By Jeffrey T. Jensen, MD, MPH, Editor
SYNOPSIS: Investigators of this well-designed, randomized, controlled trial conclusively demonstrated that progesterone supplementation does not reduce the risk of early pregnancy loss in women who experience first trimester bleeding.
SOURCE: Coomarasamy A, Devall AJ, Cheed V, et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med 2019;380:1815-1824.
First-trimester bleeding commonly precedes spontaneous abortion, but not all women who experience bleeding go on to miscarry. The “pro-gestational” steroid hormone progesterone, initially produced by the corpus luteum and later by the placenta, is essential for the maintenance of pregnancy. However, whether low progesterone levels contribute to pregnancy loss or if progesterone supplementation could reduce the risk of miscarriage is controversial. Coomarasamy and colleagues previously reported results from a randomized trial of progesterone in women with a history of unexplained recurrent pregnancy loss, finding no benefit.1 Here, they evaluated whether progesterone treatment could reduce pregnancy loss in women experiencing the common scenario of “threatened abortion,” first trimester bleeding.
Coomarasamy et al conducted a multicenter, randomized, double-blind, placebo-controlled trial. They recruited women 16 to 39 years of age presenting with vaginal bleeding in the setting of pregnancy under 12 weeks’ gestational age with evidence of a viable intrauterine pregnancy on ultrasound. They considered the absence of fetal heart activity with a crown-rump length > 7 mm or lack of a fetal pole in the setting of a mean gestational sac diameter > 25 mm evidence of a non-viable pregnancy that would not benefit from treatment. For safety, they also excluded women with life-threatening bleeding.
The authors used a central randomization facility to assign participants to treatment: twice-daily self-administration of vaginal suppositories containing either 400 mg of micronized progesterone or a matching placebo. Eligible women initiated treatment at the time of randomization and continued use of the suppositories through up to 16 completed weeks of gestation (if the pregnancy continued). The central randomization system allowed the investigators to balance the trial-group assignments according to maternal age (< 35 years vs. ≥ 35 years), body mass index < 30 kg/m2 vs. ≥ 30 kg/m2), fetal heart activity (present vs. absent), estimated gestation at presentation (< 42 days vs. ≥ 42 days), and amount of vaginal bleeding (pictorial blood loss assessment chart score of ≤ 2 vs. ≥ 3) for evaluation of the outcome with respect to these important characteristics.
The investigators defined birth of a live-born baby after at least 34 weeks of gestation as the primary outcome. Key secondary outcomes included the time from conception to the end date of pregnancy, ongoing pregnancy at 12 weeks of gestation, pregnancy loss before 24 weeks of gestation, and live birth before 34 weeks. A power analysis determined that a sample size of 1,972 women in each treatment group would provide 90% power to detect a 5% difference in the incidence of live births after at least 34 weeks of gestation (65% vs. 60%), at a two-sided alpha level of 0.05. They picked 5% as a minimally important clinical difference based on a national survey of clinical practitioners in the United Kingdom. The final sample size of 4,150 women accounted for an expected 5% loss to follow-up.
The study team screened 23,775 patients with pregnancy bleeding. Of these, 12,862 met eligibility requirements and 4,153 consented to participation (progesterone: 2,079; placebo: 2,074). Follow-up was excellent, with data available for the primary outcome in 97%. They found no difference in the incidence of live births after at least 34 weeks of gestation (progesterone: 75% [1,513/2,025]; placebo: 72% [1,459/2,013]; relative risk [RR], 1.03; 95% confidence interval [CI], 1.00-1.07). The incidence of adverse events did not differ significantly between the groups. Similarly, there was no difference in the secondary outcome, including incidence of live birth before 34 weeks and pregnancy loss before 24 weeks.
Based on these results, the authors concluded that progesterone therapy for women experiencing first trimester bleeding does not reduce the risk of pregnancy loss or increase the incidence of live birth.
COMMENTARY
One of the biggest challenges in obstetrics is the management of expectation. As a reproductive biologist, I marvel at the complex sequence of events that must occur to establish pregnancy. How amazing that this works so frequently and successfully that we actually require contraception! Reproductive loss occurs in all organisms. In mammals, one of the opportunities for loss includes failure to establish or maintain pregnancy. For a variety of reasons, many conceptuses fail to survive. Wilcox used a highly sensitive assay for βhCG and estimated that 22% of all conceptions do not result in clinical pregnancy.2 Women who go on to miss their expected menses have about a 15% chance of miscarriage. The available evidence suggests most early pregnancy loss occurs as a result of aneuploidy.3 Given the considerable energy that women must invest in pregnancy, it makes sense that the body recognizes these nonviable pregnancies and withdraws support. However, our medical system has effectively sold the public on the idea that we work miracles. I don’t know about you, but I don’t believe in miracles. I find science far more compelling.
Women experiencing first trimester bleeding are in a vulnerable position. We all have been touched by the profound sadness that accompanies early pregnancy loss. In the setting of a highly desired pregnancy, first trimester bleeding puts women on an emotional roller coaster. The inevitable questions are “what did I do?” and “what can I do now?”
The history of active treatment of threatened miscarriage provides a cautionary tale. Interest in treatment of miscarriage led to the use of thalidomide and diethylstilbestrol with disastrous consequences. When I trained, these experiences greatly influenced our approach to “first, do no harm” and avoid any medical treatments for threatened abortion. Since most first trimester loss results from genetic abnormalities not likely to benefit from medical therapy, this approach makes sense. Still, many clinicians seem pressed to offer some sort of treatment. Given that high levels of the natural steroid progesterone occur in pregnancy, and that progesterone levels drop in women experiencing pregnancy loss, progesterone replacement has emerged as an active treatment.
The group led by Coomarasamy has made major contributions to the science of management of early pregnancy loss. These investigators have designed and conducted high-quality randomized, controlled trials to evaluate whether progesterone supplementation improves outcomes in women at risk for miscarriage. They first addressed the important question of recurrent pregnancy loss by randomizing women with a history of three or more unexplained first trimester losses to receive 400 mg of micronized progesterone or placebo capsules placed in the vagina twice daily as soon as a pregnancy test became positive. They randomized 836 women (404 progesterone, 432 placebo) and found no difference between groups in the primary outcome of live birth rate beyond 24 weeks estimated gestational age (65.8% progesterone, 63.3% placebo; RR, 1.04; 95% CI, 0.94-1.15) or any of the secondary outcomes. These data provide a convincing argument against the use of progesterone as a prophylactic treatment for recurrent miscarriage.
In this study, Coomarasamy et al evaluated the same approach for women experiencing a symptomatic threatened abortion. The authors used ultrasound to exclude pregnancies with predictable outcomes: an absent fetal pole or evidence of a fetal pole > 7 mm with no fetal heart activity. They also excluded women with serious hemorrhage. The resulting evaluation group reflects symptomatic women best managed expectantly in the setting of desired pregnancy. The demonstration that supplemental progesterone did not reduce the risk of pregnancy loss provides strong evidence against treatment. Although there was no evidence of harm, the treatment involves cost and inconvenience. I also worry that women with imperfect adherence to a twice-daily treatment schedule might blame themselves if the pregnancy ultimately fails. Nothing good comes from prescribing progesterone as a preventive measure or a treatment for threatened miscarriage. Since it feels good to do something, it is better to prescribe chicken soup.
A number of DNA sequencing approaches now are being pushed for better diagnosis of genetic causes of early pregnancy loss. In my opinion, these represent an enormous waste of resources. At our institution, the lab charges patients about $300 to “hold” the specimen. If insurance will pay, the fee is refunded. If insurance does not pay, and the patient does not self-pay (about $1,500) to complete the test, the deposit is lost.
Diagnosis is not treatment and does not improve outcomes unless it informs future actions. I believe we need to go back to the basics. Women experiencing recurrent pregnancy loss deserve compassion and encouragement, not unnecessary interventions and tests. The $300 for genetic testing is better spent on a weekend at the coast and a romantic dinner.
REFERENCES
- Coomarasamy A, Williams H, Rai R. Progesterone in women with recurrent miscarriages. N Engl J Med 2016;374:894.
- Donaghay M, Lessey BA. Uterine receptivity: Alterations associated with benign gynecological disease. Semin Reprod Med 2007;25:461-475.
- Hodes-Wertz B, Grifo J, Ghadir S, et al. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril 2012;98:675-680.
Investigators of this well-designed, randomized, controlled trial conclusively demonstrated that progesterone supplementation does not reduce the risk of early pregnancy loss in women who experience first trimester bleeding.
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