Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT

Arri Coomarasamy; Hoda M Harb; Adam J Devall; Versha Cheed; Tracy E Roberts; Ilias Goranitis; Chidubem B Ogwulu; Helen M Williams; Ioannis D Gallos; Abey Eapen; 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; Thomas Holland; Feras Izzat; Jemma Johns; Mary-Ann Lumsden; Padma Manda; Jane E Norman; Natalie Nunes; Caroline E Overton; Kathiuska Kriedt; Siobhan Quenby; Sandhya Rao; Jackie Ross; Anupama Shahid; Martyn Underwood; Nirmala Vaithilingham; Linda Watkins; Catherine Wykes; Andrew W Horne; Davor Jurkovic; Lee J Middleton

doi:10.3310/hta24330

Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT

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

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Abstract

BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.

OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.

DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.

SETTING: A total of 48 hospitals in the UK.

PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding.

INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.

MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.

RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.

CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326.

FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

Original language	English
Pages (from-to)	1-70
Number of pages	70
Journal	Health Technology Assessment
Volume	24
Issue number	33
DOIs	https://doi.org/10.3310/hta24330
Publication status	Published - 1 Jun 2020

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Coomarasamy, A., Harb, H. M., Devall, A. J., Cheed, V., Roberts, T. E., Goranitis, I., Ogwulu, C. B., Williams, H. M., Gallos, I. D., Eapen, A., Daniels, J. P., Ahmed, A., Bender-Atik, R., Bhatia, K., Bottomley, C., Brewin, J., Choudhary, M., Crosfill, F., Deb, S., ... Middleton, L. J. (2020). Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Health Technology Assessment, 24(33), 1-70. https://doi.org/10.3310/hta24330

@article{478ec660e5ce455da678d9f9449274b2,

title = "Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT",

abstract = "BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.SETTING: A total of 48 hospitals in the UK.PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding.INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326.FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.",

author = "Arri Coomarasamy and Harb, {Hoda M} and Devall, {Adam J} and Versha Cheed and Roberts, {Tracy E} and Ilias Goranitis and Ogwulu, {Chidubem B} and Williams, {Helen M} and Gallos, {Ioannis D} and Abey Eapen 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 Thomas Holland and Feras Izzat and Jemma Johns and Mary-Ann Lumsden and Padma Manda and Norman, {Jane E} and Natalie Nunes and Overton, {Caroline E} and Kathiuska Kriedt and Siobhan Quenby and Sandhya Rao and Jackie Ross and Anupama Shahid and Martyn Underwood and Nirmala Vaithilingham and Linda Watkins and Catherine Wykes and Horne, {Andrew W} and Davor Jurkovic and Middleton, {Lee J}",

year = "2020",

month = jun,

day = "1",

doi = "10.3310/hta24330",

language = "English",

volume = "24",

pages = "1--70",

journal = "Health Technology Assessment",

issn = "1366-5278",

publisher = "NIHR Journals Library",

number = "33",

}

Coomarasamy, A, Harb, HM, Devall, AJ, Cheed, V, Roberts, TE, Goranitis, I, Ogwulu, CB, Williams, HM, Gallos, ID, Eapen, A, 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, Lumsden, M-A, Manda, P, Norman, JE, Nunes, N, Overton, CE, Kriedt, K, Quenby, S, Rao, S, Ross, J, Shahid, A, Underwood, M, Vaithilingham, N, Watkins, L, Wykes, C, Horne, AW, Jurkovic, D & Middleton, LJ 2020, 'Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT', Health Technology Assessment, vol. 24, no. 33, pp. 1-70. https://doi.org/10.3310/hta24330

TY - JOUR

T1 - Progesterone to prevent miscarriage in women with early pregnancy bleeding

T2 - the PRISM RCT

AU - Coomarasamy, Arri

AU - Harb, Hoda M

AU - Devall, Adam J

AU - Cheed, Versha

AU - Roberts, Tracy E

AU - Goranitis, Ilias

AU - Ogwulu, Chidubem B

AU - Williams, Helen M

AU - Gallos, Ioannis D

AU - Eapen, Abey

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, Thomas

AU - Izzat, Feras

AU - Johns, Jemma

AU - Lumsden, Mary-Ann

AU - Manda, Padma

AU - Norman, Jane E

AU - Nunes, Natalie

AU - Overton, Caroline E

AU - Kriedt, Kathiuska

AU - Quenby, Siobhan

AU - Rao, Sandhya

AU - Ross, Jackie

AU - Shahid, Anupama

AU - Underwood, Martyn

AU - Vaithilingham, Nirmala

AU - Watkins, Linda

AU - Wykes, Catherine

AU - Horne, Andrew W

AU - Jurkovic, Davor

AU - Middleton, Lee J

PY - 2020/6/1

Y1 - 2020/6/1

N2 - BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.SETTING: A total of 48 hospitals in the UK.PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding.INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326.FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

AB - BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.SETTING: A total of 48 hospitals in the UK.PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding.INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326.FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

U2 - 10.3310/hta24330

DO - 10.3310/hta24330

M3 - Article (Academic Journal)

C2 - 32609084

SN - 1366-5278

VL - 24

SP - 1

EP - 70

JO - Health Technology Assessment

JF - Health Technology Assessment

IS - 33

ER -

Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT

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