Introduction Animals exposed to anesthetics during specific age periods of brain development experience neurotoxicity, with neurodevelopmental changes subsequently observed during adulthood. The corresponding vulnerable age in children however is unknown. Methods An observational cohort study was performed using a longitudinal dataset constructed by linking individual-level Medicaid claims from Texas and New York from 1999 to 2010. This dataset was evaluated to determine whether the timing of exposure to anesthesia under age 5 years for a single common procedure (pyloromyotomy, inguinal hernia, circumcision outside the perinatal period, or tonsillectomy and/or adenoidectomy) is associated with increased subsequent risk of diagnoses for any mental disorder, or specifically developmental delay (DD) such as reading and language disorders, and attention deficit hyperactivity disorder (ADHD). Exposure to anesthesia and surgery was evaluated in 11 separate age at exposure categories: ≤28 days old, >28 days and ≤6 months, >6 months and ≤1 year, and 6 month age intervals between >1 year old and ≤5 years old. For each exposed child, five children matched on propensity score calculated using sociodemographic and clinical covariates were selected for comparison. Cox proportional hazards models were used to measure the hazard ratio of a mental disorder diagnosis associated with exposure to surgery and anesthesia. Results A total of 38,493 children with a single exposure and 192,465 propensity score matched children unexposed before age 5 were included in the analysis. Increased risk of mental disorder diagnosis was observed at all ages at exposure with an overall hazard ratio of 1.26 (95% confidence interval [CI], 1.22–1.30), which did not vary significantly with the timing of exposure. Analysis of DD and ADHD showed similar results, with elevated hazard ratios distributed evenly across all ages, and overall hazard ratios of 1.26 (95% CI, 1.20–1.32) for DD and 1.31 (95% CI, 1.25–1.37) for ADHD. Conclusions Children who undergo minor surgery requiring anesthesia under age 5 have a small but statistically significant increased risk of mental disorder diagnoses, and DD and ADHD diagnoses, but the timing of the surgical procedure does not alter the elevated risks. Based on these findings, there is little support for the concept of delaying a minor procedure to reduce long-term neurodevelopmental risks of anesthesia in children. In evaluating the influence of age at exposure, the types of procedures included may need to be considered, as some procedures are associated with specific comorbid conditions and are only performed at certain ages.

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Initial exposure to anesthesia after age 3 had no measurable effects on language or cognitive function. Decreased motor function was found in children initially exposed after age 3 even after accounting for comorbid illness and injury history. These results suggest that there may be distinct windows of vulnerability for different neurodevelopmental domains in children.

BACKGROUND: Some recent clinical studies have found that early childhood exposure to anesthesia is associated with increased risks of behavioral deficits and clinical diagnoses of attention deficit hyperactivity disorder (ADHD). While diagnoses in claims data may be subject to inaccuracies, pharmacy claims are highly accurate in reflecting medication use. This study examines the association between exposure to surgery and anesthesia and subsequent ADHD medication use. METHODS: Longitudinal data for children enrolled in Texas and New York Medicaid from 1999 to 2010 were used. We assessed the association between a single exposure to anesthesia before age 5 years for 1 of 4 common pediatric surgical procedures (pyloromyotomy, inguinal hernia repair, circumcisions outside the perinatal period, and tonsillectomy and/or adenoidectomy) and persistent ADHD medication use (event defined as the initial ADHD medication prescription, and persistent use defined as filling 2 or more ≥30-day prescriptions between 6 months following surgery until censoring). Exposed children (n = 42,687) were matched on propensity score (ie, the probability of receiving surgery) estimated in logistic regression including sociodemographic and clinical covariates, to children without anesthesia exposure before age 5 years (n = 213,435). Cox proportional hazards models were used to evaluate the hazard ratio (HR) of ADHD medication use following exposure. Nonpsychotropic medications served as negative controls to determine if exposed children simply had higher overall medication use. RESULTS: Children with a single exposure to surgery and anesthesia were 37% more likely than unexposed children to persistently use ADHD medication (HR, 1.37; 95% confidence interval [CI], 1.30–1.44). The estimated HRs for common nonpsychotropic medication use following a single anesthetic exposure were 1.06 (95% CI, 1.04–1.07) for amoxicillin, 1.10 (95% CI, 1.08–1.12) for azithromycin, and 1.08 (95% CI, 1.05–1.11) for diphenhydramine. In comparison, the risk of using other psychotropic medication to treat conditions besides ADHD was also significantly higher, with HRs of 1.37 (95% CI, 1.24–1.51) for sedative/anxiolytics, 1.40 (95% CI, 1.25–1.58) for antidepressants, 1.31 (95% CI, 1.20–1.44) for antipsychotics, and 1.24 (95% CI, 1.10–1.40) for mood stabilizers. CONCLUSIONS: Medicaid-enrolled children receiving anesthesia for a single common pediatric surgical procedure under age 5 years were 37% more likely to require subsequent persistent use of ADHD medications than unexposed children. Because the increased use of ADHD medication is disproportionately higher than that of nonpsychotropic medications, unmeasured confounding may not account for all of the increase in ADHD medication use. By evaluating Medicaid data, this study assesses children who may be particularly vulnerable to neurotoxic exposures.

Summary Introduction The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. Methods Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age 3. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for demographics and comorbidity. Results Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 minutes. Compared to unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ( [3rd quartile – Unexposed] −5.3; 95% confidence interval [CI], (−10.2 – −0.4), [4th quartile – Unexposed] −6.2; 95% CI, (−11.6 – −0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM at any quartile. Discussion Children with exposures ≤35 minutes did not differ from unexposed children, but those with exposures >35 minutes had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.