NIHR Signal Vaginal progesterone suppositories did not boost the number of live births in women with recurrent miscarriage

Published on 7 January 2016

A large trial found that vaginal progesterone suppositories taken in the first trimester of pregnancy were no better than a placebo at increasing live birth rates in women with previous unexplained recurring miscarriages.

At 36 hospitals in the UK, and nine in the Netherlands, women under 40 used suppositories twice a day soon after a positive pregnancy test up until the twelfth week of pregnancy. Live birth rates were 65.8% for women taking progesterone, no different than placebo (63.3%).

A previous systematic review identified four poor quality trials showing progesterone may prevent miscarriage, but this trial was larger and better designed, so we can be more confident in the results.

Vaginal progesterone suppositories did not boost the number of live births in women with recurrent miscarriage

Share your views on the research.

Why was this study needed?

Recurrent miscarriage, defined as the loss of three or more pregnancies, affects around one per cent of couples attempting to have a child. The hormone progesterone maintains pregnancy, so previous research has investigated whether providing additional progesterone could prevent miscarriage.

A 2013 Cochrane review found four trials suggesting live birth rate increased after women received progesterone treatment, but the trials were not reliable.

The PROMISE trial was designed to be large and reliable enough to answer the question with more confidence.

What did this study do?

This NIHR funded pragmatic randomised clinical trial was called PROMISE. 836 healthy women with unexplained recurrent miscarriage from 36 UK and nine Dutch hospitals were randomised to treatment and control groups.

The treatment group received progesterone vaginal suppositories, from at least the sixth week of pregnancy until the twelfth week. The control group received inactive suppositories (placebo). Neither the participants nor their care staff were aware of the treatment received. The main outcome was the rate of live births from 24 weeks of pregnancy.

The large size of the trial, carried out in 45 hospitals, and the rigour of its design make us confident in the findings.

What did it find?

  • The rate of live births after 24 weeks of pregnancy was no different for women receiving progesterone (65.8%) compared with placebo (63.3%). The absolute difference in live birth rate was 2.5%, 95% confidence interval −4.0 to 9.0. Meaning that there was no statistically significant difference.
  • There were also no significant differences in the rates of adverse events between the progesterone and placebo groups.
  • The age of mothers, their body mass index, smoking status and rate of previous live births were the same between groups at the start.
  • There were no significant differences between groups in the numbers of birth abnormalities or the number of weeks of pregnancy before birth.

What does current guidance say on this issue?

Although several NICE guidelines exist on pregnancy, none covers offering progesterone in early pregnancy to increase the live birth rate for women with recurrent miscarriage.

A guideline from the Royal College of Obstetricians and Gynaecologists (2011) said that there was insufficient evidence on which to base recommendations for giving progesterone supplements. It highlighted the PROMISE trial, unpublished at the time, as able to progress the evidence in this area. The guideline was reviewed in December 2014, with a decision to defer update to an unspecified future date.

What are the implications?

The PROMISE trial suggests twice daily progesterone suppositories in the first trimester of pregnancy will not significantly improve live birth rates in women with a history of recurrent miscarriage. The trial found no significant differences in the number of adverse events between the progesterone and placebo groups which may reassure women and doctors who have used progesterone for this purpose.

Citation

Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141-8.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 08/38/01).

Bibliography

Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013;(10):CD003511.

RCOG. Recurrent miscarriage, investigation and treatment of couples (Green-top Guideline No. 17). London: Royal College of Obstetricians and Gynaecologists; 2011.

Why was this study needed?

Recurrent miscarriage, defined as the loss of three or more pregnancies, affects around one per cent of couples attempting to have a child. The hormone progesterone maintains pregnancy, so previous research has investigated whether providing additional progesterone could prevent miscarriage.

A 2013 Cochrane review found four trials suggesting live birth rate increased after women received progesterone treatment, but the trials were not reliable.

The PROMISE trial was designed to be large and reliable enough to answer the question with more confidence.

What did this study do?

This NIHR funded pragmatic randomised clinical trial was called PROMISE. 836 healthy women with unexplained recurrent miscarriage from 36 UK and nine Dutch hospitals were randomised to treatment and control groups.

The treatment group received progesterone vaginal suppositories, from at least the sixth week of pregnancy until the twelfth week. The control group received inactive suppositories (placebo). Neither the participants nor their care staff were aware of the treatment received. The main outcome was the rate of live births from 24 weeks of pregnancy.

The large size of the trial, carried out in 45 hospitals, and the rigour of its design make us confident in the findings.

What did it find?

  • The rate of live births after 24 weeks of pregnancy was no different for women receiving progesterone (65.8%) compared with placebo (63.3%). The absolute difference in live birth rate was 2.5%, 95% confidence interval −4.0 to 9.0. Meaning that there was no statistically significant difference.
  • There were also no significant differences in the rates of adverse events between the progesterone and placebo groups.
  • The age of mothers, their body mass index, smoking status and rate of previous live births were the same between groups at the start.
  • There were no significant differences between groups in the numbers of birth abnormalities or the number of weeks of pregnancy before birth.

What does current guidance say on this issue?

Although several NICE guidelines exist on pregnancy, none covers offering progesterone in early pregnancy to increase the live birth rate for women with recurrent miscarriage.

A guideline from the Royal College of Obstetricians and Gynaecologists (2011) said that there was insufficient evidence on which to base recommendations for giving progesterone supplements. It highlighted the PROMISE trial, unpublished at the time, as able to progress the evidence in this area. The guideline was reviewed in December 2014, with a decision to defer update to an unspecified future date.

What are the implications?

The PROMISE trial suggests twice daily progesterone suppositories in the first trimester of pregnancy will not significantly improve live birth rates in women with a history of recurrent miscarriage. The trial found no significant differences in the number of adverse events between the progesterone and placebo groups which may reassure women and doctors who have used progesterone for this purpose.

Citation

Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141-8.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 08/38/01).

Bibliography

Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013;(10):CD003511.

RCOG. Recurrent miscarriage, investigation and treatment of couples (Green-top Guideline No. 17). London: Royal College of Obstetricians and Gynaecologists; 2011.

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

Published on 26 November 2015

Coomarasamy A, Williams H, Truchanowicz E, Seed P, Small R, Quenby S, Gupta P, Dawood F, Koot YE, Goddijn M, Bender Atik R, Bloemenkamp KWM, Brady R, Briley A, Cavallaro R, Cheong YC, Chu J, Eapen A, Ewies A, Hoek A, Kaaijk EM, Koks CA, Li TC, MacLean M, Mol BW, Moore J, Ross J, Sharpe L, Stewart J, Vaithilingam N, Farquharson R, Kilby M, Khalaf Y, Regan L, Rai R.

New England Journal of Medicine , 2015

Background Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. Methods We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. Results A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. Conclusions Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research)

Author commentary

Over time, it is likely that doctors will stop prescribing progesterone to women who are pregnant after previous miscarriages, unless there are clear reasons to do so. The research makes it clear that progesterone isn’t harmful.

Women who took progesterone in the past after having repeated miscarriages and then had a healthy pregnancy may feel sure that it was the progesterone that made the difference. We can’t say for certain that it had no effect – although the evidence suggests it is unlikely. Above all, we hope women can find comfort in the fact that whether they had progesterone or the placebo, nearly two thirds of the women in the trial had their much-wanted baby. That means there is still a good chance of a healthy pregnancy after unexplained recurrent miscarriage without any treatment at all.

Ruth Bender Atik, National Director, The Miscarriage Association