Buccal Versus Vaginal Misoprostol for Third Trimester Induction of Labor

Study Overview
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Brief Summary
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Approximately 22% of term pregnancies are induced. Misoprostol, a prostaglandin E1 analogue, is a widely accepted induction agent, that has been proven safe and effective for induction of labor. It stimulates both cervical ripening and uterine contractions, thus making it an ideal induction agent for unfavorable cervices. Research has examined the pharmacokinetics of different administration routes and effects on uterine contractility, side effects, and safety. Vaginal misoprostol has been shown to be superior over oral administration however patients often prefer a more tolerable route. Buccal administration has already been shown to be as effective as vaginal misoprostol for cervical ripening and induction in both first trimester and second trimester abortions. There is minimal research comparing buccal versus vaginal for third trimester induction of labor. The investigators study is a prospective, double blinded, randomized control trial comparing vaginal misoprostol and buccal misoprostol in equal dosages of 25 mcg. The investigators seek to answer the question whether buccal misoprostol is as effective as vaginal misoprostol for third trimester induction of labor.

Detailed Description
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Design Overview This will be a prospective, double blind, randomized, placebo-controlled trial comparing buccal versus vaginal misoprostol in equal doses (25 mcg every 4 hours). Each participant will receive one buccal and one vaginal tablet, only one containing misoprostol. The administration will be repeated every four hours if contractions are inadequate (frequency less than every 5 minutes) until the cervix is favorable, spontaneous rupture of membranes occurs, or the patient is in active labor. Patient will be continued on intermittent fetal heart monitoring 1 hour after administration. Prior to discharge women in the study will be asked to complete a questionnaire as to their preferences of route of administration and side effects. Recruitment, Consenting, and Confirming Eligibility: Women with obstetric, medical, or psychosocial indications of induction of labor at University of California, Los Angeles Ronald Reagan Medical Center will be evaluated for participation. Those who meet eligibility criteria will be invited to participate. The subject will be counseled about the study, and if interested, will undergo the consent process. Each potential subject will receive a thorough overview of the study protocol and will review the consent form with study staff. All questions will be answered. The subject will be advised that a decision not to participate in the study will not affect the quality or availability of medical services she will receive at the hospital. She will also be advised that she can stop participating in the study at any time, for any reason, and that this will not impact the services she receives. If the subject elects to participate, two copies of the consent will be signed by the subject and research staff. A signed consent, along with a copy of the Experimental Subjects Bill of Rights, will be given to the subject. The other consent will be filed in a locked file cabinet. A general medical and gynecological history and physical will be done as is standard of care. Routine obstetric labs and any other medically indicated labs will be sent as is standard of care. Patients will undergo a non-stress test and uterine contraction monitoring prior to induction of labor. Obstetrical ultrasound will be reviewed or performed if indicated per the physician. Assessment of the cervix and Bishop score, pelvis, fetal size, and presentation will be performed. An unfavorable cervix is defined as Bishop score of 6 or less (ACOG). Women with ruptured membranes will not be able to participate. Gestational age will be determined on the basis of last menstrual period, confirmed by earliest ultrasound, or a corrected estimated date of confinement by the earliest ultrasound. Misoprostol Administration/ Evaluation: The subject will be randomized to either of two groups. Each participant will receive both a vaginal and buccal tablet, with one tablet containing misoprostol. Subjects will be instructed by a nurse regarding buccal placement and to swallow any residue remaining after 20 minutes. Intravaginal administration of pill will be performed by a resident Physician or midwife. The subject will remain recumbent for at least 30 minutes. The subject will undergo fetal heart rate (FHR) and uterine contraction monitoring for at least 1 hour after misoprostol administration. The subject may undergo further FHR and uterine contraction monitoring per physician discretion. If the subject does not have adequate uterine contractions (uterine contraction occurring at least every 5 minutes), the same dosage and route of administration regimen will be repeated to 6 maximum dosage (maximum of 150mcg). Cervical assessment of Bishop score will be performed with each treatment during vaginal administration. Treatment will continue until spontaneous rupture of membranes, active labor, or favorable cervix (Bishop >6). Augmentation of labor using pitocin may start after 4 hours of last misoprostol dose according to routine protocol. Amniotomy may be performed at the discretion of the managing obstetrician. If labor is not achieved after receiving 150mcg of misoprostol, it will be categorized as a failed induction. At this time, the subject may be offered oxytocin induction, foley bulb mechanical dilation, or cesarean section, according to the fetal and participant condition. Terbutaline 0.25mg subcutaneous may be given for tachysystole (5 uterine contractions in 10 minutes) with FHR changes or FHR category II-III changes (minimal variability, prolonged deceleration, repetitive variables, sinusoidal pattern, repetitive late deceleration) that are not responsive to resuscitative measures ( oxygen supplementation, side positioning, intravenous fluids) according to physician's discretion. Follow up: A short survey questionnaire assessing gastrointestinal side effects, experiences, and preferences of route of administration will be given prior to discharge.

Official Title
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Buccal Versus Vaginal Misoprostol for Third Trimester Induction of Labor: Randomized Control Trial

Conditions
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Pregnancy

Intervention / Treatment
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* Drug: Buccal Misoprostol
* Drug: Vaginal misoprostol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to participate / consent in a placebo-controlled trial Age 18 and older Pregnancy between 34 and 42 years of gestation Admitted for labor induction because of either medical, obstetric, or psychosocial indications Live singleton fetus Bishop score less than or equal to six Cephalic presentation Reactive non-stress test or Negative contraction test Exclusion Criteria: Premature rupture of membranes Multiparity > 5 Contraindication to vaginal or labor delivery Suspected placental abruption Significant hepatic, renal or cardiac disease Known hypersensitivity to misoprostol or prostaglandin analogue Recent prostaglandin administration for induction of labor Multifetal pregnancy Macrosomia > 4500g estimated fetal weight by ultrasound or leopold

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buccal misoprostol+placebo vaginal pill<br> | Drug: Buccal Misoprostol<br>* Buccal rather than Vaginal misoprostol for induction of labor<br>* Other names: Cytotec;|
| Active Comparator: Vaginal Misoprostol+placebo buccal pill<br> | Drug: Vaginal misoprostol<br>* Vaginal rather than buccal misoprostol for induction of labor<br>* Other names: Cytotec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal Delivery Within 24 Hours of Labor Induction | Percentage of participants able to achieve vaginal delivery within 24 hours of labor induction. | Within 24 hours of labor induction | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Vaginal Delivery | Time from start of induction to vaginal delivery was computed in participants who achieved vaginal delivery. | Start of induction until vaginal delivery | 
| Time to Delivery | Time from induction to delivery. All participants were included. | Until delivery | 
| Time to Active Labor | Time from induction to active labor. Active labor defined as 4 cm and above. P-value computed by Kruskal-Wallis test. | Until active labor | 
| Rates of Vaginal Delivery | Percentage of participants who delivered vaginally | Until delivery | 
| Cesarean Delivery Rate | Percentage of participants who underwent a cesarean delivery was computed. P-value was computed using Fisher's exact test. | Until delivery | 
| Number of Misoprostol Doses | Number of misoprostol 25 mcg doses used during induction of labor. | Until delivery | 
| Arrest of Dilation | Percentage of participants who presented with arrest of dilation. Arrest of dilation was determined by the delivering physician. P-value was computed using Fisher exact test. | Until delivery | 
| Failed Induction of Labor | Percentage of participants who were determined as a failed induction of labor. Failed induction was defined as no cervical change despite 24 hours of pitocin or 12 hours of pitocin after rupture of membranes. P value was computed by Fisher exact test. | Until delivery | 
| Pitocin | Percentage of patients that used pitocin during labor. P-values were computed using Fisher exact test. | Until delivery | 
| Foley Bulb | Percentage of participants that required foley bulb use. | Until delivery | 
| Artificial Rupture of Membranes (AROM) | Percentage of participants that required AROM | Until delivery | 
| Abnormal Fetal Heart Tracing (FHT) | Feta heart tracing was reviewed for every participant until 4 hours from last misoprostol dose. Percentage of participants who presented with abnormal fetal heart tracing was computed. Abnormal fetal heart tracing was defined as category 2 and 3 fetal heart tracing according to standard criteria. Abnormal fetal heart tracing included any of the following tachycardia, bradycardia without absent variability, minimal variability, absent variability with or without recurrent decelerations, marked variability, prolonged deceleration and recurrent late deceleration, sinusoidal pattern. P values were computed by Fisher exact test. | Until 4 hours of last misoprostol dose | 
| Tachysystole With Abnormal FHT | Feta heart tracing was reviewed for every participant until 4 hours from last misoprostol dose. Percentage of participants who presented with tachysystole and abnormal fetal heart tracing was computed. Abnormal fetal heart tracing was defined as category 2 and above. Tachysystole was defined as more than 5 uterine contractions within 10 minutes. P values were computed by Fisher exact test. | Until 4 hours after last misoprostol dose | 
| Tachysystole | Fetal heart tracing was reviewed until 4 hours after last misoprostol dose. Percentage of participant with tachysystole were computed. Tachysystole was defined as more than five uterine contractions in 10 minutes. P value was computed using Fisher exact test | Until 4 hours after last misoprostol dose | 
| Neonatal Intensive Care Unit (NICU) Admission | Percentage of participants whose baby was admitted to NICU was computed from time to delivery to time of hospital discharge. P-value was computed using Fisher Exact test. | Until discharge from hospital | 
| Meconium | Percentage of participants who developed meconium was computed. Presence of meconium was evaluated by the delivering physician. P-value was computed using Fisher exact test. | Until delivery | 
| Chorioamnionitis | Percentage of participants affected with chorioamnionitis | Until 48 hours after delivery | 
| APGARS | Median (APGAR) score at 5 minutes after delivery. APGAR: Appearance, Pulse, Grimace, Activity, Respiration Apgar scale is determine by evaluating a newborn on 5 categories on a scale from 0 to 2, then summing up the five values. Score range is 0 to 10. Score above 7 are generally normal. Score below 3 may indicated poor status. | 5 minutes after delivery | 
| Patient Satisfaction With Buccal Versus Vaginal Misoprostol Administration. | All patients were given a patient satisfaction survey. Patients were asked to use a Likert scale to rate their experience on the following: Likert sub-scale: 1 to 5 1=Not at all/ Never to 5= Very Much/ Always Nausea and vomiting 1=better outcome 5=worse outcome effectiveness of misoprostol 1=worse outcome 5=better outcome concerns of misoprostol 1=better outcome 5=worse outcome overall labor experience 1=worse outcome 5=better outcome Patients will be followed for the duration of their labor(usually up to 72hrs). The satisfaction survey will be conducted after delivery but will evaluate side effects that they recollect in labor. | Until 72 hours after delivery | 
| Patient Preference | All patients were given a patient satisfaction survey after delivery. They were asked to select their preference for misoprostol intervention type: buccal, vaginal, or either. | Until 72 hours after delivery |