Title: High Or Low Dose Syntocinon for delay in labour (HOLDS)
Funder: Department of Health and Social Care

Abstract: HOLDS PROTOCOL SUMMARY DESIGN: A multicentre, prospective double blind, randomised controlled trial. SETTING: Delivery suites in approximately 30 Maternity Units. TARGET POPULATION:Nulliparous women with a singleton cephalic pregnancy at term (37-42 weeks) gestation. Confirmed delay in labour as defined by NICE Intrapartum Care Guideline and with ruptured membranes. Those with a significant maternal condition or contra-indication to oxytocin will be excluded. Confirmed delay in labour as defined per NICE Intrapartum Care Guidelines: labour is established when there are regular painful contractions and progressive cervical dilation from 4 cm. Delay is suspected when cervical dilatation of < 2 cm in 4 hours occurs once labour is established. Delay is confirmed when progress of <1 cm in 2 hours is found on repeat vaginal examination. HEALTH TECHNOLOGIES ASSESSED:Standard dose regimen of oxytocin (2mU/min increasing every 30 minutes to a maximum 32mU/min) compared to high dose regimen of oxytocin (4mU/min increasing every 30 minutes to a maximum of 64mU/min). OUTCOMES:Primary Outcome is Caesarean Section (CS). Secondary clinical maternal outcomes include: Analgesic use during labour (type and dose), duration of first, second and third stages of labour, time to birth from randomisation, mode of birth (spontaneous vaginal birth (SVB), instrumental or CS), degree of perineal trauma, reason for CS and decision to delivery interval for CS, positive fluid balance resulting in urinary retention and pulmonary oedema, tachysystole (uterine contractions greater than 5 in 10 mins for 20 minutes) requiring reduction in oxytocin and/or tocolysis, hyperstimulation (uterine contractions greater than 5 in 10 mins for 20 minutes resulting in non-ressurring or abnormal fetal heart rate), fetal blood sampling (FBS) during labour OR significant ST event, abnormal cardiotocogram leading to immediate birth without fetal blood sample, incidence of possible maternal morbidity (anaphylaxis, pulmonary oedema, postpartum haemorrhage, shoulder dystocia, chorioamnioitis, uterine rupture/hysterectomy), length of time after birth in hospital, admission to HDU/ITU, maternal death. Process outcomes: time from randomisation to commencement of allocation, total oxytocin dose, time to maximum oxytocin rate, maximum oxytocin dose reached. Neonatal secondary outcomes include: Apgar score at 1 and 5 minutes, arterial cord blood gases when collected, breastfeeding rates on discharge from hospital, length of time after birth in hospital, hyperbilirubinaemia requiring phototherapy, admission to neonatal unit (NNU) including intensive care, seizures, neonatal encephalopathy, the need for therapeutic hypothermia, intrapartum still birth, early neonatal death (within seven days of birth) ANALYSIS: The analysis will be by intention to treat. Point estimates, 95% confidence intervals and p values from two sided tests will be calculated for all main outcomes. A Statistical Analysis Plan will be drawn up by the co-applicants prior to any analysis and agreed by the Trial Steering Committee (TSC) and Data Monitoring Committee (DMC). SAMPLE SIZE: 1500 women will be recruited. The sample size is informed by the pilot study [Kenyon 2013], recent survey of practice and Cochrane review [Kenyon 2013]. The pilot study indicated a CS rate of 32% in the standard dose group (95%CI: 19% to 45%), whilst responses from the survey of practice (n=70 responses) indicate that a 25% relative reduction would be considered an important clinical difference to change practice. Detecting a difference of this size assuming a standard dose group rate of 32% (i.e. 8% absolute reduction down to 24%) with 90% power (p=0.05) will require 1320 women. If the control group rate is lower, e.g. 24%, recruiting 1500 women would give 80% power to detect the same relative difference. The independent Data Monitoring Committee (DMC) will review the event rate to monitor the control rate on a six-monthly basis throughout the recruitment period. TIMESLINES: Anticipated start date is March 2016 Months 0-9: R&D applications to obtain approvals for the first 10 sites, including CRN negotiations, telephone randomisation system developed together with database specification, recruitment of HOLDS specific midwives in these sites. Data collection forms finalised. A three month pre-recruitment period enables training of clinicians and informing nulliparous women, facilitating an approach in labour. Months 9-18: Further 20 sites set up, including appointment of HOLDS midwives By the end of year one the first woman recruited. Months 18-30: Recruitment taking place in all 30 sites for 12 months. Recruitment is planned to close at the end of month 30 with 1500 women randomised. Months 30-39: Completion of data collection, data cleaning, analysis, write-up and publication Submission of trial monograph and principle trial publication by month 39. Results posted on the website for women and distributed widely. SITES: 30 maternity sites will collaborate. Each site will have a funded HOLDS midwife at a maximum of 50%fte at each Trust (dropping to 30% after 4 months). Precise support will be tailored to each participating unit taking unit size into consideration and variable CRN support. Contracts will only be continued if pre-specified numbers of women have been recruited. For this trial having research midwives who are clinically active and part of Delivery Suite culture is particularly important. The HOLDS midwife will be responsible for training staff, actively promoting the trial and maintaining the profile within each unit, troubleshooting challenges and collecting outcome data, to minimise the impact on busy clinical staff. Sites that can provide 24/7 GCP trained midwives and obstetricians (to be compliant with MHRA Guidance) and are research active will be given priority.

Lay abstract: We currently do not know the best care for first time mothers with delayed progress in the first stage of labour and this topic is a research priority for the Royal College of Obstetricians and Gynaecologists. Delayed labour is a relatively common occurrence, affecting between 11- 30% (equivalent to between one and three in ten) of first time mothers. The only recommended treatment for women delayed in the first stage of labour is artificial oxytocin (Syntocinon®) which is given intravenously to stimulate contractions. A standard regimen (concentration and rate of administration) is recommended by NICE Guidelines 2014 and is widely used in the UK. Information from studies looking at different dose regimens of Syntocinon® in delayed labour suggest that a high dose regimen may reduce the chance of caesarean section but the available evidence is not conclusive. Syntocinon® may cause the uterus to contract too much and the baby to become distressed so both mother and baby are carefully monitored and the dose adjusted in relation to the number of contractions and how the baby is. Research shows currently around 32% (equivalent to about three in ten) of the women who need Syntocinon® for delayed labour have an unplanned caesarean section, which we know is related to a longer hospital stay, higher risk of infection, bleeding and blood clots and to increase risk of caesarean section in future pregnancies. By reducing caesarean section we can reduce these risks to women. A reduction in the Caesarean section rate of 5-8% (equivalent to nearly one in ten) in these women could save the NHS nearly £1M per year, as well as possible annual savings of £2.6M from the impact of avoiding caesarean section in future pregnancies. Our proposed trial will randomise 1500 women to standard or high dose regimens of Syntocinon® and measure differences in rates of caesarean section as well as collecting information about the birth and safety of mother and baby. Clinicians will not be aware of which regimen of Syntocinon® is being given, and care will be the same for either group. Serious adverse events are more likely in this high risk group of women and these will be reviewed by an independent group (Data Monitoring Committee). Recruiting women to clinical trials in labour is challenging, and in our pilot study we showed that informing all potentially eligible women about the study in late pregnancy, and approaching them during labour to discuss the study is acceptable. We have set a realistic target for recruitment of about 20% (equivalent to one in five) eligible women, based on the pilot and realise the importance of training staff so they can explain the study and answer any questions women and their partners may have. This application brings together a multidisciplinary team of experts-academics, clinicians, statisticians, and a service user, who together have successfully undertaken the pilot study. Information from this study will directly influence care of future women with delayed labour.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH