Plain English Summary
Background and study aims
This study was undertaken to test whether giving the hormone progesterone to pregnant women with a history of repeated unexplained early pregnancy losses could increase the number of pregnancies leading to live births after at least 24 weeks of gestation.
Who can participate?
Women aged 18-39 with unexplained recurrent miscarriages (three or more consecutive or non-consecutive first trimester miscarriages). A pregnancy loss is considered to be unexplained if conditions known to increase the risk of miscarriage are absent.
What does the study involve?
Participants were randomly allocated to one of two groups: one group received progesterone twice daily as vaginal pessaries and the other group received a placebo (dummy) with an identical appearance, from soon after a positive urinary pregnancy test, and no later than 6 weeks of pregnancy, until 12 completed weeks of pregnancy (or earlier if the pregnancy ended before 12 weeks).
What are the possible benefits and risks of participating?
There is substantial evidence from IVF practice that progesterone supplementation is safe to the mother and fetus at the proposed dose. Moreover, recent studies of vaginal progesterone in the context of prevention of preterm birth have not shown any evidence of short-term safety concerns in the participants.
Where is the study run from?
45 hospitals in the UK and the Netherlands
When is the study starting and how long is it expected to run for?
From May 2009 to September 2014
Who is funding the study?
NIHR Health Technology Assessment Programme - HTA (UK)
Who is the main contact?
1. Dr Arri Coomarasamy (email@example.com)
2. Dr Rajendra Rai (firstname.lastname@example.org)
Dr Arri Coomarasamy
Birmingham Women's Hospital
Metchley Park Road
+44 (0)121 623 6835
Dr Rajendra Rai
Department of Obstetrics & Gynaecology
St Mary's Hospital
South Wharf Road
+44 (0)207 886 2475
First trimester progesterone therapy in women with a history of unexplained recurrent miscarriages: a randomised double-blind placebo-controlled multi-centre trial (The PROMISE [PROgesterone in recurrent MIScarriagE] Trial)
1. In women with unexplained recurrent miscarriages, progesterone (400 mg pessaries, twice daily), started soon as possible after a positive pregnancy test (and no later than 6 weeks gestation) and continued to 12 weeks of gestation, compared to placebo, increases live births beyond 24 completed weeks by at least 10% (principal objective)
2. Progesterone improves secondary outcomes such as gestation at delivery, on-going pregnancy at 12 weeks, survival at 28 days of neonatal life
3. Progesterone, compared to placebo, does not incur substantial adverse effects to the mother or the neonate
4 Explore differential or subgroup effects of progesterone in prognostic subgroups
5. Perform an economic evaluation for cost-effectiveness
More details can be found at http://www.nets.nihr.ac.uk/projects/hta/083801
Protocol can be found at http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0018/52911/PRO-08-38-01.pdf
REC: West Midlands Research Ethics Committee, 19/10/2009, ref: 09/H1208/44
Randomised double-blind placebo-controlled multi-centre trial
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Unexplained recurrent miscarriages
Intervention group: Progesterone pessaries (400 mg twice daily) started soon as possible after a positive pregnancy test (and no later than 6 weeks gestation) and continued to 12 weeks of gestation
Control group: Placebo
Total duration of follow-up per participant: 42 weeks
Primary outcome measures
Live births beyond 24 weeks
Secondary outcome measures
1. Gestation at delivery
2. Clinical pregnancy at 6-8 weeks
3. Ongoing pregnancy at 12 weeks (range 11-13 weeks)
4. Miscarriage rate
5. Survival at 28 days of neonatal life
6. Congenital abnormalities with specific examination for genital anomalies
7. Adverse events
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Women with unexplained recurrent miscarriages (3 or more consecutive first trimester miscarriages)
2. Age 18-39 years at randomisation (likelihood of miscarriages due to chromosomal aberrations is higher in older women; such miscarriages are unlikely to be prevented by progesterone therapy)
3. Spontaneous conception (as confirmed by urinary pregnancy tests)
4. Willing and able to give informed consent
Target number of participants
Participant exclusion criteria
1. Inability to conceive spontaneously within 1 year of recruitment
2. Antiphospholipid syndrome (lupus anticoagulant and/or anticardiolipin antibodies [IgG or IgM]); other recognised thrombophilic conditions (testing according to usual clinic practice)
3. Intrauterine abnormalities (as assessed by ultrasound, hysterosonography, hysterosalpingogram, or hysteroscopy)
4. Fibroids distorting uterine cavity
5. Abnormal parental karyotype
6. Other identifiable causes of recurrent miscarriages (tests initiated only if clinically indicated) e.g., diabetes, thyroid disease and systemic lupus erythematosus (SLE)
Recruitment start date
Recruitment end date
Countries of recruitment
Netherlands, United Kingdom
Trial participating centre
45 hospitals in the UK and the Netherlands
Health Technology Assessment Programme
NIHR Health Technology Assessment Programme, HTA
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
Publication in the UK NIHR HTA library is anticipated before the end of 2015. Other publications may be produced but are not yet confirmed.
Intention to publish date
Participant level data
Not expected to be available
Results - basic reporting