Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns

Abstract

Introduction Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns. Methods We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile. Results The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile. Conclusions Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability.

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

“…[ 45 – 49 ] hyperEPO might also contribute to brain damage via inflammatory phenomena. [ 16 ] Another possibility is that hyperEPO adds information about maturity/vulnerability beyond that provided by gestational age at delivery, thus reflecting immaturity either of the brain itself, or of the systems that have the capacity to protect it. Alternatively, unmeasured factors, for instance the severity of the insult prompting the initial inflammatory response, may be correlated with EPO and lead to a non-causal association between hyperEPO and brain damage.…”

“…In our ELGAN sample, elevated EPO concentrations correlate with higher systemic levels of inflammatory proteins. [ 16 ] Consequently, elevated concentrations of endogenous EPO might convey information about inflammation as well as potential neuroprotection. We sought to distinguish between these two possibilities by analyzing associations between elevated endogenous EPO concentrations (defined as concentrations in the highest quartile for gestational age on postnatal day 14) and multiple indicators of brain damage and neurodevelopmental dysfunction, both in the presence and in the absence of ISSI.…”

Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns

“…The second is that an EPO blood concentration in the lowest quartile for gestational age is not associated with any postnatal disorder. These hypotheses were generated by previous findings in the ELGAN sample when we explored the relationship of EPO concentrations with those of inflammation-related proteins,11 and between thyrotropin concentrations and inflammation-related proteins and dysfunctions at age 2 years 20 21…”

“…In preterm newborns, recombinant human EPO (rh-EPO) is used to reduce transfusion requirement,6 and appears to reduce the risk of brain damage7 8 through anti-inflammatory, antiexcitatory and neuroproliferative pathways 9 10. On the other hand, among very preterm newborns, those who have elevated concentrations of endogenous EPO are more likely than others to have elevated concentrations of inflammation-related proteins in concurrent blood specimens 11. Despite this information, little is known about how endogenous EPO production might influence the risk of neonatal disorders in extremely preterm newborns.…”

Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns

“…[14–16] Consequently, we hypothesized that concentrations of NT-4, BDNF, and bFGF vary with the concentrations of inflammation-associated proteins that have been associated with brain disorders and neurodevelopmental dysfunctions in the ELGAN Study cohort. [17–24] Our measurements of concentrations of NT-4, BDNF, and bFGF on multiple days during the first postnatal month allowed us to test this hypothesis and assess the relationship between concentrations of these proteins and both indicators of placenta insufficiency/dysfunction, and inflammation.…”