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Risks of neurobehavioral teratogenicity associated with prenatal exposure to valproate monotherapy: a systematic review with regulatory repercussions

  • Salvatore Gentile (a1)

Beyond its formal indications (epilepsy, bipolar disorder, and migraine), valproate sodium (VPA) is widely used in a number of other clinical conditions. Recently, however, the U.S. Food and Drug Administration (FDA) issued a warning regarding a decrease in IQ scores in children prenatally exposed to the drug. For patients with migraine, the pregnancy labeling of VPA will be changed from Category “D” to “X.” VPA products will remain in pregnancy category “D” for treating epilepsy and manic episodes associated with bipolar disorder. Thus, this article aims to assess (through a computerized Medline/PubMed search) the neurobehavioral teratogenicity of valproate monotherapy, in order to evaluate alternative regulatory decisions. Reviewed information suggests a detrimental impact of antenatal valproate exposure on the global child neurodevelopment. Affected areas include not just reduced IQ scores, but also behavioral problems and a potential increase in the risk for a future diagnosis of attention-deficit/hyperactivity disorder. An increased risk of developing autism-spectrum disorders has also been reported. Thus, in my opinion, VPA should be assigned definitively to the Category “X,” independent of any considerations about its clinical indications, and should be strictly avoided during pregnancy, due to the demonstrated risk of both neurobehavioral and neurocognitive teratogenicity.

Corresponding author
*Address for correspondence: Salvatore Gentile, Department of Mental Health, ASL Salerno, Mental Health Centre n. 63 Cava de' Tirreni - Vietri Sul Mare, Piazza Galdi, 841013 Cava de’ Tirreni, Salerno, Italy. (Email:
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