J Korean Med Sci.  2023 Feb;38(6):e42. 10.3346/jkms.2023.38.e42.

Association Between Receipt of General Anesthesia During Childhood and Attention Deficit Hyperactive Disorder and Neurodevelopment

• Song JY
• Cha HR
• Lee SW
• Ha EK
• Kim JH
• Han MY

• KMID: 2539491
• DOI: http://doi.org/10.3346/jkms.2023.38.e42

Abstract

Background
There are inconsistent reports regarding the association between general anesthesia and adverse neurodevelopmental and behavioral disorders in children.
Methods
This nationwide administrative cohort study included children born in Korea between 2008 and 2009, and followed until December 31, 2017. The cohort included 93,717 participants who received general anesthesia with endotracheal intubation (ETI) who were matched to unexposed subjects in a 1:1 ratio. General anesthesia was defined by National Health Insurance Service treatment codes with intratracheal anesthesia, and the index date was the first event of general anesthesia. The primary outcome was attention deficit hyperactive disorder (ADHD), which was defined as at least a principal diagnosis of 10th revision of the International Classification of Diseases code F90.X after the age of 72 months. Neurodevelopment, which was assessed using a developmental screening test (Korean-Ages and Stages Questionnaire [K-ASQ]), was a secondary outcome. The K-ASQ is performed annually from 1 to 6 years of age and consists of 5 domains. The association between general anesthesia and ADHD was estimated using a Cox hazard model, and its association with neurodevelopment was estimated using a generalized estimation equation, with control for multiple risk factors beyond 1 year after the index date.
Results
The median age at the index date was 3.8 (95% confidence interval [CI], 1.7–5.8) years, and there were 57,625 (61.5%) men. During a mean follow-up period of 5 years, the incidence rate of ADHD was 42.6 and 27.7 per 10,000 person-years (PY) in the exposed and unexposed groups, respectively (absolute rate difference 14.9 [95% CI, 12.5–17.3] per 10,000 PY). Compared to the unexposed group, the exposed group had an increased risk of ADHD (adjusted hazard ratio, 1.41 [95% CI, 1.30–1.52]). In addition, a longer duration of anesthesia with ETI and more general anesthesia procedures with ETI were associated with greater risk of ADHD. General anesthesia with ETI was also associated with poorer results in the K-ASQ.
Conclusion
Administration of general anesthesia with ETI to children is associated with an increased risk of ADHD and poor results in a neurodevelopmental screening test.

Keyword

General Anesthesia; Attention Deficit Hyperactive Disorder; Neurodevelopment; Children

Figure

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  Fig. 1 Study design.ICD-10 = 10th revision of the International Classification of Diseases.

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  Fig. 2 Forest plot for sensitivity analysis of alternative definitions of ADHD. HRs and 95% CIs were calculated using a Cox proportional hazards model to assess the relationship between general anesthesia and various definitions of ADHD, adjusting for age at the index date, sex, calendar year of birth (2008 or 2009), birth weight, birth residence (Seoul/metropolitan, city, or rural area), economic status (low, middle, or high), and perinatal diseases. Recurrent ADHD 1 year apart was defined as two principal diagnoses of ICD-10 code F90.X after 72 months of age and 1 year apart between diagnoses. Wide-ranging ADHD was defined as at least a principal or second diagnosis of ICD-10 code F90.X after 72 months of age. ADHD with medication was defined as at least a principal diagnosis of ICD-10 code F90.X after 72 months of age with a prescription of methylphenidate. All outcomes were identified for at least one year (window period) after the index date. Filled rounds indicate aHRs and black lines indicate 95% CIs.ADHD = attention deficit hyperactivity disorder, PY = person-years, CI = confidence interval, HR = hazard ratio, aHR = adjusted hazard ratio, ICD-10 = 10th revision of the International Classification of Diseases.

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  Fig. 3 Forest plot of the association between GA and ADHD according to the intensity of GA and participant’s condition after GA. HRs and 95% CIs were calculated using a Cox proportional hazards model, adjusting for age at the index date, sex, calendar year of birth (2008 or 2009), birth weight, birth residence (Seoul, metropolitan, city, or rural area), economic status (low, middle, or high), and perinatal diseases. To estimate the intensity of GA and participants’ condition after GA, the exposure was divided according to the duration of GA (less than 1 hour, 1–2 hours, 2–3 hours, or over 3 hours), number of GA exposures (once, twice, or thrice or over), duration of admission at the time of GA (less than 3 days [median] or 3 days or over), and admission to the ICU (yes or no). All outcomes were identified for at least one year (window period) after the index date. Filled rounds indicate aHRs and black lines indicate 95% CIs.ADHD = attention deficit hyperactivity disorder, CI = confidence interval, aHR = adjusted hazard ratio, ICU = intensive care unit, GA = general anesthesia.

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  Fig. 4 Sensitivity analysis for the association between general anesthesia and ADHD based on the 1:1 propensity score matching method. RRs and 95% CIs were calculated using a modified Poisson regression to assess the relationship between general anesthesia and ADHD in the second cohort. ADHD as main outcome was defined as at least a principal diagnosis of ICD-10 code F90.X after 72 months old. Recurrent ADHD 1 year apart was defined as two principal diagnoses of ICD-10 code F90.X after 72 months of age and 1 year apart between diagnoses. Wide-ranging ADHD was defined as at least a principal or second diagnosis of ICD-10 code F90.X after 72 months of age. ADHD with medication was defined as at least a principal diagnosis of ICD-10 code F90.X after 72 months of age with a prescription of methylphenidate. All outcomes were identified for at least one year (window period) after the index date. Filled rounds indicate aRRs and black lines indicate 95% CIs.ADHD = attention deficit hyperactivity disorder, CI = confidence interval, RR = risk ratio, aRR = adjusted risk ratio, ICD-10 = 10th revision of the International Classification of Diseases.

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  Fig. 5 Forest plot for the association between general anesthesia and each domain of K-ASQ. ORs and their 95% CIs were calculated using generalized estimated equations with the logit link function to assess the associations between general anesthesia exposure and adverse results of the K-ASQ in children. The results of each domain were stratified into appropriate, need for follow-up, and recommendations for further evaluation categories. The results of need for follow-up and recommendation for further evaluation, which mean a score below −1 and −2 standard deviations for age, were considered adverse results. All outcomes were identified for at least one year (window period) after the index date. Filled rounds indicate aORs and black lines indicate 95% CIs.K-ASQ = Korean-Ages and Stages Questionnaire, CI = confidence interval, OR = odds ratio, aOR = adjusted odds ratio.

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