BACKGROUND:Appropriate terminology and definitions of neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and perinatal asphyxia (PA) remain controversial. Participant criteria used in therapeutic hypothermia (TH) trials are frequently used as case definitions for NE/HIE/PA but studies are inconsistent. This review aims to assess variations in terminology and case participant criteria between trials for NE/HIE/PA. METHODS:Search strategy retrieved articles from databases (Embase, MEDLINE, CENTRAL, CDSR and WHO) for randomized controlled trials (RCTs) of interventions for NE/HIE/PA using any definition for NE/HIE/PA. Outcomes were a description of the terminology, definitions, and participant criteria. Two reviewers independently screened results. Qualitative results were synthesized in a narrative summary. RESULTS:The search provided 6768 results. 67 were included in the qualitative synthesis. HIE was the most frequently used term (56/67). NE was the least frequent (16/67). Some of the common inclusion criteria were Apgar scores (63/67), metabolic acidosis (58/67), and reduced level of consciousness (57/67). Most frequently employed exclusion criteria were prematurity (63/67), major congenital abnormalities (62/67), and identification beyond 6 h from birth (62/67). DISCUSSION:This review identified variations in terminology and in-trial participant criteria between studies. These results will inform a consensus process for developing a definition and case definition of NE/HIE/PA. IMPACT:Our article demonstrated significant variations in the terminology used to describe the condition of NE/HIE/PA, which demonstrates a need for more consistent definitions in terminology. A broad but meaningful definition of the condition would provide an inclusive approach while permitting subclassifications within the condition, and permitting comparisons and benchmarking across different settings. Developing consistency across these areas, as far as possible, would allow improved interpretation of interventions on long-term prognosis and greater generalizability of trial results.

Amplitude-integrated electroencephalography (aEEG) is widely used in neonatal intensive care units for bedside neuromonitoring, seizure detection, prognostication, and guidance of therapeutic hypothermia. A recent Cochrane systematic review comparing aEEG with conventional video-electroencephalography (cEEG) questioned the value of aEEG for neonatal seizure detection. However, careful interpretation of these findings is warranted. This commentary highlights key methodological limitations of the review, including the inclusion of studies without raw EEG display, heterogeneity in electrode configurations, inconsistent reporting of interpreter expertise, and variable seizure definitions. These factors likely bias pooled estimates toward underestimating the performance of modern aEEG systems when used according to contemporary standards. We emphasize that aEEG should not be evaluated as a substitute for cEEG, but as a complementary bedside modality. Beyond seizure detection, aEEG provides clinically meaningful information through background assessment, early prognostication in hypoxic–ischemic encephalopathy, and longitudinal trend monitoring, particularly in settings where cEEG is unavailable. We conclude that dismissing aEEG technology based on methodologically limited comparisons risks undervaluing an important and pragmatic neuromonitoring tool. Future research and guidelines should prioritize optimized application, standardized protocols, training, and integration with emerging analytic approaches, including artificial intelligence, to support equitable neonatal neurocritical care worldwide.

Background: Neonatal cerebral venous sinus thrombosis (CVST) is associated with intracranial hemorrhage (ICH) and ischemic lesions. There is no scale to characterize the spectrum of brain injury secondary to neonatal CVST. Objective To develop the Neonatal CVST Hemorrhage Score (NeoCVST Score) to characterize ICH and brain injury in neonates with CVST. Methods: This was a retrospective cohort study of neonates with CVST diagnosed using brain MRI/MRV. The NeoCVST Score was developed using the study cohort, integrating elements from previous hemorrhage classification systems and expert consensus. Logistic regression examined associations between NeoCVST score and neurodevelopmental outcomes (Pediatric Stroke Outcome Measure). Interrater reliability was assessed with intraclass correlation coefficient. Results: The study included 100 neonates (77% term and 23% preterm) with CVST. Thrombosis of multiple venous sinuses was present in 62%. ICH was present in 63%. Supratentorial hemorrhage was present in 57% and included germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) grades 1-2 (22%), GMH-IVH grade 3 (15%), parenchymal (43%) and thalamic (18%) hemorrhage. Infratentorial hemorrhage was present in 19% and included cerebellar (18%) and brainstem (4%) hemorrhage. Extra-axial hemorrhage was present in 32% and included epidural (2%), subdural (26%) and subarachnoid hemorrhage (6%). Ischemic brain injury was present in 67% and included lesions in the medullary vein distribution (13%), white matter (54%), basal ganglia (17%) and thalamus (25%). Neurodevelopmental outcomes included 40% with normal outcomes and 60% with neurodevelopmental impairments. NeoCVST total score (OR=1.1, P=0.02) and subscores for thalamic hemorrhage (OR=1.9, P=0.04), thalamic ischemia (OR=2.2, P=0.005) and bilateral thalamic ischemia (OR=2.8, P=0.01) were predictors of adverse neurodevelopmental outcome. Inter-rater reliability showed moderate-good agreement between reviewers with an intraclass correlation coefficient of 0.71. Conclusions: The NeoCVST Score is a simple clinical tool to characterize ICH and brain injury secondary to neonatal CVST. Increasing NeoCVST total score and subscores for thalamic hemorrhage and ischemia were associated with worse neurodevelopmental outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement None ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Research Ethics Board (The Hospital for Sick Children) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data will be made available on request.

BACKGROUND:To assess the probability of benefit and harm with early versus late intervention for post-hemorrhagic ventricular dilatation (PHVD). METHODS:Bayesian logistic regression analysis was conducted using data from 126 preterm infants (64 Early; 62 Late) with progressive PHVD randomized to early (ventricular indices, VI >97th percentile) or late (VI >97th percentile +4 mm) intervention thresholds. Four potential prior distributions were tested: optimistic, skeptical, neutral, and informative. Posterior estimates were generated for secondary brain injury, and death or neurodevelopmental impairment (NDI) at 2 years. RESULTS:Early intervention was associated with smaller ventricles and lower global brain injury scores on term-equivalent age MRI. Across all priors, late intervention was associated with higher odds of adverse outcomes of death or NDI. Posterior odds ratios (OR) for late versus early treatment ranged from 1.56 to 2.42, corresponding to a 91.1-99.7% posterior probability of harm. Under a neutral prior, the estimated OR was 2.09 (95% credible interval 1.01-4.40). The absolute risk difference in the 2-year outcome between groups was 16%, corresponding to a number needed to treat of 7. CONCLUSION:Early, cUS-based intervention for progressive PHVD confers a high probability of improved neuroimaging and neurodevelopmental outcomes at 2 years compared with later intervention. CLINICAL TRIAL REGISTRATION NUMBER:ISRCTN43171322. IMPACT:Bayesian reanalysis of the randomized ELVIS (Early versus Late Ventricular Intervention Study) trial demonstrates a high probability (>90%) that delaying intervention for progressive post-hemorrhagic ventricular dilatation (PHVD) increases the risk of death or moderate to severe neurodevelopmental impairment at 2 years. Early cranial ultrasound-guided intervention was associated with smaller ventricular size and significantly lower global brain injury scores on term-equivalent age MRI, supporting a reduction in secondary brain injury. The absolute risk reduction of 16% translates to a number needed to treat of 7, providing clinically interpretable evidence that earlier intervention is a modifiable strategy to improve neurodevelopmental outcomes in preterm infants with progressive PHVD.

OBJECTIVE:The aim of this study was to evaluate the clinical features and surgical complication rates of preterm infants with posthemorrhagic ventricular dilatation (PHVD) who underwent CSF diversion, comparing early intervention (EI) and late intervention (LI). METHODS:This was a retrospective international multicenter study of infants born at ≤ 34 weeks' gestational age (GA) and treated between 2018 and 2022 for grade III or IV germinal matrix hemorrhage and intraventricular hemorrhage, who required intervention for PHVD. The primary outcome of interest was the rate of postoperative surgical complications. Secondary outcomes were rate of temporizing neurosurgical procedures (TNPs) after initial lumbar puncture (LP) if performed, rate of conversion from TNP to a ventriculoperitoneal shunt (VPS), and overall rate of VPS insertion. Summary statistics and univariable and multivariable logistic regression were performed to determine variables predictive of complications. RESULTS:One hundred seventy infants from 6 centers in the United States, Canada, and the Netherlands were included. Infants at LI centers were more premature (GA 26.7 ± 2.8 vs 29.3 ± 2.4 weeks, p < 0.001) with lower birth weights (BWs; 1004 ± 448 vs 1438 ± 462 g, p < 0.001) compared to those at EI centers. The first neurosurgical intervention occurred at a median day of life after birth (DOL) of 31.5 (IQR 24-45) days at LI centers versus 18 (IQR 13-21) days at EI centers (p < 0.001). Ventricular index (> 97th percentile) at the first neurosurgical intervention (TNP and/or VPS placement) was lower at EI centers (5.05 ± 2.32 vs 12.88 ± 5.70 mm, p < 0.001). Infant weight at the first neurosurgical intervention did not differ between site types (p = 0.466). EI centers had a larger proportion of patients who underwent LP (97% vs 58%, p < 0.001) and smaller proportion who required a VPS after TNP (42% vs 70%, p = 0.002). The overall VPS insertion rate was higher at LI centers (62% vs 30%, p < 0.001). There was no statistical difference in the complication rate between EI and LI centers (11% vs 24%, respectively, OR 0.42, 95% CI 0.12-1.24, p = 0.115). On univariable analysis, lower GA (p = 0.002), lower BW (p = 0.003), later DOL at first neurosurgical intervention (p = 0.035), diagnosis of meningitis before neurosurgical intervention (p = 0.047), and of necrotizing enterocolitis (p = 0.017) during the neonatal intensive care unit admission were predictive of complications. However, only lower GA (p = 0.029) and BW (p = 0.031) remained significant on multivariable analysis. CONCLUSIONS:The neurosurgical complication rate did not differ between EI and LI centers. On multivariable analysis, neurosurgical complications were associated with younger GA and lower BW but not with variables regarding the timing of intervention. These observations support cautious early CSF diversion in more preterm infants with lower BWs.

Abstract Neonatal encephalopathy (NE) following perinatal hypoxia-ischemia (HI) can lead to a wide range of neurodevelopmental consequences, ranging from mild motor problems to severe cerebral palsy, epilepsy, cognitive impairments, and behavioral issues. There is growing recognition of the long-term effects of NE during childhood, but little is known about the outcomes in adulthood, particularly from the perspective of the individuals affected and their families. Existing research primarily relies on outcome measures from neurodevelopmental assessments, which often fail to capture the lived experiences of those affected, limiting our understanding of the meaning and impact of the consequences of NE on their everyday lives. This paper tells the stories of four adults with varying outcomes following NE due to HI, ranging from largely typical development to cerebral palsy to subtle but significant cognitive challenges. Their narratives demonstrate that the long-term consequences of NE are highly variable and influenced by a complex interaction of medical, social, and environmental factors. They shared experiences of challenges, e.g., memory issues, which significantly affect their lives but are not routinely assessed in neurodevelopmental follow-up. Moreover, their narratives underscore that difficulties may emerge or evolve over time, emphasizing the need for ongoing, individualized care. Importantly, the stories of these adults also show that despite the challenges that they have faced and continue to face, they live fulfilling lives that go beyond what results from developmental assessments may indicate. These insights from lived experience experts emphasize the need for a holistic, patient-centered approach in both research and long-term follow-up care.

Methemoglobinemia is a rare but potentially serious complication of lidocaine (LDC) use for local anesthesia in infants and young children, yet its prevalence during continuous systemic infusion for neonatal seizures remains unclear. Given the increasing use of LDC as add-on therapy for neonatal seizures, this retrospective cohort study evaluated methemoglobin (MetHb) levels in 51 neonates with (serial) measurements within 96 h before and after LDC infusion. Methemoglobinemia was defined as MetHb > 2% in arterial or capillary blood gas samples. Prevalence increased from 6% (3/51) before LDC to 47% (24/51) after administration (p < 0.001). Most neonates had mildly elevated MetHb levels (< 5%); three had a MetHb level > 5%, with a highest peak of 9.5%. In one neonate LDC was discontinued due to hypoxemia, the others were asymptomatic. In neonates who developed methemoglobinemia after LDC, the mean time to peak MetHb was 29.1 h (95% CI 11.1-73.3), and mean time to recover to < 2% after the peak was 27.5 h (95% CI 8.4-75.5). Over half of neonates receiving regimen III (> 36 weeks without therapeutic hypothermia [TH]) developed methemoglobinemia, compared to none on regimen IV (with TH). This suggests an association with a higher cumulative dose and longer infusion duration.Conclusion: In conclusion, methemoglobinemia occurred in nearly half of neonates receiving continuous LDC for seizures and was associated with the dosing regimen. It is important to be aware of this complication, especially in infants who develop respiratory deterioration and oxygenation problems following continuous LDC administration.

AIM:To identify and map current knowledge regarding early upper-limb movement in infants from birth to 12 months, which are indicative for development of unilateral spastic cerebral palsy (USCP). METHOD:A scoping review was conducted involving a comprehensive and systematic literature search in PubMed/MEDLINE, Embase, and CINAHL. Articles were screened according to title and abstract and relevant data were extracted. Studies were eligible if they included infants aged 0 to 12 months at risk of developing USCP and reported early upper-limb movement characteristics indicative of USCP. RESULTS:Twelve of 5482 studies were included. Three categories of assessments were recognized: (1) spontaneous upper-limb movements; (2) pre-reaching; and (3) upper-limb skills. Across these categories, asymmetry was observed, namely in spontaneous wrist and digit movements, pre-reaching trajectories, and reduced use of the contralesional hand in infants who developed USCP. From 15 weeks of age onwards, asymmetry was more evident not only in upper-limb movement patterns but also in object-related upper-limb skills. INTERPRETATION:Clinical signs of USCP in upper-limb movements are noticeable from the age of 12 weeks. Preceding signs may be subtle. Three-dimensional motion analysis and wearable sensors may enhance early detection, enabling timely diagnosis and intervention.

Neonatal encephalopathy refers to disturbed neurological function in the neonatal period and has multiple potential aetiologies. A systematic review showed that neonatal encephalopathy, hypoxic-ischaemic encephalopathy, and perinatal asphyxia are often used interchangeably in clinical trials and communications. We aimed to establish an international, consensus-based definition as a preliminary step towards standardising terminology. Findings from a systematic review of definitions guided the creation of a real-time Delphi survey. Three consensus meetings were held to finalise the definition, which was approved by the steering committee. Participants were recruited from a broad range of stakeholder groups, including health-care providers; researchers; parents, family members, guardians, or representatives of children with neonatal encephalopathy; or adults who had neonatal encephalopathy as infants. From Feb 1 to May 31, 2024, the survey received 235 complete and 143 partial responses. Respondents were from 52 countries, with 75 (20%) from low-income and middle-income countries. Although most respondents were health-care workers, 23 (6%) represented parents and caregivers. 62 individuals participated in at least one consensus development meeting. The final definition was organised into primary, secondary, and tertiary domains. The primary domain is as follows: neonatal encephalopathy is a heterogeneous clinical condition characterised by abnormal or impaired brain function with multiple potential causes. It presents with an altered level of consciousness and may include seizures, abnormal primitive and deep tendon reflexes, altered muscle tone, posture or movements, or an abnormal brain-related breathing pattern. Neonatal encephalopathy can be associated with a heightened risk of morbidity and mortality. This Delphi process established a novel consensus definition for neonatal encephalopathy, with contributions from a diverse range of international stakeholders, including families. Adopting consensus-based terminology and definitions will enhance communication among health-care professionals and families, facilitate research and data synthesis, improve the interpretation and application of research findings, and ultimately improve care.

Perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous thrombosis (CSVT) cause significant neurological morbidity, including cerebral palsy, in preterm infants. Compared to term infants, the epidemiology, risk factors, and outcomes of PAIS and CSVT in preterm infants are less well understood. This systematic review aimed to summarize the literature on incidence, risk factors, clinical presentation, neuroimaging, and neurodevelopmental outcomes of PAIS and CSVT in infants born before 37 weeks' gestation. A comprehensive search of PubMed, Embase, and Web of Science for studies from 2004 to 2025 identified 14 eligible studies including 132 infants with PAIS and 57 with CSVT. Incidence rates were higher in infants of lower gestational age. Identified PAIS risk factors included twin-to-twin transfusion syndrome, fetal heart rate abnormalities, and hypoglycemia. Perforator artery strokes were most common, while CSVT frequently involved the transverse sinus. Many risk factors overlapped with term infants but preterm infants showed more prematurity-related complications, longer ventilation, and postoperative states. Neurodevelopmental outcomes were poor, with high rates of impairment and mortality, especially in CSVT. The review highlights urgent needs for larger, controlled studies to improve prevention, early diagnosis, and management in this vulnerable population. IMPACT: This review systematically summarizes incidence, risk factors, neuroimaging patterns, treatment, and outcomes of perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous thrombosis (CSVT) specifically in preterm infants-a group often excluded from previous studies. The findings reveal that preterm infants with PAIS and CSVT have unique and overlapping risk factors (such as twin-to-twin transfusion syndrome and hypoglycemia), often present asymptomatically, and are at high risk for poor neurodevelopmental outcomes and mortality. The review highlights urgent knowledge gaps, especially regarding the safety and effectiveness of anticoagulation therapy in preterm CSVT, and stresses the need for larger studies and targeted strategies to improve recognition, management, and long-term outcomes for this vulnerable group.

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) remains one of the most common neurological conditions in very preterm infants, with the incidence increasing with decreasing gestational age. GMH-IVH is associated with adverse neurodevelopmental outcomes and, for the purpose of prognostication, generally categorized into low-grade, i.e., grade 1 and 2 hemorrhage, and high-grade, i.e., grade 3 hemorrhage and periventricular hemorrhagic infarction. Prognosis, however, depends not only on the grade of GMH-IVH but also on co-occurring preterm brain injuries and downstream effects on brain maturation. In case of low-grade hemorrhage, outcomes are negatively affected by co-occurrence of white matter injury or cerebellar hemorrhage. High-grade hemorrhage, especially periventricular hemorrhagic infarction and when complicated by progressive post-hemorrhagic ventricular dilatation requiring neurosurgical intervention, is associated with a significantly higher likelihood of cognitive, motor, behavioral, and neurosensory impairments. Serial cranial ultrasound throughout the neonatal period is critically important to monitor the evolution of hemorrhage, its complications and overt other brain injury types. Brain MRI has additional value for detecting co-occurring subtle brain lesions and improving neuroprognostication. In this review, we summarize the neurodevelopmental outcomes across GMH-IVH grades and the influence of co-existing preterm brain injuries and secondary changes in brain maturation on outcomes. In addition, we recommend approaches to neurological and neurodevelopmental surveillance of preterm infants during neonatal intensive care admission and after discharge.

A summary is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.

OBJECTIVE:Deep medullary vein thrombosis (DMVT) is increasingly recognized on neonatal brain MRI, but its predisposing factors and clinical characteristics remain poorly defined. This study aims to evaluate the clinical characteristics and associated imaging features of DMVT in neonates. STUDY DESIGN:We performed a retrospective single-center study of infants admitted to the neonatal intensive-care unit who underwent brain MRI between 2015 and 2023. RESULT:Over the study period, 23 infants had medullary vein abnormalities on brain MRI; of them, 10 (five preterm and five term) were identified as DMVT. Among preterm infants, four (80%) had intraventricular hemorrhage (IVH). All term infants demonstrated extensive (bilateral) DMVT. CONCLUSION:Medullary vein abnormalities are not uncommon on neonatal brain MRI. In preterm infants, they are often associated with IVH, whereas term infants typically exhibit bilateral extensive DMVT. Larger studies are needed to further explore the pathogenesis and long-term outcomes.

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) continues to be a common form of brain injury in very preterm infants. Cranial ultrasonography (cUS) is the most widely used neuroimaging modality for the diagnosis of GMH-IVH, and serial cUS enables early detection, accurate grading, and monitoring of complications. Brain magnetic resonance imaging (MRI) is being used more commonly in neonates and is superior to cUS for detecting subtle hemorrhages in the temporal and occipital regions, concurrent white matter injury, and cerebellar hemorrhage, as well as for providing prognostic information. Despite major advances in perinatology and neonatology, GMH-IVH remains associated with high rates of neurodevelopmental impairment, especially when complicated by progressive post-hemorrhagic ventricular dilatation or periventricular hemorrhagic infarction. In this review, we present the neuroimaging modalities used in the neonatal intensive care unit and their role in the detection of GMH-IVH, with a focus on preterm infants.

BACKGROUND AND OBJECTIVES:We determined whether white matter injury (WMI) severity and location on early-life vs term-equivalent age (TEA) brain MRI were more strongly associated with 36-month neurodevelopment. METHODS:Very preterm infants were recruited across 3 tertiary NICUs and underwent early-life and TEA MRI. Moderate-severe WMI severity and anterior or posterior location were scored. 36-month neurodevelopmental assessments were completed with Bayley Scales of Infant Development, Third Edition; delay was defined as a composite score <85 points. Multivariable logistic regressions adjusting for birth gestational age, site, infection, retinopathy of prematurity, moderate-severe intraventricular hemorrhage, and antenatal magnesium sulfate were used to determine associations of WMI severity and location at each scan with neurodevelopment. RESULTS:A total of 393 neonates (postmenstrual age median 27.6, SD 2.3 weeks, 47% female) completed early-life and TEA MRI scans. Cognitive delay was associated with early-life moderate-severe (OR 3.82, 95% CI 1.17-9.14) and anterior (OR 5.47, 95% CI 1.72-17.29) WMI. Motor delay was associated with early-life anterior WMI (OR 3.02, 95% CI 1.12-8.2). These associations were not observed at TEA in multivariable logistic regressions. DISCUSSION:Moderate-severe and anterior WMI on early-life, but not TEA, MRI were associated with neurodevelopmental outcomes. Early-life MRI may represent a more optimal time point for assessing WMI in very preterm infants.

BACKGROUND AND AIM:The aim of this systematic review was to identify and assess the reliability of pre- and postnatal ultrasound measurements for evaluating early longitudinal brain growth. The secondary aim was to provide a reliable and feasible set of pre- and postnatal ultrasound measurements for clinical practice and future research. METHODS:This review was conducted according to PRISMA guidelines and used the validated QAREL scale to assess the risk of bias in the included studies. We included studies assessing the reliability of prenatal and/or postnatal ultrasound measurements. Articles were excluded if intraclass correlation coefficients for intra- or interobserver agreement were not provided. The primary outcome was the intraclass correlation coefficient (ICC) of the intra- and inter-observer agreement. RESULTS:A total of twenty-two studies were included, in which one study assessed both pre- and postnatal brain growth measurements, eleven studies focused on prenatal measurements, and ten on postnatal measurements. In these studies, twenty-seven prenatal and thirty-two postnatal ultrasound measurements were used to assess brain growth, showing predominantly good or excellent intra- and interobserver reliability. CONCLUSIONS:This review highlighted a significant gap in studies assessing longitudinal brain growth from the pre- to the postnatal period. Therefore, collaboration between obstetricians, radiologists and neonatologists is important for assessing longitudinal brain growth, which could help identify infants at risk of abnormal brain growth and potential neurodevelopmental impairment. We propose a set of ultrasound measurements of total brain size, ventricles, cerebellum, and corpus callosum to monitor early brain growth.