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

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. 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. Click Supplemental Materials under article title in Contents at ajog.org Click Supplemental Materials under article title in Contents at ajog.org Progesterone is essential for the establishment and maintenance of a pregnancy.1Di Renzo G.C. Giardina I. Cleriici G. Mattei A. Alajmi A.H. Gerli S. The role of progesterone in maternal and fetal medicine.Gynecol Endocrinol. 2012; 28: 925-932Crossref PubMed Scopus (33) Google Scholar Withdrawal of progesterone in early pregnancy typically results in a miscarriage, and antiprogesterone drugs are powerful inducers of abortion. The central role of progesterone in early pregnancy led clinicians and researchers to hypothesize that progesterone deficiency could be a cause of some miscarriages. This hypothesis has resulted in numerous clinical trials of progesterone supplementation in women at high risk of miscarriage. The 2 groups of women at particular risk of miscarriage are those who have a history of recurrent miscarriage and those who are bleeding in early pregnancy. The first randomized trial in women with recurrent miscarriage was published in 1953, and 11 trials followed in the subsequent decades.2Haas D.M. Hathaway T.J. Ramsey P.S. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.Cochrane Database Syst Rev. 2018; 10: CD003511PubMed Google Scholar The first trial in women with threatened miscarriage was published in 1987, and since then 7 further trials have been conducted.3Wahabi H.A. Fayed A.A. Esmaeil S.A. Bahkali K. Progestogen for treating threatened miscarriage.Cochrane Database Syst Rev. 2018; 8: CD005943PubMed Google Scholar However, these trials used different progestogens and were small and methodologically weak, producing heterogenous and unreliable results. Policy makers have therefore been unable to make evidence-based recommendations on the use of progestogen supplementation to improve outcomes in these cohorts of women. For instance, the American College of Obstetricians and Gynecologists reviewed the evidence in 2015 and concluded that “For threatened early pregnancy loss, the use of progestins is controversial, and conclusive evidence supporting their use is lacking. Women who have experienced at least three prior pregnancy losses, however, may benefit from progesterone therapy in the first trimester.”4American College of Obstetricians and GynecologistsACOG practice bulletin—clinical management guidelines for obstetricians–gynecologists: early pregnancy loss. November 2018.https://www.acog.org/-/media/Practice-Bulletins/Committee-on-Practice-Bulletins----Gynecology/Public/pb200.pdfGoogle Scholar Similarly, in the United Kingdom, the National Institute for Health and Care Excellence concluded in 2012 that “a very large multicentre randomised controlled trial of women receiving treatment with either progesterone/progestogen or placebo for threatened miscarriage should be conducted.”5National Institute for Health and Care ExcellenceNICE guideline [NG126]. Ectopic pregnancy and miscarriage: diagnosis and initial management.https://www.nice.org.uk/guidance/ng126Date: 2019Google Scholar The PROMISE (PROgesterone in recurrent MIScarriagE) and PRISM (PRogesterone In Spontaneous Miscarriage) trials were conducted to generate robust evidence on the role of progesterone therapy to prevent miscarriage and increase the live birth rate. In this review, we critically evaluate the results from the PROMISE and PRISM trials to assess what they add to our existing knowledge. We move beyond statistical inference to provide a full scientific inference by taking into account the context, biological rationale, biological gradient, external evidence, and consistency across the studies.6Wasserstein R.L. Schirm A.L. Lazar N.A. Moving to a World Beyond “p < 0.05.”.Am Stat. 2019; 73: 1-19Crossref Scopus (1129) Google Scholar We assess the evidence for key prespecified subgroup effects using robust guidelines.7Rothwell P.M. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation.Lancet. 2005; 365: 176-186Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar, 8Sun X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar, 9Burke J.F. Sussman J.B. Kent D.M. Hayward R.A. Three simple rules to ensure reasonably credible subgroup analyses.BMJ. 2015; 35: h5651Crossref Scopus (113) Google Scholar Finally, we provide our recommendations for clinical practice. 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 .08.10Coomarasamy A. Devall A.J. Cheed V. et al.A randomized trial of progesterone in women with bleeding in early pregnancy.N Engl J Med. 2019; 380: 1815-1824Crossref PubMed Scopus (77) Google Scholar 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 manuscript10Coomarasamy A. Devall A.J. Cheed V. et al.A randomized trial of progesterone in women with bleeding in early pregnancy.N Engl J Med. 2019; 380: 1815-1824Crossref PubMed Scopus (77) Google Scholar and our interpretation relates to the issue of statistical inference vs scientific inference. Statistical inference focuses on hypothesis testing. Scientific inference, in contrast, not only considers any statistical uncertainty in the findings but in addition takes into account the full extent of all other evidence, to make a The American Statistical has a of on scientific from R.L. Lazar N.A. The on context, and Stat. Scopus Google Scholar of the key from these is essential for clinical of the PROMISE and PRISM trials. The that or should not be on only a a and should for scientific R.L. Lazar N.A. The on context, and Stat. Scopus Google Scholar the that that reduce analysis or scientific inference to rules as or confidence for scientific or to and R.L. Lazar N.A. The on context, and Stat. Scopus Google Scholar The “a on one of the and on the and the that as and are the that researchers factors into to scientific the of the and other external The PROMISE A. et al.A randomized trial of progesterone in women with recurrent Engl J Med. 2015; PubMed Scopus Google Scholar is a randomized trial in women with recurrent miscarriage is a trial, with and a prespecified statistical analysis that was vaginal micronized progesterone in women with unexplained recurrent with unexplained recurrent miscarriages or to mg of micronized progesterone twice daily from of birth beyond and to a difference in live and hospitals in the United Kingdom and hospitals in the in recurrent et vaginal progesterone to prevent miscarriage: a of randomized J in a in recurrent et vaginal progesterone to prevent miscarriage: a of randomized J The analysis of the PROMISE trial found the live birth rate was in the progesterone vs in the placebo 95% confidence was a 3% greater live birth rate with progesterone, but the trial finding was as not to the large P value and the statistical uncertainty. We then a prespecified subgroup analysis by the number of previous the was into 2 one women who 3 previous miscarriages and the other women who miscarriages. We a subgroup analysis by and previous miscarriages. We that the analysis be and could only be used for hypothesis but that analysis be for a biological in these The findings to a for greater benefit with increasing number of previous miscarriages. the small in the and the large P value for of subgroup suggested subgroup the findings a hypothesis that a subgroup effect with a biological to the increasing number of previous miscarriages. of of effect is their in other P.M. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation.Lancet. 2005; 365: 176-186Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar We were to assess the of this subgroup effect by the increasing number of previous miscarriages in the PRISM A. Devall A.J. Cheed V. et al.A randomized trial of progesterone in women with bleeding in early pregnancy.N Engl J Med. 2019; 380: 1815-1824Crossref PubMed Scopus (77) Google Scholar The PRISM trial is a randomized trial in women with threatened miscarriage was and conducted with methodologic with with placebo and analysis according to a prespecified statistical analysis vaginal micronized progesterone in women with threatened with vaginal bleeding the first of mg of micronized progesterone or twice daily from of birth and to a difference in live hospitals in the United In Spontaneous et vaginal progesterone to prevent miscarriage: a of randomized J in a In Spontaneous et vaginal progesterone to prevent miscarriage: a of randomized J The analysis of PRISM trial found that the live birth rate was 75% in the progesterone vs 72% in the placebo 95% For the prespecified subgroup analysis by the number of previous the was into 3 women a history of women with 1 or 2 previous and women with previous as in 2. were 2 subgroup the first women into those who previous miscarriage or those who any number of previous and the women by previous to in for a biological The P for by were with subgroup The live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo 95% 1.03–1.15; for the subgroup of women with 1 or more previous miscarriage(s) and bleeding in the current pregnancy to 95% 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 95% 1.08–1.51; number to 95% The findings of the subgroup were in with the prespecified subgroup we the prespecified or the subgroup in all of these is a between the number of previous miscarriages and the effect of progesterone, as was observed in the PROMISE trial Supplemental Materials and should one a subgroup Subgroup from results of or results from robust guidelines have been to in the interpretation of subgroup P.M. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation.Lancet. 2005; 365: 176-186Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar, 8Sun X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar, 9Burke J.F. Sussman J.B. Kent D.M. Hayward R.A. Three simple rules to ensure reasonably credible subgroup analyses.BMJ. 2015; 35: h5651Crossref Scopus (113) Google Scholar guidelines into 11 on 2 on and on the X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar We these 11 criteria to the PRISM trial subgroup analysis by number of previous miscarriages to assess the credibility of the subgroup the subgroup a at be by at or by be by the the of findings from that on be For our the number of miscarriages is at this is the effect suggested by between A subgroup effect observed only between and not a is unreliable as the subgroup effect may be to the that is present between A subgroup effect found is more The subgroup effect we identified was the PRISM this is the hypothesis a The hypothesis was prespecified in the were for the PRISM trial the of the subgroup effect a The of the effect was in the were the subgroup effect one of a small number of effects were prespecified subgroup in the PRISM but only one was to be of clinical the subgroup were for consistency across the The between of and for was not in the PRISM but was in the of PRISM results on the a that the apparent subgroup The P value for the by the number of previous miscarriages was suggesting that it is that the observed subgroup In contrast, the subgroup P value was for all the other suggesting a subgroup effect was for all the other subgroup the subgroup effect or subgroup effects may be to other in a that one the subgroup We for by key as of fetal at at and of bleeding, and this not in any in the P the of the subgroup effect The risk for those with 1 or 2 miscarriages was and a difference was in a of clinicians the PRISM trial was For those with 3 or more the was The effect is for those with a greater number of previous the across the benefit with increasing number of prior miscarriages was noted in the PROMISE trial and the PRISM trial The of the subgroup effect with the of a biological 2 trials confidence to the finding of this subgroup the across outcomes the We this by subgroup on the outcomes of pregnancy at and miscarriage at these 2 outcomes are to live A subgroup effect by the number of previous miscarriages was observed for the outcomes of pregnancy and miscarriage. We observed increase in and a in miscarriages according to the number of previous these findings are with the observed live birth subgroup effect 3 and by the number of previous full confidence et vaginal progesterone to prevent miscarriage: a of randomized J evidence that the is very biological to greater effect from progesterone in those with increasing of previous miscarriages. miscarriage is more with increasing number of previous miscarriages M. K. S. K. of in to the number of previous 73: Full Text Full Text PDF PubMed Scopus Google Scholar one of the of miscarriage is to be progesterone be to have greater benefit in those with greater number of previous miscarriages. is to present with vaginal bleeding, greater benefit from progesterone use be in women with early pregnancy risk by the number of previous full with from et M. K. S. K. of in to the number of previous 73: Full Text Full Text PDF PubMed Scopus Google et vaginal progesterone to prevent miscarriage: a of randomized J confidence et vaginal progesterone to prevent miscarriage: a of randomized J with from et M. K. S. K. of in to the number of previous 73: Full Text Full Text PDF PubMed Scopus Google Scholar et vaginal progesterone to prevent miscarriage: a of randomized J on the interpretation of subgroup effects that subgroup effects may be in of or X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar but is and it the uncertainty that is of X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar that is more and more is to the that a subgroup effect is on a from to the is then a of on this a subgroup effect X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (474) Google Scholar We propose the subgroup effect first suggested in the PROMISE trial, and then in the PRISM trial is Renzo G.C. V. Giardina I. The biological and on 2018; PubMed Scopus Google Scholar are of micronized vaginal progesterone and other of these are small and of methodologic We the evidence from the PROMISE and PRISM first we the external evidence from other of progesterone or progestogens to for consistency in the findings across the The were in a benefit on live birth or pregnancy rate from the first-trimester use of progesterone or further confidence in our birth or pregnancy for all progesterone and progestogen full confidence et vaginal progesterone to prevent miscarriage: a of randomized J confidence et vaginal progesterone to prevent miscarriage: a of randomized J The role of first-trimester progesterone supplementation in the treatment of at high risk of miscarriage is a that has been in the for more The PROMISE and PRISM trials are 2 very trials that have the effects of first-trimester use of vaginal micronized progesterone treatment in women at risk of a miscarriage. one of all pregnancy in women with recurrent miscarriage, are to with the with maternal followed by and analysis of miscarriages from with recurrent miscarriage: a PubMed Scopus Google Scholar miscarriages are to on a that the risk of subsequent miscarriage is not in contrast, are more with increasing number of previous as in A the is to be one of the of a miscarriage. The in the progesterone early pregnancy. Progesterone is essential for the and it is that a in the of the in progesterone in may increase the risk of analysis of miscarriages from with recurrent miscarriage: a PubMed Scopus Google Scholar However, is for and are to who may have the and progesterone have been of in the of in women with threatened miscarriage: a review and Google M. in progesterone in Full Text PDF PubMed Scopus Google however, the and value of the progesterone has M. in progesterone in Full Text PDF PubMed Scopus Google S. S. Progesterone in and of progesterone treatment in with recurrent J PubMed Scopus Google Scholar of interpretation of a progesterone result, the progesterone is found to be in early we the progesterone is the cause or effect of a miscarriage. of the by et in the J Full Text PDF PubMed Scopus Google Scholar has been to have high and and between and in addition to are The is a of and that of and of the in the is evaluated critically to associated with recurrent pregnancy loss. A by et on women with a history of recurrent early pregnancy who were evaluated in the with for and for of the M. vaginal micronized progesterone pregnancy in women with recurrent pregnancy Full Text Full Text PDF PubMed Scopus Google R.L. et using and Full Text Full Text PDF PubMed Scopus Google Scholar vaginal micronized progesterone mg was on with a on the first treatment and with of progesterone not The live birth rate was greater in women vaginal micronized progesterone with vs a biological the use of vaginal micronized progesterone resulted in or of in of women with of this The of a for researchers with the of not to with progesterone the to this by targeting in the risk of miscarriage is greater the and any miscarriage, could reasonably be to be more The 2 key for were women with previous recurrent miscarriages and women with early pregnancy bleeding, the 2 for the PROMISE and PRISM trials, A history of previous miscarriage those at risk of a miscarriage, and the risk of a miscarriage with the increasing number of previous miscarriages it is the risk of miscarriages that with increasing number of previous the risk of miscarriage from This biological our confidence that the history of previous miscarriage is a for miscarriage. one of the of miscarriage is then the of be to increase with the increasing number of previous miscarriages. this biological and the hypothesis from the PROMISE trial we the number of previous miscarriages as the subgroup in the PRISM A. Devall A.J. Cheed V. et al.A randomized trial of progesterone in women with bleeding in early pregnancy.N Engl J Med. 2019; 380: 1815-1824Crossref PubMed Scopus (77) Google Scholar We used micronized progesterone in the PROMISE and PRISM trials. The results from these trials are not to progestogens as or The progesterone used in the PROMISE and PRISM trials is from and and has to progesterone in the progesterone progesterone, and and PubMed Scopus Google Scholar and have a different and as as a different safety Progesterone is not the as for J Full Text Full Text PDF PubMed Scopus Google Scholar We have our analysis to progesterone, and our not or the role of other In the PRISM and PROMISE trials found a small but treatment effect that to be on the number of miscarriages. analysis not any benefit from progesterone therapy for women with early pregnancy bleeding but history of miscarriages. We that the dual risk factors of early pregnancy bleeding and a history of one or more previous miscarriage(s) women in progesterone is of The is this should clinical practice. We that the should be to women at high risk of miscarriages to shared decision-making. is to to women with vaginal bleeding and a history of 1 or more previous miscarriage(s) a of treatment with vaginal micronized progesterone 400 mg twice at the of with vaginal bleeding and to of In the United Kingdom, we that this treatment in live We that a at high risk of a miscarriage may not scientific to to have a is the uncertainty treatment effects and available safety then could for the of Policy makers and guideline to the evidence to make a is to our of and and to women with pregnancy The of progesterone with increasing number of miscarriages that are a of miscarriages. the live birth rate and live birth rate in these this that the is and that number of vs the of miscarriage. This is with that the in the is on of and are in recurrent K. et of in recurrent pregnancy PubMed Scopus Google Scholar, K. et of by in Scholar, S. et and to and 2019; PubMed Scopus Google Scholar A may to the of current as for we on clinical history to who may have a high risk of However, this is may more targeting of who may benefit from progesterone all pregnancy may to women who may benefit from progesterone the role of using analysis further the of on first-trimester use of is to the effects of progesterone and of and trials to the of progesterone and other potential are Finally, the PROMISE and PRISM trials not any evidence of increase in or short-term The PROMISE trial, 836 found difference between the treatment and the placebo for the outcomes of progesterone placebo and progesterone placebo A. et al.A randomized trial of progesterone in women with recurrent Engl J Med. 2015; PubMed Scopus Google Scholar The PRISM 4153 found difference between women with vaginal micronized progesterone and those receiving placebo for the of and progesterone placebo A. Devall A.J. Cheed V. et al.A randomized trial of progesterone in women with bleeding in early pregnancy.N Engl J Med. 2019; 380: 1815-1824Crossref PubMed Scopus (77) Google Scholar However, we of to first-trimester This PROMISE and PRISM trials were by the National Institute for Health and The are those of the and not those of the or the of Health and This was by the to the with Supplemental

Topics & Concepts