Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial

Lucas A McLindon; Gabriel James; Michael M Beckmann; Julia Bertolone; Kassam Mahomed; Monica Vane; Teresa Baker; Monique Gleed; Sandra Grey; Linda Tettamanzi; Ben Willem J Mol; Wentao Li

doi:10.1093/humrep/dead029

Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial

Lucas A McLindon^* (Corresponding Author), Gabriel James, Michael M Beckmann, Julia Bertolone, Kassam Mahomed, Monica Vane, Teresa Baker, Monique Gleed, Sandra Grey, Linda Tettamanzi, Ben Willem J Mol, Wentao Li^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

2 Downloads (Pure)

Abstract

STUDY QUESTION: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?

SUMMARY ANSWER: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.

WHAT IS KNOWN ALREADY: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.

STUDY DESIGN, SIZE, DURATION: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.

PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.

MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.

LIMITATIONS, REASONS FOR CAUTION: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.

WIDER IMPLICATIONS OF THE FINDINGS: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.

STUDY FUNDING/COMPETING INTEREST(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.

TRIAL REGISTRATION NUMBER: ACTRN12611000405910.

TRIAL REGISTRATION DATE: 19 April 2011.

DATE OF FIRST PATIENT’S ENROLMENT: 06 February 2012.

Original language	English
Pages (from-to)	560-568
Number of pages	9
Journal	Human reproduction (Oxford, England)
Volume	38
Issue number	4
Early online date	20 Feb 2023
DOIs	https://doi.org/10.1093/humrep/dead029
Publication status	Published - 1 Apr 2023

Bibliographical note

Acknowledgements
The research team are grateful to the women and families who participated at an emotionally difficult time for them.

Funding
Mothers and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.

Supplementary data are available at Human Reproduction online.

Keywords

threatened miscarriage
progesterone
miscarriage prevention
live birth
early pregnancy

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Cite this

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title = "Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial",

abstract = "STUDY QUESTION: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?SUMMARY ANSWER: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.WHAT IS KNOWN ALREADY: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.STUDY DESIGN, SIZE, DURATION: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.LIMITATIONS, REASONS FOR CAUTION: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.WIDER IMPLICATIONS OF THE FINDINGS: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.STUDY FUNDING/COMPETING INTEREST(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.TRIAL REGISTRATION NUMBER: ACTRN12611000405910.TRIAL REGISTRATION DATE: 19 April 2011.DATE OF FIRST PATIENT{\textquoteright}S ENROLMENT: 06 February 2012.",

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note = "Acknowledgements The research team are grateful to the women and families who participated at an emotionally difficult time for them. Funding Mothers and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.",

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doi = "10.1093/humrep/dead029",

language = "English",

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T1 - Progesterone for women with threatened miscarriage (STOP trial)

T2 - a placebo-controlled randomized clinical trial

AU - McLindon, Lucas A

AU - James, Gabriel

AU - Beckmann, Michael M

AU - Bertolone, Julia

AU - Mahomed, Kassam

AU - Vane, Monica

AU - Baker, Teresa

AU - Gleed, Monique

AU - Grey, Sandra

AU - Tettamanzi, Linda

AU - Mol, Ben Willem J

AU - Li, Wentao

N1 - Acknowledgements The research team are grateful to the women and families who participated at an emotionally difficult time for them. Funding Mothers and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.

PY - 2023/4/1

Y1 - 2023/4/1

N2 - STUDY QUESTION: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?SUMMARY ANSWER: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.WHAT IS KNOWN ALREADY: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.STUDY DESIGN, SIZE, DURATION: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.LIMITATIONS, REASONS FOR CAUTION: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.WIDER IMPLICATIONS OF THE FINDINGS: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.STUDY FUNDING/COMPETING INTEREST(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.TRIAL REGISTRATION NUMBER: ACTRN12611000405910.TRIAL REGISTRATION DATE: 19 April 2011.DATE OF FIRST PATIENT’S ENROLMENT: 06 February 2012.

AB - STUDY QUESTION: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?SUMMARY ANSWER: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.WHAT IS KNOWN ALREADY: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.STUDY DESIGN, SIZE, DURATION: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.LIMITATIONS, REASONS FOR CAUTION: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.WIDER IMPLICATIONS OF THE FINDINGS: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.STUDY FUNDING/COMPETING INTEREST(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.TRIAL REGISTRATION NUMBER: ACTRN12611000405910.TRIAL REGISTRATION DATE: 19 April 2011.DATE OF FIRST PATIENT’S ENROLMENT: 06 February 2012.

KW - threatened miscarriage

KW - progesterone

KW - miscarriage prevention

KW - live birth

KW - early pregnancy

U2 - 10.1093/humrep/dead029

DO - 10.1093/humrep/dead029

M3 - Article

C2 - 36806843

SN - 0268-1161

VL - 38

SP - 560

EP - 568

JO - Human reproduction (Oxford, England)

JF - Human reproduction (Oxford, England)

IS - 4

ER -

Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial

Abstract

Bibliographical note

Data Availability Statement

Keywords

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