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Risk of autistic disorder after exposure to general anaesthesia and surgery

A nationwide, retrospective matched cohort study

Ko, Wen-Ru; Huang, Jing-Yang; Chiang, Yi-Chen; Nfor, Oswald Ndi; Ko, Pei-Chieh; Jan, Shiou-Rung; Lung, Chia-Chi; Chang, Hui-Chin; Lin, Long-Yau; Liaw, Yung-Po

European Journal of Anaesthesiology (EJA): May 2015 - Volume 32 - Issue 5 - p 303–310
doi: 10.1097/EJA.0000000000000130
Paediatric anaesthesia
Free

BACKGROUND Deficits of learning, memory and cognition have been observed in newborn animals exposed to general anaesthetics. However, conclusions from clinical studies conducted in humans to investigate the relationship between anaesthesia and neurodevelopmental disorders have been inconsistent. Autistic disorder is typically recognised earlier than other neurobehavioural disorders. Although certain genes apparently contribute to autistic disorder susceptibility, other factors such as perinatal insults and exposure to neurotoxic agents may play a crucial role in gene–environmental interaction.

OBJECTIVE This study was designed to investigate the association of exposure to general anaesthesia/surgery with autistic disorder. We hypothesised that exposure to general anaesthesia and surgery before 2 years of age is associated with an increased risk of developing autistic disorder.

DESIGN A retrospective matched-cohort study.

SETTING A medical university. Data from the National Health Insurance Research Database of Taiwan from 2001 to 2010 were analysed.

PATIENTS The birth cohort included 114 435 children, among whom 5197 were exposed to general anaesthesia and surgery before the age of 2 years. The 1 : 4 matched controls comprised 20 788 children.

MAIN OUTCOME MEASURES The primary endpoint was the diagnosis of autistic disorder after the first exposure to general anaesthesia and surgery.

RESULTS No differences were found in the incidence of autistic disorder between the exposed group (0.96%) and the unexposed controls (0.89%) (P = 0.62). Cox proportional regression showed that the hazard ratio of exposure to general anaesthesia and surgery was 0.93 [95% confidence interval (95% CI) 0.57 to 1.53] after adjusting for potential confounders. Age at first exposure did not influence the risk of autistic disorder. No relationship was found between the total number of exposures and the risk of autistic disorder.

CONCLUSION Exposure to general anaesthesia and surgery before the age of 2 years age at first exposure and number of exposures were not associated with the development of autistic disorder.

From the Institute of Medicine, Chung Shan Medical University (W-RK, L-YL), Department of Anaesthesiology, Chung Shan Medical University and Hospital (W-RK), Department of Public Health and Institute of Public Health, Chung Shan Medical University (J-YH, Y-CC, ONN, P-CK, S-RJ, C-CL, Y-PL), Department of Family and Community Medicine, Chung Shan Medical University Hospital (Y-CC, C-CL, Y-PL), Department of Public Health (H-CC), EBM Centre & Library (H-CC), College of Medicine, Chung Shan Medical University (L-YL), Department of Obstetrics and Gynaecology, Chung Shan Medical University Hospital, Taichung, Taiwan (L-YL)

Correspondence to Yung-Po Liaw, PhD, 110, Sec.1, Jianguo North Road, Taichung 40201, Taiwan E-mail: Liawyp@csmu.edu.tw

Published online 13 January 2015

This article is accompanied by the following Invited Commentary:

Loepke AW, Hansen TG. Is this your (paediatric patient's) brain on (anaesthetic) drugs? The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans. Eur J Anaesthesiol 2015; 32:298–300.

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Introduction

Various animal studies have revealed that general anaesthetics may cause apoptosis and degeneration of the immature nervous system in rodents and primates.1–13 Some authors have also observed long-term learning, memory and cognition deficits in newborn animals exposed to general anaesthetics.3–5,11–14 In humans, synaptogenesis is considered to extend from the embryonic period through 2 years of age and older.15 The conclusions from human clinical studies concerning the association between early general anaesthesia exposure and neurodevelopmental disorders have been discordant. Several studies have revealed that exposure to general anaesthesia in early life significantly increased the risk of developmental cognitive disorders,16–18 whereas other authors have found no evidence of a causal relationship between general anaesthesia and the risks of learning or behaviour disorders.19–22 Some studies that have investigated the total number of general anaesthetics have concluded that young children exposed to multiple, but not single, general anaesthetics were at a higher risk of developing attention-deficit/hyperactivity disorder23 and learning disabilities than those who were not exposed.24,25

Two studies by DiMaggio et al.16,17 included autism as one element of the composite outcomes. They reported an increased risk of developmental or behavioural disorders in children who underwent surgery in early life. Autism is a neurodevelopmental disorder with symptoms that include deficits in social interaction, learning and communication, as well as stereotypical behaviours, and is associated with negative outcomes among affected children and their families. Children with autism are considered to have developmental disorders of brain function.26 The pathogenesis of autistic disorder is not well established. Although certain types of gene have been identified and thought to contribute to susceptibility to autistic disorder,27,28 other factors including trauma,29,30 perinatal insults31–37 and exposure to neurotoxic agents38,39 could play a crucial role in gene–environment interaction. Autistic disorder is typically recognised earlier than are other neurobehavioural disorders and is considered a suitable outcome measurement for studying the neurodevelopmental effect of exposure to anaesthesia in early life.

A number of prospective investigations into the association between general anaesthesia and neurodevelopment disorders are in progress, but it will take several years to clarify this relationship. We also observed that all studies published on anaesthesia exposure and neurodevelopmental disorders were conducted in Western countries. No information has been reported regarding an Asian population. We hypothesised that exposure to general anaesthesia and surgery in early life is associated with an increased risk of autistic disorder. A nationwide population-based analysis was performed using data retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan.

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Materials and methods

We designed a retrospective matched-cohort study. The study protocol (CSMUH No. CS13180) was reviewed and approved by the Institutional Review Board of Chung Shan Medical University Hospital, Taichung, Taiwan (Chairman C.P. Han) on 26 September 2013.

The data were extracted from the NHIRD of Taiwan (http://nhird.nhri.org.tw/en/index.htm ). The National Health Research Institutes of Taiwan constructed the longitudinal database by randomly sampling one million insured people from the year registry (approximately 25 million people) of the National Health Insurance (NHI) programme every 5 years since 2000 (i.e. in 2000, 2005 and 2010). All the registration and claim data of the sampled people constituted the longitudinal database. The healthcare data from each sampled person are updated annually. The original NHIRD covers 99% of the population in Taiwan, and there were no significant differences in age and sex distributions between the people in the longitudinal databases and the people in the original NHIRD (http://nhird.nhri.org.tw/date_cohort.htm#3; http://nhird.nhri.org.tw/en/Data_Subsets.html#S3). The randomly sampled populations are thought to be representative of the insured population. The database is maintained and distributed by the Ministry of Health and Welfare and the National Health Research Institutes of Taiwan.

Two longitudinal datasets (2005 and 2010), each containing one million samples, were used for analyses. Those that were sampled repeatedly were deleted from the 2010 database. Of the approximately two million insured, children born between 1 January 2001 and 31 December 2007 were all enrolled.

The data were checked for general anaesthesia codes and autistic disorder diagnoses (ICD-9-CM 299.00). Children were allocated to the exposed group if the general anaesthesia codes were noted before the age of 2 years, and no diagnosis of autistic disorder had been found before anaesthesia occurred.

The Statistical Analysis System (SAS) programme was used to assign a random number (uniform function) to each participant in the birth cohort. Data were sorted by random numbers. Each child in the exposed group was matched to four unexposed children on the basis of sex and birth year/month using PROC SQL in SAS. The index date for the matched controls was defined as the day on which the exposed counterparts had their first exposure. The matched controls had not been diagnosed with an autistic disorder before the index date.

Data were checked for the diagnostic codes for perinatal conditions (ICD-9-CM 765, disorders relating to short gestation and low birth weight; 768, intrauterine hypoxia and birth asphyxia; 769, respiratory distress syndrome; 770, other respiratory conditions of fetus and newborn; 771, infections specific to the perinatal period; 775, endocrine and metabolic disturbances specific to the fetus and newborn), congenital anomalies (ICD-9-CM 740), anencephalus and similar anomalies; 741, spina bifida; 742, other congenital anomalies of the nervous system; 743, congenital anomalies of the eye; 744, congenital anomalies of ear, face, and neck; 758, chromosomal anomalies; 759, other and unspecified congenital anomalies), neurological diseases (ICD-9-CM 320 to 326, inflammatory diseases of the central nervous system; 330, cerebral degeneration usually manifest in childhood; 331, other cerebral degeneration; 333, other extrapyramidal diseases and abnormal movement disorders; 334, spinocerebellar disease; 335, anterior horn cell disease; 336, other diseases of the spinal cord; 337, disorders of the autonomic nervous system; 343, infantile cerebral palsy; 344, other paralytic syndromes; 345, epilepsy and recurrent seizures), endocrine diseases (ICD-9-CM 243, congenital hypothyroidism; 250, diabetes mellitus; 251, other disorders of pancreatic internal secretion; 252, disorders of the parathyroid gland; 253, disorders of the pituitary gland and its hypothalamic control; 254, diseases of the thymus gland; 255, disorders of the adrenal glands; 256, ovarian dysfunction; 257, testicular dysfunction; 258, polyglandular dysfunction and related disorders; 259, other endocrine disorders) and categories of surgery that had been undergone (skin, limbs, head and neck operations; heart and thoracic operations; abdominal operations; operations on the nervous system).

For the exposed participants, observations began on the day of the first exposure to general anaesthesia and surgery. The matched controls were entered on the same day (index date) as their exposed counterparts. All exposed children and the corresponding matched controls were considered to be at risk until a diagnosis of autistic disorder (ICD-9-CM 299.00) was made. We concluded the observation period on 31 December 2010.

Two additional analyses were performed on the basis of age at the time of first exposure and cumulative number of exposures. In the first additional analysis, the exposed group was stratified into four categories on the basis of the quartiles of age at the time of the first exposure. In the second analysis, the study participants were stratified into three categories according to the number of exposures (none, single or multiple).

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Statistical analysis

Multivariate Cox proportional hazards regression was used to assess whether exposure to general anaesthesia and surgery before the age of 2 years was a risk factor for developing an autistic disorder, both with and without adjustment for potential confounders, including home location, perinatal conditions (ICD-9-CM 765, 768 to 771, 775), congenital anomalies (ICD-9-CM 740 to 744, 758, 759), neurological diseases (ICD-9-CM 320 to 326, 330, 331, 333 to 337, 343 to 345), endocrine diseases (ICD-9-CM 243, 250, 251 to 259) and surgical operations (skin, limbs, head and neck; heart and thoracic; abdominal and nervous system). Data were censored for death, leaving the NHI programme or on the last follow-up before 31 December 2010.

In the additional analyses, the hazard ratio of autistic disorders was calculated with and without adjusting for the same potential confounders as in the main analysis.

The results were summarised as hazard ratio estimates and corresponding 95% confidence intervals (95% CIs). For nominal variables and stratified nominal variables, P values less than 0.05 in the χ2 test and Cochran Mantel Haenszel χ2 tests, respectively, were considered statistically significant. Analyses were performed using SAS statistical software (version 9.3; SAS Institute, Inc., Cary, North Carolina, USA).

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Results

A total of 114 435 children were born in Taiwan between 1 January 2001 and 31 December 2007. Among the cohort, 5197 children (3672 boys and 1525 girls) were noted to have undergone general anaesthesia and surgery before the age of 2 years. All were free of autistic disorders before exposure to anaesthesia and surgery. The 1 : 4 matched controls comprised 20 788 children who were neither exposed to general anaesthesia before 2 years of age nor diagnosed with an autistic disorder before the index date (Fig. 1).

Fig. 1

Fig. 1

The mean ± SD age at diagnosis of autistic disorder was 4.04 ± 1.80 years in this cohort, 3.82 ± 1.68 years in the exposed group and 4.10 ± 1.82 years in the matched controls (P = 0.16). The incidences of autistic disorder before 31 December 2010 were 0.96% (50 of 5197) in the exposed group and 0.89% (185 of 20 788) in the matched controls (P = 0.62). Compared with the unexposed children, those exposed to general anaesthesia and surgery before the age of 2 years were more likely to have been diagnosed with perinatal conditions (P < 0.001), congenital anomalies (P < 0.001), neurological disease (P < 0.001) or endocrine disease (P < 0.001). No significant differences were found between the two groups in home location or parental occupation (Table 1).

Table 1

Table 1

Multivariate Cox proportional hazards regression showed that congenital anomalies, neurological diseases and endocrine diseases were associated with a risk of autistic disorder without any adjustments. The association of endocrine diseases with autistic disorder became nonsignificant after adjusting for other potential confounders. The association between exposure to general anaesthesia and surgery before the age of 2 years and an autistic disorder was nonsignificant, either before or after adjusting for home location, perinatal conditions, congenital anomalies, neurological diseases, endocrine diseases and categories of surgery (Table 2).

Table 2

Table 2

Age categories at the time of first exposure were defined as 0 to 108 days, 109 to 327 days, 328 to 508 days and 509 days to 2 years according to quartiles of age at the time of first exposure. Age at the time of first exposure was not associated with risk of an autistic disorder, and no evidence of a trend was present (Table 3).

Table 3

Table 3

Neither single nor multiple exposures were associated with risk of an autistic disorder. No relationships existed between number of exposures and risk of an autistic disorder (Table 4).

Table 4

Table 4

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Discussion

The results revealed that exposure to general anaesthesia and surgery before the age of 2 years did not increase the risk of developing autistic disorder later in life.

Before determining the cut-off age of exposure, we made a general assessment of the enrolled birth cohort, which comprised 114 435 children born between 1 January 2001 and 31 December 2007. Of the 114 435 children, 772 were diagnosed with an autistic disorder before 31 December 2010. The mean age at the first diagnosis was 4.05 ± 1.78 years. Among the 772 children with autistic disorder, 86 cases had undergone general anaesthesia and surgery before being diagnosed with an autistic disorder. The median time interval between anaesthesia exposure and diagnosis of autistic disorder was 2.37 (interquartile range, IQR 1.48 to 3.32) years. We hypothesised a causal relationship between exposure to anaesthesia/surgery and an autistic disorder, and that children might be diagnosed with an autistic disorder within approximately 3 years after exposure. We considered 2 years of age as the cut-off age of exposure; 3 years after exposure, the exposed children would be between 3 and 5 years of age, which is around the mean age of 4.05 ± 1.78 years at the first diagnosis of autistic disorder in our birth cohort.

We included children born between 2001 and 2007. At the end of the observation period, approximately 7% of the study participants had not yet reached an age, 4.04 ± 1.80 years, at which autistic disorder could be diagnosed. However, the proportions of children under 4 years of age were equal in both groups because the exposed and unexposed participants were matched (1 : 4), based on age and sex. No significant difference existed for the mean age at the first diagnosis of autistic disorder between the two groups: 3.82 ± 1.68 years in the exposed group and 4.10 ± 1.82 years in the matched controls (P = 0.16). Therefore, including younger participants would not bias the results.

Children with anaesthesia exposure after 2 years of age were not excluded. Because autistic disorder might increase the need for anaesthesia in the affected children, a selection bias would be introduced if we excluded children with exposure to anaesthesia and surgery after 2 years of age. Among the exposed group, 946 (18.2%) of the 5197 children underwent general anaesthesia and surgery after 2 years of age. In the 20 788 matched controls, 1680 (8.1%) children were exposed to general anaesthesia and surgery after 2 years of age, and 12 of them were diagnosed with an autistic disorder after the exposure. If children with anaesthesia exposure after 2 years of age had been excluded from our analysis, we might have excluded a sufficiently large number of autistic disorder cases in the unexposed group, thus overestimating the association between early life anaesthesia and surgery exposure and autistic disorder. In contrast, we might have underestimated the association of anaesthesia and surgery exposure with the risk of autistic disorder when 1680 children with later exposures were allocated in the unexposed group. However, we did not verify that no exposures occurred after 2 years of age in both groups, nor did we study the association of later exposures with autistic disorder, because the objective of this analysis was to investigate whether anaesthesia and surgery exposure before 2 years of age increased the risk of developing an autistic disorder later in life.

Previous studies have used more outcome measures such as developmental and behavioural disorders,16,17 academic performance20 or learning disabilities24,25 to investigate anaesthesia and surgery-related effects on neurodevelopment. Children with learning disabilities, delays in reading, mathematics and speech development, or poor academic performance may not be identified before school age. Social behavioural disorders may not be noticeable until children are involved in group activities and have difficulty communicating and interacting with others. The matched cohort of our analysis was born between 2001 and 2007. Because approximately 30% of them were under school age at the end of the observation period, learning disabilities, behavioural disorders and academic performance were not suitable outcome measures for our study population. However, we considered other neurodevelopmental disorders as crucial and intriguing outcomes for investigating the neurotoxicity of anaesthetics. We have completed an analysis on the association of general anaesthesia with attention deficit/hyperactivity disorder,40 and would like to further investigate the effects of anaesthesia exposure on other neurodevelopmental disorders with appropriate materials and study designs.

Although some inherited factors have been shown to be associated with autistic disorder, noninheritable factors might have an effect on the mechanisms involving genetic susceptibility. Authors of previous studies have suggested that exposure to exogenous agents during a critical period of development, such as maternal drug use during pregnancy, might cause autistic disorder.41–43 In addition, perinatal insults including stress,44,45 inflammation46,47 and infection48–50 were associated with adverse outcomes in neurocognitive function. Among the nongenetic factors, obstetric suboptimality has been found to increase the risk of autistic disorder.31,33 Because of the limitation of our database, maternal conditions were unavailable; consequently, maternal factors were not considered in the current study. Alternatively, hazard ratios were adjusted for perinatal conditions including disorders relating to short gestation and low birth weight (ICD-9-CM 765), which might be used as a surrogate for suboptimal pregnancy.

Parental age and level of education may be associated with a risk of an autistic disorder. Such parental factors might differ between the exposed group and the matched controls, and thus might have affected the results. Unfortunately, neither parental age nor level of education was available because of the limitation of our database. Parental occupation data, which may serve as a surrogate for parental socioeconomic status, were available only for those born before 2006. We did not adjust for parental occupation in the regression model because of missing data (for those born after 2006). However, by reviewing the data from children born before 2006, we found no significant differences in parental occupation between the anaesthesia-exposed children and the matched controls (P = 0.69, Table 1). Parental occupation and socioeconomic status did not seem to influence the use of medical resources in our country. A similar situation might occur regarding parental age and education level. If parental age and level of education did not influence the use of medical resources and the need for anaesthesia, these factors might not be considered as confounders in our analysis.

The health status of children who required general anaesthesia and surgery may have differed from those who did not. In the current study, children in the exposed group had more frequent perinatal conditions and congenital anomalies than the matched controls did. The classifications of the American Society of Anaesthesiologists’ (ASA) physical status were unavailable in our database. Consequently, the hazard ratios were not adjusted for ASA physical status classification in our analyses. Chen et al.51 used the NHIRD of Taiwan and reported an increased risk of congenital anomalies and neurological and endocrine disorders in autistic children. Therefore, we adjusted the hazard ratios for congenital anomalies, and neurological and endocrine disorders, instead of ASA physical status.

We were also interested in whether the ‘total dose’ of exposure to anaesthesia was a key factor in causing neurodevelopmental disorders. However, neither total exposure time nor total drug dose was obtainable from our database. We could calculate only the total number of exposures and use it as a substitute for total exposure dose. Wilder et al.25 reported that repeated anaesthetic exposure at a young age was associated with poor performance on standardised achievement tests. A study by Sprung et al.23 revealed that repeated exposure to general anaesthesia before the age of 2 years increased the risk of attention deficit/hyperactivity disorder. However, in our stratified analysis based on the cumulative number of anaesthesia and surgery exposures, we observed that multiple exposures did not increase the risk of autistic disorder (adjusted hazard ratio 1.27, 95% CI 0.48 to 3.36). This result is similar to that from our previous study on the association of anaesthesia with risk of attention deficit/hyperactivity disorder.40

The time period of general anaesthesia exposure in our study was between 2001 and 2009. Sevoflurane has been used widely in paediatric anaesthetic practice instead of older inhalational agents such as halothane since the late 1990s. We examined clinical practices more recent than those reported by Flick et al.24 and Wilder et al.25

The current study has several limitations. Because our analyses were performed on the basis of health claim data, children who did not visit healthcare facilities were not documented. In addition, the diagnosis might contain some measurement errors that would consequently bias the study results towards no association. Finally, further clarification may be necessary to determine whether autistic disorder is a relevant outcome measure for studying anaesthetic effects on neurodevelopment.

The relatively large sample and the design for longitudinal observations are considered to be strengths of the current analysis. Two studies by DiMaggio et al.16,17 used the database from the New York State Medicaid programme that covers a relatively vulnerable population. This group of people may be relatively different from the general population in healthcare use and prevalence of mental diseases.52 The results of their studies could not be generalised to other populations. We used data from the NHIRD of Taiwan. The population is homogeneous because the NHI programme covers approximately 99% of the 23 million citizens in Taiwan.

On the basis of the results of this population-based, retrospective matched-cohort study, we conclude that exposure to general anaesthesia and surgery before the age of 2 years is not associated with the development of an autistic disorder later in life. Age at the time of the first exposure was not related to the risk of autistic disorder, and repeated exposure did not increase the risk of autistic disorder. However, similar to other neurocognitive disorders, a future research design could include siblings or twins to clarify the relationship between early anaesthetic exposure and autistic disorder, given the association of genetic factors with the disease.

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Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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