The study, spearheaded by Boutalbi, Dahan, Rozalen, and their colleagues, focuses on two blood-based biomarkers: neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B). Both molecules have long been associated with brain injury and neuroinflammation in adult populations, but their prognostic role in neonatal populations, especially those undergoing cardiac surgery with cardiopulmonary bypass (CPB), has remained largely unexplored until now. This research offers a pioneering investigation into how these biomarkers correlate with motor development at four months, a critical window when many infants with CCHD begin to manifest overt delays.

Complex congenital heart disease affects approximately 1% of live births worldwide, making it among the most prevalent birth defects. Despite advances in cardiac surgery and neonatal intensive care, children with CCHD remain vulnerable to neurodevelopmental impairments due to a confluence of factors including hypoxia, ischemia during surgery, and systemic inflammation. The use of CPB, while lifesaving, can induce a cascade of events that exacerbate brain vulnerability. Add to this the immature neonatal brain’s susceptibility to injury, and the challenge becomes evident: how can clinicians predict which infants will suffer neurodevelopmental setbacks, especially in the motor domain, which often sets the stage for more global impairments?

Neuron-specific enolase (NSE) is an enzyme found predominantly within neurons and neuroendocrine cells, released into the bloodstream following neuronal injury. Elevated levels of NSE thus serve as a proxy for neuronal damage. Similarly, S100B, a protein expressed mainly by astrocytes in the central nervous system, increases in serum when the blood-brain barrier integrity is compromised or astrocytic injury occurs. These characteristics render NSE and S100B prime candidates for non-invasive biomarkers capable of monitoring brain health in critically ill neonates.

In this study, the researchers enrolled newborns with confirmed CCHD who required surgical intervention involving CPB. Blood samples were obtained intraoperatively at predefined intervals to measure serum concentrations of NSE and S100B. Subsequently, these infants underwent standardized neurodevelopmental evaluations at four months of age, with a particular focus on motor function. The assessments employed validated scales designed to detect subtle signs of neuromotor delay, such as muscle tone abnormalities, reflex development, and milestone attainment.

The results revealed a striking association: elevated perioperative serum levels of NSE and S100B predicted poorer motor outcomes at the four-month mark. Infants exhibiting higher biomarker concentrations demonstrated significant delays in motor milestones compared to their counterparts with lower levels. This correlation persisted even after adjusting for confounding variables such as gestational age, birth weight, and the complexity of cardiac surgery. These findings underscore the potential of NSE and S100B as early, objective indicators of brain injury severity and developmental prognosis in this vulnerable population.

One of the study’s most compelling implications lies in its potential to refine postoperative neurodevelopmental surveillance. Currently, early identification of at-risk infants relies heavily on clinical observation and imaging studies, which may not capture subtle injuries or predict long-term outcomes with high fidelity. The integration of biomarker measurement could supplement traditional methods, offering a dynamic and quantifiable tool to flag infants likely to benefit from early neurorehabilitative therapies.

Moreover, the temporal profile of NSE and S100B release offers insights into the pathophysiological processes at play during and immediately following heart surgery. Notably, the elevation of these biomarkers reflects a period of heightened vulnerability marked by neuronal stress, blood-brain barrier disruption, and inflammatory cascades. Understanding these mechanisms opens avenues for therapeutic modulation—perhaps through neuroprotective agents aimed at reducing biomarker release or mitigating their underlying causes.

The study also raises intriguing questions about the universality of NSE and S100B as neurodevelopmental markers beyond the context of CCHD. Could these proteins serve as early warning signals following other neonatal insults, such as hypoxic-ischemic encephalopathy or preterm birth-related brain injury? The applicability of these biomarkers may extend far beyond cardiac surgery, heralding a new paradigm in neonatology where molecular surveillance complements clinical care to optimize outcomes.

It is important to note that while the findings are robust, the authors emphasize the need for longitudinal follow-up and larger sample sizes. Four months is a relatively short interval in neurodevelopmental trajectories, and longer-term studies are essential to fully elucidate how early biomarker elevations translate into functional outcomes during later infancy and childhood. Indeed, integrating biomarker data with advanced neuroimaging and genetic profiling could further enhance predictive accuracy and individualize patient care.

Nevertheless, this work situates NSE and S100B at the forefront of neonatal neuromonitoring strategies, setting a new standard for precision medicine in a challenging clinical arena. It exemplifies the power of translational research by bridging basic neurobiology with clinical practice to address a pressing unmet need in pediatric cardiology and neurology.

The trajectory from birth to early infancy represents a narrow but critical window when interventions tailored to emerging delays can dramatically improve long-term quality of life. Conventional approaches often miss this window, with neuromotor deficits only becoming apparent after substantial developmental impairment has occurred. By leveraging biomarkers like NSE and S100B, clinicians may soon have the ability to act preemptively, offering neuroprotective therapies, personalized physical and occupational therapy, or novel interventions designed to harness neuroplasticity at its peak.

In a broader context, these findings contribute to evolving understandings of how systemic illnesses affect brain development, emphasizing the intersection between organ-specific pathologies and central nervous system outcomes. Infants with CCHD embody a highly complex clinical scenario where cardiac function, cerebral perfusion, inflammatory mediators, and surgical stress intricately interplay to shape neurodevelopmental destiny.

To harness the full potential of these insights, multidisciplinary collaboration between neonatologists, cardiac surgeons, neurologists, and developmental therapists will be essential. Such teamwork can facilitate integrated care pathways that incorporate biomarker screening into routine postoperative management, optimize timing and dosing of interventions, and improve family counseling regarding prognosis and expectations.

In conclusion, this seminal study by Boutalbi and colleagues heralds a new era in early neurodevelopmental prognostication for infants with complex congenital heart disease. By identifying NSE and S100B as reliable early biomarkers of motor outcome, the research not only highlights a critical diagnostic advance but also sparks hope for more targeted, timely, and effective interventions. As science continues to unravel the molecular underpinnings of brain injury in these delicate patients, the prospect of improving lifelong developmental trajectories comes into clearer focus, promising a brighter future for children born with CCHD.

Subject of Research: The prognostic role of neuron-specific enolase (NSE) and S100B biomarkers in predicting early motor outcomes in infants with complex congenital heart disease undergoing surgery with cardiopulmonary bypass.

Article Title: Early motor outcomes in infants with complex congenital heart disease: the predictive role of NSE and S100B.

Article References:
Boutalbi, N., Dahan, S., Rozalen, W. et al. Early motor outcomes in infants with complex congenital heart disease: the predictive role of NSE and S100B. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04437-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41390-025-04437-8

The study, led by principal investigator and pediatrics professor Stephen Sheinkopf alongside postdoctoral fellow Erin Andres, leverages parent-reported data from a well-validated survey assessing infant temperament and adaptability. At nine months, parents submitted detailed reports on their infants’ behavior, focusing on metrics such as fussiness, crying frequency, irritability, ease of calming, and adaptability to new stimuli. These nuanced behavioral patterns, often overlooked in clinical settings, may harbor critical insights into neurodevelopmental trajectories.

At the subsequent twelve-month milestone, the infants underwent a comprehensive autism screening that evaluated communication capabilities, sensory responses, and the presence of restrictive or repetitive behaviors commonly associated with autism. The screening instrument probed whether the infant responded to their name or displayed intolerance to overwhelming sensory inputs like loud noises—a hallmark characteristic in many children with ASD.

The findings reveal a compelling correlation between parent-reported behavioral difficulties at nine months and increased autism likelihood at twelve months. Infants classified as fussier, exhibiting greater difficulty adapting to environmental changes, facing sleep challenges, and demonstrating developmental delays, were more prone to meet criteria indicating early signs of autism. This suggests that foundational patterns of neurodevelopmental divergence become behaviorally manifest much earlier than current diagnostic frameworks acknowledge.

This research underscores the critical value of caregiver insights, emphasizing that parents are often the most astute observers of their child’s developing behaviors. “Parents are intuitive,” Sheinkopf explained, “and they are experts on their children. Our goal is to refine tools that accurately capture and quantify their observations to enable earlier, more precise identification of risk.”

Beyond behavioral observation, the team integrates advanced measures—including state-of-the-art acoustic analyses of infant crying—to enrich their dataset. These emerging methodologies merge qualitative caregiver reports with quantitative biophysical data to forge a more holistic perspective on early infant neurodevelopment, setting a foundation for scalable, non-invasive screening protocols.

While the study prudently cautions that early behavioral signs do not equate to a definitive autism diagnosis, its implications for early intervention are profound. Detecting at-risk infants within the first year of life opens avenues for timely, tailored therapeutic strategies that could significantly improve developmental outcomes, particularly in language acquisition and social engagement.

The importance of this research is magnified by its potential to inform next-generation clinical tools. The researchers envision leveraging machine learning algorithms and integrating findings into electronic medical records systems to create predictive models that alert clinicians to elevated autism risk. This data-driven approach aspires to revolutionize pediatric developmental surveillance, prioritizing proactive care over reactive diagnosis.

Andres, who engages regularly with parent communities during her conference presentations, finds resonance with families who express both concern and optimism about the research. Many parents relate anecdotal experiences of their infants’ crying patterns or difficulty calming down, highlighting a shared desire for earlier clarity and support in developmental concerns.

The personal connections of researchers to this work deepen its significance. Andres notes a familial history of dyslexia, underscoring the broader implications of early language development on lifelong learning and reading success. Identifying infants who could benefit from supplementary supports early on offers a transformative opportunity to mitigate challenges downstream.

Published in the prestigious journal Nature, this study, titled “Caregiver report of infant behavior associated with autism likelihood in first year of life,” represents an important leap in neurodevelopmental research. It integrates psychological, pediatric, and behavioral science disciplines to advance understanding of early autism markers and paves the way for future interdisciplinary investigations.

Continued data collection and longitudinal follow-up remain essential components of the study’s design. Researchers aim to map the trajectory of infant behavior and developmental milestones comprehensively, thereby expanding the predictive power of early assessments and informing multifaceted intervention frameworks.

The emerging evidence highlights a paradigm shift in how autism spectrum disorder might be conceptualized—not merely as a condition diagnosed by overt symptoms in toddlerhood but as a continuum observable through nuanced behavioral indicators in infancy. This reconceptualization holds promise for reshaping diagnostic guidelines and improving equity in early childhood neurodevelopmental health.

Subject of Research: People

Article Title: Caregiver report of infant behavior associated with autism likelihood in first year of life

News Publication Date: 22-Jan-2025

Web References: 10.1038/s41390-025-03867-8

Image Credits: University of Missouri

Keywords: Autism, Environmental methods, Research on children, Infants, Developmental disorders, Social development, Academic researchers, Human behavior, Longitudinal studies, Children, Pediatrics, Postdoctoral work, Social studies of science, Social surveys, Communication skills, Sleep, Pattern formation, Medical diagnosis, Disease intervention, Barometric pressure