Medical management of miscarriage with mifepristone
Authors: Kurt Barnhart
Journal: The Lancet (2020)

Care of women with early pregnancy loss is changing for the better. The management of miscarriage dates back to at least 1843 with a curette invented by Recamier, which is now considered barbaric.1Grimes DA Diagnostic dilation and curettage: a reappraisal.Am J Obstet Gynecol. 1982; 142: 1-6Summary Full Text PDF PubMed Scopus (321) Google Scholar The rationale that, "Placental villosities are very frequently detected in utero after miscarriage…and their discovery points out the immediate cure of haemorrhage by removal of its inciting cause",2Mundé PF Dull wite curette.Trans Edinb Obstet Soc. 1878; 5: 48-64PubMed Google Scholar still holds true today. The goal of treatment of miscarriage is to efficiently and safely remove tissue from an early pregnancy loss to reduce haemorrhage and infection. Unfortunately, miscarriage is common and stressful.3Murphy FA Lipp A Powles DL Follow-up for improving psychological well being for women after a miscarriage.Cochrane Database Syst Rev. 2012; 3CD008679PubMed Google Scholar Both surgical and expectant management with spontaneous resolution have well established risks and benefits.4Chu J Hardy P Beeson L Coomarasamy A What is the best method for managing early miscarriage?.BMJ. 2020; 368l6438Crossref PubMed Scopus (10) Google Scholar Medical management can shorten the resolution time and reduce the unpredictability associated with expectant management, while eliminating the invasiveness and cost of vacuum aspiration. In 2005, Zhang and colleagues5Zhang J Gilles JM Barnhart K Creinin MD Westhoff C Frederick MM A comparison of medical management with misoprostol and surgical management for early pregnancy failure.N Engl J Med. 2005; 353: 761-769Crossref PubMed Scopus (215) Google Scholar showed that vaginally administered misoprostol 800 mg (a prostaglandin analogue) was non-inferior to surgical management. Subsequent studies revealed the limitations of misoprostol alone, including moderate success rates and the need for a possible second dose prolonging resolution.4Chu J Hardy P Beeson L Coomarasamy A What is the best method for managing early miscarriage?.BMJ. 2020; 368l6438Crossref PubMed Scopus (10) Google Scholar In 2018, Schreiber and colleagues6Schreiber CA Creinin MD Atrio J Sonalkar S Ratcliffe SJ Barnhart KT Mifepristone pretreatment for the medical management of early pregnancy loss.N Engl J Med. 2018; 378: 2161-2170Crossref PubMed Scopus (94) Google Scholar showed that pretreatment with mifepristone 200 mg (a competitive progesterone receptor antagonist) before misoprostol safely and statistically significantly increased efficacy from 67% to 84% in an open-label pragmatic randomised trial of 300 women in the USA. In The Lancet, Justin Chu and colleagues7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar present the findings of a large randomised trial of 711 women that evaluated mifepristone and misoprostol (357 women; mean age 32·8 years [SD 5·6]) versus misoprostol alone (354 women; mean age 32·7 years [5·7]) for the medical management of missed miscarriage. This was a meticulously done placebo-controlled, double-blind, clinical trial, with high internal validity and low loss to follow-up. The trial was done in 28 UK hospitals. The findings support and expand our understanding of the benefits of pretreatment with oral mifepristone two days before misoprostol administration for women with missed miscarriage in the first 14 weeks of pregnancy. The trial showed a significant reduction in the percentage of women who failed to pass the gestational sac within 7 days with mifepristone pretreatment compared with misoprostol alone (risk ratio [RR] 0·73, 95% CI 0·54–0·99; p=0·043). Only 17% of women randomly assigned to the combination treatment group did not spontaneously pass the gestational sac. The outcomes of trials evaluating medical management of miscarriage have varied, and have included gestational sac expulsion at 7 days,7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar expulsion with one dose of misoprostol and no additional interventions within 30 days,6Schreiber CA Creinin MD Atrio J Sonalkar S Ratcliffe SJ Barnhart KT Mifepristone pretreatment for the medical management of early pregnancy loss.N Engl J Med. 2018; 378: 2161-2170Crossref PubMed Scopus (94) Google Scholar endometrial thinness less than 15 mm,8Sinha P Suneja A Guleria K Aggarwal R Vaid NB Comparison of mifepristone followed by misoprostol with misoprostol alone for treatment of early pregnancy failure: a randomized double-blind placebo-controlled trial.J Obstet Gynaecol India. 2018; 68: 39-44Crossref PubMed Scopus (15) Google Scholar the need for additional doses of misoprostol, and the need for surgical intervention.6Schreiber CA Creinin MD Atrio J Sonalkar S Ratcliffe SJ Barnhart KT Mifepristone pretreatment for the medical management of early pregnancy loss.N Engl J Med. 2018; 378: 2161-2170Crossref PubMed Scopus (94) Google Scholar, 7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar, 8Sinha P Suneja A Guleria K Aggarwal R Vaid NB Comparison of mifepristone followed by misoprostol with misoprostol alone for treatment of early pregnancy failure: a randomized double-blind placebo-controlled trial.J Obstet Gynaecol India. 2018; 68: 39-44Crossref PubMed Scopus (15) Google Scholar Although debate remains over which of these outcomes is optimal, data from this trial support the effectiveness of mifepristone pretreatment according to several definitions; only 17% of women needed surgical intervention to complete miscarriage (only 6% within 7 days of treatment) and only 14% needed additional doses of misoprostol (only 10% within the first 7 days).7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar An additional benefit of this trial is the pragmatic efficacy in 28 clinics across the UK, contributing important generalisability of effectiveness across a range of clinical settings.7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar Although most women in this trial received vaginal administration of misoprostol (89%), the success with oral or sublingual administration was similar. Moreover, gestational age, maternal age, body-mass index, parity, or amount of bleeding before treatment did not substantially affect the outcome. However, the trial did not present effectiveness stratified by anembryonic gestation or fetal demise and did not evaluate women with an incomplete miscarriage. There is now evidence that mifepristone pretreatment is effective both 24 h6Schreiber CA Creinin MD Atrio J Sonalkar S Ratcliffe SJ Barnhart KT Mifepristone pretreatment for the medical management of early pregnancy loss.N Engl J Med. 2018; 378: 2161-2170Crossref PubMed Scopus (94) Google Scholar or 48 h7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar before misoprostol administration. Importantly, safety has also been shown, with a low incidence of serious adverse events in both this large trial7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar and a US-based trial.6Schreiber CA Creinin MD Atrio J Sonalkar S Ratcliffe SJ Barnhart KT Mifepristone pretreatment for the medical management of early pregnancy loss.N Engl J Med. 2018; 378: 2161-2170Crossref PubMed Scopus (94) Google Scholar The misoprostol and mifepristone combination strategy is also cost-effective.9Nagendra D Koelper N Loza-Avalos SE et al.Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.JAMA Netw Open. 2020; 3e201594Crossref PubMed Scopus (10) Google Scholar Safe, effective, and acceptable treatment for women with miscarriage is paramount. The results of this study should lead to a change in practice in the UK and worldwide.7Chu JJ Devall AJ Beeson LE et al.Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Lancet. 2020; (published online Aug 24.)https://doi.org/10.1016/S0140-6736(20)31788-8Summary Full Text Full Text PDF Scopus (30) Google Scholar These high-quality data provide evidence that mifepristone pretreatment is the optimal medical approach to women with missed miscarriage. The authors updated a Cochrane meta-analysis with their new data and showed a clear and statistical benefit of mifepristone pretreatment compared with misoprostol alone (RR 1·15, 95% CI 1·01–1·30). Mifepristone pretreatment for women who desire medical management of missed miscarriage should be implemented without political or logistical barriers. I declare no competing interests. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trialTreatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. Full-Text PDF Open Access