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

Официальное название

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

Обзор

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.

Подробное описание

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

Вмешательства

• Биопрепарат 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.
• Биопрепарат 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.

Первичные конечные точки

• Composite outcome of bronchopulmonary dysplasia, retinopathy of prematurity, or death in extremely prematurs [Срок оценки: From birth until 36 weeks postmenstrual age or hospital discharge (whichever occurs first).]

Вторичные конечные точки (2)

• Fetal hemoglobin (HbF) threshold at one month associated with clinical outcomes [Срок оценки: At one month of life.]
• Oxygen-free days within 90 days post-randomization [Срок оценки: Up to 90 days after randomization.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Профилактика

Центры проведения

Испания · 1 центр

• Hospital Clínic de Barcelona - Maternitat — Barcelona

Публикации

• 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. e PMID 37900679
• 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, PMID 39113069
• 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. PMID 32510635
• 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. PMID 33370228

Идентификаторы

NCT: NCT07502781 · CBLOOD - PE 01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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