Risk of orofacial clefts in offspring following maternal exposure to anti-seizure medications in a UK CPRD GOLD observational study

Orofacial clefts (OFC) are complex congenital anomalies characterised by a gap in the upper lip and/or palate, causing speech and feeding difficulties in children. Studies suggest inconsistent findings for an association between anti-seizure medications (ASM) and OFCs. Our study evaluated the association between ASM prescription during pregnancy and OFC in offspring using a United Kingdom primary care-based cohort of 393,281 mothers and 518,050 babies. 3651 and 3199 women were prescribed ASMs during preconception and first trimester respectively, irrespective of indication. Valproate prescription during preconception and first trimester was associated with higher odds of OFCs, with limited evidence after adjustment for potential confounders. Carbamazepine, pregabalin, and levetiracetam showed limited evidence for increased odds of OFCs, and no evidence was found for gabapentin or lamotrigine. No OFC cases were found in children born to mothers exposed to topiramate or phenytoin. Children exposed to ASM polytherapy during first trimester were 6 times as likely to have OFC as compared to ASM monotherapy. While ASMs may contribute to the risk of OFCs, our findings suggest they are unlikely to be a major cause, given that most exposed pregnancies did not result in a cleft and most children with OFCs were not exposed to ASMs.