The relationship between the risk of ID and GA in early childhood remains a controversial and important topic.18, 23–26 While several studies have investigated this association and have reported varying results, there are limitations in the previous studies that warrant further research.9–12, 14, 15, 18, 23–26 Given the ethical challenges of conducting randomized controlled trials (RCTs) to address this issue, we used a PSM design to mimic an RCT and balance the potential confounding factors between the case and control groups. In the current study, we demonstrate for the first time in a real-world database the association between the number, duration, and timing of GA exposure in children aged 0–3 years and the risk of future ID (Table 2 and Fig. 1). Our study is also the first to report the IR and IRR between GA and non-GA children (Table 3). Our sensitivity analysis confirmed that the impact of GA in children aged 0–3 years was associated with an increased risk of future ID, regardless of the age at which the child received GA (Table 4).
The previous studies may have used different definitions and criteria for identifying ID in children who received GA, which could have contributed to inconsistencies in the findings. For example, the EGAIN study reported differences in infant behavior and neurophysiology at 6 and 18 months after surgery in infants who underwent GA for minor surgery before 15 months compared with those who did not receive GA.14 Similarly, a Japanese study found that infants undergoing surgery under GA were more likely to experience developmental delay in all five domains of the Japanese translation of the Ages and Stages Questionnaires, third edition.36 The Mayo Anesthesia Safety in Kids (MASK) study suggested that anesthesia may affect learning and intellectual ability in children.37 However, the MASK study used tests such as the Wechsler Abbreviated Scale of Intelligence and Comprehensive Test of Large-scale Processing to evaluate intelligence and learning ability, without clear diagnosis of ID.37 In our study, we aimed to address the limitations of previous research by being the first and largest study to explore the association between early childhood exposure to GA and the risk of ID using precise diagnostic criteria.35 To ensure the accuracy of our results, we used board-certified psychiatrists who relied on precise criteria for diagnosis,35 and patients had to have two or more outpatient records by a professional psychiatrist to be included as the primary outcome in the study. Our evidence suggests that early childhood exposure to GA before the age of 3 years old is associated with an increased risk of ID. The risk is further exacerbated by a younger age at the first exposure to GA, longer duration of exposure, and multiple exposures.
The association between GA and the risk of ID has been the subject of controversial clinical report. In the General Anaesthesia and Awake-Regional Anaesthesia in Infancy (GAS) study, there was no evidence to suggest that a duration of just under one hour of GA in infancy increased the risk of adverse neurodevelopmental outcomes at 2 years of age when compared to regional anaesthesia.24 Furthermore, this type of anaesthesia did not significantly affect neurodevelopmental outcomes at age 5 years as evaluated by the full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III) tests.24 Our study appears that there may be a correlation between the duration of GA in children aged 0–3 years and a higher risk of developing ID in the future (Table 2). However, GAS study suggest that shorter durations of anaesthesia, specifically those lasting less than one hour, may be safe.24 Nevertheless, it is important to note that our study's control group does not receive any anesthesia, whereas the control group in the GAS trial receives regional anesthesia. We found that longer durations of GA were associated with a higher risk of ID (Table 2). It is important to note that our study is the largest head-to-head PSM study to date, with sufficient follow-up time to evaluate the ID risk in GA for children aged 0–3 years. Additionally, our study has uncovered a novel finding, indicating a positive correlation between the number of GA exposures and an increased risk of ID, which has not been previously reported. This finding highlights the importance of minimizing unnecessary GA exposures in young children to reduce the risk of long-term neurodevelopmental deficits. Overall, our study provides important new evidence regarding the potential risks of GA in young children and highlights the need for caution when considering the use of GA in this population. Further research is needed to better understand the underlying mechanisms linking GA exposure to neurodevelopmental deficits and to develop strategies for minimizing the risks associated with GA in young children.
Further research is necessary to understand the mechanisms behind the association of GA in young children and the risk of ID. Most evidence regarding these mechanisms is from preclinical data, and there is no clinical data to confirm the findings from preclinical reports. Based on animal studies, several factors, including GABAA receptors (GABAARs), voltage-gated calcium channels (VGCCs), intracellular calcium concentration, and inflammatory reactions, may contribute to this risk.11, 20, 38 Additionally, previous animal studies have shown that sevoflurane, a commonly used GA in young children, can induce GABAAR depolarization and activate VGCCs in neonatal mice, resulting in an increase in intracellular calcium concentration and inflammatory response.20 This inflammatory response can lead to cognitive impairment and impaired intellectual development. Moreover, sevoflurane can cause abnormal mitochondrial metabolism in microglia and decrease the function of removing damaged neurons.11, 38 Sevoflurane-induced tau phosphorylation in neonatal mice can also cause neuronal dysfunction, all of which can lead to cognitive impairment and impaired intellectual development.11, 38 Another potential mechanism for the association of GA in young children and the risk of ID is disruption of neurogenesis.39 Animal studies have shown that exposure to GA during critical periods of brain development can cause neuronal damage and impair neurogenesis, leading to cognitive impairment and other neurodevelopmental disorders.2, 8, 39 Additionally, some studies have suggested that exposure to GA may interfere with the expression of genes involved in neural development and synaptogenesis, further contributing to cognitive dysfunction.40, 41 Furthermore, emerging evidence suggests that epigenetic changes may also play a role in the link between GA and neurodevelopmental disorders.42–44 Epigenetic modifications such as DNA methylation and histone modifications can alter gene expression and lead to changes in neuronal function and connectivity. Studies have shown that exposure to GA can induce epigenetic changes in the developing brain, which may contribute to the long-term effects of GA on cognitive function.45, 46 Overall, while the exact mechanisms underlying the association between GA in young children and the risk of ID are not fully understood, preclinical studies have provided important insights into the potential mechanisms involved. Further research is imperative to comprehensively unravel these mechanisms and formulate effective strategies to alleviate the detrimental effects of GA on neurodevelopment in clinical practice.
The current study has several strengths that increase the confidence in its findings. First, the study utilized a large real-world database and representative population-based registry, allowing for a robust assessment of the association between GA exposure and the risk of intellectual disability. Additionally, the study employed strict inclusion criteria and rigorous adjustment for potential confounders, minimizing the impact of biases and enhancing the internal validity of the results. Moreover, the long-term follow-up duration of up to 10 years after exposure to GA enabled the detection of delayed and cumulative effects, providing important insights into the temporal relationship between exposure and outcome. Overall, the strengths of this real-world study support the notion that GA exposure in early childhood may increase the risk of intellectual disability, and emphasize the need for caution and judicious use of GA in pediatric populations.
While this study presents important findings on the association between GA in young children and the risk of ID, some limitations should be acknowledged. Firstly, the study population comprised only individuals of Asian ethnicity, and caution should be exercised when generalizing these results to other ethnic groups. However, to the best of our knowledge, there are no reports that suggest differences in the association between GA and the risk of ID between Asian and Western children. Secondly, the diagnoses of comorbidities were based on ICD-9-CM and ICD-10-CM codes, which may have limited the accuracy of the diagnoses. However, the NHIRD has a rigorous system to verify the accuracy of such diagnoses, including chart reviews and patient interviews, and hospitals with outlier charges or practices are audited and penalized for malpractice or discrepancies. Thirdly, the lack of detailed records on specific general anesthetic drugs limits the ability to analyze the effects of specific drugs. Despite these limitations, this study's major strength is its use of a nationwide population-based registry with detailed baseline information, which allowed for lifelong follow-up through the linkage of the registry with the National Cause of Death database. Given the substantial and statistically significant effects observed in this study, it is unlikely that the aforementioned limitations significantly influenced our results. Further research in diverse populations and with more detailed information on specific anesthetic drugs is needed to confirm and extend these findings.