Enhanced Early Nutrition for Preterm Infants to Improve Neurodevelopment and Minimize Metabolic Risk
Phase: NA
Conditions: Preterm Birth
Sponsor: University of Minnesota

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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Revised: June 28, 2017 
 
 
COVER PAGE 
 
 
Study Title: Enhanced Early Nutrition for Preterm Infants to Improve Neurodevelopment 
and Minimize Metabolic Risk  
 
 
Date of Document: 6/28/17 
 
Title of Document: Study Protocol and Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
Page 2 of 28 
Revised: June 28, 2017 
 
PROTOCOL TITLE: 
Enhanced Early Nutrition for Preterm Infants to Improve Neurodevelopment and 
Minimize Metabolic Risk  
 
PRINCIPAL INVESTIGATOR: 
  
Sara Ramel, M.D.  
Division of Neonatology 
Department of Pediatrics 
University of Minnesota 
East Building- MB628 
2450 Riverside Avenue 
Minneapolis, MN 55454 
Phone: 612-625-8723 
Email: sramel@umn.edu 
 
 
VERSION NUMBER/DATE: 2/ June 28, 2017 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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Revised: June 28, 2017 
 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
4/18/2017 
Edits to statistical design 
no 
2 
5/9/2017 
Edits to data storage per HRPP 
request 
no 
3 
6/28/17 
Edits to protocol per IRB 
stipulations 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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Table of Contents. 
 
1.0 
Objectives ................................................................................................................ 7 
2.0 
Background .............................................................................................................. 7 
3.0 
Study Outcomes ..................................................................................................... 11 
4.0 
Study Intervention .................................................................................................. 11 
5.0 
Procedures Involved............................................................................................... 12 
6.0 
Data and Specimen Banking .................................................................................. 16 
7.0 
Sharing of Results with Participants ...................................................................... 17 
8.0 
Study Duration ....................................................................................................... 17 
9.0 
Study Population .................................................................................................... 17 
10.0 Vulnerable Populations .......................................................................................... 17 
11.0 Local Number of Participants ................................................................................ 18 
12.0 Local Recruitment Methods ................................................................................... 18 
13.0 Withdrawal of Participants .................................................................................... 19 
14.0 Risks to Participants ............................................................................................... 19 
15.0 Potential Benefits to Participants ........................................................................... 20 
16.0 Data Management .................................................................................................. 20 
17.0 Confidentiality ....................................................................................................... 22 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 22 
19.0 Provisions to Protect the Privacy Interests of Participants .................................... 23 
20.0 Compensation for Research-Related Injury ........................................................... 24 
21.0 Consent Process ..................................................................................................... 24 
22.0 Setting .................................................................................................................... 25 
23.0 Multi-Site Research ............................................................................................... 25 
24.0 Resources Available............................................................................................... 25 
25.0 References .............................................................................................................. 25 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
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ABBREVIATIONS/DEFINITIONS 
• 
 VLBW: Very Low Birth Weight (weighing <1500 grams at birth) 
• NICU: Neonatal Intensive Care Unit 
• GA: Gestational Age 
• CA: Corrected age for prematurity 
• ADP: Air Displacement Plethysmography 
• ERP: electrophysiologic 
• FFM: Fat-free mass 
• FM: Fat mass 
• IGF-1: Insulin Like Growth Factor-1 
• MRI: Magnetic Resonance Imaging 
• MDI: Mental Developmental Index 
• IGF-BP3: Insulin Like Growth Factor Binding Protein-3 
• GIR: Glucose Infusion Rate 
• DOL: Day of Life 
• IL: Intralipids 
• IV: Intravenous 
• TPN: Total Parenteral Nutrition 
• MMN: Mismatch Negativity  
• VEP: Visual Evoked Potentials  
• CNBD: Center for Neurobehavioral Development 
• SNAP: Score for Neonatal Acute Physiology  
• EMR: Electronic Medical Record 
• ROP: Retinopathy of Prematurity 
• NEC: Necrotizing Entercolitis 
• CTSI: Clinical and Translational Science Institute 
• DSMC: Data Safety and Monitoring Committee 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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STUDY SUMMARY 
 
Study Title 
Enhanced Early Nutrition for Preterm Infants to 
Improve Neurodevelopment and Minimize Metabolic 
Risk 
Study Design 
Randomized, Controlled Trial 
Primary Objective 
The overall objective of the proposal is to demonstrate 
the feasibility of providing increased calories and 
protein in the first week of life to VLBW preterm 
infants. 
Secondary Objective(s) 
The secondary objective is to generate pilot data on the 
effects of this intervention on growth and 
neurodevelopmental outcomes. 
Research 
Intervention(s)/Investigational 
Agents 
Infants will be randomized to receive either standard 
parenteral nutrition via the NICU protocol or enhanced 
parenteral nutrition via the Study protocol during their 
first week of life through higher initial macronutrient 
provision and faster advancement of macronutrient 
provision. 
IND/IDE # (if applicable) 
N/A 
Study Population 
VLBW (birth weight <1500grams) preterm 
(gestational age (GA) at birth < 32 weeks) infants 
admitted to the University of Minnesota Masonic 
Children’s Hospital NICU, for which written informed 
consent can be secured from a parent within 12 hours 
of birth. 
Sample Size (number of 
participants) 
80 
Study Duration for Individual 
Participants 
From Birth through 4 months corrected age for 
prematurity (6-8 months for most) 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
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1.0 
Objectives 
 
            1.1       The overall objective of the proposal is to demonstrate the feasibility of 
providing increased calories and protein in the first week of life to VLBW 
preterm infants, and to generate pilot data on the effects of this 
intervention on growth and neurodevelopmental outcomes. We 
hypothesize that infants receiving greater calories and protein in the first 
week of life will have improved FFM gains and higher levels of IGF-1 
prior to discharge, and improved early cognition and faster speed of neural 
processing measured at term and 4 months corrected age (CA). To address 
these hypotheses, we propose the following specific aims:  
 
 
Specific Aim I. Examine whether infants receiving earlier initiation of 
intralipids and more rapid increases in energy and protein intake during 
the first week of life (“enhanced nutrition protocol”) have improved 
growth, indexed by increased FFM gains, compared to a standard 
nutrition protocol. Body composition will be measured weekly using air 
displacement plethysmography (ADP) until discharge and at term and 4 
months CA.  
 
 
Specific Aim II. Determine if infants on the “enhanced nutrition 
protocol” have improved cognition and faster speed of processing at 
term and 4 months CA compared to a standard nutrition protocol. 
Neurodevelopmental outcomes will be measured using electrophysiologic 
(ERP) techniques.  
 
 
Specific Aim III. To assess whether growth factors, including IGF-1 
and IGFBP3, mediate the relationship between improved nutritional 
provision and improved FFM gains, cognition, and speed of processing 
in preterm infants. Growth factors will be drawn at 1 week of age and 35 
weeks PMA.  
 
2.0 
Background 
 
2.1       Significance: VLBW preterm infants commonly experience growth 
failure, most significantly in length and FFM, during their first weeks of  
life while they are sick and dependent on parenteral nutrition1-5. This 
growth failure is occurring at a critical time in brain development and has  
been shown to have a lasting negative impact on their  
neurodevelopment4,6-7     The majority of these infants do not recover from  
this early growth faltering prior to hospital discharge, and in fact linear 
growth failure has been shown by our group to persist even beyond  
2 years CA1-4. In addition to the neurodevelopmental consequences, early  
growth failure also increases these infants risk of developing later  

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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hypertension, insulin resistance, obesity and other components of 
metabolic syndrome, by necessitating later rapid catch-up growth in 
infancy and toddlerhood8-11.   
 
 
There are several factors contributing to this early growth failure, and 
many (e.g. illness and inflammation) of them remain largely out of our 
control. In contrast, nutrition is a factor the health care team can control, 
and early enhancements in nutrient provision may be our opportunity to 
prevent the above described early growth failure, improve 
neurodevelopment and optimize the later metabolic health of VLBW 
preterm infants. Multiple small retrospective studies have found 
significant decreases in growth failure (defined as weight z-score <10th 
percentile at discharge) after a slight change in their NICU parenteral 
nutrition protocol12-15. In addition, multiple groups have reported 
improved neurodevelopmental outcomes, including improved language 
scores13, increased developmental quotient16 and decreased incidence of 
brain lesions on MRI17 in infants receiving more aggressive parenteral 
nutrition in the first weeks of life. Specifically, Stephens et al reported an 
increase of 4.6 points in the Mental Developmental Index (MDI) at 18 
months for every additional 10 kcal/kg/day of energy provided in the first 
week of life and an 8.2 point increase in the MDI for every additional 
gram/kg/day of protein provided in the first week18.   
 
 
Despite the potential benefits, early enhanced macronutrient provision to 
VLBW preterm infants is not routinely practiced due to concerns about 
intolerance and toxicity. These concerns are based on older trials using 
different nutritional products than those routinely used in NICU’s today. 
More recent studies (mostly small and retrospective) have found that 
earlier introduction and more rapid advancement of lipids and protein are 
safe, and in fact may decrease the incidence of hyperglycemia and 
parenteral nutrition associated cholestasis14-15. In addition, recent findings 
of increased adiposity among preterm infants at term CA has discouraged 
early enhanced nutrient provision based on a fear that this strategy, while 
being beneficial for the brain, will nonetheless lead to further increases in 
adiposity11. However, our group and others have instead found that 
increased nutrition provision, both in calories and in protein, leads to 
increased FFM gains, without accompanying increases in FM or 
adiposity7.19. Work under Specific Aims 1 and 2 will address this 
uncertainty through a comprehensive examination of both 
neurodevelopmental and metabolic outcomes (i.e., body composition) in a 
randomized nutrition intervention trial. 
 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
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While the relationships between early malnutrition, poor growth and 
worsened neurodevelopment are relatively clear, the mechanisms behind 
these associations have yet to be elucidated. IGF-I is nutritionally 
regulated and negatively influenced by early malnutrition12, 20. Levels of 
IGF-1 play an important role in early postnatal growth, body composition 
and blood pressure in childhood, and improved neurodevelopmental 
outcomes among preterm infants20-22. Circulating growth factor  
concentrations, like IGF-1, are therefore potential mediators of the effect 
of nutrition intervention on diverse preterm outcomes, which hypothesis 
we are testing in Specific Aim 3. If this hypothesis is supported, IGF-1 
could then be used as a biomarker for prediction of later outcomes and, 
relatedly, as a tool for monitoring the success of early nutrition 
interventions. In the future, development of a nutritional intervention that 
optimizes IGF-1 levels early in life for preterm infants could indicate 
whether or not the proper balance is being struck between adequate early 
FFM gains to optimize neurodevelopment and minimizing excess FM 
gains to decrease long-term metabolic risk.  
 
In summary, recent neonatal literature continues to suggest the need for 
randomized trials of nutritional interventions that focus not only on weight 
gain, but more importantly on linear growth and FFM gains, and that can 
measure both neurodevelopmental and metabolic outcomes. Our expertise 
and experience in both neonatal body composition measurement AND 
methods of measuring early neurodevelopmental outcomes put us in an 
ideal position to trial an early enhanced nutrition intervention and 
potentially become a leader for future larger multi-center studies with 
long-term follow-up. This trial will not only allow us to determine the 
feasibility of providing additional nutrition to these sick infants, through 
close monitoring of metabolic tolerance (glucose, triglyceride and 
bilirubin levels) and careful detailed tracking of nutrient intake throughout 
their hospital stays, but will also provide us with preliminary data testing 
whether increasing all macronutrients incrementally shortly after birth 
eliminates early malnutrition, subsequent growth failure and 
neurodevelopmental delays.  
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
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2.2 
Prelim Data:  In our extensive prior work we have described differences in 
body composition between preterm and term infants, developed the first 
reference curves for preterm infant body composition, and shown 
relationships between early nutrition, illness and body composition  
trajectories through infancy among preterm infants. We were the first to 
describe associations between early FFM gains (not fat mass (FM) gains) 
and speed of processing and cognition. This observational work provides 
the necessary basis for our next phase of research aimed at increasing 
FFM gains prior to discharge and improving long-term growth, 
neurodevelopment and metabolic health for VLBW preterm infants 
through a randomized controlled nutritional intervention trial.  
 
2.3  
Innovation: The proposed pilot trial will be the first, to our knowledge, to 
comprehensively assess both infant metabolic (body composition) and 
neurodevelopmental outcomes following randomization to early enhanced 
nutritional intervention for preterm infants. In aim 1 we will examine 
growth, not only in weight and length, but also in different compartments 
(FFM and FM) during a critical time period of brain development using 
weekly ADP measurements. Given that FFM is considered a better marker 
of brain growth, and is associated with improved neurodevelopment, and 
increased adiposity a potential risk factor for later metabolic disease, using 
this more specific method of growth measurement allows a more 
comprehensive assessment of the risks and benefits of an early nutritional 
intervention. We will also continue to track gains in these compartments 
beyond hospital discharge until 4 months CA, allowing us to determine the 
lasting impact of this enhanced nutrition protocol. To our knowledge there 
is only one prior preterm nutrition intervention trial that assessed total 
body composition as an outcome and they were limited to two inpatient 
measures. In Aim 2, we will utilize ERP techniques to look specifically at  
the effects of early enhanced nutrition on neural speed of processing and 
early cognition. These techniques are more sensitive than standardized  

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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developmental testing and will likely allow us to detect small, but 
potentially clinically significant, differences. In, addition, these techniques 
can be administered at younger ages than most standardized cognitive 
testing minimizing the effects of confounders such as parental education 
and home environment by allowing testing to occur closer to the 
administration of the intervention. Finally, these methods of testing are 
specifically targeting areas of the brain found previously to be impacted 
by early protein/nutritional status. Our previous observational work has 
established relationships between nutrient intake, FFM gains and speed of 
neural processing/cognition7, 23. To our knowledge there are no preterm 
infant nutritional intervention trials that have assessed early 
neurodevelopment using ERP. Aim 3 will allow us to begin to look at the 
mechanisms behind these relationships. Growth factors, especially IGF-1, 
are nutritionally regulated, associated with lean mass accretion, important 
for neuronal growth and differentiation, and have been found to be 
neuroprotective in preterm infants20. The proposed study will be the first 
nutritional intervention trial to assess growth factors, as well as 
neurodevelopmental and metabolic outcomes in preterm infants. 
 
3.0 
Study Outcomes 
 
            3.1 
Primary Outcome: The primary outcome of this feasibility trial will be to 
 
determine if infants randomized to the enhanced nutrition protocol receive 
 
higher amounts of calories and protein throughout the first week of 
 
hospitalization. 
 
            3.2    Secondary Outcomes: The secondary outcomes will include measures of  
 
growth, neurodevelopment and growth hormone levels. Specifically, we  
 
will examine growth, not only in weight and length, but also in different 
 
compartments (FFM and FM) using weekly ADP measurements. We will  
 
also continue to track gains in these compartments beyond hospital 
 
discharge until 4 months CA. For neurodevelopment, we will utilize ERP 
 
techniques to look specifically at the effects of early enhanced nutrition on 
 
neural speed of processing and early cognition. Finally, we will look at the 
 
effect of early enhanced nutrition on IGF-1 and IGF-BP3 levels.  
 
4.0 
Study Intervention 
 
 
            4.1       Description: This nutritional intervention is designed to accelerate the  
addition of macronutrients over the first week of life to minimize the  
period of malnutrition, and is based upon the findings of numerous  
smaller, less comprehensive studies and expert opinion. Once consent  
is obtained, and the infant is admitted to the NICU, enrolled infants  
will be randomized to either receive parenteral nutrition per the  
standard NICU parenteral nutrition protocol or via the enhanced nutrition 
protocol for the first week of life via random envelope selection. Stratified 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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block randomization will be performed. Infants will be stratified by 
gestational age (22-25, 26-29, 30-32 weeks). Within each stratum, 
permuted block randomization will ensure that study personal are unable 
to predict treatment allocation.  Infants  
randomized to the enhanced nutrition protocol will receive starter total  
parenteral nutrition (TPN) initiated at 80 mls/kg/day to provide protein at 
4 grams/kg/day and a glucose infusion rate (GIR) of ~5.5 mgs/kg/min as  
soon as IV access has been obtained. Enhanced nutrition protocol infants 
will also be started on intralipids (IL) at 2 grams/kg/day once IV access is 
obtained. Infants randomized to the enhanced nutrition protocol will 
receive 4 grams/kg/day of protein throughout the first week of life. IL will 
be increased to 3 grams/kg/day on day of life (DOL) 2 and to 3.5 
grams/kg/day on DOL 3. They will remain on this amount for at least the 
first week of life or until sufficient enteral feeding volumes have been 
established.  GIR will be advanced by ~1.5 mgs/kg/min per day 
throughout the first week of life to a maximum of 12-14 mgs/kg/min. 
Again, they will then remain on this  
amount until sufficient enteral feedings have been established  
(typically approximately 1-2 weeks). Infants randomized to the  
 
standard nutrition protocol will receive macronutrients per the  
caregivers discretion, most commonly initiated with starter TPN at 60  
 
mls/kg/day giving 3 grams/kg/day of protein and a GIR of ~4 and IL  
 
provided at 0-1 gram/kg/day. Advancement is most typically by 1 
mg/kg/min per day for GIR and 1 gram/kg/day per day for IL and  
protein in the standard NICU protocol. Pertinent aspects of the differences 
in nutritional treatment in intervention and control groups are summarized 
in the table below 
 
  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Control 
  
  
  
  
  
  
GIR 
4.2 
5 
6 
7 
8 
9 
10 
IL (gm/kg) 
0.5 
1.5 
2.5 
3.5 
3.5 
3.5 
3.5 
Kcals/kg 
26 
40 
55 
70 
75 
80 
85 
431 total Kcals/kg/week 
  
  
  
  
  
  
  
  
(avg 61.6 Kcals/kg/day) 
Intervention 
  
  
  
  
  
  
  
GIR 
5.5 
7 
8.5 
10 
11.5 
12 
12 
IL (gm/kg) 
2 
3 
3.5 
3.5 
3.5 
3.5 
3.5 
Kcals/kg 
47.5 
55 
77.5 
85 
92.5 
95 
95 
547.5 total kcals/kg/week 
  
  
  
  
  
  
  
  
(avg 78.2 Kcals/kg/day) 
*Each gm/kg of IL (Intralipid) provides 10 
Kcals/kg 
 Each 1 mg/kg/min of GIR (Glucose Infusion Rate) provides ~5 Kcals/kg 
5.0 
Procedures Involved 
 
5.1       Study Design: This exploratory study will use a simple randomized  
            controlled trial design, and the parents, investigators, and all study 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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            personnel (other than the in-patient study coordinator who oversees the 
            ordering of the parenteral nutrition, the dietician and the data analyst in  
            charge of assessing results of the study) will be blinded as to group  
            assignment.  
           5.2      Study Procedures: Study Sample: Inclusions: We will include VLBW  
        (birth weight <1500grams) preterm (gestational age (GA) at birth < 32 
         weeks) infants admitted to the University of Minnesota Masonic  
         Children’s  Hospital NICU, for which written informed consent can be  
         secured from a parent within 12 hours of birth. Exclusions: Infants who  
         are diagnosed prenatally with a clinical condition (other than prematurity) 
         that is known to affect growth rate, adiposity, or neurocognitive  
         development, who experienced severe birth asphyxia, who are enrolled in  
         another study affecting nutritional management, or who are likely to be  
         transferred out of the NICU will be excluded from participation. We will         
 
attempt to enroll an equal number of female and male subjects, as well as 
         those from a variety of racial and ethnic backgrounds.  
 
 
         Admissions to the antepartum unit and to the NICU will be screened daily 
         by the inpatient research coordinator for potential eligibility for the trial.  
         Once identified, the coordinator will present the mother/parents with a  
         study brochure and offer to share more information and answer questions  
         regarding the study if the family is interested. When possible, consent will  
         be obtained prior to delivery. If unable to obtain consent prior to the  
         infants delivery, the family will be approached within 12 hours of delivery 
         to explain the study, answer questions and obtain consent. They will be 
         allowed ample time to consider participation, as well as to ask questions 
         of the clinical care team/ PI regarding the study.                 
 
 
Nutritional Intervention: Once consent is obtained, and the infant is 
admitted to the NICU, enrolled infants will be randomized to either 
receive parenteral nutrition per the standard NICU parenteral nutrition 
protocol or via the enhanced nutrition protocol for the first week of life via 
random envelope selection. Infants randomized to the enhanced nutrition 
protocol will receive starter total parenteral nutrition (TPN) initiated at 80 
mls/kg/day to provide protein at 4 grams/kg/day and a glucose infusion 
rate (GIR) of ~5.5 mgs/kg/min as soon as IV access has been obtained. 
Enhanced nutrition protocol infants will also be started on intralipids (IL) 
at 2 grams/kg/day once IV access is obtained. Infants randomized to the 
enhanced nutrition protocol will receive 4 grams/kg/day of protein 
throughout the first week of life. IL will be increased to 3 grams/kg/day on 
day of life (DOL) 2 and to 3.5 grams/kg/day on DOL 3. They will remain 
on this amount for at least the first week of life or until sufficient enteral 
feeding volumes have been established.  GIR will be advanced by ~1.5 
mgs/kg/min per day throughout the first week of life to a maximum of 12 
mgs/kg/min. Again, they will then remain on this amount until sufficient 
enteral feedings have been established (typically approximately 1-2 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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weeks). Infants randomized to the standard nutrition protocol will receive 
macronutrients per the caregivers discretion, most commonly initiated 
with starter TPN at 60 mls/kg/day giving 3 grams/kg/day of protein and a 
GIR of ~4 and IL provided at 0-1 gram/kg/day. Advancement is most 
typically by 1 mg/kg/min per day for GIR and 1 gram/kg/day per day for 
IL and protein in the standard NICU protocol. 
 
 
Glucose, conjugated bilirubin and triglyceride levels will be monitored per 
standard NICU protocol and nutrition will be adjusted accordingly and 
insulin given per NICU protocol. 
 
 
Nutritional intake will be recorded daily throughout the hopitalization, 
including kcal/kg/day and g/kg/day of protein by our NICU dietician. We  
will also gather data on days requiring TPN, type of feedings given (breast 
milk vs. formula) and degree of fortification (feeding additives).  
Following hospital discharge we will monitor intake through parent 
questionnaires monthly until the final (4 month CA) follow-up visit. 
  
 
Growth and Body Composition Measures (Outcomes for Aim 1): Daily 
weights will be measured per unit protocol on an electronic scale to the 
nearest 1 gram. Weekly recumbent length (using an infant length board) 
and head circumference (using a flexible tape measure) measurements will 
be performed by a consistent measurement team to the nearest 0.1cm 
throughout their hospitalization, as well as at the term and 4 mo CA  
 
follow-up visits. Once clinically stable and able to tolerate room air for >5 
minutes, we will begin measurements of body composition (FM, FFM and 
percent body fat) via infant ADP (“Pea Pod”; COSMED, INC, Concord, 
CA) by a trained NICU nurse, physician or research staff, and repeat these 
measurements weekly as tolerated. A detailed description of the Pea Pod’s 
physical design, operating principles, validation and measurement 
procedures is provided elsewhere24-28. Briefly, the Pea Pod (1-8kg) 
measure the infant’s volume using air-displacement plethysmography, and 
then calculates the density using the infant’s mass and length. FM and 
FFM are then calculated using Fomon’s model29. At a minimum, we plan 
to obtain one body composition measurement prior to discharge home 
from the NICU.  
 
 
Families will be contacted monthly with study updates and general 
information on standard care of preterm infants following discharge to 
reduce loss to follow-up/maintain engagement in the study and will be 
scheduled for follow-up body composition and neurodevelopmental 
assessment at term (or as soon as possible post-discharge) and again at 4 
months CA, when weight, recumbent length and head circumference will 
be measured, along with body composition using ADP. Raw body 
composition variables will be converted to z scores using our new preterm 
and term-corrected infant body composition reference data for ADP.  

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
Neurodevelopment and Minimize Metabolic Risk 
VERSION DATE: 6/28/17 
 
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Neurodevelopmental Testing (Outcomes for Aim 2): Infants will be tested 
at term (or as soon as possible after hospital discharge) and 4 months CA; 
at both ages they will participate in a single one-hour session during which 
ERP data will be obtained.  In order to obtain ERP data, infants will be 
fitted with a 128-channel Geodesic Sensor net.  Once we have placed the 
electrode net on the infant’s head, the infant will sit/lay on the parent's lap 
and an auditory oddball paradigm will be administered.  The Mismatch 
Negativity (MMN) component is widely used in electrophysiological 
research to measure cognitive function; it is thought to represent 
perceptual learning and the detection of incongruence between two 
stimuli.  The MMN is most reliably elicited by improbable, distinct  
“oddball” stimuli against a background of a repeating stimulus, and 
represents the comparison of the current auditory input to memory traces  
of previous inputs. The neural generators of the MMN component are 
widely distributed throughout the brain, and there is strong evidence to 
suggest that the frontal and temporal lobes are among them30. The 
University of Minnesota is one of only a few sites around the county with 
expertise in measuring cognition in early infancy using ERP technology, 
and one of the only who also has expertise in measuring infant body 
composition as well.  
 
 
 
We will also use pattern-reversal visual evoked proteintals (VEP) at 4 
months CA (type of ERP), which provides an early indication of neuronal 
speed of processing and myelination, which are critical to cognitive 
function. Infants will view a visual stimulus which consists of a pattern-
reversing black and white checkerboard and VEPs will be recorded from 
ongoing EEG using the above mentioned net. As in our previous studies, 
the outcome variable with be the latency to the P100 waveform in msec23. 
 
 
Our prelimiary data has shown an association between speed of 
processing, cognition and FFM in other groups of preterm infants7, 23, and 
thus we hypothesize that these findings will be robust amongst this 
population of at risk infants and potentially allow us to detect changes in 
cognitive measures related to enhanced nutritional provision. Our team in 
the CNBD has performed this testing on a variety of clinical populations 
(>500 infants) as well as healthy controls for over a decade31-33. 
 
 
  Markers of Growth hormone axis activity (Outcomes for Aim 3): IGF-1 
and IGFBP3 levels will be obtained in serum at 1 week of age and ~35 
weeks CA. These specific markers were chosen as associations have been 
seen between linear growth, FFM gains, metabolic risk (e.g. increased 
adiposity and higher blood pressure), neurodevelopmental outcomes and 
IGF-1 and IGFBP3 in preterm born infants 12, 20-22. IGF-1 and IGFBP3 will 
be analyzed by the Fairview Clinical Laboratory. 
 

PROTOCOL TITLE: Enhanced Early Nutrition for Preterm Infants to Improve  
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Additional Measures: The randomized design of this trial is expected to 
make the distribution of potential confounder values and characteristics 
similar in the intervention and control groups. Nonetheless, to confirm 
their equivalence and to describe the study sample, we will obtain birth 
anthropometrics, maternal age, education, and ethnicity, infant sex, 
gestational age at birth, weight-for-age z score at birth, and degree of 
illness from the medical record or parental self-report at enrollment. 
Degree of illness will be assessed using the Score for Neonatal Acute 
Physiology (SNAP) on DOL#1, 7, 14 and 2134-35. We will also collect data 
on other non-specific markers of illness, including days on the ventilator, 
requirement for blood pressure support, sepsis evaluations and antibiotic  
therapy, steroid administration, necrotizing enterocolitis (NEC), diagnosis  
of chronic lung disease and retinopathy of prematurity (ROP) etc. These  
measures will also allow us to track the safety of the intervention to ensure 
that rates of these common morbidities are similar in both groups.  
 
         5.3  Storage and Access: The records of this study will be kept private. In any 
publications or presentations, we will not include any information that will 
make it possible to identify the mother or baby as a subject. Any hard 
copies of the baby’s research records will be kept in a locked desk in the 
locked office of the PI, co-I or study coordinator, and will be identified 
ONLY by an assigned study ID number (other identifying information will 
be removed). The study information will not be recorded in the medical 
record.  These de-identified data will be entered into electronic format for 
storage and analysis; only the PI, co-Is, study coordinators and data 
analyst will have access to this electronic dataset. 
 
6.0 
Data and Specimen Banking 
6.1 Storage and Access: Data from the various domains will be entered by the 
study personnel into a web-based secure database (RedCap) for storage, 
retrieval and analysis. This database will be password protected and only 
accessible to study personnel. The datasets will then be securely stored 
using Box.com per HRPP policy. We will need to download them to our 
University/AHC desktops for statistical analysis, however only a subset of 
the team will  be given access to all files (study coordinator and PI) and the 
rest will have access to the deidentified files only.This data will be kept 
indefinitely to allow for the possibility of adding future study visits and/or 
future analyses. There will be no specimen banking. 
6.2 Data: The full dataset for the study will be maintained as above, including 
demographic information, pregnancy history and ultrasound results, details 
of delivery, clinical history of infant including nutritional intake, blood test 
results, growth measurements and neurodevelopmental testing results. 
6.3 Release/Sharing: Sharing of this data outside of our study personnel will 
only occur after appropriate IRB approval of additional studies or analyses. 
When possible, the data shared will be de-identified.  

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7.0 
Sharing of Results with Participants 
 
 7.1     Results of routine laboratory tests will be shared with families in the usual 
            manner per clinical routine. Weekly measurement results including body 
            composition measurements will also be shared with families via a 
            weekly measurement card for their records. ERP/VEP results will be  
            shared with families  who wish to receive them.  
 
 
 
Families will be asked on the consent form if they wish to receive the  
 
study results when they are published. If they desire to receive the results,  
 
they will be emailed or mailed to the family per their preference when  
 
they are available.  
 
8.0 
Study Duration 
8.1 
Each individual participant in the study will be enrolled throughout their 
hospitalization and then out through their 4 month corrected age visit. For 
most patients, this will be a total of approximately 6-8 months. It is 
expected to take approximately 18 months to enroll all of the patients in 
this study. It is expected to take approximately 2 years to complete 
enrollment and all study visits. It will likely take an additional 6 months to 
complete data analysis.  
 
9.0 
Study Population 
9.1 Inclusion Criteria: We will include VLBW (birth weight <1500grams) 
preterm (gestational age (GA) at birth < 32 weeks) infants admitted to the 
University of Minnesota Masonic Children’s Hospital NICU, for which 
written informed consent can be secured from a parent within 12 hours of  
birth. 
 
9.2 Exclusion Criteria: Infants who are diagnosed prenatally with a clinical 
condition (other than prematurity) that is known to affect growth rate, 
adiposity, or neurocognitive development, who experienced severe birth 
asphyxia, who are enrolled in another study affecting nutritional 
management, or who are likely to be transferred out of the NICU will be 
excluded from participation. 
9.3 Screening: Admissions to the antepartum unit and to the NICU will be 
screened daily by the inpatient research coordinator for potential eligibility 
for the trial.  
 
10.0 Vulnerable Populations 
10.1 Vulnerable Populations:  

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☒ Children 
☒ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☒ Non-English speakers 
☒ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
10.2 
Additional Safeguards: This study is aimed at optimizing the nutrition 
provided to preterm born neonates. Given this and the potential benefit to 
them they will be included in the study. Consent will be obtained from 
parents (mom and/or dad (if married)). Non-English speakers and illiterate 
persons will be included in the study, but not targeted, to allow for 
diversity in the study and equal opportunity for participation and potential 
benefit. 
 
11.0 Local Number of Participants 
11.1 
Local Number of Participants to be Consented: We will plan to enroll 
approximately 80 infants in this study. We will potentially consent up to  
100 infants, as some infants who are prenatally consented will no longer 
be eligible to participate in the study at the time of birth. For example,  
parents may give consent at 26 weeks gestation, but the infant may remain 
in utero until 33 weeks gestation, at which time they would no longer be 
eligible to participate.  
 
12.0 Local Recruitment Methods 
12.1 
Recruitment Process: Admissions to the antepartum unit and to the NICU 
will be screened daily by the inpatient research coordinator for potential 
eligibility for the trial. Once identified, the coordinator will present the 
mother/parents with a study brochure and offer to share more information 
and answer questions regarding the study if the family is interested. When 
possible, and if there is IRB approval for this, consent will be obtained 
prior to delivery. If unable to obtain consent prior to the infant’s delivery, 
the family will be approached within 12 hours of delivery to explain the 
study, answer questions and obtain consent. They will be allowed ample 
time to consider participation, as well as to ask questions of the clinical 
care team/PI regarding the study. 

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12.2 
Source of Participants: The Epic (EMR) census for antepartum, labor and 
delivery and the NICU will be screened by the research coordinator.  
12.3 
Identification of Potential Participants: The unit census will be reviewed 
daily by the inpatient research coordinator to identify eligible patients.    
These patients will be drawn from the PI’s patient population. Prior to 
birth, this will include mothers who have had a Neonatal Intensive Care 
Unit consult placed. After birth, parents whose infant is under the care of 
the PI and/or her colleagues will be approached. Patients will not self-        
identify, but rather will be approached based on eligibility criteria that is 
contained in the medical record (i.e. gestational age). The inpatient study 
coordinator will present the parent(s) with a brochure describing the study. 
Following this initial contact, the study coordinator will follow-up with 
parents at their convenience to describe the study in more detail and 
answer any questions before obtaining consent. The family will also have 
an opportunity to meet with the PI or another neonatologist if requested to 
answer questions regarding the study. Those patients who have “research 
opt out” in their medical record will not be approached for participation in 
this study. 
12.4 
Recruitment Materials: Parents will initially be given a study brochure that  
generally describes the study. If the parents are then interested in hearing 
more about the study, they will be given a consent form and a time to    
discuss the details of the study with the inpatient study coordinator, their  
care teams and/or the PI.  
11.5     Payment: $25 Target gift cards will be given to each subject’s parent at 3    
           time points (including discharge and the 2 outpatient visits). 
 
13.0 Withdrawal of Participants 
13.1 
Withdrawal Circumstances: There are no specific circumstances under   
which the infant will be withdrawn from the study without parental 
consent; however changes in the nutrition protocol for the study can be 
made at the discretion of the attending neonatologist. These changes will 
not preclude continuing in the study, but rather will be adjusted for when 
analyzing the study data. On the other hand, parents can withdraw their 
infant from the study at any time point.    
13.2 
Withdrawal Procedures: If the infant is withdrawn from the study prior to             
study completion (4 months corrected age), the data collected prior to   
          
withdrawal will be analyzed, but no further data collected. 
13.3 
Termination Procedures: If the infant is withdrawn from the study, the               
remainder of their NICU care will be per standard NICU protocol. Again,             
data collected prior to withdrawal will be analyzed, but no further data   
          
collected.  
 
14.0 Risks to Participants 

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14.1 
Foreseeable Risks:  
 
Intolerance of IV nutrition: Preterm infants often experience 
 
hyperglycemia, hypertriglyceridemia and cholestasis (elevated direct 
 
bilirubin) while on total parenteral nutrition in the first few weeks of life. 
 
It is possible that rates or severity of these problems may be increased in 
 
infants receiving higher amounts and/or faster advancement of 
 
macronutrients. Infant’s glucose, triglyceride levels and direct bilirubin 
 
will be monitored per the clinical routine which is at least daily for the 
 
first week of life for glucose, twice weekly for triglycerides and at least 
 
weekly for bilirubin. More frequent checks will be initiated, again per 
 
clinical routine, should infants show any signs of intolerance. 
 
Hyperglycemia often requires treatment with insulin in very low birth 
 
weight preterm infants, and infants in the study will again be treated per 
 
the usual NICU protocol at the discretion of the care team. In addition, 
 
macronutrient provision will be decreased per clinical routine should 
 
infants show these sign of intolerance. Two recent small studies have 
 
found that earlier initiation and more rapid advancement of these 
 
macronutrients actually result in less hyperglycemia/insulin use14, similar 
 
rates of hypertriglyceridemia14 and lower rates of parenteral nutrition 
 
associated cholestasis15. Therefore, an important aspect of this 
 
exploratory research project is to assess whether early initiation and more  
 
rapid advancement will lead to increased provision of macronutrients or 
 
whether the nutrition will have to be scaled back due to intolerance and 
 
result in similar nutrient provision.  
15.0 Potential Benefits to Participants 
15.1 Potential Benefits: There may or may not be benefits to receiving higher 
amounts of macronutrients during the first week of life. In a few small 
retrospective studies infants receiving higher amounts of nutrition in the 
first week of life had improved neurodevelopmental scores on 
standardized testing and improved growth, including improved head 
growth, increased amounts of lean mass and increased weight gain. Also, 
in a few small randomized trials infants had less hyperglycemia, and lower 
rates of cholestasis. Infants who are randomized to the enhanced nutrition 
protocol may experience these benefits.  
16.0 Data Management 
 
15.1     Data Analysis Plan: Data from the various domains will be entered by the 
study personnel into a web-based secure database (RedCap) for storage, 
retrieval and analysis. The NICU dietician is responsible for abstracting 
nutritional data from the electronic medical record (Epic). ADP data will 
be entered into the database by the study coordinators. ERP data will be 
abstracted by Neely Miller and cleaned of artifacts as previously 
described. The data analyst will examine each variable for outliers and 
distributional properties and flag and correct entry errors where possible 

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and will log-transform or otherwise normalize variables prior to analysis. 
From RedCap all datasets will then be securely stored using Box.com per 
the HRPP policy. They may need to be downloaded to University/AHC 
desktops for statistical analysis, however only a subset of the team will  be 
given access to all files (study coordinator and PI) and the rest will have 
access to the de-identified files only. These laptops are password protected 
and maintained by the AHC. Although we do not anticipate many missing 
values in this short-term follow-up study, multiple imputation methods 
(e.g., Proc MI in SAS) will be used if missing data can reasonably be 
considered missing at random. Analyses will also be run without 
imputation and results compared. Analyses will be carried out using SAS 
version 9.4 (SAS Institute Inc.) using an intent-to-treat approach, with a 2-
tailed p<0.05 as the threshold for statistical significance. For Specific 
Aims 1, 2, and 3, body composition data, neurodevelopmental outcomes, 
and IGF-1 and IGFBP3 will be treated as continuously-distributed 
variables assessed at multiple time points. For the ERP outcomes (which 
are measured twice), the primary hypotheses will be addressed using a 
simple general linear regression model for term-equivalent measures, and 
another similar model for 4 month corrected age measures, with assigned 
group as the independent variable in both cases. For FFM (with up to 10 
repeated measures) and IGF-1 models, mixed effects regression models 
(using  
PROC MIXED) will be used. The primary models will test assigned group 
(standard versus enhanced nutrition protocol) and assigned group x 
time interaction as the tests of differences in the group mean values for 
initial levels, and change over time, respectively, between intervention and 
control groups. To improve the precision of estimates, variables of interest 
(e.g., gestational age at birth, anthropometric z scores at birth, degree of 
illness, etc.) will be included in additional, secondary models. In addition, 
in Specific Aim 3, IGF-1 levels at both 1 week and 35 weeks will be 
examined as predictors of later neurodevelopment and body composition 
outcomes. IGF-1 will be considered a potential mediator of the 
intervention-outcome relationships if 1) the intervention is significantly 
associated with both IGF-1 levels and outcomes, 2) IGF-1 levels are 
significantly associated with FFM and neurodevelopmental outcomes, and 
3) in a model that includes both IGF-1 and treatment group as predictors, 
the effect of treatment group on outcomes (mean differences) is 
diminished compared to results from models unadjusted for IGF-1. Other 
ways of assessing the possible role of IGF-1 in the treatment-outcome 
relationship will also be explored. 
 
           15.2      Power Analysis: A sample size of 40 infants in each treatment group (80  
 
total) allows for up to a ~12% loss to follow-up after discharge and still  
 
have 35 infants per group. Our prior work showed a significant association 
 
of early nutrition (protein and calories in first week of life) with FFM  
 
gains throughout hospitalization (p<0.01 for both) in 34 VLBW preterm  

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infants7. We have also shown that higher energy (kcal/kg/day) across  
 
hospitalization was associated with faster speed of processing (shorter  
 
latency) in 16 preterm subjects23. We therefore expect that this pilot  
 
study, which is 2-3 times as large as previous studies, will be sufficient to  
 
produce statistically significant differences between groups. As this is a  
 
pilot trial, however, we have not conducted a formal power calculation.  
 
Rather, the results of this pilot exploratory study will generate estimates of 
 
effect size that will then be used to calculate sample size for our planned 
 
larger trial. 
 
           15.3    Data Integrity: Describe any procedures that will be used for quality  
 
control of collected data. All data will be stored in a RedCap database 
 
designed by the data manager for this study prior to data collection. All 
 
necessary medical record data (including the daily information on 
 
nutritional intake, procedures, and clinical outcomes, among others) will 
 
be abstracted by the clinical research manager on a weekly or biweekly 
 
basis. Body composition and ERP data will be exported in Excel format 
 
on a weekly or biweekly basis and shared on a password protected server 
 
with the data manager. While body composition data and ERP data go 
 
directly from Excel into RedCap, there is a possibility of data entry errors 
 
for the medical record data, and so the data manager or PI will conduct 
 
biweekly (initially) then monthly checks of data accuracy by comparing 
 
RedCap data against medical records data for validation in a subset of 
 
subjects. On a monthly basis, data quality will be examined for outliers 
 
and unusual values by the data manager, who will then communicate with 
 
the clinical research manager or other data collection personnel with 
 
access to the original data to resolve the errors and insure consistency in 
 
units and data collection processes.  
 
17.0 Confidentiality 
17.1 
Each subject will be assigned a study ID number following randomization. 
A list of patient information and study ID numbers will be securely stored 
using Box.com per HRPP guidelines. Only members of the study team 
will have access to this link between the study ID number and other 
identifying information for the subject. This link is necessary in order that 
the infant's families may be contacted for future follow-up studies. 
A copy of the consent form will be placed in the infants medical record 
after randomization occurs in order that all medical providers are made 
aware of the infants enrollment in the study. The study ID will not be 
recorded in the infant’s medical record.  
 
18.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 
18.1 
Data Integrity Monitoring: 

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Independent monitoring of the clinical study for protocol, SOP, and 
regulatory compliance will be conducted periodically (i.e., at a minimum 
of annually) by qualified staff of the University of Minnesota’s Clinical 
and Translational Science Institute (CTSI) monitoring staff. Utilizing 
UMN CTSI staff for this task ensures that only qualified monitors will be 
selected. Study monitors will review study materials (documents, records, 
Case Report Forms, etc.) to assure that the study is being conducted, 
recorded, and reported in compliance with FDA Good Clinical Practice. 
They will also ensure that the study is conducted in accordance with the 
protocol and inclusion/exclusion criteria as approved by the IRB.  
 
The monitoring report will summarizes items reviewed during the 
monitoring visit. The summary will also include any data 
discrepancies/findings noted during the monitoring visit and the actions 
required by the study team to correct these discrepancies. The investigator 
will permit study monitors and appropriate regulatory authorities access to 
the study data and to the corresponding source data and documents to 
verify the accuracy of these data. 
18.2 Data Safety Monitoring 
    Data Safety and Monitoring Committee (DSMC): An independent DSMC 
will be formed prior to the initiation of the study to monitor the progress 
of the study when 50% of the trial subjects have reached hospital 
discharge. The DSMC will include individuals with expertise in 
neonatology, biostatistics and clinical trials and will review accumulated 
blinded study data at the interim study point to ensure that the intervention 
is not leading to harm. The data they will review will included all labs 
related to nutritional tolerance as described above and other common co-
morbidities of prematurity. The DSMC will not be charged with assessing 
efficacy before conclusion. Any adverse event, defined as a reaction or 
side effect that occurs during the course of the trial associated with the 
intervention, whether or not the event is considered related to the 
treatment or clinically significant will be reported to the appropriate 
institutional IRB and the DSMC. If the DSMC recommends modification 
or cessation of the study protocol at any time point, the IRB and the 
Department of Pediatrics (sponsor of the study) will be notified. 
 
 
 
 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 
Parents of eligible subjects will be approached by the study coordinator 
and given a brochure. They will be asked for their permission to spend 
time reviewing further details of the study at a time convenient to them. 
Parents will be given the opportunity to ask questions and also to speak to 
a clinician (attending neonatologist or neonatal fellow) regarding the study 
prior to consenting to the study. Data gathered for the study will not be 
shared outside of the research team. Only data described in the HIPAA 

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form will be collected. Any questions that the parents feel uncomfortable 
answering can be omitted.  
19.2 
Access to Participants: The research team will only access information 
discussed in the HIPAA release form that was signed by the subject’s 
parents. The research team has access to the data contained in the medical 
record as the PI is a caregiver for this patient population.  
20.0 Compensation for Research-Related Injury 
20.1 
Compensation for Research-Related Injury: In the event that this research 
activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed. Care for such injuries 
will be billed in the ordinary manner to you or your insurance company. If  
you think that your child has suffered a research related injury, let the 
study physicians know right away. 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained): Consent will be 
obtained either prior to delivery or within 12 hours after delivery of the 
infant. Parents will be approached for consent either in the mother’s 
inpatient room or in the NICU.  They will initially be approached by the 
study coordinator and given a brochure generally introducing the study. 
They will be asked permission and also for a convenient time to discuss 
further details of the study and potentially obtain consent. If they are 
interested, they will be allowed ample time to look over the documentation 
and ask questions of the study coordinator. They will also be allowed to 
ask questions of their own care team and/or the NICU care team including 
the attending neonatologist or fellow on service. Consent will be obtained 
and documenting in writing on the approved consent form. A copy of the 
consent will be given to the family and also included in the infant’s 
medical record.  
21.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained): N/A 
21.3 Non-English Speaking Participants: Families who are non-English 
speaking will be included but not targeted. Languages for which short 
forms are available on the University of Minnesota IRB website will be 
included.  Interpreter services will be used to review the consent form in 
detail with parents of potential participants. They will also be given an 
IRB approved short form and allowed ample time to ask questions with an 
interpreter present. Informed consent will be documented on the short 
form per IRB policy. Fairview Interpreter services will be used to ensure 
that qualified interpreters are utilized.  
21.4 Participants Who Are Not Yet Adults (infants, children, teenagers under 
18 years of age): Participants in this study are neonates and are unable to 
provide consent. Consent will be obtained from their parent(s) (mother 

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and/or father if parents are married).  
 
22.0 Setting 
22.1 Research Sites: Admissions to the antepartum unit at the University of 
Minnesota Birthplace and to the University of Minnesota Masonic 
Children’s Hospital NICU will be screened daily by the inpatient research 
coordinator for potential eligibility for the trial. Research procedures will 
be performed in the University of Minnesota Masonic Children’s Hospital 
NICU while the infants are inpatient and in the Center for 
Neurobehavioral Development (717 Delaware Ave SE, Minneapolis, MN)  
as an outpatient.  
 
23.0 Multi-Site Research 
• 
N/A 
24.0 Resources Available 
24.1 Resources Available:  Our 62 bed Level III NICU admits approximately 700 
infants per year. We expect 100 infants per year to be eligible for the study, 
and participation rate is expected to be >70% based upon our past 
experience, yielding >80 subjects over 18 months. We anticipate that 
enrollment will take approximately 18 months based on enrollment rates in 
our previous studies, which will allow for completion of the 4 month 
follow-up visit within the two year time period allotted for this grant. We 
have enrolled ~50 patients in a 12 month period in a recent longitudinal 
study on VLBW’s and ~120 infants in a 24 month period in a study on 
infant body composition after birth. We have a ~85% return to follow-up 
rate in our previous longitudinal study on body composition and speed of 
processing. 
The infants will be monitored closely for any signs of intolerance and the 
neonatal care team including the attending neonatologist will have the 
ability to change the nutritional provision the infant is receiving if these 
signs are present.  
All research staff will be adequately informed about the protocol, research 
procedures and their duties and functions. Nursing staff and other members 
of the care team will also be made aware of the protocol and research 
procedures and will have access to copies of the protocol for reference. 
 
25.0 References 
 
 
1. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan 
EF, Wright LL, et al. Longitudinal growth of hospitalized very low birth 
weight infants. Pediatrics. 1999; 104:280-9. 

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2. Cole TJ, Statnikov Y, Santhakumaran S, Pan H, Modi N, et al. Birth 
weight and longitudinal growth in infants born below 32 weeks' gestation: 
a UK population study. Arch Dis Child Fetal Neonatal Ed. 2014; 
99(1):F34-40. 
3. Horbar JD, Ehrenkranz RA, Badger GJ, Edwards EM, Morrow 
KA, Soll  RF, Buzas JS, et al. Pediatrics. Weight Growth Velocity and 
Postnatal Growth  
Failure in Infants 501 to 1500 Grams: 2000-2013. 
Pediatrics. 2015; 136(1):e84- 92.  
4. Ramel SE, Demerath E, Gray H, Younge N, Boys C, Georgieff M. The 
Relationship of Poor Linear Growth Velocity with Neonatal Illness and 
Two-Year Neurodevelopment in Preterm Infants. Neonatology. 2012; 
102:19-24. 
5. Ramel SE, Gray H, Larson Ode K, Georgieff M, Demerath EW. Body 
Composition Changes in Preterm Infants Following Hospital Discharge: A 
Comparison to Term Infants. J Pediatr Gastroenterol Nutr. 2011; 53(3): 
333-8. 
6. Ehrenkranz RA, Dusick AM, Vohr BR, et al.  Growth in the Neonatal 
Intensive Care Unit Influences Neurodevelopmental and Growth 
Outcomes of Extremely Low Birth Weight Infants. Pediatrics 2006; 117: 
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7. Ramel, SE, Gray H, Christiansen E, Boys C, Georgieff MK and 
Demerath EW. Greater Early Gains in Fat-Free Mass, but not Fat Mass, 
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for Prematurity in Very Low Birth Weight Preterm Infants. J Pediatr. 
2016; 173:108-15.  
8. Belfort MB, Gillman MW, Buka SL, Casey PH, McCormick MC. 
Preterm  
infant linear growth and adiposity gain: trade-offs for later 
weight status and intelligence quotient. J Pediatr. 2013; 163(6):1564 9.e2. 
 
9. Casey PH, Bradley RH, Whiteside-Mansell L, Barrett K, Gossett JM, 
 
Simpson PM. Evolution of obesity in a low birth weight cohort. J 
 
Perinatol.  2012; 32:91–6. 
 
 10. Euser AM, Finken MJJ, Keijzer-Veen MG, et al. Associations between 
 
 prenatal and infancy weight gain and BMI, fat mass, and fat distribution in 
 
 young adulthood: a prospective cohort study in males and females born  
 
 
 very preterm. Am J Clin Nutr. 2005; 81:480–7. 
 
11. Pfister K and Ramel SE. Optimizing Growth and Neurocognitive 
 
Development while Minimalizing Metabolic Risk in Preterm Infants. 
 
Current Pediatrics. 2014. DOI: 10.1007/s40124-014-0057-5. 
 
12. Can E, Bülbül A, Uslu S, Cömert S, Bolat F and Nuhoǧlu A. Effects 
 
of  aggressive parenteral nutrition on growth and clinical outcome in 
 
preterm infants.  Pediatrics International. 2012; 54:869–874. 
 
13. Shim S, Ahn H, Cho S and Park E. Early aggressive nutrition enhances 
 
language development in very low-birthweight infants. Pediatrics 
 
International. 2014; 56:845–850. 
 
14. Drenckpohl D, McConnell C, Gaffney S, Niehaus M and Macwan 
 
KS. Randomized Trial of Very Low Birth Weight Infants Receiving 

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Higher Rates of Infusion of Intravenous Fat Emulsions During the First 
 
Week of Life. Pediatrics 2008; 122:743–751. 
 
15. Repa A, Lochmann R, Unterasinger L, Weber M, Berger A and 
 
Haiden N. Aggressive nutrition in extremely low birth weight infants: 
 
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2016; 4:e2483; DOI  10.7717/peerj.2483.  
 
16. dit Trolli SE, Kermorvant-Duchemin E, Huon C, Bremond-Gignac D 
 
and Lapillonne A. Early lipid supply and neurological development at one 
 
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Neurodevelopment and Minimize Metabolic Risk 
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