Trial protocol OPPTIMUM : does progesterone prophylaxis for the prevention of preterm labour improve outcome?

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

Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2):An open-label randomised trial and updated meta-analysis

BackgroundPreterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.Methods and findingsWe conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.ConclusionsThese results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.Trial registrationISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181

The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix:the STOPPIT 2 RCT

Background: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting: Antenatal clinics in the UK and elsewhere in Europe. Participants: Women with twin pregnancy at < 21 weeks’ gestation with known chorionicity and gestation established by scan at ≤ 16 weeks’ gestation. Interventions: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0–20+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures: Obstetric – all births before 34+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations: There was the possibility of a type II error around smaller than anticipated benefit. Conclusions: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. Future work: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. 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. 25, No. 44. See the NIHR Journals Library website for further project information

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

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

TIF film, substrates and nonfumigant soil disinfestation maintain fruit yields

A 5-year project to facilitate the adoption of strawberry production systems that do not use methyl bromide initially focused on fumigant alternatives and resulted in increased use of barrier films that reduce fumigant emissions. The focus shifted in year 3 to evaluating and demonstrating nonfumigant alternatives: soilless production, biofumigation, anaerobic soil disinfestation (ASD) and disinfestation with steam. In the 2010–2011 strawberry production season, fruit yields on substrates were comparable to fruit yields using conventional methods. Anaerobic soil disinfestation and steam disinfestation also resulted in fruit yields that were comparable to those produced using conventionally fumigated soils. Additional work is in progress to evaluate their efficacy in larger-scale production systems in different strawberry production districts in California

Fetal fibronectin as a predictor of spontaneous preterm birth: a European perspective

Preterm birth (PTB) is estimated to account for 6-10% of all births worldwide with 13 million PTBs occurring annually and 1 million resulting in death. The diagnosis of spontaneous preterm labor and accurate prediction of preterm delivery is notoriously difficult. Identification of effective risk assessment markers can potentially improve outcomes by enabling targeted therapy while allowing efficient use of resources and avoiding unnecessary interventions. Advances in perinatal medicine have not reduced PTB and effective measures that improve outcome are yet to be established. However, considerable progress has been made in the development of accurate methods (fetal fibronectin and cervical length assessment) to predict PTB in both symptomatic and asymptomatic high-risk women. The excellent negative predictive value of fFN has the ability to facilitate decision-making regarding admission, in utero transfer, administration of antenatal corticosteroids and/or tocolysis and has been shown to be cost-effective. This review describes the European perspective on the use of fFN and describes ongoing European clinical studies, which are appropriately designed with meaningful endpoints, which will undoubtedly facilitate a better understanding of test accuracy and cost-effectiveness within different population

TIF film, substrates and nonfumigant soil disinfestation maintain fruit yields

A 5-year project to facilitate the adoption of strawberry production systems that do not use methyl bromide initially focused on fumigant alternatives and resulted in increased use of barrier films that reduce fumigant emissions. The focus shifted in year 3 to evaluating and demonstrating nonfumigant alternatives: soilless production, biofumigation, anaerobic soil disinfestation (ASD) and disinfestation with steam. In the 2010–2011 strawberry production season, fruit yields on substrates were comparable to fruit yields using conventional methods. Anaerobic soil disinfestation and steam disinfestation also resulted in fruit yields that were comparable to those produced using conventionally fumigated soils. Additional work is in progress to evaluate their efficacy in larger-scale production systems in different strawberry production districts in California

TIF film, substrates and nonfumigant soil disinfestation maintain fruit yields

A 5-year project to facilitate the adoption of strawberry production systems that do not use methyl bromide initially focused on fumigant alternatives and resulted in increased use of barrier films that reduce fumigant emissions. The focus shifted in year 3 to evaluating and demonstrating nonfumigant alternatives: soilless production, biofumigation, anaerobic soil disinfestation (ASD) and disinfestation with steam. In the 2010–2011 strawberry production season, fruit yields on substrates were comparable to fruit yields using conventional methods. Anaerobic soil disinfestation and steam disinfestation also resulted in fruit yields that were comparable to those produced using conventionally fumigated soils. Additional work is in progress to evaluate their efficacy in larger-scale production systems in different strawberry production districts in California