RESEARCH Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): double blind randomised BMJ: first published as 10.1136/bmj.n716 on 14 April 2021. Downloaded from controlled trial Sidsel Boie,1 Julie Glavind,2 Niels Uldbjerg,2 Philip J Steer,3 Pinar Bor,1 on behalf of the CONDISOX trial group 1Department of Obstetrics and ABSTRACT from randomisation to delivery 282 v 201 min; Gynaecology, Randers Regional OBJECTIVE P<0.001), a reduced risk of hyperstimulation (20/546 Hospital, Randers, Denmark To determine whether discontinuing oxytocin (3.7%) v 70/541 (12.9%); P<0.001), and a reduced 2Department of Obstetrics and Gynaecology, Aarhus University stimulation in the active phase of induced labour is risk of fetal heart rate abnormalities (153/548 Hospital, Aarhus, Denmark associated with lower caesarean section rates. (27.9%) v 219/537 (40.8%); P<0.001) but rates of 3Academic Department of DESIGN other adverse maternal and neonatal outcomes were Obstetrics and Gynaecology, International multicentre, double blind, randomised similar between groups. Chelsea and Westminster Hospital, Imperial College controlled trial. CONCLUSIONS London, London, UK SETTING In a setting where monitoring of the fetal condition Correspondence to: S Boie Nine hospitals in Denmark and one in the Netherlands and the uterine contractions can be guaranteed, [email protected] routine discontinuation of oxytocin stimulation may (or @BoieSidsel on Twitter: between 8 April 2016 and 30 June 2020. lead to a small increase in caesarean section rate but ORCID 0000-0002-8725-2117) PARTICIPANTS a significantly reduced risk of uterine hyperstimulation Additional material is published 1200 women stimulated with intravenous oxytocin online only. To view please visit and abnormal fetal heart rate patterns. the journal online. infusion during the latent phase of induced labour. TRIAL REGISTRATION C ite this as: BMJ 2021;372:n716 INTERVENTION ClinicalTrials.gov NCT02553226. http://dx.doi.org/10.1136/bmj.n716 Women were randomly assigned to have their oxytocin Accepted: 25 February 2021 stimulation discontinued or continued in the active phase of labour. Introduction MAIN OUTCOME MEASURE Approximately a quarter of all term pregnant women 1-3 Delivery by caesarean section. have their labour induced. This often includes http://www.bmj.com/ stimulation with oxytocin.4 The stimulation requires RESULTS a delicate balance between the wish for progression A total of 607 women were assigned to of labour and the risks to the fetus and mother of discontinuation and 593 to continuation of the uterine hyperstimulation, defined as more than five oxytocin infusion. The rates of caesarean section were 5-7 16.6% (n=101) in the discontinued group and 14.2% contractions in 10 minutes in response to oxytocin. (n=84) in the continued group (relative risk 1.17, 95% Different approaches to oxytocin administration have been suggested, such as pulsatile or intermittent confidence interval 0.90 to 1.53). In 94 parous women on 2 October 2021 by guest. Protected copyright. 8 9 10 with no previous caesarean section, the caesarean administration, an automatic feedback system, 11 section rate was 7.5% (11/147) in the discontinued high versus low dose, and/or discontinuation of group and 0.6% (1/155)in the continued group the stimulation when the active phase of labour is 12 (relative risk 11.6, 1.15 to 88.7). Discontinuation was reached. associated with longer duration of labour (median Four meta-analyses and two more recent studies have suggested that once a woman is in active labour, the labour will continue even if oxytocin WH AT IS ALREADY KNOWN ON THIS TOPIC stimulation is stopped, resulting in a lower risk of Four meta-analyses suggest that once a woman is in active labour, the labour caesarean section for fetal indications secondary to uterine hyperstimulation.12-17 However, only one process continues even if oxytocin stimulation is stopped and results in a lower study randomised women at time of the intervention, risk of caesarean section whereas the remaining studies randomised women in A 2018 Cochrane review questions the quality of previous studies owing to early labour and consequently included a significant design limitations and judges many of the trials to be at either high or unclear fraction of women who delivered by caesarean risk of bias across several “risk of bias” domains 12 section before they received the intervention. In WH AT THIS STUDY ADDS the Cochrane meta-analysis, a subanalysis restricted to trial participants who actually reached the active This is the largest truly double blinded trial on discontinuation of oxytocin phase of labour showed little or no effect on the stimulation in the active phase of induced labour caesarean section rate.12 Whether discontinuing In a setting where monitoring of the fetal condition and the uterine contractions oxytocin stimulation is advantageous therefore can be guaranteed, routine discontinuation of oxytocin stimulation may lead to a remains uncertain. The aim of this trial was to test small increase in the rate of caesarean section whether discontinuation of oxytocin stimulation, once However, the risks of uterine hyperstimulation and abnormal fetal heart rate the active phase of induced labour is achieved, reduces were significantly reduced after discontinuation the overall caesarean section rate. the bmj | BMJ 2021;372:n716 | doi: 10.1136/bmj.n716 1 RESEARCH Methods caesarean), and indication for oxytocin infusion Trial design (induction of labour or induction due to pre-labour BMJ: first published as 10.1136/bmj.n716 on 14 April 2021. Downloaded from We conducted a double blind, randomised, placebo rupture of membranes). The randomisation number controlled multicentre trial. Recruitment took place generated by the computer program corresponded in nine delivery wards in Denmark and one in the to the number on the study medication (Denmark: Netherlands. The protocol was published in 2018.18 masked, identical ampoules; Netherlands: masked, identical infusions). In case of technical or staff Participants difficulties with the computerised randomisation Women were eligible if they had a singleton live (n=26), the women were given the study medication fetus with a cephalic presentation at term and were with the lowest available number. Accordingly, women, stimulated with oxytocin for elective induction of care givers, and trial managers were all blinded to the labour or following spontaneous pre-labour rupture allocation. of membranes without progression in labour. The exclusion criteria were age under 18 years, need for Oxytocin stimulation protocol an interpreter to understand the information material, The stimulation regimen used in this study was similar multiple pregnancy, more than one previous caesarean to the current Danish and Dutch recommendations section, greater than 4 cm of cervical dilatation at the on oxytocin stimulation for induced labour. An time of oxytocin infusion, fetal heart rate abnormalities intravenous infusion of 10 IU oxytocin (Sigma Tau before oxytocin infusion, and an estimated fetal weight Pharmaceuticals) diluted in 1000 mL of isotonic of more than 4500 g. All participants gave verbal and saline (Denmark) or 5 IU oxytocin diluted in written informed consent before randomisation on or 50 mL of isotonic saline (Netherlands) was started at after initiation of induction of labour. 3.3 mIU/min and increased every 20 minutes by 3.3 mIU/min until regular contractions (three to five R andomisation and masking contractions every 10 minutes) were achieved. The Inclusion and randomisation were primarily facilitated maximum authorised infusion rates were 30 mIU/min by the midwives on duty. They used an internet based in Denmark and 33 mIU/minute in the Netherlands. randomisation programme to randomly assign eligible Women were randomised when the active phase women to one of the two interventions in a one to of labour was established, defined as ruptured one ratio. Random block sizes of four, six, and eight membranes with complete effacement of the cervix, were used, and the women were stratified by site, cervical dilatation of at least 6 cm, and at least three http://www.bmj.com/ parity (nulliparous; parous with or without previous contractions every 10 minutes. After randomisation, the infusion was replaced by the study medication. The continued group received oxytocin at the standard concentration, whereas the discontinued group Visual Abstract Reduced oxytocin stimulation in labour received placebo with saline. The study medication The impact of discontinuing infusion in active phase was set to the same infusion rate as the initial oxytocin infusion and was adjusted (discontinued, reduced, or Summary Routine discontinuation of oxytocin stimulation in the active phase on 2 October 2021 by guest. Protected copyright. of labour (≥ cm of cervical dilatation) may lead to a small increase increased) by the birth attendants according to the in caesarean section rate but a significantly reduced risk of uterine clinical situation. All participants were continuously hyperstimulation and abnormal fetal heart rate patterns monitored with cardiotocography. Antibiotics were Study design Randomised Double People recruited from one Dutch recommended if the woman was a candidate for controlled trial blind and nine Danish hospitals group B Streptococcus prophylaxis, in case of an 1198 isolated temperature of 38.5°C or higher, or in case of Population pregnant Mean age Nulliparous Median