Estetrol/drospirenone for combined oral contraception: a systematic review of efficacy, cycle control, and safety

Manuel Sánchez-Prieto, S Coll, Marina Romero-Domínguez, Marta Avella-Marcos, Mireia Castilla, Margarita Gómez del Valle, Silvia Franco‐Camps

Objective To systematically evaluate the evidence on the contraceptive efficacy, cycle control, safety, and selected noncontraceptive effects of estetrol 15 mg/drospirenone 3 mg (E4/DRSP) and to assess certainty of evidence by outcome using the GRADE approach. Methods A systematic review was conducted in accordance with PRISMA 2020. PubMed/MEDLINE, Scopus, and Google Scholar were searched for eligible studies published through February 2026. Clinical trials and comparative studies evaluating E4/DRSP in women of reproductive age were included. Outcomes were grouped into contraceptive efficacy, bleeding/cycle control, safety and tolerability, hemostatic and endocrine–metabolic effects, ovarian suppression, and noncontraceptive clinical outcomes. Risk of bias was assessed using design-specific tools, and certainty of evidence was graded by outcome. Results A total of 25 eligible publications/study reports were included, comprising phase 2 dose-finding studies, pivotal phase 3 contraceptive trials, pooled analyses, mechanistic comparator studies, adolescent data, and indication-specific studies. E4/DRSP demonstrated robust contraceptive efficacy, predictable bleeding patterns, and an acceptable tolerability profile. Across mechanistic studies, E4/DRSP showed less pronounced hemostatic and endocrine–metabolic effects than ethinyl estradiol–containing comparators. The most consistent biological differentiation of E4/DRSP was observed for APC resistance and thrombin-generation endpoints, which were less affected than with EE-containing comparators. The strongest noncontraceptive evidence was observed for dysmenorrhea, supported by a randomized, double-blind, placebo-controlled trial. Certainty of evidence was moderate for contraceptive efficacy, cycle control, common adverse events, and surrogate hemostatic/metabolic outcomes; high for dysmenorrhea versus placebo; low for endometriosis-related and menstrual symptom outcomes; and very low for clinical thromboembolic risk. Conclusions E4/DRSP is an effective combined oral contraceptive with favorable cycle control and a consistent biologic profile suggesting lower hepatic/hemostatic impact than ethinyl estradiol–containing formulations. However, current evidence does not establish comparative thromboembolic safety, which requires dedicated postauthorization and real-world comparative studies.