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Coomarasamy A, Williams H, Truchanowicz E, et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Southampton (UK): NIHR Journals Library; 2016 May. (Health Technology Assessment, No. 20.41.)

Cover of PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

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Chapter 1Introduction

This chapter outlines the physiological importance of progesterone in pregnancy, the individual and societal burdens of pregnancy loss, and the rationale to infer a role for progesterone in reducing the risk of miscarriage.

Existing knowledge

Progesterone in pregnancy

Progesterone is essential to achieve and maintain a healthy pregnancy. It is an endogenous hormone, secreted naturally by the corpus luteum (the remnants of the ovarian follicle that enclosed a developing ovum) during the second half of the menstrual cycle, and by the corpus luteum and placenta during early pregnancy. Progesterone prepares the tissue lining of the womb (endometrium) to allow implantation, and stimulates glands in the endometrium to secrete nutrients for the early embryo. During the first 8 weeks of pregnancy, progesterone is produced by the corpus luteum, but between 8 and 12 weeks the placenta takes over this role and maintains the pregnancy thereafter.

The importance of progesterone in pregnancy has prompted many clinicians to infer that progesterone deficiency may be aetiologically linked to recurrent miscarriage (RM), and that progesterone therapy in the first trimester of pregnancy may reduce the risk of miscarriage. In 2003 a Royal College of Obstetricians and Gynaecologists (RCOG) guideline1 and a Cochrane review2 called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained RM.

Burden of disease

Miscarriage is the commonest complication of pregnancy: one in six clinically recognised pregnancies ends in a miscarriage.3 RM, the loss of three or more pregnancies, is a distinct clinical entity. The prevalence of RM (1%) is significantly higher than that expected by chance alone (0.4%). Even after comprehensive investigations, a cause for RM is identified in fewer than 50% of cases.3 The majority of couples are, therefore, labelled as having unexplained RM.

Recurrent miscarriages affect over 6000 couples in the UK every year, and frequently result in substantial adverse physical and psychological consequences for women as well as impacting their families. For example, miscarriage has the potential to cause physical harm, including severe haemorrhage, infection, perforation of the womb during surgery for miscarriage and, rarely, maternal death. The eighth triennial Confidential Enquiry into Maternal Deaths identified several women who had died from complications related to miscarriage.4 Moreover, qualitative studies have shown the level of distress and the bereavement reaction associated with miscarriage to be equivalent to the impact of the stillbirth of a term baby.3

Costs to the NHS

It is estimated that RM costs the NHS £28M per year. This value includes the costs of diagnosis (blood tests and ultrasonography), management of miscarriages (expectant, medical or surgical), investigations for causes of miscarriages (e.g. antiphospholipid syndrome, parental karyotype and uterine cavity tests) and hospital inpatient costs. However, it does not include the management of the complications following treatment of miscarriages (such as uterine perforation, infection, bleeding or visceral damage) or any long-term health consequences of miscarriages or miscarriage management (including complications of intrauterine infections and adhesions). Thus, the true NHS perspective costs are likely to be higher than the estimated £28M per year. The societal costs, including days lost from work and out-of-pocket expenses for patients and partners, can be expected to be far greater.

Progesterone in clinical use for recurrent miscarriages

The PROMISE study was conceived to address the possibility that progesterone therapy in the first trimester of pregnancy may reduce the risk of RM. In 2007 we conducted a clinician survey in the UK (n = 114; response rate 102/114; 89.5%), and found that 2% (2/102) of clinicians use progesterone routinely and 3% (3/102) use it selectively in pregnant women with a history of RM. Over 95% (97/102) reported that they do not use progesterone for this indication and the vast majority of these (92/102; 90.2%) were willing to recruit to a trial evaluating the role of progesterone treatment for the prevention of RM.

We also carried out separate systematic reviews to examine (a) the effectiveness of progesterone in RM5 and (b) the safety of progesterone in pregnancy.

Effectiveness of progesterone in recurrent miscarriages

Two previously conducted systematic reviews2,6 had examined the role of progesterone therapy in RM, but, since these reviews were published and at the time of designing the PROMISE trial, new evidence7 had emerged. Therefore, we conducted a fresh systematic review with a meta-analysis.

We searched the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, ISI Web of Science Proceedings, International Standard Randomised Controlled Trial Number Register, metaRegister of Controlled Trials database, MEDLINE and EMBASE resources, from database inception to January 2008, for the following search terms: (‘progesterone’ OR ‘progestagen’ OR ‘progestogen’ OR ‘progestin’ OR ‘progestational [hormone or agent] ‘ OR ‘progest$’). We considered outcomes of miscarriage (as defined by the primary authors), live birth, gestation at delivery, pregnancy and neonatal outcomes.

Four randomised trials710 were identified. There were 14 trials assessing the effects of progesterone in miscarriages including spontaneous (one-time) events2 but these trials should not be confused with trials assessing the effects of progesterone in RM. The quality of the four trials was poor (modified Jadad quality scores between 0/5 and 2/5; Table 1), and participant numbers were small even when the trials were combined in meta-analysis, with only 132 women actively treated with progestogens.

TABLE 1

TABLE 1

Characteristics of the four pre-existing trials of progestogen use in RM

Our review and a subsequent review conducted for Cochrane in 201311 found that all four trials showed a trend towards benefit of progesterone, but confidence intervals (CIs) were wide and differences were not statistically significant for all but one of the four trials. A meta-analysis showed a statistically significant reduction in miscarriages (odds ratio 0.39, 95% CI 0.21 to 0.72; Figure 1). There was no evidence of statistical heterogeneity in the results (heterogeneity p-value 0.98).

FIGURE 1. Meta-analysis of the four pre-existing trials of progestogen use in RM (outcome: miscarriage).

FIGURE 1

Meta-analysis of the four pre-existing trials of progestogen use in RM (outcome: miscarriage). df, degrees of freedom.

Although this evidence would be graded level 1a in the evidence hierarchy (because it is a systematic review of randomised trials), our survey of clinicians showed that it did not result in the use of progesterone for RM by clinical practitioners, owing to the weak methods and small sample sizes employed in the four published trials. One example of weak methodology was in lack of concealment, which has been shown to exaggerate effect sizes by up to 41%,12 although there is some evidence that this exaggeration may not be a concern when the outcome is objective.13 Small sample sizes increase the likelihood of random error (generating the wide CIs in Figure 1). Nonetheless, the existing evidence presented a powerful reason to proceed with a trial of progesterone in RM, especially in consideration of the size of the effect observed and the low cost, widespread availability and convenience of the intervention, in addition to its safety profile.

Safety of progesterone supplementation in pregnancy

At the time of designing this study there was substantial evidence from in vitro fertilisation (IVF) practice that progestogen supplementation is safe to the mother and the fetus (at the proposed dose for the trial of 400 mg twice daily).1416

To further explore the question of safety, we conducted a review using the following search terms in MEDLINE (1966–2007) and EMBASE (1988–2007): (‘progesterone’ OR ‘progestational agents’ OR ‘progest$’) AND (‘adverse effects’ OR ‘complications’ OR ‘side effects’ OR ‘harm’) AND ‘pregnancy’. A systematic review of observational studies (both cohort and case–control studies) of first-trimester sex hormone exposure identified 14 studies, comprising 65,567 women.17 The sex hormone in several of these studies was progestogens alone or with other steroids.

Most of the evidence in our review did not show harm, particularly any external genital malformation in the offspring, but one case–control study suggested an association between hypospadias and progestogen use.18 Although findings from a case–control study represented weaker evidence than the better-quality evidence from larger cohort studies which did not substantiate this association, we decided to document all of the effects of progesterone in the PROMISE trial. More specifically, we decided to collect information about any neonatal genital abnormalities.

Meta-analyses of progesterone use in RM, in miscarriage2 and in the prevention of preterm birth19 did not identify any evidence of short-term safety concerns in women. However, it was not clear if these trials sought to document maternal side effects prospectively. In one study, intramuscular 17-OHP (hydroxyprogesterone) caused maternal adverse events (AEs) in 50% of women, largely due to injection site reactions.20 This concern did not apply to the PROMISE trial, in which the route of administration was vaginal. Side effects were not reported in studies of vaginal progesterone in the context of prevention of preterm births.21,22

Rationale

A trial of progesterone therapy in the treatment of unexplained RM was required for the following reasons:

  • The existing trials, although small and of poor quality, suggested a large benefit in a condition with substantial morbidity and costs.
  • A guideline by the RCOG and a Cochrane review called for a definitive trial to evaluate this research question.12
  • Participants in two unpublished surveys [one of women with RM (n = 88) and the other of gynaecologists (n = 102) treating women with RM] demonstrated an interest in progesterone therapy and a willingness to participate in a potential trial (Arri Coomarasamy, University of Birmingham, 2008, unpublished data).
  • If proven to be effective, the intervention would represent a low-cost, safe and easily deliverable therapy.

Specific objectives

Primary objective

  • To test the hypothesis that, in women with unexplained RM, progesterone (400-mg vaginal capsules, twice daily), started as soon as possible after a positive urinary pregnancy test (and no later than 6 weeks of gestation) and continued to 12 weeks of gestation, compared with placebo, would increase live births beyond 24 completed weeks of pregnancy by at least 10%.

Secondary objectives

  • To test the hypothesis that progesterone would improve various pregnancy and neonatal outcomes (such as reduced miscarriage rates and improvements in survival at 28 days of neonatal life).
  • To test the hypothesis that progesterone, compared with placebo, would not incur serious adverse events (SAEs) in either the mother or the neonate (such as genital abnormalities in the neonate).
  • To explore differential or subgroup effects of progesterone in various prognostic subgroups, including subgroups of:
    • maternal age (≤ 35 years or > 35 years)
    • number of previous miscarriages (3 or ≥ 4)
    • presence or absence of polycystic ovaries.
  • To perform an economic evaluation for cost-effectiveness.
Copyright © Queen’s Printer and Controller of HMSO 2016. This work was produced by Coomarasamy et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK362730

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