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Over 4,000 Women Trialed Progesterone for Miscarriage Prevention - Here's What They Found

Updated: Jan 10

The 'PRISM' (1. Coomarasamy et al, 2020) trial was a large United Kingdom study published in 2020, investigating whether progesterone supplementation for as little as four weeks in the first trimester of pregnancy might prevent miscarriages from occurring in cases of threatened miscarriage. Miscarriage, the spontaneous loss of a pregnancy before 20 weeks, is a common complication of early pregnancy affecting up to 1 in 5 pregnancies. About 1 in 4 females experience threatened miscarriage (bleeding in early pregnancy) with about 1 in 2 eventually miscarrying. (2. Quenby et al, 2021)



Progesterone is known to play an important role in maintaining the lining of the uterus during pregnancy. Some studies have found that women who ultimately miscarry tend to have lower progesterone levels in early pregnancy compared to women who don't miscarry. (3. Yeap et al., 2017). This had led to a hypothesis that providing extra progesterone in early pregnancy may help promote a healthy uterine environment and prevent pregnancy loss.


The PRISM study determined that while progesterone supplementation did not significantly improve live birth rates overall, it did substantially benefit women who were at highest risk of another miscarriage. The highest risk subgroup identified was women with 3 or more previous miscarriages, where progesterone treatment increased the chances of a live birth by 15% compared to placebo. And this result was from a limited window of support of only 4 weeks between 12 and 16 weeks gestation. This is a significant improvement that could mean the difference between a successful pregnancy or another heartbreaking loss for many patients. 


Below, we discuss the PRISM trial; it's findings, recommendations and limitations. Your encouraged to read the actual research as this trial is the gold standard in research; large, multicentered, randomized, double-blind and placebo-controlled. These findings have already changed clinical best practices with updated (NICE) guidelines for 2023, funded by the National Health Institute in the UK. Encouragingly, more publically funded research is underway available at www.tommys.org/


We know experiencing a miscarriage can be devastating, highlighting the urgent need for safe and effective preventative treatments that allow more pregnancies to carry through to a healthy live birth. My Fertility Labs' Progesterone Support in Pregnancy Program (ProSPr) fills the gap in obstetric healthcare in Canada. Program information is available here:



The PRISM Trial - Miscarriage Prevention using Progesterone


The PRISM trial was a large clinical trial conducted at 48 hospitals across the United Kingdom between 2010 and 2020.The goal of the study was to evaluate whether progesterone treatment could help prevent miscarriages in women experiencing early pregnancy bleeding, also known as a threatened miscarriage. 


This was large; 4,153 women with early pregnancy bleeding before 12 weeks gestation were recruited and randomly assigned to receive either progesterone treatment or a placebo. The women self-administered progesterone or placebo vaginal pessaries (wax like tablets) twice daily from 12 weeks until 16 weeks gestation. The progesterone pessaries contained 400 mg of micronized progesterone. The placebo pessaries contained an inert oil with no active ingredient.


The participants were women aged 18-39 with early pregnancy bleeding in an ongoing singleton pregnancy. Those in the trial had no major medical conditions and needed to have a gestational sac visible on ultrasound to confirm viability of the pregnancy. Participants were randomly allocated in a 1:1 ratio to either the progesterone group or the placebo control group.


The primary outcome was live birth at or beyond 34 weeks of pregnancy. Secondary outcomes included miscarriage rates, neonatal outcomes, maternal complications, and side effects. The trial was conducted double-blind so neither participants nor investigators knew who was receiving progesterone versus placebo, truly a gold standard.


PRISM Results


The PRISM trial initial results were disappointing, finding that progesterone treatment did not significantly increase the overall live birth rate at or beyond 34 weeks of pregnancy compared to placebo. This was the primary outcome measured in all women enrolled in the trial. 


However, because of the large trial size, subgroup analysis became possible and statistically significant. Subgroup analysis looking specifically at women with a history of previous miscarriages found progesterone did improve live birth rates for this higher-risk group. And the more miscarriages a woman had experienced prior to the current pregnancy, the greater the treatment benefit from progesterone was in reducing miscarriage risk. 


For women who had 3 or more previous miscarriages, progesterone therapy increased their rate of live births in the current pregnancy by 15% compared to similar women who received the placebo. So while progesterone did not show a statistical benefit in the general population, it was effective at preventing miscarriage in women with a history of recurrent pregnancy loss even when taken for a short period during early pregnancy.


PRISM provides solid evidence that progesterone can help preserve pregnancies in women with recurrent miscarriages. For those who have endured multiple pregnancy losses, an intervention that increases their chances of having a successful pregnancy is extremely valuable. Because of this, programs like ProSPr program have certain indications for entry, previous miscarriage being just one validated through the PRISM trial. Find all the indications for program entry here.


PRISM Trial Has Changed Clinical Guidelines


Updated NICE guidelines (4) for medical primary practice in the United Kingdom now recommend clinicians offer vaginal progesterone twice daily to treat women with threatened miscarriages if they have had a previous miscarriage, instead of expectant management (meaning wait and see while doing nothing for 7-14 days).


Overall, the PRISM study provides evidence to better identify high-risk women who can benefit from progesterone treatment to prevent miscarriage. The findings are guiding clinicians in the UK, at least, to offer progesterone judiciously to those most likely to respond. This more targeted use of progesterone represents an advancement in miscarriage prevention and care for women at risk of recurrence.


Progesterone Treatment


Progesterone is a natural hormone that helps maintain pregnancy. It is produced by the corpus luteum, the 'shell' left in the ovary after the egg is released during ovulation, and then predominantly by the placenta in later trimesters of pregnancy. Progesterone treatment involves giving additional progesterone medication to supplement normal hormonal production. 


In the PRISM study, progesterone was administered as a vaginal pessary, a wax like tablet, inserted twice daily. The pessaries contained micronized progesterone, progesterone that has been processed into a fine powder to increase absorption when administered vaginally. 


The women in the study began progesterone treatment early in pregnancy (within 12 weeks gestation), as soon as bleeding or spotting occurred. Bleeding often means any amount requiring sanitary products, where spotting requires no protection and is more common in threatened miscarriage. The PRISM trial had treatment stop at 16 weeks of gestation, which covers the period of early pregnancy when miscarriage risk is highest, before the placenta has fully developed. 


In the clinical practice of Restorative Reproductive Medicine (RRM), hormonal monitoring using serum blood draws guide both dosage and length of support, which might extend well into the third trimester and is not usually stopped at 16 weeks unless serum tests indicate low risk.


Cost-Effectiveness


The PRISM study provides evidence that progesterone treatment is likely a cost-effective intervention for public healthcare systems too. The economic costs of miscarriages, both medical and emotional, are considerable, while progesterone treatment itself is relatively inexpensive. Restorative Reproductive Medicine (RRM) uses only bioidentical progesterone, the exact hormone made by the body and unpatentable by drug companies. Pessaries must be specially prepared by a compounding pharmacy which are now easy to find at the Association of Compounding Pharmacists of Canada's find a pharmacy page.


By preventing miscarriages in high-risk patients, progesterone therapy can reduce healthcare costs over time. This is further supported by the surprising new findings of a 2023 meta analysis (5. Melo et al, 2023) that suggests progesterone support in early pregnancy can reduce hypertensive disorders of pregnancy (HDP) by 29% and preeclampsia by 39%, both of which raise health risks for the mother and lead to preterm birth, endangering baby. Read our research review blog here.


The PRISM findings indicate preventative treatment can be administered in a targeted way to women most likely to benefit. This focused approach maximizes the cost-effectiveness of progesterone as a therapeutic intervention during pregnancy.


Progesterone is also appropriate to recommend due the favorable safety profile for mother and child during pregnancy.


Limitations


While the PRISM study provides significant evidence on the benefits of progesterone for women at high risk of miscarriage, it does have some limitations to consider, leading to a recognition that further research is still needed on optimal progesterone dosing and length of supplementation time for maximum benefit.


-The study only included women with early pregnancy bleeding so the results may not apply to women without early pregnancy bleeding episodes that have other indicators of higher risk pregnancies such as ARTS like IVF and IUI, recurrent miscarriage without bleeding, infertility, subfertility and previous complications in pregnancy.


-Progesterone was only started when early bleeding was already present, after an ultrasound had been performed confirming the pregnancy, suggesting possible delay to treatment.


-This treatment was only provided from early pregnancy bleeding (up to 12 weeks gestation) and stopped at 16 weeks, providing some patients with only 4 weeks of progesterone support in their pregnancy. With earlier or preemptive provision of progesterone earlier in pregnancy, it is not known how many more pregnancies may have survived.


-Since the treatment was stopped at 16 weeks, the study can't determine if continuing progesterone beyond 16 weeks could provide further benefit.


-By basing the pregnancy age on the first day of the woman’s last menstrual period ( the gestational age), not on the fetal age of the pregnancy, error is introduced. As only 15% of women ovulate on day 14 of the cycle, this pregnancy dating methodology can be widely inaccurate, particularly in women with known irregular, short or long menstrual cycles.


-No tracking of progesterone hormonal levels was attempted in the study, lending no data to the serum progesterone levels of support that were actually available both pre and post treatment.


-Since participants were given progesterone vaginal pessaries, it's unclear if progesterone administered through other routes like oral progesterone (Prometrium) would have the same effect.

 

-The subgroup analysis showing a benefit for women with previous miscarriages was not pre-planned. This is important as additional studies have shown additional benefits that were also not pre-planned suggesting an underlying mechanism in pregnancy health being corrected with early progesterone supplementation.


Overall, while the study strongly suggests progesterone can help prevent miscarriage for certain high-risk women, additional research is warranted to investigate outstanding questions.


Our Conclusions:


PRISM is a group breaking study providing valuable evidence on the potential of progesterone treatment to prevent miscarriages in women at high risk of pregnancy loss. The findings show progesterone can significantly increase live birth rates, by as much as 15%, for women who have experienced multiple previous miscarriages. This robust and well-conducted trial demonstrates progesterone is likely an effective, beneficial, and cost-effective treatment option for these high-risk women. 


Though progesterone did not increase live births overall for those experiencing bleeding in early pregnancy, the results suggest it should be offered specifically to women with a history of recurrent miscarriages to help them carry pregnancies to term. The large sample size, randomized multi centered, placebo-controlled design, and double blind nature of the studdy give confidence in these conclusions. Further research can help refine exactly which women benefit most from progesterone. This new evidence indicates healthcare providers should consider progesterone treatment for women at elevated miscarriage risk to help more couples achieve a successful pregnancy.



Written by Carolyn Plican, Creighton Model FertilityCare Practitioner

Reviewed by Dr. Mary Ellen Haggerty, Restorative Reproductive Medicine Clinician


[1] 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


[2] Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J, Brosens JJ, Brewin J, Ramhorst R, Lucas ES, McCoy RC, Anderson R, Daher S, Regan L, Al-Memar M, Bourne T, MacIntyre DA, Rai R, Christiansen OB, Sugiura-Ogasawara M, Odendaal J, Devall AJ, Bennett PR, Petrou S, Coomarasamy A. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021 May 1;397(10285):1658-1667. doi: 10.1016/S0140-6736(21)00682-6. Epub 2021 Apr 27. PMID: 33915094.


[3] Xian Yeap, Valerie Shu BMBS; Tan, Thiam Chye MBBS, MMed; Ku, Chee Wai MD; Lek, Sze Min MD; Allen, John Jr PhD; Tan, Nguan Soon. Is Progesterone Deficiency Associated With Early Pregnancy Loss? A Study of 718 High-Risk and Normal Pregnancies [23P]. Obstetrics & Gynecology 129(5):p S169-S170, May 2017. | DOI: 10.1097/01.AOG.0000514096.26160.01


[4] National  Guideline  Alliance  (UK).  Ectopic  pregnancy and  miscarriage:  Diagnosis  and  initial  management. 

London:    National    Institute    for    Health    and    Care  Excellence (UK); April 2019. Available at: https://www.nice.org.uk/guidance/ng126


[5] Melo, P.; Devall, A.; Shennan A.H.; Vatish, M.; Becker, C.M.; Granne, I.; Papageorghiou, A.T.; Mol, B. & Coomarasamy, A. (2023) Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis, BJOG, https://doi.org/10.1111/1471-0528.17705

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