Management of threatened miscarriage and recurrent miscarriage: guidance on use of progesterone

Annex A

Evidence Base

Threatened Miscarriage

Progesterone is the naturally occurring hormone that maintains pregnancy. It reduces bleeding, makes the uterus less irritable, lowers inflammation and dampens down the immune system. It was suggested that some women who repeatedly miscarry may have insufficient progesterone or an insufficient response to progesterone. Therefore, the large PRISM randomised controlled trial assessed the efficacy of progesterone treatment in the prevention of miscarriage in those presenting with threatened miscarriage.

The overall findings of the PRISM study showed that progesterone treatment for threatened miscarriage did not result in a statistically significant increase in livebirth. Overall, without progesterone treatment 72% of women in that study had a livebirth (cf 76% with progesterone, P=0.08). However, the study suggested a clinically significant difference with a greater effect seen with increasing number of previous miscarriages. Post-hoc analysis of the PRISM trial found that administrating vaginal micronised progesterone, which is molecularly similar to endogenous progesterone, into the vagina may increase chance of livebirth at 34+ weeks’ gestation after bleeding in early pregnancy for women with 1 or more previous miscarriages (70% vs 75% RR 1.09 95%CI 1.03-1.15, P=0.003.

Subgroup analyses showed that women with no previous miscarriages had 1% less livebirth if treated with progesterone (74% vs 75%, RR 0.99, 95%CI 0.95-1.04, P=0.71) which was not statistically significant. However, for women with 1-2 previous miscarriages, there was a non-significant trend for 4% more livebirths in the group treated with progesterone compared to placebo (livebirth rate 76% with progesterone, 72% with placebo, RR 1.05 (95%CI 1.00-1.12), P=0.07). For women with 3 or more previous miscarriages who presented with early pregnancy bleeding, there were 15% more livebirths in the progesterone group compared to placebo (livebirth rate 72% with progesterone, 57% with placebo, RR 1.28 (95%CI 1.08-1.51), P=0.004). A single study has evaluated the cost-effectiveness of progesterone use in this setting, and suggests progesterone is cost-effective for women with a history of previous miscarriage(s).

As a result of this study NICE changed their guidance in 2021. They recommend that vaginal micronised progesterone (400mg twice daily) should be offered to women with an intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and have previously had a miscarriage. If a fetal heartbeat is confirmed, vaginal micronised progesterone should be continued until 16 completed weeks of pregnancy. The Review of evidence and justification of the recommendation and duration of treatment is available in the NICE guideline (NG126) and can specifically be found in NG126 Evidence review C on page 18.

Recurrent Miscarriage

There have been no NICE recommendations on the use of vaginal micronised progesterone without threatened miscarriage. The RCOG Green-Top Guideline on recurrent miscarriage advised that routine supplementation with progesterone should be used with caution in asymptomatic women with unexplained recurrent miscarriage. Meta-analysis have reported a possible benefit from progestogen supplementation. This document is recommending that vaginal micronised progesterone treatment should be offered for asymptomatic women with recurrent miscarriage with 4 or more miscarriages. This is based on the evidence provided from the PROMISE trial. In that study the livebirth rate was not higher for women with a history of 3 miscarriages (RR 1.01 CI 0.89-1.14, P=0.91). However, there was a trend to a benefit for women with 4 or more miscarriages (63% vs 58%, P=0.07).