{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:05:20Z","timestamp":1780380320124,"version":"3.54.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>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 \u201cHbF stewardship,\u201d 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.<\/jats:p>","DOI":"10.3389\/fped.2026.1844386","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:42:42Z","timestamp":1780378962000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The oxygen paradox in retinopathy of prematurity: could fetal hemoglobin be the key?"],"prefix":"10.3389","volume":"14","author":[{"given":"Marcus T. A.","family":"Jackson","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronny","family":"Amamoo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menaka C.","family":"Thounaojam","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela M.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravirajsinh N.","family":"Jadeja","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3390\/antiox13020148","article-title":"Retinopathy of prematurity-targeting hypoxic and redox signaling pathways","volume":"13","author":"Zhang","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1001\/jama.2013.5555","article-title":"Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial","volume":"309","author":"Schmidt","year":"2013","journal-title":"JAMA"},{"key":"B3","volume-title":"Oxygen Saturation Targets for Preterm Infants\u2014clinical Pathway","year":"2023"},{"key":"B4","year":"2020"},{"key":"B5","doi-asserted-by":"publisher","first-page":"710465","DOI":"10.3389\/fped.2021.710465","article-title":"Fetal hemoglobin and tissue oxygenation measured with near-infrared spectroscopy-a systematic qualitative review","volume":"9","author":"Priti\u0161anac","year":"2021","journal-title":"Front Pediatr"},{"key":"B6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.25259\/JHAS_41_2024","article-title":"Oxygen dissociation curve characteristics of common hemoglobin variants and its potential implications: a brief report","volume":"5","author":"Kuppusamy","year":"2025","journal-title":"J Hematol Allied Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41433-020-0938-5","article-title":"Lower foetal haemoglobin levels at 31- and 34-weeks post menstrual age is associated with the development of retinopathy of prematurity: pacIFiHER report No. 1. PacIFiHER Study Group (Preterm Infants and Fetal Haemoglobin in ROP)","volume":"35","author":"Jiramongkolchai","year":"2021","journal-title":"Eye (Lond)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.4103\/IJO.IJO_692_23","article-title":"Fetal hemoglobin, blood transfusion, and retinopathy of prematurity in preterm infants: an observational, prospective study","volume":"71","author":"Prasad","year":"2023","journal-title":"Indian J Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1136\/bjophthalmol-2020-318293","article-title":"Low fraction of fetal haemoglobin is associated with retinopathy of prematurity in the very preterm infant","volume":"106","author":"Hellstrom","year":"2022","journal-title":"Br J Ophthalmol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1136\/bjophthalmol-2021-319546","article-title":"Effects of fetal haemoglobin on systemic oxygenation in preterm infants and the development of retinopathy of prematurity PacIFiHER report No. 2","volume":"107","author":"Jiramongkolchai","year":"2023","journal-title":"Br J Ophthalmol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3478","DOI":"10.4103\/IJO.IJO_274_23","article-title":"Role of fetal hemoglobin in the development and progression of retinopathy of prematurity in preterm infants","volume":"71","author":"Prasad","year":"2023","journal-title":"Indian J Ophthalmol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2614192","DOI":"10.1080\/14767058.2026.2614192","article-title":"Fetal hemoglobin fraction is correlated to the risk of prematurity complications","volume":"39","author":"Dani","year":"2026","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3390\/biomedicines13010110","article-title":"Fetal hemoglobin as a predictive biomarker for retinopathy of prematurity: a prospective multicenter cohort study in Portugal","volume":"13","author":"Fevereiro-Martins","year":"2025","journal-title":"Biomedicines"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1038\/eye.2017.76","article-title":"Foetal haemoglobin, blood transfusion, and retinopathy of prematurity in very preterm infants: a pilot prospective cohort study","volume":"31","author":"Stutchfield","year":"2017","journal-title":"Eye (London, England)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.jaapos.2017.03.006","article-title":"Investigation of the effect of hemoglobin F and A levels on development of retinopathy of prematurity","volume":"21","author":"Erdol","year":"2017","journal-title":"J AAPOS"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0234266","DOI":"10.1371\/journal.pone.0234266","article-title":"Effect of red blood cell transfusion on the development of retinopathy of prematurity: a systematic review and meta-analysis","volume":"15","author":"Zhu","year":"2020","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41372-018-0274-9","article-title":"Early red cell transfusion is associated with development of severe retinopathy of prematurity","volume":"39","author":"Lust","year":"2019","journal-title":"J Perinatol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e294","DOI":"10.1111\/aos.15269","article-title":"Blood products transfusion and retinopathy of prematurity: a cohort study","volume":"101","author":"Uberos","year":"2023","journal-title":"Acta Ophthalmol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2916","DOI":"10.1182\/blood.V90.8.2916","article-title":"Amino acids responsible for decreased 2,3-biphosphoglycerate binding to fetal hemoglobin","volume":"90","author":"Adachi","year":"1997","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"576.e1","DOI":"10.1016\/j.ajog.2022.11.1282","article-title":"Urinary oxidative stress biomarkers are associated with preterm birth: an environmental influences on child health outcomes program study","volume":"228","author":"Eick","year":"2023","journal-title":"Am J Obstet Gynecol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1089\/ars.2023.0378","article-title":"Do lower levels of fetal hemoglobin in preterm infants relate to oxidative stress?","volume":"40","author":"Torrej\u00f3n-Rodr\u00edguez","year":"2024","journal-title":"Antioxid Redox Signaling"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1186\/s13063-022-06949-8","article-title":"BORN Study: a multicenter randomized trial investigating cord blood red blood cell transfusions to reduce the severity of retinopathy of prematurity in extremely low gestational age neonates","volume":"23","author":"Teofili","year":"2022","journal-title":"Trials"},{"key":"B23","doi-asserted-by":"publisher","first-page":"103426","DOI":"10.1016\/j.eclinm.2025.103426","article-title":"Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial","volume":"87","author":"Teofili","year":"2025","journal-title":"eClinicalMed"},{"key":"B24","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1471-2431-11-6","article-title":"NeOProM: neonatal oxygenation prospective meta-analysis collaboration study protocol","volume":"11","author":"Askie","year":"2011","journal-title":"BMC Pediatr"},{"key":"B25","year":"2021"},{"key":"B26","doi-asserted-by":"publisher","first-page":"12","DOI":"10.20455\/ros.2017.805","article-title":"Neonatal intermittent hypoxia, reactive oxygen Species, and oxygen-induced retinopathy","volume":"3","author":"Beharry","year":"2017","journal-title":"React Oxyg Species (Apex)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1152\/physrev.00043.2017","article-title":"Gestational hypoxia and developmental plasticity","volume":"98","author":"Ducsay","year":"2018","journal-title":"Physiol Rev"},{"key":"B28","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/0002-9378(86)90104-3","article-title":"Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia","volume":"155","author":"Ballew","year":"1986","journal-title":"Am J Obstet Gynecol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1038\/s41372-025-02368-0","article-title":"Involving neonatal hematology and transfusion medicine in global efforts to eliminate severe retinopathy of prematurity","volume":"45","author":"Christensen","year":"2025","journal-title":"J Perinatol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e619","DOI":"10.1542\/peds.2005-0915","article-title":"Nucleated red blood cells in preterm infants with retinopathy of prematurity","volume":"116","author":"Lubetzky","year":"2005","journal-title":"Pediatrics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3390\/children13010117","article-title":"Changes in fetal hemoglobin in very preterm infants born small for gestational age: a retrospective observational study","volume":"13","author":"Dani","year":"2026","journal-title":"Children (Basel)"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1844386\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:42:44Z","timestamp":1780378964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1844386\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":31,"alternative-id":["10.3389\/fped.2026.1844386"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1844386","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"1844386"}}