In recent years, the long-term neurodevelopmental outcomes of extremely premature infants have commanded heightened attention across the fields of neonatology and pediatric neurology. Central to this discourse is the concern over how early-life exposures—especially medical interventions such as anesthesia—may impact cognitive trajectories extending into early childhood and beyond. A newly published correction to a pivotal study by Fifen, J.J., Siddique, M., Lodha, A., and colleagues, titled “Anesthesia, extremely premature infants and full-scale intelligence quotient at 5 years of age,” sheds renewed light on these intricate relationships. The research, appearing in Pediatric Research (2025), revisits critical methodological nuances and extends discussion on the developmental implications of anesthetic exposure in this most vulnerable population.
Extremely premature infants, generally defined as those born before 28 weeks of gestational age, endure myriad challenges owing to the immaturity of organ systems at birth and the often complex medical courses they undergo in neonatal intensive care units (NICUs). Among these challenges, brain development is particularly vulnerable, with neuroplasticity during this period being highly sensitive to both endogenous and exogenous influences. Because these infants are frequently subjected to surgical procedures early in life — typically accompanied by general anesthesia — unraveling how anesthesia may modulate neurocognitive outcomes has become an urgent clinical and scientific imperative.
The original study, now clarified by the authors in this correction, examined whether exposure to anesthesia in the neonatal period correlates with differences in full-scale intelligence quotient (FSIQ) at the age of five years. The FSIQ is a comprehensive measure commonly used to estimate general cognitive ability, incorporating facets such as verbal comprehension, working memory, and processing speed. Importantly, the study compared infants who received anesthetic agents to those who had no such exposure, controlling for confounding factors such as severity of medical illness, socioeconomic status, and degree of prematurity.
Neurological impairment in extremely premature infants is multifactorial, arising from a confluence of prematurity-associated brain injuries including intraventricular hemorrhage, periventricular leukomalacia, and diffuse white matter injury. The role of anesthesia as a potential neurotoxic agent has been debated extensively, fueled by preclinical studies demonstrating that certain anesthetics can induce neuroapoptosis and alter synaptogenesis in immature animal brains. Translating these findings into human populations has proven challenging due to ethical constraints and the inherent complexity introduced by concurrent clinical variables. The corrected study provides an essential human data point, critically appraising the cognitive outcomes that ensue from neonatal anesthesia in this high-risk cohort.
Applying rigorous neuropsychological assessments at five years—a milestone that captures early school readiness and executive functioning—the researchers harnessed standardized tools to quantify intelligence metrics. Their findings, nuanced by the corrections issued, underscore that while anesthesia exposure appears associated with modest alterations in FSIQ scores, this relationship does not manifest uniformly across all infants. Instead, it is mediated by factors such as cumulative dose, duration of exposure, and underlying brain injury severity. This suggests that anesthesia itself might not be solely culpable but rather acts synergistically within the larger context of prematurity-induced vulnerability.
From a mechanistic perspective, anesthesia-induced neurotoxicity has been hypothesized to operate through disruption of neurotransmitter systems, oxidative stress pathways, and mitochondrial function within neonatal neurons. Agents commonly used in NICUs—such as volatile anesthetics and sedative opiates—can cross the immature blood-brain barrier with relative ease, thereby directly influencing neuronal survival and circuitry formation. The correction emphasizes updated interpretations of these mechanisms, exhorting caution in extrapolating animal data directly to clinical practice without accounting for dosage variance and co-treatments typical in NICU settings.
Clinically, the implications of this study bear significant weight. With prematurity rates rising globally and survival of extremely preterm infants improving due to advances in neonatal care, optimizing long-term developmental outcomes is a paramount goal. Physicians must judiciously weigh the benefits of necessary surgical interventions against potential neurodevelopmental risks posed by anesthesia. The study bolsters calls for minimizing anesthetic exposure by favoring alternative pain management strategies, refining surgical timing, and employing neuroprotective adjuncts where possible.
The correction also meticulously details updated statistical methodologies that enhance the validity of the initial conclusions. Multivariate regression analyses were recalibrated to better isolate the effect of anesthesia from confounding clinical variables, thereby reinforcing the robustness of observed associations. Importantly, sensitivity analyses revealed that certain subgroups—such as infants with extensive comorbidities or those subjected to multiple anesthetic episodes—exhibit more pronounced cognitive deviations, thus identifying potential targets for intensified follow-up and early intervention.
This research exists within a broader narrative seeking to unravel how early environmental factors sculpt the developing brain. Premature birth imposes an abrupt cessation of intrauterine neurodevelopment, and the subsequent ex uteroincubator interface constitutes a vastly different neurobiological milieu. Exposure to external stressors, inflammatory processes, and pharmacological agents converge in complex patterns. Therefore, dissecting the role of anesthesia necessitates a systems biology approach—an ethos the authors encourage in their discussion—integrating genomics, metabolomics, and advanced neuroimaging to comprehensively assess developmental trajectories.
Future directions propelled by these findings advocate for longitudinal surveillance extending beyond early childhood, potentially through adolescence and adulthood, to ascertain whether anesthesia-related neurocognitive changes persist, attenuate, or perhaps evolve over time. Additionally, the authors highlight the urgency of randomized controlled trials and prospective cohort studies employing standardized anesthesia protocols to better define causality. Moreover, a growing interest in biomarker discovery—such as circulating neurofilament proteins or cerebral metabolic markers—could potentiate early identification of infants at higher risk for adverse developmental sequelae.
Intriguingly, this correction underlines how nuanced clinical decision-making must be tailored to individual patient profiles. Not all premature infants share equal neurodevelopmental risks post-anesthesia, and stratification tools based on clinical and biological markers may refine risk-benefit analyses for surgical interventions. Furthermore, multidisciplinary care teams encompassing neonatologists, neurologists, anesthesiologists, and developmental specialists are crucial to holistically address the multifaceted needs of these patients.
The societal implications of such research resonate deeply, as cognitive impairments among survivors of prematurity carry personal, educational, and economic burdens. Enhancing understanding of modifiable risk factors, such as anesthesia exposure, offers pathways to mitigate these impacts and improve quality of life. Policymakers and healthcare systems must recognize the long-term stakes implicit in neonatal care strategies and invest accordingly in research and resource allocation.
In summation, the corrected study by Fifen et al. represents a pivotal contribution to pediatric neuroscience, refining our comprehension of how anesthesia intersects with the neurodevelopmental landscape of extremely premature infants. By elucidating the complexities of FSIQ outcomes at five years, the authors provide critical guidance for clinicians navigating the delicate balance between lifesaving interventions and safeguarding cognitive potential. As neonatal medicine advances, integrating such evidence-driven insights will be essential to optimize care paradigms and foster healthier developmental futures for the most fragile patients.
Subject of Research: Neurodevelopmental outcomes related to anesthesia exposure in extremely premature infants, with a focus on intelligence quotient at age five years.
Article Title: Correction: Anesthesia, extremely premature infants and full-scale intelligence quotient at 5 years of age.
Article References:
Fifen, J.J., Siddique, M., Lodha, A. et al. Correction: Anesthesia, extremely premature infants and full-scale intelligence quotient at 5 years of age. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04065-2
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