Neonatology pp 2019-2030 | Cite as

Inflammation and Perinatal Brain Injury

  • Henrik HagbergEmail author
  • Carina Mallard
  • Karin Sävman
Reference work entry


Inflammation is a critical contributor to both normal development and injury outcome in the immature brain. The consequences of immune activation in brain injury will be entirely different depending on context and stage of central nervous system (CNS) maturity. The immature brain can be exposed to inflammation in connection with viral or bacterial infection during pregnancy or as a result of sterile CNS insults such as hypoxia-ischemia and neonatal stroke. Through efficient anti-inflammatory and reparative processes, inflammation may resolve without any harmful effects on the brain. Alternatively, inflammation contributes to injury or enhances CNS vulnerability. Acute inflammation can also be shifted to a chronic inflammatory state and/or adversely affect brain development resulting in neurologic disease in children or adults.


  1. Almkvist J, Fäldt J, Dahlgren C et al (2001) Lipopolysaccharide induced gelatinase granule mobilization primes neutrophils for activation by galectin-3 and formylmethionyl-Leu-Phe. Infect Immun 69:832–837PubMedCrossRefPubMedCentralGoogle Scholar
  2. Aly H, Khashaba MT, El-Ayouty M et al (2006) IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev 28:178–182PubMedCrossRefGoogle Scholar
  3. Ando M, Takashima S, Mito T (1988) Endotoxin, cerebral blood flow, amino acids and brain damage in young rabbits. Brain Dev 10:365–370PubMedCrossRefGoogle Scholar
  4. Arvin KL, Han BH, Du Y et al (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 52:54–61PubMedCrossRefGoogle Scholar
  5. Bartha AI, Foster-Barber A, Miller SP et al (2004) Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res 56:960–966PubMedCrossRefGoogle Scholar
  6. Bolouri H, Sävman K, Wang W et al (2014) Innate defense regulator peptide 1018 protects against perinatal brain injury. Ann Neurol 75(3):395–410PubMedCrossRefGoogle Scholar
  7. Bona E, Andersson AL, Blomgren K et al (1999) Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 45:500–509PubMedCrossRefGoogle Scholar
  8. Borrell V, Marin O (2006) Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci 9:1284–1293PubMedCrossRefGoogle Scholar
  9. Cameron JS, Alexopoulou L, Sloane JA et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27:13033–13041PubMedCrossRefPubMedCentralGoogle Scholar
  10. Chau V, Poskitt KJ, McFadden DE et al (2009) Effect of chorioamnionitis on brain development and injury in premature newborns. Ann Neurol 66:155–164PubMedCrossRefGoogle Scholar
  11. Colnot C, Ripoche MA, Milon G et al (1998) Maintenance of granulocyte numbers during acute peritonitis is defective in galectin-3- null mutant mice. Immunology 94:290–296PubMedCrossRefPubMedCentralGoogle Scholar
  12. Coumans AB, Middelanis JS, Garnier Y et al (2003) Intracisternal application of endotoxin enhances the susceptibility to subsequent hypoxic-ischemic brain damage in neonatal rats. Pediatr Res 53:770–775PubMedCrossRefGoogle Scholar
  13. Cowan F, Rutherford M, Groenendaal F et al (2003) Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 361:736–742PubMedCrossRefGoogle Scholar
  14. Dalitz P, Harding R, Rees SM et al (2003) Prolonged reductions in placental blood flow and cerebral oxygen delivery in preterm fetal sheep exposed to endotoxin: possible factors in white matter injury after acute infection. J Soc Gynecol Investig 10:283–290PubMedGoogle Scholar
  15. Dammann O, O’Shea TM (2008) Cytokines and perinatal brain damage. Clin Perinatol 35:643–663PubMedCrossRefPubMedCentralGoogle Scholar
  16. Dammann O, Allred EN, Veelken N (1998) Increased risk of spastic diplegia among very low birth weight children after preterm labor or prelabor rupture of membranes. J Pediatr 132:531–535PubMedCrossRefGoogle Scholar
  17. de la Mano A, Gato A, Alonso MI et al (2007) Role of interleukin- 1beta in the control of neuroepithelial proliferation and differentiation of the spinal cord during development. Cytokine 37:128–137PubMedCrossRefGoogle Scholar
  18. Dean JM, Farrag D, Zahkouk SA et al (2009a) Cerebellar white matter injury following systemic endotoxemia in preterm fetal sheep. Neuroscience 160:606–615PubMedCrossRefGoogle Scholar
  19. Dean JM, Wang X, Kaindl AM et al (2009b) Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro. Brain Behav Immun 24:776–783PubMedCrossRefGoogle Scholar
  20. Dommergues MA, Patkai J, Renauld JC et al (2000) Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol 47:54–63PubMedCrossRefGoogle Scholar
  21. Doverhag C, Keller M, Karlsson A et al (2008) Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol Dis 31:133–144PubMedCrossRefGoogle Scholar
  22. Doverhag C, Hedtjärn M, Poirier F et al (2010) Galectin-3 contributes to neonatal hypoxic-ischemic brain injury. Neurobiol Dis 38:36–46PubMedCrossRefGoogle Scholar
  23. Duggan PJ, Maalouf EF, Watts TL et al (2001) Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358:1699–1700PubMedCrossRefGoogle Scholar
  24. Duncan JR, Cock ML, Scheerlinck JP et al (2002) White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 52:941–949PubMedCrossRefGoogle Scholar
  25. Duncan JR, Cock ML, Suzuki K et al (2006) Chronic endotoxin exposure causes brain injury in the ovine fetus in the absence of hypoxemia. J Soc Gynecol Investig 13:87–96PubMedCrossRefGoogle Scholar
  26. Dziembowska M, Tham TN, Lau P et al (2005) A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 50:258–269PubMedCrossRefGoogle Scholar
  27. Eklind S, Mallard C, Leverin AL et al (2001) Bacterial endotoxin sensitizes the immature brain to hypoxic – ischaemic injury. Eur J Neurosci 13:1101–1106PubMedCrossRefGoogle Scholar
  28. Fleiss B, Gressens P (2012) Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? Lancet Neurol 11:556–566PubMedCrossRefGoogle Scholar
  29. Fox C, Dingman A, Derugin N et al (2005) Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 25:1138–1149PubMedCrossRefPubMedCentralGoogle Scholar
  30. Gaulden J, Reiter JF (2008) Neur-ons and neur-offs: regulators of neural induction in vertebrate embryos and embryonic stem cells. Hum Mol Genet 17:R60–R66PubMedCrossRefGoogle Scholar
  31. Gavilanes AW, Strackx E, Kramer BW et al (2009) Chorioamnionitis induced by intra-amniotic lipopolysaccharide resulted in an interval- dependent increase in central nervous system injury in the fetal sheep. Am J Obstet Gynecol 200(437):e431–e438Google Scholar
  32. Gilles FH, Averill DR Jr, Kerr CS (1977) Neonatal endotoxin encephalopathy. Ann Neurol 2:49–56PubMedCrossRefGoogle Scholar
  33. Giulian D, Vaca K (1993) Inflammatory glia mediate delayed neuronal damage after ischemia in the central nervous system. Stroke 24:I84–I90PubMedCrossRefGoogle Scholar
  34. Giulian D, Young DG, Woodward J et al (1988) Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci 8:709–714PubMedCrossRefGoogle Scholar
  35. Goldenberg RL, Culhane JF, Iams JD et al (2008) Epidemiology and causes of preterm birth. Lancet 371:75–84CrossRefPubMedGoogle Scholar
  36. Gomez R, Romero R, Ghezzi F et al (1998) The fetal inflammatory response syndrome. Am J Obstet Gynecol 179:194–202PubMedCrossRefGoogle Scholar
  37. Grether JK, Nelson KB (1997) Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278:207–211PubMedCrossRefGoogle Scholar
  38. Hagberg H, Mallard C (2005) Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 18:117–123PubMedCrossRefGoogle Scholar
  39. Hagberg H, Gilland E, Bona E et al (1996) Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res 40:603–609PubMedCrossRefGoogle Scholar
  40. Hagberg H, Gressens P, Mallard C (2012) Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 71(4):444–457PubMedCrossRefGoogle Scholar
  41. Hagberg H, Mallard C, Ferriero DM et al (2015) The role of inflammation in perinatal brain injury. Nat Rev Neurol 11:192–208PubMedCrossRefPubMedCentralGoogle Scholar
  42. Hedtjarn M, Leverin AL, Eriksson K et al (2002) Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci 22:5910–5919PubMedCrossRefGoogle Scholar
  43. Hedtjarn M, Mallard C, Hagberg H (2004) Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J Cereb Blood Flow Metab 24:1333–1351PubMedCrossRefGoogle Scholar
  44. Hedtjarn M, Mallard C, Iwakura Y et al (2005) Combined deficiency of IL-1beta18, but not IL-1alphabeta, reduces susceptibility to hypoxia- ischemia in the immature brain. Dev Neurosci 27:143–148PubMedCrossRefGoogle Scholar
  45. Hsu DK, Yang RY, Pan Z et al (2000) Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol 156:1073–1083PubMedCrossRefPubMedCentralGoogle Scholar
  46. Hudome S, Palmer C, Roberts RL et al (1997) The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 41:607–616PubMedCrossRefGoogle Scholar
  47. Huh GS, Boulanger LM, Du H et al (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159PubMedCrossRefPubMedCentralGoogle Scholar
  48. Ikeda T, Mishima K, Aoo N et al (2004) Combination treatment of neonatal rats with hypoxia-ischemia and endotoxin induces long-lasting memory and learning impairment that is associated with extended cerebral damage. Am J Obstet Gynecol 191:2132–2141PubMedCrossRefGoogle Scholar
  49. Ikeda T, Mishima K, Aoo N et al (2005) Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats. Am J Obstet Gynecol 192:719–726PubMedCrossRefGoogle Scholar
  50. Ikeda T, Yang L, Ikenoue T et al (2006) Endotoxin-induced hypoxic- ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat. Pediatr Res 59:56–60PubMedCrossRefGoogle Scholar
  51. Imai F, Suzuki H, Oda J et al (2007) Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab 27:488–500PubMedCrossRefGoogle Scholar
  52. Jacobsson B, Hagberg G, Hagberg B et al (2002) Cerebral palsy in preterm infants: a population-based case–control study of antenatal and intrapartal risk factors. Acta Paediatr 91:946–951PubMedCrossRefGoogle Scholar
  53. Johnston MV, Hagberg H (2007) Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol 49:74–78PubMedCrossRefGoogle Scholar
  54. Kaukola T, Herva R, Perhomaa M et al (2006) Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants. Pediatr Res 59:478–483PubMedCrossRefGoogle Scholar
  55. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313PubMedCrossRefGoogle Scholar
  56. Kitamura Y, Takata K, Inden M et al (2004) Intracerebroventricular injection of microglia protects against focal brain ischemia. J Pharmacol Sci 94:203–206PubMedCrossRefGoogle Scholar
  57. Kumazaki K, Nakayama M, Sumida Y et al (2002) Placental features in preterm infants with periventricular leukomalacia. Pediatrics 109:650–655PubMedCrossRefGoogle Scholar
  58. Lalancette-Hebert M, Gowing G, Simard A et al (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605PubMedCrossRefGoogle Scholar
  59. Lathia JD, Okun E, Tang SC et al (2008) Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 28:13978–13984PubMedCrossRefPubMedCentralGoogle Scholar
  60. Lee R, Ng D, Fung G et al (2006) Chorioamnionitis with or without funisitis increases the risk of hypotension in very low birthweight infants on the first postnatal day but not later. Arch Dis Child 91:F346–F348CrossRefGoogle Scholar
  61. Lehnardt S, Lachance C, Patrizi S et al (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22:2478–2486PubMedCrossRefGoogle Scholar
  62. Lehnardt S, Massillon L, Follett P et al (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519PubMedCrossRefPubMedCentralGoogle Scholar
  63. Leviton A, Gressens P (2007) Neuronal damage accompanies perinatal white-matter damage. Trends Neurosci 30:473–478PubMedCrossRefGoogle Scholar
  64. Leviton A, Gilles F, Neff R et al (1976) Multivariate analysis of risk of perinatal telencephalic leucoencephalopathy. Am J Epidemiol 104:621–626PubMedCrossRefGoogle Scholar
  65. Leviton A, Paneth N, Reuss ML et al (1999) Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Developmental epidemiology network investigators. Pediatr Res 46:566–575PubMedCrossRefGoogle Scholar
  66. Liu XH, Kwon D, Schielke GP et al (1999) Mice deficient in interleukin- 1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab 19:1099–1108PubMedCrossRefGoogle Scholar
  67. Ma Y, Li J, Chiu I et al (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175:209–215PubMedCrossRefPubMedCentralGoogle Scholar
  68. Mallard C, Hagberg H (2007) Inflammation-induced preconditioning in the immature brain. Semin Fetal Neonatal Med 12:280–286PubMedCrossRefGoogle Scholar
  69. Mallard C, Welin AK, Peebles D et al (2003) White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res 28:215–223PubMedCrossRefGoogle Scholar
  70. Mallard C, Wang X, Hagberg H (2009) The role of toll-like receptors in perinatal brain injury. Clin Perinatol 36:763–772, v–viPubMedCrossRefGoogle Scholar
  71. Martin D, Chinookoswong N, Miller G (1994) The interleukin-1 receptor antagonist (rhIL-1ra) protects against cerebral infarction in a rat model of hypoxia-ischemia. Exp Neurol 130:362–367PubMedCrossRefGoogle Scholar
  72. Martin-Ancel A, Garcia-Alix A, Pascual-Salcedo D et al (1997) Interleukin- 6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics 100:789–794PubMedCrossRefGoogle Scholar
  73. Matsuo Y, Onodera H, Shiga Y et al (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25:1469–1475PubMedCrossRefGoogle Scholar
  74. Matsuo Y, Kihara T, Ikeda M et al (1995) Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab 15:941–947PubMedCrossRefGoogle Scholar
  75. McRae A, Gilland E, Bona E, Hagberg H (1995) Microglia activation after neonatal hypoxic-ischemia. Brain Res Dev Brain Res 84:245–252PubMedCrossRefGoogle Scholar
  76. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765PubMedCrossRefGoogle Scholar
  77. Nelson KB, Grether JK (1998) Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol 179:507–513PubMedCrossRefGoogle Scholar
  78. Nelson KB, Dambrosia JM, Grether JK et al (1998) Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44:665–675PubMedCrossRefGoogle Scholar
  79. Nitsos I, Rees SM, Duncan J et al (2006) Chronic exposure to intra-amniotic lipopolysaccharide affects the ovine fetal brain. J Soc Gynecol Investig 13:239–247PubMedCrossRefGoogle Scholar
  80. Oygur N, Sonmez O, Saka O et al (1998) Predictive value of plasma and cerebrospinal fluid tumour necrosis factor-alpha and interleukin-1 beta concentrations on outcome of full term infants with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 79:F190–F193PubMedCrossRefPubMedCentralGoogle Scholar
  81. Palmer C, Roberts RL, Young PI (2004) Timing of neutrophil depletion influences long-term neuroprotection in neonatal rat hypoxic- ischemic brain injury. Pediatr Res 55:549–556PubMedCrossRefGoogle Scholar
  82. Patni S, Flynn P, Wynen LP et al (2007) An introduction to Toll-like receptors and their possible role in the initiation of labour. BJOG 114:326–1334CrossRefGoogle Scholar
  83. Reiman M, Kujari H, Maunu J et al (2008) Does placental inflammation relate to brain lesions and volume in preterm infants? J Pediatr 152:642–647PubMedCrossRefGoogle Scholar
  84. Rolls A, Shechter R, London A et al (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9:1081–1088PubMedCrossRefGoogle Scholar
  85. Romero R, Dey SK, Fisher SJ (2014) Preterm labor: one syndrome, many causes. Science 345(6198):760–765PubMedCrossRefPubMedCentralGoogle Scholar
  86. Savman K, Blennow M, Gustafson K et al (1998) Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res 43:746–751PubMedCrossRefGoogle Scholar
  87. Shalak LF, Laptook AR, Jafri HS et al (2002) Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants. Pediatrics 110:673–680PubMedCrossRefGoogle Scholar
  88. Shimazaki T, Shingo T, Weiss S (2001) The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci 21:7642–7653PubMedCrossRefGoogle Scholar
  89. Shinjyo N, Stahlberg A, Dragunow M et al (2009) Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 27:2824–2832PubMedCrossRefGoogle Scholar
  90. Silveira RC, Procianoy RS (2003) Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy. J Pediatr 143:625–629PubMedCrossRefGoogle Scholar
  91. Stanley FJ (1994) The aetiology of cerebral palsy. Early Hum Dev 36:81–88PubMedCrossRefGoogle Scholar
  92. Stephan AH, Barres BA, Stevens B (2012) The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci 35:369–389PubMedCrossRefGoogle Scholar
  93. Stridh L, Mottahedin A, Johansson ME et al (2013) Toll-like receptor-3 activation increases the vulnerability of the neonatal brain to hypoxia-ischemia. J Neurosci 33(29):12041–12051PubMedCrossRefPubMedCentralGoogle Scholar
  94. Svedin P, Hagberg H, Savman K et al (2007) Matrix metalloproteinase- 9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci 27:1511–1518PubMedCrossRefGoogle Scholar
  95. Szaflarski J, Burtrum D, Silverstein FS (1995) Cerebral hypoxia- ischemia stimulates cytokine gene expression in perinatal rats. Stroke 26:1093–1100PubMedCrossRefGoogle Scholar
  96. Tahraoui SL, Marret S, Bodenant C et al (2001) Central role of microglia in neonatal excitotoxic lesions of the murine periventricular white matter. Brain Pathol 11:56–71PubMedCrossRefGoogle Scholar
  97. Toti P, De Felice C, Palmeri ML et al (1998) Inflammatory pathogenesis of cortical polymicrogyria: an autopsy study. Pediatr Res 44:291–296PubMedCrossRefGoogle Scholar
  98. Tran PB, Banisadr G, Ren D et al (2007) Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. J Comp Neurol 500:1007–1033PubMedCrossRefPubMedCentralGoogle Scholar
  99. Tsuji M, Wilson MA, Lange MS et al (2004) Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Exp Neurol 189:58–65PubMedCrossRefGoogle Scholar
  100. Vela JM, Molina-Holgado E, Arevalo-Martin A et al (2002) Interleukin- 1 regulates proliferation and differentiation of oligodendrocyte progenitor cells. Mol Cell Neurosci 20:489–502PubMedCrossRefGoogle Scholar
  101. Verma U, Tejani N, Klein S et al (1997) Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 176:275–281PubMedCrossRefGoogle Scholar
  102. Vilcek J (1998) The cytokines: an overview. In: Thomson AW (ed) The cytokine handbook, 3rd edn. Academic, San Diego, pp 1–21Google Scholar
  103. Walder CE, Green SP, Darbonne WC et al (1997) Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28:2252–2258PubMedCrossRefGoogle Scholar
  104. Wang X, Hagberg H, Nie C et al (2007a) Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia- ischemia. J Neuropathol Exp Neurol 66:552–561PubMedCrossRefGoogle Scholar
  105. Wang X, Svedin P, Nie C et al (2007b) N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol 61:263–271PubMedCrossRefGoogle Scholar
  106. Wang X, Stridh L, Li W et al (2009) Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner. J Immunol 183:7471–7477PubMedCrossRefGoogle Scholar
  107. Wu YW, Colford JM Jr (2000) Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 284:1417–1424PubMedCrossRefGoogle Scholar
  108. Wu YW, Escobar GJ, Grether JK et al (2003) Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 290:2677–2684PubMedCrossRefGoogle Scholar
  109. Wu YW, Croen LA, Torres AR et al (2009) Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants. Ann Neurol 66:663–670PubMedCrossRefGoogle Scholar
  110. Yan E, Castillo-Melendez M, Nicholls T et al (2004) Cerebrovascular responses in the fetal sheep brain to low-dose endotoxin. Pediatr Res 55:855–863PubMedCrossRefGoogle Scholar
  111. Yang L, Sameshima H, Ikeda T et al (2004) Lipopolysaccharide administration enhances hypoxic-ischemic brain damage in newborn rats. J Obstet Gynaecol Res 30:142–147PubMedCrossRefGoogle Scholar
  112. Yoon BH, Romero R, Park JS et al (2000) Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 182:675–681PubMedCrossRefGoogle Scholar
  113. Yoon BH, Romero R, Moon JB et al (2001) Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 185:1130–1136PubMedCrossRefGoogle Scholar
  114. Young RS, Hernandez MJ, Yagel SK (1982) Selective reduction of blood flow to white matter during hypotension in newborn dogs: a possible mechanism of periventricular leukomalacia. Ann Neurol 12:445–448PubMedCrossRefGoogle Scholar
  115. Zou YR, Kottmann AH, Kuroda M et al (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Henrik Hagberg
    • 1
    • 2
    Email author
  • Carina Mallard
    • 3
  • Karin Sävman
    • 4
  1. 1.Perinatal Center, Department of Obstetrics and GynecologySahlgrenska Academy, University of GothenburgGoteborgSweden
  2. 2.Centre for the Developing Brain, Division of Imaging Sciences and Biomedical EngineeringKing’s College London, King’s Health Partners, St. Thomas’ HospitalLondonUK
  3. 3.Department of Physiology, Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
  4. 4.Department of PediatricsSahlgrenska Academy, University of GothenburgGothenburgSweden

Personalised recommendations