Emergency Department evaluation for patients with first-trimester bleeding is fairly straightforward. Most of the time, an ultrasound identifies an unremarkable intrauterine pregnancy and patients are provided with expectant management and best wishes. However, there is some evidence progesterone supplementation – in this trial, an intravaginal progesterone supplement – may help implantation and prevent pregnancy loss. This, the Progesterone in Spontaneous Miscarriage (PRISM) trial, is the first, large, high-quality investigation of this intervention.
Over the course of two years, 12,862 women with bleeding before 12 weeks of pregnancy were screened, and 4,153 enrolled across 48 hospitals in the United Kingdom. Enrolled patients were randomized to either 400mg intravaginal micronized progesterone twice daily through 16 weeks of pregnancy, or identical placebo. The primary outcome was live birth after at least 34 weeks, with secondary outcomes being other early pregnancy milestones, as well.
Per the authors, and hewing fast to their frequentist analysis, this is a negative trial. The primary outcome occurred in 75% of the progesterone cohort and 72% of placebo, a relative rate of 1.03 (1.00 to 1.07) and a p-value of 0.08. The authors conclusion: “treatment with progesterone did not result in significant improvement in the incidence of live births among women with vaginal bleeding during the first 12 weeks of pregnancy.”
Maybe?
It is always curious to look at the statistical analysis portion of these articles and consider the decisions leading to the inability to detect a difference. In this trial they state their choice of sample size was driven by the “minimally important absolute difference of 5 percentage points between the progesterone group and the placebo group in the incidence of live births after at least 34 weeks of gestation (65% vs. 60%)”. If we had a medication for use in sepsis that was inexpensive and readily available, would we require a 5% difference in mortality for its use? Anti-hypertensives, taken for five years, prevent heart attack, stroke, and all-cause mortality with numbers-needed-to-treat swimming right around a 1% difference – and these are taken in massive numbers at the population level. Without delving into any sort of personhood argument, a lost pregnancy is effectively a mortality benefit – and, despite the massive scale required, it might have rather been more appropriate to choose a smaller “minimally important absolute difference.”
If the observed difference of 2 to 3% were to be confirmed, these are NNTs in the 33-50 range to prevent pregnancy loss. While this would not be rank as a profoundly effective intervention, we are rather talking about producing an actual new human being. No harms were detected, although a trial such as this would be expected to be even further from powered to detect very rare events such as congenital deformities. I would expect the debate regarding this to continue, and I wouldn’t be surprised if you found some groups encouraging its use or initiation in the ED.
“A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy”
https://www.nejm.org/doi/full/10.1056/NEJMoa1813730