Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project

Sarah S. Jackson, Hans Olov Adami, Gabriella Andreotti, Laura E. Beane-Freeman, Amy Berrington de González, Julie E. Buring, Gary E. Fraser, Neal D. Freedman, Susan M. Gapstur, Gretchen Gierach, Graham G. Giles, Francine Grodstein, Patricia Hartge, Mazda Jenab, Victoria Kirsh, Synnove F. Knutsen, Qing Lan, Susanna C. Larsson, I. Min Lee, Mei Hsuan LeeLinda M. Liao, Roger L. Milne, Kristine R. Monroe, Marian L. Neuhouser, Katie M. O'Brien, Jessica L. Petrick, Mark P. Purdue, Thomas E. Rohan, Sven Sandin, Dale P. Sandler, Norie Sawada, Aladdin H. Shadyab, Tracey G. Simon, Rashmi Sinha, Rachael Stolzenberg-Solomon, Shoichiro Tsugane, Elisabete Weiderpass, Alicja Wolk, Hwai I. Yang, Wei Zheng, Katherine A. McGlynn, Peter T. Campbell, Jill Koshiol

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25–2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06–1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04–1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09–1.31) and EHBDC (HR 1.11; 95% CI 1.01–1.22) in Asian women only. Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. Lay summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Original languageEnglish
Pages (from-to)863-872
Number of pages10
JournalJournal of Hepatology
Issue number4
StatePublished - Oct 2020
Externally publishedYes


  • Biliary tract cancer
  • Gallbladder cancer
  • Parity
  • Reproductive factors


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