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.

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.

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.

The trial is GCP monitored by the GCP unit of Aarhus University Hospital, Odense University Hospital, Copenhagen University and The GCP unit at the AMC

Members of the Data Monitoring Committee:

Chair: Lone Krebs (Obstetrician) Member: Gorm Greisen (Pediatrician) Member: Martin Johansen (Statistician)

Members of the Trial Steering Committee:

Chair: Jim Thornton Member: Thomas bergholt Member: Jens Fuglsang Member: Wessel Ganzevoort