Optimising Newborn Nutrition During Therapeutic Hypothermia: an Observational Study Using Routinely Collected Data
Conditions: Infant, Newborn, Asphyxia Neonatorum, Hypothermia, Induced, Parenteral Nutrition, Infant Nutrition, Necrotizing Enterocolitis, Neonatal Sepsis
Sponsor: Imperial College London

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Optimising newborn nutrition during therapeutic hypothermia: 
an observational study using routinely collected data 
 
 
 
 
Version 3.0 
Date: 15/12/2017 
 
 
 
 
SPONSOR: Imperial College London 
SPONSOR REFERENCE: 17IC4064 
FUNDER: NIHR HTA 16/79/03 
STUDY CO-ORDINATION: Neonatal Medicine Research Group, Imperial College London,  
Chelsea and Westminster Hospital campus 
IRAS project ID: 232427 
REC Reference: 17/EM/0307 – REC approval 7/8/2017, HRA approval 9/8/2017 
UKNC approval: 31/8/2017 
 
ISRCTN registration 
• Trial ID:  ISRCTN47404296 
• Date registered: 24/07/2017 
• Link: http://www.isrctn.com/ISRCTN47404296 
 
Clinicatrials.gov registration 
• NCT03278847 
• Date registered: 23/08/2017 
• Link: https://clinicaltrials.gov/show/NCT03278847 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Investigator Group 
Chief Investigators:  
1. Dr Christopher Gale, Imperial College London 
2. Dr Nicholas Longford, Imperial College London 
 
Co-investigators:  
1. Dr Shalini Ohja, University of Nottingham 
2. Miss Mehali Patel, Bliss, National Charity for the Newborn 
3. Dr Jon Dorling, University of Nottingham 
4. Dr Cheryl Battersby, Imperial College London 
5. Mrs Ella Selby, parent representative 
 
Statistician: 
Dr Nicholas Longford, Imperial College London 
 
 
 
Independent Study Steering Group 
1. Dr David Odd, Neonatologist, North Bristol NHS Trust: Clinical chair (independent) 
2. Prof James Carpenter, Professor of Statistics, LSHTM: Statistician (independent) 
3. Dr Louise Linsell, Senior Statistician, National Perinatal Epidemiology Unit, Oxford 
University: Statistician (independent) 
4. Carol Rhodes: Parent representative (independent) 
5. Dr Chris Gale: clinician (not independent) 
 
Observer: Dr Nicholas Longford, Senior Statistician 
 
 
 
 

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Sponsor 
 
Imperial College London; for further information regarding sponsorship conditions, 
please contact the Head of Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London & Imperial College Healthcare NHS Trust 
2nd Floor Medical School Building 
St Mary’s Hospital 
Praed Street 
London 
W2 1NY 
Tel: 0207 5941862 
 
 
 
This protocol describes a study entitled “Optimising newborn nutrition during 
therapeutic hypothermia: an observational study using routinely collected data” and 
provides information about procedures for entering participants.  Every care was taken 
in its drafting, but corrections or amendments may be necessary. These will be 
circulated to investigators in the study.  Problems relating to this study should be 
referred, in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance 
Framework for Health and Social Care (2nd edition). It will be conducted in compliance 
with the protocol, the Data Protection Act and other regulatory requirements as 
appropriate.  
 
 
 

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Table of Contents 
1. INTRODUCTION 
9 
2. STUDY OBJECTIVES 
11 
3. STUDY DESIGN 
12 
4. PARTICIPANT ENTRY 
14 
5. ASSESSMENT AND FOLLOW-UP 
16 
6. DATA ANALYSIS 
16 
7. REGULATORY ISSUES 
20 
7.1 ETHICS APPROVAL 
20 
7.2 CONSENT 
21 
7.3 CONFIDENTIALITY 
21 
7.4 INDEMNITY 
21 
7.5 SPONSOR 
21 
7.6 FUNDING 
21 
8. STUDY MANAGEMENT 
21 
9. PUBLICATION POLICY 
22 
10. REFERENCES 
22 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
BPD 
Bronchopulmonary dysplasia 
EPR 
Electronic Patient Record 
HIE 
Hypoxic Ischaemic Encephalopathy 
HQIP 
Healthcare Quality Improvement Partnership 
HRA 
Health Research Authority 
IV 
Intravenous 
LNU 
Local Neonatal Unit 
IVH 
Intraventricular haemorrhage 
MRC 
Medical Research Council 
NDAU 
Neonatal Data Analysis Unit 
NDS 
Neonatal Data Set 
NEC 
Necrotising Enterocolitis 
NHS 
National Health Service 
NICU 
Neonatal Intensive Care Unit 
NIHR 
National Institute for Health Research 
NNRD 
National Neonatal Research Database 
PN 
Parenteral Nutrition 
PVH 
Periventricular haemorrhage 
REC 
Research Ethic Committee 
ROP 
Retinopathy of prematurity 
SCBU 
Special Care Baby Unit 
UK 
United Kingdom 
UKNC 
United Kingdom Neonatal Collaborative 
 
 
 
 
 
 
 
 
 
 

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INVESTIGATORS 
Chief investigators 
Dr Chris Gale 
MRC Clinician Scientist, 
Clinical Senior Lecturer and 
Consultant Neonatologist – 
Imperial College London 
 christopher.gale@imperial.ac.uk 
 Dr Nicholas Longford 
 
Senior Statistician – Imperial 
College London 
 
 n.longford@imperial.ac.uk 
 
 
Co-investigators 
Dr Shalini Ojha 
 
 Associate Professor and 
Honorary Consultant 
–  University of Nottingham 
 
Shalini.Ojha@nottingham.ac.uk 
 Dr Jon Dorling 
 
 Associate Professor & 
Consultant Neonatologist – 
University of Nottingham  
 
jon.dorling@nottingham.ac.uk 
 
 Miss Mehali Patel 
 
 Research Engagement 
Officer -  Bliss - National 
Charity for the Newborn 
 
Mehalip@bliss.org.uk 
 Dr Cheryl Battersby 
 
Neonatologist – Imperial 
College London 
c.battersby@imperial.ac.uk 
 
 Mrs Ella Selby 
 
Parent of a baby that 
required therapeutic 
hypothermia 
 ellaselby@hotmail.co.uk 
 
 
 

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STUDY SUMMARY 
 
TITLE Optimising newborn nutrition during therapeutic hypothermia: 
an observational study using routinely collected data 
DESIGN Register-based retrospective epidemiological study using 
propensity score matching 
AIMS to determine the optimum enteral and parenteral nutrition 
strategy for newborns with Hypoxic Ischaemic Encephalopathy 
(HIE) during and after therapeutic hypothermia 
OUTCOME 
MEASURES 
Primary: necrotising enterocolitis and blood stream infection 
Secondary:  Survival; length of stay; breastfeeding at discharge; 
hypoglycaemia; time to full enteral feeds; growth 
POPULATION Infants born in England, Wales and Scotland at greater than or 
equal to 36 gestational weeks 
ELIGIBILITY All infants who received therapeutic hypothermia for 72 hours 
or who died during therapeutic hypothermia, and who are 
registered in the National Neonatal Research Database 
(NNRD). 
DURATION Retrospective, non-identifiable data held in a pre-existing 
research database (the NNRD) on infants born between 1st 
January 2008 and 31st December 2016 will be used.  
 
KEYWORDS 
Hypothermia, induced; neonatal encephalopathy, parenteral nutrition, breast milk, 
matching, NNRD 
 
 
 

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PLAIN ENGLISH SUMMARY 
Every year about 1200 babies in England, Wales and Scotland suffer from a lack of 
oxygen around birth which can lead to long-term brain injury or death. This is called 
Hypoxic Ischaemic Encephalopathy (HIE). Research has shown that cooling babies 
with HIE by a few degrees for the first 3 days protects the brain; all babies with 
moderate or severe HIE in the UK are treated with therapeutic hypothermia (cooling). 
 
Doctors do not know how best to care for babies while they are cooled. A key 
question is “how to provide nutrition to babies during cooling”. There are two main 
parts to this question, milk feeds (“enteral” nutrition) and intravenous nutrition 
(“parenteral” nutrition). We don’t know how best to provide either milk or intravenous 
nutrition to cooled babies. 
- MILK FEEDS: Some neonatal units in the UK carefully feed babies (usually with 
maternal breast milk) while they are cooled. This avoids intravenous lines and is 
believed to help them feed and go home earlier. Other neonatal units do not feed 
cooled babies because they worry about a condition called necrotising enterocolitis 
(a devastating and often fatal disease) which might be more common with feeding. 
- INTRAVENOUS NUTRITION: All cooled babies need intravenous fluid (even when 
milk feeds are given it takes several days before enough fluid can be given this way). 
Some neonatal units give babies intravenous nutrition (which contains fat, protein, 
carbohydrate, vitamins and minerals) as this may improve growth and recovery. 
Other neonatal units only give intravenous dextrose with simple salts because of 
concerns that intravenous nutrition leads to more infections.  
 
This study will compare these different ways of providing nutrition. It will use a 
research database called the National Neonatal Research Database (NNRD). In 
England, Scotland and Wales doctors and nurses looking after babies in neonatal 
care (including all cooled babies) use an Electronic Health Record system. Data from 
this system are anonymised (no baby can be identified) and form the NNRD, so the 
NNRD holds data from all babies who have been looked after on NHS neonatal 
units. We have worked closely with parents and charities in developing the NNRD. 
 
We will use the NNRD to study all term babies who received cooling in England, 
Scotland and Wales since 2008. We will compare the milk feeding and intravenous 
nutrition they receive. 
- MILK FEEDING: We will compare babies who are fed milk while cooled with those 
that are not fed any milk. Our main goal is to establish whether there is any 
difference in rates of necrotising enterocolitis. 
- INTRAVENOUS NUTRITION: We will compare babies who get intravenous 
nutrition with those that only get intravenous dextrose. The main difference we are 
looking for is in the rate of infection. We will also study how many babies die, how 
long they stay in neonatal care, how soon breastfeeding starts and many are 
breastfed when they go home. 
 
We will apply a statistical approach called “potential outcomes framework” in which 
babies are matched in each group (e.g. babies who are fed and those who are not 
fed) as closely as possible. This will ensure that any difference in outcomes is due to 
the different nutritional treatments and not due to background differences or other 
confounders (like how sick a baby is). 
 
 

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1. INTRODUCTION  
 
1.1 BACKGROUND 
Therapeutic hypothermia, cooling the whole body to 33-34°C for 72 hours, is the 
standard of care for infants with hypoxic ischemic encephalopathy (HIE) (1); this 
treatment has been recommended by NICE since 2010.  Approximately 1200 babies 
receive therapeutic hypothermia annually in England, Scotland and Wales 
(unpublished data; National Neonatal Research Database (NNRD)). 
 
Administration of therapeutic hypothermia itself (e.g. temperature, duration and 
rewarming) is well defined and follows a protocol based on high quality randomised 
controlled trials (1, 2).  Optimal concurrent supportive care for infants while they 
receive therapeutic hypothermia is however, not evidence based.  One contentious 
component of concurrent supportive care is provision of nutrition, including both 
enteral (milk) and parenteral (or intravenous) nutrition. 
 
Normal healthy term babies would be expected to breast or bottle feed independently 
(or ‘on demand’) shortly after birth.  Babies that receive therapeutic hypothermia for 
HIE cannot feed independently.  They have suffered a hypoxic insult to their brain and 
other organ systems; they are often unable to coordinate sucking and swallowing 
safely, cannot regulate fluid balance (due to renal injury) or glucose metabolism (due 
to hepatic damage) often resulting in hypoglycaemia which can worsen brain injury.  
All babies receiving therapeutic hypothermia therefore will be commenced on 
intravenous fluid shortly after admission for neonatal care (3).  
 
The intravenous fluid can be simple intravenous dextrose solution (with electrolytes 
such as sodium and potassium as required) or a more complex parenteral nutrition 
(PN) delivering protein, fat, vitamins, minerals and carbohydrate – this is the parenteral 
component of nutritional support.   
 
Babies can be kept on only simple intravenous dextrose or parenteral nutrition while 
they are receiving therapeutic hypothermia (i.e. have no milk feeds), or they can be 
started on enteral (milk) feeds gradually – this is the enteral component of nutritional 
support. 
 
Background and rationale for different enteral nutrition options 
The reason that enteral (milk) feeds are withheld during therapeutic hypothermia is 
because of concerns about necrotising enterocolitis (NEC).  Necrotising enterocolitis 
is a feared and often devastating condition that it is associated with considerable 
mortality and morbidity (4).  While it is predominantly seen in preterm infants, it does 
occur in term babies with predisposing conditions such as HIE (5).  The UK 
randomised TOBY trial of whole body hypothermia for HIE (2) reported one case of 
NEC (an infant in the hypothermia group) among 325 participants. The pathogenesis 
of NEC is incompletely understood; one putative mechanism links impaired 
gastrointestinal blood flow (seen in infants with HIE) and intraluminal substrate such 
as milk, as a trigger for the proinflammatory cascade and gastrointestinal necrosis that 
characterizes NEC (6, 7).  Therefore, withholding enteral (milk) feeds is practiced to 
reduce the risk of developing NEC, despite an absence of evidence that withholding 
enteral feeds reduces the incidence of NEC (8).  
 

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The alternative approach, starting and gradually increasing enteral feeds while a baby 
is receiving hypothermia, is supported by limited animal and human physiological data.  
Animal studies indicate that hypothermia decreases inflammatory, histological and 
metabolic gastrointestinal damage by mechanisms such as reducing intestinal 
infiltration with neutrophils, alleviating oxidative stress by preventing overproduction of 
nitric oxide and by altering fatty acid metabolism pathways (9, 10). In humans, a study 
that compared infants who underwent therapeutic hypothermia with a historical cohort 
showed improved feeding tolerance and GI morbidity in the therapeutic hypothermia 
group (11). Infants in the therapeutic hypothermia cohort reached full enteral feeds 
significantly sooner that the infants in the historical cohort preceding therapeutic 
hypothermia. In summary, these limited studies suggest that following a hypoxic insult, 
hypothermia, may have a protective effect on the GI system.  The potential benefits of 
starting enteral (milk) feeds during hypothermia include earlier establishment of full 
enteral feeds and earlier discharge home, improved feed tolerance, greater comfort 
for the baby and improved parental bonding. 
 
Background and rationale for different parenteral nutrition options 
Intravenous 
dextrose 
provides 
sufficient 
carbohydrate 
energy 
to 
prevent 
hypoglycaemia, but does not provide other nutritional components such as protein and 
fat; therefore infants will break down fat and muscle stores while they receive 
therapeutic hypothermia.  Parenteral (intravenous) nutrition contains fat, protein, 
vitamins and essential trace minerals in addition to carbohydrate, and as such 
provides more complete nutritional support and limits catabolism.  This is the rationale 
for giving parenteral nutrition to babies receiving therapeutic hypothermia: it will 
improve overall growth and potentially improve brain growth and development.  This 
conjecture is not backed up by any human studies. 
 
The counter-argument comes from the PEPaNIC trial (12), which raised the possibility 
that early provision of PN may be harmful.  The PEPaNIC trial randomised 1440 
critically ill children (including 209 term infants less than 28 days old) to receive PN 
within 24 hours of admission or for PN to be delayed until for 7 days.  While mortality 
was similar between the two groups, children who had PN withheld for 7 days had a 
significantly lower rate of new infection (10.7% vs 18.5%).  The late PN group also had 
a shorter hospital stay and shorter duration of ventilation.  A post-hoc subgroup 
analysis of term infants less than 28 days old found that the benefits of late PN were 
similar or greater than the overall study group.  The PEPaNIC trial was carried out on 
paediatric intensive care units, rather than neonatal units and so was unlikely to have 
included many (or potentially any) babies treated with therapeutic hypothermia for HIE.  
Therefore, the results cannot be extrapolated to this group.  The PEPaNIC trial does 
however raise concerns about potential harms of early PN, and the findings are in 
keeping with similar studies in adult intensive care (13).  Parenteral nutrition is an 
important contributor to the cost of neonatal care (14). If PN is not beneficial, or indeed 
harmful, in this group of babies, standardized, limited use of PN in this population 
would save the NHS money. 
 
As yet, no trials have been performed to identify the best strategies to provide nutrition 
to infants with HIE during and after therapeutic hypothermia. Current UK feeding 
practices for these infants are therefore not supported by any evidence based 
guidelines and are very variable: A recent survey of UK Neonatal Intensive Care Units 
(NICUs) demonstrated wide variation in clinical practice (15). The survey, performed 

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in 2014, revealed that 45% of NICUs do not feed infants during therapeutic 
hypothermia, 40% feed depending on the clinical condition and the rest use trophic 
feeds or give incremental volumes of milk at different rates (15). In addition, 55% of 
units report routinely using parenteral nutrition while 6% report never using parenteral 
nutrition in this group of infants.  
 
These findings are in keeping with the report of Thayagarajan et al. (3) which 
compared practice between two NICUs in Sweden and one NICU in the UK. Most 
Swedish infants (91%) were fed enterally during therapeutic hypothermia; in the UK 
only 33% received enteral feeding.  This study did not find any difference in the time 
taken to reach full feeds between Swedish and UK neonatal units, but its small size 
(only 84 infants) and well known differences in feeding practices and attitudes between 
the two countries make it difficult to apply the results to the UK population (a 
significantly larger proportion of the Swedish cohort was exclusively breastfed).  
Finally, a very small single-centre observational study in the UK (25 infants) found no 
difference  in time to reach full feeds by day or risk of gastrointestinal complications 
between infants fed and those not fed during therapeutic hypothermia (16). 
 
1.2 RATIONALE FOR CURRENT STUDY 
There is weak evidence that infants with HIE who undergo therapeutic hypothermia 
tolerate enteral feeding. There is insufficient evidence to recommend the optimal 
feeding strategy that would minimise gastrointestinal complications (such as NEC), 
expedite enteral feeding, and reduce the length of hospital stay.  In relation to 
parenteral nutritional support, there is strong evidence from other population groups 
that early parenteral nutrition is harmful, but insufficient evidence to guide practice for 
babies with HIE. 
 
There are two overarching uncertainties in the nutritional support of babies receiving 
therapeutic hypothermia: 
1. ENTERAL: Some UK units gradually increase milk feeds while others omit all milk 
feeds. Potential benefits of milk feeds include greater comfort for the baby, earlier 
establishment full milk feeds, reduced intravenous therapy, fewer complications 
(such as infections), increased parental involvement in care and earlier discharge 
home. 
Conversely, milk feeds may increase the risk of necrotising enterocolitis.  
2. INTRAVENOUS: All babies treated with therapeutic hypothermia receive 
intravenous therapy; some UK units administer this as intravenous (parenteral) 
nutrition and some as intravenous dextrose. Parenteral nutrition may lead to better 
growth but may increase the risk of infection. The PEPaNIC trial (12) compared 
early with late parenteral nutrition in paediatric intensive care and found fewer 
infections among children who had no parenteral nutrition in the first week of 
intensive care. 
 
2. STUDY OBJECTIVES 
The overarching aim of this project is to determine the optimum enteral and parenteral 
nutrition strategy for newborns with HIE during therapeutic hypothermia. 
 
2.1 RESEARCH QUESTIONS 
We will perform two primary comparisons: 

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1. ENTERAL: the objective of this comparison will be to determine whether any 
enteral (milk) feeding, compared to withholding enteral feeding (no milk), 
during therapeutic hypothermia, is associated with a difference in the 
incidence of necrotising enterocolitis. 
2. PARENTERAL: the objective of this comparison will be to determine whether 
provision of intravenous dextrose, compared to provision of parenteral 
nutrition, during therapeutic hypothermia, is associated with a difference in the 
incidence of blood stream infection. 
 
2.2 HEALTH TECHOLOGIES BEING ASSESSED 
Current nutritional practice for babies receiving therapeutic hypothermia varies in the 
both enteral and parenteral (intravenous) components.  This proposal will examine 
health technologies in enteral and parenteral aspects. 
 
In the enteral component of nutrition, the health technology to be assessed is the 
gradual introduction of enteral (milk) feeds during therapeutic hypothermia: 
• Included in this is any type of milk (e.g. expressed maternal breast milk, 
expressed donor breast milk and artificial formula) 
• This health technology includes different routes of administering enteral feeds 
such as nasogastric tube (gavage feeding) and bottle 
• This health technology also includes different rates of increasing enteral feeds 
(for example by 15ml/kg/day, by 30ml/kg/day or faster) 
This enteral health technology will be compared against withholding enteral feeds 
(keeping a baby nil per os) for the duration of hypothermia. 
 
In the parenteral component, the health technology being assessed is administration 
of parenteral nutrition during therapeutic hypothermia: 
• Included in this are different compositions of parenteral nutrition (for example 
standard, pre-prepared bags of nutrition and individually tailored parenteral 
nutrition) 
• This health technology includes different routes of administration of parenteral 
nutrition such as via a peripheral intravenous cannula, percutaneous central 
venous catheter (‘long line’) or umbilical venous catheter. 
• This health technology also includes different volumes of parenteral nutrition (e.g. 
40ml/kg/day, 60ml/kg/day or greater). 
This parenteral health technology will be compared against standard intravenous 
fluids (10% dextrose with additional electrolytes added where required) for the 
duration of hypothermia. 
 
3. STUDY DESIGN 
Retrospective cohort study using existing data held in the National Neonatal Research 
Database (NNRD). The analysis will apply the potential outcomes framework using 
propensity score matching. 
 
All analysis will be using anonymised data held in an approved research database, the 
NNRD.  No patient identifiable information will be used in this study. 
 
3.1 STUDY OUTCOME MEASURES 
For the enteral comparison, the primary outcome will be necrotising enterocolitis 
defined according to the UKNC case definition of Battersby et al (17).  This case 

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definition uses clinical and x-ray findings, as these will not be complete for all babies 
in the NNRD (in particular pre 2010) we will also use 2 other definitions as sensitivity 
analyses, outlined below.  
• Severe necrotising enterocolitis: defined as necrotising enterocolitis confirmed at 
surgery or post-mortem, or in infants what died of necrotising enterocolitis where 
no post-mortem was performed, and as used in (19) 
• Necrotising enterocolitis (non-UKNC definition): Defined as recorded diagnosis of 
necrotising enterocolitis and received at least 5 consecutive days antibiotics and 
nil by mouth. 
 
For the parenteral comparison, the primary outcome will be late onset blood stream 
infection (>72 hours after birth) defined according to the Healthcare Quality 
Improvement Partnership (HQIP) National Neonatal Audit Programme (NNAP) case 
definition, which is determined using NNRD data: 
• Infection cultures (episodic): Pure growth of pathogen from blood OR either a pure 
growth of a skin commensal or a mixed growth with ≥3 clinical signs at the time of 
blood sampling, recorded >72 hours after birth (18) 
This definition uses data that is recorded using an ad hoc form in the summary 
electronic patient record from which the NNRD is derived.  The data completeness for 
this ad hoc form is variable over time and between neonatal units, hence we will also 
use a more pragmatic definition for late onset blood stream infection as a sensitivity 
analysis: 
• 
Late onset blood stream infection (5 consecutive days of antibiotic treatment): 5 
consecutive days of antibiotic treatment after 72 hours following birth, OR where 
antibiotics were commenced in the first 72 hours: a change in antibiotic type after 
72 hours with continuation of these new antibiotics for at least 5 days.  
 
 
Secondary outcomes for both enteral and parenteral comparisons will include: 
1. Survival: defined as alive at final neonatal unit discharge 
2. Length of stay: defined as number of days between first neonatal unit admission 
and final neonatal unit discharge for surviving infants.   
3. Hypoglycaemia: defined as any diagnosis of hypoglycaemia recorded after 
therapeutic hypothermia is commenced and before the final neonatal unit 
discharge 
4. Breastfeeding at discharge: defined as any breastfeeding (suckling at the breast) 
at discharge, this outcome is audited annually by the NNAP and data on method 
of feeding (differentiating for example “suckling at the breast” from “bottle feeding 
with expressed breast milk”). 
5. Onset of breastfeeding (days): defined as the first day at which a baby is recorded 
to be feeding at the breast (suckling) – this does not include maternal breast milk 
given by bottle or nasogastric tube 
6. Time to first maternal breast milk feed (days): defined as the first day where a baby 
is recorded to be receiving maternal breast milk by any route (including suckling at 
the breast, by bottle or nasogastric tube) 
7. Duration of parenteral nutrition (days): the number of days that an infant is recorded 
to be receiving parenteral nutrition, this comparison will only be performed for the 
ENTERAL COMPARISON 
8. Number of days an infant has a central venous line in situ: the number of days 
where a baby is recorded to have a central venous line in situ 

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9. Growth: weight for post-menstrual age standard deviation score at final neonatal 
unit discharge. 
 
4. PARTICIPANT ENTRY  
 
4.1 INCLUSION CRITERIA 
There will be no active recruitment of patients as this is an epidemiological study using 
routinely recorded, anonymised data held within an established research database, 
the NNRD. 
Eligible infants within the NNRD: 
1. Received neonatal care at a unit that is part of the UK Neonatal Collaborative; this 
includes all NHS neonatal units in England, Scotland and Wales 
2. Recorded gestational age at birth ≥36 weeks  
3. Recorded as receiving therapeutic hypothermia for 72 hours or died during 
therapeutic hypothermia 
 
4.2 EXCLUSION CRITERIA 
Infants with missing data for principal background and outcome variables.  Missing 
values for other variables will be dealt with using multiple imputation. 
 
The number of infants with missing data will be identified and recorded at each stage. 
If this is non-trivial it will be explored in sensitivity analyses. 
 
 

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Gestation at birth <36 weeks 
Infants with data held in the National Neonatal 
Research Database NNRD  
(estimated ~600,000)
Did not receive 72 hours or 
more of therapeutic 
hypothermia (unless died during 
therapeutic hypothermia) 
Missing principal background or 
outcome variables (e.g. 
gestational age at birth) 
Did not receive therapeutic 
hypothermia 
Received parenteral 
nutrition during 
therapeutic 
hypothermia 
(estimated 30% ~2160 
infants) 
Final population 
(estimated ~7200 infants) 
Received enteral 
(milk) feeds during 
therapeutic 
hypothermia 
(estimated 40% ~2880 
infants) 
Did not receive 
parenteral nutrition 
during therapeutic 
hypothermia 
(estimated 70% ~5040 
infants) 
PARENTERAL 
comparison 
(estimated ~7200 
infants) 
ENTERAL 
comparison 
(estimated ~7200 
infants) 
Enteral (milk) feeds 
WIHHELD during 
therapeutic 
hypothermia 
(estimated 60% ~4320 
infants) 
4.3 STUDY FLOW CHART 

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5. ASSESSMENT AND FOLLOW-UP  
There will be no assessment or follow-up.  
 
5.1 TIME PERIOD 
NNRD data will be extracted for the period January 1st 2008-December 31st 2016 (9 
years) 
 
6. DATA ANALYSIS 
Anonymised data held within the NNRD will be used for this study. 
 
6.1 DATA SOURCE 
National Neonatal Research Database (NNRD): the NNRD holds data from all infants 
admitted to NHS neonatal units in England, Scotland and Wales (approximately 
90,000 infants annually). The NNRD is formed from data extracted from the neonatal 
electronic health record system used by health professionals during routine clinical 
care. This study will use routinely collected data. 
 
Briefly, daily clinical information on neonatal unit admissions is recorded in a point-of-
care, clinician-entered Electronic Patient Record.  A defined data extract, the Neonatal 
Dataset (NHS Information Standard SCCI595) is transmitted quarterly to the Neonatal 
Data Analysis Unit at Imperial College London and Chelsea and Westminster NHS 
Foundation Trust where patient episodes across different hospitals are linked, data 
are cleaned, and entered into the NNRD (20).  Contributing neonatal units are known 
as the UK Neonatal Collaborative (UKNC).  
 
The NNRD holds the Neonatal Data Set, approximately 450 data items that form a 
NHS data standard (21). Data items include demographic and admission items (e.g. 
maternal conditions, birthweight), daily items (entered every day for all infants, e.g. 
respiratory support, feeding information), discharge items (e.g. feeding and weight at 
discharge) and ad hoc items (entered if and when they occur e.g. suspected infection, 
ultrasound scan findings, abdominal x-ray findings). 
 
Data extracted from the neonatal Electronic Health Record are cleaned; records with 
implausible data configurations are queried and corrected by the treating clinicians. 
Cleaning is carried out by the Neonatal Data Analysis Unit before data are 
incorporated into the NNRD. The robustness of core NNRD data (birth weight, sex, 
length of stay and death) has been previously demonstrated for research purposes 
(19, 22).  Data held in the NNRD are used for multiple purposes including national 
audit (the HQIP funded NNAP) and analyses for the Department of Health, NHS 
England and the Chief Medical Officer. 
 
A formal comparison of NNRD data items against those recorded in Case Record 
Forms of a multicentre, randomised placebo controlled trial (Probiotics in Preterms, 
NIHR HTA 05/501/04 (23)) was undertaken as part of a NIHR Programme Grant for 
Applied Research (RP-PG-0707-10010); this work (submitted for publication) 
demonstrated a high degree of data agreement (>95%) between the NNRD and 
clinical trial Case Report Forms for core variables: e.g. 98.3% (95% CI 97.4-99) 
concordance for birth weight, 98.9% (98.1-99.4) concordance for instrumental 
delivery, 96% (95.1-96.8) concordance for length of neonatal unit stay, 99.4% (98.9-

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99.8) concordance for antibiotic administration and 99.8% (99.4-99.98) concordance 
for survival to neonatal discharge. 
 
Similar methods to those in the UK Neonatal Collaborative NEC Study (17) will be 
used to identify infants with NEC. These involve using daily, diagnostic, Abdominal X-
ray and procedural variables held on the NNRD and verifying these patient-level data 
with study leads. 
 
6.2 STATISTICAL METHODS 
In each analysis (enteral and intravenous), we will apply the potential outcomes 
framework (24) to estimate the average effect of a treatment over its alternative. In this 
framework, a subset is found within each treatment group so that the two subsets have 
nearly identical distributions of all the background variables. This can be motivated as 
post-observational design (25), arranging the data so that they have the appearance 
of having arisen in a randomised study and can be analysed by methods appropriate 
for such studies. In particular, the two subgroups can be compared straightforwardly 
(by their means, medians, or the like), without any involvement of the background 
variables. This is an important conceptual strength of the framework. The analysis 
comprises two parts: in the first, matched subgroups are formed using only the 
treatment and background variables, without any involvement of the outcome 
variables; in the second, these subgroups are analysed without any involvement of the 
background variables. The treatment indicator is the sole link of the two parts.  
 
Usually the first part is complex and time-consuming because it entails modelling of 
the selection process – the association of the treatment assignment to the background 
variables. We propose to do this by propensity analysis. Its output is the fitted 
propensities – fitted probabilities of being assigned a treatment as a function of the 
background variables. The matched subgroups are formed through matched pairs of 
infants, one from each treatment group. The propensity model is chosen so as to 
achieve a fine balance of the two subgroups. The theoretical support for this method 
is provided by (26) and (27).  
 
A key prerequisite for successful matching is an extensive set of background variables 
that cover all aspects of potential confounding.  While no set of variables can be 
confirmed as complete in this regard, we believe that we can extract from the NNRD 
a set of background variables that is much richer and has a higher degree of 
completeness than could be achieved by using an alternative source of data or an 
alternative method of data collection.  The large sample (or population) size is another 
strength of our approach.   
 
 
6.2.1 DATA VARIABLES TO BE INCLUDED IN PROPENSITY SCORE MATCHING 
The following data items will be used to force a match 
1. Cord blood gas pH in bands: >7.0, 6.9-7.0, <6.9 
2. Birth year: in 2 year bands 
 
The following variables will be included within a propensity score for the purpose of 
matching: 
1. Demographic data items 
a. Gestational age week 

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b. Birthweight standard deviation quartile 
c. Sex 
d. Multiplicity 
2. Maternal factors 
a. Maternal age 
b. Maternal duration of rupture of membranes (time in hours) 
c. Maternal pyrexia 
d. Maternal suspected chorioamnionitis 
e. Maternal smoking status 
f. Maternal ethnicity 
g. Maternal deprivation score (from LSOA) 
h. Maternal hypothyroid (Y/N) 
i. Maternal diabetes (Y/N) 
j. Mode of delivery of infant (vaginal or Caesarean) 
k. Parity of mother (primiparous Y/N) 
3. Infant factors: resuscitation 
a. Apgar score at 1 minute 
b. Apgar score at 5 minutes 
c. Chest compressions administered 
d. Emergency resuscitation drugs administered 
e. Intubated at resuscitation 
f. Umbilical cord base excess 
g. Time to first spontaneous breath 
4. Infant factors: condition on neonatal unit prior to therapeutic hypothermia 
a. Admission mean blood pressure 
b. Admission blood glucose 
c. Admission heart rate 
d. Admission oxygen saturation 
e. Admission temperature 
5. Infant factor: early onset infection 
a. Positive blood or cerebrospinal fluid culture with a recognised pathogen 
recorded in the first 3 days 
6. Treatments on day 1 
a. Treatment for low blood pressure with an intravenous inotrope (e.g. 
dopamine, noradrenaline) 
b. Mechanical ventilation method 
c. Received inhaled nitric oxide (Y/N) 
7. Organisational factors 
a. Required acute postnatal transfer, within 24 hours (Y/N) 
b. Neonatal network 
 
Treatments that occur after neonatal unit admission will not be matched as these are 
not independent of the health technology being assessed (nutrition during therapeutic 
hypothermia). 
 
Logistic regression model is fitted to the treatment (a dichotomous variable) in terms 
of the background variables.  The model is supplemented by transformations of the 
continuous background variables and by interactions with the purpose of obtaining a 
good balance.  The fitted propensities (probabilities of being assigned the focal 
treatment) for the babies in the study are divided into percentiles (100 propensity 

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groups), or pairs of percentiles (50 groups), and matched pairs are formed within these 
groups; in each pair, there is one baby from either treatment group.  The babies in 
these matched pairs are re-formed as two treatment subgroups and their balance on 
all the background variables is assessed by means of a balance plot; see 
supplementary materials in (19) for an example.  The logistic regression model is 
reviewed (an interaction or transformation term added to it) and the balance plot 
constructed.  This procedure is iterated until no improvement in the balance can be 
achieved.  The ‘final’ logistic model has no interpretation; its sole purpose is to 
construct two treatment subgroups of babies that have similar distributions of the 
background variables, so that they have the appearance of having been obtained by 
a randomised study.  These two subgroups are then analysed by methods that would 
be appropriate for a randomised study.  The sampling variance of the estimator of the 
average treatment effect is estimated from replicate matched treatment groups as the 
sum of the average of the estimated sampling variances for the replicates and  
the adjusted (inflated) variance of the estimates across the replicates. Details are 
given in Appendix 1 (Rubin's rule) 
 
 
6.2.2 SUBGROUP AND SENSITIVITY ANALYSES 
Sensitivity analysis will be conducted by constructing an additional background 
variable, a dichotomy, in such a way as to stack the odds against the treatment inferred 
to be superior.  This can be done for a range of odds ratios.  We will find the borderline 
odds ratio, for which the treatment effect vanishes, or becomes not significant (as 
appropriate).  Then we'll pose the question whether, in view of the background 
variables used in the analysis, it is plausible that there might be such a binary variable 
missing from the list of background variables. 
 
In relation to missing background (confounder) variables, where the proportion of 
missing entries for a variable is substantial, we will form matched subgroups by 
regarding nonresponse as a separate category for a categorical variable or a binary 
variable for continuous variable.  In addition, when a principal (important) background 
variable has many missing entries, we will conduct a sensitivity analysis by imputing 
for these missing entries values generated according to a missing not at random 
mechanism that is stacked against the original conclusion of the analysis, exploring 
pessimistic scenarios. 
 
The following sensitivity analyses will be undertaken: 
1. Restricted to the use of data from 2012 onwards in England (where neonatal 
unit coverage by the NNRD was complete), to determine whether increased 
drop out seen prior to 2012 introduces bias that altered direction or magnitude 
of findings 
2. Restrict population to infants where enteral or parenteral feeding has been 
actively recorded. i.e. restrict population to infants where enteral feeding, 
parenteral nutrition, intravenous glucose or nil by mouth has been recorded 
(and exclude those infants where no data has been entered during the first 4 
days) 
3. Using alternate diagnostic criteria for the primary outcomes (necrotising 
enterocolitis and late onset infection) 
4. Excluding infants with extreme high and low propensity scores 

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The following subgroup analyses will be undertaken: 
1. Excluding all babies whose first admission to neonatal care is from the postnatal 
ward; to exclude babies where therapeutic hypothermia is administered 
following postnatal collapse 
 
6.2.3 SAMPLE SIZE 
 
It is estimated that approximately 7200 infants whose de-identified data are held in the 
NNRD will meet the study inclusion criteria. 
 
Pilot data extracted from the NNRD shows the approximate spread of infants receiving 
different nutritional therapies in 2014 and 2015, tables 1 and 2. 
 
Year 
Number of 
babies in 
cohort 
Number (%) of babies 
receiving any enteral feeds 
Number of babies where 
enteral feeds were 
withheld 
2014 
796 
301 (38) 
495 (62) 
2015 
809 
320 (40) 
489 (60) 
Table 1: Infants treated with therapeutic hypothermia in England, Scotland and Wales 
who received different enteral nutrition strategies 
 
Year 
Number of 
babies in 
cohort 
Number of babies 
receiving Parenteral 
Nutrition 
Number of babies not 
receiving parenteral 
nutrition 
2014 
796 
250 (31) 
546 (69) 
2015 
809 
238 (29) 
571 (71) 
Table 2: Infants treated with therapeutic hypothermia in England, Scotland and Wales 
who received different parenteral nutrition strategies 
 
Assuming the proportions of infants receiving different enteral and parenteral nutrition 
options is similar to that seen in pilot data (tables 1 and 2), a sample size of 7200 
infants receiving therapeutic hypothermia will detect (two-sided significance 5%, 
power 90%) a difference of: 
• 0.7% in NEC with 2000 matched pairs, assuming that the rate of NEC is negligible 
in the reference treatment 
• 2% blood stream infection with 1500 pairs, assuming that the rates of BSI are 1% 
and 3% 
 
6.2.4 MISSING DATA 
Imputation will be applied to deal with missing values. Single imputation will be applied 
only when the fraction of the missing items is negligible, otherwise multiple imputation 
will be applied. List-wise deletion will be applied only to records that are missing the 
majority of entries relevant to the analysis. 
 
7. REGULATORY ISSUES 
 
7.1 ETHICS APPROVAL 
This study will be carried out using data held in the Neonatal Research Database 
(NNRD).  The NNRD holds derived from operational electronic neonatal data.  
 

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The Neonatal Data Analysis Unit (NDAU) holds UK Research Ethics Committee (REC) 
approval, 16/LO/1093, and Confidential Advisory Group (CAG) approval, ECC 8-
05(f/2010), to form the National Neonatal Research Database (NNRD). 
 
Study specific Research Ethics Committee approval was granted on 7th August 2017 
by East Midlands – Leicester Central Research Ethics Committee.  Health Research 
Authority (HRA) approval was granted on 9th August 2017. 
 
Approval for this study was granted by the NDAU director and board at the steering 
group meeting 11th October 2016.  Approval from the 200 neonatal units that make up 
the UKNC was granted on 1st September 2017. 
 
The study will be conducted in accordance with the recommendations for physicians 
involved in research on human subjects adopted by the 18th World Medical Assembly, 
Helsinki 1964 and later revisions. 
 
7.2 CONSENT  
This study will only use anonymised data held in an established research database, 
the NNRD. 
 
7.3 CONFIDENTIALITY 
Only anonymised data will be used in this study.   
 
7.4 INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study.  Gallagher London negligent (public liability) and 
non-negligent harm (no fault) policy number: B1262FI0114916. 
 
7.5 SPONSOR 
Imperial College London  
 
7.6 FUNDING 
The study is funded through NIHR HTA grant 16/79/03. 
 
8. STUDY MANAGEMENT 
An independent Study Steering Committee (SSC) will be appointed by the study 
funder (NIHR).  This will include the Chief Investigator (Dr Gale), an independent 
chair, and independent statistician and a parent/patient representative.  The SSC will 
meet before the end of month 2 of the study and again in the second year of the 
study. 
 
A Clinical Investigator Group (CIG) will be formed of all members of the project team.  
The CIG will meet 3 times: 
1. 
At the end of month 1 to agree the final protocol and data extraction plan 
2. 
At the end of month 6 to review the data extraction and analysis plan 
3. 
At the end of month 13 to review analysis results, discuss conclusions, agree 
write up and dissemination strategy 
A core study management group consisting of CG and NL (Co-Chief Investigators) 
will meet at least monthly throughout the study to co-ordinate the project with other 
members of the team co-opted as deemed appropriate.  Where necessary, decisions 

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will be referred to the steering group.  Administrative support, for example contacting 
United Kingdom Neonatal Collaborative (UKNC) units, will be provided by the 
Neonatal Data Analysis Unit (NDAU). 
 
9. PUBLICATION POLICY 
The results of this study will be reported as a manuscript in a peer-reviewed scientific 
journal.  All members of the study group will be authors with additional contributors as 
appropriate.  Publications will acknowledge the NIHR and NNRD as set out in relevant 
guidance. 
 
10. REFERENCES 
1. 
NICE. Therapeutic hypothermia with intracorporeal temperature monitoring for 
hypoxic perinatal brain injury [IPG347] 
. In: NICE, editor. Manchester: National Institute for Health and Clinical Excellence; 2010. 
2. 
Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. 
Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 
2009;361(14):1349-58. 
3. 
Thyagarajan B, Tillqvist E, Baral V, Hallberg B, Vollmer B, Blennow M. Minimal 
enteral nutrition during neonatal hypothermia treatment for perinatal hypoxic-ischaemic 
encephalopathy is safe and feasible. Acta Paediatr. 2015;104(2):146-51. 
4. 
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364(3):255-64. 
5. 
Al Tawil K, Sumaily H, Ahmed IA, Sallam A, Al Zaben A, Al Namshan M, et al. Risk 
factors, characteristics and outcomes of necrotizing enterocolitis in late preterm and term 
infants. J Neonatal Perinatal Med. 2013;6(2):125-30. 
6. 
Polin RA, Pollack PF, Barlow B, Wigger HJ, Slovis TL, Santulli TV, et al. Necrotizing 
enterocolitis in term infants. J Pediatr. 1976;89(3):460-2. 
7. 
Lambert DK, Christensen RD, Henry E, Besner GE, Baer VL, Wiedmeier SE, et al. 
Necrotizing enterocolitis in term neonates: data from a multihospital health-care system. J 
Perinatol. 2007;27(7):437-43. 
8. 
Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to 
prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst 
Rev. 2014(12):CD001970. 
9. 
Stefanutti G, Pierro A, Parkinson EJ, Smith VV, Eaton S. Moderate hypothermia as a 
rescue therapy against intestinal ischemia and reperfusion injury in the rat. Critical care 
medicine. 2008;36(5):1564-72. 
10. 
Hassoun HT, Kozar RA, Kone BC, Safi HJ, Moore FA. Intraischemic hypothermia 
differentially modulates oxidative stress proteins during mesenteric ischemia/reperfusion. 
Surgery. 2002;132(2):369-76. 
11. 
Thornton KM, Dai H, Septer S, Petrikin JE. Effects of whole body therapeutic 
hypothermia on gastrointestinal morbidity and feeding tolerance in infants with hypoxic 
ischemic encephalopathy. Int J Pediatr. 2014;2014:643689. 
12. 
Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, et al. 
Early versus Late Parenteral Nutrition in Critically Ill Children. N Engl J Med. 
2016;374(12):1111-22. 
13. 
Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. 
Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506-17. 
14. 
Walter E, Liu FX, Maton P, Storme T, Perrinet M, von Delft O, et al. Cost analysis of 
neonatal and pediatric parenteral nutrition in Europe: a multi-country study. Eur J Clin Nutr. 
2012;66(5):639-44. 
15. 
Kimkool P, Duckworth EC, Ollerenshaw RH, King K, Beardsall K. Current Practice in 
regarding feeding/nurition in babies being cooled for HIE in the UK. Arch Dis Child Fetal 
Neonatal Ed. 2014;99:A1-A180. 

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16. 
Kimkool P, Duckworth EC, Ollerenshaw RH, King K, Beardsall K. How do we and 
how should we optimise nutrition during therapeutic hypothermia? Arch Dis Child Fetal 
Neonatal Ed. 2014;99:A1-A180. 
17. 
Battersby C, Longford N, Costeloe K, Modi N, Group UKNCNES. Development of a 
Gestational Age-Specific Case Definition for Neonatal Necrotizing Enterocolitis. JAMA 
Pediatr. 2017. 
18. 
RCPCH. National Neonatal Audit Programme 
2016 Annual Report on 2015 data. RCPCH; 2016. 
19. 
Battersby C, Longford NT, Mandalia S, Costeloe K, Modi N. Incidence and enteral 
feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in 
England, 2012–13: a whole-population surveillance study. The Lancet Gastroenterology & 
Hepatology. 2017;2(1):43-51. 
20. 
Spencer A, Modi N. National neonatal data to support specialist care and improve 
infant outcomes. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2012. 
21. 
Digital N. National Neonatal Data Set. In: Dictionary ND, editor. 3 ed. 
http://www.datadictionary.nhs.uk/web_site_content/navigation/national_neonatal_data_sets_
menu.asp2016. 
22. 
Gale C, Santhakumaran S, Nagarajan S, Statnikov Y, Modi N. Impact of managed 
clinical networks on NHS specialist neonatal services in England: population based study. 
BMJ. 2012;344:e2105. 
23. 
Costeloe K, Hardy P, Juszczak E, Wilks M, Millar MR, Probiotics in Preterm Infants 
Study Collaborative G. Bifidobacterium breve BBG-001 in very preterm infants: a 
randomised controlled phase 3 trial. Lancet. 2016;387(10019):649-60. 
24. 
Imbens GW, Rubin DB. Causal Inference for Statistics, Social, and Biomedical 
Sciences.  
An Introduction. New York: Cambridge University Press; 2015. 
25. 
Rosenbaum PR. Design of Observational Studies. New York: Springer; 2010. 
26. 
Rosenbaum PR, Rubin DB. The central role of propensity scores in observational 
studies of causal effects. Biometrika. 1983;70:41-55. 
27. 
Rubin DB, Thomas N. Matching using estimated propensity scores:  relating theory to 
practice. . Biometrics. 1996;52:249-64. 
 
 
 

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Record of changes  
 
Version 
Stage 
Version 
No 
Version 
Date 
Protocol 
updated & 
finalised by 
Appendix No detail the reason(s) for the 
protocol update 
Superseded V1.3 
24/7/17 
 Chris Gale 
addition of trial registration information on 
page 1 
 
Superseded V1.4 
28/7/17 
Chris Gale 
change of study management to include 
NIHR mandated independent Study 
Steering Committee; co-investigator group 
now formed into Clinical Investigator Group 
(CIG). 
Superseded V1.5 
12/9/17 
Chris Gale 
Addition of REC and HRA approval details 
and UKNC approval 
Superseded V1.6 
6/10/17 
Chris Gale 
Updated with details of independent SSC 
Superseded V2.0 
24/10/17 Chris Gale on 
behalf of CIG 
1. Removal of “moderate to severe” in 1.1 
to reflect practice where babies with mild 
HIE receive cooling 
2. Addition of defined subgroup and 
sensitivity analyses in section 6.2.2 
3. Addition of secondary outcome (3.1) 
necrotising enterocolitis (recorded as a 
definition and received 5 consecutive days 
antibiotics and nil by mouth)  
4. Clarification of the primary outcome (3.1)  
for the parenteral comparison – late onset 
infection (>72 hours following birth) 
5. Addition of secondary outcome (3.1)  late 
onset blood stream infection (defined as 5 
consecutive days of antibiotic treatment) 
6. Secondary outcome length of stay will be 
examined in 2 ways  
7. The secondary outcome (3.1)  time to full 
feeds was removed as it has no agreeable 
definition 
8. The secondary outcome (3.1) Time to 
first maternal breast milk feed (days) was 
added 
9. The secondary outcome (3.1) duration of 
parenteral nutrition (days) was added for 
the enteral comparison only 
10. The secondary outcome (3.1) Number 
of days an infant has a central venous line 
in situ was added 
11. Force match items were specified in 
6.2.1 
12. Variables to be included in the 
propensity score were refined.   

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v3.0 15/12/2017 
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The following were removed: UVC in situ 
on day one; UAC in situ on day one; 
Umbilical cord pH 
The following were added: Maternal pyrexia; 
Maternal duration of rupture of membranes 
would be used as a continuous variable 
rather 
than 
a 
dichotomous 
variable; 
Maternal 
smoking; 
Maternal 
ethnicity; 
Maternal 
deprivation 
score; 
Maternal 
hypothyroid; Maternal diabetes; Mode of 
delivery of infant (vaginal or Caesarean); 
Parity of mother (primiparous Y/N); Apgar 
score at 1 minute; Umbilical cord base 
excess; Time to first spontaneous breath; 
Received inhaled nitric oxide (Y/N) 
 
Superseded V2.1 
27/10/17 Chris Gale 
following 
circulation to 
CIG of v2.0 
1. Additional clarification added to 3.1 to 
describe the two primary outcomes of NEC 
defined using UKNC definition and late 
onset blood stream infection. 
2. Addition of a secondary outcome of 
severe NEC 
3. Addition of details of REC/HRA approval 
Current 
V3.0 
15/12/17 Chris Gale on 
behalf of the 
Study 
Steering 
Committee 
1. Section 3.1: Alternative outcomes for 
NEC and late onset infection moved to 
sensitivity analyses (rather than secondary 
outcomes) 
2. Section 4.2: additional statement to 
describe reporting of missingness 
3. Section 6.2.1: Additional Infant factor to 
include in propensity score: positive blood 
culture in first 3 days