BORN study: a multicenter randomized trial investigating cord blood red blood cell transfusions to reduce the severity of retinopathy of prematurity in extremely low gestational age neonates

Abstract

Background Extremely low gestational age neonates (ELGANs, i.e., neonates born before 28 weeks of gestation) are at high risk of developing retinopathy of prematurity (ROP), with potential long-life visual impairment. Due to concomitant anemia, ELGANs need repeated red blood cell (RBC) transfusions. These produce a progressive replacement of fetal hemoglobin (HbF) by adult hemoglobin (HbA). Furthermore, a close association exists between low levels of HbF and severe ROP, suggesting that a perturbation of the HbF-mediated oxygen release may derange retinal angiogenesis and promote ROP. Methods/design BORN (umBilical blOod to tRansfuse preterm Neonates) is a multicenter double-blinded randomized controlled trial in ELGANs, to assess the effect of allogeneic cord blood RBC transfusions (CB-RBCs) on severe ROP development. Recruitment, consent, and randomization take place at 10 neonatology intensive care units (NICUs) of 8 Italian tertiary hospitals. ELGANs with gestational age at birth comprised between 24+0 and 27+6 weeks are randomly allocated into two groups: (1) standard RBC transfusions (adult-RBCs) (control arm) and (2) CB-RBCs (intervention arm). In case of transfusion need, enrolled patients receive transfusions according to the allocation arm, unless an ABO/RhD CB-RBC is unavailable. Nine Italian public CB banks cooperate to make available a suitable amount of CB-RBC units for all participating NICUs. The primary outcome is the incidence of severe ROP (stage 3 or higher) at discharge or 40 weeks of postmenstrual age, which occurs first. Discussion BORN is a groundbreaking trial, pioneering a new transfusion approach dedicated to ELGANs at high risk for severe ROP. In previous non-randomized trials, this transfusion approach was proven feasible and able to prevent the HbF decrease in patients requiring multiple transfusions. Should the BORN trial confirm the efficacy of CB-RBCs in reducing ROP severity, this transfusion strategy would become the preferential blood product to be used in severely preterm neonates. Trial registration ClinicalTrials.gov NCT05100212. Registered on October 29, 2021

Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns

“…Accordingly, besides strategies aiming at the prevention of preterm anaemia, strategies aiming at the avoidance of HbF replacement may reduce the risk of ROP, and severe ROP. An ongoing multicentre randomised trial ( Umbilical Blood to Transfuse Preterm Neonates , BORN) is currently investigating whether transfusion of cord blood RBCs instead of standard RBC units may reduce the severity of ROP in ELGANs 23 . Multiple RBC transfusions may further contribute to retinal damage by promoting accumulation of free iron and subsequently increased production of free hydroxyl radicals 22,24 .…”

“…An ongoing multicentre randomised trial (Umbilical Blood to Transfuse Preterm Neonates, BORN) is currently investigating whether transfusion of cord blood RBCs instead of standard RBC units may reduce the severity of ROP in EL-GANs. 23 Multiple RBC transfusions may further contribute to retinal damage by promoting accumulation of free iron and subsequently increased production of free hydroxyl radicals. 22,24 Finally, pro-, and anti-inflammatory mediators, such as transfusion-related increase in haem, may promote retinal morbidity.…”

Differences in Cerebral Tissue Oxygenation in Preterm Neonates Receiving Adult or Cord Blood Red Blood Cell Transfusions

“…The present study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies. The BORN trial is an ongoing, double-blind, multicenter randomized clinical trial that was designed to investigate whether transfusion of preterm neonates with CB-RBCs instead of A-RBCs reduces the severity of ROP . The BORN trial was approved by the ethics committee of the Fondazione Policlinico Universitario A. Gemelli IRCCS.…”

“…The units not suitable for transplant for a low, total nucleated cell content were used. Cord blood units were processed as previously described . Units were γ irradiated, and neonates received a PRBC dose of 20 mL/kg by continuous infusion during a 4-hour period (BD Alaris pump infusion sets).…”

“…Patients’ data were gathered through the REDCap database hosted at the Fondazione Policlinico Universitario A. Gemelli IRCCS and retrieved on May 31, 2023, for the prespecified interim analysis of the BORN trial . Data at birth included demographics, gestational age, weight, maternal obstetrical history, hematologic parameters (Hb, Hct, and HbF values, expressed as the percentage of total Hb), Apgar score at 1 minute and 5 minutes, and the Clinical Risk Index for Babies II (CRIB II) score (scores range from 0 to 27, with lower scores indicating a better prognosis) .…”