Continued Versus Discontinued Oxytocin Stimulation of Labour
Condition: Adverse Reaction to Oxytocin
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Oxytocin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Both arms will initially receive routine treatment with oxytocin according to national guidelines. When active phase of labour is established both arms will have their infusion-set changed for a blinded infusion-set.; Both arms will initially receive routine treatment with oxytocin according to national guidelines. When active phase of labour is established both arms will have their infusion-set changed for a blinded infusion-set.
Other intervention name(s): syntocinon; Isotonic saline
Intervention MeSH terms: Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Active phase of labour; Discontinuation; Caesarean section