Advertisement

The Ca2+-Binding S100B Protein: An Important Diagnostic and Prognostic Neurobiomarker in Pediatric Laboratory Medicine

  • Diego Gazzolo
  • Francesca Pluchinotta
  • Giuseppe Lapergola
  • Simone Franchini
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1929)

Abstract

In recent decades a significant scientific effort has focused on projects regarding the use of neurobiomarkers in perinatal medicine with a view to understanding the mechanisms that interfere with physiological patterns of brain development and lead to ominous effects in several human diseases. Numerous potential neurobiomarkers have been proposed for use in monitoring high-risk fetuses and newborns, including markers of oxidative stress, neuroproteins, and vasoactive agents. Nonetheless, the use of these markers in clinical practice remains a matter of debate. Recently, the calcium-binding S100B protein has been proposed as being an ideal neurobiomarker, thanks to its simple availability and easy reproducibility, to the possibility of detecting it noninvasively in biological fluids with good reproducibility, and to the possibility of a longitudinal evaluation in relation to reference curves. The present chapter contains an overview of the most significant studies on the assessment of S100B in different biological fluids as a trophic factor and/or marker of brain damage in high-risk fetuses and newborns.

Key words

S100B Fetus Newborn Brain IUGR Perinatal asphyxia Congenital heart disease Biomarker Calcium-binding protein EF hand 

References

  1. 1.
    Douglas-Escobar M, Weiss MD (2015) Hypoxic-ischemic encephalopathy – a review for the clinician. JAMA Pediatr 169(4):397–403PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Kuschinsky W, Wahl M (1978) Local chemical and neurogenic regulation of cerebral vascular resistance. Physiol Res 58:656Google Scholar
  3. 3.
    Lassen NA, Christensen MS (1976) Physiology of cerebral blood flow. Br J Anaesth 48:719–734PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Paulson OB, Strandgaard S, Edvinsson L (1990) Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2:161–192PubMedPubMedCentralGoogle Scholar
  5. 5.
    Florence G, Seylaz J (1992) Rapid autoregulation of cerebral blood flow: a laser-Doppler flowmetry study. J Cereb Blood Flow Metab 12:674–680PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    MacKenzie ET, Strandgaard S, Graham DI et al (1976) Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res 39:33–41PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Mchedlishvili GI, Nikolaishvili LS, Antia RV (1976) Are the pial arterial responses dependent on the direct effect of intravascular pressure and extravascular and intravascular pO2, pCO2, and pH? Microvasc Res 10:298–311CrossRefGoogle Scholar
  8. 8.
    Rubanyi GM, Botelho LH (1991) Endothelins. FASEB J 5:2713–2720PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Faraci FM (1991) Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 26:H1038–H1042Google Scholar
  10. 10.
    Greenberg DA, Chan J, Sampson HA (1992) Endothelins and the nervous system. Neurology 42:25–31PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Harteman JC, Nikkels PG, Benders MJ et al (2013) Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury. J Pediatr 163(4):968–995.e2PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Wassink G, Gunn ER, Drury PP et al (2014) The mechanisms and treatment of asphyxia encephalopathy. Front Neurosci 8:40.  https://doi.org/10.3389/fnins.2014.00040CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ferriero DM (2004) Neonatal brain injury. N Engl J Med 351(19):1985–1995PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Bennet L, Roelfsema V, Pathipati P et al (2006) Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep. J Physiol 572(pt 1):141–154PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Bennet L, Tan S, Van den Heuij L et al (2012) Cell therapy for neonatal hypoxia-ischemia and cerebral palsy. Ann Neurol 71(5):589–600PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Gazzolo D, Li Volti G, Gavilanes AWD et al (2015) Biomarkers of brain function and injury: biological and clinical significance. Biomed Res Int 2015:389023.  https://doi.org/10.1155/2015/389023CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Serpero LD, Bellissima V, Colivicchi M et al (2013) Next generation biomarkers for brain injury. J Matern Fetal Neonatal Med 26(S2):44–49PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Serpero LD, Pluchinotta F, Gazzolo D (2015) The clinical and diagnostic utility of S100B in preterm newborns. Clin Chim Acta 444:193–198PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Yang Q, Hamberger A, Hyden H et al (1995) S100B has a neuronal localization in the rat hindbrain revealed by an antigen retrieval method. Brain Res 696:49–61PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Zuckerman JE, Herschman HR, Levine L (1970) Appearance of a brain specific antigen (the S-100 protein) during human foetal development. J Neurochem 17:247–251PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Haimoto H, Hosoda S, Kato K (1987) Differential distribution of immunoreactive S100α and S100β proteins in normal non-nervous human tissues. Lab Invest 57:489–498PubMedPubMedCentralGoogle Scholar
  22. 22.
    Michetti F, Dell’Anna E, Tiberio G et al (1983) Immunochemical and immunocytochemical study of S100 protein in rat adipocytes. Brain Res 262:352–356PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Jönsson H (2003) S100B and cardiac surgery: possibilities and limitations. Restor Neurol Neurosci 21(3-4):151–157PubMedPubMedCentralGoogle Scholar
  24. 24.
    Varrica A, Satriano A, Frigiola A et al (2015) Circulating S100B and adiponectin in children who underwent open heart surgery and cardiopulmonary bypass. Biomed Res Int 2015:402642.  https://doi.org/10.1155/2015/402642CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Marinoni E, Di Iorio R, Gazzolo D et al (2002) Ontogenetic localization and distribution of S100h protein in human placental tissues. Obstet Gynecol 99:1093–1099PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wijnberger LD, Nikkels PG, van Dongen AJ et al (2002) Expression in the placenta of neuronal markers for perinatal brain damage. Pediatr Res 51:492–496PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Gazzolo D, Marinoni E, di Iorio R et al (2002) Circulating S100beta protein is increased in intrauterine growth-retarded fetuses. Pediatr Res 51:215–219PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Jönsson H, Johnsson P, Höglund P et al (2000) Elimination of S100B and renal function after cardiac surgery. J Cardiothorac Vasc Anesth 14:698–701PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Petzold A, Eikelenboom M, Gveric D et al (2002) Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 125(Pt 7):1462–1473PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Syeda T, Muhammad Hashim AS, Rizvi HA et al (2013) Serum S100B in patients with brain tumours undergoing craniotomy. J Coll Physicians Surg Pak 23(2):112–115PubMedPubMedCentralGoogle Scholar
  31. 31.
    Chen DQ, Zhu LL (2005) Dynamic change of serum protein S100b and its clinical significance in patients with traumatic brain injury. Chin J Traumatol 8(4):245–224PubMedCrossRefGoogle Scholar
  32. 32.
    Bustamante A, López-Cancio E, Pich S et al (2017) Blood biomarkers for the early diagnosis of stroke: the Stroke-Chip Study. Stroke 48(9):2419–2425PubMedCrossRefGoogle Scholar
  33. 33.
    Berger RP, Pierce MC, Wisniewski SR et al (2002) Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics 109:E31PubMedCrossRefGoogle Scholar
  34. 34.
    Hardemark HG, Ericsson N, Kotwica Z et al (1989) S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. J Neurosurg 71:727–731PubMedCrossRefGoogle Scholar
  35. 35.
    Blennow M, Sävman K, Ilves P et al (2001) Brain-specific proteins in the cerebrospinal fluid of severely asphyxiated newborn infants. Acta Paediatr 90:1171–1175PubMedCrossRefGoogle Scholar
  36. 36.
    Whitelaw A, Rosengren L, Blennow M (2001) Brain specific proteins in posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed 84(2):F90–F91PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Sellman M, Ivert T, Ronquist G et al (1992) Central nervous system damage during cardiac surgery assessed by 3 different biochemical markers in cerebrospinal fluid. Scand J Thorac Cardiovasc Surg 26:39–45PubMedCrossRefGoogle Scholar
  38. 38.
    Michetti F, Gazzolo D (2002) S100B protein in biological fluids: a tool for perinatal medicine. Clin Chem 48(12):2097–2104PubMedGoogle Scholar
  39. 39.
    Persson L, Hardemark HG, Gustafsson J et al (1987) S-100 protein and neurospecific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. Stroke 18:911–918PubMedCrossRefGoogle Scholar
  40. 40.
    Bhattacharya K, Westaby S, Pillai R et al (1999) Serum S100B and hypothermic circulatory arrest in adults. Ann Thorac Surg 68(4):1225–1229PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Westaby S, Johnsson P, Parry AJ et al (1996) Serum S100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 61:88–92PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Gazzolo D, Vinesi P, Geloso MC et al (1998) S100 blood concentrations in children subjected to cardiopulmonary by-pass. Clin Chem 44:1058–1060PubMedPubMedCentralGoogle Scholar
  43. 43.
    Gazzolo D, Vinesi P, Marinoni E et al (2000) S100B protein concentrations in cord blood: correlations with gestational age in term and preterm deliveries. Clin Chem 46:998–1000PubMedPubMedCentralGoogle Scholar
  44. 44.
    Gazzolo D, Michetti F, Bruschettini M et al (2003) Pediatric concentrations of S100B protein in blood: age- and sex-related changes. Clin Chem 49:967–970PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Gazzolo D, Vinesi P, Bartocci M et al (1999) Elevated S100 blood level as early indicators of intraventricular hemorrhage in preterm infants. Correlation with cerebral Doppler velocimetry. J Neurol Sci 170:32–35PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Gazzolo D, Masetti P, Vinesi P et al (2002) S100B blood levels correlate with rewarming time and cerebral Doppler in pediatric open heart surgery. J Card Surg 17(4):279–284PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Gazzolo D, Visser GHA, Lituania M et al (2002) S100B protein cord blood levels and fetal behavioural states of development: a study in normal and small for dates fetuses. J Maternal-Fetal Neonat Med 11:378–384CrossRefGoogle Scholar
  48. 48.
    Gazzolo D, Bruschettini M, Di Iorio R et al (2002) Maternal nitric oxide supplementation decreases cord blood S100B in intrauterine growth-retarded fetuses. Clin Chem 48:647–650PubMedPubMedCentralGoogle Scholar
  49. 49.
    Pawluski JL, Galea LA, Brain U et al (2009) Neonatal S100B protein levels after prenatal exposure to selective serotonin reuptake inhibitors. Pediatrics 124:e662–e670PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Straus RG (1995) Neonatal anemia: pathophysiology and treatment. Immunol Invest 24:341–351CrossRefGoogle Scholar
  51. 51.
    Garnier Y, Berger R, Alm S et al (2006) Systemic endotoxin administration results in increased S100B protein blood levels and periventricular brain white matter injury in the preterm fetal sheep. Eur J Obstet Gynecol Reprod Biol 124(1):15–22PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Garnier Y, Frigiola A, Li Volti G et al (2009) Increased maternal/fetal blood S100B levels following systemic endotoxin administration and periventricular white matter injury in preterm fetal sheep. Reprod Sci 16:758–766PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Gazzolo D, Marinoni E, Di Iorio R et al (2006) High maternal blood S100B concentrations in pregnancies complicated by intrauterine growth restriction and intraventricular hemorrhage. Clin Chem 52:819–826PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Sannia A, Zimmermann LJ, Gavilanes AW et al (2011) S100B protein maternal and fetal bloodstreams gradient in healthy and small for gestational age pregnancies. Clin Chim Acta 412(15-16):1337–1340PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Serpero LD, Bianchi V, Pluchinotta F et al (2017) S100B maternal blood levels are gestational age- and gender-dependent in healthy pregnancies. Clin Chem Lab Med 55(11):1770–1776PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Moore BW (1965) A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 19:739–744PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Heizmann CW (1999) Ca2+-binding S100 proteins in the central nervous system. Neurochem Res 24:1097–1100PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Gazzolo D, Bruschettini M, Lituania M et al (2001) Increased urinary S100B protein as an early indicator of intraventricular hemorrhage in preterm infants: correlation with the grade of hemorrhage. Clin Chem 47:1836–1838PubMedPubMedCentralGoogle Scholar
  59. 59.
    Gazzolo D, Bruschettini M, Lituania M et al (2001) S100b protein concentrations in urine are correlated with gestational age in healthy preterm and term newborns. Clin Chem 47:1132–1133PubMedPubMedCentralGoogle Scholar
  60. 60.
    Usai A, Kato K, Abe T et al (1989) S100ao protein in blood and urine during open-heart surgery. Clin Chem 35:1942–1944Google Scholar
  61. 61.
    Risso FM, Serpero LD, Zimmermann LJ et al (2012) Perinatal asphyxia: kidney failure does not affect S100B urine concentrations. Clin Chim Acta 413:150–153PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Nagdyman N, Komen W, Ko HK et al (2001) Early biochemical indicators of hypoxic-ischemic encephalopathy after birth asphyxia. Pediatr Res 49:502–506PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Liu L, Zheng CX, Peng SF et al (2010) Evaluation of urinary S100B protein level and lactate/creatinine ratio for early diagnosis and prognostic prediction of neonatal hypoxic-ischemic encephalopathy. Neonatology 97:41–44PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Florio P, Marinoni E, Di Iorio R et al (2006) Urinary S100B protein concentrations are increased in intrauterine growth-retarded newborns. Pediatrics 118:e747–e754PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Gazzolo D, Frigiola A, Bashir M et al (2009) Diagnostic accuracy of S100B urinary testing at birth in full-term asphyxiated newborns to predict neonatal death. PLoS One 4:e4298.  https://doi.org/10.1371/journal.pone.0004298CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Gazzolo D, Florio P, Ciotti S et al (2005) S100B protein in urine of preterm newborns with ominous outcome. Pediatr Res 58(6):1170–1174PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Sannia A, Risso FM, Serpero LD et al (2010) Antenatal glucocorticoid treatment affects preterm infants’ S100B urine concentration in a dose-dependent manner. Clin Chim Acta 411:1539–1541PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    The American College of Obstetricians and Gynecologists – Women’s Health Care Physicians (2016) Practice Bulletin No. 162 Summary: prenatal diagnostic testing for genetic disorders. Obstet Gynecol 127(5):976–978CrossRefGoogle Scholar
  69. 69.
    Anneren G, Esscher T, Larsson L et al (1988) S-100 protein and neuron-specific enolase in amniotic fluid as markers of abdominal wall and neural tube defects in the fetus. Prenat Diagn 8:323–328PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Sindic CJ, Freund M, Van Regemorter N et al (1984) S-100 protein in amniotic fluid of anencephalic fetuses. Prenat Diagn 4:297–302PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Eriksen JL, Gillespieb R, Druseb MJ (2002) Effects of ethanol and 5-HT1A agonists on astroglial S100B. Develop Brain Res 139:97–105CrossRefGoogle Scholar
  72. 72.
    Clarke C, Clarke K, Muneyyirci J et al (1996) Prenatal cocaine delays astroglial maturation: immunodensitometry shows increased markers of immaturity (vimentin and GAP 43) and decreased proliferation and production of the growth factor S-100. Brain Res Dev Brain Res 91:268–273PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Akbari HM, Whitaker-Azmitia PM, Azmitia E (1994) Prenatal cocaine exposure decreases the trophic factor S100b and induced microcephaly: reversal by postnatal 5-HT1A receptor agonist. Neurosci Lett 170:141–144PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Michetti F, Gazzolo D (2003) S100B testing in pregnancy. Clin Chim Acta 335(1-2):1–7PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Gazzolo D, Bruschettini M, Corvino V et al (2001) S100b protein concentrations in amniotic fluid correlate with gestational age and with cerebral ultrasound scanning results in healthy fetuses. Clin Chem 47:954–956PubMedPubMedCentralGoogle Scholar
  76. 76.
    Florio P, Michetti F, Bruschettini M et al (2004) Amniotic fluid S100B protein in mid-gestation and intrauterine fetal death. Lancet 364:270–272PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Humphrey SP, Williamson RT (2001) A review of saliva: normal composition, flow, and function. J Prosthet Dent 85:162–169PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Gazzolo D, Michetti F (2010) Perinatal S100B protein assessment in human unconventional biological fluids: a minireview and new perspectives. Cardiovasc Psychiatry Neurol 2010:703563.  https://doi.org/10.1155/2010/703563CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gazzolo D, Lituania M, Bruschettini M et al (2005) S100B protein levels in saliva: correlation with gestational age in normal term and preterm newborns. Clin Biochem 38:229–233PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Gazzolo D, Pluchinotta F, Bashir M et al (2015) Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the “Cooperative Multitask against Brain Injury of Neonates” (CoMBINe) International Study. PLoS One 10(1):e0115194.  https://doi.org/10.1371/journal.pone.0115194CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Michetti F, Massaro A, Murazio M (1979) The nervous system-specific S100 antigen in cerebrospinal fluid of multiple sclerosis patients. Neurosci Lett 11:171–175PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Michetti F, Massaro A, Russo G et al (1980) The S-100 antigen in cerebrospinal fluid as a possible index of cell injury in the nervous system. J Neurol Sci 44:259–263PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Fagnart OC, Sindic CJ, Laterre C (1988) Particle counting immunoassay S100 protein in serum. Possible relevance in tumors and ischemic disorders of the central nervous system. Clin Chem 34:1387–1391PubMedPubMedCentralGoogle Scholar
  84. 84.
    Yang YH, Kim IK, Oh SH et al (1998) Rapid prenatal diagnosis of trisomy 21 by polymerase chain reaction-associated analysis of small tandem repeats and S100B in chromosome 21. Fetal Diagn Ther 13:361366CrossRefGoogle Scholar
  85. 85.
    Zhang H, Qi S, Rao J et al (2013) Development of a rapid and high-performance chemiluminescence immunoassay based on magnetic particles for protein S100B in human serum. Luminescence 28:927–932PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Gazzolo D, Frulio R, Roletti A et al (2007) S100A1B and S100BB urine levels in preterm and term healthy newborns. Clin Chim Acta 384:186–187PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Sannia A, Risso FM, Zimmermann LJ et al (2013) S100B urine concentrations in late preterm infants are gestational age and gender dependent. Clin Chim Acta 417:31–34PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Gazzolo D, Vinesi P, Bartocci M et al (1999) Elevated S100 blood level as early an indicator of intraventricular hemorrhage in preterm infants. Correlation with cerebral Doppler velocimetry. J Neurol Sci 170:32–35PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Sousa N, Madeira MD, Paula-Barbosa MM (1998) Effects of corticosteroids treatment and rehabilitation on the hippocampal formation of neonatal and adult rats. An unbiased stereological study. Brain Res 794:199–210PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Lattimore KA, Donn SM, Kaciroti N et al (2005) Selective Serotonin Reuptake Inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: a meta-analysis. J Perinatol 25:595–604PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Austin MP, Kildea S, Sullivan E (2007) Maternal mortality and psychiatric morbidity in the perinatal period: challenges and opportunities for prevention in the Australian setting. Med J Aust 186(7):364–367PubMedPubMedCentralGoogle Scholar
  92. 92.
    Noorlander CW, Ververs FF, Nikkels PG et al (2008) Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioural abnormalities. PLoS One 3(7):e2782.  https://doi.org/10.1371/journal.pone.0002782CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Hemels ME, Einarson A, Koren G et al (2005) Antidepressant use during pregnancy and the rates of spontaneous abortions; a meta-analysis. Ann Pharmacother 39:803–809PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Hagberg H, Mallard C (2000) Antenatal brain injury: aetiology and possibilities of prevention. Semin Neonatol 5:41–51PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Bates JA, Evans JA, Mason G (1996) Differentiation of growth retarded from normally grown fetuses and prediction of intrauterine growth retardation using Doppler ultrasound. Br J Obstet Gynaecol 103:670–675PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Behrman RE, Lees MH, Peterson EN et al (1970) Distribution of the circulation in the normal and asphyxiated fetal primate. Am J Obstet Gynecol 108:956–969PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Levene MI, Fenton AC, Evans DH et al (1989) Severe birth asphyxia and abnormal cerebral blood-flow velocity. Dev Med Child Neurol 31:427–434PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    van Bel F, van de Bor M, Stijnen T et al (1987) Cerebral blood flow velocity pattern in healthy and asphyxiated newborns: a controlled study. Eur J Pediatr 146:461–467PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Fellman V, Raivio KO (1997) Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 41:599–606PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Florio P, Marinoni E, Di Iorio R et al (2006) Urinary S100B protein concentrations are increased in intrauterine growth-retarded newborns. Pediatrics 118(3):e747–e754PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Freeman JM, Nelson KB (1988) Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240–249PubMedPubMedCentralGoogle Scholar
  102. 102.
    Hagberg B, Hagberg G, Beckung E et al (2001) Changing panorama of cerebral palsy in Sweden: VII. Prevalence and origin in the birth year period 1991–1994. Acta Paediatr 90:271–277PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Rennie JM, South M, Morely CJ (1987) Cerebral blood flow velocity variability in infants receiving assisted ventilation. Arch Dis Child 62:1247–1251PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ilves P, Talvik R, Talvik T (1998) Changes in Doppler ultrasonography in asphyxiated term infants with hypoxic-ischaemic encephalopathy. Acta Paediatr 87:680–684PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Hellstrom-Westas L, Rosen I, Svenningsen NW (1995) Predictive value of early continuous amplitude EEG recordings on outcome after severe birth asphyxia in full term infants. Arch Dis Child 72:F34–F38CrossRefGoogle Scholar
  106. 106.
    Huang CC, Wang ST, Chang YC et al (1999) Measurement of the urinary lactate:creatinine ratio for the early identification of newborn infants at risk from hypoxic-ischemic encephalopathy. N Engl J Med 341:328–335PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Nagdyman N, Grimmer I, Scholz T et al (2003) Predictive value of brain-specific proteins in serum for neurodevelopmental outcome after birth asphyxia. Pediatr Res 54(2):270–275PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Gazzolo D, Di Iorio R, Marinoni E et al (2002) S100B protein is increased in asphyxiated term infants developing intraventricular hemorrhage. Crit Care Med 30(6):1356–1360PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Gazzolo D, Marinoni E, Di Iorio R et al (2003) Measurement of urinary S100B protein concentrations for the early identification of brain damage in asphyxiated full-term infants. Arch Pediatr Adolesc Med 157(12):1163–1168PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Gazzolo D, Marinoni E, Di Iorio R et al (2004) Urinary S100B protein measurements: a tool for the early identification of hypoxic-ischemic encephalopathy in asphyxiated full-term infants. Crit Care Med 32(1):131–136PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Albuerne M, Mammola CL, Naves FJ et al (1998) Immunohistochemical localization of S100 proteins in dorsal root, sympathetic and enteric ganglia of several mammalian species, including man. J Peripher Nerv Syst 3:243–253PubMedPubMedCentralGoogle Scholar
  112. 112.
    Hachem S, Aguirre A, Vives V et al (2005) Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia 51:81–97PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Haglid KG, Yang Q, Hamberger A et al (1997) S-100beta stimulates neurite outgrowth in the rat sciatic nerve grafted with acellular muscle transplants. Brain Res 753:196–201PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Bashir M, Frigiola A, Iskander I et al (2009) Urinary S100A1B and S100BB to predict hypoxic ischemic encephalopathy at term. Front Biosci (Elite Ed) 1:560–567CrossRefGoogle Scholar
  115. 115.
    Lee SK, Kim EC, Chi JG et al (1993) Immunohistochemical detection of S-100, S-100 alpha, S-100 beta proteins, glial fibrillary acidic protein, and neuron specific enolase in the prenatal and adult human salivary glands. Pathol Res Pract 189(9):1036–1043PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Volpe JJ (1995) Intracranial hemorrhage: germinal matrix-intraventricular hemorrhage of the premature infant. In: Volpe JJ (ed) Neurology of the newborn. WB Saunders, Philadelphia, pp 403–463Google Scholar
  117. 117.
    Risso FM, Serpero LD, Zimmermann LJ et al (2013) Urine S100 BB and A1B dimers are valuable predictors of adverse outcome in full-term asphyxiated infants. Acta Paediatr 102(10):e467–e472.  https://doi.org/10.1111/apa.12343CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Duda I, Krzych Ł, Jędrzejowska-Szypułka H et al (2017) Serum levels of the S100B protein and neuron-specific enolase are associated with mortality in critically ill patients. Acta Biochim Pol 64(4):647–652PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Sieber M, Dreßler J, Franke H et al (2018) Post-mortem biochemistry of NSE and S100B: a supplemental tool for detecting a lethal traumatic brain injury? J Forensic Leg Med 55:65–73PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Crowley PA (1995) Antenatal corticosteroid therapy: a meta-analysis of the randomized trial, 1972 to 1994. Am J Obstet Gynecol 173:3223–3235CrossRefGoogle Scholar
  121. 121.
    O’Shea TM, Kothadia JM, Klinepeter KL et al (1999) Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants. Pediatrics 104:15–21PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Vidaeff AC, Mastrobattista JM (2001) Controversies in the use of antenatal steroids for fetal maturation. Semin Perinatol 25:385–396PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Whitelaw A, Thoresen M (2000) Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 83:154–157CrossRefGoogle Scholar
  124. 124.
    Gilstrap LC, Christensen R, Clewell WH et al (1995) The effect of corticosteroids for fetal maturation on perinatal outcomes. National Institutes of Health Consensus Development Panel. JAMA 273:413–418CrossRefGoogle Scholar
  125. 125.
    Mulder EJ, Derks JB, Visser GH (1997) Antenatal corticosteroid therapy and fetal behaviour: a randomized study of the effects of betamethasone and dexamethasone. Br J Obstet Gynecol 104:1239–1247CrossRefGoogle Scholar
  126. 126.
    Huang WL, Beazley LD, Quinlivan JA et al (1999) Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 94:213–218PubMedPubMedCentralGoogle Scholar
  127. 127.
    Uno H, Lohmiller L, Thiem C et al (1990) Brain damage induced by perinatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res 53:157–167PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Gazzolo D, Kornacka M, Bruschettini M et al (2003) Maternal glucocorticoid supplementation and S100B protein concentrations in cord blood and urine of preterm infants. Clin Chem 49(7):1215–1218PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Lyall F, Greer IA, Young A et al (1996) Nitric oxide concentrations are increased in the feto-placental circulation in intrauterine growth restriction. Placenta 17:165–168PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Di Iorio R, Marinoni E, Coacci F et al (1997) Amniotic fluid nitric oxide and uteroplacental blood flow in pregnancy complicated by intrauterine growth retardation. Br J Obstet Gynaecol 104:1134–1139PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Cacciatore B, Halmesmaki E, Kaaja R et al (1998) Effects of transdermal nitroglycerin on impedance to flow in the uterine, umbilical, and fetal middle cerebral arteries in pregnancies complicated by preeclampsia and intrauterine growth retardation. Am J Obstet Gynecol 179:140–145PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Grunewald C, Kublickas M, Carlström K et al (1995) Effects of nitroglycerin on the uterine and umbilical circulation in severe preeclampsia. Obstet Gynecol 86:600–604PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Bennett HA, Einarson A, Taddio A et al (2004) Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 103:698–709PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Austin MP (2006) To treat or not to treat: maternal depression. SSRI use in pregnancy and adverse neonatal effects. Psychol Med 36(12):1663–1670PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Bellissima V, Ververs TF, Visser GH et al (2012) Selective serotonin reuptake inhibitors in pregnancy. Curr Med Chem 19(27):4554–4561PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Moses-Kolko EL, Bogen D, Perel J et al (2005) Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 293:2372–2383PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Louik C, Lin AE, Werler MM et al (2007) First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 356:2675–2683PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Latendresse G, Ruiz RJ (2011) Maternal corticotropin-releasing hormone and the use of selective serotonin reuptake inhibitors independently predict the occurrence of preterm birth. J Midwifery Womens Health 56:118–126PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Kallen BA, Otterblad Olausson P (2007) Maternal use of selective serotonin reuptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 79:301–308PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Levinson-Castiel R, Merlob P, Linder N et al (2006) Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 160:173–176PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Bellissima V, Vesser GHA, Tessa F (2015) Antenatal maternal antidepressants drugs affect S100B concentrations in fetal-maternal biological fluids. CNS Neurol Disord Drug Targets 14(1):49–54PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Azzopardi DV, Strohm B, Edwards AD et al (2009) Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 361:1349–1358PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Edwards AD, Brocklehurst P, Gunn AJ et al (2010) Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 340:c363.  https://doi.org/10.1136/bmj.c363CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Massaro AN, Chang T, Baumgart S et al (2014) Biomarkers S100B and neuron-specific enolase predict outcome in hypothermia-treated encephalopathic newborns. Pediatr Crit Care Med 15(7):615–622PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Massaro AN, Chang T, Kadom N et al (2012) Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia. J Pediatr 161(3):434–440PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Roka A, Kelen D, Halasz J et al (2012) Serum S100B and neuron-specific enolase levels in normothermic and hypothermic infants after perinatal asphyxia. Acta Paediatr 101(3):319–323PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Massaro AN, Wu YW, Bammler TK et al (2018) Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy. J Pediatr 194:67–75PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Çelik Y, Atıcı A, Gülaşı S et al (2015) The effects of selective head cooling versus whole-body cooling on some neural and inflammatory biomarkers: a randomized controlled pilot study. Ital J Pediatr 41:79PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Alshweki A, Pérez-Muñuzuri A, López-Suárez O et al (2017) Relevance of urinary S100B protein levels as a short-term prognostic biomarker in asphyxiated infants treated with hypothermia. Medicine 96(44):e8453.  https://doi.org/10.1097/MD.0000000000008453CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Abella R, Varrica A, Satriano A et al (2015) Biochemical markers for brain injury monitoring in children with or without congenital heart diseases. CNS Neurol Disord Drug Targets 14(1):12–23PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Newburger JW, Jonas JA, Wernovsky G (1993) A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 329:1057–1064PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Bellinger D, Wypij D, duPlessis AJ et al (2003) Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 126:1385–1396PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Bellinger DC, Jonas RA, Rappaport LA et al (1995) Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 332:549–555PubMedCrossRefGoogle Scholar
  154. 154.
    Bellinger DC, Rappaport LA, Wypij D et al (1997) Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries. J Dev Behav Pediatr 18:75–83PubMedCrossRefGoogle Scholar
  155. 155.
    Bellinger DC, Wernovsky G, Rappaport LA et al (1991) Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics 87:701–707PubMedGoogle Scholar
  156. 156.
    Arrica M, Bissonnette B (2007) Therapeutic hypothermia. Semin Cardiothorac Vasc Anesth 11:6–15PubMedCrossRefGoogle Scholar
  157. 157.
    Alcaraz AJ, Manzano L, Sancho L et al (2005) Different proinflammatory cytokine serum pattern in neonate patients undergoing open heart surgery. Relevance of IL-8. J Clin Immunol 25:238–245PubMedCrossRefGoogle Scholar
  158. 158.
    Golej J, Trittenwein G (1999) Early detection of neurologic injury and issues of rehabilitation after pediatric cardiac extracorporeal membrane oxygenation. Artif Organs 23:1020–1025PubMedCrossRefGoogle Scholar
  159. 159.
    Trakas E, Domnina Y, Panigrahy A et al (2017) Serum neuronal biomarkers in neonates with congenital heart disease undergoing cardiac surgery. Pediatr Neurol 72:56–61PubMedCrossRefGoogle Scholar
  160. 160.
    Yuan SM (2014) S100 and S100β: biomarkers of cerebral damage in cardiac surgery with or without the use of cardiopulmonary bypass. Rev Bras Cir Cardiovasc 29(4):630–641 + 40 192,193PubMedPubMedCentralGoogle Scholar
  161. 161.
    Varrica A, Satriano A, Tettamanti G et al (2015) Predictors of ominous outcome in infants undergone to cardiac surgery and cardiopulmonary by-pass: S100B protein. CNS Neurol Disord Drug Targets 14:1CrossRefGoogle Scholar
  162. 162.
    Varrica A, Satriano A, Gavilanes ADW et al (2017) S100B increases in cyanotic versus noncyanotic infants undergoing heart surgery and cardiopulmonary bypass (CPB). J Matern Fetal Neonatal Med 28:1–7Google Scholar
  163. 163.
    Gazzolo D, Bruschettini M, Lituania M et al (2004) Levels of S100B protein are higher in mature human milk than in colostrum and milk-formulae milks. Clin Nutr 23:23–26PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Diego Gazzolo
    • 1
    • 2
  • Francesca Pluchinotta
    • 3
  • Giuseppe Lapergola
    • 1
  • Simone Franchini
    • 1
  1. 1.Neonatal Intensive Care Unit, Department of PediatricsUniversity of ChietiChietiItaly
  2. 2.Neonatal Intensive Care Unit, Department of Maternal, Fetal and Neonatal MedicineC. Arrigo Children’s HospitalAlessandriaItaly
  3. 3.Department of Pediatric Cardiac SurgeryIRCCS San Donato Milanese HospitalMilanItaly

Personalised recommendations