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Oxygen affinity of fetal and adult hemoglobin in action: shifting our understanding of red blood cell transfusions in neonates

Pediatric Research volume 97, pages 1767–1768 (2025)Cite this article

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Preterm infants commonly receive red blood cell (RBC) transfusions, yet much remains uncertain about the safety and effectiveness of these transfusions.1 Most research efforts have focused on ‘when’ to transfuse these infants, specifically which hemoglobin (Hb) thresholds should trigger a RBC transfusion. Two recent randomized trials comparing higher (liberal) versus lower (restrictive) transfusion thresholds found restrictive policies to be non-inferior to liberal ones.2 However, little evidence is available regarding many aspects of neonatal transfusion care other than thresholds, such as ‘how’ to transfuse (optimal transfusion volumes and transfusion rate) and in particular ‘what’ to transfuse. RBC transfusions in neonates are performed using blood from adult donors. However, there is a developmental mismatch between RBCs from adult blood donors and those of preterm infants. Preterm infants carry predominantly fetal Hb (HbF), which has a higher oxygen affinity to facilitate oxygen transfer from the maternal circulation to the fetus in utero. When preterm infants receive multiple transfusions with adult RBCs, this causes progressive displacement of HbF by adult Hb (HbA). Increased oxygen delivery from HbA may result in a condition of hyperoxia at the cellular level, resulting in the overproduction of reactive oxygen species.3 Several studies concluded that transfusions were associated with prematurity-related comorbidities such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD).4 RBCs derived from umbilical cord blood (UCB) have therefore been suggested as a promising alternative as it contain primarily HbF instead of HbA. The first clinical studies are currently underway to evaluate their efficacy and safety.5,6,7 However, much remains unknown about how adult RBCs affect neonatal oxygen affinity and what the optimal oxygen affinity of RBCs transfused to preterm infants is.

In this issue of the journal, Yazdanbaksh and colleagues studied the impact of adult RBC transfusion on fetal RBC oxygen affinity in an in vitro model.8 They titrated stored adult-packed RBCs (pRBCs) into UCB samples of 19 preterm infants to measure the concentration-dependent change in p50. The p50 represents the partial pressure of oxygen (PaO2, in mmHg) required to saturate 50% of Hb, with a lower p50 indicating a higher oxygen affinity. Interestingly, the authors found that the p50 of the titrations decreased as the proportion of adult pRBCs in the cord blood sample increased, indicating a left shift of the oxygen dissociation curve (ODC). This suggests that adult pRBCs contribute a higher oxygen affinity compared to the fetal RBCs in cord blood. Additionally, they assessed the effect of the biological age of adult pRBCs on fetal RBC oxygen affinity. Their findings showed that titrating old pRBCs into cord blood samples resulted in a lower p50 than titrations with young RBCs. This suggests that transfusing old pRBCs may have a stronger influence on oxygen binding. With this small proof-of-concept study, the authors provided new insights into our understanding of the impact of adult pRBCs on fetal Hb-oxygen affinity. Importantly, these findings appear to contradict the hypothesis that, due to the naturally lower oxygen affinity of HbA, transfusing adult RBCs would shift the ODC to the right, resulting in a higher p50 and reduced oxygen affinity.

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Authors and Affiliations

  1. Division of Neonatology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, the Netherlands

    Nina A. M. Houben & Enrico Lopriore

  2. Sanquin Research, Sanquin Blood Supply Foundation, Amsterdam, the Netherlands

    Nina A. M. Houben

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  1. Nina A. M. Houben
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  2. Enrico Lopriore
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Correspondence to Enrico Lopriore.

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Houben, N.A.M., Lopriore, E. Oxygen affinity of fetal and adult hemoglobin in action: shifting our understanding of red blood cell transfusions in neonates. Pediatr Res 97, 1767–1768 (2025). https://doi.org/10.1038/s41390-024-03784-2

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