Progestin-only implant and breast cancer risk in adolescents and premenopausal women: A systematic review and meta-analysis.

Abstract

10594 Background: Progestin-only long-acting reversible contraception via subdermal etonogestrel implants (Implanon/Nexplanon) is widely used. However, the breast cancer (BC) risk signal potentially attributable to implant exposure remains under-characterized, limiting evidence-based, shared contraceptive counseling. Methods: We systematically searched PubMed/MEDLINE, Embase, and the Cochrane Library and screened reference lists for observational cohort and case-control studies comparing etonogestrel/progestin-only implant exposure versus non-use in adolescents and reproductive-aged/premenopausal women (as defined by each study) without prior BC. Studies restricted to hereditary breast cancer predisposition cohorts (BRCA1/2 pathogenic variant carriers) were excluded. The primary endpoint was incident BC (invasive with/without in situ). Maximally adjusted estimates were extracted and harmonized to odds ratios (ORs). Risk of bias was assessed using ROBINS-E. Pooled estimates were generated using inverse-variance random-effects meta-analysis. Heterogeneity was quantified with I2 and Tau2. Results: Five studies met inclusion criteria, including three nationwide cohort studies from Denmark/Sweden and two nested case–control studies from the UK and Australia. Across cohort studies, implant exposure contributed 1,659,309 person-years of follow-up with 510 incident BC events. The largest case-control dataset included 67,470 BC cases. Study-specific adjusted ORs ranged from 0.93 to 1.24. In pooled analysis, implant exposure was associated with an increased risk of incident BC (OR 1.23. 95% CI 1.19–1.27, P < 0.0001), with no between-study heterogeneity (I2 = 0%, Tau2 = 0). Conclusions: In large, contemporary population-based observational studies excluding hereditary breast cancer predisposition cohorts, use of etonogestrel/progestin-only subdermal implants is consistently associated with a modestly increased risk of incident breast cancer (~23%) compared with non-use. While the absolute risk increase is likely small in younger women, the consistent signal across study designs supports its relevance for individualized risk–benefit discussions and shared contraceptive counseling in routine clinical practice. Study (Year) Design / Country Population Implant Type Odds Ratio (95% CI) Mørch et al. (2017) Nationwide cohort, Denmark Women 15-49 y Progestin-only 0.93 (0.48-1.80) Fitzpatrick et al. (2023) Case-control, UK Women 16-39 y Progestin-only 1.22 (0.93-1.60) Hadizadeh et al. (2025) Register-based cohort, Sweden Women 13-49 y Etonogestrel 1.22 (1.11-1.35) Hultstrand et al. (2022) Nationwide cohort, Sweden Women 15-34 y Etonogestrel 1.22 (0.98-1.52) Tuesley et al. (2025) Case-control, Australia Women 20-55 y Etonogestrel 1.24 (1.17-1.32)