Feasibility of Neurodevelopmental Outcome Assessments after Early and Extended Erythropoietin Monotherapy for Neonatal Encephalopathy in Low- and Middle-Income Countries: An External Pilot Randomised Controlled Trial
File(s)
Accepted version
Author(s)
Thayyil, Sudhin
Consortium for Time-Critical Neuroprotection Trials in Neonatal Encephalopathy (CONNECTIONS) group
Type
Journal Article
Abstract
Objective: To assess the feasibility of a randomised controlled trial of early erythropoietin therapy with neurodevelopmental follow-up.
Design: Multicentre, double-blind, external pilot randomised controlled trial.
Setting: Eight tertiary neonatal units in India and Bangladesh who were part of the Consortium for Time-Critical Neuroprotection Trials in Neonatal Encephalopathy (CONNECTIONS)
Patients: Fifty infants (≥36 weeks) with moderate or severe HIE.
Interventions: Infants were randomised to EPO 500 U/kg/day for nine doses (n=26) or placebo (n=24) within 6h of birth. Therapeutic hypothermia was not allowed.
Main outcome measures: Feasibility of recruitment, protocol adherence, timing of intervention delivery, magnetic resonance imaging (MRI) acquisition, and completion of assessment at 18–22 months using Bayley IV scales of infant and toddler development.
Results: Among 50 infants, 45 (90%) had moderate HIE and 5 (10%) had severe HIE and the trial intervention was given at a mean (SD) age of 4.4 (1.2) hours. Adherence to the trial protocol was excellent. All 33 infants who survived beyond a week had MRI scans which was abnormal in 30 (91%). Overall, 16 (32%) died before hospital discharge, 21 (42%) by 18 to 22 months; 29 (58%) met the composite outcome of death or moderate to severe disability with a 100% follow up. All four infants discharged against medical advice, subsequently died.
Conclusions: Robust research governance, early erythropoietin administration in infants with HIE, MRI acquisition, and complete neurodevelopmental follow-up can be achieved in South Asian neonatal units. CONNECTIONS provides a platform for high-quality multi-country randomised controlled trials.
Trial registration: ClinicalTrials.gov (NCT05395195)
Imperial College Research Ethics Committee (ICREC) reference number: 22IC7793
Design: Multicentre, double-blind, external pilot randomised controlled trial.
Setting: Eight tertiary neonatal units in India and Bangladesh who were part of the Consortium for Time-Critical Neuroprotection Trials in Neonatal Encephalopathy (CONNECTIONS)
Patients: Fifty infants (≥36 weeks) with moderate or severe HIE.
Interventions: Infants were randomised to EPO 500 U/kg/day for nine doses (n=26) or placebo (n=24) within 6h of birth. Therapeutic hypothermia was not allowed.
Main outcome measures: Feasibility of recruitment, protocol adherence, timing of intervention delivery, magnetic resonance imaging (MRI) acquisition, and completion of assessment at 18–22 months using Bayley IV scales of infant and toddler development.
Results: Among 50 infants, 45 (90%) had moderate HIE and 5 (10%) had severe HIE and the trial intervention was given at a mean (SD) age of 4.4 (1.2) hours. Adherence to the trial protocol was excellent. All 33 infants who survived beyond a week had MRI scans which was abnormal in 30 (91%). Overall, 16 (32%) died before hospital discharge, 21 (42%) by 18 to 22 months; 29 (58%) met the composite outcome of death or moderate to severe disability with a 100% follow up. All four infants discharged against medical advice, subsequently died.
Conclusions: Robust research governance, early erythropoietin administration in infants with HIE, MRI acquisition, and complete neurodevelopmental follow-up can be achieved in South Asian neonatal units. CONNECTIONS provides a platform for high-quality multi-country randomised controlled trials.
Trial registration: ClinicalTrials.gov (NCT05395195)
Imperial College Research Ethics Committee (ICREC) reference number: 22IC7793
Date Acceptance
2026-10-01
Citation
Archives of Disease in Childhood: Fetal and Neonatal Edition
ISSN
1359-2998
Publisher
BMJ Publishing Group
Journal / Book Title
Archives of Disease in Childhood: Fetal and Neonatal Edition
Copyright Statement
Subject to copyright. This paper is embargoed until publication. Once published the author’s accepted manuscript will be made available under a CC-BY License in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy).
License URL
Publication Status
Accepted