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.
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Progesterone is essential for the establishment and maintenance of a pregnancy. 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. The first trial in women with threatened miscarriage was published in 1987, and since then 7 further trials have been conducted. 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.” 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.” 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. We assess the evidence for key prespecified subgroup effects using robust guidelines. Finally, we provide our recommendations for clinical practice.
Statistical and Scientific Inferences
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. 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 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 considered judgemnt. The American Statistical Association (ASA) has issued a series of 44 instructive articles on drawing scientific inferences from studies. Appreciation of the key messages from these ASA articles is essential for making clinical sense of the PROMISE and PRISM trials.
The ASA’s statements recommend that “scientific conclusions or policy decisions should not be based on only whether a P -value passes a specific threshold” and “no single index should substitute for scientific reasoning.” Further, the ASA states that “practices that reduce data analysis or scientific inference to mechanical ‘bright-line’ rules (such as P <.05, or equivalent confidence intervals) for justifying scientific claims or conclusions can lead to erroneous beliefs and poor decision making.” The ASA notes “a conclusion doesn’t immediately become ‘true’ on one side of the divide ( P <.05) and ‘false’ on the other,” and the ASA recommends that phrases such as “statistically significant” and “statistically nonsignificant” are no longer used. Instead, the ASA recommends that researchers bring many contextual factors into play to derive scientific inferences, including the design of the study, replicability, and other external evidence.
The PROMISE Trial
The PROMISE Trial is a well-powered randomized trial in women with recurrent miscarriage ( Table 1 ). It is a high-quality trial, with computer-generated third-party randomization, allocation concealment, double-blinding, placebo-control, excellent follow-up rate, and a prespecified statistical analysis plan that was diligently implemented.
| Population | Women with unexplained recurrent miscarriages (≥3 consecutive or nonconsecutive miscarriages), trying to conceive naturally |
| Intervention | 400 mg of micronized progesterone taken vaginally twice daily from no later than 6 weeks until 12 weeks of gestation |
| Comparison | Placebo |
| Primary outcome | Live birth beyond 24 weeks |
| Sample size and power | 836 patients randomized; 90% power to detect a 10% difference in live births |
| Hospitals and countries | 36 hospitals in the United Kingdom and 9 hospitals in the Netherlands |
The primary analysis of the PROMISE trial found the live birth rate was 66% (262/398) in the progesterone group vs 63% (271/428) in the placebo group (risk ratio [RR], 1.04, 95% confidence interval [CI], 0.94–1.15, P =.45). There was a 3% greater live birth rate with progesterone, but the trial finding was reported as not statistically significant due to the large P value ( P =.45) and the consequent statistical uncertainty. We then performed a prespecified subgroup analysis by the number of previous miscarriages; the study population was split into 2 subgroups; one included women who had 3 previous miscarriages and the other included women who had ≥4 miscarriages. We also performed a post-hoc subgroup analysis by 3, 4, 5, and ≥6 previous miscarriages. We understood that the post-hoc analysis would be underpowered and could only be used for hypothesis generation but considered that such an analysis would still be useful for assessing a biological gradient in these subgroups. The findings ( Figure 1 ) appeared to suggest a trend for greater benefit with increasing number of previous miscarriages. Although the small sample sizes in the subgroups and the large P value for test of subgroup interaction ( P =.41) suggested an inconclusive subgroup effect, the findings generated a hypothesis that a subgroup effect existed with a biological gradient related to the increasing number of previous miscarriages. As Rothwell published, “The best test of validity of subgroup-treatment effect interactions is their reproducibility in other trials.” We were able to assess the reproducibity of this subgroup effect by the increasing number of previous miscarriages in the PRISM trial.
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 follow-up rate, and analysis according to a prespecified statistical analysis plan.
| Population | Women with vaginal bleeding during the first 12 weeks of pregnancy |
| Intervention | 400 mg of micronized progesterone taken vaginally or rectally twice daily from randomization until 16 weeks of gestation |
| Comparison | Placebo |
| Primary outcome | Live birth ≥34 weeks |
| Sample size and power | 4153 patients randomized, 90% power to pick up a 5% difference in live births |
| Hospitals | 48 hospitals in the United Kingdom |
The primary analysis of PRISM trial found that the live birth rate was 75% (1513/2025) in the progesterone group vs 72% (1459/2013) in the placebo group (RR, 1.03; 95% CI, 1.00–1.07, P =.08). For the prespecified subgroup analysis by the number of previous miscarriages, the study population was split into 3 subgroups: women without a history of miscarriage; women with 1 or 2 previous miscarriages; and women with ≥3 previous miscarriages, as shown in Figure 2 . There were 2 post-hoc subgroup analyses: the first grouping women into those who had no previous miscarriage or those who had any number of previous miscarriages; and the second grouping women by 0, 1, 2, ≥3 previous miscarriages, to explore in detail for a possible biological gradient ( Figure 2 ). The P values for “subgroup by treatment” interactions were consistent with differential subgroup effects. The live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (RR, 1.09; 95% CI, 1.03–1.15; P =.003) for the subgroup of women with 1 or more previous miscarriage(s) and bleeding in the current pregnancy (number needed to treat = 20; 95% CI, 19–22). The benefit was even 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 (RR, 1.28; 95% CI, 1.08–1.51; P =.004; number needed to treat = 8, 95% CI, 7–10).
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