Cytokines and Posthemorrhagic Ventricular Dilation in Premature Infants

 

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Abstract

Objective To determine in extremely low-birth-weight infants if elevated blood interferon-γ (IFN-γ), interleukin (IL)-1β, IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β are associated with need for shunt following severe intraventricular hemorrhage (IVH) or with ventricular dilation following milder grades/no IVH.

Study Design Whole blood cytokines were measured on postnatal days 1, 3, 7, 14, and 21. Maximum IVH grade in the first 28 days, and shunt surgery or ventricular dilation on subsequent ultrasound (28 days' to 36 weeks' postmenstrual age) were determined.

Results Of 902 infants in the National Institute of Child Health and Human Development Neonatal Research Network Cytokine study who survived to 36 weeks or discharge, 3.1% had shunts. Of the 12% of infants with severe (grade III to IV) IVH, 26% had a shunt associated with elevated TNF-α. None of the infants without IVH (69%) or with grade I (12%) or II (7%) IVH received shunts, but 8.4% developed ventricular dilation, associated with lower IFN-γ and higher IL-18.

Conclusion Statistically significant but clinically nondiscriminatory alterations in blood cytokines were noted in infants with severe IVH who received shunts and in those without severe IVH who developed ventricular dilation. Blood cytokines are likely associated with brain injury but may not be clinically useful as biomarkers for white matter damage.

• References

• 1 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529-534
  CrossrefPubMedGoogle Scholar
• 2 Mayne M, Ni W, Yan HJ , et al. Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 2001; 32: 240-248
  CrossrefPubMedGoogle Scholar
• 3 Martin-Villalba A, Hahne M, Kleber S , et al. Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ 2001; 8: 679-686
  CrossrefPubMedGoogle Scholar
• 4 Whitelaw A, Christie S, Pople I. Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus?. Pediatr Res 1999; 46: 576-580
  CrossrefPubMedGoogle Scholar
• 5 Kitazawa K, Tada T. Elevation of transforming growth factor-beta 1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 1994; 25: 1400-1404
  CrossrefPubMedGoogle Scholar
• 6 Takizawa T, Tada T, Kitazawa K , et al. Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res 2001; 23: 724-730
  CrossrefPubMedGoogle Scholar
• 7 Hansen-Pupp I, Harling S, Berg AC, Cilio C, Hellström-Westas L, Ley D. Circulating interferon-gamma and white matter brain damage in preterm infants. Pediatr Res 2005; 58: 946-952
  CrossrefPubMedGoogle Scholar
• 8 Schmitz T, Heep A, Groenendaal F , et al. Interleukin-1beta, interleukin-18, and interferon-gamma expression in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus—markers of white matter damage?. Pediatr Res 2007; 61: 722-726
  CrossrefPubMedGoogle Scholar
• 9 Morganti-Kossmann MC, Hans VH, Lenzlinger PM , et al. TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma 1999; 16: 617-628
  CrossrefPubMedGoogle Scholar
• 10 Ellison VJ, Mocatta TJ, Winterbourn CC, Darlow BA, Volpe JJ, Inder TE. The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn. Pediatr Res 2005; 57: 282-286
  CrossrefPubMedGoogle Scholar
• 11 Carlo WA, McDonald SA, Tyson JE , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J Pediatr 2011; 159: 919-925 , e3
  CrossrefPubMedGoogle Scholar
• 12 Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996; 87: 163-168
  CrossrefPubMedGoogle Scholar
• 13 Skogstrand K, Thorsen P, Nørgaard-Pedersen B, Schendel DE, Sørensen LC, Hougaard DM. Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology. Clin Chem 2005; 51: 1854-1866
  CrossrefPubMedGoogle Scholar
• 14 Skogstrand K, Ekelund CK, Thorsen P , et al. Effects of blood sample handling procedures on measurable inflammatory markers in plasma, serum and dried blood spot samples. J Immunol Methods 2008; 336: 78-84
  CrossrefPubMedGoogle Scholar
• 15 Adams-Chapman I, Hansen NI, Stoll BJ, Higgins R ; NICHD Research Network. Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion. Pediatrics 2008; 121: e1167-e1177
  Google Scholar
• 16 Brouwer A, Groenendaal F, van Haastert IL, Rademaker K, Hanlo P, de Vries L. Neurodevelopmental outcome of preterm infants with severe intraventricular hemorrhage and therapy for post-hemorrhagic ventricular dilatation. J Pediatr 2008; 152: 648-654
  CrossrefPubMedGoogle Scholar
• 17 Sävman K, Blennow M, Hagberg H, Tarkowski E, Thoresen M, Whitelaw A. Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatr 2002; 91: 1357-1363
  PubMedGoogle Scholar
• 18 Kadhim H, Tabarki B, Verellen G, De Prez C, Rona AM, Sébire G. Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurology 2001; 56: 1278-1284
  PubMedGoogle Scholar
• 19 Yoon BH, Romero R, Kim CJ , et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997; 177: 406-411
  CrossrefPubMedGoogle Scholar
• 20 Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA ; South Australian Cerebral Palsy Research Group. The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol 2006; 194: 674 , e1–e11
  PubMedGoogle Scholar
• 21 Tarkowski E, Tullberg M, Fredman P, Wikkelsö C. Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha. Neurobiol Aging 2003; 24: 707-714
  CrossrefPubMedGoogle Scholar
• 22 Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Bührer C, Stahel PF. IL-18: a key player in neuroinflammation and neurodegeneration?. Trends Neurosci 2005; 28: 487-493
  CrossrefPubMedGoogle Scholar
• 23 Hedtjärn M, Mallard C, Arvidsson P, Hagberg H. White matter injury in the immature brain: role of interleukin-18. Neurosci Lett 2005; 373: 16-20
  PubMedGoogle Scholar
• 24 Minagawa K, Tsuji Y, Ueda H , et al. Possible correlation between high levels of IL-18 in the cord blood of pre-term infants and neonatal development of periventricular leukomalacia and cerebral palsy. Cytokine 2002; 17: 164-170
  CrossrefPubMedGoogle Scholar
• 25 Yoon BH, Jun JK, Romero R , et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997; 177: 19-26
  CrossrefPubMedGoogle Scholar
• 26 Folkerth RD, Keefe RJ, Haynes RL, Trachtenberg FL, Volpe JJ, Kinney HC. Interferon-gamma expression in periventricular leukomalacia in the human brain. Brain Pathol 2004; 14: 265-274
  PubMedGoogle Scholar
• 27 Sival DA, Felderhoff-Müser U, Schmitz T, Hoving EW, Schaller C, Heep A. Neonatal high pressure hydrocephalus is associated with elevation of pro-inflammatory cytokines IL-18 and IFNgamma in cerebrospinal fluid. Cerebrospinal Fluid Res 2008; 5: 21
  CrossrefPubMedGoogle Scholar
• 28 Wong G, Goldshmit Y, Turnley AM. Interferon-gamma but not TNF alpha promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp Neurol 2004; 187: 171-177
  CrossrefPubMedGoogle Scholar
• 29 Pawliński R, Janeczko K. Intracerebral injection of interferon-gamma inhibits the astrocyte proliferation following the brain injury in the 6-day-old rat. J Neurosci Res 1997; 50: 1018-1022
  CrossrefPubMedGoogle Scholar
• 30 Hayashi N, Leifer DW, Cohen AR. Chronologic changes of cerebral ventricular size in a transgenic model of hydrocephalus. Pediatr Neurosurg 2000; 33: 182-187
  CrossrefPubMedGoogle Scholar
• 31 Cherian S, Thoresen M, Silver IA, Whitelaw A, Love S. Transforming growth factor-betas in a rat model of neonatal posthaemorrhagic hydrocephalus. Neuropathol Appl Neurobiol 2004; 30: 585-600
  CrossrefPubMedGoogle Scholar
• 32 Aquilina K, Hobbs C, Tucker A, Whitelaw A, Thoresen M. Do drugs that block transforming growth factor beta reduce posthaemorrhagic ventricular dilatation in a neonatal rat model?. Acta Paediatr 2008; 97: 1181-1186
  CrossrefPubMedGoogle Scholar
• 33 Tomoda T, Shirasawa T, Yahagi YI , et al. Transforming growth factor-beta is a survival factor for neonate cortical neurons: coincident expression of type I receptors in developing cerebral cortices. Dev Biol 1996; 179: 79-90
  CrossrefPubMedGoogle Scholar
• 34 Broitman E, Ambalavanan N, Higgins RD , et al; National Institute of Child Health and Human Development Neonatal Research Network. Clinical data predict neurodevelopmental outcome better than head ultrasound in extremely low birth weight infants. J Pediatr 2007; 151: 500-505 , 505, e1–e2
  PubMedGoogle Scholar