Mifepristone Followed by Misoprostol Compared with Placebo Followed by Misoprostol as Medical Treatment for Early Pregnancy Loss (the Triple M trial): A Double-Blind Placebo-Controlled Randomised Trial

Abstract

Background: Worldwide, millions of women seek treatment for early pregnancy loss (EPL) annually. Medical management with misoprostol is widely used, but only effective 60% of the time. Pre-treatment with mifepristone prior to misoprostol might improve the success rate of medical management. Methods: This was a multi-centre, double-blind, placebo-controlled randomised trial in 17 Dutch hospitals. Women with a non-viable pregnancy between 6 and 14 weeks of gestation were eligible for inclusion after at least one week of expectant management. Participants were randomised (1:1) between oral mifepristone 600 mg or an oral placebo tablet. Participants took 400 mg misoprostol orally, repeated after four hours on day two and, if necessary, day three. Primary outcome was expulsion of gestational sac and endometrial thickness <15 mm after 68 weeks. Analyses were done according to intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT03212352. Findings: Between June 28th 2018 and January 8th 2020, 175 women were randomised to mifepristone and 176 to placebo, including 344 in the intention-to-treat analysis. In the mifepristone group 136 (79.1%) of 172 participants reached complete evacuation compared to 101 (58.7%) of 172 participants in the placebo group (p<0.0001, RR 1.35, 95% CI 1.16-1.56). Incidence of serious adverse events was significantly lower in the mifepristone group with 24 (14%) patients affected versus 55 (32%) in the placebo group (p = 0.0005). Interpretation: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL.