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. 2025 May 14;184(6):339.
doi: 10.1007/s00431-025-06167-9.

Lower bilirubin levels in newborns with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia may indicate suppressed heme oxygenase activity

Tomonori Sunakawa #  1 , Sota Iwatani #  1 , Shinji Hagimoto  1   2 , Toshihiko Ikuta  1 , Seiji Yoshimoto  1
Affiliations

Lower bilirubin levels in newborns with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia may indicate suppressed heme oxygenase activity

Tomonori Sunakawa et al. Eur J Pediatr. .

Abstract

Despite having risk factors for hyperbilirubinemia, newborns with hypoxic ischemic encephalopathy (HIE) often exhibit unexpectedly low bilirubin levels, potentially due to reduced heme oxygenase (HO) activity. This study aims to evaluate bilirubin dynamics and HO activity in moderate to severe HIE newborns undergoing therapeutic hypothermia (TH) within a Japanese cohort. In this matched case-control study, newborns with HIE who underwent TH (case group) and control newborns without HIE (control group) treated at our perinatal center between 2019 and 2024 were retrospectively studied. Control newborns, admitted for respiratory distress or other conditions, were matched by gestational age, birth weight, sex, and birth date. Clinical data, including the total serum bilirubin (TsB), transcutaneous bilirubin (TcB), and carboxyhemoglobin (COHb) levels (an indicator of HO activity) were collected and analyzed during the first week of life. A total of 32 cases were analyzed in both the case and control groups. The case group had significantly lower TsB and TcB levels over time. COHb levels were comparable between the groups until 96 h of life but became significantly higher in the case group thereafter.

Conclusion: In this Japanese cohort, TsB and TcB levels were consistently lower in HIE newborns undergoing TH during the first week of life. COHb levels were initially comparable but increased later in the case group. These findings suggest that reduced HO activity may contribute to suppressed heme degradation in moderate to severe HIE cases receiving TH.

What is known: • Newborns with hypoxic ischemic encephalopathy (HIE) often exhibit lower bilirubin levels than expected, despite risk factors for hyperbilirubinemia.

What is new: • This study indicates that reduced heme oxygenase activity may contribute to the lower bilirubin levels observed in HIE newborns undergoing therapeutic hypothermia.

Keywords: Asphyxia; Carboxyhemoglobin; Jaundice; Total serum bilirubin; Transcutaneous bilirubin.

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Conflict of interest statement

Declarations. Ethics approval: This retrospective study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee at Hyogo Prefectural Kobe Children’s Hospital (approval no. R6-205). Consent to participate: Informed consent was waived due to the retrospective nature of the study and the use of anonymized data. Instead, information about the study was disclosed to the public through the institutional website and bulletin board. Competing interests: The authors declare no competing interests.

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