Early Childhood General Anesthesia and Neurodevelopmental Outcomes in the Avon Longitudinal Study of Parents and Children Birth Cohort

Abstract

Background Most common anesthetic agents have been implicated in causing neurodegeneration in the developing animal brain, leading to warnings regarding their use in children. The hypothesis of this study was that exposure to general anesthesia and surgery before 4 yr would associate with adverse neurodevelopmental outcomes at age 7 to 16 yr. Methods This cohort study comprised 13,433 children enrolled in the Avon Longitudinal Study of Parents and Children, a prospective, population-based birth cohort born between 1991 and 1993 in southwest England. Children were grouped by none, single, or multiple exposures to general anesthesia and surgery by 4 yr. Motor, cognitive, linguistic, educational, social, and behavioral developmental outcomes were evaluated at 7 to 16 yr using school examination results, validated parent/teacher questionnaires, or clinic assessments. Continuous outcomes were z-scored. P-value thresholds were corrected using false discovery rate procedures. Results This study compared 46 neurodevelopmental outcomes in 13,433 children: 8.3% (1,110) exposed singly and 1.6% (212) exposed multiply to general anesthesia and surgery. Of these, the following reached predefined levels of statistical significance (corrected P < 0.00652): dynamic balance scores were 0.3 SD (95% CI, 0.1, 0.5; P < 0.001) lower in multiply exposed children; manual dexterity performance was 0.1 SD (95% CI, 0.0, 0.2; P = 0.006) lower in singly and 0.3 SD (95% CI, 0.1, 0.4; P < 0.001) lower in multiply exposed children; and social communication scores were 0.1 SD (95% CI, 0.0, 0.2; P = 0.001) and 0.4 SD (95% CI, 0.3, 0.5; P < 0.001) lower in singly and multiply exposed children, respectively. General anesthesia and surgery were not associated with impairments in the remaining neurodevelopmental measures including: general cognitive ability; attention; working memory; reading, spelling, verbal comprehension and expression; behavioral difficulties; or national English, mathematics, and science assessments (all ≤0.1 SD; corrected P ≥ 0.00652). Conclusions Early childhood general anesthesia and surgery were not associated with a global picture of clinically and statistically significant neurodegenerative effects, providing reassurance about the neurotoxic potential of general anesthesia. Exposure to anesthesia and surgery was associated with significantly lower motor and social linguistic performance. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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“…11,12 Recent findings from large-cohort and population-based studies have been conflicting, with some showing developmental delays after anesthetic exposure prior to age 2 years 13,14 and others concluding no impact of a single exposure before age 3 to 4 years on adverse behavior or learning outcomes in later life. 15,16…”

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“…The major comorbidities justifying exclusion for each study are described in eTable 5 in the Supplement and include congenital heart disease, extreme prematurity, or medulloblastoma. A further 16 studies were excluded for using cohorts that overlapped with other studies or not reporting outcome scores that could be evaluated (eTable 6 in the Supplement ), and 8 studies were excluded for not reporting overall domain scores, leaving 31 studies 27 , 31 , 33 , 35 , 36 , 40 , 45 , 48 , 56 , 60 , 61 , 63 , 64 , 72 , 76 , 79 , 82 , 87 , 88 , 90 , 91 , 95 , 102 , 103 , 104 , 105 , 107 , 108 , 120 , 122 , 130 contributing data for meta-analysis ( Table ). Owing to a limited number of eligible studies (less than 3 studies) evaluating adaptive behavior, general health and well-being, sensory, and social cognition, these domains could not be evaluated.…”

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“…The safety of anesthetic exposure in the developing brain of children and infants has attracted significant public attention. Increasing clinical trials have shown that the administration of general anesthesia is associated with deficits in long-term motor coordination and social behavior in children and infants (Ing and Brambrink, 2019;Zaccariello et al, 2019;Feng et al, 2020;Ing et al, 2020;Kobayashi et al, 2020;Walkden et al, 2020). Sevoflurane, the most common anesthetic used in children, is the main object of interest in the study of neurotoxicity of general anesthetics.…”