Association Between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort

Danqing Hu, M.D.; Randall P. Flick, M.D., M.P.H.; Michael J. Zaccariello, Ph.D., L.P.; Robert C. Colligan, Ph.D., L.P.; Slavica K. Katusic, M.D.; Darrell R. Schroeder, M.S.; Andrew C. Hanson, B.S.; Shonie L. Buenvenida, R.N.; Stephen J. Gleich, M.D.; Robert T. Wilder, M.D.; Juraj Sprung, M.D., Ph.D.; David O. Warner, M.D.

Disclosures

Anesthesiology. 2017;127(2):227-240. 

In This Article

Abstract and Introduction

Abstract

Background: Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes.

Methods: A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models.

Results: For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability.

Conclusions: These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

Introduction

SUBSTANTIAL preclinical evidence shows that exposure to anesthetics changes the developing brain.[1–4] These changes are linked to long-term learning and behavioral deficits in various animal models, including nonhuman primates.[1,5–7] To explore whether these findings translate to humans, several studies have investigated the association of receiving procedures requiring general anesthesia with long-term neurodevelopmental outcomes in children. Multiple exposures to procedures requiring general anesthesia affect learning and behavior in most retrospective studies.[8–14] Some, but not all, human studies also find an association between single exposures and a variety of outcomes related to learning and behavior.[8,12,13,15–24] This heterogeneity of results is perhaps not surprising given the wide range of study designs and outcomes used among these studies. Indeed, if exposure is associated with changes in specific domains of cognition or behavior, results should depend on the outcomes examined.[25,26]

A series of previous studies based on a birth cohort of children born in Olmsted County, Minnesota, found an association between multiple, but not single, exposures to procedures requiring general anesthesia before ages 2 to 4 yr and subsequent learning disabilities (LDs) and attention-deficit/hyperactivity disorder (ADHD), with multiple exposures associated with approximately a doubling in the incidence of both outcomes.[9–11] Multiple, but not single, exposures also impaired performance on school-administered group tests of cognitive ability and academic performance.[9] The particular impact of multiple exposures is consistent with emerging data from animal studies.[27,28]

Nonetheless, these previous birth cohort studies[9–11] had several limitations, as extensively discussed at the time of their publication[29] and subsequently. As with many frequently cited studies of this issue,[18,21,22,30] children in the previous cohort (born 1976 to 1982) were anesthetized before the transition from halothane to sevoflurane and the routine adoption of pulse oximetry and capnography, which does not reflect contemporary anesthesia practice. In addition, the number of exposed children was relatively modest in the original studies, making it difficult to determine whether exposure is associated with a particular pattern of LDs or whether even single exposures may affect some domains of cognitive function. Finally, given the considerable potential limitations of observational studies and the relatively small number of children with the outcomes of interest in the previous studies, it is critically important to confirm or refute the fundamental observations of this first series of studies, which have proved to be one of the drivers of research in this field.

The aim of this study was to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr (i.e., before the child's third birthday) are associated with adverse neurodevelopmental outcomes, including LD, ADHD, need for individualized education programs (IEPs) for emotional/behavioral and speech/language disorders, and impaired performance in group-administered ability and achievement tests. This hypothesis was evaluated using a new population-based birth cohort (born between 1996 and 2000) in which children were anesthetized with largely contemporary anesthetic techniques.

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