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

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 DebW 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

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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. opens in new tab.)

Original language	English
Pages (from-to)	1815-1824
Number of pages	10
Journal	The New England Journal of Medicine
Volume	380
Issue number	19
DOIs	https://doi.org/10.1056/NEJMoa1813730
Publication status	Published - 9 May 2019

ASJC Scopus subject areas

Medicine(all)

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Devall_et_al_A_randomized_trial_of_progesterone_New_England_Journal_of_Medicine_2019
This document is the final version of Record of a work that appeared in the New England Journal of Medicine, copyright Copyright © 2019 Massachusetts Medical Society. All rights reserved. This work can be found at: https://doi.org/10.1056/NEJMoa1813730
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Cite this

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., ... Jurkovic, D. (2019). A randomized trial of progesterone in women with bleeding in early pregnancy. The New England Journal of Medicine, 380(19), 1815-1824. https://doi.org/10.1056/NEJMoa1813730

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title = "A randomized trial of progesterone in women with bleeding in early pregnancy",

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. CONCLUSIONSAmong 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. opens in new tab.)",

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

year = "2019",

month = may,

day = "9",

doi = "10.1056/NEJMoa1813730",

language = "English",

volume = "380",

pages = "1815--1824",

journal = "The New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "19",

}

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, M-A, 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 2019, 'A randomized trial of progesterone in women with bleeding in early pregnancy', The New England Journal of Medicine, vol. 380, no. 19, pp. 1815-1824. https://doi.org/10.1056/NEJMoa1813730

TY - JOUR

T1 - A randomized trial of progesterone in women with bleeding in early pregnancy

AU - Coomarasamy, Arri

AU - Devall, Adam J

AU - Cheed, Versha

AU - Harb, Hoda

AU - Middleton, Lee J

AU - Gallos, Ioannis D

AU - Williams, Helen

AU - Eapen, Abey K

AU - Roberts, Tracy

AU - Ogwulu, Chriscasimir C

AU - Goranitis, Ilias

AU - Daniels, Jane P

AU - Ahmed, Amna

AU - Bender-Atik, Ruth

AU - Bhatia, Kalsang

AU - Bottomley, Cecilia

AU - Brewin, Jane

AU - Choudhary, Meenakshi

AU - Crosfill, Fiona

AU - Deb, Shilpa

AU - Duncan, W Colin

AU - Ewer, Andrew

AU - Hinshaw, Kim

AU - Holland, Tom

AU - Izzat, Feras

AU - Johns, Jemma

AU - Kriedt, Kathiuska

AU - Lumsden, Mary-Ann

AU - Manda, Padma

AU - Norman, Jane E

AU - Nunes, Natalie

AU - Overton, Caroline E

AU - Quenby, Siobhan

AU - Rao, Sandhya

AU - Ross, Jackie

AU - Shahid, Anupama

AU - Underwood, Martyn

AU - Vaithilingam, Nirmala

AU - Watkins, Linda

AU - Wykes, Catherine

AU - Horne, Andrew

AU - Jurkovic, Davor

PY - 2019/5/9

Y1 - 2019/5/9

N2 - 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. CONCLUSIONSAmong 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. opens in new tab.)

AB - 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. CONCLUSIONSAmong 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. opens in new tab.)

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U2 - 10.1056/NEJMoa1813730

DO - 10.1056/NEJMoa1813730

M3 - Article

C2 - 31067371

SN - 0028-4793

VL - 380

SP - 1815

EP - 1824

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

IS - 19

ER -

A randomized trial of progesterone in women with bleeding in early pregnancy

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