Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates

PLoS One. 2015 Mar 20;10(3):e0115083. doi: 10.1371/journal.pone.0115083. eCollection 2015.


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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Injuries / blood*
  • Brain Injuries / complications
  • Brain Injuries / physiopathology
  • Cerebral Palsy / blood
  • Cerebral Palsy / complications
  • Cerebral Palsy / physiopathology
  • Confidence Intervals
  • Erythropoietin / blood*
  • Gestational Age
  • Humans
  • Infant, Extremely Premature / blood*
  • Infant, Newborn
  • Inflammation / pathology
  • Logistic Models
  • Microcephaly / blood
  • Microcephaly / complications
  • Microcephaly / physiopathology
  • Odds Ratio
  • Psychomotor Performance
  • Risk Factors


  • Erythropoietin