Effect of Early Hydrocortisone on Risk of Gastrointestinal Perforations in Extremely Preterm Infants: A Protocol for a Retrospective Cohort Study Using Routinely Collected Data
Conditions: Intestinal Perforation
Sponsor: Imperial College London

 
 
 
 
 
 
 
 
 
EFFECT OF EARLY HYDROCORTISONE ON RISK OF GASTROINTESTINAL PERFORATIONS IN 
EXTREMELY PRETERM INFANTS: A PROTOCOL FOR A RETROSPECTIVE COHORT STUDY 
USING ROUTINELY COLLECTED DATA  
 
Version 1.5  
17th July 2024  
 
 
MAIN SPONSOR: Imperial College London  
STUDY COORDINATION CENTRE: Imperial College London  
IRAS Project ID: 293603 
REC reference: 21/EM/0130 
 
 
Protocol authorised by Cheryl Battersby, Principal Investigator  
Date 17/07/2024 
 
 
 

 
 
 
Alice Aveline1,5, Alex Bottle2, Chris Gale1,5, Anna Milan3, Sarah McLoughlin1, Mireille 
Toledano4, Sabita Uthaya1,5 and Cheryl Battersby1,5 
1. Neonatal Medicine Research Group, Imperial College London, London, UK and Centre for 
Paediatrics and Child Health, Imperial College, London, UK 
2. School of Public Health, Imperial College London, UK  
3. Department of Neonatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 
4. Mohn Centre for Children’s Health and Wellbeing, School of Public Health, Imperial 
College London, UK and MRC Centre for Environment and Health, School of Public Health, 
Imperial College London, UK and Department of Epidemiology and Biostatistics, School of 
Public Health, Imperial College London, UK. 
5. Centre for Paediatrics and Child Health, Imperial College London 
 
Correspondence to Dr Cheryl Battersby; c.battersby@imperial.ac.uk 
 
 
 
 
 
 
 
 
 

 
 
 
ABSTRACT 
Introduction 
A large, randomised control trial, the PREMILOC trial, has established that giving low dose 
hydrocortisone prophylactically in the first ten days of life reduces the risk of 
bronchopulmonary dysplasia in babies born before 32 weeks’ gestation. However, the 
PREMILOC trial was underpowered to investigate rarer side effects, such as gastrointestinal 
perforation. This study aims to establish whether the odds of gastrointestinal perforation 
increase when extremely preterm infants are given prophylactic hydrocortisone in the first 
ten days of life. 
Methods and analysis 
This retrospective cohort study will use routinely collected data from the U.K. National 
Neonatal Research Database. We will examine the records of all infants born before 28 
weeks’ gestation and cared for in English and Welsh neonatal units between 2016 and 2023. 
Infants will be considered exposed if they received hydrocortisone for at least eight 
consecutive days, beginning on postnatal day 1 or 2. The primary outcome will be 
gastrointestinal perforation, as recorded in the infant’s neonatal unit record. This outcome 
will be validated with the original care teams for a sample of babies. Data will be analysed 
using a propensity score matched approach to reduce the impact of confounding. 
Ethics and dissemination 
Ethics approval for this study was granted as part of NeoWONDER: Neonatal Whole 
Population Data linkage approach to improving long-term health and wellbeing of preterm 
and sick babies (REC ref: 21/EM/0130). The results of this study will be disseminated via 
peer-reviewed academic journals, conferences and the social media channels of the study 
team. 
STRENGTHS AND LIMITATIONS OF THIS STUDY 
▪ Use of the National Neonatal Research Database provides data on the complete 
population of babies treated in English and Welsh neonatal units during the study period. 
▪ The National Neonatal Research Database is a rich dataset, which includes data on the 
primary outcome and many potential confounders. 
▪ Propensity matching is utilised to reduce the impact of confounding. 
▪ The National Neonatal Research Database does not include information about dosages or 
indications, so it is possible that the exposure (prophylactic hydrocortisone to prevent 
bronchopulmonary dysplasia) may be miscategorised. 
▪ It can be clinically difficult to distinguish gastrointestinal perforation from necrotising 
enterocolitis unless the diagnosis is confirmed at surgery. As the database records may 
not be  
updated with surgical or histological findings, misclassification of outcome status is possible. 
The impact of this is estimated by the validation of a sample of the outcomes. 

 
 
 
INTRODUCTION 
Bronchopulmonary dysplasia (BPD) is a serious, but common, complication of preterm birth. 
It is estimated that between 26% and 40% of babies born before 32 weeks’ gestation will be 
diagnosed with BPD (1-3). Advances in neonatal care mean that the smallest and sickest 
babies, who are more likely to develop this complication, are also more likely to survive than 
previously. BPD is a leading cause of mortality in very preterm infants and is associated with 
long-term respiratory morbidity (4) and poor neurological and motor outcomes (5).  
Corticosteroids, primarily dexamethasone, have been used to both prevent and treat BPD 
since the 1980s. However, concerns were raised as early as 1998 about the long term effects 
of dexamethasone on neurodevelopment (6). Subsequent meta-analyses have found high 
certainty evidence that early exposure to dexamethasone is associated with an increased risk 
of cerebral palsy (7, 8). The most common dexamethasone treatment regimen analysed by 
Doyle et al (7) consisted of a total dose of 2.76mg/kg, beginning with 0.5mg/kg for postnatal 
days 1-3 and tapering over the first 12 days of life. In response to the concerns about 
dexamethasone, clinicians have increasingly used hydrocortisone as an alternative to prevent 
BPD (9). Whilst exposure to hydrocortisone does not appear to be associated with increased 
risk of cerebral palsy (7, 10), there is evidence that early exposure to hydrocortisone may 
increase the risk of gastrointestinal perforation (7).  
A l multicentre trial (n=521) published in 2016 (PREMILOC) treated preterm babies born 
before 28 weeks’ gestation with either a placebo or 1mg/kg hydrocortisone daily for the first 
week of life from the day of birth, followed by 0.5mg/kg on postnatal days 8-10. The trial team 
concluded that prophylactic, early treatment with low dose hydrocortisone reduced the 
incidence of BPD (11). The authors investigated gastrointestinal perforations as one of several 
secondary outcomes and found no evidence of an association between early hydrocortisone 
treatment and gastrointestinal perforation. However, the trial was terminated early before 
reaching its target sample size and, even at the target sample size, the study would have been 
underpowered to investigate gastrointestinal perforations. The numbers of perforations in 
the trial were small, leading to an imprecise estimate of the association between 
hydrocortisone and gastrointestinal perforations.  
Since gastrointestinal perforations occur in around 5% of very preterm infants, very large 
numbers of participants would be required to adequately power a clinical trial investigating 
the effect of early hydrocortisone on this outcome. We propose using routinely collected data 
from all neonatal units in England and Wales to examine whether early hydrocortisone 
exposure is associated with an increased risk of gastrointestinal perforation.  We anticipate 
that our study will include three times as many babies treated with early hydrocortisone as 
the PREMILOC trial and therefore we will be better powered to examine the association 
between early treatment with hydrocortisone and gastrointestinal perforations.  
This study aims to: 

 
 
 
1. determine the prevalence and patterns of use of early hydrocortisone for BPD 
prevention in English and Welsh neonatal units; 
2. examine the extent of any association between early exposure to hydrocortisone 
and gastrointestinal perforations in the first 14 days of life 
METHODS AND ANALYSIS 
Study design 
This study is an analysis of an existing national electronic population cohort using 
anonymised, routinely recorded clinical data from the National Neonatal Research Database 
(NNRD).  
Data source 
The NNRD is an approved research database constituting real-world prospective clinical data 
extracted from point-of-care neonatal electronic health records with complete coverage of 
infants admitted for neonatal care to National Health Service (NHS) neonatal units in England 
and Wales since 2012. A defined data extract of approximately 450 items (the Neonatal Data 
Set) is transmitted quarterly to the Neonatal Data Analysis Unit at Imperial College London 
for data linkage and cleaning prior to entry into the NNRD. To date, the NNRD contains data 
for over a million babies (approximately 80,000 babies annually). High completeness and 
accuracy (>95%) of a selection of the variables held in the NNRD has been confirmed by formal 
comparison with a multi-centre, randomised placebo-controlled trial (12).  
Extracted data items will include baby and maternal demographic characteristics (such as 
birthweight, gestational age at delivery, gender), antenatal and labour/delivery variables 
(such as medical complications in current pregnancy, provision of antenatal steroids and 
magnesium sulphate and antibiotics), care procedures in the neonatal unit (such as provision 
of hydrocortisone, other corticosteroids and inotropic support) and neonatal outcome data 
(such as survival to discharge, proportion of days on mechanical ventilation and diagnoses 
e.g. gastrointestinal perforation, sepsis, BPD, brain injury, necrotising enterocolitis (NEC)). 
Please see Appendix for the full data extraction schema. 
 
Validation study of gastrointestinal perforation data to distinguish between gastrointestinal 
perforations and necrotising enterocolitis 
Diagnosis data is collected in the NNRD to identify which babies have experienced a 
gastrointestinal perforation or necrotising enterocolitis. However, the two conditions have 
some similarities at clinical presentation and a definitive differential diagnosis may only be 
possible during surgery. The NNRD record may therefore contain multiple or preliminary 
diagnoses that are not updated when the diagnosis is confirmed at surgery. To resolve this 

 
 
 
issue, we will conduct a validation study to differentiate between babies who had 
gastrointestinal perforations and those who had necrotising enterocolitis. 
 
All babies whose NNRD records show diagnoses of both gastrointestinal perforation and 
necrotising enterocolitis, but no record of surgery for necrotising enterocolitis in the first 14 
days of life, will be included in the validation study. Although the NNRD includes an internal 
NHS baby ID, the study team are unable to access any identifiable data using this ID. Only the 
clinical care team who cared for the baby can review the complete care notes using this ID. 
Therefore using secure NHS email, the NHS baby ID of the sample babies will be sent by a 
clinician to the neonatal units who cared for them. The units will be asked to review the baby’s 
clinical notes and confirm by email the diagnosis of gastrointestinal perforation or necrotising 
enterocolitis and the corrected gestational age when any gastrointestinal perforation 
occurred. All staff involved in accessing and reviewing clinical data have received and comply 
with institutional confidentiality and data protection policies and research conduct. 
 
All neonatal units that contribute data to the NNRD will be informed about the study 
beforehand and will have the possibility to opt out from the validation study if they wish to.  
 
Participant entry criteria 
Inclusion criteria 
The cohort will be extracted from the NNRD and will include babies who fulfil all the following 
criteria: 
▪ were admitted to a neonatal unit between the 1st January 2016 and 31st March 2023 
and 
▪ received any of their care in a NHS neonatal unit in England and Wales (part of UK 
Neonatal Collaborative and therefore contributing data to the NNRD) and 
▪ born before 28 weeks’ gestation. 
 
Exclusion criteria 
Infants will be excluded if: 
▪ They have missing data for principal background variables (gestational age at birth, 
birth weight, year of birth and date of death for those that died).  
▪ Their NNRD birthweight absolute value z score exceeds 4 or is missing. 
▪ They died on postnatal day 1 or 2. 

 
 
 
Definition of exposure to prophylactic hydrocortisone 
A baby will be considered to be exposed if: 
1. They receive early hydrocortisone started on postnatal day 1 or 2 and given for more than 
seven consecutive days OR 
2. They receive early hydrocortisone started on postnatal day 1 or 2 and are being cared for 
in a PROHYDRO unit but die on or before postnatal day 8. 
PROHYDRO units are defined as units who, at the time the baby was born, had implemented 
a protocol for use of prophylactic hydrocortisone as part of routine care for babies born less 
than 28 weeks’ gestation. A unit may change from being a non-PROHYDRO unit to a 
PROHYDRO unit if a new early hydrocortisone protocol is introduced during the study period 
(2016-2023). We will use data from NNRD to identify potential PROHYDRO units i.e. units 
that have high proportions of cohort babies that receive early hydrocortisone started on 
postnatal day 1 or 2 and given for >7 consecutive days. We will then check the status of any 
PROHYDRO units with the neonatal unit NNRD coordinator and determine the date a new 
early hydrocortisone protocol was introduced. 
Outcomes 
Principal outcome 
A baby will be considered to have had a gastrointestinal perforation if their NNRD record 
includes a record of a GI perforation in the diagnoses field. The primary outcome data will 
be validated prior to data analysis (see the previous “Data Source” section).  
Secondary outcomes 
▪ Survival without gastrointestinal perforation  
▪ Mortality before discharge to home 
▪ Total length of stay 
▪ 
Proportion of days in neonatal unit on mechanical ventilation 
▪ BPD (defined as any respiratory or ventilatory support or supplemental oxygen at 36 
weeks’ postmenstrual age (PMA)  
▪ BPD (defined using an adapted Jensen criteria (13) based on the highest level of 
respiratory support at 36 weeks PMA) 
Other outcomes of interest 
We will also report on other outcomes that have been identified by Webbe et al (14) as of 
importance to key stakeholders, such as patients, parents, clinical staff and researchers. 
These include: 
▪ NEC is defined as: 

 
 
 
o UK National Neonatal Audit Programme (NNAP) definition i.e. at least one clinical 
feature (bilious gastric aspirate or emesis, abdominal distension, occult, gross blood 
in stool) and at least one radiographic feature (pneumatosis, hepato-biliary gas, 
pneumoperitoneum) (15) 
o Severe NEC as per Battersby et al (16) i.e. necrotising enterocolitis confirmed at 
surgery or post-mortem or stated as cause of death 
o Pragmatically defined NEC i.e. babies who had a recorded diagnosis of necrotising 
enterocolitis and received at least 5 consecutive days of antibiotics whilst also nil by 
mouth 
▪ Late onset sepsis (defined as one or more episodes of a positive blood or cerebrospinal 
fluid culture with either a pure or mixed growth of a known pathogenic organism after 
the first three days following birth) 
▪ Brain injury occurring at or soon after birth including intracranial haemorrhage, perinatal 
stroke, central nervous system infection, kernicterus (bilirubin encephalopathy), 
periventricular leukomalacia or any recorded seizure 
▪ Treated retinopathy of prematurity (defined as cryotherapy, laser therapy or injection of 
anti-vascular endothelial growth factor therapy for ROP in either or both eyes) 
Data analysis plan 
Determining the prevalence and patterns of use of early hydrocortisone within the cohort 
The number of babies who received early hydrocortisone, in line with our definition of 
exposure, will be presented by birth year as a proportion of the total number of babies 
included in the study and born in the same year. This analysis will therefore describe any 
changes in patterns of steroid use over time.  
The number of babies who received early hydrocortisone treatment will be presented by 
gestational age as a proportion of the total number of babies included. 
The number of units providing early hydrocortisone treatment will be recorded and 
presented by birth year.  
Examine the extent of any association between early exposure to hydrocortisone and 
gastrointestinal perforations  
 
The background maternal and neonatal characteristics, birth and neonatal admission details, 
clinical course and outcomes of the cohort will be described. Results will be presented as 
means (with standard deviation), medians (with interquartile ranges) or count and 
proportions as appropriate.  
 
Levels of missingness will be described for each potential confounder or mediator. Variables 
for consideration are shown in Appendix 1 NNRD Data Extraction Schema (potential risk 
factors). These demographic and clinical characteristics will be described for those babies 

 
 
 
with complete and incomplete records. If levels of missingness are less than 5%, then a 
complete case analysis will be conducted. If levels of missingness are between 5% and 40% 
then multiple imputation will be used to create a minimum of ten complete datasets. Any 
variables with more than 40% missing will be excluded from the analysis. 
We will use propensity score matching to improve balance in covariate distributions between 
groups. The methods described by Imbens and Rubins will be used to select the demographic 
and clinical variables that are used in the propensity score model (17). The potential variables 
for inclusion in the propensity score model are shown in supplementary materials appendix 
1, “NNRD data extraction schema potential risk factors”. Gestational age and birthweight z 
score will be included a priori in the propensity score model. A propensity score will be 
calculated for every baby in the cohort. Each baby receiving early hydrocortisone treatment 
will be matched with at least two other babies who have similar propensity scores and who 
did not receive hydrocortisone treatment consistent with our exposure definition. 
 
Logistic regression will be used to calculate a measure of association between early 
hydrocortisone and odds of gastrointestinal perforation in the matched sample. Any variables 
included in the propensity score model will be included as covariates in the logistic regression 
to reduce any residual confounding that remains in the matched sample. An identical 
regression analysis will be performed for each of the imputed datasets. Effect estimates will 
be combined to create a pooled effect estimate. General estimating equations will be used in 
the logistic regression to take account of correlation within a neonatal unit.  
 
Sensitivity analyses 
In addition to the main analyses we will conduct a number of pre-planned sensitivity 
analyses. The sensitivity analyses will include analyses that address the definition of 
exposure. The main exposure of interest is the use of prophylactic hydrocortisone for BPD 
prevention. Whilst the NNRD does contain data describing daily drugs, there are no data 
describing dosages or indication for use. It is therefore not possible to easily distinguish the 
use of hydrocortisone for BPD from treatment of low blood pressure (another common 
indication in extremely preterm infants).  
It is biologically plausible that early hydrocortisone treatment for either indication may 
increase the risk of gastrointestinal perforation, hence we will conduct a sensitivity analysis 
where we define hydrocortisone exposure broadly. We will conduct an analysis contrasting 
all babies who received hydrocortisone on postnatal day 1 or 2 with babies who did not 
receive any hydrocortisone in the first ten postnatal days. 
Treatment for low blood pressure is of a higher dose and will usually be for a shorter 
duration compared with hydrocortisone prophylaxis to prevent BPD. Hence our main 
definition of exposure requires that babies receive hydrocortisone for at least eight 
consecutive days in the first 10 days of life. This length of exposure makes it more likely 

 
 
 
hydrocortisone is being used to prevent BPD, rather than as a treatment for low blood 
pressure. To address any remaining potential concerns about the indication for receipt of 
hydrocortisone, we will conduct two analyses with a narrower definition of hydrocortisone 
exposure. These sensitivity analyses attempt to further isolate those babies receiving 
prophylactic hydrocortisone in contrast to receipt for other indications: 
1. An analysis contrasting babies who received hydrocortisone treatment consistent with 
our hydrocortisone exposure definition AND were treated in a PROHYDRO unit, vs babies 
who did not receive hydrocortisone in line with our main definition of exposure. 
 
2. An analysis that excludes from the exposed group babies who received inotropes, 
paracetamol or ibuprofen during the period when they also received hydrocortisone. 
 
Sample size  
We expect to extract anonymised data on approximately 15,000 admissions to neonatal units 
in England and Wales between 2016 and 2023 for babies born before 28 weeks’ gestation. A 
small pilot study has suggested approximately 5.3% of neonatal unit admissions in the NNRD 
receive early hydrocortisone treatment consistent with the exposure definition. We have 
therefore projected that approximately 800 babies are exposed to early hydrocortisone.   
Based on the PREMILOC trial, we anticipate rates of gastrointestinal perforation of 
approximately 4.5%. Using this data, we have calculated sample sizes using the R package pwr 
(18). We anticipate being able to detect a difference in the risk of gastrointestinal perforation 
between the early hydrocortisone and not early hydrocortisone groups of approximately 2.8% 
i.e. rates of gastrointestinal perforation of 4.5% in the control group and 7.3% in the early 
hydrocortisone group.  This calculation assumes power of 80% and a two-sided alpha of 5% 
and 2:1 matching.  
ETHICS AND DISSEMINATION 
Existing anonymised data will be extracted from the NNRD for use in this study and patient 
consent was not required. Approval was granted for use of the NNRD data via the 
NeoWONDER: Neonatal Whole Population Data linkage approach to improving long-term 
health and wellbeing of preterm and sick babies (IRAS 293603; REC ref: 21/EM/0130). An 
amendment to the original approval was agreed to allow the study team to contact the 
original care teams as part of the validation study.  
The results of this study will be published in peer-reviewed academic journals, presented at 
conferences and local meetings and promoted on the social media channels of the Imperial 
College Neonatal Medicine Research Group. A summary of the study will also be publicised 
on the NNRD website.  

 
 
 
 
 
REFERENCES 
1. 
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Comparison Between the Two Most Used Diagnostic Criteria. Frontiers in pediatrics. 2018;6:397-. 
2. 
Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of 
extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics (Evanston). 
2010;126(3):443-56. 
3. 
Ancel P-Y, Goffinet F, Kuhn P, Langer B, Matis J, Hernandorena X, et al. Survival and Morbidity 
of Preterm Children Born at 22 Through 34 Weeks’ Gestation in France in 2011: Results of the 
EPIPAGE-2 Cohort Study. JAMA pediatrics. 2015;169(3):230-8. 
4. 
Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, et al. Lung Function and Respiratory 
Symptoms at 11 Years in Children Born Extremely Preterm: The EPICure Study. American journal of 
respiratory and critical care medicine. 2010;182(2):237-45. 
5. 
Majnemer A, Riley P, Shevell M, Birnbaum R, Greenstone H, Coates AL. Severe 
bronchopulmonary dysplasia increases risk for later neurological and motor sequelae in preterm 
survivors. Developmental medicine and child neurology. 2000;42(1):53-60. 
6. 
Yeh TF, Lin YJ, Huang CC, Chen YJ, Lin CH, Lin HC, et al. Early Dexamethasone Therapy in 
Preterm Infants: A Follow-up Study. Pediatrics (Evanston). 1998;101(5):e7-e. 
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Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (< 7 days) systemic postnatal 
corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane database 
of systematic reviews. 2021;10(5):CD001146-CD. 
8. 
Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone Treatment in the First Week of Life for 
Preventing Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review. Neonatology (Basel, 
Switzerland). 2010;98(3):217-24. 
9. 
Yao S, Uthaya S, Gale C, Modi N, Battersby C. Postnatal corticosteroid use for prevention or 
treatment of Bronchopulmonary Dysplasia in England and Wales 2012-2019: a retrospective 
population cohort study. BMJ Open. 2022. 
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Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late (≥ 7 days) systemic postnatal 
corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane database 
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11. 
Baud OP, Maury LMD, Lebail FMD, Ramful DMD, El Moussawi FMD, Nicaise CMD, et al. Effect 
of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely 
preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. The 
Lancet (British edition). 2016;387(10030):1827-36. 
12. 
Battersby C, Statnikov Y, Santhakumaran S, Gray D, Modi N, Costeloe K. The United Kingdom 
National Neonatal Research Database: A validation study. PloS one. 2018;13(8):e0201815-e. 
13. 
Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The Diagnosis of 
Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. American journal 
of respiratory and critical care medicine. 2019;200(6):751-9. 
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Webbe JWH, Duffy JMN, Afonso E, Al-Muzaffar I, Brunton G, Greenough A, et al. Core 
outcomes in neonatology: development of a core outcome set for neonatal research. Archives of 
disease in childhood Fetal and neonatal edition. 2020;105(4):425-31. 
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National Neonatal Audit Programme: A guide to the 2023 audit measures. 2023. 
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Battersby C, Longford N, Costeloe K, Modi N. Development of a Gestational Age–Specific Case 
Definition for Neonatal Necrotizing Enterocolitis. JAMA pediatrics. 2017;171(3):256-63. 
17. 
Imbens GW, Rubin DB. Causal Inference for Statistics, Social, and Biomedical Sciences : An 
Introduction. Cambridge: Cambridge University Press; 2015. 

 
 
 
18. 
S C. _pwr: Basic Functions for Power Analysis_. 2020 [R package version 1.3-0:[Available from: 
https://CRAN.R-project.org/package=pwr. 
AUTHOR CONTRIBUTIONS 
CB had the original idea for the study and submitted for approvals. CB and AA undertook 
the DAG. AA, CB, SU, AB and CG planned statistical analysis. AA, CB, SU, AM, AB, MT and CG 
all contributed to overall study design, protocol development and the writing and review of 
this paper. SM distributed the data validation requests and collated responses. 
FUNDING STATEMENT 
This work was supported by a NIHR Advanced Fellowship awarded to Dr Cheryl Battersby 
(reference: NIHR300617) and a related PhD studentship awarded to Dr Alice Aveline by Imperial 
College, London. 
COMPETING INTERESTS STATEMENT 
None declared 
 
 
 

 
 
 
 
SUPPLEMENTARY MATERIALS APPENDIX 1: NNRD DATA 
EXTRACTION SCHEMA  
Purpose: Potential risk factors 
NNRD data items to extract 
Baby demographic 
- 
Year and month of birth 
- 
Phenotypic sex 
- 
Gestational age at birth 
- 
Birthweight and birthweight z score 
Maternal demographic 
- 
Deprivation decile for maternal address 
- 
Maternal ethnicity 
- 
Maternal age 
Antenatal variables 
- 
Maternal pre-eclampsia 
- 
Maternal chorioamnionitis 
- 
Maternal hypertension 
- 
Maternal diabetes 
- 
Maternal smoker at booking 
Labour and delivery 
- 
Prelabour rupture of membranes 
- 
Placental abruption 
- 
Number of steroid courses given antenatally 
and completion status  
- 
Maternal magnesium sulphate 
- 
Maternal nifedipine 
- 
Multiple fetuses 
- 
Mode of delivery 
- 
Umbilical cord base excess 
- 
Apgar score at 5 and 10 minutes 
- 
Cardiac massage at birth 
- 
Resuscitation drugs administered 
- 
Intubated at resuscitation 
- 
Surfactant administered at birth 
Baby condition on postnatal  
day 1 & 2 
- 
Constituent items of CRIB-II score 
- 
Surfactant given on postnatal day 1 
- 
Invasive ventilation on postnatal day 1 & 2 
- 
Day 1 & 2 Inotropes 
- 
Day 1 & 2 Nitric oxide 
- 
Day 1 &2 Ibuprofen 
- 
Day 1& 2 Paracetamol 
- 
Day 1 Indomethacin  
- 
Early onset infection 
Other risk factors 
- 
Any congenital gastrointestinal abnormalities 
- 
Any congenital cardiac abnormalities 
- 
Transfer in first 24 hours 

 
 
 
- 
Transfer in first 48 hours 
- 
Postnatal age (in days) when enteral feeds are 
initiated 
Purpose: Postnatal drugs 
excluding hydrocortisone 
NNRD data items to extract 
Other drug exposures in first 14 
days 
(Duration in days, first day 
administered and daily data for 
days 1-14) 
- 
Inotropes 
- 
Ibuprofen 
- 
Paracetamol 
 
Purpose: Exposure 
NNRD data items to extract 
Hydrocortisone exposure 
- 
Duration in days (for first 14 days and in total), 
first day administered and daily data for days 
1-14. 
- 
Hydrocortisone given consistent with the Yao 
et al definition (i.e. started on postnatal day 1 
or 2 and given for >7 consecutive days). 
Place of birth and subsequent 
place of care 
- 
Unit of first admission and level of unit of first 
admission 
- 
Unit and level of unit of second admission if 
baby is transferred in postnatal days 1-10  
 
Purpose: Outcomes 
NNRD data items to extract 
Primary outcomes 
 
- 
Death before discharge  
- 
Gastrointestinal perforation  
- 
Major surgery in the first 14 days of life and 
Severe NEC used in definition of 
gastrointestinal perforation 
 
Secondary outcomes 
 
- 
Total length of stay 
- 
Number of days of invasive respiratory 
support (to calculate proportion of stay on 
invasive respiratory support) 
- 
Bronchopulmonary dysplasia 
Other outcomes 
- 
NEC diagnosis consistent with the NNAP 
definition  
- 
Severe NEC as per Battersby et al (16) 
- 
Pragmatically defined NEC i.e. babies who had 
a recorded diagnosis of necrotising 

 
 
 
enterocolitis and received at least 5 
consecutive days of antibiotics whilst also nil 
by mouth 
- 
Late onset sepsis  
- 
Brain injury  
- 
Retinopathy of prematurity