Repeated Early Anesthesia Exposure Linked to Learning Disabilities

Pauline Anderson

March 26, 2009

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March 26, 2009 — Repeated exposure to anesthesia prior to the age of 4 years is associated with almost double the risk of developing a learning disability (LD) later on, according to a new study.

But although the research showed a clear association between multiple episodes of anesthesia and learning disabilities, it cannot yet be concluded that anesthesia causes the disability, said Randall P. Flick, MD, chair of the division of pediatric anesthesiology and an assistant professor of anesthesiology and pediatrics at the Mayo Clinic in Rochester, Minnesota.

"The information has not reached a level that we can make recommendations about change in practice," Dr. Flick told Medscape Psychiatry. "The data are preliminary, it's concerning, it has the attention of the Food and Drug Administration [FDA] and others, and we'll continue to do the necessary research that will help us to better define the problem, if one really exists."

The study is published in the April issue of the journal Anesthesiology.

Dr. Flick and his colleagues analyzed outcomes in a cohort of children born in and around Rochester, Minnesota between January 1, 1976 and December 31, 1982. They tapped into resources from the Rochester Epidemiology Project to identify children from this cohort who underwent surgical or diagnostic procedures that necessitated general anesthesia. The data index included information on the type and duration of surgery, number of anesthetic exposures, age at exposure, type of anesthetic agent, and mode of delivery (inhaled, intravenous, sedative), as well as information on comorbidities.

From the original cohort, 5357 children were included in this current study. Of these, 593 underwent procedures requiring general anesthesia before the age of 4 years. These 593 children underwent 875 procedures.

Most anesthetics included halothane (88%) and nitrous oxide (91%). Dr. Flick said this was typical practice at the time of the study, although halothane is no longer used in the United States, having been replaced by a similar agent.

Assessing Disabilities

The researchers also accessed educational records from all area schools for every child in the birth cohort as well as resources of the privately owned Reading Center/Dyslexia Institute of Minnesota. To test for LD, they used standard formulas, IQ scores, and academic-achievement results to detect the presence of reading, writing, language, or mathematics disabilities.

A total of 932 children developed an LD before the age of 19 years. Compared with children not exposed to anesthesia, the risk for developing an LD was not increased for the 449 children exposed to a single anesthetic. However, the risk was significantly increased for children exposed to 2 or more doses of anesthesia.

Risk for Learning Disabilities Associated With Exposure to Anesthetics

Number of Anesthetics Adjusted Hazard Ratio 95% CI
Single exposure (n = 449) 1.00 0.79 – 1.27
2 anesthetics (n = 100) 1.59 1.06 – 2.37
3 or more anesthetics (n = 44) 2.60 1.60 – 4.24

The estimated incidence of LD by the age of 19 years was 20.0% (95% CI, 18.8% – 21.3%) in those with no exposure to anesthesia; 20.4% (95% CI, 16.3% – 24.3%) in those with a single exposure; and 35.1% (95% CI, 26.2% – 42.9%) in those with multiple exposures.

In addition, the risk for LD was increased with longer duration of anesthesia exposure; it reached statistical significance at a cumulative duration of 120 minutes or more.

The researchers were able to control for potential confounding factors known to affect the frequency of LD such as sex, gestational age, Apgar score, and birth weight.

Risks for Sicker Children

The researchers looked at whether sicker children with multiple exposures to anesthesia are more likely than healthier ones to develop an LD. They compared children who were categorized as American Society of Anesthesiologists Physical Status (ASA PS) III and IV, which signifies significant comorbidity, with patients classed as ASA PS I and II, with fewer comorbidities. In the study, 144 children received multiple doses of anesthesia.

The numbers were too small to come to any definitive conclusions, according to Dr. Flick. "One would expect that the sickest kids in our cohort who were exposed to anesthesia would be the most likely group to have learning disability, but that is not what the data showed," he said. "However, we need a much bigger cohort to be able to answer the question" of whether sicker kids develop more LDs.

Similarly, the numbers were too small to determine whether exposure to anesthesia early in life is associated with any particular type of learning disability. The researchers are collaborating with the FDA to carry out a study to try to answer this and other outstanding questions, said Dr. Flick.

Exposure Before the Age of 2 Years

Although the study included surgeries up to the age of 4 years, the authors repeated their analysis restricting exposure to anesthesia to before the age of 2 years and found the risk for LD to be similar. In fact, "the analysis showed that the effect seemed most pronounced among children whose initial exposure to anesthesia occurred between their first and second birthday," said Dr. Flick.

This study was the next step following extensive animal research that had similar results. "We have a large and growing body of animal evidence that not only is there pathologic brain injury but there are also learning deficits, memory deficits, and behavioral deficits in animals" exposed to anesthesia at an early stage, said Dr. Flick. "These findings have been repeated in various labs with various species and using different tests, so the animal data is pretty strong. The question was, does this translate to humans or not?"

Among the study's limitations is its inability to distinguish the effects of anesthesia from that of other factors such as the stress response to surgical injury. As well, the authors said they could not exclude the possibility that requiring anesthesia is a marker for something other than LD. Because of its superior healthcare, the population under study may overrepresent children with medical needs. The study population is also predominantly white and middle class, so these findings may not apply to other populations.

Best Learning Opportunities

Asked to comment on this study, Scott Benson, MD, a child and adolescent psychiatrist in private practice in Pensacola, Florida, noted that the vast majority of school-aged children who have a diagnosis of LD have never had any major surgery. A child who requires 3 and 4 surgeries before his fourth birthday "is in a group that is going to have a lot of medical problems," he said.

"If there's anything about anesthesia that's causing these kinds of defects, then we should avoid it," said Dr. Benson. "But obviously there are children who have such desperate health problems that they're going to be exposed to repeated anesthesia, and for them, like all children, we have to pay close attention to their education and make sure they get the best learning opportunities."

The message, he said, is that parents should be cautious about any surgery their child undergoes and make sure the intervention is necessary. He pointed out that once it was common for children to routinely have their tonsils removed and be treated with antibiotics for any ear infection, practices now judged unnecessary.

Support was provided by the Department of Anesthesiology at the College of Medicine, Mayo Clinic, and from research grants from the National Institutes of Health.

Anesthesiology. 2009;110:796-804. Abstract

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