BACKGROUND AND PURPOSE:Neonatal hypoxic-ischemic encephalopathy (HIE) remains a leading cause of mortality and long-term morbidities, and therapeutic hypothermia (TH), while the standard of care, is not universally effective. The objective of the study was to use T2* values as a surrogate marker of myelination to characterize early myelination after HIE and explore whether sildenafil, used as an adjunct to TH, is associated with improved myelination. MATERIAL AND METHODS:This prospective neuroimaging study included neonates with HIE treated with TH; a subset of neonates with MRI-confirmed brain injury received sildenafil in addition to TH. Myelination was assessed using a T2* mapping. T2* values were measured in eight brain regions at three time-points (days 2, 10, and 30). T2* values were compared among neonates without brain injury treated with TH alone (NoBI+TH), neonates with brain injury treated with TH alone (BI+TH), and neonates with brain injury treated with TH plus sildenafil (BI+TH/S). RESULTS:A total of 167 MRI scans were obtained from 77 neonates: 32 NoBI+TH neonates, 25 BI+TH neonates, and 20 BI+TH/S neonates. On day 2, neonates with brain injury exhibited significantly higher T2* values in the thalamus, posterior limb of the internal capsule [PLIC], anterior white matter [AWM], and anterior corpus callosum [ACC] than the NoBI+TH group. By day 10, elevated T2* values persisted in AWM and ACC in both brain injury groups, and also in PLIC in the BI+TH group. At day 30, T2* values in the BI+TH group remained persistently elevated across these regions, with additional increases in the thalamus, optic radiations [OR], and posterior corpus callosum [PCC]. In contrast, the BI+TH/S group demonstrated significantly lower T2* values in thalamus, PLIC, AWM, OR, ACC, and PCC compared to BI+TH; in several regions (thalamus, PLIC, AWM), T2* values in the BI+TH/S group were no longer different from NoBI+TH. CONCLUSIONS:T2* values were increased after HIE despite TH, consistent with a possible disruption of early myelination. Sildenafil as an adjunct to TH was associated with lower T2* values over the first month of life, suggesting a potential neurorestorative effect on myelination.

BACKGROUND AND OBJECTIVES:Neonatal encephalopathy (NE)-including hypoxic-ischemic encephalopathy (HIE)-is associated with significant morbidity and mortality worldwide. While data registries provide hypothesis-generating data, aid in quality improvement, and track management/outcomes over time, we recently demonstrated that only 4 of 1,281 (0.3%) variables were collected by all 22 international NE/HIE registries: birth weight, gestational age, and 1- and 5-minute Apgar scores. In response, our team set out to develop a set of common inpatient data elements to enable future harmonization of NE/HIE registry data. METHODS:Using a modified Delphi method, a panel of 14 international NE experts voted to separate the 1,281 variables from our previous study into "core elements," "supplemental elements," or those that "do not need to be collected." Based on the anonymous survey results, we created draft lists of core and supplemental common data elements (CDEs). These lists were further revised through group consensus meetings and external feedback from global registry leaders and attendants at 2 international conferences. RESULTS:The final data forms include 164 core elements and 225 supplemental elements stratified into 11 domains: demographics; pregnancy, labor, and delivery; delivery room; transport; acid-base; therapeutic hypothermia; neuromonitoring and seizures; neuroimaging; laboratory values (other than acid-base); hospital course; and discharge. DISCUSSION:The CDEs are the first of several important steps to further standardize research and reporting of NE/HIE investigations to perform more efficient and powerful clinical research in the field moving forward. Future studies need to establish a clinical and research definition of HIE and develop CDEs for collecting long-term, family-centered follow-up data postdischarge.

We conducted a retrospective analysis of data collected prospectively from a cohort of 114 neonates with hypoxic-ischemic encephalopathy. Magnetic resonance imaging (MRI) obtained during therapeutic hypothermia (TH) showed 95% concordance with MRI obtained at a median postnatal age of 11 days in regard to injury pattern and severity. These results support MRIs during TH as a reliable tool to assess brain injury, facilitating timely clinical decisions, parental counseling and trial enrollment.

OBJECTIVE:To evaluate the association of intraventricular hemorrhage-neuroprotection bundle (IVH-NB) implementation on intraventricular hemorrhage (IVH) rates in infants born at <29 weeks' gestation. STUDY DESIGN:This multicenter, retrospective, preimplantation and postimplementation cohort study included neonates of <29 weeks' gestation admitted to Canadian neonatal intensive care units (NICUs) participating in the Canadian Neonatal Network. Sites which implemented IVH-NB were identified via a survey. Data were collected for 36 months each for preimplantation and postimplementation periods per NICU, with 1-month washout. Infants with major anomalies or admitted >2 days after birth were excluded. Primary outcome was a composite of severe IVH (grade III/IV) or death ≤ first 7 days. Secondary outcomes included severe IVH, posthemorrhagic ventricular dilatation, and severe neurological injury (severe IVH or periventricular leukomalacia). RESULTS:Seventeen NICUs that implemented IVH-NB were included, contributing a total of 6522 infants (3216 preimplementation and 3306 postimplementation). Postimplementation, deferred cord clamping (56% vs 62%, P < .0001), prophylactic indomethacin (15% vs 19%, P < .0001), and normothermia (50% vs 56%, P < .0001) increased, and cardiopulmonary resuscitation (29% vs 25%, P < .0001) and endotracheal intubation at birth decreased (46% vs 41%, P < .0001). After implementation, aOR for the composite outcome (aOR 1.07, 95% CI 0.84, 1.35), severe IVH (aOR 1.02, 95% CI 0.80, 1.31), and posthemorrhagic ventricular dilatation (aOR 1.18 95% CI 0.78, 1.79) were unchanged. The only bundle component associated with improved outcomes was early patent ductus arteriosus treatment adopted by 2 sites (aOR 0.30, 95% CI 0.17, 0.55). No temporal trend in outcomes was identified. CONCLUSION:In this large multicenter cohort, IVH-NB implementation was associated with improved practices but not with improved outcomes.

Neonatal hypoxic-ischemic encephalopathy (HIE) can cause lifelong neurological impairments. In its tertiary phase, ongoing neuroinflammation creates a toxic environment that promotes neuronal and oligodendrocyte loss. Sildenafil has shown neuroprotective effects in adult models by reducing inflammation and supporting oligodendrocyte survival, but its role in HIE remains unexplored. This study investigated the effects of sildenafil on neuroinflammation and white matter injury in a rat model of term neonatal HIE. Hypoxia–ischemia (HI) was induced in postnatal day 10 (P10) male Long-Evans rats via a left carotid ligation followed by 2 h of hypoxia (8% oxygen). Pups were randomized to receive oral sildenafil or vehicle starting 12 h post-HI, twice daily for 7 days. White matter integrity (corpus callosum and external capsule), oligodendrocyte presence, and glial activation were assessed by histology and immunohistochemistry. Inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA), and signaling pathways were examined by Western blot. Outcomes were compared to sham and untreated HI controls. HI significantly increased number of GFAP + reactive astrocytes and Iba1 + microglia, alongside elevated TNFα and IL-1β levels. Thickness of the corpus callosum and left external capsule was reduced. Sildenafil treatment — particularly at medium and high doses — attenuated astrocytes and microglia activation, restored microglial morphology, and normalized cytokine expression. White matter thickness was significantly improved, with increased numbers of total Olig2 + and mature CC1 + oligodendrocytes. Mechanistically, sildenafil restored p-AKT levels, which suggests involvement of the PI3K/AKT/mTOR pathway. Sildenafil significantly reduced neuroinflammation, improved white matter integrity, and supported oligodendrocyte recovery after neonatal HI. These findings highlight the potential of sildenafil as a neurorestorative therapy during the tertiary phase of injury in neonatal HIE.

OBJECTIVE:To evaluate the safety and tolerability of higher doses of sildenafil in neonates with hypoxic-ischemic encephalopathy (HIE) and brain injury. STUDY DESIGN:A phase 1b open-label dose-finding clinical trial in neonates with moderate-severe HIE and confirmed brain injury on a day-2 magnetic resonance imaging during therapeutic hypothermia (TH). Enteral sildenafil was administered every 12 hours (q12 h) for 7 days. All participants received an initial dose 2.0 mg/kg, and a second dose of 2.5 mg/kg. Starting from the third dose, group 1 received 2.5 mg/kg q12 h and group 2 received 3.0 mg/kg q12 h. Primary outcome was incidence of dose-limiting toxicities. Secondary outcomes explored day-30 neuroimaging and 18-month neurodevelopment. RESULTS:Among the 30 neonates born between October 2019 and December 2021, 20 displayed day-2 brain injury and 13 received sildenafil (8 in group 1; 5 in group 2). In group 1, 25% (2/8) experienced transient hypotension after the first dose, linked to antiseizure medications. No significant hypotension occurred in group 2 when sildenafil was administered separately. At the 3.0 mg/kg/dose, steady-state sildenafil concentrations persisted beyond TH. Death or significant 18-month neurodevelopmental impairment occurred in 50% (4/8) of group 1 and 60% (3/5) of group 2. Among the survivors, partial recovery of brain injury was seen in 80% (4/5) of group 1 and 75% (3/4) of group 2; cerebral palsy developed in 0% (0/5) and 50% (2/4), respectively. CONCLUSIONS:Enteral sildenafil up to 3.0 mg/kg q12 h was safe and well tolerated in a small single-center cohort of neonates with HIE treated with TH. Phase 2 trials are needed to assess multicenter feasibility and efficacy. TRIAL REGISTRATION:ClinicalTrials.gov NCT04169191.

Worldwide, hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of nervous system disabilities. Therapeutic hypothermia is the current standard-of-care treatment in high-income countries, because it was shown to reduce associated mortality and morbidities. However, up to 29% of treated neonates still experience adverse neurodevelopmental outcomes, and its efficacy in low- and middle-income countries remains debated, highlighting the need for adjunct or alternative therapies. Treatments for HIE targeting neuroprotection and/or neurorestoration are under investigation. Meanwhile, attentive daily management of multiorgan failure during the first days of life continues to be essential to limit further brain injury.

OBJECTIVE:To assess variability among data elements collected among existing neonatal hypoxic-ischemic encephalopathy (HIE) data registries worldwide and to determine the need for future harmonization of standard common data elements. STUDY DESIGN:This was a cross-sectional study of data elements collected from current or recently employed HIE registry data forms. Registries were identified by literature search and email inquiries to investigators worldwide. Data elements were categorized by group consensus. RESULTS:A total of 1281 data elements were abstracted from 22 registries based in 14 countries, including 3 middle-income countries. Registries had a median of 106.5 distinct data elements per registry (range 59-458). The most commonly collected data were related to pregnancy, therapeutic hypothermia, and short-term hospital outcomes. The least consistently collected data were laboratory values other than acid/base status values. Only 4 variables were consistently collected in every registry. Five registries included neurodevelopmental follow-up fields and 5 others linked their data to a separate follow-up registry. CONCLUSION:Many HIE registries are collecting patient data around the world, but there is considerable variability in the number, type, and format of data collected. Future attempts to develop standard common data elements to harmonize data collection globally will be crucial to facilitate worldwide collaboration and to optimize management and outcome of neonatal HIE.

Introduction: Congenital heart disease (CHD) is one of the most common birth defects. Cerebral (cStO2) and renal (rStO2) saturations measured by near-infrared spectroscopy (NIRS) and the corresponding fractional tissue oxygen extraction (FTOE) during the first week of life in neonates with CHD are described comparing those with and without diastolic steal. METHODS:Single-center prospective cohort study (Montreal Children's Hospital, Montreal, QC, Canada) was conducted, including neonates >34 weeks with CHD without chromosomal anomalies. CStO2/rStO2 was monitored from enrollment until day 7 of life. FTOE was calculated using systemic saturation (SpO2) as [SpO2 - (cStO2 or rStO2)]/SpO2. Daily echocardiography was performed during the monitoring period. Random mixed-effects models were constructed to assess the association between NIRS/FTOE and the presence of retrograde postductal aortic flow on last available echocardiography. RESULTS:Among 49 included neonates, 27 (55%) exhibited retrograde flow in the postductal aorta on the last day of monitoring. Prostaglandin exposure was 100% in the retrograde group vs. 27% in the non-retrograde group. CStO2/rStO2 progressively declined in neonates with CHD over the first week of life. Retrograde aortic flow was associated with negative cStO2 (β = -9.1%, 95% CI [-14.3; -3.8]) and rStO2 (β = -8.4%, 95% CI [-14.5; -2.3]). Cerebral FTOE was lower in the non-retrograde group, while renal FTOE was similar between groups. CONCLUSION:During the first week of life, neonates with CHD who displayed retrograde aortic flow exhibited lower cStO2 and rStO2 as well as higher cerebral FTOE. Future studies should evaluate whether these markers in neonates with CHD are modifiable factors that could influence cerebral or renal injury when addressed. .

BACKGROUND:Neonatal encephalopathy (NE) and hypoxic-ischemic encephalopathy (HIE) are linked to significant neurodevelopmental impairments. Magnetic resonance imaging (MRI) is the preferred modality for classifying brain injury severity in HIE, yet considerable variability exists among institutions in terms of MRI timing, protocols, injury classification, and scoring systems for predicting long-term outcomes. METHODS:A Canadian taskforce comprising radiologists and neonatologists was established to develop a consensus on the optimal timing of brain MRI, appropriate MRI protocols, and a unified approach to the classification and scoring of brain injury in infants with NE secondary to hypoxic-ischemic insult. The taskforce proposed a radiological classification and scoring system that is both simplified and modified from previously validated systems. RESULTS:The consensus resulted in a standardized MRI protocol and a streamlined classification system designed to reduce interinstitutional variability. This proposed system offers a uniform framework for assessing the severity of brain injury and serves as a potential tool for predicting long-term neurodevelopmental outcomes. CONCLUSION:Once validated, the proposed radiological classification and scoring system can be applied across centers to facilitate consistent outcome comparisons, improve prognostication for neonates with NE/HIE, and enhance the quality of family counseling regarding long-term neurodevelopmental prospects.

Background: Neonatal encephalopathy (NE) and hypoxic-ischemic encephalopathy (HIE) are linked to significant neurodevelopmental impairments. Magnetic resonance imaging (MRI) is the preferred modality for classifying brain injury severity in HIE, yet considerable variability exists among institutions in terms of MRI timing, protocols, injury classification, and scoring systems for predicting long-term outcomes. Methods: A Canadian taskforce comprising radiologists and neonatologists was established to develop a consensus on the optimal timing of brain MRI, appropriate MRI protocols, and a unified approach to the classification and scoring of brain injury in infants with NE secondary to hypoxic-ischemic insult. The taskforce proposed a radiological classification and scoring system that is both simplified and modified from previously validated systems. Results: The consensus resulted in a standardized MRI protocol and a streamlined classification system designed to reduce interinstitutional variability. This proposed system offers a uniform framework for assessing the severity of brain injury and serves as a potential tool for predicting long-term neurodevelopmental outcomes. Conclusion: Once validated, the proposed radiological classification and scoring system can be applied across centers to facilitate consistent outcome comparisons, improve prognostication for neonates with NE/HIE, and enhance the quality of family counseling regarding long-term neurodevelopmental prospects. (c) 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE:Study the association between cardiac biomarkers and echocardiography parameters of ventricular performance in neonates with neonatal encephalopathy (NE). METHODS:Prospective observational study (2016-2021) of neonates undergoing therapeutic hypothermia (TH). Neonates with brain injury had repeated echocardiography and biomarkers measurements on day of life (DOL) 2, 3, 4, and 10. Pearson correlation and generalized linear mixed effect models were used to account for repeated measurements. Receiver operating characteristic curves were constructed to assess sensitivity/specificity. RESULTS:56 neonates had 128 measurements. Creatine Kinase (CK) and cardiac troponin-I (CTn-I) were associated with right ventricular (RV) function. A CK of 1961 U/L and a CTn-I of 91 ng/L identified low Tricuspid Annular Plane Systolic Excursion (<7 mm) with sensitivities of 93% and 79%, and specificities of 55% and 74%, respectively. CONCLUSIONS:Elevated CK and CTn-I were associated with decreased RV performance. Trending these markers can be used to suspect altered RV function and may flag optimal timing for evaluation(s) by echocardiography during TH.

To assess the association between day-2 cardiac function and brain injury in neonates with HIE undergoing therapeutic hypothermia. A prospective single-center study (2016–2021) including neonates ≥36 weeks gestation with moderate to severe HIE treated with TH. Brain injuries were evaluated using MRI and a validated scoring system, and logistic regression identified cardiovascular predictors. Among 55 neonates, 33 (60

Introduction: The aim of the study was to explore the relationship between near-infrared spectroscopy parameters (cerebral saturation [CSat] and corresponding cerebral fractional tissue oxygen extraction [cFTOE]) with resistive (RI) and pulsatility indices (PI) of the anterior cerebral artery (ACA) obtained simultaneously in neonates with congenital heart defect (CHD) during the first week of life. METHODS:Prospective observational study on neonates ≥35 weeks with CHD was conducted. Cerebral FTOE was based on concomitant pre-ductal oxygen saturation (SpO2) during CSat measurement. ACA was assessed via Doppler ultrasound (US). Continuous CSat/SpO2 monitoring was collected during the first week of life. Daily ACA Doppler was obtained from day 1-7. RESULTS:A total of 142 concomitant measurements of NIRS and US parameters during the first week of life were collected in 34 neonates with various CHD. Mixed effect models showed significant association between CSat/cFTOE and time-corresponding RI-ACA (p = 0.02 and 0.005) and PI-ACA (p = 0.006 and 0.002), respectively. A 0.1-point increase in RI was associated to a 2.3% decrease in CSat and a 3-point increase in cFTOE. A 0.1-point increase in PI was associated to a 0.9% decrease in CSat and 1.1-point increase in cFTOE. CONCLUSIONS:In neonates with CHD during their first week of life, lower CSat and higher cerebral FTOE were associated with elevated RI and PI values of the ACA obtained simultaneously. Future research should assess whether a multimodal bedside approach to monitoring cerebrovascular hemodynamics can facilitate early detection of cerebral hypoperfusion and prevent brain injury, as well as adverse neurodevelopmental outcomes in this vulnerable population. .

Objective: To evaluate sildenafil’s effects on cardiac function and hemodynamic stability in neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Study Design: Two phase Ib trials (SANE-01/02; NCT02812433, NCT04169191) enrolled neonates with MRI-confirmed brain injury receiving sildenafil (n=20) or placebo (n=4) enterally (2.0–3.0 mg/kg q12h × 14 doses). Targeted echocardiography, speckle-tracking, and biomarkers were measured on days 2–10. Results: Sildenafil improved left and right ventricular outputs (p=0.02; p<0.001), decreased pulmonary hypertension markers (p=0.001), and enhanced ventricular strain (p<0.001 for LV; p=0.02 for RV). Inotropic support and lactate levels declined, and cardiac biomarkers improved. Improvements were greatest during TH. Conclusion: Sildenafil was well tolerated and improved cardiovascular function, supporting its potential as an adjunctive therapy in HIE.

Therapeutic hypothermia (TH) significantly reduces mortality and morbidities in neonates with Neonatal Encephalopathy (NE). NE may result in neonatal death and multisystem organ impairment, including acute kidney injury (AKI). Our study aimed to utilize machine learning (ML) methods to predict the outcome of TH-treated NE neonates developing AKI and death during TH. In this retrospective multinational study, 1149 TH-treated NE neonates and 801 controls were included. AKI was classified using KDIGO neonatal criteria based on serum creatinine measurements. The ML model incorporated gestational age, birth weight, postnatal age, and serum creatinine values. The algorithm used all these covariates to predict one of five outcomes: survival with/without AKI, mortality with/without AKI, and hospitalized non-NE controls. The XGBoost model achieved an AUC of 95% and an accuracy of 75.08% in predicting AKI and survival, surpassing other ML classifiers that demonstrated accuracy levels ranging from 54% to 65%. To our knowledge this is the first ML model trained on multicenter, multinational data specifically aimed at predicting neonates' AKI, death, and survival within the first three days. Our ML scoring systems' code and user interface are freely available ( https://github.com/NUBagciLab/Therapeutic-Hypothermia-Outcome-Classification , https://thprediction.streamlit.app/ ). This tool has potential to support neonatologists to personalize therapies, and to optimize pharmacotherapy for renally cleared drugs.

Neonates with congenital heart disease (CHD) are at risk for adverse neurodevelopmental outcomes. This scoping review summarizes neuromonitoring methods in neonates with CHD. We identified 84 studies investigating the use of near-infrared spectroscopy (NIRS) (n = 37), electroencephalography (EEG) (n = 20), amplitude-integrated electroencephalography (aEEG) (n = 10), transcranial Doppler sonography (TCD) (n = 6), and multimodal monitoring (n = 11). NIRS was used to evaluate cerebral oxygenation, identify risk thresholds and adverse events in the intensive care unit (ICU), and outcomes. EEG was utilized to screen for seizures and to predict adverse outcomes. Studies of aEEG have focused on characterizing background patterns, detecting seizures, and outcomes. Studies of TCD have focused on correlation with short-term clinical outcomes. Multimodal monitoring studies characterized cerebral physiologic dynamics. Most of the studies were performed in single centers, had a limited number of neonates (range 3-183), demonstrated variability in neuromonitoring practices, and lacked standardized approaches to neurodevelopmental testing. We identified areas of improvement for future research: (1) large multicenter studies to evaluate developmental correlates of neuromonitoring practices; (2) guidelines to standardize neurodevelopmental testing methodologies; (3) research to address geographic variation in resource utilization; (4) integration and synchronization of multimodal monitoring; and (5) research to establish a standardized framework for neuromonitoring techniques across diverse settings. IMPACT: This scoping review summarizes the literature regarding neuromonitoring practices in neonates with congenital heart disease (CHD). The identification of low cerebral oxygenation thresholds with NIRS may be used to identify neonates at risk for adverse events in the ICU or adverse neurodevelopmental outcomes. Postoperative neuromonitoring with continuous EEG screening for subclinical seizures and status epilepticus, allow for early and appropriate therapy. Future studies should focus on enrolling larger multicenter cohorts of neonates with CHD with a standardized framework of neuromonitoring practices in this population. Postoperative neurodevelopmental testing should utilize standard assessments and testing intervals.

Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12-18 months of a child's life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia.