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

Multicenter, Randomized, Double-Blind Pilot Clinical Trial Evaluating the Impact of Transfusion With Heterologous Cord Blood-Derived Red Blood Cells Versus Adult Red Blood Cells in Extremely Premature Infants

Anemia is a condition in which there are not enough red blood cells to carry oxygen throughout the body. It is very common in extremely preterm infants (born before 28 weeks of pregnancy), and many of these babies require red blood cell transfusions during their hospital stay.

Currently, transfusions are given using red blood cells donated by adults. An alternative option is to use red blood cells collected from umbilical cord blood, which may be more similar to a newborn's own blood. This approach has been used in some neonatal units with encouraging results and no reported safety concerns.

This study aims to determine whether transfusion with umbilical cord blood improves clinical outcomes and reduces potential side effects compared to standard adult donor blood transfusion in extremely preterm infants. We hypothesize that umbilical cord blood transfusion will be at least as safe as adult donor blood and may provide clinical benefits.

About 115 extremely preterm infants admitted to neonatal units in Catalonia will participate. If parents agree, their baby will be randomly assigned to receive either compatible umbilical cord blood or compatible adult donor blood if a transfusion becomes necessary. Babies will only receive a transfusion if they clinically need one. If cord blood is not available at the time of transfusion, the baby will receive compatible adult donor blood regardless of the assigned group.

To evaluate the response to treatment, small blood samples will be collected at birth, at one month of life, and 24 hours after any transfusion. These samples are taken at the same times as routine blood tests, so participation does not require additional needle sticks. The amount of blood collected is minimal (about 0.2 mL per sample).

In addition, a painless and non-invasive sensor will be placed on the baby's head for 24 hours to measure oxygen delivery to the brain. Urine samples will also be collected before and after transfusion to help assess how oxygen reaches body tissues.

Participation will continue until the baby reaches 36 weeks of postmenstrual age or is discharged from the hospital, whichever comes first.

Study Overview

• Status: Not yet recruiting
• Conditions: Blood Transfusion; Retinopathy of Prematurity (ROP); Bronchopulmonary Dysplasia (BPD); Intensive Care Units, Neonatal; Anemia Neonatal; Umbilical Cord Blood; Death; Neonatal; Fetal Hemoglobin; Extremely Premature Infant
• Intervention / Treatment: Biological: Cord Blood Red Blood Cells; Biological: Standard Adult Donor Red Blood Cells

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 176
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Miguel Maria Alsina Casanova, MD; Phone Number: 7503 +34932275600; Email: mmalsina@clinic.cat
• Study Contact Backup: Name: Dinara Smarkanova, MD; Phone Number: 6563 +34935573500; Email: dsamarkanova@bst.cat

Study Locations

• Spain
  • Barcelona, Spain, 08028
    • Hospital Clínic de Barcelona - Maternitat
    • Contact: Miguel Maria Alsina Casanova, MD; Phone Number: 7447 +34932275600; Email: mmalsina@clinic.cat
    • Principal Investigator: Miguel Ramón Jimenez, MD
    • Principal Investigator: Fátima Camba Longueira, MD
    • Principal Investigator: María José García Borau, MD
    • Principal Investigator: Marta Ocaña Rico, MD
    • Principal Investigator: Mònica Domingo Puiggròs, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cord Blood-Derived Red Blood Cell Transfusion; Extremely preterm infants randomized to this arm will receive red blood cell transfusions derived from umbilical cord blood (CB-RBC) when a transfusion is clinically indicated according to standard neonatal guidelines. If compatible cord blood units are not available at the time of transfusion, standard adult donor red blood cells may be used.	Biological: Cord Blood Red Blood Cells; Neonates receive transfusions of red blood cells derived from allogeneic umbilical cord blood, ABO/RhD compatible. Dosage: 15-20 mL/kg per transfusion, administered according to clinical indication and availability. If cord blood is not available at the time of transfusion, adult donor red blood cells (CH-SA) are given instead. Monitoring: Vital signs, complete blood count, hematocrit, fetal hemoglobin (HbF), and tissue oxygenation (via NIRS) are recorded before and after transfusion.; Other Names: CH-SCU
Active Comparator: Adult Donor Red Blood Cell Transfusion; Extremely preterm infants randomized to this arm will receive standard adult donor red blood cell transfusions when a transfusion is clinically indicated according to standard neonatal guidelines.	Biological: Standard Adult Donor Red Blood Cells; Neonates receive transfusions of red blood cells derived from adult donors, ABO/RhD compatible. Dosage: 15-20 mL/kg per transfusion, administered according to clinical indication and the protocol of each neonatal unit. Transfusions are performed only when medically necessary. Monitoring: Vital signs, complete blood count, hematocrit, fetal hemoglobin (HbF), and tissue oxygenation (via NIRS) are recorded before and after transfusion.; Other Names: CH-SA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome of bronchopulmonary dysplasia, retinopathy of prematurity, or death in extremely prematurs	The primary outcome is the occurrence of: Bronchopulmonary dysplasia (BPD, any grade) defined as the need for oxygen therapy or any respiratory support at 36 weeks postmenstrual age (PMA). Classified according to Jensen et al. (2019), assessed at 36 weeks PMA.; Retinopathy of prematurity (ROP, any stage) diagnosed according to the International Classification of Retinopathy of Prematurity, assessed by ophthalmologists blinded to group allocation using ophthalmoscopy and the Catalonia Ophthalmic Telemedicine Network (RTOC).; Death before 36 weeks postmenstrual age or hospital discharge, whichever occurs first. This composite outcome is used to evaluate the clinical benefit of cord blood-derived red blood cell transfusions compared to standard adult donor transfusions in extremely preterm infants.	From birth until 36 weeks postmenstrual age or hospital discharge (whichever occurs first).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fetal hemoglobin (HbF) threshold at one month associated with clinical outcomes	To evaluate the fetal haemoglobin (HbF) percentage cutoff at one month of life that best correlates with a reduction in the composite outcome of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or death, as well as with each outcome individually. Due to limited availability of cord blood units (CB-RBC), some infants assigned to this group may receive adult donor red blood cells. This analysis aims to identify protective or critical HbF thresholds for the development of ROP and BPD.	At one month of life.
Oxygen-free days within 90 days post-randomization	To evaluate the impact of cord blood-derived red blood cell transfusion (CB-RBC) versus standard adult donor red blood cell transfusion (AD-RBC) on intermediate outcomes, specifically the number of oxygen-free days during the 90 days following randomization.	Up to 90 days after randomization.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic parameters post-transfusion (1)	Assessment of transfusion efficacy via changes in total hematocrit.An increment in hematocrit by 12 ± 5 points 24 hours after the transfusion will be considered effective. This analysis aims to demonstrate non-inferiority of CB-RBC vs AD-RBC.	Pre-transfusion, 24 hours post-transfusion, and at 1 month of age
Hematologic parameters post-transfusion (2)	Assessment of transfusion efficacy via changes in total hemoglobin. An increment in total hemoglobin by 4 ± 2 g / dL 24 hours after the transfusion will be considered effective. Samples will be analysed by microhematocrit method. This analysis aims to demonstrate non-inferiority of CB-RBC vs AD-RBC.	Pre-transfusion, 24 hours post-transfusion, and at 1 month of age
Fetal hemoglobin (HbF) percentage evolution	Measure changes in HbF percentage over time (at birth, pre- and post-transfusion, and at 1 month), evaluating its association with intermediate and clinical outcomes.	At birth, 24 hours post-transfusion, and 1 month of age
Tissue oxygenation measured by NIRS	Evaluate cerebral oxygenation changes using near-infrared spectroscopy (NIRS ("INVOS 5100C Cerebral/somatic oximeter "(Medtronic Minneapolis, MM)) during and 24 hours after transfusion to assess tissue oxygen delivery.	From transfusion initiation until 24 hours post-transfusion
Red blood cell transfusion requirements (1)	Total volume of transfusions (mililiters) received until 36 weeks PMA or hospital discharge, comparing CB-RBC vs AD-RBC.	From birth until 36 weeks PMA or hospital discharge
Red blood cell transfusion requirements (2)	Total number of transfusions received until 36 weeks PMA or hospital discharge, comparing CB-RBC vs AD-RBC.	From birth until 36 weeks PMA or hospital discharge
Markers of oxidative stress	Measure urinary isoprostanes as an oxidative stress marker at birth, post-transfusion and 1 month of age	At birth, post-transfusion, and 1 month of age
Bone marrow regeneration parameters	Reticulocyte counts will be measured at 1 month of life as an indicator of marrow regeneration	1 month of life
Iron metabolism values	Ferritin levels at 1 month of life will be measured as an indicator of iron metabolism	1 month of life

Collaborators and Investigators

• Sponsor: Hospital Clinic of Barcelona
• Collaborators: Germans Trias i Pujol Hospital; Hospital Vall d'Hebron; Hospital Sant Joan de Deu; Hospital de la Santa creu i Sant Pau - Barcelona; Parc Taulí Hospital Universitari
• Investigators: Principal Investigator: Miguel Maria Alsina Casanova, MD, Hospital Clinic of Barcelona; Study Director: Dinara Smarkanova, MD, Banc de Sang i Teixits; Principal Investigator: Miguel Ramón Jiménez, MD, Hospital Sant Joan de Déu; Principal Investigator: Fátima Camba Longueira, MD, Hospital Vall d'Hebron; Principal Investigator: María José García Borau, MD, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau; Principal Investigator: Marta Ocaña Rico, MD, Germans Trias i Pujol Hospital; Principal Investigator: Mònica Domingo Puiggròs, MD, Hospital Parc Tauli

Publications and helpful links

General Publications

• Teofili L, Papacci P, Orlando N, Bianchi M, Molisso A, Purcaro V, Valentini CG, Giannantonio C, Serrao F, Chiusolo P, Nicolotti N, Pellegrino C, Carducci B, Vento G, De Stefano V. Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study. Br J Haematol. 2020 Oct;191(2):263-268. doi: 10.1111/bjh.16851. Epub 2020 Jun 8.
• Gonzalez EG, Casanova MA, Samarkanova D, Aldecoa-Bilbao V, Teresa-Palacio M, Busquets EF, Figueras-Aloy J, Salvia-Roiges M, Querol S. Feasibility of umbilical cord blood as a source of red blood cell transfusion in preterm infants. Blood Transfus. 2021 Nov;19(6):510-517. doi: 10.2450/2020.0169-20. Epub 2020 Dec 18.
• Torrejon-Rodriguez L, Pinilla-Gonzalez A, Lara Canton I, Albiach-Delgado A, Cascant-Vilaplana MM, Cernada M, Kuligowski J, Solves Alcaina MP, Gomez I, Vento M, Aguar Carrascosa M. Effect of autologous umbilical cord blood transfusion in the development of retinopathy of prematurity: randomized clinical trial - study protocol. Front Pediatr. 2023 Oct 12;11:1269797. doi: 10.3389/fped.2023.1269797. eCollection 2023.
• Teofili L, Papacci P, Dani C, Cresi F, Remaschi G, Pellegrino C, Bianchi M, Ansaldi G, Campagnoli MF, Vania B, Lepore D, Franco FGS, Fabbri M, de Vera d' Aragona RP, Molisso A, Beccastrini E, Dragonetti A, Orazi L, Pasciuto T, Mozzetta I, Baldascino A, Locatelli E, Valentini CG, Giannantonio C, Carducci B, Gabbriellini S, Albiani R, Ciabatti E, Nicolotti N, Baroni S, Mazzoni A, Besso FG, Serrao F, Purcaro V, Coscia A, Pizzolo R, Raffaeli G, Villa S, Mondello I, Trimarchi A, Beccia F, Ghirardello S, Vento G. Cord blood transfusions in extremely low gestational age neonates to reduce severe retinopathy of prematurity: results of a prespecified interim analysis of the randomized BORN trial. Ital J Pediatr. 2024 Aug 7;50(1):142. doi: 10.1186/s13052-024-01714-w.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: March 16, 2026
• First Submitted That Met QC Criteria: March 27, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Bronchopulmonary dysplasia; Fetal hemoglobin; Retinopathy of prematurity; Oxygen delivery; Neonatal anemia; Extremely preterm infants; Umbilical cord blood transfusion; Cord blood red blod cell transfusion; Adult donor red blood cells; Days requiring oxygen supplementation
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Pregnancy Complications; Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Death; Eye Diseases; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Retinal Diseases; Lung Injury; Ventilator-Induced Lung Injury; Thalassemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; beta-Thalassemia; Retinopathy of Prematurity; Perinatal Death; Bronchopulmonary Dysplasia; Anemia, Neonatal
• Other Study ID Numbers: CBLOOD - PE 01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No