Risks of Congenital Malformations in Offspring Exposed to Valproic Acid in Utero: A Systematic Review and Cumulative Meta-analysis

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.