In this population-based birth cohort, exposure to anesthesia prior to age 4 was a risk factor for the development of LD in children receiving multiple, but not single, anesthetics. The cumulative incidence of LD diagnosed by age 19 among those with repeated anesthetic exposures was almost twice as high (35.1%) compared to children not exposed to anesthesia (20.0%).
Late prenatal and early postnatal neural development is vulnerable to pharmacological and environmental influences.20–22
Exposure of immature animals to compounds with gamma-aminobutyric acid-mimetic receptor-agonist or N-methyl d-aspartate
receptor-antagonist properties induces apoptotic degeneration of neurons in various brain regions.1–4,7,23
In particular, several drugs with sedative and anesthetic properties (including isoflurane, nitrous oxide, ketamine, benzodiazepines, halothane, and propofol) produce neurodegeneration when administered at sufficient doses and durations of exposure.7,8,23–26
In some animal models, these histological changes have been associated with impaired learning and memory assessed by water and radial arm mazes.7,27
Although these data have raised concerns and stimulated further research on the part of the Food and Drug Administration and others,5
it is not known whether exposure to anesthetics produces neuropathological or neurobehavioral sequelae in humans. A recent review28
summarized reports describing neurologic sequelae following surgery and anesthesia in children. Some studies of developmental outcomes in patients undergoing repair of congenital heart disease suggest neurologic impairment, although others do not.9–11,29–31
Similarly, studies comparing neurodevelopmental outcomes of neonates with patent ductus arteriosis and necrotizing enterocolitis managed either surgically or medically provide conflicting results.32–34
In the majority of these studies it was not possible to distinguish between potential effects of comorbidities, clinical characteristics and surgery from the effects of anesthesia, and the potential for selection bias is high.9,11,29,30,35,36
We examined a birth cohort originally created to study the incidence of learning disabilities in a population.13,15,37–39
This cohort provided several unique advantages. All these children resided in the same community, attended identified public and private schools, and received health care at one of two local facilities (Mayo Clinic and Olmsted County Medical Center), making it possible to review all available medical and educational records. These records, combined with rigorous definitions of LD, made it possible to perform a population assessment of a clinically-significant outcome that plausibly reflects the learning abnormalities observed in animal model post anesthesia. Nearly complete data available from birth records made it possible to control for potential confounding factors known to affect the frequency of LD (sex, gestational age, and birth weight). Complete anesthesia records were available for all procedures, and anesthetic technique was remarkably consistent. The distribution of surgical procedures reflected the population-based nature of the cohort, so is not weighted towards sicker patients undergoing more extensive procedures, as is the case with many studies at academic centers.
If exposure to anesthesia significantly affects neurodevelopment, there should be a dose-response relationship between exposure and a relevant outcome. We found evidence for such a dose-response relationship between anesthetic exposure and LD in two respects. First, risk was increased for children requiring multiple exposure (adjusted hazard ratio of 1.6 for two exposures, and 2.6 for ≥3 exposures, ), but not for single exposures to anesthesia (adjusted hazard ratio of 1.0). Second, risk was increased for longer durations of anesthesia, reaching statistical significance for cumulative duration ≥ 120 min (). When anesthesia exposure was analyzed as a dichotomous variable (any exposure prior to age 4), exposure was a significant risk factor for LD in unadjusted (hazard ratio of 1.27) but not adjusted (hazard ratio of 1.20) analysis. The latter finding likely reflects the fact that the majority of children received only one exposure, which again was not associated with increased risk.
This study has several limitations. We cannot distinguish between potential effects of anesthesia itself and other factors associated with anesthesia such as the stress response to surgical injury. Perhaps most importantly, children requiring anesthesia may differ in important ways from those who do not, and such differences may affect risk for LD. Thus, we cannot exclude that requiring multiple anesthetics is a marker for conditions that increase LD risk, and that exposure to anesthetic drugs themselves is not causative. We adjusted for known factors (for which data were available) contributing to LD risk that differed between the groups with the exception of maternal education, because data was missing in a significant number of children. However, when analysis was repeated excluding children with missing data and including maternal education as a covariate, the qualitative results were the same (data not shown). Children requiring repeated procedures may have a higher burden of illness, which may increase risk for LD. For example, premature infants and children requiring repair of congenital heart defects may require more procedures. Indeed, children requiring multiple procedures were judged by their anesthesiologist to have more severe systemic disease, as indicated by higher ASA PS. We did not review the medical records of the children not requiring anesthesia, so cannot use medical diagnoses as covariates in the analysis – and ASA PS classification is not available in these children. However, among the 144 children receiving multiple anesthetics, LD was not more frequent in children with higher ASA status and among all children receiving anesthesia, LD frequency did not differ with ASA PS in univariate analysis (data not shown). Furthermore, the association of LD with repeated anesthetic exposure was still present when the analysis was repeated after eliminating surgical patients with ASA ≥ PS 3. These findings suggest that ASA PS was not associated with LD risk in our cohort, and that the increased frequency of LD observed in children receiving multiple anesthetics cannot be primarily attributed to those children with multiple medical problems.
The relative homogeneity of anesthetic technique is an experimental advantage, but conversely we cannot comment of the potential of anesthetics other than halothane26,40
and nitrous oxide 2,7
to cause neurodegeneration. Insufficient numbers of children received ketamine to perform a separate analysis for this drug.
In animal studies, there is a definite time window of vulnerability to the effects of anesthetic exposure (e.g., approximately 7 days after birth in rodents), thought to correspond to a period of maximal synaptogenesis.20,41
Thus, the ages chosen to study the effects of anesthetic exposure may be important. In humans, the period of synaptogenesis has been considered to extend through three years of age,20,41
which was the basis for our choice of the 4th
birthday as the upper age limit to define anesthetic exposure. However, the correspondence between stages of human and animal neurodevelopment is controversial, and other authors suggest that the period corresponding to the time of greatest risk observed in animal models (e.g., approximately between 1–2 days before birth until 2 weeks after birth in rodents) is actually perinatal in humans (last month of gestation and first 6 months after birth).2
We repeated our analysis examining anesthetic exposure before the age of 2 (rather than age 4) on the risk of LD, and found similar results (data provided as figure, Supplemental Digital Content 4
, which illustrates the cumulative percentage of learning disabilities by the age of exposure and table, Supplemental Digital Content 5
, which illustrates the effects of anesthetic exposure before the age of 2 on risk for developing learning disabilities). We did not have sufficient numbers of cases to meaningfully examine a more restricted age range (e.g., infancy).
Another potential limitation is related to emigration from the original birth cohort of 8,548 children. Birth cohort studies can be biased due to migration from the community. For example, given the accessibility and quality of health care available in Rochester, children with a higher level of medical need may tend not to migrate and thus be overrepresented in the cohort. This could tend to bias the surgical group towards children with more severe illness. However, a previously published comparison of children who left the community before age 5 and those who stayed after age 5 (the usual age of school enrollment) indicates that the children included in the study are representative of the entire birth cohort.14
A further limitation related to the nature of this cohort is that in these years Rochester was a predominantly white, middle class community which may limit the generalization of these results to other populations.42
Finally, it remains to be determined whether LD is a relevant outcome measure for any potential neurotoxic effects of anesthesia in humans, recognizing that many other genetic, family, and socioeconomic factors may also impact LD. Based on the animal studies showing an association between the neurodegeneration caused by exposure to anesthetics and behavioral learning deficits,7
we argue that LD is a relevant endpoint in humans. It also remains to be determined whether the observed increase in the frequency of LD among children with multiple anesthetic exposures is specific to one type of LD (i.e., math, written language, and reading disabilities). For purposes of this analysis we chose a broad definition of LD to maximize the number of children with LD and thus the ability to detect effects. Analysis by specific type of LD would be of interest, but would be complicated by the overlap between types (i.e., some children have more than one type of LD), and the need for increased numbers of subjects to detect effect sizes of the magnitude noted in the current study. There are a wide variety of other neurodevelopmental outcomes that could be sought, but many require specialized testing that is difficult to administer in large population-based studies.
In conclusion, in this population-based birth cohort, exposure to anesthesia prior to age 4 was a significant risk factor for the later development of LD in children receiving multiple, but not single, anesthetics. These data cannot reveal whether exposure to anesthesia itself may contribute to the pathogenesis of LD, or whether the need for anesthesia is a marker for other unidentified confounding factors that contribute to LD. However, these results suggest that the possibility of potential adverse effects of repeated anesthetic exposures on human neurodevelopment cannot be excluded.