Included studies

This review is a targeted review. No literature search was conducted for this review and a study identified by the surveillance report has been included. One randomised control trial (Chu 2020) was included in this review. This study compared 200 mg oral mifepristone plus 800 micrograms vaginal, oral, or sublingual misoprostol to oral placebo plus 800 micrograms vaginal, oral, or sublingual misoprostol in women diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy (by last menstrual period) and who chose to have medical management of miscarriage.

The included study is summarised in Table 2.

Excluded studies

There are no excluded studies for this review as no literature search was conducted.

Included studies

This review is a targeted review. No literature search was conducted for this review, with only papers identified by the surveillance report included. One economic study (Devall 2021) was included in this review.

Excluded studies

There are no excluded studies for this review as no literature search was conducted.

The outcomes that matter most

The aim of this review was to determine the effectiveness of the administration of mifepristone and misoprostol compared to misoprostol and placebo for the medical management of missed miscarriage.

As this is a targeted review that includes only one study identified by surveillance, the outcomes that matter the most have been taken from this study. These outcomes have been categorised as critical if they were specified as primary outcomes or as important if they were key secondary outcomes and these critical and important outcomes provide the most direct information about the effectiveness of the treatment to complete the miscarriage process.

The critical outcomes for this review are failure to spontaneously pass the gestational sac within 7 days after random assignment and surgical intervention to complete the miscarriage up to discharge from hospital care.

The important outcomes for this review are those that were categorised as secondary outcomes by the study and these provide additional detail about the benefits and possible harms of the treatments being investigated. The important outcomes for this review are; surgical intervention to complete the miscarriage up to and including 7 days after random assignment and from after day 7 up to discharge; need for further doses of misoprostol within 7 days after random assignment and up to discharge; infection requiring outpatient antibiotic treatment; infection requiring inpatient antibiotic treatment; negative pregnancy test result 21 days (±2 days) after random assignment; duration of bleeding as reported by the participant and requirement for blood transfusion. The additional outcomes of side-effects, any serious complications and maternal death have also been included. Evidence was available for all the above critical and important outcomes.

The quality of the evidence

The overall rating of the included RCT was high quality. This was a large double-blind trial so the risk of bias due to deviations from the intended intervention was low. The quality of the evidence ranged from low to high. The evidence from the critical outcomes was of moderate quality and the evidence from the important outcomes ranged from low to high. Outcomes were only downgraded for imprecision. The committee took into account the quality of the evidence, including the uncertainty in their interpretation of the evidence.

Benefits and harms

The committee’s discussion focused on the evidence for the use of mifepristone in combination with misoprostol for the treatment of missed miscarriage as the included trial did not provide evidence for use in incomplete miscarriage. A missed miscarriage is diagnosed when a non-viable pregnancy is identified on ultrasound scan during the first 14 weeks of gestation but all pregnancy tissue is retained in the uterus.

The committee discussed that the evidence clearly supports the use of the combination of mifepristone with misoprostol for the management of missed miscarriage, as a more clinically and cost effective treatment than misoprostol alone and that the combination should be offered to women at the doses stated in the evidence. They acknowledged that there was some uncertainty around the point estimates. They based their decision on the moderate quality evidence for the critical outcomes and one important outcome, suggesting an important benefit for the outcomes failure to pass the gestational sac after 7 days and need for surgical intervention to complete the miscarriage up to discharge, or from 7 days to discharge. The committee agreed that there was no evidence of difference for any other outcomes, and no evidence of negative effects from low to high quality evidence for mifepristone in combination with misoprostol compared to misoprostol and placebo for all the outcomes relating to possible harms (for example infection, bleeding, side-effects of the medication, or maternal death). This allowed them to make a strong recommendation.

The committee also noted that both mifepristone and misoprostol were not approved for use in the treatment of missed miscarriage, but were approved for termination of pregnancy. However, the mode of action would be the same in both conditions and so the committee agreed to recommend the combination for missed miscarriage

The committee had some concerns about the lack of a lower limit for the timing of the pelvic ultrasound scan that was used to diagnose missed miscarriage because there is the potential for error in pregnancies that are under 8 weeks’ gestation as it is more difficult to diagnose miscarriage at that timepoint due to the crown to rump length potentially being less than 7mm. The committee emphasised the importance of having two ultrasonographers to reduce the chance of an incorrect diagnosis. The committee then discussed that it was reassuring that the included trial had conducted a subgroup analysis for pregnancies greater than or less than 70 days’ gestation and found no evidence of a subgroup effect.

The evidence had not included women diagnosed with incomplete miscarriage. The committee discussed that evidence for missed miscarriage cannot be extrapolated to women diagnosed with incomplete miscarriage. However, the committee agreed that a research recommendation was not needed for incomplete miscarriage as mifepristone primes the uterus to the action of misoprostol, which causes uterine contractions and expulsion of the products of conception. In an incomplete miscarriage, the expulsion of the products of conception has already begun, so the use of mifepristone is not required, and the use of misoprostol alone is sufficient.

The committee discussed the importance of advising women and people experiencing miscarriage about the process which would occur after taking the medication and what to expect. The committee emphasised the need to have an open and clear discussion as it is important that women and people experiencing miscarriage are supported throughout the process and not left to cope alone after medical management. Based on the timings used in the evidence and their knowledge and experience the committee recommended that women and people experiencing miscarriage should contact their healthcare professional if bleeding had not started 48 hours after taking misoprostol. The committee also discussed the need for units to be able make alternative follow up arrangements for women and people experiencing miscarriage who would not or could not contact the unit. Based on their knowledge and experience, the committee also agreed that women and people who are experiencing miscarriage should be given advice on when and how to seek help during the miscarriage process.

The committee acknowledged the importance of follow-up for women and people experiencing miscarriage with a positive pregnancy test at 3 weeks as this would indicate the treatment had not been successful. They also discussed the importance of follow up for women and people with worsening symptoms such as bleeding, in order to be able to assess their need for further investigations or treatment. These people should be reviewed by a health care professional to rule out retained pregnancy tissue and to assess the need for any further investigations or management strategies.

The committee agreed, based on their knowledge and experience, that although a complete molar or ectopic pregnancy (including a heterotopic pregnancy) should have been ruled out before the medical management of miscarriage began this may need to be considered as a potential diagnosis if the pregnancy test was still positive after 3 weeks. Based on stakeholder feedback, the committee also added an additional recommendation to state that even if the pregnancy test was negative, if the woman or person still had heavy bleeding or other symptoms they would require further investigation.

The committee considered whether units should provide pregnancy tests for women and people experiencing miscarriage to use after 3 weeks or if they should advise people to buy their own urine pregnancy test to use at home. They noted that the current recommendations on expectant management of miscarriage required women and people experiencing miscarriage to obtain their own pregnancy test, whereas the guidance following medical management advised that women and people having a miscarriage should be supplied with a pregnancy test. To ensure parity of treatment between all groups experiencing miscarriage, the committee recommended that units treating women with miscarriage should provide a urine pregnancy test to use after 3 weeks for both expectant and medical management.

Cost effectiveness and resource use

The committee were aware of one study (Devall 2021) that found that mifepristone plus misoprostol led to significantly reduced costs of £182 per woman (95% confidence interval £26 to £338) when compared to placebo plus misoprostol for the medical management of missed miscarriage. This was because reduced surgery and hospital visits more than offset the higher intervention costs of mifepristone plus misoprostol. The analysis also reported that mifepristone plus misoprostol also resulted in a statistically significant increase in successfully managed miscarriages and therefore it was concluded that mifepristone plus misoprostol dominated placebo plus misoprostol.

Therefore, the committee concluded that there was strong cost effectiveness evidence to support their recommendation to offer 200 mg oral mifepristone, and 48 hours later, 800 micrograms misoprostol (vaginal, oral or sublingual), unless the gestational sac has already been passed, for the medical management of missed miscarriage.

As missed miscarriage affects approximately 1–5% of pregnancies (Levono 2013) this would be approximately 6,000 to 30,000 pregnancies in the NHS. The committee did not think that their recommendation would have a significant resource impact to the NHS (>£1 million) even when only the intervention cost is taken into account. Overall, the committee considered that their recommendation would be cost saving to the NHS as a result of reduced surgery and hospital visits.

The committee noted that the recommendations now advised people to contact their healthcare professional if bleeding had not started 48 hours after the misoprostol (previously this recommendation had advised after 24 hours) so this may reduce resource use, but that also settings are now advised to pro-actively contact people if necessary, and so this may increase resource use. The overall impact of these changes are likely to offset each other to some extent.

The changes to the recommendations on expectant management regarding the provision of pregnancy tests to women (instead of advising them to purchase them) will lead to an increase in the number of pregnancy tests supplied to women by the NHS. Pregnancy tests are inexpensive and this recommendation is not expected to have a significant resource impact to the NHS.

Excluded effectiveness studies

There was no literature search done for this review therefore there are no excluded studies.

Excluded economic studies

There was no literature search done for this review therefore there are no excluded studies.