Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

Abstract

Background In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks’ gestation) infants. Methods Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). Findings Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years. Interpretation Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice. Funding PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods

“…Specifically, we report deficient HIF2α mRNA expression at term equivalent (P7) and toddler equivalent (P21) developmental timepoints supporting longer term alterations in the setting of ongoing inflammation. We also report differential circulating levels of EPO and MLT in the serum compared to brain emphasizing the importance of both tissue Frontiers in Physiology frontiersin.org 09 levels and serum expression when evaluating injury and therapeutic response (Juul et al, 2020;Wood et al, 2021). Interestingly, MLT-SIRT1-HIF2α deficiency may contribute to the attenuated effect of exogenous EPO seen in preterm infants, and it is possible that increasing SIRT1 levels could allow for exogenous MLT to synergize with exogenous EPO to promote recovery after early brain damage (Robinson et al, 2018a;Jantzie et al, 2018;Robinson and Jantzie, 2022).…”

Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy

“…We also did not find evidence that erythropoietin treatment reduced other brain injury biomarker levels, consistent with the lack of benefit from erythropoietin treatment in the HEAL Trial 9 and also consistent with our prior reports that evaluated the effect of erythropoietin on circulating biomarkers in the Phase 2 NEATO Study (NCT01913340) 25 and in the Preterm Epo Neuroprotection Trial (NCT01378273). 26 Our second hypothesis, that a combination of 1 or more brain-specific proteins or cytokines would be associated with the presence and severity of brain injury, was confirmed. We demonstrated an association of several circulating biomarkers with death or NDI at 2 years of age across all biomarker categories (pro-inflammatory, anti-inflammatory, brain-specific proteins, and other growth factors) and at all time points.…”

Predicting the brain age of children with cerebral palsy using a two-dimensional convolutional neural networks prediction model without gray and white matter segmentation

“…This implies that as children with CP grow older, the difference between cerebral and physiological age reduces. Children with CP after fetal or infantile brain damage caused by different factors have a corresponding decline in markers such as Tau protein after treatment ( 26 ). Even with treatment, the damage may continue to affect cerebral development in children with CP, and the effect peaks before age 5 and maintains a certain level.…”