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. 2021 Apr 19;4(4):CD013792.
doi: 10.1002/14651858.CD013792.pub2.

Progestogens for preventing miscarriage: a network meta-analysis

Adam J Devall  1 , Argyro Papadopoulou  1 , Marcelina Podesek  1 , David M Haas  2 , Malcolm J Price  3 , Arri Coomarasamy  1 , Ioannis D Gallos  1
Affiliations

Progestogens for preventing miscarriage: a network meta-analysis

Adam J Devall et al. Cochrane Database Syst Rev. .

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.

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Conflict of interest statement

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 the Tommy's National Centre for Miscarriage Research, which is held by Prof Arri Coomarasamy (AC). This review is supported by an award from the NIHR Incentive Awards Scheme 2020, NIHR133289.

Argyro Papadopoulou (AP): is undertaking a PhD studentship supported by Tommy's Charity who fund the Tommy's National Centre for Miscarriage Research, which is held by Prof Arri Coomarasamy. This review is supported by an award from the NIHR Incentive Awards Scheme 2020, NIHR133289.

Marcelina Podesek (MP): is supported by Tommy's Charity who fund the Tommy's National Centre for Miscarriage Research, which is held by Prof Arri Coomarasamy (AC). This review is supported by an award from the NIHR Incentive Awards Scheme 2020, NIHR133289.

David M Haas (DMH): holds National Institutes of Health (NIH) research grants that are unrelated to this work. DMH was the lead author on a Cochrane review on progestogens for recurrent miscarriage and attends to patients with recurrent miscarriage.

Malcolm J Price (MJP): none known.

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.

Ioannis D Gallos (IDG): was an author 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)'. IDG 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 Prof Arri Coomarasamy (AC). This review is supported by an award from the NIHR Incentive Awards Scheme 2020, NIHR133289.

Figures

1
1
Process for using the Cochrane Pregnancy and Childbirth criteria for assessing the trustworthiness of a study
2
2
Study flow diagram.
3
3
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
5
5
Network diagram for the outcome of live birth in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
6
6
Network diagram for the outcome of miscarriage in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, orange for low‐certainty evidence, and red for very low‐certainty evidence.
7
7
Network diagram for the outcome of preterm birth in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, and orange for low‐certainty evidence.
8
8
Network diagram for the outcome of stillbirth in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, and red for very low‐certainty evidence.
9
9
Network diagram for the outcome of ectopic pregnancy in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
10
10
Network diagram for the outcome of congenital abnormalities in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, and red for very low‐certainty evidence.
11
11
Network diagram for the outcome of adverse drug events in women with threatened miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, and red for very low‐certainty evidence.
12
12
Network diagram for the outcome of live birth in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, and red for very low‐certainty evidence.
13
13
Network diagram for the outcome of miscarriage in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence, orange for low‐certainty evidence, and red for very low‐certainty evidence.
14
14
Network diagram for the outcome of preterm birth in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
15
15
Network diagram for the outcome of stillbirth in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
16
16
Network diagram for the outcome of ectopic pregnancy in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
17
17
Network diagram for the outcome of congenital abnormalities in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
18
18
Network diagram for the outcome of adverse drug events in women with recurrent miscarriage. The nodes represent an intervention and their size is proportional to the number of trials comparing this intervention to any other. The lines connecting each pair of interventions represent a direct comparison and are drawn proportional to the number of trials making each direct comparison. Numbers on the lines represent the number of trials and participants for each comparison. The colour of the line is light green for moderate‐certainty evidence.
1.1
1.1. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 1: Live birth
1.2
1.2. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 2: Miscarriage (defined as delivery before 24 weeks of gestation)
1.3
1.3. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 3: Preterm birth (defined as birth before 37 weeks of gestation)
1.4
1.4. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 4: Stillbirth
1.5
1.5. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 5: Ectopic pregnancy
1.6
1.6. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 6: Congenital abnormalities
1.7
1.7. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 7: Adverse drug events
1.8
1.8. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 8: Live birth (subgrouped by no previous miscarriages and one or more previous miscarriages)
1.9
1.9. Analysis
Comparison 1: Threatened miscarriage: Vaginal micronized progesterone versus placebo, Outcome 9: Live birth (subgrouped by maternal age)
2.1
2.1. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 1: Live birth
2.2
2.2. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 2: Miscarriage (defined as delivery before 24 weeks of gestation)
2.3
2.3. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 3: Preterm birth (defined as birth before 37 weeks of gestation)
2.4
2.4. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 4: Stillbirth
2.5
2.5. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 5: Congenital abnormalities
2.6
2.6. Analysis
Comparison 2: Threatened miscarriage: Dydrogesterone versus placebo, Outcome 6: Adverse drug events
3.1
3.1. Analysis
Comparison 3: Threatened miscarriage: Oral micronized progesterone versus dydrogesterone, Outcome 1: Miscarriage (defined as delivery before 24 weeks of gestation)
3.2
3.2. Analysis
Comparison 3: Threatened miscarriage: Oral micronized progesterone versus dydrogesterone, Outcome 2: Adverse drug events
4.1
4.1. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 1: Live birth
4.2
4.2. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 2: Miscarriage (defined as delivery before 24 weeks of gestation)
4.3
4.3. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 3: Preterm birth (defined as birth before 37 weeks of gestation)
4.4
4.4. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 4: Stillbirth
4.5
4.5. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 5: Ectopic pregnancy
4.6
4.6. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 6: Congenital abnormalities
4.7
4.7. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 7: Adverse drug events
4.8
4.8. Analysis
Comparison 4: Recurrent miscarriage: Vaginal micronized progesterone versus placebo, Outcome 8: Live birth (subgrouped by maternal age)
5.1
5.1. Analysis
Comparison 5: Recurrent miscarriage: Dydrogesterone versus placebo, Outcome 1: Live birth
5.2
5.2. Analysis
Comparison 5: Recurrent miscarriage: Dydrogesterone versus placebo, Outcome 2: Miscarriage (defined as delivery before 24 weeks of gestation)
6.1
6.1. Analysis
Comparison 6: Recurrent miscarriage: 17‐α‐hydroxyprogesterone versus placebo, Outcome 1: Miscarriage (defined as delivery before 24 weeks of gestation)
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013792

References

References to studies included in this review

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Govaerts‐Videtzky 1965 {published data only}
    1. Govaerts-Videtzky M, Martin L, Hubinont PO. A double-blind study of progestogen treatment in spontaneous abortion. (Preliminary report). Journal of Obstetrics & Gynaecology of the British Commonwealth 1965;72(6):1034. - PubMed
Ismail 2018 {published data only}
    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 (Oxford, England) 2015;30:i194.
    1. Ismail AM, Abbas AM, Ali MK, Amin AF. Peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial. Journal of Maternal-Fetal & Neonatal Medicine 2018;31(3):388-94. - PubMed
Johnson 1975 {published data only}
    1. Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor. New England Journal of Medicine 1975;293(14):675-80. - PubMed
Klopper 1965 {published data only}
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LeVine 1964 {published data only}
    1. LeVine L. Habitual abortion. A controlled clinical study of progestational therapy. Western Journal of Surgery 1964;72:30-6. - PubMed
Moller 1966 {published data only}
    1. Moller KJ, Fuchs F. [Treatment of threatened abortion with methylprogesterone acetate]. Ugeskrift for Laeger 1966;128:1457-60. - PubMed
Nyboe Andersen 2002 {published data only}
    1. Nyboe Andersen A, Popovic-Todorovic B, Schmidt KT, Loft A, Lindhard A, Højgaard A, et al. Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial. Human Reproduction (Oxford, England) 2002;17(2):357-61. - PubMed
Ozer 2020 {published data only}
    1. Ozer G, Yuksel B, Yucel Cicek OS, Kahraman S. Oral dydrogesterone vs. micronized vaginal progesterone gel for luteal phase support in frozen-thawed single blastocyst transfer in good prognosis patients. Journal of Gynecology Obstetrics and Human Reproduction 2020;50(5):1020-30. - PubMed
Porcaro 2015 {published data only}
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Prietl 1992 {published data only}
    1. Prietl G, Diedrich K, Ven HH, Luckhaus J, Krebs D. The effect of 17 alpha-hydroxyprogesterone caproate/oestradiol valerate on the development and outcome of early pregnancies following in vitro fertilization and embryo transfer: a prospective and randomized controlled trial. Human Reproduction (Oxford, England) 1992;7 Suppl 1:1-5. - PubMed
Pustotina 2018 {published data only}
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Rehal 2020 {published data only}
    1. Rehal A, Benko Z, De Paco Matallana C, Syngelaki A, Janga D, Cicero S. Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial. American Journal of Obstetrics & Gynecology 2020;26:26. - PubMed
Reijnders 1988 {published data only}
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Shu 2002 {published data only}
    1. Shu J, Miao P, Wang RJ. [Clinical observation on effect of Chinese herbal medicine plus human chorionic gonadotropin and progesterone in treating anticardiolipin antibody-positive early recurrent spontaneous abortion]. Chinese Journal of Integrated Traditional & Western Medicine 2002;22(6):414-6. - PubMed
Sondergaard 1985 {published data only}
    1. Sondergaard F, Ottesen B, Detlefsen GU. Treatment with progesterone in threatened abortion and low level of serum progesterone. A double blind randomized trial. Contraception Fertilite Sexualite 1985;13(12):1227-31.
Song 2007 {published data only}
    1. Song YL, Zhu LP. [The fetus protection effects of Zhixue Baotai Decoction on women of early threatened abortion with dark area surrounding pregnancy sac]. Chinese Journal of Integrated Traditional & Western Medicine 2007;27(11):1025-8. - PubMed
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Tomic 2015 {published data only}
    1. Tomic V, Tomic J, Klaic DZ, Kasum M, Kuna K. Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2015;186:49-53. - PubMed
Zhang 2000 {published data only}
    1. Zhang J, Zhang Y, Liu G. [Clinical and experimental study on yun'an granule in treating threatened abortion]. Chinese Journal of Integrated Traditional & Western Medicine 2000;20(4):251-4. - PubMed

References to studies awaiting assessment

Abrar 2017 {published data only}
    1. Abrar S, Abrar T, Tahir M, Sayyed E. Role of progesterone in the treatment of threatened miscarriage in first trimester. Journal of Medical Sciences (Peshawar) 2017;25(4):407-10.
Agarwal 2016 {published data only}
    1. Agarwal N. Role of inflammatory markers in recurrent pregnancy loss and effect of oral micronized therapy on these cases. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=14740.
Alimohamadi 2013 {published data only}
    1. Alimohamadi S, Javadian P, Gharedaghi MH, Javadian N, Alinia H, Khazardoust, S. Progesterone and threatened abortion: a randomized clinical trial on endocervical cytokine concentrations. Journal of Reproductive Immunology 2013;98(1-2):52-60. - PubMed
Czajkowski 2007 {published data only}
    1. Czajkowski K, Sienko J, Mogilinski M, Bros M, Szczecina R, Czajkowska A. Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone. Fertility & Sterility 2007;87(3):613-8. - PubMed
Ghosh 2014 {published data only}
    1. Ghosh S, Chattopadhyay R, Goswami S, Chaudhury K, Chakravarty B, Ganesh A. Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study. Journal of Obstetrics & Gynaecology Research 2014;40(7):1871-6. - PubMed
Kumar 2014 {published data only}
    1. Kumar A, Begum N, Prasad S, Aggarwal S, Sharma S. Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial. Fertility & Sterility 2014;102(5):1357-63.e3. - PubMed
Omar 2005 {published data only}
    1. Omar MH, Mashita MK, Lim PS, Jamil MA. Dydrogesterone in threatened abortion: pregnancy outcome. Journal of Steroid Biochemistry & Molecular Biology 2005;97(5):421-5. - PubMed
Palagiano 2004 {published data only}
    1. Palagiano A, Bulletti C, Pace MC, DE Ziegler D, Cicinelli E, Izzo A. Effects of vaginal progesterone on pain and uterine contractility in patients with threatened abortion before twelve weeks of pregnancy. Annals of the New York Academy of Sciences 2004;1034:200-10. - PubMed
Pandian 2009 {published data only}
    1. Pandian RU. Dydrogesterone in threatened miscarriage: a Malaysian experience. Maturitas 2009;65 Suppl 1:S47-50. - PubMed
Vincze 2006 {published data only}
    1. Vincze E, Molnar-GB, Foldesi I, Pal A. Treatment possibilities using progestagens and progesteron-like preparations in threatened abortion. Magyar Noorvosok Lapja 2006;69(4):281-4.
Yadav 2015 {published data only}
    1. Yadav R, Yadav S, Jain A. To study the impact of progesterone (dydrogesterone) on proinflammatory (IL-6 and TNF-alpha) and antiinflammatory (IL-10) cytokines in threatened abortion. International Journal of Gynaecology and Obstetrics 2015;131:E196.
Yassaee 2014 {published data only}
    1. Yassaee F, Shekarriz-Foumani R, Afsari S, Fallahian M. The effect of progesterone suppositories on threatened abortion: a randomized clinical trial. Journal of Reproduction & Infertility 2014;15(3):147-51. - PMC - PubMed

References to ongoing studies

ACTRN12611000405910 {published data only}
    1. ACTRN12611000405910. In women with threatened miscarriage, does progesterone supplementation increase the likelihood of live birth? https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336813.
ChiCTR‐IOR‐15007526 {published data only}
    1. ChiCTR-IOR-15007526. Chinese herbal medicine and micronized progesterone for threatened miscarriage: an international cooperation multicenter randomized controlled trial. http://www.chictr.org.cn/showproj.aspx?proj=12677.
CTRI/2020/10/028244 {published data only}
    1. CTRI/2020/10/028244. A clinical trial to study the effects of two drugs dydrogesterone and micronized progesterone in pregnant women with threatened abortion. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=38656.
IRCT20120104008611N10 {published data only}
    1. IRCT20120104008611N10. The effect of dydrogesterone and micronized progesterone on threatened abortion. http://en.irct.ir/trial/33884.
IRCT20120104008611N8 {published data only}
    1. IRCT20120104008611N8. The effect of dydrogesterone and Cyclogest on threatened abortion. http://en.irct.ir/trial/32531.
IRCT20120104008611N9 {published data only}
    1. IRCT20120104008611N9. Comparison of the effect of two progesteron drugs in protection of abortion. http://en.irct.ir/trial/30167.
IRCT20120918010876N5 {published data only}
    1. IRCT20120918010876N5. Evaluation of the effect of oral dydrogesterone (Duphaston) in threatened abortion at first trimester. http://en.irct.ir/trial/28300.
NCT02145767 {published data only}
    1. NCT02145767. Progesterone for the prevention of miscarriage and preterm birth in women with first trimester bleeding: PREEMPT Trial. https://ClinicalTrials.gov/show/NCT02145767.
NCT02690129 {published data only}
    1. NCT02690129. Vaginal progesterone for treatment of threatened miscarriage. https://ClinicalTrials.gov/show/NCT02690129.
NCT03930212 {published data only}
    1. NCT03930212. Progesterone supplementation in threatened abortion. https://clinicaltrials.gov/show/NCT03930212.

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References to other published versions of this review

Devall 2020
    1. Devall AJ, Papadopoulou A, Haas DM, Price MJ, Coomarasamy A, Gallos ID. Progestogens for preventing miscarriage: a network meta‐analysis. Cochrane Database of Systematic Reviews 2020, Issue 11. Art. No: CD013792. [DOI: 10.1002/14651858.CD013792] - DOI - PMC - PubMed

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