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).
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).
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.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre