Spontaneous running wheel exercise during pregnancy prevents later neonatal-anoxia-induced somatic and neurodevelopmental alterations.

Introduction: About 15-20 % of babies that suffer perinatal asphyxia die and around 25 % of the survivors exhibit permanent neural outcomes. Minimization of this global health problem has been warranted. This study investigated if the offspring of pregnant female rats allowed to spontaneously exercise on running wheels along a 11-day pregnancy period were protected for somatic and neurodevelopmental disturbs that usually follow neonatal anoxia. Methods: spontaneous exercise was applied to female rats which were housed in cages allowing free access to running wheels along a 11-day pregnancy period. Their offspring were submitted to anoxia 24-36 h after birth. Somatic and sensory-motor development of the pups were recorded until postnatal day 21 (P21). Myelin basic protein (MBP)-stained areas of sensory and motor cortices were measured at P21. Neuronal nuclei (NeuN)-immunopositive cells and synapsin-I levels in hippocampal formation were estimated at P21 and P75. Results: gestational exercise and / or neonatal anoxia increased the weight and the size of the pups. In addition, gestational exercise accelerated somatic and sensory-motor development of the pups and protected them against neonatal-anoxia-induced delay in development. Further, neonatal anoxia reduced MBP stained area in the secondary motor cortex and decreased hippocampal neuronal estimates and synapsin-I levels at P21; gestational exercise prevented these effects. Therefore, spontaneous exercise along pregnancy is a valuable strategy to prevent neonatal-anoxia-induced disturbs in the offspring. Conclusion: spontaneous gestational running wheel exercise protects against neonatal anoxia-induced disturbs in the offspring, including (1) physical and neurobehavioral developmental impairments, and (2) hippocampal and cortical changes. Thus, spontaneous exercise during pregnancy may represent a valuable strategy to prevent disturbs which usually follow neonatal anoxia.

No Short-Term Effect of Low-Dose Nicotine on Inflammation after Global Hypoxia in Newborn Piglets.

INTRODUCTION: Perinatal asphyxia initiates cytokine release and complement activation with risk of brain damage. We assessed the effect of nicotine on innate immunity and hypothesized that nicotine infusion in a newborn piglet model of asphyxia would decrease the immune response and be neuroprotective. METHODS: Newborn piglets (n = 41) were randomized to one of three groups after hypoxia: two groups receiving nicotine, (1) 18 µg/kg/h (n = 17), (2) 46 µg/kg/h (n = 15), and (3) control group receiving saline (n = 9). C3a, IL-6, TNF, and IL-10 were measured in plasma and IL-6 and IL-8 in microdialysis fluid from cerebral periventricular white matter, using immuno-assays. RESULTS: Plasma C3a and IL-6 increased significantly from start to end hypoxia (mean 4.4 ± 0.55 to 5.6 ± 0.71 ng/mL and 1.66 ± 1.04 to 2.68 ± 0.71 pg/mL, respectively), while IL-10 and TNF increased significantly after 4 h (mean 1.4 ± 1.08 to 2.9 ± 1.87 and 3.3 ± 0.67 to 4.0 ± 0.58 pg/mL, respectively) (p < 0.001 for all). IL-6 increased significantly (p < 0.001) in microdialysis samples from end hypoxia to end experiment (mean 0.65 ± 0.88 to 2.78 ± 1.84 ng/mL). No significant differences were observed between the nicotine groups and the control group neither in plasma nor in microdialysis samples. CONCLUSION: Hypoxia leads to rapid release of cytokines in plasma and cerebral microdialysis fluid, and complement activation measured on C3a. However, low-dose nicotine administration did not affect the immune response.

Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment.

AIMS: Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects. MATERIALS AND METHODS: Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨm) (Safranin O) were evaluated at P1 and P7 in the hippocampus. KEY FINDINGS: Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨm at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission. SIGNIFICANCE: This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.

Causes and Terminology in Neonatal Encephalopathy: What is in a Name? Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy or Perinatal Asphyxia.

Neurologic depression in term/near-term neonates (neonatal encephalopathy, NE) is uncommon with modern obstetric care. Asphyxial birth, with or without co-factors, accounts for a minority of NE, while maldevelopment (congenital malformations, growth aberrations, genetic, metabolic and placental abnormalities) plays an enlarging role in identifying etiologic subgroups of NE. The terms NE and hypoxic-ischemic encephalopathy (HIE) have not been employed uniformly, hampering research and clinical care. The authors propose the term NE as an early working-diagnosis, to be supplemented by a diagnosis of NE due to HIE or to other factors, as a final diagnosis once workup is complete.

Key Inflammatory Biomarkers in Perinatal Asphyxia: A Comprehensive Review.

This article summarizes the current evidence regarding inflammatory biomarkers (placental and postnatal) and provides a comprehensive understanding of their roles: (1) diagnostic accuracy to predict the severity of hypoxic-ischemia encephalopathy (HIE), (2) value in assessing treatment responses, and (3) prediction of both short- and long-term neurodevelopmental outcomes. In the early critical stages of perinatal asphyxia, inflammatory biomarkers may guide clinical decision-making. Additional research is required to increase our understanding of the optimal utility of biomarkers to predict the severity, evolution, and developmental outcomes after exposure to HIE.

Ethical and Legal Perspectives on the Treatment of Hypoxic Ischemic Encephalopathy in the Newborn.

Hypoxic ischemic encephalopathy (HIE) in neonates can cause severe, life-long functional impairments or death. Treatment of these neonates can involve ethically challenging questions about if, when, and how it may be appropriate to limit life-sustaining medical therapy. Further, parents whose infants suffer severe neurologic damage may seek recourse in the form of a medical malpractice lawsuit. This study uses several hypothetical cases to highlight important ethical and legal considerations in the care of infants with HIE.

Early automated classification of neonatal hypoxic-ischemic encephalopathy - An aid to the decision to use therapeutic hypothermia.

OBJECTIVE: The study aimed to address the challenge of early assessment of neonatal hypoxic-ischemic encephalopathy (HIE) severity to identify candidates for therapeutic hypothermia (TH). The objective was to develop an automated classification model for neonatal EEGs, enabling accurate HIE severity assessment 24/7. METHODS: EEGs recorded within 6 h of life after perinatal anoxia were visually graded into 3 severity groups (HIE French Classification) and quantified using 6 qEEG markers measuring amplitude, continuity and frequency content. Machine learning models were developed on a dataset of 90 EEGs and validated on an independent dataset of 60 EEGs. RESULTS: The selected model achieved an overall accuracy of 80.6% in the development phase and 80% in the validation phase. Notably, the model accurately identified 28 out of 30 children for whom TH was indicated after visual EEG analysis, with only 2 cases (moderate EEG abnormalities) not recommended for cooling. CONCLUSIONS: The combination of clinically relevant qEEG markers led to the development of an effective automated EEG classification model, particularly suited for the post-anoxic latency phase. This model successfully discriminated neonates requiring TH. SIGNIFICANCE: The proposed model has potential as a bedside clinical decision support tool for TH.

Burst-Suppression EEG Reactivity to Photic Stimulation-A Translational Biomarker in Hypoxic-Ischemic Brain Injury.

The reactivity of an electroencephalogram (EEG) to external stimuli is impaired in comatose patients showing burst-suppression (BS) patterns following hypoxic-ischemic brain injury (HIBI). We explored the reactivity of BS induced by isoflurane in rat models of HIBI and controls using intermittent photic stimulation (IPS) delivered to one eye. The relative time spent in suppression referred to as the suppression ratio (SR) was measured on the contralateral fronto-occipital cortical EEG channel. The BS reactivity (BSR) was defined as the decrease in the SR during IPS from the baseline before stimulation (SRPRE). We found that BSR increased with SRPRE. To standardize by anesthetic depth, we derived the BSR index (BSRi) as BSR divided by SRPRE. We found that the BSRi was decreased at 3 days after transient global cerebral ischemia in rats, which is a model of brain injury after cardiac arrest. The BSRi was also reduced 2 months after experimental perinatal asphyxia in rats, a model of birth asphyxia, which is a frequent neonatal complication in humans. Furthermore, Oxytocin attenuated BSRi impairment, consistent with a neuroprotective effect in this model. Our data suggest that the BSRi is a promising translational marker in HIBI which should be considered in future neuroprotection studies.

Circulating MicroRNAs as a biomarker signature of perinatal asphyxia.

AIM: This study aimed to explore whether microRNAs (miRNAs) could serve as biomarkers of perinatal asphyxia and whether they were correlated with severity of brain magnetic resonance imaging. METHODS: We prospectively enrolled 26 full-term newborns, including 10 with perinatal asphyxia and 16 healthy controls. Plasma samples were collected at 0-6 h and 7 days of age. Encephalopathy was classified according to modified Sarnat staging. Magnetic resonance imaging was performed in surviving infants within 30 days of birth, and a score was established. We used next-generation sequencing to explore differentially expressed miRNAs, which were then further validated using quantitative reverse transcription real-time polymerase chain reaction (RT-PCR). RESULTS: A significantly lower expression of miR-486-5p was found at 0-6 h of age in the asphyxiated newborns compared with the healthy controls (p = 0.005). The area under the receiver operating characteristic curve (AUC) of miR-486-5p at 0-6 h of age to differentiate the perinatal asphyxia group from the healthy control group was 0.831, and the AUC to differentiate newborns eligible for therapeutic hypothermia from others was 0.782. In addition, a lower expression of miR-486-5p at 7 days of age was noted in the asphyxiated newborns with adverse outcomes compared to those with normal outcomes. CONCLUSION: MiR-486-5p may be a biomarker of perinatal asphyxia in newborns, and further research is warranted to clarify its role.

Capillary blood parameters are gestational age, birthweight, delivery mode and gender dependent in healthy preterm and term infants.

OBJECTIVES: The measurement of blood pH and gas analytes (BPGA), soon after birth, constitutes the first-line standard of care procedure in high-risk newborns. However, no data is available in capillary blood on perinatal bias such as gestational age (GA), weight at birth (BW), delivery mode, and gender. The aims of the present study were to investigate whether in a cohort of healthy preterm (PT) and term (T) infants BPGA were GA, BW, delivery mode and gender dependent, thus affecting BPGA reliability as diagnostic test. METHODS: We performed a prospective case-control study in 560 healthy infants (PT: n=115, T: n=445). BPGA was measured within 24-h from birth. Perinatal characteristics, outcomes, and clinical examination were also recorded. RESULTS: PT infants showed higher (p<0.001) carbon dioxide partial pressure (pCO2), fraction of fetal hemoglobin (HbF), base excess (BE), bicarbonate (HCO3), and lower lactate (Lac) levels. When corrected for delivery mode, higher (p<0.001) HbF, BE, HCO3, and lower Lac levels were found. Similarly, higher (p<0.05, for all) pCO2, HbF, BE, HCO3 and lower Lac levels were found between female and male PT and T infants. Repeated multiple logistic regression analysis showed that BPGA was GA, BW, delivery mode and gender dependent. CONCLUSIONS: The present results showing that BPGA can be affected by a series of perinatal outcomes open the way to further investigations providing longitudinal BPGA reference curves in the transitional phase, thus empowering BPGA role as a reliable diagnostic and therapeutic strategies efficacy marker.