BMJ

Confidential: For Review Only Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX)- A double-blind randomised controlled trial

Journal: BMJ

Manuscript ID BMJ-2020-063027

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the 09-Nov-2020 Author:

Complete List of Authors: Boie, Sidsel; Randers Regional Hospital, Obstetrics and Gynaecology Glavind, Julie; Aarhus University Hospital, Obstetrics and Gynaecology Uldbjerg, Niels; Aarhus University Hospital, Obstetrics and Gynecology Steer, Philip; Imperial College London, Academic Department of Obstetrics and Gynaecology Bothazi, Attila; Aalborg University Hospital, Obstetrics and Gynaecology Sundtoft, Iben ; Hospitalsenheden Vest, Obstetrics and Gynaecology Bakker, Jannet; Amsterdam UMC Location AMC, Obstetrics and Gynaecology Van der Post, Joris; Amsterdam UMC Location AMC, Obstetrics and Gynaecology Renault, Kristina; Rigshospitalet, Obstetrics and Gynaecology Huusom, Lene; Hvidovre Hospital, Obstetrics and Gynaecology Hvidman, Lone; Aarhus University Hospital, Obstetrics and Gynaecology Rask, Maja; Odense University Hospital, Obstetrics and Gynaecology Khalil, Mohammed; Sygehus Lillebalt Kolding Sygehus, Obstetrics and Gynaecology Møller, Nini; Nordsjaellands Hospital, Obstetrics and Gynaecology Greve, Tine; Hvidovre Hospital, Obstetrics and Gynaecology Bor, Pinar; Randers Regional Hospital, Obstetrics and Gynaecology

induction of labour, oxytocin, discontinuation, Caesarean section, active Keywords: phase of labour, uterine tachysystole

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CONDISOX paper 2020-11-08 1 2 3 Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX)- A double-blind 4 randomised controlled trial 5 6 Sidsel Boie1, Julie Glavind2, Niels Uldbjerg2, Philip J Steer3, CONDISOX trial group*, Pinar Bor1 7 8 *The following are members of CONDISOX trial group: 9 Attila Bothazi4, Iben Sundtoft5, Jannet Bakker6, Joris Van der Post6, Kristina Martha Renault7, Lene Drasbek Huusom8, 10 Lone Hvidman2, Maja Thode Rask9, Mohammed Khalil10, Nini Møller11, Tine Greve8 11 12 Affiliations Confidential: For Review Only 13 1. Department of Obstetrics and Gynaecology, Randers Regional Hospital, Randers, Denmark 14 2. Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark 15 3. Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, Imperial College London, 16 London, UK 17 4. Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark 18 5. Department of Obstetrics and Gynaecology, Herning Regional Hospital, Herning, Denmark 19 6. Department of Obstetrics and Gynaecology, Amsterdam UMC, Amsterdam University Hospital, Amsterdam, The 20 Netherlands. 21 7. Department of Obstetrics and Gynaecology, Juliane Marie Centre, Copenhagen University Hospital, Rigshospitalet, 22 Copenhagen, Denmark 23 8. Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Hvidovre Hospital, Hvidovre, 24 Denmark 25 9. Department of Obstetrics and Gynaecology, Odense University Hospital, Odense, Denmark 26 10. Department of Obstetrics and Gynaecology, Lillebaelt Hospital, Kolding, Denmark 27 11. Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Nordsjaelland Hospital, Hilleroed, 28 Denmark 29 30 Corresponding author: 31 Sidsel Boie, MD 32 Department of Obstetrics and Gynaecology 33 Randers Regionalhospital 34 Denmark 35 +45 60 63 68 35 36 [email protected] 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Abstract 4 Objective 5 Small studies have suggested that discontinuing oxytocin stimulation in the active phase of induced labour is associated 6 7 with lower caesarean section rates. 8 Design: 9 10 An international multicentre double-blind trial. 11 Setting 12 Confidential: For Review Only The trial was conducted in one Dutch and nine Danish Hospitals between April 8, 2016 to June 30, 2020. 13 14 Participants: 15 The population was women stimulated with intravenous oxytocin infusion during the latent phase of induced labour. 16 17 Intervention: 18 Women were randomly assigned to have their oxytocin stimulation discontinued or continued in the active phase of 19 20 labour. 21 Main outcome measure: 22 Delivery by caesarean section. 23 24 Results: 25 A total of 607 women were assigned to discontinuation and 593 to continuation of the oxytocin infusion. The rates of 26 27 caesarean section were 16.6 % in the discontinued group and 14.2 % in the continued group (Relative Risk, 1.17; 95% 28 confidence interval [CI], 0.90 to 1.53). 29 30 31 Discontinuation was associated with longer duration of labour (median from randomisation to delivery 282 versus 201 32 33 minutes, p<0.001), a reduced risk of hyperstimulation (3.7% vs 12.9%, p<0.001), a reduced risk of fetal heart rate 34 abnormalities (27.9% vs 40.8%, p<0.001), and similar rates of other adverse maternal and neonatal outcomes. 35 36 37 Conclusions: 38 In a setting where monitoring of the fetal condition and the uterine contractions can be guaranteed routinely 39 40 discontinuing oxytocin in the active phase of induced labour is neither beneficial nor harmful. 41 42 43 Trial registration: ClinicalTrials.gov registration number NCT02553226 44 Keywords: Induction of labour, oxytocin, discontinuation, Caesarean section, active phase of labour, uterine 45 46 tachysystole 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Funding 4 Randers Regional Hospital Research Fund. Aarhus University. Health Research Fund of Central Denmark Region. 5 Dagmar Marshall Foundation. The Danish Regions Medical Foundation. Aase and Ejnar Danielsen Foundation. The 6 7 A.P. Moeller Foundation for the Advancement of Medical Science. The Soren Segels and Johanne Wiibroe Segels 8 Research Fund. The funders had no role in the design of the study, the data collection, the data analysis, interpretation 9 10 of data, nor in writing the manuscript. 11 12 ContributorsConfidential: For Review Only 13 14 SB, PB, JG, NU, and PS conceived and designed the study. The members of TSC and DMEC contributed to the design. 15 SB, PB, JG, NU, JB, AB, LH, IS, MK, MR, KR, LDH, TG, and NM performed the study. Representatives of each 16 17 centre entered the data, and the data was crosschecked by Good Clinical Practices monitors at all centres. SB did the 18 statistical analysis, overviewed by an external statistician and PS. Data interpretation was done by SB, PB, JG, NU, and 19 PS. SB drafted the original manuscript with major contributions from PB, JG, NU and PS. All authors reviewed and 20 21 revised the manuscript. All authors read and approved the final manuscript. Furthermore, all authors have agreed to be 22 personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part 23 24 of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and 25 the resolution documented in the literature. 26 27 28 Acknowledgement 29 We wish to thank all the families who participated in this trial, the dedicated staff from all participating departments. 30 31 Furthermore, we want to acknowledge the valuable contributions from each member of the Trial Steering Committee; 32 Jim Thornton (chair), Thomas Bergholt, Wessel Ganzevoort, and Jens Fuglsang. Each member of the Data Monitoring 33 34 and Ethics Committee consisting of Lone Krebs (chair), Gorm Greisen and Martin Johansen should also be personally 35 acknowledged for their contributions. 36 37 38 Declaration of interest 39 40 All authors have completed the ICMJE uniform disclosure form and declare no financial relationships with any 41 organisations that might have an interest in the submitted work in the previous three years and no other relationships or 42 activities that could have influenced the submitted work. 43 44 45 Data availability 46 47 Due to Danish legislation data will only be available after approval of Danish Data Protection Agency and with a signed 48 access agreement. 49 50 51 Abbreviations 52 CEQ Experience Questionnaire 53 54 DMEC Data Monitoring and Ethics Committee 55 GCP Good Clinical Practice 56 57 IOL Induction of labour 58 IU International Unit 59 60

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CONDISOX paper 2020-11-08 1 2 3 NICU Neonatal Intensive Care Unit 4 PROM Prelabour Rupture of Membranes 5 REDCap Research Electronic Data Capture 6 7 TSC Trial Steering Committee 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Summary boxes 4 What is already known on this topic 5 6 Four meta-analyses suggest that once a woman is in active labour, the labour process continues even if oxytocin 7 stimulation is stopped, and results in a lower risk for caesarean section. 8 9 The 2018 Cochrane review questions the quality of previous studies due to design limitations and judge many of the 10 trials to be at either high or unclear risk of bias across a number of 'risk of bias' domains. 11 12 Confidential: For Review Only 13 What this study adds 14 This is the largest, truly double-blinded trial on discontinuation of oxytocin stimulation in the active phase of induced 15 16 labour. 17 In a setting where close monitoring of the fetal condition can be guaranteed and proper action is taken in case of 18 19 hyperstimulation, routinely discontinuing oxytocin in the active phase of induced labour is neither beneficial nor 20 harmful. 21 22 In case of fetal heart rate abnormalities or , turning off the oxytocin is an important first step to 23 safeguard the and mothers, and birth attendants can be reassured that this will not significantly increase the 24 likelihood of caesarean section, or adversely affect other outcome measures. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Introduction 4 5 Approximately one fourth of all term pregnant women have their labour induced1–4. This often includes oxytocin 6 stimulation5. The stimulation requires a delicate balance between the wish for progression of labour and the risks to the 7 8 fetus and mother of uterine hyperstimulation, defined as more than five contractions in ten minutes in response to 9 oxytocin6–8. Different approaches to oxytocin administration have been suggested such as pulsatile or intermittent 10 administration9,10, an automatic feed-back system11, high versus low dose 12, and/or discontinuation of the stimulation 11 12 when the activeConfidential: phase of labour is reached13. For Review Only 13 Four meta-analyses 13–16 and two more recent studies 17,18 have suggested that once a woman is in active labour, the 14 15 labour will continue even if oxytocin stimulation is stopped, resulting in a lower risk for caesarean section for fetal 16 indications secondary to uterine hyperstimulation. However, only one study randomised at time of the intervention, 17 18 whereas the remaining studies conducted randomisation in early labour and consequently included a significant fraction 19 of women who delivered by caesarean section before they received the intervention13. In the Cochrane meta-analysis a 20 21 subanalysis restricted to trial participants who actually reached the active phase of labour showed little or no effect on 22 the caesarean section rate13. Whether there is an advantage to discontinuing oxytocin stimulation therefore remains 23 uncertain. The aim of the CONDISOX trial was to test the hypothesis that discontinuation of oxytocin stimulation, once 24 25 the active phase of induced labour is achieved, reduces the overall caesarean section rate. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Methods 4 5 Trial design 6 7 We conducted a double-blind, randomised, placebo-controlled multicentre trial. Recruitment took place in one Dutch 8 and nine Danish delivery wards. The protocol was published in 201819. 9 10 11 Participants 12 Confidential: For Review Only Women were eligible if they had a singleton live fetus with a cephalic presentation at term and were stimulated with 13 14 oxytocin for elective induction of labour or following spontaneous prelabour rupture of membranes (PROM) without 15 progression in labour. The exclusion criteria were age <18 years, need of an interpreter to understand the information 16 17 material, multiple , more than one previous caesarean section, > 4 cm of cervical dilatation at time of 18 oxytocin, fetal heart rate abnormalities prior to oxytocin infusion, and an estimated fetal weight of more than 4500 g. 19 20 Verbal and written informed consent were obtained from all participants prior to randomisation. 21 22 Randomisation and masking 23 24 Inclusion and randomisation were primarily facilitated by the midwives on duty. Eligible women were randomly 25 assigned to one of the two interventions in a 1:1 ratio using an internet-based randomisation programme. Random 26 27 block-sizes of 4, 6, and 8 were used, and the women were stratified by site, parity (nulliparous, parous with or without 28 previous caesarean), and indication for oxytocin infusion (induction of labour (IOL) or induction due to PROM). The 29 30 randomisation number generated by the computer program corresponded to the number on the study medication 31 (Denmark: Masked, identical ampoules, The Netherlands: Masked, identical infusions). In case of technical or staff 32 33 difficulties with the computerised randomisation (n=26), the women were given the study medication with the lowest 34 available number. Accordingly, women, caregivers, and trial managers were all blinded to the allocation. 35 36 37 Oxytocin stimulation protocol 38 The stimulation regime used in this study was similar to the current Danish and Dutch recommendations on oxytocin 39 40 stimulation for induced labour. An intravenous infusion of 10 IU oxytocin (Producer: Sigma Tau Pharmaceuticals Inc.) 41 diluted in 1000 ml of isotonic saline (Denmark) or 5 IU oxytocin diluted in 50 ml of isotonic saline (The Netherlands) 42 43 was started at 3.3 mIU/minute and increased every 20 min by 3.3 mIU/minute until regular contractions (three to five 44 contractions every 10min) were achieved. The maximum authorised infusion rate was 30 mIU/minute and 33 45 mIU/minute, respectively. Women were randomised when the active phase of labour was established, defined as 46 47 ruptured membranes with complete effacement of the cervix, cervical dilatation ≥6 cm, and ≥3 contractions per 10 min. 48 After randomisation, the infusion was replaced by the study medication. The continued group received oxytocin with 49 50 the standard concentration whereas the discontinued group received placebo with saline. The study medication was set 51 to the same infusion rate as the initial oxytocin infusion and was adjusted (discontinued, reduced, or increased) by the 52 53 birth attendants according to the clinical situation. All participants were continuously monitored with . 54 Antibiotics were recommended if the woman was a candidate for GBS prophylaxis, in case of an isolated temperature 55 56 ≥38.5 °C, or in case of maternal pyrexia during labour (temperature ≥38.2 °C with epidural, without epidural: ≥38 °C) 57 combined with signs of intrauterine infection or combined with an interval since rupture of membranes exceeding 18 58 hours. 59 60

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CONDISOX paper 2020-11-08 1 2 3 4 Slow progress (dystocia) in the first stage of labour was defined as a cervical dilatation of less than 2 cm every four 5 hours despite three to five uterine contractions in ten minutes and/or after reaching the maximum infusion dose. Slow 6 7 labour progress in the passive second stage was defined as descent of the presenting part not reaching two centimeters 8 below the ischial spines within 3 hours, and in the active second stage if delivery was not achieved within 2 hours of 9 10 maternal expulsive efforts. In women who fulfilled these dystocia criteria, the study medication was replaced with 11 open-label administration of oxytocin infusion with a start dose rate of 3.3 mIU/minute 12 Confidential: For Review Only 13 14 Trial outcomes 15 16 The primary outcome was caesarean section. Secondary maternal and neonatal outcomes are listed in the table of results 17 (Table 2 and Table 3). 18 The data collection was carried out by the researcher (midwife or physician) at each participating site and managed 19 20 using an electronic data capturing tool hosted at Aarhus University, REDCap (Research Electronic Data Capture)20. The 21 Childbirth Experience Questionnaire (CEQ), was sent to the women one month after the birth to evaluate the mothers’ 22 23 expectations and childbirth experience. The transcultural adapted Danish CEQ assesses three domains of the experience 24 of childbirth: the woman’s own capacity (her sense of control and personal feelings during childbirth), professional 25 26 support (the woman’s receipt of information and midwifery care), and participation in the birth (the woman’s ability to 27 influence the birthing process)21. Responses were scored according to the scoring instructions of the Danish 28 questionnaire21. Scores in each domain range from 1 to 4, with higher scores indicating a better childbirth experience. 29 30 31 Statistical analysis 32 33 The power calculation was based on data from an earlier Danish study where the caesarean section rate in women 34 35 continuously stimulated with oxytocin was 22% as compared to 15% in the discontinued group22. Based on these 36 numbers and with an alpha of 0.05, a total sample size of 1200 women (600 per group) would provide a power of at 37 38 least 80% to detect a difference of 7% in the caesarean section rate between the two regimes. 39

40 41 Participants were analysed according to intention to treat in their assigned group, regardless of their adherence to the 42 assignment. Baseline demographic data was presented with counts and percentages for categorical variables, mean and 43 44 standard deviation for continuous Gaussian distributed variables, and median and interquartile range for continuous 45 non-Gaussian variables. The primary outcome variable was assessed by comparing the event rates in the two groups 46 47 using a chi-square test with a significance threshold p-value of < 0.05. Results were presented as absolute and relative 48 risks along with 95% confidence intervals (Cl). Categorical secondary outcomes were assessed in the same way as the 49 50 primary outcome. For continuous secondary outcomes with a Gaussian distribution (following log transformation if 51 appropriate) we assessed differences between groups using the student’s t-test, and with a non-parametric Mann- 52 53 Whitney U test if the data were non-Gaussian. Non-inferiority testing was performed with a pre-stated margin of non- 54 inferiority boundary at 1.09. 55 56 57 To assess the women’s experience of childbirth as measured with the use of the Childbirth Experience Questionnaire, 58 we performed a complete case analysis, using the unpaired t-test, to compare the mean subscale scores and the mean 59 60

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CONDISOX paper 2020-11-08 1 2 3 total score (the average of the individual subscale scores) between women in the two groups. We used a Mann–Whitney 4 U test to calculate P values. In cases with a few missing items, the half-scale method was used so that when the 5 respondent had answered at least half the items in the scale, the sum of the scores was divided by the number of 6 7 answered items.23 8 9 10 For the primary outcome, pre-specified subgroup analyses according to parity (nulliparous, parous, and parous with 11 previous caesarean section), and indication for stimulation (PROM or IOL) were conducted. 12 Confidential: For Review Only 13 All analyses were performed with the use of Stata software, version 14. 14 15 16 Trial monitoring 17 The trial was approved by Danish and Dutch authorities (EudraCT number 2015-002942-30), monitored according to 18 Good Clinical Practice (GCP) regulations and registered at clinicaltrials.gov (NCT02553226) prior to randomisation of 19 20 the first participant. Assessment for safety and adverse events was based on the most recent available Summary of 21 Products for oxytocin. An independent Data Monitoring and Ethics Committee (DMEC) met yearly throughout the trial 22 23 to discuss the yearly interim analyses conducted during the course of the trial for the purpose of monitoring efficacy and 24 safety. DMEC elaborated a yearly report for the independent Trial Steering Committee (TSC) with a conclusion on trial 25 26 safety and progression based on the interim analysis. The TSC provided independent advice to the trialists based on the 27 DMEC conclusion. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Results 4 5 A total of 1200 women underwent randomisation from April 8, 2016 through June 30, 2020 (Figure 1). Two women in 6 the continued group subsequently withdrew consent and their data were therefore not included in the final analysis. The 7 8 number of women recruited from each site is presented in Table 13. 9 10 11 A total of 1849 women signed the informed consent form; 649 of these women (35%) were not randomised; in 202 12 women (11%)Confidential: due to rapid progression of labour (Table For 11). For Review reasons shown in Figure Only 1, 127 women (11%) never 13 14 received the allocated intervention (65 women in the discontinued group and 62 women in the continued group). 15 16 The baseline characteristics were similar in the two groups (Table 1). 17 18 19 Data on the primary outcome were available for all women included in the intention to treat analysis. There was no 20 21 statistically significant difference in the frequency of caesarean section between the discontinued group (101 caesarean 22 sections in 607 women [16.6%]) and the continued group (84 caesarean sections in 591 women [14.2%]); RR 1.17; 95% 23 24 confidence interval [CI], 0.90 to 1.53. The pre-specified non-inferiority testing (with a boundary of 1.09) was 25 inconclusive (p=0.70). 26 27 28 29 Data on secondary outcomes showed that oxytocin discontinuation was associated a with longer duration of labour 30 (median from randomisation to delivery 282 vs 201 minutes, p<0.001), a reduced risk of hyperstimulation (3.7% vs 31 32 12.9%, p<0.001), a reduced risk of fetal heart rate abnormalities (27.9% vs 40.8%, p<0.001), and similar rates of other 33 adverse maternal and neonatal outcomes (Table 2 and Table 3). 34 35 36 Among the 858 women (72%) who returned the Childbirth Experience Questionnaire four weeks postpartum, there 37 were no significant differences between the two groups in the subscale scores or total scores (indicating level of 38 39 satisfaction with the childbirth experience) (Table 4). 40 41 42 The pre-specified subgroup analysis in parous women with no previous caesarean section found a caesarean section rate 43 of 7.5% in the discontinued vs 0.6% in the continued group (RR 11.6; 95% CI, 1.15 to 88.7), Table 7. The other 44 45 prespecified subgroup analyses did not find any significant difference in caesarean section rate between groups, Table 46 6, Table 8, Table 9, and Table 10. 47 48 49 Stopping the study medication happened both in accordance and not in accordance to protocol for the reasons listed in 50 Table 5. The total number of women who stopped the study medication differed between the two groups; 314 (51.7%) 51 52 in the discontinued group and 193 (32.7%) in the continued group (p<0.0001). In cases of slow labour progress as the 53 reason for stopping, all women had study medication changed to open label oxytocin. Among the women who had 54 55 study medication stopped for other reasons than slow labour progress, 32/72 (44.4%) women in the discontinued group 56 had stimulation restarted compared to 53/95 (55.8%) women in the continued group. Among these, study medication 57 58 was chosen for 19/32 (59.4%) and 32/53 (60.4%), respectively, whereas the birth attendants chose to restart open label 59 oxytocin for the remains. 60

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CONDISOX paper 2020-11-08 1 2 3 4 One neonatal death was reported in the discontinued group. The macrosomic baby was born vaginally of a diabetic 5 mother, with an Apgar score of 1/1 and 7/5. The baby was immediately resuscitated by intubation and was then 6 7 admitted to the neonatal intensive care unit. The baby was diagnosed with severe haemolysis and a subgaleal 8 haematoma and died aged five days. 9 10 11 12 The randomisationConfidential: code was broken prior to delivery For in two women Review and in one woman Only postpartum. In two cases 13 allocation was revealed due to withdrawal of consent and upon maternal request in order to change for open-label 14 15 administration if not already given. In the last case the randomisation code was broken three months postpartum upon 16 maternal request in a participant with postnatal depression, at this point all relevant data had already been entered in the 17 database. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Discussion 4 5 A policy of routinely discontinuing oxytocin stimulation in the active phase of induced labour had no significant effect 6 7 on the caesarean section rate. It reduced the incidence of uterine hyperstimulation and fetal heart rate abnormalities, but 8 at the expense of a longer duration of labour. 9 10 Other maternal and neonatal outcomes, and the women’s birth experience did not differ significantly between the 11 groups. 12 Confidential: For Review Only 13 The strength of our study is the well-organised, multicentred and truly double-blinded design and the large sample size. 14 15 In our study, randomisation and intervention were concomitant, resulting in only two post-randomisation dropouts (due 16 to withdrawn consent) compared to 5.0%-13.2 % dropouts in previous trials13. 17 18 19 A significant limitation of the trial was the relatively high proportion of women who stopped the study medication for 20 21 reasons other than labour dystocia, uterine tachysystole and abnormal FHR as specified in the protocol (117/607, 19.3% 22 in the discontinued group vs 94/591, 15.9% in the continued group). For reasons not recorded, if the birth attendants 23 decided to restart stimulating the labour, they usually chose to use open label oxytocin rather than the study medication, 24 25 a phenomenon we had not anticipated. This resulted in some loss of power with regard to our primary hypothesis. 26 Anecdotally, birth attendants involved with the trial reported a general impatience with slower than average rates of 27 28 cervical dilatation, leading to pressure from medical and midwifery colleagues to recommence oxytocin even though 29 the trial criteria for this had not been met. Ambiguity about oxytocin use among birth attendants has been reported 30 25 31 previously . Furthermore, the high number of women being changed to open-label infusion could also reflect insecurity 32 among the birth attendants as to whether placebo is a safe option. This could be an argument for repeating the trial, 33 since the results demonstrate that discontinuing oxytocin in the active phase of labour is not harmful. 34 35 36 With respect to external validity, the current trial included women from secondary- and tertiary- level hospitals, and the 37 38 results are generalisable to countries with similar demographic details. There is considerable heterogeneity in the 39 methods used for induction around the world4,5. The methods of induction have differing efficacy. Most participating 40 41 units in the study used oral prostaglandin ripening followed by amniotomy and oxytocin infusion. However, for parous 42 women with a previous caesarean delivery cervical priming with a double balloon catheter was preferred. We did not 43 44 pre-define the indications for induction of labour. Hence it is unclear whether the results of this trial would be 45 generalisable to centres that use other methods of induction or other oxytocin stimulation regimens. 46 47 48 During the inclusion period, there were an additional 202 women, who consented for participation, but staff were left 49 with no time for randomisation and intervention due to rapid progression of labour. These women might potentially 50 51 have benefitted the most from discontinuation of oxytocin, and this might explain the lack of difference in the caesarean 52 section rates between the two groups in our study. There may thus be an advantage in discontinuing oxytocin infusion 53 54 selectively, i.e. in women with faster than average cervical dilatation rates. Future studies could focus on this subgroup. 55 56 The result of the trial differs from that of previous published studies and meta-analyses which suggested that 57 58 discontinuation reduces the risk of caesarean section13–18. However, most of the previous studies were designed to 59 60

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CONDISOX paper 2020-11-08 1 2 3 measure another primary outcome, namely duration of labour. Many of these studies had limitations; imbalanced post- 4 randomisation drop outs prior to intervention, open-labelled administration, and small sample sizes of 100-200 women. 5 Furthermore, our population differs in terms of cervical dilatation at the time of intervention, inclusion of women with 6 7 previous caesarean section, proportion of nulliparous women, and birthweight13. 8 As also reported in several previous studies13,24, we found oxytocin stimulation to have little or no effect on the duration 9 10 of the second stage of labour. This suggests that oxytocin might not be necessary during descent and expulsion of the 11 fetus. 12 Confidential: For Review Only 13 14 We conclude that in a setting where close monitoring of the fetal condition can be guaranteed and proper action is taken 15 in case of hyperstimulation, routinely discontinuing oxytocin in the active phase of induced labour is neither beneficial 16 17 nor harmful. In case of fetal heart rate abnormalities or uterine hyperstimulation, turning off the oxytocin is an 18 important first step to safeguard the fetus and mothers, and birth attendants can be reassured that this will not 19 significantly increase the likelihood of caesarean section, or adversely affect other outcome measures. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 4 5 6 7 8 9 3312 women assessed for eligibility 10 11 12 Confidential: For Review Only 13 2119 women were excluded 1235 declined to participate 14 649 consented, but were not randomized 15 228 unrecorded 16 17 18 19 1200 women randomised 20 21 22 23 24 25 26 27 607 allocated to discontinued stimulation 593 allocated to continued stimulation 28 29 30 31 32 33 542 received allocated intervention 529 received allocated intervention 34 35 65 did not receive allocated intervention 62 did not receive allocated intervention 36 24 Rapid progression 26 Rapid progression 37 9 Participant preference 4 Participant preference 38 13 Obstetric complication 7 Obstetric complication 39 9 Randomisation failure 5 Randomisation failure 40 1 Staff preference 4 Staff preference 16 Unknown reason 41 9 Unknown reason 42 117 discontinued intervention not in accordance with protocol 94 discontinued intervention not in accordance with protocol 43 44 2 women excluded due to withdrawn consent 45 46 47 48 49 607 women analysed 50 591 women analysed 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Figure 1. Consort flowdiagram 4 5 Study population 6 Baseline characteristics* Discontinued Continued 7 N=607 N=591 8 Maternal age, mean (SD) 31.0 (4.9) 31.3 (4.9) 9 White European n (%) 531 (91.1%) 510 (90.9%) Pre-pregnancy BMI, median (IQR) 25.2 (22.2-29.8) 24.8 (22.1-29.0) 10 Pre-pregnancy BMI >30kg/m2 n (%) 151(24.9%) 126 (21.3%) 11 Smoking during pregnancy n (%) 96 (16.2%) 79 (13.6%) 12 Married or livingConfidential: with partner n (%) For538 (90.1%) Review534 (91.1%) Only 13 Parity, n (%) Nulliparous 404 (66.5%) 398 (67.3%) 14 Parous with no prior Caesarean section 147 (24.2%) 155 (26.2%) 15 Parous with previous Caesarean section 56 (9.2%) 38 (6.4%) 16 Medical history during pregnancy, n (%) 53 (8.7%) 58 (9.8%) 17 Diabetes Mellitus type 1 8 (1.3%) 5 (0.9%) 18 Diabetes Mellitus type 2 7 (1.2%) 1 (0.2%) 19 Hypertensive disorders** 97 (16.0%) 92 (15.5%) SGA*** 13 (2.1%) 15 (2.5%) 20 Autoimmune/Inflammatory disease **** 31 (5.1%) 35 (5.9%) 21 Use of anti-depressive medication at term 21 (3.5%) 18 (3.0%) 22 Length of gestation at birth, median (IQR) 40+3 (39+1-41+2) 40+3 (39+1-41+3) 23 Indication for labour induction, n (%) Ruptured membranes 230 (37.9%) 221 (37.4%) 24 Diabetes 43 (7.1%) 39 (6.6%) 25 Postdate pregnancy ***** 102 (16.8%) 120 (20.3%) 26 Hypertensive disorders ****** 66 (10.9%) 71 (12.0%) BMI 35 ******* 24 (4.0%) 18 (3.1%) 27 ******** 14 (2.3%) 8 (1.4%) 28 Maternal request 27 (4.5%) 21 (3.6%) 29 Other ********* 101 (16.5%) 93 (15.6%) 30 Cervical ripening, n (%) Prostaglandins 253 (41.7%) 237 (40.0%) 31 Cervical ripening catheter 84 (13.8%) 85 (14.3%) 32 Both 39 (6.4%) 40 (6.8%) 33 Cervical dilatation at time of randomisation <6 cm 15 (2.5%) 7(1.2%) 34 6 cm 256 (42.2%) 272 (46.0%) 35 7 cm 108 (17.8%) 118 (20.0%) 36 8 cm 96 (15.8%) 71 (12.0%) 37 9 cm 52 (8.6%) 33 (5.6%) 10 cm 63 (10.4%) 64 (10.8%) 38 Birthweight in grams, mean (SD) 3646 (509) 3596 (502) 39 Female sex of newborn, n (%) 283 (46.6%) 275 (46.6%) 40 Table 1 Baseline characteristics *Number of missing data: White European=54, Smoking during pregnancy=25, Married or living with 41 partner=15, cervical dilatation at time of randomisation=43 ** pre-pregnancy hypertension, , and preeclampsia ***Small for gestational age26 ****Inflammatory bowel disease, systemic lupus erythematosus, hyperthyroidism, hypothyroidism *****IOL at Gestational age 42 41+3 - 41+5 ******Pre-pregnancy hypertension, gestational hypertension, and preeclampsia ********IOL at Gestational age 41+0 ********Largest 43 fluid pocket less than two cm diameter27 *********Suspected macrosomina26, reduced fetal movements, or obstetric cholestasis 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 4 Study population Relative risk P (95% CI) 5 Maternal outcomes* Discontinued Continued 6 N=607 N=591 7 Primary outcome 8 Caesarean section 101 (16.6%) 84 (14.2%) 1.17 (0.90-1.53) 0.25 Secondary maternal outcomes 9 Indication for caesarean section, n (%) ^ .. .. 10 Dystocia 62 (10.2%) 58 (9.8%) 11 Suspicion of fetal asphyxia 26 (4.2%) 13 (2.1%) 12 SuspicionConfidential: of For3 (0.5%) Review1 (0.2%) Only 2 (0.3%) 1 (0.2%) 13 Other 8 (1.3%) 11 (1.8%) 14 Assisted vaginal delivery (use of forceps or vacuum) 64 (10.5%)** 67 (11.3%)** 0.93 (0.67-1.28) 0.66 15 Duration from start of initial oxytocin infusion to delivery .. Median 535 minutes 477 minutes 0.01 16 IQR 314-797 272-727 17 Duration from time of randomisation to delivery .. 18 Median 282 minutes 203 minutes <0.001 19 IQR 119-484 77-397 Duration of second stage of labour*** ^ .. 20 Median 95 minutes 78 minutes 0.07 21 IQR 31-198 29-182 22 Epidural use, n (%) 386 (63.6%) 350(59.2%) 1.07 (0.98-1.17) 0.14 prior to randomisation 304 (50.1%) 295 (49.9%) 1.00 (0.90-1.12) 0.95 23 after randomisation 83 (13.7%) 57 (9.6%) 1.42 (1.03-1.95) 0.03 24 Uterine tachysystole during labour, n (%) 25 Prior to intervention 61 (10.2%) 80 (13.7%) 0.74 (0.54-1.02) 0.06 26 During intervention 20 (3.7%) 70 (12.9%) 0.28 (0.17-0.46) <0.001 Third- or fourth-degree perineal tears****, n (%) 25 (4.9%) 27 (5.3%) 0.92 (0.54-1.57) 0.76 27 Postpartum haemorrhage within 24h 28 > 1000 ml n (%) 84 (13.8%) 102 (17.3%) 0.80 (0.61-1.05) 0.10 29 >1500 ml 43 (7.1%) 51 (8.6%) 0.82 (0.56-1.21) 0.32 30 Postpartum blood transfusion 8 (13.2%) 11 (18.6%) 0.71 (0.29-1.75) 0.45 Evacuation of retained tissue 39 (7.7%) 45 (8.9%) 0.86 (0.58-1.31) 0.50 31 Maternal pyrexia during labour, n (%) ^ 70 (11.6%) 52 (8.8%) 1.31 (0.93-1.85) 0.12 32 Uterine rupture 0 0 33 Urinary retention*****, n (%) 25 (4.2%) 20 (3.4%) 1.22 (0.68-2.17) 0.50 34 Puerperal infection during admission******, n (%) 26 (4.3%) 27 (4.6%) 0.95 (0.56-1.60) 0.83 Postpartum hospital stay 35  2 days 261 (43.0%) 284 (48.1%) 0.89 (0.79-1.10) 0.08 36 >2 days 346 (57.0%) 307 (51.9%) 1.10 (0.99-1.22) 0.08 37 Exclusive breastfeeding at discharge ^ 403 (68.4%) 378 (66.4%) 1.03 (0.95-1.12) 0.47 38 Readmission within 7 days n (%) 31 (5.1%) 41 (7.0%) 0.74 (0.47-1.16) 0.18 Puerperal infection******* 11 (1.8%) 9(1.5%) 39 Bowel obstruction 1 (0.2%) 2 (0.4%) 40 Thrombo-embolic complication 0 1 (0.2%) 41 Other******** 19 (3.1%) 29 (4.9%) 42 within 7 days 0 0 .. .. Table 2 Maternal outcomes. *Number of missing data: Hyperstimulation prior to intervention=14, Hyperstimulation after intervention=111, 43 Postpartum haemorrhage=3, Maternal pyrexia during labour=1, Urinary retention=11, Puerperal infection during admission=6, Exclusive 44 breastfeeding=40, Readmission within 7 days=4 ** All vacuum extractions except for one forceps delivery ***Reported for the ones reaching this 45 stage of labour ****vaginal deliveries only ***** No spontaneous urination 6 h after vaginal delivery or 6 h after removal of catheter if caesarean section ******Two confirmed maternal temperatures of ≥38 °C at least 4 h apart ******* Endometritis, urinary tract infection, wound infection 46 ********Suspected infection, to accompany sick neonate, or preeclampsia/ ^not a pre-specified outcome measure 47 48 Note: The following pre-specified secondary outcome measures were not collected due to logistical difficulties: Breastfeeding (time to establishment 49 and duration of exclusive breastfeeding), episiotomy, dose and duration of oxytocin stimulation, and time of birth of placenta. 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 4 Study population Relative risk p Neonatal outcomes* Discontinued Continued (95% CI) 5 N=607 N=591 6 Perinatal death, n (%) 7 0 0 8 Within 7 days postpartum 1 (0.2%) 0 Fetal heart rate abnormalities during labour** n (%) 9 Prior to intervention 103 (17.1%) 90 (15.4%) 1.11 (0.86-1.44) 0.44 10 During intervention 153 (27.9%) 219 (40.8%) 0.68 (0.57-0.81) <0.001 11 Apgar score at 5 minutes, n (%) 12 < 4 Confidential: For0 Review0 Only 4-7 6 (1.0%) 4 (0.7%) 1.46 (0.45-5.24) 0.55 13 Umbilical cord arterial pH, n (%) 14 <7.00 3 (0.5%) 0 15 7.00-7.10 39 (6.4%) 40 (6.8%) 0.95 (0.62-1.45) 0.81 CPAP*** treatment - 24h postpartum n (%) 84 (13.8%) 72 12.2%) 1.13 (0.84-1.52) 0.41 16 Intubation - 24 h postpartum n (%) 1 (0.2%) 1 (0.2%) 0.97 (0.61-15.5) 0.98 17 Neonatal Care Unit admission, n (%) 53 (8.7%) 52 (8.8%) 0.99 (0.69-1.43) 0.96 18 Diagnosis during NICU admission, n (%) .. .. 19 Respiratory distress 19 (3.1%) 21(3.6%) Infection 10 (1.6%) 6 (1.0%) 20 Neonatal asphyxia 1 (0.2%) 1 (0.2%) 21 Neonatal seizure 1 (0.2%) 1 (0.2%) 22 Birth trauma**** 1 (0.2%) 2 (0.3%) Hyperbilirubinemia 2 (0.3%) 2 (0.3%) 23 Hypoglycaemia 4 (0.7%) 0 24 Other ***** 12 (2.0%) 14 (2.4%) 25 Unknown 3 (0.5%) 5 (0.8%) 26 Treated for hyperbilirubinemia during admission 31 (5.1%) 31 (5.2%) 0.98 (0.60-1.59) 0.94 Table 3 Neonatal outcomes * Number of missing data: Fetal heart rate abnormalities prior to intervention=11, Fetal heart rate abnormalities 27 during intervention=113, umbilical cord arterial pH=156, CPAP treatment=2, treated for hyperbilirubinemia=23 ** Classification by FIGO 198528 28 *** Continuous positive airway pressure **** Cephalohaematoma and/or subgaleal haematoma ***** Low birthweight, congenital malformations, 29 dehydration, or suspected infection 30 31 32 CEQ scores p Childbirth Experience Questionnaire Discontinued n=451 (75%) Continued n=407 (69%) 33 Own capacity, mean(sd) 2.79 (0.63) 2.84 (0.61) 0.21 34 Participation, mean (sd) 3.16 (0.76) 3.10 (0.79) 0.34 35 Professional support, mean (sd) 3.79 (0.40) 3.76 (0.42) 0.26 36 Overall score, mean (sd) 3.11 (0.47) 3.13 (0.50) 0.66 Table 4 Childbirth experience, CEQ scores on a scale from 1 to 4, with 4 being the optimum. 37 38 Study population 39 Reason for discontinuation of study medication Discontinued Continued P 40 n=607 n=591 41 Slow labour progress in accordance with protocol 163 (26.9%) 44 (7.4%) <0.001 42 Slow labour progress not in accordance with protocol 79 (13.0%) 54 (9.1%) 0.04 Uterine tachysystole or FHR abnormalities 34 (5.6%) 55 (9.3%) 0.02 43 Other (pyrexia, maternal request, postpartum haemorrhage) 34(5.6%) 38 (6.4%) 0.63 44 Unrecorded 4 (0.7%) 2 (0.3%) 0.69 45 Total 314 (51.7%) 193 (32.6%) <0.001 46 Table 5 Reasons for discontinuation of study medication 47 Nulliparous Relative risk (95% CI) p 48 Discontinued- p0 (n=404) Continued- p0 (n=398) 49 Caesarean section 76 (18.8%) 75 (18.8%) 1.00 (0.75-1.33) 0.99 50 Table 6 Subgroup analysis, nulliparous 51 52 Parous without previous caesarean section Relative risk (95% CI) p Discontinued- p>0 (n=147) Continued- p>0 (n=155) 53 Caesarean section 11 (7.5%) 1 (0.6%) 11.6 (1.15-88.7) 0.002 54 Table 7 Subgroup analysis, parous without previous caesarean section 55 56 Parous with previous caesarean section Relative risk (95% CI) p 57 Discontinued- p>0 with previous Continued- p>0 with previous CS (n=56) CS (n=38) 58 Caesarean section 14 (25%) 8 (21.1%) 1.19 (0.55-2.55) 0.61 59 Table 8 Subgroup analysis, parous with previous caesarean section 60

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CONDISOX paper 2020-11-08 1 2 3 4 Induced labour Relative risk (95% CI) p Discontinued- IOL (n=400) Continued- IOL (n=379) 5 Caesarean section 70 (17.5%) 64 (16.9%) 1.04 (0.76-1.41) 0.82 6 Table 9 Subgroup analysis, induced labour 7 8 Sub group Relative risk (95% CI) p 9 Discontinued- PROM (n=207) Continued- PROM (n=212) Caesarean section 31(15.0%) 20 (9.5%) 1.58 (0.94-2.69) 0.08 10 Table 10 Subgroup analysis, prelabour rupture of membranes 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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CONDISOX paper 2020-11-08 1 2 3 Non-participants n=649, n (%) Signed informed consent but not randomised due to 4 Rapid progression 202 (31.1%) 5 Hyperstimulation 16 (2.5%) 6 Consent withdrawal 33 (5.1%) 7 Randomisation fault 5 (0.8%) 8 Other 33 (5.1%) 9 Unrecorded 360 (55.5%) 10 Table 11 Reasons for non-randomisation 11 12 Confidential: For ReviewNon-participants n=1463, Only n (%) 13 Declined to participate n=1235 14 “Lack of energy to familiarize myself with the trial” 521 (35.6%) “Fear of lack of progression in case of placebo” 312 (21.3%) 15 “Not confident in participating in the trial” 167 (11.4%) 16 “Prefer continuous stimulation” 51 (3.5%) 17 “Prefer discontinued stimulation” 20 (1.4%) 18 “Not interested in sharing personal data” 12 (0.8%) 19 “I Don’t know” 152 (10.4%) 20 Unrecorded 228 (15.6%) 21 Table 12 Reasons for not participating 22 23 Study population 24 Site Discontinued Continued Aalborg University Hospital, DK 73 69 25 Aarhus University Hospital, DK 80 79 26 Amsterdam UMC, NL 49 60 27 Herning Regional Hospital, DK 54 52 28 Nordsjaellands Hospital, Hilleroed, DK 34 31 29 Hvidovre Hospital, DK 56 52 Kolding Regional Hospital, DK 74 66 30 Odense University Hospital, DK 23 22 31 Randers Regional Hospital 69 68 32 Rigshospitalet, Copenhagen, DK 95 92 33 Total 607 591 Table 13 Recruitment according to site, the inclusion period differed between sites 34 35 36 37 References 38 1. Kirby RS. Trends in labor induction in the United States: Is it true that what goes up must come down? Birth. 39 2004;31(2):148-151. doi:10.1111/j.0730-7659.2004.00294.x 40 2. Moleti CA. Trends and controversies in labor induction. MCN Am J Matern Nurs. 2009;34(1):40-47. 41 doi:10.1097/01.NMC.0000343864.49366.66 42 3. Hedegaard M, Lidegaard Ø, Skovlund CW, Mørch LS, Hedegaard M. Reduction in at term after new 43 birth induction paradigm: Results of a national intervention. BMJ Open. 2014;4(8):1-8. doi:10.1136/bmjopen- 44 2014-005785 45 4. Ramos de Amorim MM, Fox C, Gülmezoglu AM, Khanna J, Matthews M, Souza JP. WHO recommendations 46 for induction of labour. World Heal Organ. Published online 2011. doi:10.1016/j.ogrm.2019.09.004 47 5. Daly D, Minnie KCS, Blignaut A, et al. How much synthetic oxytocin is infused during labour? A review and 48 analysis of regimens used in 12 countries. PLoS One. 2020;15(7):e0227941. doi:10.1371/journal.pone.0227941 49 6. Simpson KR, Knox GE. Oxytocin as a high-alert medication: Implications for perinatal patient safety. MCN Am 50 J Matern Nurs. 2009;34(1):8-15. doi:10.1097/01.NMC.0000343859.62828.ee 51 7. Oláh KS, Steer PJ. The use and abuse of oxytocin. Obstet Gynaecol. 2015;17(4):265-271. 52 doi:10.1111/tog.12222 53 8. Mussi S, Incerti M, Plevani C, Ghidini A, Pezzullo JC, Locatelli A. Effect of oxytocin during labor on neonatal 54 acidemia. J Matern Neonatal Med. 2015;7058(December):1-6. doi:10.3109/14767058.2015.1114088 55 9. Tribe RM, Crawshaw SE, Seed P, Shennan AH, Baker PN. Pulsatile versus continuous administration of 56 oxytocin for induction and augmentation of labor: Two randomized controlled trials. Am J Obstet Gynecol. 57 2012;206(3):230.e1-230.e8. doi:10.1016/j.ajog.2011.11.001 58 10. Bostancı E, Kilicci C, Ozkaya E, Abide Yayla C, Eroglu M. Continuous oxytocin versus intermittent oxytocin 59 for induction of labor: a randomized study. J Matern Fetal Neonatal Med. Published online 10 September 60

Page 19 https://mc.manuscriptcentral.com/bmj BMJ Page 20 of 44

CONDISOX paper 2020-11-08 1 2 3 2018:1-6. doi:10.1080/14767058.2018.1499092 4 11. Steer PJ, Carter MC, Choong K, Hanson M, Gordon AJ, Pradhan P. A multicentre prospective randomized 5 controlled trial of induction of labour with an automatic closed-loop feedback controlled oxytocin infusion system. Br J Obstet Gynaecol. 1985;92(11):1127-1133. Accessed June 29, 2018. 6 http://www.ncbi.nlm.nih.gov/pubmed/3904817 7 12. Budden A, Chen LJY, Henry A. High-dose versus low-dose oxytocin infusion regimens for induction of labour 8 at term. Cochrane Database Syst Rev. 2014;2016(3). doi:10.1002/14651858.CD009701.pub2 9 13. Boie S, Glavind J, Velu A V, et al. Discontinuation of intravenous oxytocin in the active phase of induced 10 labour. Cochrane database Syst Rev. 2018;8:CD012274. doi:10.1002/14651858.CD012274.pub2 11 14. Hernández-Martínez A, Arias-Arias A, Morandeira-Rivas A, Pascual-Pedreño AI, Ortiz-Molina EJ, Rodriguez- 12 AlmagroConfidential: J. Oxytocin discontinuation after the For active phase Review of induced labor: AOnly systematic review. Women and 13 Birth. 2019;32(2):112-118. doi:10.1016/j.wombi.2018.07.003 14 15. Vlachos D-EG, Pergialiotis V, Papantoniou N, Trompoukis S, Vlachos GD. Oxytocin discontinuation after the 15 active phase of labor is established. J Matern Neonatal Med. 2015;28(12):1421-1427. 16 doi:10.3109/14767058.2014.955000 17 16. Saccone G, Ciardulli A, Baxter JK, et al. Discontinuing Oxytocin Infusion in the Active Phase of Labor. Obstet 18 Gynecol. 2017;130(5):1090-1096. doi:10.1097/AOG.0000000000002325 19 17. Eissaa AN, Sayyeda TM, El‐Halabya AE, Tahoonb RA. The outcome of induced labor after oxytocin infusion 20 discontinuation in the active phase. Menoufia Med J. 2019;32(1):441-447. doi:10.4103/mmj.mmj_652_17 21 18. Mitra M, Sengupta M, Ghosal R, Saha C, Bandhya D, Ghosh D. Continuation versus Discontinuation of 22 Oxytocin in Active Phase of Labour- A Randomised Trial. 2019;8(44):3342-3346. 23 doi:10.14260/jemds/2019/725 24 19. Boie S, Glavind J, Uldbjerg N, et al. CONDISOX-continued versus discontinued oxytocin stimulation of 25 induced labour in a double-blind randomised controlled trial. BMC Pregnancy Childbirth. 2019;19(1):1-7. 26 doi:10.1186/s12884-019-2461-x 27 20. Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an international community of 28 software platform partners. J Biomed Inform. 2019;95(April):103208. doi:10.1016/j.jbi.2019.103208 21. Boie S, Lauridsen HH, Glavind J, Smed MK, Uldbjerg N, Bor P. The Childbirth Experience Questionnaire 29 (CEQ)—Validation of its use in a Danishspeaking population of new mothers stimulated with oxytocin during 30 labour. PLoS One. 2020;15(5):1-14. doi:10.1371/journal.pone.0233122 31 22. Bor P, Ledertoug S, Boie S, Knoblauch NO, Stornes I. Continuation versus discontinuation of oxytocin infusion 32 during the active phase of labour: A randomised controlled trial. BJOG An Int J Obstet Gynaecol. 33 2016;123(1):129-135. doi:10.1111/1471-0528.13589 34 23. Fayers PM, Machin D. Quality of Life: The Assessment, Analysis, and Interpretation of Patient-Reported 35 Outcomes. Second. John Wiley & Sons 36 24. Dencker A, Berg M, Bergqvist L, Ladfors L, Thorsén LS, Lilja H. Early versus delayed oxytocin augmentation 37 in nulliparous women with prolonged labour - A randomised controlled trial. BJOG An Int J Obstet Gynaecol. 38 2009;116(4):530-536. doi:10.1111/j.1471-0528.2008.01962.x 39 25. Ekelin M, Svensson J, Evehammar S, Kvist LJ. Sense and sensibility: Swedish midwives ambiguity to the use 40 of synthetic oxytocin for labour augmentation. Midwifery. 2015;31(3). doi:10.1016/j.midw.2014.12.006 41 26. Maršál K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on 42 ultrasonically estimated foetal weights. Acta Paediatr Int J Paediatr. 1996;85(7):843-848. doi:10.1111/j.1651- 43 2227.1996.tb14164.x 44 27. Magann EF, Doherty DA, Chauhan SP, Busch FWJ, Mecacci F, Morrison JC. How well do the 45 index and single deepest pocket indices (below the 3rd and 5th and above the 95th and 97th percentiles) predict 46 oligohydramnios and hydramnios? Am J Obstet Gynecol. 2004;190(1):164-169. doi:10.1016/S0002- 47 9378(03)00859-7 48 28. Rooth G, Huch A, Huch R. Guidelines for the use of Fetal Monitoring. Int J Gynecol Obs. 1987;25(3):159-167. 49 50 51 52

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Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 https://doi.org/10.1186/s12884-019-2461-x 1 2 3 4 5 STUDYPROTOCOL Open Access 6 7 8 CONDISOX- continued versus discontinued 9 10 oxytocinConfidential: stimulation of For induced Review labour Only in a 11 12 13 double-blind randomised controlled trial 14 Sidsel Boie1* , Julie Glavind2, Niels Uldbjerg2, Jannet J. H. Bakker3, Joris A. M. van der Post3, Philip J. Steer4 and 15 Pinar Bor1 16 17 18 19 Abstract 20 Background: Oxytocin is an effective drug for induction of labour, but is associated with serious adverse effects of 21 which uterine tachysystole, and the need of immediate delivery are the most common. 22 Discontinuation of oxytocin once the active phase of labour is established could reduce the adverse effects. 23 The objective is to investigate how the caesarean section rate is affected when oxytocin stimulation is discontinued 24 in the active phase of labour compared to labours where oxytocin is continued. 25 Methods: CONDISOX is a double-blind multicentre randomised controlled trial conducted at Danish and Dutch 26 Departments of Obstetrics and Gynaecology. The first participant was recruited on April 8 2016. 27 Based on a clinically relevant relative reduction in caesarean section rate of 7%, an alpha of 0.05, a beta of 80%, we 28 aim for 1200 participating women (600 in each arm). 29 The CONDISOX trial includes women at a gestational age of 37–42 complete weeks of pregnancy, who have uterine 30 activity stimulated with oxytocin infusion for the induction of labour. Women are randomised when the active phase 31 of labour becomes established, to study medication containing either oxytocin (continuous group) or placebo 32 (discontinued group) infusion. Women are stratified by birth site, indication for oxytocin stimulation (induction of 33 labour, prelabour rupture of membranes) and parity (nulliparous, parous +/− previous caesarean section). 34 We will compare the primary outcome, caesarean section rate, in the two groups using a chi-square test with 35 a p-value of 0.05. If superiority is not demonstrated, we have a pre-defined post hoc non-inferiority boundary 36 (margin, delta) at 1.09. 37 Secondary outcomes include duration of the active phase of labour, incidence of uterine tachysystole, 38 postpartum haemorrhage, admission to the neonatal intensive care unit, Apgar score, umbilical arterial blood 39 pH, and birth experience. 40 41 Discussion: The high frequency of oxytocin use and the potential risks of both maternal and fetal adverse 42 effects of oxytocin emphasise the need to determine the optimal oxytocin regime for induction of labour. 43 Trial registration: NCT02553226 (registered September 17, 2015). Eudra-CT number: 2015–002942-30. 44 Keywords: Induction of labour, Oxytocin, Discontinuation, Caesarean section 45 46 47 48 49 50 51

52 * Correspondence: [email protected] 53 1Department of Obstetrics and Gynaecology, Randers Regional Hospital, 54 Randers, Denmark 55 Full list of author information is available at the end of the article 56 © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 57 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to 58 the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver 59 (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 60 https://mc.manuscriptcentral.com/bmj BMJ Page 22 of 44

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 2 of 7 1 2 3 4 Background reached the active phase of labour, there was little or no 5 Syntocinon® (synthetic oxytocin) is one of the most difference on the caesarean section rate between the two 6 widely used medications in obstetrics for induction of groups. 7 labour. In Denmark 2018, 27% nulliparous (8065 of 29, 8 414) and 21% parous women (6636 of 31,502) had Objectives 9 labour induced. Nearly half of these women received 10 The objective is to investigate how the caesarean section oxytocin stimulationConfidential: as a single treatment method, For or in rate Review is affected when oxytocin Only stimulation is discontinued 11 combination with other methods (http://end2019. 12 in the active phase of induced labour compared to labours esundhed.dk/sundhedsregistre/MFR/Sider/MFR06A. where oxytocin is continued. 13 aspx). Despite the extensive use of oxytocin only a few 14 The incidence of other maternal and neonatal compli- studies have focused on the duration of the infusion. cations will be accessed as secondary outcomes. 15 There is no consensus as to whether oxytocin should be 16 continued until delivery or discontinued after the onset 17 of the active phase of labour [1–4]. Methods 18 The current regimen for induction of labour with oxyto- CONDISOX is a double-blinded multicentre rando- 19 cin described in the national Danish Society of Obstetrics mised controlled trial conducted at Danish and Dutch 20 and Gynaecology (DSOG) guidelines [5]recommendsthat DepartmentsofObstetricsandGynaecologywith 21 the infusion continues until delivery, unless complications approximately 24,000 annual births. 22 (e.g. uterine tachysystole) occur, at which point the 23 infusion rate is reduced or discontinued. Sites 24 Although oxytocin is used in a high proportion of la- Denmark 25 bours, its use is associated with adverse effects. The 26 most frequent complication is uterine tachysystole [6], 1. Department of Obstetrics and Gynaecology 27 which increases the risk of fetal distress and birth as- 28 phyxia, requiring instrumental delivery or caesarean sec- Randers Regional Hospital 29 tion. A less frequent but serious adverse event associated Local investigator: Sidsel Boie 30 with the use of oxytocin is uterine rupture [7]. It is well 31 established that oxytocin administration during labour 2. Department of Obstetrics and Gynaecology, Aarhus 32 causes a persisting down regulation of the oxytocin re- University Hospital, Skejby 33 ceptors [7], which persists postpartum and increases the 34 risk of postpartum haemorrhage. Furthermore, initiation Local investigator: Lone Hvidman 35 and duration of breastfeeding may also be adversely af- 36 fected in women who undergo oxytocin stimulation [8]. 3. Department of Obstetrics and Gynaecology, 37 We conducted a pilot study to investigate the effects of Sygehus Lillebælt, Kolding 38 discontinued oxytocin infusion in the active phase of 39 labour compared to continued oxytocin infusion on Local investigator: Mohammad Khalil 40 labour outcomes [9]. Between 2009 and 2011, two 41 hundred women admitted for induction (188 cases) or 4. Department of Obstetrics and Gynaecology, 42 augmentation of labour (12 cases) at the Regional Hospital Aalborg University Hospital 43 of Randers were randomised to continued or discontinued 44 oxytocin once the active phase of labour was established. Local investigator: Attila Bothazi 45 The total caesarean section rate (secondary pre-specified 46 outcome) for the oxytocin-discontinued group was 15% 5. Department of Obstetrics and Gynaecology 47 compared to 22% in the continued group, which was a Regional Hospital Herning 48 non-significant reduction (p =0.39). However, in the 49 discontinued group, there were statistically significant Local investigator: Iben Sundtoft 50 fewer cases of postpartum haemorrhage, uterine tachysys- 51 tole, and non-reassuring fetal heart pattern [9]. 6. Department of Obstetrics and Gynaecology Hillerød 52 A recent published Cochrane review [10] concluded Regional Hospital 53 that discontinuation of oxytocin stimulation when the 54 active phase of labour is established may reduce the cae- Local Investigator: Nini Møller 55 sarean section rate. However, the quality of evidence of 56 the included trials was low, and when the analysis was 7. Department of Obstetrics and Gynaecology 57 restricted to results from participants who actually Rigshospitalet, Copenhagen 58 59 60 https://mc.manuscriptcentral.com/bmj Page 23 of 44 BMJ

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 3 of 7 1 2 3 4 Local investigator: Kristina Renault Participants 5 The CONDISOX trial will include women at 37–42 6 8. Department of Obstetrics and Gynecology, Odense complete weeks of gestation stimulated with oxytocin in- 7 University Hospital fusion for induction of labour (with or without cervical 8 priming by prostaglandin). 9 Local investigator: Maja Thode Rask Exclusion criteria are as follows: 10 Confidential: For Review Only 11 9. Department of Obstetrics and Gynecology,  Age < 18 years 12 Hvidovre Hospital  Unable to give written informed consent 13  Cervical dilation more than 4 cm when stimulation 14 Local investigator: Lene Huusom is initiated 15  Multiple 16 The Netherlands  Non-vertex presentation 17  Persistent pathological cardiotocography (CTG) 18 1. Department of Obstetrics and Gynaecology, before oxytocin infusion 19 academic medical Centre, Amsterdam  Estimated fetal weight of more than 4500 g. 20 21 Local investigator: Jannet Bakker. Figure 1 shows the study flow as outlined by the 22 Further centres will be included. An updated list is al- CONSORT (CONsolidated Standards Of Reporting 23 ways available in ClinicalTrials.Gov. Trials). 24 25 Study dates 26 The first participant was recruited the 8th of April Oxytocin stimulation protocol 27 2016. The anticipated date of recruitment completion Standard procedures will be followed prior to stimula- 28 is February 2020. tion [11, 12] 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Fig. 1 Flowchart 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 24 of 44

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 4 of 7 1 2 3 4 Stimulation will be given according to national Danish postpartum infection (defined as two confirmed 5 [5] and Dutch [13] guidelines. The guidelines and the ob- maternal temperatures of ≥38 °C at least 4 h apart), 6 stetrical care are comparable between the two countries. urinary retention. 7 Intravenous infusion of 10 IU Syntocinon® diluted in 1000 – Fetal/Neonatal: Death, non-reassuring fetal heart 8 ml of isotonic saline (Denmark) or 5 IU Syntocinon® rate pattern in labour, birth weight, fetal scalp pH 9 diluted in 50 ml of isotonic saline (The Netherlands) is values, Apgar score at 1 and 5 min, umbilical cord 10 initiated at 3.3Confidential: mIU/minute and increased every 20 minFor by Reviewarterial pH and blood Only gas values, antibiotic 11 3.3 mIU/minute until regular contractions (three to five treatment, hyperbilirubinaemia, rate of admission to 12 contractions every 10 min) are achieved. The maximal neonatal intensive care unit (NICU), or any need for 13 dose of infusion is 30 mIU/minute. resuscitation (bag and mask or intubation, time to 14 Women will be included in the study when the active onset of spontaneous ventilation). 15 phase of labour becomes established. The definition of – Breastfeeding (successful establishment and duration 16 the active phase of labour is in accordance with latest of exclusive breastfeeding) 17 ACOG guideline [14]: complete effacement, cervical – Birth experience and patient satisfaction 4 weeks 18 dilatation ≥6 cm, ≥3 contractions per 10 min, and rup- postpartum (Childbirth Experience Questionnaire, 19 ture of membranes. Randomisation will be performed, CEQ1 [15]) 20 and the infusion will be replaced by the study medica- 21 tion, which will be either Syntocinon® at the same All outcome data will be registered in an eCRF (see 22 concentration, or a placebo infusion with saline: Additional file 1) designed for the trial using the 23 REDCap database (including range checks for data 24 1. Denmark: values and double entry for primary outcome and 25 Continued group; 10 IE Syntocinon® diluted in 1000 selected secondary outcomes). The data collection form 26 ml 0.9% NaCl infusion; discontinued group; 1 ml can be obtained by contacting the corresponding author. 27 0.9% NaCl diluted in 1000 ml 0.9% NaCl infusion. For participants who discontinue or deviate from the 28 (prepared by the pharmacy in ampoules identified trial protocol all of the above outcomes are still to be 29 only by study number) collected if available. 30 2. The Netherlands: 31 Continued group; 5 IU Syntocinon® diluted in 50 ml Randomisation, blinding and informed consent 32 0.9% NaCl infusion, discontinued group; 50 ml 0.9% Women will be informed of the trial when induction of 33 NaCl. (Infusions are prepared by the pharmacy and labour is planned or at the first visit to the labour ward 34 identified only by study number). in case of prelabour rupture of membranes. Subjects’ 35 signed informed consent to participation will be 36 Outcome measures obtained prior to randomisation and intervention (i.e. 37 Primary outcome before any oxytocin stimulation). 38 Women will be randomised in a 1:1 ratio to either the 39 – Caesarean section rate continued oxytocin group or the discontinued oxytocin 40 group using an Internet-based randomisation programme 41 Secondary outcomes (Trialpartner). Random block-sizes of four will be used, and 42 the women will be stratified by site, parity (nulliparous or 43 – Maternal: Mode of delivery, indication for caesarean parous +/− previous caesarean) and indication for oxytocin 44 section or instrumental delivery, duration of the infusion (induction of labour or induction due to prelabour 45 active phase of labour (from time of randomisation rupture of membranes (PROM)). The randomisation num- 46 to delivery), total duration of labour from time of ber generated by the computer programme corresponds to 47 initiation of oxytocin stimulation until delivery, number of the studymedication (masked, identical am- 48 duration of time from admission to the delivery poules). The personnel of the delivery ward will administer 49 ward to delivery, incidence of uterine tachysystole, the medication according to existing guidelines concerning 50 use of epidural analgesia, the total dosage of and administration [5, 12, 13]. Women, caregivers, and trialma- 51 duration of oxytocin infusion, rate of pyrexia during nagers will be blinded to the allocation due to the use of 52 labour (defined as ≥38.2 °C with epidural, without identical study medication preparations. 53 epidural: ≥38 °C), rate of 3rd and 4th degree perineal 54 tears, rate of uterine rupture, estimated volume of Complications 55 blood loss at delivery and postpartum, postpartum In accordance with guidelines [5, 13] The infusion will 56 blood transfusion, the need for evacuation of be reduced or discontinued at any point of labour, if the 57 retained placenta, use of antibiotics during labour, following occur: 58 59 60 https://mc.manuscriptcentral.com/bmj Page 25 of 44 BMJ

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 5 of 7 1 2 3 4 – Tachysystole (> 5 contractions per 10 min, averaged that are fatal or life threatening is recorded. The primary 5 over a 30-min window) investigator will report as soon as possible (and in any 6 – Uterine contractions lasting 2 min or more case no later than seven days) to the competent author- 7 – Non-reassuring CTG (recurrent variable ities concerned. The primary investigator will ensure 8 decelerations, fetal tachycardia or bradycardia, that any relevant follow-up information is subsequently 9 minimal to absent baseline variability, late communicated within an additional eight days. 10 decelerations)Confidential: or significant STAN event(s) For TheReview primary investigator Only will report to the competent 11 – Suspicion of uterine rupture authorities concerned and to the Ethics Committees all 12 other suspected unexpected serious adverse reactions as 13 Dystocia soon as possible but within a maximum of 15 days of 14 If there is failure to progress, defined as less than two first knowledge. 15 cm dilation over 4 h despite apparently adequate con- 16 tractions, and/or maximal infusion rates (oxytocin or Power calculation and statistical analysis 17 placebo), the study medication can be replaced with Based on the pilot study [9] we expect a caesarean 18 open-labelled oxytocin infusion. section rate of 22% in the continued group. A clinic- 19 If failure to progress persists, despite open-labelled ally relevant relative reduction in the caesarean sec- 20 oxytocin infusion for 4 h, caesarean section can be tion rate would be 30%, corresponding to a caesarean 21 considered. section rate of 15% in the discontinued group. Aiming 22 for a power (beta) of 80% and an alpha of 0.05, su- 23 Side effects and risks periority can be shown with a sample size of 482 24 We expect a rate of persistent failure to progress of 8– women in each group. Allowing for crossover and a 25 46% among the participants in the discontinued group dropout of 5% we aim to recruit a total of 600 26 versus 3–17% in the continued group [1–4]. Based on women per treatment arm (1200 in total). 27 data from the pilot study [9], we expect a caesarean sec- If superiority of oxytocin discontinuation vs. contin- 28 tion rate of 15% in the discontinued group versus 22% in ued oxytocin stimulation for the reduction of the 29 the continued group. According to the pilot study and incidence of caesarean section cannot be shown, non- 30 previous studies [1–4], maternal and neonatal complica- inferiority testing is a relevant alternative. It is plaus- 31 tions in the discontinued group are expected to be lower ible that improvements in secondary outcomes will be 32 than in the continued group (The 2018 data for labour seen, even if there is no superiority on the primary 33 that are induced in Denmark indicate an acute caesarean outcome. To allow formal non-inferiority testing as 34 section rate of 14.6%. However, the latter figure includes an alternative, we define a post hoc non-inferiority 35 women who respond to prostaglandin alone and there boundary (margin, delta) at 1.09. This boundary is to 36 are no data for women who require oxytocin infusion in exclude a rate of 22% in the continued oxytocin 37 addition). group as compared to 24% in the discontinued group. 38 All women will be monitored with continuous elec- Data will be analysed according the intention-to-treat 39 tronic fetal heart rate monitoring during labour to detect principle. Basic demographic data will be presented with 40 complications such as uterine tachysystole and non-re- counts and percentages for categorical variables, mean 41 assuring/pathological fetal heart rate in accordance with and standard deviation for continuous Gaussian distrib- 42 national guidelines. Women and their newborns will be uted variables, and median and interquartile range for 43 observed for at least 3–6 h postpartum (termination of continuous non-Gaussian variables. The primary out- 44 study medication) according to the current practice on come variable will be assessed by comparing the event 45 the delivery ward before discharged home. rates in the two groups using a chi-square test with a 46 Delivery ward staff is responsible for timely reporting significance threshold p-value of < 0.05. Results will be 47 of any adverse reactions to the trial manager. presented as absolute and relative risks along with 95% 48 Adverse reactions/events will be registered immedi- confidence intervals (Cl) and the numbers needed to 49 ately in the electronic medical file of the patient. The treat (if applicable). Categorical secondary outcomes will 50 Summary of Product Characteristics (SPC) of Syntoci- be assessed in the same way as the primary outcome. 51 non® will be used as reference [6] to determine whether For continuous secondary outcomes with a Gaussian 52 a Serious Adverse Reaction is expected or unexpected. distribution (following log transformation if appropriate) 53 The primary investigator or a nominated deputy will go we will assess differences between groups using the stu- 54 through the participants’ electronic medical record 7– dent’s t-test, and with a non-parametric Mann-Whitney 55 30 days postpartum during data collection. The primary U test if the data are non-Gaussian. We will present 56 investigator will ensure that all relevant information time to delivery using Kaplan-Meier estimates and sur- 57 about suspected serious unexpected adverse reactions vival curves, and test the differences between the two 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 26 of 44

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 6 of 7 1 2 3 4 groups using the log-rank test. We will use multivariate Abbreviations 5 logistic regression with adjustment for indifferences in Amsterdam UMC: Amsterdam University Medical Centre; CEQ1: Childbirth Experience Questionnaire 1; CI: Confidence Interval; CONSORT: Consolidated 6 baseline characteristics to calculate odds ratios with 95% 7 Standards of Reporting Trials; CTG: Cardio Toco Graphy; DMEC: Data confidence intervals. Monitoring and Ethics Committee; NICU: Neonatal Intensive Care Unit; 8 Subgroup analysis will be undertaken for the following PROM: Prelabour Rupture Of Membranes; SPC: Summary of Product Characteristics; STAN: ST-analysis; TSC: Trial Steering Committee 9 subgroups: 10 Confidential: ForAcknowledgements Review Only 11  Indication for stimulation (PROM and induction) The datamanager, Jakob Hjort has designed the randomization programme 12  Parity (nulliparous and parous) and the connection to the trial database. 13  Previous caesarean section Authors’ contributions 14 PB had the idea for the trial. SB designed the trial with substantial 15 contributions from PB, JG, NU and PS. The TSC, DMEC contributed with 16 Monitoring minor, but important details to the design. The protocol was written by SB The trial is continuously monitored according to Good with substantial contributions from PB, JG, JB, NU, JVP and PS. SB registered 17 the trial on clinicaltrials.gov. PB is registered as the sponsor of the trial and 18 Clinical Practice (GCP). Each recruiting site is visited at SB as the principal investigator and contact person for both the Dutch and 19 least once per year by the external monitor who per- Danish sites. All authors read and approved the final manuscript. forms an audit on selective outcome measures. Furthermore all authors have agreed to be personally accountable for their 20 contributions and to ensure that questions related to the accuracy or 21 An interim analysis is performed each year during the integrity of any part of the work, even ones in which the author was not 22 inclusion period. Three independent members have been personally involved, are appropriately investigated, resolved, and the assigned to the data monitoring committee (DMEC, see resolution documented in the literature.The staff and the direction at every 23 participating site also have to be acknowledged for their efforts during 24 Additional file 2) and they have access to the results of the implementation of the trial. 25 interim analysis. DMEC members safeguard the interests of trial participants, assess the safety of the intervention Funding 26 Funding for the trial has been obtain from the below mentioned 27 during the trial, and monitor the overall conduct of the organisations and foundations: 28 clinical trial. No formal stopping rules have been made. A Randers Regional Hospital report is sent to the Trial Steering Committee (TSC, see Aarhus University 29 Health Research Fund of Central Denmark Region 30 Additional file 3) on the conclusion of the assessment Dagmar Marshall Foundation 31 made by the DMEC. The TSC provides independent The Danish Regions Medical Foundation advice to the trialists based on the DMEC conclusion. Aase and Ejnar Danielsens Foundation 32 The A.P. Moeller Foundation for the Advancement of Medical Science 33 The charter for the DMEC and/or the TSC can be The Soren Segels and Johanne Wiibroe Segels Research Fund 34 obtained by contacting the corresponding author of the The mentioned organisations and foundations have no role in the design of trial. the study, collection, analysis, interpretation of data, nor in writing the 35 manuscript. 36 In case of important protocol changes, the amendment 37 will be communicated to the relevant parties (site inves- Availability of data and materials 38 tigators, trial registry etc.). The trial is on going. When the primary data from the trial are published the data will become publicly available. The results will be presented in 39 international peer reviewed journals and at relevant international 40 Discussion conferences. 41 The high frequency of oxytocin use and the potential risks Ethics approval and consent to participate 42 of both maternal and fetal adverse effects of oxytocin The CONDISOX trial will be conducted in accordance with the ethical 43 emphasise the need to determine the optimal oxytocin re- principles outlined in the latest version of the ‘Declaration of Helsinki’ and 44 the ‘Guideline for Good Clinical Practice’ related to experiments on humans. gime for induction of labour. Adverse effects of oxytocin The Central Denmark Region Committee on Biomedical Research Ethics and 45 are associated with considerable socio-economic and hu- The Danish Health Authority have approved the study. The Medical Research 46 man costs. Reducing the duration of oxytocin stimulation Ethics Committees of the Amsterdam University Medical Centre has 47 approved the Dutch part of the study. All the eligible women will have both during labour may reduce the risk of acute caesarean sec- written and oral information about the study methods, the aims of the 48 tion, the number of newborn with asphyxial sequelae and research and the possible adverse events related to the interventions, and 49 the number of maternal and neonatal adverse events dur- will give written informed consent prior to randomisation. The consent 50 forms will be kept safe during the study period in accordance with Danish ing labour and delivery. and Dutch legislation. 51 52 Additional files Competing interests 53 The authors declare that they have no competing interests.

54 Additional file 1: Electronic case record form eCRF. (PDF 106 kb) Author details 55 Additional file 2: Data Monitoring and Ethics Committee. (DMEC) 1Department of Obstetrics and Gynaecology, Randers Regional Hospital, 56 (DOCX 39 kb) Randers, Denmark. 2Department of Obstetrics and Gynaecology, Aarhus 3 Additional file 3: Trial Steering Committee (TSC). (DOCX 51 kb) University Hospital, Aarhus, Denmark. Department of Obstetrics and 57 Gynaecology, Amsterdam University Medical Centre, Amsterdam, The 58 59 60 https://mc.manuscriptcentral.com/bmj Page 27 of 44 BMJ

Boie et al. BMC Pregnancy and Childbirth (2019) 19:320 Page 7 of 7 1 2 3

4 Netherlands. 4Academic Department of Obstetrics and Gynaecology, Division 5 of cancer Imperial College London, London, UK. 6 7 Received: 28 June 2018 Accepted: 15 August 2019 8 9 References 10 1. Daniel-Spiegel E, Weiner Z, Ben-Shlomo I, Shalev E. For how long should oxytocin beConfidential: continued during induction of labour? BJOG Int J Obstet For Review Only 11 Gynaecol. 2004;111(4):331–4. https://doi.org/10.1111/j.1471-0528.2004.00096.x. 12 2. Diven LC, Rochon ML, Gogle J, Eid S, Smulian JC, Quinones JN. Oxytocin discontinuation during active labor in women who undergo labor 13 induction. Am J Obstet Gynecol. 2012;207(6):471.e1–471e8. 14 3. Girard B, Vardon D, Creveuil C, Herlicoviez M, Dreyfus M. Discontinuation of 15 oxytocin in the active phase of labor. Acta Obstet Gynecol Scand. 2009; 88(2):172–7. 16 4. Ustunyurt E, Ugur M, Ustunyurt BO, Iskender TC, Ozkan O, Mollamahmutoglu L. 17 Prospective randomized study of oxytocin discontinuation after the active 18 stage of labor is established. J Obstet Gynaecol Res. 2007;33(6):799–803. 5. National Danish Guideline for the use of Oxytocin, (DSOG 2013), http:// 19 www.dsog.dk/files/Syntocinon2013.pdf. Accessed Aug 2019. 20 6. The Summary of Product Characteristics of Syntocinon®, Danish Health and 21 Medicine Authority, 2018, http://produktresume.dk/ 7. Phaneuf S, Rodriguez Linares B, TambyRaja RL, MacKenzie IZ, Lopez Bernal 22 A. Loss of myometrial oxytocin receptors during oxytocin-induced and 23 oxytocin-augmented labour. J Reprod Fertil. 2000;120(1):91–7. 24 8. Fernández IO, Gabriel MM, Martínez AM, Morillo AF, Sánchez FL, Costarelli V. Newborn feeding behaviour depressed by intrapartum oxytocin : a pilot 25 study. Acta Paediatr. 2012;101(7):749–54. https://doi.org/10.1111/j.1651-222 26 7.2012.02668.x. 27 9. Bor P, Ledertoug S, Boie S, Knoblauch NO, Stornes I. Continuation versus discontinuation of oxytocin infusion during the active phase of labour: a 28 randomised controlled trial. BJOG. 2016;123(1):129–35. 29 10. Boie S, Velu AH, Glavind J, Bor P, Uldbjerg N, Mol B, Post JVD, Thornton J, 30 Bakker J. Cochrane review: Discontinuation of intravenous oxytocin in the active phase of induced labour for improving outcomes; 2018. https://doi. 31 org/10.1002/14651858.CD012274.pub2. 32 11. Danske regioner, Safe deliveries (2012) http://universitetshospitalskejby.dk/ 33 tvaerfaglig_kommunikation/pdf/sikre_foedsler.pdf 12. Administration of Medication (in Danish), Regional Guideline (2012) 34 http://e-dok.rm.dk: lægemiddeladministration, regional retningslinje. 35 13. National Dutch guideline for the use of oxytocin (in Dutch), Inductie van de 36 baring 1.0 (NVOG 2006) https://www.nvog.nl/wp-content/uploads/2017/12/ Inductie-van-de-baring-1.0-20-09-2006.pdf. Accessed Aug 2019. 37 14. Caughey AB, Cahill AG, Guise J-M, Rouse DJ. Safe prevention of the primary 38 cesarean delivery. Am J Obstet Gynecol. 2014;210(3):179–93. https://doi. 39 org/10.1016/j.ajog.2014.01.026. 15. Dencker A, Taft C, Bergqvist L, Lilja H, Berg M. Childbirth experience 40 questionnaire (CEQ): development and evaluation of a multidimensional 41 instrument. BMC Pregnancy Childbirth. 2010;10(1):81. https://doi.org/10.11 42 86/1471-2393-10-81. 43 44 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in 45 published maps and institutional affiliations. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 28 of 44

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