Gestational Exposure to Benzodiazepines, 3: Clobazam and Major Congenital Malformations

Clobazam is a 1,5-benzodiazepine that has been approved for use, in various parts of the world, as an add-on treatment for seizure disorders and as a treatment for anxiety. Pharmacoepidemiological data from different countries show that a small percentage of women with epilepsy (WWE) receive clobazam during pregnancy. Surprisingly, there has been little to no discussion in literature on the teratogenicity of clobazam. A network meta-analysis published in 2017 found a markedly elevated rate of overall and specific major congenital malformations (MCMs) with clobazam; whereas statistical significance was not established in any analysis, the 95% compatibility intervals did suggest increased risk. In the same meta-analysis, however, the risk with clobazam was not elevated in polytherapy. Indications of increased MCM risk also emerged in data from India and Sri Lanka. In all studies, the exposure numbers were small and information on trimester of exposure was unavailable. Given the nature of the data, adjustment for confounding would not have been possible. It is concluded that there appears to be a signal for an increased risk of MCMs in the infants of WWE who use clobazam during pregnancy. This signal merits examination in data that exist in national registers and pregnancy registries.