Introduction: Screening and treatment of seizures (Sz) in neonates suffering from hypoxic-ischemic encephalopathy (HIE) is routine. Understanding if Sz worsen brain injury and outcomes would optimize treatment decisions, recognizing risks and benefits. We hypothesized that serum central nervous system (CNS)-specific biomarkers would discriminate neonates with Sz and relate to outcomes. Methods: This retrospective cohort study was conducted between April 28, 2009 and November 15, 2019, including neonates diagnosed with seizures (Sz) and/or HIE treated with therapeutic hypothermia (TH), who had sufficient remnant serum for biomarker analysis. Neonates were grouped in i) only Sz without HIE (Sz-no HIE), ii) HIE with Sz (Sz-HIE) and iii) HIE without Sz (no Sz-HIE). Levels of glial fibrillary acidic protein (GFAP, astrocytic reactivity), Tau (neuronal injury) and neurofilament light chain (NF-L, axonal degeneration) were studied at admission, <72h and 72-144h of life against time to full oral feeds and brain injury in MRI. Results: After exclusions 145 neonates were included (61% male; 33% Black). Admission GFAP levels were higher in Sz-HIE than in no Sz-HIE neonates. During the first 72h of life, levels of all 3 biomarkers were similar between Sz groups (Sz-no HIE & Sz-HIE), but higher than in no Sz-HIE. After 72h, NF-L and Tau remained higher in both Sz groups vs. no Sz-HIE. Stroke diagnosed in 31% (Sz-no HIE), 8% (Sz-HIE) and 11% (no Sz-HIE) of neonates had no effect in biomarkers levels. In adjusted regression models higher Tau and NF-L percentiles related to longer time to reach full oral feeding and higher odds of significant brain injury in MRI in both Sz groups. Conclusions: In this study, Tau and NF-L levels are higher in those neonates developing Sz, irrespective of their HIE diagnosis. These results provide additional support for the notion that Sz may worsen brain injury and outcomes in neonates with HIE even with TH.

The authors have declared no competing interest.

Supported by National Institutes of Health RO1 HD110091 (KBA, JK, CP, GJG, AT, EMG, ADE, FJN, RC-V); RO1 NS126549 (GJG, FJN, RC-V); U01NS114144 (CD, MS, GS, JW) and the Thomas Wilson Foundation (RC-V).

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