Inflammatory indices and HALP score as accessible biomarkers of severity in neonatal hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy (HIE) involves systemic inflammatory responses that may be reflected by routine blood-derived indices.

To evaluate the associations of systemic inflammatory indices and the hemoglobin-albumin-lymphocyte-platelet (HALP) score with HIE severity and short-term outcomes, and to characterize their temporal changes from the pre-hypothermia measurement to the post-treatment measurement at 72-96 postnatal hours.

This retrospective study included 555 neonates: 185 with mild HIE, 185 with moderate-to-severe HIE treated with therapeutic hypothermia, and 185 controls. Systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and HALP were calculated at 0-6 h (T1); repeat measurements at 72-96 h (T2) were assessed in the hypothermia group.

Systemic inflammatory indices showed limited discriminatory performance for distinguishing HIE from controls but showed stronger associations with HIE severity. For distinguishing moderate-to-severe HIE from mild HIE, SII showed the highest, although modest, discriminatory performance (AUC = 0.706), while lower hemoglobin, lower SII, and higher HALP remained associated with moderate-to-severe HIE in the adjusted analysis. In an exploratory analysis of the severe HIE subgroup (n = 18), SII showed the highest discriminatory performance (AUC = 0.770); however, these findings should be interpreted cautiously because of the limited subgroup size. Between T1 and T2, SII, SIRI, PIV, HALP score, and NLR significantly decreased (all p < 0.001), whereas PLR increased (p = 0.005). These findings should be interpreted as temporal biomarker changes across the treatment period; in the absence of a comparable non-cooled moderate-to-severe HIE group, they cannot be attributed specifically to therapeutic hypothermia. In an exploratory mortality analysis based on seven deaths, baseline albumin showed significant discrimination (AUC = 0.863); however, this estimate should be interpreted cautiously because of the small number of events.

Routine blood-derived indices, particularly SII and HALP, were associated with HIE severity and may complement established clinical and neurological assessment. Prospective multicenter validation is required.