Helen Williams

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

BACKGROUND Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

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

BACKGROUND AND OBJECTIVES Progesterone 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 SETTING A 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 INTERVENTIONS Women 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 MEASURES Live 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. METHODS Participants 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. RESULTS A 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 Excellences threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK Future 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 REGISTRATION Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. 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. 20, No. 41. See the NIHR Journals Library website for further project information.

Progesterone in Women with Recurrent Miscarriages: Author Reply

To the Editor: In summarizing their well-executed randomized trial, Progesterone in Recurrent Miscarriages (PROMISE), Coomarasamy et al. (Nov. 26 issue)1 state that there is no evidence of benefit from progesterone supplementation “in the first trimester” of pregnancy among women who have had three or more miscarriages. We wish to clarify three points. First, the trial did not address progesterone supplementation in women with coexisting subfertility. Nearly 33% of the women screened for the trial were excluded because of subfertility (515 of 1568 women). Second, because progesterone plays a key role in the implantation of the embryo, benefit from supplementation may be realized if progesterone is administered before and at the time of implantation. In women undergoing fertility treatments, it is common to administer progesterone before and at the time of implantation,2 but in the trial by Coomarasamy et al., administration began after implantation. Third, a short luteal phase (<10 days) is associated with a lower probability of clinical pregnancy, and it may also be associated with miscarriage.3,4 The correction of a lutealphase defect before implantation may improve the chance of ongoing pregnancy. The initiation of progesterone supplementation before pregnancy testing in women with subfertility, lutealphase defect, or both deserves further investigation to determine whether it would increase the chance of successful implantation and ongoing pregnancy.

Global women's health: current clinical trials in low‐ and middle‐income countries

Clinical trials in low‐ and middle‐income countries (LMICs) are necessary to develop evidence‐based approaches to improve womens health. Understanding what research is currently being conducted will allow the identification of research gaps, avoidance of duplication, planning of future studies, collaboration amongst research groups, and geographical targeting for research investments.

First-line uterotonics for treating postpartum haemorrhage: a systematic review and network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Primary To assess the relative effectiveness and produce a clinically meaningful hierarchy of first-line uterotonic drugs for the treatment of postpartum haemorrhage (PPH). Secondary To assess the relative risks and produce side effect hierarchies of first-line uterotonic drugs for the treatment of PPH.

Uterotonic agents for preventing postpartum haemorrhage: a network meta‐analysis

This is the protocol for a review and there is no abstract. The objectives are as follows: We aim to assess the clinical effectiveness and side-effect profile of uterotonic drugs to prevent PPH, and to generate a clinically useful ranking of available uterotonics according to their effectiveness and side-effects. We will explore the effects according to various key prognostic and treatment factors. The population of interest is women following a vaginal birth or a caesarean section in the hospital or the community setting. All uterotonic drugs considered by the WHO are eligible and the outcomes include blood loss-related outcomes and side-effects.

Prenatal central nervous system anomaly with skeletal dysplasia associated with a de novo interstitial tandem triplication of chromosome 14

Georgina K. Hall , Fiona L. Mackie , Helen Williams, Denise Williams, Phillip Cox, Dominic J. McMullan, Stephanie Allen and Mark D. Kilby West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, UK; Fetal Medicine Centre, Birmingham Women’s NHS Foundation Trust, Birmingham, UK; Centre for Womens and Childrens Health, University of Birmingham, Birmingham, UK; Department of Radiology, Birmingham Children’s NHS Foundation Trust, Birmingham, UK; Department of Clinical Genetics, Birmingham Women’s NHS Foundation Trust, Birmingham, UK; Department of Perinatal Pathology, Birmingham Women’s NHS Foundation Trust, Birmingham, UK

Methods for managing miscarriage: a network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objectives of this review are: • to estimate the relative effectiveness and safety profiles for methods of management of miscarriage; • to provide a ranking of the available methods according to their effectiveness and safety profile.