Clinical trial NCT03489928: Misoprostol Labour Induction Study
Official title: A Randomized Controlled Trial of Oral Misoprostol, Low Dose Vaginal Misoprostol and Vaginal Dinoprostone for Induction of Labour
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Induction of Labour
Labour, Induced
Keywords: Labour
Induction
Misoprostol
Dinoprostone
Oxytocin
Lead sponsor: IWK Health Centre
Sponsor class: OTHER
First posted: 2018-04-06
Enrollment: 511
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomly assigned to one of three approaches to initiation of labour induction. Study group allocation will be stratified based on membrane status (ruptured/intact). Sequentially numbered opaque envelopes contain group assignment prepared using computer generated random number tables, in blocks of 4 and 6. Group 1 will receive misoprostol 50µgs, repeated at 4hr intervals until one of the following occurs: progressive labour, contraction frequency of 3 per 10 minutes, non-reassuring fetal heart rate tracing, or delivery. Group 2 will receive misoprostol 25µg initial dose and then 25-50µg placed in the vagina at 6hr intervals to the same effect. Group 3 will have induction of labour managed by the usual method here at the IWK (intravaginal or intracervical prostaglandin gel and IV oxytocin drip). All care decisions will be made by the attending physician. The patient will be reassessed before each administration of misoprostol.
Primary purpose: TREATMENT

Brief summary: Labour induction is a frequent obstetric intervention (\~20%). Prostaglandins (PGs) are effective agents, but gastrointestinal (GI) intolerance has limited use to non-oral routes. The traditional oxytocin "drip" requires intravenous (IV) use and discourages mobility. Misoprostol, a PG analogue, is marketed for oral treatment of GI disorders, but initiates uterine contraction, an undesirable GI side effect. Recently, there has been a research "boom" on vaginal misoprostol use in pregnancy to induce term labour drawing on this "side effect:". The principal investigator has led one of three groups worldwide which has published on oral misoprostol to study effectiveness, GI tolerance, and safety for mother/baby in term labour induction. Cost per patient has been less then one percent that of other PGs, even less than IV oxytocin.

Detailed description: Labour induction is a frequent obstetric intervention (20-30%). Prostaglandins (PGs) are effective agents, but gastrointestinal (GI) intolerance has limited use to intracervical and vaginal administration of PGE2 gels. Misoprostol, a prostaglandin E2 (PGE1) analogue, is marketed for oral treatment of upper GI disorders. The past five years has seen mushrooming literature on its use to initiate uterine contractions for pregnancy termination in the first and second trimesters, and labour induction in the third. Vaginal administration has been used almost exclusively, has been cost effective (less than one percent the cost of PGE2) and without demonstrated harm to mother or newborn. The investigators have published a randomized control trial (RCT) on vaginal use, and have also published a 275 subject RCT of oral misoprostol versus a traditional induction regime of (physician chosen combinations of intracervical or vaginal dinoprostone, intravenous (IV) oxytocin and artificial membrane rupture). Oral misoprostol was effective, well tolerated and without harm to mother or newborn. The investigators have in press a double blind RCT or oral versus vaginal misoprostol in 206 subjects. Oral misoprostol was effective, though time to vaginal birth was 226 min longer, due to more time before labour was initiated. Oral misoprostol was associated with less uterine hyperstimulation (P\<0.04). The investigators have also completed an RCT of oral misoprostol versus IV oxytocin with term pre-labour membrane rupture. Again, effectiveness was shown. There is no larger published collective experience with oral misoprostol labour induction. Before embarking on a costly RCT to evaluate more substantive outcomes (Caesareans or neonatal asphyxia) with sample size greater than 10,000, funding has been received for this three-group RCT of labour induction at term: oral misoprostol, vaginal misoprostol, and our centre's established approach.

PRIMARY RESEARCH QUESTION When induction of labour at term is indicated, is there more than a four-hour difference in time to vaginal birth between vaginal misoprostol (25µg initial dose, followed by 25-50µg every six hours as needed), oral misoprostol (50µg every four hours as needed) and the Izaak Walton Killam (IWK) Health Centre established protocol? Secondary outcomes address harm to the newborn (including cord blood acid base analysis, and defined birth asphyxia criteria) and mother (Caesareans, peripartum interventions, maternal GI intolerance and excessive uterine activity).

RESEARCH PLAN Eligible subjects will be at gestations greater than 37 completed weeks, with a cephalic presenting live single fetus, who have an indication for induction, and no contraindication to induction, vaginal birth, or PG use. Random allocation will be blocked and stratified (on membrane status). Sample size calculations were based on: ∆=240 minutes, α(2 tailed) = 0.05, β=0.05, with a σ=588 minutes from the investigators' prior publications. Adjustments for anticipated Caesareans (\<20%) were made. Sample size is 510. Recruitment within a year is supported by the group's prior research \[more than 1000 inductions per year at IWK Grace ( the centre's name officially changed in November, 2000, to IWK Health Centre)\].

Eligibility criteria: Inclusion Criteria:

* pregnant women
* gestational age 37 weeks or more based on ultrasound before 24 weeks
* live single fetus in cephalic presentation
* indication for induction of labour

Exclusion Criteria:

* non reassuring fetal heart rate tracing
* maternal prior uterine surgery
* known hypersensitivity to misoprostol or other prostaglandin
* contraindication to vaginal birth
* fetal anomaly identified on antenatal ultrasound
* uncontrolled maternal asthma or epilepsy

Primary outcomes:
measure: Time interval from induction (at randomization) to vaginal birth
timeFrame: Randomization to newborn vaginal birth, assessed through to study completion, up to 10 weeks
Secondary outcomes:
measure: Time interval from induction (at randomization) to birth
timeFrame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks
measure: Profound newborn acidemia
timeFrame: Cord blood gas sample collected at birth
measure: Newborn respiratory depression
timeFrame: Assessed at 5 minutes after birth
measure: Newborn birth asphyxia
timeFrame: Birth to newborn hospital discharge, assessed up to 10 weeks
measure: Newborn severe metabolic acidemia
timeFrame: Cord blood gas sample collected at birth
measure: Newborn moderate metabolic acidemia
timeFrame: Cord blood gas sample collected at birth
measure: Birth method
timeFrame: At newborn birth
measure: Oxytocin Use
timeFrame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks
measure: Epidural Use
timeFrame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks
measure: Perineal Trauma
timeFrame: Randomization to maternal hospital discharge, assessed up to 10 weeks
measure: Caesarean Section
timeFrame: At newborn birth
measure: Maternal nausea
timeFrame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks
measure: Maternal vomiting
timeFrame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks
measure: Maternal diarrhea
timeFrame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks
measure: Excessive uterine activity
timeFrame: Randomization to birth, assessed through to study completion, up to 10 weeks
Other outcomes:
measure: Vaginal birth in less than 24 hours
timeFrame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks
measure: Time interval from randomization to full dilation
timeFrame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks
measure: First stage of labor duration
timeFrame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks
measure: Second stage of labor duration
timeFrame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks
measure: Maternal satisfaction questionaire
timeFrame: Randomization to maternal hospital discharge, assessed up to 10 weeks
measure: Maternal satisfaction choice
timeFrame: Randomization to maternal hospital discharge, assessed up to 10 weeks
Locations:
Study officials:
affiliation: IWK Health Centre
name: David C Young, MD MSc FRCSC
role: PRINCIPAL_INVESTIGATOR
affiliation: IWK Health Centre
name: B A Armson, MD MSc FRCSC
role: STUDY_DIRECTOR
References: