Investigating the neurodevelopmental consequences of anesthesia and surgical interventions on cognitive and behavioral outcomes: A comprehensive Mendelian randomization study

Anesthesia is indispensable to modern surgical practice and clinical care; however, its potential impact on neurodevelopment and behavioral outcomes has raised growing concerns. Discrepancies among previous studies may partly arise from difficulties in disentangling the effects of anesthesia from those of surgical interventions. Mendelian randomization (MR) offers an approach to explore these associations while minimizing confounding and reverse causation. We analyzed genetic instruments related to exposure to different types of anesthesia and the number of surgical operations, in conjunction with 39 genome-wide association study datasets covering a broad range of neurodevelopmental, cognitive, and behavioral outcomes. Both univariable and multivariable MR analyses were conducted using inverse-variance weighted, MR-Egger, and weighted median and mode methods. Sensitivity analyses were performed to assess robustness, and the Steiger test was applied to evaluate potential reverse causality. No significant causal associations were observed between exposure to either general or regional anesthesia and neurodevelopmental outcomes. In contrast, a higher number of surgical operations was causally associated with fewer years of schooling (odds ratio [OR] 0.9088, 95% confidence interval [CI] 0.8569-0.9639, P = .0015), a younger age at completion of full-time education (OR 0.8911, 95% CI 0.8346-0.9516, P = 5.77 × 10-4), an increased risk of neuroticism (OR 1.5962, 95% CI 1.2727-2.0018, P = 5.18 × 10-5), depression (OR 1.0951, 95% CI 1.0544-1.1374, P = 2.58 × 10-6), and emotionally unstable personality disorder (OR 2.4124, 95% CI 1.2408-4.6906, P = .0094). Multivariable MR analyses demonstrated that adjusting for anesthesia exposure did not attenuate the associations between surgical procedures and educational outcomes, neuroticism, or depression. Notably, adjustment for inhalational or intravenous anesthesia reduced the effect of surgery on emotionally unstable personality disorder, whereas adjustment for local or epidural anesthesia did not. These findings suggest that anesthesia exposure itself may not exert a significant causal effect on neurodevelopmental outcomes. However, surgical procedures appear to be associated with long-term consequences related to academic attainment, emotional well-being, and personality traits.