{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:41:13Z","timestamp":1781286073390,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cSpecial Account for Research Grants\u201d of the University of West Attica, Athens, Greece"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case\u2013control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (&lt;34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case (n = 29) with a neonate who had a normal head ultrasound scan (n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life (p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II\u2013IV degree IVH and all other neonates (p = 0.003), and (c) between control and the five (n = 5) neonates that died from the case group (p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.<\/jats:p>","DOI":"10.3390\/biom14040434","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:58:38Z","timestamp":1712105918000},"page":"434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Serum Neuron-Specific Enolase as a Biomarker of Neonatal Brain Injury\u2014New Perspectives for the Identification of Preterm Neonates at High Risk for Severe Intraventricular Hemorrhage"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1788-3818","authenticated-orcid":false,"given":"Dimitra","family":"Metallinou","sequence":"first","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"},{"name":"School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grigorios","family":"Karampas","sequence":"additional","affiliation":[{"name":"Second Department of Obstetrics and Gynaecology, Aretaieio Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7011-7324","authenticated-orcid":false,"given":"Maria-Loukia","family":"Pavlou","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Ioanna","family":"Louma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Biotechnology, University of Thessaly, 41500 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6606-8647","authenticated-orcid":false,"given":"Aimilia","family":"Mantzou","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Medical School, Aghia Sophia Children\u2019s Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3316-8566","authenticated-orcid":false,"given":"Antigoni","family":"Sarantaki","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Nanou","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kleanthi","family":"Gourounti","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tzeli","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoletta","family":"Pantelaki","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Tzamakos","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Boutsikou","sequence":"additional","affiliation":[{"name":"Department of Neonatology, School of Medicine, Aretaieio Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Lykeridou","sequence":"additional","affiliation":[{"name":"Department of Midwifery, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Iacovidou","sequence":"additional","affiliation":[{"name":"Department of Neonatology, School of Medicine, Aretaieio Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1177\/1925362118821468","article-title":"Birth injury: Birth Asphyxia and Birth Trauma","volume":"8","author":"Collins","year":"2018","journal-title":"Acad. Forensic Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3389\/fped.2019.00142","article-title":"Neonatal Encephalopathy: Need for Recognition of Multiple Etiologies for Optimal Management","volume":"7","author":"Aslam","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1600-0609.2007.00971.x","article-title":"High prevalence of inherited thrombophilia in \u2018presumed peri-neonatal\u2019 ischemic stroke","volume":"80","author":"Suppiej","year":"2008","journal-title":"Eur. J. Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"634092","DOI":"10.3389\/fped.2021.634092","article-title":"Precision Medicine in Neonates: A Tailored Approach to Neonatal Brain Injury","volume":"9","author":"Tataranno","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.cca.2020.09.013","article-title":"S100B as a biomarker of brain injury in premature neonates. A prospective case\u2013control longitudinal study","volume":"510","author":"Metallinou","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_6","first-page":"8","article-title":"Neonatal periventricular leukomalacia: Current perspectives","volume":"2018","author":"Ahya","year":"2018","journal-title":"Res. Rep. Neonatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00381-017-3610-z","article-title":"A clinical scoring system to predict the development of intraventricular hemorrhage (IVH) in premature infants","volume":"34","author":"Coskun","year":"2018","journal-title":"Childs Nerv. Syst."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.1542\/neo.22-3-e148","article-title":"Neonatal Encephalopathy: Beyond Hypoxic-Ischemic Encephalopathy","volume":"22","author":"Russ","year":"2021","journal-title":"Neoreviews"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"664445","DOI":"10.3389\/fneur.2021.664445","article-title":"Biomarkers of Brain Damage\u2014A Complex Challenge with Great Potential","volume":"12","author":"Tenovuo","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1159\/000522617","article-title":"Prognostic Neurobiomarkers in Neonatal Encephalopathy","volume":"44","author":"Wassink","year":"2022","journal-title":"Dev. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1515\/cclm-2019-0725","article-title":"Early predictors of perinatal brain damage: The role of neurobiomarkers","volume":"58","author":"Bersani","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gazzolo, D., Pluchinotta, F., Bashir, M., Aboulgar, H., Said, H.M., Iman, I., Ivani, G., Conio, A., Tina, L.G., and Nigro, F. (2015). Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: The \u201cCooperative Multitask against Brain Injury of Neonates\u201d (CoMBINe) international study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0115194"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/B978-0-444-64029-1.00013-8","article-title":"Biomarkers in neonatal hypoxic\u2013ischemic encephalopathy\u2014Review of the literature to date and future directions for research","volume":"162","author":"Murray","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.26574\/maedica.2021.16.2.281","article-title":"Pharmacological and Non-Pharmacological Brain-Focused Clinical Practices for Premature Neonates at High Risk of Neuronal Injury","volume":"16","author":"Metallinou","year":"2021","journal-title":"Maedica"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"318","DOI":"10.4103\/1673-5374.317972","article-title":"Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy","volume":"17","author":"Arnaez","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Huang, H.Z., Hu, X.F., Wen, X.H., and Yang, L.Q. (2022). Serum neuron-specific enolase, magnetic resonance imaging, and electrophysiology for predicting neurodevelopmental outcomes of neonates with hypoxic-ischemic encephalopathy: A prospective study. BMC Pediatr., 22.","DOI":"10.1186\/s12887-022-03329-8"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Xu, C.M., Luo, Y.L., Li, S., Li, Z.X., Jiang, L., Zhang, G.X., Owusu, L., and Chen, H.L. (2019). Multifunctional neuron-specific enolase: Its role in lung diseases. Biosci. Rep., 39.","DOI":"10.1042\/BSR20192732"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Haque, A., Polcyn, R., Matzelle, D., and Banik, N.L. (2018). New Insights into the Role of Neuron-Specific Enolase in Neuro-Inflammation, Neurodegeneration, and Neuroprotection. Brain Sci., 8.","DOI":"10.3390\/brainsci8020033"},{"key":"ref_19","first-page":"46","article-title":"Serum glial fibrillary acidic protein as a biomarker of brain injury in premature neonates","volume":"22","author":"Metallinou","year":"2022","journal-title":"Bosn. J. Basic. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1620\/tjem.149.67","article-title":"Urine neuron-specific enolase and its clinical implication in patients with neuroblastoma","volume":"149","author":"Gotoh","year":"1986","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1203\/00006450-200204000-00015","article-title":"Expression in the Placenta of Neuronal Markers for Perinatal Brain Damage","volume":"51","author":"Wijnberger","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_22","first-page":"269","article-title":"Prognostic value of neuron specific enolase in serum for outcome of infants with birth asphyxia","volume":"22","author":"Attia","year":"2016","journal-title":"ZUMJ"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Perrone, S., Grassi, F., Caporilli, C., Boscarino, G., Carbone, G., Petrolini, C., Gambini, L.M., Di Peri, A., Moretti, S., and Buonocore, G. (2023). Brain Damage in Preterm and Full-Term Neonates: Serum Biomarkers for the Early Diagnosis and Intervention. Antioxidants, 12.","DOI":"10.3390\/antiox12020309"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kelen, D., Andorka, C., Szab\u00f3, M., Alafuzoff, A., Kaila, K., and Summanen, M. (2017). Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184593"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pedneo.2014.07.005","article-title":"Serum neuron-specific enolase levels in preterm and term newborns and in infants 1\u20133 months of age","volume":"56","author":"Abbasoglu","year":"2015","journal-title":"Pediatr. Neonatol."},{"key":"ref_26","first-page":"63","article-title":"Clinical efficacy of gangliosides on premature infants suffering from white matter damage and its effect on the levels of IL-6, NSE and S100\u03b2","volume":"18","author":"Wang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_27","first-page":"141","article-title":"Mobilization of circulating progenitor cells following brain injury in premature neonates could be indicative of an endogenous repair process. A pilot study","volume":"19","author":"Efstathiou","year":"2015","journal-title":"Hippokratia"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Metallinou, D., Karampas, G., Lazarou, E., Iacovidou, N., Pervanidou, P., Lykeridou, K., Mastorakos, G., and Rizos, D. (2021). Serum Activin A as Brain Injury Biomarker in the First Three Days of Life. A Prospective Case\u2014Control Longitudinal Study in Human Premature Neonates. Brain Sci., 11.","DOI":"10.3390\/brainsci11091243"},{"key":"ref_29","unstructured":"(2024, March 19). European Foundation for the Care of Newborn Infants. Available online: https:\/\/newborn-health-standards.org\/standards\/standards-english\/medical-care-clinical-practice\/neurological-monitoring-in-the-high-risk-infant-ultrasound-and-mri-scanning\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0022-3476(78)80282-0","article-title":"Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm","volume":"92","author":"Papile","year":"1978","journal-title":"J. Pediatr."},{"key":"ref_31","first-page":"57","article-title":"Prevalence and risk factors for periventricular leukomalacia in preterm infants. A systematic review","volume":"65","year":"2017","journal-title":"Rev. Neurol."},{"key":"ref_32","unstructured":"Efstathiou, N., Kyriazis, G., Bougiouklis, D., Drossou, V., and Soumbasi, V. (2012, January 5\u20139). Circulating progenitor cells in preterm neonates with CNS injury\u2014A preliminary report. Proceedings of the 4th Congress of the European Academy of Paediatric Societies (EAPS), Istanbul, Turkey."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.pediatrneurol.2012.10.010","article-title":"Pluripotent possibilities: Human umbilical cord blood cell treatment after neonatal brain injury","volume":"48","author":"Verina","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dhama, K., Latheef, S.K., Dadar, M., Samad, H.A., Munjal, A., Khandia, R., Karthik, K., Tiwari, R., Yatoo, M., and Bhatt, P. (2019). Biomarkers in Stress Related Diseases\/Disorders: Diagnostic, Prognostic, and Therapeutic Values. Front. Mol. Biosci., 6.","DOI":"10.3389\/fmolb.2019.00091"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.18410\/jebmh\/2016\/781","article-title":"Study of neuron specific enolase (NSE) in perinatal asphyxia & its role as an early marker of brain injury","volume":"3","author":"Paliwal","year":"2016","journal-title":"J. Evid. Based Med. Healthc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.neuroimage.2018.07.057","article-title":"Neonatal brain injury and aberrant connectivity","volume":"185","author":"Smyser","year":"2019","journal-title":"Neuroimage"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.nicl.2017.08.015","article-title":"Clinical neuroimaging in the preterm infant: Diagnosis and prognosis","volume":"16","author":"Harmony","year":"2017","journal-title":"Neuroimage Clin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1212\/WNL.58.12.1726","article-title":"Practice parameter: Neuroimaging of the neonate: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society","volume":"58","author":"Ment","year":"2002","journal-title":"Neurology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.clp.2018.05.004","article-title":"Neuroimaging for Neurodevelopmental Prognostication in High-Risk Neonates","volume":"45","author":"Sewell","year":"2018","journal-title":"Clin. Perinatol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/4\/434\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:22:43Z","timestamp":1760106163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/4\/434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["biom14040434"],"URL":"https:\/\/doi.org\/10.3390\/biom14040434","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]}}}