Clinical trial NCT02553226: Continued Versus Discontinued Oxytocin Stimulation of Labour
Official title: Continued Versus Discontinued Oxytocin Stimulation of Labour in a Double-blind Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Adverse Reaction to Oxytocin
Keywords: Active phase of labour
Discontinuation
Caesarean section
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Randers Regional Hospital
name: Aarhus University Hospital
name: Kolding Sygehus
name: Aalborg University Hospital
name: Herning Hospital
name: Rigshospitalet, Denmark
name: University of Amsterdam
name: Hillerod Hospital, Denmark
name: Odense University Hospital
name: Hvidovre University Hospital
First posted: 2015-09-17
Enrollment: 1200
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Background:

The proposed study will investigate the effect of Syntocinon® (synthetic oxytocin) to induce labour. The hypothesis to be studied is that once the active phase of labour has commenced, Syntocinon® can be discontinued and the labour process will continue.

Design:

Double-blind randomised controlled multicentre trial

Setting:

Aarhus University Hospital, Denmark and Regional Hospital of Randers, Denmark

Population:

1200 women (600 in each group) stimulated in the latent phase of labour with oxytocin for induction

Methods:

The Syntocinon® infusion will be replaced with either continuous isotonic saline (placebo) or Syntocinon® infusion (control group), when the active phase of labour is reached.

Main outcome measures:

Caesarean section (primary outcome), tachysystole, neonatal asphyxia, birth experience

Perspective:

Syntocinon® is on the list high-alert medications and associated with complications for mother and child during labour. Reducing the duration of stimulation during labour may lower the number of asphyxial sequelae and the number of caesarean sections.

Detailed description: Randomisation:

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 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 8 are used, and the participants will be stratified by site (Aarhus University Hospital, Randers Regional Hospital, Aalborg University hospital, or Sygehus Lillebælt Kolding), parity (nulliparous or parous) and indication for Syntocinon® infusion (induction or induction due to premature rupture of membranes).

The randomisation number corresponds to number of the project medicine (ampoule). The personnel of the delivery ward will administer the ampoules according to existing guidelines concerning medicine administration

Oxytocin stimulation protocol:

Existing national procedures prior to stimulation will be followed, including use of the existing checklists. No further examination will be done prior to inclusion and stimulation, no blood samples nor ECG to identify e.g. unknown QT-syndrome will be performed as this is never performed as a standard procedure prior to induction.

Latent phase: Stimulation will be given according to national DSOG guidelines7. Initially 20 ml/hour of 10 IE Syntocinon® diluted in 1000 ml 0,9% NaCl. The dose rate will be increased every 20 minutes by 20 ml/hour until appropriate uterine activity of 3-5 contractions per 10 minutes is achieved. The maximum allowed dose rate 180 ml/hour for induction of labour.

Active phase: The woman will be included in the study, when the active phase of labour is established (cervical dilatation ≥ 6 cm, ≥3 contractions per 10 minutes, and rupture of membranes). Randomisation is performed, and the infusion will be replaced by the trial solution, which will be either Syntocinon® at the same concentration, or a placebo infusion which will not contain Syntocinon®:

1. Control group; 10 IE Syntocinon® diluted in 1000 ml 0,9% NaCl infusion
2. Intervention group; 1ml 0,9% NaCl diluted in 1000ml 0,9% NaCl infusion. The infusion will be continued to achieve uterine activity of 3-5 contractions per 10 minutes. Maximum allowed dose is 180 ml/hour for induction. The procedure for administration of the trial solution is identical with the existing procedure.

Complications:

The infusion will be reduced or discontinued at any point of labour, if the following occur:

* Hyperstimulation (\>5 contractions per 10 minutes and non-reassuring CTG13). A management algorithm for this situation is made.
* Uterine contractions lasting 2 minutes or more
* Non-reassuring CTG (recurrent variable decelerations, fetal tachycardia or bradycardia, minimal to absent baseline variability, late decelerations)
* Suspicion of uterine rupture These conditions will be managed according to the guidelines of the local delivery wards.

Dystocia:

If there is failure to progress, defined as less than two cm dilation over 4 hours despite apparently adequate contractions and/or maximal infusion rates (Syntocinon® or placebo), the project medicine will be replaced with open-labelled Syntocinon® infusion. Stimulation will be given according to national DSOG guidelines7. Initially 20 ml/hour of 10 IE Syntocinon® diluted in 1000 ml 0,9% NaCl. The dose rate will be increased every 20 minutes by 20 ml/hour until appropriate uterine activity of 3-5 contractions per 10 minutes is achieved. The maximum allowed dose rate is180 ml/hour for induction.

Woman receiving open-labelled Syntocinon® infusion for 4 hours and continuous failure to progress: Consider caesarean section.

Unconcealment The primary investigator or a nominated deputy will at all time be able to break the randomisation code and reveal the allocation group, if needed. The Internet Based Randomisation Programme will provide the primary investigator or a nominated deputy with this possibility. (A 24/7 availability of the allocation group is thereby provided).

Side effects and risks:

Persistent failure to progress can be expected in 8-46% of the participants in the placebo group versus 3-17% in the control group. 3 4 5 6 Based on data from the pilot study, the risk of caesarean section is expected to be 15% in the placebo group versus 22% in the control group. According to the pilot study and previous studies 3 4 5 6, the maternal and neonatal complications in the placebo group are expected to be lower than in the control group.

All participants are monitored with continuous electronic fetal heart rate monitoring during labour to detect complications such as uterine tachysystole and non-reassuring/pathological fetal heart rate, in accordance with national guidelines.

The personnel of the delivery ward are responsible for registering of adverse reactions and adverse events.

Following adverse reactions and event will be registered immediately in the electronic medical journal of the patient:

* Cesarean delivery
* Postpartum hemorrhage \>500 ml
* Manual placenta removal
* Rupture of the anale sphincter
* Urine retention
* Neonatal: pH \<7,10 and/or Apgar score ≤ 6 at 5 minutes

Following serious adverse reactions and adverse events will be also registered immediately in the electronic medical journal of the patient:

* Intrauterine dead during labour
* Maternal amniotic fluid emboli or thromboembolic event
* Maternal cardiac arrest
* Maternal Pulmonary edema
* Uterine rupture The women will be followed for at least 3-6 hours postpartum (termination of project medicine) according current practice on the delivery ward.

The product resume of Syntocinon® will be used as reference to determine whether a Serious Adverse Reaction is expected or unexpected. Primary investigator or a nominated deputy will go through the participants medical file 7-30 days postpartum during data management and Primary investigator will ensure that all relevant information about suspected serious unexpected adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible to the competent authorities concerned, and to the Ethics Committee, and in any case no later than seven days after the knowledge such a case, and that relevant follow-up information is subsequently communicated within an additional eight days.

Primary investigator will report to the competent authorities concerned and to the Ethics Committee concerned all other suspected unexpected serious adverse reactions as soon as possible but within a maximum of 15 days of first knowledge.

Eligibility criteria: Inclusion Criteria:

* Women stimulated with Syntocinon® infusion for induction of labour (with or without cervical priming by prostaglandin)

Exclusion Criteria:

* 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® initiation
* Fetal weight estimation \> 4500 g (clinical or ultrasonic)
* Subject declines participation
* Gestational age less than 37 completed weeks

Definition: Stimulation with Syntocinon® following Premature Rupture of membranes (PROM) is induction of labour if there is no cervical change prior to starting the infusion, whereas stimulation with Syntocinon after PROM but following the establishment of significant cervical change is augmentation.

Primary outcomes:
measure: Caesarean section
timeFrame: labour
Secondary outcomes:
measure: Instrumental delivery
timeFrame: 0-48 hours
measure: Birth experience
timeFrame: 4 weeks postpartum
measure: Breastfeeding
timeFrame: 0-6months
measure: Duration of the active phase of labour
timeFrame: 0-48 hours
measure: Total duration of labour
timeFrame: 0-48 hours
measure: Uterine tachysystoli
timeFrame: 0-48 hours
measure: Uterine hyperstimulation
timeFrame: 0-48 hours
measure: Use of epidural analgesia
timeFrame: 0-48 hours
measure: Dose and duration of oxytocin infusion
timeFrame: 0-48 hours
measure: Use of episiotomy
timeFrame: 0-48 hours
measure: Rupture of the anal sphincter
timeFrame: 0-48 hours
measure: Uterine rupture
timeFrame: 0-48 hours
measure: Volume of blood loss at delivery and postpartum
timeFrame: 0-48 hours
measure: Need for evacuation of retained products of conception
timeFrame: 0-48 hours
measure: Maternal use of antibiotics during labour
timeFrame: 0-48 hours
measure: Maternal readmission
timeFrame: 0-168 hours
measure: Retention of urine
timeFrame: 0-48 hours
measure: Vaginal explorations
timeFrame: 0-48 hours
measure: Cardiotocogram (CTG) classification
timeFrame: 0-48 hours
measure: Fetal scalp pH values or Fetal scalp lactate
timeFrame: 0-48 hours
measure: Apgar score at 1 and 5 minutes
timeFrame: 0-48 hours
measure: Umbilical cord arterial pH
timeFrame: 0-48 hours
measure: Neonatal use of antibiotics - postpartum
timeFrame: 0-48 hours
measure: Neonatal hyperbilirubinaemia
timeFrame: 0-48 hours
measure: Neonatal admission
timeFrame: 0-48 hours
measure: Need for resuscitation/ventilation of the newborn
timeFrame: 0-48 hours
measure: Neonatal death
timeFrame: 0-7 days
measure: Time of birth of placenta
timeFrame: 0-2 hours
measure: Cause of maternal readmission
timeFrame: 0-7 days
Other outcomes:
Locations:
city: AArhus
country: Denmark
facility: Aarhus University Hospital
state: Aarhus N
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Herning
country: Denmark
facility: Regionshospitalet Herning
city: Hillerød
country: Denmark
facility: Nordsjællandshospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Kolding
country: Denmark
facility: Sygehus LIllebælt
city: Odense
country: Denmark
facility: Odense University Hospital
city: Randers
country: Denmark
facility: Department of Gynecology and Obstetrics
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
state: Amsterdam-Zuidoost
Study officials:
affiliation: Aarhus University Hospital
name: Niels Uldbjerg, DMSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Regionalhospital Randers
name: Pinar Bor, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Regionalhospital Randers
name: Julie Glavind, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial College, London, England
name: Philip Steer, BSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Boie S, Glavind J, Uldbjerg N, Steer PJ, Bor P; CONDISOX trial group. Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): double blind randomised controlled trial. BMJ. 2021 Apr 14;373:n716. doi: 10.1136/bmj.n716.
citation: Boie S, Glavind J, Uldbjerg N, Bakker JJH, van der Post JAM, Steer PJ, Bor P. CONDISOX- continued versus discontinued oxytocin stimulation of induced labour in a double-blind randomised controlled trial. BMC Pregnancy Childbirth. 2019 Sep 2;19(1):320. doi: 10.1186/s12884-019-2461-x.