A holistic view of anesthesia-related neurotoxicity in children

Figures & data

Table 1 Retrospective epidemiological studies – an overview stratified according to positive findings and negative findings

Study title	Data source	Study subjects	Outcome	Results
Positive findings
The effects of exposure to GA in i nfancy on AP at age 12^Citation54	Children born at term between 1998 and 1999 at KK Children’s and Women’s Hospital Singapore	Exposure group: children within the cohort who had surgery and anesthesia for any kind of surgery (n=257) Controls: Children within the cohort without any history of surgery and anesthesia	1. PSLE aggregate score; PSLE is administered by the Ministry of Education. 2. LD - parental reported 3. LD - formally diagnosed Information on anesthetic agents, periprocedural vital parameters and type of surgery retrieved in patient journal	N=I00 exposed children were included in analysis and compared to n=107 controls; Adjusted difference in PSLE score between exposed and unexposed not significant. OR for exposed relative to controls of being formally diagnosed with LD 4.5% (95% Cl: 1.44 – 14.4)
Neurosurgical conditions and procedures in infancy are associated with mortality and APs in adolescence: a nationwide cohort study^Citation51	Danish birth cohort 1986–1990; retrospective birth cohort study based on Danish National CPR registry^Citation3	Exposed to surgery and anesthesia for the following neurosurgical procedures: n=228 (n=130 hydrocephalus; n=43 craniotomy; n=55 myelomeningocele/ encephalocele); Controls: randomly selected, age- matched 5% sample of the same cohort, n= 14,698	Comparison of 1. APs at ninth grade exam 2. Mortality 3. NA at exam between exposed and controls	Average test scores were significantly lower than those of controls in the hydrocephalus and craniotomy children; Mortality was higher among exposed than controls NA at exam was significantly higher among exposed than controls
Cognition and brain structure following early childhood surgery with anesthesia^Citation50	Matched-control design study; cross-sectional MRI database including 5-18-year-old healthy volunteers; anesthesia records	Exposed n=53 with history of anesthesia and any kind of surgery before 4 years of age and n=53 matched controls	OWLS and Wechsler Performance IQ Intelligence Scale for Children Findings on MRI scans conducted without anesthesia	Lower performance IQ was associated with decreased gray matter in cerebellum; mean cognitive test scores were comparable between exposed and unexposed but subgroup analysis showed significant lower scores among exposed for performance IQ and OWLS-listening comprehension.
Early exposure to anesthesia and learning disabilities in a population-based birth cohort^Citation43	Population-based retrospective birth cohort study in Olmstead County, Minnesota	593 children born during 1976-1982 and exposed to GA for any kind of surgery <4 years of age; exposed n=449 (single GA) n=100 (2 × GA) n=44 (3 × GA)	LD	Single GA exposure: not a risk factor for development of LD Multiple GA exposure: significant risk factor forLD
Comparative analysis of outcome used in examining neurodevelopmental effects of early childhood anesthesia exposure^Citation52	Western Australian Pregnancy Cohort; n=2,868 subjects born 1989-1992 included	Individuals within the cohort exposed to GA for any kind of surgery <3 years of age and with available records of complete outcome data	At age 10 years: 1. Neuropsychological testing, 2. ICD, ninth revision, clinical modification-coded clinical disorders 3. Academic achievement	Individuals within the cohort with complete outcome data n=781; Exposed to GA <3 years of age n=l 12 Unexposed to GA <3 years of age n=669 Exposed showed 1. Lower scores in neuropsychological testings Increased diagnosis of behavioral and language deficits, cognitive disorders
Cognitive and behavioral outcomes after early exposure to anesthesia and surgery^Citation44	Matched cohort study based on birth cohort in Rochester, Minnesota	n=350 children exposed to any kind of surgery <2 years of age compared to n=700 controls matched for age and known risk factors for LD	Learning disabilities Need for IEP Results of TCA	Multiple exposures <2 years of age 1. Increased risk of LD, but not of behavioral problems; 2. Increased risk of need for IEP
ADHD after early exposure to procedures requiring GA^Citation45	Retrospective birth cohort study, Rochester, Minnesota	Within the birth cohort of n=5,357 children, n=34l had a diagnosis of ADHD; exposed to surgery and GA prior to 2 years of age, n=350	Association between ADHD and exposure to surgery and GA <2 years of age	Incidence of ADHD among nonexposed approximately 7%; Increased risk of being diagnosed with ADHD after exposure with ≥2 × GA
Behavior and development in children and age at the time of first anesthetic exposure^Citation53	Children undergoing urological surgery in the years 1987, 1991, 1993, and 1995 at the University Medical Center Utrecht Retrospective cohort study	n=3 14 children operated for 1. Ureteropelvic junction obstruction 2. Obstructive megaureter 3. Posterior urethral valves between 0 and 6 years of age; A properly powered cohort study would require at least 2,268 children	120-item parental child behavior checklist/4-18 - a set of measures for assessing children from parent, teacher, and self-report	Questionnaires n=243 returned; Adjusted OR for presence of clinically deviant outcome when operated 1. <6 months: 1.38 (95% Cl: 0.59-3.22) 2. 6-12 months: 1.19 (95% Cl: 0.45-3.18) and - between 12 and 24 months: 1.20 (95% Cl: 0.45-3.20) (reference: operated at age >24 months)
A retrospective cohort study of the association of anesthesia for hernia repair surgery with behavioral and developmental disorders in young children^Citation46	New York State Medicaid program; Retrospective cohort analysis	n=383 children within the birth cohort from 1999 to 2001 and having surgery for inguinal hernia repair <3 years of age	Diagnostic codes for 1. Delayed development or behavioral disorder 2. Mental retardation 3. Autism 4. Language/speech problems	Increased risk of diagnosis of behavioral development disorders among exposed children Compared to a random sample from the same birth cohort, n=5,050 children
Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort^Citation47	New York State Medicaid program; Retrospective twin-sibling study	Twin siblings born during 1999-2005; n=668 exposed to any kind of surgery <3 years of age	Diagnosis of BDP compared to 10,980 unexposed twin siblings in the cohort	60% increase in BDP among exposed
Are anesthesia and surgery during infancy associated with altered AP during childhood?^Citation49	Department of Anesthesia Billing Records searched for patients between 7 and 17.9 years on January 28, 2008, who had been operated on for: 1) circumcision; 2) pyloromyotomy; and 3) inguinal hernia repair and orchiopexy	Of n=623 eligible individuals, n=l85 could be included in data analysis; Composite scores were available for n= 133 individuals; among these n=58 were identified as not having any risk factors for poor AP	Scores on Iowa tests of basic skills and education - (lowa tests): standardized tests assessing basic, general intellectual skills and abilities in verbal, mathematical, and other areas - composite score in second to fourth grade, corresponding to 7- 10 years of age	Children undergoing anesthesia and surgery during infancy had very low achievement test scores (below the fifth percentile), both in overall sample and the subgroup of 58 patients without CNS problems /potential risk factors
Long-term differences in language and cognitive function after childhood exposure to anesthesia^Citation48	Western Australian Pregnancy Cohort containing 2,868 subjects from 1989 to 1992	Within the cohort, n=321 individuals were exposed to GA for any kind of surgery <3 years of age	Results of neuropsychological tests at age 10 years; exposed individuals compared to unexposed (n=2,287) within the same cohort	Individuals exposed to GA <3 years of age performed poorer in areas of receptive, expressive, and total language
Negative findings
Risk of autistic disorder after exposure to GA and surgery^Citation54	Nationwide (Taiwan) population- based retrospective matched- cohort study using data retrieved from the NHIRD	Birth cohort from January 1, 2001 to December 31, 2007 n=114,435; exposed: n=5,197; GA and surgery before 2 years of age. Matched controls 1:4 n=20,788	Autistic disorder according to ICD- 9-CM 299.000 diagnosed after GA and surgery exposure and before December 31, 2010	Neither single nor multiple exposures were associated with risk of an autistic disorder. Age at first exposure was not associated with risk of an autistic disorder
Anesthesia and cognitive performance in children: no evidence for a causal relationship^Citation39	Young Netherlands Twin Registry	1,143 monozygotic twin pairs born during 1986-1995; exposed to any surgery and anesthesia from <3 years of age to 3-12 years of age	LD at age 12 years, assessed by 1. Dutch CITO-test results 2. CP assessed by Conners’ Teacher Rating Scale	1. One twin exposed, other twin nonexposed: no difference in EA or CP 2. Male twin pairs - nonexposed: higher EA than pairs with both or one exposed 3. Female twin pairs - nonexposed: less CP than pairs with both or one exposed 4. Males in general - exposed: EA lower than any nonexposed 5. Same tendency among females
AP in adolescence after inguinal hernia repair in infancy: a nationwide cohort study^Citation1	Retrospective birth cohort study based on Danish National CPR registry^Citation3	2,689 children in the Danish birth cohort from 1986 to 1990 having surgery for inguinal hernia repair < 1 year of age	AP at national ninth grade exam NA at exam	Compared to n= 14,575 controls randomly selected from the birth cohort, exposed children showed 1. No significant difference in AP 2. Higher risk of NA among exposed
Cognitive outcome after spinal anesthesia and surgery during i nfancy^Citation42	VIRS - a computerized database containing demographic and intraoperative data on patients < 1 year having spinal anesthesia since 1979; Vermont Department of Education	n=365 children born between January 1, 1989 and August 31, 2003 with gestational age 28 weeks or more and before 5 years of age having spinal anesthesia for 1. Pyloromyotomy 2. Inguinal hernia repair 3. Circumcision	Academic results in 1. New Standards Reference Examination achievement tests in reading, writing, mathematics (assessed in fourth, eighth, tenth grades) or 2. New England Common Assessment Program examination in grades three to eight and eleven and 3. Need for individual educational plan	Duration of surgery in spinal anesthesia did not associate with poor academic outcome; Exposure to spinal anesthesia did not relate to very poor academic achievement in elementary school
Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study^Citation40	Retrospective birth cohort study based on Danish National CPR registry^Citation3	779 infants in the Danish birth cohort from 1986 to 1990 having surgery for pyloric stenosis repair <3 months of age	AP at national ninth grade exam NA at exam	Compared to 14,665 controls randomly selected in the birth cohort, exposed children showed 1. No significant difference in AP 2. Higher risk of NA among exposed

Note: ^aCPR, a Danish national register, holding individual numbers assigned at birth.

Abbreviations: GA, general anesthesia; ADHD, attention deficit hyperactivity disorder; OR, odds ratio; EA, educational achievement in Dutch CITO elementary test; CP, cognitive problems; LD, learning disability; BDP, behavioral or developmental problems; AP, academic performance; NA, nonattainment; PSLE, primary school leaving examination; VIRS, Vermont infant’s spinal registry; IEP, individual education program; ICD, international classification of diseases; TCA, test of cognition and achievement; NHIRD, national health insurance research database; MRI, magnetic resonance imaging; OWLS, oral and written language scales; CPR, central person register; CNS, central nervous system; CITO-test, final test primary education in the Netherlands.

Table 2 Ongoing prospective trials

Study name	Design	Cohort	Primary outcome
GAS^a study	Multisite randomized controlled trial	Newborns randomized to spinal or GA for inguinal hernia repair	IQ score at age 2 and 5 years in WPPSI-III
MASK study	Cohort study, retrospective regarding exposure, prospective regarding outcome	Children born between 1994 and 2007 exposed to single or multiple GA before 3 years of age compared to controls from the same cohort	Results in single 4-hour neuropsychological test battery
PANDA study	Ambidirectional cohort study	Sibling exposed to GA before 3 years of age for inguinal hernia repair compared to nonexposed sibling	WASI-II scores and NEPSY II scores between 8 and 15 years of age

Note: ^aA multisite randomized controlled trial comparing regional and general anesthesia for effects on neurodevelopmental outcome and apnea in infants.

Abbreviations: GA, general anesthesia; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence – third edition; MASK, Mayo Safety for Kids; PANDA, Pediatric Anesthesia and Neurodevelopmental Assessment; WASI-II, Wechsler Abbreviated Scale for Intelligence – second edition; NEPSY II, A Developmental Neuropsychological Assessment – second edition; GAS, General Anaesthesia compared to Spinal Anaesthesia.

Ko WR, Huang JY, Chiang YC, et al. Risk of autistic disorder after exposure to general anaesthesia and surgery: a nationwide, retrospective matched cohort study. Eur J Anaesthesiol. 2015;32(5):303–310.

 Web of Science ®Google Scholar

Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study. Paediatr Anaesth. 2015;25(2):186–192.

 Web of Science ®Google Scholar

Jevtovic-Todorovic V, Absalom AR, Blomgren K, et al. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg seminar. Br J Anaesth. 2013; 111(2):143–151.

 Web of Science ®Google Scholar

Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics. 2015;136(1):e1–e12.

 PubMed Web of Science ®Google Scholar

Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796–804.

 PubMed Web of Science ®Google Scholar

Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology. 2014; 120(6):1319–1332.

 Web of Science ®Google Scholar

Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053–e1061.

 PubMed Web of Science ®Google Scholar

Sprung J, Flick RP, Katusic SK, et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc. 2012;87(2):120–129.

 PubMed Web of Science ®Google Scholar

Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110(4):805–812.

 PubMed Web of Science ®Google Scholar

DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286–291.

 PubMed Web of Science ®Google Scholar

DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113(5):1143–1151.

 PubMed Web of Science ®Google Scholar

Block RI, Thomas JJ, Bayman EO, Choi JY, Kimble KK, Todd MM. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117(3):494–503.

 Web of Science ®Google Scholar

Ing C, Dimaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476–e485.

 PubMed Web of Science ®Google Scholar

Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12(3):246–253.

 PubMed Web of Science ®Google Scholar

Nemergut ME, Aganga D, Flick RP. Anesthetic neurotoxicity: what to tell the parents? Paediatr Anaesth. 2014;24(1):120–126.

 PubMed Web of Science ®Google Scholar

Williams RK, Black IH, Howard DB, et al. Cognitive outcome after spinal anesthesia and surgery during infancy. Anesth Analg. 2014; 119(3):651–660.

 Web of Science ®Google Scholar

Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth. 2013;23(10):883–890.

 Web of Science ®Google Scholar