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NIHR Signal Routine use of progesterone does not prevent miscarriage

Published on 16 July 2019

doi: 10.3310/signal-000792

Progesterone did not affect the chance of live birth among women presenting with vaginal bleeding in the first 12 weeks of pregnancy. Live birth rates were 72% with placebo and 75% with progesterone, which is not a clinically or statistically important difference.

Progesterone has been prescribed for threatened miscarriage in some centres since the 1950s, but there has been poor evidence for its use. NICE recently highlighted this as a priority area for research asking for large, robust trials to settle continuing uncertainties on its use.

This NIHR-funded trial included over 4,000 women from across the UK. They were assigned to twice-daily vaginal progesterone (400mg twice daily) or placebo until 16 weeks of pregnancy.

A subgroup analysis did find that progesterone improved the chance of live birth amongst 285 women with three or more previous miscarriages (72% vs 57% with placebo).

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Why was this study needed?

It is estimated that around 20% of pregnant women experience ‘threatened miscarriage’, vaginal bleeding before the time when a fetus would be able to survive outside of the uterus (24 weeks usually).

Progesterone, produced by the ovaries, prepares the uterus lining (endometrium) for implantation of the embryo and supports early placental development. After around 12 weeks, the placenta becomes the main source of progesterone, and levels continue to rise throughout pregnancy.

Two recently updated Cochrane reviews pooling the results of small trials found that progesterone supplementation might help prevent miscarriages both in women with a history of recurrent miscarriage, and in women with threatened abortion. However, researchers noted that results differed between some trials.

This large trial aimed to provide more robust evidence on the effects of progesterone.

What did this study do?

This double-blind, randomised placebo-controlled trial included 4,153 women recruited from 48 hospitals across the UK. Participants were aged 16 to 39, less than 12 weeks pregnant, with vaginal bleeding, and a gestational sac visible on ultrasound. They were assigned to receive twice-daily vaginal suppositories containing either 400mg of progesterone or matching placebo, until 16 completed weeks of pregnancy.

The main outcome was the birth of a live baby after at least 34 weeks, analysed by intention-to-treat. The trial had sufficient sample size to detect a 5% difference in this outcome, defined by the researchers as the minimal clinically important difference.

Randomisation was found to be reasonably balanced according to participant characteristics. Ten subgroups were also analysed, including two subgroups of women with previous miscarriages (1-2 miscarriages or 3 and more). Results from such a large number of subgroups should be interpreted with caution.

What did it find?

  • There was no statistically significant difference in the live birth rate between groups, which was 75% in the progesterone group and 72% in the placebo group (relative rate [RR] 1.03, 95% confidence interval [CI] 1.00 to 1.07).
  • There was no difference in the incidence of miscarriage; 20% of the progesterone group and 22% of the placebo group (RR 0.91, 95% CI 0.81 to 1.01). Stillbirth (after 24 weeks) affected less than 1% of both groups.
  • An effect of progesterone was identified for only one of the 10 pre-specified subgroups: among women who’d had three or more previous miscarriages, the live birth rate was 72% (98/137) for the progesterone group and 57% (85/148) for the placebo group (RR 1.28, 95% CI 1.08 to 1.51). The effect for women with one or two previous miscarriages did not reach statistical significance but followed a similar trend.
  • There was no difference between groups in the rate or maternal or neonatal adverse effects, which affected 5% of both groups. Congenital abnormalities occurred in 3% of both groups.

What does current guidance say on this issue?

The NICE guideline on ectopic pregnancy and miscarriage (2019) does not give any recommendation for preventing miscarriage. NICE recommends that women with threatened miscarriage and a fetal heartbeat are assessed if bleeding persists beyond 14 days, and to continue with normal antenatal care if bleeding stops.

NICE noted that meta-analysis of several small studies indicated that progestogens might be better than placebo for threatened miscarriage. However, they stated that several biases, the lack of strong evidence and the theoretical risks of prescribing in early pregnancy made this uncertain and a research priority.

Earlier guidance from the Royal College of Obstetricians and Gynaecologists similarly noted the insufficient evidence for progesterone.

What are the implications?

This well-designed and conducted trial provides the best evidence so far on the effect of progesterone for threatened miscarriage.

A Cochrane systematic review found a more pronounced effect of progesterone in women following three or more miscarriages, but noted need for caution due to differing results from individual studies.

There is no evidence supporting the routine use of progesterone for women who bleed in early pregnancy for the first time.

There may be a place for progesterone for some women who have had previous miscarriages but more, reliable evidence is needed.

Citation and Funding

Coomarasamy A, Devall AJ, Cheed V et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19).

This project was funded by the NIHR Health Technology Assessment Programme (project number 12/167/26).

Bibliography

Haas DM, Hathaway TJ and Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev. 2018;(10):CD003511.

NICE. Ectopic pregnancy and miscarriage: diagnosis and initial management. NG126. London: National Institute for Health and Care Excellence; 2019.

RCOG. Recurrent miscarriage, investigation and treatment of couples. Green-top guideline 17. London: Royal College of Obstetricians and Gynaecologists; 2011; updated 2017.

Wahabi HA, Fayed AA, Esmaeil, SA and Bahkali KH. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018;(8):CD005943.

Why was this study needed?

It is estimated that around 20% of pregnant women experience ‘threatened miscarriage’, vaginal bleeding before the time when a fetus would be able to survive outside of the uterus (24 weeks usually).

Progesterone, produced by the ovaries, prepares the uterus lining (endometrium) for implantation of the embryo and supports early placental development. After around 12 weeks, the placenta becomes the main source of progesterone, and levels continue to rise throughout pregnancy.

Two recently updated Cochrane reviews pooling the results of small trials found that progesterone supplementation might help prevent miscarriages both in women with a history of recurrent miscarriage, and in women with threatened abortion. However, researchers noted that results differed between some trials.

This large trial aimed to provide more robust evidence on the effects of progesterone.

What did this study do?

This double-blind, randomised placebo-controlled trial included 4,153 women recruited from 48 hospitals across the UK. Participants were aged 16 to 39, less than 12 weeks pregnant, with vaginal bleeding, and a gestational sac visible on ultrasound. They were assigned to receive twice-daily vaginal suppositories containing either 400mg of progesterone or matching placebo, until 16 completed weeks of pregnancy.

The main outcome was the birth of a live baby after at least 34 weeks, analysed by intention-to-treat. The trial had sufficient sample size to detect a 5% difference in this outcome, defined by the researchers as the minimal clinically important difference.

Randomisation was found to be reasonably balanced according to participant characteristics. Ten subgroups were also analysed, including two subgroups of women with previous miscarriages (1-2 miscarriages or 3 and more). Results from such a large number of subgroups should be interpreted with caution.

What did it find?

  • There was no statistically significant difference in the live birth rate between groups, which was 75% in the progesterone group and 72% in the placebo group (relative rate [RR] 1.03, 95% confidence interval [CI] 1.00 to 1.07).
  • There was no difference in the incidence of miscarriage; 20% of the progesterone group and 22% of the placebo group (RR 0.91, 95% CI 0.81 to 1.01). Stillbirth (after 24 weeks) affected less than 1% of both groups.
  • An effect of progesterone was identified for only one of the 10 pre-specified subgroups: among women who’d had three or more previous miscarriages, the live birth rate was 72% (98/137) for the progesterone group and 57% (85/148) for the placebo group (RR 1.28, 95% CI 1.08 to 1.51). The effect for women with one or two previous miscarriages did not reach statistical significance but followed a similar trend.
  • There was no difference between groups in the rate or maternal or neonatal adverse effects, which affected 5% of both groups. Congenital abnormalities occurred in 3% of both groups.

What does current guidance say on this issue?

The NICE guideline on ectopic pregnancy and miscarriage (2019) does not give any recommendation for preventing miscarriage. NICE recommends that women with threatened miscarriage and a fetal heartbeat are assessed if bleeding persists beyond 14 days, and to continue with normal antenatal care if bleeding stops.

NICE noted that meta-analysis of several small studies indicated that progestogens might be better than placebo for threatened miscarriage. However, they stated that several biases, the lack of strong evidence and the theoretical risks of prescribing in early pregnancy made this uncertain and a research priority.

Earlier guidance from the Royal College of Obstetricians and Gynaecologists similarly noted the insufficient evidence for progesterone.

What are the implications?

This well-designed and conducted trial provides the best evidence so far on the effect of progesterone for threatened miscarriage.

A Cochrane systematic review found a more pronounced effect of progesterone in women following three or more miscarriages, but noted need for caution due to differing results from individual studies.

There is no evidence supporting the routine use of progesterone for women who bleed in early pregnancy for the first time.

There may be a place for progesterone for some women who have had previous miscarriages but more, reliable evidence is needed.

Citation and Funding

Coomarasamy A, Devall AJ, Cheed V et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19).

This project was funded by the NIHR Health Technology Assessment Programme (project number 12/167/26).

Bibliography

Haas DM, Hathaway TJ and Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev. 2018;(10):CD003511.

NICE. Ectopic pregnancy and miscarriage: diagnosis and initial management. NG126. London: National Institute for Health and Care Excellence; 2019.

RCOG. Recurrent miscarriage, investigation and treatment of couples. Green-top guideline 17. London: Royal College of Obstetricians and Gynaecologists; 2011; updated 2017.

Wahabi HA, Fayed AA, Esmaeil, SA and Bahkali KH. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018;(8):CD005943.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy

Published on 9 May 2019

Coomarasamy, A.,Devall, A. J.,Cheed, V.,Harb, H.,Middleton, L. J.,Gallos, I. D.,Williams, H.,Eapen, A. K.,Roberts, T.,Ogwulu, C. C.,Goranitis, I.,Daniels, J. P.,Ahmed, A.,Bender-Atik, R.,Bhatia, K.,Bottomley, C.,Brewin, J.,Choudhary, M.,Crosfill, F.,Deb, S.,Duncan, W. C.,Ewer, A.,Hinshaw, K.,Holland, T.,Izzat, F.,Johns, J.,Kriedt, K.,Lumsden, M. A.,Manda, P.,Norman, J. E.,Nunes, N.,Overton, C. E.,Quenby, S.,Rao, S.,Ross, J.,Shahid, A.,Underwood, M.,Vaithilingam, N.,Watkins, L.,Wykes, C.,Horne, A.,Jurkovic, D.

N Engl J Med Volume 380 Issue 19 , 2019

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Expert commentary

This trial showed no statistically significant, or clinically worthwhile, overall benefit from progesterone treatment for threatened miscarriage, but a possible benefit among women with more than three previous miscarriages. Since this was one of ten subgroups tested and had not been identified a priori as of special interest, the authors noted in the main report that it required validation.

However, the lead author has subsequently claimed that, although not properly documented as such, the subgroup was one of special interest on the grounds that fetuses of women with multiple previous miscarriages are less likely to have an abnormal number of chromosomes, and therefore have more potential to benefit. He also argues that a smaller trial of progesterone prophylaxis for women with recurrent miscarriage showed a similar trend, albeit also not statistically significant, in women with more previous miscarriages.

Those who accept his hypothesis may decide to prescribe progesterone for this subgroup.

Others who remember the harms from previous miscarriage treatments, such as diethylstilboestrol, which was later found to cause vaginal cancer in the offspring, or who fear non-specific risks from up to ten weeks of twice-daily vaginal tablets in women who are already bleeding, may prefer to wait for a trial in this subgroup.

Jim Thornton, Professor of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham

The commentator declares no conflicting interests