In Focus
The BORN trial
A new hope for protecting vision in preterm neonates
Neonates born before 28 weeks of pregnancy or weighing less than 1000 grams (known as Extremely Low Gestational Age Neonates, or ELGANs), constitute a profoundly fragile patient population. These infants face enormous challenges, carrying high risks for serious health issues and long-term consequences.
One of the major threats is an eye disease called Retinopathy of Prematurity (ROP). Normally, retinal blood vessels development starts at week 16 of gestation and persists throughout pregnancy. In neonates born too early this process can halt, leading the retina to compensate by growing new, abnormal, blood vessels. In most severe forms, the abnormal vessels can pull the retina away from the back of the eye, leading to irreversible vision impairment or blindness.
Nearly all ELGANs develop a severe form of anemia that needs to be treated with repeated red blood cell (RBC) transfusions. Numerous studies have found a concerning connection between transfusion burden and incidence of ROP or other diseases of prematurity. This correlation suggested that the damaging effect of RBC transfusions could be provoked by the difference between fetal and adult hemoglobin. Developing fetuses primarily produce fetal hemoglobin (HbF), which is perfectly suited for life in utero because it binds to oxygen more tightly than adult hemoglobin (HbA). As the due date approaches, the fetus body naturally begins switching from producing HbF to HbA, a transition normally completed 6 to 12 months after birth. Transfusing preterm neonates with adult RBCs (A-RBCs), which contains HbA, produces a progressive dilution of the baby's natural, protective reserve of HbF. While A-RBC transfusions correct anemia, they non-physiologically accelerate the transition to adult blood. Accordingly, recent studies have shown that when a preterm neonate’s HbF level drops, the risk of ROP significantly increases.
Figure 1. Patients enrolled in the BORN study, types of RBC units received and set of analysis.
Cord Blood RBC transfusions: lesson from the CB-Trip and BORN trials The evidence above inspired a core idea: transfusing preterm neonates with RBCs obtained from cord blood (CB-RBCs), which are naturally rich of HbF, could correct anemia without compromising the neonate’s HbF reserve. After establishing a method to produce CB-RBC concentrates with comparable quality and safety characteristics to A-RBC concentrates, a group of Italian researchers carried out a proof-of-concept study, the CB-Trip trial1. This study successfully demonstrated the transfusing CB-RBCs maintains the baby's HbF levels at physiologically high concentrations1. Building on this, the same authors launched the groundbreaking BORN trial2. This randomized study compared the innovative CB-RBC transfusions against standard A-RBC transfusions2. The primary objective was to determine if CB-RBCs could reduce the severity of ROP. Secondary objectives included evaluating the impact on other major premature neonatal issues, such as chronic lung disease (Bronchopulmonary Dysplasia, or BPD). Among 142 enrolled ELGANs, 30 died and 112 were finally evaluated, 56 per arm (Figure 1). The BORN trial confirmed that transfusing CB-RBCs successfully maintained high, stable levels of HbF in the recipient infants. Critically, maintaining these protective HbF levels translated into significant clinical benefits. Neonates receiving CB-RBCs experienced a lower rate of severe ROP compared to the control group receiving A-RBCs. This reduction in severe ROP was mirrored by a parallel reduction of ROP requiring medical or surgical treatments. Beyond this central breakthrough, the BORN trial also provided promising evidence that the CB-RBCs reduced the severity of BPD (Figure 2).
Since both ROP and BPD are pathologies driven by similar mechanisms related to oxidative stress, the concurrent reduction in both diseases strongly suggests that sustained HbF provides a generalized, systemic protective effect throughout the baby's developing body. For instance, evaluation of cerebral tissue oxygenation in BORN patients revealed significant differences following A-RBC or CB-RBC transfusions, with an excess of oxygen delivery observed in the case of A-RBCs3. A major logistical problem was highlighted during the BORN trial: the limited availability of cord blood units, due to the short shelf-life of CB-RBCs and the need of bacterial testing before the unit release. Neonates in the experimental arm, who were candidates for CB-RBCs were often transfused with A-RBCs, simply because a matched CB-RBC unit was not immediately available. This resulted in the trial's impactful results being achieved primarily by analyzing data from only the patient population who received the proper transfusion type (per-protocol analysis), rather than the whole population (intention-to-treat analysis) (Figure 1). This reliance on the immediate availability of CB-RBC units underscores a critical issue: the current cord blood banking system, which is generally designed for long-term stem cell storage, is not adequate for meeting the urgent, on-demand needs of a neonatal transfusion program.
Figure 2. Schematic representation of clinical trials evaluating the most relevant effects of CB-RBC transfusions in preterm neonates.
Looking ahead in preterm neonate transfusion The BORN trial strongly suggests that standard adult blood transfusions may be detrimental due to the dilution of protective fetal components, and that CB-RBCs are a superior product for this vulnerable population. These promising results indicate that, pending confirmation in larger international studies, cord blood should become the preferential blood product used for severely preterm neonates. Public cord blood banks routinely collect and store the blood remaining in the placenta and umbilical vessels after full-term deliveries. Due to the high content of hematopoietic stem cells, these units are used for the transplantation of patients with hemoglobinopathies or hematological cancers. To successfully move cord blood RBC transfusion from research to standard practice, the current transplant-focused cord blood banking system should be revised to support urgent neonatal needs.
Key steps include:
- Refining donors’ eligibility criteria based on the transfusion use.
- Improving shelf-life: implement rapid bacterial testing and better storage methods to extend the viability of CB-RBC units.
- Establishing new quality standards specific to CB- RBCs.
- Identifying maximum benefit: considering the limited availability of CB, research should continue to identify which preterm neonates will maximally benefit from this transfusion approach.
Above all considerations, it is vital to promote cord blood donation from full-term pregnancies. This effort must be conducted with the utmost commitment to evidence-based obstetric care. Paramount emphasis must be placed on ensuring that donation practices do not compromise maternal or neonatal outcomes and are strictly aligned with current clinical guidelines (e.g., preserving practices like delayed cord clamping).
References
1. Teofili L, Papacci P, Orlando N, et al. Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study. Br J Haematol. 2020;191(2):263-268 2. Teofili L, Papacci P, Pellegrino C, et al. Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial. EClinicalMedicine. 2025;87:103426. 3. Pellegrino C, Papacci P, Beccia F, et al. Differences in Cerebral Tissue Oxygenation in Preterm Neonates Receiving Adult or Cord Blood Red Blood Cell Transfusions. JAMA Netw Open. 2023;6(11):e2341643.
