title: Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis.
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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Tanoshima
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Tanoshima
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Beyene
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Ito
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000927:Anticonvulsants / Q000009:adverse effects*; D005260:Female; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects*; D016017:Odds Ratio; D011247:Pregnancy; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid