Contraceptive Use as a Risk Factor for Gallbladder Cancer: Findings From the Chile Biliary Longitudinal Study
Rime Jebai, Ruth M. Pfeiffer, Paz Cook, Sarah S. Jackson, Allan Hildesheim, Juan Carlos Araya, Catterina Ferreccio, Jill KoshiolPURPOSE
Gallbladder cancer (GBC) occurs predominantly in women, unlike other biliary tract cancers, suggesting that sex hormones may contribute to carcinogenesis. However, evidence linking contraceptive use with GBC risk remains inconsistent. We examined the association between contraceptive use and high-grade dysplasia (HGD) and GBC risk in a high-risk population of women with gallstones.
METHODS
The Chile Biliary Longitudinal Study enrolled 4,711 women aged 50-74 years with ultrasound-confirmed gallstones from south-central Chile between 2016 and 2019. Ever contraceptive use, mode of delivery (pills, other, none), and duration of use (0-1; >1-4; 5-9;≥10 years) were self-reported at baseline. Incident HGD/GBC cases were identified through pathology reports and linkage with national death registries. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (aHRs) and 95% CIs for associations between contraceptive (ever use, mode of use, and duration) and HGD/GBC risk. Confounders, including ethnicity (Mapuche/non-Mapuche), number of gallstones, waist-to-height ratio, region (Araucania/Maule), parity, and menopausal hormone therapy (MHT), were selected using logistic regression for factors associated with exposure and Cox regression models for associations with outcome.
RESULTS
Over a median follow-up of 4.8 years (range 2.0-7.7), 120 women (2.5%) were diagnosed with HGD/GBC. The median age at diagnosis was 64 years, 34% of cases occurred among women identifying as Mapuche, and 62% reported ever contraceptive use. Ever use of contraceptives was associated with increased HGD/GBC risk (aHR 1.8, 95% CI 1.2 to 2.8). Among women with duration data, high risks were observed for >1-4 years of contraceptive use (aHR 2.3, 95% CI 1.3 to 3.9) and 5-9 years of use (aHR 2.8, 95% CI 1.6 to 4.9) but not for ≥10 years (aHR 1.3, 95% CI 0.7 to 2.2), compared with non-use. Most women reported pills as the mode of contraceptive delivery, and the association for pill use compared with non-use was similar to the overall association (aHR 1.5, 95% CI 1.0 to 2.3).
CONCLUSION
Among women with gallstones, ever use of contraceptives was associated with increased HGD/GBC risk. Analyses by duration showed higher risks at intermediate durations but not with longer use, differing from patterns observed for some hormone-related cancers. These results support a potential hormone-related mechanism in GBC development and may help identify women at high risk.