title: Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.
abstract: BACKGROUND
  We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).
  
  
  METHODS
  Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.
  
  
  RESULTS
  Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.
  
  
  CONCLUSIONS
  hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.
authors: Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States of America; Department of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, United States of America.
authors: Steven J
authors: SJ
authors: Korzeniewski
authors: Neurology Departments, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States of America.
authors: Elizabeth
authors: E
authors: Allred
authors: Department of Neonatology, Nationwide Children's Hospital, Columbus, OH, United States of America.
authors: J Wells
authors: JW
authors: Logan
authors: Departments of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Raina N
authors: RN
authors: Fichorova
authors: Department of Pediatrics, East Carolina University Brody School of Medicine, Greenville, NC, United States of America.
authors: Stephen
authors: S
authors: Engelke
authors: Departments of Pediatrics, Boston Medical Center and Boston University, Boston, MA, United States of America.
authors: Karl C K
authors: KC
authors: Kuban
authors: Department of Pediatrics, Wake Forest University, Winston-Salem, NC, United States of America.
authors: T Michael
authors: TM
authors: O'Shea
authors: Department of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, United States of America; Department of Pediatrics & Human Development, Michigan State University, East Lansing, MI, United States of America.
authors: Nigel
authors: N
authors: Paneth
authors: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, United States of America.
authors: Mari
authors: M
authors: Holm
authors: Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, United States of America; Neuroepidemiology Unit, Hannover School of Medicine, Hannover, Germany.
authors: Olaf
authors: O
authors: Dammann
authors: Neurology Departments, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States of America.
authors: Alan
authors: A
authors: Leviton
mesh_terms: D001930:Brain Injuries / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D002547:Cerebral Palsy / Q000097:blood / Q000150:complications / Q000503:physiopathology; D016001:Confidence Intervals; D004921:Erythropoietin / Q000097:blood*; D005865:Gestational Age; D006801:Humans; D062071:Infant, Extremely Premature / Q000097:blood*; D007231:Infant, Newborn; D007249:Inflammation / Q000473:pathology; D016015:Logistic Models; D008831:Microcephaly / Q000097:blood / Q000150:complications / Q000503:physiopathology; D016017:Odds Ratio; D011597:Psychomotor Performance; D012307:Risk Factors
chemical_list: D004921:Erythropoietin