Clinical trial NCT05289869
Conditions: Pregnant Patients With Obesity
Keywords: Oxytocin Pregnant patients with obesity Induction of labor
Sponsor: Ohio State University
Start date: 2022-04-06; Completion date: 2022-10-28
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pregnant patients with obesity are more likely to undergo induction of labor and have a higher risk of failed induction compared to patients with normal weight. The association between maternal obesity and labor dysfunction leading to cesarean delivery is poorly understood. Oxytocin is the mostly common medication used in induction of labor, yet optimal dosing of this medication is unknown. Studies have suggested that patients with obesity may be less responsive to oxytocin. This trial will compare a high and low dose oxytocin dosing regimen for the induction of labor in women with obesity.

Detailed description:
This study is a pragmatic single center randomized, double blinded controlled trial. Nulliparous women with a pre-pregnancy body mass index (BMI) ≥30 kg/m2 undergoing induction of labor at ≥37 weeks' gestation will be eligible for enrollment. Women will be randomly allocated to receive oxytocin using either a high-dose or low-dose regimen. Patients, providers, and research staff will be blinded to the dosing regimen. All other aspects of obstetric management will be at the discretion of the patient's clinical care team.

Postpartum maternal, neonatal, and delivery outcomes will be collected. Postpartum data through hospital discharge will be collected from the medical record. Information about complications following hospital discharge through 6 weeks after delivery will be collected during a research follow-up telephone call performed 6-8 weeks following delivery.

Arms: arm 1: Starting dose 6 mU/min and increased by 6 mU/min every 30 minutes until adequate contractions achieved, at the discretion of the obstetric providers. arm 2: Starting dose 2 mU/min and increased by 2 mU/min every 30 minutes until adequate contractions achieved, at the discretion of the obstetric providers.
Interventions: intervention 1: High-dose oxytocin intervention 2: Low-dose oxytocin
Intervention descriptions: intervention 1: Starting dose 6 mU/min and increased by 6 mU/min every 30 minutes until adequate contractions achieved, at the discretion of the obstetric providers. intervention 2: Starting dose 2 mU/min and increased by 2 mU/min every 30 minutes until adequate contractions achieved, at the discretion of the obstetric providers.

Protocol documents:
Prot_SAP_000.pdf: 
The HILIO Trial: High vs. Low Oxytocin Dosing for Induction of labor 
in Pregnant Patients with Obesity 
PILOT STUDY 
Protocol 
NCT 05289869
Approved by the IRB on March 21, 2022 


1. INTRODUCTION 
1.1  Study Abstract 
Women with obesity are more likely to undergo induction of labor and have a higher risk 
of failed induction compared to women with normal weight. The association between 
maternal obesity and labor dysfunction leading to cesarean delivery is poorly understood. 
Oxytocin is the mostly common medication used in induction of labor, yet optimal dosing 
of this medication is unknown. Studies have suggested that women with obesity may be 
less responsive to oxytocin. This trial will compare a high and low dose oxytocin dosing 
regimen for the induction of labor in women with obesity. 
 
1.2  Hypothesis 
 
A higher oxytocin dosing regimen (increase by 6 mU/min every 30 minutes) will result in 
a decreased risk of cesarean delivery compared to a lower oxytocin dosing regimen 
(increase by 2 mU/min every 30 minutes) in nulliparous women with a pre-pregnancy 
body mass index ≥30 kg/m2 undergoing induction of labor at >37 weeks gestation. 
 
 
2. BACKGROUND 
2.1 Introduction 
It is estimated that nearly 40% of reproductive-aged women in the United States (U.S.) 
are obese,1,2 and rates of obesity are projected to further increase over the next 
decade.3 Maternal obesity, defined as body mass index (BMI) ≥30 kg/m2, is a major risk 
factor for adverse obstetric outcomes. It has been suggested that the dramatic rise in 
the prevalence of obesity is, at least in part, responsible for the increase in the cesarean 
delivery rate that has observed over the past 50 years.4 It is currently reported that 
nearly one in three women in the U.S. deliver by cesarean,5 and women with obesity 
are twice as likely to have a cesarean compared to normal weight women.6-9 Overall, 
abnormal labor progress is the most common indication for primary cesarean delivery in 
the U.S.,10,11 but rates of cesarean for this indication are disproportionately higher in 
obese women.11 Unfortunately, women with obesity are also more likely to experience 
complications following a cesarean delivery including wound infections12-14 and venous 
thromboembolism.15 Thus, there is a critical need to develop interventions that optimize 
labor management in women with higher BMIs in order to curb the rise in cesarean 
delivery rates in an obstetric population that is becoming increasingly obese.   
2.2 Obesity and Labor Outcomes 


Multiple studies in the U.S. have shown that there is a dose response relationship 
between increasing maternal BMI and risk of cesarean delivery.8,9,11 In a large 
multicenter U.S. study, Kominiarek et al. reported that there was a 5% increase in the 
risk of cesarean for each 1-kg/m2 increase in maternal BMI among both laboring 
nulliparous and multiparous women without a prior cesarean delivery.8 Among 
nulliparous women with cephalic term fetuses who underwent labor, rates of cesarean 
delivery were 11.1%, 17.7%, 25.1%, 33.0%, and 42.8% for women with delivery BMI 
<25.0 kg/m2, 25.0-29.0 kg/m2, 30.0-34.9 kg/m2, 35.0-39.9 kg/m2, and ≥40 kg/m2, 
respectively. Furthermore, the association between increasing maternal BMI and 
cesarean delivery was shown to be independent of age, race, diabetes status, cervical 
dilation at admission, and induction of labor.  
In general, labor progresses more slowly among women with obesity. In a cohort study 
of women who successfully achieved complete cervical dilation, Norman et al. found 
that the median duration of time for a women to progress from 4 cm dilation to 10 cm  
was significantly longer in obese compared to non-obese women (4.7 hours vs 4.1 
hours, p <0.01).16 Similarly, Kominiarek et al. reported that the time to progress from 
centimeter to centimeter in cervical dilation increases with rising maternal BMI in both 
nulliparous and multiparous women.17 Given this association between maternal BMI and 
impaired labor progress, it is not surprising that the most common indication of primary 
cesarean delivery in women with obesity is arrest of labor. In a large study that included 
66,502 nulliparous women, Kawakita et al. found that a significantly higher proportion of 
primary cesarean deliveries in obese women were performed for the indication of labor 
arrest compared to non-obese (47% vs 33%).11 Interestingly, the higher risk of cesarean 
in women with obesity seems to be confined to the first stage of labor during which the 
cervix dilates; once women reach complete dilation, rates of cesarean are similar 
among women with and without obesity.18  
While there is strong epidemiologic evidence for the association between maternal BMI 
and labor dysfunction, the biologic mechanisms underlying this association are largely 
unknown. One leading theory is that maternal obesity is leads impaired myometrial 
contractility.19 Differences in the pharmacokinetics of drugs commonly used for labor 
induction and augmentation in obese and non-obese women may also contribute to the 
association between maternal BMI and labor outcomes.20-22 With these potential 
biological factors in mind, and the significant individual and public health benefits that 
would be gained by reducing the chance of cesarean among obese individuals, 
research focused on the clinical relationship between the medications used to stimulate 
labor and obstetric outcomes among women with obesity is needed. 
2.3 Oxytocin Dosing in Labor 
2.3.1 High vs. Low Dosing Regimens 


Induction of labor, defined as the artificial initiation of labor before spontaneous labor 
onset, is performed in approximately 30% of all births.5 Intravenous synthetic oxytocin is 
the most commonly used agent for the induction and augmentation of labor since being 
introduced into the market in the 1950’s.23,24 A non-peptide hormone, oxytocin is 
released in large amounts during the labor process from the posterior pituitary. Despite 
its frequent use in the U.S., there remains little to no consensus regarding the optimal 
protocols for the dosing and duration of synthetic oxytocin in labor.23,25 
There have been a number of studies that have evaluated the dose of oxytocin for labor 
augmentation. In a systematic review and meta-analysis of 4 studies including 644 
women published in 2013, higher dose oxytocin regimens were associated with lower 
rates of cesarean delivery and shorter duration of labor compared to lower dose 
regimens.26 However, the results of a large single center trial comparing high-dose (6 
mu/min) compared to low-dose (2 mu/min) regimens for augmentation of labor that 
included over 1000 participants was recently published.27 The investigators found that 
while the higher oxytocin dosing regimen reduced the time from randomization to 
delivery and risk of chorioamnionitis, there were no differences in rates of cesarean 
delivery. This study, however, was within a general population of obese and non-obese 
individuals, and was specifically targeted toward those having augmentation, not 
induction. 
The question of oxytocin dosing for induction of labor – let alone among obese 
individuals – has been less well studied. In 2014, Budden et al. conducted a systematic 
review and meta-analysis to address this clinical question.28 Nine clinical trials involving 
2391 women were included in the review. They found no differences in rates of 
cesarean or time from induction to delivery among women randomized to high-dose 
compared to low-dose oxytocin infusion regimens, but reported higher-dose regimens 
were associated with an increase in the incidence of “hyperstimulation”.  However, the 
studies included in the review were heterogeneous, specifically with regards to the 
dosing regimen used and population studied. In fact, the only study in the review that 
was published in the past 20 years was not designed to compare high to low dose 
oxytocin regimens but rather pulsatile versus continuous oxytocin infusion strategies.29 
Additionally, all of the studies included in the systematic review were deemed to be at 
moderate-to-high risk of bias emphasizing that well-designed, high quality studies are 
still needed. 
2.3.2 Maternal Body Mass Index and Oxytocin Dosing 
Women with obesity are more likely to undergo induction of labor, but also more likely to 
experience failed induction of labor compared to non-obese women.30 Oxytocin is the 
most common drug used in induction of labor. Women with a higher BMI seem to be 
less responsive to oxytocin. In one retrospective study of women who reached the 


second stage of labor, only 2.6% of women with BMI <30 kg/m2 required maximum 
oxytocin doses >20 mu/min compared to 4.3% of women with BMI ≥30.0 kg/m2.31 A 
subsequent study of women who had a vaginal delivery confirmed that increasing 
maternal BMI was associated with higher maximum doses of oxytocin as well as 
increasing cumulative amounts of oxytocin.20 These data would suggest that women 
with obesity require higher doses of oxytocin, and are a group who would preferentially 
benefit from higher oxytocin dosing regimens. 
2.3.3 Oxytocin Safety 
The use of oxytocin in the United States is ubiquitous, with 78% of women receiving it 
during labor in one large multicenter study.32 Nevertheless, intravenous oxytocin is 
labeled as a “high alert” medication by the Institute of Safe Medication Practices.33 This 
risk category was assigned to oxytocin due to risks related to infusion including 
maternal risks of uterine tachysystole, water intoxication with prolonged use, and fetal 
risks including intrauterine heart rate changes and neonatal acidemia at birth. Yet, these 
outcomes are rare. In a recently published large randomized trial of high- versus low-
oxytocin regimens for labor augmentation, no differences in neonatal outcomes were 
reported.27 
2.4 Rationale for Randomized Trial 
There is a general consensus that the current cesarean delivery rate of 31% in the United 
States is higher than it ought to be.5,34 The increasing prevalence of obesity among 
pregnant women is thought to be an important contributing factor. As obesity rates are 
projected to further increase over the next decade, the development of evidenced-based 
intrapartum interventions to improve obstetric outcomes for women with obesity are 
needed. Observational data suggest that women with obesity may benefit from receiving 
higher doses of oxytocin to achieve a vaginal delivery. Thus, a rigorous trial investigating 
the optimal dosing of oxytocin in obese women is needed.  
 
3. STUDY DESIGN 
3.1 Primary Research Question 
This double blinded randomized controlled trial will address the primary research 
question: 
Does a high-dose oxytocin regimen reduce the chance of cesarean delivery compared 
to a low-dose oxytocin regimen among nulliparous women with obesity undergoing 
induction of labor at 37 weeks’ gestation or later? 
 


 
3.2 Design Summary 
This study is a pragmatic single center randomized, double blinded controlled trial. 
Nulliparous women with a pre-pregnancy body mass index (BMI) ≥30 kg/m2 undergoing 
induction of labor at ≥370 weeks’ gestation will be eligible for enrollment. Women will be 
randomly allocated to receive oxytocin using either a high-dose or low-dose regimen. 
Patients, providers, and research staff will be blinded to the dosing regimen. 
High-dose oxytocin regimen: Starting dose 6 mU/min and increased by 6 mU/min every 
30 minutes until adequate contractions achieved, at the discretion of the obstetric 
providers.  
Low-dose oxytocin regimen: Starting dose 2 mU/min and increased by 2 mU/min every 
30 minutes until adequate contractions achieved, at the discretion of the obstetric 
providers.  
Adequate contractions will be defined as >200 Montevideo units averaged over 30 
minutes in women with an intrauterine pressure catheter (IUPC), or contractions every 
2-3 minutes in women without an IUPC. 
3.3 Blinding 
Participants, research staff, and clinical care providers will be blinded to the dosing 
regimen. This will be achieved by using identical appearing study drug preparations with 
different concentrations of oxytocin. In the low-dose group, the oxytocin solution will be 
prepared using 30 units of oxytocin in 500 mL of normal saline (concentration 60 
mU/mL). The oxytocin concentration in the high-dose group will be prepared using 90 
units of oxytocin in 500 mL of normal saline (180 mU/mL). The study drug in both 
groups will be administrated at a rate of 2 mL/hour with an increase in rate of 2 mL/hour 
every 30 minutes.  
3.4 Eligibility Criteria 
3.4.1 Inclusion Criteria 
 
1. Nulliparity 
2. Maternal age >18 years 
3. Gestational age ≥37w0d 
4. Induction of labor, defined as initiation of labor with medication or intracervical 
Foley catheter in a patient without observed spontaneous cervical change and <6 


contractions per hour (average of one contraction every 10 minutes) at the time 
of initial presentation. Women with prelabor rupture of membranes (PROM) can 
be included if the other criteria are also met with regards to cervical dilation and 
contractions. 
5. Singleton gestation 
6. Cephalic presentation 
7. Indication for oxytocin use in the first stage of labor 
8. No contraindication to labor or vaginal delivery 
9. Pre-pregnancy BMI ≥30 kg/m2 based on patient report and confirmed by pre-
pregnancy or first trimester weight as recorded in the medical record 
10. Cervical dilation ≤4 cm at time of initiation of induction 
3.4.2 Exclusion Criteria 
 
1. Fetal demise 
 
2. Major fetal congenital malformation or known chromosomal abnormality 
 
3. Prior uterine surgery (e.g., cesarean, myomectomy) 
 
4. Non-reassuring fetal wellbeing as indication for induction 
 
6. Intraamniotic infection suspected or diagnosed prior to randomization 
 
7. Non-English 
 
8. Multifetal gestation 
 
9. Gestational age <37 weeks  
 
10. Spontaneous labor 
11. Cervical dilation > 4 cm at initiation of induction 
12. Initiation of oxytocin in the second stage of labor 
13. Use of oxytocin prior to randomization or planned use of oxytocin with foley 
catheter for cervical ripening 
14. Fetal malpresentation 


15. Estimated fetal weight >4500 g in a patient with diabetes, or estimated fetal 
weight >5000 g in a non-diabetic patient 
16. Abnormal placentation (e.g. previa, suspected placenta accreta spectrum) 
17. Physician/provider or patient refusal 
3.5 Informed Consent Criteria 
Written informed consent will be obtained prior to randomization into the study. The 
details of the study will also be reviewed with the patient by research personnel. 
Participants will be provided with a signed copy of the consent form.  
3.6 Randomization 
Patients will be approached for possible enrollment in the study when they are admitted 
to the labor and delivery unit for induction of labor. Women who chose to participate in 
the study will be randomized to the high- or low-dose oxytocin regimen prior to the 
initiation of oxytocin in the labor course. Women will be randomized in a 1:1 ratio to the 
high and low-dose oxytocin regimens.  
A block randomization method will be used to generate the randomization sequence 
because it provides a high probability of balance of treatment assignments. A computer-
generated randomization scheme using block sizes of four will be designed by the study 
statistician. The randomization sequence will be provided to the investigational 
pharmacy staff who will prepare the study drug for each participant.  
 
4. STUDY PROCEDURES 
4.1 Screening for Eligibility and Consent 
Women who are admitted for delivery to the Ohio State University Wexner Medical 
Center Labor & Delivery unit will be screened for potential enrollment. The inclusion/ 
exclusion criteria will be reviewed in the patient’s medical record and documented on 
the screening log.  
If the patient meets all eligibility criteria for enrollment, then she will be approached by 
research personnel to discuss the study in detail. Patients may be approached any time 
after admission to the Labor & Delivery unit, but prior to the initiation of oxytocin for 
labor induction. If the patient is interested in enrollment, the informed consent process 
will be conducted by trained research staff. The study consent and HIPAA authorization 
will be signed after all questions have been discussed and answered. The participant 
will be given a copy of the signed consent form.  


4.2 Randomization 
Randomization will occur when the obstetric provider decides to begin oxytocin for labor 
induction. At that time, the patient will be assigned the next sequential study 
identification number and central pharmacy will dispense the study drug (high- or low-
dose oxytocin concentration) depending on the randomization allocation sequence. The 
pharmacist will not be blinded to the allocation.  
4.3 Baseline Procedures 
In addition to information collected for eligibility, the following information will be 
obtained at randomization from the patient interview followed by review of the medical 
record: 
• Demographic information: age, race, insurance coverage, marital status 
• Medical history: pre-pregnancy weight, current weight, height, chronic disease 
history 
• Current pregnancy labor data: cervical dilation, cervical effacement and fetal 
station at time of admission and randomization, time and date of admission and 
randomization, other labor induction methods used (e.g.; misoprostol, cervidil, 
foley catheter), membrane status (ruptured or intact) at time of randomization 
• Obstetrical history including gravidity and parity 
 
4.4 Patient Management and Follow-up 
This is a pragmatic clinical trial. The study drug will be started at a rate of 2 mL/hour (6 
mU/min in high-dose group and 2 mU/min in low-dose group) with the intent to increase 
the rate by 2 mL/hour every 30 minutes until adequate contractions are achieved, 
defined as >200 Montevideo units averaged over 30 minutes in women with an 
intrauterine pressure catheter (IUPC),34 or contractions every 2-3 minutes in women 
without an IUPC. All changes in study drug administration will be at the discretion of the 
obstetric provider and nursing staff. Decrease in the rate of administration or 
discontinuation of the study drug in response to clinical findings should be performed in 
accordance with local standard of care. All other aspects of obstetric management will 
be at the discretion of the patient’s clinical care team. Cord gases will be collected on all 
participants enrolled in the study. 
Postpartum maternal, neonatal, and delivery outcomes will be collected. Postpartum 
data through hospital discharge will be collected from the medical record. Information 
about complications following hospital discharge through 6 weeks after delivery will be 
collected during a research follow-up telephone call performed 6-8 weeks following 
delivery. Relevant maternal and neonatal records related to hospital readmissions 


outside of the Ohio State University will be requested if indicated based on the follow-up 
research call.  
All participants will be asked to complete two surveys postpartum to assess their 
experience during labor, delivery, and postpartum. The first survey incorporates the 
Childbirth Perception Scale, which is a 12-item instrument developed to assess a 
patient’s perception of the labor and birthing experience as well as the first few days 
postpartum.35 In a recent systematic review of patient satisfaction instruments, the 
Childbirth Perception Scale was found to have high validity and reliability.36 Additionally, 
our survey incorporates an assessment of pain during labor (worse pain and overall 
pain) using a visual analog scale as described by Ludington et al.37 The second survey 
of Labor Agentry is designed to assess expectants and experiences of control in labor.38 
Research staff will meet with study participants after they have been transferred to the 
postpartum unit and before hospital discharge to complete the surveys.  
4.4.1 Emergency unblinding 
Rare clinical circumstances may arise in which unblinding is necessary. The only 
indication for breaking the randomization code is a life-threatening medical emergency, 
as in the case of a serious adverse event. Unmasking the study drug assignment is 
limited to patients in which it is medically necessary in order to know how to treat the 
patient for their serious adverse event in a way not foreseen in this trial. In this 
circumstance, the study pharmacist will provide the necessary information about the 
concentration of the study drug to the participant’s obstetric care team.   
4.5 Study Outcomes Measures and Ascertainment 
4.5.1 Primary Outcome 
The primary outcome is cesarean delivery. 
 
4.5.2 Secondary outcomes 
1. Indication for cesarean including arrest of dilation, arrest of descent, non-reassuring 
fetal heart rate, other 
2. Time from start of induction to delivery 
3. Duration of first stage of labor 
4. Duration of second stage of labor 
5. Occurrence of tachysystole, defined as more than 5 contractions in 10 minutes 
averaged over 30 minutes39 
6. Occurrence of tachysystole with category 2 or 3 fetal heart rate tracing 
7. Uterine rupture defined as a complete disruption of all uterine layers including serosa 
8. Clinical chorioamnionitis 


9. Postpartum maternal infectious morbidity: endomyometritis, puerperal sepsis, 
surgical site infection within 6 weeks following delivery 
10. Maternal death within 6 weeks of delivery 
11. Postpartum hemorrhage defined as >1000 mL of blood loss within 24 hours of 
delivery40 
12. Maternal blood transfusion defined as need for blood transfusion from 
randomization through hospital discharge 
13. Maternal ICU admission from randomization through discharge 
14. Composite neonatal morbidity outcomes: Apgar score <5 at 5 min, arterial cord pH 
<7.0 or base deficit >12 mmol/dL, perinatal death 
15. NICU admission 
16. Maternal length of stay 
17. Neonatal length of stay 
18. Perception of the labor, birth, and postpartum experience  
  
 
5. DATA SAFETY AND MONITORING 
5.1 Data Safety  
For this pilot study, patient safety will be monitored closely by the primary investigator 
and research team. The primary investigator will be responsible for monitoring study 
data for signs of adverse trends in maternal and neonatal outcomes throughout the 
duration of the pilot study. 
5.2 Definition of Adverse Events 
An adverse event (AE) will be defined as any untoward or unfavorable medical 
occurrence in a study participant, whether or not considered related to the subject’s 
participation in the research. All serious SAEs will be reported to the Ohio State 
University Office of Responsible Research Practices. Likelihood of relatedness of each 
AE to study intervention will be determined by the primary investigator upon review of 
the event. 
Maternal Severe Adverse Events: 
• Hyponatremia, defined as serum sodium level <135 mEq/L 
• Pulmonary edema 
• Maternal ICU admission during delivery hospitalization or up to 6 weeks 
postpartum 
• Hospitalization >168 hours (7 days) after delivery 
• Readmission to the hospital within 6 weeks after delivery 


• Hysterectomy or uterine artery embolization 
• Death 
Infant Severe Adverse Events: 
• Infant hospitalization >96 hours (4 days) after birth 
• Readmission to the hospital within 6 weeks after birth 
• NICU admission 
• Administration of whole body hypothermia 
• Death 
 
 
 
6. STATISTICAL CONSIDERATIONS 
 
6.1 Data Relevant to the Primary Outcome 
Using institutional data collected for a retrospective study evaluating the relationship 
between BMI and labor management, we estimated that the cesarean delivery rate 
among nulliparous obese women who labored was 31.6%. This is a similar rate to what 
has been reported in the literature.8 The cesarean delivery rate is even higher for those 
who undergo induction of labor, but will use this as a conservative baseline estimate. 
Current standard oxytocin dosing at the Ohio State University Wexner Medical Center 
uses the low-dose regimen.  
6.2  Sample Size  
This is a pilot study that will be used to inform the design of a future large randomized 
controlled trial. We plan to enroll 20 participants today. Ten participants will be 
randomized to the high-dose and 10 participants randomized to the low-dose oxytocin 
dosing regimen.  
 
6.3  Feasibility 
Based on internal institutional quality metric data, there were approximately 250 
nulliparous women with prepregnancy BMI ≥30 kg/m2 who underwent induction of labor 
at the Ohio State University Wexner Medical Center in 2020. If 40% of obese women 
undergoing induction meet other eligibility criteria and agree to participate in the study, 


then we would anticipate complete the pilot study with a total sample size of 20 women 
in 10 weeks. 
Information about the proportion of eligible women who agree to participant in the study 
will be used to determine the feasibility of a larger clinical trial. 
6.4 Analysis Plan 
All analyses will be performed based on the intent-to-treat principle. The primary 
outcome will be assessed by comparing the proportion of women delivered by cesarean 
in each of the treatment groups. Relative risks with 95% confidence intervals will be 
calculated. Similarly, secondary outcomes will be assessed using the chi-square and 
Fisher’s exact tests for categorical variables. Continuous variables will be assessed for 
normality and compared using a Student’s t-test or Mann Whitney U test as appropriate. 
 
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