Amorfrutin B Compromises Hypoxia/Ischemia-induced Activation of Human Microglia in a PPARγ-dependent Manner: Effects on Inflammation, Proliferation Potential, and Mitochondrial Status.

Amorfrutin B is a selective PPARγ modulator that we demonstrated to be a promising neuroprotective compound in cellular models of stroke and perinatal asphyxia. Although neuronal mechanisms of amorfrutin B-evoked neuroprotection have been identified, none of them reflects the actions of the compound on microglia, which play a pivotal role in brain response to hypoxia/ischemia. Here, we provide evidence for amorfrutin B-induced effects on human microglia subjected to hypoxia/ischemia; the compound counteracts inflammation, and influences mitochondrial status and proliferation potential in a PPARγ-dependent manner. Post-treatment with amorfrutin B decreased the IBA1 fluorescence intensity, reduced caspase-1 activity, and downregulated IL1B/IL-1ß and TNFA but not IL10/IL-10 expression, which was upregulated. Amorfrutin B also stimulated PPARγ signaling, as evidenced by increased mRNA and/or protein levels of PPARγ and PGC1α. In addition, amorfrutin B reversed the hypoxia/ischemia-evoked effects on mitochondria-related parameters, such as mitochondrial membrane potential, BCL2/BCL2 expression and metabolic activity, which were correlated with diminished proliferation potential of microglia. Interestingly, the inhibitory effect of amorfrutin B on the proliferation potential and mitochondrial function of microglia is opposite to the stimulatory effect of amorfrutin B on mouse neuronal survival, as evidenced by increased neuronal viability and reduced neurodegeneration. In summary, this study showed for the first time that amorfrutin B compromises hypoxia/ischemia-induced activation of human microglia in a PPARγ-dependent manner, which involves inhibiting inflammation, normalizing mitochondrial status, and controlling proliferation potential. These data extend the protective potential of amorfrutin B in the pharmacotherapy of hypoxic/ischemic brain injury, targeting not only neurons but also activated microglia.

The Impact of Time to Initiate Therapeutic Hypothermia on Short-Term Neurological Outcomes in Neonates with Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Therapeutic hypothermia is the standard treatment for neonates with hypoxic-ischemic encephalopathy. Preclinical evidence indicates that the time to initiate therapeutic hypothermia correlates with its therapeutic success. This study aims to explore whether there is a correlation between the early initiation of therapeutic hypothermia and improved short-term neurological outcomes in cooled asphyxiated newborns. METHODS: A retrospective analysis was conducted, involving 68 neonates from two different neonatal intensive care units. The impact of time to initiate treatment, time to reach the target temperature, and time between initiation and target temperature was correlated with short-term outcomes on MRI. RESULTS: We did not find a significant difference between outcomes regarding the time to start treatment and the time to achieve the target temperature. Interestingly, neonates with a poor outcome were treated on average earlier than neonates with a favorable outcome but required more time to reach the target temperature. Additionally, the study results did not support the hypothesis that a shorter time to initiate treatment would lead to shorter times to achieve the target temperature. CONCLUSION: Based on our findings, it is recommended to prioritize a thorough evaluation of neonatal encephalopathy before initiating therapeutic hypothermia. Early initiation of treatment should be balanced with the time required for precise assessment to ensure better outcomes.

Perinatal asphyxia leads to acute kidney damage and increased renal susceptibility in adulthood.

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 minutes) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat-shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (KIM-1, NGAL), hypoxic- and heat shock factors (HIF-1α, HSF-1, HSP-27), pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, MCP-1), and fibrotic markers (TGF-ß, CTGF, Fibronectin) promptly after PA. Moreover, a machine learning model was identified through Random Forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic-, heat-shock-, pro-inflammatory-, and pro-fibrotic response after renal IRI compared to controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. Additionally, the parameters identified through Random Forest analysis provide a robust foundation for future biomarker research in the context of PA.

Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen-Glucose Deprivation Conditions.

Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen-glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT's potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT's precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection.

Brain MRI Injury Patterns across Gestational Age among Preterm Infants with Perinatal Asphyxia.

INTRODUCTION: Brain injury patterns of preterm infants with perinatal asphyxia (PA) are underreported. We aimed to explore brain magnetic resonance imaging (MRI) findings and associated neurodevelopmental outcomes in these newborns. METHODS: Retrospective multicenter study included infants with gestational age (GA) 24.0-36.0 weeks and PA, defined as ≥2 of the following: (1) umbilical cord pH ≤7.0, (2) 5-min Apgar score ≤5, and (3) fetal distress or systemic effects of PA. Findings were compared between GA <28.0 (group 1), 28.0-31.9 (group 2), and 32.0-36.0 weeks (group 3). Early MRI (<36 weeks postmenstrual age or <10 postnatal days) was categorized according to predominant injury pattern, and MRI around term-equivalent age (TEA, 36.0-44.0 weeks and ≥10 postnatal days) using the Kidokoro score. Adverse outcomes included death, cerebral palsy, epilepsy, severe hearing/visual impairment, or neurodevelopment <-1 SD at 18-24 months corrected age. RESULTS: One hundred nineteen infants with early MRI (n = 94) and/or MRI around TEA (n = 66) were included. Early MRI showed predominantly hemorrhagic injury in groups 1 (56%) and 2 (45%), and white matter (WM)/watershed injury in group 3 (43%). Around TEA, WM scores were highest in groups 2 and 3. Deep gray matter (DGM) (aOR 15.0, 95% CI: 3.8-58.9) and hemorrhagic injury on early MRI (aOR 2.5, 95% CI: 1.3-4.6) and Kidokoro WM (aOR 1.3, 95% CI: 1.0-1.6) and DGM sub-scores (aOR 4.8, 95% CI: 1.1-21.7) around TEA were associated with adverse neurodevelopmental outcomes. CONCLUSION: The brain injury patterns following PA in preterm infants differ across GA. Particularly DGM abnormalities are associated with adverse neurodevelopmental outcomes.

Digital biomarkers: 3PM approach revolutionizing chronic disease management - EPMA 2024 position.

Non-communicable chronic diseases (NCDs) have become a major global health concern. They constitute the leading cause of disabilities, increased morbidity, mortality, and socio-economic disasters worldwide. Medical condition-specific digital biomarker (DB) panels have emerged as valuable tools to manage NCDs. DBs refer to the measurable and quantifiable physiological, behavioral, and environmental parameters collected for an individual through innovative digital health technologies, including wearables, smart devices, and medical sensors. By leveraging digital technologies, healthcare providers can gather real-time data and insights, enabling them to deliver more proactive and tailored interventions to individuals at risk and patients diagnosed with NCDs. Continuous monitoring of relevant health parameters through wearable devices or smartphone applications allows patients and clinicians to track the progression of NCDs in real time. With the introduction of digital biomarker monitoring (DBM), a new quality of primary and secondary healthcare is being offered with promising opportunities for health risk assessment and protection against health-to-disease transitions in vulnerable sub-populations. DBM enables healthcare providers to take the most cost-effective targeted preventive measures, to detect disease developments early, and to introduce personalized interventions. Consequently, they benefit the quality of life (QoL) of affected individuals, healthcare economy, and society at large. DBM is instrumental for the paradigm shift from reactive medical services to 3PM approach promoted by the European Association for Predictive, Preventive, and Personalized Medicine (EPMA) involving 3PM experts from 55 countries worldwide. This position manuscript consolidates multi-professional expertise in the area, demonstrating clinically relevant examples and providing the roadmap for implementing 3PM concepts facilitated through DBs.

Predictors of poor neurodevelopmental outcomes in neonates with clinically observed seizures: A prospective observational study in a tertiary care hospital of Bangladesh.

Neonatal seizures can lead to long-term neurodevelopmental problems. This study aims to identify predictors of poor developmental outcomes in neonates with seizures to aid in early intervention and referral for follow-up and rehabilitation. This observational study was conducted in the Department of Neonatology and Institute of Paediatric Neurodisorder and Autism, Bangabandhu Sheikh Mujib Medical University. Among 75 study cases of neonatal seizure, 23 died, and 46 were followed-up at 6 and 9 months after discharge. EEGs were performed on every patient. A comprehensive neurological examination and developmental evaluation were performed using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III). Three-fourths of neonates were born at term (76.1 %), and over half were male (56.5 %). The majority were appropriate for gestational age (79.7 %) and had an average birth weight of 2607 ± 696 g (±SD). Over half of the neonates (52.2 %) had adverse neurodevelopmental outcomes, with global developmental delay being the most common. Recurrent seizures, the number of anticonvulsants needed to control seizures, and abnormal Electroencephalograms were identified as independent predictors of adverse neurodevelopmental outcomes. The study highlights the need for early referral for follow-up and rehabilitation of neonates with seizures having abnormal electroencephalograms, recurrent seizures and requiring more anticonvulsants to control seizures.

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation.

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Clinical-functional correlation with brain volumetry in severe perinatal asphyxia: a case report.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental. CASE PRESENTATION: A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases. CLINICAL OUTCOMES: spastic cerebral palsy, microcephaly, treatment-refractory epilepsy. CONCLUSIONS: Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.

Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China.

Neonatal acute liver failure (NALF), as a rare disease with high mortality, has limited relevant literature reports in China. We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28 days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group (P < 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48 days; 26 days for hypoxic/ischemic injury and 43 days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients (P = 0.018).   Conclusion: Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology. What is Known: • Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China. • Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations. • There are no reliable biochemical markers to predict the outcome of NALF. What is New: • In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF. • The overall prognosis of NALF is poor, and its etiology determines the short-term outcome.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Intrapartum cardiotocography with simultaneous maternal heart rate registration improves neonatal outcome.

BACKGROUND: Intrapartum cardiotocographic monitoring of fetal heart rate by abdominal external ultrasound transducer without simultaneous maternal heart rate recording has been associated with increased risk of early neonatal death and other asphyxia-related neonatal outcomes. It is unclear, however, whether this increase in risk is independently associated with fetal surveillance method or is attributable to other factors. OBJECTIVE: This study aimed to compare different fetal surveillance methods and their association with adverse short- and long-term fetal and neonatal outcomes in a large retrospective cohort of spontaneous term deliveries. STUDY DESIGN: Fetal heart rate and maternal heart rate patterns were recorded by cardiotocography during labor in spontaneous term singleton cephalic vaginal deliveries in the Hospital District of Helsinki and Uusimaa, Finland between October 1, 2005, and September 30, 2023. According to the method of cardiotocography monitoring at birth, the cohort was divided into the following 3 groups: women with ultrasound transducer, women with both ultrasound transducer and maternal heart rate transducer, and women with internal fetal scalp electrode. Umbilical artery pH and base excess values, low 1- and 5-minute Apgar scores, need for intubation and resuscitation, neonatal intensive care unit admission for asphyxia, neonatal encephalopathy, and early neonatal death were used as outcome variables. RESULTS: Among the 213,798 deliveries that met the inclusion criteria, the monitoring type was external ultrasound transducer in 81,559 (38.1%), both external ultrasound transducer and maternal heart rate recording in 62,268 (29.1%), and fetal scalp electrode in 69,971 (32.7%) cases, respectively. The rates of both neonatal encephalopathy (odds ratio, 1.48; 95% confidence interval, 1.08-2.02) and severe acidemia (umbilical artery pH <7.00 and/or umbilical artery base excess ≤-12.0 mmol/L) (odds ratio, 2.03; 95% confidence interval, 1.65-2.50) were higher in fetuses of women with ultrasound transducer alone compared with those of women with concurrent external fetal and maternal heart rate recording. Monitoring with ultrasound transducer alone was also associated with increased risk of neonatal intubation for resuscitation (odds ratio, 1.22; 95% confidence interval, 1.03-1.44). A greater risk of severe neonatal acidemia was observed both in the ultrasound transducer (odds ratio, 2.78; 95% confidence interval, 2.23-3.48) and concurrent ultrasound transducer and maternal heart rate recording (odds ratio, 1.37; 95% confidence interval, 1.05-1.78) groups compared with those monitored with fetal scalp electrodes. No difference in risk of neonatal encephalopathy was found between newborns monitored with concurrent ultrasound transducer and maternal heart rate recording and those monitored with fetal scalp electrodes. CONCLUSION: The use of external ultrasound transducer monitoring of fetal heart rate without simultaneous maternal heart rate recording is associated with higher rates of neonatal encephalopathy and severe neonatal acidemia. We suggest that either external fetal heart rate monitoring with concurrent maternal heart rate recording or internal fetal scalp electrode be used routinely as a fetal surveillance tool in term deliveries.

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.

Impact of an e-learning training for interpreting intrapartum fetal heart rate monitoring to avoid perinatal asphyxia: A before-after multicenter observational study.

INTRODUCTION: Perinatal asphyxia, a condition that results from compromised placental or pulmonary gas exchange during the birth process, is rare but can lead to serious neonatal and long-term consequences. The visual analysis of cardiotocography (CTG) is designed to avoid perinatal asphyxia, but its interpretation can be difficult. Our aim was to test the impact of an e-learning training program for interpreting CTG on the rate of avoidable perinatal asphyxia at term. METHOD: We conducted a retrospective multicenter before-after study comparing two periods, before and after the implementation of e-learning training program from July 1, 2016 to December 31, 2016, in CTG interpretation for midwives and obstetricians in five maternity hospitals in the Paris area, France. The training involved theoretical aspects such as fetal physiology and heart rhythm abnormalities, followed by practical exercises using real case studies to enhance skills in interpreting CTG. We included all term births that occurred between the "before" period (July 1 to December 31, 2014) and the "after period (January 1 to June 30, 2017). We excluded multiple pregnancies, antenatal detection of congenital abnormalities, breech births and all scheduled caesarean sections. Perinatal asphyxia cases were analyzed by a pair of experts consisting of midwives and obstetricians, and avoidability of perinatal asphyxia was estimated. The main criterion was the prevalence of avoidable perinatal asphyxia. RESULTS: The e-learning program was performed by 83 % of the obstetrician-gynecologists and 65 % of the midwives working in the delivery rooms of the five centers. The prevalence of perinatal asphyxia was 0.45 % (29/7902 births) before the training and 0.54 % (35/7722) after. The rate of perinatal asphyxia rated as avoidable was 0.30 % of live births before the training and 0.28 % after (p = 0.870). The main causes of perinatal asphyxia deemed avoidable were delay in reactions to severe CTG anomalies and errors in the analysis and interpretation of the CTG. These causes did not differ between the two periods. CONCLUSION: One session of e-learning training to analyze CTG was not associated with a reduction in avoidable perinatal asphyxia. Other types of e-learning, repeated and implemented over a longer period should be evaluated.

Perinatal asphyxia does not influence presepsin levels in neonates: A prospective study.

AIM: To compare Presepsin (presepsin) levels in plasma and urine of uninfected newborn infants with perinatal asphyxia with those of controls. METHODS: In this prospective study, we enrolled 25 uninfected full-term infants with perinatal asphyxia and 19 controls. We measured presepsin levels in whole blood or urine. In neonates with perinatal asphyxia, we compared presepsin levels in blood and urine at four time points. RESULTS: In neonates with perinatal asphyxia, blood and urinary presepsin levels matched each other at any time point. At admission, the median presepsin value in blood was similar in both groups (p = 0.74), while urinary levels were higher in hypoxic neonates (p = 0.05). Perinatal asphyxia seemed to increase serum CRP and procalcitonin levels beyond normal cut-off but not those of presepsin. CONCLUSION: In uninfected neonates with perinatal asphyxia, median blood and urinary presepsin levels matched each other at any point in the first 72 h of life and seemed to be slightly affected by the transient renal impairment associated with perinatal hypoxia in the first 12 h of life. Perinatal asphyxia did not influence presepsin levels within the first 72 h of life, while those of CRP and procalcitonin increased.

Neuro-Specific and Immuno-Inflammatory Biomarkers in Umbilical Cord Blood in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: The aim of the study was to evaluate neuronal injury and immuno-inflammatory biomarkers in umbilical cord blood (UCB) at birth, in cases with perinatal asphyxia with or without hypoxic-ischemic encephalopathy (HIE), compared with healthy controls and to assess their ability to predict HIE. STUDY DESIGN: In this case-control study, term infants with perinatal asphyxia were recruited at birth. UCB was stored at delivery for batch analysis. HIE was diagnosed by clinical Sarnat staging at 24 h. Glial fibrillary acidic protein (GFAP), the neuronal biomarkers tau and neurofilament light protein (NFL), and a panel of cytokines were analyzed in a total of 150 term neonates: 50 with HIE, 50 with asphyxia without HIE (PA), and 50 controls. GFAP, tau, and NFL concentrations were measured using ultrasensitive single-molecule array (Simoa) assays, and a cytokine screening panel was applied to analyze the immuno-inflammatory and infectious markers. RESULTS: GFAP, tau, NFL, and several cytokines were significantly higher in newborns with moderate and severe HIE compared to a control group and provided moderate prediction of HIE II/III (AUC: 0.681-0.827). Furthermore, the levels of GFAP, tau, interleukin-6 (IL-6), and interleukin-8 (IL-8) were higher in HIE II/III cases compared with cases with PA/HIE I. IL-6 was also higher in HIE II/III compared with HIE I cases. CONCLUSIONS: Biomarkers of brain injury and inflammation were increased in umbilical blood in cases with asphyxia. Several biomarkers were higher in HIE II/III versus those with no HIE or HIE I, suggesting that they could assist in the prediction of HIE II/III.

Cranial MRI beyond the Neonatal Period and Neurodevelopmental Outcomes in Neonatal Encephalopathy Due to Perinatal Asphyxia: A Systematic Review.

BACKGROUND: Magnetic resonance imaging (MRI) including diffusion-weighted imaging within seven days after birth is widely used to obtain prognostic information in neonatal encephalopathy (NE) following perinatal asphyxia. Later MRI could be useful for infants without a neonatal MRI or in the case of clinical concerns during follow-up. Therefore, this review evaluates the association between cranial MRI beyond the neonatal period and neurodevelopmental outcomes following NE. METHODS: A systematic literature search was performed using PubMed and Embase on cranial MRI between 2 and 24 months after birth and neurodevelopmental outcomes following NE due to perinatal asphyxia. Two independent researchers performed the study selection and risk of bias analysis. Results were separately described for MRI before and after 18 months. RESULTS: Twelve studies were included (high-quality n = 2, moderate-quality n = 6, low-quality n = 4). All reported on MRI at 2-18 months: seven studies demonstrated a significant association between the pattern and/or severity of injury and overall neurodevelopmental outcomes and three showed a significant association with motor outcome. There were insufficient data on non-motor outcomes and the association between MRI at 18-24 months and neurodevelopmental outcomes. CONCLUSIONS: Cranial MRI performed between 2 and 18 months after birth is associated with neurodevelopmental outcomes in NE following perinatal asphyxia. However, more data on the association with non-motor outcomes are needed.

Perinatal asphyxia and hypothermic treatment from the endocrine perspective.

Introduction: Perinatal asphyxia is one of the three most important causes of neonatal mortality and morbidity. Therapeutic hypothermia represents the standard treatment for infants with moderate-severe perinatal asphyxia, resulting in reduction in the mortality and major neurodevelopmental disability. So far, data in the literature focusing on the endocrine aspects of both asphyxia and hypothermia treatment at birth are scanty, and many aspects are still debated. Aim of this narrative review is to summarize the current knowledge regarding the short- and long-term effects of perinatal asphyxia and of hypothermia treatment on the endocrine system, thus providing suggestions for improving the management of asphyxiated children. Results: Involvement of the endocrine system (especially glucose and electrolyte disturbances, adrenal hemorrhage, non-thyroidal illness syndrome) can occur in a variable percentage of subjects with perinatal asphyxia, potentially affecting mortality as well as neurological outcome. Hypothermia may also affect endocrine homeostasis, leading to a decreased incidence of hypocalcemia and an increased risk of dilutional hyponatremia and hypercalcemia. Conclusions: Metabolic abnormalities in the context of perinatal asphyxia are important modifiable factors that may be associated with a worse outcome. Therefore, clinicians should be aware of the possible occurrence of endocrine complication, in order to establish appropriate screening protocols and allow timely treatment.