Misoprostol Labour Induction Study

Study Overview
=================
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)].

Official Title
-----------------
A Randomized Controlled Trial of Oral Misoprostol, Low Dose Vaginal Misoprostol and Vaginal Dinoprostone for Induction of Labour

Conditions
-----------------
Induction of Labour, Labour, Induced

Intervention / Treatment
-----------------
* Drug: Oral Misoprostol
* Drug: Vaginal Misoprostol
* Drug: Dinoprostone


Participation Criteria
=================
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
Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Misoprostol<br>50ug po q4h orally, as needed | Drug: Oral Misoprostol<br>* Prostaglandin E1 - 100ug tablet, divided in half by pharmacy staff to be administered by mouth.<br>* Other names: Oral Cytotec;|
| Experimental: Low dose vaginal misoprostol<br>25-50ug q6h, vaginally, as needed | Drug: Vaginal Misoprostol<br>* Prostaglandin E1 - 100ug oral tablet, divided in quarters by pharmacy staff, vaginal placement of one or two quarters as needed every 6 hours<br>* Other names: Vaginal Cytotec;|
| Experimental: Usual vaginal dinoprostone<br>1-2mg q6h, vaginally as needed | Drug: Dinoprostone<br>* Prostaglandin E2 - 1-2mg gel manufactured for vaginal use; placed vaginally every 6 hours as needed.<br>* Other names: Prostin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time interval from induction (at randomization) to vaginal birth | The chosen clinically important difference: 4 hours (240 minutes) difference. Caesarean sections could not be included in this planned parametric analysis (ANOVA) comparison of means | Randomization to newborn vaginal birth, assessed through to study completion, up to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time interval from induction (at randomization) to birth | Rank order nonparametric analysis [Kruskal Wallis (KW)] where a Caesarean is a failure to deliver vaginally and ranked longer than any vaginal birth- comparison of medians (KW ANOVA). | Randomization to newborn birth, assessed through to study completion, up to 10 weeks | 
| Profound newborn acidemia | Frequency of newborns with umbilical cord blood arterial pH < 7.0 | Cord blood gas sample collected at birth | 
| Newborn respiratory depression | Frequency of newborns with Apgar score at 5 minutes < 4 | Assessed at 5 minutes after birth | 
| Newborn birth asphyxia | Frequency of participants whose newborn experiences birth asphyxia as defined in the American College of Obstetrics and Gynecology Committee Opinion # 197 (Int J Gynecol Obstet 1998;61:309-10). The newborn with birth asphyxia must have each of the following four criteria :[1] profound academia (umbilical cord blood arterial pH< 7.0, obtained at birth); and (2) Apgar score <4 at five minutes as assessed by neonatal caregivers; and [3] neonatal neurologic sequelae (newborn with one or more of seizures, hypotonia, coma);and [4] dysfunction in one or more of the cardiovascular, gastrointestinal, hematologic, pulmonary, hepatic or renal systems. Criteria (3) and (4) are as assessed by neonatal caregivers from birth to newborn hospital discharge. | Birth to newborn hospital discharge, assessed up to 10 weeks | 
| Newborn severe metabolic acidemia | Frequency of newborns with umbilical cord arterial blood base deficit >16.0 mmol/L | Cord blood gas sample collected at birth | 
| Newborn moderate metabolic acidemia | Frequency of newborns with umbilical cord arterial blood base deficit >12.0 mmol/L | Cord blood gas sample collected at birth | 
| Birth method | Frequency of spontaneous, operative vaginal (vacuum and/or forceps), or caesarean birth | At newborn birth | 
| Oxytocin Use | Frequency of participants who received intrapartum use of oxytocin for labor augmentation or induction | Randomization to maternal delivery, assessed through to study completion, up to 10 weeks | 
| Epidural Use | Frequency of participants who received an epidural for intrapartum analgesia | Randomization to maternal delivery, assessed through to study completion, up to 10 weeks | 
| Perineal Trauma | Frequency of participants who had received suture perineal repair of a laceration or episiotomy | Randomization to maternal hospital discharge, assessed up to 10 weeks | 
| Caesarean Section | Frequency of Caesarean section | At newborn birth | 
| Maternal nausea | Frequency of participants who had nausea during labor | Randomization to maternal delivery, assessed through to study completion, up to 10 weeks | 
| Maternal vomiting | Frequency of participants who had vomiting during labor | Randomization to maternal delivery, assessed through to study completion, up to 10 weeks | 
| Maternal diarrhea | Frequency of participants experiencing diarrhea during labor | Randomization to maternal delivery, assessed through to study completion, up to 10 weeks | 
| Excessive uterine activity | Frequency of tachysystole and/or hyperstimulation - blind review of fetal heart rate, uterine contraction tracings by research team physician, remote from delivery. | Randomization to birth, assessed through to study completion, up to 10 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Labour, Induction, Misoprostol, Dinoprostone, Oxytocin