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

Abstract

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, in order to determine if anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes.

Methods: We identified 134,388 healthy children with appendectomy and examined the incidence of subsequent externalizing or behavioral disorders (conduct, impulse control, oppositional defiant, or attention-deficit/hyperactivity disorder); or internalizing or mood/anxiety disorders (depression, anxiety, or bipolar disorder) when compared to 671,940 matched healthy controls as identified in Medicaid data between 2001-2018. For comparison, we 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. We also 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 (the hazard ratio (HR) was 1.04 (95% CI 1.01, 1.06), P = 0.0010), and mood/anxiety disorders (HR: 1.15 (95% CI 1.13, 1.17), P < 0.0001). Relative to controls, children with medical admissions were also more likely to have subsequent behavioral (HR: 1.20 (95% CI 1.18, 1.22), P < 0.0001), and mood/anxiety (HR: 1.25 (95% CI 1.23, 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.