Heterologous Cord Blood-Derived Red Blood Cell for Transfusion in Extremely Preterm Infants

Neonatal anemia is a common condition in extremely preterm infants (born before 28 weeks of gestation) and is associated with significant health risks. Despite the implementation of evidence-based strategies to reduce anemia, such as delayed umbilical cord clamping and cord milking, many extremely preterm infants still require red blood cell transfusions during the first weeks of life due to a multifactorial decline in hemoglobin levels.

Currently, red blood cell transfusions for these infants use blood from adult donors. Transfusion of adult donor blood has been associated with complications linked to fluctuations in tissue oxygen levels, including retinopathy of prematurity and bronchopulmonary dysplasia. One key factor contributing to these complications is the lower proportion of fetal hemoglobin (HbF) in adult donor blood compared to the infant's natural blood. HbF has a higher affinity for oxygen and releases oxygen more slowly, whereas adult hemoglobin (HbA) delivers oxygen more rapidly to tissues, increasing the risk of oxygen toxicity. Additionally, adult donor blood may contain trace amounts of heavy metals, which could potentially affect extremely preterm infants, although this has not been formally studied.

Red blood cell concentrates derived from umbilical cord blood (CB-RBC) provide an alternative that is closer to the infant's own blood composition. CB-RBC transfusions contain higher levels of HbF, which may reduce tissue oxygen stress. Pilot studies in our center have shown that CB-RBC transfusions are feasible, safe, and effective. In one preliminary study, ten extremely preterm infants (<28 weeks gestation) received a total of 23 CB-RBC transfusions without adverse reactions, indicating that this approach is safe in clinical practice. However, medium- and long-term benefits of CB-RBC transfusions remain unclear.

Recent research shows that higher HbF levels are inversely correlated with morbidities related to tissue hyperoxygenation, such as bronchopulmonary dysplasia and retinopathy of prematurity. Studies in Italy, including those by Teofili et al., have shown encouraging trends toward reducing severe retinopathy, although small sample sizes prevented statistical significance. These findings support the need for a larger randomized multicenter trial to evaluate clinical outcomes more conclusively.

This study is a randomized multicenter clinical trial coordinated among all major level 3A and 3B public neonatal units in the Barcelona area, with unanimous support from participating units. Approximately 115 extremely preterm infants will be enrolled. Eligible infants will be randomly assigned to receive either CB-RBC transfusions or standard adult donor red blood cell transfusions if a transfusion is clinically indicated. Transfusions will only be performed when medically necessary. If cord blood is not available at the time of transfusion, compatible adult donor blood will be used regardless of assigned group.

To assess the effects of transfusion, small blood samples will be collected at birth, at one month of age, and 24 hours after any transfusion. Blood collection follows routine clinical practice, and volumes are minimal (~0.2 mL per sample). Non-invasive sensors will be placed on the infant's head for 24 hours to monitor cerebral oxygenation. Urine samples will also be collected before and after transfusion to evaluate tissue oxygen delivery. All procedures are designed to minimize risk and discomfort for participants.

Study Hypothesis: We hypothesize that transfusion with cord blood red blood cell concentrates will reduce the combined outcome of bronchopulmonary dysplasia, retinopathy of prematurity, and death before 36 weeks postmenstrual age or hospital discharge (whichever occurs first), compared to transfusions with standard adult donor red blood cells.

The results of this study aim to provide strong evidence regarding the clinical benefits of CB-RBC transfusions in extremely preterm infants, including the potential to reduce transfusion-related complications and improve outcomes. If successful, this approach could be implemented more widely to enhance neonatal care for this vulnerable population

Inclusion criteria

• Signed informed consent obtained from parents or legal guardians.
• Gestational age at birth < 28 weeks or birth weight < 1000 g.
• Admission to one of the participating neonatal intensive care units (NICUs) in the Barcelona area.

Exclusion criteria

• Prior red blood cell transfusion during the fetal or neonatal period.
• Maternal-fetal immunization (e.g., isoimmunization).
• Fetal hydrops.
• Major congenital malformations.
• Congenital infections.
• Immediate need for blood before randomization (e.g., hemorrhagic shock, consumptive coagulopathy).
• Participation in another clinical trial that could interfere with the primary outcome.