Historically, a lack of methodologically strong and generalizable studies has limited policymakers fromrecommending the use of progesterone supplementation to improve outcomes in women at high risk of miscarriage. The PROMISE and PRISM trials were carried out to rectify this and generate robust evidence on the role of progesterone supplementation to prevent miscarriage. This review aims to evaluate the PROMISE and PRISM trials and their impact on collective academic understanding of the use of progesterone supplementation for miscarriage prevention, as well as to provide recommendations for clinical practice. The PROMISE trial was a randomized double-blind, placebo-controlled study that included 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% increase in live birth rate with progesterone supplementation; however, the P value associated with this finding was 0.45. A post hoc subgroup analysis was performed with cohorts stratified according to number of previous miscarriages that revealed a trend for greater benefit with increasing number of previous miscarriages. Small sample sizes in this subgroup analysis resulted in a P value of 0.41; however, these results were hypothesis-generating that a biological gradient existed with respect to improved benefit of progesterone treatment among women with an increasing number of prior miscarriages. The PRISMtrial was a randomized, double-blind, placebo-controlled study that involved 4153 women from48 hospitals in the United Kingdom and noted a 3% increase in live birth rate with vaginal micronized progesterone; however, the P value associated with this finding was 0.08. To followup on the gradient effect observed in the PROMISE trial, this study included a prespecified subgroup analysis analyzing the number of previous miscarriages with population split into 3 subgroups: women with zero prior miscarriages, women with 1 to 2 prior miscarriages, and women with 3 or more prior miscarriages. Among women with 1 or more priormiscarriages and bleeding in the current pregnancy, the live birth rate was 75%with progesterone versus 70% with placebo (risk ratio, 1.09; 95% confidence interval, 1.03 1.15; P = 0.003). Among women with 3 or more prior miscarriages and bleeding in the current pregnancy, live birth rate was 72% with progesterone versus 57% with placebo (risk ratio, 1.28; 95% confidence interval, 1.08 1.51; P = 0.004). Guidelines for interpretation of subgroup analyses translate into 11 criteria to assess credibility and therefore clinical applicability; 5 on design, 2 on analysis, and 4 on context. The PRISM trials subgroup analysis meets all 11 criteria in women with dual risk factors of previous miscarriage and current pregnancy bleeding, suggesting the subgroup effect of a gradient existing in the context of improving live birth rate with progesterone treatment is highly plausible. Given biologic plausibility, lack of short-term safety concerns, and observed positive treatment effect, providers should consider offering women with vaginal bleeding and a history of 1 or more previous miscarriages a course of treatment with vaginal micronized progesterone 400 mg twice daily.