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

Arri Coomarasamy; Adam J Devall; Jan J Brosens; Siobhan Quenby; Mary D Stephenson; Sony Sierra; Ole B Christiansen; Rachel Small; Jane Brewin; Tracy E Roberts; Rima Dhillon-Smith; Hoda Harb; Hannah Noordali; Argyro Papadopoulou; Abey Eapen; Matt Prior; Gian Carlo Di Renzo; Kim Hinshaw; Ben W Mol; Mary Ann Lumsden; Yacoub Khalaf; Andrew Shennan; Mariette Goddijn; Madelon van Wely; Maya Al-Memar; Phil Bennett; Tom Bourne; Raj Rai; Lesley Regan; Ioannis D Gallos

doi:10.1016/j.ajog.2019.12.006

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

Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, Christiansen OB, Small R, Brewin J, Roberts TE, Dhillon-Smith R, Harb H, Noordali H, Papadopoulou A, Eapen A, Prior M, Di Renzo GC, Hinshaw K, Mol BW, Lumsden MA, Khalaf Y, Shennan A, Goddijn M, van Wely M, Al-Memar M, Bennett P, Bourne T, Rai R, Regan L, Gallos ID

Published August 2020 American Journal of Obstetrics and Gynecology, 223(2), 167-176

DOI 10.1016/j.ajog.2019.12.006 PMID 32008730 PMC PMC7408486

RRM Academy Synopsis

Progesterone linked to live birth with bleeding and past miscarriage

In a PRISM subgroup, vaginal progesterone went with more live births in women with bleeding and a prior miscarriage. The trial authors reviewed PROMISE and PRISM. Live birth followed in 75 out of 100 on progesterone, against 70 out of 100 on placebo.

Live birth, bleeding and past loss: Vaginal progesterone, 75 in 100; Placebo, 70 in 100. Source: Coomarasamy A et al., 2020, PMID 32008730.

Study at a glance, placebo-controlled trials: Progesterone linked to live birth with bleeding and past miscarriage — Study at a glance, placebo-controlled trials of women with threatened miscarriage: Progesterone linked to live birth with bleeding and past miscarriage. Source: Coomarasamy A et al., 2020, PMID 32008730.

Key Findings

PROMISE, women with recurrent miscarriage: live birth in 66% (262/398) on progesterone and 63% (271/428) on placebo (RR, 1.04, 95% CI, 0.94–1.15, P=.45).
PRISM, women with threatened miscarriage: live birth in 75% (1513/2025) on progesterone and 72% (1459/2013) on placebo (RR, 1.03; 95% CI, 1.00–1.07, P=.08).
PRISM subgroup with 1 or more previous miscarriage(s) and bleeding: 75% (689/914) on progesterone and 70% (619/886) on placebo (RR, 1.09; 95% CI, 1.03–1.15; P=.003).
PRISM subgroup with 3 or more previous miscarriages and bleeding: 72% (98/137) on progesterone and 57% (85/148) on placebo (RR, 1.28; 95% CI, 1.08–1.51; P=.004).
Congenital disorders: 23/2025 on progesterone and 22/2013 on placebo in PRISM (P=.90); any congenital anomaly 8/266 and 11/276 in PROMISE (P=.54).

Interpretation

The authors rated the PRISM subgroup effect as highly plausible. They checked it against 11 set criteria for judging subgroup findings. PROMISE showed a similar pattern in its own subgroup by number of past miscarriages. The benefit rose with each added miscarriage. Women with bleeding but no prior loss saw no added benefit from progesterone. Both trials used vaginal micronized progesterone. The authors kept this drug apart from synthetic progestogens like dydrogesterone. The authors note that subgroup analyses can produce false-positive results. The findings support larger trials of progesterone in women with bleeding and a history of miscarriage.

RRM Context

The authors point to luteal phase defect as the biological reason for the subgroup effect. This is a hypothesized cause of euploid miscarriage. They note it has no clear definition and no reliable test. Restorative reproductive medicine treats the luteal phase as a question to evaluate in each woman. The paper also keeps progesterone and synthetic progestogens apart.

Our editorial summary of this paper, not the article's abstract.

Abstract

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, 1.03-1.15; P=.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, 1.08-1.51; P=.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.

Topics

Pregnancy › Early Pregnancy › Progesterone Support · Therapeutics › Hormonal Agents › Progesterone and Progestins · Reproductive Endocrinology › Ovarian Hormones › Progesterone

Arri Coomarasamy, Adam J Devall, Jan J Brosens, Siobhan Quenby, Mary D Stephenson, Sony Sierra, Ole B Christiansen, Rachel Small, Jane Brewin, Tracy E Roberts, Rima Dhillon-Smith, Hoda Harb, Hannah Noordali, Argyro Papadopoulou, Abey Eapen, Matt Prior, Gian Carlo Di Renzo, Kim Hinshaw, Ben W Mol, Mary Ann Lumsden, Yacoub Khalaf, Andrew Shennan, Mariette Goddijn, Madelon van Wely, Maya Al-Memar, Phil Bennett, Tom Bourne, Raj Rai, Lesley Regan, Ioannis D Gallos

A Coomarasamy, A Devall, J Brosens, S Quenby, M Stephenson, S Sierra, O Christiansen, R Small, J Brewin, T Roberts, R Dhillon-Smith, H Harb, H Noordali, A Papadopoulou, A Eapen, Matthew Prior, M Prior, G Renzo, K Hinshaw, Benjamin Mol, B Mol, M Lumsden, Y Khalaf, Andy Shennan, Drew Shennan, A Shennan, M Goddijn, M Wely, M Al-Memar, Philip Bennett, Phillip Bennett, P Bennett, Thomas Bourne, T Bourne, R Rai, L Regan, I Gallos

PMID 32008730 32008730 DOI 10.1016/j.ajog.2019.12.006 10.1016/j.ajog.2019.12.006 Coomarasamy et al. 2020, Coomarasamy 2020

Keywords

Progestins, Progesterone