The impact of anesthesia and surgery on neurocognitive function and behavioral development in infants and young children remains a topic of ongoing concern, without definitive consensus. The US Food and Drug Administration (USFDA) has cautioned against the potential risk of anesthetic neurotoxicity in pediatric patients under 3 years of age, identifying this period as a critical “vulnerable window” for synaptogenesis (Clausen et al., 2018; Ing et al., 2022). Growth and developmental processes during this early stage of life involve crucial cranial, subarachnoid, cerebrospinal fluid dynamics, and brain-specific anatomical and pathophysiological characteristics (Kolb et al., 2014). Therefore, undergoing anesthesia and surgery between the ages of 0 and 3 years is recognized as a significant event that could potentially result in abnormalities in neurocognitive development and brain function.

A large amount of preclinical evidence suggests that the developing brain is vulnerable to stressors such as anesthetic drugs and surgery, with effects that are highly dependent on age and drug dosage. Specifically, earlier exposure and higher doses are associated with more severe consequences. However, clinical studies investigating the neurotoxic effects of anesthesia and surgery have yielded inconsistent results. Many of these studies have focused on assessing cognitive performance in young children shortly after anesthesia exposure, typically during hospitalization or within 7 days thereafter. Recent research indicates no consistent significant impacts of anesthesia on general intelligence, memory, or language abilities (Clausen et al., 2018; Ing et al., 2022). A systematic review encompassing 13 retrospective studies highlighted that exposure to general anesthesia before age three may moderately increase the risk of neurodevelopmental disorders (Zhang et al., 2015). In a case–control study involving 47 infants and toddlers aged 1–36 months undergoing noncardiac surgery, no significant differences in overall cognitive performance were observed (Waitayawinyu et al., 2023). Notably, inhalation anesthetics, commonly used as primary agents in pediatric general anesthesia, have been implicated in cognitive effects such as postoperative delirium (Fan et al., 2018). General anesthesia can also induce delirium upon awakening and postoperative behavioral abnormalities among preschoolers (Kim et al., 2021). While short-term observation post-anesthesia/surgery can enhance case monitoring efficiency, findings may be confounded by factors such as hospitalization-related pain, anxiety, perioperative medications like analgesics and sedative-hypnotics, and other neurocognitive disorders (Kolb et al., 2014; Cusick et al., 2022). Additionally, nutritional status during hospitalization might influence children’s behavioral and cognitive performance, potentially contributing to the variability observed in study outcomes.

Extended observation periods effectively mitigate perioperative impacts on neurocognitive and behavioral performance in young children, prompting researchers’ heightened concern regarding the long-term consequences of early-life exposure to anesthesia and surgery. Recent studies indicate that early exposure to anesthesia and surgery does not correlate with subsequent intelligence and developmental outcomes, after controlling for age and genetic factors (Sun et al., 2016; O’Leary et al., 2019). Conversely, multiple studies suggest otherwise; for instance, anesthesia or surgery before the age of 4 is linked to reduced academic achievement and intellectual performance in later adolescence (16–18 years) (Glatz et al., 2017). Consequently, a definitive consensus regarding the enduring impacts of early anesthesia and surgical experiences remains elusive.

The perioperative period involves complex and stressful events that may impact brain and systemic functions. Factors such as surgical type/site, medication usage, awakening times, and hospitalization duration may influence the recovery of postoperative multiorgan function. It remains uncertain whether these factors affect behavioral and intellectual-cognitive development in the short or long term, given the current lack of evidence on their potential impact on developmental abnormalities in children. Consequently, this study aims to examine children who underwent anesthesia or surgery between 0 and 3 years of age to assess how this exposure affects their behavioral development and intellectual-cognitive performance at ages 4–6. Additionally, it seeks to investigate correlations between various factors—such as surgical site, anesthetic drugs, number of procedures, awakening time, and weight at exposure—and behavioral and cognitive outcomes. This study offers a chance to identify potential risk factors influencing cognitive and behavioral development in infants and young children exposed to surgical anesthesia between ages 0 and 3. Findings may inform the enhancement of perioperative care protocols tailored for children.

Each year, millions of children undergo medical procedures requiring anesthesia, primarily employing general anesthesia for pediatric surgeries. Commonly used anesthetic agents such as sevoflurane, midazolam, propofol, and fentanyl are recognized for their neurotoxic potential, including neuronal cell death induction, synaptic dysfunction, and impaired energy metabolism, which can lead to behavioral and cognitive abnormalities (Xu et al., 2019; Diana et al., 2020; Zhang and Li, 2023; Zhou et al., 2024). Animal studies have demonstrated that exposure to general anesthesia may promote programmed neuronal cell death early in life, resulting in impaired learning and behavioral functions (Jevtovic-Todorovic and Useinovic, 2023; Kim et al., 2023). For instance, Jevtovic-Todorovic et al. (2003) observed apoptotic changes in brain neurons of 7-day-old rats exposed to imipramine, nitrous oxide, and isoflurane for 6 h, with inhibited induction of hippocampal long-term potentiation (LTP). Long-term behavioral and cognitive impairments persisted into adulthood in rats exposed to anesthesia during the neonatal period, indicating potential long-lasting effects on brain development (Gentry et al., 2013). Kong et al. (2012) demonstrated that maternal inhalation of 3% isoflurane for 1 h in neonatal rats resulted in impaired learning and memory, increased caspase-3 activity, and disrupted synaptic structures. Human cohort studies investigating the neurodevelopmental impacts of early-life anesthesia and surgery have yielded inconsistent conclusions due to variations in case inclusion/exclusion criteria and inherent biases (O'Leary, 2019). A study focusing on preschool children, particularly infants and those aged 0–3 years, found associations between surgery/anesthesia exposure and impaired social competence development from 0 to 6 years of age (Waitayawinyu et al., 2023).

In the present study, we found that infants and children aged 0–3 years who underwent general anesthesia and surgery had lower WMI scores at 4–6 years of age compared to normal children, while no significant differences were observed in FSlQ, VCI, VSI, FRI, PSI, DQ, and CBCL scores. WMI is commonly used to assess the breadth and speed of processing information during cognitive activities. Decreased WMI reflects deficits in attention, concentration control, and reasoning (Anker et al., 2022). Our findings suggest that anesthesia and surgery have affected the efficiency of children in performing cognitive activities. Despite the importance of FSIQ as an indicator of cognitive and intellectual development in children, it has been shown in similar studies that the effects of anesthesia and surgery on FSIQ in children are not significant. For example, dental treatment under sevoflurane, nitrous oxide, and propofol anesthesia did not result in significant differences in preoperative and postoperative FSlQ comparisons in 4- to 6-year-old children (Zhou et al., 2021). In a randomized controlled trial of 447 infants at 60 weeks undergoing inguinal hernia repair under awake regional anesthetics or sevoflurane-based general anesthesia, the average FSIQ score was 99.08 (SD, 18.35) in the awake regional anesthesia group and 98.97 (SD, 19.66) in the general anesthesia group, suggesting that exposure to general anesthesia early in life for a relatively restricted period does not alter postoperative neurodevelopmental outcomes (McCann et al., 2019).

We analyzed 447 children who underwent anesthesia and surgery, examining factors such as ethnicity, age, weight, surgical site, surgery duration, awakening time, anesthetic medications, and number of surgeries. Our findings indicate that gender, ethnicity, and surgical site did not significantly affect cognitive and behavioral outcomes post-surgery and anesthesia. However, younger age and lower body weight at the time of anesthesia and surgery correlated with later impaired cognitive and behavioral development. This association may stem from the timing of exposure during critical stages of brain development. Previous research has linked anesthesia exposure during the rapid brain development period (between 28 weeks and 24 months) with subsequent neurodevelopmental deficits (Houck and Vinson, 2017). Another cohort study highlighted reduced academic and cognitive performance in adolescents who underwent anesthesia and surgery before age 4, suggesting heightened risks with younger age at exposure (Naumann et al., 2012).

We also investigated the impact of various anesthetic drugs on children’s postoperative cognition and behavior. The commonly used drugs included midazolam, fentanyl, remifentanil, propofol, sevoflurane, cis-atracurium, and vecuronium bromide. Our findings revealed that fentanyl administration was associated with elevated CBCL behavioral abnormality scores, while children administered remifentanil exhibited lower postoperative GSCH scores (DQ) compared to non-users. This observation is intriguing as both traditional long-acting and ultrashort-acting fentanyl analgesics may contribute to impaired cognitive and behavioral development. Animal studies, using zebrafish as a model, suggest potential adverse effects of opioids on neurodevelopment and behavior. For instance, exposure to a 5 mg/L fentanyl solution induced heightened anxiety, reduced aggression, and behavioral sensitization in zebrafish larvae. Furthermore, embryonic exposure to fentanyl resulted in significant alterations in neural activity and neuronal plasticity (Wang et al., 2022). In vitro studies with isolated neuronal cells exposed to fentanyl and remifentanil indicated increased neuroinflammation and oxidative stress, with remifentanil showing more pronounced neuroinflammatory effects (Taghizadehghalehjoughi et al., 2024). Moreover, research by Jantzie et al. (2020) demonstrated persistent peripheral inflammatory hyperreactivity in perinatally methadone-exposed young rats, suggesting a potential exacerbation of brain damage secondary to opioid exposure and increased susceptibility to neuroinflammation and neurological disorders. Studies on perinatally methadone-exposed rats have shown MRI-documented cerebral white matter microstructural damage, neuroimmune dysfunction, and cognitive deficits, alongside systemic inflammatory response syndromes and persistent brain inflammation. These findings suggest alterations in the central nervous system microenvironment, disruption of neurodevelopmental homeostasis, and concurrent neurological injury. Similar effects have been observed in offspring born to mothers administered methadone, potentially resulting in long-term impairments in associative learning, executive control, and an increased likelihood of behavioral and attention deficits (Lotsch, 2005; Franchi et al., 2019). Both methadone and remifentanil act as μ-opioid receptor agonists and appear to have analogous effects on neurological development. Our study’s results indicate that the use of remifentanil decreased Gesell test DQ scores in children, suggesting poorer gross and fine motor development compared to typical children. This outcome may be linked to remifentanil-triggering mechanisms akin to those observed with methadone in neurodevelopment.

While we have not observed an association between some anesthetic drugs and impaired cognitive and behavioral development, an increasing body of evidence highlights the adverse effects of various anesthetic agents such as midazolam, propofol, and sevoflurane on the physiological functioning of nerve cells. A study involving 841 children exposed to general anesthetics found that anesthesia exposure was associated with significantly higher scores on CBCL questions, indicating more pronounced internalizing behavioral problems, though exposure did not affect Full-Scale IQ (FSIQ) scores (Ing et al., 2021). Another study involving 147 very preterm infants, with a median gestational age of 27.7 weeks, suggested that early exposure to midazolam may adversely affect hippocampal growth and development, with reductions in hippocampal volume correlating negatively with midazolam dosage and leading to reduced cognitive performance at a corrected age of 18.7 months (Duerden et al., 2016). Multiple studies have also provided evidence implicating propofol in developmental neurotoxicity, characterized by neuronal and mitochondrial apoptosis, oxidative stress, and inhibition of the electron transport chain (He et al., 2020; Liang et al., 2022; She et al., 2023). It is important to note, however, that the doses used in animal or in vitro studies are often much higher than those used clinically. Clinical practice typically involves combination regimens aimed at minimizing the dose of any single drug to mitigate potential adverse effects, tailored to the specific surgical and physiological needs of the child. Despite efforts to minimize drug-related adverse effects in clinical settings, the potential impact of anesthetic drugs on neuronal cell function remains a concern. Prolonged surgery and recovery times, as well as multiple early-life surgeries, have been identified as potential factors contributing to impaired intellectual and behavioral development in children. Previous research supports this, indicating that children exposed to general anesthesia and multiple surgeries may face long-term risks related to processing speed, fine motor function, and behavioral assessment, especially following repeated anesthesia exposures (O'Leary, 2019). For instance, Warner et al. (2021) reported decreased scores in fine motor skills and processing speed among children with multiple anesthesia exposures, underscoring concerns regarding developmental neurotoxicity associated with anesthetic drugs.

This study has several limitations. We retrospectively recorded anesthesia/surgical exposure data and prospectively evaluated children’s neurocognition and behavior. One of our main purposes was to observe the effects of experiencing anesthesia and surgery early in life on later neurocognitive and behavioral development. Our study design lacked strict control over the timing of exposure and outcome assessments, leading to variability in the age at which children in the anesthesia-surgery group were exposed and assessed post-exposure. Although we controlled for the risk of confounding by matching controls for age, sex, and region, however, as an observational study, the ability to infer causality is limited, and the retrospective study design introduces a risk of bias and unmeasured sources of confounding from other factors that cannot be fully mitigated by the use of matching. Additionally, surgery duration correlated with disease severity, surgical complexity, and surgeon expertise, affecting anesthesia exposure duration. We did not quantitatively compare disease severity among children who underwent surgery. Prolonged surgery or anesthesia durations imply higher anesthetic doses and fluid loss, potentially impacting awakening times. Future studies should explore how varying drug doses and intraoperative factors like bleeding and fluid management influence postoperative cognitive and behavioral outcomes. Furthermore, our study did not incorporate brain imaging data (MRI or CT) due to its retrospective collection of perioperative data from non-cranial surgeries, as brain imaging is not routine for most children undergoing surgery.

This study offers insights into the potential adverse effects of surgical anesthesia exposure in infants and young children on postoperative cognitive and behavioral development. However, it remains uncertain whether these effects persist, amplify, or lead to more serious consequences over the longer term.

This study investigated the impact of surgery and anesthesia exposure on cognitive and behavioral development in infants and young children aged 0–3 years. The findings indicate that higher frequency of exposure to surgeries and anesthesia, younger age at exposure, and lower body weight all have negative effects on cognitive and behavioral development. Furthermore, opioid analgesics potentially affect behavior and cognition in young children, suggesting a need for cautious use of opioid analgesics like remifentanil and fentanyl.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

XJ: Conceptualization, Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing, Funding acquisition. ST: Conceptualization, Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. YQ: Conceptualization, Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. YW: Data curation, Formal analysis, Methodology, Software, Writing – review & editing. YJ: Data curation, Formal analysis, Methodology, Software, Writing – review & editing. SP: Data curation, Formal analysis, Methodology, Software, Writing – review & editing. CL: Data curation, Formal analysis, Methodology, Software, Writing – review & editing. JC: Conceptualization, Data curation, Project administration, Supervision, Writing – review & editing. TL: Conceptualization, Data curation, Project administration, Supervision, Writing – review & editing. YX: Conceptualization, Data curation, Funding acquisition, Project administration, Supervision, Writing – review & editing.