A Randomized Trial of Progesterone in Women With Bleeding in Early Pregnancy

Abstract

BACKGROUNDBleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODSWe conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTSA total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONSAmong women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo.

The cost‐effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial

“…Outcomes were assessed at three points: 11-14 weeks of gestation, end of pregnancy and 28 days after delivery. 7 The primary outcome for the cost-effectiveness analysis (CEA) was live birth at ≥34 completed weeks of gestation. An additional outcome of the PRISM trial was neonatal…”

“…Detailed information about the trial design and findings is published elsewhere. 7 Briefly, between May 2015 and July 2017, 4153 women with early pregnancy bleeding and an ultrasonography-confirmed intrauterine sac were recruited from 48 hospitals across the UK.…”

“…Thirty (0.7%) women withdrew from the trial and 85 (2%) women were lost to follow up; hence data were available for 4038 women (2025 in the intervention arm and 2013 in the placebo arm). 7 Outcomes Table 2 presents the results of the trial outcomes required for the economic analysis. For the primary outcome, the proportion of women with live births at ≥34 completed weeks of pregnancy was higher in the progesterone (74.72%) than the placebo (72.48%) arman effect difference of approximately 0.022 (2.2%) (95% CI À0.004 to 0.050).…”

“…However, women in the placebo arm had more admissions to the HDU and their babies had on average a higher number of admissions to the HDU and the neonatal special care unit than in the intervention. 7 Table S2 (see Supplementary material) presents the mean costs per woman by trial arm. The average cost of the trial intervention was £204 (95% CI £200 to £207) per pregnancy.…”

“…4 Its physiological importance has led clinicians, researchers and patients to consider progesterone supplementation during early pregnancy as a miscarriage prevention strategy, particularly in women at high risk of miscarriage, such as those with a history of recurrent miscarriages or early pregnancy bleeding. 7 In 2012, the National Institute for Health and Care Excellence (NICE) guidelines on 'Ectopic Pregnancy and Miscarriage' called for a large randomised clinical trial to explore the potential role of progesterone in women with early pregnancy bleeding. 6,8 The PRogesterone In Spontaneous Miscarriage (PRISM) trial was funded by the UK National Institute for Health Research (NIHR) to investigate the effectiveness and cost-effectiveness of progesterone on pregnancy outcomes in women with first-trimester vaginal bleeding.…”