title: The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns.
abstract: BACKGROUND
  We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration.
  
  
  METHODS
  In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing six functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14. We evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers screen, and in a subset of these children from 12 of 14 sites (n = 826), an attention problem identified with the Child Behavior Checklist.
  
  
  RESULTS
  The risk of abnormal brain structure and function overall was increased among children who had recurrent and/or persistent elevations of the 25 proteins. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index on the Bayley Scales of Infant Development-II, microcephaly, and a Child Behavior Checklist-defined attention problem increased with higher numbers of these recurrently and/or persistently elevated proteins.
  
  
  CONCLUSIONS
  Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely preterm.
authors.affiliation: Department of Pediatrics, Boston Medical Center, Boston, Massachusetts. Electronic address: karl.kuban@bmc.org.
authors.forename: Karl C K
authors.initials: KC
authors.lastname: Kuban
authors.affiliation: Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: T Michael
authors.initials: TM
authors.lastname: O'Shea
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Allred
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Obstetrics, Gynecology & Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Tim
authors.initials: T
authors.lastname: Heeren
authors.affiliation: Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan.
authors.forename: Nigel
authors.initials: N
authors.lastname: Paneth
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, Massachusetts.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hirtz
authors.affiliation: Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston Massachusetts.
authors.forename: Olaf
authors.initials: O
authors.lastname: Dammann
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Alan
authors.initials: A
authors.lastname: Leviton
mesh_terms: D001321:Autistic Disorder / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D002547:Cerebral Palsy / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D002657:Child Development; D002675:Child, Preschool; D003072:Cognition Disorders / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007249:Inflammation / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D016015:Logistic Models; D008831:Microcephaly / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D016017:Odds Ratio; D011379:Prognosis; D011446:Prospective Studies; D012306:Risk
keywords: adverse neurological outcomes, early life predictors of outcome; extremely preterm infants; inflammation-related proteins