CONTEMPORARY BIOMARKERS OF BLOOD-BRAIN BARRIER INJURY AND NEUROINFLAMMATION IN PRETERM INFANTS WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Emina Hadzimuratovic; Suada Brankovic; Admir Hadzimuratovic

doi:10.5937/sanamed0-66353

Emina Hadzimuratovic University Clinical Center Sarajevo, Pediatric Clinic, Department of Neonatology and Neonatal Intensive Care, Sarajevo, Bosnia and Herzegovina
Suada Brankovic University of Sarajevo, Faculty of Health Studies, Sarajevo, Bosnia and Herzegovina
Admir Hadzimuratovic University Clinical Center Sarajevo, Pediatric Clinic, Department of Nephrology, Sarajevo, Bosnia and Herzegovina

DOI: https://doi.org/10.5937/sanamed0-66353

Keywords: hypoxic–ischemic encephalopathy, preterm infants, biomarkers, GFAP, neurofilament light chain, endothelin-1, NR2 antibodies, neuroinflammation

Abstract

Background: Hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and long-term neurodevelopmental impairment, particularly in preterm infants. Early diagnosis remains challenging, and there is growing interest in biomarkers that reflect underlying mechanisms such as neuroinflammation and blood–brain barrier disruption.

Objective: To evaluate the diagnostic and prognostic value of selected circulating biomarkers in preterm infants with HIE, with emphasis on a multimarker approach.

Methods: This prospective cohort study included 120 preterm infants (gestational age 28–36 weeks), divided into HIE (n=90) and control (n=30) groups. Serum levels of NR2 antibodies, endothelin-1, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured at 24–48 hours, day 5–7, and day 14. Statistical analysis included t-test, ANOVA, correlation analysis, logistic regression, and ROC curve analysis.

Results: Biomarker levels were significantly higher in the HIE group (p<0.001). GFAP and NfL showed the highest diagnostic performance (AUC 0.86 and 0.88). The combined model achieved the best accuracy (AUC=0.89). Biomarker levels correlated with disease severity.

Conclusion: A multimarker approach improves diagnostic accuracy and may support early risk stratification and individualized management in preterm infants with HIE.

References

Chansarn P, Torgalkar R, Wilson D, Fan CS, Widjaja E, Whyte H, et al. Correlation of Thompson and modified Sarnat scores in neonatal hypoxic ischemic encephalopathy. J Perinatol. 2021; 41(6): 1522–3. doi: 10.1038/s41372-021-00987-x.

Greco P, Nencini G, Piva I, Scioscia M, Volta CA, Spadaro S, et al. Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future. Acta Neurol Belg. 2020; 120(2): 277–88. doi: 10.1007/s13760-020-01308-3.

Perretta L, Reed R, Ross G, Perlman J. Is there a role for therapeutic hypothermia administration in term infants with mild neonatal encephalopathy? J Perinatol. 2020; 40(3): 522–9. doi: 10.1038/s41372-019-0562-z.

Chalak L, Latremouille S, Mir I, Sánchez PJ, Sant‘Anna G. A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward. Early Hum Dev. 2018; 120: 88–94. doi: 10.1016/j.earlhumdev.2018.02.008.

Chalak L. New horizons in mild hypoxic-ischemic encephalopathy: a standardized algorithm to move past conundrum of care. Clin Perinatol. 2022; 49(1): 279–94. doi: 10.1016/j.clp.2021.11.016.

Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S, et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months. Pediatr Res. 2018; 84(6): 861–8. doi: 10.1038/ s41390-018-0174-x.

Hadžimuratović E, Hadžimuratović A, Pokrajac D, Branković S, Đido V. Early detection of acute kidney injury in preterm newborns with perinatal asphyxia using serum cystatin. Sanamed. 2023; 18(1): 21-5. doi: 10.5937/sanamed0-42616.

Sarnat HB, Flores-Sarnat L, Fajardo C, Leijser LM, Wusthoff C, Mohammad K. Sarnat grading scale for neonatal encephalopathy after 45 years: an update proposal. PediatrNeurol. 2020; 113: 75–9. doi: 10.1016/j.pediatrneurol.2020.08.014.

Saw CL, Rakshasbhuvankar A, Rao S, Bulsara M, Patole S. Current practice of therapeutic hypothermia for mild hypoxic ischemic encephalopathy. J Child Neurol. 2019; 34(7): 402–9. doi: 10.1177/0883073819828625.

DuPont TL, Baserga M, Lowe J, Zamora T, Beauman S, Ohls RK. Darbepoetin as a neuroprotective agent in mild neonatal encephalopathy: a randomized, placebo-controlled, feasibility trial. J Perinatol. 2021; 41(6): 1339–46. doi: 10.1038/s41372- 021-01081-y.

DuPont TL, Chalak LF, Morriss MC, Burchfield PJ, Christie L, Sánchez PJ. Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy. J Pediatr. 2013; 162(1): 35–41. doi: 10.1016/j. jpeds.2012.06.042.

Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatr. 2020; 174(1):48–55. doi:10.1001/jamapediatrics.2019.4011.

Dhillon SK, Gressens P, Barks J, Gunn AJ. Uncovering the role of inflammation with asphyxia in the newborn. Clin Perinatol. 2024;51(3):551-64 doi: 10.1016/j.clp.2024.04.012.

Hadzimuratovic E, Hadzimuratovic A, Pokrajac D, Selimovic A, Muhasilovic S. A predictive value of early clinical parameters for abnormal brain MRI scan in neonates treated with therapeutic hypothermia. Sanamed. 2022;17(1): 11-5. doi: 10.5937/sanamed17-36698.

Annink KV, de Vries LS, Groenendaal F, Vijlbrief DC, Weeke LC, Roehr CC et al. The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy. Pediatr Res. 2020; 87(Suppl 1): 59-66. doi: 10.1038/s41390-020-0782-0.

Alderliesten T, de Vries LS, Staats L, van Haastert IC, Weeke L, Benders MJ, et al. MRI and spectroscopy in (near) term neonates with perinatal asphyxia and therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2017; 102(2): 147- 52. doi: 10.1136/archdischild-2016-310514.

Alderliesten T, Nikkels PG, Benders MJ, de Vries LS, Groenendaal F. Antemortem cranial MRI compared with postmortem histopathologic examination of the brain in term infants with neonatal encephalopathy following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed. 2013; 98(4): 304-9. doi: 10.1136/archdischild-2012-301768.

Weeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, et al A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. J Pediatr. 2018; 192: 33-40. e2. doi: 10.1016/j.jpeds.2017.09.043.

Liu W, Yang Q, Wei H, Dong W, Fan Y, Hua Z. Prognostic value of clinical tests in neonates with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia: a systematic review and meta-analysis. Front Neurol. 2020;11:133. doi: 10.3389/fneur.2020.00133.

Hadders-Algra M. Early diagnostics and early intervention in neurodevelopmental disorders-age-dependent challenges and opportunities. J Clin Med. 2021;10(4):861. doi: 10.3390/jcm10040861.

Locci E, Bazzano G, Demontis R, Chighine A, Fanos V, d'Aloja E. Exploring perinatal asphyxia by metabolomics. Metabolites. 2020;10(4):141. doi: 10.3390/metabo10040141.

Thoresen M. Patient selection and prognostication with hypothermia treatment. Semin Fetal Neonatal Med. 2010;15(5):247-52. doi: 10.1016/j.siny.2010.05.008.

Elstad M, Whitelaw A, Thoresen M. Cerebral Resistance Index is less predictive in hypothermic encephalopathic newborns. ActaPaediatr. 2011;100(10):1344-9. doi: 10.1111/j.1651-2227.2011.02327.x.