Clinical trial NCT02121184
Conditions: Pregnancy Labor Pain
Keywords: Oxytocin Labor, Obstetric Non-reassuring fetal heart rate Epidural
Sponsor: Northwestern University
Start date: 2014-04-01; Completion date: 2021-09-21
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Fetal heart rate patterns are an important parameter in the diagnosis of non-reassuring fetal status. Combined-spinal epidural analgesia is a method of initiating labor analgesia used by approximately 90% of the parturients at Prentice Women's Hospital. Optimizing the variables which could affect fetal heart rate patterns at the time of initiation of analgesia, such as fluid administration and oxytocin management, could help us provide better care for our patients and their fetuses.

Hypotheses: Patients who receive a 1000 mL fluid bolus and lower rates of oxytocin administration will have fewer non-reassuring fetal heart rate (FHR) changes.

Detailed description:
Informed, written consent will be obtained. At the time of request for labor analgesia, group assignment will be determined by opening an opaque envelope. Patients will be randomized to one of four groups.

All subjects will receive a maintenance infusion of 125 mL Lactated Ringers (LR) solution throughout the study. For patients in Groups A or B, an intravenous bolus of 1000 mL LR will be initiated when the patient is positioned for epidural placement. The bolus will be administered through a free-flowing wide open intravenous catheter until complete.

Patients in Groups C and D will not receive any additional fluid bolus and will only receive the maintenance infusion of 125 mL LR during the study period. Blinding will be maintained by the Labor and Delivery nurse by covering up the LR bolus fluid bag.

If the patient is randomized to groups B or D, the dose of oxytocin currently being administered will be halved and not increased for the duration of the study period (60 minutes after the initiation of CSE).

Arms: arm 1: Lactated Ringers bolus of 1000 mL will be initiated when the patient is positioned for epidural placement. Oxytocin management will continue as per the routine oxytocin protocol arm 2: Lactated Ringers bolus of 1000 mL will be initiated when the patient is positioned for epidural placement. A half-dose oxytocin will be initiated and not increased until 60 minutes after.
Interventions: intervention 1: Routine oxytocin intervention 2: Half-dose oxytocin
Intervention descriptions: intervention 1: per regular oxytocin protocols intervention 2: The dose of oxytocin currently being administered will be halved and not increased until after 60 minutes initiation of labor analgesia

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 10
 P. Toledo, M.D.
 V  1.5 04/30/2019
Research Protocol Form
Northwestern University Feinberg School of Medicine
Department of Anesthesiology Research Committee
Title:  A Randomized Controlled Trial Evaluating the Effect of the Oxytocin Infusion Rate 
on Fetal Heart Rate Changes and Maternal Fetal Outcomes during the Initiation of 
Combined Spinal-Epidural Labor Analgesia
Principal Investigator:  Paloma Toledo, M.D. 
Affiliation: Department of Anesthesiology, Department of Obstetrics and Gynecology, Section 
of Maternal Fetal Medicine; Northwestern University Feinberg School of Medicine
 
Institution: Northwestern Memorial Hospital
1.0 Research Aims: 
.1 Research Questions(s):                                                                                                          
11. Is there an association between the rate of oxytocin administration and non-
reassuring FHR changes after the initiation of combined spinal- epidural (CSE) 
analgesia?  
.2 Hypotheses:   Patients who receive a lower rate of oxytocin administration will have 
fewer non-reassuring FHR changes.  
2.0 Research significance:
Background:
Combined spinal-epidural (CSE) analgesia is a well-accepted technique for labor 
analgesia. The incidence of fetal heart rate changes after the initiation of neuraxial 
analgesia has been reported between 3-23% (1,2)  and it is controversial whether the risk 
is increased with a CSE technique compared to an epidural analgesia technique (3). This 
wide range in reported risk may be due to fluid and oxytocin management prior to and 
during the initiation of neuraxial analgesia. 
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.P Toledo, M.D.
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There are many factors that contribute to alterations in the fetal heart rate 
including stage of labor, fetal head compression, cord compression, and uteroplacental 
insufficiency. Oxytocin is used in labor and delivery to increase the frequency of 
contractions and augment uterine contractile strength, thereby establishing a regular 
pattern of labor. However, the administration of exogenous oxytocin in the presence of an 
uncoordinated labor pattern confers a risk for increase in uterine contraction frequency, 
resulting in inadequate relaxation periods. This leads to an increase in the basal tone of 
the uterus, which may lead to a tetanic contraction with risk decreased uteroplacental 
blood flow and fetal hypoxemia (3,4).  Since the introduction of oxytocin for labor 
induction in 1948, there have been multiple protocols for the administration of oxytocin, 
both for labor induction, as well as for augmentation of labor. Many institutions use an 
active management of labor protocol (AMOL) to facilitate labor and delivery through 
oxytocin management. Use of the AMOL protocol decreases the duration of labor and the 
Cesarean delivery rate for dystocia (5).  The evidence is divided as to the effect of high- 
versus low-dose oxytocin administration on fetal heart rate abnormalities (6-10). Merrill 
et al. randomized patients to low- versus high-dose oxytocin for augmentation or 
induction of labor (9).  Oxytocin was decreased or discontinued more commonly in the 
high-dose group, both for uterine hyperstimulation and FHR abnormalities. In contrast, a 
study comparing high-dose oxytocin management with standard care found that there 
were no differences in fetal outcomes or the incidence of fetal distress between groups 
(10). One of the limitations of the previous studies is that the labor analgesia was not 
standardized; and consisted of either traditional epidural (high dose) analgesia or 
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.P Toledo, M.D.
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intravenous opioids. Labor analgesia itself has been implicated as a cause of non-
reassuring fetal heart rate tracings.  The combination of low-dose combined spinal 
epidural analgesia and the high-/low-dose oxytocin have not been evaluated.
One of the proposed mechanisms for non-reassuring fetal heart tracings after 
initiation of analgesia is that the pain relief from neuraxial analgesia causes a decrease in 
catecholamine release by the sympathetic nervous system (5). The subsequent decrease in 
the circulating epinephrine concentration contributes to an increase in uterine tone, as 
epinephrine is a potent tocolytic agent. The increased tone, in turn, leads to a decrease in 
placental blood flow, and eventually fetal bradycardia. 
The optimal oxytocin management in the peri-analgesia initiation period in terms 
of effects on uterine activity, uteroplacental perfusion, and fetal oxygenation, is not 
known. Anecdotally, some institutions arbitrarily decrease (or do not increase) the 
oxytocin infusion rate during initiation of analgesia. We hypothesize that decreasing the 
oxytocin infusion rate immediately before the initiation of CSE analgesia will cause 
fewer adverse fetal heart rate changes in the first 60 minutes following initiation of labor 
analgesia compared with maintaining the infusion rate. 
3.0 Literature:  
1.
Hofmeyr GJ, Cyna AM, Middleton P. Prophylactic intravenous preloading for regional analgesia in labour. 
The Cochrane Database of Systematic Reviews. 2007.
2.
Mardirosoff C, Dumont L, Boulvain M, Tramer MR. Fetal bradycardia due to intrathecal opioids for labour 
analgesia: a systematic review. BJOG 2002;109: 274-281.
3.
Abrão KC, Francisco RP, Miyadahira S, Cicarelli DD, Zugaib M. Elevation of uterine basal tone and fetal 
heart rate abnormalities after labor analgesia: a randomized controlled trial. Obstet Gynecol. 2009; 113:41-
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.P Toledo, M.D.
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7. PMID: 19104358
4. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl for analgesia 
during labor: a cause of fetal bradycardia? Anesthesiology 1994; 81: 1083.
5. Lopez-Zeno JA, Peaceman AM, Adashek JA, Socol ML. A controlled trial of a program for the active 
management of labor. N Eng J Med 1992;326:450.
6. Lindmark G, Nilsso B. A comparative study of uterine activity in labour induced with prostaglandin F2 
or oxytocin and in spontaneous labor. Acta Obstet Gynecol Scand 1976; 55: 453-60.
7. Satin AJ, Leveno KJ, Sherman ML, Brewster DS, Cunningham FG. High versus low-dose oxytocin for 
labor stimulation. Obstet Gynecol 1992; 80: 111-116.
8. Hourvitz A, Alcalay M, Korach J, Lusky A, Barkai G, Seidman DS. A prospective study of high-versus 
low-dose oxytocin for induction of labor. Acta Obstet Gynecol Scand 1996; 75: 636-641.
9. Merrill DC., Zlatnik FJ. Randomized double masked comparison of oxytocin dosage in induction and 
augmentation of labor. Obstet Gynecol; 1999: 455-463.
10.Sadler LC, Davison T, McCowan LM. A randomized controlled trial and meta-analysis of active 
management of labour. BJOG 2000; 107: 909-15.
11.Kinsella SM, Pirlet M., Mills MS, Tuckey JP, Thomas TA. Randomized study of intravenous fluid preload 
before epidural analgesia during labour. Br J Anesth. 2000; 85: 311-3.
.1Significance:   Fetal heart rate patterns are an important parameter in the diagnosis of 
non-reassuring fetal status. Combined-spinal epidural analgesia is a method of 
initiating labor analgesia used by approximately 90% of the parturients at Prentice 
Women’s Hospital. Optimizing the variables which could affect fetal heart rate 
patterns at the time of initiation of analgesia, such as oxytocin management, could 
help us provide better care for our patients and their fetuses.
4.0Investigational Plan
.1Study design:  Double blinded randomized, controlled study.  
.2Methods:
.2.1Size of study groups The primary endpoint is the incidence of non-reassuring 
IRB #: STU00074673 Approved by NU IRB for use on or after 3/16/2020 through 3/15/2021.
fetal heart rate tracings after the placement of CSE. Group sample sizes of 162 in 
each of two groups 80% power to detect an effect size (W) of 0.1560 using a 1 


 
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degree  of freedom Chi-Square Test with a significance level (alpha) of 0.05000.  
The incidence of fetal heart rate changes was estimated based on data from 
Kinsella, et al (11). The proportion of subjects with adverse fetal heart rate 
changes in the low-oxytocin and fluid bolus treatment group is estimated to be 
8%, Therefore 350 patients will be enrolled to account for patient drop-out or 
ineligibility.
.2.2   Subject entry, exclusion and dropout criteria: Healthy nulliparous or 
multiparous women with a term ( 37> week gestation), singleton pregnancy in 
spontaneous labor or with spontaneous rupture of membranes, who request 
neuraxial analgesia, and who receive oxytocin augmentation per institutional 
protocols, will be eligible to participate in the study. Maternal exclusion criteria 
will include the presence of any systemic disease (e.g., diabetes mellitus, 
hypertension, preeclampsia); use of chronic analgesic medications; prior 
administration of systemic opioid labor analgesia; non-vertex presentation; 
scheduled induction of labor; or any contraindication to neuraxial analgesia.   
.2.3   Protocol specific methods:  Eligible women will be asked to participate shortly 
after admission to the Labor & Delivery Unit at Prentice Women’s Hospital 
during the routine pre-anesthetic interview.  Informed, written consent will be 
obtained.  Randomization based on a computer generated random number table; 
group assignments will be concealed in sealed, opaque envelopes.  At the time of 
request for labor analgesia, group assignment will be determined by opening an 
opaque envelope. Patients will be randomized to one of two groups:
Group 
Assignment
Oxytocin Regimen
A
Routine oxytocin
B
Half-dose oxytocin
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Fluid Management:
For patients in Groups A or B, an intravenous bolus of 500 mL LR will be 
initiated when the patient is positioned for CSE placement by the L & D nurse. 
The bolus will be administered through a free-flowing wide open intravenous 
catheter until complete. 
Oxytocin Management:
The Prentice Women’s Hospital oxytocin augmentation protocols will be used. At 
the time of request for analgesia, if the patient is in group A the oxytocin 
management will continue as per the normal oxytocin protocol. 
If the patient is randomized to groups B the dose of oxytocin currently being 
administered will be halved and not increased for the duration of the study period 
(60 minutes after the initiation of CSE).  Care providers other than the Labor & 
Delivery nurse managing the fluid and oxytocin infusions, will be blinded to 
group assignment.
Analgesia Management:
All subjects will receive a maintenance infusion of 125 mL lactated Ringers (LR) 
solution throughout the study period as per Labor and Delivery protocol. Per 
institutional protocol, all patients will receive a 500 mL bolus of LR solution at 
the start of the neuraxial procedure (“wide-open rate”) via the mainline IV. Labor 
analgesia will be initiated in the sitting position at the L3-4 or L2-3 interspace 
with a routine combined spinal-epidural (CSE) technique.  The epidural space will 
be located with the loss of resistance technique and a 27-g x 5-in pencil point 
spinal needle will be passed through the epidural needle to the subarachnoid 
space.  The intrathecal injection will consist of bupivicaine 2.5 mg and fentanyl 
15 g.  A 20 gauge epidural catheter will be threaded and secured 4-5 cm in the 
epidural space. A test dose of 3 mL lidocaine 1.5% with epinephrine 1:200,000 
will be administered through the epidural catheter.  The epidural catheter will be 
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secured and the patient will be positioned in a lateral recumbent position. Patient-
controlled epidural analgesia (PCEA) infusion of bupivicaine 0.0625% with 
fentanyl 1.95 g/mL will be started at a rate of  8  mL/h with bolus dose = 8  mL, 
lock-out interval =  10 min and maximum volume = 32 mL/h.
Fetal heart rate monitoring:
Fetal heart rate monitoring and frequency of uterine contractions will be recorded 
by external tocodynamometry. 
Treatment of hypotension: 
Any decrease of 10% or greater from baseline in maternal systolic blood pressure 
after placement of the CSE will be treated by the IV administration of ephedrine 
or phenylephrine as guided by maternal heart rate, as per standard practice. 
Treatment of non-reassuring fetal heart rate changes: 
If there are prolonged fetal heart rate decelerations, recurrent late decelerations, 
severe variable decelerations, or tachysystole, the Prentice Women’s Hospital 
protocol for oxytocin management and intrauterine resuscitation will be followed. 
Study completion: 
The study is complete after 60 min after the intrathecal injection.  After this time, 
obstetric and anesthesia management, including fluid and oxytocin management, 
will not be dictated by study protocol. 
Fetal heart rate tracing assessment: 
Fetal heart rate tracings will be examined for 30 minutes before and 60 minutes 
after the initiation of analgesia by a perinatologist blinded to study group off-line 
after delivery.  NICHD guidelines (13) will be used to assess FHR patterns. Non-
reassuring FHR patterns will be defined as any one or more of the following: 
minimal or absent variability, late decelerations, and persistent deceleration (see 
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Appendix).
.2.4   Risks/Benefits:  All of the techniques and medications used in this study are 
routinely used for CSE analgesia during labor and for management of labor.  The 
risks of the CSE procedure itself are unchanged by participating in this study.  
These risks include: epidural analgesia may not be effective, the epidural 
procedure may need to be repeated, pruritus, nausea, vomiting, or hypotension.  
Less common risks include maternal postdural puncture headache.  Rare 
complications include maternal or fetal respiratory depression, total spinal 
anesthesia, a toxic reaction to the anesthetic agents, and bleeding or infection in 
the epidural or spinal space that may lead to nerve damage. The risk of oxytocin 
administration includes nausea, vomiting, confusion, allergic reaction, uterine 
hyper stimulation, fetal bradycardia, or maternal cardiac arrhythmias.  There are 
no direct benefits to the patient for participating in the study.
.2.4.1  Confidentiality: 
      The subjects’ identity will be guarded by assigning a numerical code which is only
      known by the principal investigator.  Data is stored in a department computer 
      which is password protected.  Each study subject will be assigned a study code 
      number. The code will be used to link study data to patient identification (name) in 
      a separate database.  Subject data will be stored on secured computers at 
      Northwestern University.  Data access will be password protected and only 
      available to study investigators. The data forms will be de-identified after the chart 
      review prior to analysis. 7 years after manuscript the data both electronic and paper 
      will be destroyed using the current departmental standards.  
                            
5.0  Data Analysis:
.1 Data collection form:  The following data will be collected: 
Demographic data:  age, race, height, weight, gravidity, parity, and gestational age, 
history of prior inductions.
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Labor data: time of rupture of membranes, cervical examination prior to placement of 
CSE (dilation, effacement, and station); start and stop time of fluid bolus, time of 
intrathecal injection, oxytocin dose at time of placement of CSE, vasopressor use and 
dose, maximum oxytocin dose in 60 minutes following placement of CSE, number of 
times oxytocin infusion is stopped or decreased for hyperstimulation or non-
reassuring fetal status, time to complete cervical dilation, time of delivery, maximal 
maternal body temperature in study period.
Mode of delivery:  normal spontaneous vaginal, instrumental vaginal, Cesarean.
Neonatal data: 1- and 5-minute Apgar scores; fetal umbilical cord gases (if taken); 
birth weight; neonatal sepsis workup or ICU admission.
Fetal heart rate tracing data: see appendix
.2 Data evaluation: 
The primary endpoint is the incidence of non-reassuring fetal heart rate tracings during 
the first 60 minutes after the placement of CSE.  Cross tabulation tables will be 
constructed with the presence or absence of the endpoint as rows and the groups as 
columns.  Differences in the frequency among groups will be assessed using a Χ 2 
statistic.  Exact tests will be computed using Monte-Carlo sampling of 10,000 samples 
with a confidence level of 99%. An interim data analysis will be conducted after 
completion of the first 175 evaluable participants.   
Secondary outcomes and demographics: Age, height, weight, gestational age, fetal 
station, and frequency of contractions will be compared using ANOVA or Kruskal 
Wallis ANOVA with post-hoc comparisons correction for multiple comparisons.  
Binominal and ordinal data will be compared between groups using the Χ 2 statistic or 
the Fisher’s exact test. A P < 0.05 will be required to reject the null hypothesis.
6.0 Interpretation of Anticipated Results:  
We anticipate that the lower dose of oxytocin will cause fewer adverse fetal heart rate 
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changes in the first 60 minutes following initiation of labor analgesia. 
7.0 Budget:
.1 Materials:   No additional materials will be required as all of the materials used in 
the study are routinely used in the management of patients.
            .2   Labor Requirements:  Existing anesthesia personnel on Labor & Delivery Unit.
      .3  Presentation Cost:  Anticipated presentations at MARC, SOAP and ASA meetings.
8.0 Consent:   see attached
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