Abstract
To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of 11 cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-α, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- CP:
-
cerebral palsy
- GA:
-
gestational age
- PVL:
-
periventricular leukomalacia
- TNF:
-
tumor necrosis factor
- CSF:
-
colony-stimulating factor
- IFN:
-
interferon
- VIP:
-
vasoactive intestinal peptide
- VEGF:
-
vascular endothelial growth factor
- MIP:
-
macrophage inflammatory protein
References
Goncalves LF, Chaiworapongsa T, Romero R 2002 Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 8: 3–13
Paul VL, Dawar R, Gupta SD, Singh M, Buckshee K, Gupta U, Bhan MK, Bhargava VL, Takkar K, Deorari AK 1998 Histologic chorioamnionitis and its association with prematurity in a hospital-based study. Indian J Med Res 108: 272–278
Guinn D, Gibbs RS 2002 Infection-related preterm birth: a review of the evidence. Neoreviews 3: 386–396
Goldenberg RL, Rouse DJ 1998 Prevention of premature birth. N Engl J Med 339: 313–320
Cummins SK, Nelson KB, Grether JK, Velie EM 1993 Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr 123: 230–237
Murphy DJ, Hope PL, Johnson A 1997 Neonatal risk factors for cerebral palsy in very preterm babies: case-control study. BMJ 314: 404–408
Nelson KB, Ellenberg JH 1986 Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 315: 81–86
Grether JK, Nelson KB 1997 Maternal infection and cerebral palsy in infants of normal birthweight. JAMA 278: 207–211
Walstab J, Bell R, Reddihough D, Brennecke S, Bessell C, Beischer N 2002 Antenatal and intrapartum antecedents of cerebral palsy: a case-control study. Aust N Z J Obstet Gynaecol 2: 138–146
Nelson KB, Willoughby RE 2000 Infection, inflammation and the risk of cerebral palsy. Curr Opin Neurol 13: 133–139
Nelson KB, Dambrosia JM, Grether JK, Phillips TM 1998 Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44: 666–675
Foster-Barber A, Ferriero DM 2002 Neonatal encephalopathy in the term infant: neuroimaging and inflammatory cytokines. Ment Retard Dev Disabil Res Rev 8: 20–24
Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi J-H, Kim I-O 1997 Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 177: 19–26
Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi J-W, Han TR 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: 675–681
Baud O, Foix-L'helias L, Kaminski M, Audibert F, Jarreau P-H, Papiernik E, Huon C, Lepercq J, Dehan M, Lacaze-Masmonteil T 1999 Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 341: 1190–1196
Duggan PJ, Maalouf EF, Watts TL, Sullivan MHF, Counsell SJ, Allsop J, Al-Nakib L, Rutherford MA, Battin M, Roberts I, Edwards AD 2001 Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358: 1699–1670
Minagawa K, Tsuji Y, Ueda H, Koyama K, Tanizawa T, Okamura H, Hashiimoto-Tamaoki T 2002 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 17: 164–170
Kitchen WH, Doyle LW, Ford GW, Rickards AL, Lissenden JV, Ryah MM 1987 Cerebral palsy in very low birthweight infants surviving to 2 years with modern perinatal intensive care. Am J Perinatol 4: 29–35
Nelson KB, Grether JK 1995 Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?. Pediatrics 95: 263–269
Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M 1998 Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med 122: 1091–1099
Grether JK, Nelson KB, Walsh E, Willoughby RE, Redline RW 2003 Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 157: 26–32
Grether JK, Nelson KB, Emery ES, Cummins SK 1996 Prenatal and perinatal factors associated with cerebral palsy in very low birthweight infants. J Pediatr 128: 407–414
Phillips TM, Krum JM 1998 Recycling immunoaffinity chromatography for multiple analyte analysis in biological samples. J Chromatogr B Biomed Sci Appl 715: 55–63
Phillips TM, Dickens BF 2000 Affinity and Immunoaffinity: Purification Techniques. BioTechnique Books, Eaton Press, Natick, MA
Vignali DA 2000 Multiplexed particle-based flow cytometric assays. J Immunol Methods 243: 243–255
Prabhakar U, Eirikis E, Davis HM 2002 Simultaneous quantification of proinflammatory cytokines in human plasma using the LabMap assay. J Immunol Methods 260: 207–218
Wu YW, Colford JM 2000 Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 284: 1417–1424
Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K, Kuwano M 1996 Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem 271: 28220–28228
Webb NJA, Myers CR, Watson CJ, Bottomley MJ, Brenchley PEC 1998 Activated human neutrophils express vascular endothelial growth factor (VEGF). Cytokine 10: 25425–25427
Berse B, Hunt JA, Diegel RJ, Morganelli P, Yeo K-T, Brown F, Fava RA 1999 Hypoxia augments cytokine (transforming growth factor-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Immunol 115: 176–182
Acknowledgements
Dr. Li Xia Yang, LDN/NICHHD, assisted in setting up the protein determinations. This study would not have been possible without the cooperation of the California Children's Medical Services Branch, Department of Health Services, the local California Children's Services programs, and the California Department of Developmental Services. Newborn blood specimens were provided by the Genetic Disease Branch of the Department of Health Services, whose decision to archive these valuable specimens has contributed to many scientific investigations.
Author information
Authors and Affiliations
Additional information
This work was supported in part by funds provided by the March of Dimes/Birth Defect Foundation.
Rights and permissions
About this article
Cite this article
Nelson, K., Grether, J., Dambrosia, J. et al. Neonatal Cytokines and Cerebral Palsy in Very Preterm Infants. Pediatr Res 53, 600–607 (2003). https://doi.org/10.1203/01.PDR.0000056802.22454.AB
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000056802.22454.AB
This article is cited by
-
Caffeine and Its Neuroprotective Role in Ischemic Events: A Mechanism Dependent on Adenosine Receptors
Cellular and Molecular Neurobiology (2022)
-
High-mobility group box-1 and receptor for advanced glycation end products in preterm infants with brain injury
World Journal of Pediatrics (2017)
-
New means to assess neonatal inflammatory brain injury
Journal of Neuroinflammation (2015)
-
Neutrophil and monocyte toll-like receptor 4, CD11b and reactive oxygen intermediates, and neuroimaging outcomes in preterm infants
Pediatric Research (2015)
-
Plasma cytokines and markers of endothelial activation increase after packed red blood cell transfusion in the preterm infant
Pediatric Research (2013)
