Progesterone for bleeding in the first trimester is not effective to prevent miscarriage

Reference

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(19):1815-1824.

Synopsis

A Cochrane Review of small and often poorly designed trials of progesterone to prevent miscarriage suggested a possible benefit. So, these investigators undertook a large, multicenter, randomized, double-blind, placebo-controlled trial by enrolling 4153 women in the United Kingdom who presented with vaginal bleeding before 12 completed weeks' gestation and a potentially viable pregnancy. Women were randomized to receive 400 mg vaginal suppositories or identical placebo to use twice daily from the date of presentation and enrollment to 16 completed weeks. Based on survey data from UK maternity providers, a 5 percentage point difference in live birth at a minimum of 34 weeks' gestation was chosen as the clinically meaningful primary outcome, and the sample size needed was calculated accordingly. Women were included if they were between 16 years and 39 years of age and had a visible uterine sac on ultrasonography. They were excluded for several parameters that suggested nonviable pregnancy, life-threatening bleeding, current or recent use of progesterone supplementation, or contraindication to progesterone therapy. Groups were balanced on several important parameters using a computer algorithm: age < 35 or 35+, body mass index < 30 or 30+, fetal heart activity present or not, estimated gestational age < 42 days or 42+, small or large amount of vaginal bleeding using pictorial chart. The main result of live birth at 34 or more weeks' did not reach statistical significance: 75% (1513/2025) vs 72% (1459/2013) (relative risk [RR] 1.03; 95% CI 1.00 - 1.07; P = .08). Sensitivity analyses using multiple imputations for missing data produced the same results. Among 10 planned subgroup analyses one reached statistical significance: the group of women with a history of 3 or more prior miscarriages (98/137 [72%] vs 85/148 [57%]; RR 1.28; 1.08 - 1.51; P = .007; NNT = 7; 4 - 34). This outcome deserves further focused trial data to confirm. There were no significant differences for secondary outcomes, such as preterm birth at 24 to 34 weeks' gestation (3% of each group). There were no significant differences in adverse effects, including potentially teratogenic effects.