Coagulation profiles are associated with early clinical outcomes in neonatal encephalopathy

Introduction: Neonatal encephalopathy (NE) is associated with coagulation abnormalities. We aimed to investigate the serial alterations in coagulation profiles in term infants with NE and correlate with their clinical outcomes. This was a prospective cohort study in a tertiary referral, university-affiliated maternity hospital. Neonates exposed to perinatal asphyxia were recruited (n = 82) and 39 received therapeutic hypothermia. Infants had serial coagulation tests including platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen in the first week of life. The main outcome measures included MRI brain and EEG seizures. Our results show that mortality was predicted on day 1 by decreased Fibrinogen (AUC = 0.95, p = 0.009) and by PT on day 2 with a cutoff of 22 s. An abnormal MRI was predicted by Fibrinogen on day 3 with a cut-off value of 2 g/L. For prediction of grade II/III NE, PT on day 2 of life was strongest with a cut-off value of 14 s. Only elevated APTT levels on day 1 of life were predictive of seizures (AUC = 0.65, p = 0.04). Conclusion: Coagulation parameters are strong predictors of outcomes such as abnormal NE grade, seizures, and mortality

Altered inflammasome activation in neonatal encephalopathy persists in childhood

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1 beta, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1 beta and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1 beta gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention

CHAMPION STUDY: Childhood Assessment of Multi-organ dysfunction Post Neonatal encephalopathy

Neonatal brain injury is an important cause of neonatal death and disability such as cerebral palsy. Perinatal global hypoxic ischaemia associated with neonatal encephalopathy results in multi-organ dysfunction which may persists in later childhood. The aim of our study was to examine multi-organ dysfunction in childhood in children with neonatal encephalopathy (NE). Detailed multi organ dysfunction (MOD) was completed in infants with NE, quantified organ outcomes including serum, urine and cerebrospinal fluid (CSF) biomarkers. We followed-up this cohort at school-age measuring multiorgan outcomes at school-age compared to age matched controls and children with Cerebral palsy (CP). We also assessed the sleep pattern, quality of life (QOL) in children with NE. Persistent or sustained inflammation has been implicated in neonatal brain injury, therefore we examined the innate immune response including expression of the inflammasome, HIF-1?, CD11b and Toll-like receptor-4 expression on the surface of neutrophils and cytokine response in children with NE. We recruited children who had NE (n=55), 65 age-matched controls (n=65) and with CP and complex needs (n=26). Blood & urine samples, questionnaires (developmental, sleep and QOL) and clinical examination were performed. Increased incidence of sleep disorders and low QOL scores were seen in children with NE in comparison to children in the control group. Persistently deranged renal function including elevated urea and creatinine were found in children with NE. Persistently high white cell and neutrophil count were noted in children with NE and a correlation between low cognitive score at 2 years and elevated neonatal white cell count was noted. Increased expression of inflammasome NLRP3, HIF-1? and circadian rhythm genes were noted, increased with LPS and subsided by melatonin. Elevated cytokine response of pro and anti-inflammatory cytokines was also noted in children with NE at school age suggesting persistent altered inflammation. This study demonstrated the extent of multiorgan dysfunction (MOD) including neurological, renal, haematological involvement and sleep disorders in infants and in children who had NE. Quantifying multiorgan dysfunction in the neonatal period to ensure appropriate follow-up of all organs is merited. This would help in advanced clinical planning and long term follow up. Understanding, the immune response in these children with NE and exploring systemic inflammation holds promise for future development of immunomodulatory adjunctive therapies