Supplementary Material for: Maternal Smoking During Pregnancy, Smoking Initiation and the Risk of Epilepsy in the UK Biobank

Objectives: The impact of early-life tobacco smoke exposure on epilepsy remains underexplored. Our study examines the associations between maternal smoking during pregnancy (MSDP), age of smoking initiation (ASI) and epilepsy risk, while investigating the mediating role of insulin-like growth factor-1 (IGF-1). Methods: We analyzed data from 427,285 participants for MSDP and 428,178 for ASI from the UK Biobank (UKB). Accelerated failure time (AFT) models and Cox proportional hazard models with time-dependent covariates were applied to evaluate the associations between MSDP, ASI and epilepsy onset. Mediation analyses were conducted to assess the role of IGF-1. Results: Our study involved 427,258 participants in survival analyses for MSDP and 428,178 for ASI. Participants exposed to maternal smoking during pregnancy had an 8% shorter epilepsy-free time (Time Ratio [TR]: 0.92, 95% Confidence Interval [CI]: 0.87-0.98, P<0.01) and significantly higher epilepsy risk (Hazard Ratio [HR]: 9.25, 95% CI: 1.91-44.83, P<0.01). Compared with never-smokers, childhood, adolescent and adult smoking initiation shortened epilepsy-free time by 27%, 18% and 13%, respectively, according to AFT models (P<0.001). Cox models indicated a 62%, 33% and 22% higher risk of epilepsy for smoking initiation during childhood, adolescence and adulthood (P<0.001). IGF-1 mediated 9% (95% CI: 5%-39%) of the effect for MSDP and 5% (95% CI: 3%-11%) for ASI. Conclusions: Smoking exposure in the early life stages, encompassing both prenatal and postnatal periods, accelerates the onset and increases the risk of epilepsy, with IGF-1 serving as a potential mediator. Further research is needed to elucidate these mechanisms.