Comparative effectiveness and safety of different progestins in combined oral contraceptives: a systematic review and network meta-analysis of randomized controlled trials.

Purpose: This systematic review and network meta-analysis (NMA) compares four progestins-gestodene (GSD), desogestrel (DSG), drospirenone (DRSP), and levonorgestrel (LNG)-in combined oral contraceptives (COCs) regarding safety, and efficacy for personalized contraceptive selection.

Methods: This systematic review, which searched PubMed, Cochrane, Embase and Medline through Jan 28, 2025, to identify published and unpublished randomised controlled trials (RCTs). We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using NMA with random effects by STATA and GeMTC software. The outcomes included breakthrough bleeding (BTB), irregular bleeding (IB), withdrawal bleeding days, pregnancy rates, and adverse events.

Results: Eighteen RCTs were included. GSD demonstrated the lowest incidence of BTB and IB (OR 0.41 (0.26, 0.66); OR 0.67 (0.52, 0.86)). For withdrawal bleeding days, DRSP ranked highest (SUCRA 40.1; I² = 27%, p = 0.222), followed by GSD, LNG and DSG. Contraceptive efficacy was highest for DSG (OR 0.74, (0.31-1.73); SUCRA = 51.3%) followed by DRSP and GSD, with LNG being the least effective. Regarding safety, DRSP had the lowest adverse event rate (OR 0.84, 0.60-1.19); SUCRA = 66.9%), followed by LNG and DSG, while GSD was associated with the highest.

Conclusion: The four progestogens demonstrate comparable contraceptive efficacy while exhibiting distinct therapeutic advantages in their respective clinical applications. DSG for routine use, GSD for bleeding control, DRSP for minimizing androgenic effects, and LNG for emergency contraception.

Trial registration: PROSPERO ID: CRD42024582991.