The oxygen paradox in retinopathy of prematurity: could fetal hemoglobin be the key?

Retinopathy of prematurity (ROP) remains a leading preventable cause of childhood blindness in preterm infants. Although established risk factors such as gestational age, birth weight, and oxygen exposure are well characterized, they do not fully capture the biological variability that influences disease development. Recently emerging data suggested that the postnatal decline in fetal hemoglobin (HbF) may be an important, potentially traceable, and modifiable ROP risk factor. Lower HbF levels, particularly between 31 and 34 weeks postmenstrual age, have been associated with increased incidence and severity of ROP in infants. In addition, red blood cell transfusions from adult donors have been shown to accelerate the replacement of HbF with adult hemoglobin (HbA). This may increase retinal oxygen exposure and in turn, oxidative stress, disrupting physiologic retinal vascular development in premature infants. Mechanistically, HbF's higher oxygen affinity and redox handling properties may buffer hyperoxic injury in the premature retina. Although a multicenter randomized trial of cord blood red blood cell transfusions did not demonstrate a significant intention-to-treat benefit, analyses of protocol-adherent infants showed reduced ROP severity and treatment requirements, highlighting both therapeutic potential and practical challenges. In this perspective, we propose a precision-care approach termed "HbF stewardship," that integrates routine HbF monitoring, transfusion optimization, selective use of cord blood products, and HbF-informed oxygen titration as a preventive strategy for ROP. We further outline potential clinical trial designs and implementation strategies to support the safe integration of hemoglobin-guided care across diverse neonatal intensive care settings.