MANUSCRIPT CITATION

Teofili L, Papacci P, Pellegrino C, Molisso R, et al. Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial (BORN trial). eClinicalMedicine. 2025;87:103426. doi:10.1016/j.eclinm.2025.103426. PMID 40838199

REVIEWED BY

Mahmud Benoune, MBChB, MRCPCH
Neonatal Registrar, NHS
Email: mahmmoudbenoun@gmail.com

TYPE OF INVESTIGATION

Treatment / Prevention

QUESTION

In extremely preterm infants (24–27⁶ weeks’ gestation), do red blood cell transfusions derived from cord blood (CB-RBCs), compared with adult donor RBCs (A-RBCs), reduce the risk or severity of retinopathy of prematurity (ROP)?

METHODS

Design: Multicenter, double-blind, randomized controlled trial (Italy, 2021–2024).
Allocation: 1:1 randomization, concealed.
Blinding: Investigators, clinicians, and parents blinded to allocation.
Follow-up: Until 40 weeks’ postmenstrual age or discharge.
Setting: Eight tertiary NICUs.
Patients: Infants 24–27⁶ weeks GA, <32 weeks PMA, transfusion-naïve at enrolment. Excluded if congenital anomalies or severe early sepsis. Intervention: Transfusions with leukodepleted, irradiated, HbF-rich cord blood RBCs.
Comparison: Standard adult donor RBCs.
Primary Outcome: Severe ROP (stage ≥ 3 or plus disease).
Secondary Outcomes: ROP needing treatment, BPD, NEC, mortality, transfusion efficacy, and safety.
Analysis / Sample size: 142 infants randomized (73 control, 69 intervention). ITT and per-protocol analyses; study powered for 50% ROP reduction.
Patient follow-up: >95% included in final analyses.

MAIN RESULTS

– Neonates receiving cord RBC transfusions had significantly lower rates of severe ROP progression compared to controls.
– The need for rescue interventions (laser/anti-VEGF) was reduced in the cord RBC group.
– No excess in adverse events, mortality, or systemic morbidity was reported in the intervention group.
– Findings support biological plausibility, as cord RBCs contain higher fetal hemoglobin levels, potentially reducing oxidative stress.

CONCLUSION

Cord blood RBC transfusions were feasible and safe. In per-protocol analysis, they were associated with reduced severe ROP and BPD, suggesting a protective role of fetal hemoglobin (HbF). Findings require confirmation in larger, adequately powered studies.

COMMENTARY

This multicenter randomized trial explores an innovative approach to transfusion in preterm neonates—preserving fetal hemoglobin (HbF) via cord blood–derived RBCs to mitigate oxidative complications such as ROP and BPD. The investigators deserve recognition for demonstrating both feasibility and safety of cord blood transfusions in ELGANs, addressing a major logistical challenge in neonatal transfusion medicine.

 

Methodologically, the study was robust—randomized, blinded, and multicenter—with clinically meaningful endpoints. The biological rationale is sound: HbF’s high oxygen affinity may reduce retinal hyperoxia and free radical–mediated injury. The results are promising—no severe ROP or BPD among infants who received only cord blood—but interpretation must remain cautious.

 

Nearly half of the intervention group received mixed transfusions due to unit shortages, severely limiting statistical power in the ITT analysis. The striking benefit in the per-protocol subgroup, though compelling, was based on only 17 infants and is therefore hypothesis-generating rather than definitive. Additionally, logistical and cost barriers—cord collection, processing, and inventory constraints—would currently prevent large-scale adoption.

 

This trial aligns with previous observational data linking lower HbF levels to higher ROP and BPD risk (1,2). It adds randomized evidence supporting a potential causal mechanism but falls short of establishing clinical efficacy. Future studies should ensure adequate HbF exposure, standardized transfusion thresholds, and long-term visual and neurodevelopmental follow-up.

 

The clinical message is that cord-derived transfusions may hold protective potential, but the evidence remains preliminary. Neonatal units should continue to follow existing restrictive transfusion guidelines while further multicenter trials clarify the role of HbF-preserving strategies.

 

REFERENCES

1. Aher SM, Ohlsson A. Early versus late erythrocyte transfusion for preterm infants. Cochrane Database Syst Rev. 2020;2:CD005090.
2. Dani C, et al. Low fetal hemoglobin levels and risk of retinopathy of prematurity. Pediatr Res. 2021;90:1242–8.
3. Teofili L, et al. eClinicalMedicine. 2025;87:103426.
4. Stutchfield CJ, et al. Transfusion thresholds and outcomes in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2022;107:F72–F79.