Mifepristone pretreatment appears more effective than misoprostol alone for active management of first trimester miscarriage in women with a closed cervical os

Resident Focus - Volume 14, Issue 2

Reference: N Engl J Med 2018 Jun 7;378(23):2161
Level 2 [mid-level] evidence

About 1 in 4 women experience early pregnancy loss at some point in their lifetime (Am Fam Physician 2011 Jul 1;84(1):75). Twenty to thirty percent of these women will opt for medical management over surgical evacuation (BMJ 2013 Jun 19;346:f3676), though recommended treatment strategies have shown poor efficacy in some cases. The standard of care, according to the American College of Gynecology (ACOG Practice Bulletin 150), is a single 800 μg dose of misoprostol that may be repeated up to 7 days later. Misoprostol is a prostaglandin that promotes uterine contractions for gestational sac expulsion. While single dose misoprostol has been shown to be highly effective for incomplete or inevitable abortions (those with an open cervical os) across a wide body of evidence, it appears to be less effective for missed abortions (those with a closed cervix). The limited available data evaluating combination therapy with mifepristone/misoprostol for missed abortions is mixed. Higher quality data is needed to answer the question: does mifepristone pretreatment lead to safer and more effective management of first trimester miscarriage with a closed cervix?

A recent randomized trial without placebo control compared combination therapy with mifepristone pretreatment to misoprostol alone in 300 women aged 18 years and older with ultrasound-confirmed non-viable pregnancies between 5-12 weeks gestation. Women with an open cervical os were excluded. The study population included women from various ethnicities and educational levels, with varying obstetric histories. The women were randomly assigned to receive either mifepristone 200 ug orally given 24 hours before misoprostol 800 mg vaginally, or a single dose of misoprostol 800 mg vaginally. At a follow-up visit 1-4 days after treatment, if the gestational sac was still present women could either receive a second misoprostol dose or opt for expectant or surgical management. The primary outcome was gestational sac expulsion completed by the initial 1-4 day follow up visit, determined by endovaginal ultrasound (defined as “treatment success”). Outcome assessors were blinded, though patients were not. Patients had subsequent visits at 8 and 30 days to monitor subsequent outcomes. Loss to follow-up at 30 days was 6%, but 99% of women were included in analysis.

At initial follow up, gestational sac expulsion had occurred in 83.8% of women in the mifepristone-pretreatment group compared to 67.1% of the misoprostol-only group (risk ratio [RR] 1.25, 95% CI 1.09-1.43), which corresponds to a number needed to treat (NNT) of 6 for the pretreatment group. By day 8, complete expulsion occurred in 87.8% of women in mifepristone-pretreatment group, compared to 71.1% of the misoprostol-only group (RR 1.23; 95% CI 1.10- 1.39; NNT 7). At 1 month, gestational sac expulsion with up to two doses of misoprostol had occurred in 91.2% of the mifepristone-pretreatment group and 75.8% of the misoprostol-only group (RR 1.2, 95% CI 1.08-1.33 NNT 7). In the mifepristone pretreatment group, 8.8% underwent uterine aspiration compared to 23.5% of the misoprostol-only group (RR 0.37, 95% CI 0.21-0.68; NNT 7). Rates of serious adverse events (including bleeding requiring transfusion and pelvic infection) were low (3.4% vs. 2%) and not statistically significant between the two groups.

This trial suggests a statistically and clinically significant improvement in gestational sac expulsion and a similar safety profile with combination mifepristone/misoprostol compared to misoprostol alone for non-viable early pregnancies with a closed cervical os. It was a larger study with fewer threats to validity than previous trials and may offer a more reliable answer to the question of whether combination therapy is better than misoprostol monotherapy for missed abortions.

For more information, see the First trimester pregnancy loss topic in Dynamed Plus. DynaMed users, see the First trimester pregnancy loss topic in Dynamed Classic.

DANIEL RING , MD is a Connecticut native who studied business at the University of Michigan and then attended medical school at Tufts University. He is currently a PGY-2 family medicine resident at the University of Virginia in Charlottesville. He has special interests in pediatric and adolescent medicine, behavioral health, and teaching.

Faculty contributions by Kate DeGeorge, MD.