Clinical Question:
29 y/o female pt presenting with a history of recurrent miscarriages and is interested in some sort of therapy to help reduce the likelihood of future miscarriages. She has heard that progesterone supplementation may lower the risk of recurrent miscarriages and would like to know if that is true.
PICO Question:
In female patients with a history of recurrent miscarriages does progesterone supplementation when compared to standard care reduce the risk of future miscarriages?
PICO Search Terms:
| P | I | C | O |
| Women with recurrent miscarriages | Progesterone therapy | Placebo | Improved outcomes |
| Females with multiple miscarriages | Progesterone supplementation | Standard care | Reduced risk of recurrent miscarriages |
| Recurring miscarriages | Progesterone treatment | Alternative treatment | Decrease likelihood of miscarriages |
Google Scholar:
Progesterone therapy for women with recurrent miscarriages = 24,500 results
Progesterone therapy for women with recurrent miscarriages (Filters: 2020-2024, Sort by relevance, Review articles) = 5,110 results
– After applying the filters, I read the titles and abstracts of the articles from the first 5 pages and chose the ones that were most relevant.
Pub Med:
Progesterone therapy for women with recurrent miscarriages = 183 results
Progesterone therapy for women with recurrent miscarriages (Filters: Within last 5 years) = 31 results
– After applying the filters, I read the titles of all 31 results and read the abstracts of the articles that were relevant and chose the articles for my PICO based on that.
Science Direct:
Progesterone therapy for women with recurrent miscarriages = 2,292 results
Progesterone therapy for women with recurrent miscarriages (Filters: 2020-2024, Review articles) = 196 results
– After applying the filters, I read the titles and abstracts for the first 4 pages and chose the ones that were most relevant to my search question. After the 4th page I noticed that the results weren’t relevant to my question.
Articles Chosen:
Article 1: Devall , Adam, & Papadopoulou, Argyro. (n.d.). Progestogens for preventing miscarriage: A network meta-analysis. The Cochrane database of systematic reviews. https://pubmed.ncbi.nlm.nih.gov/33872382/
| Author (Date) | Level of Evidence | Sample/Setting
(# of subjects/ studies, cohort definition etc. ) |
Outcome(s) studied | Key Findings | Limitations and Biases |
| Devall , Adam, & Papadopoulou, Argyro, etc 2021 | Meta-anaylsis | 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.
Meta-analysis included seven randomised trials involving 5,682 women, and all provided data for meta-analysis. |
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. | 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) makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. |
There are limited data and very low-certainty evidence on congenital abnormalities and adverse drug events for the other progestogens. |
| Yan Y;Chen Z;Yang, etc 2021 | Meta-anaylsis | PubMed, EMBASE, and the Cochrane Library
Nine RCTs comparing 4907 patients were included in this study |
Evaluate the correlation between progesterone and improving pregnancy outcomes in women with threatened miscarriage. | Compared with placebo or no treatment, progesterone supplementation had a relationship with a reduction in the rate of miscarriage [RR 0.70 95% Cl (0.52, 0.94)].
There was no significant difference between progesterone supplementation and placebo or no treatment in preterm birth [RR 0.87 95% Cl (0.52, 1.47) and live birth (RR 1.02 95% Cl (0.98, 1.07)]. |
Due to the lack of relevant randomized, double-blind trials, only two trials met the inclusion criteria for the live birth, so we should be cautious about this endpoint.
Also, the quality of the meta-analysis was related to the quality of the included studies. Differences in progesterone type, dose, and time of administration may affect the outcome. |
| Haas, David, Taylor Hathaway, etc 2019 | Systemic Review | Cochrane Pregnancy and Childbirth’s Trials Register, and the WHO International Clinical Trials Registry Platform
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. |
To assess the efficacy and safety of progestogens as a preventative therapy against recurrent miscarriage. | 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).
There was 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). |
High risk of bias for two trials: one used alternation, and one randomized by day of the week.
One center allocated by alternation, while the paper stated that the other used “randomization”. However, the method of randomization was not stated and thus risk of bias is unclear. |
| Li L;Zhang Y;Tan H; etc 2020 | Systemic Review and Meta-anaylsis | Ovid MEDLINE, Ovid Embase and Cochrane CENTRAL Register of Controlled Trials
Ten trials with a total of 5056 participants were eligible for analysis. |
To investigate whether the use of progestogen is associated with improved event rate of live birth and other benefits in women with threatened miscarriage. | The use of progesterone increased the incidence of live birth (RR 1.07, 95% CI 1.00-1.15; P = 0.04; I2 = 18%), with benefit only seen with the use of oral progestogen (RR 1.17, 95% CI 1.04-1.31; P = 0.008; I2 = 0%) and not with vaginal progesterone (RR 1.04, 95% CI 1.00-1.08; P = 0.07; I2 = 0%).
Similarly, progestogen reduced the risk of miscarriage (RR 0.73, 95% CI 0.59-0.92), with benefit only seen with oral progestogen and not with vaginal progesterone. |
Biases/limitations may include the different types of progesterone, the dosage, and time that it was administered may affect the results of the studies. |
Conclusions:
Article 1:
– Overall, the evidence of this article suggests that for women with past medical history of threathened or recurrent miscarriages, there is slight to no difference in live birth rate when given progestogens.
– Evidence of this article did however show that women with PMH of one or more miscarriages may have an increase in live birth rate with no difference in adverse events when taking vaginal micronized progesterone.
Article 2:
– The meta-analysis results showed that treatment with progesterone did not significantly improve the incidence of preterm birth and live birth, progesterone supplementation may not improve the pregnancy outcome of pregnant women with threatened miscarriage.
– Need to critically assess the efficacy of progesterone on threatened miscarriage from more rigorous, randomized, placebo-controlled, large-sample, and international trials.
Article 3:
– Results of this meta‐analysis show that moderate‐quality evidence demonstrates that progestogen supplementation can reduce the miscarriage rate for women with recurrent miscarriage.
– It is clear from the literature about preventing preterm birth that progestogen therapy, vaginally or intramuscularly, can reduce preterm birth rates for some women but long term therapy needs further studies.
Article 4:
– Progestogens may have benefits on live birth rate and miscarriage rate for women with threatened miscarriage.
– These benefits appear to be confined to the use of oral progestogen, and no statistically significant improvements were seen with vaginal progesterone.
Overarching Conclusion:
– In conclusion, some women with history of prior miscarriages may receive some benefit from progesterone therapy in prevention of future miscarriage but there needs to be more studies done on the long term use of progesterone. Two of the articles show that progesterone therapy does not really improve the incidence of live birth rate while the other two show that progesterone may help but there needs to be more research done on the type of progesterone, the dosage, and the time of administration.
Clinical Bottom Line:
Weight of Evidence:
Article 4: This article had the best evidence and data when compared to the rest of the articles as it is a Systemic review and Meta-analysis article. The data included 10 trials with a total of 5,056 participants that were eligible for the anaylsis. Compared to the rest of the articles, this article contains the least amount of limitations/bias which means it has the most reliable data compared to the rest.
Article 3: I would rank this article as second on my weight of evidence as it is a Systemic Review article. This article discusses studies of 12 trials of 1,856 women and 8 of those trials compared treatment with placebo while 4 compared it to no treatment. This allows there to be comparison of using progesterone with placebo and with no treatment at all and allows to see the advantages/disadvantages of progesterone to prevent miscarriages for women who have prior history of them. This article does contain some biases/limitations which may affect the results which is why I ranked it under article 4.
Article 2: I would rank this article as third on my weight of evidence as it Meta-anaylsis but contains many bias/limitations. This article is beneficial because it contains 9 RCTs comparing 4907 patients in the studies. The bias/limitations is the main reason I have this at number 3.
Article 1: I am ranking this on the bottom of my weight of evidence because although this is a Meta-anaylsis that includes 7 RCTs involving 5.682 women in the studies, there is limited data and low-certainty evidence on congenital abnormalities and the adverse effects for other progesterogens.
Magnitude of any effects:
– My 4th article which I ranked as the best on my weight of evidence showed that there was only benefits seen with the use of oral progesterone and not with vaginal progesterone. Only oral progesterone was shown to decrease risk of miscarriage (RR 0.73, 95% CI 0.59-0.92) and not vaginal progesterone. There is further evidence/studies that are needed to determine the effects of long-term use of prgesterone therapy and if it helps reduce risk of miscarriages.
Clinical Significance:
– Overall, I would recommend prescribing progesterone therapy for my patients with recurrent miscarriages. Majority of the results show that progesterone therapy can definitively reduce the risk of miscarriages in women with prior history of it. There is however mixed results amongst the articles on whether oral progesterone may actually show more benefits than vaginal progesterone. My 4th article as clearly mentioned showed that oral progesterone showed benefits and decreased risk of miscarriages (RR 0.73, 95% CI 0.59-0.92). My 1st article however, showed that vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). The 2nd and 3rd articles don’t specify whether oral or vaginal progesterone may be more beneficial in reducing the risk of miscarriages but show that overall the use of progesterone therapy decreases risk of miscarriages. Majority of the evidence from the articles shows that progesterone can help prevent miscarriages in patients with history of miscarriages but not much improvement in patients that don’t have history. Article #3 had 13 trials totalling 2556 women with history of miscarriages and results found that progesterone lowered the rates of miscarriage from 27.5% to 20.1%. This is a significant percentage and therefore based on all of the evidence, I would prescribe progesterone for patients who come in with history of recurrent miscarriages.
