PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

Abstract

Background and objectivesProgesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.Design and settingA randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).Participants and interventionsWomen with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan®, Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).Main outcome measuresLive birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6–8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.MethodsParticipants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.ResultsA total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15;p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence’s threshold of £20,000–30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.ConclusionsThere is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LimitationsThis study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.Future workFuture research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.Trial registrationCurrent Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Paternal HLA‐C is a risk factor in unexplained recurrent miscarriage

“…After revision of the classification criteria, the presence of IgG or IgM β2‐glycoprotein I antibodies was added to the work‐up . Most of the women who visited the clinic were counseled to participate in randomized controlled trials such as the Habenox (NCT0095962) and Promise (ISRCTN92644181) . In the Habenox trial, women were randomly allocated to one of three intervention groups (enoxaparin 40 mg, or enoxaparin 40 mg and aspirin 100 mg, or aspirin 100 mg).…”

Efficacy of progesterone on threatened miscarriage: Difference in drug types

“…According to the relevant keywords and subject words, we found a total of 1113 studies, including 286 duplicates. By reading the title and abstract of the articles, 18 references were preliminarily selected . After reading the full texts carefully, 10 studies were excluded, and the specific reasons are shown in Figure .…”

“…By reading the title and abstract of the articles, 18 references were preliminarily selected. 2,4,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] After reading the full texts carefully, 10 studies were excluded, [7][8][9][10][11]13,16,17,20,21 and the specific reasons are shown in Figure 1. Eight randomized trials including 845 pregnant women who faced threatened miscarriage were finally analyzed.…”

Evaluation of Correlation of Serum Progesterone Level With Pregnancy Occurrence in Frozen Embryo Transfer

“…It also suppresses uterine contractions. (9,10) The impact of progesterone rise on IVF outcomes has been the subject of many studies. (11,16,17) Some studies rejected the relationship between progesterone and pregnancy rates, (11,12) while others reported an inverse association.…”

“…It also suppresses uterine contractility by attaching to its receptors. (9,10) Although, some studies rejected the relationship between progesterone and pregnancy ratio, (11,12) others reported an inverse relationship. (13,14) In this study, we evaluated the rate of implantation and abortion in patients whose embryos were frozen due to complications such as inappropriate thickness of the endometrium, uterine bleeding etc.…”