Abstract
Background: Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks’ gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime, and 15% to 20% of pregnancies ending in a miscarriage. Progesterone has an important role in maintaining a pregnancy, and supplementation with different progestogens in early pregnancy has been attempted to rescue a pregnancy in women with early pregnancy bleeding (threatened miscarriage), and to prevent miscarriages in asymptomatic women who have a history of three or more previous miscarriages (recurrent miscarriage). Objectives: To estimate the relative effectiveness and safety profiles for the different progestogen treatments for threatened and recurrent miscarriage, and provide rankings of the available treatments according to their effectiveness, safety, and side-effect profile. Search methods: We searched the following databases up to 15 December 2020: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. Selection criteria: We included all randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage. Cluster-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded quasi- and non-randomised trials. Data collection and analysis: At least two review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We performed pairwise meta-analyses and indirect comparisons, where possible, to determine the relative effects of all available treatments, but due to the limited number of included studies only direct or indirect comparisons were possible. We estimated the relative effects for the primary outcome of live birth and the secondary outcomes including miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy, congenital abnormalities, and adverse drug events. Relative effects for all outcomes are reported separately by the type of miscarriage (threatened and recurrent miscarriage). We used the GRADE approach to assess the certainty of evidence. Main results: Our meta-analysis included seven randomised trials involving 5,682 women, and all provided data for meta-analysis. All trials were conducted in hospital settings. Across seven trials (14 treatment arms), the following treatments were used: three arms (21%) used vaginal micronized progesterone; three arms (21%) used dydrogesterone; one arm (7%) used oral micronized progesterone; one arm (7%) used 17-α-hydroxyprogesterone, and six arms (43%) used placebo. Women with threatened miscarriage. Based on the relative effects from the pairwise meta-analysis, vaginal micronized progesterone (two trials, 4090 women, risk ratio (RR) 1.03, 95% confidence interval (CI) 1.00 to 1.07, high-certainty evidence), and dydrogesterone (one trial, 406 women, RR 0.98, 95% CI 0.89 to 1.07, moderate-certainty evidence) probably make little or no difference to the live birth rate when compared with placebo for women with threatened miscarriage. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with threatened miscarriage. The pre-specified subgroup analysis by number of previous miscarriages is only possible for vaginal micronized progesterone in women with threatened miscarriage. In women with no previous miscarriages and early pregnancy bleeding, there is probably little or no improvement in the live birth rate (RR 0.99, 95% CI 0.95 to 1.04, high-certainty evidence) when treated with vaginal micronized progesterone compared to placebo. However, for women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). Women with recurrent miscarriage. Based on the results from one trial (826 women) vaginal micronized progesterone (RR 1.04, 95% CI 0.95 to 1.15, high-certainty evidence) probably makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. The evidence for dydrogesterone compared with placebo for women with recurrent miscarriage is of very low-certainty evidence, therefore the effects remain unclear. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with recurrent miscarriage. Additional outcomes. All progestogen treatments have a wide range of effects on the other pre-specified outcomes (miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy) in comparison to placebo for both threatened and recurrent miscarriage. Moderate- and low-certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened (congenital abnormalities RR 1.00, 95% CI 0.68 to 1.46, moderate-certainty evidence; adverse drug events RR 1.07 95% CI 0.81 to 1.39, moderate-certainty evidence) or recurrent miscarriage (congenital abnormalities 0.75, 95% CI 0.31 to 1.85, low-certainty evidence; adverse drug events RR 1.46, 95% CI 0.93 to 2.29, moderate-certainty evidence) compared with placebo. There are limited data and very low-certainty evidence on congenital abnormalities and adverse drug events for the other progestogens. Authors' conclusions: The overall available evidence suggests that progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage. However, vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early pregnancy bleeding, with likely no difference in adverse events. There is still uncertainty over the effectiveness and safety of alternative progestogen treatments for threatened and recurrent miscarriage.
Original language | English |
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Article number | CD013792 |
Journal | Cochrane Database of Systematic Reviews |
Volume | 2021 |
Issue number | 4 |
DOIs | |
Publication status | Published - 19 Apr 2021 |
Bibliographical note
Funding Information:Arri Coomarasamy (AC): was the National Clinical Co-ordinator for the UK National Institute for Health Research HTA Project Award 08/38/01 entitled 'First trimester progesterone therapy in women with a history of unexplained recurrent miscarriages: A randomised, double-blind, placebo-controlled, multi-centre trial [The PROMISE (PROgesterone in recurrent MIScarriage) Trial]'. AC was also the Chief Investigator for the UK National Institute for Health Research HTA Project Award 12/167/26 entitled 'Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial)'. AC did not participate in any decisions regarding these trials (i.e. assessment for inclusion/exclusion, trial quality, data extraction) for the purposes of this review or future updates; these tasks have been carried out by other members of the team who were not directly involved in the trial. This work is supported by Tommy's Charity who fund the Tommy's National Centre for Miscarriage Research, which is held by AC. This review is supported by an award from the NIHR Incentive Awards Scheme 2020, NIHR133289.
Funding Information:
This project is funded by the National Institute for Health Research (NIHR) [NIHR Review Incentive Award number (NIHR133289). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
Contact with study authors for additional information: yes. Additional data from authors: no. This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). The authors declare that they have no competing interests.
Funding Information:
As part of the pre-publication editorial process, this protocol has been commented on by five peers (an editor and four referees who are external to the editorial team), a member of our international panel of consumers, and our Group's Statistical Adviser. The review authors are grateful to the following peer reviewers for their time and comments: Dr LC Morley (MRC Clinical Research Fellow, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, UK); Dr Nigel AB Simpson (Senior Lecturer in Obstetrics and Gynaecology, Division of Women's and Children's Health, School of Medicine, University of Leeds, UK); and to two referees who wish to remain anonymous. This project was supported by the National Institute for Health Research (NIHR), via Evidence Synthesis Programme funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, National Health Service (NHS) or the Department of Health and Social Care. This project is funded by the National Institute for Health Research (NIHR) [NIHR Review Incentive Award number (NIHR133289). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
This review includes seven two-arm randomised trials, published between 1963 and 2020, involving 5,682 women. All studies were reported in English and were conducted in hospital settings across five countries: Australia, Germany, Hong Kong, United Kingdom, and Singapore. The included trials included a median of 141 participants (interquartile range (IQR) 53, 621). Two studies were funded by the NIHR Health Technology Assessment programme, UK (Coomarasamy 2015; Coomarasamy 2019), one study was funded by Health and Medical Research Fund, Hong Kong Special Administrative Region (Chan 2020), one study was funded by Khoo Student Research Award and Pitch for Grant Award, Singapore (Siew 2018), one study was funded by Schering AG (Shearman 1963) and two studies did not report a source of funding (Gerhard 1987; MacDonald 1972). None of the studies reported any declarations of interest.
Funding Information:
Adam J Devall (AJD): was the trial manager for the UK National Institute for Health Research HTA Project Award 12/167/26 entitled 'Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial)'. AJD did not participate in any decisions regarding these trials (i.e. assessment for inclusion/exclusion, trial quality, data extraction) for the purposes of this review or future updates; these tasks have been carried out by other members of the team who were not directly involved in the trial. This work is supported by Tommy's Charity who fund
Funding Information:
Contact with study authors for additional information: no. Additional data from authors: no. The study was funded by Schering AG. Declarations of interest were not reported.
Publisher Copyright:
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ASJC Scopus subject areas
- Pharmacology (medical)