Abstract
Background:A 2024 meta-analysis by Douxfils et al. reported a 33% lower risk of venous thromboembolism (VTE) with body-identical estrogens compared with ethinyl estradiol (EE)–based combined oral contraceptives (COCs).
Objective:To update that meta-analysis by incorporating the most recent evidence and to further characterize the increased VTE risk associated with EE-based COCs compared with body-identical estrogen formulations.
Method:This systematic review and meta-analysis followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was conducted in June 2025 using Medline (Ovid) and Embase to identify observational longitudinal studies reporting VTE risk for synthetic estrogens versus body-identical estrogens. Body-identical estrogens (E2-based COCs) served as the reference. Effect sizes were expressed as Peto odds ratios (95% CI) for crude analyses and hazard ratios (95% CI) for adjusted analyses. A random-effects model was used. The protocol was registered in the Open Science Framework (ID https://osf.io/n9dav/).
Results:Five observational studies evaluating VTE risk among users of E2-based versus EE-based COCs were included. The dataset comprised 2,343,585 women-years from cohort studies and 8,514 women from case–control studies. The updated meta-analysis demonstrated a significant 51% increased VTE risk among EE-based COC users (Peto OR 1.51; 95% CI 1.17–1.95) compared with E2-based COC users. In adjusted analyses (k = 2), EE/levonorgestrel was associated with a hazard ratio of 1.95 (95% CI 1.11–3.41) versus E2-based COCs.
Conclusion:This updated meta-analysis corroborates previous findings supporting the safer thrombotic profile of body-identical estrogen–based COCs. Given the accumulating evidence, a reassessment of current recommendations is warranted, with consideration of body-identical estrogens as first-line COCs.
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