An association between multiple exposures to general anesthesia in the first two years of life and increased risk for neurocognitive impairment was not found in two large Canadian studies. Exposures from 2 to 4 years of age, however, were another matter.
“It remains uncertain whether the anesthetic neurotoxicity that’s been clearly demonstrated in animal studies is of concern to our pediatric patients,” said M. Ruth Graham, MD, associate professor of anesthesia at the University of Manitoba, in Winnipeg. “And while two of the ongoing prospective studies have been reassuring in this regard, both are limited by the fact that they examined a single anesthetic exposure of fairly short duration.”
To help shed more light on the subject, Dr. Graham and her colleagues undertook a retrospective matched-cohort study, which compared children exposed to general anesthesia in their first four years of life with those who had not been exposed. For comparative purposes, the investigators used the Early Development Instrument (EDI) as their outcome measure, which focuses on five primary domains:
- physical health and well-being;
- social competence;
- emotional maturity;
- language and cognitive development; and
- communication skills and general knowledge.
“This particular test is given to all kindergarten children in public schools across Canada, and is quite predictive of future academic performance,” Dr. Graham noted.
Large Study Used Multiple Test Results
As Dr. Graham reported at the 2016 annual meeting of the Canadian Anesthesiologists’ Society (abstract 151903), a total of 18,056 children were studied. “The study group consisted of all children for whom EDI results from four consecutive test years were available,” she explained.
Of these, 3,850 underwent a single general anesthetic and 620 underwent multiple general anesthetics. These children were matched to 13,586 nonexposed children. “We restricted the multiple-exposure groups to those children who were exposed between birth and 2 years [of age] or between 2 and 4 years [of age], so there was no age overlap for multiple exposures,” she added.
The majority of operations were either general surgery; ear, nose and throat (ENT); or dental procedures, although the distribution differed by age. Children between 0 and 2 years of age were more likely to have had ENT and general surgical procedures, while the 2- to 4-year-olds primarily underwent dental procedures.
Results Differ by Age Cohort
“If you look at the entire cohort, our results are similar to what was found in previous meta-analyses,” Dr. Graham revealed. Exposure to a single general anesthetic was associated with small but significant deficits in the communication/general knowledge and language/cognition domains.
However, these findings were completely accounted for by the older children, whose general anesthetic exposure occurred between 2 and 4 years of age: communication/general knowledge (estimate, –0.7; 95% CI, –0.93 to –0.47; P<0.0001) and language/cognition (estimate, –0.34; 95% CI, –0.52 to –0.16; P<0.0001) domains.
In children younger than 2 years of age, there was no independent association between single or multiple general anesthetic exposures and EDI test results. On the other hand, exposure to a single general anesthetic in children between 2 and 4 years was associated with deficits, most significant in the communication/general knowledge (estimate, –0.7; 95% CI, –0.93 to –0.47; P<0.0001) and language/cognition (estimate, –0.34; 95% CI, –0.52 to –0.16; P<0.0001) domains.
With respect to the number of exposures, the investigators found a small but significant association between either single or multiple anesthetic exposures and all EDI domains, with the exception of emotional maturity. “But the confidence intervals have such wide overlaps. We found no significant difference between single and multiple anesthetic exposures,” she explained.
“The novel finding in this analysis is that the association between exposure and deficit was entirely dependent on the age of exposure,” Dr. Graham said. “Children from birth to 2 years of age have always been presumed to be at the age of greatest risk because this correlates with the period of rapid synaptogenesis, … yet there was no association between either single or multiple general anesthetic exposure and EDI scores in this age group.”
The inclusion of multiple covariates in the analysis also allowed the researchers to report on other factors associated with much more important effects on EDI results than anesthetic exposure, most notably sociodemographic factors.
“We also looked at an index of the tightness of the confidence intervals around the estimates and found that the greatest confidence was in the sociodemographic covariates, far less so than in general anesthetic exposure.”
Another Large Study Agrees
Perhaps equally interesting were the comments of Mark Crawford, MD, associate professor of anesthesia at the University of Toronto. As Dr. Crawford explained, a similar study has been performed at his institution, with comparable results.
“It’s fascinating that we essentially did the same study at the same time working completely independently of each other, and had findings that are almost identical with respect to age groups, outcomes and single-versus-multiple exposures. Our exposed group comprised approximately 25,000 children, and we had a total of nearly 80,000, which is larger than anything that’s been published to date,” Dr. Crawford noted.
As with Dr. Graham’s study, Dr. Crawford’s found no association between either single or multiple exposures to anesthesia and children between 0 and 2 years of age. “So it leads us to the question of what are the responsible factors?” he asked. “We also found that socioeconomic factors had a far greater effect size than did age of exposure. So we think the two studies—performed in different populations but at approximately the same time, and demonstrating the same results—are a very strong indicator that this impact is not at all a significant one.”
Dr. Graham agreed. “These findings actually refute our assumptions that the earlier the general anesthetic exposure, the greater the likelihood of long-term neurocognitive risk,” she said. “And it seems that the age-specific risk for children is at a much later stage of neural development than we previously believed, raising the possibility that confounding—due to a combination of biological and sociodemographic factors—accounts for both the anesthetic exposure and the EDI deficits reported.”