Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates

Abstract

BackgroundWe 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).MethodsProtein 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.ResultsNewborns 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.ConclusionhyperEPO, 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.

Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses

“…This net Epo influx aids cerebral tissue recovery [11,13,15]. We therefore propose that elevated endogenous serum Epo may be a marker of severity of hypoxic-ischaemic insult and brain injury, a theory that is supported by studies of preterm brain injury [16]. …”

Inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates: A Systematic Review

“…The selected studies (n = 11) investigated in this systematic review had very diverse populations with different risk factors (Tilley et al, 2017; Magalhaes et al, 2017; Korzeniewski et al, 2015; Kuban et al, 2015; Rose et al, 2015; Korzeniewski et al, 2014; Leviton et al, 2013; O'Shea et al, 2013; O'Shea et al, 2012; Kinjo et al, 2011; Silveira and Procianoy, 2011). In regard to gestational age, only preterm delivered before 32 weeks were described in all selected studies and, in seven studies, the sample was composed only by patients born before the 28th week of gestation (Tilley et al, 2017; Korzeniewski et al, 2015; Kuban et al, 2015; Korzeniewski et al, 2014; Leviton et al, 2013; O'Shea et al, 2013; O'Shea et al, 2012) (Table 2). The inflammatory molecules and neurotrophic factors were measured during the first 2 weeks after birth and, in most studies, were considered elevated if concentrations were in the top quartile on two separate time‐points during this period (Korzeniewski et al, 2015; Kuban et al, 2015; Korzeniewski et al, 2014; Leviton et al, 2013; O'Shea et al, 2013; O'Shea et al, 2012).…”

“…Overall, high levels of inflammatory biomarkers, including cytokines, chemokines adhesion molecules, growth factors, neurotrophic factors, liver‐produced molecules and activated neutrophils, during the first few weeks after birth, have been associated with poor motor and cognitive performances at later time (Tilley et al, 2017; Magalhaes et al, 2017; Korzeniewski et al, 2015; Kuban et al, 2015; Rose et al, 2015; Korzeniewski et al, 2014; Leviton et al, 2013; O'Shea et al, 2013; O'Shea et al, 2012; Kinjo et al, 2011; Silveira and Procianoy, 2011). Metalloproteinases were the only class of molecules analyzed that did not have any association with neurodevelopment impairment.…”

“…However, conflicting results were also reported. Increased levels of CXCL8/IL‐8 were associated with typical motor development (Magalhaes et al, 2017) and also with cognitive and motor delay (Korzeniewski et al, 2015; Leviton et al, 2013). This finding reinforces the hypothesis that inflammation may be both beneficial and harmful to the CNS, depending on its regulation and intensity.…”

Regeneration in the nervous system with erythropoietin

“…EPO in the amniotic fluid of patients with diabetes can be elevated (162). It is unclear if this suggests an attempt to repair tissue at risk for injury by EPO, but EPO blood levels are elevated and associated with greater disability during brain maturation exposed to a toxic environment (163). Insulin can stimulate EPO production in specific cells that include astrocytes (164).…”