Hemostatic safety profile of estetrol vs. ethinylestradiol in oral contraceptives: a systematic review and meta-analysis.

OBJECTIVE

To evaluate the hemostatic profile of estetrol/drospirenone (E4/DRSP) compared with ethinylestradiol/drospirenone (EE/DRSP) in adult women.

METHODS

A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed according to PRISMA guidelines. Eligible studies compared E4/DRSP with EE/DRSP in adult women and assessed coagulation, anticoagulation, or fibrinolytic markers. Three RCTs (n=183) met inclusion criteria. Data were extracted independently, and pooled mean differences (MD) were calculated using random-effects models.

RESULTS

Compared to EE/DRSP, E4/DRSP was associated with higher protein S activity (MD = 21.23; 95% CI: 11.83 to 30.64; p<0.00001) and lower levels of fibrinogen (MD = -24.17; 95% CI: -39.15 to -9.19; p=0.002), plasminogen (MD = -27.28; 95% CI: -27.28 to - 22.89; p<0.00001), and SHBG (MD = -183.38; 95% CI: -183.38; 95% CI: -210.93 to -155.84; p<0.00001). No significant differences were observed for D-dimer and antithrombin. Protein C activity was higher in the EE group, though this was an isolated finding with limited interpretability.

CONCLUSION

E4/DRSP demonstrates a more favorable hemostatic profile than EE/DRSP, potentially reducing thrombotic risk. Despite the limited number of RCTs, consistency across markers supports E4 as a safer estrogenic component for contraceptive formulations, with implications for women at increased risk of venous thromboembolism.PROSPERO registry: #CRD420251074961.