Exposure to Operative Anesthesia in Childhood and Subsequent Neurobehavioral Diagnoses: A Natural Experiment using Appendectomy

Background Observational studies of anesthetic neurotoxicity may be biased because children requiring anesthesia commonly have medical conditions associated with neurobehavioral problems. This study takes advantage of a natural experiment associated with appendicitis to determine whether anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes. Methods This study identified 134,388 healthy children with appendectomy and examined the incidence of subsequent externalizing or behavioral disorders (conduct, impulse control, oppositional defiant, attention-deficit hyperactivity disorder) or internalizing or mood or anxiety disorders (depression, anxiety, or bipolar disorder) when compared to 671,940 matched healthy controls as identified in Medicaid data between 2001 and 2018. For comparison, this study also examined 154,887 otherwise healthy children admitted to the hospital for pneumonia, cellulitis, and gastroenteritis, of which only 8% received anesthesia, and compared them to 774,435 matched healthy controls. In addition, this study examined the difference-in-differences between matched appendectomy patients and their controls and matched medical admission patients and their controls. Results Compared to controls, children with appendectomy were more likely to have subsequent behavioral disorders (hazard ratio, 1.04; 95% CI, 1.01 to 1.06; P = 0.0010) and mood or anxiety disorders (hazard ratio, 1.15; 95% CI, 1.13 to 1.17; P < 0.0001). Relative to controls, children with medical admissions were also more likely to have subsequent behavioral (hazard ratio, 1.20; 95% CI, 1.18 to 1.22; P < 0.0001) and mood or anxiety (hazard ratio, 1.25; 95% CI, 1.23 to 1.27; P < 0.0001) disorders. Comparing the difference between matched appendectomy patients and their matched controls to the difference between matched medical patients and their matched controls, medical patients had more subsequent neurobehavioral problems than appendectomy patients. Conclusions Although there is an association between neurobehavioral diagnoses and appendectomy, this association is not specific to anesthesia exposure and is stronger in medical admissions. Medical admissions, generally without anesthesia exposure, displayed significantly higher rates of these disorders than appendectomy-exposed patients. Editor’s Perspective What We Already Know About This Topic What This Article Tells Us That Is New