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

Abstract

Background: Infants with neonatal encephalopathy (NE) of hypoxic-ischaemic origin are at risk of oxidative and ischaemia-reperfusion injury, which may induce abnormal inflammatory responses involving excessive cytokine production and release in serum and cerebrospinal fluid (CSF). Systemic inflammation is found in infants with NE, and we therefore were interested in cytokines associated with hypoxia, including vascular endothelial growth factor (VEGF) and erythropoietin (Epo). Objective: To investigate the relationship between Epo, VEGF levels, brain injury and outcome in a group of term infants exposed to perinatal asphyxia (PA) compared to controls. Methods: Serum and CSF biomarkers associated with hypoxia (VEGF, Epo) were serially measured using multiplex immunoassays over days 1-4 in term infants exposed to PA including infants with NE and controls. Results were compared to severity of encephalopathy, MR brain imaging and mortality. Results: Ninety-four infants had 247 serum samples collected (n = 12 controls, 82 exposed to PA with 34 CSF samples), and 4 infants died. Controls had significantly lower serum Epo levels on days 1 and 2 compared to those exposed to PA (p = 0.02). Grade II/III NE was significantly associated with elevated day 2 Epo and decreased day 1 VEGF (p < 0.05; day 2 Epo AUC = 0.74, cut-off 10.05 IU/ml). Elevated serum Epo was associated with severely abnormal MRI. Mortality was associated with elevated day 3 Epo and decreased day 1 VEGF. CSF levels were all after hypothermia and were not significantly associated with outcome. Conclusion: Serum Epo and VEGF may be markers of severity of hypoxia-ischaemia and brain injury as they are closely related to hypoxic exposure.

The fetus at the tipping point: modifying the outcome of fetal asphyxia

“…Recently, elevated serum Epo concentrations were reported in full term infants exposed to perinatal asphyxia on days 1 and 2 after birth, and were associated with severity of HIE on MRI (Sweetman et al . ). Similarly, baseline endogenous Epo levels (pre‐Epo infusion and therapeutic hypothermia) in term infants with moderate to severe injury undergoing hypothermia were positively correlated with injury in the basal ganglia and brainstem (Massaro et al .…”

Cytokine dysregulation persists in childhood post Neonatal Encephalopathy

“…This study is a follow up of a previous cohort of infants with Neonatal encephalopathy recruited in the neonatal period and performed follow up at school age. The recruitment of these babies as neonates has been previously described [2]. The following groups were enrolled:…”

“…Fifteen of 24 children in the NE II/ III group had received therapeutic hypothermia (TH) in the neonatal period in accordance with the TOBY (Total Body Hypothermia for Neonatal Encephalopathy) criteria [16] and were treated for 72 h duration. Infants with congenital abnormalities, confirmed sepsis or evidence of maternal substance abuse were not enrolled [2].…”

“…The injury processes can persist for months and years and a tertiary mechanism of damage has been proposed, which includes inflammation and epigenetic changes [1], decreased plasticity and reduced number of neurons. Infants with NE have a persistent inflammatory response over the first week of life correlating with the degree of brain injury [2,3]. Studies have shown that intermittent and sustained Inflammation demonstrated in preterm newborns may contribute to adverse neurodevelopmental outcome [4].…”

“…We have previously demonstrated altered VEGF and Epo in the same cohort of babies with NE in the first week of life [2] and therefore followed them in childhood to assess immune function. We hypothesised that the inflammatory response persists in childhood and aimed to examine the cytokine profile of school aged children with Neonatal Encephalopathy in comparison to healthy age-matched controls.…”