587094
research-article2015
JADXXX10.1177/1087054715587094Journal of Attention DisordersJournal of Attention DisordersTsai et al.
Article
Risk of ADHD After Multiple Exposures to General Anesthesia: A Nationwide Retrospective Cohort Study
Journal of Attention Disorders 1–11 © 2015 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054715587094 jad.sagepub.com
Chia-Jui Tsai1, Charles Tzu-Chi Lee2,3, Sophie Hsin-Yi Liang4,5, Pei-Jung Tsai6, Vincent Chin-Hung Chen5,7, and Michael Gossop8
Abstract Objective: To study the association between general anesthesia exposure before age 3 years and having a later ADHD diagnosis. Method: In a birth cohort, data were collected from a nationwide population database for children born between 1997 and 1999 who were exposed to general anesthesia before their third birthday. Age- and gender-matched enrollees without general anesthesia exposure were taken as the comparison. Groups were compared to identify the incidence of ADHD after age 4 and anesthesia-related predictive factors. Results: Among the 1,146 exposed children, 74 ADHD cases were identified, and 158 ADHD cases were identified in 3,438 matched controls. After adjusting for comorbid conditions and possible confounding factors, if exposure on more than one occasion or ≥3 hr, an increased likelihood of having a later ADHD diagnosis was found (HR, 1.71 and 2.43, respectively). Conclusion: Children with multiple or ≥3 hr general anesthesia exposures before age 3 years have an increased likelihood of a later ADHD diagnosis. (J. of Att. Dis. XXXX; XX(X) XX-XX) Keywords general anesthesia, risk, ADHD, NHIRD
Introduction The benefits of anesthesia in children include alleviation of pain, anxiety, maintaining stable vital signs, and providing adequate conditions for surgery or other procedures. An estimated 6 million children (including 1.5 million infants) undergo surgery and anesthesia each year in the United States alone, so the clinical relevance of anesthetic neurotoxicity is an urgent matter of public health (Sun, 2010). General anesthesia can induce neurodegeneration and subsequent maladaptive behaviors in animals, including rats and primates. Its neurotoxicity in animals develops after exposure above threshold doses and durations during a critical neurodevelopmental window of maximal synaptogenesis (Brambrink et al., 2010; Hays & Deshpande, 2013). Implicated drugs include N-methyl-D-aspartate (NMDA) glutamate receptor antagonists and γ-aminobutyric acid (GABA) agonists such as midazolam, nitrous oxide, isoflurane, and ketamine. These were found to cause widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments. Also, their damage to the infant animal brain was dose dependent (Ikonomidou et al., 1999; Jevtovic-Todorovic et al., 2003; Young et al., 2005). Neonatal exposure to NMDA antagonists in rodents
produces neural injury associated with hyperactivity and it can be reversed by a low dose of D-amphetamine (Fredriksson & Archer, 2003). This preclinical evidence of anesthetic neurotoxicity from in vitro and in vivo animal studies raises serious concern that the use of anesthetic agents in children might lead to long-term adverse neurodevelopmental outcomes or psychiatric symptoms, but this issue has not been adequately investigated in human participants (Sun, 2010). Recent human studies tried to find evidence of anesthesia-induced injury, and the outcome focused mostly on the diagnosis of neurodevelopmental disorders, behavioral 1
Taichung Veterans General Hospital, Taiwan Kaohsiung Medical University, Taiwan 3 National Taiwan Normal University, Taipei, Taiwan 4 Chang Gung Memorial Hospital, Taoyuan, Taiwan 5 Chang Gung University, Taoyuan, Taiwan 6 Lu-Tung Christian Hospital, Changhua, Taiwan 7 Chiayi Chang Gung Memorial Hospital, Taiwan 8 King’s College London, UK 2
Corresponding Author: Vincent Chin-Hung Chen, Chang Gung Medical Foundation, Chiayi Chang Gung Memorial Hospital, 6-8, West Section, Jiapu Road, Puzi City, Chiayi County 613, Taiwan. Email: [email protected]
Downloaded from jad.sagepub.com by guest on November 16, 2015
2
Journal of Attention Disorders
disorders, learning problems, cognitive impairment, or the measurement of academic achievements (DiMaggio, Sun, Ing, & Li, 2012; DiMaggio, Sun, Kakavouli, Byrne, & Li, 2009; DiMaggio, Sun, & Li, 2011; Flick et al., 2011; Wilder et al., 2009). However, clinical evidence regarding negative long-term cognitive and behavioral effects of multiple anesthesia in young children has typically been based on retrospective and observational studies (Hays & Deshpande, 2013; Olsen & Brambrink, 2013). Two retrospective cohort studies using Medicaid data by DiMaggio et al. found that children with exposure to general anesthesia before 3 years of age were more than twice as likely as children in the comparison group to be subsequently diagnosed with developmental or behavioral disorder (DBD; DiMaggio et al., 2009; DiMaggio et al., 2011). DBD is a spectrum of diagnoses that includes ADHD, developmental delay, coordination disorder, and language of speech problems. ADHD, as a major component of DBD, is one of the most prevalent and researched childhood-onset psychiatric disorders and affects 4% to 12% of children around the world (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007). It has been suggested that anesthetic agents that block NMDA receptors might play a role in the development of ADHD (Lehohla, Kellaway, & Russell, 2004). Two previous studies explored the relationship between general anesthesia and ADHD, but their results were conflicting. Sprung et al. (2012) conducted a birth cohort study in Rochester and found that exposure to multiple procedures requiring general anesthesia before the age of 2 years was associated with an increased risk for ADHD. However, the study population was only regional but not nationwide. Another study using a population-based database failed to show any association between exposure to general anesthesia before 3 years of age and ADHD (Ko et al., 2014). But their study participants were aged 5 to 10 years, which may underestimate the risk as children may receive a diagnosis of ADHD after 10 years of age. The present study investigates the association between exposure to general anesthesia during surgery or other procedures before age 3 years and subsequent ADHD diagnoses in a nationwide study sample.
diagnostic codes in the format of the International Classification of Disease, Revision 9, Clinical Modification (ICD-9-CM), all drug prescriptions, medical checkup and therapy, medical costs, use of medical care facilities, and physician specialties. The data set used in this study is the “one million people data set,” contained about 5% of the total number of beneficiaries covered by Taiwan’s NHI and people included in the data set are randomly selected from the nationwide population.
Materials and Method
ADHD Case Identification
Database
ADHD cases were identified based on recorded ICD-9-CM codes of 314, which contained all subtypes and presentations of ADHD. All medical claims made under this diagnostic code between 2000 and 2009 were collected from NHIRD for further analysis. The definition of having ADHD in this analysis required an inpatient diagnosis and/ or at least one year’s worth of diagnosed ADHD from outpatient services after four-year-old retrieved from the database, a definition consistent with other researches using this database (P. H. Chou et al., 2013; I. C. Chou, Lin, Sung, & Kao, 2014; Huang, Chu, Cheng, & Weng, 2014).
The Taiwan National Health Insurance (NHI) program, which was launched on March 1, 1995, and maintained by the Department of Health and the National Health Research Institutes, is a universal, state-operated health program that covers more than 98% of the population. It is one of the largest insurance databases in the world and provides valuable information for an epidemiological study (Tsai et al., 2012). The database provides various patient data, including date of birth, gender, identification card number,
Study Participants and Design The study sample comprised children who received general anesthesia before 3 years of age and who were born between January 1, 1997, and December 31, 1999. This birth cohort design has a study period from January 1, 2000, to December 31, 2009. Children who emigrated or died during the followup period or ever had diagnoses of moderate or severe intellectual disability (ICD-9 CM code: 318) in the database were excluded. The final cohort analyzed consisted of 1,146 children. The end point of this study was the presence of ADHD diagnosis or the end of follow-up date on December 31, 2009 (whichever came first). The control group, without receiving any general anesthesia before age 3, was age- and gendermatched with the study patients in a 1:3 ratio. The flowchart of data collection in this study is shown in Figure 1.
Identification of General Anesthesia Exposure All children who underwent any kind of surgery or procedure requiring general anesthesia before their third birthday comprised the exposure group. The general anesthesia treatment codes were used as exposure identification. We can sum up the total exposure time because different treatment codes of general anesthesia represent different exposure times. The code representative of post-operation care was used as confirmation of surgery. For the exposure group, the anesthetic agents used (whether inhalation, intravenous, or sedatives), number of anesthetic exposures and total duration of exposure before age 3 years were abstracted and calculated.
Downloaded from jad.sagepub.com by guest on November 16, 2015
3
Tsai et al.
Longitudinal Health Insurance Database (LHID) (From 1997 to 2009, N = 1000000)
Birthday in 1997-1999 (n = 37187)
With general anesthesia before three years old (n = 1223)
Without general anesthesia before three years old (n = 35964) Diagnoses moderate or severe intellectually disability (n = 110)
Diagnoses moderate or severe intellectually disability (n = 9) Death before 2009 (n = 22)
Death before 2009 (n = 150) Migration before 2009 (n = 1026)
Migration before 2009 (n = 46) Case cohort (n = 1146)
Control pool (n = 34678)
Matching by sex and age (within 1 year)
Figure 1. Flowchart of data collection.
Note. LHID = Longitudinal Health Insurance Database.
Confounding Factors/Assessment of Health Status Factors and complications noted at prenatal, perinatal, and postnatal periods played important roles as risk factors of ADHD, such as maternal mental condition, maternal smoking, increased maternal stress during pregnancy, as well as pregnancy and delivery complications (i.e., toxemia), advanced maternal age, long duration of labor, fetal distress, low APGAR score, and low birth weight (Ben Amor et al., 2005; Freitag et al., 2012; Halmoy, Klungsoyr, Skjaerven, & Haavik, 2012; Ketzer, Gallois, Martinez, Rohde, & Schmitz, 2012; Li, Olsen, Vestergaard, & Obel, 2011; Motlagh et al., 2010; Sagiv, Epstein, Bellinger, & Korrick, 2013; Smidts & Oosterlaan, 2007). In the database, preterm labor and small for gestational age (SGA) was coded on the presence of ICD-9-CM code 765765.19. Perinatal complications were detected by the ICD9-CM code 760-764, 766-779, and V137. Brain conditions that require an operation, such as brain tumor (ICD-9: 225, 191, 655), brain abscess (ICD-9-CM: 324), hemorrhage (ICD9-CM: 430-432), and hydrocephalus (ICD-9:331.3, 331.4,
742.3) and congenital anomalies (ICD-9-CM: 740-759), were also identified and controlled. It is not possible to determine mother’s education and socioeconomic status (SES) in the database directly. We tried to minimize the influence of SES by using living area (rural, urban) as a proxy. Also, the person to provide the child’s insurance premium was considered as a proxy index of their parent. Parental economic status was classified as one of three categories: less than New Taiwan Dollars (NT$) 20,000, NT$20,000~NT$39,999, and NT$40,000 or more. Parental occupation was classified as one of four categories: (a) civil servants, teachers, employees of governmental or private business, professionals, or technicians; (b) people without particular employers, self-employed, or seamen; (c) farmers or fishermen; and (d) low-income families supported by social welfare or veterans.
Statistical Analysis Cox regression analysis was used to assess whether exposure to procedures requiring general anesthesia was a risk factor for ADHD. The main explanatory variable, general
Downloaded from jad.sagepub.com by guest on November 16, 2015
4
Journal of Attention Disorders
anesthesia, was assessed by three kinds of measurements including binary (yes vs. no), times (no exposure, 1, or 2, or more exposures), and hours (0,
research-article2015
JADXXX10.1177/1087054715587094Journal of Attention DisordersJournal of Attention DisordersTsai et al.
Article
Risk of ADHD After Multiple Exposures to General Anesthesia: A Nationwide Retrospective Cohort Study
Journal of Attention Disorders 1–11 © 2015 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054715587094 jad.sagepub.com
Chia-Jui Tsai1, Charles Tzu-Chi Lee2,3, Sophie Hsin-Yi Liang4,5, Pei-Jung Tsai6, Vincent Chin-Hung Chen5,7, and Michael Gossop8
Abstract Objective: To study the association between general anesthesia exposure before age 3 years and having a later ADHD diagnosis. Method: In a birth cohort, data were collected from a nationwide population database for children born between 1997 and 1999 who were exposed to general anesthesia before their third birthday. Age- and gender-matched enrollees without general anesthesia exposure were taken as the comparison. Groups were compared to identify the incidence of ADHD after age 4 and anesthesia-related predictive factors. Results: Among the 1,146 exposed children, 74 ADHD cases were identified, and 158 ADHD cases were identified in 3,438 matched controls. After adjusting for comorbid conditions and possible confounding factors, if exposure on more than one occasion or ≥3 hr, an increased likelihood of having a later ADHD diagnosis was found (HR, 1.71 and 2.43, respectively). Conclusion: Children with multiple or ≥3 hr general anesthesia exposures before age 3 years have an increased likelihood of a later ADHD diagnosis. (J. of Att. Dis. XXXX; XX(X) XX-XX) Keywords general anesthesia, risk, ADHD, NHIRD
Introduction The benefits of anesthesia in children include alleviation of pain, anxiety, maintaining stable vital signs, and providing adequate conditions for surgery or other procedures. An estimated 6 million children (including 1.5 million infants) undergo surgery and anesthesia each year in the United States alone, so the clinical relevance of anesthetic neurotoxicity is an urgent matter of public health (Sun, 2010). General anesthesia can induce neurodegeneration and subsequent maladaptive behaviors in animals, including rats and primates. Its neurotoxicity in animals develops after exposure above threshold doses and durations during a critical neurodevelopmental window of maximal synaptogenesis (Brambrink et al., 2010; Hays & Deshpande, 2013). Implicated drugs include N-methyl-D-aspartate (NMDA) glutamate receptor antagonists and γ-aminobutyric acid (GABA) agonists such as midazolam, nitrous oxide, isoflurane, and ketamine. These were found to cause widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments. Also, their damage to the infant animal brain was dose dependent (Ikonomidou et al., 1999; Jevtovic-Todorovic et al., 2003; Young et al., 2005). Neonatal exposure to NMDA antagonists in rodents
produces neural injury associated with hyperactivity and it can be reversed by a low dose of D-amphetamine (Fredriksson & Archer, 2003). This preclinical evidence of anesthetic neurotoxicity from in vitro and in vivo animal studies raises serious concern that the use of anesthetic agents in children might lead to long-term adverse neurodevelopmental outcomes or psychiatric symptoms, but this issue has not been adequately investigated in human participants (Sun, 2010). Recent human studies tried to find evidence of anesthesia-induced injury, and the outcome focused mostly on the diagnosis of neurodevelopmental disorders, behavioral 1
Taichung Veterans General Hospital, Taiwan Kaohsiung Medical University, Taiwan 3 National Taiwan Normal University, Taipei, Taiwan 4 Chang Gung Memorial Hospital, Taoyuan, Taiwan 5 Chang Gung University, Taoyuan, Taiwan 6 Lu-Tung Christian Hospital, Changhua, Taiwan 7 Chiayi Chang Gung Memorial Hospital, Taiwan 8 King’s College London, UK 2
Corresponding Author: Vincent Chin-Hung Chen, Chang Gung Medical Foundation, Chiayi Chang Gung Memorial Hospital, 6-8, West Section, Jiapu Road, Puzi City, Chiayi County 613, Taiwan. Email: [email protected]
Downloaded from jad.sagepub.com by guest on November 16, 2015
2
Journal of Attention Disorders
disorders, learning problems, cognitive impairment, or the measurement of academic achievements (DiMaggio, Sun, Ing, & Li, 2012; DiMaggio, Sun, Kakavouli, Byrne, & Li, 2009; DiMaggio, Sun, & Li, 2011; Flick et al., 2011; Wilder et al., 2009). However, clinical evidence regarding negative long-term cognitive and behavioral effects of multiple anesthesia in young children has typically been based on retrospective and observational studies (Hays & Deshpande, 2013; Olsen & Brambrink, 2013). Two retrospective cohort studies using Medicaid data by DiMaggio et al. found that children with exposure to general anesthesia before 3 years of age were more than twice as likely as children in the comparison group to be subsequently diagnosed with developmental or behavioral disorder (DBD; DiMaggio et al., 2009; DiMaggio et al., 2011). DBD is a spectrum of diagnoses that includes ADHD, developmental delay, coordination disorder, and language of speech problems. ADHD, as a major component of DBD, is one of the most prevalent and researched childhood-onset psychiatric disorders and affects 4% to 12% of children around the world (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007). It has been suggested that anesthetic agents that block NMDA receptors might play a role in the development of ADHD (Lehohla, Kellaway, & Russell, 2004). Two previous studies explored the relationship between general anesthesia and ADHD, but their results were conflicting. Sprung et al. (2012) conducted a birth cohort study in Rochester and found that exposure to multiple procedures requiring general anesthesia before the age of 2 years was associated with an increased risk for ADHD. However, the study population was only regional but not nationwide. Another study using a population-based database failed to show any association between exposure to general anesthesia before 3 years of age and ADHD (Ko et al., 2014). But their study participants were aged 5 to 10 years, which may underestimate the risk as children may receive a diagnosis of ADHD after 10 years of age. The present study investigates the association between exposure to general anesthesia during surgery or other procedures before age 3 years and subsequent ADHD diagnoses in a nationwide study sample.
diagnostic codes in the format of the International Classification of Disease, Revision 9, Clinical Modification (ICD-9-CM), all drug prescriptions, medical checkup and therapy, medical costs, use of medical care facilities, and physician specialties. The data set used in this study is the “one million people data set,” contained about 5% of the total number of beneficiaries covered by Taiwan’s NHI and people included in the data set are randomly selected from the nationwide population.
Materials and Method
ADHD Case Identification
Database
ADHD cases were identified based on recorded ICD-9-CM codes of 314, which contained all subtypes and presentations of ADHD. All medical claims made under this diagnostic code between 2000 and 2009 were collected from NHIRD for further analysis. The definition of having ADHD in this analysis required an inpatient diagnosis and/ or at least one year’s worth of diagnosed ADHD from outpatient services after four-year-old retrieved from the database, a definition consistent with other researches using this database (P. H. Chou et al., 2013; I. C. Chou, Lin, Sung, & Kao, 2014; Huang, Chu, Cheng, & Weng, 2014).
The Taiwan National Health Insurance (NHI) program, which was launched on March 1, 1995, and maintained by the Department of Health and the National Health Research Institutes, is a universal, state-operated health program that covers more than 98% of the population. It is one of the largest insurance databases in the world and provides valuable information for an epidemiological study (Tsai et al., 2012). The database provides various patient data, including date of birth, gender, identification card number,
Study Participants and Design The study sample comprised children who received general anesthesia before 3 years of age and who were born between January 1, 1997, and December 31, 1999. This birth cohort design has a study period from January 1, 2000, to December 31, 2009. Children who emigrated or died during the followup period or ever had diagnoses of moderate or severe intellectual disability (ICD-9 CM code: 318) in the database were excluded. The final cohort analyzed consisted of 1,146 children. The end point of this study was the presence of ADHD diagnosis or the end of follow-up date on December 31, 2009 (whichever came first). The control group, without receiving any general anesthesia before age 3, was age- and gendermatched with the study patients in a 1:3 ratio. The flowchart of data collection in this study is shown in Figure 1.
Identification of General Anesthesia Exposure All children who underwent any kind of surgery or procedure requiring general anesthesia before their third birthday comprised the exposure group. The general anesthesia treatment codes were used as exposure identification. We can sum up the total exposure time because different treatment codes of general anesthesia represent different exposure times. The code representative of post-operation care was used as confirmation of surgery. For the exposure group, the anesthetic agents used (whether inhalation, intravenous, or sedatives), number of anesthetic exposures and total duration of exposure before age 3 years were abstracted and calculated.
Downloaded from jad.sagepub.com by guest on November 16, 2015
3
Tsai et al.
Longitudinal Health Insurance Database (LHID) (From 1997 to 2009, N = 1000000)
Birthday in 1997-1999 (n = 37187)
With general anesthesia before three years old (n = 1223)
Without general anesthesia before three years old (n = 35964) Diagnoses moderate or severe intellectually disability (n = 110)
Diagnoses moderate or severe intellectually disability (n = 9) Death before 2009 (n = 22)
Death before 2009 (n = 150) Migration before 2009 (n = 1026)
Migration before 2009 (n = 46) Case cohort (n = 1146)
Control pool (n = 34678)
Matching by sex and age (within 1 year)
Figure 1. Flowchart of data collection.
Note. LHID = Longitudinal Health Insurance Database.
Confounding Factors/Assessment of Health Status Factors and complications noted at prenatal, perinatal, and postnatal periods played important roles as risk factors of ADHD, such as maternal mental condition, maternal smoking, increased maternal stress during pregnancy, as well as pregnancy and delivery complications (i.e., toxemia), advanced maternal age, long duration of labor, fetal distress, low APGAR score, and low birth weight (Ben Amor et al., 2005; Freitag et al., 2012; Halmoy, Klungsoyr, Skjaerven, & Haavik, 2012; Ketzer, Gallois, Martinez, Rohde, & Schmitz, 2012; Li, Olsen, Vestergaard, & Obel, 2011; Motlagh et al., 2010; Sagiv, Epstein, Bellinger, & Korrick, 2013; Smidts & Oosterlaan, 2007). In the database, preterm labor and small for gestational age (SGA) was coded on the presence of ICD-9-CM code 765765.19. Perinatal complications were detected by the ICD9-CM code 760-764, 766-779, and V137. Brain conditions that require an operation, such as brain tumor (ICD-9: 225, 191, 655), brain abscess (ICD-9-CM: 324), hemorrhage (ICD9-CM: 430-432), and hydrocephalus (ICD-9:331.3, 331.4,
742.3) and congenital anomalies (ICD-9-CM: 740-759), were also identified and controlled. It is not possible to determine mother’s education and socioeconomic status (SES) in the database directly. We tried to minimize the influence of SES by using living area (rural, urban) as a proxy. Also, the person to provide the child’s insurance premium was considered as a proxy index of their parent. Parental economic status was classified as one of three categories: less than New Taiwan Dollars (NT$) 20,000, NT$20,000~NT$39,999, and NT$40,000 or more. Parental occupation was classified as one of four categories: (a) civil servants, teachers, employees of governmental or private business, professionals, or technicians; (b) people without particular employers, self-employed, or seamen; (c) farmers or fishermen; and (d) low-income families supported by social welfare or veterans.
Statistical Analysis Cox regression analysis was used to assess whether exposure to procedures requiring general anesthesia was a risk factor for ADHD. The main explanatory variable, general
Downloaded from jad.sagepub.com by guest on November 16, 2015
4
Journal of Attention Disorders
anesthesia, was assessed by three kinds of measurements including binary (yes vs. no), times (no exposure, 1, or 2, or more exposures), and hours (0,
