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

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

doi:10.1056/nejmoa1813730

Cited by 138 publications

(159 citation statements)

References 18 publications

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“…The New England Journal of Medicine article on the PRISM trial noted a 3% increase in live birth rate with vaginal micronized progesterone, but suggested it was a negative result, as the P value associated with this finding was .08. 10 However, our interpretation of the PRISM trial in this review takes into account the totality of available evidence, suggesting a potential role for progesterone for women at high risk of a miscarriage. We propose the apparent discordance between the published New England Journal of Medicine manuscript 10 and our interpretation relates to the issue of statistical inference vs scientific inference.…”

Section: Statistical and Scientific Inferencesmentioning

confidence: 99%

“…10 However, our interpretation of the PRISM trial in this review takes into account the totality of available evidence, suggesting a potential role for progesterone for women at high risk of a miscarriage. We propose the apparent discordance between the published New England Journal of Medicine manuscript 10 and our interpretation relates to the issue of statistical inference vs scientific inference. Statistical inference focuses on hypothesis testing.…”

Section: Statistical and Scientific Inferencesmentioning

confidence: 99%

“…7 We were able to assess the reproducibity of this subgroup effect by the increasing number of previous miscarriages in the PRISM trial. 10 The PRISM Trial The PRISM trial is a well-powered randomized trial in women with threatened miscarriage ( Table 2). It was designed and conducted with methodologic rigor, with appropriate randomization, allocation concealment, double-blinding with placebo control, excellent followup rate, and analysis according to a prespecified statistical analysis plan.…”

Section: The Promise Trialmentioning

confidence: 99%

“…Given this biological understanding and the hypothesis generated from the PROMISE trial findings, we considered the number of previous miscarriages as the most important subgroup in the PRISM study. 10 Type of progestogen used in the PROMISE and PRISM trials We used vaginal, micronized progesterone in the PROMISE and PRISM trials.…”

Section: Expert Reviewsmentioning

confidence: 99%

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Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence

Coomarasamy

Devall

Brosens

et al. 2020

American Journal of Obstetrics and Gynecology

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111

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Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03e1.15; P¼.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08e1.51; P¼.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

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Section: Statistical and Scientific Inferencesmentioning

confidence: 99%

Section: Statistical and Scientific Inferencesmentioning

confidence: 99%

Section: The Promise Trialmentioning

confidence: 99%

Section: Expert Reviewsmentioning

confidence: 99%

See 2 more Smart Citations

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence

Coomarasamy

Devall

Brosens

et al. 2020

American Journal of Obstetrics and Gynecology

Self Cite

111

View full text Add to dashboard Cite

show abstract

“…In this review, the authors have combined progesterone with progestogens; however, they are not the same, in the same way that estrogen and diethylstilbestrol are not the same. Vaginal micronised progesterone, which we used in our large and high‐quality trials (the PROMISE 2 and PRISM 3 trials), has an identical molecular structure to natural progesterone but the other drugs included in this review do not (Table 1). We chose to study vaginal micronised progesterone, as it is identical in structure to natural progesterone, and the available evidence and expert opinion suggested that this is least likely to cause harm.…”

Section: Drug Chemical Structurementioning

confidence: 99%