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Using a Medicaid database from 2001 – 2018, researchers undertake an observational study that takes advantage of a natural experiment associated with appendicitis to determine whether anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes.

Data gathered from the original Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial provided a unique, optimal opportunity to examine the long-term effects of multiple exposures to general anaesthesia in a randomised controlled trial setting. 

The association between prenatal exposure to general anaesthesia for maternal surgery during pregnancy and subsequent risk of disruptive or internalising behavioural disorder diagnosis in the child has not been well-defined.

Columbia researchers, led by Caleb Ing, MD,  undertook the task to better define the association by linking a nationwide sample of pregnant women to their liveborn infants using the Medicaid Analytic eXtract (MAX, 1999e2013). Multivariate matching was used to match each child prenatally exposed to general anaesthesia owing to maternal appendectomy or cholecystectomy during pregnancy with five unexposed children. The primary outcome was diagnosis of a disruptive or internalising behavioural disorder in children. Secondary outcomes included diagnoses for a range of other neuropsychiatric disorders.

34,271 prenatally exposed children were matched with 171,355 unexposed children in the database. Prenatally exposed children were more likely than unexposed children to receive a diagnosis of a disruptive or internalizing behavioural disorder (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.23e1.40). For secondary outcomes, increased hazards of disruptive (HR, 1.32; 95% CI, 1.24e1.41) and internalising (HR, 1.36; 95% CI, 1.20e1.53) behavioural disorders were identified, and also increased hazards of attention-deficit/hyperactivity disorder (HR, 1.32; 95% CI, 1.22e1.43), behavioural disorders (HR, 1.28; 95% CI, 1.14e1.42), developmental speech or language disorders (HR, 1.16; 95% CI, 1.05e1.28), and autism (HR, 1.31; 95% CI, 1.05e1.64).

Researchers found that prenatal exposure to general anaesthesia is associated with a 31% increased risk for a subsequent diagnosis of a disruptive or internalising behavioural disorder in children. However, caution is advised when making any clinical decisions regarding care of pregnant women, as avoidance of necessary surgery during pregnancy can have detrimental effects on mothers and their children.

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Anesthesia makes painful or uncomfortable diagnostic and interventional health care procedures tolerable, however, it may also disrupt key cellular processes in neurons and glia, harm the developing brain, and thereby impair cognition and behavior in children. Many years of studies using in vitro, animal behavioral, retrospective database studies in humans, and several prospective clinical trials in humans have been invaluable in discerning the potential toxicity of anesthetics. The objective of the scoping review conducted by Matthew Thomas Borzage, PhD, and Bradley S. Peterson, MD, was to synthetize the evidence from preclinical studies for various mechanisms of toxicity across diverse experimental designs and relate their findings to those of recent clinical trials in real-world settings.  Their review found an unequivocal yes, that most anesthetics cause neurotoxicity, at least in rodents. When trying to determine a definitive answer as to how their findings relate to the human situation, unfortunately that question still remains elusive. The strongest evidence for neurotoxic effects in humans is from multiple exposures, most likely in the domains of attention and disruptive behaviors, and possibly executive functioning, memory, motor skills, and language abilities.

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