Economic evaluation of a randomized controlled trial comparing mifepristone and misoprostol with misoprostol alone in the treatment of early pregnancy loss.

BACKGROUND: In case of early pregnancy loss (EPL) women can either choose for expectant, medical or surgical management. One week of expectant management is known to lead to spontaneous abortion in approximately 50% of women. Medical treatment with misoprostol is known to be safe and less costly than surgical management, however less effective in reaching complete evacuation of the uterus. Recently, a number of trials showed that prompt treatment with the sequential combination of mifepristone with misoprostol is superior to misoprostol alone in reaching complete evacuation. In this analysis we evaluate whether the sequential combination of mifepristone with misoprostol is cost-effective compared to misoprostol alone, in the treatment of EPL. METHODS AND FINDINGS: A cost-effectiveness analysis (CEA) from a healthcare perspective was performed alongside a randomised controlled trial (RCT) in which standard treatment with misoprostol only was compared with a combination of mifepristone and misoprostol, in women with EPL after a minimum of one week of unsuccessful management. A limited societal perspective scenario was added. This RCT, the Triple M trial, was a multicentre, randomized, double-blinded, placebo-controlled trial executed at 17 hospitals in the Netherlands. The trial started on June 27th 2018, and ended prematurely in January 2020 due to highly significant outcomes from the predefined interim-analysis. We included 351 women with a diagnosis of EPL between 6 and 14 weeks gestation after at least one week of unsuccessful expectant management. They were randomized between double blinded pre-treatment with oral mifepristone 600mg (N = 175) or placebo (N = 176) taken on day one, both followed by misoprostol orally. In both groups, an intention-to-treat analysis was performed for 172 patients, showing a significant difference in success rates between participants treated with mifepristone and misoprostol versus those treated with misoprostol alone (79.1% vs 58.7% respectively). In this cost-effective analysis we measured the direct, medical costs related to treatment (planned and unplanned hospital visits, medication, additional treatment) and indirect costs based on the IMTA Productivity Cost Questionnaire (iPCQ). Quality Adjusted Life Years (QALY's) were calculated from participants' scores on the SF-36 questionnaires sent digitally at treatment start, and one, two and six weeks later. We found medical treatment with placebo followed by misoprostol to be 26% more expensive compared to mifepristone followed by misoprostol (p = 0.001). Mean average medical costs per patient were significantly lower in the mifepristone group compared to the placebo group (€528.95 ± 328.93 vs €663.77 ± 456.03, respectively; absolute difference €134.82, 95% CI 50,46-219,18, p = 0.002). Both indirect costs and QALY's were similar between both groups. CONCLUSION: The sequential combination of mifepristone with misoprostol is cost-effective compared with misoprostol alone, for treatment of EPL after a minimum of one week of unsuccessful expectant management.

Diagnostic criteria for retained products of conception-A scoping review.

INTRODUCTION: Numerous studies have been performed assessing optimal treatment regimens for evacuating (retained) products of conception from the uterus, but standardized criteria for diagnosing retained products of conception (RPOC) are still lacking. We aim to provide an overview of diagnostic criteria in current literature, used to diagnose RPOC after induced first-trimester abortion or early pregnancy loss. MATERIAL AND METHODS: Pubmed, EMBASE, and the Cochrane library were searched systematically up until March 2020 for English articles reporting on induced abortion or early pregnancy loss. Articles not specifying diagnostic criteria used to assess completeness of treatment were excluded, as were conference abstracts, expert opinions, reviews, and case reports. Four elements of diagnostic criteria were described: diagnostic tools, parameters used within these tools, applied cut-off values, and timing of follow up. Additionally, a meta-analysis was performed assessing diagnostic qualities of the most often applied diagnostic tool and parameter. RESULTS: The search strategy yielded 1233 unique articles, of which 248 were included, with a total of 339 517 participants. In the 79 included randomized controlled trials, six diagnostic tools to assess RPOC were identified, combined in 14 ways, with 55 different cut-off values. In 169 observational studies, seven diagnostic tools were identified, used in 28 combinations, applying 89 different cut-off values. Transvaginal ultrasonographic measurement of endometrial thickness with a cut-off value of at least 15 mm indicating RPOC, was used most frequently. In the timing of follow-up there was great variation, with 55 and 107 different combinations in randomized controlled trials and observational studies, respectively. Assessment of treatment success was scheduled most often around 2 weeks after treatment. Diagnostic qualities of endometrial thickness of 15 mm or more was not adequately assessed. CONCLUSIONS: There is wide variation in the way RPOC are assessed, and the criteria used to define RPOC following induced abortion and early pregnancy loss; ultrasonographic measurement of endometrial thickness, with a cut-off of 15 mm or more 2 weeks after primary treatment is the most widely used diagnostic approach. A meta-analysis on diagnostic accuracy of endometrial thickness of 15 mm or more did not lead to solid results. These findings can be a first step to develop a workable standard of establishing RPOC after induced abortion or early pregnancy loss.

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.