Background Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. We studied association between anesthetic exposure prior to age 4 and the development of reading, written language and math learning disabilities (LD). Methods This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976–1982 and who remained in the community at 5 years of age were reviewed to identify children with LD. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of LD, adjusting for gestational age at birth, gender, and birth weight. Results Of the 5,357 children in this cohort, 593 received general anesthesia before age 4. Compared to those not receiving anesthesia (N=4,764), a single exposure to anesthesia (N=449) was not associated with an increased risk of LD (hazard ratio =1.0, 95% CI 0.79–1.27). However, children receiving 2 anesthetics (N=100) or ≥3 anesthetics (N=44) were at increased risk for LD (hazard ratio =1.59, 95% CI 1.06–2.37, and hazard ratio =2.60, 95% CI 1.60–4.24, respectively). The risk for LD increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable) (P=0.016). Conclusion Exposure to anesthesia was a significant risk factor for the later development of LD in children receiving multiple, but not single anesthetics. We cannot determine whether anesthesia itself may contribute to LD, or whether the need for anesthesia is a marker for other unidentified factors that contribute to LD.

WHAT'S KNOWN ON THIS SUBJECT:Exposure to virtually all anesthetic drugs has been shown to cause neurodegeneration in young animals. Studies of learning and cognition in children exposed to anesthesia and surgery have been few, have relied on single outcome measures, and have not controlled for comorbidity. WHAT THIS STUDY ADDS:In this study of children exposed to anesthesia/surgery before the age of 2, multiple group and individual measures of learning and behavior are examined by using a matched design with adjustment for comorbidity using 2 separate methods. abstract + BACKGROUND: Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests. METHODS:This was a matched cohort study in which children (N ϭ 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n ϭ 350) before the age of 2 were matched to unexposed controls (n ϭ 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of groupadministered tests of cognition and achievement were outcomes. RESULTS:Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26 -3.54]), even when accounting for health status. A similar pattern was observed for decrements in groupadministered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program. CONCLUSIONS:Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.

Background Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes. Methods Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports. Results In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, −3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, −2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading. Conclusions Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

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.