Karl C K Kuban1, T Michael O'Shea2, Elizabeth N Allred3, Raina N Fichorova4, Tim Heeren5, Nigel Paneth6, Deborah Hirtz7, Olaf Dammann8, Alan Leviton9. 1. Department of Pediatrics, Boston Medical Center, Boston, Massachusetts. Electronic address: karl.kuban@bmc.org. 2. Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina. 3. Harvard Medical School, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts. 4. Harvard Medical School, Boston, Massachusetts; Department of Obstetrics, Gynecology & Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts. 5. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 6. Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan. 7. National Institute of Neurological Disorders and Stroke, Bethesda, Massachusetts. 8. Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston Massachusetts. 9. Harvard Medical School, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
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. INTERPRETATION: 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.
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 ChildBehavior 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 ChildBehavior Checklist-defined attention problem increased with higher numbers of these recurrently and/or persistently elevated proteins. INTERPRETATION: 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: Karl C K Kuban; Michael O'Shea; Elizabeth Allred; Alan Leviton; Herbert Gilmore; Adré DuPlessis; Kalpathy Krishnamoorthy; Cecil Hahn; Janet Soul; Sunila E O'Connor; Karen Miller; Paige T Church; Cecilia Keller; Richard Bream; Robin Adair; Alice Miller; Elaine Romano; Haim Bassan; Kathy Kerkering; Steve Engelke; Diane Marshall; Kristy Milowic; Janice Wereszczak; Carol Hubbard; Lisa Washburn; Robert Dillard; Cherrie Heller; Wendy Burdo-Hartman; Lynn Fagerman; Dinah Sutton; Padu Karna; Nick Olomu; Leslie Caldarelli; Melisa Oca; Kim Lohr; Albert Scheiner Journal: J Child Neurol Date: 2005-10 Impact factor: 1.987
Authors: Karl C K Kuban; T Michael O'Shea; Elizabeth N Allred; Nigel Paneth; Deborah Hirtz; Raina N Fichorova; Alan Leviton Journal: J Child Neurol Date: 2014-03-18 Impact factor: 1.987
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