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

Graham J. Walkden, M.B.Ch.B.; Hannah Gill, F.R.C.A., Ph.D.; Neil M. Davies, Ph.D.; Alethea E. Peters, B.M.B.Ch.; Ingram Wright, D.Clin.Psychol., Ph.D.; Anthony E. Pickering, F.R.C.A., Ph.D.

Disclosures

Anesthesiology. 2020;133(5):1007-1020. 

In This Article

Abstract and Introduction

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.

Introduction

ALL commonly used intravenous and inhalational anesthetic agents have been shown to increase neuronal apoptosis in immature animals, including nonhuman primates, with some drugs adversely affecting long-term learning and behavior.[1,2] Although long-term neurotoxic risks in humans remain uncertain, the U.S. Food and Drug Administration recently cautioned against lengthy or repeated general anesthesia or sedation in the third trimester of pregnancy and children aged less than 3 yr.[3] Defining the risk of anesthetic-induced neurotoxicity is a pressing public health issue because 5% of children aged less than 6 yr in the United Kingdom undergo general anesthesia annually.[4,5]

Concerns that fetuses, babies, and young children exposed to general anesthesia may experience long-lasting neurotoxic effects has motivated a number of clinical studies, predominantly in Europe, North America, and Australia, over the last decade.[6] Most have employed retrospective study designs because of ethical and practical challenges associated with randomization to omit general anesthesia and the need for lengthy follow-up. These observational studies are heterogeneous in their methodologies, limited by residual confounding and often analyze small samples. Although some studies have offered reassurance,[7–10] others have reported long-term neurodevelopmental deficits after single exposures[11–18] and larger deficits after multiple exposures.[18–22] Pooled effect estimates from observational studies indicate at least a modest risk of impaired neurodevelopment after general anesthesia and surgery in childhood.[23,24] To date, one randomized controlled trial of 722 children undergoing spinal versus general anesthesia for herniorrhaphy before 60 weeks postmenstrual age has reported equivalent cognitive scores at age 2[25] and 5 yr.[26] However, the authors caution that more comprehensive cognitive assessment, possible in later childhood, may yet detect latent neurotoxic effects and that repeated or prolonged exposures remain concerning.

We hypothesized that exposure to general anesthesia (single or multiple) and any surgery before 4 yr of age would associate with adverse neurodevelopmental outcomes at age 7 to 16 yr. We tested this hypothesis in a large, population-based, representative birth cohort from the United Kingdom that contains a rich description of confounding factors and detailed, prospective assessment of multiple neurodevelopmental domains into adolescence.

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