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

Arri Coomarasamy; Adam J Devall; Versha Cheed; Hoda Harb; Lee J Middleton; Ioannis D Gallos; Helen Williams; Abey K Eapen; Tracy Roberts; Chriscasimir C Ogwulu; Ilias Goranitis; Jane P Daniels; Amna Ahmed; Ruth Bender-Atik; Kalsang Bhatia; Cecilia Bottomley; Jane Brewin; Meenakshi Choudhary; Fiona Crosfill; Shilpa Deb; W Colin Duncan; Andrew Ewer; Kim Hinshaw; Tom Holland; Feras Izzat; Jemma Johns; Kathiuska Kriedt; Mary-Ann Lumsden; Padma Manda; Jane E Norman; Natalie Nunes; Caroline E Overton; Siobhan Quenby; Sandhya Rao; Jackie Ross; Anupama Shahid; Martyn Underwood; Nirmala Vaithilingam; Linda Watkins; Catherine Wykes; Andrew Horne; Davor Jurkovic

doi:10.1056/NEJMoa1813730

Pregnancy · Early Pregnancy

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

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

Published May 9, 2019 New England Journal of Medicine, 380(19), 1815-1824

DOI 10.1056/NEJMoa1813730 PMID 31067371

RRM Academy Synopsis

Progesterone Did Not Raise Live Births After Bleeding, Overall

Progesterone did not significantly raise the overall live birth rate in women with bleeding in early pregnancy. A large, placebo-controlled trial across 48 UK hospitals found 75 of 100 women on progesterone had a live birth, versus 72 of 100 on placebo.

Key Findings

4,153 women at 48 UK hospitals were randomly assigned to progesterone (2,079) or placebo (2,074); 97% had primary-outcome data.
Live births after 34 weeks occurred in 75% (1,513 of 2,025) on progesterone versus 72% (1,459 of 2,013) on placebo (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08).
Miscarriage occurred in 20% (410 of 2,025) on progesterone versus 22% (451 of 2,013) on placebo (relative rate, 0.91; 95% CI, 0.81 to 1.01).
Of 10 prespecified subgroups, only the number of previous miscarriages showed a significant interaction (P = 0.007).
Women with three or more previous miscarriages had live births in 72% on progesterone versus 57% on placebo (relative rate, 1.28; 95% CI, 1.08 to 1.51).

Interpretation

This randomized, double-blind, placebo-controlled trial is a strong design for isolating a treatment's own effect. Across the full group studied, it found no clear overall difference in live births between progesterone and placebo. Ten subgroup comparisons were planned in advance. Only one showed a significant interaction: the number of previous miscarriages, with the largest apparent gain in women who had three or more. The authors call this a reason for further study. They also note a related finding, more ongoing pregnancies at 12 weeks on progesterone, was not adjusted for multiple testing, so it carries less weight than the trial's main result.

RRM Context

Within NaProTechnology, progesterone support in early pregnancy is typically guided by a woman's own history, aimed at the women most likely to benefit. This trial's subgroup finding is consistent with that pattern. The clearest signal sat in women with a history of recurrent miscarriage, the group a history-guided approach would target first.

Our editorial summary of this paper, not the article's abstract.

Abstract

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.).

Topics

Pregnancy › Early Pregnancy › Progesterone Support · Therapeutics › Hormonal Agents › Progesterone and Progestins · Reproductive Endocrinology › Ovarian Hormones › Progesterone

Arri Coomarasamy, Adam J Devall, Versha Cheed, Hoda Harb, Lee J Middleton, Ioannis D Gallos, Helen Williams, Abey K Eapen, Tracy Roberts, Chriscasimir C Ogwulu, Ilias Goranitis, Jane P Daniels, Amna Ahmed, Ruth Bender-Atik, Kalsang Bhatia, Cecilia Bottomley, Jane Brewin, Meenakshi Choudhary, Fiona Crosfill, Shilpa Deb, W Colin Duncan, Andrew Ewer, Kim Hinshaw, Tom Holland, Feras Izzat, Jemma Johns, Kathiuska Kriedt, Mary-Ann Lumsden, Padma Manda, Jane E Norman, Natalie Nunes, Caroline E Overton, Siobhan Quenby, Sandhya Rao, Jackie Ross, Anupama Shahid, Martyn Underwood, Nirmala Vaithilingam, Linda Watkins, Catherine Wykes, Andrew Horne, Davor Jurkovic

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

PMID 31067371 31067371 DOI 10.1056/NEJMoa1813730 10.1056/NEJMoa1813730 Coomarasamy et al. 2019, Coomarasamy 2019

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

Progesterone Did Not Raise Live Births After Bleeding, Overall

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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