Progesterone for Miscarriage Prevention: Insights from the PROMISE and PRISM Trials

Introduction

Miscarriage, or spontaneous abortion, is a common complication of early pregnancy, occurring in approximately 10-20% of clinically recognized pregnancies. This loss can be a devastating experience for expecting parents, leading them to seek various interventions to prevent it from happening. One of the treatments that has gained significant attention is the use of progesterone supplements, particularly for women with a history of recurrent miscarriages. While progesterone is an essential hormone in maintaining pregnancy, recent studies suggest that its supplementation may not be as effective in preventing miscarriage as once believed.

In this article, we will explore the role of progesterone in pregnancy, the evidence surrounding its use as a preventive measure for miscarriage, and why current research suggests that progesterone supplements may not be the solution that many hope for. Additionally, we will discuss the implications of these findings for clinical practice and patient care.

The Role of Progesterone in Pregnancy

Progesterone is a critical hormone in pregnancy, produced primarily by the corpus luteum in the early stages and later by the placenta. Its main functions include:

Preparing the Uterine Lining: Progesterone helps thicken the endometrium, the lining of the uterus, making it receptive for embryo implantation.

Supporting the Early Pregnancy: Once the embryo implants, progesterone maintains the uterine environment, ensuring that it remains suitable for the developing fetus.

Preventing Uterine Contractions: Progesterone inhibits uterine contractions, which could otherwise lead to the expulsion of the embryo.

Given these vital roles, it seems intuitive that low levels of progesterone could contribute to miscarriage, particularly in the first trimester. As a result, progesterone supplements have been prescribed for decades to women with recurrent miscarriages or those considered at high risk. However, the effectiveness of this approach has come under scrutiny in recent years.

Progesterone Supplements: Historical Context and Usage

The use of progesterone supplementation in pregnancy dates back to the 1950s, with clinicians prescribing it to women who had experienced recurrent miscarriages. Progesterone supplements are available in various forms, including oral pills, vaginal suppositories, and intramuscular injections. The rationale for this treatment is based on the assumption that progesterone deficiency is a significant cause of miscarriage, especially in the early stages of pregnancy.

For decades, progesterone has been the go-to treatment for women with recurrent pregnancy loss (RPL), which is defined as having two or more consecutive miscarriages. Many physicians believed that progesterone supplementation could correct hormonal imbalances, thereby reducing the risk of miscarriage. However, despite its widespread use, the evidence supporting progesterone's efficacy in preventing miscarriage has been inconsistent.

The Evidence Against Progesterone for Miscarriage Prevention

In recent years, several large-scale studies have questioned the effectiveness of progesterone supplements in preventing miscarriage, particularly in women without a diagnosed progesterone deficiency.

1. The PROMISE Trial

One of the most significant studies on this topic is the PROMISE Trial (Progesterone in Miscarriage Treatment), conducted in the United Kingdom. This randomized, double-blind, placebo-controlled trial involved 836 women who had experienced three or more unexplained miscarriages. The women were randomly assigned to receive either progesterone supplements or a placebo from the time of a positive pregnancy test until 12 weeks of gestation.

The results, published in 2015, were disappointing for advocates of progesterone therapy. The study found no significant difference in the live birth rate between the progesterone group and the placebo group. Specifically, 65.8% of the women who received progesterone had a live birth, compared to 63.3% of those who received the placebo. The difference was not statistically significant, leading the researchers to conclude that progesterone supplementation does not improve outcomes in women with a history of unexplained recurrent miscarriage.

2. The PRISM Trial

The PRISM Trial (Progesterone in Spontaneous Miscarriage), another major study conducted in the UK, aimed to assess whether progesterone could prevent miscarriage in women with early pregnancy bleeding, a common symptom of threatened miscarriage. The trial included over 4,000 women who were randomly assigned to receive either progesterone or a placebo.

The results, published in 2019, showed that progesterone did not significantly reduce the overall miscarriage rate. However, there was a slight benefit observed in a subgroup of women who had experienced three or more previous miscarriages. In this subgroup, 72% of women who received progesterone had a live birth, compared to 57% in the placebo group. While this finding is promising, it applies to a small subset of women, and the overall conclusion of the trial was that progesterone supplementation is not an effective treatment for preventing miscarriage in most cases.

3. Cochrane Review

A 2021 Cochrane Review analyzed the results of multiple randomized controlled trials (RCTs) on progesterone supplementation for preventing miscarriage. The review concluded that while there is some evidence suggesting that progesterone may benefit women with a history of recurrent miscarriages, the overall quality of the evidence is low. The review also noted that progesterone supplementation does not appear to significantly reduce the risk of miscarriage in women with early pregnancy bleeding.

Why Progesterone May Not Be the Answer

Given the biological importance of progesterone in maintaining pregnancy, why do progesterone supplements fail to prevent miscarriage in many cases? Several factors may explain this discrepancy:

1. Miscarriage Has Multiple Causes

One of the key reasons progesterone supplements may not be effective in preventing miscarriage is that miscarriage is a complex condition with multiple causes. Chromosomal abnormalities, which account for up to 50% of miscarriages, are the most common cause. These genetic issues are unrelated to progesterone levels and cannot be corrected by hormone supplementation.

Other potential causes of miscarriage include uterine abnormalities, immune system disorders, and infections. In many cases, progesterone supplementation would not address the underlying cause of the miscarriage, rendering the treatment ineffective.

2. Timing and Route of Administration

The timing and route of progesterone administration may also play a role in its effectiveness. Some studies suggest that progesterone may need to be administered before conception to have a meaningful impact on pregnancy outcomes. Additionally, the route of administration (oral vs. vaginal vs. intramuscular) may affect the hormone's bioavailability and efficacy. However, there is currently no consensus on the optimal timing or route for progesterone supplementation in pregnancy.

3. Progesterone Deficiency vs. Miscarriage

While low progesterone levels can lead to miscarriage, not all miscarriages are caused by progesterone deficiency. In many cases, progesterone levels may drop as a result of an impending miscarriage rather than being the cause. This distinction is critical because it suggests that supplementing progesterone in women without a diagnosed deficiency may not be effective in preventing miscarriage.

Implications for Clinical Practice

The findings from recent studies have significant implications for clinical practice. While progesterone supplements may still be considered for certain subgroups of women, such as those with a history of recurrent miscarriages or diagnosed luteal phase defects, routine use of progesterone for miscarriage prevention is not supported by the evidence.

Clinicians should have open and honest discussions with their patients about the potential benefits and limitations of progesterone supplementation. It is essential to manage expectations and provide patients with evidence-based information to help them make informed decisions about their care.

Conclusion

Progesterone supplementation has been widely used as a treatment to prevent miscarriage, particularly in women with a history of recurrent pregnancy loss. However, recent large-scale studies, including the PROMISE and PRISM trials, have shown that progesterone is not effective in preventing miscarriage in most cases. While there may be a slight benefit for a small subset of women, the overall evidence does not support the routine use of progesterone supplements for miscarriage prevention.

As healthcare providers, it is crucial to rely on high-quality evidence when making treatment recommendations. Progesterone supplementation should not be viewed as a universal solution for preventing miscarriage, and clinicians must consider the individual patient's history and risk factors before prescribing this treatment. By staying informed about the latest research and engaging in open discussions with patients, we can provide the best possible care for women experiencing the challenges of miscarriage.