Clinical Question: Brief description of patient problem/setting (summarize the case very briefly)

Miscarriage is a common complication observed in pregnancies. It is the spontaneous loss of pregnancy prior to the 20-week gestation mark. Progesterone, a hormone with pivotal physiological functions, serves to prime the uterus for embryo implantation, and inhibit contractions. Consequently, it may play a role in preventing the miscarriage of the embryo. A deficiency in progesterone secretion during early pregnancy has been associated with miscarriages. To counter this, progesterone supplementation has been employed as a therapeutic approach for averting impending miscarriages and curtailing spontaneous pregnancy loss. A patient wants to know how effective progesterone is and what are some complications from the usage of it.

PICO Question: Clearly state the question (including outcomes or criteria to be tracked)

In cases of threatened abortions, does the administration of progesterone lead to lower complications/adverse events compared to no intervention?

PICO search terms:

P	I	C	O
Threatened abortions	Progesterone	Control	Effectiveness
Threatened miscarriage	Dydrogesterone	Placebo	Pregnancy related complications
	Progesterone supplementation	No intervention	Mortality
	Vaginal micronized progesterone (Utrogestan)		Adverse Events

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.

Database	Terms	Filter	Articles
Wiley Online Library	Threatened abortions and progesterone	JournalsFrom 2015-2023Full Access	2
Cochrane Library (Wiley)	Threatened abortions and progesterone	Best Match, English	1
PubMed	Threatened abortions and progesterone	Best Match, Free Full Text, English, Meta-Analysis, Randomized Controlled Trial, Controlled Clinical Trial, Systematic	13
JAMA	Threatened abortions and progesterone	Relevance	2
TRIP Database	Threatened abortions and progesterone	Toggle All Filters, Systematic Review	2
Google Scholar	Threatened abortions and progesterone	Sort by Relevance, Review Articles, 2015- 2023	330

Results found: 350

Explain how you narrow your choices to the few selected articles.

I chose to pick the most recent articles and the ones more relevant to my topic. Some search databases like Google Scholar had limited filter options, however, not all of the research articles were relevant to the topic of threatened abortions or progesterone usage. During my research, I needed to sort through the results to find those related to threatened abortions and progesterone usage. A lot of the articles I found from PubMed, Cochrane, JAMA, and Trip Database reappeared in Google Scholar. In addition, most of the results from Google Scholar were not relevant to the search. Therefore, consideration only of the articles from JAMA, TRIP Database, Pubmed, and Cochrane was made. I extracted these articles by reading the titles of the articles and abstract to ensure they met my goals or were related to it. When narrowing down to 6 articles that answer my specific question I looked for Systematic Reviews, Cohort and RCTs which have higher levels of evidence unlike a case study. 

Articles Chosen:

Citation:Lee, H. J., Park, T. C., Kim, J. H., Norwitz, E., & Lee, B. (2017). The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis. BioMed research international, 2017, 3616875. https://doi.org/10.1155/2017/3616875

Abstract Objective: To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion.Methods: In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria.Results: The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; P = 0.001; I2, 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups.Conclusion: Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion.

Citation:Devall, A. J., Papadopoulou, A., Podesek, M., Haas, D. M., Price, M. J., Coomarasamy, A., & Gallos, I. D. (2021). Progestogens for preventing miscarriage: a network meta-analysis. The Cochrane database of systematic reviews, 4(4), CD013792. https://doi.org/10.1002/14651858.CD013792.pub2

AbstractBackground: 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.

Citation:McLindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., Vane, M., Baker, T., Gleed, M., Grey, S., Tettamanzi, L., Mol, B. W. J., & Li, W. (2023). Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial. Human reproduction (Oxford, England), 38(4), 560–568. https://doi.org/10.1093/humrep/dead029

AbstractStudy question: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?Summary answer: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.What is known already: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.Study design, size, duration: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.Participants/materials, setting, methods: This trial was conducted at the Mater Mothers’ Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.Main results and the role of chance: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.Limitations, reasons for caution: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.Wider implications of the findings: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.Study funding/competing interest(s): Mothers’ and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.

Citation:Coomarasamy, A., Harb, H. M., Devall, A. J., Cheed, V., Roberts, T. E., Goranitis, I., Ogwulu, C. B., Williams, H. M., Gallos, I. D., Eapen, A., Daniels, J. P., Ahmed, A., Bender-Atik, R., Bhatia, K., Bottomley, C., Brewin, J., Choudhary, M., Crosfill, F., Deb, S., Duncan, W. C., … Middleton, L. J. (2020). Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Health technology assessment (Winchester, England), 24(33), 1–70. https://doi.org/10.3310/hta24330

Abstract:Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.Setting: A total of 48 hospitals in the UK.Participants: Women aged 16-39 years with early pregnancy bleeding.Interventions: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.Main outcome measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.Results: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.

Citation:Wang, X. X., Luo, Q., & Bai, W. P. (2019). Efficacy of progesterone on threatened miscarriage: difference in drug types. Journal of Obstetrics and Gynaecology Research, 45(4), 794-802.

AbstractAimTo investigate whether treatment with progesterone would decrease the incidence of miscarriage in women who faced threatened miscarriage.MethodsRandomized controlled trials (RCT) were identified by searching PubMed, Embase, Cochrane Library and Web of Science. Trials were included if they compared progesterone with placebo, no treatment or any other treatment given in an effort to treat threatened miscarriage. Pregnant prophylaxis drugs were not included without strict progesterone type, language and progesterone management. The primary outcome was the incidence of miscarriage. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI).ResultsEight RCT including 845 women who faced threatened miscarriage were analyzed. Pooled data from the eight trials showed that women with threatened miscarriage who were randomized to the progesterone group had a lower risk of threatened miscarriage (RR = 0.64, 95% CI 0.48–0.85). Dydrogesterone was shown to have a lower risk of miscarriage (RR = 0.49, 95% CI 0.33–0.75) than natural progesterone (RR = 0.69, 95% CI 0.40–1.19). Oral management was demonstrated to have a lower risk of miscarriage (RR = 0.55, 95% CI 0.38–0.79) compared with vaginal administration (RR = 0.58, 95% CI 0.28–1.21).ConclusionOur findings show that progesterone agents are effective in reducing the incidence of miscarriage in threatened miscarriage. Dydrogesterone, but not natural progesterone, was associated with a lower risk of miscarriage. Given the limitations of the studies included in our meta-analysis, it is difficult to recommend route and dose of progesterone therapy. Further head-to-head trials of gestational weeks and long-time follow-up are required.

Citation:Zhao, H., He, W., & Yang, Z. (2022). A pairwise and network meta-analysis comparing the efficacy and safety of progestogens in threatened abortion. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 156(3), 383-393.

AbstractBackground: Progesterone is widely used to prevent threatened miscarriage.Objective: To determine the efficacy and safety of progestogens in the treatment of threatened miscarriage.Search strategy: PubMed, Cochrane Library, EMBASE, CNKI, CBM, and WanFang databases were searched for randomized controlled trials (RCTs) published from the date of inception of the database to August 2020. The search terms included “abortion, threatened,” “progesterone,” and “progestogens.”Selection criteria: A network meta-analysis was conducted of all the RCTs on threatened abortion so far to compare the efficacy and safety of different progestogens in the treatment of threatened abortion.Data collection and analysis: Odds ratios for dichotomous data with 95% confidence intervals were calculated and the data were pooled using a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated for efficacy and safety with different interventions.Main results: A total of 59 RCTs with 10 424 participants were included. Oral dydrogesterone (DYD) had the lowest risk of miscarriage (SUCRA 100.0%), followed by vaginal progesterone (SUCRA 67.9%). Oral micronized progesterone had the highest risk of miscarriage (SUCRA 15.7%).Conclusion: Oral DYD is effective in the treatment of threatened miscarriage. The results of the present study can help patients make informed decisions about treatment options for threatened miscarriage.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Lee, H. J., Park, T. C., Kim, J. H., Norwitz, E., & Lee, B. (2017).	Systematic Review and Meta-Analysis	9 RCT Trials were used. There was a total of 913 pregnant women.322 were treated with oral dydrogesterone213 were treated with vaginal progesterone378 were in the control group Inclusion criteria:-Pregnant women dx with threatened abortion before 20 weeks gestation.- Studies that compared any type of progesterone therapy with either placebo or conservative treatment. -Studies that compared different administration routes of progesterone therapy.-Studies that reported the incidence of miscarriage, and randomized or quasi-randomized controlled studies.  Exclusion criteria: Studies that were not case-match controlled, noncomparative studies, studies not in English, review articles, editorials, letters, case reports, in vitro research studies, and studies using other therapeutic agents.	The outcome measured:(1) The incidence of miscarriage	– Progesterone therapy may be effective in preventing miscarriages in pregnant women with threatened abortion. In particular, oral dydrogesterone prevented miscarriage in pregnant women more effectively than the control-treated groups (placebo or conservative treatment), although there was no difference between oral and vaginal progestational agents in preventing miscarriages in pregnant women experiencing threatened abortion. – Additionally, the oral and vaginal routes of administration are associated with acceptable and minimal side effects, respectively, whereas side effects were reported in one-third of pregnant women who received weekly intramuscular injections of progesterone to prevent recurrent preterm delivery.	-Some limitation of the study was the small numbers of pregnant women and studies that were included. -The study only compared oral and vaginal administration, the study did not include intramuscular progesterone administration
Devall, A. J., Papadopoulou, A., Podesek, M., Haas, D. M., Price, M. J., Coomarasamy, A., & Gallos, I. D. (2021).	Systematic Review & Meta-analysis	-Authors used databases like: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). 7 RCT involving 5,682 women:-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, -six arms (43%) used placebo –Inclusion Criteria: (1) All randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage(2) Cluster-randomised trials were eligible for inclusion(3) Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. -Exclusion Criteria: Quasi- and non-randomised trials.	1* Outcomes: -Live Birth 2ndry Outcomes:-Miscarriage (<24 weeks of gestation).-Preterm birth (< 37 weeks of gestation). -Stillbirth.-Ectopic pregnancy and congenital abnormalities.-Adverse drug events.	-Available progestogen treatments overall make little to no difference in live birth and miscarriage rates for women with threatened miscarriage. -Vaginal micronized progesterone is the only treatment that shows it may improve the live birth rates in comparison to placebo; however, this improvement in live birth is only observed in women with early pregnancy bleeding and previous history of at least one miscarriage. There is also evidence of a biological gradient of effect, with the improvement in live birth rate greatest in women with three or more previous miscarriages.	-A limitation of this study was that it was not possible to perform a network meta‐analysis and rank the available progestogens, because of the limited number of trials. -Also women with significant co‐morbidities were largely excluded from all trials, and the dosage and route of administration for each progestogen also varied by trial.
McLindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., Vane, M., Baker, T., Gleed, M., Grey, S., Tettamanzi, L., Mol, B. W. J., & Li, W. (2023).	RCT	-Inclusion Criteria:  Pregnant <10+0 weeks, over 18 years of age, diagnosed as having threatened miscarriage as apparent from bleeding with or without pain. Only singleton pregnancies were eligible. -Exclusion Criteria:Women bleeding for other diagnoses such as vulvar, vaginal, or cervical trauma or lesion were not eligible. Women were not eligible if they were pregnant as a result of ART often being on luteal phase/early pregnancy hormonal support, or if participating in another clinical trial. -139 women were randomized to the intervention group and 139 women to the placebo group. -Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.	1* Outcome:-Live Birth (a delivery of one or more living babies ≥23+0 week’s gestation)	-In women with threatened miscarriage, 400 mg progesterone applied vaginally and nightly, from onset until 12 weeks, did not increase live birth rates. -There were also no significant differences in the rates of miscarriage, preterm birth, and perinatal outcomes.	-Some limitations of the study in that it was a single centre trial which limits the generalizability of the findings. -Also, there was a low participation rate (21%) which may be explained by the fact that women with threatened miscarriage were experiencing immense physical and psychological stress at the time of being asked to consider trial participation. -Additionally, this trial was stopped prematurely at the interim analysis and did not reach the planned sample size. -Finally, this trial cannot provide direct evidence with respect to other forms and administration routes of progesterone.
Coomarasamy, A., Harb, H. M., Devall, A. J., Cheed, V., Roberts, T. E., Goranitis, I., Ogwulu, C. B., Williams, H. M., Gallos, I. D., Eapen, A., Daniels, J. P., Ahmed, A., Bender-Atik, R., Bhatia, K., Bottomley, C., Brewin, J., Choudhary, M., Crosfill, F., Deb, S., Duncan, W. C., … Middleton, L. J. (2020).	RCT	-A total of 4153 women from 48 hospitals in the UK were looked at. -Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Inclusion Criteria:– Women aged 16-39 years with early pregnancy bleeding. Exclusion Criteria: The exclusion criteria were kept to a minimum. Centres participating in the study were geographically spread across the UK, improving the generalizability of the results for women with early pregnancy bleeding. Women in the trial did not belong to a ‘selected population’, such as those with a history of previous miscarriage.	1* Outcomes:– live birth at ≥ 34 weeks	– The administration of vaginal progesterone during the first trimester of pregnancy did not lead to a significant increase in the rate of live births at ≥ 34 weeks of gestation in women who experienced early pregnancy bleeding.- However, the study’s substantial sample size, revealed that women with early pregnancy bleeding who had a history of previous miscarriages derived benefits from progesterone therapy. This subgroup effect displayed a discernible biological gradient, whereby individuals with no prior miscarriages experienced no advantages, those with one or two previous miscarriages received some benefits, and those with three or more prior miscarriages enjoyed substantial benefits. This biological gradient, combined with the overall positive direction of the primary analysis results, instills confidence in the effectiveness of progesterone for high-risk women in this context.- Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group.- Treatment with progesterone did not appear to have any negative effects.	– An important limitation of this study includes the exclusive focus on vaginal progesterone, with no exploration of other progesterone formulations.
Wang, X. X., Luo, Q., & Bai, W. P. (2019)	Systematic Review	Eight RCT from PubMed, Embase, Cochrane Library and Web of Science were used. A total of 845 women who faced threatened miscarriage were randomized into:DydrogesteroneNatural ProgesteronePlacebo GroupOral administrationVaginal administration	1* Outcome:-Incidence of Miscarriage	-Progesterone agents are effective in reducing the incidence of miscarriage in threatened miscarriage. – Dydrogesterone, not natural progesterone, was associated with a lower risk of miscarriage. – Oral management was demonstrated to have a lower risk of miscarriage compared with vaginal administration.	– The study’s primary limitations stemmed from the randomized controlled trial (RCT), primarily due to the unreliability of clinical assessments for threatened miscarriage in many cases. – Out of the total RCTs, only three were conducted with a double-blind design. In the majority of the studies, they were either single-blind, or there was insufficient information provided, raising concerns about potential bias. -Dydrogesterone was the primary type of synthetic progesterone discussed, and there were no discussions on the usage of other synthetic progesterones.
Zhao, H., He, W., & Yang, Z. (2022).	Meta-Analysis	Authors used Databases like: PubMed, Cochrane Library, EMBASE, CNKI, CBM, and WanFang for RCTs.A total of 59 RCTs with 10424 participants were used.All groups were 2 armed (1 groups was given progesterone drug and the other group was given different types or routes of progesterone administration, placebo). There were 5 treatments: -vaginal progesterone-oral dydrogesterone-oral micronized progesterone-intramuscular progesterone-placeboInclusion Criteria:A) Pregnant women with:- any type or route of administration of progesterone regardless of dose- threatened miscarriage at or less than 28 weeks with a singleton embryo or fetusExclusion Criteria:-Studies that were not RCT. Duplication. Contains recurrent abortion. Incomplete data. Contains progesterone, estrogen, and traditional Chinese medicine.	1* Outcome:-Miscarriage risk 2* Outcomes:-Low birth weight-Preterm Birth-Congenital Abnormalities-Postpartum Hemorrhage-Pregnancy-induced HTN	-Oral dydrogesterone had the lowest risk of miscarriage followed by vaginal progesterone.-Oral micronized progesterone had the highest risk of miscarriage. The treatment of preterm birth was noted to be safest with the administration of oral micronized progesterone.-Congenital anomalies were the lowest with vaginal progesterone administration.	-Limitations of this study include the insufficient direct head to head studies between the interventions. Most of the results obtained were derived from indirect evidence. -Second the data of the original study were of low quality with a high risk of data bias. Only 38.6% of the 59 RCTs included in the present study had a low risk of bias, 50.9% had an inaccurate risk of bias, and 10.5% had a high risk of bias. -Third the number of studies included in the meta-analysis was small especially regarding the follow up on data safety. Only 7 studies reported the impact of progesterone supplementation on the risk of congenital malformations and prematurity in patients with threatened abortions.

Conclusion(s):
– Briefly summarize the conclusions of each article, then provide an overarching conclusion.

Lee, H. J., Park, T. C., Kim, J. H., Norwitz, E., & Lee, B. (2017):

Progesterone therapy may be effective in preventing miscarriages in pregnant women with threatened abortion. In particular, oral dydrogesterone prevented miscarriage in pregnant women more effectively than the control-treated groups (placebo or conservative treatment), although there was no difference between oral and vaginal progestational agents in preventing miscarriages in pregnant women experiencing threatened abortion. Both routes of administration are associated with acceptable and minimal side effects. Side effects were reported in one-third of pregnant women who received weekly intramuscular injections of progesterone.

Devall, A. J., Papadopoulou, A., Podesek, M., Haas, D. M., Price, M. J., Coomarasamy, A., & Gallos, I. D. (2021):

Available progestogen treatments overall make little to no difference in live birth and miscarriage rates for women with threatened miscarriage. Vaginal micronized progesterone is the only treatment that shows it may improve the live birth rates in comparison to placebo; however, this improvement in live birth is only observed in women with early pregnancy bleeding and previous history of at least one miscarriage. There is also evidence of a biological gradient of effect, with the improvement in live birth rate greatest in women with three or more previous miscarriages.

McLindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., Vane, M., Baker, T., Gleed, M., Grey, S., Tettamanzi, L., Mol, B. W. J., & Li, W. (2023):

In this double-blinded, placebo-controlled randomized clinical trial in women with threatened miscarriage, 400 mg progesterone applied vaginally and nightly, from onset until 12 weeks, did not increase live birth rates. There were also no significant differences in the rates of miscarriage, preterm birth, and perinatal outcomes.

Coomarasamy, A., Harb, H. M., Devall, A. J., Cheed, V., Roberts, T. E., Goranitis, I., Ogwulu, C. B., Williams, H. M., Gallos, I. D., Eapen, A., Daniels, J. P., Ahmed, A., Bender-Atik, R., Bhatia, K., Bottomley, C., Brewin, J., Choudhary, M., Crosfill, F., Deb, S., Duncan, W. C., … Middleton, L. J. (2020):

The administration of vaginal progesterone during the first trimester of pregnancy did not lead to a significant increase in the rate of live births at ≥ 34 weeks of gestation in women who experienced early pregnancy bleeding. However, the study’s substantial sample size, revealed that women with early pregnancy bleeding who had a history of previous miscarriages derived benefits from progesterone therapy. This subgroup effect displayed a discernible biological gradient, whereby individuals with no prior miscarriages experienced no advantages, those with one or two previous miscarriages received some benefits, and those with three or more prior miscarriages enjoyed substantial benefits. This biological gradient, combined with the overall positive direction of the primary analysis results, instills confidence in the effectiveness of progesterone for high-risk women in this context.

Wang, X. X., Luo, Q., & Bai, W. P. (2019):

Progesterone agents are effective in reducing the incidence of miscarriage in threatened miscarriage. Dydrogesterone, but not natural progesterone, was associated with a lower risk of miscarriage. This may be related to the resorption process of natural progesterone, which is rapidly metabolized in the liver and results in lower bioavailability. Given the limitations of the studies included in the meta-analysis, it is difficult to recommend route and dose of progesterone therapy.

Zhao, H., He, W., & Yang, Z. (2022):

The risk of miscarriage was lowest with oral dydrogesterone, followed by vaginal progesterone. On the other hand, oral micronized progesterone had the highest risk of miscarriage. When it came to the treatment of preterm birth, the administration of oral micronized progesterone was found to be the safest. The incidence of congenital anomalies was lowest when vaginal progesterone was administered.

Clinical Bottom Line:

Please include an assessment of the following:

– Clinical significance (not just statistical significance)

– Any other considerations important in weighing this evidence to guide practice  – If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc)

Weight of Evidence

1 Devall, A. J., Papadopoulou, A., Podesek, M., Haas, D. M., Price, M. J., Coomarasamy, A., & Gallos, I. D. (2021):

This is a systematic review and meta-analysis published less than 5 years ago that uses multiple databases. The inclusion and exclusion criteria were explicit. Although it used 7 RCTs, it was unable to to perform a network meta‐analysis and rank the available progestogens, because of the limited number of trials.

2 Wang, X. X., Luo, Q., & Bai, W. P. (2019):

This is a systematic review published 4 years ago that used eight RCTs from multiple databases like PubMed, Embase, Cochrane Library and Web of Science. The study’s primary limitations stemmed from the randomized controlled trial (RCT), primarily due to the unreliability of clinical assessments for threatened miscarriage in many cases. Out of the total RCTs, only three were conducted with a double-blind design. In the majority of the studies, they were either single-blind, or there was insufficient information provided, raising concerns about potential bias.

3 Zhao, H., He, W., & Yang, Z. (2022):

This is a meta-analysis published last year that used a total of 59 RCTs from databases like PubMed, Cochrane Library, EMBASE, CNKI, CBM, and WanFang. Limitations of this study include the insufficient direct head to head studies between the interventions. Most of the results obtained were derived from indirect evidence. Second the data of the original study were of low quality with a high risk of data bias. Only 38.6% of the 59 RCTs included in the present study had a low risk of bias, 50.9% had an inaccurate risk of bias, and 10.5% had a high risk of bias.

4  Lee, H. J., Park, T. C., Kim, J. H., Norwitz, E., & Lee, B. (2017):

This is a systematic review and meta-analysis published 6 years ago that used 9 RCTs. The inclusion and exclusion criteria were explicit. However, the study only looked at oral and vaginal administration, the study did not include intramuscular progesterone administration.

5  Coomarasamy, A., Harb, H. M., Devall, A. J., Cheed, V., Roberts, T. E., Goranitis, I., Ogwulu, C. B., Williams, H. M., Gallos, I. D., Eapen, A., Daniels, J. P., Ahmed, A., Bender-Atik, R., Bhatia, K., Bottomley, C., Brewin, J., Choudhary, M., Crosfill, F., Deb, S., Duncan, W. C., … Middleton, L. J. (2020):

This RCT that looked at 48 hospitals in the UK. Since the centers participating in the study were geographically spread across the UK, this helped improve the generalizability of the results for women with early pregnancy bleeding.

6. McLindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., Vane, M., Baker, T., Gleed, M., Grey, S., Tettamanzi, L., Mol, B. W. J., & Li, W. (2023):

This was a double-blinded, placebo-controlled randomized clinical trial published this year that used a single center trial, however this limits the generalizability of the findings.

Scenario:

Spontaneous threatened abortions can be a common complication observed in pregnancies. It typically occurs prior to the 20-week gestation mark. Progesterone, a hormone with pivotal physiological functions, serves to prime the uterus for embryo implantation, and inhibit contractions and can play a role in preventing the miscarriage of the embryo.

PICO Question:  In cases of threatened abortions, what are the results of administering progesterone?

Clinical Bottom Line & Clinical Significance:

In summary, progesterone therapy has demonstrated its effectiveness in preventing miscarriages, particularly in cases of threatened abortions, especially among women who have experienced two or more miscarriages (Coomarasamy et al. 2020). Additionally, McLinden et al. (2023) observed that high doses of progesterone (specifically 800 mg QD) were beneficial in managing recurrent miscarriages. However, there remains conflicting evidence regarding the preferred mode of progesterone administration, whether vaginal or oral.

For instance, Lee et al. (2017) reported that oral dydrogesterone was effective in preventing miscarriages, while Devall et al. (2021) found that vaginal micronized progesterone was more effective in this regard. Notably, there is a scarcity of data assessing the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone.

To establish a clearer understanding of the impact of progesterone therapy, particularly with regard to the form of administration, further large-scale studies are needed. It is advisable to conduct dedicated trials specifically targeting women with a history of previous miscarriages to generate conclusive and unambiguous evidence on this matter.