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.

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 µg 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 6-8 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) (Table 3). INTERPRETATION: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL. FUNDING: Healthcare Insurers Innovation Foundation, Radboud University Medical Centre, Canisius Wilhelmina Hospital.

Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: study protocol for a randomized double blinded placebo-controlled comparison (Triple M Trial).

BACKGROUND: Early pregnancy failure (EPF) is a common complication of pregnancy. If women do not abort spontaneously, they will undergo medical or surgical treatment in order to remove the products of conception from the uterus. Curettage, although highly effective, is associated with a risk of complications; medical treatment with misoprostol is a safe and less expensive alternative. Unfortunately, after 1 week of expectant management in case of EPF, medical treatment with misoprostol has a complete evacuation rate of approximately 50%. Misoprostol treatment results may be improved by pre-treatment with mifepristone; its effectiveness has already been proven for other indications of pregnancy termination. This study will test the hypothesis that, in EPF, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation (primary outcome), patient satisfaction, complications, side effects and costs (secondary outcomes). METHODS: The trial will be performed multi-centred, prospectively, two-armed, randomised, double-blinded and placebo-controlled. Women with confirmed EPF by ultrasonography (6-14 weeks), managed expectantly for at least 1 week, can be included and randomised to pre-treatment with oral mifepristone (600 mg) or oral placebo (identical in appearance). Randomisation will take place after receiving written consent to participate. In both arms pre-treatment will be followed by oral misoprostol, which will start 36-48 h later consisting of two doses 400 µg (4 hrs apart), repeated after 24 h if no tissue is lost. Four hundred sixty-four women will be randomised in a 1:1 ratio, stratified by centre. Ultrasonography 2 weeks after treatment will determine short term treatment effect. When the gestational sac is expulsed, expectant management is advised until 6 weeks after treatment when the definitive primary endpoint, complete or incomplete evacuation, will be determined. A sonographic endometrial thickness < 15 mm using only the allocated therapy by randomisation is considered as successful treatment. Secondary outcome measures (patient satisfaction, complications, side effects and costs) will be registered using a case report form, patient diary and validated questionnaires (Short Form 36, EuroQol-VAS, Client Satisfaction Questionnaire, iMTA Productivity Cost Questionnaire). DISCUSSION: This trial will answer the question if, in case of EPF, after at least 1 week of expectant management, sequential treatment with mifepristone and misoprostol is more effective than misoprostol alone to achieve complete evacuation of the products of conception. TRIAL REGISTRATION: Clinicaltrials.gov (d.d. 02-07-2017): NCT03212352. Trialregister.nl (d.d. 03-07-2017): NTR6550. EudraCT number (d.d. 07-08-2017): 2017-002694-19. File number Commisie Mensgebonden Onderzoek (d.d. 07-08-2017): NL 62449.091.17.

Current and future expectations of mifepristone treatment in early pregnancy failure: a survey among Dutch gynaecologists.

To investigate the current and future addition of mifepristone to misoprostol treatment in case of early pregnancy failure (EPF), a digital questionnaire was distributed to a representative sample of all Dutch hospitals (25/79). In non-teaching centres, the presence of a local protocol was significantly lower compared to academic and teaching hospitals (p=.012). If a local protocol was present, the first choice of treatment was medical in 54.5%. Four respondents (16%) always prescribed mifepristone in case of EPF. The most common reason not prescribing mifepristone was the lack of sufficient scientific evidence. An average increase in success rate of 21.7% was desired to prescribe mifepristone in the future for EPF. Completeness of evacuation of products of conception from the uterus was usually assessed after 1 week by ultrasonography combined with clinical signs. If a complete evacuation was not achieved by the initial medical treatment, expectant management was proposed just as often as surgical intervention. Impact Statement What is already known on this subject? In case of early pregnancy failure (EPF), women can choose from both expectant medical (misoprostol, whether or not combined with mifepristone) and surgical (D and C) treatment. In The Netherlands, a national guideline concerning the treatment of EPF is still lacking. A questionnaire performed by Verschoor et al. ( 2014 ) showed there was a large practice variety between Dutch clinics. What the results of this study add? In this study, a representative sample of all Dutch clinics received a questionnaire about the treatment of EPF. The results confirm a large practice variation regarding treatment of EPF. The first choice of treatment, the medical treatment regimen, and the assessment of whether or not the treatment have been variations of successful between clinics. With regards to the addition of mifepristone to the medical treatment regime with misoprostol, gynaecologists are willing to consider mifepristone if an improvement of efficacy of approximately 20% is scientifically proven. What the implications are of these findings for clinical practice and/or further research? In our opinion, these results emphasise the need for a national guideline concerning the treatment of EPF. Our results also demonstrate that, if the addition of mifepristone to medical treatment with misoprostol proves to be more efficient than misoprostol alone, gynaecologists are willing to prescribe mifepristone in the future. Whether the addition is indeed more effective than misoprostol alone, will be the subject of a multicentre, double-blind, placebo-controlled randomised controlled trial, planned to begin in the first half of 2018.

The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: a systematic review of the literature.

OBJECTIVE(S): Early pregnancy failure (EPF) is a common complication of pregnancy. Surgical intervention carries a risk of complications and, therefore, medical treatment appears to be a safe alternative. Unfortunately, the current medical treatment with misoprostol alone has complete evacuation rates between 53% and 87%. Some reports suggest that sequential treatment with mifepristone and misoprostol leads to higher success rates than misoprostol alone. STUDY DESIGN: To evaluate the added value of mifepristone to current non-surgical treatment regimens in women with EPF we performed a systematic literature search. Electronic databases were searched: PubMed, Cochrane Library, Current Controlled Trials, and ClinicalTrials.gov. Clinical studies, both randomised and non-randomised trials, reporting on the added value of mifepristone to current non-surgical treatment regimens in women with EPF were included. Data of sixteen studies were extracted using a data extraction sheet (based on the Cochrane Consumers and Communication Review Group's data extraction template). The methodological quality was assessed using the Cochrane Collaboration Risk of Bias tool. RESULTS: In five randomised and eleven non-randomised trials, success rates of sequential treatment with mifepristone and misoprostol in case of EPF varied between 52% and 95%. Large heterogeneity existed in treatment regimens and comparators between studies. CONCLUSION(S): The existing evidence is insufficient to draw firm conclusions about the added value of mifepristone to misoprostol alone. A sufficiently powered randomised, double blinded placebo-controlled trial is urgently required to test whether, in EPF, the sequential combination of mifepristone with misoprostol is superior to misoprostol only.

Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: a retrospective study.

OBJECTIVE: Is treatment of early pregnancy failure (EPF) with sequential use of mifepristone and misoprostol more effective than treatment with misoprostol alone? STUDY DESIGN: In a retrospective cohort study at the Department of Obstetrics and Gynaecology of the Radboud University Medical Centre, 301 women with early pregnancy failure receiving medical treatment between January 2008 and March 2013 were included. Of these, 199 women were pre-treated with 200mg mifepristone (orally) followed by 2 consecutive doses of 800mcg misoprostol (vaginally) and 102 women were treated with 2 consecutive doses of 800mcg misoprostol (vaginally) alone. RESULTS: Complete expulsion was achieved in 66.8% of the women treated with a sequential combination of mifepristone and misoprostol versus 54.9% of the women treated with misoprostol alone. The difference in rates of complete expulsion was 11.9% (P<0.05; 95% CI 0.3-23.6%). CONCLUSIONS: Medical treatment of early pregnancy failure with a sequential combination of mifepristone and misoprostol was more effective than treatment with misoprostol alone. Our findings will have to be confirmed by a large prospective multicentre double blinded-randomized trial.