MifeMiso study methods

The MifeMiso trial was a multicentre, pragmatic design, double-blind placebo-controlled trial of mifepristone and misoprostol versus placebo and misoprostol in the management of missed miscarriage in the first 14 weeks of pregnancy, diagnosed by pelvic ultrasound up to 14 weeks gestation. Participants were randomly allocated to a single dose of oral mifepristone 200 mg or an oral matched placebo tablet, followed by a single dose of vaginal, oral, or sublingual misoprostol (800 micrograms) 48 hours later. Participants in both arms (mifepristone or placebo) did not receive the subsequent misoprostol if they had successfully passed the gestational sac within the 48 hours. Outcome was assessed by pelvic ultrasound performed 7 days after random assignment. The participants were discharged from the trial if they passed the gestational sac within 7 days and had a negative urinary pregnancy test 3 weeks after randomisation. If participants failed to pass the gestational sac within 7 days after randomisation, they were managed according to local hospital practice, which generally involved offering participants further doses of misoprostol 800 micrograms or surgical management if clinically indicated.

The primary outcome was failure to spontaneously pass the gestational sac within 7 days after randomisation, which was confirmed by pelvic ultrasound scan. Participants who did not undergo ultrasound scan on day 6 or 7 had their clinical data (including vaginal bleeding, abdominal pain, and passage of pregnancy tissues) assessed by a masked endpoint review committee who decided whether the primary outcome was met. Secondary outcomes included: surgical intervention to complete the miscarriage up to and including day 7 after randomisation and up to discharge from hospital; need for further doses of misoprostol within 7 days after randomisation and up to discharge; infection associated with miscarriage; duration of bleeding; negative pregnancy test result 21 days after randomisation and time from random assignment to discharge.

Sample size was calculated, and 710 women included to provide 90% power to detect a minimally important absolute difference of 10% points between the mifepristone plus misoprostol group and the placebo plus misoprostol group for the primary outcome (failure to pass the gestational sac within 7 days). Log binomial regression and liner regression models were used to calculate adjusted risk ratios for binary outcomes and to estimate adjusted mean differences for continuous outcomes.

All estimates of treatment effects between groups were adjusted for maternal age, body mass index, gestational age, parity, bleeding score and randomising centre.

MifeMiso results

The study recruited 711 women (aged 16 to 39 years) diagnosed by pelvic ultrasound with a missed miscarriage across 28 hospitals in the UK (696 women had available data for the primary outcome).

Key findings included:

• For the primary outcome, 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (RR 0.73, 95% CI 0.54 to 0.99). A further sensitivity analysis (excluding women for whom the primary outcome was determined using information from the masked endpoint review committee) showed statistically non-significant finding (RR 0.75, 95% CI 0.55 to 1.02). However, there is uncertainty whether these findings suggested any clinical important differences.
• For the key secondary outcome, 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage up to discharge versus 87 (25%) of 353 women in the placebo plus misoprostol group (RR 0.71, 95% CI 0.53 to 0.95).

There was no statistically significant difference between intervention and placebo group in any of the following outcomes: duration of bleeding reported by women, negative pregnancy test result 21 days after randomisation, incidence of serious adverse events, infection rate requiring inpatient antibiotic treatment, and need for further doses of misoprostol within 7 days after randomisation.

Economic analysis based on the MifeMiso trial

The cost effectiveness analysis published in the BJOG was carried out to assess mifepristone and misoprostol (MifeMiso) compared with placebo and misoprostol for the medical management of a missed miscarriage. The analysis was based on the primary outcome of the MifeMiso trial (failure to spontaneously pass the gestational sac within 7 days after randomisation) and was reported in terms of cost per successfully managed miscarriage and quality-adjusted life years (QALYs). The findings from the cost effectiveness analysis suggest that the MifeMiso intervention was more effective than misoprostol alone, with a benefit of 7 successfully managed miscarriages per 100 women. The MifeMiso intervention resulted in a cost saving of £182 (95% CI £26 to £338) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%).

The model-based analysis showed that the MifeMiso intervention was more effective and less costly when compared with expectant management and with the current NICE recommended medical management strategy of misoprostol alone.

The analysis also looked at the surgical management of miscarriage, which is covered in the NICE guideline. Surgical management was found to be more costly and more effective than the MifeMiso intervention.

Other considerations

At the time of the NICE guideline publication in 2012 misoprostol did not have a UK marketing authorisation for treatment of missed or incomplete miscarriage. As of September 2021, it still doesn't have a UK marketing authorisation for the treatment of missed miscarriage. Use of mifepristone in combination with misoprostol for the treatment of missed miscarriage would be off-label.

The current price (NHS indicative price) of mifepristone 200 mg is £10.14 per tablet (see BNF monograph) and misoprostol price is £10.03 for a pack of 60 × 200 microgram (August Drug Tariff).

The cost effectiveness analysis of the MifeMiso trial showed that women in the placebo arm used more resources (hospital visits/admissions, need for surgery, additional dose of misoprostol) than women in the MifeMiso intervention arm and these differences were reflected in the costs.

Topic expert feedback

Feedback from all topic experts (n=4) indicated that the recommendations on medical management of missed miscarriage (recommendations 1.5.9 to 1.5.17) should be updated based on the MifeMiso evidence. One expert commented that mifepristone is included in medical management regimens in their service following the MifeMiso trial publication.

Impact

The NICE guideline does not make recommendations on the combined use of mifepristone and misoprostol (MifeMiso) for the management of missed miscarriage as, at the time of guideline development in 2012, there was insufficient evidence and there was relatively high cost of mifepristone (although no cost effectiveness analysis was performed). The data from the MifeMiso trial indicates that treatment with mifepristone plus misoprostol was more clinically and cost effective than misoprostol alone, which is currently recommended in the guideline for management of missed miscarriage (recommendations 1.5.9 to 1.5.11).

Therefore, we will update the recommendations on medical management of missed miscarriage.

VESPA study methods

The VESPA study employed a multimethod approach and included a:

• prospective cohort study of women attending EPAUs (to measure clinical outcomes)
• health economic evaluation (including skill mix and cost–utility model development)
• patient satisfaction survey
• qualitative interviews with service users
• EPAU staff survey
• hospital emergency care audit for women presenting with early pregnancy complications.

Corresponding to the study methods, data collection was organised into 7 data strands: 1. clinical outcomes in EPAUs; 2. emergency hospital care audit; 3. patient satisfaction; 4. staff satisfaction; 5. qualitative interviews; 6. health economic evaluation and 7. workforce analysis.

Main outcome measure:

• The primary outcome of the study was the proportion of women attending EPAUs who were admitted to hospital for further investigations and treatment (data strand 1).

Secondary outcome measures:

• Total number of emergency admissions of women presenting with early pregnancy complications (data strands 1 and 2).
• Ratio of new to follow-up visits (data strand 1).
• Rate of non-diagnostic ultrasound scans (pregnancy of unknown location; data strand 1).
• Proportion of laparoscopies performed for a suspected ectopic pregnancy with a negative finding (data strand 2).
• Patient satisfaction with the quality of care received (data strand 3).
• Staff experience of providing care in EPAUs (data strand 4).
• Quality-of-life measures, and anxiety levels of women before and after assessment at the EPAU (data strand 6).
• Cost effectiveness of different staffing models (data strand 7).

VESPA study results

Clinical data were collected from 6,606 women who attended the 44 participating EPAUs in the UK. The majority of the EPAUs (37/44) had a unit volume of <4,000 visits per year and 22 EPAUs had a volume of <2,500 visits per year. A cut-off point of 2,500 visits was used to describe the units as high or low volume in the study's data analysis. A large number of the EPAUs (25/44) had no planned consultant presence. Out of the 19 remaining EPAUs 15 had planned consultant presence of <35% of opening time.

Findings from the 7 data strands:

Overall

The finding showed that the highest admission rate was recorded in women diagnosed with ectopic pregnancies. The study showed that consultant presence in EPAUs has limited impact on the clinical outcomes measured (that is the proportion of women who are admitted to hospital for further investigations/treatment, proportion of women who are admitted as emergencies, pregnancy of unknown location rates, negative laparoscopy rate and patient satisfaction). The study indicated that this finding could be explained by the generally low level of consultant presence in EPAUs.

Study limitations

The authors stated that they were unable to establish the amount of time that a consultant should spend to deliver optimal patient care because the time that consultants spent in the units were generally very low. Another limitation of the study was inconsistent use of clinical care pathway protocols across EPAUs, a lack of information regarding the competencies of ultrasound operators, variations in patient diagnosis, and the low response rates to health economic and patient satisfaction questionnaires.

Topic expert feedback

Topic experts were asked whether the VESPA study has any impact on the NICE guideline recommendations on appropriate models for EPAU. Three out of 4 topic experts who responded believed that the recommendations should not be updated in response to evidence from the VESPA study. One expert expressed a lack of confidence in the findings because of the heterogeneity present in the included EPAUs (remote versus on-site, different access hours and varied staff skill, consultant presence) and felt the findings may not be applicable to all institutions in the UK. One expert responded that they could not anticipate how the VESPA results could be interpreted into recommendations and that the existing recommendations were satisfactory. One topic expert who responded 'yes' to update, indicated that units are safer when they are staffed by people experienced in the area of expertise. This is in line with current recommendations that an early pregnancy assessment service should be a dedicated service provided by healthcare professionals competent to diagnose and care for women with pain and/or bleeding in early pregnancy (recommendation 1.2.2).

Impact

Current recommendations suggest that an early pregnancy assessment service should be a dedicated service provided by healthcare professionals competent to diagnose and care for women with pain and/or bleeding in early pregnancy (recommendation 1.2.2). Recommendations do not suggest a specific staffing model for EPAUs.

Although the VESPA trial provides valuable insight into EPAUs model organisation, it was unable to estimate the potential impact of factors such as level of supervision, quality of ultrasound equipment, variation in clinical care pathway protocols, and staff experience or competence on the primary and secondary outcomes.

Following consideration of the results from the VESPA study, previous evidence, as well as topic expert feedback, we will not update the guideline recommendations on EPAUs.