Leukemia in users of contemporary hormonal contraception: A nationwide registry-based cohort study among premenopausal women in Denmark

BACKGROUND: Sex hormones have been implicated in leukemogenesis, but evidence regarding hormonal contraceptive use and leukemia risk remains limited and primarily based on older formulations. Given the widespread use of contemporary hormonal contraceptives, clarification of this potential association is needed. This study examines the association between contemporary hormonal contraceptives and leukemia risk.

METHODS AND FINDINGS: In a nationwide cohort design, we assessed associations between the use of contemporary hormonal contraceptives and the risk of leukemia based on a cohort of all women aged 15-49 years residing in Denmark from 1995 to 2021 with no previous cancer, hysterectomy, oophorectomy, or sterilization. Information on hormonal contraception use, leukemia diagnoses, and potential confounders (age, calendar year, education) was obtained from nationwide registries. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals [CIs] were estimated for any leukemia, and specific types of leukemia, associated with any hormonal contraceptive use, current and recent use, and previous use, type of product used, duration, and time since last use. Among 1,957,490 pre-menopausal women followed for 24.5 million person-years (median 12.5 years, interquartile range: 5.9,20.5), 671 were diagnosed with leukemia. The incidence rate for leukemia among current and recent users was similar to that among women who had never used hormonal contraception: IRR 0.95 (95% CI [0.78,1.16]; p = 0.62). No association with different durations of use was found: 0-5 years; IRR 0.93 (95% CI [0.75,1.14]; p = 0.48), >5-10 years; IRR 1.16 (95% CI [0.84,1.61]; p = 0.37), >10 years; IRR 0.67 (95% CI [0.33,1.37]; p = 0.27); nor for time since last use: 0-5 years; IRR 1.01 (95% CI [0.78,1.29]; p = 0.96), >5-10 years; IRR 1.05 (95% CI [0.76,1.45]; p = 0.75), >10 years; IRR 0.88 (95% CI [0.60,1.29]; p = 0.52). Also, the IRRs for leukemia with use of different hormonal contraceptive types (e.g., combined products; IRR 0.91 (95% CI [0.73,1.14]; p = 0.42) and progestin-only products; IRR 1.05 (95% CI [0.78,1.40]; p = 0.75)), as well as for product-specific durations of use, were for the majority close to 1. The IRRs were similar for different types of leukemia. Main study limitations include small case numbers in some analyses; therefore, additional large-scale studies are warranted to reliably exclude weak associations.

CONCLUSIONS: Contemporary hormonal contraceptives were not associated with leukemia, independent of product used, duration of use, time since last use, and type of leukemia. While estimates were imprecise for some subgroups, the overall findings do not support an association.