Evidence
Alert

Missed miscarriage should be treated with mifepristone plus misoprostol rather than misoprostol alone

A combination of two drugs – mifepristone and misoprostol – was more effective than mifepristone alone for treating missed miscarriage. A large, multi-centre trial found that women given the combination were more likely to have completed their miscarriage within a week, and less likely to need follow-up surgery.

During a miscarriage of pregnancy, the baby may not pass out of the womb naturally. This is called a ‘missed miscarriage’ and the parents might only find out that their baby has died at a routine ultrasound scan. Women who suffer a missed miscarriage need treatment to expel all pregnancy tissue, to reduce the chance of developing complications. One option is medication which can speed up the natural process. But if this is not successful, the woman may require surgery, involving general anaesthetic.

Two drugs are available to encourage the body to pass the baby: mifepristone and misoprostol. Since 2012, NICE has recommended using misoprostol alone for the medical management of missed miscarriage.

The MifeMiso trial showed that mifepristone followed by misoprostol improves the success of resolving a missed miscarriage compared to treatment with mifepristone alone.

What’s the issue?

It is estimated that one in five pregnancies ends in miscarriage. Most occur in the first 12 weeks of pregnancy, and many begin with symptoms such as pain or bleeding. But for a missed miscarriage, the woman may have no symptoms. It is often only diagnosed at a routine scan, which may show that the baby has no heartbeat.

Following a missed miscarriage, a woman will need treatment to make sure that all the remaining pregnancy tissue is released from her womb. Three treatment options are available: waiting for the miscarriage to happen naturally (expectant management), taking medicine to speed up the miscarriage (medical management), or having surgery to remove remaining pregnancy tissue.

Before 2012, most doctors prescribed mifepristone plus misoprostol for the medical management of missed miscarriage. But following a small trial of 115 women, the NICE guidelines were changed to recommend misoprostol alone. However a single dose of misoprostol is not always effective and up to two-in-five (15-40%) women require a further dose which prolongs treatment. This initial failure also means that more women will need surgery, which can be particularly distressing for those who chose to have medical management.

This recommendation was retained in the 2019 version of the NICE guidance. However, NICE identified the need for further research to investigate the effectiveness of mifepristone and misoprostol.

The MifeMiso study was designed and performed to address this question.

What’s new?

Between 2017 and 2019, the MifeMiso trial included 711 women at 28 UK hospitals. They all had a missed miscarriage in the first 14 weeks of pregnancy and chose medical management. Half of the women  received mifepristone followed by misoprostol two days later. The rest received a dummy pill (instead of mifepristone) and misoprostol. The women taking part in the study did not know whether they were receiving mifepristone or the dummy pill – and neither did their doctors, nurses or midwives.

The number of women who had completed their miscarriage within seven days was:

  • 289 of 348 women (83%) who received mifepristone plus misoprostol
  • 266 of 348 women (76%) who received misoprostol alone.

The number of women who needed surgery to complete their miscarriage was:

  • 62 of 355 women (17%) who received mifepristone plus misoprostol
  • 87 of 353 women (25%) who received misoprostol alone.

Some women also took part in a discussion with researchers about their experiences of the study. The findings of this work will be reported separately, but an initial analysis found that most of the women would choose medical management again. They would also recommend it to someone they knew who was having a missed miscarriage. They felt it was important that they were supported, felt in control and that the treatment was successful so that they did not also need surgery.

Why is this important?

The results of this large randomised controlled trial show that mifepristone and misoprostol are more effective than misoprostol alone for completing a missed miscarriage. This provides strong evidence that this drug combination should become the standard of care for women who opt for medical management to resolve their pregnancy. If these findings are widely implemented in clinical practice, more women will undergo effective medical management and avoid the need for surgery.

The researchers have sent this evidence to NICE to be considered when the guidelines for managing a miscarriage are next updated.

What’s next?

The researchers carried out a survey in May 2020 through the Association of Early Pregnancy Units (AEPU) to find out what treatments women with missed miscarriage currently receive. They will repeat this to find out whether clinicians are changing their practice in response to initial publicity about the MifeMiso study. They are also analysing the MifeMiso data to determine whether the combination regimen is cost-effective.

Beyond this trial, the team is combining the results from all available studies on managing miscarriage. They will compare all treatment options (expectant, surgical, and medical management) to find out which is the most effective.

You may be interested to read

The full paper: Chu JJ, and others. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396:770–778

NICE guideline. Ectopic pregnancy and miscarriage: diagnosis and initial management (NG126), 2019

Tommy’s PregnancyHub: Missed miscarriage - information and support.

The Miscarriage Association: information about missed miscarriage.

Funding

This research was commissioned by the National Institute for Health Research (NIHR) and was funded by the NIHR Health Technology Assessment Programme.

Commentaries

Study author

We were delighted to find a benefit for women. We needed an answer to this specific question and I think we’ve got the evidence now to make the change. We are very hopeful that these results will be considered quickly, put into NICE guidelines and into practice.

Adam Devall, Trials Management Team Leader, Birmingham Clinical Trials Unit (BCTU)

Patient

Anything that can improve the likelihood of a swift conclusion to the miscarriage is desirable. During my missed miscarriage I was given three rounds of misoprostol over several weeks, which caused painful contractions and bleeding resulting in anaemia, before finally undergoing surgical management which still did not entirely remove the pregnancy and left me with scarring in my womb. It is possible that this waste of hospital resources, and the emotional and physical trauma that I experienced, could have been avoided with a single dose of mifepristone. I hope other women will avoid similar experiences in the future once the findings of the research are implemented.

Jenny Hall, Cheltenham

Conflicts of Interest

Some of the authors declare fees and grants from various pharmaceutical companies.