REVIEW

Recent advances in diagnostics of neonatal hypoxic ischemic encephalopathy

Starodubtseva NL, Eldarov ChM, Kirtbaya AR, Balashova EN, Gryzunova AS, Ionov OV, Zubkov VV, Silachev DN
About authors

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia

Correspondence should be addressed: Denis N. Silachev
Akademika Oparina, 4, Moscow, 117997, Russia; ur.4anirapo@vehcalis_d

About paper

Funding: the study was supported by the Russian Science Foundation grant number 22-15-00454; https://rscf.ru/project/22-15-00454/

Author contribution: Starodubtseva NL, Eldarov ChM, Kirtbaya AR, Balashova EN, Gryzunova AS, Ionov OV, Zubkov VV and Silachev DN — literature analysis, manuscript writing and editing.

Received: 2022-07-06 Accepted: 2022-07-20 Published online: 2022-07-29
|
  1. Manuck TA, Rice MM, Bailit JL, Grobman WA, Reddy UM, Wapner RJ, et al. Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. Am J Obstet Gynecol. 2016 [cited 2022 Jun 28]; 215 (1): 103.e1–103.e14. Available from: https:// pubmed.ncbi.nlm.nih.gov/26772790/.
  2. Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Pædiatrica. 1995 [cited 2022 Jun 28]; 84 (8): 927–32. Available from: https://pubmed.ncbi.nlm.nih.gov/7488819/.
  3. Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: a population-based register study of 1 million term births. Obstet Gynecol. 2001 [cited 2022 Jun 28]; 98 (1): 65–70. Available from: https://pubmed.ncbi.nlm.nih.gov/11430958/.
  4. Volpe JJ. Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol. 2012 [cited 2022 Jun 28]; 72 (2): 156–66. Available from: https://pubmed.ncbi.nlm. nih.gov/22926849/.
  5. Lawn J, Shibuya K, Stein C. No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths. Bull World Health Organ. 2005 [cited 2022 Jun 28]; 83 (6): 409. Available from: https://pmc/articles/PMC2626256/?report=abstract.
  6. Hoehn T, Hansmann G, Bührer C, Simbruner G, Gunn AJ, Yager J, et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation. 2008 [cited 2022 Jun 28]; 78 (1): 7–12. Available from: https:// pubmed.ncbi.nlm.nih.gov/18554560/.
  7. Okereafor A, Allsop J, Counsell SJ, Fitzpatrick J, Azzopardi D, Rutherford MA, et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics. 2008 [cited 2022 Jun 28]; 121 (5): 906–14. Available from: https://pubmed.ncbi.nlm.nih. gov/18450893/.
  8. Long M, Brandon DH. Induced hypothermia for neonates with hypoxic-ischemic encephalopathy. J Obstet Gynecol neonatal Nurs JOGNN. 2007 [cited 2022 Jun 28]; 36 (3): 293–8. Available from: https://pubmed.ncbi.nlm.nih.gov/17489937/.
  9. Pierrat V, Haouari N, Liska A, Thomas D, Subtil D, Truffert P. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. Arch Dis Child Fetal Neonatal Ed. 2005 [cited 2022 Jun 28];90(3). Available from: https://pubmed.ncbi.nlm.nih.gov/15846019/.
  10. Lee ACC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, et al. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatr Res. 2013 [cited 2022 Jun 28]; 74 Suppl 1(Suppl 1): 50–72. Available from: https://pubmed.ncbi.nlm.nih. gov/24366463/.
  11. Wang LS, Cheng GQ, Zhou WH, Sun JQ, Cao Y, Shao XM. Metaanalysis of mild hypothermia for gestational age over 35-week newborns with hypoxic- ischemic encephalopathy. Natl Med J China. 2012 [cited 2022 Jun 28]; 92 (20): 1400–4. Available from: https://pubmed.ncbi.nlm.nih.gov/22883198/.
  12. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010 [cited 2022 Jun 28]; 340 (7743): 409. Available from: https:// pubmed.ncbi.nlm.nih.gov/20144981/.
  13. Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, et al. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed. 2018 [cited 2022 Jun 28]; 103 (4): F1–3. Available from: https://pubmed.ncbi.nlm.nih.gov/28942433/.
  14. Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, et al. Prospective research on infants with mild encephalopathy: The PRIME study. Journal of Perinatology. J Perinatol. 2018 [cited 2022 Jun 28]; 38: 80–5. Available from: https://pubmed.ncbi.nlm. nih.gov/29095433/.
  15. 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 [cited 2022 Jun 28]; 84 (6): 861–8. Available from: https:// pubmed.ncbi.nlm.nih.gov/30250303/.
  16. Murray DM, O’Connor CM, Anthony Ryan C, Korotchikova I, Boylan GB. Early EEG Grade and Outcome at 5 Years After Mild Neonatal Hypoxic Ischemic Encephalopathy. Pediatrics. 2016 [cited 2022 Jun 28]; 138 (4). Available from: https://pubmed.ncbi. nlm.nih.gov/27650049/.
  17. Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome — A systematic review. Early Hum Dev. 2018 [cited 2022 Jun 28]; 120: 80–7. Available from: https://pubmed.ncbi.nlm.nih.gov/29496329/.
  18. Nanavati T, Seemaladinne N, Regier M, Yossuck P, Pergami P. Can We Predict Functional Outcome in Neonates with Hypoxic Ischemic Encephalopathy by the Combination of Neuroimaging and Electroencephalography? Pediatr Neonatol. 2015 [cited 2022 Jun 28]; 56 (5): 307–16. Available from: https://pubmed.ncbi.nlm. nih.gov/25862075/.
  19. Polat M, Şimşek A, Tansuǧ N, Sezer RG, Özkol M, Başpinar P, et al. Prediction of neurodevelopmental outcome in term neonates with hypoxic-ischemic encephalopathy. Eur J Paediatr Neurol. 2013 [cited 2022 Jun 28];17 (3): 288–93. Available from: https: // pubmed.ncbi.nlm.nih.gov/23231917/.
  20. Shellhaas RA, Kushwaha JS, Plegue MA, Selewski DT, Barks JDE. An Evaluation of Cerebral and Systemic Predictors of 18-Month Outcomes for Neonates With Hypoxic Ischemic Encephalopathy. J Child Neurol. 2015 [cited 2022 Jun 28]; 30 (11): 1526–31. Available from: https://pubmed.ncbi.nlm.nih.gov/25724376/.
  21. Chang T, Du Plessis A. Neurodiagnostic techniques in neonatal critical care. Curr Neurol Neurosci Rep. 2012 [cited 2022 Jun 29]; 12 (2):145–52. Available from: https://pubmed.ncbi.nlm.nih.gov/22318538/.
  22. Van Laerhoven H, De Haan TR, Offringa M, Post B, Van Der Lee JH. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics. 2013 [cited 2022 Jun 29]; 131 (1): 88–98. Available from: https://pubmed. ncbi.nlm.nih.gov/23248219/.
  23. Rasmussen LA, Cascio MA, Ferrand A, Shevell M, Racine E. The complexity of physicians’ understanding and management of prognostic uncertainty in neonatal hypoxic-ischemic encephalopathy. J Perinatol. 2019 [cited 2022 Jun 29]; 39 (2): 278–85. Available from: https://pubmed.ncbi.nlm.nih. gov/30568164/.
  24. Natarajan N, Pardo AC. Challenges in neurologic prognostication after neonatal brain injury. Semin Perinatol. 2017 [cited 2022 Jun 29]; 41 (2): 117–23. Available from: https://pubmed.ncbi.nlm.nih. gov/28139254/.
  25. Merchant N, Azzopardi D. Early predictors of outcome in infants treated with hypothermia for hypoxic-ischaemic encephalopathy. Dev Med Child Neurol. 2015 [cited 2022 Jun 29]; 57 (S3): 8–16. Available from: https://pubmed.ncbi.nlm.nih.gov/25800487/.
  26. Merhar SL, Chau V. Neuroimaging and Other Neurodiagnostic Tests in Neonatal Encephalopathy. Clin Perinatol. 2016 [cited 2022 Jun 29]; 43 (3): 511–27. Available from: https://pubmed.ncbi.nlm.nih.gov/27524451/.
  27. Del Río R, Ochoa C, Alarcon A, Arnáez J, Blanco D, García-Alix A. Amplitude integrated electroencephalogram as a prognostic tool in neonates with hypoxic-ischemic encephalopathy: A systematic review. PLoS One. 2016 [cited 2022 Jun 29]; 11 (11). Available from: https://pubmed.ncbi.nlm.nih.gov/27802300/.
  28. Mizrahi EM. Neonatal seizures and neonatal epileptic syndromes. Neurol Clin. 2001 [cited 2022 Jun 29]; 19 (2): 427–63. Available from: https://pubmed.ncbi.nlm.nih.gov/11358751/.
  29. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2008 [cited 2022 Jun 29]; 93 (3). Available from: https://pubmed.ncbi.nlm.nih.gov/17626147/.
  30. Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia. 1988 [cited 2022 Jun 29]; 29 (3): 256–61. Available from: https://pubmed.ncbi.nlm.nih.gov/3371282/.
  31. Weeke LC, Boylan GB, Pressler RM, Hallberg B, Blennow M, Toet MC, et al. Role of EEG background activity, seizure burden and MRI in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischaemic encephalopathy in the era of therapeutic hypothermia. Eur J Paediatr Neurol. 2016 [cited 2022 Jun 28]; 20 (6): 855–64. Available from: https://pubmed.ncbi.nlm.nih. gov/27370316/.
  32. Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi D, Ballard R, et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr. 2008 [cited 2022 Jun 29]; 152 (1). Available from: https://pubmed.ncbi.nlm.nih.gov/18154900/.
  33. Boudes E, Tan X, Saint-Martin C, Shevell M, Wintermark P. MRI obtained during versus after hypothermia in asphyxiated newborns. Arch Dis Child Fetal Neonatal Ed. 2015 [cited 2022 Jun 29]; 100 (3): F238–42. Available from: https://pubmed.ncbi. nlm.nih.gov/25605620/.
  34. Bonifacio SL, deVries LS, Groenendaal F. Impact of hypothermia on predictors of poor outcome: how do we decide to redirect care? Semin Fetal Neonatal Med. 2015 [cited 2022 Jun 29]; 20 (2): 122–7. Available from: https://pubmed.ncbi.nlm.nih.gov/25577654/.
  35. Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013 [cited 2022 Jun 29]; 104 (3): 228–33. Available from: https://pubmed.ncbi.nlm.nih.gov/24030160/.
  36. Basu SK, Kaiser JR, Guffey D, Minard CG, Guillet R, Gunn AJ. Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: A post hoc analysis of the CoolCap Study. Arch Dis Child Fetal Neonatal Ed. 2016 [cited 2022 Jun 29]; 101 (2): F149–55. Available from: https://pubmed.ncbi.nlm.nih. gov/26283669/.
  37. Shah DK, Wusthoff CJ, Clarke P, Wyatt JS, Ramaiah SM, Dias RJ, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014 [cited 2022 Jun 29]; 99 (3). Available from: https://pubmed.ncbi.nlm.nih.gov/24443407/.
  38. Sabir H, Jary S, Tooley J, Liu X, Thoresen M. Increased inspired oxygen in the first hours of life is associated with adverse outcome in newborns treated for perinatal asphyxia with therapeutic hypothermia. J Pediatr. 2012 [cited 2022 Jun 29]; 161 (3): 409– 16. Available from: https://pubmed.ncbi.nlm.nih.gov/22521111/.
  39. Osredkar D, Thoresen M, Maes E, Flatebø T, Elstad M, Sabir H. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation. 2014 [cited 2022 Jun 29]; 85 (4): 567–72. Available from: https://pubmed. ncbi.nlm.nih.gov/24361672/.
  40. Uziel G, Ghezzi D, Zeviani M. Infantile mitochondrial encephalopathy. Seminars in Fetal and Neonatal Medicine. Semin Fetal Neonatal Med. 2011 [cited 2022 Jun 29]; 16: 205–15. Available from: https://pubmed.ncbi.nlm.nih.gov/21620787/.
  41. Bruyland M, Liebaers I, Sacre L, Vandeplas Y, De Meirleir L, Martin JJ. Neonatal myotubular myopathy with a probable X-linked inheritance: observations on a new family with a review of the literature. J Neurol. 1984 [cited 2022 Jun 29]; 231 (4): 220–2. Available from: https://pubmed.ncbi.nlm.nih.gov/6512577/.
  42. Danti FR, Galosi S, Romani M, Montomoli M, Carss KJ, Lucy Raymond F, et al. GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome. Neurol Genet. 2017 [cited 2022 Jul 4]; 3 (2). Available from: https://pubmed. ncbi.nlm.nih.gov/28357411/.
  43. Solis GP, Kozhanova TV, Koval A, Zhilina SS, Mescheryakova TI, Abramov AA, et al. Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease. Cells. 2021 [cited 2022 Jul 4]; 10 (10). Available from: https://pubmed.ncbi.nlm.nih.gov/34685729/.
  44. Cuzzolin L, Zaccaron A, Fanos V. Unlicensed and off-label uses of drugs in paediatrics: a review of the literature. Fundam Clin Pharmacol. 2003 [cited 2022 Jun 30]; 17 (1): 125–31. Available from: https://pubmed.ncbi.nlm.nih.gov/12588640/.
  45. Robertson NJ, Thayyil S, B. Cady E, Raivich G. Magnetic resonance spectroscopy biomarkers in term perinatal asphyxial encephalopathy: from neuropathological correlates to future clinical applications. Curr Pediatr Rev. 2014 [cited 2022 Jun 30]; 10 (1): 37–47. Available from: https://pubmed.ncbi.nlm.nih.gov/25055862/.
  46. Massaro AN, Chang T, Kadom N, Tsuchida T, Scafidi J, Glass P, et al. Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia. J Pediatr. 2012 [cited 2022 Jun 30]; 161 (3): 434– 40. Available from: https://pubmed.ncbi.nlm.nih.gov/22494878/.
  47. Jones R, Heep A, Odd D. Biochemical and clinical predictors of hypoxic-ischemic encephalopathy after perinatal asphyxia. J Matern Fetal Neonatal Med. 2018 [cited 2022 Jun 30]; 31 (6): 791– 6. Available from: https://pubmed.ncbi.nlm.nih.gov/28274150/.
  48. Fatemi A, Wilson MA, Johnston M V. Hypoxic-Ischemic Encephalopathy in the Term Infant [Internet]. Clinics in Perinatology. Clin Perinatol. 2009 [cited 2022 Jun 30]; 36: 835–58. Available from: https://pubmed.ncbi.nlm.nih.gov/19944838/.
  49. Ennen CS, Huisman TAGM, Savage WJ, Northington FJ, Jennings JM, Everett AD, et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. Am J Obstet Gynecol. 2011 [cited 2022 Jun 30]; 205 (3): 251.e1-251.e7. Available from: https://pubmed. ncbi.nlm.nih.gov/21784396/.
  50. Kim HJ, Tsao JW, Stanfill AG. The current state of biomarkers of mild traumatic brain injury. JCI insight. 2018 [cited 2022 Jun 30]; 3 (1). Available from: https://pubmed.ncbi.nlm.nih.gov/29321373/.
  51. Orrock JE, Panchapakesan K, Vezina G, Chang T, Harris K, Wang Y, et al. Association of brain injury and neonatal cytokine response during therapeutic hypothermia in newborns with hypoxicischemic encephalopathy. Pediatr Res. Available from: https:// pubmed.ncbi.nlm.nih.gov/26717001/.
  52. Tann CJ, Martinello KA, Sadoo S, Lawn JE, Seale AC, VegaPoblete M, et al. Neonatal Encephalopathy With Group B Streptococcal Disease Worldwide: Systematic Review, Investigator Group Datasets, and Meta-analysis. Clin Infect Dis. 2017 [cited 2022 Jun 30]; 65 (suppl_2): S173–89. Available from: https://pubmed.ncbi.nlm.nih.gov/29117330/.
  53. Murray DM. Biomarkers in neonatal hypoxic-ischemic encephalopathy-Review of the literature to date and future directions for research. Handb Clin Neurol. 2019 [cited 2022 Jun 30]; 162: 281–93. Available from: https://pubmed.ncbi.nlm.nih. gov/31324315/.
  54. Alkholy UM, Abdalmonem N, Zaki A, Ali YF, Mohamed SA, Abdelsalam NI, et al. Early predictors of brain damage in full-term newborns with hypoxic ischemic encephalopathy. Neuropsychiatr Dis Treat. 2017 [cited 2022 Jun 30]; 13: 2133–9. Available from: https://pubmed.ncbi.nlm.nih.gov/28860770/.
  55. Douglas-Escobar M, Weiss MD. Biomarkers of brain injury in the premature infant. Front Neurol; 2013 [cited 2022 Jun 30]; 3 JAN. Available from: https://pubmed.ncbi.nlm.nih.gov/23346073/.
  56. Massaro AN, Wu YW, Bammler TK, Comstock B, Mathur A, McKinstry RC, et al. Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2018 [cited 2022 Jun 30]; 194: 67–75.e1. Available from: https://pubmed.ncbi.nlm. nih.gov/29478510/.
  57. Shah DK, Ponnusamy V, Evanson J, Kapellou O, Ekitzidou G, Gupta N, et al. Raised plasma neurofilament light protein levels are associated with abnormal MRI outcomes in newborns undergoing therapeutic hypothermia. Front Neurol. 2018 [cited 2022 Jun 30]; 9 (MAR). Available from: https://pubmed.ncbi.nlm.nih.gov/29556208/.
  58. Sweetman DU, Onwuneme C, Watson WR, Murphy JFA, Molloy EJ. Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses. Neonatology. 2017 [cited 2022 Jul 4]; 111 (3): 253–9. Available from: https://pubmed.ncbi. nlm.nih.gov/27902983/.
  59. Lv H, Wang Q, Wu S, Yang L, Ren P, Yang Y, et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta. 2015 [cited 2022 Jul 4]; 450: 282–97. Available from: https://pubmed.ncbi.nlm.nih. gov/26320853/.
  60. Hasslacher J, Lehner GF, Harler U, Beer R, Ulmer H, Kirchmair R, et al. Secretoneurin as a marker for hypoxic brain injury after cardiopulmonary resuscitation. Intensive Care Med. 2014 [cited 2022 Jul 4]; 40 (10): 1518–27. Available from: https://pubmed. ncbi.nlm.nih.gov/25138227/.
  61. Risso FM, Sannia A, Gavilanes DAW, Vles HJ, Colivicchi M, Ricotti A, et al. Biomarkers of brain damage in preterm infants. J Matern Fetal Neonatal Med. 2012 [cited 2022 Jul 4]; 25 (SUPPL.4): 93–6. Available from: https://pubmed.ncbi.nlm.nih.gov/22958034/.
  62. Chaparro-Huerta V, Flores-Soto ME, Merin Sigala ME, Barrera de León JC, Lemus-Varela M de L, Torres-Mendoza BM de G, et al. Proinflammatory Cytokines, Enolase and S-100 as Early Biochemical Indicators of Hypoxic-Ischemic Encephalopathy Following Perinatal Asphyxia in Newborns. Pediatr Neonatol. 2017 [cited 2022 Jul 4]; 58 (1): 70–6. Available from: https:// pubmed.ncbi.nlm.nih.gov/27522459/.
  63. Chalak LF, Sánchez PJ, Adams-Huet B, Laptook AR, Heyne RJ, Rosenfeld CR. Biomarkers for severity of neonatal hypoxicischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr. 2014 [cited 2022 Jul 4]; 164 (3). Available from: https://pubmed.ncbi.nlm.nih.gov/24332821/.
  64. Chiesa C, Pellegrini G, Panero A, De Luca T, Assumma M, Signore F, et al. Umbilical cord interleukin-6 levels are elevated in term neonates with perinatal asphyxia. Eur J Clin Invest. 2003 [cited 2022 Jul 4]; 33 (4): 352–8. Available from: https://pubmed.ncbi. nlm.nih.gov/12662167/.
  65. Jenkins DD, Rollins LG, Perkel JK, Wagner CL, Katikaneni LP, Bass WT, et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2012 [cited 2022 Jul 4]; 32 (10): 1888–96. Available from: https://pubmed.ncbi.nlm.nih.gov/22805873/.
  66. Hou X, Yuan Z, Wang X, Cheng R, Zhou X, Qiu J. Peptidome analysis of cerebrospinal fluid in neonates with hypoxic-ischemic brain damage. Mol Brain. 2020 [cited 2022 Jul 4]; 13 (1). Available from: https://pubmed.ncbi.nlm.nih.gov/33008433/.
  67. Zhu Y, Yun Y, Jin M, Li G, Li H, Miao P, et al. Identification of novel biomarkers for neonatal hypoxic-ischemic encephalopathy using iTRAQ. Ital J Pediatr. 2020 [cited 2022 Jul 4]; 46 (1). Available from: https://pubmed.ncbi.nlm.nih.gov/32448169/.
  68. Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood. 2005 [cited 2022 Jul 4]; 105 (7): 2955–62. Available from: https:// pubmed.ncbi.nlm.nih.gov/15598812/.
  69. Ehrchen JM, Sunderkötter C, Foell D, Vogl T, Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol. 2009 [cited 2022 Jul 4]; 86 (3): 557–66. Available from: https://pubmed.ncbi.nlm.nih.gov/19451397/.
  70. Zhao X, Song S, Sun G, Strong R, Zhang J, Grotta JC, et al. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci. 2009 [cited 2022 Jul 4]; 29 (50): 15819– 27. Available from: https://pubmed.ncbi.nlm.nih.gov/20016097/.
  71. Zhou Y, Bhatia I, Cai Z, He QY, Cheung PT, Chiu JF. Proteomic analysis of neonatal mouse brain: Evidence for hypoxia- and ischemia-induced dephosphorylation of collapsin response mediator proteins. J Proteome Res. 2008 [cited 2022 Jul 4]; 7 (6): 2507–15. Available from: https://pubmed.ncbi.nlm.nih. gov/18471005/.
  72. Solberg R, Kuligowski J, Pankratov L, Escobar J, Quintás G, Lliso I, et al. Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air. Pediatr Res. 2016 [cited 2022 Jul 4]; 80 (2): 284–92. Available from: https://pubmed.ncbi.nlm.nih.gov/27055187/.
  73. Li H, Kittur FS, Hung CY, Li PA, Ge X, Sane DC, et al. Quantitative Proteomics Reveals the Beneficial Effects of Low Glucose on Neuronal Cell Survival in an in vitro Ischemic Penumbral Model. Front Cell Neurosci. 2020 [cited 2022 Jul 4]; 14. Available from: https://pubmed.ncbi.nlm.nih.gov/33033473/.
  74. Shi Y, Cai EL, Yang C, Ye CY, Zeng P, Wang XM, et al. Protection of melatonin against acidosis-induced neuronal injuries. J Cell Mol Med. 2020 [cited 2022 Jul 4]; 24 (12): 6928–42. Available from: https://pubmed.ncbi.nlm.nih.gov/32364678/.
  75. Bjerkhaug AU, Granslo HN, Klingenberg C. Metabolic responses in neonatal sepsis-A systematic review of human metabolomic studies. Acta Paediatr. 2021 [cited 2022 Jun 29]; 110 (8): 2316– 25. Available from: https://pubmed.ncbi.nlm.nih.gov/33851423/.
  76. Beckstrom AC, Ricca RL, Gow KW, McAdams RM. Persistent posterior pneumomediastinum in a neonate. Pediatr Int. 2012 [cited 2022 Jul 4]; 54 (3): 441–2. Available from: https://pubmed.ncbi.nlm.nih.gov/22631580/.
  77. Nicholson JK, Lindon JC. Systems biology: Metabonomics. Nature. 2008 [cited 2022 Jul 4]; 455 (7216): 1054–6. Available from: https://pubmed.ncbi.nlm.nih.gov/18948945/.
  78. Atzori L, Antonucci R, Barberini L, Griffin JL, Fanos V. Metabolomics: a new tool for the neonatologist. J Matern Fetal Neonatal Med. 2009 [cited 2022 Jul 4]; 22 (SUPPL. 3): 50–3. Available from: https://pubmed.ncbi.nlm.nih.gov/19701858/.
  79. Locci E, Noto A, Puddu M, Pomero G, Demontis R, Dalmazzo C, et al. A longitudinal 1H-NMR metabolomics analysis of urine from newborns with hypoxic-ischemic encephalopathy undergoing hypothermia therapy. Clinical and medical legal insights. PLoS One. 2018 [cited 2022 Jul 4]; 13 (4). Available from: https:// pubmed.ncbi.nlm.nih.gov/29668681/.
  80. Sarafidis K, Efstathiou N, Begou O, Soubasi V, Agakidou E, Gika E, et al. Urine metabolomic profile in neonates with hypoxic-ischemic encephalopa-thy. Hippokratia. 2017 [cited 2022 Jul 4]; 21 (2): 80. Available from: /pmc/articles/PMC6239088/.
  81. Denihan NM, Kirwan JA, Walsh BH, Dunn WB, Broadhurst DI, Boylan GB, et al. Untargeted metabolomic analysis and pathway discovery in perinatal asphyxia and hypoxic-ischaemic encephalopathy. J Cereb Blood Flow Metab. 2019 [cited 2022 Jul 4]; 39 (1): 147–62. Available from: /pmc/articles/PMC6311668/.
  82. Jia Y, Jia X, Xu H, Gao L, Wei C, Li Y, et al. Blood Plasma Metabolic Profile of Newborns with Hypoxic-Ischaemic Encephalopathy by GC-MS. Biomed Res Int. 2021 [cited 2022 Jul 4]; 2021. Available from: https://pubmed.ncbi.nlm.nih.gov/34258280/.
  83. Reinke SN, Walsh BH, Boylan GB, Sykes BD, Kenny LC, Murray DM, et al. 1H NMR derived metabolomic profile of neonatal asphyxia in umbilical cord serum: implications for hypoxic ischemic encephalopathy. J Proteome Res. 2013 [cited 2022 Jul 4]; 12 (9): 4230–9. Available from: https://pubmed.ncbi.nlm.nih.gov/23931672/.
  84. Longini M, Giglio S, Perrone S, Vivi A, Tassini M, Fanos V, et al. Proton nuclear magnetic resonance spectroscopy of urine samples in preterm asphyctic newborn: a metabolomic approach. Clin Chim Acta. 2015 [cited 2022 Jul 4]; 444: 250–6. Available from: https://pubmed.ncbi.nlm.nih.gov/25727514/.
  85. Johnston M V. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005 [cited 2022 Jul 4]; 15 (3): 234–40. Available from: https:// pubmed.ncbi.nlm.nih.gov/16196390/.
  86. Pietz J, Guttenberg N, Gluck L. Hypoxanthine: a marker for asphyxia. Obstet Gynecol. 1988 [cited 2022 Jul 4]; 72 (5): 762–6. Available from: https://pubmed.ncbi.nlm.nih.gov/3140152/.
  87. Penry JT, Manore MM. Choline: An important micronutrient for maximal endurance-exercise performance? Int J Sport Nutr Exerc Metab. 2008 [cited 2022 Jul 4]; 18: 191–203. Available from: https://pubmed.ncbi.nlm.nih.gov/18458362/.
  88. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013 [cited 2022 Jul 4]; 200 (4): 373–83. Available from: https://pubmed.ncbi.nlm.nih.gov/23420871/.
  89. Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R. Emerging role of neuronal exosomes in the central nervous system. Front Physiol. 2012 [cited 2022 Jul 4]; 3. Available from: https://pubmed.ncbi.nlm.nih.gov/22654762/.
  90. Chiva-Blanch G, Suades R, Crespo J, Peña E, Padró T, JiménezXarrié E, et al. Microparticle Shedding from Neural Progenitor Cells and Vascular Compartment Cells Is Increased in Ischemic Stroke. PLoS One. 2016 [cited 2022 Jul 4]; 11 (1). Available from: https://pubmed.ncbi.nlm.nih.gov/26815842/.
  91. Patz S, Trattnig C, Grünbacher G, Ebner B, Gülly C, Novak A, et al. More than cell dust: microparticles isolated from cerebrospinal fluid of brain injured patients are messengers carrying mRNAs, miRNAs, and proteins. J Neurotrauma. 2013 [cited 2022 Jul 4]; 30 (14): 1232–42. Available from: https://pubmed.ncbi.nlm.nih. gov/23360174/.
  92. Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, et al. Low neural exosomal levels of cellular survival factors in Alzheimer’s disease. Ann Clin Transl Neurol. 2015 [cited 2022 Jul 4]; 2 (7): 769–73. Available from: https://pubmed.ncbi.nlm.nih. gov/26273689/.
  93. Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015 [cited 2022 Jul 4]; 85 (1): 40–7. Available from: https://pubmed.ncbi.nlm.nih. gov/26062630/.
  94. Silachev DN, Goryunov KV, Plotnikov EY, Shevtsova YA, Babenko VA, Burov AA, et al. Urinary extracellular vesicles as markers for kidney diseases. Pediatria n.a. G.N. Speransky. 2020 [cited 2022 Jul 4]; 99 (5): 154–63. Available from: https://pediatriajournal.ru/ archive?show=378§ion=6017. Russian.
  95. Goetzl L, Merabova N, Darbinian N, Martirosyan D, Poletto E, Fugarolas K, et al. Diagnostic Potential of Neural Exosome Cargo as Biomarkers for Acute Brain Injury. Ann Clin Transl Neurol. 2018 [cited 2022 Jul 4]; 5 (1): 4–10. Available from: https://pubmed. ncbi.nlm.nih.gov/29376087/.
  96. Pineles B, Mani A, Sura L, Rossignol C, Albayram M, Weiss MD, et al. Neuronal exosome proteins: novel biomarkers for predicting neonatal response to therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2022 [cited 2022 Jul 4]; 107 (1): F60–4. Available from: https://pubmed.ncbi.nlm.nih.gov/34021027/.
  97. Chen S, Chen XC, Lou XH, Qian SQ, Ruan ZW. Determination of serum neutrophil gelatinase-associated lipocalin as a prognostic biomarker of acute spontaneous intracerebral hemorrhage. Clin Chim Acta. 2019 [cited 2022 Jul 4]; 492: 72–7. Available from: https://pubmed.ncbi.nlm.nih.gov/30771300/.
  98. Plotnikov EY, Silachev DN, Pavlenko TA, Pavlova VS, Kryukov DS, Zubkov VV, et al. Acute kidney injury in newborns. From experiment to clinic. Neonatologiya. 2017; (4): 58–63. Russian.
  99. Xu D, Hopf C, Reddy R, Cho RW, Guo L, Lanahan A, et al. Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron. 2003 [cited 2022 Jul 4]; 39 (3): 513–28. Available from: https://pubmed.ncbi.nlm.nih.gov/12895424/.