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Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects. [ABSTRACT FROM AUTHOR]

Introduction: Melatonin has been suggested an adjunctive therapy in neonatal encephalopathy (NE). Melatonin reduces oxidative stress and neutrophil activation; however, the immunological effects in NE have not been studied. Methods: Infants with NE and neonatal controls were prospectively recruited. Whole blood was sampled in the first week of life. Following endotoxin and or melatonin treatment, diurnal variation was measured by RT PCR for circadian rhythm genes (brain and Muscle Arnt-Like protein [BMAL1], circadian locomotor output cycles kaput [CLOCK], Nuclear Receptor Subfamily 1 Group D Member 2 [REV Erβ], and cryptochrome circadian clock [CRY]). Neutrophil and monocyte cell surface markers of activation CD11b, reactive oxygen intermediates (ROIs), and Toll-like receptor (TLR)-4 were also examined by flow cytometry in matching samples. Results: Serum and RNA samples from forty infants were included (controls n = 20; NE n = 20) over the first week of life. Melatonin reduced neutrophil CD11b and TLR-4 expression in response to LPS in infants with NE compared to controls. There were no differences in ROIs. BMAL1 and CLOCK baseline gene expression levels were similar. BMAL1 was significantly decreased with LPS stimulation in NE. There was no significant diurnal variation in melatonin, neutrophil, and monocyte function or circadian genes. Conclusions: Melatonin alters immune function ex vivo in infants with NE. Infants with NE have altered immune circadian responses following LPS stimulation, which have potential for modulation. [ABSTRACT FROM AUTHOR]

Aim: Neonatal encephalopathy (NE) is associated with an increased risk of multi‐organ injury. The lack of standardised definitions for multi‐organ dysfunction in NE hinders accurate quantification of these complications. Methods: A simple multi‐organ dysfunction in neonatal encephalopathy scoring (MODE) system was created to include the cardiovascular, respiratory, gastrointestinal, haematological and neurological systems with a maximum score of 15. The MODE score was then compared with the grade of NE, Bayley Scales of Infant Development (Bayley‐III) at 2 years of age and mortality. The Bayley score was used as it gave an objective score making it easier to compare the MODE score. Bayley score of <90 and/or abnormal MRI as an adverse outcome. Results: Infants with perinatal asphyxia (PA:n = 85) were prospectively enrolled (PA only n = 9; NE I = 23; NE II = 42; NE III = 11). Infants with higher MODE scores were significantly more likely to have moderate/severe NE (NE II/III: median scores (IQR) 7(5–10) versus mild NE 2 (1–3); p‐value < 0.001) The MODE score was highly predictive of mortality (AUC 0.96, p‐value = 0.002). Infants who had an abnormal neurological examination at discharge or abnormal Bayley‐III scores had significantly higher MODE scores (p‐value = 0.001). Conclusion: Quantifying multi‐organ injury is important to plan optimal early management and long‐term follow‐up. Additional use of clinical biomarkers may be useful as surrogate endpoints in future clinical trials and link to multi‐organ longer‐term developmental follow‐up. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that earlier diagnosis and initiation of treatment immediately after birth is critical for improved neurodevelopmental outcomes following neonatal encephalopathy (NE). Current diagnostic tests are, however, mainly restricted to clinical diagnosis with no molecular tests available. Purines including adenosine are released during brain injury such as hypoxia and are also present in biofluids. Whether blood purine changes can be used to diagnose NE has not been investigated to date. Methods: Blood purines were measured in a mouse model of neonatal hypoxia and infants with NE using a novel point-of-care diagnostic technology (SMARTChip) based on the summated electrochemical detection of adenosine and adenosine metabolites in the blood. Results: Blood purine concentrations were ∼2–3-fold elevated following hypoxia in mice [2.77 ± 0.48 μM (Control) vs. 7.57 ± 1.41 μM (post-hypoxia), p = 0.029]. Data in infants with NE had a 2–3-fold elevation when compared to healthy controls [1.63 ± 0.47 μM (Control, N = 5) vs. 4.87 ± 0.92 μM (NE, N = 21), p = 0.0155]. ROC curve analysis demonstrates a high sensitivity (81%) and specificity (80%) for our approach to identify infants with NE. Moreover, blood purine concentrations were higher in infants with NE and seizures [8.13 ± 3.23 μM (with seizures, N = 5) vs. 3.86 ± 0.56 μM (without seizures, N = 16), p = 0.044]. Conclusion: Our data provides the proof-of-concept that measurement of blood purine concentrations via SMARTChip technology may offer a low-volume bedside test to support a rapid diagnosis of NE. [ABSTRACT FROM AUTHOR]

Aim: Neonatal encephalopathy (NE) is associated with altered cognitive, motor, sensory abilities and behavioural outcomes. This case‐control study aimed to assess whether Quality of Life (QoL) and sleep disorders are affected in older children following NE compared to age‐matched controls. Methods: Children at school‐age post‐NE were recruited and compared to age‐matched controls. Sleep and QoL were assessed with the Pediatric Quality of Life Inventory and the Child Sleep Habit Questionnaire. Results: One hundred children were recruited with an age range of 4–6 years, including children post‐NE (n=45) and age‐matched controls (n = 55). Significantly higher pathological sleep scores were evident in 58% of children post‐NE compared to controls (43.8 vs 40.2; p = 0.001). Children post‐NE had increased bedtime resistance (p = 0.028) and sleep anxiety (p = 0.01) compared to controls. Children in the post‐NE group had lower total QoL scores versus controls (mean score 82.5 vs 95.8; p < 0.01). Children with mild NE also had lower total QoL scores than controls (90.0 vs 95.8, p = 0.003). There was a strong correlation between low QoL with high total sleep scores (Rho 0.339, p = 0.014). Conclusion: There were high rates of sleep issues in school‐aged children with mild and moderate‐severe NE. Consideration and management of sleep problems may improve QoL in childhood post‐NE. [ABSTRACT FROM AUTHOR]

Background and Objective: Diffusion tensor imaging (DTI) during the first few days of life can be used to assess brain injury in neonates with neonatal encephalopathy (NE) for outcome prediction. The goal of this review was to identify specific white matter tracts of interest that can be quantified by DTI as being altered in neonates with this condition, and to investigate its potential prognostic ability.Methods: Searches of Medline and the Cochrane Database of Systematic Reviews were conducted to identify studies with diffusion data collected in term-born neonates with NE.Results: 19 studies were included which described restricted diffusion in encephalopathic neonates as compared with healthy controls, with the posterior limb of the internal capsule and the genu and splenium of the corpus callosum identified as particular regions of interest. Restricted diffusion was related to adverse outcomes in the studies that conducted a follow-up of these infants.Conclusions: Obtaining diffusion measures in these key white matter tracts early in life before pseudonormalisation can occur can not only identify the extent of the damage but also can be used to examine the effectiveness of treatment and to predict neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Acute kidney injury frequently develops following the term perinatal hypoxia-ischaemia. Quantifying the degree of acute kidney injury is difficult, however, as the methods currently in use are suboptimal. Acute kidney injury management is largely supportive with little evidence basis for many interventions. This review discusses management strategies and novel biomarkers that may improve diagnosis and management of renal injury following perinatal hypoxia-ischaemia. Conclusion Following perinatal hypoxia-ischaemia, acute kidney injury is common. Management of neonatal acute kidney injury is largely supportive. Novel acute kidney injury biomarkers may play a role in optimizing new categorical definitions of renal injury. Studies are needed to investigate the impact of neonatal acute kidney injury on long-term outcome. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is associated with abnormality of neurological function and involves multiorgan dysfunction. There are long-term complications such as cerebral palsy and developmental delay. Cardiac, renal, neurological and other organ dysfunctions are well described. Haematological dysfunction is relatively common and includes anaemia, thrombocytopenia, monocyte and neutrophil activation, hypofibrinogenemia and coagulopathy. There is a lack of consensus definitions of hematological parameters and optimal levels for intervention due to the lack of interventional studies in term neonates and the lack of knowledge of the optimal values during therapeutic hypothermia. However, derangements in hematological values are also associated with neurodevelopmental outcomes. This article outlines the different hematological complications associated with NE and therapeutic hypothermia and suggests a framework for management. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) scoring systems are used in the neonatal period to predict outcome in infants with neonatal encephalopathy. Our aim was to assess the relationship between three MRI scores and neurodevelopmental outcome assessed using Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), at two years in infants with neonatal encephalopathy.Methods: Term-born neonates with evidence of perinatal asphyxia born between 2011 and 2015 were retrospectively reviewed. MRI scanning was performed within the first two weeks of life and scored using Barkovich, National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and Weeke systems by a single assessor blinded to the infants clinical course. Neurodevelopmental outcome was assessed using composite scores on the Bayley-III at two years. Multiple linear regression analyses were used to assess the association between MRI scores and Bayley-III composite scores, with postmenstrual age at scan and sex included as covariates.Results: Of the 135 recruited infants, 90 infants underwent MRI, and of these, 66 returned for follow-up. MRI abnormalities were detected with the highest frequency using the Weeke score (Barkovich 40%, NICHD NRN 50%, Weeke 77%). The inter-rater agreement was good for the Barkovich score and excellent for NICHD NRN and Weeke scores. There was a significant association between Barkovich, NICHD NRN, and Weeke scores and Bayley-III cognitive and motor scores. Only the Weeke score was associated with Bayley-III language scores.Conclusions: Our findings confirm the predictive value of existing MRI scoring systems for cognitive and motor outcome and suggest that more detailed scoring systems have predictive value for language outcome. [ABSTRACT FROM AUTHOR]

We enumerated conventional and innate lymphocyte populations in neonates with neonatal encephalopathy (NE), school-age children post-NE, children with cerebral palsy and age-matched controls. Using flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural killer T cell and Vδ2+ γδ T cell numbers and frequencies were strikingly higher in neonates with NE, children post-NE and children with cerebral palsy compared to age-matched controls, whereas mucosal-associated invariant T cells and Vδ1 T cells were depleted from children with cerebral palsy. Upon stimulation ex vivo , T cells, natural killer cells and Vδ2 T cells from neonates with NE more readily produced inflammatory cytokines than their counterparts from healthy neonates, suggesting that they were previously primed or activated. Thus, innate and conventional lymphocytes are numerically and functionally altered in neonates with NE and these changes may persist into school-age. [Display omitted] • Circulating invariant natural killer T cells and Vδ2 T cells expand in neonates and children with neonatal encephalopathy. • Mucosal-associated invariant T cells and Vδ1 T cells are depleted from children with cerebral palsy. • T cells, natural killer cells and Vδ2 T cells from neonates with neonatal encephalopathy are primed to produce inflammatory cytokines. • Innate and conventional T cells may contribute to persistent neuroinflammation in children. [ABSTRACT FROM AUTHOR]