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Clin Pharmacol Ther. 2015 Oct;98(4):417-41. doi: 10.1002/cpt.158. Epub 2015 Aug 10.

Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis.

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Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Department of Obstetrics and Gynecology, Yokohama City University Hospital, Yokohama, Japan.
Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development.
Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.
Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.


Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty-nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale 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-associated CMs are 2-7-fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient.

[Indexed for MEDLINE]

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