ADC-FNN Online First, published on August 31, 2016 as 10.

1136/archdischild-2015-309976
Original article

Developmental problems in patients with

oesophageal atresia: a longitudinal follow-up study
Wouter J Harmsen,1 Femke J Aarsen,1 Monique H M van der Cammen-van Zijp,1
Joost M van Rosmalen,2 Rene M H Wijnen,1 Dick Tibboel,1 Hanneke IJsselstijn1
1
Intensive Care and ABSTRACT
Department of Pediatric Objective To longitudinally evaluate motor What is already known on this topic?
Surgery, Erasmus MC—Sophia
Children’s Hospital, Rotterdam, development and predictive factors in school-age
The Netherlands children with oesophageal atresia.
2 ▸ Children with oesophageal atresia are at risk of
Department of Biostatistics, Design Cohort study with prospective longitudinal
Erasmus MC, Rotterdam, long-term morbidity.
follow-up.
The Netherlands ▸ Mental development of oesophageal atresia
Setting Outpatient clinic of a tertiary university
patients is normal in infancy and at preschool
Correspondence to paediatric hospital.
age.
Dr Hanneke IJsselstijn, Patients Children with oesophageal atresia born
Intensive Care and Department
▸ Gross motor difficulties have been reported in
between January 1999 and May 2006 were assessed at
of Pediatric Surgery, Erasmus 5-year-old patients with oesophageal atresia.
5 and 8 years of age.
MC, Sophia Children’s
Hospital, Rotterdam 3015 GJ, Interventions None.
The Netherlands; Main outcome Motor performance was evaluated at
[email protected] 5 and 8 years using the Movement Assessment Battery
What this study adds?
for Children (M-ABC). Additionally, we evaluated
Received 16 October 2015
Revised 5 August 2016
perinatal characteristics, duration of anaesthesia within
Accepted 8 August 2016 the first 24 months, socioeconomic status, sports ▸ Gross motor problems persist in school-age
participation and school performance at time of follow- patients with oesophageal atresia.
up and intelligence and sustained attention at the age ▸ Oesophageal atresia patients have normal
of 8 years. intelligence, but problems with sustained
Results In 5-year-olds (n=54), the mean (SD) z-score attention.
M-ABC was slightly, but significantly lower than age- ▸ Sustained attention problems and duration of
predicted normative values (−0.75 (0.83), p<0.001). In general anaesthetic procedures were negatively
8-year-olds (n=49), the z-score M-ABC was −0.53 associated with motor performance; sports
(0.91) ( p<0.001), intelligence was normal, but sustained participation was positively associated with
attention was impaired: z-score speed (−1.50 (1.73)) motor performance.
and raw score attentional fluctuation (3.99 (1.90)) (both
p<0.001). Motor problems mainly concerned gross
motor performance. Duration of anaesthesia and
sustained attention were negatively associated with previously showed normal mental development but
motor development; sports participation was positively impaired motor outcome in 2-year-old3 and gross
associated. motor problems in 5-year-old children with OA.5
Conclusions Longer duration of anaesthesia and The above studies reported negative associations
sustained attention problems were associated with gross between motor performance and duration of hospi-
motor problems in school-age patients with oesophageal talisation, number of surgical interventions and
atresia. Parental awareness of risks for motor problems associated congenital anomalies.3–5
may provide the opportunity to offer timely intervention. As respiratory and gastrointestinal morbidity in
children with OA improve with age,6 we hypothe-
sised that motor problems at a young age will have
Oesophageal atresia (OA) is a major congenital ana- decreased at school age. The aim of the present
tomical anomaly characterised by a discontinuity of study was to longitudinally evaluate motor develop-
the oesophagus. It affects one in 2500 newborns ment in OA at the ages of 5 and 8 years and to
and requires early neonatal surgery.1 Advances in identify associated factors.
surgical and neonatal management have progres-
sively increased survival rates; in the absence of risk METHOD
factors like extreme prematurity or major cardiac Participants
anomalies survival is nearly 100%.1 Consequently, All newborns diagnosed with OA between January
attention has shifted from mortality towards the 1999 and May 2006 and subsequently treated at
To cite: Harmsen WJ, evaluation of long-term morbidity. the intensive care unit of a level-III university hos-
Aarsen FJ, van der Cammen- There is a growing number of studies evaluating pital, that is, the Erasmus MC–Sophia Children’s
van Zijp MHM, et al. Arch motor and cognitive development in children who
Dis Child Fetal Neonatal Ed
Hospital, were eligible. Since 1999, children born
Published Online First:
survived invasive neonatal surgery.2 Motor pro- with major anatomical congenital anomalies and
[please include Day Month blems and cognitive deficits have been reported in their families are followed by a multidisciplinary
Year] doi:10.1136/ children with congenital anatomical anomalies, team.3 5 7–9 The Board of the Medical Ethics
archdischild-2015-309976 including children with OA.3 4 Our group Committee of the Erasmus MC stated that the rules
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976 F1
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
 Original article

laid down in the Dutch Medical Research Involving Human test for differences in neurodevelopmental outcome across SES
Subjects Act do not apply for the present study. All parents were categories. To compare data with reference values, paired
informed that data were used for research purposes. samples t-tests were used for continuous data and χ2 tests for
categorical data. To test for differences between 5 and 8 years,
Procedures linear mixed models were used for continuous data and
The present study is part of a structured follow-up programme McNemar’s tests for categorical data. Only the data of children
for children born with OA with nine standardised assessments tested at both ages were used in the McNemar’s tests.
from the age of 6 months until the age of 17 years.3 5 7–9 The To combine the outcome scores of the M-ABC-I and
following data were collected: gender, gestational age, birth M-ABC-II, percentile scores were transformed into z-scores
weight, ethnicity, type of OA, the presence and type of asso- using probit transformations (ie, an inverse normal transform-
ciated congenital anomalies, genetic syndromes, sepsis, duration ation). Motor performance changes over time were investigated
of ventilatory support, duration of initial hospitalisation, dur- in longitudinal analyses using linear mixed models with z-score
ation of parenteral nutrition, antireflux surgery, number of pro- M-ABC as dependent variable (with mean=0 and SD=1, refer-
cedures under general anaesthesia within the first 24 months of ence population). In each model, the independent variables
life, total duration of anaesthetic exposure within the first were age and one of the following predictors: birth weight, the
24 months of life, and hospital admissions with duration of hos- presence of associated congenital anomalies, ventilatory
pitalisation within the first 5 years. Longitudinal follow-up data support, sepsis, duration of parenteral nutrition, duration of
are prospectively collected at 5 and 8 years of age. Motor devel- general anaesthetic events and duration of hospitalisation.
opment was evaluated by an experienced paediatric physiother- A random intercept was included to account for the within-
apist. Information about education, sports participation (yes/no) subject correlations. Linear mixed models allow subjects for
and physical therapeutic support (yes/no) was recorded. who some data are missing to be included in the analyses, pro-
Psychological assessment at 8 years was performed by an experi- vided that the data are missing at random, as explained previ-
enced paediatric psychologist. We classified socio-economic ously.7 Correlation of motor performance between ages 5 and
status (SES) as low, middle or high based on the highest degree 8 years was calculated using the intraclass correlation coefficient.
of maternal education.10 With the exception of the attention fluctuations score, intelli-
gence and sustained attention scores were converted into
PRIMARY OUTCOME z-scores using normative data. The raw score for attention fluc-
Motor development tuations was compared with the mean raw score (ie, 2.3).
Motor skills were examined with the Movement Assessment A higher raw score means more attentional fluctuations. A
Battery for Children (M-ABC).11 12 The M-ABC consists of sep- paired samples t-test was used to determine whether the data of
arate age-related item bands with increasing difficulty as children the intelligence tests had the same mean score and could be
get older. Each band contains eight items, which evaluate three pooled.
domains: manual dexterity (3 items), ball (2 items) and balance Correlation coefficients between z-score M-ABC at the age of
skills (3 items). Until October 2012, we used the first edition of 8 years and sports participation and sustained attention were
the M-ABC, but in November 2012, we switched to the second calculated. Furthermore, correlation coefficients between partici-
edition. Both editions contain similar content and are assumed pants’ characteristics and sustained attention were calculated.
to be comparable.13 M-ABC percentile scores are divided Pearson’s correlation coefficients were calculated for continuous
into three categories, namely normal, borderline and motor data and Spearman’s for dichotomous data. All statistical tests
problem. were two sided; significance level was p<0.05. Statistical ana-
lyses were performed using IBM-SPSS-Statistics-21 (SPSS,
SECONDARY OUTCOMES Chicago, Illinois, USA).
Intelligence
For children born after December 2001, the Dutch version of RESULTS
the Wechsler Intelligence Scale for Children (WISC-III-NL) was Of the 78 newborns with OA admitted between February 1999
used to assess full-scale IQ (FSIQ), total verbal IQ (TVIQ) and and August 2006, seven died (9.0%). The parents of seven chil-
total performance IQ (TPIQ).13 For children born earlier, the dren refused to participate (9.0%) and three children were lost
short version of the Revised Amsterdam Intelligence Test to follow-up (3.8%). One child had been operated elsewhere
(RAKIT)14 15 and the short version of the TVIQ scale of the and was first seen at 8 years. Four children with intellectual dis-
WISC-III-NL were used. For both tests, the IQ has a mean (SD) ability ((genetic syndrome (n=3) and unknown cause (n=1))
of 100 (15) in the normative population. could not be tested. Thus, 58 children were included in the ana-
lysis (figure 1).
Sustained attention Perinatal characteristics are shown in table 1. Surgical proce-
Attention was assessed with the Dot cancellation test (Bourdon- dures included thoracotomy for oesophageal correction (all
Vos test). This test is a continuous performance paper and patients), cardiac surgery (n=3) and Nissen fundoplication
pencil test that measures sustained attention in terms of speed (n=14).
and attentional fluctuations. Speed and attentional fluctuations More children received physiotherapeutic support at the age
are continuous variables, respectively, expressed in z-score and of 5 than at the age of 8 years (25% vs 10%, respectively;
raw score (higher score indicating more fluctuations).16 p<0.001). Participation in sports activities did no differ
between 5-year-olds and 8-year-olds (55% vs 73%, respectively;
Statistical analysis p=0.117).
Data are presented as mean (SD) unless otherwise indicated. Five 8-year-olds (10.2%) followed special education, 10
To compare data of participants and non-participants, regular education with remedial teaching (20.4%) and 34
Mann-Whitney U tests were used for continuous data and χ2 regular education without remedial teaching (69.4%) (χ2=2.86,
tests for categorical data. The Kruskal-Wallis test was used to p=0.239 compared with age peers in the general Dutch
F2 Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
 Original article

Figure 1 Flow chart follow-up programme. OA, oesophagus atresia; ICU, intensive care unit; M-ABC, Movement Assessment Battery for Children.

Table 1 Characteristics of participating and non-participating children

Participants Non-participants
n=58 N=10 p Value

Boys, n (%) 34 (59%) 6 (60%) 0.610

Gestational age (weeks), median (ranges) 39 (29 to 42) 39 (31 to 41) 0.932
Birth weight (gram), median (ranges) 2830 (750 to 4505) 2990 (1780 to 3775) 0.476
Dutch ethnicity, n (%) 53 (91%) 7 (70%) 0.088
OA type C, n (%) 53 (91%) 10 (100%) 0.440
Cardiac anomaly, n (%)* 7 (12%) 3 (30%) 0.158
VACTER-L, n (%) 3 (5%) 2 (20%) 0.153
Sepsis during first hospital admission, n (%)† 11 (19%) 4 (40%) 0.157
Duration of initial hospital stay, days, median (range) 26 (9 to 196) 35 (13 to 182) 0.567
Ventilatory support, days, median (range) 2 (1 to 44) 2 (1 to 42) 0.992
Duration of parenteral nutrition, days, median (range) 7 (0 to 68) 6 (4 to 22) 0.589
Nissen fundoplication, n (%) 14 (24%) 2 (20%) 0.567
Duration of anaesthetic exposure within the first 24 months of life, hours, median (range) 7 (2 to 38) 7 (3 to 24) 0.897
General anaesthetic events within the first 24 months of life, median (range)‡ 4 (1 to 23) 3 (2 to 19) 0.818
Hospital admissions within the first 5 years of life, median (range) 4 (1 to 20) 4 (2 to 15) 0.702
Duration of hospital stay within the first 5 years of life in days, median (range) 55 (11 to 469) 42 (19 to 217) 0.890
*Cardiac anomalies included: ventricular septal defect (n=3), atrium septal defect with ventricular septal defect (n=1), coarctation of the aorta (n=2) and patent ductus ateriosus with
ventricular septal defect (n=1). Surgical correction was performed in three patients.
†Sepsis was indicated based on positive blood cultures.
‡General anaesthetic events included oesophageal dilatations performed on clinical indication.
OA, oesophageal atresia; VACTER-L, vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies, and limb abnormalities.

population) special education: 5%; regular education with extra Motor development
support: 20%; and regular education: 75%).17 Forty-five children (78%) were tested with the M-ABC at both
SES was determined for the parents of 56 participants (97%) ages (figure 1).
and classified as low in 12.5% (n=7), middle in 50% (n=28) At 5 years, mean z-score M-ABC was lower than normative
and high in 37.5% (n=21). Neurodevelopmental outcome was values (z-score M-ABC=−0.75, n=54, p<0.001). Sixty-five per
not different across the SES categories for: motor performance cent had an M-ABC score within the normal range, which per-
at 5 years (χ2=1.201, p=0.549) and 8 years (χ2=0.393, centage is lower than that in the reference population (85%)
p=0.822), IQ (χ2=3.215, p=0.200) and sustained attention (figure 2). Problems were observed mainly for the gross motor
(speed: χ2=0.021, p=0.990; fluctuations χ2=0.694, p=0.707). abilities, such as ball skills (48% normal) and balance skills
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976 F3
 Original article

Figure 2 Motor developmental

outcome in 5-year-old and 8-year-old
children treated for oesophagus
atresia. Total Movement Assessment
Battery for Children score and the
separate domain scores: manual
dexterity, ball and balance skills. In
white, we indicate the children with
normal motor development, grey
represents the children with borderline
motor development and in dark grey
we show children with a definite
motor function problem. Number of
categorised children are indicated in
the bars. The first bar indicates motor
developmental outcome in the Dutch
reference population.

Table 2 Associations with motor developmental outcome Table 3 Associations with motor developmental outcome at the
Z-score M-ABC age of 8 years

Parameter Z-score M-ABC at 8 years

Predictor Estimate p Value 95% CI r p Value

Birth weight (kilogram) 0.155 0.268 −0.123 to 0.432 Sports participation (yes/no) 0.440 0.002
The presence of other associated −0.388 0.153 −0.924 to 0.149 Sustained attention fluctuations† −0.360 0.021
CA (yes/no)
Sustained attention speed (z-score) 0.318 0.043
Ventilatory support, in days −0.002 0.849 −0.028 to 0.023
Pearson’s correlation coefficients were calculated for continuous data and Spearman’s
Duration of anaesthetic exposure −0.029 0.018 −0.054 to −0.005
correlation coefficients for dichotomous data.
within the first 24 months of life †Individual SD (raw score).
CA, congenital anomaly; Presence of other associated CA (yes=1, no=0), Sports M-ABC, Movement Assessment Battery for Children.
participation (yes=1, no=0); M-ABC, Movement Assessment Battery for Children. Each
predictor was included in a separate linear mixed model with adjustment for age.

FSIQ was 102 (14), mean (SD) TVIQ was 103 (14) and mean
(61% normal), but not for fine motor skills. One child with (SD) TPIQ was 98 (14); the distributions of all scales were con-
Opitz syndrome was included and completed the M-ABC satis- sistent with Dutch normative data.
factorily at 5 years. Although the result suggested delayed motor
development overall results did not change after exclusion of
this child (data not shown). Sustained attention
At the age of 8, mean z-score M-ABC was lower than norma- Sustained attention was assessed in 41/49 children; two missed
tive values (z-score M-ABC=−0.53, n=49, p<0.001). the appointment; two had been tested elsewhere; reasons for
Sixty-nine per cent had an overall M-ABC score within the four were unknown. Sustained attention was weaker compared
normal range. Considering the different domains, 53% scored with norms: mean (SD) z-score for Dot cancellation test speed
within the normal range for ball skills, 82% for balance skills −1.50(1.73); p<0.001 and mean (SD) raw score for Dot cancel-
and 82% for manual dexterity. lation test fluctuations +3.99 (1.90); p<0.001.
Motor performance did not improve from 5 to 8 years of age
(z-score M-ABC=+0.24, 95% CI −0.03 to +0.49, p=0.074). Determinants of developmental outcome
There was a significant correlation between z-score M-ABC at Longitudinal linear mixed model analyses revealed that the dur-
5 and 8 years (r=0.346, p=0.007). ation of anaesthetic exposure within the first 24 months was
negatively associated with z-score M-ABC ( p=0.018) (table 2).
Intelligence At 8 years, sustained attention was negatively associated with
Intelligence was assessed in 46/49 children (full-scale z-score M-ABC in terms of speed and attentional fluctuations,
WISC-III-NL, n=37; RAKIT and TVIQ of the WISC-III-NL, whereas sports participation was positively associated with
n=9). Data of three children who had recently been tested else- z-score M-ABC (table 3). Other potential risk factors, such as
where were not included. The data on total intelligence were sepsis, prolonged parenteral nutrition or prolonged hospitalisa-
pooled, because there was no difference between the RAKIT and tion, did not influence developmental outcome (data not
WISC-III-NL full-scale intelligence scores ( p=0.26). Mean (SD) shown).
F4 Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
 Original article

DISCUSSION systems were not yet in use. Second, sustained attention could
The present study is—to our knowledge—the first that longitu- not be assessed in eight children which might have led to some
dinally evaluated developmental outcome and associated factors selection bias. Third, assessment lasted a whole day. Although
in children operated on for OA. Assessments showed impaired we schedule sufficient breaks, the children’s performance might
motor performance up until 8 years without improvement over have been influenced by fatigue. However, the strength of this
time. Intelligence was normal, indicating that these children do study is the highly structured follow-up with a considerable
not suffer from general developmental delay. Sustained attention study population in view of the rare diagnosis.3 5 7–9 Lastly, we
and duration of anaesthetic exposure within the first 24 months did not enrol healthy controls as this is hardly feasible for a lon-
of life were negatively associated with motor performance. gitudinal study in school-age children. However, within the
Most of the comparable studies reported normal motor per- infrastructure of routine patient care, we exclusively used stan-
formance within the first 3 years of life in comparison with dardised assessments with population norms obtained in healthy
population norms3 4 or with healthy controls.18 In line with Dutch children.
previous studies of our research group, the present study found
impaired gross motor performance at 5 years. Further, motor
development at 5 years was predictive of motor performance at CONCLUSIONS
8 years, which suggests sustained risk of impairment. Similarly, Children operated on for OA may be at risk of long-term
in children with non-cardiac anatomical congenital malforma- developmental difficulties—especially in the area of gross motor
tions, motor development at 6, 12 and 24 months was predic- performance. Sports participation should be encouraged as it
tive of motor performance at 5 years.8 can improve motor development. The duration of anaesthetic
In our cohort, we observed normal intelligence but impair- exposure within the first 24 months of life was associated with
ments in sustained attention at 8 years. Little is known about gross motor problems. The same was true for impaired
long-term cognition of patients with OA; most studies found sustained attention at 8 years. Future studies should focus on
normal mental development within the first years of life.3 4 18 neurocognitive evaluation and the effects of anaesthetics, neuro-
Two studies reported impaired intelligence at school age.19 20 toxic drugs and perioperative management during the critical
However, these findings should be interpreted with caution neonatal phase.
because both studies were retrospective and selection bias might Acknowledgements The authors thank the paediatric surgical long-term
have occurred. Moreover, Kubota and colleagues did not report follow-up team, consisting of paediatricians, paediatric surgeons, psychologists,
on selection procedures.20 In the present study, we found speech–language pathologists and paediatric physiotherapists and especially Saskia
impaired sustained attention at the age of 8 years. Attention pro- J. Gischler and Marjolein Spoel (medical staff ) and Anne Zirar-Vroegindeweij and
Annabel van Gils-Frijters ( psychologists). Ko Hagoort provided editorial advice.
blems have also been reported in children with congenital dia-
phragmatic hernia and in neonatal ECMO survivors.9 Contributors WJH collected data, performed data analysis and drafted the first
version of the manuscript. FJA collected data, performed data analysis, drafted the
Despite a normal intelligence, 10% of the children needed
manuscript and critically reviewed the manuscript. MHMvdC-vZ designed the study,
special education, which is twice as high as in the normal Dutch collected data, performed data analysis, drafted the manuscript and critically
population.17 In previous literature, 11% to 53% of patients reviewed the manuscript. JMvR performed data analysis and critically reviewed the
with OA had special educational needs in relation to learning dis- manuscript. RMHW critically reviewed the manuscript. DT designed the study and
abilities, speech–language problems or intellectual disability.19 21 critically reviewed the manuscript. HI designed the study, collected data, critically
reviewed the manuscript and is responsible for the overall content as guarantor.
Previously identified risk factors for developmental problems,
such as sepsis, prolonged parenteral nutrition or hospitalisation, Funding Financially support: Stichting Swart van Essen, Rotterdam.
were not found risk factors in the present study. In previous Competing interests None declared.
studies, motor performance was negatively associated with the Provenance and peer review Not commissioned; externally peer reviewed.
longer duration of hospitalisation, more surgical interventions
and additional congenital anomalies.3 5 The impact of general
anaesthesia on developmental outcome is still speculative;22 REFERENCES
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F6 Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976