Congenital diaphragmatic hernia (CDH) is a rare anomaly with a prevalence of 2.3 per 10,000 births (1). This anomaly brings along a broad spectrum of problems, of which lung hypoplasia and pulmonary hypertension contribute considerably to the mortality rate of ~28% (2). Over the last decade, improved treatment of CDH has increased the survival rates as well as the prevalence of long-term morbidity (1, 3). The latter may last into adolescence and beyond, affecting several domains of development (4, 5). Among all domains, motor impairment is frequently reported, and gross motor function deficits in particular (3). This is of concern, given that motor impairments may affect the child's life on multiple levels, such as not being fully able to participate in sports and lagging behind one's peers. The underlying cause of these impairments remains unknown; yet, a number of determinants have been suggested, disease- as well as treatment-related (6–8). Nevertheless, the identification of specific risk factors might help to develop a tool for risk stratification. Survivors of CDH are already at risk for motor delay in the first years of life (9), although contradictory results on motor development in toddlers born with CDH have been published (10, 11). Aged 5 and 8 years, children born with CDH have been found to be at risk for impaired motor function, regardless of having received extracorporeal membrane oxygenation (ECMO) treatment (6, 12). In a longitudinal study concerning motor development in children with a variety of diagnoses treated with ECMO, the ones diagnosed with CDH appeared to be at the highest risk of impaired motor function (8). However, the course of motor function impairment over time in the complete spectrum of CDH-survivors is yet to be discovered (3). We hypothesized that children born with CDH are at risk for longitudinal motor function impairment. We longitudinally studied motor function, establishing total scores on motor function as well as subskills scores, together with its determinants, in a population of CDH-survivors treated either with or without ECMO.

Between January 1999 and December 2007, 120 children born with CDH were admitted to our PICU, of whom 81 (68%) survived to date. After applying the exclusion criteria, 64 patients were eligible for this study, of whom 9 were not assessed for various reasons, resulting in 55 participants. This number includes two participants of our program who were born in another CDH-center (Figure 1). The clinical baseline characteristics of the participants did not differ significantly from those of the non-participants who were lost to follow up, but the frequencies of several characteristics differed significantly between ECMO-treated and non-ECMO-treated participants, such as length of stay and treatment with inhaled nitric oxide (Table 1). At twelve years of age, 52 children (94.5%) had obtained a swimming certificate.

To the best of our knowledge, this is the first study to longitudinally evaluate the course of motor function in school-aged CDH survivors. We distinguished between those who had been treated with ECMO and those who had not, since it had been shown before that ECMO-treated CDH patients were at risk for impaired motor function (8). Strikingly, at ages 8 and 12 years, the estimated mean z-scores for motor function in non-ECMO-treated participants were not significantly lower than the norm scores, whereas the scores of those treated with ECMO were. At five years of age, scores in both groups were significantly lower than the norm. In multivariate analysis, length of hospital stay was independently associated with poorer motor outcome.

Several groups have studied motor function in children with CDH. Tureczek and co-workers cross-sectionally studied outcome in 3-to-16-year-old non-ECMO-treated children born with CDH. They found that younger children, up till age five years, performed better than older children on adaptive fine and gross motor components, although this finding might have been due to the application of different tests at the various ages (21). Danzer and co-workers longitudinally evaluated motor performance within the first three years of life of children born with CDH, and reported average motor function in the majority of children (10). Church and co-workers performed a retrospective observational study in CDH survivors aged from 4 months to 7.5 years old and found overall motor function to be below average, mainly due to gross motor problems (7). Overall, despite the variability in type of assessment and age of testing, all studies in CDH survivors are consistent in the occurrence of gross motor problems.

Earlier studies in CDH as well as ECMO-survivors revealed need for methadone, CLD and lower observed-to-expected total fetal lung volume as determinants for motor function problems (6–8). In our study, length of hospital was negatively associated with motor function, whereas CLD was not. This association has previously been found in survivors of CDH at toddler age (9, 10). The results of our multivariable analysis suggest that the z-score of M-ABC decreases with 0.01 for every week of initial hospitalization, but our model does not allow to determine a critical threshold of length of hospital stay to predict need of follow-up of motor function. Nevertheless, we propose that risk-stratification should not rely solely on ECMO-treatment, but include length of hospital stay as well. Longer length of stay itself might not be contributive to impaired motor function; it rather reflects severity of disease with underlying problems, such as pulmonary hypertension and failure to thrive.

The five-year-olds in our study appeared to be at risk for poor motor functioning, but motor performance improved thereafter – especially in CDH-survivors who had not received ECMO-treatment. Our data do not allow to conclude what actually has contributed to the improvement, although enrolment in our longitudinal follow-up program, with more timely referral to pediatric physical therapists and active stimulation to sports participation, is likely to have contributed (6, 8, 12, 22).

A few issues relating to this study need to be addressed. First, all but one of the included children underwent laparotomy, which in the study period (1999–2007) was standard of care for surgical correction of CDH. Nowadays, more infants undergo minimal access surgery (23). The question whether gross motor function might be affected by impaired truncal muscle strength after laparotomy has not yet been answered, but deserves further investigation. Second, children with CDH born today are treated with a standardized perinatal protocol introduced in 2008 (24). This protocol resulted in a decline in both mortality and need for ECMO (25, 26). Moreover, CDH is more and more predicted prenatally through standardized ultrasound examination at 20 weeks gestational age. The large majority of the participants in our study were born before the introduction of the protocol and the standardized ultrasound, so that the studied children overall are not fully representative of patients born today.

Although we have previously reported that CDH survivors at school age are at risk for pulmonary morbidity (27), we did not include data concerning lung function. In a randomized controlled trial involving CDH patients with airflow obstruction, we concluded that both exercise tolerance and motor function improved irrespective of intervention, and that parental awareness of reduced exercise capacity rather than specific interventions may have contributed to the improvement (28). This might indicate that lifestyle factors, rather than decreased lung function, contribute to impaired motor function.

Regarding awareness, both the child and its parents tend overestimate the child's motor competence as compared to the results of the M-ABC (29, 30). After having seen their child in a state of critical illness, the urge for well-developed motor function might seem futile to parents (29). Additionally, some parents might consider their child too vulnerable to actively participate in sports. Yet, this underlines the importance of comprehensive counseling of parents.

Moreover, treatment-related causes of motor function impairment might play a role, too. Abnormal cerebral ultrasound findings are not uncommon in this group, especially in ECMO-treated patients, although those findings are not linked to motor development yet (8, 31). Future studies concerning outcome should include the results of close neuromonitoring, as is currently being done in the NEMO-trial (NTR7160), which aims to gain more insight in the physiology of the brain of CDH-patients perioperatively. Also, neuroimaging during the period of critical illness as determinant for future motor development could be of use, to allow detailed risk stratification and prognostication.

Several limitations of our study must be taken into account. First, over the study period, two consecutive versions of the M-ABC were applied. Nevertheless, converting the scores to z-scores allowed comparison between test results (16). Second, this is a single-center study, which limits the transferability of the results. Third, we did not include a score for critical illness, which limited the identification of predictive determinants for impaired motor function. In a previous study by our group, the vaso-active inotropic score (VIS) was found to be predictive of neurocognitive outcome in ECMO-treated patients, and we therefore recommend to take this score into account in further studies concerning development (32). Until 2005 cumulative drug doses were lacking as digital records were unavailable. We were therefore unable to properly retrieve data and calculate VIS for our cohort. Other factors that might have been of interest but were not taken into account in our analyses were social and environmental characteristics, such as time outdoors, availability of toys and space to play, which have been reported to influence motor development (33, 34). We were unable to use those since these data were not collected in the past. However, taking into account the sociodemographic background of the participants (ISCED level mother, Table 1) and the policy of the Dutch government to stimulate sports and swimming classes for low income families, we think that this may not have had an important role. Moreover, we did not investigate cognitive competence and school achievement in this study. Yet, our group has previously studied neurocognitive outcome in school-aged CDH-survivors with and without ECMO, and found problems on several neurocognitive domains. Therefore, persisting problems on several neurodevelopmental domains, such as motor and cognitive function, warrant further evaluation regarding the growing into deficit theory (32).

The strengths of our study can be found in the relatively large cohort with a follow up of 12 years, and the fact that 86% of the eligible candidates actually participated in our follow-up. We found no evidence for selection bias, since the baseline characteristics between the non-participants and participants did not significantly differ.

In conclusion, children born with CDH are at risk for motor function impairment at the age of five, and impairment may persist up till 12 years of age in those who were treated with ECMO. Length of hospital stay appeared to be an independent risk factor for impaired motor function. Early recognition of motor problems and timely referral to pediatric physical therapists could help prevent worsening. A clinical implication of our findings is that motor function should be monitored up to five years of age in all CDH-survivors. The decision to extend follow up until adolescence should take both need for ECMO-treatment and prolonged hospital stay into account.

The datasets presented in this article are currently not available. Requests to access the datasets should be directed to h.ijsselstijn@erasmusmc.nl.

The studies involving human participants were reviewed and approved by Medical Ethical Review Committee Erasmus MC Rotterdam. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

SdM contributed to the conception and design, acquisition of data, analysis and interpretation of data, and writing of the first draft. MvdC-vZ and HI contributed to the conception and design, acquisition of data, analysis and interpretation of data, writing of the first draft, and critically revising the manuscript. TZ-vdA contributed to acquisition of data and critically revising the manuscript. SC-dO and NvH contributed to interpretation of data and critically revising the manuscript. RW and SG contributed to the conception and design, and critically revising the manuscript. JvR contributed to statistical analysis, interpretation of the data and critically revising the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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