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Meta-Analysis
. 2018 Oct 8;10(10):CD003511.
doi: 10.1002/14651858.CD003511.pub4.

Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology

David M Haas  1 , Taylor J Hathaway, Patrick S Ramsey
Affiliations
Meta-Analysis

Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology

David M Haas et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, clinicians use progestogens (drugs that interact with the progesterone receptors), beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. This is an update of a review, last published in 2013.

Objectives: To assess the efficacy and safety of progestogens as a preventative therapy against recurrent miscarriage.

Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (6 July 2017) and reference lists from relevant articles, attempting to contact trial authors where necessary, and contacted experts in the field for unpublished works.

Selection criteria: Randomized or quasi-randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage.

Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two reviewers assessed the quality of the evidence using the GRADE approach.

Main results: Thirteen trials (2556 women) met the inclusion criteria. Nine of the included trials compared treatment with placebo and the remaining four trials compared progestogen administration with no treatment. The trials were a mix of multicenter and single-center trials, conducted in Egypt, India, Jordan, UK and USA. In six trials women had had three or more consecutive miscarriages and in seven trials women had suffered two or more consecutive miscarriages. Routes, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Eleven trials (2359 women) contributed data to the analyses.The meta-analysis of all women, suggests that there is probably a reduction in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.51 to 0.92, 11 trials, 2359 women, moderate-quality evidence). A subgroup analysis comparing placebo-controlled versus non-placebo-controlled trials and different routes of administration showed no differences between subgroups for miscarriage. However, there appears to be a subgroup difference for miscarriage between women with three or more prior miscarriages compared to women with two or more miscarriages, with a more pronounced effect in women with three or more prior miscarriages. However, it should be noted that there was high heterogeneity in the subgroup of women with three or more prior miscarriages.None of the trials reported on any secondary maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility.There was probably a slight benefit for women receiving progestogen seen in the outcome of live birth rate (RR 1.11, 95% CI 1.00 to 1.24, 7 trials, 2086 women, moderate-quality evidence). While the rate of preterm birth is probably reduced for women receiving progestogen, this outcome was mainly driven by one trial and thus should be interpreted with great caution (RR 0.59, 95% CI 0.39 to 0.89, 5 trials, 811 women, moderate-quality evidence). No clear differences were seen for women receiving progestogen for the other secondary outcomes of neonatal death or fetal genital abnormalities. A possible reduction in stillbirth was seen, but again this outcome was driven mainly by one trial and should be interpreted with caution (RR 0.38, 95% CI 0.24 to 0.58, 3 trials, 1199 women). There may be little or no difference in the rate of low birthweight and trials did not report on the secondary child outcomes of teratogenic effects or admission to a special care unit.

Authors' conclusions: For women with unexplained recurrent miscarriages, supplementation with progestogen therapy probably reduces the rate of miscarriage in subsequent pregnancies.

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Conflict of interest statement

David M Haas: none known

Taylor J Hathaway: none known

Patrick S Ramsey: I serve as an officer in Section 5 of District XI of the American College and Congress of Obstetricians and Gynecologists. I received compensation for this general work with ACOG but have not engaged in any specific work relevant to the topic of this review. I also serve on the Data Safety Monitoring Board for the KV Pharmaceutical RCT designed to evaluate the efficacy of 17‐hydroxyprogesterone caproate to prevent preterm birth. I received compensation for service as the DSMB chair from an independent data management organization and not from the pharmaceutical company.

Figures

Figure 1
Figure 1
Funnel plot of comparison 1. Progestogen versus placebo/no treatment, outcome 1.1 Miscarriage (all trials)
Figure 2
Figure 2
Study flow diagram
Figure 3
Figure 3
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figure 4
Figure 4
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Analysis 1.1
Analysis 1.1
Comparison 1 Progestogen versus placebo/no treatment, Outcome 1 Miscarriage (all trials).
Analysis 1.2
Analysis 1.2
Comparison 1 Progestogen versus placebo/no treatment, Outcome 2 Miscarriage (placebo‐controlled trials only).
Analysis 1.3
Analysis 1.3
Comparison 1 Progestogen versus placebo/no treatment, Outcome 3 Miscarriage (women with previous recurrent miscarriage only).
Analysis 1.4
Analysis 1.4
Comparison 1 Progestogen versus placebo/no treatment, Outcome 4 Miscarriage (by route of administration versus placebo).
Analysis 1.5
Analysis 1.5
Comparison 1 Progestogen versus placebo/no treatment, Outcome 5 Live birth rate.
Analysis 1.6
Analysis 1.6
Comparison 1 Progestogen versus placebo/no treatment, Outcome 6 Preterm birth.
Analysis 1.7
Analysis 1.7
Comparison 1 Progestogen versus placebo/no treatment, Outcome 7 Neonatal death.
Analysis 1.8
Analysis 1.8
Comparison 1 Progestogen versus placebo/no treatment, Outcome 8 Fetal genital abnormalities/virilization.
Analysis 1.9
Analysis 1.9
Comparison 1 Progestogen versus placebo/no treatment, Outcome 9 Stillbirth.
Analysis 1.10
Analysis 1.10
Comparison 1 Progestogen versus placebo/no treatment, Outcome 10 Low birthweight (< 2500 g).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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    3. ISRCTN92644181. 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). controlled‐trials.com/ISRCTN92644181 (first received 17 March 2009). - PMC - PubMed
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References to studies excluded from this review

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References to studies awaiting assessment

    1. Ismail A, Nasr A, Amin A, Al‐Inany H. Peri‐conceptional progesterone treatment in women with unexplained recurrent miscarriage, a randomized double‐blind controlled trial. Human Reproduction 2015;30:i194, abstract no: P‐167.
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References to ongoing studies

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    1. IRCT2013100114853N1. Effect of concomitant administration of vaginal progesterone and vitamin D3 in the treatment of unexplained recurrent abortion in pregnant women. en.search.irct.ir/view/15255 (first received 30 October 2013).
    1. NCT00193674. Oral dydrogesterone treatment during the first trimester of pregnancy in women with recurrent miscarriage: a double‐blind, prospectively randomized, placebo‐controlled, parallel group trial. clinicaltrials.gov/ct2/show/NCT00193674 (first received 11 Septamber 2005). - PubMed
    1. NCT02706470. A randomized, controlled trial of cyclosporin a for women with unexplained recurrent miscarriage. clinicaltrials.gov/ct2/show/record/NCT02706470 (first received 12 March 2016).
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References to other published versions of this review

    1. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD003511.pub2] - DOI - PubMed
    1. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2013, Issue 10. [DOI: 10.1002/14651858.CD003511.pub3] - DOI - PubMed
    1. Oates‐Whitehead RM, Haas DM, Carrier JAK. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD003511] - DOI - PubMed

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