ADC-FNN Online First, published on August 31, 2016 as 10.
1136/archdischild-2015-309976
1
Intensive Care and
Department of Pediatric
Surgery, Erasmus MC—Sophia
Children’s Hospital, Rotterdam,
The Netherlands
2 ▸ Children with oesophageal atresia are at risk of
Department of Biostatistics,
Erasmus MC, Rotterdam,
The Netherlands
Correspondence to
Dr Hanneke IJsselstijn,
Intensive Care and Department
of Pediatric Surgery, Erasmus
MC, Sophia Children’s
Hospital, Rotterdam 3015 GJ,
The Netherlands;
h.ijsselstijn@erasmusmc.nl
Received 16 October 2015
Revised 5 August 2016
Accepted 8 August 2016
To cite: Harmsen WJ,
Aarsen FJ, van der Cammen-
van Zijp MHM, et al. Arch
Dis Child Fetal Neonatal Ed
Published Online First:
[please include Day Month
Year] doi:10.1136/
archdischild-2015-309976
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
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
ABSTRACT
Objective To longitudinally evaluate motor
development and predictive factors in school-age
children with oesophageal atresia.
Design Cohort study with prospective longitudinal
follow-up.
Setting Outpatient clinic of a tertiary university
paediatric hospital.
Patients Children with oesophageal atresia born
between January 1999 and May 2006 were assessed at
5 and 8 years of age.
Interventions None.
Main outcome Motor performance was evaluated at
5 and 8 years using the Movement Assessment Battery
for Children (M-ABC). Additionally, we evaluated
perinatal characteristics, duration of anaesthesia within
the first 24 months, socioeconomic status, sports
participation and school performance at time of follow-
up and intelligence and sustained attention at the age
of 8 years.
Results In 5-year-olds (n=54), the mean (SD) z-score
M-ABC was slightly, but significantly lower than age-
predicted normative values (−0.75 (0.83), p<0.001). In
8-year-olds (n=49), the z-score M-ABC was −0.53
(0.91) ( p<0.001), intelligence was normal, but sustained
attention was impaired: z-score speed (−1.50 (1.73))
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
motor development; sports participation was positively
associated.
Conclusions Longer duration of anaesthesia and
sustained attention problems were associated with gross
motor problems in school-age patients with oesophageal
atresia. Parental awareness of risks for motor problems
may provide the opportunity to offer timely intervention.
Oesophageal atresia (OA) is a major congenital ana-
tomical anomaly characterised by a discontinuity of
the oesophagus. It affects one in 2500 newborns
and requires early neonatal surgery.1 Advances in
surgical and neonatal management have progres-
sively increased survival rates; in the absence of risk
factors like extreme prematurity or major cardiac
anomalies survival is nearly 100%.1 Consequently,
attention has shifted from mortality towards the
evaluation of long-term morbidity.
There is a growing number of studies evaluating
motor and cognitive development in children who
survived invasive neonatal surgery.2 Motor pro-
blems and cognitive deficits have been reported in
children with congenital anatomical anomalies,
including children with OA.3 4 Our group
What is already known on this topic?
long-term morbidity.
▸ Mental development of oesophageal atresia
patients is normal in infancy and at preschool
age.
▸ Gross motor difficulties have been reported in
5-year-old patients with oesophageal atresia.
What this study adds?
▸ Gross motor problems persist in school-age
patients with oesophageal atresia.
▸ Oesophageal atresia patients have normal
intelligence, but problems with sustained
attention.
▸ Sustained attention problems and duration of
general anaesthetic procedures were negatively
associated with motor performance; sports
participation was positively associated with
motor performance.
previously showed normal mental development but
impaired motor outcome in 2-year-old3 and gross
motor problems in 5-year-old children with OA.5
The above studies reported negative associations
between motor performance and duration of hospi-
talisation, number of surgical interventions and
associated congenital anomalies.3–5
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
decreased at school age. The aim of the present
study was to longitudinally evaluate motor develop-
ment in OA at the ages of 5 and 8 years and to
identify associated factors.
METHOD
Participants
All newborns diagnosed with OA between January
1999 and May 2006 and subsequently treated at
the intensive care unit of a level-III university hos-
pital, that is, the Erasmus MC–Sophia Children’s
Hospital, were eligible. Since 1999, children born
with major anatomical congenital anomalies and
their families are followed by a multidisciplinary
team.3 5 7–9 The Board of the Medical Ethics
Committee of the Erasmus MC stated that the rules
F1
 Original article
laid down in the Dutch Medical Research Involving Human
Subjects Act do not apply for the present study. All parents were
informed that data were used for research purposes.
Procedures
The present study is part of a structured follow-up programme
for children born with OA with nine standardised assessments
from the age of 6 months until the age of 17 years.3 5 7–9 The
following data were collected: gender, gestational age, birth
weight, ethnicity, type of OA, the presence and type of asso-
ciated congenital anomalies, genetic syndromes, sepsis, duration
of ventilatory support, duration of initial hospitalisation, dur-
ation of parenteral nutrition, antireflux surgery, number of pro-
cedures under general anaesthesia within the first 24 months of
life, total duration of anaesthetic exposure within the first
24 months of life, and hospital admissions with duration of hos-
pitalisation within the first 5 years. Longitudinal follow-up data
are prospectively collected at 5 and 8 years of age. Motor devel-
opment was evaluated by an experienced paediatric physiother-
apist. Information about education, sports participation (yes/no)
and physical therapeutic support (yes/no) was recorded.
Psychological assessment at 8 years was performed by an experi-
enced paediatric psychologist. We classified socio-economic
status (SES) as low, middle or high based on the highest degree
of maternal education.10
PRIMARY OUTCOME
Motor development
Motor skills were examined with the Movement Assessment
Battery for Children (M-ABC).11 12 The M-ABC consists of sep-
arate age-related item bands with increasing difficulty as children
get older. Each band contains eight items, which evaluate three
domains: manual dexterity (3 items), ball (2 items) and balance
skills (3 items). Until October 2012, we used the first edition of
the M-ABC, but in November 2012, we switched to the second
edition. Both editions contain similar content and are assumed
to be comparable.13 M-ABC percentile scores are divided
into three categories, namely normal, borderline and motor
problem.
SECONDARY OUTCOMES
Intelligence
For children born after December 2001, the Dutch version of
the Wechsler Intelligence Scale for Children (WISC-III-NL) was
used to assess full-scale IQ (FSIQ), total verbal IQ (TVIQ) and
total performance IQ (TPIQ).13 For children born earlier, the
short version of the Revised Amsterdam Intelligence Test
(RAKIT)14 15 and the short version of the TVIQ scale of the
WISC-III-NL were used. For both tests, the IQ has a mean (SD)
of 100 (15) in the normative population.
Sustained attention
Attention was assessed with the Dot cancellation test (Bourdon-
Vos test). This test is a continuous performance paper and
pencil test that measures sustained attention in terms of speed
and attentional fluctuations. Speed and attentional fluctuations
are continuous variables, respectively, expressed in z-score and
raw score (higher score indicating more fluctuations).16
Statistical analysis
Data are presented as mean (SD) unless otherwise indicated.
To compare data of participants and non-participants,
Mann-Whitney U tests were used for continuous data and χ2
tests for categorical data. The Kruskal-Wallis test was used to
F2 Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
test for differences in neurodevelopmental outcome across SES
categories. To compare data with reference values, paired
samples t-tests were used for continuous data and χ2 tests for
categorical data. To test for differences between 5 and 8 years,
linear mixed models were used for continuous data and
McNemar’s tests for categorical data. Only the data of children
tested at both ages were used in the McNemar’s tests.
To combine the outcome scores of the M-ABC-I and
M-ABC-II, percentile scores were transformed into z-scores
using probit transformations (ie, an inverse normal transform-
ation). Motor performance changes over time were investigated
in longitudinal analyses using linear mixed models with z-score
M-ABC as dependent variable (with mean=0 and SD=1, refer-
ence population). In each model, the independent variables
were age and one of the following predictors: birth weight, the
presence of associated congenital anomalies, ventilatory
support, sepsis, duration of parenteral nutrition, duration of
general anaesthetic events and duration of hospitalisation.
A random intercept was included to account for the within-
subject correlations. Linear mixed models allow subjects for
who some data are missing to be included in the analyses, pro-
vided that the data are missing at random, as explained previ-
ously.7 Correlation of motor performance between ages 5 and
8 years was calculated using the intraclass correlation coefficient.
With the exception of the attention fluctuations score, intelli-
gence and sustained attention scores were converted into
z-scores using normative data. The raw score for attention fluc-
tuations was compared with the mean raw score (ie, 2.3).
A higher raw score means more attentional fluctuations. A
paired samples t-test was used to determine whether the data of
the intelligence tests had the same mean score and could be
pooled.
Correlation coefficients between z-score M-ABC at the age of
8 years and sports participation and sustained attention were
calculated. Furthermore, correlation coefficients between partici-
pants’ characteristics and sustained attention were calculated.
Pearson’s correlation coefficients were calculated for continuous
data and Spearman’s for dichotomous data. All statistical tests
were two sided; significance level was p<0.05. Statistical ana-
lyses were performed using IBM-SPSS-Statistics-21 (SPSS,
Chicago, Illinois, USA).
RESULTS
Of the 78 newborns with OA admitted between February 1999
and August 2006, seven died (9.0%). The parents of seven chil-
dren refused to participate (9.0%) and three children were lost
to follow-up (3.8%). One child had been operated elsewhere
and was first seen at 8 years. Four children with intellectual dis-
ability ((genetic syndrome (n=3) and unknown cause (n=1))
could not be tested. Thus, 58 children were included in the ana-
lysis (figure 1).
Perinatal characteristics are shown in table 1. Surgical proce-
dures included thoracotomy for oesophageal correction (all
patients), cardiac surgery (n=3) and Nissen fundoplication
(n=14).
More children received physiotherapeutic support at the age
of 5 than at the age of 8 years (25% vs 10%, respectively;
p<0.001). Participation in sports activities did no differ
between 5-year-olds and 8-year-olds (55% vs 73%, respectively;
p=0.117).
Five 8-year-olds (10.2%) followed special education, 10
regular education with remedial teaching (20.4%) and 34
regular education without remedial teaching (69.4%) (χ2=2.86,
p=0.239 compared with age peers in the general Dutch
 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
support: 20%; and regular education: 75%).17
SES was determined for the parents of 56 participants (97%)
and classified as low in 12.5% (n=7), middle in 50% (n=28)
and high in 37.5% (n=21). Neurodevelopmental outcome was
not different across the SES categories for: motor performance
at 5 years (χ2=1.201, p=0.549) and 8 years (χ2=0.393,
p=0.822), IQ (χ2=3.215, p=0.200) and sustained attention
(speed: χ2=0.021, p=0.990; fluctuations χ2=0.694, p=0.707).
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
Motor development
Forty-five children (78%) were tested with the M-ABC at both
ages (figure 1).
At 5 years, mean z-score M-ABC was lower than normative
values (z-score M-ABC=−0.75, n=54, p<0.001). Sixty-five per
cent had an M-ABC score within the normal range, which per-
centage is lower than that in the reference population (85%)
(figure 2). Problems were observed mainly for the gross motor
abilities, such as ball skills (48% normal) and balance skills
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.

(61% normal), but not for fine motor skills. One child with
Opitz syndrome was included and completed the M-ABC satis-
factorily at 5 years. Although the result suggested delayed motor
development overall results did not change after exclusion of
this child (data not shown).
At the age of 8, mean z-score M-ABC was lower than norma-
tive values (z-score M-ABC=−0.53, n=49, p<0.001).
Sixty-nine per cent had an overall M-ABC score within the
normal range. Considering the different domains, 53% scored
within the normal range for ball skills, 82% for balance skills
and 82% for manual dexterity.
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).
There was a significant correlation between z-score M-ABC at
5 and 8 years (r=0.346, p=0.007).
Intelligence
Intelligence was assessed in 46/49 children (full-scale
WISC-III-NL, n=37; RAKIT and TVIQ of the WISC-III-NL,
n=9). Data of three children who had recently been tested else-
where were not included. The data on total intelligence were
pooled, because there was no difference between the RAKIT and
WISC-III-NL full-scale intelligence scores ( p=0.26). Mean (SD)
F4
FSIQ was 102 (14), mean (SD) TVIQ was 103 (14) and mean
(SD) TPIQ was 98 (14); the distributions of all scales were con-
sistent with Dutch normative data.
Sustained attention
Sustained attention was assessed in 41/49 children; two missed
the appointment; two had been tested elsewhere; reasons for
four were unknown. Sustained attention was weaker compared
with norms: mean (SD) z-score for Dot cancellation test speed
−1.50(1.73); p<0.001 and mean (SD) raw score for Dot cancel-
lation test fluctuations +3.99 (1.90); p<0.001.
Determinants of developmental outcome
Longitudinal linear mixed model analyses revealed that the dur-
ation of anaesthetic exposure within the first 24 months was
negatively associated with z-score M-ABC ( p=0.018) (table 2).
At 8 years, sustained attention was negatively associated with
z-score M-ABC in terms of speed and attentional fluctuations,
whereas sports participation was positively associated with
z-score M-ABC (table 3). Other potential risk factors, such as
sepsis, prolonged parenteral nutrition or prolonged hospitalisa-
tion, did not influence developmental outcome (data not
shown).
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976

DISCUSSION
The present study is—to our knowledge—the first that longitu-
dinally evaluated developmental outcome and associated factors
in children operated on for OA. Assessments showed impaired
motor performance up until 8 years without improvement over
time. Intelligence was normal, indicating that these children do
not suffer from general developmental delay. Sustained attention
and duration of anaesthetic exposure within the first 24 months
of life were negatively associated with motor performance.
Most of the comparable studies reported normal motor per-
formance within the first 3 years of life in comparison with
population norms3 4 or with healthy controls.18 In line with
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
8 years, which suggests sustained risk of impairment. Similarly,
in children with non-cardiac anatomical congenital malforma-
tions, motor development at 6, 12 and 24 months was predic-
tive of motor performance at 5 years.8
In our cohort, we observed normal intelligence but impair-
ments in sustained attention at 8 years. Little is known about
long-term cognition of patients with OA; most studies found
normal mental development within the first years of life.3 4 18
Two studies reported impaired intelligence at school age.19 20
However, these findings should be interpreted with caution
because both studies were retrospective and selection bias might
have occurred. Moreover, Kubota and colleagues did not report
on selection procedures.20 In the present study, we found
impaired sustained attention at the age of 8 years. Attention pro-
blems have also been reported in children with congenital dia-
phragmatic hernia and in neonatal ECMO survivors.9
Despite a normal intelligence, 10% of the children needed
special education, which is twice as high as in the normal Dutch
population.17 In previous literature, 11% to 53% of patients
with OA had special educational needs in relation to learning dis-
abilities, speech–language problems or intellectual disability.19 21
Previously identified risk factors for developmental problems,
such as sepsis, prolonged parenteral nutrition or hospitalisation,
were not found risk factors in the present study. In previous
studies, motor performance was negatively associated with the
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
studies reported associations with learning disabilities,23 behav-
ioural problems24 25 and developmental disorders.25 We found
a negative association of anaesthetic exposure with motor devel-
opmental outcome. This finding cannot be ignored but should
be interpreted with caution because we do not know what
anaesthetics were used. Still, the question is whether develop-
mental problems can be explained by neurotoxic effects of
anaesthetics. Frequent or prolonged anaesthesia may also be
indicative of the presence of comorbidities that may independ-
ently affect developmental outcome.26
Approximately half of the children had impaired ball and
balance skills at 5 years. Interestingly, balance skills improved
afterwards as a result of more exercise. Sports participation was
indeed positively associated with improved motor abilities.
Although children with poor motor performance may refrain
from sports activities, we believe that sports participation should
be encouraged. It helps develop motor skills, increases
health-related physical activity and improves quality of life.27 28
Some limitations should be discussed. First, data on pre-
scribed anaesthetics were not available. All patients were oper-
ated on more than 8 years ago, when electronic patient data
Harmsen WJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F6. doi:10.1136/archdischild-2015-309976
Original article
systems were not yet in use. Second, sustained attention could
not be assessed in eight children which might have led to some
selection bias. Third, assessment lasted a whole day. Although
we schedule sufficient breaks, the children’s performance might
have been influenced by fatigue. However, the strength of this
study is the highly structured follow-up with a considerable
study population in view of the rare diagnosis.3 5 7–9 Lastly, we
did not enrol healthy controls as this is hardly feasible for a lon-
gitudinal study in school-age children. However, within the
infrastructure of routine patient care, we exclusively used stan-
dardised assessments with population norms obtained in healthy
Dutch children.
CONCLUSIONS
Children operated on for OA may be at risk of long-term
developmental difficulties—especially in the area of gross motor
performance. Sports participation should be encouraged as it
can improve motor development. The duration of anaesthetic
exposure within the first 24 months of life was associated with
gross motor problems. The same was true for impaired
sustained attention at 8 years. Future studies should focus on
neurocognitive evaluation and the effects of anaesthetics, neuro-
toxic drugs and perioperative management during the critical
neonatal phase.
Acknowledgements The authors thank the paediatric surgical long-term
follow-up team, consisting of paediatricians, paediatric surgeons, psychologists,
speech–language pathologists and paediatric physiotherapists and especially Saskia
J. Gischler and Marjolein Spoel (medical staff ) and Anne Zirar-Vroegindeweij and
Annabel van Gils-Frijters ( psychologists). Ko Hagoort provided editorial advice.
Contributors WJH collected data, performed data analysis and drafted the first
version of the manuscript. FJA collected data, performed data analysis, drafted the
manuscript and critically reviewed the manuscript. MHMvdC-vZ designed the study,
collected data, performed data analysis, drafted the manuscript and critically
reviewed the manuscript. JMvR performed data analysis and critically reviewed the
manuscript. RMHW critically reviewed the manuscript. DT designed the study and
critically reviewed the manuscript. HI designed the study, collected data, critically
reviewed the manuscript and is responsible for the overall content as guarantor.
Funding Financially support: Stichting Swart van Essen, Rotterdam.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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