Abstract
Objective
To study the association between exposure to procedures performed under general anesthesia before age 2 years and development of attention-deficit/hyperactivity disorder (ADHD).
Patients and Methods
Study patients included all children born between January 1, 1976, and December 31, 1982, in Rochester, MN, who remained in Rochester after age 5. Cases of ADHD diagnosed before age 19 years were identified by applying stringent research criteria. Cox proportional hazards regression assessed exposure to procedures requiring general anesthesia (none, 1, 2 or more) as a predictor of ADHD using a stratified analysis with strata based on a propensity score including comorbid health conditions.
Results
Among the 5357 children analyzed, 341 ADHD cases were identified (estimated cumulative incidence, 7.6%; 95% confidence interval [CI], 6.8%-8.4%). For children with no postnatal exposure to procedures requiring anesthesia before the age of 2 years, the cumulative incidence of ADHD at age 19 years was 7.3% (95% CI, 6.5%-8.1%). For single and 2 or more exposures, the estimates were 10.7% ( 95% CI, 6.8%-14.4%) and 17.9% ( 95% CI, 7.2%-27.4%), respectively. After adjusting for gestational age, sex, birth weight, and comorbid health conditions, exposure to multiple (hazard ratio, 1.95; 95% CI, 1.03-3.71), but not single (hazard ratio,1.18; 95% CI, 0.79-1.77), procedures requiring general anesthesia was associated with an increased risk for ADHD.
Conclusion
Children repeatedly exposed to procedures requiring general anesthesia before age 2 years are at increased risk for the later development of ADHD even after adjusting for comorbidities.
Exposure of the developing brains of animals to anesthetics and sedatives causes neurodegenerative changes.
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Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
Implicated drugs include
N-methyl-D-aspartate glutamate receptor antagonists and γ-aminobutyric acid agonists.
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Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
When administered to young animals, including primates, in doses and durations that approximate those employed in clinical anesthetic care, these drugs cause apoptotic neurodegeneration affecting primarily cortical regions (depending on drug and species).
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These changes are associated with behavioral deficits in both rodents and nonhuman primates, with deficits noted in learning, attentiveness, and other aspects of behavior.
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Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
, 3- Brambrink A.M.
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- et al.
Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain.
, 4- Paule M.G.
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- Allen R.R.
- et al.
Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.
The clinical significance of these observations remains unclear, and it is difficult to predict the expected phenotype of anesthesia-induced injury in humans based on preclinical work. The relatively few extant human studies seeking evidence of anesthesia-induced injury have examined several outcomes, including medical record diagnostic codes possibly related to learning problems, group-administered measures of academic achievement, and learning disabilities (LD).
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Using the last-mentioned approach, our group found an association between multiple, but not single, exposures to procedures requiring anesthesia and subsequent LD in children in a population-based birth cohort, with multiple exposures associated with an approximate 2-fold increase in the incidence of LD.
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Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
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Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.
Although LD is a reasonable outcome to seek on the basis of the preclinical findings,
2- Jevtovic-Todorovic V.
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Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
others are also plausible. For example, neonatal exposure of rodents to
N-methyl-D-aspartate antagonists produces neural injury associated with hyperactivity that can be ameliorated by dextroamphetamine and indeed has been proposed as a model for human attention-deficit/hyperactivity disorder (ADHD).
9Hyperactivity following postnatal NMDA antagonist treatment: reversal by D-amphetamine.
Children with ADHD exhibit inattention, impulsivity, and motor restlessness, a clinical presentation consistent with a neuropsychological disorder (ie, cerebral dysfunction from a physical cause).
10American Psychiatric Association
Diagnostic and Statistical Manual of Mental Disorders: DSM-IV.
The cause(s) of ADHD symptoms are not known, but current theories emphasize the role of executive dysfunction such as behavioral disinhibition.
11ADHD and the Nature of Self-Control.
Although ADHD is a heritable disorder, a gene-environment interaction may be important for its clinical expression.
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Gene-environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective.
The current study examined the association between exposure to surgery or other procedures (eg, diagnostic procedures) requiring general anesthesia before age 2 years and ADHD in the same birth cohort that we previously used to examine LD as the outcome.
7- Wilder R.T.
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Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
This cohort has supported several prior investigations of the epidemiology of ADHD,
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How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn.
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Case definition in epidemiologic studies of AD/HD.
such that rigorous ascertainment of ADHD by well-defined research criteria is available.
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Case definition in epidemiologic studies of AD/HD.
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How common is attention-deficit/hyperactivity disorder? Towards resolution of the controversy: results from a population-based study.
We hypothesized that exposure to multiple, but not single, procedures requiring general anesthesia would be associated with risk for ADHD, similar to our previous findings for LD.
7- Wilder R.T.
- Flick R.P.
- Sprung J.
- et al.
Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
Discussion
The results of this study support the hypothesis that, similar to the pattern of our results previously observed for LD,
7- Wilder R.T.
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Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
, 8- Flick R.P.
- Katusic S.K.
- Colligan R.C.
- et al.
Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.
multiple, but not single, exposures to procedures requiring general anesthesia during the first 2 years of life are associated with an increased incidence of ADHD.
The clinical diagnosis of ADHD is made on the basis of symptoms of impulsivity, inattention, and motor restlessness that are not developmentally appropriate and using other criteria specified in DSM-IV.
10American Psychiatric Association
Diagnostic and Statistical Manual of Mental Disorders: DSM-IV.
Children with ADHD typically exhibit deficits in vigilance, verbal learning, working memory, and measures of executive function.
20Neuropsychological functioning in people with ADHD across the lifespan.
They frequently have comorbid mood, anxiety, or learning disorders, but neuropsychological abnormalities are present independent of such comorbidities.
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For this study, we used research criteria for identification of ADHD incident cases in a population-based cohort, a concept well established in epidemiology and clinical research.
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How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn.
, 14- Katusic S.K.
- Barbaresi W.J.
- Colligan R.C.
- et al.
Case definition in epidemiologic studies of AD/HD.
The etiology of ADHD is unknown, but evidence suggests a neuropsychological disorder, with anatomic correlates reported in imaging studies.
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Preliminary evidence of altered gray and white matter microstructural development in the frontal lobe of adolescents with attention-deficit hyperactivity disorder: a diffusional kurtosis imaging study.
Family, twin, and adoption studies suggest an important genetic component, and molecular genetic studies suggest several candidate genes, such as those associated with dopamine receptors and transport.
12- Thapar A.
- Langley K.
- Asherson P.
- Gill M.
Gene-environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective.
, 24- Biederman J.
- Faraone S.V.
Current concepts on the neurobiology of Attention-Deficit/Hyperactivity Disorder.
Environmental factors are also associated with ADHD, suggesting that gene-environment interactions are also operative.
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Gene-environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective.
Implicated environmental factors include maternal smoking, prenatal alcohol exposure, viral infections, nutritional deficiencies, low parental education level, perinatal stress, and others.
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Many children with ADHD also have a LD, which is characterized by a discrepancy between intellectual capacity and performance on tasks related to reading, language, and written skills.
20Neuropsychological functioning in people with ADHD across the lifespan.
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Rates of overlap vary depending on how LD is defined; estimates of the proportion of children with ADHD who also meet LD criteria range from 10% to more than 90%.
20Neuropsychological functioning in people with ADHD across the lifespan.
, 27- Mayes S.D.
- Calhoun S.L.
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Learning disabilities and ADHD: overlapping spectrumn disorders.
Of the 5357 children analyzed in this birth cohort, 932 (17.4%) were diagnosed with LD (either reading, math, or written skills) before age 19, 341 (6.4%) were diagnosed with ADHD, and 240 (4.5%) were diagnosed with both. Common genetic influences may explain this overlap, at least in part.
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Hypotheses to explain the relationship between ADHD and LD include that children with features of both have a qualitatively distinct condition (as supported by the genetic studies) and that there is a continuum of ADHD severity, with children with both ADHD and LD exhibiting more severe executive dysfunction compared with children exhibiting just ADHD.
20Neuropsychological functioning in people with ADHD across the lifespan.
Several studies in rodents have shown that histologic neurodegeneration produced by neonatal exposure to anesthetics is associated with a diminished capacity to retain learned behaviors,
2- Jevtovic-Todorovic V.
- Hartman R.E.
- Izumi Y.
- et al.
Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.
, 29Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD.
including a study that specifically examined the effect of repeated exposures in rodents and found a reduction in hippocampal neurogenesis (nonapoptotic) as well as profound deficits in learning and memory in later behavioral studies.
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Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.
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found that ketamine given to neonatal rats produced hyperactivity that could be ameliorated by dextroamphetamine, which is used to treat ADHD. Studies using the rhesus monkey have produced histologic results that are similar to those observed in rodents.
3- Brambrink A.M.
- Evers A.S.
- Avidan M.S.
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Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain.
, 4- Paule M.G.
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- Allen R.R.
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Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.
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Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain.
Exposing neonatal monkeys to 24 hours of ketamine affects performance in tasks related to both learning and executive function (including motivation and working memory) up to 4 years after exposure (equivalent to human adolescence).
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- Allen R.R.
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Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.
Thus, although these findings in rodents and nonhuman primates cannot be directly extrapolated to humans, it is plausible to postulate effects of anesthetic exposure on both learning and executive functions.
Children receiving anesthesia also experience surgery or other procedures, and it is possible that factors associated with the procedure itself could cause neurodegeneration. Accumulating evidence suggests that insults before and after birth, including stress
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and inflammation,
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may be associated with later adverse neurocognitive outcomes. For example, in an animal model of systemic inflammation produced by bacterial infection in early development, deficits in learning and memory are produced by increases in the cytokine interleukin-1β after later exposure to a “second hit” of lipopolysaccharide.
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In another example, in infants with necrotizing enterocolitis, bacteremia is associated with developmental dysfunction, suggesting that systemic inflammation may affect the developing brain.
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Surgery can produce stress and inflammatory responses in proportion to the severity of surgical injury.
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However, it is unclear whether the magnitude of these responses produced by surgery or other procedures in our cohort (procedures that varied widely in intensity) are comparable to those produced in animal or human studies examining neurodevelopment. Also, anesthesia itself modulates these responses,
41The stress response to trauma and surgery.
further complicating understanding of potential causative mechanisms.
When taken together with our prior analyses,
7- Wilder R.T.
- Flick R.P.
- Sprung J.
- et al.
Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
, 8- Flick R.P.
- Katusic S.K.
- Colligan R.C.
- et al.
Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.
we find an association between exposure to multiple procedures requiring anesthesia and both LD and ADHD. Even though there is considerable overlap between these conditions,
27- Mayes S.D.
- Calhoun S.L.
- Crowell E.W.
Learning disabilities and ADHD: overlapping spectrumn disorders.
similar results are found if those children with only ADHD are considered. The same is true if children with only LD are considered. In this cohort, there were 692 children (12.9% of the total cohort) who were diagnosed with only LD (no ADHD). If the propensity-stratified analysis is performed with this as the dependent variable, excluding children with ADHD, again multiple, but not single, exposures to procedures requiring anesthesia were associated with the diagnosis of LD before age 19 (HR, 1.11; 95% CI, 0.81-1.54;
P=.51, and HR 2.26; 95% CI, 1.34-3.79;
P=.002 for single and multiple exposures, respectively). To the extent that ADHD and LD are produced by distinct mechanisms, this suggests that exposure to procedures requiring general anesthesia may affect both.
In our prior analysis, we found no association between exposure to procedures requiring anesthesia and implementation of an IEP-EBD.
8- Flick R.P.
- Katusic S.K.
- Colligan R.C.
- et al.
Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.
Typically, indications for an IEP-EBD include mood disorders such as anxiety and depression, unusual behavior patterns, and more severe forms of disruptive behaviors. Indeed, the majority of our children diagnosed with ADHD did not receive an IEP-EBD (eg, of the 341 children with ADHD in the entire cohort, only 79 [23%] had an IEP-EBD). It thus appears that any adverse effects of procedures requiring anesthesia on behavior were not of sufficient severity to trigger IEP-EBD implementation. Alternatively, because the requirement for an IEP-EBD captures a broad spectrum of behaviors of widely differing etiologies, one can postulate that the significant association between procedures requiring anesthesia and ADHD may reflect an effect on the risk for core aspects of ADHD (inattention, hyperactivity, and impulsivity) but not on associated severe behavior problems that trigger the need for IEP-EBD.
Limitations of analyses using this birth cohort have been extensively discussed.
14- Katusic S.K.
- Barbaresi W.J.
- Colligan R.C.
- et al.
Case definition in epidemiologic studies of AD/HD.
, 15- Barbaresi W.
- Katusic S.
- Colligan R.
- et al.
How common is attention-deficit/hyperactivity disorder? Towards resolution of the controversy: results from a population-based study.
, 42- Katusic S.K.
- Colligan R.C.
- Barbaresi W.J.
- et al.
Incidence of reading disability in a population-based birth cohort, 1976-1982, Rochester, Minn.
To highlight the most salient limitation, as mentioned previously in this article, we cannot distinguish between the effects of anesthesia per se and the potential effects of the procedure or surgery accompanying the anesthesia. Also, children who require anesthesia may differ in ways relevant to the outcomes studied compared with those who do not. Although we attempted to control for health status using the ADG scoring system, this method may or may not capture relevant confounders and certainly does not adjust for family factors that may suggest genetic predisposition. Finally, there was substantial overlap between LD and ADHD in our cohort, and the relatively few children with only ADHD limits the statistical power to examine associations in these children. Nonetheless, we were still able to detect an association between multiple exposures and ADHD in these children with only ADHD.
Acknowledgments
We thank our colleagues Bob A. Rappaport, MD, Wendy R. Sanhai, PhD, and Chekesha S. Clingman, PhD, LCDR, USPHS, at the United States Food and Drug Administration for their support and their commitment to protecting the public's health. We acknowledge the late Leonard T. Kurland, MD, (Division of Epidemiology, Mayo Clinic, Rochester, MN) for his vision in initiating the Rochester Epidemiology Project. Finally, we would like to thank our research coordinator Shonie Buenvenida, RN, for help in abstracting the data and Mrs Theresa Hanson for secretarial help.
Drs Sprung and Flick and Mr Schroeder had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Drs Sprung and Flick contributed equally to this article.
Article Info
Footnotes
For editorial comment, see page 110
Grant Support: This study was funded by a United States Food and Drug Administration contract (HHSF223200810037C; Principal Investigator: Randall Flick, MD), Mayo Foundation for Medical Education and Research, Rochester, MN, the National Institutes of Health (Grant number R01 HS29745 ; Principal Investigator: William Barbaressi), and the Rochester Epidemiology Project (Grant number R01 AG034676 ; Principal Investigator: Walter A. Rocca, MD).
Copyright
© 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.