Early antibiotic use and intestinal disease (necrotising enterocolitis) in premature babies

ISRCTN	ISRCTN55101779
DOI	https://doi.org/10.1186/ISRCTN55101779
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	312574
Protocol serial number	IRAS 312574
Sponsor	Newcastle upon Tyne Hospitals NHS Foundation Trust
Funders	Investigator initiated and funded, Novo Nordisk Fonden (postdoctoral fellowship to René Shen, BRIDGE Translational Excellence Programme, grant no. NNF18SA0034956)

Submission date: 09/06/2022
Registration date: 13/07/2022
Last edited: 07/12/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Neonatal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Necrotising enterocolitis (NEC) is a key cause of death and disease in preterm infants. Early antibiotic use has been shown to impact on rates of NEC, with data suggesting that receipt in the first days after birth is protective, but long duration has adverse impact on NEC rates. We aim to use the large UK dataset of preterm births known as The National Neonatal Research Database (NNRD) to further delineate this relationship. The NNRD holds data on 'every' preterm neonate admitted in the United Kingdom in a link anonymised fashion, allowing exploration of the role of antibiotics in NEC development in a much bigger population than previously explored.

Who can participate?
Premature babies born at <32 weeks gestation with data entered into The National Neonatal Research Database

What does the study involve?
Analysis of data already collected in the National Neonatal Research Database exploring impact of antibiotics on NEC

What are the possible benefits and risks of participating?
There are no benefits or risks to individuals as this is a database analysis of existing data

Where is the study run from?
Newcastle upon Tyne Hospitals NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
January 2020 to December 2023

Who is funding the study?
1. Investigator initiated and funded
2. Novo Nordisk Fonden

Who is the main contact?
Dr Janet Berrington
janet.berrington1@nhs.net

Contact information

Dr Janet Berrington
Principal investigator

Neonatal Unit
Ward 35
Royal Victoria Infirmary
Richardson Road
Newcastle
NE1 4LP
United Kingdom

ORCID ID	0000-0002-6185-2843
Phone	+44 (0)1912829323
Email	janet.berrington1@nhs.net

Study information

Primary study design	Observational
Study design	Analysis of data already collected in the National Neonatal Research Database exploring impact of antibiotics on NEC
Secondary study design	Case-control study
Study type	Participant information sheet
Scientific title	Early antibiotic use and incidence of necrotising enterocolitis in very preterm infants: A UK based observational study using routinely recorded data
Study objectives	Early antibiotic timing and duration impacts incidence of necrotising enterocolitis (NEC) in preterm infants
Ethics approval(s)	Approval pending, Ref: 22/NE/0113
Health condition(s) or problem(s) studied	Preterm infant
Intervention	We will access and extract details about infants with gestation <32 completed weeks, and the primary outcome measure of developing necrotising enterocolitis. We will also extract data on antibiotic exposure in the first 2 days to compare NEC incidence in those on antibiotics in the first 2 days with those without. We will collect additional data to allow for the effects of confounding factors as determined by the directed acyclic graph of other essential factors to consider in this analysis, including the availability of these items within the National Neonatal Research Database (NNRD), which holds this data routinely. There is no patient intervention, all data already exists.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)
Primary outcome measure(s)	Incidence of severe necrotising enterocolitis resulting in death or surgery developed before discharge from neonatal care as measured by the ‘Battersby’ definition and collected from the National Neonatal Research Database (NNRD)
Key secondary outcome measure(s)	All are measured before discharge from the neonatal unit and collected from the NNRD between 01/07/2022 and 31/12/2022: 1. Late onset sepsis (bloodstream or CSF confirmed pure growth in culture (NNAP definition) after the first 3 days and/or treatment with 5 days of antibiotics and a concurrent diagnosis of infection after the first 3 days) 2. Total antibiotic use (number of days with any treatment of antibiotics during admission) 3. Length of stay (postnatal age at discharge or death) 4. Time to reach full feeding (first day of 3 consecutive days where parenteral nutrition or intravenous fluid are not recorded) 5. Growth (change in standard deviation score (SDS) between birth and 36 weeks and discharge) 6. Total pre-discharge mortality 7. Further, we will analyse effects on some relevant adverse outcomes: 7.1 Total pre-discharge mortality 7.2. Death prior to day 7, day 14, day 28 7.3 Bronchopulmonary dysplasia (BPD; respiratory support given at 36 weeks) 7.4. Retinopathy of prematurity (ROP; in receipt of treatment, according to NNRD standard operating procedure) 7.5. Brain injury (intraventricular hemorrhage grade 3 or above or periventricular leukomalacia diagnoses recorded) 7.6. Need for surgical procedures
Completion date	31/12/2023

Eligibility

Participant type(s)	Patient
Age group	Neonate
Sex	All
Target sample size at registration	45000
Key inclusion criteria	1. Preterm infant born at <32 weeks gestation 2. Data entered into the The National Neonatal Research Database
Key exclusion criteria	Death before 3 days
Date of first enrolment	01/07/2022
Date of final enrolment	31/12/2023

Locations

Countries of recruitment

United Kingdom
England
Scotland
Wales

Study participating centre

Royal Victoria Infirmary

Neonatal Unit
(Ward 35)
Richardson Road
Newcastle
NE1 4LP
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Janet Berrington janet.berrington1@nhs.net

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article		15/11/2022	23/11/2022	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

07/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2022 to 31/12/2023.
2. The overall end date was changed from 31/12/2022 to 31/12/2023.
3. The intention to publish date was changed from 01/07/2023 to 31/12/2024.
4. The plain English summary was updated to reflect these changes.
23/11/2022: Protocol added.
13/06/2022: Trials existence confirmed NHS REC.