"given":"M","family":"Tanoshima","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children University of Toronto Toronto Ontario Canada"},{"name":"Department of Obstetrics and Gynecology Yokohama City University Hospital Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children University of Toronto Toronto Ontario Canada"},{"name":"Department of Development Strategy, Center for Clinical Research and Development National Center for Child Health and Development"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Tanoshima","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children University of Toronto Toronto Ontario Canada"},{"name":"Department of Pediatrics Yokohama City University Hospital Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Beyene","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology &amp; Biostatistics McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Koren","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,8,10]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"441","article-title":"Major malformations with valproic acid","volume":"52","author":"Koren G.","year":"2006","journal-title":"Can. 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