Effect of Early Hydrocortisone on Risk of Gastrointestinal Perforations in Extremely Preterm Infants

Effect of Early Hydrocortisone on Risk of Gastrointestinal Perforations in Extremely Preterm Infants: A Protocol for a Retrospective Cohort Study Using Routinely Collected Data

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.

This retrospective cohort study will use routinely collected data from the U.K. National Neonatal Research Database. The investigators 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Intestinal Perforation
• Intervention / Treatment: Drug: Hydrocortisone

• Study Type: Observational
• Enrollment (Estimated): 16000

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Infants born before 28 weeks' gestation and admitted to English and Welsh neonatal units.

Description

Inclusion Criteria:

Infants who:

• 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
• were born before 28 weeks' gestation.

Exclusion Criteria:

• 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 recorded birthweight absolute value z score exceeds 4 or is missing.
• They died on postnatal day 1 or 2 .

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Not exposed to early hydrocortisone	Drug: Hydrocortisone; Cohort members will be considered to be exposed to early hydrocortisone if either: They receive early hydrocortisone started on postnatal day 1 or 2 and given for more than seven consecutive days OR; 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).
Exposed to early hydrocortisone	Drug: Hydrocortisone; Cohort members will be considered to be exposed to early hydrocortisone if either: They receive early hydrocortisone started on postnatal day 1 or 2 and given for more than seven consecutive days OR; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal (GI) perforation	A baby will be considered to have had a gastrointestinal perforation if their National Neonatal Research Database record includes a record of a GI perforation in the diagnoses field.	From date of birth until day 14 of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival without gastrointestinal perforation	Baby survived to discharge from neonatal unit without a gastrointestinal perforation	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Mortality before discharge home	Baby died before discharge from neonatal unit	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Total length of stay	Length of stay in neonatal care	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Proportion of days on unit being mechanically ventilated		From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Bronchopulmonary dysplasia	any respiratory or ventilatory support or supplemental oxygen at 36 weeks' postmenstrual age (PMA)	From date of birth until 36 weeks' postmenstrual age (PMA)
Bronchopulmonary dysplasia	Using an adapted Jensen criteria based on the highest level of respiratory support at 36 weeks PMA	From date of birth until 36 weeks' postmenstrual age (PMA)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Necrotising enterocolitis	UK National Neonatal Audit Programme definition	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Severe necrotising enterocolitis	Necrotising enterocolitis confirmed at surgery or post-mortem or stated as cause of death	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Pragmatically defined necrotising enterocolitis	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	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	From postnatal day 3 until the date of discharge from final neonatal unit, assessed up to 24 months
Brain injury occurring at or soon after birth	Intracranial haemorrhage, perinatal stroke, central nervous system infection, kernicterus (bilirubin encephalopathy), periventricular leukomalacia or any recorded seizure	From date of birth until the date of discharge from final neonatal unit, assessed up to 24 months
Treated retinopathy of prematurity	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

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: July 17, 2024
• First Submitted That Met QC Criteria: July 22, 2024
• First Posted (Actual): July 23, 2024

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Hydrocortisone; Preterm Infant
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Perforation; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: 293603

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.