Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Reighard (2022)

A: Lv (2018)

B: Bong (2013)

C: Ing (2012)

D: Stratmann (2014)

Conflict of Interest: none reported.

Funding/Support: Dr Ing is supported by the Agency for Healthcare Research and Quality (AHRQ) (award No.

R01HS026493). AHRQ had however no role of interference.

SR and meta-analysis of RCTs

Search algorithms

were applied to PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library.

Search algorithms were previously published by Clausen and colleagues, identifying 67 English language

studies published before June 17, 2017. In this study, the same algorithms were used, save

for minor modifications in search term formatting to identify additional studies published June 17, 2017, to August 31, 2021.

A: Prospective study

B: Bong (2013): Retrospective observational cohort study

C: Ing (2012): prospective birth cohort

D: Prospective study

Inclusion criteria SR:

- children exposed to

general anaesthesia, as well as an unexposed comparison group, and report outcomes from at least 1

of the psychologist-identified domains.

Exclusion criteria SR:

-Studies that focused primarily on children with major

preexisting comorbidities or congenital anomalies were excluded. This process was adopted owing

to the difficulty of determining the contribution of the anesthetic to neurodevelopment in children

with significant baseline comorbidity and major perioperative physiological insult, such as children

who required cardiopulmonary bypass for heart surgery.

Additionally: where duplicate reports evaluating the same population were found, only the study with the

largest sample size was chosen. For studies that reported outcomes of the same cases (e.g., at

different ages), selection was determined by longest follow-up interval. For studies evaluating the

same cohorts but reporting different outcomes (ie, scores from different domains) outcomes from all

different domains were evaluated.

4 studies included

Important patient characteristics at baseline:

N patients:

A: total of 201 children (101 patients and 100 healthy children)

B: 206 (compared 100 healthy children exposed to anaesthesia for minor surgery with an age-matched cohort of 106 never exposed to anaesthesia or sedation.

C: birth cohort with a total of n=2868 children. 321 were exposed to anaesthesia before age 3, and 2287 were unexposed.

Mean age:

A: Young children (less than 2 years old)

B: Age at GA in months (mean ± SD) was

4.39 ± 3.15

C: infants aged between 1 and 3 years being included.

Type of procedure:

A: Children undergoing palatoplasty (a type of operation which requires less than 1 hour in our hospital)

B: These children had minor surgeries, which included inguinal herniotomies, circumcisions, cystoscopies, and pyloromyotomies. All surgeries lasted between 30 and 120 minutes, involved relatively little tissue dissection, and the children did not require long-term follow-up

C: Any child who had a surgical or diagnostic procedure requiring anesthesia

Number of exposures:

A: single exposure

B: single with possible multiple exposures

C: single and multiple exposures.

Describe intervention:

A: receiving palatoplasty with sevoflurane anaesthesia

B: children who were exposed to general anesthesia for minor surgery before age 1

C: exposed children to anaesthesia before age 1

D: exposed children to anaesthesia before age 1

Describe control:

A: healthy children in the community of Shanghai

B: an age-matched cohort of children whom were never exposed to anesthesia or sedation.

C: unexposed children to anaesthesia included in cohort

D: an age-matched cohort of children whom were never exposed to anesthesia

End-point of follow-up:

A: 18 months follow-up measurements the day before surgery, 6 months and 18 months after the operation)

B: not specified: approx.. 11 years (children at age 12 were telephonically retrospectively interviewed and medical records during time of operation were used).

C: After birth, all children were assessed at 1, 2, 3, 5, 8, 10, 13, and 16

D: 5-10 years after surgery. Mean age at testing 9.4 (1.6)

For how many participants were no complete outcome data available?

(intervention/control)

Loss to follow-up occurred – either due to no response or loss to follow-up.

A: among the 116 patients recruited in the study,

11 children were excluded owning to hemodynamic or/and respiratory adverse events. In the remaining 105 cases, 4 cases and 15

cases were excluded respectively during the 6

months and 18 months periods because of

loss to follow-up. As a result, 101 patients with a 6 months follow-up and 86 patients with an 18 months follow-up were analyzed.

B: not reported

C: solely reported that loss to follow-up occurred.

D: not reported

Outcome measure-1

Intelligence (IQ)

Effect measure: RR, RD, mean difference [95% CI]:

Learning ability

Effect measure: RR, RD, mean difference [95% CI]:

A: not reported

B:

PSLE Score at age 12 (Mean, 95% CI):

I: 197.0 (185.6–208.4)

C: 194.0 (182.9–205.1)

MD: 3.0 (95% CI −8.3 to 14.3).

C: not reported

D: Full-scale IQ

I: 111.7 (16.4)

C: 110.2 (16.2)

Outcome measure-2

Behavioural problems

e.g. change in behaviour, autism, adhd)

Effect measure: RR, RD, mean difference [95% CI]:

A: not reported

B: not reported

C: CBCL total sore at age 10 (Mean, SD)

I: 48.7 (10.6)

C: 47.4 (11.5)

Score difference: 1.4.

D: CBCL total sore at age 9.4 (Mean, SD)

I: 46.5 (8.0)

C: 46.1 (8.0)

Outcome measure-3

Neurological damage

Effect measure: RR, RD, mean difference [95% CI]:

A: Neurodevelopmental outcomes (using the BSID-II)

Motor function (SMD, 95% CI)

I: 86

C: 100

[SMD 0.26, 95% CI -0.55 to 0.03].

When compared with normal healthy children, there were also no statistically significant differences between postoperative patients and normal healthy children the age of 3-4 years in PDI scores 91.1±4.4 vs 92.5±6.2, (P=0.0820). ) (no follow-up period specified à probably at ages 3-4 years).

Cognition (SMD, 95% CI)

I: 86

C: 100

[SMD 0.14, 95% CI -0.15 to 0.43].

When compared with normal healthy children, there were also no statistically significant differences between postoperative patients and normal healthy children the age of 3-4 years in the MDI scores (patients vs health): 94.1±5.4 vs 93.4±4.7, (P=0.3458) (no follow-up period specified à probably at ages 3-4 years).

B: not reported

C: MAND NDI (motor tasks) at age 10 (mean, SD)

I: 92.6 (14.7)

C: 94.3 (13.8

Score difference: 1.7

D: not reported

Pooling was not possible.

Risk of bias (high, some concerns or low):

Tool used by authors:

Critical appraisals were conducted using the Cochrane risk of bias tool for randomized clinical trials (RCTs) and the Risk Of Bias in Nonrandomised Studies of Interventions (ROBINS-I) for nonrandomized studies.

A: ROBINS-I overall: serious risk of bias

B: ROBINS-I overall: moderate risk of bias

C: ROBINS-I overall: moderate risk of bias

D: ROBINS-I overall: serious risk of bias

The overall quality of the evidence is low and it should be interpreted with caution; All studies were at risk of bias, with the highest risks due to confounding, the retrospective determination of intervention status, and presence of cointervention (e.g., surgical procedure) with anaesthesia exposure.

Conclusion:

The results from this systematic review and meta-analysis help identify patterns of deficits in specific domains, with comparatively larger effect sizes seen in the executive function, nonverbal reasoning,

motor function, and behavioural problems, particularly externalizing behavioural problems, domains, coupled with an increased incidence of neurodevelopmental disorder diagnoses, particularly ADHD

diagnosis. The effect sizes in children with multiple exposures were also found to be 2-fold as large as those with single exposure.

Outcome measure -1:

B: Primary School Leaving Examination (PSLE) score was used to measure the academic achievement at age 12 years as well as the presence of formally diagnosed Learning disabilities by age 12 years.

PSLE which is a high-stakes national examination administered to all children attending state schools in Singapore before completion of their primary school education, typically at 12 years of age.

The PSLE is a national examination administered by the MOE taken by all students attending state schools in Singapore near the end of their sixth year in primary school (grade 6 equivalent), typically when the children are 12 years old. Typically aggregate scores range from 0 to 300.

Outcome measure – 2:

C: Child Behaviour Checklist (CBCL), a questionnaire evaluating both internalizing problems such as depression and somatic complaints, as well as externalizing problems that involve conflict with others, such as aggressive behaviour and rule breaking. In addition to internalizing and externalizing scores, the CBCL also generates a total behaviour score. As opposed to the other neuropsychological tests, in CBCL scoring, higher scores show dysfunction, with scores <60 considered normal.

Outcome measure – 3:

A: BSID-II (MDI and PDI): BSID-II is widely used in early diagnosis of neurological impairment and developmental disorders in children. In this study, BSID-II was used to measure neurological impairment and developmental disorders (PDI used to measure motor function, and MDI to measure cognition). The Bayley Scales of Infant Development-Second Edition (BSID-II) is successfully used to predict neurodevelopmental outcomes after surgery in infants and is suitable for infants between 1 and 42 months of age.

C: the McCarron Assessment of Neuromuscular Development (MAND) was used to measure fine and gross motor tasks

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Waitayawinyu (2023)

Type of study:

Prospective observational case-control pilot study

Setting and country:

conducted from November 2017 to November 2019 at the Faculty of Medicine, Siriraj Hospital, Mahidol University.

Funding and conflicts of interest:

Funding: This work was supported by a grant from the Siriraj Research Development Fund of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (No. [IO] R016135023).

Conflict of interest: The authors have no conflicts of interest to declare.

Inclusion criteria:

Normal developing children aged 1–36 months without exposure to general anaesthesia were included.

Exclusion criteria:

Premature infants, known developmental delays, children with neurological diseases, and children with a history of neurotoxic agent exposure were excluded.

N total at baseline: 59

Intervention: 39

Control: 20

Important prognostic factors²:

age

I: median (P25, P75) ages were 8.3 (4.1, 14.2) months

C: 16.5 (10.2, 28.2) months

Sex (male):

I: 63.8 % M

C: 50.0% % M

Groups comparable at baseline?

No, The baseline cognitive scale score of the anaesthesia group was statistically and clinically lower than that of the control group

Describe intervention (treatment/procedure/test):

 Children aged between 1and 36 months: scheduled for elective noncardiac surgery were recruited to the anaesthesia group.

Describe control (treatment/procedure/test):

Healthy participants were recruited from the Siriraj Daycare Center for the control group using consecutive convenience samples.

Length of follow-up:

7 days post op

Loss-to-follow-up: not reported

Intervention:

N (%):

Control: not reported

N (%):

Reasons (describe):

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure-1:

Intelligence (IQ), learning disability

Not reported

Outcome measure-2

Behavioural problems

e.g. change in behaviour, autism, adhd)

Not reported

Outcome measure-3

Neurological damage

Neurodevelopmental assessment: Cognitive scores between baseline and post-anaesthesia assessment (Mean difference, 95% CI) [Intervention group solely]:

Baseline score 9.33 (2.12)

Post-anaesthesia score: 10.31 (2.12)

Mean difference: 0.97 (95% CI 0.15 to 1.80)

Conclusion:

Children in the anaesthesia group had lower baseline cognitive composite scores than those in the healthy control group. Overall, the cognitive composite score did not decline after anaesthetic exposure, but anaesthetic exposure resulted in a decline in the cognitive composite score in 17.9% of the participants.

-Trial registered at thaiclinicaltrials.org (No. TCTR20211209006).

To evaluate the cognitive developmental function of infants and toddlers, Bayley-III is widely used to measure the developmental function of infants and toddlers aged 1–42 months. The Bayley-III consists of five distinct scales: cognitive, language, motor, social-emotional, and adaptive behavior. Only the cognitive scale was assessed in this study because it is least likely to be disturbed by perioperative events compared to the other subscales.

Study reference

(first author, publication year)

Domain 1: confounding:

Domain: selection:

Domain 3: classification of intervention:

Domain 4: deviation from interventions:

Domain 5: missing data:

Domain 6: measurement of outcomes:

Domain 7: selection of reported result:

Overall risk of bias

Lv (2018)

Serious

None

Moderate

Moderate

none

Serious

Low

ROBINS-I overall: Serious RoB

Bong (2013)

Moderate

Low

Moderate

Moderate

Moderate

Low

Low

ROBINS-I overall: moderate RoB

Ing (2012)

Moderate

Low

Moderate

Moderate

Low

Low

Low

ROBINS-I overall: moderate RoB

Stratmann (2014)

Serious

Serious

Moderate

Moderate

Low

Moderate

Low

ROBINS-I overall: Serious RoB

Study reference

(first author, publication year)

Domain 1: confounding:

Domain: selection:

Domain 3: classification of intervention:

Domain 4: deviation from interventions:

Domain 5: missing data:

Domain 6: measurement of outcomes:

Domain 7: selection of reported result:

Overall risk of bias

Waitayawinyu (2023)

Moderate

Low

Moderate

Moderate

Moderate

Low

Low

ROBINS-I overall: Moderate RoB