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Effectiveness of mifepristone and misoprostol compared to misoprostol alone in the medical management of missed miscarriage
Review question
Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
Introduction
During the development of the NICE guideline on ectopic pregnancy and miscarriage in 2019 the committee considered evidence on medication for the effective management of missed miscarriage, defined as a non-viable pregnancy identified on ultrasound scan during the first 14 weeks of gestation but all pregnancy tissue is retained in the uterus. While there was evidence for the effectiveness of misoprostol there was only very limited evidence for the combination of mifepristone and misoprostol from a pilot study. The committee therefore agreed not to recommend the combination but instead made a research recommendation. In 2020 a UK multi-centre randomised controlled trial addressed this research question. Called MifeMiso (Chu 2020) this study compared the effectiveness of mifepristone and misoprostol with misoprostol alone for the management of missed miscarriage.
The aim of this review is to examine the evidence from the MifeMiso study and identify the effectiveness of the combination of mifepristone and misoprostol for the management of missed miscarriage.
Summary of the protocol
See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
For further details see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. The decision making process for a targeted review is described in appendix N of the NICE manual. Methods specific to this review question are described below.
Minimally important differences (MID) were used to assess clinically important differences. Cut-offs of confidence intervals of 0.8 and 1.25 were used for dichotomous outcomes and for continuous outcomes 0.5x the SD of the control group was used. Outcomes were considered to have an important benefit or harm, no evidence of an important difference, or no important difference using the following approach:
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Point estimate (PE) > +MID, 95% CI do not cross line of no effect = important benefit
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Point estimate (PE) > +MID, 95% CI cross the line of no effect = no evidence of an important difference.
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Point estimate (PE) between two MIDs = no important difference.
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Point estimate (PE) < -MID, 95% CI cross the line of no effect = no evidence of an important. Difference
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Point estimate (PE) < -MID, 95% CI do not cross line of no effect = important harm Declarations of interest were recorded according to NICE’s conflicts of interest policy.
Effectiveness evidence
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.
Summary of included studies
Summaries of the studies that were included in this review are presented in Table 2.
Table 2
Summary of included studies.
See the full evidence tables in appendix D. No meta-analysis was conducted (and so there are no forest plots in appendix E).
Summary of the evidence
Evidence from one RCT comparing mifepristone plus misoprostol versus placebo plus misoprostol suggested that there was important benefit for the combination therapy for the following outcomes: failure to spontaneously pass the gestational sac within 7 days after random assignment; surgical intervention to complete the miscarriage up to discharge from hospital care and surgical intervention to complete the miscarriage from after day 7 and up to discharge from hospital care. For all other outcomes (surgical intervention to complete the miscarriage up to and including 7 days after random assignment; 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 reported by the woman; requirement for blood transfusion; side-effects; any serious complications; maternal death) there was either no evidence of an important difference or no important difference.
The quality of the evidence across all outcomes ranged from low to high with the critical outcomes being rated as moderate quality and most concerns were around imprecision.
See appendix F for full GRADE tables.
Economic evidence
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.
Summary of included economic evidence
See Table 3 for the economic evidence profile of the included study.
Table 3
Economic evidence profile of a targeted review of economic evaluations of mifepristone and misoprostol compared to misoprostol alone in the medical management of missed miscarriage.
Economic model
No economic modelling was undertaken for this review because surveillance had identified a recent and applicable UK economic evaluation which could be used to assess cost-effectiveness.
Unit costs
Resource | Unit costs | Source |
---|---|---|
Mifepristone 200 mg tablet | £17.55 | BNF https://bnf |
Misoprostol 800 microgram (2 × 400 microgram) | £16.00 | BNF https://bnf |
Mifepristone 200 mg oral tablet and 4 × misoprostol 200 micrograms vaginal tablets (Medabon combipack) | £17 | BNF https://bnf |
The committee's discussion and interpretation of the evidence
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.
Recommendations supported by this evidence review
This evidence review supports recommendations 1.5.11 to 1.5.19.
References – included studies
Chu 2020
Chu JJ; Devall AJ; Beeson LE; Hardy P; Cheed V; Sun Y; Roberts TE; Ogwulu CO; Williams E; Jones LL; La Fontaine Papadopoulos JH; Bender-Atik R; Brewin J; Hinshaw K; Choudhary M; Ahmed A; Naftalin J; Nunes N; Oliver A; Izzat F; Bhatia K; Hassan I; Jeve Y; Hamilton J; Deb S; Bottomley C; Ross J; Watkins L; Underwood M; Cheong Y; Kumar CS; Gupta P; Small R; Pringle S; Hodge F; Shahid A; Gallos ID; Horne AW; Quenby S; Coomarasamy A; Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.; Lancet (London, England); 2020; vol. 396 (no. 10253) [PMC free article: PMC7493715] [PubMed: 32853559]- Devall A; Chu J; Beeson L; Hardy P; Cheed V; Sun Y, et al Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT. Health Technol Assess 2021;25(68). [PubMed: 34821547]
- Leveno, K.J.; Corton, M.M.; Bloom, S.L. Manual of Pregnancy Complications, 23th ed.; McGraw-Hill Medical: New York, NY, USA, 2013.
Effectiveness
Economic
Other
Appendices
Appendix A. Review protocols
Appendix B. Literature search strategies
Literature search strategies for review question: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
There was no literature search conducted for this review.
Appendix C. Effectiveness evidence study selection
Study selection for: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
There was no study selection for this review: 1 study identified by surveillance was included.
Appendix D. Evidence tables
Appendix E. Forest plots
Forest plots for review question: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
No meta-analysis was conducted for this review question and so there are no forest plots.
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Study selection for: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
There was no study selection for this review: 1 study identified by surveillance was included.
Appendix I. Economic evidence tables
Appendix J. Economic model
Economic model for review question: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
No economic analysis was conducted for this review question.
Appendix K. Excluded studies
Excluded studies for review question: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
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.
Appendix L. Research recommendations – full details
Research recommendations for review question: Is the combination of mifepristone and misoprostol more effective than misoprostol alone in the medical management of missed miscarriage?
No research recommendations were made for this review question.
Final version
Evidence review underpinning recommendations 1.5.11 to 1.5.19 in the NICE guideline
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT.[Health Technol Assess. 2021]Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT.Devall A, Chu J, Beeson L, Hardy P, Cheed V, Sun Y, Roberts T, Ogwulu CO, Williams E, Jones L, et al. Health Technol Assess. 2021 Nov; 25(68):1-114.
- Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.[BJOG. 2021]Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.Okeke Ogwulu CB, Williams EV, Chu JJ, Devall AJ, Beeson LE, Hardy P, Cheed V, Yongzhong S, Jones LL, La Fontaine Papadopoulos JH, et al. BJOG. 2021 Aug; 128(9):1534-1545. Epub 2021 Jun 7.
- Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.[Lancet. 2020]Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.Chu JJ, Devall AJ, Beeson LE, Hardy P, Cheed V, Sun Y, Roberts TE, Ogwulu CO, Williams E, Jones LL, et al. Lancet. 2020 Sep 12; 396(10253):770-778. Epub 2020 Aug 24.
- Review Medication to Manage Abortion and Miscarriage.[J Gen Intern Med. 2020]Review Medication to Manage Abortion and Miscarriage.Beaman J, Prifti C, Schwarz EB, Sobota M. J Gen Intern Med. 2020 Aug; 35(8):2398-2405. Epub 2020 May 14.
- Review Cervical priming before surgical abortion between 14 and 24 weeks: a systematic review and meta-analyses for the National Institute for Health and Care Excellence-new clinical guidelines for England.[Am J Obstet Gynecol MFM. 2021]Review Cervical priming before surgical abortion between 14 and 24 weeks: a systematic review and meta-analyses for the National Institute for Health and Care Excellence-new clinical guidelines for England.O'Shea LE, Lohr PA, Lord J, Hasler E, Cameron S. Am J Obstet Gynecol MFM. 2021 Jan; 3(1):100283. Epub 2020 Nov 28.
- Medical management of miscarriageMedical management of miscarriage
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