Early Childhood Exposure to Anesthesia and Risk of Developmental and Behavioral Disorders in a Sibling Birth Cohort

Abstract

Introduction In vitro and in vivo studies of anesthetics have demonstrated serious neurotoxic effects on the developing brain. However the clinical relevance of these findings to children undergoing anesthesia remains unclear. Using data from a sibling birth cohort, we assessed the association between exposure to anesthesia in the setting of surgery in patients younger than 3 years and the risk of developmental and behavioral disorders. Methods We constructed a retrospective cohort of 10,450 siblings who were born between 1999 and 2005 and who were enrolled in the New York State Medicaid program. The exposed group was 304 children without a history of developmental or behavioral disorders who underwent surgery when they were younger than 3 years. The unexposed group was 10,146 children who did not receive any surgical procedures when they were younger than 3 years. Exposed children were entered into analysis at the date of surgery. Unexposed children were entered into analysis at age 10 months (the mean age at which exposed children underwent surgery). Both exposed and unexposed children were followed until diagnosis with a developmental or behavioral disorder, loss to follow-up, or the end of 2005. The association of exposure to anesthesia with subsequent developmental and behavioral disorders was assessed with both proportional hazards modeling, and pair-matched analysis. Results The incidence of developmental and behavioral disorders was 128.2 diagnoses per 1000 person-years for the exposed cohort and 56.3 diagnoses per 1000 person-years for the unexposed cohort. With adjustment for sex and history of birth-related medical complications, and clustering by sibling status, the estimated hazard ratio of developmental or behavioral disorders associated with any exposure to anesthesia when they were younger than 3 years was 1.6 (95% CI 1.4, 1.8). The risk increased from 1.1 (95% CI 0.8, 1.4) for one surgery to 2.9 (94% CI 2.5, 3.1) for two surgeries and 4.0 (95% CI 3.5, 4.5) for three or more surgeries. The risk in a matched analysis of 138 sibling pairs was 0.9 (95% CI 0.6, 1.4) Conclusion The risk of being subsequently diagnosed with developmental and behavioral disorders in children who were enrolled in a state Medicaid program and who had surgery when they were younger than 3 years was 60% greater than that of a similar group of siblings who did not undergo surgery. More tightly matched pairwise analyses indicate that the extent to which the excess risk is causally attributable to anesthesia or mediated by unmeasured factors remains to be determined.

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

“…However, variations in these human study approaches such as different assessment tools have led to inconsistent conclusions; some groups reported cognitive impairment (DiMaggio et al. 2009, 2011; Sprung et al. 2009; Wilder et al.…”

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia

“…12 Findings from clinical studies are mixed, with some studies showing a twofold increase in cognitive disability in children with anesthetic exposure, whereas others show no association. [13][14][15][16][17][18][19][20] In studies demonstrating an association of anesthesia with disability, only children with multiple anesthetic exposures have been associated with deficits, but an effect with a single exposure has not been identified. 14,18,20 These clinical studies have used International Classification of Diseases, 9th Revision diagnosis codes, standardized tests, and evaluations by parents and teachers as outcome measures, but none to date has used a battery of multiple directly assessed neuropsychological outcome measures.…”

“…[13][14][15][16][17][18][19][20] In studies demonstrating an association of anesthesia with disability, only children with multiple anesthetic exposures have been associated with deficits, but an effect with a single exposure has not been identified. 14,18,20 These clinical studies have used International Classification of Diseases, 9th Revision diagnosis codes, standardized tests, and evaluations by parents and teachers as outcome measures, but none to date has used a battery of multiple directly assessed neuropsychological outcome measures. We therefore studied a prospective birth cohort to determine if (1) exposure to anesthesia for surgery or a diagnostic test during the first 3 years of life is associated with differences in any of a range of directly assessed neuropsychological outcomes; and (2) if the differences persist with only a single episode of anesthetic exposure.…”

Developmental Disability in the Young and Postoperative Cognitive Dysfunction in the Elderly After Anesthesia and Surgery: Do Data Justify Changing Clinical Practice?

“…51 The same concerns apply to a recent report from DiMaggio and coauthors. 52 They looked for developmental effects in children exposed to anesthesia and surgery prior to 3 years of age and replicated the Bartels et al finding for twins on a smaller but more refined subsample. Nevertheless, only 6 or 7 of the 304 anesthesiaexposed children included in the DiMaggio and coauthors epidemiological investigation were aged <6 months at time of exposure, with the vast majority having been anesthetized for short procedures.…”

“…and there is evidence that patients with the apolipoprotein epsilon 4 allele experience postoperative delirium at more than twice the rate of patients without apolipoprotein epsilon, adding a genetic link to account for some of the variability. 130 If the association between POCD and deep sedation had been discovered before the association between POCD and general anesthesia, perhaps we would have come more readily to the hypothesis that lighter anesthesia 119 -122 and deeper sedation 128,129 occupy an equivalent middle ground (approximately BIS [45][46][47][48][49][50][51][52][53][54][55] when it comes to increasing the risk of POCD relative to both lighter sedation (approximately BIS ≥60) and deeper anesthesia (approximately BIS [35][36][37][38][39][40][41][42][43][44][45]. 131 …”