Do Probiotics Reduce The Risk Of Severe Necrotising Enterocolitis (NEC) In Infants Born Before 32 Weeks Gestation?

Do Probiotics Reduce The Risk Of Severe Necrotising Enterocolitis (NEC) In Infants Born Before 32 Weeks Gestation? An Observational Study Using Routinely Collected Data.

Necrotising enterocolitis (NEC) is one of the leading causes of mortality and morbidity in very preterm infants. This study aims to determine whether NEC rates are different between infants who receive probiotics versus infants who do not receive probiotics. The study has a retrospective cohort design and will utilise routinely collected data from the UK National Neonatal Research Database (NNRD). The cohort will comprise all infants born before 32 weeks gestation and cared for in neonatal units in England and Wales between 2016 and 2022. A propensity score matched approach will be used to conduct two comparisons: i) the risk of necrotising enterocolitis (NEC) between who do and those who do not receive probiotics in the first 14 days of life ii) the risk of NEC between babies who receive the two most common probiotic products used in UK units, (Labinic and Proprems).

Study Overview

• Status: Enrolling by invitation
• Conditions: Enterocolitis, Necrotizing
• Intervention / Treatment: Dietary supplement: Probiotics

• Study Type: Observational
• Enrollment (Estimated): 48000

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9NH
    • Imperial College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Infants born very preterm i.e. before 32 weeks gestation

Description

Inclusion Criteria:

• Eligible infants must have been born at less than 32 weeks gestation and be cared for in a English or Welsh unit which contributes data to the National Neonatal Research Database (this includes all NHS neonatal units in England and Wales).
• Infants born in the period January 1st, 2016, to December 31st, 2022 (7 years) will be included.

Exclusion Criteria:

• They have missing data for any of: gestational age at birth, birth weight, year of birth and date of death (for those that died).
• Their NNRD record does not include details of their first admission or begins after Day 3 of life.
• The absolute value of their recorded birthweight for gestational age z score exceeds 4 or is missing.
• They die in the first two postnatal days of life.
• They have a major congenital abnormality

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Exposed to probiotics; Receipt of any probiotic in the first 14 days of life. Probiotics to include: Labinic, Proprems probiotic, Acidophillus, Bifidobacterium, Bio-kult, Infloran, LB2. To address potential recording error, infants whose NNRD records show minimal (one day) of probiotic exposure will only be classed as exposed if they are cared for in a probiotic unit. Probiotic units are defined as: units who have confirmed that a guideline was in place to provide probiotics to infants born before 32 weeks gestation and that the guideline was in place at any point in the year that the infant was born OR; units where more than 50% of the infants eligible to be part of the cohort received probiotics in the six months after the infant was born.	Dietary supplement: Probiotics; Any exposure to probiotics in first 14 days of life; Other Names: Infloran; Bifidobacterium; Labinic; Proprems; Acidophillus; Bio-kult; LB2
No probiotic exposure; Did not receive any probiotic in the first 14 days of life.	Dietary supplement: Probiotics; Any exposure to probiotics in first 14 days of life; Other Names: Infloran; Bifidobacterium; Labinic; Proprems; Acidophillus; Bio-kult; LB2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe necrotising enterocolitis (NEC)	NEC confirmed at surgery or postmortem or listed as a cause of death	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Necrotising enterocolitis (NNAP definition)	NEC diagnosed at postmortem or NEC diagnosed during surgery or NEC diagnosed using clinical and radiographic features (where the infant has 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)).	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Pragmatically defined NEC	Infants who had a recorded diagnosis of necrotising enterocolitis and received at least 5 consecutive days of antibiotics whilst also nil by mouth	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Late onset sepsis	HQIP NNAP case definition	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Pragmatically defined late onset sepsis	Growth of any organisms that appear in the NNAP lists of "Clearly pathogenic organisms" and "Other organisms"	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Survival to discharge home		On date of discharge from final neonatal unit, assessed up to 24 months
Survival without severe NEC or late onset sepsis (LOS)	LOS is defined according to the Healthcare Quality Improvement Partnership (HQIP) National Neonatal Audit Programme (NNAP) case definition i.e. blood stream or cerebrospinal fluid confirmed pure growth in culture after first three days of life	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Survival without any NEC	NEC is defined as per the NNAP definition	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Brain injury	Either left or right grade 3 or higher intra-ventricular haemorrhage or cystic periventricular leukomalacia	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
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	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Stage of retinopathy of prematurity		From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Bronchopulmonary dysplasia	Defined as any respiratory or ventilatory support or supplemental oxygen at 36 weeks postmenstrual age	36 weeks postmenstrual age
Severe bronchopulmonary dysplasia	Defined as ventilation via endotracheal tube or trachestomy, and excluding non-invasive support or CPAP, at 36 weeks postmenstrual age	36 weeks postmenstrual age
Length of stay	Number of days between first neonatal unit admission and final neonatal unit discharge for surviving infants	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Time to full feeds	Defined as the number of days until an infant is recorded as not requiring any parenteral nutrition or fluid (i.e. no parenteral nutrition or intravenous dextrose)	Before discharge from final neonatal unit
Growth	Weight for post-menstrual age standard deviation score	36 weeks corrected gestational age

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: University of Nottingham; Queen Mary University of London; Newcastle University

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2024
• Primary Completion (Estimated): July 30, 2025
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: April 24, 2024
• First Submitted That Met QC Criteria: May 18, 2024
• First Posted (Actual): May 21, 2024

Study Record Updates

• Last Update Posted (Actual): May 7, 2025
• Last Update Submitted That Met QC Criteria: May 4, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Probiotics
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Enterocolitis; Enterocolitis, Necrotizing
• Other Study ID Numbers: IRAS323099

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Study protocol available now. Analysis code will be available after publication of results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No