Foley Bulb With Oral Misoprostol Versus Oral Misoprostol for Induction of Labor: A Cluster Randomized Trial
Phase: NA
Conditions: Pregnancy, Labor, Induced
Sponsor: University of Texas Southwestern Medical Center

Adhikari 
 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
trial 
 
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Study Title:  Induction of labor with Oral misoprostol alone versus Combined Oral 
misoprostol with Foley bulb: a Cluster Randomized Trial 
 
NCT03407625 
 
Date: 11/16/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Adhikari 
 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
trial 
 
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University of Texas Southwestern Medical Center Institutional Review Board Protocol 
Principal Investigator:  Emily Adhikari, MD 
Faculty Sponsor: Kenneth Leveno, MD 
Study Title:  Induction of labor with Oral misoprostol alone versus Combined Oral misoprostol 
with Foley bulb: a Cluster Randomized Trial 
Co-investigators:  
Don McIntire, PhD 
David Nelson, MD 
Research Coordinator: Lisa Moseley, RN 
Study Personnel:  
Melissa Wafford, RN 
Jordan Gerald, RN 
Mary Ann Kelly, RN 
Marissa Santillan, RN 
Lisa Fay-Randall, RN 
Andranecia Cox, RN 
Clinical Data Specialists:  
Maria Garcia 
Yolanda Delira 
Ana Sias 
Katherine Gonzales 
Barbara Massey 
Andrea Castille 
 
Funding Sponsor: Departmental-Internal 
 
Purpose:   

Adhikari 
 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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We propose a prospective, cluster-randomized clinical trial to compare standard of care 
(oral misoprostol) with a combination method of oral misoprostol and transcervical foley 
bulb (study group) in patients requiring induction of labor. We hypothesize that the use of 
the combined method of oral misoprostol plus intracervical foley bulb for cervical ripening 
and induction of labor will reduce the rate of primary cesarean delivery when compared 
with oral misoprostol alone. We also aim to evaluate the time to delivery, intrapartum and 
postpartum infectious morbidities, fetal distress, blood loss at delivery, uterine activity, 
and neonatal outcomes including APGAR scores, umbilical cord blood pH, and neonatal 
intensive care unit (NICU) admission. 
Background:  
Induction of labor is associated with increased cesarean delivery rate, especially 
in those women with an unfavorable cervix.1 Both pharmacologic and mechanical 
methods have been utilized for cervical ripening and labor induction. Evidence on the 
safety and effectiveness of various mechanical and pharmacologic methods of cervical 
ripening and labor induction is abundant, and yet the cost of these different methods of 
induction varies widely when taking into consideration medication storage, cost, and 
staffing requirements. Given the high immediate and long term costs of cesarean delivery, 
and the national priority to reduce the rate of primary cesarean delivery in the United 
States,2 a randomized trial powered to detect a reduction in the rate of primary cesarean 
delivery has the potential benefit of changing obstetric practice both at Parkland Hospital 
and nationwide.  
Beginning in the 1980s, the overall rate of induction of labor in the United States 
gradually increased, reaching a peak of 23.8% in 2010.3 Likewise, the rate of cesarean 

Adhikari 
 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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delivery in the United States has increased steadily to peak in 2009 above 32%.4 There 
is increased maternal morbidity among women with primary cesarean delivery compared 
with vaginal delivery, including higher rates of transfusion, unplanned hysterectomy, and 
ICU admission.5 Although the problem of reducing the rate of primary cesarean delivery 
is complex, there is a continued need to determine the most effective and safest way to 
promote cervical change in women with an unfavorable cervix who require labor 
induction.  
 
A cervical ripening agent may be needed for women with an indication for induction 
of labor who have an unfavorable cervix.6 Both pharmacologic and mechanical methods 
have been utilized for cervical ripening prior to labor induction. Among pharmacologic 
methods, prostaglandins have been recognized as more effective than intravenous 
oxytocin alone at both cervical ripening and induction of labor, achieving higher rates of 
vaginal delivery.1 There is abundant clinical experience on the safety and efficacy of oral 
and vaginal misoprostol when used appropriately for cervical ripening and induction of 
labor, and both are supported by the American College of Obstetricians and 
Gynecologists.6 Based on prior studies of various dosing and administration regimens,7-
10 oral misoprostol (100μg) given every four hours for a maximum of two doses is currently 
the standard of care at our institution for cervical ripening and labor induction in those 
women with gestations of 36 weeks or greater, without a prior uterine scar, who are not 
in labor and who otherwise meet strict criteria for fetal well-being. 
Controversy exists on whether the accepted mechanical technique of cervical 
ripening and dilation with transcervical foley catheter used in combination with a 
pharmacologic method may be more effective than prostaglandins alone in achieving 

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 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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cervical ripening and induction of labor.  Most trials comparing combination foley and 
misoprostol are powered to detect a shortened time to delivery rather than the more 
clinically relevant outcome of reduced primary cesarean delivery rate.7,9,11-17  Available 
evidence suggests that the combination of foley catheter with misoprostol for induction of 
labor reduces the time to vaginal delivery, but what remains unclear is whether this 
method also reduces the rate of primary cesarean delivery. Additionally, although the 
theoretical risk exists, evidence is conflicting regarding the risk of chorioamnionitis with 
the use of transcervical foley catheter in women with intact membranes.14,17-19 There is 
no current evidence that the use of transcervical foley contributes to adverse neonatal 
outcomes. The largest published randomized trial comparing oral misoprostol alone to 
foley catheter alone, in which the primary outcome was a composite of neonatal morbidity 
and/or maternal hemorrhage, demonstrated similar safety and effectiveness of the two 
methods in induction of labor.19  However, a comparison arm involving the combination 
of the two methods was not included in the study. 
The purpose of this study is to determine whether the use of a transcervical foley 
catheter, in combination with the standard oral misoprostol regimen will result in a 
decreased primary cesarean delivery rate among women with a cervical dilation of 2 
centimeters of less who require induction of labor at term.  This study is not an FDA-
regulated study: there is no intent to test the foley bulb under an FDA-regulated protocol. 
Likewise, there is no intent to submit the results of this study for a change in the labeling 
of the foley used for this study.  
Concise Summary of Project:  

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 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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This will be a prospective, cluster-randomized trial comparing two methods of 
induction of labor at term among women who present for delivery at Parkland Hospital.  
Eligible participants will include nulliparous and multiparous women at 37 weeks gestation 
or greater, with a living, singleton fetus and no major fetal malformations, in cephalic 
presentation, with intact membranes, no prior uterine scar, who qualify for prostaglandin 
administration and who have a cervical dilation of 2 centimeters or less, measured at the 
level of the internal os. Patients with non-reassuring fetal status, HIV, active herpes 
outbreak, a prior uterine scar, or any contraindication to prostaglandins (including 4 or 
more painful contractions per 10 minutes prior to prostaglandin administration) will be 
excluded from participation in the study.  Computer-generated cluster randomization will 
occur on a weekly basis for all study participants, to either the combination method of 
foley bulb plus oral misoprostol regimen (study group/standard of care plus foley bulb) or 
to oral misoprostol alone regimen (control/standard of care).  
According to the randomization protocol each week, participants will be 
randomized to either the standard of care (oral misoprostol/control group) or standard of 
care plus foley bulb (study group). The study group will undergo placement of a 30 French 
foley catheter filled with 30-35cc sterile saline into the cervix in addition to the standard 
regimen of oral misoprostol 100 micrograms given every 4 hours for a maximum of 2 
doses, for patients who meet criteria for fetal well-being, and do not had more than 4 
painful contractions in 10 minutes. Misoprostol will not be administered to patients who 
have progressed to active labor, defined as 4 centimeters cervical dilation. The control 
group will undergo induction with the standard of care misoprostol protocol alone.  

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The primary outcome will be the rate of vaginal delivery. Secondary outcomes will 
include obstetric outcomes, maternal outcomes, and neonatal outcomes. Obstetric 
outcomes will include indication for induction, need for oxytocin, indication for cesarean 
delivery, time to active labor, time to delivery, labor analgesia, presence of 
chorioamnionitis, meconium-stained amniotic fluid, terbutaline use, tachysystole (defined 
as 6 or more contractions in 10 minutes or tetanic contraction of 120 seconds or longer) 
or hyperstimulation syndrome (defined as tachysystole accompanied by fetal heart rate 
decelerations).  Maternal outcomes will include estimated blood loss, transfusion 
requirement, postpartum fever, uterine rupture, and unplanned hysterectomy.  Neonatal 
outcomes will include umbilical cord blood pH, 5-minute APGAR score, intubation or 
ventilation in the delivery room, neonatal sepsis, and admission to Neonatal Intensive 
Care Unit (NICU) admission.   
Data from these pregnancies will be obtained using several methods: data entry 
encounter forms completed by research nurses from the electronic medical record; and 
from the Parkland Hospital Obstetric Database.  This database is maintained for 
operations, including quality assurance, and is able to be accessed only by the 
epidemiologist within the Obstetrics Department (Don McIntire, listed as co-investigator).  
The database uses a secure file server that is password protected and encrypted.  
Specific variables queried will include the date and gestational age at delivery, age, race, 
parity, singleton or multiple gestation, mode of delivery, the maternal weight and body 
mass index at initial prenatal visit, perineal laceration, labor induction and/or 
augmentation, intrapartum complications such as chorioamnionitis, infant condition at 
birth including APGAR score (Appearance, Pulse, Grimace, Activity, and Respiration), 

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infant cord gas (arterial pH), Neonatal Intensive Care Unit (NICU) admissions, and infant 
complications such as intraventricular hemorrhage and ventilator requirement.  
The data entry encounter forms will include data regarding presenting cervical 
examination, time of induction, and cervical examinations (see attached Data Encounter 
Form).  The data obtained from the data encounter forms will be entered into a 
computerized database operated by the departmental biostatistician (Don McIntire, co-
investigator).  This data will be supplemented with information obtained from review of 
the medical record.  Maternal and neonatal outcome data from the existing obstetric 
operations database will be linked to the labor subset database created from the 
encounter forms and prenatal record.  All data collected will be de-identified with a link 
maintained between research data and identifiable information using a key.  The key to 
the coding system will be located in an electronic file that is password protected and 
encrypted and able to be accessed only by the departmental biostatistician listed (Don 
McIntire, co-investigator).  Following publication, the key to the coding system will be 
destroyed by purging the file so that there is no direct or indirect link to subject identifiers 
or other information.   
In summary, the research team will not have direct contact with the patient. All 
information will be obtained either using the Obstetric database or data entry forms with 
information obtained from the electronic medical record. These indices are routinely 
recorded by labor and delivery unit staff for labor induction (eg. Time of misoprostol given, 
etc.). 
Calculations for statistical analysis will be conducted with the departmental 
biostatistician (Don McIntire, co-investigator).  This is prospective study will be submitted 

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 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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under the full review status of the University of Texas Southwestern Institutional Review 
Board (IRB).   
Study Procedures:  
Management of labor will proceed according to the standard induction protocols in 
place at Parkland Hospital. The number of misoprostol doses (up to 2 doses for a single 
induction event) will be recorded. The need for oxytocin following misoprostol will be 
determined according to routine obstetric management currently used at Parkland 
Hospital. All women meeting inclusion criteria as described above who require induction 
of labor will be included in the study. According to the cluster randomization protocol, 
either a combination method of standard of care plus foley bulb, or standard of care (oral 
misoprostol) alone will be implemented each week on the Labor and Delivery unit. During 
weeks randomized to the standard of care plus foley bulb, all eligible women undergoing 
induction of labor will receive prostaglandin using the current labor stimulation regimen 
as well as transcervical placement of a 30 French foley catheter with a 30cc balloon, filled 
with 30 to 35 cc of 0.9% sodium chloride solution, according to FDA guidelines for filling 
the foley bulb. Induction start time and foley bulb placement time will be recorded. 
Success of foley bulb placement and time to successful placement will be recorded. 
Complications of induction will be recorded, such as vaginal bleeding, fetal distress, 
rupture of membranes, or emergent delivery within 30 minutes of foley bulb placement. 
Failed foley bulb placement will be determined ultimately by the faculty on Labor and 
Delivery as per management practices.  Analgesia requirement during labor will be 
recorded. Transcervical foley bulb will remain in place until expelled spontaneously, or for 
up to 12 hours during induction.  The need for removal of foley bulb prior to being 

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 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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spontaneously expelled at less than 12 hours will be left up to the discretion of the faculty 
on Labor and Delivery, and the time of removal and reason for removal will be 
documented. Maternal complications and will be documented, and neonatal 
complications will be recorded as previously described. Postpartum infectious morbidities 
and readmission to the hospital will be recorded, with review of the patient’s medical 
record at least 2 weeks after hospital discharge to determine readmission for wound 
morbidity. The patient’s participation the study will be concluded after this final review of 
the medical record.  Neonatal outcomes will be abstracted from the infant’s medical 
record at discharge.  
Sub-Study Procedures: N/A 
Criteria for Inclusion of Subjects:  
Nulliparous and multiparous pregnant women at 37 weeks gestation or greater, 
with a living, singleton fetus and no major fetal malformations, in cephalic presentation, 
no prior uterine scar, with intact fetal membranes, who qualify for prostaglandin 
administration and who have a cervical dilation of 2 centimeters or less, measured at the 
level of the internal os, requiring induction at Parkland Health and Hospital System. 
Criteria for Exclusion of Subjects:  
Any patient not meeting above inclusion criteria will be deemed ineligible for the 
study. Patients with latex allergy, non-reassuring fetal status, HIV, active herpes outbreak, 
a prior uterine scar, or any contraindication to prostaglandins (including 4 or more painful 
contractions per 10 minutes prior to prostaglandin administration) or to vaginal delivery 
will be excluded from participation in the study.  Because of the potential risk of vertical 
transmission in the case of inadvertent rupture of fetal membranes during placement of 

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 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
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foley bulb and the lack of data regarding the use of foley bulb in this population, patients 
with HIV will be excluded from the study.  
Sources of Research Material:  
Data from these pregnancies will be obtained using two methods: data entry 
encounter forms completed by research nurses from the electronic medical record; and 
the Parkland Hospital Obstetric Database.  This database is maintained for operations, 
including quality assurance, and is able to be accessed only by the epidemiologist within 
the Obstetrics Department (Don McIntire, listed as co-investigator).  The database uses 
a secure file server that is password protected and encrypted.  Specific variables queried 
will include the date and gestational age at delivery, age, race, parity, singleton or multiple 
gestation, mode of delivery, the maternal weight and body mass index at initial prenatal 
visit, perineal laceration, labor induction and/or augmentation, infant condition at birth 
including APGAR score (Appearance, Pulse, Grimace, Activity, and Respiration), infant 
cord gas (arterial pH), Neonatal Intensive Care Unit (NICU) admissions, and infant 
complications such as intraventricular hemorrhage and ventilator requirement.  
The data entry encounter forms will include data regarding presenting cervical 
examination, time of induction, and cervical examinations (see attached Data Encounter 
Form).  The data obtained from the data encounter forms will be entered into a 
computerized database operated by the departmental biostatistician (Don McIntire, co-
investigator).  This data will be supplemented with information obtained from review of 
the medical record.  Maternal and neonatal outcome data from the existing obstetric 
operations database will be linked to the labor subset database created from the 
encounter forms and prenatal record.  All data collected will be de-identified with a link 

Adhikari 
 Induction of labor with oral miso versus combined oral miso plus foley: a Cluster randomized 
trial 
 
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maintained between research data and identifiable information using a key.  The key to 
the coding system will be located in an electronic file that is password protected and 
encrypted and able to be accessed only by the departmental biostatistician listed (Don 
McIntire, co-investigator).  Following publication, the key to the coding system will be 
destroyed by purging the file so that there is no direct or indirect link to subject identifiers 
or other information.   
In summary, the research team will not have direct contact with the patient. All 
information will be obtained either using the Obstetric database or data entry forms with 
information obtained from the electronic medical record. These indices are routinely 
recorded by labor and delivery unit staff for labor induction (eg. Time of misoprostol given, 
etc.). 
Recruitment methods and consenting process: 
All subjects will be women who deliver at Parkland Health and Hospital System. 
The cluster randomized trial design is such that each week, the chosen method of 
induction of labor in patients meeting inclusion criteria is randomized to either standard 
of care (oral misoprostol) or standard of care plus foley bulb.  The weekly cluster 
randomization method is chosen because randomizing on an individualized basis would 
create risk on a busy labor an delivery unit where nurses administer medications to more 
than one patient during a shift.  All patients who would meet criteria for induction of labor 
will be participants in the study.  A waiver of consent will be requested for this study, as 
the two methods of induction being compared are both widely accepted and practiced 
methods used for women with an unfavorable cervix who require induction of labor. The 
risks and benefits of induction of labor will be discussed with each patient prior to 

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administration and consent for delivery obtained, consistent with the current standard of 
care on Labor and Delivery at Parkland Hospital. Patients will be fully informed about the 
agents used for induction of labor (i.e., misoprostol alone or foley bulb and misoprostol, 
as well as oxytocin) and verbal consent as standard of care for induction will be obtained. 
The risk of transcervical foley bulb is minimal, and the primary risk of participation in the 
study is breach of confidentiality. The waiver of consent is appropriate because all 
patients will receive the same standard of care, and all methods of induction utilized are 
approved by the American College of Obstetricians and Gynecologists. Furthermore, 
obtaining consent from individual patients is impractical on a busy labor and delivery unit 
that would require research staffing for 24 hours a day, 7 days per week.  
Data will abstracted from the medical record as described above and all patient 
identifiers removed prior to data analysis.  Therefore, patients who meet inclusion criteria 
and who require induction of labor will be automatically enrolled in the study and data 
from induction and delivery will be abstracted without direct contact with any research 
personnel.  
Potential Risks: 
 
Potential risks of participation in the study include the risks associated with 
induction of labor with any standard pharmacologic or mechanical method. Additional 
risks include breach of confidentiality. However, as stated below, every effort will be made 
to reduce the risk of loss of confidentiality.  
 
Risks of mechanical induction of labor include the same risks as pharmacologic 
induction of labor, except for the potential risk of inadvertent rupture of the foley balloon 
(0.5%). Benefits to foley bulb placement include potential shortened time to vaginal 

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delivery and fewer fetal heart rate changes when compared with prostaglandins alone, 
and potentially reduced risk of cesarean delivery. Induction of labor is carried out only 
when the benefit to mother and fetus outweigh the potential risk, and the current 
standards of care at Parkland Hospital regarding induction of labor timing and methods 
will not change for this study.  
 
Confidentiality and protection of patient health information will be protected to the 
best of our ability. Data will be abstracted from medical records by research personnel 
and all data will be de-identified and located on a secure server in a locked research 
office. The database will be only accessible to the study personnel. This study does not 
deviate from accepted standard of care for labor induction. 
Subject Data and Safety Monitoring: 
 
At 50% of enrollment, a planned analysis by the Data Safety and Monitoring (DSM) 
committee for this study will be performed. If analysis shows a statistically significant 
harmful impact of using foley bulb in combination with oral misoprostol in women with an 
unfavorable cervix undergoing induction of labor, the study will be halted. Likewise, if a 
strong, statistically significant increase in vaginal delivery can be correlated with foley 
bulb use in combination with oral misoprostol for induction of labor, consideration will be 
made in early study termination, as not to deny the combination method to women who 
would benefit from it in achieving vaginal delivery.  Thirdly, if the trial is deemed to be 
futile, meaning that further sampling will yield little additional useful information (or a 
negligible chance of demonstrating efficacy if fully enrolled, given the results to date), 
consideration will be made to halt the study.  
 

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Procedures to Maintain Confidentiality:  
To maintain patient confidentiality, all records will remain within the hospital 
system.  After the study dataset has been created by the departmental biostatistician (Don 
McIntire, co-investigator) using datasets maintained for operations with a secure file 
server that is password protected and encrypted, all identifiers will be removed and 
replaced with a non-identifiable code.  The key to the coding system will be located in an 
electronic file that is also password protected and encrypted and able to be accessed 
only by the departmental biostatistician (Don McIntire, co-investigator).  Following 
publication, the key to the coding system will be destroyed by purging the file so there is 
no direct or indirect link to subject identifiers or other information. 
Results will only be furnished to the investigators, and to the UT Southwestern 
IRB, as needed. The information obtained from this study may be published, but the 
subjects will not be identified individually.  
Potential Benefits:  
As women who have primary cesarean delivery are more likely to have subsequent 
repeat cesarean than vaginal delivery, the potential benefit of a successful vaginal 
delivery can result in savings to the patient in hospitalization days, maternal and fetal 
complications from multiple cesarean deliveries, and in complications from surgery itself 
including wound infections, organ injuries and delayed recovery.  
 
With the increasing frequency of cesarean delivery and the increasing morbidity of 
multiple cesarean deliveries, a successful vaginal delivery in a woman whose only 
alternative is cesarean delivery has the potential to improve quality of life, save cost in 
hospitalization days, wound complications, and improve the chance for subsequent 

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vaginal delivery, compounding the savings during a woman’s lifetime. If the study shows 
no improvement in vaginal delivery rates or increased adverse outcomes in the study 
group, the study may prevent healthcare providers from utilizing an induction method 
which has little potential benefit other than convenience to the provider.  
Biostatistics:  
 
The current vaginal delivery rate at Parkland Hospital among women undergoing 
induction of labor is 76%, which has been consistent for at least the past 4 years (internal 
data).  This study will be conducted as a superiority trial with analysis performed as intent 
to treat. To detect a 5% increase in vaginal delivery from 76% to 81% with a power of 
80% and a type I error of 5%, a sample size of 2118 is required, with 1059 women in each 
group with comparisons using the Pearson chi-squared test.  A planned interim analysis  
by the Data Safety Monitoring Board take place at 50% recruitment. In order to preserve 
the overall type I error rate of 0.05 we will apply the Lan-DeMets spending function with 
the O’Brien-Fleming type boundaries.  This reduces the ultimate significance level of the 
trial through the completion of the trial from 0.05 to 0.049 and alters the sample size to 
1065 women in each arm or 2130 total.  A ten percent dropout rate still requires 
approximately 2500 participants to be screened (2130/0.90 = 2367). 
In 2015 at Parkland Hospital, approximately 885 women at term (greater or equal to 37 
weeks gestation) with cervical dilation equal to or less than 2cm received at least one 
dose of oral misoprostol for induction of labor. Based on these frequencies, recruitment 
will take approximately 2.5 years to achieve the study goal of 2130 women who meet 
inclusion criteria. Statistical analysis will be performed using SAS 9.3 and include 
Student’s t-test, Wilcoxon rank-sum test, Pearson chi-squared test, and logistic 

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regression. We will plan a prespecified secondary analysis of the primary outcome 
stratified by parity.    
 
 
 
 
 
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