Comparative effectiveness of misoprostol plus letrozole versus misoprostol alone for pharmacological abortion: a systematic review and meta-analysis of randomized controlled trials

To compare the effectiveness of vaginal or oral misoprostol combined with letrozole versus misoprostol alone for medical abortion and medical management of miscarriage, assessing complete abortion rate, time-to-abortion, haemoglobin decline, and side effects. This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420251165732). PubMed, EMBASE, Cochrane Library, and Clinical Trials were searched for randomised controlled trials (RCTs) comparing letrozole plus misoprostol versus misoprostol alone. Analyses were conducted in Review Manager, dichotomous outcomes (complete abortion, side effects) were expressed as risk ratios (RR) and continuous outcomes (time-to-abortion, haemoglobin decline) as mean differences (MD), with 95% confidence intervals (CI) in a random-effect model. Risk of bias was assessed with RoB2, and certainty with GRADE. Twelve RCTs (1,524 women) were included. Letrozole pre-treatment increased complete abortion rates (RR = 1.45; 95% CI 1.25–1.68; p < 0.00001; I²=73%), reduced time-to-abortion (MD = −5.47h; 95% CI −8.68 to −2.26; p = 0.0008; I²=99%), and minimised haemoglobin decline (MD = +0.26 g/dL;95% CI 0.13–0.39;p < 0.001;I²=0%). Side effects were comparable (RR = 1.04; 95% CI 0.88–1.23;p = 0.67;I²=57%). Letrozole pre-treatment improves medical abortion efficacy, without raising side effects. Letrozole pre-treatment before misoprostol significantly improves first-trimester medical abortion outcomes, raising complete abortion rates, shortening procedure time, and reducing blood loss without increasing side effects.