Search Results (149)

Umbilical cord mesenchymal stromal cells (UC-MSCs) are a key element of regenerative medicine due to their ability to secrete growth factors that stimulate proliferation and angiogenesis, and modulate the inflammatory response. Despite their widespread use, the influence of the perinatal microenvironment on their biological properties remains poorly understood. The aim of this study was to assess the influence of pH and blood gas parameters in umbilical cord blood on the global transcriptomic profile of UC-MSCs and to analyze the correlation between the metabolic status of the newborn and the expression of key trophic factors: EGF, FGF2, FGFR1, FGFR3, GDNF, HGF, IGF1, NES, NGF, and PGF. Methods: The study was conducted in two stages. In the first phase, transcriptomic screening was performed using Affymetrix HuGene 2.0 ST microarray on cells isolated from three environmental groups defined by cord blood pH: acidic (pH < 7.35), physiological (7.35–7.39), and alkaline (pH ≥ 7.4). In the second phase, the results were validated using qPCR on an expanded study group (N = 50). Gene expression levels (RQ) were related to blood gas parameters (pH, pCO₂, pO₂, cHCO₃) and the presence of clinical features of threatened neonatal asphyxia. Results: Microarray analysis revealed that environmental pH acts as a molecular phenotypic switch. Under low pH conditions (<7.35), a shift in cell profile from proliferative to structural–migratory was observed. Significant overexpression of genes responsible for extracellular matrix (ECM) organization and adhesion (e.g., COMP, DCN, LUM, FMOD) was observed, while pathways related to cell cycle and cell division (↓CDK1, AURKA, TOP2A) were downregulated. qPCR validation confirmed these observations, demonstrating a strong positive correlation between blood pH and the expression of regenerative mediators: FGFR1 (r = 0.28), EGF (r = 0.30), NGF (r = 0.39), and IGF1 (r = 0.30). A negative correlation was also found between carbon dioxide pressure (pCO₂) and the expression of NGF, FGFR1, and EGF. A significant clinical finding was that in newborns diagnosed with threatened asphyxia, EGF, FGFR1, and NGF gene expression was significantly reduced, indicating impaired trophic potential of the cells in response to metabolic stress. Conclusions: These results indicate that cord blood gas parameters are critical regulators of the genetic activity of UC-MSCs. Metabolic and respiratory acidosis not only inhibit the cells’ proliferative potential but also force them into a matrix remodeling mode, permanently modifying their transcriptomic profile. This suggests that the neonatal acid–base status may serve as an objective indicator of the “biological quality” of isolated stromal cells, which has significant implications for their future applications in cell therapies. Full article

Renal venous thrombosis (RVT) is a location of unusual-site venous thromboembolism. RVT occurs more commonly in males, and shows a bimodal age distribution, with a neonatal and adult peak. Abdominal malignancies and nephrotic syndrome are prominent risk factors in adults, whereas hypotension, birth asphyxia, sepsis, umbilical venous catheters and prematurity are the predominant causes in children. The most common symptoms of RVT include abdominal pain and macroscopic haematuria. A palpable abdominal mass is often observed in neonates, while antenatal RVT may present with signs of foetal distress. Bilateral RVT can lead to acute renal failure. Anticoagulation is the cornerstone of treatment, traditionally with unfractionated heparin, low molecular weight heparin and vitamin K antagonists, although recent evidence is emerging on the use of the direct oral anticoagulants in selected RVT patients. Endovascular procedures (e.g., local thrombolysis or mechanical thrombectomy) are usually reserved for more severe cases, such as bilateral acute RVT causing kidney dysfunction. Outcome data show variability in mortality rates, with some adult cohorts reporting high mortality linked to underlying malignancies and other comorbidities. In paediatric cohorts, mortality is low, but RVT can lead to long-term complications, including kidney atrophy, kidney dysfunction and hypertension. This narrative review aims to synthesise the current evidence on RVT, with a particular focus on anticoagulant prophylaxis and treatment, and clinical outcomes in adult and paediatric populations. Full article

Perinatal asphyxia is a major contributor to neonatal morbidity and mortality, particularly among preterm infants, whose brains are highly vulnerable to hypoxic–ischemic injury. The germinal matrix (GM), owing to its vascular fragility and high metabolic demand, is especially susceptible in this context. This study analyzed 118 germinal matrix samples from neonates, stratified into three groups according to gestational age—Extremely Preterm (EP), Late Preterm (LP), and Term (T)—to investigate the immunopositivity of hypoxia-inducible factor 1-alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF), correlating these findings with gestational age, the presence of asphyxia, neuronal injury, and survival time. BDNF expression showed a positive association with postnatal survival in neonates without neuronal injury (ρ = 0.309; p = 0.012). Linear regression analysis further demonstrated that BDNF immunopositivity was a significant predictor of survival time, with each 11.82% increase in positive staining corresponding to an additional predicted hour of survival (p < 0.001). HIF-1α expression was positively associated with survival in asphyxiated extremely preterm neonates (ρ = 0.492; p = 0.024) and demonstrated a strong correlation that approached, but did not reach, conventional statistical significance in late preterm neonates with neuronal injury (ρ = 0.949; p = 0.051). Collectively, these findings suggest a complementary role for BDNF and HIF-1α in neonatal neuroprotective responses, with BDNF showing potential as a prognostic biomarker in neonates without neuronal injury and HIF-1α reflecting adaptive responses to hypoxic–ischemic stress in a gestational age-dependent manner. However, additional studies are required to validate these associations and further clarify their prognostic and therapeutic relevance in neonatal hypoxic–ischemic conditions. Full article

Neonatal hypoxic–ischemic encephalopathy (HIE) remains a critical neurological emergency resulting from perinatal asphyxia, often leading to lifelong neurodevelopmental disabilities or mortality. The accurate and timely grading of HIE severity is paramount for initiating therapeutic interventions such as therapeutic hypothermia. This work proposes a diagnostic framework that uses long-duration electroencephalogram (EEG) recordings through a hierarchical classification strategy and advanced sequence modeling. A Hybrid Mamba-inspired architecture was developed to effectively capture long-range temporal dependencies in multi-channel neonatal EEG while maintaining computational efficiency. In order to enhance clinical consistency and initialize the models appropriately, a Self-Supervised Learning step based on Masked Signal Modeling is implemented with a mask ratio of 30%. The model structure takes into consideration clinically verified biomarkers, including the suppression ratio, Delta–Alpha Ratio, Spectral Edge Frequency, and Rhythmicity Index, extracted from signals at a microvolt level prior to normalization for physiological interpretability purposes. These features are combined with waveforms using feature gating. In an experiment conducted on a dataset of 169 records using 5-fold subject-wise cross-validation, the designed Hybrid Mamba-based model achieves significant stability and generalizability, achieving an accuracy score of 90%, with an average accuracy of 88.45% ± 6.8% per hierarchical level. Full article

Background/Objectives: Birth asphyxia is a frequent neonatal complication in humans. Its outcome is variable, and the factors underlying this variability remain incompletely understood. Maternal gut microbiome impairment has been proposed as one factor that may influence offspring neurodevelopment, especially when the immature brain is exposed to additional vulnerability such as perinatal asphyxia (PA). Building on our previous maternal microbiome disruption model and on our prior observation that electroencephalography (EEG) reactivity to photic stimulation under deep anesthesia detects functional impairment two months after PA, we assessed whether this reactivity was further impaired after prolonged gestational antibiotic administration and whether probiotics modulated this effect. Methods: Wistar dams received antibiotics, probiotics, antibiotics with probiotics, or control treatment, and offspring underwent PA. Adult EEG reactivity to photic stimulation was assessed during chloral hydrate-induced burst suppression. Burst count reactivity (BCR) was used as the primary event-based readout of stimulus-evoked burst recruitment and was compared with the suppression-ratio-based burst-suppression reactivity index (BSRi). Results: Burst suppression remained reactive to photic stimulation in all groups. BCR was lower after gestational antibiotic treatment than in controls. The magnitude of the effect was attenuated by probiotics coadministration. BSRi showed the same overall pattern. Conclusions: Prolonged gestational antibiotic exposure increased the severity of perinatal asphyxia as measured by EEG reactivity in the adult offspring. The converging BCR and BSRi results support burst-suppression reactivity as a functional neurophysiological readout in this PA model and support further methodological development of EEG reactivity measures for translational studies of hypoxic–ischemic brain injury. Full article

Background: Birth asphyxia is a leading cause of neonatal mortality. More than half of these deaths are due to low-quality care. Objectives: To describe the frequency, sequence, timing, and duration of interventions after birth and newborn outcomes. Methods: This prospective observational study in rural Tanzania included newborns ≥28 weeks gestation. Trained research assistants observed and recorded all deliveries and resuscitations 24 h a day, 7 days a week, logging interventions in real time using the Liveborn Observation app. Results: Of 2564 newborns born, 2431 (94.9%) were enrolled in the study. Macerated stillbirth (n = 52), newborns with no parental consent (n = 67) or incomplete Liveborn data (n = 14) were excluded. Additionally, 2193/2431 (90.2%) newborns did not receive bag-mask ventilation (BMV), and 1755/2431 (72.2%) started breathing before 30 s from birth at median (quartiles) 6 (3, 13) s, 438/2431 (18.0%) started breathing beyond 30 s at 49 (38, 67) s. Moreover, 238/2431 (9.8%) received BMV at 82 (54, 120) s after birth, 1/3 within the first min. Finally, 159/238 (66.8%) were suctioned for 26 (17, 40) s. The first suction sequence was initiated at 44 (24, 78) s after birth. In 24/238 (10.1%) newborns, BMV continued for more than 10 min, with an increased risk of dying within 24 h (RR = 4.26, 95% CI; 1.3–10.0, p = 0.016) and seven days (RR = 8.14, 95% CI; 3.5–17.6, p < 0.001) compared to those ventilated for less than 10 min. Conclusions: Almost 10% of newborns received BMV at birth, but only one-third were ventilated within the first recommended minute. Excessive use of suctioning likely delayed the start of BMV, and prolonged ventilation beyond 10 min was associated with higher mortality. Full article

Background: Preterm birth, the leading cause of neonatal mortality, is associated with reduced nephron endowment and an increased risk of kidney disease in later life. In preterm infants, the interruption of nephrogenesis leads to a lower nephron number and structural abnormalities. Prenatal factors such as intrauterine growth restriction, and postnatal factors including nephrotoxic medications, patent ductus arteriosus, perinatal asphyxia, and infections contribute to this deficit. Ultrasound is a key tool for assessing renal volume at birth and can, when indexed to body weight, be used to estimate nephron endowment, which is known to vary widely among individuals. Methods: This study analyzed 52 preterm infants with birth weight < 1000 g, assessing combined renal volume (sum of right and left kidney volumes) indexed to body weight. Results: The mean combined kidney volume-to-body weight ratio was 12.12 (SD = 2.03). Values below the 10th percentile (9.46) or more than one standard deviation below the mean (10.11) may indicate nephron deficiency at birth. Conclusions: Standardized ultrasound-based parameters enable the early identification of neonates at risk for nephron deficit, supporting targeted preventive strategies. Long-term follow-up is essential to detect early renal functional impairment and reduce the risk of chronic kidney disease. Full article

Background: Neonatal mortality remains a significant public health challenge in Ethiopia. Despite efforts to implement key evidence-based interventions, their coverage and utilization remain low. The Saving Little Lives (SLL) program aims to scale-up a Minimum Care Package (MCP) of synergistic, life-saving interventions for all liveborn neonates, with a focus on preterm and low birth weight (LBW) infants, across 290 hospitals in Ethiopia (206 primary, 69 general, and 15 referral hospitals), representing 82% of all hospitals in the country at the time of the study, and evaluate the impact on neonatal mortality. Methods: A non-randomized stepped-wedge trial will be conducted to evaluate the impact of implementing the SLL MCP interventions. Quantitative evaluation data will be collected from 36 primary hospitals, selected from 206 primary hospitals across four regions, receiving the interventions. An independent evaluation research assistant will be deployed in each of the hospitals to collect data using Open Data Kit (ODK) through interviewing mothers before discharge, on the 29th day of life if discharged, and reviewing medical records. A mixed-method, cross-sectional formative assessment will be conducted prior to implementation, employing quantitative facility assessment and qualitative interviews with mothers, healthcare providers, and facility managers. This will be followed by continuous program learning assessment once implementation begins. Descriptive data will be presented using numbers, percentages, tables, and graphs. Regression modeling and generalized estimating equations (GEEs) will be used to estimate the impact of the SLL MCP interventions. Qualitative data will be gathered through in-depth interviews, digitally recorded, transcribed, and thematically analyzed using ATLAS.ti Version 7.5 software to assess facility readiness, barriers, and enablers of implementing the SLL MCP interventions. Expected Outcome: We hypothesize that achieving 80% coverage of the SLL MCP interventions among eligible neonates will result in a 35% reduction in neonatal mortality at implementation facilities. Full article

Background/Objectives: Neonates with hypoxic–ischemic encephalopathy (HIE) are born in delivery facilities with different levels of neonatal care. The objective of this study was to investigate differences in the incidence of HIE and postnatal management between different levels of neonatal care in delivery facilities. Methods: This is a retrospective, multi-center cohort study of neonates with moderate-to-severe HIE receiving therapeutic hypothermia (TH) in the Canton of Zurich, Switzerland, registered in the Swiss National Asphyxia and Cooling Register between 2015 and 2023. Incidences of HIE receiving TH were calculated for all delivery facilities according to the national levels of neonatal care on site (Level I—basic; Level IIB—intermediate (no Level IIA facility in the Canton of Zurich); Level III—intensive neonatal care). Perinatal characteristics and variables on transport and outcomes were compared between neonates born in Level I and Level IIB facilities (the majority of the HIE population) and reported for neonates born in all other facilities (for completeness). Results: A total of 173 neonates (79 (45.7%) born in Level I; 80 (46.2%) in Level IIB; 9 (5.2%) in Level III; 5 (2.9%) in birthing centers) were admitted to a neonatal cooling center to receive TH. The average number of annual cases of HIE receiving TH per facility was 0.67 (0.11–1.50) in Level I and 2.22 (0.22–3.11) in Level IIB facilities (p = 0.088), respectively. There was no difference in Apgar score, worst pH (within 60 min after birth) and the severity of encephalopathy between neonates born in Level I and Level IIB facilities. Neonatal transport team requests were initiated earlier in Level I facilities (median 12 vs. 34 min of life, p < 0.001). There was no difference in age at initiation of TH (median 3 vs. 3 h, p = 0.431) and the time when target temperature was reached (median 4 vs. 4 h, p = 0.431) between neonates born in Level I and Level IIB facilities. Conclusions: The level of neonatal care available in delivery facilities influenced the management of neonates with HIE receiving TH. Full article

Background: Neonatal myocytes rely predominantly on glycolytic metabolism for survival during hypoxic conditions. During asphyxia, metabolic pathway dysregulation impairs cardiac myocyte contractility. Co-administration of dextrose and insulin may help restore metabolic homeostasis and improve cardiac function. Methods: Following blinded randomization and instrumentation, near-term lambs (138–140 days gestational age) were asphyxiated by umbilical cord occlusion until complete cardiac arrest, followed by 7 min of continued arrest to model severe asphyxia. Return of spontaneous circulation (ROSC) was defined as heart rate ≥ 100 beats per minute (bpm) and diastolic blood pressure ≥ 20 mmHg. Results: The incidence of ROSC was 3/6 in the control group compared to 5/5 in the experimental group receiving dextrose–insulin therapy, although this difference did not reach statistical significance. Conclusions: In this proof-of-concept study using a near-term ovine model of prolonged asphyxial cardiac arrest, dextrose and insulin co-administered with epinephrine were associated with improved ROSC rates although could be an association. Larger studies are needed to confirm these findings and evaluate clinical translation Full article

Background/Objectives: The renin–angiotensin–aldosterone system (RAAS) is pivotal for neonatal circulation and renal adaptation; however, postnatal changes in serum renin and aldosterone immediately after birth remain unclear. This study aimed to establish postnatal changes in these hormones at birth and over the first week of life. Methods: We retrospectively analyzed 374 neonates admitted to Kobe University Hospital between October 2020 and September 2023, with serum renin and aldosterone measured on days 0 and 5 of life. Exclusion criteria were multiple congenital anomalies, severe asphyxia, major peripartum hemorrhage, and in utero exposure to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Hormone levels were compared between term and preterm infants, and correlations with gestational age were assessed. Results: Serum renin concentrations were higher on day 0 than on day 5 (median 99.9 pg/mL [2.6–773.3] vs. 19.9 pg/mL [0.6–2304], p < 0.0001), and aldosterone concentrations similarly decreased (714 pg/mL [6.9–6334] vs. 551 pg/mL [0–11,930], p < 0.0001). At birth, renin and aldosterone levels did not differ significantly between groups. By day 5, both renin (32.8 pg/mL [0.6–2304] vs. 14.5 pg/mL [0.6–208]) and aldosterone (689 pg/mL [4–11,930] vs. 471 pg/mL [13–4697]) concentrations were significantly higher in preterm than in term neonates (p < 0.0001). Conclusions: This study describes early postnatal changes in renin and aldosterone, with higher concentrations at birth than on day 5 and persistently elevated levels in preterm infants. These findings indicate increased RAAS activity in preterm neonates and suggest a greater vulnerability to fluid, electrolyte, and blood pressure instability during early life. Full article

Perinatal asphyxia (PA) remains a common cause of neonatal death and long-term disability, with an incidence of 20 per 1000 live births. Even mild PA, without significant neurological distress at birth, is linked to neurodevelopmental disorders. Premature babies are at high risk for both PA and long-term neurobehavioral deficits. The use of peripherally inserted central venous catheters in neonatal intensive care units has reduced mortality and morbidity in preterms. Given their prevalent use and associated complications, such as thrombosis, the present study aimed to investigate the effects of hypoxia associated with the ligation of the external jugular vein (JH model) in 5-day-old mice, whose central nervous system development shares similarities with that of human preterms. Diffuse white matter (WM) injury is associated with later neurodisabilities following very premature birth before 32 weeks of gestation. The present study aimed to investigate whether the murine JH model replicates a key phenotype of non-cystic WM injury, namely permanent hypomyelination and sensorimotor deficits. The second aim was to determine whether sodium phenylbutyrate (PBA), which is already prescribed in neonates for another indication, could prevent these disabilities. JH induced lasting dysmyelination in males, not prevented by PBA, contrary to the discrete JH-induced neurobehavioral deficits observed in both sexes in the short and long term. Full article

Hypoxic–ischaemic encephalopathy (HIE) is a major cause of neonatal brain injury and is associated with a high rate of death and lifelong disability. Its pathogenesis is still poorly understood, and there is no proven treatment for preterm infants. Therapeutic hypothermia for term and near-term infants partially improves outcomes, highlighting the need to target additional mechanisms. This review evaluates evidence that necrosis and necroptosis contribute materially to evolving brain injury in both term and preterm brains. Serial imaging studies suggest that lesions typically develop over many days after birth for term infants and over many weeks after birth for preterm infants. Growing evidence from animal studies shows that severe white matter injury can be mediated by programmed necroptosis. In particular, lesions that evolve late after acute HI are characterised by necrosis in association with agglomerations of microglia, with little apoptotic cell death. Critically, preclinical studies in large and small animals show that outcomes can be dramatically improved by very delayed intervention after HI including with cell therapy, anti-inflammatory agents, and endogenous neurotrophins. These findings strongly support the hypothesis that there may be a window of therapeutic opportunity for days or even weeks after birth to prevent delayed necrotic lesions. Full article

Neonatal hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term disability, despite therapeutic hypothermia (TH) treatment, underscoring the need for further preclinical research. In the present study, we compared the neuroprotection afforded by TH and inhaled molecular hydrogen (H₂) treatment in a translational newborn pig HIE model. Following 20 min of asphyxia induced by a hypoxic/hypercapnic gas mixture, piglets were reoxygenated and monitored for 48 h. Animals were randomly assigned to normothermia, continuous H₂ ventilation (2.1%), or TH (33.5 °C for 37 h followed by slow rewarming) groups. Physiological parameters, electroencephalography (EEG), visual evoked potentials (VEPs), and neuropathology were assessed. TH eliminated post-asphyxia seizures and improved VEP latency, while H₂ delayed seizure onset and increased quantitative EEG markers of signal complexity. Neuropathology revealed severe thalamic injury in normothermic controls, which was significantly attenuated by both H₂ and TH, while neocortical, hippocampal, and basal ganglia injury was less extensive and not significantly altered by either of the neuroprotective interventions. These findings demonstrate that continuous H₂ inhalation provides neuroprotection in HIE comparable to TH, particularly in the thalamus. H₂ also exerts distinct electrophysiological effects, suggesting its therapeutic potential as a treatment for neonatal HIE. Full article

Background: There is inadequate evidence to support recommendations for the delayed clamping of umbilical cords in preterm neonates who are born non-vigorous. Objective: In a preterm bradycardic ovine model, our objective was to compare the effects of early cord clamping with ventilation (ECCV) and various time periods of delayed cord clamping with ventilation (DCCV) at 1 min (DCCV1), 2 min (DCCV2), 3 min (DCCV3), 4 min (DCCV4), and 5 min (DCCV5). The primary composite outcome was (i) incidence of achieving a combined heart rate (HR) ≥ 100 bpm and preductal saturation (SpO₂) ≥80% by 5 min, and (ii) time to attain this outcome. Secondary outcomes were to evaluate gas exchange/hemodynamics. Methods: 32 preterm lambs of 126–128-day gestational age were randomized to one of six groups: ECCV (n = 5), DCCV1 (n = 6), DCCV2 (n = 5), DCCV3 (n = 6), DCCV4 (n = 6), and DCCV5 (n = 4). Asphyxia was induced by umbilical cord occlusion to attain a HR ≤ 90 beats per minute (bpm). Results: All lambs in DCCV5 achieved a primary composite outcome by 5 min. The time taken to achieve the primary composite outcome in DCCV5 was significantly lower (p = 0.02). Partial pressure of arterial carbon dioxide (PaCO₂) was significantly lower (p = 0.0001) in DCCV5. Peak pulmonary blood flow (PBF) was significantly higher (p = 0.0001) in DCCV5 while peak carotid blood flow (CBF) was highest in the ECCV (p < 0.0001) compared to other groups. Conclusions: In a preterm ovine model of asphyxia, resuscitation with an intact umbilical cord for 5 min increased the incidence and reduced the time to achieve the primary composite outcome, while also improving gas exchange by enhancing pulmonary blood flow, compared to shorter durations of DCCV and ECCV. These findings suggest that DCCV for 5 min may offer physiological advantages in the resuscitation of non-vigorous preterm neonates, warranting further investigation in clinical settings. Full article