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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.

Author information

1
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
2
Department of Obstetrics and Gynecology, Yokohama City University Hospital, Yokohama, Japan.
3
Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development.
4
Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.
5
Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.

Abstract

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.

PMID:
26044279
DOI:
10.1002/cpt.158
[Indexed for MEDLINE]

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