The Effects of Holding on Stress and Bonding in Mother-Infant Dyads During Therapeutic Hypothermia
Phase: NA
Conditions: Hypoxic-Ischemic Encephalopathy
Sponsor: Alexa Craig

IRB approved 4/28/2017 
 
The Effects of Holding on Stress and Bonding in Mother-Infant Dyads During 
Therapeutic Hypothermia  
 
Principal Investigator and Mentor: Alexa K. Craig, MD 
Co-Investigators: Julia Jacobs, MS4, Kyle Deerwester, MS4 
 
A.   Introduction 
 
Therapeutic hypothermia (TH) is a standard of care intervention that decreases death and 
disability in newborn term infants at risk for hypoxic brain injury. It involves placing the 
newborn infant on a cooling blanket for 72 hours in the Neonatal Intensive Care Unit 
(NICU). While TH has unmistakable neurological benefits to the newborn, prior research 
conducted with nurses and parents of infants treated with TH indicates that the 
experience is psychologically traumatic.1-3 Specifically, both groups identified parents’ 
inability to touch and hold their infants during TH as a major source of stress.  
 
Past research demonstrates that the experience of being a patient in the NICU is 
associated with neonatal stress.4-6 Longitudinal studies show lasting effects of NICU-
associated stress on infants as measured by persistent alterations in cortisol reactivity at 
eight months of age.7 It is likely that this stress profile also applies to infants who 
undergo TH while in the NICU. However, the association between TH and infant stress 
has not been studied quantitatively.  
 
A complementary field of study has examined maternal holding as a therapeutic 
intervention for maternal and neonatal stress. Kangaroo, or skin-to-skin care, is widely 
used to facilitate mother-infant bonding and has been shown to have an analgesic effect 
on infants8 and cortisol lowering effects9 on mothers and infants. Likewise, oxytocin, a 
hormone produced by the pituitary gland and associated with maternal-infant bonding 
and stress reduction, has been shown to increase in mothers while they hold their 
infants14. It is unclear whether holding has the same effects during TH because skin-to-
skin contact is not possible and morphine is often used to suppress infants’ discomfort 
and shivering. The first specific aim of the present study is to evaluate the safety of 
allowing mothers to hold their infants during the TH protocol. The second specific aim is 
to investigate whether holding impacts mothers’ and nurses’ perception of stress during 
TH treatment.  
 
B. Specific Aims and Significance 
 
Specific Aim 1: Assess the safety and feasibility of a new holding protocol for stable 
infants undergoing therapeutic hypothermia in the NICU. We hypothesize that there will 
not be a significant change in temperature variation, and there will be no increase in 
adverse events during holding. 
Specific Aim 2: Assess mothers’ and nurses’ qualitative experience related to the holding 
during hypothermia intervention using a questionnaire with a combination of closed and 
open-ended questions.  We hypothesize that mothers and nurses will respond positively 
to the opportunity to hold during hypothermia.  

IRB approved 4/28/2017 
 
Adverse Effects: Given the vulnerability of infants in the NICU, potential adverse 
effects of the holding intervention and the monitoring strategy for these adverse effects 
are outlined here. 
1. Holding during hypothermia could result in unintentional rewarming of the 
infant due to the proximity of the normothermic mother.  In order to prevent 
rewarming, a thermal barrier will be placed between the mother and infant and the 
infant’s esophageal temperature will be monitored every two minutes during 
holding and the intervention stopped early if the infant rewarms more than 1°C. 
Retrospective review of 16 medical records of infants treated with hypothermia at 
Maine Medical Center with gestational ages ranging from 34 -40+ weeks 
document a usual range of temperatures during cooling from 33-34°C (goal is 
33.5°C)10.  The research team has made the determination that the intervention 
will be stopped early if the infant rewarms more than 1°C based on this data.   
 
 
2. Holding during hypothermia could result in dislodging of central lines.  Only 
experienced NICU nurses will move the infant from the isolette into the mother’s 
arms with assistance from a member of the research team.  Critically ill infants 
that are intubated are considered too great a risk for accidental extubation and are 
therefore excluded.   
 
 
 
 

IRB approved 4/28/2017 
 
C. Materials and Methods 
 
Study Design: This is a single center safety study of the feasibility of a novel holding 
protocol for infants undergoing therapeutic hypothermia. 
 
Study Population: As this is a pilot study to investigate concept and feasibility, a 
convenience sample of ten infants and their mothers in the MMC NICU being treated 
with TH will be recruited for the study according to the following criteria: 
 
Inclusion criteria:  
• Infant with gestational age ≥35 weeks treated with therapeutic hypothermia 
• Infant without seizures in the first 24 hours on EEG 
• Infants who are clinically stable on bubble CPAP, nasal cannula or who have no 
respiratory support.  This criterion MUST be confirmed by the Attending 
Neonatologist. 
• Infants with all types of vascular access are eligible. 
o Use appropriate caution and attention to peripheral arterial lines and 
central lines (PICC, UAC, UVC, tunneled central catheters) 
• Informed consent for research study signed by mother who is at MMC. 
 
Exclusion criteria: 
• 
Intubated status 
• 
Use of inhaled nitric oxide 
• 
Persistent pulmonary hypertension of the newborn 
• 
Presence of seizures on EEG 
• 
Use of vasopressors or paralytic agents 
• 
Presence of chest tubes, wound vacuum or drains 
• 
Neonatal abstinence syndrome 
 
Eligibility for enrollment and consent process: Dr. Craig is the Neonatal Neurologist 
involved in the clinical care of all infants at MMC treated with therapeutic hypothermia.  
Dr. Craig will describe the research study to parents of infants who meet the inclusion 
criteria.  Dr. Craig and/or the co-investigators will obtain signed informed consent from 
the mother on behalf of herself and from the mother or father on behalf of the infant.  
Intervention: After obtaining consent, on the second or third day of hypothermia 
treatment, consented mothers will be assisted with holding their infants for a single 30-
minute period. Holding will take place with the assistance of the NICU nurse according 
to the protocol developed for this study (see attached). The infant’s vital signs will be 
measured before, during and after holding.   Esophageal temperatures will also be 
measured and recorded every 2 minutes during holding to ensure that holding does not 
impact the infant’s body temperature.  If temperature deviations +/-1°C occur or if the 
infant becomes hypoxic with oxygen saturations below 90%, the holding session will be 
terminated and the baby will be returned to his or her isolette. Prior observation of 
therapeutic hypothermia indicates that 1 degree Celsius is the average temperature 
deviation that occurs in typical therapeutic hypothermia sessions. 10  

IRB approved 4/28/2017 
 
 
Implementation of questionnaires: 
• Parent Questionnaire: 
A questionnaire using the Likert scale will be administered on paper to mothers 30-60 
minutes after completion of the holding session. Results will be linked by a patient 
identification number to the hormonal samples.  Responses to the questionnaire will 
be entered into a password-protected REDCap database.  
• Nurse Questionnaire: 
The nurse questionnaire starts with an alteration of consent and consists of a 
combination of closed and open-ended questions that will be provided to the nurse on 
paper at completion of the holding procedure. The nurse’s questionnaire will be 
identified by the case number that is assigned to the mother-infant dyad to protect 
their identities. The results of the questionnaire will be entered into a password-
protected REDCap database.  
 
Data collected: 
As all of the patients treated with therapeutic hypothermia in our NICU are recorded in 
the Maine Medical Center Neonatal Encephalopathy REDCap database (IRB 
NET976245-1), we will use the same data for this holding study. In addition to the data 
already recorded in the REDCap database, we will also record the infant’s current 
medication doses during holding, temperature recording taken at 2 minute intervals 
during holding and their vital signs before, during, and after holding.  These vital sign 
recordings include temperature, heart rate, blood pressure, oxygen saturation and 
respiratory rate.  If the infant does not have an arterial line in place, blood pressure will 
be measured every 10 minutes using a blood pressure cuff so as not to agitate the infant. 
 
D. Analytical Methods 
• Safety 
Frequency of adverse events (as defined above) will be compared in this experimental 
cohort to data from historical controls in our therapeutic hypothermia database. 
• Questionnaires 
Answers from questions using a Likert scale will be simplified into nominal 
agree/disagree categories and compared with χ2 test or Fisher’s Exact Test as 
applicable. Open-ended responses will be analyzed by Thompson’s general inductive 
technique. 
 
 
 
E. References 
 
1. 
Nassef S, Blennow M, Jirwe M. Experiences of parents whose newborns 
undergo hypothermia treatment following perinatal asphyxia. Journal of 
Obstetric, Gynecological and Neonatal Nursing. 2012;42:38-47. 
2. 
Heringhaus A, Dellenmark Blom M, Wigert H. Becoming a parent to a child 
with birth asphyxia. From a traumatic delivery to living with the experience 
at home. International Journal of Qualitative Studies on Health and Well-being. 
2013;8. 

IRB approved 4/28/2017 
 
3. 
Craig A, James C, Bainter J, Lucas F, Evans S, Glazer J. Survey of Neonatal 
Intensive Care Unit Nurse Attitudes Toward Therapeutic Hypothermia 
Treatment. Advances in Neonatal Care. 2016;0(0):1-8. 
4. 
Morelius E, He H-G, Shorey S. Salivary Cortisol Reactivity in Preterm Infants 
in Neonatal Intensive Care: An Integrative Review. International Journal of 
Environmental Research and Public Health 2016;13(3):337. 
5. 
Morelius E, Theodorsson E, Nelson N. Salivary cortisol and mood and pain 
profiles during skin-to-skin care for an unselected group of mothers and 
infants in neonatal intensive care. Pediatrics. 2005;116(5):1105-1113. 
6. 
Grunau RE, Holsti L, Haley DW, et al. Neonatal procedural pain exposure 
predicts lower cortisol and behavioral reactivity in preterm infants in the 
NICU. Pain. 2005;113(3):293-300. 
7. 
Grunau RE, Weinberg J, Whitfield MF. Neonatal Procedural Pain and Preterm 
Infant Cortisol Response to Novelty at 8 Months. Pediatrics. 2004;114(1):77-
84. 
8. 
Gray L, Watt L, Blass E. Skin-to-skin contact is analgesic in healthy newborns. 
Pediatrics. 2000;105(1). 
9. 
Gitau R, Modi N, Gianakoulopoulos X, Bond C, Glover V, Stevenson J. Acute 
effects of maternal skin-to-skin contact and massage on saliva cortisol in 
preterm babies. Journal of Reproductive and Infant Psychology. 2002;20:83-
88. 
10. 
Grant L. Therapeutic Hypothermia Temperatures in all Gestational Ages. 
2016. 
11. 
Becker KL. Endocrinology and Metabolism. Philadelphia, PA: Lipcott Williams 
and Wilkins; 2001. 
12. 
Mitchell AJ, Chang J, Yates C, Hall RW. Challenges, Guidelines, and Systematic 
Review of Salivary Cortisol Research in Preterm Infants. e-journal of 
Neonatology Research. 2012;2(1):44-51. 
13. 
van IJzendoorn M, Bhandari R, van der Veen R, Grewen KM, Bakermans-
Kranenburg MJ. Elevated salivary levels of oxytocin persist more thna 7h 
after intranasal administration. Frontiers in Neuroscience. 2012;6(174):1-6. 
14. 
Cong, X., Ludington-Hoe, S. M., Hussain, N., Cusson, R. M., Walsh, S., Vazquez, 
V., ... & Vittner, D. (2015). Parental oxytocin responses during skin-to-skin 
contact in pre-term infants. Early human development, 91(7), 401-406.