Oxytocin Rest to Reduce Cesarean Delivery in Prolonged Labor: An Open-Label, Randomized Controlled Trial
Phase: NA
Conditions: Prolonged Labor, Failed Induction, Labor Dystocia
Sponsor: Christiana Care Health Services

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TITLE: Oxytocin Rest to Reduce Cesarean Delivery in Prolonged Labor: An Open-Label Randomized Controlled 
1 
Trial (the “ORCA” trial) 
2 
 
3 
PRINCIPAL INVESTIGATOR: Teresa C. Logue, MD MPH 
4 
 
5 
SUB-INVESTIGATORS:  
6 
Matthew K. Hoffman, MD MPH; Lindsay Gugerty, DO; Sneha Paranandi, MD; Anne Reed-Weston, MD; Lauren 
7 
Roby, MD; Amanda Jones MD; Cassidy O’Sullivan, MD; Alexandra Mulliken, MD; Bethany Dus, MD; Nakia 
8 
Wighton, MD; R. Zach Fender, MD; Samantha Barta, DO; Savanah Richter, MD; Anthony Sciscione, DO 
9 
 
10 
BACKGROUND: 
11 
Nearly 1 in 3 births in the United States occur by cesarean.1 This is a rate substantially higher than other 
12 
high-income countries.2 Because cesarean is associated with greater risk for maternal morbidity and mortality, there 
13 
has been increasing attention to reducing medically unnecessary cesarean deliveries in the United States –
14 
particularly in nulliparous, term, singleton, vertex pregnancies.3 Labor dystocia is one of the most common 
15 
indications for cesarean delivery among those at low risk for cesarean and has been a focus of national efforts to 
16 
reduce the cesarean rate.3-5 
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The standard of care for prolonged labor is active management with continuous oxytocin infusion and 
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amniotomy, with the goal of improving uterine contraction efficacy.6 However, a small subset of women will 
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develop protracted labor that persists even after these interventions. About half of these patients will ultimately 
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deliver by cesarean.3,7,8 Few interventions have been proposed to improve labor progress and prevent cesarean in 
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this group. Recent studies have shown no evidence of benefit to propranolol as an adjunctive agent for prolonged 
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labor.7,9  
23 
Oxytocin “rest” or washout has been described in the literature as an alternative strategy to resolve 
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protracted labor in patients who have received prolonged oxytocin stimulation. This strategy involves discontinuing 
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oxytocin then restarting infusion after a period of time – typically 30 to 60 minutes, though no ideal time has been 
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established – under the theory that this will re-sensitize the oxytocin receptor and improve myometrial 
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contractility.10,11 There is limited in vitro evidence that prolonged exposure to synthetic oxytocin can result in down-
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regulation or desensitization of the oxytocin receptor12 but the clinical utility of oxytocin washout has not been 
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demonstrated. One single-institution retrospective cohort study did find an association between oxytocin rest of >8 
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hours and decreased risk for cesarean,10 though this interval may not be practical following amniotomy due to 
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increased infection risk associated with prolonged rupture of membranes.13 
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There is no randomized or prospective data to support oxytocin rest. A PubMed search using several terms 
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(“oxytocin rest,” “oxytocin break,” “oxytocin washout,” “oxytocin” AND “discontinue,” “oxytocin” AND “stop”) 
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indicates that no randomized controlled trial has previously been published on this topic. 
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The purpose of this study is to assess whether oxytocin rest of 60 minutes in patients with prolonged labor 
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reduces risk for cesarean delivery. 
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STUDY OBJECTIVES: 
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Primary Outcome: 
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The primary outcome is cesarean delivery. 
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42 
Secondary Outcomes: 
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• 
Measures of length of labor: 
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o 
Time to delivery (hours), defined as time from enrollment to delivery time, regardless of mode of 
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delivery 
46 
o 
Time to vaginal delivery (hours), defined as time from enrollment to delivery time, for patients 
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with vaginal delivery (cesarean delivery censored) 
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o 
Time to active labor (hours), defined as time from enrollment to first exam with cervical dilation 
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≥6cm (cesarean delivery at <6cm dilation censored) 
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o 
Duration of active labor (hours), defined as time from first exam with cervical dilation ≥6cm to 
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delivery time (cesarean delivery censored) 
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• 
Composite maternal adverse outcomes (CAMO): 
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o 
Operative vaginal delivery (OVD) 
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o 
Obstetric anal sphincter injury (OASIS) 
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o 
Postpartum wound complications 
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§ 
Wound cellulitis requiring antibiotics 
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§ 
Wound reopened for fluid collection or infection 
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§ 
Wound dehiscence during delivery hospitalization 
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o 
Incidence of intraamniotic infection (IAI), determined via chart abstraction as:  
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§ 
(1) maternal temperature ≥ 38.0°C in the intrapartum period AND 
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§ 
(2) initiation of antibiotics in the intrapartum period 
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o 
Incidence of postpartum endometritis, determined via chart abstraction as: 
63 
§ 
(1) maternal temperature ≥ 38.0°C in the postpartum period AND 
64 
§ 
(2) initiation of antibiotics in the postpartum period 
65 
o 
Incidence of postpartum hemorrhage, determined via chart abstraction as: 
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§ 
Quantitative blood loss ≥ 1000 mL (preferred) OR 
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§ 
Estimated blood loss ≥ 1000 mL 
68 
o 
Deep vein thrombosis (DVT)/pulmonary embolism (PE) 
69 
o 
ICU admission 
70 
o 
Maternal death 
71 
• 
Composite neonatal adverse outcomes (CANO): 
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o 
Neonatal intensive care unit (NICU) admission ≥48 hours 
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o 
APGAR score at 5 minutes <7 
74 
o 
Cord pH <7.00 
75 
o 
Severe respiratory distress (defined as intubation and mechanical ventilation for a minimum of 12 
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hours) 
77 
o 
Culture proven-presumed neonatal sepsis 
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o 
Hypoxic ischemic encephalopathy 
79 
o 
Stillbirth or neonatal death 
80 
• 
Measures of patient autonomy and sense of control: 
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o 
Labor Agentry Scale (LAS) score. The LAS is a validated tool that captures patient perception of 
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control over the labor process.14,15 It will be administered to all enrolled patients between 6 and 96 
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hours after delivery. 
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Maternal Demographic and Clinical Characteristics: 
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• 
Age 
87 
• 
Race/ethnicity 
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• 
Gestational age 
89 
• 
Parity 
90 
• 
Maternal medical comorbidities 
91 
• 
BMI at delivery 
92 
• 
Cigarette use during pregnancy 
93 
• 
Substance use during pregnancy 
94 
• 
Insurance status 
95 
  
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Additional Clinical Measures (including Process Measures): 
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• 
Induction of labor versus spontaneous labor 
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• 
Agents used for induction of labor 
99 
• 
Duration of continuous oxytocin infusion 
100 
• 
Maximum oxytocin dose achieved during induction or augmentation 
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• 
Use of intrapartum interventions after randomization 
102 
o 
Interventions associated with management of nonreassuring fetal heart tracing: 
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§ 
Amnioinfusion 
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§ 
Fetal scalp electrode/intrauterine pressure catheter 
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§ 
Terbutaline 
106 
§ 
Fetal bradycardia alert 
107 
o 
Interventions associated with management of abnormal labor progress in the active stage: 
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§ 
Intrauterine pressure catheter 
109 
• 
Indication for cesarean delivery (if performed), determined via chart abstraction and grouped into the 
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following standard categories: 
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o 
Labor dystocia (failed induction, arrest of dilation, arrest of descent) 
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o 
Non-reassuring fetal status 
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o 
Cephalopelvic disproportion 
114 
o 
Fetal malpresentation 
115 
o 
Other 
116 
• 
Intrapartum analgesia (epidural) use before randomization 
117 
• 
Estimated blood loss (EBL) at delivery 
118 
• 
Quantitative blood loss (QBL) at delivery 
119 
• 
Use of interventions associated with management of postpartum hemorrhage: 
120 
o 
Uterotonics 
121 
§ 
Methergine 
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§ 
Hemabate 
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§ 
Cytotec 
124 
o 
Tranexamic acid 
125 
o 
JADA device 
126 
o 
Other (Bakri balloon, uterine embolization, B-Lynch sutures, etc.) 
127 
• 
Receipt of blood transfusion during delivery hospitalization 
128 
• 
Receipt of antibiotic medications commonly used for IAI or postpartum endometritis, either intrapartum or 
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postpartum: 
130 
o 
Tobramycin/gentamycin, piperacillin-tazobactam, ampicillin/gentamicin, cefazolin/gentamicin, 
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clindamycin, clindamycin/gentamicin, vancomycin/gentamicin, ampicillin-sulbactam, cefotetan, 
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cefoxitin, ertapenem, etc. 
133 
• 
Maternal length of stay (days), defined as length of time from admission to discharge postpartum  
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Additional Demographic Characteristics: 
136 
• 
CDC ATSDR Social Vulnerability Index score (if available) 
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138 
 
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CHARACTERISTICS OF STUDY POPULATION: 
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Target Population: 
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18 to 55-year-old women with singleton pregnancies at ≥36 weeks gestation. 
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Inclusion Criteria: 
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• 
≥18 years of age 
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• 
Singleton gestation in vertex presentation 
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• 
≥36 weeks gestation as determined by routine obstetrical guidelines 
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• 
Prolonged latent labor, defined as cervical dilation <6cm after ≥8 hours since rupture of membranes and on 
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continuous oxytocin7 
149 
o 
We will include both patients undergoing induction of labor and patients undergoing augmentation 
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of spontaneous labor 
151 
• 
No contraindication to continuous oxytocin infusion at time of randomization 
152 
• 
Cesarean section not anticipated at the time of randomization 
153 
• 
≤18 hours between rupture of membranes and randomization 
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Exclusion Criteria: 
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• 
<36 weeks gestation 
157 
• 
Multifetal gestation 
158 
• 
Fetal demise 
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• 
Any contraindication to vaginal delivery 
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• 
Maternal eclampsia 
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• 
Any contraindication to continuous oxytocin infusion at time of randomization 
162 
o 
We will exclude patients with nonreassuring fetal heart rate tracing for whom discontinuation of 
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oxytocin infusion is indicated for fetal resuscitation at time of randomization 
164 
• 
Cesarean section anticipated by the clinical team 
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o 
We will exclude patients for whom cesarean section is anticipated for nonreassuring fetal heart 
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rate tracing or any other indication (excepting labor dystocia) at time of randomization 
167 
• 
Prolonged rupture of membranes, defined as >18 hours between rupture of membranes and randomization 
168 
• 
Intraamniotic infection (IAI), defined as:  
169 
o 
(1) maternal temperature ≥ 38.0°C in the intrapartum period AND 
170 
o 
(2) initiation of antibiotics in the intrapartum period 
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RESEARCH STUDY DESIGN: 
173 
Design: 
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This study is a prospective, open-label, randomized-controlled trial. We are tentatively planning for the trial to take 
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place at three institutions. Our primary site will be ChristianaCare Health System. 
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Project Duration: 
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Two years 
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Intervention: 
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Our intervention will be discontinuing continuous oxytocin for 60-minute period and then restarting infusion at 2 
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mU/min. The best estimate for the half-life of intravenous oxytocin is 3-6 minutes.12 If oxytocin infusion is started at 
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2 mU/min and increased by 2 mU/min every 30 minutes (contraction pattern allowing), we anticipate that many 
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subjects will reach a relatively high dose (≥20 mU/min) by the time that they become eligible to participate in the 
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study. We have selected 60 minutes for the duration of the rest period as a conservative estimate for the interval at 
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which this concentration of the drug will be expected to have been cleared. 
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Power Calculations: 
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The target sample size is 350. We assume a baseline cesarean rate of 50% in patients who met criteria for prolonged 
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labor, based on evidence reported in the literature.7,10 We consider a 30% reduction in risk for cesarean delivery to 
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be clinically meaningful. Assuming 80% power, equal group sizes, a two-sided p-value with alpha 0.05, and a 3% 
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crossover rate, we estimate that we will require a total sample size of 350 (175 patients per group).  
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Randomization: 
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We will assign subjects to interventions with using blocked randomization via a computer-generated randomization 
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scheme using a 1:1 allocation ratio. Because our trial will be unblinded, large block sizes will be used, and block 
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sizes will be randomly varied to reduce the risk that the assignment schedule may be deciphered by recruiting 
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clinicians. 
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Statistical Considerations: 
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Primary statistical analyses will be performed using an intention-to-treat principle. Baseline demographic and 
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clinical characteristics will be reported for the study groups. For bivariate analyses, categorical variables will be 
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compared using chi-squared or Fisher exact tests and continuous variables will be compared using a Wilcoxon 
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signed-rank test. For estimates of the effect of the intervention on length of labor and time to delivery, Kaplan-Meier 
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estimates will be performed, with censoring of cesarean deliveries. A p value of < 0.05 will be considered 
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statistically significant. 
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Interim Analysis: 
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An independent statistician will perform an interim analysis of the first 175 patients enrolled in the study. The 
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DSMB will use a group sequential method with the O’Brien-Fleming boundary as a stopping rule for benefit, and 
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conditional power analysis as a stopping rule for futility. A full description of the interim analysis plan, including 
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detailed description of these stopping rules, is included in Appendix A. 
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RESEARCH STUDY PROCEDURE: 
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All patients will be admitted to the labor and delivery unit and receive usual care by the clinical team, including 
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confirmation of pregnancy dating and sonography to verify fetal presentation. If indicated by the clinical team, 
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oxytocin infusion will be started at 2 mU/min for labor induction or augmentation. Infusion will be increased by 2 
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mU/min every 30 minutes to a maximum dose of 30 mU/min or until adequate contractions are noted, per labor and 
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delivery protocol. In all patients receiving continuous oxytocin infusion, continuous fetal heart rate and uterine 
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activity will be monitored per existing protocols. 
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Potential subjects will be identified through the electronic patient board on the CCHS Labor & Delivery Unit and 
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screened for study eligibility by a member of the study team. At or before the time that they meet eligibility criteria, 
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potential subjects will be approached on the labor and delivery unit by trained study personnel. They will be 
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consented to participation. Written informed consent will be obtained. There will be no monetary incentives for 
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study participation.  
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Subjects then will be randomized to either 60-minute oxytocin rest or routine care. Subjects in the intervention 
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group will undergo 60-minute oxytocin rest. After 60 minutes, oxytocin will be restarted at 2 mU/min and 
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subsequently increased by 2 mU/min every 30 minutes to a maximum dose of 30 mU/min or until adequate 
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contractions are seen, per labor and delivery protocol. Subjects in the control group will receive continuous oxytocin 
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infusion, increased by 2 mU/min every 30 minutes to a maximum dose of 30 mU/min or until adequate contractions 
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are noted, per existing labor and delivery protocol.  
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Otherwise, subjects will be managed by the clinical team under existing labor and delivery protocols. If subjects in 
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either group develop persistent abnormal fetal heart rate, standard maneuvers including change in maternal position, 
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bolus fluids, amnioinfusion, subcutaneous terbutaline, and discontinuing or decreasing oxytocin infusion will be 
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performed as directed by the clinical team. If these measures are unsuccessful, urgent or emergent cesarean delivery 
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will be performed at the discretion of the clinical team. If patients in either group develop episodes of uterine 
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tachysystole, defined as ≥5 contractions in 10 minutes averaged over 30 minutes, the oxytocin rate will be halved 
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per labor and delivery protocol. If patients in either group develop an intrauterine infection, they will be treated with 
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standard antibiotics. 
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All patients who are assessed for eligibility and all patients who are approached about study participation will be 
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counted on a separate log. For patients who do not ultimately meet eligibility criteria and for patients who are 
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approached but decline participation, minimal information on eligibility for the study will be included in this log. No 
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outcome data will be collected on these patients. 
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249 
 
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ANTICIPATED RISKS AND BENEFITS: 
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 Despite lack of evidence of clinical benefit, oxytocin rest is widely used as a strategy to resolve prolonged 
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labor; and the intervention is broadly considered to be safe. The primary risk of oxytocin rest is further prolonging 
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time to delivery following rupture of membranes. Theoretically, in patients requiring high doses of oxytocin to reach 
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contractions with the strength and frequency to cause cervical change, the intervention may lengthen the time 
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required for induction or augmentation. Prolonged labor following membrane rupture has been associated with 
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increased risk for intraamniotic infection,13 though current guidelines allow for up to 24 hours before infection risk 
257 
is considered clinically significant.3 We will exclude patients with >18 hours since membrane rupture prior to study 
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participation. 
259 
 
The primary potential benefit of oxytocin rest is to reduce risk for cesarean delivery by improving uterine 
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contraction efficacy. Prolonged oxytocin exposure has also been hypothesized to increase risk for postpartum 
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hemorrhage due to atony from diminished myometrial contractility;11 thus a secondary potential benefit of the 
262 
intervention is to decrease hemorrhage risk. Finally, with the permission of the clinical team, the intervention will 
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provide laboring patients with an opportunity to briefly break from continuous fetal monitoring to rest, shower, 
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walk, or eat a light snack – all of which may also have therapeutic benefit and improve patient sense of control 
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during childbirth.10  
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267 
Safety: 
268 
A Data Safety Monitoring Board (DSMB) will be created to ensure patient safety. Members of the DSMB will 
269 
include: 
270 
- 
Melanie Chichester, BSN, RNC-OB, CPLC, RNC-IAP, FAWHONN 
271 
- 
Casey Bedder, DO 
272 
- 
Ursula Guillen, MD 
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An independent statistician will perform an interim analysis using the methodology described above, which will 
274 
then be submitted to the DSMB. The DSMB will review this interim analysis with the potential to halt study 
275 
enrollment for early benefit or futility if the above prespecified stopping criteria are met. The DSMB will also have 
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the ability to make recommendations to the investigators to modify the conduct of the study if any potential harms to 
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participants are identified based on their review of maternal and neonatal outcomes. A full description of the role 
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and responsibilities of the DSMB is included in Appendix A. 
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280 
Training: 
281 
Prior to the start of enrollment, all CCHS OB/GYN residents included as sub-investigators will receive training in 
282 
the ethical conduct of human subjects’ research through the Collaborative Institutional Training Initiative (CITI) 
283 
program. These residents will then be trained the study protocol, recruitment and consent process, and 
284 
randomization procedures and in use of HIPAA and CITI-compliant methods for entering patient enrollment and 
285 
consent information. Nursing education will be provided regarding study procedures.  
286 
 
287 
Confidentiality and Privacy: 
288 
Patient enrollment and consent information will be collected using paper forms, which will remain in a locked 
289 
cabinet on the labor and delivery floor. Patient demographic, clinical and outcome information will then be entered 
290 
and stored into REDCAP – a secure, HIPAA-compliant application for data capture in research. 
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References 
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Osterman MJK HB, Mar@n JA, et al Births: Final Data for 2021. Natl Vital Stat Rep. 
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in caesarean sec@ons. Lancet. 2018;392(10155):1341-1348. 
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American College of O, Gynecologists, Society for Maternal-Fetal M, et al. Safe 
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Barber EL, Lundsberg LS, Belanger K, Pe[ker CM, Funai EF, Illuzzi JL. Indica@ons 
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McCoy JA, Walheim L, McCabe MG, Levine LD. Eﬃcacy of Propranolol to Reduce 
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McAdow M, Xu X, Lipkind H, Reddy UM, Illuzzi JL. Associa@on of Oxytocin Rest During 
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