Title: High or low dose Syntocinon®, for induction of labour in nulliparous women: a double blind, randomised controlled trial (The iHOLDS Trial)
Funder: Department of Health and Social Care

Abstract: In the UK each year, around 34% of first time mothers (70,730 women) have their labour induced. This figure is increasing as a result of new evidence suggesting benefit of induction for more groups of women (e.g. for prolonged pregnancy, large size of baby, broken waters, diabetes, high blood pressure, and advanced age). _x000D_ Labour can be induced in different ways. Usually the cervix (neck of the womb) is softened using vaginal prostaglandins. Some women will go into labour at this point but most first time mothers require their waters to be broken and, a drug is offered to start contractions. This is artificial oxytocin (Syntocinon®) which is given by an intravenous drip, and is given to around 60% of women (42,438) during the induction process. A widely used standard regimen (dose and rate of administration) is recommended by national guidance. Information from studies looking at different dose regimens of Syntocinon is very limited and it is difficult to know whether a higher dose may be better or worse than the standard dose regimen. Syntocinon can cause the uterus to contract too much and the baby to become distressed so both mother and baby are carefully monitored. The dose is adjusted in relation to the number of contractions and the baby’s heart rate tracing (CTG). _x000D_ We have obtained information from UK maternity units showing that around 30% of the first time mothers who receive Syntocinon for induction of labour have an unplanned (emergency) caesarean section (CS). CS is related to a longer hospital stay, higher risk of infection, bleeding and thrombosis and an increased chance of the woman having future babies born by CS. Reducing CS rates would lessen these risks, and potentially save the NHS money. It is thought that using a higher dose regimen of Syntocinon during the induction process may shorten labour and decrease the numbers of women having a CS._x000D_ Our proposed trial will recruit 2400 first time mothers and randomise them to either a standard or higher dose regimen of Syntocinon. We will measure any differences in the number of CS between the two groups as well as collecting information about the birth and safety of mother and baby. Clinicians will not be aware which regimen of Syntocinon is being given, and all other aspects of labour care will be the same for both groups. _x000D_ This trial will be run in 30 UK maternity units. Recruiting women to clinical trials in labour is challenging, and we plan to follow national guidance. A discussion will take place when the induction is booked and information will be sent to women at that time. For many women it can take up to 24 hours for cervical ripening so discussion will take place throughout this process. We have consulted 122 women in 11 maternity units who felt this would be acceptable. We realise the importance of training staff so they can explain the study and answer any questions. _x000D_ This application brings together a successful collaborative group of 30 maternity units led by a multidisciplinary team of experts-academics, clinicians, statisticians, and a service user. Information obtained will directly influence care of future women being induced and will be widely disseminated.

Lay abstract: Research question_x000D_ To determine the clinical effectiveness and costs of a high dose compared to the current standard dose regimen of Syntocinon for nulliparous women for whom it is prescribed as part of induction of labour._x000D_ _x000D_ Background _x000D_ Evidence is limited, with mixed results and unclear findings for clinically relevant indicators to guide practice. There are no ongoing trials and there is need for a definitive one. _x000D_ _x000D_ Aims and objectives _x000D_ To provide robust evidence of clinical effectiveness and costs of high dose compared to standard dose regimen of Syntocinon for nulliparous women when prescribed during induction of labour. _x000D_ _x000D_ Methods _x000D_ Multicentre, randomised, double blind, controlled trial in approximately 30 UK maternity units._x000D_ _x000D_ Target population _x000D_ Nulliparous women with a singleton pregnancy undergoing induction of labour for whom Syntocinon is prescribed who clinicians are willing to randomise and who consent to participate._x000D_ _x000D_ Health technologies assessed_x000D_ The high dose regimen of Syntocinon (4mU/min increasing every 30 minutes to a maximum of 64mU/min) compared to the standard dose regimen recommended by national guidance (2mU/min increasing every 30 minutes to a maximum 32mU/min)._x000D_ _x000D_ Treatment allocation: Randomisation will be by telephone available 24 hours a day to an automated secure system which includes a minimisation algorithm to ensure balance with respect to important prognostic factors._x000D_ _x000D_ Outcomes_x000D_ Primary outcome; Caesarean section (CS). Secondary outcomes: maternal and neonatal birth outcome data that are routinely collected and include the recently published Core Outcome set and a quantitative assessment of maternal psychological outcomes using validated tools two weeks after birth via mobile phone technology. An in-trial cost comparison will compare the costs associated with a high dose regimen of Syntocinon with the standard dose. We will ask for consent from women and their babies so that long term follow-up is possible._x000D_ _x000D_ Sample size_x000D_ Our survey of 22 obstetric units indicated that the average rate of caesarean section in nulliparous women undergoing induction and given standard-dose Syntocinon to be approximately 30% (95%CI: 28%-32%). To detect an absolute reduction of 6% (equivalent to a 20% relative reduction) with 90% power (p=0.05) would require 2400 women in total (including a conservative 4% inflation for any loss to follow-up or withdrawals). _x000D_ _x000D_ Analysis_x000D_ 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 outcomes. _x000D_ _x000D_ Timelines for delivery_x000D_ The trial will last 36 months. The set-up period is nine months and an internal pilot will form the first eight months of recruitment. This has clear, realistic recruitment targets, including protocol adherence and data collection. Recruitment will take 21 months in total, followed by a 6 month close down. _x000D_ _x000D_ Anticipated impact and dissemination_x000D_ We have a comprehensive plan for dissemination and impact that utilises multiple communication methods and involving both informing national guidelines as well as both clinicians and women

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