The Efficacy of Transcervical Foley Balloon Plus Vaginal Misoprostol Versus Vaginal Misoprostol Alone For Cervical Ripening In Nulliparous Obese Women: A Randomized, Comparative Effectiveness Trial
Phase: PHASE4
Conditions: Obesity, Labor Induction, Cesarean Delivery
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HS1C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
 
 
 
 
 
 
 
 
 
The Efficacy of Transcervical Foley Balloon Plus Vaginal Misoprostol Versus Vaginal 
Misoprostol Alone For Cervical Ripening In Nulliparous Obese Women: A Randomized, 
Comparative Effectiveness Trial 
 
NCT02639429 
 
Version Date: 07/16/2018 
 
 

IRB NUMBER: HS2C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
 
 
 
 
The Efficacy of Transcervical Foley Balloon Plus Vaginal 
Misoprostol Versus Vaginal Misoprostol Alone For Cervical 
Ripening In Nulliparous Obese Women: A Randomized, 
Comparative Effectiveness Trial 
 
 
 
Protocol 
 
 
 
 
Cervical Ripening for Obese 
WomeN (CROWN) 
 
 
 
Principal Investigator: Mesk Alrais, M.D. 
 
Division of Maternal-Fetal Medicine 
Department of Obstetrics, Gynecology and Reproductive Sciences 
The University of Texas Health Science Center at Houston 
 
 
 
November, 2015 
 
 
 
1. BACKGROUND 

IRB NUMBER: HS3C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
Induction of labor (IOL) is the initiation of labor in a viable pregnancy by artificial 
means, and occurs before the spontaneous onset of labor. A common obstetric 
intervention, the rate of IOL increased from 9.5% to 22.8% in the US from 1990 to  
20121. Obese women (BMI ≥ 30 kg/m2) are more likely than their normal-weight 
counterparts to require IOL because of increased rates of obstetric complications 
including pregnancy related hypertensive disorders, diabetes, and prolonged gestations2,3. 
Several studies have shown that obese women experience increased labor duration and 
oxytocin needs when compared to normal-weight women4–8. This in turn results in 
increased rates for unplanned cesarean delivery (CD) as a result of failed IOL, arrest 
disorders and non-reassuring fetal heart rate tracing, that is dose-dependent with 
increasing class of obesity9. 
 
Mechanical and pharmacological agents are routinely used for IOL. The supracervical 
insertion of a Foley balloon catheter acts by overstretching the lower uterine segment and 
the cervix. This process strips the fetal membranes from the lower uterine segment and 
causes rupture of the lysosomes in the decidual cells. The lytic enzymes released include 
phospholipase A, which acts on phospholipids to form arachidonic acid and is converted 
to prostaglandins10. Misoprostol (prostaglandin E1, PGE1) is a prostaglandin analogue 
used to induce labor that is associated with enzymatic collagen degradation, increased 
water content in the extracellular matrix and stimulation of the myometrium resulting in 
intrauterine contractions10. Both methods are supported and recommended by the 
American College of Obstetricians and Gynecologists (ACOG) due to their high safety 
profile and comparative effectiveness11. In addition, they are often preferred over 
oxytocin alone, PGE2 tablet, gel and insert given their low cost, availability and ease of 
use. 
 
A number of randomized trials have compared the use of the Foley balloon in 
combination with misoprostol, against misoprostol alone for labor induction (Table 1). 
Carbone et.al.12 randomized 123 women undergoing IOL with singleton pregnancies at ≥ 
24 weeks’ gestation with unfavorable cervix (Bishop score ≤ 6) to Foley balloon plus 
vaginal misoprostol or vaginal misoprostol alone. The mean induction-to-delivery time 
was shorter with the combined approach when compared to vaginal misoprostol alone 
(15.3 ± 6.5 compared with 18.3 ± 8.7 hours, difference -3.1 hours, 95% CI -5.9 to -0.30). 
No differences were noted in labor complications, CD rates (37.3 vs 26.2 %, P = 0.90) or 
neonatal outcomes, likely due to small sample size. These findings contrast with the 
results by Kashanian et.al.13 and Lanka et.al.14, who did not find such an association. 
However, the results from Kashanian et.al. must be interpreted with caution given 
potential biases due to unclear random sequence generation, high allocation concealment 
and selective reporting. In a recent meta-analysis of eight studies and 1153 patients by 
Chen et.al.15, the use of Foley balloon plus misoprostol was associated with a significant 
reduction in the mean time to delivery when compared to misoprostol alone (mean 
difference -2.36 hours, 95% CI -4.07 to -0.66; P = 0.007). Differences in cesarean 
delivery rates, however, remain elusive likely due to the small sample sizes of the trials 
included. 
To our knowledge no studies have compared  the  effects  of these  interventions     in 

IRB NUMBER: HS4C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
women with obesity (BMI ≥ 30 kg/m2). The exact mechanism of failed cervical ripening 
and dysfunctional labor patterns in obese women is not completely understood. Elevated 
cholesterol levels have been shown to decrease uterine contractility, and obese women  
are more likely to have elevated cholesterol levels than are normal-weight women16. In 
addition, obesity has been associated with lower prostaglandin sensitivity when used 
locally for cervical ripening8. This association is directly proportional to obesity class. 
Although many reviews list obesity as a risk factor for failed IOL, this risk has yet to be 
quantified by obesity class in relation to the various methods available for cervical 
ripening. In a large study of 1273 women who underwent IOL with vaginal misoprostol, 
obese women had a longer induction-to-delivery interval (median 22.7, 24.9 and 27.0 
hours for normal weight, BMI between 30-39.9 kg/m2 and BMI ≥40 kg/m2, respectively; 
P < 0.01) and higher CD rates (21.3%, 29.8% and 36.5% for normal weight, BMI 
between 30-39.9 kg/m2 and BMI ≥ 40 kg/m2, respectively; aOR 2.32, 95% CI 1.58-3.42). 
These results were adjusted for parity, race and treatment group. Noteworthy, obese 
women were more likely to require a CD during the first stage of labor when compared to 
normal-weight women (74% and 83% vs 62%, respectively). These results were further 
confirmed by Wolfe et.al.9 in a large cohort of 80,887 women from the Ohio Department 
of Health’s Birth Certificate Database. Indeed, pregnant women with class III obesity had 
a 2.89 aOR of failed IOL rates when compared to normal-weight women. These authors 
concur that more research is required to define the best method of cervical ripening that 
would decrease CD rates in this high risk populations. 
 
The combination of Foley balloon plus vaginal misoprostol has not been 
prospectively compared to the use of vaginal misoprostol alone among women with BMI 
≥ 30 kg/m2. We hypothesize that obese pregnant women and unfavorable cervix (Bishop 
score ≤ 6), IOL ≥ 32 weeks gestation using the Foley balloon plus vaginal misoprostol 
will result in reduced cesarean delivery rates when compared to vaginal misoprostol 
alone. To prove this hypothesis, we propose a comparative-effectiveness, open-label, 
randomized controlled trial of induction of labor with transcervical foley balloon and 
vaginal misoprostol versus misoprostol alone for cervical ripening in obese pregnant 
women and a Bishop score ≤ 6. 

 
 
Table 1. Studies on Foley balloon and vaginal misoprostol for labor induction 
 
Foley catheter 
and duration 
Dose of 
misoprostol 
Mean induction-to 
delivery 
interval ± SD (h) 
in combination 
group 
Mean induction-to 
delivery 
interval ± SD (h) 
in misoprostol 
group 
Rate of 
cesarean 
delivery in 
combination 
group 
Rate of 
cesarean 
delivery in 
misoprostol 
group 
Rust et al. 
24-Fr 50 mL for 
25-μg 3-hourly 
16.38 ± 7.8 
17.65 ± 8.6 
29.7% 
27.5% 
200117 
12 h 
for 12 h 
(n = 81) 
Chung et al. 
16-Fr 30 mL for 
25-μg 3-hourly, 
16.6 ± 8.2 
17.5 ± 9.3 
41.2% 
36.7% 
200318 
12 h 
6 doses 
(n = 146) 
Kashanian et 
16-Fr traction 
25-μg 3-hourly, 
11.7 ± 2.5 
10.5 ± 3 
35.0% 
40.0% 
al. 200513 
with 
6 doses 
(n = 300) 
500 mL serum 
bag 
Carbone et al. 
60-mL balloon 
25-μg 4-hourly till 
15.3 ± 6.5 
18.3 ± 8.7 
27.3% 
26.2% 
201312 
Bishop score >6 
(n = 123) 
Lanka et.al. 
16-Fr 30 mL for 
25-μg 4-hourly, 
26.52 ± 15.24 
27.64 ± 15.63 
35.0% 
35.0% 
201414 
12 h 
8 doses 
(n = 126) 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-M4S-15-0895 
IRB APPROVAL DATE: 07/16/2018 

IRB NUMBER: HS5C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
2. METHODS 
 
2.1. Study Objectives 
 
2.1.1. Objective 
 
To compare the CD rate when transcervical Foley balloon plus misoprostol versus 
vaginal misoprostol alone is used for cervical ripening among nulliparous obese women 
(BMI ≥ 30 kg/m2) and unfavorable cervix (Bishop score ≤ 6). 
 
2.1.2. Rationale 
 
Obese pregnant women are less sensitive to local use of prostaglandins for 
cervical ripening. Although the best agent and method for IOL remains uncertain among 
obese women, it is biologically plausible that a combination of a mechanical device 
(Foley balloon) and a local pharmacological agent (misoprostol) may have an additive or 
synergistic effect, resulting in a greater degree of cervical ripening, shorter induction-to- 
delivery time and reduced need for CD due to dystocic labor patterns. The addition of 
misoprostol to the Foley balloon may also overcome the frequent observation of cervical 
dilation with the Foley balloon without significant effacement. 
 
2.1.3. Primary Outcome Measures 
 
 Cesarean delivery rate 
 
2.1.4. Secondary Outcome Measures: Maternal 
 
 Indication for CD 
 Induction-to-delivery interval (hours) 
 Need for oxytocin augmentation 
 Occurrence of tachysystole (≥ 5 contractions in a 10 minute period 
averaged over a 30-minute window) requiring terbutaline or Pitocin 
cessation. 
 Clinical chorioamnionitis: maternal fever ≥ 100.4F, uterine fundal 
tenderness, maternal or fetal tachycardia (>100/min and >160/min, 
respectively) and purulent or foul amniotic fluid19 
 Need for operative vaginal delivery 
 Composite of maternal morbidity: 
o Maternal ICU admission 
o Postpartum endometritis 
o Surgical-site infections prior to discharge 
o Venous thromboembolism 
o Need for transfusion 
o Maternal death 

IRB NUMBER: HS6C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
2.1.5. Secondary Outcome Measures: Neonatal 
 
 Neonatal intensive care unit (NICU) admission 
 Transient tachypnea of the newborn (TTS) 
 Respiratory distress syndrome (RDS) 
 Meconium aspiration syndrome 
 Culture proven sepsis 
 Seizures 
 Composite of adverse neonatal outcomes: 
o Apgar score ≤ 7 at 5 mins 
o Umbilical cord pH < 7.1 
o Neonatal injury: brachial plexus injury, fracture 
o Perinatal death 
 
2.2. Design Summary 
 
This is a comparative-effectiveness, open-label, randomized controlled trial of 
induction of labor with transcervical Foley balloon and vaginal misoprostol versus 
misoprostol alone in nulliparous obese pregnant women and Bishop score ≤ 6. 
 
2.3. Inclusion Criteria 
 
 Nulliparous women aged 18 or above 
 BMI ≥ 30 at the time of labor induction 
 Singleton gestation 
 Cephalic presentation (includes successful external cephalic version) 
 Intact fetal membranes 
 Unfavorable cervix (Bishop score of ≤ 6) 
 Gestational age ≥ 32 weeks 
 
2.4. Exclusion Criteria 
 
 Patient not candidate for IOL with misoprostol as deemed by the treating 
physician 
 Multiple gestation 
 Major fetal anomalies 
 Fetal demise 
 
2.5. Recruitment and Feasibility 
 
Recruitment will occur at the Labor and Delivery units at Memorial-Hermann 
Hospital – Texas Medical Center, Lyndon B. Johnson General Hospital and Kern 
Medical, Bakersfield, CA. 

IRB NUMBER: HS7C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
2.6. Randomization 
 
Randomization will be achieved by computer-generated random sequences. 
Permuted block randomization will be performed, stratified by center. Women will be 
randomized to either Foley balloon plus misoprostol or misoprostol alone as the method 
of choice for IOL. Enrollment number and assignments will be placed in opaque sealed 
envelopes. Envelopes will be kept secured in a locked office and will be accessible only 
by the research personnel. 
 
2.7. Intervention and Procedures 
 
Nulliparous pregnant women at ≥ 32 weeks’ gestation admitted to labor and 
delivery for IOL and who meet the inclusion and exclusion criteria will be approached by 
the research staff (Figure 1). Group 1 will be composed of women allocated to the Foley 
balloon plus misoprostol. These women will receive vaginal misoprostol per standard 
protocol at 25 micrograms every 4 hours. In addition, a 26 Fr-Foley balloon catheter will 
be inserted by routine clinical standards. The Foley will be inserted through the internal 
cervical os, filled with 60 mL of normal saline, and then pulled snugly against the  
internal os. The catheter of the Foley will be taped to the patient’s inner thigh under 
gentle traction. If the Foley is unable to be placed, the patient will be reexamined in 1 
hour and placement will be reattempted if Bishop’s score is still 6 or less by the  
healthcare provider. When the Foley balloon had fallen out or had to be removed because 
12 hours have passed since insertion as per protocol, further management of labor will be 
left at the discretion of the labor team. 
 
Group 2 will be composed of women allocated to vaginal misoprostol-only. These 
women will receive 25 micrograms of misoprostol per vagina every 4 hours. This time 
interval has been shown to be more effective that different time intervals in a Cochrane 
review20. Once the cervix becomes favorable (Bishop score > 6), misoprostol 
administration will be discontinued. Similarly, further management will be left at the 
discretion of the labor team. 
 
In both groups, if IV oxytocin is indicated, it will be withheld until 4 hours after 
the last dose of misoprostol to prevent uterine hyperstimulation. Other aspects of labor 
management will be similar for both groups, including continuous electronic fetal 
monitoring with external Doppler device or fetal scalp electrode. Uterine contraction 
assessment will be performed with either an external tocodynamometer or an intrauterine 
pressure catheter. 
 
Participant data including demographic characteristics, medical and obstetric 
history, labor course and outcomes will be collected by a dedicated research nurse. 

IRB NUMBER: HS8C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
 
Figure 1. Flow Diagram – CROWN Trial 
 
 
2.8. Safety Assessment 
 
2.8.1 Risks Associated with Vaginal Misoprostol of Foley Balloon for Labor 
Induction 
 
There is biologic plausibility that a Foley balloon catheter for cervical ripening 
may be associated with an increased rate of chorioamnionitis because it represents a 
foreign body in the lower uterine segment and could potentially facilitate an ascending 
infection. However, a systematic review by Fox et.al.21 (Figure 2) and a Cochrane review 
from Jozwiak et.al.22,23 (Figure 3) concluded that the rates of chorioamnionitis were 
comparable for the Foley balloon and misoprostol when used independently. Carbone et. 
al.12 also reported no differences in the rates of chorioamnionitis when the Foley balloon 
was used concomitantly with misoprostol versus misoprostol alone. 
Nulliparous obese women with unfavorable 
cervix requiring IOL per year meeting 
inclusion criteria 
N = 517* 
250 women randomized 
Foley balloon plus 
Vaginal Misoprostol 
(N = 125) 
Vaginal misoprostol 
only 
(N = 125) 
Primary Outcome: Cesarean Delivery Rate 
Secondary Outcomes 

IRB APPROVAL DATE: 07/16/2018 
 
 
Figure 2. Impact of Misoprostol vs Foley Balloon on Risk of Chorioamnionitis 
 
Adapted from Fox NS, Saltzman DH, Roman AS, Klauser CK, Moshier E, Rebarber A. Intravaginal misoprostol versus 
Foley catheter for labour induction: a meta-analysis. BJOG Int J Obstet Gynaecol 2011;118:647–54. 
Abbreviations: CI, confidence interval; LCI, lower confidence interval; UCI, upper confidence interval 
 
 
Figure 3. Impact of Prostaglandins vs Balloon catheter on Risk of Chorioamnionitis 
 
Adapted from Jozwiak M, Bloemenkamp KWM, Kelly AJ, Mol BWJ, Irion O, Boulvain M. Mechanical methods for 
induction of labour. Cochrane Database Syst Rev 2012;3:CD001233. 
Abbreviations: CI, confidence interval 
 
Tachysystole is a common complication of misoprostol administration  for 
cervical ripening, and tachysystole with FHRT changes is more frequent among women 
receiving misoprostol than among those treated with mechanical devices, alternate 
prostaglandin compounds or oxytocin20,24,25. However, the frequency of uterine 
tachysystole with FHRT changes was lower when a Foley balloon catheter was added to 
misoprostol than when misoprostol alone was used22,26, purportedly due to the reduced 
need for additional doses of vaginal misoprostol. The combination could provide extra 
benefits to patients who are at higher risk of fetal hypoxemia, such as those with sickle 
cell disease, oligohydramnios, fetal growth restriction or other chronic diseases for which 
the use of misoprostol is not considered contraindicated27,28. 
 
 
 
 
 
IRB NUMBER: HS9C-MS-15-0895 

IRB NUMBER: H1S0C-MS-15-0895 
IRB APPROVAL DATE: 07/16/2018 
 
 
2.8.2. Specification of Safety Parameters 
 
Both of the interventions proposed are done in routine clinical care and have been 
tested in prior trials. Choriamnionitis is in fact a risk but is comparable to standard of  
care. The medications/interventions are not new in pregnancy and misoprostol is known 
to not be teratogenic in the third trimester. Therefore, the establishment of a safety data 
monitoring board is not necessary. The principal investigator (PI) and mentor will 
monitor the progress of study and determine the safety parameters. 
 
2.8.3. Management of Adverse Events 
 
Any adverse events will be reported to the Committee for the Protection  of 
Human Subjects (CPHS). Due to the use of medications that have been used in pregnancy 
in the past, there is no increased anticipation of severe adverse events. 
 
2.8.4. Procedures in the Event of Abnormal Clinical Findings 
 
In the event of an abnormal clinical finding, the health care provider caring for the 
participant will be notified to allow treatment in the usual clinical manner. 
 
2.9. Statistical Considerations 
 
2.9.1. Sample Size 
 
Assuming a cesarean delivery rate of 53% at Memorial Herman Hospital among 
nulliparous obese women who underwent IOL in 2012 at ≥ 32 weeks and met our 
inclusion criteria, 250 women (125 women per group) would be required for 80% power 
to detect a 33% cesarean delivery rate reduction between the 2 groups using a two-tailed t 
test and α of 0.05 (Table 2). Interim analysis after 50% enrollment will be performed in 
order to determine if the risk of adverse events discussed in the secondary outcomes is 
increased in one arm relative to the other arm. 
 
Table 2. Proposed Sample Size 
 
% decrease 
in CD rate 
Power (%) 
80 
85 
90 
33 
250 
270 
316 
40 
172 
196 
228 

IRB NUMBER: H1S1C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
50 
100 
114 
134 
 
2.9.2. Statistical Tests 
 
An intent-to-treat analysis will be conducted. Selected baseline characteristics and 
outcome measures will be compared using the independent t test for continuous variables 
and the X2 or Fisher’s exact test for categorical variables as appropriate. Mann-Whitney  
U test will be used for non-parametric comparisons. Tests with a p-value < 0.05 will be 
considered significant. 
 
2.10. Ethical Considerations 
 
2.10.1. Informed Consent 
 
A copy of the informed consent document in both English and Spanish to be used 
will be submitted by the PI to the Institutional Review Board (IRB) for review and 
approval prior to the start of the study. A properly executed written informed consent 
shall be obtained from each patient prior to entering the study. All prospective study 
candidates will be given a full explanation of the consent form, allowed to read the 
approved form, and be provided the opportunity to ask any questions. Once all questions 
have been answered and the Investigator is assured that the individual understands the 
requirements of the study, the subject will be asked to sign the consent. The Investigator 
shall provide a copy of the signed and dated informed consent to the patient and the 
original shall be maintained in the patient’s study files. Patients who do not sign the 
consent form will not be permitted to participate in the study. 
 
2.10.2. Institutional Review Board 
 
Before initiation of the study, the PI will obtain approval of the research protocol 
and from the IRB. The study will be registered in www.clinicaltrials.gov as required by 
the US law for public access. 
 
2.10.3. Subject Confidentiality 
 
Each study’s subject anonymity will be maintained throughout the study. Prior to 
collection of the data a unique study number will be assigned to each case thus de- 
identifying the individual subject. Each study site will maintain a log of the study subject 
to the assigned study number. 

IRB NUMBER: H1S2C-MS-15-0895
IRB APPROVAL DATE: 07/16/2018 
 
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IRB APPROVAL DATE: 07/16/2018 
 
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IRB APPROVAL DATE: 07/16/2018 
 
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