In the complex and critical field of neonatal medicine, precise language and uniform criteria are indispensable to advancing research and improving outcomes for the most vulnerable patients—newborns suffering from brain injuries linked to oxygen deprivation. A groundbreaking systematic review published recently in Pediatric Research confronts a pervasive and often overlooked problem: the inconsistency and lack of standardization in terminology, diagnostic definitions, and eligibility criteria across clinical trials concerning neonatal encephalopathy, hypoxic-ischemic encephalopathy (HIE), and perinatal asphyxia. This meticulous analysis by Hurley, Quirke, Branagan, and colleagues offers a clarion call for harmonizing the language and frameworks used in this crucial research area.
Neonatal encephalopathy broadly refers to a syndrome of disturbed neurological function in newborns, manifesting as altered consciousness, abnormal muscle tone, and seizures, frequently caused by hypoxic or ischemic events during the perinatal period. Despite its widespread clinical relevance, the terms ‘neonatal encephalopathy,’ ‘hypoxic-ischemic encephalopathy,’ and ‘perinatal asphyxia’ are often used interchangeably or inconsistently in research, which undermines the comparability of studies and the synthesis of evidence necessary for clinical advances. The comprehensive review scrutinizes how leading clinical trials define these entities, revealing a fragmented landscape riddled with variability and ambiguity.
These semantic discrepancies matter profoundly because clinical trials form the backbone of evidence-based medicine. When definitions of pathological conditions fluctuate, it becomes impossible to aggregate data meaningfully or generalize findings across diverse cohorts. For example, some trials narrowly define HIE strictly by biochemical markers of hypoxia, while others rely more heavily on clinical presentation or neuroimaging findings. Similarly, eligibility criteria pertaining to the timing of injury recognition, severity thresholds, and diagnostic tools differ widely, which further complicates recruiting and stratifying patients for trials intended to evaluate neuroprotective interventions.
The review painstakingly cataloged the terminologies used by major trials, noting that nearly half lacked any explicit criteria for defining neonatal encephalopathy or hypoxic-ischemic injury. Among studies that did stipulate criteria, many relied on outdated or non-uniform scoring systems, such as Sarnat staging or Apgar scores, that vary in sensitivity and specificity. The authors argue that these methodological inconsistencies contribute to discrepancies in reported outcomes and pose barriers to replicability, evidence synthesis, and meta-analysis.
A particularly illuminating insight from the review is that ‘perinatal asphyxia’ is often used imprecisely, sometimes describing any compromised oxygen delivery around birth without differentiating between timing, severity, or causative pathology. This broad brush diminishes the clinical and prognostic utility of the term. Additionally, the conflation of metabolic acidosis with hypoxic-ischemic injury, without clear clinical correlation, further muddies the waters, illustrating the urgent need for refined, consensus-driven definitions that reflect underlying pathophysiological mechanisms.
Beyond terminology, eligibility criteria in clinical trials also show pronounced divergence. The temporal windows for inclusion criteria vary, with some trials enrolling neonates based on immediate postnatal status, while others permit enrollment up to days or even weeks after birth. This variability impacts not only patient selection but also the timing and potential efficacy of neuroprotective treatments administered during therapeutic windows. The review underscores that these differences complicate understanding trial efficacy and hinder the development of standardized therapeutic protocols.
This troubling heterogeneity has real-world clinical implications. Newborns with similar clinical presentations may be enrolled in different studies under varying inclusion frameworks, receiving divergent treatments or being classified differently in outcomes reporting. Such inconsistency raises critical ethical and scientific questions about trial design, comparability of results, and the eventual translation of research into standardized care guidelines that improve neurodevelopmental outcomes.
Hurley and colleagues advocate for the establishment of a globally accepted, multidisciplinary consensus on defining neonatal encephalopathy and related conditions. By leveraging advances in biomarkers, neurophysiological monitoring, and neuroimaging, a unified definition embracing both clinical and mechanistic dimensions could foster enhanced trial design. This would facilitate cross-study comparisons, meta-analytic pooling of data, and ultimately accelerate the discovery of effective neuroprotective strategies.
Importantly, the review highlights that harmonizing terminology is not merely an academic exercise but a necessity for facilitating equitable healthcare globally. Low-resource settings, disproportionately burdened with neonatal brain injury, often rely on clinical criteria rather than advanced diagnostics, so clear and universally applicable definitions are paramount. A shared lexicon would support the development of protocols adaptable worldwide and promote inclusivity in clinical trials, ensuring benefits reach populations most in need.
This systemic review also draws attention to the dynamic nature of neonatal encephalopathy pathophysiology. The authors emphasize that definitions must evolve alongside emerging scientific understanding, including the recognition of secondary neuronal injury, inflammation, and genetic susceptibilities. Static or rigid definitions risk becoming obsolete and misguiding clinical practice or research.
Furthermore, it shines a spotlight on the critical role of interdisciplinary collaboration. Neonatologists, neurologists, researchers, and methodologists must engage collectively to formulate, test, and refine criteria that comprehensively capture the heterogeneity of neonatal brain injury. The review thereby positions standardized terminology as a foundational step toward integrating clinical trials, mechanistic research, and long-term follow-up studies in a coherent research ecosystem.
Significantly, this work arrives as the field stands on the brink of novel therapeutic advancements, such as precision medicine in neonatal neurology and emerging neuroprotective agents. Without consensus definitions and eligibility frameworks, evaluating these innovations’ safety and efficacy risks becoming muddled by inconsistent study populations and outcomes. Thus, the timing of this review is crucial, offering a roadmap to optimize future research infrastructure.
By dissecting over a decade of trials, this exhaustive review underlines the urgent need to reconcile divergent nomenclature and standardize criteria to foster robust, high-quality evidence generation. It is a call to action for the neonatal research community to prioritize lexicon harmonization alongside therapeutic discoveries, ensuring that the scientific rigor and clinical relevance of trials match the profound challenges faced by newborns affected by hypoxic and ischemic brain injuries.
As neonatal encephalopathy continues to impose lifelong neurodevelopmental challenges on survivors, the implications of this review ripple far beyond academic discourse. Reliable, standardized definitions will translate into improved diagnosis, trial transparency, treatment efficacy, and, ultimately, better outcomes for infants worldwide. This systematic interrogation of the field’s heterogeneity is a pivotal milestone, heralding a new era of clarity and collaboration in neonatal brain injury research.
The findings presented by Hurley et al. embody a critical step toward the alignment of research efforts and clinical practice. Their work serves not only as a thorough critique of the status quo but as a beacon guiding future endeavors to harmonize and innovate. Scientific truth, as demonstrated here, begins with language, and nowhere is this truer than in the fragile, high-stakes realm of neonatal encephalopathy.
Subject of Research: Terminology, definitions, and eligibility criteria in clinical trials of neonatal encephalopathy, hypoxic-ischemic encephalopathy, and perinatal asphyxia.
Article Title: Systematic review of terminology, definitions, and eligibility criteria in trials of neonatal encephalopathy, hypoxic-ischemic encephalopathy, and perinatal asphyxia.
Article References:
Hurley, T., Quirke, F., Branagan, A. et al. Systematic review of terminology, definitions, and eligibility criteria in trials of neonatal encephalopathy, hypoxic-ischemic encephalopathy, and perinatal asphyxia. Pediatr Res (2026). https://doi.org/10.1038/s41390-025-04750-2
Image Credits: AI Generated
DOI: 27 February 2026
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