Progesterone to prevent miscarriage in women with early pregnancy bleeding: The PRISM RCT

Background Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting A total of 48 hospitals in the UK. Participants Women aged 16–39 years with early pregnancy bleeding. Interventions Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results A total of 4153 women from 48 hospitals in the UK received either progesterone ( n = 2079) or placebo ( n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. Trial registration Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

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

(N Engl J Med. 2019;380(19):1815–1824) This study aimed to determine whether the controversial use of progesterone therapy in women with early bleeding in pregnancy could result in a higher incidence of live births than use of a placebo. It was a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women received vaginal suppositories of progesterone, or a placebo, from presentation of bleeding to 16 weeks to determine if progesterone therapy helps improve pregnancy outcomes for women with vaginal bleeding in early pregnancy.

Who is at risk of endometrial cavity breach at laparoscopic myomectomy?

Background: Submucous and large intramural fibroids cause heavy menstrual bleeding and can negatively impact reproductive outcomes. Large submucous and non-cavity distorting fibroids need to be removed laparoscopically. One of the risks of a laparoscopic myomectomy is breaching the endometrial cavity and there have been suggestions that this increases the risk of intrauterine adhesions. The aim of this study was to examine the role of various demographic and pre-operative ultrasound variables at predicting the risk of endometrial cavity breach during laparoscopic myomectomy. Methods: This was a retrospective study of women who underwent a laparoscopic myomectomy. Women who had more than one fibroid removed and women who did not have pre-operative ultrasound images available were excluded. The size of the fibroid, minimum distance from the endometrial cavity, surface area, intra-cavity surface area, protrusion ratio and extra-cavity size as well as the women's age, parity and pre-operative GnRH analogue use were recorded. The outcome measure was the breach of the endometrial cavity at myomectomy. Univariate analysis was performed to identify variables that are associated with a cavity breach. A logistic regression analysis was used to identify the most significant predictor of a breach. Results: A total of 66 women were included in the study. From these, 10 women sustained a cavity breach. All pre-operative ultrasound variables, i.e. minimum distance of the fibroid from the cavity (p=0.001), protrusion ratio (p=0.001), total surface area (p=0.020), intra-cavity surface area (p=0.001), size (p=0.030) and extra-cavity size (p=0.001) were statistically different between the group that had a cavity breach and the group that did not. In a logistic regression model, protrusion ratio was selected as the best predictor of a breach (OR 1.22; 95% CI 1.10 - 1.37). All breaches occurred in women who were not given GnRH analogue. Conclusion: Identifying patients at increased risk of a cavity breach facilitates better individualized pre-operative counselling regarding the risk of a breach and the possibility of intrauterine adhesions. It will also trigger more intra-operative vigilance to minimize the risk of breaching the cavity and, subsequently, the risk of intrauterine adhesions if a breach does occur.