February 7, 2022
Preventing Miscarriage with Micronized Vaginal Progesterone: A Review of Research
By Ciara Gorman
Editor’s Note: This is a summary of an in-depth review  of the PROMISE and PRISM trials that sought to translate research into clinical practice. These two high-quality trials added power to the literature assessing whether micronized vaginal progesterone has a proven clinical role to prevent miscarriages in the setting of first trimester bleeding. Ciara Gorman summarized the review that was published in 2020 by Coomarasamy et al, titled, “Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.”
Progesterone is an endogenous steroid hormone that is essential for the continuation of a healthy intrauterine pregnancy. The corpus luteum, formed after ovulation, produces progesterone and will do so until about the tenth week of pregnancy. Progesterone is responsible for preventing uterine contractions and maintaining the decidua that supports implantation in early pregnancy. Inadequate levels or withdrawal of the hormone frequently results in miscarriages, and abortive medications target and oppose progesterone. Over half of miscarriages are due to chromosome errors and considered aneuploid—having extra or missing chromosomes—a process thought to occur randomly. In women with a history of multiple miscarriages, luteal phase defects with low progesterone are thought to be one cause.
A meta-analysis  published in 2020 in the American Journal of Obstetrics and Gynecology by Coomarasamy et al evaluated results from two pivotal trials, the PROMISE and PRISM trials. Both trials demonstrated positive associations between live birth rates and the use of vaginal micronized progesterone . The use of first trimester progesterone supplementation and its potential correlation to miscarriage prevention has been researched and debated in many studies. The purpose of the 2020 study by Coomarasamy et al was to review the results of both trials with full scientific inference to provide a strong basis for recommendations for clinical practice.
The study aimed to look critically at both the PROMISE and PRISM trial data. The PROMISE trial was a randomized, double-blind, multinational study that enrolled women with a history of three or more unexplained miscarriages. Patients were randomly assigned to either receive 400 mg of micronized progesterone twice daily or placebo vaginal capsules starting after a positive pregnancy test through twelve weeks gestation. The live birth rate in the progesterone group was 66%, and in the placebo group, it was 63%, giving a relative risk of 1.04 with a 95% confidence interval (CI) of 0.94 to 1.15 (p-value=.45) .
The PRISM trial was a randomized, double-blind study evaluating the role of progesterone in women with first-trimester vaginal bleeding. Patients were randomly assigned to either receive 400 mg of progesterone twice daily or matching placebo starting at presentation of bleeding through 16 weeks gestation, with a primary outcome of live birth after at least 34 weeks gestation. Results showed the progesterone group with a 75% incidence of live birth vs 72% incidence of live birth in the placebo group, with relative risk of 1.03, 95% CI of 1.00 to 1.07 and p value of .08 .
The study points out that there is importance in not only the statistical inference of these trials but also the scientific inference, as that includes the full extent of additional evidence including biological rationale and gradient and other variables. Coomarasamy et al (2020) sought to further analyze both trials by first splitting the study populations into subgroups based on the number of previous miscarriages. In the PROMISE trial, 2 subgroups were identified: women who had 3 miscarriages, and women with 4 or more miscarriages.
Similar subgroups were created from the PRISM trial. The first subgroup included women from the trial with no history of miscarriage. The second subgroup consisted of women with 1 or 2 previous miscarriages, and the third included women with a history of 3 or more miscarriages.
A total of 826 and 4,038 women completed the PROMISE and PRISM trials, respectively. As the study divided women into subgroups for further analysis, the findings from the PROMISE subgroups suggest a trend for greater benefit with progesterone with an increased number of previous miscarriages. Coomarasamy et al (2020) acknowledges the small sample sizes in the subgroups but counters that the findings generated a hypothesis that a subgroup effect existed with a biological gradient in relation to an increasing number of past miscarriages .
The PRISM subgroups provide more evidence for increased benefit for subgroups of women with past miscarriages. Live birth rates for women in one subgroup resulted in 72% (98/137) with progesterone vs 57% (85/148) with placebo with a p-value of .004, relative risk of 1.28 and a 95% CI of 1.08-1.51.
The purpose of subgrouping data from these two decisive trials was to further identify whether a relationship exists between the number of previous miscarriages and the effect of progesterone. The study addresses the fact that subgroup analyses may lead to insufficient power. However, this study created robust guidelines to assess the credibility including the characteristic—in this case, previous number of miscarriages—measured at baseline. Other important criteria include consistent interaction across the studies, which held to be true with a positive association of increased benefit from progesterone and number of prior miscarriages.
There is also indirect evidence that supported a better outcome with progesterone in those patients with increasing numbers of previous miscarriages. Biological rationale was an important pillar of this study as well. It is known that euploid miscarriages are more common with increasing number of previous miscarriages . Luteal phase defects are hypothesized to be one of the causes of euploid miscarriages and are also likely to present with vaginal bleeding, a criterion in the original PRISM trial. It is important to note that the subgroups that produced the strongest p-value in both the PROMISE and PRISM subgroups were those women with a history of multiple previous miscarriages.
Ultimately, this is an important study that strengthens the association between progesterone supplementation and miscarriage prevention, specifically in those with a previous history of multiple miscarriages. When women are trying to conceive, assuming there are no underlying medical conditions, recording a full gynecological history proves important and relevant to future treatment options. Future studies investigating cycle charting and progesterone supplementation would provide further insight in helping women achieve their fertility goals.
 Coomarasamy A, Devall AJ, Brosens JJ, et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020;223(2):167-176. doi:10.1016/j.ajog.2019.12.006.
 Coomarasamy A, Williams H, Truchanowicz E, et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol Assess. 2016;20(41):1-92. doi: 10.3310/hta20410. PMID: 27225013; PMCID: PMC4904188.
 Coomarasamy A, Harb HM, Devall AJ, Cheed V, Roberts ET, Goranitis I, et al. Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Health Technol Assess. 2020;24(33):1-70. doi: 10.3310/hta24330. PMID: 32609084; PMCID: PMC7355406.
About the Author
Ciara Gorman is a fourth-year medical student at Pacific Northwest University of Health Sciences College of Osteopathic Medicine. She completed her undergraduate studies at the University of Montana and is applying to Ob-Gyn residency programs. She wrote this summary while on the FACTS elective during her fourth year of medical school and looks forward to helping educate patients on various methods of fertility awareness and cycle charting.