Preventing Hypothermia in Moderate and Late Preterm Neonates - a Pilot Randomized Controlled Trial
Phase: NA
Conditions: Hypothermia
Sponsor: University of Oklahoma

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RESEARCH PROTOCOL OUTLINE
Title of Project:
Preventing hypothermia in moderate and late preterm neonates – a pilot randomized controlled trial
Principal Investigators:
Pavan Parikh, MD, MS – Department of Obstetrics and Gynecology, Division of Maternal 
Fetal Medicine
Birju Shah, MD, MPH, MBA – Department of Pediatrics, Division of Neonatology
Abstract
Preterm births make up 10% of all births in the United States and the cost to care for these 
infants is approximately 10 times higher than term infants. One of the complications that 
is common in preterm infants is hypothermia. Hypothermia which has been linked to an 
increased risk of mortality, leads to low glucose, apnea and respiratory distress in preterm 
infants amongst other complications. Currently, after preterm babies are born we keep 
them connected to the mother via the umbilical cord for at least 60 seconds because it 
reduces the risk of complications for the neonate, however, this allows for a significant 
period of time during which hypothermia may develop. We are proposing a pilot 
randomized controlled trial evaluating the benefit of immediately warming preterm babies 
using a warming mattress and a plastic wrap, while we delay clamping the umbilical cord 
at the time of c-section in babies born between 32 and 36 weeks to determine if it reduces 
the risk of hypothermia
A.
Specific Aims
We hypothesize that neonates delivered preterm and wrapped with a sterile polyethylene 
wrap while being warmed with a standard neonatal transport warming mattress 
immediately after birth and awaiting delayed cord clamping will be less likely to be 
hypothermic at arrival to the neonatal warmer. Since this is not currently a method that 
is employed, we have insufficient preliminary data to determine a sufficient sample size 
needed for a randomized controlled trial. The aim of this grant is to perform a pilot 
trial investigating the effect size of immediate neonatal warming and wrapping of 
preterm infants on neonatal temperature. Our team is well positioned to address these 
questions as there is tremendous synergy between the maternal fetal medicine and 
neonatology groups at OU, and our large referral base for preterm deliveries—we accept 
600 maternal transfers yearly.
We propose a pragmatic randomized pilot trial evaluating the effect size of this strategy 
employed for moderate and late preterm infants (32 weeks 0 days to 36 weeks 6 days) 
who are being delivered by non-emergent cesarean. We plan on enrolling 74 patients and 
allocating patients to the intervention and control groups 1:1 using a block randomization 
scheme stratified by gestational age. Patients and clinicians cannot be practically blinded 
to the interventions given the physical nature of the interventions; however, statisticians 
will be blinded to the group assignments. Primary outcome will be the difference in 
temperature of the neonate at time of arrival to the warmer for neonatal evaluation 
between groups. Secondary outcomes will include temperature at completion of 
resuscitation, need for NICU admission, temperature upon leaving the delivery room, 
temperature upon admission to the NICU (if required), hypoglycemia (less than 30mg/dL 
in the first 24 hours), highest bilirubin level, respiratory support in the form of intubation or 
continuous positive airway pressure, pulmonary hemorrhage, hyperthermia (>37.5
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degrees C), days in the NICU, and composite neonatal morbidity and mortality outcome 
of death or intraventricular hemorrhage (all grades), sepsis (determined by treating 
neonatologist). Data obtained from this pilot trial will be used to apply for a NIH K08 grant 
in order to perform an adequately powered multi-center randomized controlled  trial in 
order to investigate the efficacy of this approach and associated outcomes.
B.
Background and Significance
Preterm delivery is a significant public health issue, with approximately 10% of births in 
the United States occurring prior to 37 weeks of gestation, and is a leading cause of 
perinatal mortality and childhood morbidity. In Oklahoma, 144 babies are born preterm on 
a weekly basis, representing an average of 11.1% of births in 2017. Although infants born 
less than 28 weeks are at highest risk for morbidity and mortality, approximately 80% of 
infants born preterm are born between 32-36-weeks gestation representing the largest 
proportion of affected neonates. Apart from mortality, these children are at risk for 
complications that impact multiple organ systems including sepsis, intraventricular 
hemorrhage, retinopathy of prematurity and respiratory distress1. An initial step in 
improving outcomes according to neonatal resuscitation algorithms includes drying infants 
and maintaining euthermia, as hypothermia has been associated with an increase in 
mortality of 28% for each 1C below 36.5 degree C1,2. Such measures are significant as 
the current rate of mortality ranges from 70% in those born at 23 weeks to less than 1% 
at 37 weeks, with an even higher proportion suffering from long term morbidity3.
Recent recommendations from the American Academy of Pediatrics (AAP) and American 
College of Obstetricians and Gynecologists (ACOG) recommend delayed clamping of the 
umbilical cord by 30-60 seconds to minimize severe complications such as intraventricular 
hemorrhage, necrotizing enterocolitis, and anemia in preterm infants. During this period, 
the infant remains at risk of hypothermia as heat loss starts immediately after delivery. 
The infant moves from an environment of the 37C womb to the temperature in the 
delivery room, with decreases in temperature between 0.2-1 degree every minute4. With 
the above recommended interventions, the neonate typically does not arrive at the radiant 
warmer for assessment by the neonatology team until 2-3 minutes of life. Prior studies 
have investigated warming the neonate using transport mattresses and polyethylene 
wraps after evaluation by the neonatology team and demonstrated efficacy in minimizing 
hypothermia at admission to the NICU5. There are no contemporary studies evaluating 
strategies to maintain infant euthermia during delayed cord clamping. As such, there 
remains a critical gap during which hypothermia may develop and adversely affect the 
neonatal transition to extrauterine life.
Preterm delivery and resuscitation in the late preterm period
As a result of the significant physiologic changes that occur postnatally and the risks of 
morbidity and mortality outlined earlier, strategies to optimize the neonate’s transition to 
extrauterine life have been developed The first intervention for any preterm neonate 
consists of delivery at a hospital where neonatal needs are matched by available 
services. Previous studies indicating that post-natal transfer may increase the risk of 
neurological dysfunction and death. In addition to expedient maternal transfer, 
obstetricians administer betamethasone prior to delivery and delay cord clamping after 
delivery to minimize respiratory distress, intraventricular hemorrhage, minimize the risk 
of anemia and mortality6. Further, there may be an improvement in long term respiratory 
and neurodevelopmental outcomes, and short term cardiovascular function after delayed 
cord clamping7-9. Interestingly, the infant is not attended by a
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neonatologist during this period of delayed cord clamping6. Prior to the recommendation 
for universal delayed cord clamping in 2017, this period had been acknowledged as the 
“golden minute” during which neonatologists assessed the infant’s resuscitation needs 
starting with a maintenance of euthermia, followed by optimization of airway, breathing 
and circulation over the ensuing ‘golden hour’. While obstetricians stimulate babies, 
attempt to clear the airway with bulb suction and dry the infant, these measures are 
executed with significant heterogeneity and variable efficacy. To this end, efforts are 
underway to investigate the utility of initiating positive pressure ventilation before cord 
clamping. Such efforts emphasize the perceived importance of the first minutes after 
birth, since these interventions can improve transition to post-natal life and reduce the 
risk of morbidity and mortality.
Hypothermia and Neonatal outcomes
An important component of care in the first few minutes of life, especially in the preterm 
neonate is ensuring euthermia. Neonates have decreases in their body temperature of 
0.2-1 degrees per minute after birth1. Preterm neonates are at increased risk for 
hypothermia due to their increased body surface to weight ratios, thin skin and lower 
amounts of insulating subcutaneous fat10,11, thus resulting in increased evaporative heat 
losses. Hypothermia results in increased metabolic and oxygen demands and impaired 
resuscitation1. From an outcome perspective, hypothermic neonates are at an increased 
risk for respiratory distress, chronic lung disease, metabolic derangements such as 
hypoglycemia, intraventricular hemorrhage, and late onset sepsis. Even moderate 
hypothermia (<36 degrees C) has been linked to mortality1. De Almeida et al noted that 
44% of preterm neonates admitted to one of 12 university hospitals were hypothermic at 
5 minutes of life, with 51% experiencing hypothermia at NICU admission. As such, 
various interventions have been studied during the golden hour and at the time of 
neonatal transport to the NICU5. These include using polyethylene wraps and caps, 
warming mattresses, warmed humidified gases and maintaining delivery room 
temperatures at 24 degrees C. Though such interventions may result in hyperthermia 
(>37.5 degrees C), no correlation between iatrogenic hyperthermia and adverse 
neonatal outcomes has been demonstrated12. However, strategies to avoid hypothermia 
reduce the need for respiratory support and lower the risk of pulmonary hemorrhage1.
Thus, beginning to prevent hypothermia during delayed cord clamping presents itself as 
an opportunity for improvement in outcomes.
C. Preliminary Studies/Progress Report
This proposal includes two Co-PIs, both of whom currently work synergistically within the 
healthcare delivery system. The question to be addressed is at the transition of life which 
represents a strength for both PIs as we and our divisions currently collaborate in the care 
for these patients on a daily basis. The two divisions meet at least twice a month to discuss 
care related to fetuses and neonates with complex congenital anomalies that require a 
synergistic and longitudinal approach to care from the womb to the mother’s arms. 
Individually, each PI will be responsible for ensuring that we lend both of our expertise to 
the design and execution of this proposal. Troubleshooting concerns and ensuring that 
stakeholders in each department are invited for and complete training in the study 
methodology will be an individual mandate for each PI. However, these training sessions, 
enrollment and data acquisition will be collaborative. Finally, it was via a collaborative effort 
that we were able to generate a grant application and obtain funding.
D. Research Design and Methods (What, When, How, Where)
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Recruitment
The trial will be advertised and introduced to patients admitted to the OU Children’s 
Hospital labor and delivery or antepartum units by research nurses. Interested 
participants will be consented. We are choosing to only include patients undergoing non-
emergent cesarean in order to improve our ability to control parameters such as room 
temperature and labor-related clinical or subclinical maternal infection, which are known 
confounders. Further, we are limiting our investigation to fetuses 32-36 weeks gestation, 
since this population represents the largest preterm delivery population. Recruitment and 
randomization will be stratified by gestational age with an aim to enroll at least 44 
pregnancies at 32- 34weeks and 6 days and 20 pregnancies between 35- 36weeks and 
6days. Last, it is impossible to recruit patients outside of the inpatient setting for a study 
investigating preterm delivery, as such deliveries are rarely predictable in the outpatient 
setting. There will only be one site for this study, the OU Children’s Hospital labor and 
delivery and antepartum units.
Protocol
The proposed study is a pragmatic randomized controlled pilot trial of neonatal warming 
techniques with participants allocated in a 1:1 ratio using a random block allocation table 
using blocks of size 4 and 6 that are stratified by gestational age ranges of 35-36 weeks 
and 6 days and 32-34 weeks and 6 days. Since there cannot be a placebo intervention, 
neither the patient nor the neonatal team will be blinded to the group assignment. The 
group assignments will be made and coded by a third party at the time of randomization. 
Patients will be randomized to their respective groups immediately prior to surgery.
We will aim for an operating room temperature of 65-70 degrees F. The surgical 
technician will be provided with the necessary neonatal wraps and mattresses in a sterile 
fashion, and they will ensure these are available on the surgical field once the cesarean 
has begun. In the intervention group, the thermal mattress will be activated immediately 
prior to hysterotomy and placed on the sterile field with delivery of the infant directly onto 
the mattress. The infant will be dried, stimulated and bulb suctioned as deemed 
necessary per standard of care followed by wrapping. In the non- intervention group, the 
infant will be delivered onto the sterile field, dried and suctioned as deemed necessary 
per OU standard. Cord clamping will be delayed for 60 seconds in all infants under the 
supervision of both the obstetrician and the neonatal resuscitation team. If either team 
believes delayed cord clamping is no longer considered safe, as is our usual protocol, 
the cord will be clamped and cut and the  baby will be handed off to the neonatology 
team. After the infant is handed to the neonatology team along with all group assignment 
specific materials (wrap and thermal mattress, if in the intervention group), neonatal 
temperature will be assessed immediately upon arrival to the resuscitation warmer using 
a digital thermometer placed in the axillary space. Infant temperature will be recorded at 
1) arrival to the warmer, 2) after the neonatologist deems that in-room resuscitation is 
complete and 3) at admission to the Neonatal Intensive Care Unit (NICU), Mother Baby 
Unit (MBU) or Post-Anesthesia Care Unit (PACU) depending on the baby’s needs; 
determined by the resuscitating physicians. These measurements will be recorded by 
research nurses in a data collection sheet. Further, the research nurse will record the 
time from delivery to the time it takes for the infant to arrive at the warmer. Upon arrival 
at the warmer, the mattress and wrap will be removed as neonatal evaluation takes place.
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As immediate neonatal temperature is not generally discussed with patients unless there 
is an issue such as concern for infection, neonatal temperature will not be routinely 
discussed with all participants. Only if there is concern for neonatal infection or if there 
is hyperthermia (>37.5 degrees C) will the study results be discussed with the patient.
Identifiers might be removed and the de-identified information may be used for future 
research without additional informed consent from the subject.
E.
Chart Review
All outcomes will be recorded in a REDCap database by research nurses and data 
managers on the OUHSC campus in prospective fashion. Data will be obtained from 
maternal and neonatal electronic medical records and only de-identified data will be 
analyzed from the REDCap database. The primary outcome will be the proportion of 
hypothermic newborns. Secondary outcomes will include temperature at completion of 
resuscitation, need for NICU admission, temperature upon leaving the delivery room, 
temperature upon admission to the NICU (if required), hypoglycemia (less than 30mg/dL 
in the first 24 hours), highest bilirubin level, maximal respiratory support and duration of 
respiratory support including but not limited to supplemental oxygen and mechanical 
ventilation, pulmonary hemorrhage, hyperthermia (>37.5 degrees C), days in the NICU, 
and composite neonatal morbidity and mortality outcome inclusive of 1) death, 2) 
intraventricular hemorrhage (all grades), 3) sepsis (determined by treating neonatologist) 
and 4) Necrotizing enterocolitis . Confounders that will be assessed will include delivery 
room temperature as reported on the room thermostat, maternal temperature as recorded 
by anesthesia at the time of delivery, time from delivery to arrival at the neonatal warmer, 
indication for delivery, indication for cesarean, infant weight, timing of betamethasone 
administration (time for administration to delivery) and gestational age. Access to the 
database will be controlled and logged using REDCap’s internal systems. Finally, at the 
completion of the study, the data will be stored for 7 years in order to complete analysis 
and apply for additional grants prior to being destroyed.
F.
Inclusion / Exclusion Criteria
Inclusion criteria: Patients who have non-emergent cesarean deliveries, gestational age 
between 32 weeks and 0 days and 36 weeks and 6 days determined per usual clinical 
parameters.
Exclusion Criteria: Fetal anomalies or death, neonates with blistering skin conditions, 
reversed end diastolic umbilical artery flow, placental abruption, chorioamnionitis, 
monochorionic multifetal pregnancies, inability to provide consent, provider perception that 
patient is in significant pain and provider perceived contraindications to delayed cord 
clamping.
Since this is a pilot trial, we will not establish early termination criteria. However, if the 
DSMB asks us to stop the trial due to concern for patient safety we will comply.
G.
Gender/Minority/Pediatric Inclusion for Research
Since this study aims to optimize outcomes for newborn preterm neonates with an 
intervention that is performed at the time of delivery such a study cannot be completed 
without participation of neonates or their mothers. As mentioned, the risks to mothers
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should not be increased because of this intervention as there are no additional 
interventions beyond standard of care delayed cord clamping that will be required of 
mothers. On the neonatal side, there is a risk for neonatal iatrogenic hyperthermia 
defined as temperature >37.5 degrees Celsius; however, no clinically important adverse 
outcomes have been identified in previous studies1.
This study involves viable neonates (gestational age ≥32 weeks) and pregnant women. 
The proposed interventions are aimed at neonatal resuscitation, as such they should not 
impact maternal wellbeing. The intervention will be completed in a sterile fashion similar 
to all the procedures of the cesarean delivery. The research is aimed at directly 
improving neonatal outcomes, and this particular intervention has been demonstrated to 
be safe if applied at a different time point in the neonatal resuscitation process1. The 
informed consent process will include the risks and potential benefits associated with the 
proposed study. As expected, assent cannot be obtained from neonates. When 
obtaining consent from mothers younger than 18 years old, we will obtain consent from 
the patient and her parents, as she will be making decisions regarding her child’s 
wellbeing immediately after birth and is considered empowered to do so under 
Oklahoma law. The overall risk level for pregnant patients is low as the procedures do 
not affect their wellbeing. The risk for neonates is also low because similar interventions 
have been investigated in the past at a different time point in the neonatal resuscitation 
process without evidence of significant adverse consequences1.
H. Recruitment and Enrollment
Women who are admitted to the University of Oklahoma Children’s Hospital Labor and 
Delivery or Antepartum unit will be screened by study personnel for eligibility. They will 
be approached about voluntary participation by trained study personnel. Research 
nurses are independent of the treatment team. Patients to be screened will be identified 
from the EMR by research nurses or by phone call from admitting physicians. If the 
patient is eligible the study will be introduced by research nurses independent of the 
treating/admitting physicians and they will be provided with an informed consent form. 
Interested participants will be consented either on the antepartum unit or the labor and 
delivery unit.
Last, it is impossible to recruit patients outside of the inpatient setting for a study 
investigating preterm delivery, as such deliveries are rarely predictable in the outpatient 
setting. There will only be one site for this study, the OU Children’s Hospital labor and 
delivery and antepartum units. Patients who are imminently delivering, or in significant 
pain per the judgement of treating physician or nurse will not be approached to minimize 
the risk of coercion. Study personnel will administer an informed consent interview with 
each participant, which includes a verbal explanation of the study in lay terms.
Participants will also receive a written informed consent form. Potential participants are 
told that they need not participate in this research study, that the study may or may not 
benefit them directly, that they would be contributing toward a better understanding of 
treatments for preterm newborns, and that they may decline participation. The consent 
process also describes alternative options for the person considering research 
participation (including the right to decide not to participate in any research), privacy 
protections, potential circumstances involving loss of privacy, and what to do in case of 
adverse events. All potential participants are given adequate time to make a decision, 
have a chance to have their questions answered prior to making a decision, and are 
encouraged to include trusted relatives, friends, and/or other healthcare providers when 
making a decision. Once the informed consent has been signed, the participant is 
considered enrolled in the study. At this time, study-specific procedures may be
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performed. Informed consent forms will be available in both English and Spanish, and if 
required hospital translator services will be used to assist in translations during the 
consent process. A patient’s capacity to consent will be determined by her treating 
physician, if in their opinion they cannot consent to clinically relevant procedures they 
will not be approached for consent.
Enrollment will be stratified by gestational age with a goal recruitment of at least 44 
pregnancies at 32-34weeks and 6 days gestation and 20 pregnancies between 35- 
36weeks gestation.
I.
Risks and Benefits
This intervention has been previously evaluated at a different time point in the neonatal 
stabilization process in various studies. A previous study where infants were wrapped from 
the initiation of resuscitation until admission to the neonatal intensive care unit a 7% risk 
of hyperthermia with no associated adverse neonatal clinically important consequences4. 
Hyperthermia in this population is defined as temperature >37.5 degrees C. The effect of 
a combination of warming mattresses and polyethylene wraps is mixed as one study notes 
a 28% risk of hyperthermia at admission to the NICU in neonates born at less than 31 
weeks, while another did not identify any children with hyperthermia1-3. Neither study 
reported adverse clinical consequences. Perlman and colleagues evaluated 3 
observational studies for a total of 8985 patients showing no increase in the risk of 
hyperthermia1. Certainly, we would expect a lower rate of hyperthermia, as the intervention 
will only be applied until the infant can be brought to the neonatal warmer for a total of 2-
3 minutes, contrasted with a longer exposure in the above studies. Of note, none of the 
above studies have demonstrated an increased risk of adverse clinical outcomes in the 
setting of iatrogenic hyperthermia. As such, the risk level from the proposed study is likely 
very low. Similarly, since the study will involve extraction of identifiable data there is an 
extremely low risk of violating privacy and confidentiality as all staff involved are trained to 
follow HIPAA and the data will be stored on a secure server.
All study procedures will follow good clinical practice. Risks of adverse events will be 
reduced by the study personnel and the investigators regularly monitoring participants’ 
progress, by oversite of the IRB, and the data safety monitoring board (DSMB). Patient 
participation may be stopped by the delivering physician if there is concern for 
intrauterine infection or placental abruption. In addition, the neonate will be evaluated by 
a physician or nurse practitioner trained in neonatal resuscitation during the intervention 
as is currently the standard of care. The intervention may be discontinued or halted from 
initiation if the neonatal health care provider deems that there is a blistering skin disease 
that makes the neonate unsuitable for participation. Immediate access to higher levels of 
care from staff neonatologists are available at University of Oklahoma Children’s 
Hospital Labor and Delivery 24 hours a day with direct access available via the use of an 
internal paging system. Finally, both devices to be used during this study (neonatal wrap 
and warming mattress) will follow FDA labeling.
Participant confidentiality will be protected by our strict adherence to HIPAA guidelines. 
As specified in the informed consent process, it is not possible to ensure complete 
protection of a subject’s identity. However, any breaches of good clinical practice in this 
regard would be taken extremely seriously, with appropriate reporting and regulatory 
actions. All patients will be assigned a study participation number, which will be used to 
track the patient and their neonate throughout the study. All patient related data will be
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stored on secure University servers with access limited to only relevant research 
personnel and will be password protected (REDCap database). All study personnel are 
accredited by university-approved online Human Subjects in Research Safety Programs. 
The PIs will be responsible for steps to protect against risks, including but not limited to 
training in Protection of Human Subjects for all study personnel, security of database 
systems, locking of any areas containing medical records, and protection of vulnerable 
populations.
1. Perlman JM, Wyllie J, Kattwinkel J, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on 
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment 
Recommendations. Circulation. 2015;132(16 Suppl 1):S204-241.
2. McCarthy LK, O'Donnell CP. Warming preterm infants in the delivery room: polyethylene bags, exothermic 
mattresses or both? Acta Paediatr. 2011;100(12):1534-1537.
3. Billimoria Z, Chawla S, Bajaj M, Natarajan G. Improving admission temperature in extremely low birth weight 
infants: a hospital-based multi-intervention quality improvement project. J Perinat Med. 2013;41(4):455-460.
4. Vohra S, Roberts RS, Zhang B, Janes M, Schmidt B. Heat Loss Prevention (HeLP) in the delivery room: A 
randomized controlled trial of polyethylene occlusive skin wrapping in very preterm infants. J Pediatr. 
2004;145(6):750-753.
J.
Statistical Methods
Since this intervention has not been studied previously and requires cohesion between 
pediatricians and obstetricians, we will plan on hosting in-person and virtual training for 
key study personnel. Currently, at OU we deliver approximately 250 neonates between 
32 and 36 weeks gestation via cesarean each year. Assuming a 33% rate of 
enrollment, it would take us approximately 11 months to enroll our target sample size 
of 74 patients.
Two prior studies, one evaluating epidemiology and the other an intervention, 
demonstrated that 29% of neonates born in the late preterm period were hypothermic in 
the delivery room with a standard deviation of 8.8. With the proposed enrollment of 74 
preterm infants that meet inclusion criteria, we would have approximately 80% power to 
detect a difference between the two groups of 20%. Since this intervention has not been 
evaluated previously and we are using indirect data from other institutions and other 
interventions, we are assuming a 10% increase in sample size (calculated at 68) to 
account for variations (total of 74). This is a pilot trial to generate the parameters needed 
to guide the development of the next-step full-scale multicenter trial. Thus, power 
calculations for the efficacy of the intervention were completed to ensure we did not need 
to start with a larger or smaller sample size, given the pilot nature of the project.
For this pilot trial, the baseline characteristics of patients assigned to the intervention and 
control groups will be estimated and compared as means, medians or proportions, as 
appropriate for the distribution of the data. Descriptive statistics (i.e., proportions, 95% 
confidence intervals, means, standard deviation, medians, and interquartile range) will 
be used to characterize the distribution of the primary and secondary outcome measures 
among the intervention and control groups. Using an intent-to-treat approach, the primary 
and secondary outcomes will be compared between treatment groups using Student’s t-
tests, Wilcoxson rank sum tests, chi- square tests or Fisher’s exact tests, as appropriate 
for the variable distributions.
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K. Data and Safety Monitoring Plan
Chair: Edgardo Szyld, MD, MSc (Neonatology); Members: Hugh Nadeau, MD, MS 
(Maternal Fetal Medicine), Statistician to be determined (we are currently in the 
process of identifying an epidemiologist from the School of Public Health to assist 
with this aspect of the DSMB).
Overview
This section defines the types of safety data that will be collected under this protocol and 
outlines the procedures for appropriately collecting, grading, recording, and reporting 
those data. Adverse events that are classified as serious according to the definition of 
health authorities must be reported promptly (per Section 4, Reporting of Serious 
Adverse Events and Adverse Events) to the sponsor (OSCTI). Appropriate notifications 
will also be made to principal investigators, Institutional Review Boards (IRBs), and 
health authorities.
Information in this section complies with ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: 
Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the 
standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0. http://ctep.cancer.gov/reporting/ctc.html.
Definitions, Grading, and Attribution of Adverse Events
Definitions
Adverse Event (AE)
Any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research (modified from the definition of adverse events in the 1996 
International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) 
(from OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Subjects or Others and Adverse Events (1/15/07)” at 
http://www.hhs.gov/ohrp/policy/advevntguid.html
For this study, an adverse event will include any untoward or unfavorable medical 
occurrence associated with:
Study therapy regimen. Since the study processes involve only the 2-4 minutes 
between delivery and arrival to the neonatal resuscitation warmer, adverse events will be 
collected during this time period.
Suspected Adverse Reaction (SAR)
Any adverse event for which there is a reasonable possibility that the investigational 
procedure caused or contributed to the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the procedure and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a procedure (21 CFR 312.32(a)).
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Unexpected Adverse Event
An adverse event or suspected adverse reaction may be related to the study agent, or 
study procedures, or may be unrelated. Procedure-related adverse events or suspected 
adverse events are considered “unexpected” if not listed in the relevant package insert 
or not listed at the specificity, severity or rate of occurrence that has been observed. 
“Unexpected” also refers to adverse events or suspected adverse reactions that are 
mentioned in the package insert as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation (21 CFR 312.32(a)).
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or OSCTI, it results in any of the following outcomes (21 CFR 
312.32(a)):
1.
Death.
2.
A life-threatening event: An AE or SAR is considered “life-threatening” if, in 
the view of either the investigator or OSCTI, its occurrence places the subject at 
immediate risk of death. It does not include an AE or SAR that, had it occurred in 
a more severe form, might have caused death.
3.
Prolongation of existing hospitalization. Depending on the gestational age, 
hospitalization for a period of time (at least until the mother’s due date) is 
expected. If hospitalization is extended beyond this time frame and there is not 
an alternative medical explanation for this outcome.
4.
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.
Grading Criteria
The study site will grade the severity of adverse events experienced by the study 
subjects according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events 4.0, referred to herein as the NCI-CTCAE 
manual. This document provides a common language to describe levels of severity, to 
analyze and interpret data, and to articulate the clinical significance of all adverse 
events. Adverse events will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual: Grade 1 = mild adverse event. Grade 2 = 
moderate adverse event. Grade 3 = severe and undesirable adverse event. Grade 4 = 
life-threatening or disabling adverse event. Grade 5 = death.
Events grade 3 or higher will be recorded on the appropriate AE case report form for this 
study, which will be a printable pdf form that can be filled out electronically or printed on 
paper, such that the form can be scanned or uploaded into electronic data system(s).
For grading an abnormal value or result of a clinical or laboratory evaluation (including, 
but not limited to, a radiograph, ultrasound, electrocardiogram, etc.), a treatment- 
emergent adverse event is defined as an increase in grade from baseline or from the last 
post-baseline value that doesn’t meet grading criteria. Changes in grade from screening 
to baseline will also be recorded as adverse events, but are not treatment-emergent. If a 
specific event or result from a given clinical or laboratory evaluation is not included in the
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NCI-CTCAE manual, then an abnormal result would be considered an adverse event if 
changes in therapy or monitoring are implemented as a result of the event/result.
Attribution Definitions
The relationship, or attribution, of an adverse event to the study therapy regimen or 
study procedure(s) will initially be determined by the site investigator and recorded on 
the appropriate AE pdf /printed case report form. Final determination of attribution for 
safety reporting will be determined by DSMB. The relationship of an adverse event to 
study procedures will be determined using the descriptors and definitions provided in 
Table 1. For additional information and a printable version of the NCI-CTCAE manual, 
consult the NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html.
Table 1. Attribution of Adverse Events
Code
Descriptor
Relationship (to primary investigational 
product and/or other concurrent 
mandated study therapy or study 
procedure)
UNRELATED CATEGORY
1
Unrelated
The adverse event is clearly not related: 
there is insufficient evidence to suggest a 
causal relationship.
RELATED CATEGORIES
The adverse event has a reasonable 
possibility to be related; there is evidence to
2
Possible
suggest a causal relationship.
3
Definite
The adverse event is clearly related.
Collection and Recording of Adverse Events 
Collection Period
Adverse events will be collected from delivery until hospital discharge.
Collecting Adverse Events
Adverse events (including SAEs) may be discovered through any of these methods:

Interviewing the subject or parent

Receiving an unsolicited complaint from the subject or parent.

In addition, an abnormal value or result from a clinical or laboratory 
evaluation can also indicate an adverse event, as defined in Section 2, 
Definitions, Grading and Attribution of Adverse Events.
Recording Adverse Events
Throughout the study, the investigator will record adverse events and serious adverse 
events as described previously (Section 2.1, Definitions) on the uploadable pdf or printed 
AE/SAE CRF) regardless of the relationship to study procedure. Once recorded, an
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AE/SAE will be followed until it resolves with or without sequelae, or until the end of 
study participation, or until 30 days after the subject prematurely withdraws (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first.
Reporting of Serious Adverse Events and Adverse Events
This section describes the responsibilities of the site investigator to report serious 
adverse events to the sponsor via the electronic safety system. Timely reporting of 
adverse events is required by 21 CFR and ICH E6 guidelines.
Reporting of Serious Adverse Events to OSCTI
Site investigators will report all serious adverse events (see Section 2.1, Serious 
Adverse Event), regardless of relationship or expectedness within 24 hours of 
discovering the event. For serious adverse events, all requested information on the 
AE/SAE uploadable CRF will be provided. However, unavailable details of the event will 
not delay submission of the known information. As additional details become available, 
the AE/SAE uploadable CRF will be updated and submitted.
Reporting to Health Authority
After an adverse event requiring 24 hour reporting (per Section 4.1, Reporting of Serious 
Adverse Events to Sponsor) is submitted by the site investigator and assessed by 
OSCTI there are two options for OSCTI to report the adverse event to the appropriate 
health authorities:
Annual Reporting
OSCTI will include in the annual study report to health authorities all adverse events 
classified as:

Serious, expected, suspected adverse reactions (see Section 2.1,
Suspected Adverse Reaction and Unexpected Adverse Event).

Serious and not a suspected adverse reaction (see Section 2.1,
Suspected Adverse Reaction).
Safety data will be made public in a timely manner on clinicaltrials.gov and through 
publications.
Expedited Safety Reporting
This option applies if the adverse event is classified as one of the following:
Category 1: Serious and unexpected suspected adverse reaction [SUSAR] The 
sponsor shall report any suspected adverse reaction that is both serious and 
unexpected (see Section 2.1, Suspected Adverse Reaction and Unexpected Adverse 
Event and 21 CFR 312.32(c)(1)i). The sponsor shall report an adverse event as a 
suspected adverse reaction only if there is evidence to suggest a causal relationship 
between the study drug and the adverse event, such as:
1. A single occurrence of an event that is uncommon and known to be strongly 
associated with procedure exposure (e.g., burns);
2. One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to the 
procedure.
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3. An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation 
or other events that commonly occur in the study population independent of the 
intervention) that indicates those events occur more frequently in the treatment 
group than in a concurrent or historical control group.
Category 2: Any findings from studies that suggests a significant human risk 
The sponsor shall report any findings from other epidemiological studies, analyses of 
adverse events within the current study or pooled analysis across clinical studies or 
animal or in vitro testing (e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest 
a significant risk in humans exposed to the intervention that would result in a safety- 
related change in the protocol, informed consent, investigator brochure or package insert 
or other aspects of the overall conduct of the study.
OSCTI shall notify the appropriate health authorities and all participating investigators of 
safety reporting within 15 calendar days; unexpected fatal or immediately life-threatening 
suspected adverse reaction(s) shall be reported as soon as possible or within 7 calendar 
days.
Reporting of Adverse Events to IRB
All investigators shall report adverse events, including expedited reports, in a timely 
fashion to the IRB in accordance with applicable regulations and guidelines. All Safety 
Reports shall be distributed by OSCTI or designee for IRB submission.
Reporting of Other Safety Information
An investigator shall promptly notify the site IRB as well as the OSCTI Safety Officer 
when an “unanticipated problem involving risks to subjects or others” is identified, which 
is not otherwise reportable as an adverse event.
Review of Safety Information 
Medical Monitor Review
The OSCTI and DSMB shall compile new and accumulating information on AEs, and 
SAEs recorded by the study site(s) on appropriate, uploadable CRFs. In addition, DSMB 
shall review and make decisions on the disposition of the SAE reports received (See 
Section 4.1, Reporting of Serious Adverse Events to Sponsor).
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DSMB Review
The PIs will establish an independent DSMB to review and interpret data generated from 
the study and to review the protocol prior to their implementation. Its primary objectives 
are to ensure the safety of study subjects, the integrity of the research data and to 
provide the PIs with advice on the ethical and safe progression of the study. The DSMB 
advises on research design issues, data quality and analysis, and research participant 
protections.
The DSMB members will be invited by the PIs and will include three experts in the 
following fields: biostatistics, neonatology and obstetrics. The DSMB will schedule 
regular committee meetings, recording all meeting minutes and summarizing the 
committee recommendations for the PIs.
The DSMB will have semiannual teleconferences to review the protocol with respect to 
ethical and safety standards, monitor the safety of the ongoing trial, the integrity of the 
data with respect to original study design, and provide advice on study conduct. The 
DSMB will periodically monitor data quality, including accrual, retention, data submission 
timeliness, data completeness, protocol adherence and adverse events. The DSMB may 
recommend protocol modifications based on concern for subject welfare and scientific 
integrity.
Planned DSMB Reviews
The Data and Safety Monitoring Board (DSMB) shall review safety data semiannually 
during planned DSMB Data Review Meetings. Data for the planned safety reviews will 
include, at a minimum, a listing of all reported AEs and SAEs. The DSMB will be 
informed of an Expedited Safety Report within 24 hours by uploading the report to a 
secure site and informing DSMB members by email that there is a message for them.
Ad hoc DSMB Reviews
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB 
may be called upon for ad hoc reviews. The DSMB will review any event that potentially 
affects safety at their own initiative or at the request of the PIs or OSCTI. In addition, the 
following events will trigger an ad hoc comprehensive DSMB Safety Review:

Any death that occurs in the study, which is possibly or definitely related to 
study intervention.

The occurrence of a Grade 3 or higher unexpected SAE in 3 or more of the 
study participants who have received the study intervention.
After review of the data, the DSMB will make recommendations regarding study conduct 
and/or continuation.
Temporary Suspension of enrollment for ad hoc DSMB Safety Review
[Please also see below Stopping Rules and Withdrawal Criteria]
In the event of a death or occurrence of Grade 3 or higher related and unexpected SAE 
in 3 or more study participants, there will be a temporary halt in enrollment.
Interim Analyses
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Interim Analysis of Efficacy Data
A formal interim efficacy analysis is not planned. Given the timing of recruitment, 
duration of follow-up, and targeted sample size, interim efficacy findings would not likely 
impact the conduct of the trial.
Interim Analysis of Safety Data
Safety data will be collected throughout the trial. A DSMB will be formed and will review 
the blinded data at semi-annual intervals. Formal interim statistical analysis will be 
performed after every third of the participants have completed the trial using the Lan 
DeMets (αt) spending function for between-group comparisons.
The following events will be formally monitored among the maternal/infant dyads:

Wound infections

Skin burns

Hyperthermia at arrival to the warmer - Temperature > 37.5 degrees 
Celsius

Length of NICU admission

Sepsis

Intraventricular hemorrhage

Death
Each of these events will be monitored separately.
Futility Analysis
No futility analysis will be performed, due to the pilot nature of this trial.
Study Stopping Rules
The study may be prematurely terminated for the following reasons:
1.
Unexpected rates of severe or serious adverse events
2.
Any other reason deemed appropriate by the DSMB
L.
Confidentiality
Electronically recorded patient information will be stored in a REDCap database on 
University computers with password protection. Paper consent forms will be stored in 
locked cabinets in the MFM research nurse office. At this point, no entities outside of the 
research team will have access to the data. The data will be stored for 7 years prior to 
being destroyed.
M.
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International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular 
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241.
2. Laptook AR, Salhab W, Bhaskar B, Neonatal Research N. Admission temperature of low 
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3. In: WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. 
Geneva2015.
4. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015
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American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care (Reprint). Pediatrics. 2015;136 Suppl 2:S196-218.
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hypothermia at birth in preterm and/or low birth weight infants. Cochrane Database Syst 
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Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age: A Randomized 
Clinical Trial. JAMA Pediatr. 2015;169(7):631-638.
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gestational-age neonate: a gentle approach. Neonatology. 2009;95(4):286-298.
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experience. Clin Pediatr (Phila). 2009;48(4):383-388.
11. Engle WA, Tomashek KM, Wallman C, Committee on F, Newborn AAoP. "Late- 
preterm" infants: a population at risk. Pediatrics. 2007;120(6):1390-1401.
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delivery room: A randomized controlled trial of polyethylene occlusive skin wrapping in 
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