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Misoprostol Labour Induction Study

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ClinicalTrials.gov Identifier: NCT03489928
Recruitment Status : Completed
First Posted : April 6, 2018
Last Update Posted : April 6, 2018
Sponsor:
Information provided by (Responsible Party):
David Young, IWK Health Centre

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.

Condition or disease Intervention/treatment Phase
Induction of Labour Labour, Induced Drug: Oral Misoprostol Drug: Vaginal Misoprostol Drug: Dinoprostone Phase 3

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)].

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 511 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Masking Description: Group assignment will be concealed until time induction is to begin, when randomization will occur. No attempt will be made at formal blinding of caregivers following concealed randomization, although neonatal assessment will be carried out by a team unaware of study group assignment.
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Oral Misoprostol, Low Dose Vaginal Misoprostol and Vaginal Dinoprostone for Induction of Labour
Actual Study Start Date : April 1, 1999
Actual Primary Completion Date : December 1, 2000
Actual Study Completion Date : December 1, 2000

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Oral Misoprostol
50ug po q4h orally, as needed
Drug: Oral Misoprostol
Prostaglandin E1 - 100ug tablet, divided in half by pharmacy staff to be administered by mouth.
Other Name: Oral Cytotec

Experimental: Low dose vaginal misoprostol
25-50ug q6h, vaginally, as needed
Drug: Vaginal Misoprostol
Prostaglandin E1 - 100ug oral tablet, divided in quarters by pharmacy staff, vaginal placement of one or two quarters as needed every 6 hours
Other Name: Vaginal Cytotec

Experimental: Usual vaginal dinoprostone
1-2mg q6h, vaginally as needed
Drug: Dinoprostone
Prostaglandin E2 - 1-2mg gel manufactured for vaginal use; placed vaginally every 6 hours as needed.
Other Name: Prostin




Primary Outcome Measures :
  1. Time interval from induction (at randomization) to vaginal birth [ Time Frame: Randomization to newborn vaginal birth, assessed through to study completion, up to 10 weeks ]
    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


Secondary Outcome Measures :
  1. Time interval from induction (at randomization) to birth [ Time Frame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks ]
    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).

  2. Profound newborn acidemia [ Time Frame: Cord blood gas sample collected at birth ]
    Frequency of newborns with umbilical cord blood arterial pH < 7.0

  3. Newborn respiratory depression [ Time Frame: Assessed at 5 minutes after birth ]
    Frequency of newborns with Apgar score at 5 minutes < 4

  4. Newborn birth asphyxia [ Time Frame: Birth to newborn hospital discharge, assessed up to 10 weeks ]
    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.

  5. Newborn severe metabolic acidemia [ Time Frame: Cord blood gas sample collected at birth ]
    Frequency of newborns with umbilical cord arterial blood base deficit >16.0 mmol/L

  6. Newborn moderate metabolic acidemia [ Time Frame: Cord blood gas sample collected at birth ]
    Frequency of newborns with umbilical cord arterial blood base deficit >12.0 mmol/L

  7. Birth method [ Time Frame: At newborn birth ]
    Frequency of spontaneous, operative vaginal (vacuum and/or forceps), or caesarean birth

  8. Oxytocin Use [ Time Frame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks ]
    Frequency of participants who received intrapartum use of oxytocin for labor augmentation or induction

  9. Epidural Use [ Time Frame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks ]
    Frequency of participants who received an epidural for intrapartum analgesia

  10. Perineal Trauma [ Time Frame: Randomization to maternal hospital discharge, assessed up to 10 weeks ]
    Frequency of participants who had received suture perineal repair of a laceration or episiotomy

  11. Caesarean Section [ Time Frame: At newborn birth ]
    Frequency of Caesarean section

  12. Maternal nausea [ Time Frame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks ]
    Frequency of participants who had nausea during labor

  13. Maternal vomiting [ Time Frame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks ]
    Frequency of participants who had vomiting during labor

  14. Maternal diarrhea [ Time Frame: Randomization to maternal delivery, assessed through to study completion, up to 10 weeks ]
    Frequency of participants experiencing diarrhea during labor

  15. Excessive uterine activity [ Time Frame: Randomization to birth, assessed through to study completion, up to 10 weeks ]
    Frequency of tachysystole and/or hyperstimulation - blind review of fetal heart rate, uterine contraction tracings by research team physician, remote from delivery.


Other Outcome Measures:
  1. Vaginal birth in less than 24 hours [ Time Frame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks ]
    Frequency of newborns with vaginal birth in less than 24 hours from randomization (induction).

  2. Time interval from randomization to full dilation [ Time Frame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks ]
    ANOVA analysis for mothers with vaginal birth

  3. First stage of labor duration [ Time Frame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks ]
    ANOVA analysis of time interval from labor onset to full dilation for mothers with vaginal birth

  4. Second stage of labor duration [ Time Frame: Randomization to newborn birth, assessed through to study completion, up to 10 weeks ]
    ANOVA analysis of time interval from full dilation to vaginal birth for mothers with vaginal birth

  5. Maternal satisfaction questionaire [ Time Frame: Randomization to maternal hospital discharge, assessed up to 10 weeks ]
    ANOVA analysis of participants' total score on the Labour Agentry Scale(LAS). The LAS will be given to consenting participants as a written questionnaire prior to maternal discharge. A mother will be asked to try to remember how she felt during her recent birth experience. If a response is not received by eight weeks following maternal discharge a single reminder telephone contact will made. The LAS is a seven point Likert scale. It measures a mother's sense of control during labor. Score range is from one to seven on each of 18 items. The minimum score is 18 and maximum score is 126. A higher score indicates a greater sense of control. (Hodnett ED, Simmons-Tropea DA. The Labour Agentry Scale: Psychometric properties of an instrument measuring control during childbirth. Res Nurs Health 1987;10:301-10)

  6. Maternal satisfaction choice [ Time Frame: Randomization to maternal hospital discharge, assessed up to 10 weeks ]
    Frequency of response (yes/no) by participants to written question "If you needed a labor induction in another pregnancy would you want to have the same induction method ?" This question was administered with the questionnaire in Outcome 21 above, given to mother prior to hospital discharge.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Women giving birth at the IWK Health Centre
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03489928


Sponsors and Collaborators
David Young
Investigators
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Principal Investigator: David C Young, MD MSc FRCSC IWK Health Centre
Study Director: B A Armson, MD MSc FRCSC IWK Health Centre
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Responsible Party: David Young, Active Staff Physician, IWK Health Centre
ClinicalTrials.gov Identifier: NCT03489928    
Other Study ID Numbers: REB#1415
051.731.7303088 ( Other Grant/Funding Number: IWK Research Services Grant )
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: April 6, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: no sharing plan is in place

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Young, IWK Health Centre:
Labour
Induction
Misoprostol
Dinoprostone
Oxytocin
Additional relevant MeSH terms:
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Misoprostol
Dinoprostone
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Anti-Ulcer Agents
Gastrointestinal Agents
Oxytocics