The results of this study support the hypothesis that, similar to the pattern of our results previously observed for LD,7,8
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.10
Children with ADHD typically exhibit deficits in vigilance, verbal learning, working memory, and measures of executive function.20
They frequently have comorbid mood, anxiety, or learning disorders, but neuropsychological abnormalities are present independent of such comorbidities.21,22
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.13,14
The etiology of ADHD is unknown, but evidence suggests a neuropsychological disorder, with anatomic correlates reported in imaging studies.23
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.12,24
Environmental factors are also associated with ADHD, suggesting that gene-environment interactions are also operative.12
Implicated environmental factors include maternal smoking, prenatal alcohol exposure, viral infections, nutritional deficiencies, low parental education level, perinatal stress, and others.25,26
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.20,27
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%.20,27
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.28
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.20
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,2,29
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.30
Frederickson et al9,29,31-34
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.3,4,35
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).4
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 stress36
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.38
In another example, in infants with necrotizing enterocolitis, bacteremia is associated with developmental dysfunction, suggesting that systemic inflammation may affect the developing brain.39
Surgery can produce stress and inflammatory responses in proportion to the severity of surgical injury.40,41
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,41
further complicating understanding of potential causative mechanisms.
When taken together with our prior analyses,7,8
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
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
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.14,15,42
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.