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PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

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PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. / Coomarasamy, Arri; Williams, Helen; Truchanowicz, Ewa; Seed, Paul T; Small, Rachel; Quenby, Siobhan; Gupta, Pratima; Dawood, Feroza; Koot, Yvonne E; Atik, Ruth Bender; Bloemenkamp, Kitty Wm; Brady, Rebecca; Briley, Annette; Cavallaro, Rebecca; Cheong, Ying C; Chu, Justin; Eapen, Abey; Essex, Holly; Ewies, Ayman; Hoek, Annemieke; Kaaijk, Eugenie M; Koks, Carolien A; Li, Tin-Chiu; MacLean, Marjory; Mol, Ben W; Moore, Judith; Parrott, Steve; Ross, Jackie A; Sharpe, Lisa; Stewart, Jane; Trépel, Dominic; Vaithilingam, Nirmala; Farquharson, Roy G; Kilby, Mark David; Khalaf, Yacoub; Goddijn, Mariëtte; Regan, Lesley; Rai, Rajendra.

In: Health technology assessment, Vol. 20, No. 41, 41, 05.2016, p. 1-92.

Research output: Contribution to journalArticle

Harvard

Coomarasamy, A, Williams, H, Truchanowicz, E, Seed, PT, Small, R, Quenby, S, Gupta, P, Dawood, F, Koot, YE, Atik, RB, Bloemenkamp, KW, Brady, R, Briley, A, Cavallaro, R, Cheong, YC, Chu, J, Eapen, A, Essex, H, Ewies, A, Hoek, A, Kaaijk, EM, Koks, CA, Li, T-C, MacLean, M, Mol, BW, Moore, J, Parrott, S, Ross, JA, Sharpe, L, Stewart, J, Trépel, D, Vaithilingam, N, Farquharson, RG, Kilby, MD, Khalaf, Y, Goddijn, M, Regan, L & Rai, R 2016, 'PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation', Health technology assessment, vol. 20, no. 41, 41, pp. 1-92. https://doi.org/10.3310/hta20410

APA

Coomarasamy, A., Williams, H., Truchanowicz, E., Seed, P. T., Small, R., Quenby, S., ... Rai, R. (2016). PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health technology assessment, 20(41), 1-92. [41]. https://doi.org/10.3310/hta20410

Vancouver

Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health technology assessment. 2016 May;20(41):1-92. 41. https://doi.org/10.3310/hta20410

Author

Coomarasamy, Arri ; Williams, Helen ; Truchanowicz, Ewa ; Seed, Paul T ; Small, Rachel ; Quenby, Siobhan ; Gupta, Pratima ; Dawood, Feroza ; Koot, Yvonne E ; Atik, Ruth Bender ; Bloemenkamp, Kitty Wm ; Brady, Rebecca ; Briley, Annette ; Cavallaro, Rebecca ; Cheong, Ying C ; Chu, Justin ; Eapen, Abey ; Essex, Holly ; Ewies, Ayman ; Hoek, Annemieke ; Kaaijk, Eugenie M ; Koks, Carolien A ; Li, Tin-Chiu ; MacLean, Marjory ; Mol, Ben W ; Moore, Judith ; Parrott, Steve ; Ross, Jackie A ; Sharpe, Lisa ; Stewart, Jane ; Trépel, Dominic ; Vaithilingam, Nirmala ; Farquharson, Roy G ; Kilby, Mark David ; Khalaf, Yacoub ; Goddijn, Mariëtte ; Regan, Lesley ; Rai, Rajendra. / PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. In: Health technology assessment. 2016 ; Vol. 20, No. 41. pp. 1-92.

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@article{cf6378e9a64c4ec781c4085aaf9e1a0e,
title = "PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation",
abstract = "BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan({\circledR}), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8{\%}). The live birth rate in the progesterone group was 65.8{\%} (262/398) and in the placebo group it was 63.3{\%} (271/428), giving a relative risk of 1.04 (95{\%} confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.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. 20, No. 41. See the NIHR Journals Library website for further project information.",
keywords = "Journal Article",
author = "Arri Coomarasamy and Helen Williams and Ewa Truchanowicz and Seed, {Paul T} and Rachel Small and Siobhan Quenby and Pratima Gupta and Feroza Dawood and Koot, {Yvonne E} and Atik, {Ruth Bender} and Bloemenkamp, {Kitty Wm} and Rebecca Brady and Annette Briley and Rebecca Cavallaro and Cheong, {Ying C} and Justin Chu and Abey Eapen and Holly Essex and Ayman Ewies and Annemieke Hoek and Kaaijk, {Eugenie M} and Koks, {Carolien A} and Tin-Chiu Li and Marjory MacLean and Mol, {Ben W} and Judith Moore and Steve Parrott and Ross, {Jackie A} and Lisa Sharpe and Jane Stewart and Dominic Tr{\'e}pel and Nirmala Vaithilingam and Farquharson, {Roy G} and Kilby, {Mark David} and Yacoub Khalaf and Mari{\"e}tte Goddijn and Lesley Regan and Rajendra Rai",
note = "{\circledC} Queen’s Printer and Controller of HMSO 2016.",
year = "2016",
month = "5",
doi = "10.3310/hta20410",
language = "English",
volume = "20",
pages = "1--92",
journal = "Health technology assessment",
issn = "1366-5278",
publisher = "NHS National Institute for Health Research",
number = "41",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

AU - Coomarasamy, Arri

AU - Williams, Helen

AU - Truchanowicz, Ewa

AU - Seed, Paul T

AU - Small, Rachel

AU - Quenby, Siobhan

AU - Gupta, Pratima

AU - Dawood, Feroza

AU - Koot, Yvonne E

AU - Atik, Ruth Bender

AU - Bloemenkamp, Kitty Wm

AU - Brady, Rebecca

AU - Briley, Annette

AU - Cavallaro, Rebecca

AU - Cheong, Ying C

AU - Chu, Justin

AU - Eapen, Abey

AU - Essex, Holly

AU - Ewies, Ayman

AU - Hoek, Annemieke

AU - Kaaijk, Eugenie M

AU - Koks, Carolien A

AU - Li, Tin-Chiu

AU - MacLean, Marjory

AU - Mol, Ben W

AU - Moore, Judith

AU - Parrott, Steve

AU - Ross, Jackie A

AU - Sharpe, Lisa

AU - Stewart, Jane

AU - Trépel, Dominic

AU - Vaithilingam, Nirmala

AU - Farquharson, Roy G

AU - Kilby, Mark David

AU - Khalaf, Yacoub

AU - Goddijn, Mariëtte

AU - Regan, Lesley

AU - Rai, Rajendra

N1 - © Queen’s Printer and Controller of HMSO 2016.

PY - 2016/5

Y1 - 2016/5

N2 - BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.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. 20, No. 41. See the NIHR Journals Library website for further project information.

AB - BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.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. 20, No. 41. See the NIHR Journals Library website for further project information.

KW - Journal Article

U2 - 10.3310/hta20410

DO - 10.3310/hta20410

M3 - Article

VL - 20

SP - 1

EP - 92

JO - Health technology assessment

JF - Health technology assessment

SN - 1366-5278

IS - 41

M1 - 41

ER -