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Cited by 130Reproductive System and PregnancyReproductive Health and ContraceptionPregnancy and Medication Impact

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

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Haas, David M, Hathaway, Taylor J, Ramsey, Patrick S·2018·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd003511.pub4PMC PMC6516817
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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. Since publication of the 2018 update of this review, we have been advised that the Ismail 2017 study is currently the subject of an investigation by the Journal of Maternal-Fetal & Neonatal Medicine. We have now moved this study from 'included studies' to 'Characteristics of studies awaiting classification' until the outcome of the investigation is known. 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from relevant articles, attempting to contact trial authors where necessary, and contacted experts in the field for unpublished works.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: Twelve trials (1,856 women) met the inclusion criteria. Eight 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 India, Jordan, UK and USA. In five 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. Ten trials (1684 women) contributed data to the analyses. The meta-analysis of all women, suggests that there may be a reduction in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (average risk ratio (RR) 0.73, 95% confidence interval (CI) 0.54 to 1.00, 10 trials, 1684 women, moderate-quality evidence). A subgroup analysis comparing placebo-controlled versus non-placebo-controlled trials, trials of women with three or more prior miscarriages compared to women with two or more miscarriages and different routes of administration showed no clear differences between subgroups for miscarriage. 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 1.07, 95% CI 1.00 to 1.13, 6 trials, 1411 women, moderate-quality evidence). We are uncertain about the effect on the rate of preterm birth because the evidence is very low-quality (RR 1.13, 95% CI 0.53 to 2.41, 4 trials, 256 women, very low-quality evidence). No clear differences were seen for women receiving progestogen for the other secondary outcomes including neonatal death, fetal genital abnormalities or stillbirth. 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 may reduce the rate of miscarriage in subsequent pregnancies.

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72 of 72 references verified0 citation errors · 0 not checkable

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  • In the 2018 Cochrane meta-analysis, subgroup analysis showed a significantly more pronounced effect in women with three or more versus two or more prior miscarriages.

    “with subgroup analysis showing a significantly more pronounced effect in women with three or more versus two or more prior miscarriages.196”

    From Recurrent MiscarriageGreen‐top Guideline No. 17 (2023) · cites this paper as [196]

    In “Trials with placebo controls,” the review reports no evidence of a difference between the prior-miscarriage subgroups (interaction test P = 0.15). Although the estimated reduction was larger in the three-or-more group, the review does not find that the difference was statistically significant. (LLM, conf=0.94)

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  • A 2018 Cochrane meta-analysis reported that progestogen supplementation compared with placebo/controls reduces the number of miscarriages (RR 0.69, 95% CI 0.51-0.92; 11 trials, 2359 women; moderate-quality evidence).

    “A meta-analysis of the Cochrane collaboration in 2018 reported a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/ controls (RR 0.69, 95% CI 0.51-0.92,11 trials, 2359 women, moderate-quality evidence)”

    From Recurrent MiscarriageGreen‐top Guideline No. 17 (2023) · cites this paper as [196]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • The updated meta-analysis concluded that there may still be a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/controls (RR 0.73, 95% CI 0.54-1.00; ten trials, 1684 women; moderate-quality evidence).

    “The updated meta-analysis concluded that there may still be a reduction in the number of miscarriages for women given progestogen supplementation compared with placebo/controls (RR 0.73, 95% CI 0.54-1.00,ten trials, 1684 women, moderate-quality evidence)”

    From Recurrent MiscarriageGreen‐top Guideline No. 17 (2023) · cites this paper as [198]

  • In the updated meta-analysis, subgroup analysis did not show significant differences between women with three or more versus two or more prior miscarriages.

    “A subgroup analysis on this occasion did not show significant differences between women with three or more versus two or more prior miscarriages.198”

    From Recurrent MiscarriageGreen‐top Guideline No. 17 (2023) · cites this paper as [198]

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1 of the 73 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Berle P, Budenz M, Michaelis J. Is hormonal therapy still justified in imminent abortion?. Zeitschri fur Geburtshilfe und Perinatologie 1980;184:353-8.
  2. Deeks JJ, Higgins JP, Altman DG (editors) on behalf of the Cochrane Statistical Methods Group. Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017), Cochrane, 2017. Available from www.training.cochrane.org/handbook.
  3. Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm Dyregrove 1987 Dyregrove A, Mathieson SB. Stillbirth, neonatal death and SIDS: parental reactions. Scandanavian Journal of Psychology 1987;28:104-14.
  4. Grudzinskas JG. Endocrinocolgical and metabolical assessment of early pregnancy. In: Chamberlain G editor(s). Tumbull's Obstetrics. London: Pearson Professional Ltd, 1995.
  5. Howie PG. Abortion and ectopic pregnancy. In: Whitfield CR editor(s). Dewhurst's Textbook of Obstetrics and Gynaecology for Postgraduates. Oxford: Blackwell Science Ltd, 1995.
  6. Review Manager 2014 [Computer program] Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Royal 2001 Royal College of Obstetricians and Gynaecologists. The management of recurrent miscarriage. www.rcog.org.uk/ guidelines/recurrent.html (accessed 2001).

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Authors
Haas, D. M., Hathaway, T. J., & Ramsey, P. S.
Affiliations
  • Indiana University School of Medicine (US)
  • Uniformed Services University of the Health Sciences (US)
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2018-10-09
Volume
10
Issue
11
Pages
CD003511-CD003511
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd003511.pub4
PMC
PMC6516817
OpenAlex
W2897567760
Cited by
130
References
73
Citations by year
2025: 8 · 2024: 19 · 2023: 22 · 2022: 23 · 2021: 26 · 2020: 21 · 2019: 9 · 2018: 2
FWCI
1.48
Type
journal article
Language
en
Update notices
new_version (2019-11-20)
Open access
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute for Health and Care Research
  • National Institutes of Health
  • Evidence Synthesis Programme
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
Keywords
progestogens, recurrent pregnancy loss, miscarriage prevention, progesterone supplementation, first trimester, treatment efficacy, treatment safety, route of administration, subgroup analysis, risk of bias, implantation, pregnancy loss prevention
MeSH terms
Abortion, Spontaneous, Abortion, Habitual, Female, Humans, Placebos, Pregnancy, Pregnancy Trimester, Second, Progestins, Randomized Controlled Trials as Topic, Premature Birth, Live Birth

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