Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy.

AIM: Several studies in animal models have found that exposure to anesthetics in early life can cause cognitive dysfunction. Human studies show conflicting results and studies of cognitive function after anesthesia and neonatal surgery are scarce. The aim of this study was to investigate whether exposure to anesthesia and abdominal surgery during infancy was associated with cognitive dysfunction from the perspective of educational level, disposable income and attention deficit hyperactivity disorders (ADHD) in adolescent and adult individuals.
METHODS: A cohort study with patients born 1976 to 2002 that underwent abdominal surgery during infancy at a pediatric surgical center were matched by age, sex, and gestational age to ten randomly selected individuals from the Swedish Medical Birth Register. Individuals with chromosomal aberrations were excluded. Data on highest level of education and annual disposable income were attained from Statistics Sweden and the diagnosis of ADHD were retrieved from the Swedish National Patient Register.
RESULTS: 485 individuals and 4835 controls were included. Median gestational age was 38 weeks (24-44) and median age at surgery was seven days (0-365). Three hundred sixty-six individuals (70.0%) underwent surgery during the neonatal period (< 44 gestational weeks). Median operating time was 80 minutes (10-430). The mean age at follow-up was 28 years. Fisher's exact test for highest level of education for the exposed and unexposed groups were respectively: university 35% and 33%, upper secondary 44% and 47%, compulsory 21% and 20% (p = 0.6718). The median disposable income was 177.7 versus 180.9 TSEK respectively (p = 0.7532). Exposed individuals had a prevalence of ADHD of 5.2% and unexposed 4.4% (p = 0.4191).
CONCLUSIONS: This study shows that exposure to anesthesia and abdominal surgery during infancy is not associated with cognitive dysfunction from the perspective of educational level, disposable income and ADHD in adolescent and adult individuals. Further studies in larger cohorts at earlier gestational ages are needed to verify these findings.

Introduction

There is increasing concern that exposure to anesthesia and surgery in early childhood may increase the risk of later neurocognitive dysfunction and impaired educational level later in life [1, 2]. Studies in different experimental animal models with mice, rats, pigs and monkeys have found that exposure to commonly used anesthetics during infancy can cause life-long cognitive dysfunction [3-12]. In neonatal piglets, 15 min of surgery designed to replicate an inguinal repair increased cell death in eight areas of the brain compared to anesthesia alone [13].

It is unclear whether these findings in animals can be extrapolated to children. In humans, several studies have reported an increased risk of adverse cognitive development after exposure to general anesthesia and surgery and the risk increased with prolonged or multiple procedures [14-19]. Yet, other studies found that exposure to general anesthesia and surgery in early-life had no association with adverse cognitive development [20, 21]. Possible explanations for the conflicting results have been proposed, such as different indications for surgery and a vulnerability to cognitive dysfunction in infants who undergo anesthesia and surgery [1, 2, 22, 23]. Previous studies have found a doubling of the incidence of learning disabilities (LD) and attention deficit hyperactivity disorders (ADHD) after repeated exposure to general anesthesia before age 2–4 years [17-19]. In a more recent study, an increased risk of ADHD was observed in children under age 5 with a single exposure to minor surgery requiring anesthesia [24].

ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of hyperactivity, impulsivity and inattention [25, 26]. The worldwide prevalence of childhood and adolescent ADHD is estimated to be approximately 5% [27, 28]. Children and adolescents with a diagnosis of ADHD are more likely to drop out of school, to perform poorly on standardized tests and to score lower grades [29].

The aim of this study was to investigate whether exposure to anesthesia and abdominal surgery during infancy was associated with cognitive dysfunction from the perspective of educational level, disposable income and ADHD in adult and adolescent individuals.

Patients and methods

This study was approved by the ethical review board in Uppsala, Sweden (Dnr 2016/535; Dnr 2016/535/1; Dnr 2016/535/3). Consent was not obtained as the data from the registries were attained and analyzed anonymously.

This cohort study was based on data from the Swedish national population-based registries from a cohort of patients born 1976 to 2002 that underwent anesthesia and abdominal surgery before the age of one year at the Department of Pediatric Surgery at the University Children’s Hospital in Uppsala, Sweden. The personal identity number assigned to every Swedish citizen at birth or at immigration was used to link information across registries.

Data from four registers were included in this study: the Swedish Income and Taxation Register (updated annually), with information about disposable income, which is the sum of all income, excluding taxes, per individual and year, the Education Register which reports the highest level of education achieved by all Swedish individuals from 16 years of age (started 1985 and updated annually), the Swedish Medical Birth Register which includes 98% of all births in Sweden since 1973 and it contains information about gender and gestational week, the Swedish National Patient Register which was started in 1964 and in which all hospitals in Sweden have been included since 1987, the register contains information about gender, age, date of admission and discharge. It also contains diagnoses according to the International Classification of Disease, ICD. During the study period different ICDs were used: ICD-8 from 1969–1986, ICD-9 from 1987–1996 and ICD-10 from 1997 and onwards. The register also keeps codes for surgical procedures according to the Classification of Surgery from 1963–1996, and from 1997 the Classification of Surgical Procedures, KKÅ, has been used. Since 2001 the register covers outpatient visits to a physician, including psychiatric care by both private and public caregivers. In the year 2010 the register had almost 100% coverage for inpatient care whereas the coverage for outpatient care was lower, about 80% [30].

Study cohort

This study was based on a cohort from our previous study of 898 patients that had undergone laparotomy during infancy (the first year of life) between the years 1976 to 2011 at the Department of Pediatric Surgery at the University Children’s Hospital in Uppsala, Sweden [31]. Only individuals exposed to abdominal surgery during infancy were included and no other type of surgery or other procedures requiring anesthesia.

Data were extracted from the patients’ medical records. Parameters retrieved were gestational age, sex, date of birth, diagnosis and operating time. Each operation report was reviewed to exclude the risk of faulty registration. Patients with Hirschsprung’s disease were operated according to Rehbein’s procedure with an initial colostomy followed by an anterior resection of the aganglionic segment. No laparoscopic procedures were included [31].

Out of 898 patients, 523 patients matched the criteria of being aged over16 years at study start. Through linkage with the Swedish Patient Register exclusions were made of individuals with any chromosomal aberrations diagnosed using the ICD8-10, ICD-8 (759.30–759.59), ICD-9 (758A-X), ICD-10 (Q90-Q99). ADHD was defined using ICD9-10 codes relevant for the different subtypes of ADHD, the codes for hyperkinetic disorders: ICD-9 (314J, 314W, 314X), ICD-10 (F90.0A, F90.0B, F90.0C, F90.0X).

Control cohort

From the Swedish Medical Birth Register, ten controls were drawn at random for each individual in the exposed cohort, matched on sex, age and gestational week. Individuals with the exposure, anesthesia and abdominal surgery before one year of age, were excluded through linkage with the Swedish Patient Register. As for the cohort, exclusion for chromosomal aberrations was made.

Statistical analysis

Categorical data were presented as frequencies or proportions. Continuous data were presented as either mean with standard deviation or median with range. Highest educational level and ADHD were analyzed using Fischer´s exact test. Since the outpatient register started in 2001, we decided to make two different comparisons of ADHD for the cohort. One for the whole cohort and a subgroup analysis for individuals born from 1995 and later. Further, the highest level of education was analyzed using mixed ordinal regression to look at differences between groups and sex. Incidence rate ratio (IRR) shows the probability of having a higher level of education. Differences in disposable income were analyzed using the non-parametric Mann-Whitney U-test. In order to be able to take the matching into account a mixed ordinal regression was estimated. Taking specific care by treating a case and its matched controls as a cluster would assist in preventing that the results could be biased by for example unequal number of controls between cases due to missing data. All analyses were performed using R version 3.6.0.

Results

The study cohort consisted of 523 patients. After exclusion of individuals with chromosomal aberrations, a total number of 485 individuals were included (Fig 1). The unexposed, control group consisted of 4835 individuals. In the control group 15 individuals received no data due to inaccurate personal identification numbers. 472 cases had 10 controls, 12 cases had 9 controls and 1 case had 7 controls (Table 1). Mean age and gestational week of the cases was 28.23 years (5.33 SD) and 37.53 weeks (3.63 SD) respectively. Mean age and gestational week of the control group was 28.34 years (5.24 SD) and 37.54 weeks (3.62).

Fig 1

Flow diagram of the study population.

Table 1

Overview of the cohort.

Number of controls per case	Number of cases	Number of controls in total	Number of total (cases+controls)
10	472	4720	5191
9	12	108	120
7	1	7	8

In the control group 15 individuals received no data due to inaccurate personal identification numbers.

There were 61.4% males in the cohort (Table 2). Median gestational age was 38 weeks (24–44) and median age at surgery was 7 days (0–365), whereas 366 (70.0%) of the exposed individuals underwent surgery during the neonatal period (< 44 gestational weeks). During the study median follow-up 14.7 years (0.0–36.), the median number of surgeries was one (1–13), 26.6% had two surgeries and 16.8% had three or more abdominal surgical procedures.

Table 2

Characteristics of the exposed individuals*.

Total number of patients	523
Male gender, n (%)	321 (61.4)
Gestational age in weeks, n** (%)
• <28	19 (3.7)
• 28–32	29 (5.7)
• 33–37	160 (31.2)
• >37	305 (59.4)
Median gestational age in weeks (range)	38 (24–44)
Median age in days at surgery (range)	7 (0–365)
Median gestational weeks at surgery (range)	40.1 (25.6–90.1)
Median number of surgeries (range)	1 (1–13)
Number of individuals with one surgery (%)***	296 (56.6)
Number of individuals with two surgeries (%)***	139 (26.6)
Number of individuals with three or more surgeries (%)***	88 (16.8)

*The cohort of exposed individuals before the exclusion of 38 individuals with chromosomal aberrations.

**Missing data in 10 individuals.

***The total number of surgeries during median follow-up 14.7 years (0.0–36.0).

The most common diagnosis for the study cohort was pyloric stenosis 21.4%, followed by duodenal obstruction 10.3%, diaphragmatic hernia 10.1%, gastroschisis 9.8% and Hirschsprungs disease 9.4% (Table 3). Median operating time was 80 min (10–430).

Table 3

Diagnosis and operating time in exposed individuals*.

Diagnosis	Number of patients, n (%)	Median operating time in min
	(n = 523)	(range)
Pyloric stenosis	112 (21.4)	35 (10–110)
Duodenal obstruction	54 (10.3)	90 (55–220)
Diaphragmatic hernia	53 (10.1)	85 (25–430)
Gastroschisis	51 (9.8)	100 (15–200)
Hirschsprungs disease	49 (9.4)	150 (45–355)
Others**	39 (7.5)	80 (35–235)
Anorectal malformation	30 (5.7)	72.5 (30–320)
Omphalocele	27 (5.2)	92.5 (30–180)
Malrotation	25 (4.8)	82.5 (55–155)
Necrotizing enterocolitis	19 (3.6)	82.5 (45–135)
Intestinal atresia	19 (3.6)	112.5 (65–240)
Gastrostomy	13 (2.5)	52.5 (35–105)
Abdominal tumour	13 (2.5)	125 (45–285)
Biliary atresia	11 (2.1)	200 (55–335)
Intussusception	8 (1.5)	70 (20–110)

*Exposed individuals before the exclusion of 38 individuals with chromosomal aberrations.

**Omphaloenteric duct, ovarian cyst, Meckel’s diverticulum, intestinal duplication.

Academic performance and disposable income

Level of education was divided into three categories: compulsory school, upper secondary school and university education. Fisher’s exact test for highest level of education did not show any significant differences (p-value 0.6718) between exposed and unexposed individuals (Table 4). Mixed ordinal regression for educational level did not show any significant differences for gender (p-value 0.2285) or exposure (p-value 0.4094) (Table 5).

Table 4

Highest educational level.

	Controls	Cases
	n = 4221	n = 454
University	1391 (33%)	157 (35%)
Upper secondary school	1967 (47%)	202 (44%)
Compulsory school	863 (20%)	95 (21%)

Fisher’s exact test for highest level of education did not show any significant differences between exposed and unexposed individuals (p = 0.6718).

Table 5

Mixed ordinal regression for educational level.

Variable	IRR	95% CI	P-value
Case: yes	1.09	(0.89–1.34)	0.4094
Gender: female	1.25	(0.87–1.81)	0.2285

Mixed ordinal regression for educational level did not show any significant differences for gender or exposure.

The median annual disposable income did not differ significantly between exposed and unexposed individuals, 177.7 versus 180.9 TSEK respectively (p = 0.7532) (Table 6).

Table 6

Disposable income.

Income (1000 SEK)	Controls n = 4493	Cases = 483
Median	177.7	180.9

Mann-Whitney U-test for disposable income did not differ significantly between exposed and unexposed individuals (p-value = 0.7532).

Mixed linear regression on disposable income showed that females in the whole cohort had a significantly lower disposable income compared with males on average -34.75 TSEK CI 95% (-53.7- -15.8) (p<0.001) (Table 7).

Table 7

Gender differences for disposable income.

Variable	Coefficient	95% CI	p-value
(intercept)	201.68	(190.0–213.4)	<0.001
Case: Yes	1.74	(-9.6–13.1)	0.763
Gender: Female	-34.75	(-53.7- -15.8)	<0.001

Mixed linear regression on disposable income showed that females in the whole cohort had a significantly lower disposable income compared with males.

Attention deficit hyperactivity disorders

Fisher’s exact test for prevalence of ADHD showed no significant differences between the exposed and unexposed individuals. For the whole cohort, exposed individuals had a prevalence of 5.2% and unexposed 4.4% (p = 0.4191). As for the subgroup, exposed individuals had a prevalence of 8.9% and unexposed 7.6% (p = 0.5781) (Table 8).

Table 8

ADHD diagnosis.

	Controls	Cases
All	P-value = 0.4191
No diagnosis	4623 (95.6%)	460 (94.8%)
Diagnosis	212 (4.4%)	25 (5.2%)
1995-	P-value = 0.5781
No diagnosis	1010 (92.4%)	102 (91.1%)
Diagnosis	83 (7.6%)	10 (8.9%)

Fisher’s exact test for prevalence of ADHD showed no significant differences between the exposed and unexposed individuals.

Discussion

This cohort registry study examined the association of exposure to anesthesia and abdominal surgery during infancy with cognitive dysfunction from the perspective of educational level, disposable income and prevalence of ADHD in adult and adolescent individuals. The majority of the exposed individuals (70.0%) underwent surgery during the neonatal period (< 44 gestational weeks).

We found that the prevalence of ADHD, highest level of education and annual disposable income did not differ significantly between individuals that underwent anesthesia and abdominal surgery during infancy and their matched controls.

In several animal experiments there are strong evidences that exposure to anesthesia in the neonatal period leads to neuronal cell death in the brain and adverse cognitive development [4–6, 8–10, 32, 33] but the results from studies in humans are still conflicting [1, 2, 14–23, 34–36].

In contrast to our study, several others have reported an association between exposure to anesthesia and surgery with later LD and poor academic performance [14–16, 18, 19]. A major difference from our study is that they investigated children of pre-school and school age. Our study includes adult and adolescent individuals with a mean age of 28 years. Other possible explanations for the unaffected educational level in the exposed individuals in our study might be the results of adequate educational support with special education and remedial teaching in our patients. During normal brain development, 50–70% of the entire neuronal cell population is removed by physiological apoptosis but the brain has a significant capacity to recovery function during childhood [37]. We speculate that this ability of the brain may contribute to the unaffected level of academic performance in the exposed adult and adolescent individuals in our study.

Most previous studies include children exposed to anesthesia and surgery beyond infancy with various diagnoses, different operating times, outcome measures, experimental design and small sample sizes of neonates and infants, making it problematic to compare the results [14-20]. A study including similar diagnoses to the current study found that in early adolescence, children who had undergone neonatal surgery performed less well academically compared with their peers. However, it is hard to draw any conclusions from that study as only 30 patients were included, and it involved 12 different diagnosis [38]. Bartels et al. showed that 1143 monozygotic twin pairs exposed to anesthesia and surgery before the age of three years had at the age of 12 years significantly lower educational achievement scores and more cognitive problems than twins not exposed to anesthesia [20]. However, the unexposed co-twin from discordant pairs did not differ from their exposed co-twin. The authors’ conclusion of the study was that there was no evidence for a causal relationship between anesthesia and later LD. Instead, early anesthesia was a marker of an individual’s vulnerability to later LD. A retrospective cohort study by Wilder et al. of various types of surgical procedures in children before four years of age found that exposure to anesthesia and surgery was a significant risk factor for the later development of LD in children receiving multiple, but not single anesthetics [19]. However, these results may be explained by confounders as children with more serious diagnosis and comorbidities are more likely to need surgery.

Epidemiologic studies are few but those available are in agreement with our findings [21, 39]. A Danish nationwide study by Hansen et al found no evidence that a single, anesthetic exposure in conjunction with hernia repair in infancy reduced academic performance at age 15 or 16 years after adjusting for known confounding factors [21]. However, the study is difficult to compare to ours as the anesthesia/ operating time was shorter than in our study. A more similar recent Swedish nationwide study found that exposure to anesthesia and surgery before the age of four years had a small association with later academic performance or cognitive performance in adolescence on a population level [39]. In the exposed group, 8.7% of the individuals were born preterm compared to 40.6% in our study. They found no reduction in school grades among children with surgery before the age of one.

The median annual disposable income did not differ significantly between exposed and unexposed individuals in our study, which is supported by a Swedish nationwide population-based cohort study of 389 patients with Hirschsprung’s disease [40]. Neither the individual disposable income nor the highest educational level differed between patients with Hirschsprung’s disease and controls [40]. Another Swedish registry study including 522,310 individuals born in 1973–1979 reported that preterm birth was associated with a lower chance of completing a university education and a lower net salary [41]. With the matching of controls for gestational week this potential confounder was omitted in our study. To further decrease the risk of confounders, we also matched for age and gender and excluded individuals with chromosomal aberrations. There may be other important differences between the groups that were not measured such as socioeconomic status of the families or baseline health characteristics. The matching could have been made with more potential confounders but it would decrease the number of individuals in the control group. Matching by gestational age had higher priority in our study. We found that exposed as well as unexposed females had significantly lower disposable incomes compared to males. The gender wage gap is well known and has been described in previous studies [42, 43].

The prevalence of ADHD was not significantly increased in exposed individuals in our study. A retrospective study by Sprung et al. including individuals that underwent surgery before the age of two could not find an increased level of ADHD at age 19 following one surgical procedure [17]. However, with repeated exposures to general anesthesia there was an increased risk of development of ADHD later in life. A more recent retrospective study including 573 children exposed to anesthesia and surgery prior to the age of three found that multiple, but not single, exposures were associated with an increased frequency of both LD and ADHD [44]. In recent years there seems to be an increased awareness of ADHD. A Swedish registry study showed that the number of individuals diagnosed with ADHD is increasing. In 2006 the prevalence for the whole population was 1.1 per 1000 persons and in 2011, 4.8 per 1000 persons, the highest increase was seen in females as well as in ages 22 years and above [45]. In 2011, 57.8% of the individuals with an ADHD diagnosis were under the age of 22 [45]. In our study, since the outpatient register started in 2001, we carried out two different analyses for the prevalence of ADHD. We did this since we believed that ADHD would be underestimated for both exposed and unexposed individuals even though the relative difference between the groups was believed to be correct. The subgroup analysis included individuals born in 1995 and later. By doing this we could find an increase of ADHD in both groups but still no significant difference was seen between the groups.

The Swedish National Patient Register is a valuable source for register research, the validity is high but not for all diagnoses [30]. Strengths of the present study were that the diagnoses and exposure were ensured by previous review of the patients’ charts and that the matched controls were drawn at random by the National Board of Health and Welfare, thus reducing the risk of selection bias. For the unexposed controls, we used codes for surgical procedures rather than ICD codes for diagnoses to decrease the risk of misclassification. Other strengths are the high number of included neonates and infants that underwent anesthesia and abdominal surgery with a long follow-up time and data on the duration of surgery.

Limitations of this study were that the outcome measure of educational level may not detect subtle effects from anesthesia and surgery in early childhood. Furthermore, various diagnoses among included patients with different operating times may challenge the interpretation of the results. Another limitation to the study was that 15 controls were missing due to invalid identification numbers. However it is unlikely that this would markedly influence the results. As the majority of neonates were exposed at a later gestational age (>33 weeks) the results regarding exposure at much earlier gestational age might be different and can not be generalized.

Conclusions

This study shows that exposure to anesthesia and abdominal surgery during infancy is not associated with cognitive dysfunction from the perspective of educational level, disposable income and ADHD in adult and adolescent individuals, despite the fact that the majority of surgeries (70%) were in neonates. It is important to identify pediatric surgical diagnoses of high risk of cognitive dysfunction to arrange for early educational support. This knowledge is also important to professionals and caregivers of these patients. Although our results are reassuring, they cannot exclude more subtle effects in cognitive function. Future studies with larger cohorts of individuals that have undergone surgery at earlier gestational ages are needed.

Excluding codes for abdominal surgery.

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16 Jul 2020

PONE-D-20-10556

Exposure to anesthesia and abdominal surgery during infancy is not associated with cognitive dysfunction later in life

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Reviewer #1: This is case control study to evaluate whether exposure to anesthesia and abdominal surgery during infancy was associated with attainment in educational level and income in adult lives. The strengths of the study is that a uniform type of surgery was performed. However, although the study adds information to this literature, the title of the paper is mis-leading as the study is mis-leading and should be revised to properly reflect what was done.

There are a few areas that need further discussion:

1. The study was conducted over a long period of time. Whether changing practice (such as surgical approaches or anesthetic management) might have affected the outcomes was not discussed.

2. Measurement of ADHD - it is not clear whether it was well captured, as likely not all patients with ADHD sought medical consultation.

3. Age of exposure – it appears that the majority of the subjects were exposed to anesthesia and surgery at a later gestational age (>33 weeks). Whether these results can be generalized to those exposure at much earlier gestational age need to be included in the discussion.

4. Similarly, the number of repeated exposures to anesthesia and surgery was also not high. It is unclear whether the authors only measured repeated abdominal surgery, and not other type of surgery.

Reviewer #2: This is an interesting manuscript evaluating a number of different outcomes in children exposed to anesthesia for abdominal surgery.

Specific comments:

Page 4, Line 73: While some studies have found a near doubling of ADHD, this was only found in the children with multiple exposures. In the same study by Sprung et al., the HR for a single exposure was 1.18, which was not statistically significant. In more recent studies published in Anesth Analg. by Ing et al. the HRs for an increased risk of ADHD was found to be between 1.25 and 1.37.

Page 7, Line 131: It would be helpful to know how many total patients were in the Swedish Medical Birth Register and how they were drawn at random based on sex, age, and gestational week. Were they manually selected by one of the researchers or was there a computer program that would randomly select from anywhere in the database?

Page 7, Line 133: Is it possible that the controls had surgery after age 1 year old? Therefore, if anesthetics had an adverse effect in children between ages 1 and 3 and the controls included children exposed at those ages, is it possible that these results may be biased towards a null effect?

Page 7, Line 147: Is there a reason why the 1995 cutoff was chosen?

Page 7, line 148: It would be helpful to explain why mixed models are needed for these regression analyses. This data does not seem to be hierarchical in nature.

Page 8, Line 157: If there were 485 cases and it is 1:10 matching, shouldn’t there be 4850 controls instead of 4835?

Figure 1: This flow diagram would be more informative if it also included the selection of the controls.

Table 1: It may be more informative to show the demographic characteristics of the 485 patients included in the study. I believe the 523 patients includes patients who were excluded due to chromosomal aberrations. If there was missing gestational age data in 10 patients, how was the matching done? Was matching done on only age and sex for those patients? In the children with multiple procedures (2 or 3 or more) were these all procedures done before age 1, or at any time during their life? It would also be helpful to note the demographic characteristics in the matched controls, which should confirm exact matching and give information on whether they had surgery or anesthesia later on in their life.

Table 2: It may be more informative to show the surgical characteristics of the 485 patients included in the study.

Table 3: If there are n=485 exposed children and n=4835 matched controls, why is there only data for n=454 exposed children and n=4221 controls? Is there missing outcome data for the cases and controls?

Table 4: It would be helpful to define IRR.

Table 7: If there are n=485 exposed children and n=4835 matched controls, why is there only data for n=431 exposed children yet there is data for all n=4835 controls? If this is missing diagnosis data, is there a reason why it is only missing in the exposed children and not the matching controls?

Page 14, Line 279: Given that the incidence of ADHD diagnosis has increased over time, it would be interesting to know if the birth years of the exposed and matched controls were similar. If they were born in different eras, it may bias the results.

Page 15, Line 298: While the exposed children and matched controls were matched on age, sex, and gestational week, is it possible that there may be other important differences between the groups that were not measured such as socioeconomic status of the families or baseline health characteristics?

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17 Aug 2020

Dear Academic Editor.

Thank you for your valuable comments regarding the manuscript. We have taken careful consideration of all the comments and the manuscript has been changed according to yours and the reviewers suggestions. We think that the manuscript has improved and hope that it can be accepted for publication in PLOS ONE. Please see our response on the comments listed below.

Our manuscript meets PLOS ONE's style requirements, including those for file naming. We have rephrased and omitted some minor occurrence of overlapping text with a previous publication and we have made data underlying the findings in the manuscript fully available as supporting information.

Sincerely

Cecilia Arana Håkanson, corresponding author

Department of Women's and Children's Health, Uppsala University.

e-mail: cecilia.arana_hakanson@kbh.uu.se

Response to reviewers

Reviewer #1: This is case control study to evaluate whether exposure to anesthesia and abdominal surgery during infancy was associated with attainment in educational level and income in adult lives. The strengths of the study is that a uniform type of surgery was performed. However, although the study adds information to this literature, the title of the paper is mis-leading as the study is mis-leading and should be revised to properly reflect what was done.

Response: We have changed the title to “Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after abdominal surgery during infancy”

There are a few areas that need further discussion:

1. The study was conducted over a long period of time. Whether changing practice (such as surgical approaches or anesthetic management) might have affected the outcomes was not discussed.

Response: The study was conducted over a long period of time and both surgical approaches and anesthetic management have changed over that period. However, our study uses a case-control approach with the individuals being exposed to abdominal surgery during infancy and the controls not. The cases are not compared to each other but only to their controls matched on sex, age and gestational week. Therefore, these changes should not affect the outcome.

2. Measurement of ADHD - it is not clear whether it was well captured, as likely not all patients with ADHD sought medical consultation.

Response: The measurement of ADHD was drawn from the Swedish National Patient Register, hence we do miss individuals that does not seek medical consultation. However, we believe that there should not be a difference in the pattern of seeking medical consultation between the cases and their controls.

3. Age of exposure – it appears that the majority of the subjects were exposed to anesthesia and surgery at a later gestational age (>33 weeks). Whether these results can be generalized to those exposure at much earlier gestational age need to be included in the discussion.

Response: We have in the discussion page 16, lines 312-314 added “As the majority of neonates were exposed at a later gestational age (>33 weeks) the results regarding exposure at much earlier gestational age might be different and can not be generalized”.

4. Similarly, the number of repeated exposures to anesthesia and surgery was also not high. It is unclear whether the authors only measured repeated abdominal surgery, and not other type of surgery.

Response: Only exposure to abdominal surgery during infancy were included and no other type of surgery or other procedures requiring anaesthesia. This information is added in Study Cohort page 6 ,lines 122-123.

Reviewer #2: This is an interesting manuscript evaluating a number of different outcomes in children exposed to anesthesia for abdominal surgery.

Specific comments:

Page 4, Line 73: While some studies have found a near doubling of ADHD, this was only found in the children with multiple exposures. In the same study by Sprung et al., the HR for a single exposure was 1.18, which was not statistically significant. In more recent studies published in Anesth Analg. by Ing et al. the HRs for an increased risk of ADHD was found to be between 1.25 and 1.37.

Response: Page 4, lines 76-78 we have added repeated to the sentence ”Previous studies have found a doubling of the incidence of learning disabilities (LD) and attention deficit hyperactivity disorders (ADHD) after repeated exposure to general anesthesia before age 2-4 years (1-3). We also added this sentence: ”In a more recent study, an increased risk of ADHD was observed in children under age 5 with a single exposure to minor surgery requiring anesthesia” (4).

Page 7, Line 131: It would be helpful to know how many total patients were in the Swedish Medical Birth Register and how they were drawn at random based on sex, age, and gestational week. Were they manually selected by one of the researchers or was there a computer program that would randomly select from anywhere in the database?

Response: The Swedish Medical Birth Register includes 98% of all births in Sweden since 1973. Register data is protected by strict confidentiality but can be made available for research after a special application following ethical approval as in our study. The data withdrawal and the random selection were made by statisticians employed at the Register service unit using computer programs.

Page 7, Line 133: Is it possible that the controls had surgery after age 1 year old? Therefore, if anesthetics had an adverse effect in children between ages 1 and 3 and the controls included children exposed at those ages, is it possible that these results may be biased towards a null effect?

Response: Yes, there is a possibility that the controls and their cases had surgery and/or anesthetics after the age of one year. However we set the exposure of the cases to abdominal surgery before the age of one. Since the 4835 controls were drawn at random we believe that the group should reflect the common exposure to surgery and/or anesthetics in the Swedish population in general.

Page 7, Line 147: Is there a reason why the 1995 cutoff was chosen?

Response: The diagnose of ADHD is mainly found in the outpatient registers and this register started in 2001. The diagnose of ADHD is hard to confirm in very young children. With the cutoff 1995 the individuals were 6 years or older and more likely to have the diagnose code for ADHD in the register.

Page 7, line 148: It would be helpful to explain why mixed models are needed for these regression analyses. This data does not seem to be hierarchical in nature.

Response: In order to be able to take the matching into account a mixed ordinal regression was estimated. Taking specific care by treating a case and its matched controls as a cluster would assist in preventing that the results could be biased by for example unequal number of controls between cases due to missing data. We have added this information under statistics pages 7-8, lines 155-159.

Page 8, Line 157: If there were 485 cases and it is 1:10 matching, shouldn’t there be 4850 controls instead of 4835?

Response: A very valid comment. The control group was drawn at random by statisticians at the Register service unit. When recieving the data from the registers the personal identification number was replaced by a serial number due to confidentiality. In the control group 15 individuals had the same serial number due to inaccurate personal identification numbers, therefore no data would be found on these individuals. 12 were matched to different cases and 3 were matched to the same case. Please see added table in supporting information, S2.

Figure 1: This flow diagram would be more informative if it also included the selection of the controls.

Response: We have changed the flow diagram to include selection of the controls.

Table 1: It may be more informative to show the demographic characteristics of the 485 patients included in the study. I believe the 523 patients includes patients who were excluded due to chromosomal aberrations. If there was missing gestational age data in 10 patients, how was the matching done? Was matching done on only age and sex for those patients? In the children with multiple procedures (2 or 3 or more) were these all procedures done before age 1, or at any time during their life? It would also be helpful to note the demographic characteristics in the matched controls, which should confirm exact matching and give information on whether they had surgery or anesthesia later on in their life.

Response: Correct, the 523 patients include the excluded patients. We agree that it would be more informative with the demographic data on only the included 485 individuals. Due to confidentiality in the registers we do not have the information on which ones that were excluded and therefore we were not able to only show the demographic characteristics of only the 485 individuals. The missing gestational age in 10 individuals were when we manually collected the data from the local patients charts at the hospital. The matching of controls was made by the information in the Swedish Birth Register connected to the personal identification code of 10 digits that all citizens are given at birth and not from the data that were manually collected. All controls were matched on age, sex and gestational age (week). This study was based on a cohort from our previous study of 898 patients that had undergone laparotomy during the first year of life between the years 1976 tom 2011. 523 patients matched the criteria of being aged over 16 years at study start. The number of surgeries were the total number of surgeries during the follow up period of the previous study with a median follow up of 14.7 years (0.0 – 36.0). We did not collect register data on whether the controls were exposed to surgery and/or anesthesia later in life. In the children with multiple procedures (2 or 3 or more) only the first procedure had to be done before age 1. Most reoperations were done close in time from the primary surgery e.g 70% undergoing laparotomy for small bowel obstruction occurred within 2 years of the primary surgery.

Table 2: It may be more informative to show the surgical characteristics of the 485 patients included in the study.

Response: We agree that it would be more informative with the surgical characteristics on only the included 485 individuals. Due to confidentiality in the registers we do not have the information on which ones that were excluded and therefore we were not able to only show the data of the 485 individuals.

Table 3: If there are n=485 exposed children and n=4835 matched controls, why is there only data for n=454 exposed children and n=4221 controls? Is there missing outcome data for the cases and controls?

Response:

There are 31 cases and 399 controls that miss the outcome of highest educational level. With a case missing this outcome also its controls were excluded in the analysis. Please see added table in supporting information, S2.

Table 4: It would be helpful to define IRR.

Response: IRR, incidence rate ratio shows the probability of having a higher level of education. Added in the statistics section page 7,lines 153-154.

Table 7: If there are n=485 exposed children and n=4835 matched controls, why is there only data for n=431 exposed children yet there is data for all n=4835 controls? If this is missing diagnosis data, is there a reason why it is only missing in the exposed children and not the matching controls?

Response: Thank you for your careful review, we made a mistake here. The right number of cases is 460 (and not 406) with no ADHD diagnosis and 25 with the diagnosis. We must have mixed up the numbers when editing the table. Now corrected in the Table 7.

Page 14, Line 279: Given that the incidence of ADHD diagnosis has increased over time, it would be interesting to know if the birth years of the exposed and matched controls were similar. If they were born in different eras, it may bias the results.

Response: The matching of age was made by the same year of birth for cases and controls so this would not be a source of bias.

Page 15, Line 298: While the exposed children and matched controls were matched on age, sex, and gestational week, is it possible that there may be other important differences between the groups that were not measured such as socioeconomic status of the families or baseline health characteristics?

Response: We are aware that there may be other important differences between the groups that were not measured such as socioeconomic status of the families or baseline health characteristics. The matching could have been made with more potential confounders but it would decrease the number of individuals in the control group. Matching by gestational age had higher priority in our study. We have added this section in discussion page 14, lines 272-276.

1. Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanic K, et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc. 2012;87(2):120-9.

2. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053-61.

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

4. Ing C, Sun M, Olfson M, DiMaggio CJ, Sun LS, Wall MM, et al. Age at Exposure to Surgery and Anesthesia in Children and Association With Mental Disorder Diagnosis. Anesth Analg. 2017;125(6):1988-98.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

8 Sep 2020

PONE-D-20-10556R1

Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy

PLOS ONE

Dear Dr. Arana Håkanson,

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

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Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors did a nice job answering the queries and comment. There are however a few additional comments and follow-up concerns based on the author’s responses.

Page 8, line 162: If there is inaccuracy in the ID numbers received from the Register service and those controls had to be excluded, that is a valid reason why there are fewer than 10 controls for each case. This also justifies why it would be important to analyze these groups in clusters since there are missing patients from some of the matched sets. It is unlikely that this would markedly influence the results, but this should however be disclosed and explained to the reader in the Results and Discussion.

Figure 1b: If possible, it would be preferable to combine both cases and controls into one flow diagram in order for the reader to appreciate where the cases and matched controls originated from. From the new diagram it appears that the exclusion criteria of no chromosomal aberrations was applied to the cases, but not to the control patients. However in the text (Page 7, line 143) it seems that this exclusion criteria was made. It would be helpful to include this in the flow diagram so the readers can see that the same exclusions were made to both cohorts.

Table 1: Thank you for the clarification. It makes sense that if the authors cannot differentiate the patients, it would be impossible to give the patients characteristics for only the 485 included individuals. However, this should be disclosed in a footnote for this demographic table, that the table includes data for 38 patients who were ultimately excluded from analysis due to chromosomal anomalies. Otherwise it would be confusing to the reader why the numbers do not match up.

Page 9, line 172 and Table 1: It should also be mentioned that the additional surgeries did not necessarily occur during the study period, and could have occurred at any time during the follow-up period which was between 0 and 36 years of age. Otherwise it looks like your exposure cohort had a multiple surgery rate of nearly 50% at under 1 year of age.

Table 2: It should also be disclosed that this table of procedures and operating room times included procedures for 38 patients who were excluded from analysis as a footnote in this table.

Page 7, line 140: The authors mention that they matched on age, sex, and gestational week. In their response to a reviewer comment, they mention that they also match on year of birth to ensure that children were born in the same era. If year of birth is an additional matching criteria, it would be helpful to mention this in the text. Also if the authors have data on these variables for the cases and controls including the year of birth, it may be helpful to add this data to the Table 1 patient characteristics table.

Ideally it would be helpful to display the characteristics for the controls in a patient characteristics table. Is that possible, or do the authors not have any data for the controls other than ID numbers to match to their cases? Also It seems that authors cannot identify which cases got matched since they were unable to display the characteristics of which of the 523 cases were chosen and which were excluded. I believe the Swedish Birth Register data has been widely used and is likely to be reliable. However, these aspects of the study should likely be mentioned if this is the case.

Page 7, line 155: If a mixed ordinal regression was used to take into account matched sets and missing controls in the primary analysis, shouldn’t a similar analysis be used in the ADHD analysis instead of Fisher’s exact tests since the title of the study is now the evaluation of ADHD?

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Reviewer #2: No

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25 Sep 2020

Review Comments to the Author

Reviewer #2: The authors did a nice job answering the queries and comment. There are however a few additional comments and follow-up concerns based on the author’s responses.

Page 8, line 162: If there is inaccuracy in the ID numbers received from the Register service and those controls had to be excluded, that is a valid reason why there are fewer than 10 controls for each case. This also justifies why it would be important to analyze these groups in clusters since there are missing patients from some of the matched sets. It is unlikely that this would markedly influence the results, but this should however be disclosed and explained to the reader in the Results and Discussion.

Response: We have added this extra information plus an explaining table (Table 1) in Results page 8 lines 164-166 and in the discussion section page 16 lines 319-321.

Figure 1b: If possible, it would be preferable to combine both cases and controls into one flow diagram in order for the reader to appreciate where the cases and matched controls originated from. From the new diagram it appears that the exclusion criteria of no chromosomal aberrations was applied to the cases, but not to the control patients. However in the text (Page 7, line 143) it seems that this exclusion criteria was made. It would be helpful to include this in the flow diagram so the readers can see that the same exclusions were made to both cohorts.

Response: Thank you for this input. We have now made a new flow diagram which replaces Fig 1a and 1b.

Table 1: Thank you for the clarification. It makes sense that if the authors cannot differentiate the patients, it would be impossible to give the patients characteristics for only the985 included individuals. However, this should be disclosed in a footnote for this demographic table, that the table includes data for 38 patients who were ultimately excluded from analysis due to chromosomal anomalies. Otherwise it would be confusing to the reader why the numbers do not match up.

Response: The information that it includes individuals that later were excluded for chromosomal aberration is already in the table. However, we now added the number, 38, to the table footnote to make it clearer to the reader plus added an extra asterix to “highlight the information”.

Page 9, line 172 and Table 1: It should also be mentioned that the additional surgeries did not necessarily occur during the study period, and could have occurred at any time during the follow-up period which was between 0 and 36 years of age. Otherwise it looks like your exposure cohort had a multiple surgery rate of nearly 50% at under 1 year of age.

Response: We have added this information to the table as a footnote as well as on page 9 line 179.

Table 2: It should also be disclosed that this table of procedures and operating room times included procedures for 38 patients who were excluded from analysis as a footnote in this table.

Response: We have added this information to the table as a footnote.

Page 7, line 140: The authors mention that they matched on age, sex, and gestational week. In their response to a reviewer comment, they mention that they also match on year of birth to ensure that children were born in the same era. If year of birth is an additional matching criteria, it would be helpful to mention this in the text. Also if the authors have data on these variables for the cases and controls including the year of birth, it may be helpful to add this data to the Table 1 patient characteristics table.

Ideally it would be helpful to display the characteristics for the controls in a patient characteristics table. Is that possible, or do the authors not have any data for the controls other than ID numbers to match to their cases? Also It seems that authors cannot identify which cases got matched since they were unable to display the characteristics of which of the 523 cases were chosen and which were excluded. I believe the Swedish Birth Register data has been widely used and is likely to be reliable. However, these aspects of the study should likely be mentioned if this is the case.

Response: The year of birth is not an additional matching criteria, it is the same criteria as the criteria for matching on age. We have also added information on median age and median gestational week of the cases and control group to page 8 lines 167-169.

Page 7, line 155: If a mixed ordinal regression was used to take into account matched sets and missing controls in the primary analysis, shouldn’t a similar analysis be used in the ADHD analysis instead of Fisher’s exact tests since the title of the study is now the evaluation of ADHD?

Response: In theory it would be possible to analyze ADHD using a mixed logistic regression, however limitations in the data causes issues with convergence when estimating the model. The issue is caused due to the few number of ADHD diagnoses in the group of cases.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

6 Oct 2020

Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy

PONE-D-20-10556R2

Dear Dr. Arana Håkanson,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Antonio Palazón-Bru, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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Reviewer #2: No

12 Oct 2020

PONE-D-20-10556R2

Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy

Dear Dr. Arana Håkanson:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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