CompletedPregnancy, Children & Inherited ConditionsDiabetes, Hormones & Metabolism
Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial)
Every year, thousands of women in early pregnancy who experience vaginal bleeding are given progesterone, but until now no one knew for certain whether it actually prevents miscarriage. The PRISM trial is a large, double-blind, placebo-controlled study testing whether progesterone pessaries (400mg twice daily, taken until 16 weeks of pregnancy) can increase the number of live births beyond 34 weeks by at least 5% in women with first-trimester bleeding. The trial also examines how the drug works in different subgroups based on maternal age, fetal heart activity, bleeding severity, and body mass index. If progesterone proves effective, the finding would directly change clinical practice in NHS early pregnancy units and gynaecology departments, offering a simple, low-cost intervention to reduce miscarriage rates in a common and distressing scenario. The study includes a health economic evaluation, so funders and policymakers would also gain clear data on cost-effectiveness. If progesterone shows no benefit, the trial will still provide definitive evidence to stop an unnecessary treatment, saving patients from side effects and the NHS from wasted expenditure.
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The PRISM trial is a large, double blind, placebo-controlled trial to test the hypothesis that in women presenting with vaginal bleeding in the first trimester, progesterone (400mg vaginal capsules, twice daily) continued to 16 completed weeks of gestation, compared with placebo, increases maternities with live births beyond 34 completed weeks by at least 5%. The project also explores the effects of progesterone in prognostic subgroups, according to maternal age, fetal heart activity, gestation at presentation, amount of bleeding and body mass index. We hope the findings of the study will represent a major breakthrough in the prevention of miscarriage. DESIGN: A randomised, double-blind, placebo-controlled multicentre trial, with health economic evaluation. SETTING: Early pregnancy units and gynaecology departments in NHS hospitals. TARGET POPULATION: Women presenting with recent vaginal bleeding (within the last 4 days) in the first 12 weeks of pregnancy with an intrauterine gestation sac visible on ultrasonography. EXCLUSION CRITERIA: Women of age less than 18 years, or 40 years or more at randomisation; women with life-threatening bleeding; women already taking progesterone supplementation therapy or participating in other blinded, placebo-controlled trials of investigational medicinal products; contraindications to progesterone use; pregnancies with a crown-rump length measuring 7mm or more with no visible heartbeat; and pregnancies with a gestation sac of 25mm or more with no visible fetal pole on ultrasonography. STUDY INTERVENTION: Progesterone (Utrogestan) pessaries 400mg twice daily from confirmation of an intrauterine gestation sac on ultrasonography, to 16 completed weeks of pregnancy or until miscarriage is confirmed. COMPARISON: Identical appearance placebo (both progesterone and placebo will be provided as overencapsulated tablets). DOSE: Our choice of 400mg twice daily was made after an extensive review of: all the relevant research literature; current healthcare practice; a survey of clinicians from across the UK; and other related evidence. The Summary of Product Characteristics and the British National Formulary suggest a dose of up to 400mg twice daily. Progesterone vaginal capsules are commonly used for luteal support in Assisted Conception at a treatment dose of 400mg twice daily, with no specific concerns on safety raised on this dose. Moreover, the PROMISE trial (HTA 08/38/01), that has already randomised over 810 women to 400mg of progesterone or placebo twice daily, has not identified any acceptability or adverse effect issues. Hence we consider the dosage of 400 mg twice daily of vaginal progesterone to be the optimal choice in order to ensure a clinically effective dose, and to minimise the risk of a negative trial result from therapy with a suboptimal dose. ROUTE: An immuno-modulatory effect of progesterone within the uterus is the key presumed mechanism for preventing miscarriage. The vaginal route is therefore rational since it delivers a greater proportion of the drug to the uterus. Furthermore, existing miscarriage studies and preterm birth studies have shown effectiveness when given via the vaginal route. For instance, 14 of 36 studies of second/third trimester progesterone to prevent preterm birth (identified by a recent systematic review) used vaginal progesterone, with significant improvements being observed for various clinical outcomes, confirming the biological effects of vaginal progesterone. Finally, a survey of women has found very high acceptability for the vaginal route. PRIMARY OUTCOME: Live births beyond 34 completed weeks of gestation, as a proportion of all women randomised. SECONDARY OUTCOMES: Time to pregnancy end; ongoing pregnancy at 12 weeks (range 11 - 13 weeks) gestation; miscarriage rate; pregnancy end outcomes (such as ectopic pregnancy, stillbirth); gestation at delivery; mode of delivery; birth weight; arterial and venous cord pH and
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