Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of Preterm Infants
Phase: NA
Conditions: Prematurity, Stress Reaction
Sponsor: Ohio State University

Official Title: Pilot Study of Nursing Touch and 
Biobehavioral Stress 
NCT Number: NCT05030233 
Document Name: Study Protocol and Statistical Analysis Plan 
Document Date: November 8, 2021 
 
 
 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
2 
HRP-503  v.12.10.18 
 
PROTOCOL TITLE: 
Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of Preterm 
Infants (Pilot NAT-BIO Study) 
PRINCIPAL INVESTIGATOR: 
Name: Leif Nelin, MD 
Department/Center: Center for Perinatal Research 
Telephone Number: 614-355-6719 
Email Address: leif.nelin@nationwidechildrens.org 
Co-Investigator: Marliese D. Nist, PhD, RNC-NIC (The Ohio State University College of 
Nursing) 
 
VERSION NUMBER/DATE: 
Version 2.1 / 11.08.2021 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent Change? 
1.1 
02.05.2021 
Pre-approval revision: clarify data storage, clarify 
IRB reporting of AEs 
No 
1.2 
02.10.2021 
Pre-approval revision: clarify nursing involvement in 
intervention and saliva collection 
No 
1.3 
02.22.2021 
Pre-approval revision: change data retention period in 
section 27-3 from 3 to 6 years 
No 
1.4 
03.29.2021 
Pre-approval revision: (1) change to pilot study with 
up to 20 infants, (2) change from sequential to 
randomized cross-over with one version of 
intervention, (3) remove measure of behavioral 
responses 
Yes 
1.5 
03.30.2021 
Pre-approval revision: clarify PI 
Yes 
1.6 
04.02.2021 
Pre-approval revision: (1) change title of parent 
demographic form, (2) add optional photographs to 
procedure 
Yes 
2.0 
07.14.2021 
Post-approval revisions: (1) aims – add 
neurobehavioral assessment 2) change inclusion ages 
and add exclusion for special isolation; (3) 
recruitment – add flier, add option for phone 
discussion, add infant/nurse compensations; (4) 
procedures – change infant age at time of 
observations, change to bare-handed touch, change to 
“nurse-only” caregiving (5) measures – change from 
Yes 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
3 
HRP-503  v.12.10.18 
NCH monitors to Holter monitors, change timing of 
saliva collections, change saliva collection to swabs, 
add neurobehavioral assessment a 35 weeks; (6) data 
– add collection of pain score from electronic health 
record and Neonatal Infant Stressor Scale; (7) remove 
Deborah Steward from DSMB 
2.1 
11.08.2021 
Post-approval revisions: (1) change from nurse-
collected to researcher-collected saliva and nurse-
applied to researcher-applied electrodes, (2) add 
behavioral sleep measure, (3) change from cellulose 
microsponges to medical swabs for saliva collection. 
Yes 
 
 
 
 
 
 
 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
4 
HRP-503  v.12.10.18 
1.0 
Study Summary 
 
Study Title 
Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
Study Design 
Randomized cross-over clinical trial 
Primary 
Objective 
Determine the effect of a nurse-administered touch intervention (NaTI) on 
biobehavioral stress responses of preterm infants during essential nursing care. 
Secondary 
Objective(s) 
 (2) Identify factors to increase feasibility of the NaTI as a nurse-administered, 
integrated part of essential, procedural care, (3) Determine associations between 
biobehavioral responses and early neurobehavior. 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
NaTI (NaTI): NaTI is a systematic touch intervention consisting of 3 static, brief 
touches lasting a total duration of 2.5 minutes provided by bedside nurses at 
specified points during essential care. The intervention is provided with bare hands 
(i.e. gloves are not worn). 
IND/IDE #  
N/A 
Study Population 
Preterm infants born 27 to 30 weeks post-menstrual age; NICU nurses 
Sample Size 
Up to 20 infants; up to 20 nurses 
Study Duration 
for individual 
participants 
Infant participation on each of 2 days will last approximately 6 hours from the 
attachment of electrodes for skin conductance responses and heart rate/heart rate 
variability to the removal of these electrodes. Infant participation will include data 
collection on two consecutive days for a total duration of 24-48 hours. Infant 
neurobehavior will be assessed at 35 weeks post-menstrual age. The assessment 
takes 20-30 minutes. Total infant participation will last from the time of the first 
observation to neurobehavioral assessment (approximately 5-7 weeks), depending 
on anticipated discharge and clinical stability for the neurobehavioral assessment. 
Nurse participation will last approximately 15 minutes per survey completion. 
Study Specific 
Abbreviations/ 
Definitions  
NaTI: nurse-administered touch intervention 
SC: standard care 
NAPI: Neurobehavioral Assessment of the Preterm Infant 
AIM: Acceptability of Intervention Measure 
IAM: Intervention Appropriateness Measure 
FIM: Feasibility of Intervention Measure 
SID: study-specific identification 
Observation period: period of active study participation for infants lasting 
approximately 6 hours and beginning with the attachment of electrodes before the 
scheduled care episode during which data collection will occur and ending with 
the following scheduled care episode when electrodes are removed. 
 
 
2.0 
Objectives 
2.1 The objective of the proposed study is to determine the effect of a nurse-administered touch 
intervention (NaTI) on preterm infants’ stress responses during essential nursing care, 
measured by changes in biobehavioral stress responses (vital signs, skin conductance 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
5 
HRP-503  v.12.10.18 
responses [SCRs], heart rate variability [HRV], behaviors, and cortisol)1,2. We will 
accomplish this objective through the following specific aims: 
• Aim 1 (primary): Determine the effect of a NaTI on biobehavioral stress 
responses of preterm infants during essential nursing care.  
• Aim 2: Identify factors to increase the feasibility of the NaTI as a nurse-
administered, integrated part of essential, procedural care. We will examine 
nurse-related factors that may affect the feasibility of intervention implementation 
in clinical practice for every episode of essential care.  
• Aim 3 (exploratory): Determine associations between biobehavioral responses 
and early neurobehavior. 
2.2 We hypothesize that the NaTI will attenuate activation of the physiologic stress response 
systems. 
3.0 
Background 
3.1 Infants born preterm experience neurodevelopmental impairments in cognition3, motor 
function3, and language acquisition4,5. In the United States, 50% of cerebral palsy cases and 
8% of learning disabilities are attributable to preterm birth6. While many preterm infants 
receive early intervention services after neonatal intensive care unit (NICU) discharge, 
these services are costly and not available to all eligible infants7-9. Interventions during 
NICU hospitalization may improve neurodevelopment and reduce the human, societal, and 
economic burdens of neurodevelopmental impairment in preterm infants. 
Stress exposure in the NICU is associated with abnormal brain development10-12 and 
cognitive, motor, and behavioral neurodevelopmental impairments13-16. Preterm infants 
experience an average of 7.5-17.3 painful procedures17 and 22.97 acute stressors16 per day 
of hospitalization. Seemingly benign procedures (e.g. diaper changes, repositioning) are 
among the most frequent stressors16,18 and are commonly clustered together during 
essential nursing care. Essential nursing care is a frequent, repeated stressor, typically 
occurring every 3 or 4 hours during the infant’s hospitalization. Most episodes (86%) of 
essential care begin with an abrupt rather than a gradual approach18, without time for 
infants to acclimate. Because essential care is repeated, frequent, and abrupt, interventions 
targeting how essential care is provided may affect preterm infant stress responses and 
improve outcomes. 
Essential nursing care activates the sympathomedullary (SAM) pathway and hypothalamic-
pituitary-adrenal (HPA) axis, resulting in measurable biobehavioral effects2,19-22. SAM 
pathway activation increases sympathetic nervous system (SNS) activity and suppresses 
parasympathetic nervous system (PNS) activity in response to painful procedures23,24 and 
essential nursing care21,22,25,26. Stress responses resulting from SAM pathway activation can 
be measured as changes in vital signs (heart rate [HR], respiratory rate [RR], oxygen 
saturation [SpO2])27, HRV27, and SCRs24. The release of catecholamines from the adrenal 
medulla in response to SNS stimulation28 causes stimulation of the cardiac sinoatrial node 
and measurable changes in HR, RR, SpO2, and HRV27. HRV represents the beat-to-beat 
variations in HR, as measured by the R-R interval, and is sensitive to inputs from the SNS 
and PNS29,30. SCRs, produced by the filling and emptying of palmar and plantar sweat 
glands in response to SNS stimulation24, are valid measures of SAM pathway activation in 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
6 
HRP-503  v.12.10.18 
the first weeks of life in infants born <34 weeks post-menstrual age (PMA)31. Further, 
activation of the HPA axis causes a release of cortisol from the adrenal cortex28. Cortisol 
can be quantified from saliva28, providing a non-invasive measure that is highly correlated 
with blood levels32,33. Salivary cortisol levels increase in preterm infants in response to 
bathing26, routine handling34, and painful procedures34 and decrease in response to pain 
management interventions34. Early, repeated activation of the immature SAM pathway and 
HPA axis during essential caregiving may cause aberrant changes in the form of neural 
programming of these stress response systems, altering their function and contributing to 
NDI35. Neonatal HRV, for example, is associated with childhood neurodevelopment36,37 
and may be an important end-point for powering future studies. Thus, we will determine 
associations between HRV, as well as HR, SCRs, and cortisol, and infant neurobehavior at 
35 weeks PMA. 
Activation of the SAM pathway and HPA axis in response to essential caregiving may be a 
consequence of the mismatch between the preterm infant’s neurologic expectation for 
touch and his/her NICU reality. The fetus in utero experiences comforting touch from the 
surrounding amniotic fluid, uterine containment, and external touches to the mother’s 
abdomen38. Conversely, much of the touch experienced by preterm infants in the NICU is 
procedural or painful39-42; preterm infants receive little comforting touch during their 
hospitalization18,41-43. During the last weeks of gestation, neuronal circuits to support the 
peripheral touch receptors that formed early in gestation become connected to the limbic 
system, giving social and emotional meaning to touch44. These circuits are affected by 
touch experiences in the NICU44,45, potentially leading to touch aversion from comfort 
touch deprivation38. Thus, preterm infants may begin to associate any touch with early 
noxious touch experiences in the NICU, resulting in a poorer tolerance for future 
interaction and touch46. 
While noxious touch from essential caregiving induces a physiologic stress response21,22,47, 
comforting touch enhances PNS activity48, increases HRV48, decreases cortisol levels49,50, 
decreases behavioral responses to pain51, and improves neurodevelopment48. Maternal skin-
to-skin contact, during which mothers hold their diaper-clad infants between their breasts, 
reduces stress responses of preterm infants during painful procedures52,53 and increases 
PNS activity54. However, maternal presence in the NICU is minimal55, hindered by family 
and job responsibilities and access to transportation56. On average, mothers are present for 
50% of the days of their infant’s hospitalization and provide skin-to-skin care for 0.2 days 
each week55. With limited maternal presence, preterm infants receive little comforting 
touch18,41-43. Nurses provide 87.8% of the direct contacts experienced by preterm infants, 
but only 3.5% of these contacts are comforting touch57. Clinician-administered touch 
interventions (i.e. massage therapy48,58 and Gentle Human Touch49,50,58,59) are effective in 
attenuating preterm infant stress responses and promoting neurodevelopment. However, 
these interventions require training and are typically delivered for only a few minutes each 
day for a few days48,60,61. Comforting touch provided during specific painful procedures 
such as heel lance51,62,63 and endotracheal suctioning62,64 is effective in reducing the stress 
responses of preterm infants. A case study revealed that 5 seconds of comforting touch to 
gently awaken a preterm infant at 28 weeks PMA prior to essential care was associated 
with fewer stress behaviors during the care episode and faster recovery of HR and SpO2 
after the care65. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
7 
HRP-503  v.12.10.18 
Much research on preterm infants’ stress responses is limited by a narrow focus of 
measures and insufficient consideration of infant age. Many studies focus on behavioral 
responses and measures of either SAM pathway21-24 or HPA axis66-68 activation. Studies 
including a broad spectrum of measures needed for comparisons across studies are lacking. 
Also, many studies include multidimensional indices of pain/stress, scoring infants on 
behavioral cues, physiologic measures, and/or demographic characteristics (e.g. PMA)69. 
Such indices (e.g. Premature Infant Pain Profile, Neonatal Infant Pain Scale), are difficult 
to compare across studies and are complicated by developmental factors (i.e. age69) and 
subjective interpretation of scores70. We will build on previous research by measuring a 
broad spectrum of objective stress responses, including measures of SAM pathway and 
HPA axis activation. 
Previously conducted randomized controlled trials (RCTs) testing the efficacy of 
comforting touch have a high risk for bias, resulting in low62 or very low70 quality evidence 
based on the Grading of Recommendations Assessment, Development and Evaluation 
system. Moreover, heterogeneity among trials makes it difficult to accurately determine 
effects48,62. Much of the bias in these studies results from failure to measure contextual 
factors (e.g. infant age, previous pain exposures)70 or lack of blinding48,62,70. While it may 
be impossible to conceal group assignment from caregivers in a touch RCT, we will blind 
outcome assessors and analysts. Importantly, studies of touch interventions for painful 
procedures commonly use multidimensional indices of pain/stress62,63,70 that include subject 
measures of behavioral responses and may include infant age, making comparisons across 
infants difficult as previously described69 and increasing performance bias. We designed 
this study to reduce the performance bias affecting previous studies by collecting data on 
context of care, blinding outcome assessors and analysts, using objective stress response 
measures that can be compared across studies, and following published procedures for 
quantifying behavioral responses in research studies71. 
We are aware of only one study testing the effect of comforting touch during essential care. 
In a small study (n=12) of preterm infants, comforting touch was effective in reducing 
scores on the Premature Infant Pain Profile, a multidimensional index that includes 
behavioral observations and vital signs72. However, this study used two caregivers to 
provide the intervention, which cannot be feasibly implemented for every episode of 
essential nursing care during the infant’s hospitalization73. In addition, infant ages ranged 
from 24 to 32 weeks PMA at birth, timing of the intervention was not standardized, and the 
study included only one multidimensional outcome measure72. To test the NaTI, an 
intervention intended for delivery by one nurse, we will standardize intervention delivery 
and measure multiple objective outcomes. 
3.2 Recent work by our study team shows that preterm infants are frequently exposed to 
stressors associated with essential nursing care and that standard care (SC) includes very 
little comforting touch74,75. PI Nist found that infants born 28-31 weeks PMA experienced a 
median of 24 skin-breaking procedures (e.g. heel lance, venipuncture, venous cannulation) 
and 30 invasive procedures (i.e. skin-breaking procedures plus entrances into a body 
cavity) during their first 2 weeks of life76. Preterm infants also experienced numerous non-
painful stressors during essential care, including a median of 109 diaper changes, 104 
gavage feedings, and 79 episodes of gastric aspiration77. Because infants experienced these 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
8 
HRP-503  v.12.10.18 
stressors during clustered essential nursing care, the manner in which this essential care is 
delivered is critical.  
In a RCT, Co-I Pickler tested the effect of a touch intervention provided during preterm 
infant feedings75. Over 195 mean gavage feedings, infants in the experimental group 
received a touch experience on average 57% of the time versus 16% for infants in the 
control group; the touch varied from 6-15 minutes based on feeding duration. Importantly, 
some control group infants received no touch during feedings. Infants receiving greater 
amounts of touch achieved feeding milestones sooner78 and had improved neurobehavior at 
discharge79. These data demonstrate that comforting touch does not occur as part of routine 
caregiving, even though the frequency and essential nature of these activities would suggest 
their importance to optimal development80. We will build on this work by measuring acute 
stress responses and standardizing the duration of touch. 
3.3 The NaTI is a theory-guided, systematically delivered intervention provided during 
essential nursing care. The Neonatal Stress Embedding Model provides the theoretical 
foundation for this study and posits that NICU stress exposure activates the SAM pathway 
and HPA axis; repeated activation of these immature systems in the preterm infant results 
in aberrant programming, affecting brain structure and neurodevelopment35. We will test 
the short-term effect of the NaTI on the stress response systems and will build on this work 
in a future study by examining the effect of routine implementation on neurodevelopment. 
We hypothesize that the NaTI will attenuate activation of the SAM pathway and HPA axis 
(Fig 1). To determine the effect, we will measure a broad spectrum of stress responses (HR, 
HRV, SRCs, cortisol), advancing the work of previous researchers who measured infant 
responses to specific procedures (e.g. heel lance51,62,63, endotracheal suctioning62,64) using a 
small number of biobehavioral measures. In contrast to other tested interventions, the NaTI 
requires no specialized training and a minimal time commitment (<5 minutes) from nurses 
and can be integrated as part of on-going essential care. The NaTI addresses how routine, 
necessary care is delivered. While the positive effects of comforting touch are well known, 
comforting touch is not a routine part of essential nursing care.  
Routine comforting touch interventions may promote positive long-term outcomes for 
preterm infants by buffering the effect of noxious touches and providing the necessary, 
neurologically expected touch that promotes normal sensorineural development. In this 
study, we will test the preliminary effect of a systematic NaTI provided during essential 
nursing care on infant stress responses. This study is based on the scientific premise that 
comforting touch, provided through a systematic NaTI, meets the preterm infant’s 
neurologic expectation for touch and increases PNS activity, attenuating activation of the 
SAM pathway and HPA axis, and reducing the aberrant programming of these stress 
response systems.  
4.0 
Study Endpoints 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
9 
HRP-503  v.12.10.18 
4.1 Data collection to accomplish aims 1 & 2 will last the duration of two observation 
periods, one each on two consecutive days. Infant participation will last 
approximately six hours for each observation period. Participation will begin 
approximately three hours prior to a scheduled care episode (i.e. data collection 
period) when monitoring electrodes are attached and will end approximately 2.5 
hours after the scheduled care episode (i.e. data collection period) when the next 
care episode begins and study electrodes are removed. Infants will receive a 
neurobehavioral assessment at approximately 35 weeks PMA. The timing of this 
assessment will depend on anticipated discharge and clinical stability. Infant 
participation for the entire study will last between 5-7 weeks, depending on infant 
PMA at birth and timing of the neurobehavioral assessment. 
4.2 The NaTI will be stopped for infants experiencing bradycardia, defined as HR less 
than 100 beats per minute for 10 seconds, or oxygen desaturation, defined as 
oxygen saturation less than 85% for 10 seconds. To prevent the overstimulation of 
infants during intervention delivery, the NaTI will be stopped for tachycardia, 
defined as HR greater than 200 beats per minute for 10 seconds. NaTI delivery may 
resume with the next planned intervention point in the care but will be discontinued 
for the remainder of the care for two or more episodes of bradycardia, oxygen 
desaturation, or tachycardia occurring during intervention delivery as defined 
above. A few infants may not tolerate the handling required to complete the 
neurobehavioral assessment. The Neurobehavioral Assessment of the Preterm 
Infant (NAPI) is intended to be administered in a specified, fixed sequence to 
minimize infant handling and potential distress. While we expect that infants at 35 
weeks PMA will not find the assessment distressing, for those who exhibit signs of 
distress (e.g. bradycardia, oxygen desaturation, inconsolable crying), the assessment 
will be terminated.  
5.0 
Study Intervention/Investigational Agent 
5.1 Description. The NaTI is a systematic touch intervention consisting of three static, 
brief touches provided by bedside nurses at specified points during essential care. 
To provide the NaTI, nurses will cradle the top of the infant’s head with one hand, 
using their other hand to contain the infant’s lower body. Nurses will provide the 
touch for one minute at the start of the care to allow infants time to acclimate to the 
stimulation, 30 seconds after the diaper change, and one minute at the conclusion of 
the care to provide a gradual end to the care and facilitate infant recovery and sleep. 
Nurses will provide the touches using bare hands (i.e. no gloves) to provide infants 
with human skin-to-skin contact and will perform hand hygiene before and after 
each touch. Nurses often provide discretionary comforting touch, commonly 
referred to as hand containment or facilitated tucking, in the same manner as the 
NaTI as part of their routine care (NCH Patient/Family Care Policy 30:23). The 
NaTI differs from discretionary comforting touch in that it is provided at specific 
points during the care and for a prescribed length of time. A member of the research 
team will be present during the care, perform timing for the intervention, and 
provide verbal instructions for nurses to begin and end the NaTI. 
6.0 
Procedures Involved* 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
10 
HRP-503  v.12.10.18 
6.1 Study Design. Aim 1. Infants will be assigned to standard care or standard care with 
the addition of the NaTI in a randomized cross-over manner to determine the effect 
of a NaTI on biobehavioral stress responses during essential nursing care. We 
define essential nursing care as a scheduled episode of clustered caregiving 
activities related to health monitoring, hygiene, and clinical needs that includes at 
least a diaper change and feeding. We will enroll up to 20 infants for this pilot study 
to collect complete, usable data on 16 infants.  
Aim 2.  To identify factors to increase the feasibility of the NaTI as a nurse-
administered, integrated part of essential, procedural care, we will conduct a survey 
study of nurses who have provided the NaTI to enrolled infants. We will 
specifically ask nurses to describe barriers and facilitators of implementation.  
Aim 3. We will use a longitudinal cohort design to determine associations between 
biobehavioral responses and early neurobehavior. We will collect biobehavioral 
stress response data during the two observed episodes of care and will administer 
the NAPI to each enrolled infant at approximately 35 weeks PMA. 
6.2 Procedures. Aims 1. Infants will be enrolled during the first 10 days of life. We will 
collect demographic and clinical data from the infant’s electronic health record 
(EHR) after enrollment and throughout the hospitalization. Because stress 
responses may differ based on postnatal age81, data collection for stress responses 
will occur between 10 and 20 days of life. To eliminate variance in cortisol due to 
diurnal patterns, we will perform all observations at the same time of day for all 
infants, between 1000 and 1300. Observations will occur on two consecutive days 
unless infants are not available due to off-unit or other scheduled procedures. In this 
case, the second observation will occur on the next day that the infant is available. 
Infants will be assigned to receive standard care or standard care with a NaTI in a 
randomly assigned sequence. For the two observed care episodes, we will require 
that nurses provide this care exclusively to limit confounding by the participation of 
additional caregivers. With assistance from the bedside nurse, the researcher, who is 
a Registered Nurse, will attach monitoring electrodes for vital signs, HRV, and 
SCRs during the care episode prior to the observed care to minimize stress 
responses from handling and monitoring prior to the baseline period (Fig 2). Nurses 
commonly attach monitoring electrodes as part of their clinical practice. 
 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
11 
HRP-503  v.12.10.18 
Measures, Aims 1: 
• SAM pathway activation. Heart rate will be measured continuously during the 
observed care episode, using external monitors. HR, a measure of SNS response, is 
our primary outcome measure because nurses can use HR in clinical practice to 
identify SAM pathway activation. Heart rate variability, specifically high 
frequency HRV (HF HRV), provides an index of PNS activity and is generally 
reduced in response to internal or external stressors82. Continuous 
electrocardiogram (ECG) data during baseline, care episode, and recovery will be 
collected using external Holter monitors. Electrodes for ECG data will be applied 
by the researcher with assistance from the bedside nurse during the care prior to 
each observed care. Raw ECG waveform data will be imported into Co-I Harrison’s 
MARS® Ambulatory ECG Analysis and Editing System (General Electric, Inc.) 
and processed according to recommended protocols82,83. During processing, 
artifact will be eliminated with final calculations based on normal sinoatrial node-
initiated complexes. Analysis will include HF HRV calculated in one-minute 
epochs averaged for each phase (i.e. baseline, care episode, recovery). Skin 
conductance responses will be measured by attaching two disposable electrodes 
with isotonic electrode gel (Biopac Systems, Goleta, CA) to one foot approximately 
three hours prior to data collection (i.e. during the episode of care prior to the 
observed episode of care). Electrodes are connected to an amplifier to record SCRs 
during the entire observed care. At the beginning and end of each period (baseline, 
care episode, recovery), we will record ambient (i.e. room or incubator) and infant 
skin temperatures; ambient and skin temperatures <24⁰C and <32⁰C, respectively, 
may affect SCRs84,85.  
• HPA axis activation. Salivary cortisol will be measured from saliva samples taken 
immediately prior to the start of care (baseline), 30 minutes after the care has ended 
(post-care), and 60 minutes after the care has ended (recovery; Fig 2) using medical 
sponges gently introduced into the infant’s mouth.. We have previously used these 
sponges for saliva collection from preterm infants without causing infant distress. A 
member of the research team, who is a Registered Nurse, will collect saliva samples 
with the assistance of the bedside nurse. Saliva collection is non-invasive and  may 
be collectedas part of  clinical practice (test code XSCRT according to the NCH 
Laboratory Medicine website; see protocol Appendix). We will batch process 
samples and quantify cortisol levels using a commercially available enzyme-linked 
immunosorbent assay (ELISA; Salimetrics, State College, PA). 
• Recovery. We will measure infant recovery by recording episodes of bradycardia, 
tachycardia, oxygen desaturation, or other monitor alarms during the 30-minute 
recovery period following the episode of essential nursing care. We will observe 
sleep behaviors to determine if the infant is awake, asleep, or drowsy during this 
30-minutes recovery period using the Anderson Behavioral State Scale (ABBS). 
Behavioral data will be collected through observation without disturbing or 
handling the infant. 
• Context of care. We will record the duration of the caregiving episode and the 
procedures included. We will use the acute scale of the Neonatal Infant Stressor 
Scale (NISS)88 to quantify the procedural stressors experienced by infants during 
the observed care episode. We have previously modified this measure to account for 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
12 
HRP-503  v.12.10.18 
the procedural stressors commonly experienced by preterm infants77. Additionally, 
we will observe and record all direct touches experienced by the infant for one hour 
prior to the caregiving episode. Direct touches are those defined as direct physical 
contact between a caregiver and infant and might include parent skin-to-skin care, 
interventions for apneic episodes, and adjustment of a respiratory interface. We will 
use these data to compare the context of care for infants between assigned 
conditions and will examine moderation of infant responses to care episodes by this 
context. 
• Demographic and clinical data. We will collect maternal demographic information 
and clinical data including age, race, prenatal medications, labor/delivery 
complications and infant demographic and clinical data including sex, PMA, 
birthweight, clinical comorbidities, and medications at enrollment and throughout 
hospitalization from the EHR and through parent report. We will record PMA based 
on first trimester ultrasound, if available, as this method of dating is most 
accurate69. Otherwise, we will use the best obstetric estimate, second/third trimester 
ultrasound, or postnatal assessment. In addition, we will record the pain score 
documented by nurses during the observed care. We will retrospectively collect 
data from the EHR on the number of invasive procedures (e.g. lab draws, 
intubations, intravenous line insertion) experienced by enrolled infants from the 
time of birth through the observed care episode(s). Finally, we will collect clinical 
data from the EHR to calculate a Score for Neonatal Acute Physiology (SNAP)-II, 
a validated measure of illness severity for preterm infants that includes clinical data 
from the first 12 hours of life (blood pressure, temperature, oxygenation indices, 
serum pH, urine output, and presence of seizures)89. Finally, we will quantify the 
amount of parental skin-to-skin contact that infants have received from the time of 
birth through the observation period(s). 
 
Optional infant photographs. With parental consent, we will take photographs of infants 
for use in future scientific and educational presentations. We will not disclose any 
information about these infants, but they may be identifiable by their photographs. 
Photographs will be stored on OSU’s password protected research server. Parents may 
further opt to provide an email address where photographs may be sent for their personal 
use. 
Procedures. Aim 2. Nurses providing the NaTI to infants will be invited to 
participate in a survey study. Those who choose to participate will complete a 
demographic questionnaire once and a NaTI survey, Acceptability of Intervention 
Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of 
Intervention Measure (FIM) each time he/she provides the NaTI for a study infant. 
Nurses will be assigned study identification numbers (SIDs) to track participation 
and to link nursing data to infant data. We will provide phone/text reminders for 
nurses to complete and return the questionnaires. 
Measures, Aim 2: 
• Demographic questionnaire. This questionnaire will include baseline data on 
participating nurses such as age, sex, race, nursing education, and nursing 
experience. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
13 
HRP-503  v.12.10.18 
• NaTI survey. This investigator-developed survey uses Likert-style ratings and 
open-ended questions to evaluate nurses’ experiences, attitudes, perceptions, and 
suggested improvements for the NaTI.  
• Acceptability, appropriateness, and feasibility measures. Nurses will complete the 
Acceptability of Intervention Measure (AIM), Intervention Appropriateness 
Measure (IAM), and Feasibility of Intervention Measure (FIM)90. Each measure 
includes four Likert-style questions evaluating the degree to which respondents like 
the intervention, find the intervention useful, and believe that the intervention can 
be practically implemented.  
• Preliminary cost. We will estimate preliminary cost of the intervention as part of 
the feasibility assessment using the nursing time required to deliver the intervention 
and nursing time and interventions required to respond to infant physiologic 
instability during the recovery period. 
Procedures. Aim 3. At approximately 35 weeks PMA, we will administer the NAPI 
to each enrolled infant. If discharge is anticipated prior to 35 weeks PMA, we will 
coordinate with clinical staff to perform the assessment prior to the infant’s 
discharge. For infants who are not clinically stable based on nursing judgment or 
are requiring invasive ventilation or continuous positive airway pressure (CPAP) at 
35 weeks PMA, we will delay the neurobehavioral assessment until the infant is 
clinically stable. Neurobehavioral assessments will be coordinated with the clinical 
staff so as not to interfere with clinical operations and will occur prior to a 
scheduled episode of essential nursing care. 
Measures, Aim 3: 
• NAPI. The NAPI is a neurobehavioral assessment for preterm infants 
between 32 weeks PMA and term equivalent age 91. The assessment 
includes seven “clusters” – motor development and vigor, scarf sign, 
popliteal angle, alertness and orientation, percent asleep ratings, irritability, 
and vigor of crying – that, together, define the developmental maturity of 
the preterm infant 92. A recently published systematic review of neonatal 
assessments concluded that the NAPI had excellent content validity and 
adequate reliability and construct and criterion validity 93. The NAPI can be 
used for evaluative or discriminative purposes and has published preterm 
infant norms 93. The NAPI is able to discriminate between extremely low 
birthweight and very low birthweight infants and is significantly correlated 
with neurodevelopmental assessment scores at 18 and 30 months corrected 
age 94. Moreover, previous research found that acute stress and degree of 
prematurity predicted scores on two clusters of the NAPI 95. The NAPI is 
administered approximately one hour prior to a feeding and in a specified, 
invariable sequence to minimize the variance in infant responses attributable 
to inconsistencies in test administration 91. Co-I Nist has previously used the 
NAPI in her studies of preterm infants74. 
6.3 Infant participants. To protect the privacy of infants and their parents, we will 
meet with bedside caregivers prior to contacting parents to ensure that it is an 
appropriate time to discuss the study. If parents indicate at any time that they are 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
14 
HRP-503  v.12.10.18 
not interested in participation, we will make no further contact. To protect the 
confidentiality of infants and their data, enrolled infants will be assigned a SID that 
will be used to label all data and samples. No other identifying information will be 
included on data forms. The key linking identifying information and SIDs will be 
encrypted and stored on an electronic password-protected encrypted research server 
at the OSU CON. The key linking names and SIDs, electronic and paper data forms, 
and consent forms will be stored in separate locations. Electronic access to the 
research server is restricted to the OSU CON local area network or virtual private 
network by a Cisco ASA 5510 firewall. Paper data forms and consent forms will be 
stored in locked filing cabinets in a locked office at the OSU CON. Access to the 
key, data, and consent forms will be limited to research team members who have 
been approved by the Institutional Review Board (IRB) and are compliant with all 
required training in the protection of human subjects.  
To minimize risks to the physical safety of infants during the study, we are using 
only non-invasive methods to measure biobehavioral responses. HR and HRV will 
be measured using three infant-sized electrodes attached to the infant’s chest. Two 
additional electrodes attached to the infant’s foot are required to measure SCRs. We 
will use the BIOPAC EL512 electrodes designed specifically for infants and will 
use moistened gauze to remove the electrodes after the observation period to 
minimize the risk of skin irritation. Infants with skin conditions that preclude the 
attachment of additional sensors will be excluded from the study. To minimize 
infant agitation, we will use medical swabs attached to a handle to collect saliva for 
salivary cortisol analysis. These swabs are similar to those used for oral care in the 
NICU and are not distressing to infants. 
For the safe delivery of the NaTI, we have developed specific criteria to determine 
when the intervention should be stopped. The NaTI will be stopped for infants 
experiencing bradycardia, defined as HR less than 100 beats per minute for 10 
seconds, or oxygen desaturation, defined as oxygen saturation less than 85% for 10 
seconds. To prevent the overstimulation of infants during intervention delivery, the 
NaTI will be stopped for tachycardia, defined as HR greater than 200 beats per 
minute for 10 seconds. NaTI delivery may resume with the next planned 
intervention point in the care but will be discontinued for the remainder of the care 
for two or more episodes of bradycardia, oxygen desaturation, or tachycardia 
occurring during intervention delivery as defined above. Additionally, nurses will 
provide clinical interventions, including increasing supplemental oxygen, based on 
their clinical judgement. All adverse events will be recorded and reviewed to 
determine expectedness, relatedness, and severity. 
Nurse participants. We will protect the confidentiality of data for nursing surveys 
by assigning each participating nurse a SID that will be used to label all data. The 
key linking nurse identities to SID will be encrypted and stored on an electronic 
password-protected encrypted research server at the CON. The key linking names 
and SIDs, electronic and paper data forms, and consent forms will be stored in 
separate locations. Electronic access to the research server is restricted to the OSU 
CON local area network or virtual private network by a Cisco ASA 5510 firewall. 
Paper data forms and consent forms will be stored in locked filing cabinets in a 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
15 
HRP-503  v.12.10.18 
locked office in the OSU CON. Access to the key, data, and consent forms will be 
limited to research team members who have been approved by the IRB and are 
compliant with all required training in the protection of human subjects. Surveys 
will request nurse feedback on the intervention and will not include sensitive data. 
Nurses always have the option to skip questions that they do not wish to answer. 
6.4 Infant data will be generated from the study procedures (e.g. SCRs, HR, HRV, 
behaviors, neurobehavioral assessments) and will be collected from parents of 
participating infants, bedside monitors, and EPIC (e.g. demographic and clinical 
data). Nurse data will be collected from nurses on study forms. 
 
Table 1. Data Categories and Source 
Participant 
Data Item 
Data Source 
Infant 
Heart rate  
Research activity 
 
ECG data for heart rate variability 
Research activity 
 
Skin conductance responses 
Research activity 
 
Salivary cortisol 
Research activity 
 
Behavioral states 
Research activity 
 
NAPI 
Research activity 
 
 
 
 
Infant Data Form (attached) 
Research activity, 
bedside monitors, 
EPIC 
 
Mother Demographic Form (attached) 
Parent  
 
 
 
Nurse 
Demographic Form (attached) 
Nurse 
 
NaTI Survey (attached) 
Nurse 
 
Acceptability, Appropriateness, and Feasibility 
for Nurses Form (attached) 
Nurse 
 
7.0 
Data and Specimen Banking* 
7.1 With parental consent for infant data and nurse consent for nurse data, all data will 
be stored indefinitely on the OSU CON’s secure research server or in locked filing 
cabinets within a locked office in the OSU CON. After the required data retention 
period, the encrypted key linking SIDs with participant identities will be deleted. 
The resulting dataset will contain only de-identified data. We will not store samples 
collected during this study long-term. There will be no samples remaining after this 
study is complete.  
7.2 Data may be used for future unspecified research with parental and nurse consent, 
which will be provided with the initial consent for this study. Future studies will be 
related to this research and will undergo IRB review prior to the use of any data 
collected during this study, as required. Data will not be available for use outside of 
this research team. 
8.0 
Sharing of Results with Subjects* 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
16 
HRP-503  v.12.10.18 
8.1 Individual results will not be shared with participants. If parents are present at the 
time of the neurobehavioral assessment, we will explain the range of responses 
possible for preterm infants and will describe mature versus immature responses. 
Parents of participating infants and nurse participants may request aggregate data to 
be distributed at the conclusion of the study by writing to Marliese Nist, Newton 
Hall, 1585 Neil Avenue, Columbus OH 43210. Study results will also be 
disseminated through peer-reviewed publications and internal and external research 
presentations. 
9.0 
Study Timelines* 
9.1 Participation for infants each day will last approximately 6 hours and will begin 
when electrodes to measure SCRs are attached to the infant during the care episode 
prior to the observed care. Infant participation to measure biobehavioral responses 
to care will last approximately 24-48 hours and will include two 6-hour observation 
periods as described above, one each on two consecutive days. If a participating 
infant is not available on the second consecutive day due to an off-unit or scheduled 
procedure, data collection will resume on the next possible day. Total infant 
participation in the study will last between 5-7 weeks, depending on PMA at birth 
and the timing of the neurobehavioral assessment planned for 35 weeks PMA. 
Nurse participation is expected to last 15-20 minutes or the time required to 
complete the demographic questionnaire and study questionnaires. Nurses may be 
asked to complete additional sets of questionnaires if they provide the NaTI more 
than once. 
We expect that infant enrollment will require four months. Nurse participants will 
be enrolled at the time of infant data collection for infants. 
Preliminary data analysis should be complete 9 months after enrollment of the first 
infant participant. 
10.0 Inclusion and Exclusion Criteria* 
10.1 Infant participants. We will request a partial HIPAA waiver for activities 
preparatory to research to periodically screen the NICU census for eligible infants. 
We will first screen the census to identify infants born in the specified age range 
(i.e. 27-30 PMA). Infants who are eligible by PMA at birth will be further screened 
for eligibility based on inclusion and exclusion criteria. 
Nurse participants. Eligible nurse participants will be identified by the research 
team during infant data collection as those caring for infants receiving the NaTI. No 
screening of nurse participants will be required. 
10.2 Infant participants. Infants will be included if they are (1) born between 27-30 
weeks PMA, (2) born to mothers who are English-speaking and able to provide 
informed consent, and (3) no more than 10 days old at the time of enrollment. 
Infants will be excluded if they (1) are diagnosed with Grade III/IV intraventricular 
hemorrhage or other neurologic abnormality (e.g. seizure disorder) affecting 
sensory perception or motor function, (2) are diagnosed with a congenital anomaly 
requiring surgery during the neonatal period, (3) are receiving scheduled steroids or 
vasopressors, (4) have skin conditions that preclude the attachment of sensors, (5) 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
17 
HRP-503  v.12.10.18 
are diagnosed with neonatal abstinence syndrome or born to mothers with known 
illicit drug use, except marijuana, during pregnancy, (6) are diagnosed with 
chromosomal abnormalities, or (7) require special isolation that includes universal 
gloving for potentially infectious pathogens. 
Nurse participants. Eligible nurses will be those providing care to infants receiving 
the NaTI. There are no additional inclusion or exclusion criteria for nurses. 
10.3 Infant participants. All infant participants will be preterm infants. 
Nurse participants. Nurse participants will be nurses working in the NICU. There 
may be pregnant nurses in the sample of nurse participants. 
11.0 Vulnerable Populations* 
11.1 Infant participants. Participants in this study will be preterm infants born 27-30 
weeks PMA. We will not enroll extremely preterm infants of uncertain viability. 
The study procedures pose no more than minimal risk to infant participants and may 
have potential, if slight, benefit for infants. We will obtain written informed consent 
from parents prior to the initiation of any study procedures. Parents will be given 
adequate time to consider participation in the study prior to providing written 
informed consent. Infant participants will not provide assent, as infants are 
developmentally unable to do so. 
Nurse participants. Nurse participants may include pregnant women. This is a 
minimal risk study for nurse participants and poses no physical risk to a pregnant 
nurse’s fetus. Nurse participants will provide written informed consent prior to 
participation. 
12.0 Local Number of Subjects 
12.1 Infant participants. All infants will be enrolled from the NCH NICUs. We will 
enroll up to 20 infants to collect complete, usable data from 16 infants. 
Nurse participants. Nurses will be those employed in the NCH NICUs. We will 
invite all nurses who provide care to infants receiving the NaTI to participate in the 
survey study, providing up to 20 total opportunities for nurse responses. Assuming 
80% participation, we expect up to 16 nurse responses. 
13.0 Recruitment Methods 
13.1 Infant participants. After identifying an eligible infant, study staff will meet with 
parents in the NICU or in the mother’s postpartum hospital room to introduce the 
study. Study staff will wait until parents have visited the NICU to see their infant 
and receive a medical update prior to attempting to contact parents. Study staff will 
check with bedside caregivers in the NICU or the postpartum unit to ensure that it is 
an appropriate time to meet with parents. During the first meeting, study staff will 
provide parents with an informational flier that outlines the study purpose and 
procedures. We will ask parents if it is a good time to discuss their infant’s 
eligibility for a research study and will conduct any follow-up discussion either in-
person or over the phone based on parental preference. Study staff will provide a 
thorough overview of the study, including the study purpose, procedures, potential 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
18 
HRP-503  v.12.10.18 
risks and benefits, and the voluntary nature of participation and will inform parents 
that they may withdraw from the study at any time. Parents will have until their 
infant reaches two weeks of age to decide whether or not to participate in the study. 
For this minimal risk study, written informed consent will be required from one 
parent. If parents are unmarried without a paternity affidavit, consent will be 
obtained from the mother according to Ohio law. 
Nurse participants. Prior to beginning infant enrollment, we will provide unit-
based education for staff to introduce the intervention and the nursing survey study. 
Nurses will be individually approached at the time of infant observation. Study staff 
will provide an overview of the nursing survey study, including a discussion of the 
study purpose, surveys, potential risks, and the voluntary nature of the study. 
Nurses will have until the end of their shift to decide whether or not to participate in 
the study. At the time that consent is obtained, we will explain to nurses that they 
may be asked to complete additional surveys if they provide the NaTI again. They 
will be told at the time of consent and reminded, if they are asked to complete 
additional surveys, that study participation is completely voluntary. Study staff will 
further inform nurses that their decision to participate in the study will have no 
effect on their employment. 
13.2 All infant participants will be hospitalized patients in the NCH NICUs. Nurse 
participants will be registered or licensed practical nurses employed in the NCH 
NICUs and providing care to infants receiving the NaTI. 
13.3 Potential infant participants will be identified through periodic screening of the 
NICU census for recently admitted infants who meet inclusion criteria. Potential 
nurse participants will be identified during data collection for infants. 
13.4 We will provide nurses employed in the NCH NICUs with an educational 
PowerPoint prior to the enrollment of infants. This PowerPoint will provide an 
overview of the study and will introduce nurses to the nursing survey study. 
13.5 We will provide a small board book to participating infants at the time of the first 
observation and data collection. We will provide nurses with a $10 Target gift card 
at the time of data collection each time they agree to complete a set of surveys. 
14.0 Withdrawal of Subjects* 
14.1 Infant participants may be withdrawn from the study if they become ineligible for 
participation based on the inclusion and exclusion criteria between the time that 
written informed consent is obtained from parents and the time that data collection 
commences. Nurse participants will not be withdrawn from the study. 
14.2 If infants are withdrawn from the study prior to data collection, we will inform 
parents that their infant is no longer participating in the study due to pre-established 
inclusion and exclusion criteria. 
14.3 If infants are withdrawn from the study, previously collected data (i.e. demographic 
data) may be used but further data collection will cease. 
15.0 Risks to Subjects* 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
19 
HRP-503  v.12.10.18 
15.1 Infant risks. We do not expect the static touches provided during the NaTI to 
increase the risk for physiologic decompensation beyond the risk that exists for 
essential nursing care. We expect that infants will experience physiologic regulation 
during these touches. However, the NaTI will extend the duration of the care 
episode by 2.5 minutes. Some studies of massage in preterm infants report no 
adverse events related to the intervention96-98. A few investigators have reported 
infrequent occurrences of bradycardia, apnea, or desaturation associated with 
massage99,100. In a study of tactile stimulation in preterm infants 26-32 weeks PMA, 
Fucile and Gisel (2010) paused the intervention for 1.1% of the administrations due 
to bradycardia, apnea, or oxygen desaturation. While these are possible risks in our 
study, we expect the occurrence of bradycardia, apnea, and oxygen desaturation to 
be infrequent, especially given the static nature of the NaTI in contrast to the 
stimulation of massage or tactile stimulation.  
We will collect biobehavioral data from infants. HR and HRV will be collected 
from monitoring equipment similar to that used as part of clinical care in the NICU. 
The collection of HR and HRV data will require the attachment of three additional 
ECG electrodes to the infant’s chest. If the infant’s chest is not large enough to 
accommodate the additional electrodes, electrodes for clinical monitoring can be 
moved to the infant’s back at the nurse’s discretion. The additional ECG electrodes 
may cause mild erythema after removal, similar to the removal of electrodes used 
for clinical monitoring. SCRs will require the attachment of two additional 
electrodes with isotonic gel to the infant’s foot. These electrodes may cause mild 
erythema after removal, similar to the removal of electrocardiogram electrodes used 
for clinical monitoring. Salivary cortisol will be collected three times during the 
observation period (prior to the start of the care episode, 30 minutes after the care 
episode, 60 minutes after the care episode) using small medical swabs similar to 
those used to provide oral care to preterm infants. The swab will be gently 
introduced into the infant’s mouth and held securely using the attached handle. 
There are no expected risks to infants from the saliva collection. Protected health 
information (PHI), including maternal prenatal data and infant clinical data, will be 
collected from each infant’s EHR. There is a small risk of loss of confidentiality. 
Nurse participants. Nurses will be asked to complete a demographic questionnaire 
once and an investigator-developed NaTI survey, the AIM90, the IAM90, and the 
FIM90 each time they provide the NaTI to an infant. There is a small risk of loss of 
confidentiality for nurses who agree to participate. Surveys request nurse feedback 
on the intervention and will not include sensitive data. 
15.2 As part of the biobehavioral data collection, there may be risks to infant participants 
that are not foreseeable. 
15.3 If a pregnant nurse chooses to participant in the nursing survey study, there are no 
risks to her fetus. 
16.0 Potential Benefits to Subjects* 
16.1 Infants may directly benefit from the comforting touches provided by the NaTI 
although we can neither offer nor guarantee this potential benefit. We hypothesize 
that these touches will attenuate activation of the infant’s stress response systems. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
20 
HRP-503  v.12.10.18 
16.2 There is no direct benefit to nurses who participate in the nursing survey study. The 
survey study provides nurses with the opportunity to describe their perception of the 
NaTI and their suggestions for NaTI revisions. In this way, nurses will have the 
opportunity to be part of the decision-making process for their practice. 
17.0 Data Management* and Confidentiality 
17.1 Aim 1. The primary aim is to determine the effect of a NaTI on biobehavioral stress 
responses of preterm infants during essential nursing care. Our primary analysis 
will compare mean values of biobehavioral stress responses during an episode of 
essential care between cohorts (comparison vs interventions conditions). We will 
begin by examining sequence effects. We will then compare the biobehavioral 
stress responses of infants assigned to each condition using linear mixed models to 
account for multiple observations within infants. Additional variables may be added 
if potential confounding variables are identified between conditions, although none 
are anticipated. Secondary analyses will consider total area under the curve (AUC) 
for each biobehavioral response variable to identify important differences in overall 
recovery between conditions. For the primary (i.e. comparison of means during 
care) and secondary (i.e. comparisons of AUC) analyses, we will examine 
differences in outcomes by important biological variables (e.g. infant sex) and will 
repeat the analysis, including interactions to identify possible moderation of the 
effect by infant sex, race, ethnicity, and PMA at birth. 
Aim 2. We will use measures of central tendency and variance to describe nurses’ 
Likert responses. We will identify barriers and facilitators of intervention 
implementation for each episode of essential care during hospitalization from 
narrative responses. 
Aim 3. We will use correlation analysis and regression models to determine the 
associations between biobehavioral stress responses and neurobehavioral outcomes.  
17.2 To protect the confidentiality of infant and nurse participants and their data, infant 
and nurse participants will be assigned a SID that will be used to label all data and 
samples. No other identifying information will be included on data forms. The key 
linking identifying information and SIDs will be encrypted and stored on an 
electronic password-protected research server at the OSU CON. The key linking 
names and SIDs, electronic and paper data forms, and consent forms will be stored 
in separate locations. Electronic access to the research server is restricted to the 
OSU CON local area network or virtual private network by a Cisco ASA 5510 
firewall. Paper data forms and consent forms will be stored in locked filing cabinets 
in a locked office at the OSU CON. Access to the key, data, and consent forms will 
be limited to research team members who have been approved by the IRB and are 
compliant with all required training in the protection of human subjects.  
17.3 We will verify 100% of the data collected from the EHR for 25% of infant 
participants against the source documentation (i.e. EPIC).  
17.4 All data and samples will be transported to the OSU CON under a Data Transport 
Authorization from the NCH Privacy Office and stored at the OSU CON under 
Data Use and Materials Transfer Agreements. With parental consent for infant data 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
21 
HRP-503  v.12.10.18 
and samples and nurse consent for nurse data, data and samples will be stored 
indefinitely. Access to the data and samples will be limited to study staff who have 
been approved by the IRB, are compliant with human subjects protections training, 
and have been trained by the PI on data storage procedures. Data and samples will 
be transported only by the study PI. 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
18.1 A data safety and monitoring plan has been developed for this clinical trial. 
Purpose. The purpose of our data safety and monitoring plan (DSMP) is to 
safeguard the welfare of human subjects participating in the clinical trial through 
the regular review of safety data related to the intervention. The DSMP ensures that 
the research staff and principal investigator (PI) follow specific guidelines with 
respect to accurate data management and the assessment and timely reporting of 
adverse events associated with the investigational study Nursing Touch and 
Biobehavioral Stress Responses of Very Preterm Infants. The DSMP for the 
proposed study incorporates the Policies on Data and Safety Monitoring specified 
by OSU, NCH, the IRB, the Office of Regulatory Knowledge and Support in the 
Center for Clinical and Translational Science, and the OSU CON Data Safety 
Monitoring Committee (DSMC).   
Data Safety Monitoring Committee. The DSMC is comprised of tenured faculty 
from the OSU CON with expertise in the conduct and analysis of clinical trials in 
the acute care setting. Members of the DSMC include Dr. Mary Beth Happ, 
Distinguished Professor of Critical Care Research and Associate Dean of Research 
and Innovation; and Dr. Alai Tan, Research Associate Professor and biostatistician. 
Members of the DSMC have no apparent conflicts of interest related to the 
proposed study and are not current collaborators of any study investigators. DSMC 
members will report arising conflicts of interest to fellow members and the study 
investigators. DSMC members who develop significant conflicts of interest will 
resign from the DSMC.  
DSMC members who leave OSU or resign their position prior to the conclusion of 
the clinical trial will be replaced with a new member appointed by the study 
investigators. 
Interim Monitoring Procedures. On a monthly basis, the PI will produce interim 
reports specifically focusing on missing data and entry errors. The progress of the 
study will be monitored biannually by the college DSMC. On a biannual basis, the 
PI will prepare a written report on the progress of the study that will include data 
on: enrollment, comparison of target to actual enrollment, information on race, 
ethnicity, sex, overall status of the study participants, protocol deviations, and 
adverse or serious adverse events. These data will be collected in a spreadsheet 
format and reviewed by Marliese Nist (Study PI). All reports will be reviewed by 
the DSMC on a biannual basis. After each report is reviewed, the Committee will 
recommend whether the study should continue, continue with modifications, or be 
terminated. PI reports and minutes from DSMC meetings will also be sent to the 
Office of Responsible Research Practices. Co-I Pickler, who has extensive 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
22 
HRP-503  v.12.10.18 
experience with DSMCs and the conduct of clinical trials, will assist the PI in 
developing these reports. 
Procedures for Adverse Events 
Identification of adverse events. Study staff will be at the bedside during infant 
data collection and will record the occurrence of adverse events in real time. 
Adverse events (AEs) will be reported immediately to the PI. Adverse events may 
also be identified by parents or neonatal intensive care unit staff, who are 
encouraged to alert the PI of these events. During the consent process, participating 
nurses and parents of participating infants will be informed of the minimal risk 
nature of this study and encouraged to report any AEs immediately to study staff. 
The PI will maintain an electronic record of AEs and will include a description of 
AEs in the written report submitted biannually to the DSMC. Given the short-term 
duration of infant participation in the study, AEs will be tracked from the time that 
infant participation begins following the attachment of sensors for data collection 
and will continue until the end of the recovery period (i.e. 30 minutes after the final 
direct touch of the care episode). 
Definitions. Adverse Event: Any unfavorable and unintended sign, regardless of 
whether it is considered related to the intervention; also an “unanticipated problem” 
of any nature (e.g., psychological or social harm; designated as unrelated, definitely 
related, probably related, or possible related; see below). Serious adverse event 
(SAE): Any adverse event that is fatal or life threatening, is permanently disabling 
or requires prolongation of hospitalization. Life-threatening event: Any adverse 
event in which the subject is at immediate risk of death from the reaction as it 
occurs; does not include a reaction that, if it were to occur in a more serious form, 
might cause death. Unexpected event: Any adverse event that is not identified in 
nature, severity, or frequency in the study protocol or consent or the event was more 
serious than anticipated. Definitely Related: An adverse event that has a timely 
relationship to the administration of the investigational study procedure and follows 
a known pattern of response for which no alternative cause is present. Probably 
Related: An adverse event that has a timely relationship to the administration of the 
investigational study procedure and follows a known pattern of response, but for 
which a potential alternative cause may be present. Possibly Related:  An adverse 
event that has a timely relationship to the administration of the investigational study 
procedure and follows no known pattern of response, but a potential alternative 
cause does not exist. Unrelated:  An adverse event for which there is evidence that 
it is definitely related to a cause other than the investigational study procedure; in 
general no timely relationship to the administration of the procedure exists, or if so, 
the event does not follow a pattern of response and an alternative cause is present. 
Grading scale for adverse event severity. Mild: Transient bradycardia (defined by 
clinical parameters established for each patient, usually heart rate <100 beats per 
minute), apnea, or oxygen desaturation requiring no intervention or an increase in 
supplemental oxygen. Bradycardia and oxygen desaturation are defined by clinical 
parameters established for each patient, usually heart rate <100 beats per minute or 
oxygen saturation <85% lasting 10 seconds. Erythema resulting from monitoring 
electrodes. Moderate: Bradycardia, apnea, or oxygen desaturation requiring an 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
23 
HRP-503  v.12.10.18 
increase in respiratory support (i.e. hand-bagging). Epidermal stripping (i.e. non-
intact skin) resulting from monitoring electrodes. Severe: Physiologic 
decompensation requiring intubation or cardiopulmonary resuscitation. 
Review of adverse events. The study investigators will provide an initial review of 
all AEs to the DSMC to determine their relatedness to the research and preliminary 
grading of severity. For each AE, the PI will record the onset, duration, intensity, 
treatment required, outcome and action taken. SAEs are not expected to occur 
during this study. Possibly, probably, or definitely related AEs, as determined by 
the study team, will be reported within 24 hours to the DSMC chair for further 
review. The DSMC will make the final determination on AE severity and 
relatedness. 
Reporting of adverse events. Final evaluation of relatedness and severity of AEs 
will be determined by the DSMC. In accordance with NCH IRB Adverse Event 
Reporting Policy, an AE is reportable to the IRB within 5 business days if it meets 
all of the following criteria: (1) the event is unexpected, (2) the event is related or 
probably related to study participation, and (3) is serious and/or suggests that the 
research places subjects or others at a greater risk of physical or psychological harm 
than was previously known or recognized. Additionally, per NCH IRB policy, all 
protocol deviations or violations that harmed participants or indicate that others 
might be at increased risk of harm, breaches of confidentiality, and new literature 
that may affect willingness to participate are reportable events within 5 business 
days. AEs that must be reported annually with continuing review include: (1) minor 
protocol deviations that do not indicate an increased risk of harm, and (2) AEs that 
are not serious or unexpected. After review by the DMSC, all reportable AEs will 
be submitted by the PI to the NCH IRB. Reportable AEs will be forwarded to the 
NIH/NINR Program Officer by the NCH IRB. In addition, reportable AEs and the 
IRB acknowledgement letter and cumulative reportable AEs, SAEs, and 
unanticipated problems will be forwarded to the NIH/NINR Program Officer with 
the PI’s Annual Progress Report. .   
Assessment of External Factors. Because essential nursing care involves the 
handling of preterm infants, we do not expect 2.5 minutes of comforting touch 
provided during the care episode to increase the risk for AEs beyond what is 
expected during essential nursing care. The study investigators will meet monthly to 
discuss new developments and safety concerns. Prior to each monthly meeting, the 
PI will conduct a literature search to identify new developments that might affect 
the evaluation of risk for this study. 
 
19.0 Provisions to Protect the Privacy Interests of Subjects 
19.1 Study staff will approach parents for infant recruitment only after they have visited 
the NICU to see their infant and received a medical update. Study staff will check 
with bedside caregivers in the NICU or the postpartum unit to ensure that it is an 
appropriate time to meet with parents. During the first meeting, study staff will ask 
parents if it is a good time to discuss their infant’s eligibility for a research study. 
We will contact parents no more than three times for enrollment unless parents 
request additional meetings and will cease all recruitment efforts if parents indicate 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
24 
HRP-503  v.12.10.18 
that they are not interested in the study. We will access the minimum necessary PHI 
to determine infant eligibility. 
We will provide unit education to all staff prior to the enrollment of infants so that 
nurses will be familiar with the study prior to any efforts to recruit individual 
nurses. To recruit individual nurses, study staff will approach nurses at the time of 
infant observation for an enrolled infant. We will cease all recruitment efforts if 
nurses indicate that they are not interested in participation.  
19.2 We will fully explain all study procedures prior to participant enrollment and will 
remind parents and nurses that they may withdraw from the study at any time 
without penalty. We will provide participants with an explanation of our data safety 
procedures to code data with a SID. Although we will not be collecting sensitive 
data, we will inform parents of participating infants and nurse participants at the 
time of data collection that they may leave questions blank if they are not 
comfortable answering them. 
19.3 Parents of participating infants will provide some data for their infants (i.e. 
demographic data) and will provide written HIPAA authorization included in the 
consent form for the study team to collect data from the EHR. Data to address Aim 
2 will be collected directly from nurses. 
20.0 Compensation for Research-Related Injury 
20.1 This is a minimum risk study for which we do not anticipate research-related 
injuries.  
21.0 Economic Burden to Subjects 
21.1 There will be no costs incurred by participants in the study. 
22.0 Consent Process 
22.1 Infant participants. Written informed consent will be obtained from parents of 
eligible infants either in the NICU or in the mother’s postpartum hospital room. 
Study staff will approach parents any time after parents have visited their infant. 
Parents may complete the written informed consent document any time after the 
study team has discussed the study with parents and will have until their infant 
reaches 10 days of life to decide whether or not to participate in the study. For this 
minimum risk study, written informed consent will be required from one parent. If 
parents are unmarried without a paternity affidavit, consent will be obtained from 
the mother according to Ohio law. In addition to the initial discussion of the study, 
we will provide an explanation of the study procedures when we provide parents 
with the demographic data form and again when we collect infant data in the NICU 
if the parents are present.  
Nurse participants. Written informed consent will be obtained from nurses who 
choose to participate in the study. Study staff will approach potential nurse 
participants at the time of infant observation. Nurses may provide written informed 
consent any time after the study has been fully explained and all questions answered 
by study staff and may have until the end of their shift to decide whether or not to 
participate. Nurses will be told during the initial consent process that they may be 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
25 
HRP-503  v.12.10.18 
approached again if they care for another enrolled infant during infant data 
collection but that they have the right to withdraw from the study at any time. If the 
same nurse is approached a second time for participation, study staff will remind 
him/her that participation is completely voluntary. 
Informed consent from parents and nurses will be obtained following “SOP: 
Informed Consent Process for Research (HRP-090)”. 
Non-English Speaking Subjects – if known, skip if not known 
• 
Study staff will recruit only English-speaking participants for the study. 
Subjects who are not yet adults (infants, children, teenagers) 
• 
Consent for infant participation will be obtained from one of the infant’s 
biological parents or his/her legal guardian. Parents who are not yet adults are 
legally authorized to provide consent for their minor children. For this 
minimum risk study, written informed consent will be required from one 
parent/legal guardian. If parents are unmarried without a paternity affidavit, 
consent will be obtained from the mother according to Ohio law. Assent will 
not be obtained from infants, as infants are developmentally unable to provide 
assent. 
• 
Consent for nurse participation will be obtained from nurses, who are legal 
adults and able to provide consent for themselves. 
23.0 Process to Document Consent in Writing 
23.1 Study staff will follow “SOP: Written Documentation of Consent (HRP-091)” to 
document consent in writing for infant and nurse participants. 
 
24.0 Setting 
24.1 Infant participants will be identified through periodic screening of the EHR. Infants 
will be recruited either in the NCH NICUs or in the mother’s postpartum hospital 
room. Nurse participants will be recruited during their normal working hours in the 
NCH NICUs. 
All study procedures will take place in the NCH NICUs. Surveys for nurse 
participants will be distributed in the NICU, but nurses may take these home and 
return them during their next scheduled shift. 
Data storage and analysis and sample processing, storage, and analysis will take 
place at the OSU CON.  
The study protocol will be submitted to the NCH and OSU IRBs. OSU is expected 
to cede review to NCH. IRB oversight for the study will be provided by the NCH 
IRB. 
25.0 Resources Available 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
26 
HRP-503  v.12.10.18 
25.1 The NCH Neonatal Network admitted 372 infants born 27-30 weeks PMA in 2020, 
and the study team has extensive experience working with preterm infants in this 
age range and within the NCH NICUs. PI Nist, who is certified by the National 
Certification Corporation in neonatal intensive care nursing, worked for 10 years in 
the NCH main campus NICU, caring for preterm infants as a bedside nurse. For a 
study conducted between October 2017 and December 2018, this study team 
enrolled a sample of 73 preterm infants born 28-31 weeks PMA from the NCH 
Neonatal Network. 
25.2 PI Nist (OSU) will oversee all aspects of the study, including ensuring compliance 
with regulatory, IRB, and organizational requirements. Dr. Nist will screen and 
recruit eligible infants and will obtain informed consent from parents. Working with 
the graduate research assistants, Dr. Nist will perform nurse training and on-site 
data collections. She will work with the Co-Is to clean and analyze physiologic data 
(i.e. HR, HRV, and SCRs). In cooperation with Co-I Pickler, Dr. Nist will oversee 
all salivary cortisol laboratory assays. Dr. Nist will work with the graduate research 
assistants to complete all data entry. She will coordinate efforts among the research 
team and plan and initiate disseminations efforts.  
Co-I Harrison (OSU) will provide access to and training for the MARS® 
Ambulatory ECG Analysis and Editing System. Dr. Harrison will oversee cleaning 
and analysis of HRV data. In collaboration with the research team, Dr. Harrison 
will assist with data interpretation and dissemination efforts.  
Co-I Pickler (OSU) will assist the PI in ensuring regulatory compliance and 
maintaining regulatory documentation for this clinical trial, including reviewing and 
reporting adverse events, as required. Dr. Pickler will provide oversight of 
intervention fidelity and will work with the PI to train laboratory personnel in the 
CON Stress Science Lab on protocols for the extraction of salivary cortisol from 
filter paper. Dr. Pickler will assist with data interpretation and dissemination efforts.  
Co-I Shoben (OSU) will provide all statistical support for the project. Dr. Shoben 
will develop the randomization scheme for the cross-over trial and will assist in 
addressing data collection issues related to missing data or other unforeseen 
circumstances. Dr. Shoben will conduct the statistical analysis to address the aims. 
Dr. Shoben will participate in interpretation of study findings and dissemination 
efforts. 
Co-Nelin (NCH) will serve as site PI for NCH and will act as liaison between OSU 
and NCH, assisting with the identification and recruitment of participants at the 
clinical site. Dr. Nelin will ensure the safety of all study participants and will assist 
with reviewing and reporting adverse events, as required. Dr. Nelin will assist with 
data interpretation and dissemination efforts. 
Graduate Research Assistants will be hired to assist the PI in completing the day-
to-day operations of the study, including on-site data collection, cleaning and 
analysis of physiologic data in preparation for statistical analysis, and data entry. 
The Research Assistants will perform HRV analysis under the supervision of the PI.  

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
27 
HRP-503  v.12.10.18 
25.3 All members of the study team will be required to complete and maintain current 
CITI Program training as required by NCH and OSU. PI Nist will train all study 
staff on relevant standard operating procedures relevant to each person’s assigned 
responsibilities and will document this training in study records. 
25.4 All equipment and supplies need to perform study activities are available at NCH or 
OSU or will be purchased from the study budget. 
26.0 Multi-Site Research* 
26.1 Participant recruitment and enrollment will fall under the authority of the NCH 
IRB. We will enroll up to 20 infant participants from the NCH NICUs for the study. 
We will recruit all eligible nurses for participation. Eligible nurses are registered or 
licensed practical nurses providing the NaTI to infants, providing up to 20 total 
opportunities for nurse responses. Assuming 80% participation, we expect up to 16 
nurse responses. Infant and nurse participants will be recruited from the NCH 
NICUs. 
26.2 PI Nist is a PI at OSU and external collaborator at NCH. Dr. Nist will be 
responsible for all communication between NCH and OSU, including 
correspondence with the IRB. Communication between sites will be enhanced by 
monthly study meetings that will include all study staff at NCH and OSU. 
26.3 Data and samples will not be stored at NCH and will be immediately transported to 
OSU for secure storage. 
27.0  Protected Health Information Recording 
 
1.0 
Indicate which subject identifiers will be recorded for this research. 
☒  Name 
☐  Complete Address 
☐  Telephone or Fax Number 
☐  Social Security Number (do not check if only used for ClinCard) 
☒  Dates (treatment dates, birth date, date of death) 
☒  Email address, IP address or url 
☒  Medical Record Number or other account number 
☐  Health Plan Beneficiary Identification Number 
☒  Full face photographic images and/or any comparable images (x-rays) 
☐  Account Numbers 
☐  Certificate/License Numbers 
☐  Vehicle Identifiers and Serial Numbers (e.g. VINs, License Plate Numbers) 
☐  Device Identifiers and Serial Numbers 
☐  Biometric identifiers, including finger and voice prints 
☐  Other number, characteristic or code that could be used to identify an individual 
☐  None (Complete De-identification Certification Form) 
 
2.0   
Check the appropriate category and attach the required form* on the Local Site 
Documents, #3. Other Documents, page of the application.  (Choose one.) 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
28 
HRP-503  v.12.10.18 
☒  Patient Authorization will be obtained. (Include the appropriate HIPAA language (see 
Section 14 of consent template) in the consent form OR attach the HRP-900, HIPAA 
AUTHORIZATION form.) 
☐  Protocol meets the criteria for waiver of authorization. (Attach the HRP-901, WAIVER OF 
HIPAA AUTHORIZATION REQUEST form.) 
☐  Protocol is using de-identified information. (Attach the HRP-902, DE-IDENTIFICATION 
CERTIFICATION form.) (Checked "None" in 1.0 above) 
☐  Protocol involves research on decedents. (Attach the HRP-903, RESEARCH ON 
DECEDENTS REQUEST form.) 
☐  Protocol is using a limited data set and data use agreement. (Contact the Office of 
Technology Commercialization to initiate a Limited Data Use Agreement. 
 
*Find the HIPAA forms in the IRB Website Library, Templates. 
 
Attach the appropriate HIPAA form on the “Local Site Documents, #3. Other Documents”, 
page of the application. 
 
3.0 
How long will identifying information on each participant be maintained? 
 
Identifying information will be maintained with research records for six years after the study is 
closed, in accordance with NCH IRB requirements. After this time, identifiers will be removed 
from study records. Signed and dated consent documents and HIPAA authorizations will be 
maintained for six years after the study is closed, in accordance with NCH IRB requirements. All 
study records, consent documents, and HIPAA authorizations will be stored in a locked filing 
cabinet within a locked office at the OSU CON or on a password-protected research server at the 
OSU CON. Access to study records will be limited to IRB-approved study staff. 
 
4.0 
Describe any plans to code identifiable information collected about each participant. 
 
Each participating infant and nurse will be assigned a SID to label paper data forms and 
electronic data. The key linking identifiers and SIDs will be encrypted and kept on a password-
protected research server at the OSU CON in a separate folder from study data. Identifiers will 
be removed from this key six years after the study is closed.  
 
5.0 
Check each box that describes steps that will be taken to safeguard the confidentiality of 
information collected for this research: 
X     Research records will be stored in a locked cabinet in a secure location 
X     Research records will be stored in a password-protected computer file 
X     The list linking the assigned code number to the individual subject will be maintained 
separately from the other research data 
X     Only certified research personnel will be given access to identifiable subject information 
 
6.0 
Describe the provisions included in the protocol to protect the privacy interests of subjects, 
where "privacy interests" refer to the interest of individuals in being left alone, limiting 
access to them, and limiting access to their information. (This is not the same provision to 
maintain the confidentiality of data.) 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
29 
HRP-503  v.12.10.18 
 
Study staff will approach parents for infant recruitment only after they have visited the 
NICU to see their infant and receive a medical update. Study staff will check with 
bedside caregivers in the NICU or the postpartum unit to ensure that it is an appropriate 
time to meet with parents. During the first meeting, study staff will ask parents if it is a 
good time to discuss their infant’s eligibility for a research study. We will contact parents 
no more than three times for enrollment unless parents request additional meetings and 
will cease all recruitment efforts if parents indicate that they are not interested in the 
study. We will access the minimum necessary PHI to determine infant eligibility. 
We will provide unit education to all staff prior to the enrollment of infants so that nurses 
will be familiar with the study prior to any efforts to recruit individual nurses. To recruit 
individual nurses, study staff will approach nurses for participation at the time of infant 
observation for an enrolled infant. We will cease all recruitment efforts if nurses indicate 
that they are not interested in participation.  
 
 
Confidential Health Information 
 
1.0 
Please mark all categories that reflect the nature of health information to be accessed and 
used as part of this research. 
 
☒  Demographics (age, gender, educational level) 
☒  Diagnosis 
☒  Laboratory reports 
☒  Radiology reports 
☒  Discharge summaries 
☒  Procedures/Treatments received 
☒  Dates related to course of treatment (admission, surgery, discharge) 
☒  Billing information 
☒  Names of drugs and/or devices used as part of treatment 
☒  Location of treatment 
☐  Name of treatment provider 
☒  Surgical reports 
☒  Other information related to course of treatment 
☐  None 
 
2.0 
Please discuss why it is necessary to access and review the health information noted in your 
response above. 
 
Clinical information for infants is required to describe illness severity, treatment course, and 
diagnosis to determine study eligibility, differences in the effect of the intervention based on 
these variables, and differences between cohorts. Demographic information is needed to 
determine study eligibility and differences in the intervention’s effect based on infant sex. Billing 
information is needed to determine insurance type, a proxy for socioeconomic status. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
30 
HRP-503  v.12.10.18 
 
Demographic information for nurse participants will be collected directly from enrolled nurses. 
No PHI will be collected from nurses. 
 
3.0 
Is the health information to be accessed and reviewed the minimal necessary to achieve the 
goals of this research?  ☒ Yes    ☐ No 
 
4.0 
Will it be necessary to record information of a sensitive nature?  ☐ Yes   ☒ No 
 
5.0 
Do you plan to obtain a federally-issued Certificate of Confidentiality as a means of 
protecting the confidentiality of the information collected?  ☒ Yes   ☐ No 
 
 
 
References 
1. 
Gardner FC, Adkins CS, Hart SE, Travagli RA, Doheny KK. Preterm stress behaviors, 
autonomic indices, and maternal perceptions of infant colic. Advances in neonatal care : official 
journal of the National Association of Neonatal Nurses. 2018;18(1):49-57. 
2. 
Marques AH, Silverman MN, Sternberg EM. Evaluation of stress systems by applying 
noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate 
variability and salivary cortisol. Neuroimmunomodulation. 2010;17(3):205-208. 
3. 
Allotey J, Zamora J, Cheong-See F, et al. Cognitive, motor, behavioural and academic 
performances of children born preterm: a meta-analysis and systematic review involving 64 061 
children. BJOG: An International Journal of Obstetrics and Gynaecology. 2018;125(1):16-25. 
4. 
Ionio C, Riboni E, Confalonieri E, et al. Paths of cognitive and language development in healthy 
preterm infants. Infant behavior & development. 2016;44:199-207. 
5. 
van Noort-van der Spek IL, Franken MC, Weisglas-Kuperus N. Language functions in preterm-
born children: a systematic review and meta-analysis. Pediatrics. 2012;129(4):745-754. 
6. 
Schieve LA, Tian LH, Rankin K, et al. Population impact of preterm birth and low birth weight 
on developmental disabilities in US children. Annals of epidemiology. 2016;26(4):267-274. 
7. 
Clements KM, Barfield WD, Ayadi MF, Wilber N. Preterm birth-associated cost of early 
intervention services: an analysis by gestational age. Pediatrics. 2007;119(4):e866-874. 
8. 
Curry AE, Pfeiffer MR, Slopen ME, McVeigh KH. Rates of early intervention referral and 
significant developmental delay, by birthweight and gestational age. Maternal and child health 
journal. 2012;16(5):989-996. 
9. 
Fefferman ML, Andrews BL, Msall ME. Disparities in access to early intervention services for 
extremely preterm infants by family income. International Public Health Journal. 
2017;9(2):155-167. 
10. 
Brummelte S, Grunau RE, Chau V, et al. Procedural pain and brain development in premature 
newborns. Annals of neurology. 2012;71(3):385-396. 
11. 
Ranger M, Zwicker JG, Chau CM, et al. Neonatal Pain and Infection Relate to Smaller 
Cerebellum in Very Preterm Children at School Age. The Journal of pediatrics. 
2015;167(2):292-298.e291. 
12. 
Smith GC, Gutovich J, Smyser C, et al. Neonatal intensive care unit stress is associated with 
brain development in preterm infants. Annals of neurology. 2011;70(4):541-549. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
31 
HRP-503  v.12.10.18 
13. 
Valeri BO, Holsti L, Linhares MB. Neonatal pain and developmental outcomes in children born 
preterm: a systematic review. The Clinical journal of pain. 2015;31(4):355-362. 
14. 
Coviello C, Popple Martinez M, Drovandi L, et al. Painful procedures can affect post-natal 
growth and neurodevelopment in preterm infants. Acta paediatrica (Oslo, Norway : 1992). 
2018;107(5):784-790. 
15. 
Gaspardo CM, Cassiano RGM, Gracioli SMA, Furini GCB, Linhares MBM. Effects of neonatal 
pain and temperament on attention problems in toddlers born preterm. Journal of pediatric 
psychology. 2018;43(3):342-351. 
16. 
Cong X, Wu J, Vittner D, et al. The impact of cumulative pain/stress on neurobehavioral 
development of preterm infants in the NICU. Early human development. 2017;108:9-16. 
17. 
Cruz MD, Fernandes AM, Oliveira CR. Epidemiology of painful procedures performed in 
neonates: A systematic review of observational studies. European journal of pain (London, 
England). 2016;20(4):489-498. 
18. 
Cameron EC, Raingangar V, Khoori N. Effects of handling procedures on pain responses of very 
low birth weight infants. Pediatric physical therapy : the official publication of the Section on 
Pediatrics of the American Physical Therapy Association. 2007;19(1):40-47. 
19. 
Lyngstad LT, Tandberg BS, Storm H, Ekeberg BL, Moen A. Does skin-to-skin contact reduce 
stress during diaper change in preterm infants? Early human development. 2014;90(4):169-172. 
20. 
Fernandez D, Antolin-Rodriguez R. Bathing a Premature Infant in the Intensive Care Unit: A 
Systematic Review. Journal of pediatric nursing. 2018. 
21. 
Zeiner V, Storm H, Doheny KK. Preterm infants' behaviors and skin conductance responses to 
nurse handling in the NICU. The journal of maternal-fetal & neonatal medicine : the official 
journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania 
Perinatal Societies, the International Society of Perinatal Obstet. 2016;29(15):2531-2536. 
22. 
Allinson LG, Denehy L, Doyle LW, et al. Physiological stress responses in infants at 29-32 
weeks' postmenstrual age during clustered nursing cares and standardised neurobehavioural 
assessments. BMJ paediatrics open. 2017;1(1):e000025. 
23. 
Avila-Alvarez A, Pertega-Diaz S, Vazquez Gomez L, et al. Pain assessment during eye 
examination for retinopathy of prematurity screening: Skin conductance versus PIPP-R. Acta 
paediatrica (Oslo, Norway : 1992). 2019. 
24. 
Hellerud BC, Storm H. Skin conductance and behaviour during sensory stimulation of preterm 
and term infants. Early human development. 2002;70(1-2):35-46. 
25. 
Cong X, Ludington-Hoe SM, McCain G, Fu P. Kangaroo Care modifies preterm infant heart rate 
variability in response to heel stick pain: pilot study. Early human development. 2009;85(9):561-
567. 
26. 
de Freitas P, Bueno M, Holditch-Davis D, Santos HP, Kimura AF. Biobehavioral responses of 
preterm infants to conventional and swaddled tub baths: A randomized crossover trial. The 
Journal of perinatal & neonatal nursing. 2018;32(4):358-365. 
27. 
Kim HG, Cheon EJ, Bai DS, Lee YH, Koo BH. Stress and Heart Rate Variability: A Meta-
Analysis and Review of the Literature. Psychiatry Investig. 2018;15(3):235-245. 
28. 
Nater UM, Skoluda N, Strahler J. Biomarkers of stress in behavioural medicine. Current opinion 
in psychiatry. 2013;26(5):440-445. 
29. 
Stein PK, Bosner MS, Kleiger RE, Conger BM. Heart rate variability: a measure of cardiac 
autonomic tone. American Heart Journal. 1994;127(5):1376-1381. 
30. 
Porges SW. Cardiac vagal tone: A physiological index of stress. Neuroscience and Behavioral 
Reviews. 1995;19(2):225-233. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
32 
HRP-503  v.12.10.18 
31. 
Storm H. Development of emotional sweating in preterms measured by skin conductance 
changes. Early human development. 2001;62(2):149-158. 
32. 
Chou IC, Lien HC, Lin HC, et al. The relationship of salivary and cord blood cortisol in preterm 
infants. Journal of pediatric endocrinology & metabolism : JPEM. 2011;24(1-2):85-88. 
33. 
Amin H, Wynne-Edwards K, Amin P, et al. Is the Correlation between Salivary Cortisol and 
Serum Cortisol Reliable Enough to Enable Use of Salivary Cortisol Levels in Preterm Infants? 
American journal of perinatology. 2017;34(13):1302-1305. 
34. 
Morelius E, He HG, Shorey S. Salivary Cortisol Reactivity in Preterm Infants in Neonatal 
Intensive Care: An Integrative Review. Int J Environ Res Public Health. 2016;13(337). 
35. 
Nist MD, Harrison TM, Steward DK. The biological embedding of neonatal stress exposure: A 
conceptual model describing the mechanisms of stress-induced neurodevelopmental impairment 
in preterm infants. Res Nurs Health. 2019;42(1):61-71. 
36. 
DiPietro JA, Bornstein MH, Hahn CS, Costigan K, Achy-Brou A. Fetal heart rate and variability: 
stability and prediction to developmental outcomes in early childhood. Child development. 
2007;78(6):1788-1798. 
37. 
Doussard-Roosevelt JA, McClenny BD, Porges SW. Neonatal cardiac vagal tone and school-age 
developmental outcome in very low birth weight infants. Developmental psychobiology. 
2001;38(1):56-66. 
38. 
Field T. Touch. 2 ed: MIT Press; 2014. 
39. 
Jones CL. Environmental analysis of neonatal intensive care. J Nerv Ment Dis. 1982;170(3):130-
142. 
40. 
Marton PL, Dawson H, Minde K. The interaction of ward personnel with infants in the 
premature nursery. Infant Behavior and Development. 1980;3(4):307-313. 
41. 
Miller DB, Holditch-Davis D. Interactions of parents and nurses with high-risk preterm infants. 
Res Nurs Health. 1992;15(3):187-197. 
42. 
Horton J, Waldenstrom U, Bowman E. Touch of low birth weight babies in neonatal intensive 
care: observations over a 24 hour period. Journal of Neonatal Nursing. 1998;4(2):24-28. 
43. 
Pohlman S, Beardslee C. Contacts experienced by neonates in intensive care environments. 
Matern Child Nurs J. 1987;16(3):207-226. 
44. 
Graven SN, Browne JV. Sensory development in the fetus, neonate, and infant: introduction and 
overview. Newborn & Infant Nursing Reviews. 2008;8(4):169-172. 
45. 
Maitre NL, Key AP, Chorna OD, et al. The Dual Nature of Early-Life Experience on 
Somatosensory Processing in the Human Infant Brain. Curr Biol. 2017;27(7):1048-1054. 
46. 
Weiss SJ, Wilson P. Origins of tactile vulnerability in high-risk infants. Advances in neonatal 
care : official journal of the National Association of Neonatal Nurses. 2006;6(1):25-36. 
47. 
Valizadeh L, Avazeh M, Bagher Hosseini M, Asghari Jafarabad M. Comparison of clustered 
care with three and four procedures on physiological responses of preterm infants: randomized 
crossover clinical trial. Journal of caring sciences. 2014;3(1):1-10. 
48. 
Alvarez MJ, Fernandez D, Gomez-Salgado J, Rodriguez-Gonzalez D, Roson M, Lapena S. The 
effects of massage therapy in hospitalized preterm neonates: A systematic review. International 
journal of nursing studies. 2017;69:119-136. 
49. 
Asadollahi M, Jabraeili M, Mahallei M, Asgari Jafarabadi M, Ebrahimi S. Effects of Gentle 
Human Touch and Field Massage on Urine Cortisol Level in Premature Infants: A Randomized, 
Controlled Clinical Trial. Journal of caring sciences. 2016;5(3):187-194. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
33 
HRP-503  v.12.10.18 
50. 
Im H, Kim E. Effect of Yakson and Gentle Human Touch versus usual care on urine stress 
hormones and behaviors in preterm infants: a quasi-experimental study. International journal of 
nursing studies. 2009;46(4):450-458. 
51. 
Herrington CJ, Chiodo LM. Human touch effectively and safely reduces pain in the newborn 
intensive care unit. Pain management nursing : official journal of the American Society of Pain 
Management Nurses. 2014;15(1):107-115. 
52. 
Johnston C, Campbell-Yeo M, Disher T, et al. Skin-to-skin care for procedural pain in neonates. 
The Cochrane database of systematic reviews. 2017;2(2):Cd008435. 
53. 
Pillai Riddell RR, Racine NM, Gennis HG, et al. Non-pharmacological management of infant 
and young child procedural pain. The Cochrane database of systematic reviews. 
2015(12):Cd006275. 
54. 
Marvin MM, Gardner FC, Sarsfield KM, Travagli RA, Doheny KK. Increased Frequency of 
Skin-to-Skin Contact Is Associated with Enhanced Vagal Tone and Improved Health Outcomes 
in Preterm Neonates. American journal of perinatology. 2019;36(5):505-510. 
55. 
Pineda R, Bender J, Hall B, Shabosky L, Annecca A, Smith J. Parent participation in the 
neonatal intensive care unit: Predictors and relationships to neurobehavior and developmental 
outcomes. Early human development. 2018;117:32-38. 
56. 
Lewis TP, Andrews KG, Shenberger E, et al. Caregiving can be costly: A qualitative study of 
barriers and facilitators to conducting kangaroo mother care in a US tertiary hospital neonatal 
intensive care unit. BMC pregnancy and childbirth. 2019;19(1):227. 
57. 
Werner NP, Conway AE. Caregiver contacts experienced by premature infants in the neonatal 
intensive care unit. Matern Child Nurs J. 1990;19(1):21-43. 
58. 
Smith JR. Comforting touch in the very preterm hospitalized infant: an integrative review. 
Advances in neonatal care : official journal of the National Association of Neonatal Nurses. 
2012;12(6):349-365. 
59. 
Modrcin-Talbott MA, Harrison LL, Groer MW, Younger MS. The biobehavioral effects of 
gentle human touch on preterm infants. Nurs Sci Q. 2003;16(1):60-67. 
60. 
Bahman Bijari B, Iranmanesh S, Eshghi F, Baneshi MR. Gentle Human Touch and Yakson: The 
Effect on Preterm's Behavioral Reactions. ISRN Nurs. 2012;2012:750363. 
61. 
Im H, Kim E, Cain KC. Acute effects of Yakson and Gentle Human Touch on the behavioral 
state of preterm infants. Journal of child health care : for professionals working with children in 
the hospital and community. 2009;13(3):212-226. 
62. 
Gomes Neto M, da Silva Lopes IA, Araujo A, Oliveira LS, Saquetto MB. The effect of 
facilitated tucking position during painful procedure in pain management of preterm infants in 
neonatal intensive care unit: a systematic review and meta-analysis. European journal of 
pediatrics. 2020;179(5):699-709. 
63. 
Ranjbar A, Bernstein C, Shariat M, Ranjbar H. Comparison of facilitated tucking and oral 
dextrose in reducing the pain of heel stick in preterm infants: a randomized clinical trial. BMC 
pediatrics. 2020;20(1):162. 
64. 
Taplak A, Bayat M. Comparison the effect of breast milk smell, white noise and facilitated 
tucking applied to Turkish preterm infants during endotracheal suctioning on pain and 
physiological parameters. Journal of pediatric nursing. 2020. 
65. 
Gonya J, Niski J, Cistone N. Using a behavior analytics approach to change nursing care of 
extremely premature infants: A pilot study. Journal of Nursing Education and Practice. 
2019;9(5):14-23. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
34 
HRP-503  v.12.10.18 
66. 
Osman M, Elsharkawy A, Abdel-Hady H. Assessment of pain during application of nasal-
continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm 
infants. Journal of perinatology : official journal of the California Perinatal Association. 
2015;35(4):263-267. 
67. 
Herrington CJ, Olomu IN, Geller SM. Salivary cortisol as indicators of pain in preterm infants: a 
pilot study. Clin Nurs Res. 2004;13(1):53-68. 
68. 
Morelius E, Hellstrom-Westas L, Carlen C, Norman E, Nelson N. Is a nappy change stressful to 
neonates? Early human development. 2006;82(10):669-676. 
69. 
Menin D, Dondi M. Methodological Issues in the Study of the Development of Pain 
Responsivity in Preterm Neonates: A Systematic Review. Int J Environ Res Public Health. 
2020;17(10). 
70. 
Hatfield LA, Murphy N, Karp K, Polomano RC. A Systematic Review of Behavioral and 
Environmental Interventions for Procedural Pain Management in Preterm Infants. Journal of 
pediatric nursing. 2019;44:22-30. 
71. 
Pressler JL, Hepworth JT. A quantitative use of the NIDCAP tool. The effect of gender and race 
on very preterm neonates' behavior. Clin Nurs Res. 2002;11(1):89-102. 
72. 
Hill S, Engle S, Jorgensen J, Kralik A, Whitman K. Effects of facilitated tucking during routine 
care of infants born preterm. Pediatric physical therapy : the official publication of the Section 
on Pediatrics of the American Physical Therapy Association. 2005;17(2):158-163. 
73. 
Cignacco E, Axelin A, Stoffel L, Sellam G, Anand K, Engberg S. Facilitated tucking as a non-
pharmacological intervention for neonatal pain relief: is it clinically feasible? Acta paediatrica 
(Oslo, Norway : 1992). 2010;99(12):1763-1765. 
74. 
Nist MD, Pickler RH, Steward DK, Harrison TM, Shoben AB. Inflammatory mediators of stress 
exposure and neurodevelopment in very preterm infants: Protocol for the Stress Neuro-Immune 
Study. Journal of advanced nursing. 2019;75(10):2236-2245. 
75. 
Pickler RH, Wetzel PA, Meinzen-Derr J, Tubbs-Cooley HL, Moore M. Patterned feeding 
experience for preterm infants: study protocol for a randomized controlled trial. Trials. 
2015;16:255. 
76. 
Nist MD, Harrison TM, Pickler RH, Shoben AB. Measures of Stress Exposure for Hospitalized 
Preterm Infants. Nursing research. 2020;69(5S Suppl 1):S3-S10. 
77. 
Nist MD, Harrison TM, Pickler RH, Shoben AB. Measures of stress exposure for hospitalized 
preterm infants. State of Science Congress on Nursing Research; 2020; Washington, D.C. 
78. 
Pickler RH, Meinzen-Derr J, Moore M, Sealschott S, Tepe K. Effect of Tactile Experience 
During Preterm Infant Feeding on Clinical Outcomes. Nursing research. 2020. 
79. 
Pickler RH, Moore M, Sealschott S, Tubbs-Cooley H. Patterned experience and neurobehavioral 
outcomes in preterm infants. International Congress of Infant Studies; 2018; Philadeliphia, PA. 
80. 
Pickler RH, McGrath JM, Reyna BA, et al. A model of neurodevelopmental risk and protection 
for preterm infants. The Journal of perinatal & neonatal nursing. 2010;24(4):356-365. 
81. 
Waxman JA, Pillai Riddell RR, Tablon P, Schmidt LA, Pinhasov A. Development of 
Cardiovascular Indices of Acute Pain Responding in Infants: A Systematic Review. Pain Res 
Manag. 2016;2016:8458696. 
82. 
Berntson GG, Bigger JT, Jr., Eckberg DL, et al. Heart rate variability: origins, methods, and 
interpretive caveats. Psychophysiology. 1997;34(6):623-648. 
83. 
Harrison TM, Brown RL. Autonomic nervous system function in infants with transposition of 
the great arteries. Biological research for nursing. 2012;14(3):257-268. 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
35 
HRP-503  v.12.10.18 
84. 
Vetrugno R, Liguori R, Cortelli P, Montagna P. Sympathetic skin response: basic mechanisms 
and clinical applications. Clinical autonomic research : official journal of the Clinical 
Autonomic Research Society. 2003;13(4):256-270. 
85. 
Gutrecht JA. Sympathetic skin response. J Clin Neurophysiol. 1994;11(5):519-524. 
86. 
Granger DA, Kivlighan KT, Fortunato C, et al. Integration of salivary biomarkers into 
developmental and behaviorally-oriented research: problems and solutions for collecting 
specimens. Physiology & behavior. 2007;92(4):583-590. 
87. 
Neu M, Goldstein M, Gao D, Laudenslager ML. Salivary cortisol in preterm infants: Validation 
of a simple method for collecting saliva for cortisol determination. Early human development. 
2007;83(1):47-54. 
88. 
Newnham CA, Inder TE, Milgrom J. Measuring preterm cumulative stressors within the NICU: 
the Neonatal Infant Stressor Scale. Early human development. 2009;85(9):549-555. 
89. 
Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: Simplified 
newborn illness severity and mortality risk scores. The Journal of pediatrics. 2001;138(1):92-
100. 
90. 
Weiner BJ, Lewis CC, Stanick C, et al. Psychometric assessment of three newly developed 
implementation outcome measures. Implementation science : IS. 2017;12(1):108. 
91. 
Korner AF, Kraemer HC, Reade EP, Forrest T, Dimiceli S, Thom VA. A methodological 
approach to developing an assessment procedure for testing the neurobehavioral maturity of 
preterm infants. Child development. 1987;58(6):1478-1487. 
92. 
Korner AF, Constantinou J, Dimiceli S, Brown BW, Jr., Thom VA. Establishing the reliability 
and developmental validity of a neurobehavioral assessment for preterm infants: a 
methodological process. Child development. 1991;62(5):1200-1208. 
93. 
Noble Y, Boyd R. Neonatal assessments for the preterm infant up to 4 months corrected age: a 
systematic review. Developmental medicine and child neurology. 2012;54(2):129-139. 
94. 
Constantinou JC, Adamson-Macedo EN, Mirmiran M, Ariagno RL, Fleisher BE. 
Neurobehavioral assessment predicts differential outcome between VLBW and ELBW preterm 
infants. Journal of perinatology : official journal of the California Perinatal Association. 
2005;25(12):788-793. 
95. 
Gorzilio DM, Garrido E, Gaspardo CM, Martinez FE, Linhares MB. Neurobehavioral 
development prior to term-age of preterm infants and acute stressful events during neonatal 
hospitalization. Early human development. 2015;91(12):769-775. 
96. 
Mathai S, Fernandez A, Mondkar J, Kanbur W. Effects of tactile-kinesthetic stimulation in 
preterms: a controlled trial. Indian Pediatr. 2001;38(10):1091-1098. 
97. 
Lee HK. The effect of infant massage on weight gain, physiological and behavioral responses in 
premature infants. Taehan Kanho Hakhoe Chi. 2005;35(8):1451-1460. 
98. 
Dieter JN, Field T, Hernandez-Reif M, Emory EK, Redzepi M. Stable preterm infants gain more 
weight and sleep less after five days of massage therapy. Journal of pediatric psychology. 
2003;28(6):403-411. 
99. 
Arora J, Kumar A, Ramji S. Effect of oil massage on growth and neurobehavior in very low birth 
weight preterm neonates. Indian Pediatr. 2005;42(11):1092-1100. 
100. 
Fucile S, Gisel EG. Sensorimotor interventions improve growth and motor function in preterm 
infants. Neonatal network : NN. 2010;29(6):359-366. 
 
 
 

PROTOCOL TITLE: Pilot Study of Nurse-Administered Touch and Biobehavioral Stress Responses of 
Preterm Infants (Pilot NAT-BIO Study) 
 
36 
HRP-503  v.12.10.18 
Appendix 
 
Salivary cortisol collection from NCH Laboratory Medicine