Alternative diagnoses in neonates undergoing therapeutic hypothermia for presumed hypoxic–ischemic encephalopathy

Background – Early identification of hypoxic–ischemic encephalopathy (HIE) remains challenging during the first hours of life, and therapeutic hypothermia (TH) is often initiated before the underlying diagnosis can be established. Objective – The primary aim of this work is to compare the clinical characteristics, laboratory findings, and short-term outcomes of neonates treated with TH for presumed HIE according to their predominant underlying diagnosis. Methods – We retrospectively reviewed all neonates who received TH for suspected HIE between 2019 and 2023. Infants were categorized according to the predominant underlying diagnosis identified following comprehensive clinical, neurophysiological, neuroimaging, metabolic, genetic, and subspecialty evaluations. Demographic, clinical, neurologic, and laboratory parameters—including inflammation- and oxidative stress-related indices—were compared between groups. Results – Among 92 neonates treated with TH, nine (10%) were subsequently found to have non-hypoxic–ischemic etiologies of neonatal encephalopathy. Baseline neurological severity assessed by Sarnat staging and initial amplitude-integrated electroencephalography patterns did not differ between groups. However, infants in the non-HIE group demonstrated significantly higher rates of myocardial injury (77% vs. 22%, p < 0.001) and severe thrombocytopenia (66% vs. 25%, p = 0.016). These infants also had substantially longer hospitalizations [median (25P–75P): 28 (17–38) vs. 7 (5–11) days, p = 0.002] and higher mortality rates (55.6% vs. 6%, p = 0.001). The median day of death was earlier in the non-HIE group [median (25P–75P): 3 (1–57) vs. 16 (8–77) days; p = 0.30]. However, it was not statistically significant. Inflammatory and oxidative stress indices did not differ significantly between groups. Conclusion – Approximately 10% of neonates undergoing therapeutic hypothermia for presumed HIE were ultimately found to have non-hypoxic–ischemic causes of neonatal encephalopathy despite similar early neurologic presentations. These infants experienced greater systemic morbidity and poorer short-term outcomes. While the small and heterogeneous non-HIE cohort warrants cautious interpretation, disproportionately severe systemic manifestations—particularly myocardial injury and thrombocytopenia—may represent early clinical clues prompting broader diagnostic evaluation beyond hypoxic–ischemic injury.