Oxygen for Category II Intrauterine Fetal Resuscitation: A Randomized, Noninferiority Trial
Phase: NA
Conditions: Electronic Fetal Monitoring, Fetal Hypoxia, Fetal-Placental Circulation
Sponsor: Washington University School of Medicine

Oxygen for Category II Intrauterine Fetal Resuscitation: a randomized, noninferiority trial 
“O2C2 Trial” 
Protocol (November 2, 2016)  
 
 
 
Principle Investigator: Nandini Raghuraman, MD MS 
 
 
 
Washington University School of Medicine in St Louis  
660 S Euclid Ave 
Maternity Building-5th Floor 
St Louis, MO 63110 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Specific Aims 
 
Maternal oxygen administration for concerning fetal heart rate tracing (FHT) patterns is common practice 
on Labor and Delivery units in the United States. Despite the broad use of oxygen, it is unclear if this 
practice is beneficial for the fetus. Category II FHT, as defined by the National Institute of Child Health 
and Human Development (NICHD), is a broad class of FHT patterns that may suggest cord compression 
and/or placental insufficiency for which oxygen is most commonly administered. Although some animal 
and human studies have demonstrated that maternal hyperoxygenation can alleviate such fetal heart rate 
decelerations, this purported benefit has not been shown to translate into improved fetal outcomes, 
particularly in relation to acid-base status. In fact, some studies suggest harm with oxygen use due to 
lower umbilical artery pH and increased delivery room resuscitation or increased free radical activity. 
Given the indeterminate evidence for this ubiquitously employed resuscitation technique, there is an 
urgent need to further study the utility of maternal oxygen administration in labor for fetal benefit.   
We propose a randomized controlled non-inferiority trial comparing oxygen to room air in patients with 
Category II FHT. Our central hypothesis is that room air alone is not inferior to oxygen administration 
with regard to neonatal acid-base status and FHT and may in fact, be a safer option for resuscitation due 
to less production of reactive oxygen species.  
Primary Aim: Determine the effect of maternal oxygen administration for Category II FHT on 
arterial umbilical cord lactate.   
Hypothesis: Room air, as a substitute for oxygen supplementation, is no different than oxygen in 
altering the acid-base status of the neonate as reflected in umbilical arterial (UA) lactate. 
Fetal hypo-oxygenation, as reflected by decelerations in the FHT, results in metabolic acidosis due to a 
shift from aerobic to anaerobic metabolism in which lactate and hydrogen ion production significantly 
increase causing a decrease in pH. Elevated umbilical cord lactate has been shown to be a surrogate for 
fetal metabolic acidosis and resultant neonatal morbidity. The primary outcome will be umbilical arterial 
(UA) lactate, and secondary outcomes will be other components of a UA gas. 
 
Secondary Aim #1: Characterize the effect of oxygen administration on fetal heart tracing patterns 
Hypothesis: Oxygen administration will be associated with a rate of persistent Category II FHT 
that is not different from those exposed to room air.  
Oxygen is typically administered in response to FHT interpretation. Hence, evaluating the effect of 
oxygen on subsequent FHT is pivotal to labor management. The primary outcome will be resolution of 
Category II FHT. We will also investigate the effect of oxygen administration on mode of delivery, 
particularly cesarean delivery for non-reassuring fetal status.  
 
Secondary Aim #2: Evaluate the safety of oxygen administration by measuring reactive oxygen 
species (ROS) in maternal and neonatal blood.  
Hypothesis: Oxygen administration will be associated with increased oxidative stress in maternal 
and neonatal cord blood as represented by malondialdehyde (MDA). 
Over-oxygenation can result in free radical or ROS formation that have detrimental downstream effects. 
The presence of reactive oxygen species results in degradation of lipids in the cell membrane and 
resultant formation of malondialdehyde (MDA), which has been studied as a surrogate for oxidative 
stress.  
 
 
 

Background/Significance 
Maternal oxygen administration for fetal heart rate tracing (FHT) changes is a common practice 
on Labor and Delivery units in the Unites States. Despite the broad use of oxygen for intrauterine 
resuscitation of fetal heart rate decelerations, it is unclear if this practice is beneficial for the 
fetus. In a recent review of maternal oxygen administration in labor, Hamel et al1 concluded that 
there is insufficient evidence for routine oxygen administration for intrauterine resuscitation and 
that such administration may even be harmful via production of free radicals. The 2012 
Cochrane review evaluating maternal oxygen administration for fetal distress also found limited 
evidence to evaluate the effectiveness of oxygen for fetal distress.2  
Category II FHT, as defined by the National Institute of Child Health and Human Development 
(NICHD)3, is a broad class of FHT patterns which can include both variable and/or late 
decelerations, representing cord compression and placental insufficiency, respectively. These 
decelerations are often thought to be a reflection of fetal hypooxygenation. The underlying 
hypothesis for oxygen benefit and the primary motivation for generalized use in labor is to 
transfer oxygen to the fetus and therefore improve or reverse the perceived fetal 
hypooxygenation determined by the FHT.  
Although some animal and human studies have demonstrated that maternal hyperoxygenation 
can alleviate fetal heart rate decelerations4, 5 and increase fetal oxygen saturation6-9, this 
purported benefit has not been shown to translate into improved fetal outcomes, particularly in 
relation to acid-base status. For example, a study in primates by Morishima et al demonstrated 
that maternal oxygen administration to those with acidotic hypoxic fetuses elevated fetal oxygen 
levels and eliminated late decelerations but did not correct acidosis.10   
There are a limited number of clinical trials addressing maternal oxygen administration for fetal 
distress in labor. In 1995, Thorp et al conducted a randomized trial of oxygen versus room air in 
the second stage of labor, and found no benefit to oxygen exposure and in fact discovered that 
the oxygen group had a lower umbilical artery pH. This difference was theorized to be a result of 
fetoplacental vasoconstriction as a result of prolonged oxygen exposure.11 Similarly, Nesterenko 
et al performed a trial of laboring women randomized to oxygen or room air and found that more 
infants in the oxygen group required delivery room resuscitation.12  Excess oxygen exposure in 
this setting has also been linked with increased free radical activity. In a 2002 trial by Khaw et al, 

women were randomized to oxygen or room air during cesarean delivery. There was no 
difference in umbilical artery pH between groups, however the oxygen exposed group had 
increased free radical activity in cord blood samples8. Studies such as these have prompted 
questioning of both the safety and the efficacy of oxygen for Category II FHT and highlight the 
urgent need for further investigation, particularly given its wide-spread use.  
The primary objective of this study is to evaluate whether oxygen for intrauterine fetal 
resuscitation of Category II FHT affects fetal metabolic acid-base status as determined by 
umbilical cord lactate values. Secondary objectives include analysis of additional cord gas 
parameters used to predict neonatal wellbeing, changes to FHT patterns, and cord blood and 
maternal MDA as a marker of free radical activity. We hypothesize that room air exposure for 
Category II FHT in labor is no different from maternal oxygen administration with regard to fetal 
acid-base status.  
Specific Aim 1: Determine the effect of maternal oxygen administration for Category II 
FHT on arterial umbilical cord lactate.  Fetal hypooxygenation, as reflected by decelerations 
in the FHT, results in a metabolic acidosis due to a shift from aerobic to anaerobic metabolism in 
which lactate and hydrogen ion production significantly increases as a result of glucose 
breakdown and pyruvate conversion.14 This rise in lactate results in decreased pH or an acidotic 
state. Elevated umbilical cord lactate has been shown to be a surrogate for metabolic acidosis in 
the fetus and is associated with neonatal morbidity.15 It has also been shown to precede pH 
changes in the setting of hypooxygenation.14, 16   
The theorized benefit of maternal oxygen administration is increase oxygen 
delivery to the fetus via the umbilical cord vein (Figure 1) resulting in 
prevention or reversal of anaerobic metabolism and a subsequent 
reflection in umbilical cord artery findings. This, however, has not been 
substantiated by evidence thus far. We hypothesize that room air, as a 
substitute for oxygen supplementation, is no different than oxygen in altering 
the acid-base status of the neonate as reflected in umbilical cord gas 
parameters. Secondary outcomes will be additional components of an 
umbilical artery gas.  
Figure 1: Fetoplacental circulation  
Placenta
Umbilical 
vein
Fetal 
heart
Sytemic 
fetal 
circulation
Umbilical 
arteries

Specific Aim 2: Characterize the effect of oxygen administration on fetal heart tracing 
patterns 
In clinical practice, oxygen is administered to patients with Category II FHT in order to 
resuscitate potential fetal hypooxygenation that manifests as heart rate decelerations. Evidence 
thus far shows that Category II FHT are associated with a wide spectrum of neonatal outcomes 
and therefore do not uniformly reflect fetal acid-base status19, 20. Hence, evaluating the effect of 
oxygen on subsequent FHT categorization is pivotal to labor management. The outcome that will 
be investigated is rate of persistent Category II FHT after intervention. We will also evaluate the 
types and frequency of deceleration patterns present both pre and post intervention. We 
hypothesize that oxygen administration for Category II FHT will be associated with a rate of 
persistent Category II FHT that is not different from those exposed to room air.  
 
Specific Aim 3:  Evaluate the safety of oxygen administration by measuring reactive oxygen 
species in maternal and cord blood  
In order to safely apply maternal oxygen administration for intrauterine fetal resuscitation, the 
risks of oxygen exposure must be further explored. Over-oxygenation can result in free radical 
formation, downstream effects of which include cell membrane and DNA damage and resultant 
carcinogenesis.21 Although oxygen supplementation is often critical to resuscitation in most 
settings, studies evaluating hyperoxygenation in adults and animals have shown detrimental 
cardiac22,pulmonary23,and cerebral effects24. Over-oxygenation in neonates has been shown to be 
associated with bronchopulmonary dysplasia and retinopathy1, 25. Furthermore, reintroduction of 
oxygen after a period of hypooxygenation can result in adverse effects as the fetus and newborn 
lack robust antioxidant systems1, 26.  
One of the primary markers of oxidative stress studied in the 
literature is malondialdehyde (MDA).  The presence of 
reactive oxygen species results in degradation of lipids and 
resultant formation of MDA27which then modifies endogenous 
proteins. MDA levels, therefore, have been studied as a 
surrogate for oxidative stress.28-32 (Figure 2)  
Figure 2: Pathway of oxidative stress  
Oxygen
exposure
Reactive 
oxygen 
species
Lipid 
peroxidation
MDA

Increased MDA levels in the neonate may be consequential and have been associated with 
morbidity including hyperbilirubinemia33 and hypoxic-ischemic encephalopathy34.There is also 
evidence that MDA can be transplacentally transported and thus, both mother and fetus are at 
risk for downstream effects.35 
Prior studies have evaluated the relationship between maternal oxygen administration in labor 
and markers of free radical formation8, 12 with mixed results. We hypothesize that maternal 
hyperoxygenation for Category II FHT is associated with increased oxidative stress in the mother 
and fetus. We will measure MDA in maternal and neonatal cord blood samples as a gage for 
oxidative stress and to assess the relationship between oxygen administration and subsequent 
free radical formation.   
Significant and Potential Impact  
Current practice on our Labor and Delivery is maternal oxygen administration in the presence of 
Category II FHT for the duration of labor. This practice is unproven in benefit thus far and in 
fact, some studies suggest harm11, 12. Although it may improve fetal oxygenation, evidence thus 
far does not show an improvement in fetal acid-base status which ultimately correlates with 
neonatal outcomes. Our study has the potential to create a paradigm shift in intrauterine fetal 
resuscitation and has significant clinical implications for the fetus and mother. No prior clinical 
trials in this setting have used cord lactate as a primary outcome. Umbilical cord lactate is an 
established marker of asphyxia and predictor of neonatal morbidity14 and serves as a useful 
assessment of the benefit, or lack thereof, of oxygen for fetal resuscitation. Prior studies have 
mainly evaluated cord pH as the primary outcome which not only falls behind lactate as a 
predictor of neonatal outcomes, but also does not serve as an accurate reflection of the degree of 
metabolic acidosis that may be present due to hypooxygenation17. Furthermore, previous trials 
addressing oxygen administration for similar indications have not employed a similar three-
pronged approach to evaluating outcomes via neonatal acid-base status, FHT patterns, and free 
radical activity.  If our stated hypothesis is proven, room air may be an equally efficacious, safer, 
and cost saving alternative to oxygen. Additionally, it would pave the way for further 
investigation into the most effective strategies for intrauterine fetal resuscitation.  
 

Strategy 
The aim of this study is to compare maternal oxygen administration to room air for intrauterine 
resuscitation of Category II FHT in relation to cord gas parameters, FHT patterns, and oxidative 
stress in the fetus and mother. The study will be a prospective, randomized non inferiority trial to 
be conducted at Barnes Jewish Hospital.  Current practice at our institution for intrauterine fetal 
resuscitation of Category II FHT include any of the combination of (1) oxygen administration via 
nonrebreather face mask at 10L/min (FiO2 approximately 0.80)36 continued for the duration of 
labor (2) intravenous fluid bolus (3) maternal repositioning (4) discontinuation of oxytocin. We 
hypothesize that room air for Category II FHT will be no different than oxygen administration in 
reducing the degree of fetal metabolic acidosis.  This study will include term, singleton patients 
admitted to Labor& Delivery for spontaneous labor or labor induction. Multiples, fetal 
anomalies, Category III FHT, umbilical artery doppler abnormalities and preterm pregnancies 
will be excluded. Additionally, women will be excluded if oxygen is required for maternal 
indications such as hypooxygenation or cardiopulmonary disease. Our primary objective will be 
umbilical cord lactate. Secondary objectives include additional cord gas parameters including 
umbilical artery pH, umbilical artery base deficit, and umbilical vein oxygen saturation; FHT 
categorization and deceleration patterns; maternal and umbilical cord blood measurement of 
malondialdehyde.  
Consent will be obtained at time of admission to Labor & Delivery. Randomization to either the 
oxygen group or room air group will be performed when the patient is in active labor (defined as 
regular contractions and  ≥ 6cmcervical dilation) and develops Category II FHT necessitating 
intrauterine resuscitation as determined by the care provider team (Figure 3). This will be 
performed via a computer-generated randomization sequence in a 1:1 ratio. Patients randomized 
to the oxygen group will receive the above stated current management of oxygen via 
nonrebreather face mask at 10L/min and “per-protocol” defined as receiving the mask for at least 
90% of the remaining duration of labor including during cesarean delivery. Patients randomized 
to the room air group will not receive oxygen for Category II FHT unless otherwise required for 
maternal indications. Alternative and/or additional intrauterine resuscitation techniques for both 
groups (i.e. fluid bolus, maternal repositioning, and discontinuation of oxytocin) will be left to 

the discretion of the medical team.  The initial 6 patients consented and randomized will be part 
of a compliance run-in with the same protocol as above.  
.  
 
 
 
Specific Aim 1:  Determine the effect of maternal oxygen administration for Category II FHT on 
neonatal cord gas parameters   
After delivery of the infant, a segment of the umbilical cord will be removed with immediate 
collection of umbilical artery and vein samples by trained providers. These samples will be sent 
to the hospital laboratory for routine cord gas measurements as is universally practiced on our 
Labor and Delivery unit.   
Specific Aim 2: Characterize the effect of oxygen administration on fetal heart tracing patterns 
The patient’s primary nurse will document the time at which intervention is initiated. A blinded 
investigator will then retrospectively assess FHT categorization and deceleration patterns both 
pre and post intervention.  
Specific Aim 3:  Evaluate the safety of oxygen administration by measuring ROS in maternal 
and neonatal blood  
We will be measuring serum MDA in both cord and maternal blood as a marker of oxidative 
stress. MDA is a byproduct of lipid peroxidation, which occurs as a result of oxidative stress. 
Measurement of Thiobarbituric Acid Reactive Substances (TBARS) is a commonly used assay 
Admission to L&D 
for delivery
Category II FHT in 
active labor:
Oxygen for 
duration of labor 
until delivery  
Room air for 
duration of labor 
until delivery  
Enrollment 
Figure 3: Flow diagram for randomization and treatment groups 
L&D: Labor and Delivery    FHT: fetal heart tracing 
Randomization 

for quantifying MDA30 37 This assay is performed by fluorometrically measuring the MDA-TBA 
complex formed in plasma or serum by the reaction of MDA and TBA.   
Upon delivery of the infant, an additional sample of umbilical artery blood will be collected for 
this analysis. An optional sample of maternal blood will also be drawn within 60 minutes of 
delivery. Both blood samples will be centrifuged to collect plasma which will then be stored at -
80◦C until the TBARS assay is performed.  
Data Collection  
The patient’s primary nurse will perform real-time documentation of oxygen initiation, any 
disruption in intervention, administration of amnioinfusion and additional resuscitation 
techniques performed (number of times patient is repositioned, total intravenous fluids, 
discontinuation of oxytocin). Study staff will collect data from medical records on: 
1) Antepartum history:  
a. Demographic data: Maternal age, race 
b. Obstetric history: parity, prior cesarean, gestational age at delivery 
c. Medical history: BMI at initial prenatal visit, diabetes, chronic hypertension, 
severe anemia (Hemoglobin <7), tobacco use, illicit drug use 
d. Prenatal course: diagnosis of hypertensive disorders, gestational diabetes, 
abruption, intrauterine growth restriction, oligohydramnios 
2) Intrapartum data: 
a. Indication for admission/induction 
b. Oxytocin (duration, total received dose) 
c. Analgesia 
d. Duration of labor (first and second stage) 
e. Diagnosis of chorioamnionitis 
f. Mode of delivery  
g. Indication for cesarean 
h. Electronic fetal monitoring  
3) Neonatal course: 
a. APGARs 
b. Neonatal weight 

c. Admission to special care nursery (SCN) or neonatal intensive care unit (NICU) 
d. Duration of admission to SCN or NICU  
e. Diagnosis of any of the following: hypoxic ischemic encephalopathy, respiratory 
distress syndrome, oxygen requirement, requirement of hypothermia therapy, 
seizures, sepsis or suspected sepsis, neonatal death  
Data and Safety Monitoring Plan 
In addition to principle investigator review of adverse events, a data and safety monitoring board 
(DSMB) will be established. This board will have three individuals (Dr. Collen McNicholas, Dr. 
Omar Young, Dr. Emily Fishman) not directly involved in the study. The DSMB will meet once 
50% of participants have been recruited to review any adverse neonatal or maternal events 
among the study cohort and determining safety of continuing the study to completion. The 
DSMB will receive a report of any severe and/or non-severe adverse neonatal outcomes within 
72 hours of occurrence. Reportable severe adverse neonatal outcomes include intrapartum 
stillbirth and neonatal death. Reportable non-severe adverse neonatal outcomes include need for 
hypothermia protocol, seizures, and prolonged NICU stay >72 hours.   
Statistical Analysis 
Intention-to-treat (primary analysis) and per protocol analyses will be performed. Chi-squared 
and Fisher’s exact tests will be used to compare categorical variables as appropriate. Continuous 
variables will initially be assessed for distribution pattern via the Kolmogorov-Smirnov test. 
Normally distributed variables will be compared using Student’s t-tests and non-normally 
distributed variables will be analyzed with the Mann-Whitney U test. These analyses will be 
supplemented by multivariable logistic regressions to adjust for confounders.  
Tests with p <0.05 will be considered statistically significant. Analyses will be performed using 
Stata (Stata Corp., College Station, TX). 
For the primary outcome of lactate, 95% confidence intervals (CI) will be calculated for the 
mean cord lactate levels in each group. Comparison of the 95% CI in each group will then 
determine non-inferiority or inferiority.  
Additional interaction analyses for the primary outcome will be performed for the following 
subgroups:   
1) Presence of chronic medical conditions (hypertensive disorder, diabetes)  

a. Patients with hypertensive disorders (chronic hypertension, gestational 
hypertension, preeclampsia)  
b. Patients with diabetes mellitus (gestational diabetes, T1DM, T2DM)  
2) Recurrent late decelerations pre intervention  
3) Recurrent variable decelerations pre intervention  
4) Prolonged deceleration pre intervention  
5) Fetal tachycardia pre intervention  
6) Fetuses with intrauterine growth restriction  
7) Chorioamnionitis  
8) Within oxygen group: Duration of oxygen exposure 
a. <50% of total duration of active labor (onset of active labor to delivery) 
b. >50% of total duration of active labor (onset of active labor to delivery) 
 
Odds ratios and 95% CI will be calculated for the secondary outcome of persistent Category II 
FHT. Kaplan-Meir analyses will be performed for fetal monitoring analyses.   
For the outcome of maternal and cord blood MDA, a fetal MDA will be calculated by 
subtracting umbilical artery MDA from maternal MDA for each sample. The calculated mean 
fetal MDA and maternal MDA values will then be compared between groups using either 
Student t test or Mann Whitney U test.  
  
Sample size analysis 
 A review of previously collected data from our institution of 5182 term singleton pregnancies 
revealed a mean cord lactate of 3.5±1.6 mmol/L in women with Category II FHT within 30 
minutes of delivery. All of these deliveries were managed using our current protocol of routine 
oxygen administration for Category II FHT. Given the normal mean lactate seen in our 
population of patients with Category II FHT, a noninferiority approach was selected to test our 
hypothesis that room air is not inferior to oxygen administration in treating Category II FHT. A 
total sample size of 98 patients will be needed to detect a non-inferiority margin of 30% with 
90% power, using a one-sided two-sample t-test (alpha 0.025). To accommodate a 15% drop 
out/cross over rate, a total of 114 patients will be needed. We plan on performing an initial 
compliance run-in of 6 patients making the total enrollment 120 patients. Data analysis will only 
be performed on the 114 patients enrolled after the initial 6 patients enrolled/randomized in the 
compliance run-in/pilot. Previous studies have shown an increased risk for neonatal morbidity 
with cord lactate cut-offs ranging from 3.2-6.014, 15, 38-41. The margin of noninferiority was 

therefore set at a lactate cut-off of 4.5, above which there is a clear association with neonatal 
morbidity.  
 
 
 
 
 
 
 
 

 
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