Combined effects of smoking and hormonal contraceptives in the occurrence of inflammatory bowel disease – A weighted Cox analysis in a nested case-control study in Quebec, Canada

Hormonal contraceptives increase nicotine absorption. Their joint effect with smoking on inflammatory bowel disease remains unclear. We assessed independent and joint associations of smoking and hormonal contraception with Crohn's disease and ulcerative colitis. In 2021, we conducted a nested case-control study with cumulative sampling of controls, in Quebec, Canada. Cases were identified with health services-based validated algorithms. Smoking, hormonal contraception, and covariates were self-reported. Time-dependent exposures were analyzed in 2024 using weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) and assess additive and multiplicative interactions. The study included 1718 women (591 controls, 790 Crohn's disease, 337 ulcerative colitis cases). Compared with non-smokers non-users of hormonal contraception, former smokers using hormonal contraceptives had increased Crohn's disease (HR = 2.45; 95% CI: 1.51, 3.96) and ulcerative colitis risks (HR = 2.88; 95% CI: 1.65,5.02). Current smokers using hormonal contraceptives had elevated risks of Crohn's disease (HR = 2.62; 95% CI: 1.93, 3.56) but not ulcerative colitis (HR = 0.72; 95% CI: 0.42, 1.17). A negative additive interaction was observed for ulcerative colitis with no multiplicative interactions. Smoking and hormonal contraception are independently associated with Crohn's disease, but not ulcerative colitis, with implications for inflammatory bowel disease risk assessment in women. • Consistent with previous studies, smoking increased Crohn's disease risk. • Current smokers using hormonal contraceptives were at the highest risk of Crohn's disease. • Former smokers using hormonal contraceptives experienced the highest risk of ulcerative colitis. • Both exposures exerted independent effects on Crohn's disease risk. • A negative additive interaction was observed among current smokers for ulcerative colitis.