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Progestogens (vaginal progesterone and intramuscular 17-hydroxyprogesterone acetate) are widely recommended for women at high risk of preterm birth. Typical regimens include 17-hydroxyprogesterone caproate (250 mg intramuscularly weekly), starting at 16-20 gestational weeks until 36 weeks or delivery for women with a singleton gestation and a history of spontaneous preterm birth, or vaginal progesterone (90-mg vaginal gel or 200-mg micronized vaginal soft capsules) for women with a short cervix (typically ≤25 mm). Although some randomized trials support this approach, neither of the largest trials (PROLONG for 17-hydroxyprogesterone acetate or OPPTIMUM for vaginal progesterone) demonstrated efficacy. There are almost no data on long-term effects, and none that shows benefit beyond the neonatal period. Although some analyses suggest the cost-effectiveness of the approach, a cervical length screening program followed by progesterone for those with a short cervix will reduce preterm birth rates by less than 0.5%. The present review assesses evidence on the efficacy, likely impact, and long-term effects of implementing the recommendations for progestogens in full. Clinicians and pregnant women can look forward to resolution of the conflicting views on efficacy once the Patient-Centered Outcomes Research Initiative (PCORI)-funded individual patient data meta-analysis is published., (© 2020 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

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., Competing Interests: Jane P Daniels declares membership of the Clinical Trials Unit Standing Advisory Committee. Meenakshi Choudhary declares membership of Health Technology Assessment (HTA) Maternal, Newborn and Child Health (MNCH) Panel and the HTA Prioritisation Committee. Jane E Norman declares membership of the HTA MNCH Panel, that she currently receives funding from the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, that she participates in a Data Monitoring and Ethics Committee for GlaxoSmithKline plc (Brentford, UK) and that she is a paid consultant for Dilafor AB (Solna, Sweden). She was a member of the HTA and EME Editorial Board from 2012 to 2014. Caroline Overton declares that she was a Mylan clinical educator for general practitioner education about hormone replacement therapy and incorporated private practice in April 2017 (now called Bristol Women’s Clinic Ltd).

Background: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data., Results: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups., Conclusions: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome., Objective: To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes., Design: Double-blind, randomised placebo-controlled trial., Setting: Obstetric units in the UK and Europe between February 2009 and April 2013., Participants: Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks +0 of gestation or a cervical length of ≤ 25 mm., Interventions: Fibronectin test at 18 +0 to 23 +0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22 +0 to 24 +0 until 34 +0 weeks' gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete., Main Outcome Measures: There were three primary outcomes, as follows: (1) obstetric - fetal death or delivery before 34 +0 weeks' gestation; (2) neonatal - a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood - the Bayley-III cognitive composite score at 22-26 months of age., Results: In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Forty-six out of 589 (8%) babies of women in the progesterone group and 62 out of 587 (11%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.72, 95% CI 0.44 to 1.17]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n  = 430] in the progesterone group and 97.7 points (SD 17.5 points; n  = 439) in the placebo group (difference in means -0.48, 95% CI -2.77 to 1.81)., Limitations: Overall compliance with the intervention was 69%., Harms: There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42)., Conclusions: In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth., Trial Registration: Current Controlled Trials ISRCTN14568373., Funding: This trial was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership., Competing Interests: Jane E Norman reports grants from the Medical Research Council (MRC), non-financial support from Besins Healthcare [(London, UK) in the form of donation of drugs for OPPTIMUM] during the conduct of the study, grants from other government bodies, including the National Institute for Health Research (NIHR), grants from Tommy’s baby charity and activity on a Data Safety and Monitoring Committee for GlaxoSmithKline plc (GSK; GSK House, Middlesex, UK) outside the submitted work. She chaired the National Institute for Health and Care Excellence (NICE) guideline development group on preterm labour and birth (the NICE guidelines were finalised before the OPPTIMUM study data were available), provides consultancy for GSK and for Dilafor (Solna, Sweden) and is a member of the Health Technology Assessment (HTA) Women and Children’s Health panel. Neil Marlow reports personal fees from Shire Plc (Dublin, Ireland), personal fees from Novartis International AG (Basel, Switzerland) and other from the NIHR Biomedical Research Centre, outside the submitted work. In addition, funding was obtained from the Department of Health and Social Care’s NIHR Biomedical Research Centre’s funding scheme at University College Hospital/University College London. Claudia-Martina Messow is Consultant Statistician at the Robertson Centre for Biostatistics, which conducts and supports collaborative research in major international multicentre clinical trials, epidemiological studies and other research projects, and was funded from the MRC–NIHR Efficacy and Mechanism Evaluation (EME) grant, which contributed to salary costs for this trial. Andrew Shennan reports grants from GSK and grants and non-financial support from Hologic Inc. (Marlborough, MA, USA) outside the submitted work. Philip R Bennett reports personal fees and grants from ObsEva Pharmaceuticals (Geneva, Switzerland), personal fees and grants from GSK and other from NIHR Biomedical Research Centre, outside the submitted work; In addition, he has a patent issued for microRNA markers to predict cervical shortening and preterm birth. Steven Thornton reports grants, personal fees and non-financial support from GSK, grants and non-financial support from Hologic, non-financial support from Ferring Pharmaceutical (Saint-Prex, Switzerland) and other from NIHR, outside the submitted work. John Norrie reports grants from the University of Glasgow and the University of Aberdeen. From 2010 to 2016, he was a member of the NIHR Health Technology Assessment (HTA) Commissioning Board. From 2015 to date, he is a member of the NIHR Journal Editorial Library and, from 2016 to date, he is Deputy Chair of the NIHR HTA General Board.

Globally, preterm birth rates are rising and have a significant impact on neonatal morbidity and mortality. Preterm birth remains difficult to prevent and a number of strategies for preterm birth prevention (progesterone, cervical pessaries, cervical cerclage, tocolytics, and antibiotics) have been identified. While some of these show more promise, there is a paucity of evidence regarding the long-term effects of these strategies on childhood outcomes. Strategies used to improve the health of babies if born preterm, such as antenatal magnesium sulfate for fetal neuroprotection and antenatal corticosteroids for fetal lung maturation, show evidence of short-term benefit but lack large-scale follow-up data of long-term childhood outcomes. Future research on preterm birth interventions should include long-term follow-up of the children, ideally with similar outcome measures to allow for future meta-analyses., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In a Perspective, Jane Norman and Phillip Bennett argue that it is time to explore alternatives to progesterone for preventing preterm birth.

Background: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child., Methods: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373., Findings: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27)., Interpretation: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age., Funding: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales., (Copyright © 2016 Norman et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine the long-term effects of in utero progesterone exposure in twin children., Methods: This study evaluated the health and developmental outcomes of all surviving children born to mothers who participated in a double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth in twin pregnancies (STOPPIT, ISRCTN35782581). Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory and the Health Utilities Index., Results: Record linkage was successfully performed on at least one record in 759/781 (97%) children eligible for follow-up. There were no differences between progesterone-exposed and placebo-exposed twins with respect to incidence of death, congenital anomalies and hospitalisation, nor on routine national child health assessments. Questionnaire responses were received for 324/738 (44%) children. The mean age at questionnaire follow-up was 55.5 months. Delay in at least one developmental domain on the Child Development Inventory was observed in 107/324 (33%) children, with no evidence of difference between progesterone-exposed and placebo-exposed twins. There was no evidence of difference between the progesterone and placebo groups in global health status assessed using the Health Utilities Index: 89% of children were rated as having 'excellent' health and a further 8% as having 'very good' health., Conclusions: In this cohort of twin children there was no evidence of a detrimental or beneficial impact on health and developmental outcomes at three to six years of age due to in utero exposure to progesterone.

Background: Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the "progesterone" group having a lower incidence of preterm birth., Methods/design: The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 - 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites., Discussion: OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome., Trial Registration: ISRCTN14568373.

Objective: We aimed to investigate the effects of progesterone on gene expression and function of both myometrium and circulating leukocytes., Methods: We recruited women participating in a randomized clinical trial of progesterone to prevent preterm delivery. These participants had a twin pregnancy and were managed in 1 of 2 tertiary referral centers. Participants were treated with progesterone (90 mg vaginally) or placebo from 24 to 34 weeks of pregnancy. The outcome measures were myometrial and leukocyte gene expression and expression of cell surface markers in circulating leukocytes, all quantified ex vivo., Results: Prolonged in vivo administration of progesterone inhibited myometrial expression of connexins 26 and 43, endothelial nitric acid synthase (eNOS), and the prostaglandin receptor EP2 ex vivo. Administration of progesterone also increased numbers of circulating neutrophils while decreasing lymphocyte proportions and decreasing neutrophil CD11b expression., Conclusion: The observed effects of prolonged in vivo administration of progesterone will minimize the ability of the uterus to contract as a synctium and the ability of peripheral blood leukocytes to migrate into the myometrium during parturition. We suggest that these are putative mechanisms by which progesterone might prevent preterm birth in women at high risk.

Objectives: Preterm birth contributes to a range of healthcare problems amongst infants surmounting to sizeable healthcare costs. Twin pregnancies are at particular risk of preterm birth. The objective of this study was to assess the cost-effectiveness of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies., Methods: An economic evaluation was conducted alongside a randomized placebo controlled trial (the STOPPIT trial) of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies. Five hundred women were recruited from nine maternity hospitals in the United Kingdom. The outcomes of the economic evaluation were presented in terms of net benefit statistics, cost-effectiveness acceptability curves, generated using the nonparametric bootstrap method, and the expected value of perfect information., Results: Mean health service costs between the period of randomization and discharge for mother and infant were 28,031 pound sterling in the progesterone group and 25,972 pound sterling in the placebo group, generating a mean nonsignificant cost difference of 2,059 pound sterling (bootstrap mean cost difference 2,334 pound sterling; 95 percent confidence interval: -5,023 pound sterling, 9,142 pound sterling; p = .33). The probability of progesterone being cost-effective was 20 percent at a willingness to pay threshold of 30,000 pound sterling per preterm birth prevented. There is little economic justification for conducting further research into the use of vaginal progesterone gel in twin pregnancies for the prevention of preterm birth., Conclusions: Further studies of preventive interventions for preterm birth more generally are required given the scale of the clinical and economic burden of this condition. These studies should be sufficiently powered for economic endpoints and extend beyond hospital discharge.

Objectives: Recent clinical trials have demonstrated a beneficial effect of supplementation with progesterone to prevent preterm labor. We aimed to determine the effects of progesterone treatment in vitro and in vivo and 17alpha-hydroxyprogesterone caproate (17OHPC) in vitro on myometrial contractions., Methods: Myometrial strips were taken from women undergoing cesarean delivery at term. We also obtained myometrial biopsies from women participating in a clinical trial of progesterone to prevent preterm labor in twins (STOPPIT). After establishment of spontaneous contractions, strips were exposed to progesterone or 17OHPC. Separate strips were exposed to oxytocin and tocolytics alone and in combination with progesterone. Potassium channel blockers were added in conjunction with progesterone. STOPPIT samples were used to compare the effects of in vivo progesterone and placebo. We measured amplitude, frequency and activity integral of contractions., Results: Maximum inhibition of contraction amplitude was 93 +/- 2% and 67 +/- 14% for progesterone at 30 microM and vehicle (70% ethanol), respectively, P < 0.05. 17OHPC did not exert an inhibitory effect. Water soluble progesterone exerted a maximal inhibitory effect on amplitude of contractions of 82 +/- 10% at 100 microM, P < 0.05. The inhibitory effect of progesterone was unaffected by potassium channel blockers. There was no difference between in vivo placebo and progesterone-treated groups in either amplitude or frequency of contractions, nor was there any difference in the response to oxytocin or the tocolytic drugs., Conclusions: Progesterone exerts rapid inhibition of the amplitude of myometrial contractions in vitro but 17OHPC does not. The action of progesterone does not appear to operate via potassium channels nor does it enhance the activity of certain tocolytic drugs.

Background: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy., Methods: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581., Findings: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51)., Interpretation: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy., Funding: Chief Scientist Office of the Scottish Government Health Directorate.

Key content: Twin pregnancies are associated with a three‐fold greater perinatal mortality than singleton pregnancies. Prematurity is a main contributor, with 50% of twin pregnancies delivering before 37 weeks and 10% delivering before 32 weeks of gestation. The aetiology of preterm delivery in twin pregnancies is likely multifactorial and different from that of singletons. Cervical cerclage reduces preterm birth rates in singletons but has mixed results in twins with some studies showing harm. The use of progesterone to prevent preterm birth in singletons has conflicting results and has not been proven to prevent preterm birth in twins. Studies continue to determine whether the cervical pessary is effective in preventing preterm birth in multiple pregnancies. There is a paucity of data available on the prevention of preterm birth in triplets/higher order multiples but similar principles to twin pregnancy apply. Learning objectives: To review the burden of preterm birth in multiple pregnancy. To understand the methods available for preventing preterm birth in multiple pregnancies and the evidence surrounding the use of each one. To be aware of the use of the Arabin pessary. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to analyse placental hormone profiles in twin pregnancies to determine if they could be used to predict preterm birth. Study design: Progesterone, estradiol, estriol and corticotropin-releasing hormone were measured using competitive immunoassay and radioimmunoassay in serum and saliva samples of 98 women with twin pregnancies,at 3 or more gestational timepoints. Hormone profiles throughout gestation were compared between very preterm (<34 weeks; n = 8), preterm (<37 weeks; n = 40) and term (37+ weeks; n = 50) deliveries. Results: No significant differences were found between preterm and term deliveries in either absolute hormone concentrations or ratios. Estimated hormone concentrations and ratios at 26 weeks did not appear to predict preterm delivery. Salivary and serum hormone concentrations were generally poorly correlated. Conclusion: Our results suggest that serial progesterone, estradiol, estriol and corticotropin-releasing hormone measurements in saliva and serum are not robust biomarkers for preterm birth in twin pregnancies. [ABSTRACT FROM AUTHOR]

The article focuses on strategies for preventing preterm birth. The mechanism of action of progesterone prevents preterm birth. This drug reduces synthesis of prostaglandin and inflammatory mediators. In the U.S., 17-hydroxyprogesterone caproate is approved for the prevention of pretermbirth in women with previous preterm-birth.

Abstract: Reducing the impact of preterm birth is one of the challenges in modern obstetric practice. This article provides a case-based discussion of management of women with a previous preterm birth. Estimating the risk of a subsequent preterm delivery can be improved by assessment of obstetric history. Primary preventative strategies include lifestyle advice and modification of pre-pregnancy risk factors. Antenatal care involves increased monitoring and supportive care. The usefulness of screening for preterm birth using cervical length ultrasound or biochemical tests of cervicovaginal secretions lie mainly in their negative predictive value, allowing recognition of women in whom subsequent preterm birth is unlikely. Potential prophylactic therapies in high-risk women include marine oils, progesterone pessaries and cervical cerclage, but none have been shown to improve neonatal outcome. The need for further research is highlighted. [Copyright &y& Elsevier]

Summary: The association between multiple pregnancy and preterm labour is well-established, with >50% of multiple births delivering before 37 weeks. However, there remains limited understanding of the factors predisposing to early delivery of twins. Physiological stimuli to the onset of parturition, including stretch, placental corticotrophin-releasing hormone and lung maturity factors, may be stronger in multiple pregnancies due to the increased fetal and placental mass. Pathological processes including infection and cervical insufficiency also have a role. Treatments that prevent preterm birth in singleton pregnancies, such as progesterone and cervical cerclage appear to be ineffective in multiple pregnancies. This article reviews aspects of preterm birth in twins and higher order multiples including epidemiology, prediction and prevention of preterm labour and potential mechanisms controlling onset of parturition. Evidence relating to the management of labour in preterm and term multiples is also discussed. [ABSTRACT FROM AUTHOR]

Abstract: Reducing the impact of preterm birth is one of the challenges in modern obstetric practice. This article provides a case-based discussion of management of women with a previous preterm birth. Estimating the risk of a subsequent preterm delivery can be improved by assessment of obstetric history. Primary preventative strategies include lifestyle advice and modification of pre-pregnancy risk factors. Antenatal care involves increased monitoring and supportive care. The usefulness of screening for preterm birth using cervical length ultrasound or biochemical tests of cervicovaginal secretions lie mainly in their negative predictive value, allowing recognition of women in whom subsequent preterm birth is unlikely. Potential prophylactic therapies in high-risk women include marine oils, progesterone pessaries and cervical cerclage, but none have been shown to improve neonatal outcome. The need for further research is highlighted. [Copyright &y& Elsevier]

This study investigated the regulatory effect of progesterone on decidual prolactin (dPRL) production during early human pregnancy (6–7 weeks). Patients (n = 7) were treated with the antiprogestin-mifepristone (RU 486; 600 mg single oral dose) for 24 – 36 h before termination of pregnancy by curettage. Tissue was also obtained from patients without pretreatment in vivo (n = 8) and acted as controls. Decidual tissue was incubated with and without progesterone and mifepristone for 5 days and the medium changed daily. Prolactin production by decidua parietalis decreased over the period of incubation and was unaffected by addition of progesterone or mifepristone. However, in the group pretreated with mifepristone, the production of dPRL was markedly lower than in the control group. In contrast, the production of dPRL by decidua capsularis to which trophoblast was attached, was maintained at a constant level over 5 days of culture and was unaffected by pretreatment with mifepristone or its addition , or by progesterone. Prolactin was immunolocalized using avidin-biotin immunoperoxidase staining to decidualized cells within the decidua and the intensity of staining was reduced or absent in the decidua parietalis from the mifepristone group compared to controls, but was similar in decidua capsularis in both control and mifepristone groups, in good agreement with the in-vitro production of dPRL. Our findings suggest that the effect of progesterone may be only facilitative, maintaining decidual differentiation, and dPRL production might only be associated with the presence of progesterone-dependent differentiated decidual cells. Apart from progesterone, factors from trophoblast cells can maintain dPRL production during pregnancy. [ABSTRACT FROM PUBLISHER]

Women at high risk of preterm birth (either a previous spontaneous preterm birth and/or sonographic short cervix) with a singleton gestation should be offered daily vaginal progesterone or weekly 17-OHPC treatment to prevent preterm birth. Benefit is most significant in those with prior history of preterm birth and a short cervix. For women with a previous spontaneous preterm birth and a cervix ≥30 mm the effectiveness of progesterone is uncertain. In asymptomatic women with no prior history of previous preterm birth, no mid-trimester loss, or no short cervical length, progesterone therapy is not recommended for the prevention of preterm birth. For those with unselected multiple pregnancies, progesterone therapy is not recommended for the prevention of preterm birth. Daily vaginal progesterone or weekly 17-OHPC treatment can be used for the prevention of preterm birth. The preparation used should be decided by the woman and her clinician. There is no evidence of neurological or developmental benefit or harm in babies whose mothers use progestogens for preterm birth prevention antenatally. [ABSTRACT FROM AUTHOR]