Project title: CONDISOX: Continued versus discontinued oxytocin stimulation of labour in a double-blind randomised controlled trial. Research group: PhD Student, primary investigator: Sidsel Boie, MD Department of Obstetrics and Gynaecology, Regional Hospital of Randers, Randers, Denmark Skovlyvej 1, 8900 Randers E-mail: [email protected] Main supervisor, Sponsor: Pinar Bor, associate professor, MD, PhD Department of Obstetrics and Gynaecology, Regional Hospital of Randers, Randers, Denmark Co-supervisor: Julie Glavind, MD, PhD Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark Co-supervisor: Niels Uldbjerg, Professor, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark Extern supervisor: Philip J. Steer, Emeritus Professor, BSc, MD, FRCOG Academic Department of Obstetrics and Gynaecology, division of cancer Imperial College London, London, England Centres: Department of Obstetrics and Gynaecology Regionshospitalet Randers Skovlyvej 1 8930 Randers SØ Denmark Department of Obstetrics and Gynaecology Aarhus Universitetshospital Palle Juul Jensens vej 100 8200 Aarhus N Denmark 1 of 13 01042016 Version 11.1 Department of Obstetrics and Gynaecology Sygehus Lillebælt, Kolding Skovvangen 2-8 6000 Kolding Denmark Department of Obstetrics and Gynaecology Aalborg Universitetshospital Reberbansgade 15 9000 Aalborg Denmark LOCAL INVESTIGATORS Lone Hvidman Local investigator Aarhus, associate professor, MD, PhD [email protected] Mohammed Khalil Local investigator Kolding, MD, PhD-student [email protected] Margrethe Møller Local investigator Aalborg, MD, PhD [email protected] 2 of 13 01042016 Version 11.1 TRIAL STEERING COMMITTEE (TSC) Jim Thornton Chief of TSC, professor, PhD [email protected] Inger Stornes Independent member of TSC, MD [email protected] Thomas Bergholt Independent member of TSC, associate professor, PhD, MD [email protected] Sidsel Boie, Principal investigator, MD, PhD-student [email protected] Pinar Bor, Sponsor, associate professor, MD, PhD [email protected] DATA MONITORING AND ETHICS COMMITTEE (DMEC) Lone Krebs Chair of DMEC, clinician, associate professor, DMSc, MD [email protected] Martin Berg Johansen Member of DMEC, Statistician, MSc [email protected] Gorm Greisen Member of DMEC, professor and Chair of Danish Ethic Committee [email protected] Leslie Foldager Member of DMEC, Statistician, PhD, MSc [email protected] 3 of 13 01042016 Version 11.1 Objective The proposed study will investigate the effect of Syntocinon® (synthetic oxytocin) to induce labour. The hypothesis to be studied is that once labour is established and the active phase of labour has commenced, Syntocinon® can be discontinued and the labour process will continue. The primary outcome will be the rate of caesarean delivery. The main secondary outcomes will be the duration of labour, neonatal conditions, maternal outcomes and satisfaction. Background In Denmark approximately 45% of nulliparous women are given stimulation with synthetic oxytocin (Syntocinon®) for either induction or augmentation of labour.1 Syntocinon® is used in more than 50% of the deliveries in the United States of America.2 Despite the extensive use of Syntocinon®, only few studies have focused on how long it needs to be given once labour is established. Currently, there is no consensus whether oxytocin should be continued until delivery or discontinued after the onset the active phase of labour.3 4 5 6 Theoretically, once labour contractions are established, the endogenous production of prostaglandin from the endometrium disrupted by the contractions may be enough to maintain appropriate uterine activity without further stimulation with Syntocinon®. The current protocol used in Denmark for induction of labour with Syntocinon® is described in the Danish Society of Obstetrics and Gynaecology (DSOG) guidelines 7. It recommends that the infusion continue until delivery, unless complications (e.g. uterine tachysystole) occur, in which case, the dose being administered should be reduced or discontinued. Although Syntocinon® is used in a high proportion of labours, many professionals underestimate the associated adverse effects. The most frequent complication is tachysystole,8 which increases the risk of fetal distress and birth asphyxia, requiring delivery by caesarean section or forceps/ventouse. In addition, the use of Syntocinon® increases the risk of uterine rupture.8 A continuous high dose of Syntocinon® has been associated with a high caesarean delivery rate when compared with a continuous low dose. 9 It is well established that Syntocinon® administration during labour causes down regulation of the oxytocin receptors,10 which persists postpartum causing an increased risk of postpartum haemorrhage. Initiation and duration of breastfeeding may also be adversely affected in women who undergo 4 of 13 01042016 Version 11.1 Syntocinon® stimulation.11 Recently it was reported there is an inverse association between stress incontinence (1 year after the first vaginal delivery) and augmentation with Syntocinon®.12 A few small studies (sample size ranging from 104 to 342) report a reduction in the caesarean delivery rate, when Syntocinon® is discontinued at the active stage of labour; however, because of small numbers, this difference was not statistically significant even on meta-analysis.3 4 5 6 Recently, a Danish pilot study was conducted to investigate the effects of discontinued Syntocinon® infusion compared to continued Syntocinon® infusion on labour outcomes13. Between 2009 and 2011, two hundred women admitted for induction or augmentation of labour at the Regional Hospital of Randers were randomised to continued or discontinued Syntocinon® once active phase of labour had become established. Though not being the primary study outcome, the total caesarean delivery rate for the Syntocinon® continued group was 22% compared with 15% in the discontinued group (p = 0.2745 by Fisher’s exact test). Moreover, in the discontinued group, there were significantly fewer cases of postpartum haemorrhage, uterine tachysystole, and pathological fetal heart rate pattern. The current study is planned as a double-blind, randomised controlled trial with caesarean section rate as the primary outcome. A power calculation based on the above pilot study shows that with an alpha of 0.05, a beta of 80% and a misclassification of 5 %, 482 women in each group will be needed to test the hypothesis of a caesarean delivery rate of 22% versus 15%. With a drop out of 5%, 506 women will be needed in each group. Therefore we plan to include 600 in each group Basic demographic data will be presented counts and percentages for categorical variables, with mean and standard deviation for continuous variables, and with median and interquartile range for continuous non-Gaussian variables. We will use the intention-to-treat principle to compare the designated outcomes between participants with continued or discontinued Syntocinon®. We will use multivariate logistic regression with adjustment for indifferences in baseline characteristics to calculate odds ratios with 95% confidence intervals. Adjustment for multiple comparisons (Bonferroni) will be made in the evaluation of secondary outcomes. The analyses will be stratified by the indication for oxytocin (labor induction or induction due to Premature Rupture of Membranes) and parity (nullipara or multipara). 5 of 13 01042016 Version 11.1 STUDYDESIGN Study type: Double-blind, randomised multicentre trial. Setting Sygehus Lillebælt, Kolding, Aalborg University Hospital, Aarhus University Hospital and Randers Regional Hospital, Denmark. Inclusion criteria: Women stimulated with Syntocinon® infusion for induction of labour (with or without cervical priming by prostaglandin). Exclusion criteria: <18 years Unable to read and understand the Danish language or to give informed consent Cervical dilatation > 4 cm Non-cephalic presentation Multiple gestation Pathological fetal heart rate pattern (cardiotocogram, CTG) before Syntocinon® initiation14 Fetal weight estimation > 4500 g (clinical or ultrasonic) Subject declines participation Gestational age less than 37 completed weeks Definition: Stimulation following Premature Rupture of Membranes Stimulation with Syntocinon® following Premature Rupture of membranes is induction of labour if there is no cervical change prior to starting the infusion, whereas stimulation with Syntocinon after Premature Rupture of Membranes but following the establishment of significant cervical change is augmentation. Randomisation and blinding: When the orificium ≥6 cm, regular painful contractions (≥3 per 10 minutes) and rupture of membranes participants will be randomised in a 1:1 ratio to either the control (continued Syntocinon®) or intervention (discontinued Syntocinon®) group using an Internet-based randomisation programme. The 6 of 13 01042016 Version 11.1 randomisation can only be performed when the woman consents to participation. Written consent can be given after the commencement of the Syntocinon® infusion, provided the woman previously has received sufficient information for her to give properly informed consent. Random block-sizes of 4 are used, and the participants will be stratified by site (Aarhus University Hospital, Randers Regional Hospital, Sygehus Lillebælt Kolding or Aalborg University Hospital), parity (nulliparous or parous) and indication for Syntocinon® infusion (induction or induction due to Premature Rupture of Membranes).