pediatrics
August 2017, VOLUME140 /ISSUE 2

Congenital Diaphragmatic Hernia and Growth to 12 Years

  1. Lisette Leeuwen, MDa,
  2. Daphne S. Mous, MDa,
  3. Joost van Rosmalen, PhDb,
  4. Joanne F. Olieman, RD, PhDa,c,
  5. Laura Andriessen, MDa,
  6. Saskia J. Gischler, MD, PhDa,
  7. Koen F.M. Joosten, MD, PhDa,
  8. Rene M.H. Wijnen, MD, PhDa,
  9. Dick Tibboel, MD, PhDa,
  10. Hanneke IJsselstijn, MD, PhDa, and
  11. Marjolein Spoel, MD, PhDa
  1. aIntensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands;and
  2. bDepartment of Biostatistics, and
  3. cDepartment of Dietetics, Erasmus Medical Center, Rotterdam, Netherlands
  1. Dr Leeuwen collected data, conducted the initial analyses, and drafted the initial manuscript; Dr Mous conceptualized the study, collected data, and reviewed and revised the manuscript; Dr van Rosmalen conducted the initial analyses and reviewed and revised the manuscript; Drs Olieman, Andriessen, and Wijnen collected data and reviewed and revised the manuscript; Dr Gischler designed the study and reviewed and revised the manuscript; Dr Joosten analyzed and interpreted data and reviewed and revised the manuscript; Dr Tibboel conceptualized and designed the study and reviewed and revised the manuscript; Dr IJsselstijn conceptualized and designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript; Dr Spoel conceptualized the study, conducted the initial analyses, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Abstract

OBJECTIVES: Growth problems are reported in patients with congenital diaphragmatic hernia during the first years of life. However, it is unknown if poor growth persists during childhood. We therefore evaluated growth of patients longitudinally until 12 years of age.

METHODS: This prospective study included 172 patients (43 treated with extracorporeal membrane oxygenation [ECMO]) born from 1999 to 2014. Z scores of height-for-age (HFA), weight-for-height, and distance-to-target height were calculated at 6 months of age and at 1, 2, 5, 8, and 12 years of age. Data were analyzed by using general linear models.

RESULTS: At 1 year of age, the mean weight-for-height z score had declined in ECMO (−1.30, 95% confidence interval: −1.62 to −0.97) and non-ECMO patients (−0.72, 95% confidence interval: −0.91 to −0.54; P < .05). Thereafter in ECMO patients, the mean HFA z score deteriorated between 1 (−0.43, 95% confidence interval: −0.73 to −0.13) and 5 years of age (−1.08, 95% confidence interval: −1.38 to −0.78; P < .01). In non-ECMO patients, the mean HFA z score deteriorated between 2 (−0.35, 95% confidence interval: −0.53 to −0.17) and 5 years of age (−0.56, 95% confidence interval: −0.75 to −0.37; P = .002). At 12 years of age, the mean HFA z score was still less than the norm in both groups: ECMO (−0.67, 95% confidence interval: −1.01 to −0.33) versus non-ECMO (−0.49, 95% confidence interval: −0.77 to −0.20; P < .01). Adjusting for target height improved the mean height z scores but did not bring them to normal range.

CONCLUSIONS: Poor linear growth persisted at 12 years of age. The pattern of early deterioration of weight gain followed by a decline in linear growth is suggestive of inadequate nutrition during infancy. Therefore, nutritional assessment and intervention should be started early and should be continued during childhood.

  • Abbreviations:
    CDH
    congenital diaphragmatic hernia
    ECMO
    extracorporeal membrane oxygenation
    DTH
    distance-to-target height
    GERD
    gastroesophageal reflux disease
    HFA
    height-for-age
    IQR
    interquartile range
    REE
    resting energy expenditure
    STRONGkids
    Screening Tool for Risk on Nutritional status and Growth
    TH
    target height
    WFH
    weight-for-height
  • What’s Known on This Subject:

    Survivors of congenital diaphragmatic hernia are at risk for long-term morbidities, including growth problems. The risk of failure to thrive is especially high in the first year of life, with widely varying prevalence rates between 8% and 69%.

    What This Study Adds:

    Longitudinal evaluation showed that the mean weight-for-height z score declined during the first year, after which the mean height-for-age z scores declined until age 5. This suggests inadequate nutrition to meet energy needs. Early risk stratification with nutritional assessments is recommended.

    Patients with congenital diaphragmatic hernia (CDH) may suffer from long-term morbidities that could affect development later in life, including obstructive lung function,1 gastroesophageal reflux,2 and impaired physical growth.3 This indicates the need for long-term follow-up of patients with CDH. Therefore, in 2008 the American Academy of Pediatrics published guidelines for structured long-term follow-up.4 Growth problems are an important issue in patients with CDH. Prevalence rates of wasting, indicating acute malnutrition, vary between 8% and 69% at 1 year of age.5,6 Malnutrition in infancy has been associated with adverse long-term outcomes such as impaired neurodevelopment in otherwise healthy children.7,8 Previous studies reported growth problems in survivors during the first months of life with catch-up growth starting after the first 6 months.6,9 Still, a recent longitudinal study showed that growth failure persisted in 13.5% of patients at 6 years of age.10

    Growth problems are worse among patients who were treated with neonatal extracorporeal membrane oxygenation (ECMO), possibly because they have more severe lung hypoplasia and, consequently, higher energy needs to compensate for the increased work of breathing.3,11 So far, growth of patients with CDH after 6 years has not been studied longitudinally. We aimed to evaluate growth longitudinally until 12 years of age in patients with CDH who were treated with and without ECMO. We hypothesized that patients were at risk for impaired growth in the long-term, especially those treated with neonatal ECMO. Furthermore, we aimed to find clinical variables associated with growth.

    Methods

    Patients

    In 1999, we started a prospective longitudinal follow-up program to monitor growth, lung function, and neurodevelopment of patients with CDH until 18 years of age.12 This prospective longitudinal study was conducted within the framework of our follow-up program and included surviving patients with CDH admitted to the Erasmus Medical Center-Sophia Children’s Hospital between January 1999 and December 2014. For the purposes of this evaluation, we excluded data from patients diagnosed with CDH after 7 days of age, those with paraesophageal diaphragmatic defects, those with a diaphragmatic eventration, and those with genetic syndromes that affect physical growth. ECMO treatment was applied in cases of reversible severe respiratory failure by using the entry criteria reported by Stolar et al13 until November 2007. After November 2007, children were treated according to the standardized CDH EURO Consortium consensus treatment protocol.14 The Erasmus Medical Center Medical Ethical Review Board stated that the “Medical Research in Human Subjects Act does not apply to this study,” and waived institutional review board approval (MEC-2016-111).

    Data Collection

    The following data were collected: gestational age; birth weight; sex; ethnicity; side and type of repair of the diaphragmatic defect; age at repair; duration of initial mechanical ventilation; ECMO treatment status; duration of PICU stay; presence of chronic lung disease (oxygen dependency at 28 days of life)15; need for supplemental oxygen at discharge; and presence of cardiac anomalies, gastroesophageal reflux disease (GERD), or Nissen fundoplication. All patients were treated with antireflux medication until evaluation of GERD by using 24-hour pH-metry. Until 2013, GERD was evaluated by 24-hour pH-metry only; afterward, we used 24-hour pH-metry with impedance.

    Growth was evaluated at each routine outpatient visit at 6 months of age and at 1, 2, 5, 8, and 12 years of age. At each follow-up visit, we recorded the use of tube feeding, calorie-enriched feeds, and GERD medication.

    Growth Measurements

    Growth parameters were expressed as z scores in relation to Dutch norms by using the reference data from the Fifth Dutch Growth Study.16 Reference values for Dutch children of Moroccan or Turkish origin were used where applicable.17 Height-for-age (HFA) and weight-for-height (WFH) z scores were calculated.18 Target height (TH) and TH z scores were calculated by using parental heights.19 To correct HFA z score for TH, we calculated distance-to-target height (DTH) z score as follows: DTH z score = HFA z score−TH z score. Stunting was defined as HFA z score <−2.20 Wasting was defined as WFH z score <−2.20 Stunting corrected for TH was defined as DTH z score <−2.

    Pilot Study: Indirect Calorimetry

    To assess the role of increased energy expenditure in 11 patients with growth problems, we measured resting energy expenditure (REE) by indirect calorimetry (Cosmed Quark RMR with Canopy; Tulipmed, Nieuwegein, Netherlands). In addition, these patients had dietary consultations. For more details, see Supplemental Information.

    Statistical Analyses

    To evaluate differences in patient characteristics between ECMO and non-ECMO patients, we performed χ2 or Fisher’s exact tests for categorical variables. Independent sample t tests were used for normally distributed variables, and Mann–Whitney U tests were used for variables not normally distributed. To evaluate growth longitudinally and compare growth of patients with the norm population (z score = 0), we used general linear models. This method can account for within-subject correlations and allows for missing values in the dependent variable. We compared ECMO and non-ECMO patients with the norm population by using general linear models that included z scores for HFA, WFH, and DTH as dependent variables and z scores for time point, ECMO, and the interaction between time point and ECMO as independent variables. Paired-sample t tests were used to compare the mean z scores of HFA and DTH at each time point.

    To find associations between growth and clinical variables, we estimated general linear models in which the following independent variables were considered in addition to ECMO and time point: gestational age, patch repair, presence of cardiac anomalies, duration of initial mechanical ventilation, duration of PICU stay, supplemental home oxygen use at discharge, the presence of Nissen fundoplication, the use of tube feeding, the use of calorie-enriched feeds, and the presence of a new treatment protocol (after November 2007). We used a stepwise backward approach to select the independent variables from this list of variables, with a P value cutoff of P = .20 for removal of independent variables. Two-way interaction effects were then added to the resulting model if the interaction effect was statistically significant. Pearson correlation coefficients between independent variables were calculated to assess the level of multicollinearity. All correlations among the included independent variables were lower than 0.6. To account for within-subject correlations, all general linear models were estimated with an unstructured error covariance matrix for the repeated measurements of each patient. The results of general linear models were summarized by using the estimated marginal means, which are the predicted values of the dependent variable adjusted for the effects of the independent variables. Analyses were performed by using SPSS 21.0 (IBM Corporation, Armonk, NY). Statistical tests were 2-sided and used a significance level of 0.05.

    Results

    Patients

    Of 298 patients with CDH, 78 (26%) died before hospital discharge (Fig 1). Forty-eight of the 220 patients who survived were excluded for various reasons. Therefore, the study group consisted of 172 patients, of whom 43 (25%) received ECMO treatment. None of the 172 included children had a Morgagni-Larrey hernia.

    FIGURE 1

    Flowchart of study population. The enrollment of patients with CDH was n = 172. For each routine visit, the actual number of patients from whom growth data were obtained and the number of patients who were eligible for follow-up are shown. a ECMO patients (n = 58); non-ECMO patients (n = 20). b 16p11.2 deletion syndrome (n = 1); Cohen syndrome (n = 1); Down syndrome (n = 2); Loeys-Dietz syndrome (n = 1); Ohtahara syndrome (n = 1); Simpson-Golabi-Behmel syndrome (n = 3); Wolf-Hirschhorn syndrome (n = 1). c CDH correction at the median age of 8.1 months (IQR: 1.5–19.9). d No follow-up visit because of organizational reasons: n = 2. e No follow-up visit because of the following reasons: organizational reasons: n = 9; refusal of follow-up: n = 4. f No follow-up visit because of the following reasons: organizational reasons: n = 9; refusal of follow-up: n = 6; emigration: n = 2; lost to follow-up: n = 1; died: n = 1. g No follow-up visit because of the following reasons: organizational reasons: n = 2; refusal of follow-up: n = 11; emigration: n = 2; lost to follow-up: n = 1; died: n = 1. h No follow-up visit because of the following reasons: refusal of follow-up: n = 4; emigration: n = 1; died: n = 1. i No follow-up visit because of the following reasons: refusal of follow-up: n = 2; died: n = 1. [large]

    Table 1 shows patient characteristics. Of all 172 patients, 138 (80%) underwent 24-hour pH-metry at the median age of 2.9 months (interquartile range [IQR]: 1.7–4.4), and 53 (38%) patients were diagnosed with GERD. Twenty-three patients were asymptomatic; the 30 others had the following symptoms: regurgitation (n = 11), regurgitation with feeding difficulties (n = 18), and oxygen saturation dips (n = 1). Twenty (12%) patients underwent a Nissen fundoplication at the median age of 0.7 years (IQR: 0.3–2.6). Nineteen patients experienced regurgitation with feeding difficulties and 1 asymptomatic patient had histologically proven esophagitis despite adequately dosed drug therapy. Seventeen (10%) patients had a gastrostomy placement at the median age of 0.5 year (IQR: 0.3–0.9; 12 patients underwent Nissen fundoplication). Supplemental Table 4 shows the numbers of patients who were tube fed at follow-up. None of the patients were tube fed at 8 and/or 12 years of age.

    TABLE 1

    Patient Characteristics

    Height Measurements

    The mean HFA was less than the norm at all ages in ECMO and non-ECMO patients (all P < .05; Fig 2). ECMO-treated patients were significantly shorter than non-ECMO patients at 2, 5, and 8 years of age (P = .048, P = .004 and P = .02, respectively). In non-ECMO patients, the mean HFA declined from the ages of 2 to 5 years (P = .002). In ECMO patients, the mean HFA declined from the ages of 1 to 2 years and 2 to 5 years (P = .01 and P < .001, respectively). From 8 to 12 years of age, the mean HFA significantly improved in the ECMO patients (P = .002).

    FIGURE 2

    HFA in patients with CDH treated with and without ECMO until 12 years of age. Estimated marginal means with error bars representing 95% confidence intervals were plotted, and the presentation of data is based on a general linear model, with time point, ECMO, and their interaction effect as independent variables. The solid line represents the ECMO patients; the dashed line represents the non-ECMO patients. a The data indicate a significant difference between ECMO and non-ECMO patients.

    Target heights were available for 160 patients. In ECMO patients, the mean DTH was higher than the mean HFA at 2 years of age (Table 2). In non-ECMO patients, the mean DTH was higher than the mean HFA from 6 months to 8 years of age. The mean DTH was still less than the norm from 2 to 12 years of age in both groups. The prevalence of stunting remained high in ECMO patients, but correcting for TH decreased stunting rates (Fig 3 A and B).

    TABLE 2

    HFA and DTH in Patients With CDH Treated With and Without EMCO Until 12 Years of Age

    FIGURE 3

    Prevalence rates of wasting and stunting in patients with CDH treated with and without ECMO until 12 years of age. A, Prevalence rates of stunting.1 Stunting is defined as a HFA z score <−2. B, Prevalence rates of stunting corrected for TH.2 Stunting corrected for TH is defined as DTH z scores <−2. C, Prevalence rates of wasting.3 Wasting is defined as a WFH z score <−2. Bars show the percentages of wasting or stunting at follow-up, calculated as: the number of cases / the total number of patients seen at each time point. The numbers within the bars represent the number of cases at each time point. The white bars represent the ECMO patients; the gray bars represent the non-ECMO patients. a The data indicates a significant difference between ECMO and non-ECMO patients.

    Weight Measurements

    The mean WFH was less than the norm until the age of 5 years in non-ECMO patients and until the age 8 of years in ECMO patients (all P < .05; Fig 4). ECMO patients had lower mean WFH than non-ECMO patients from 6 months to 8 years of age (all P < .05). The mean WFH declined from 6 months to 1 year of age in ECMO patients (P = .01) and non-ECMO patients (P = .001). In ECMO patients, the mean WFH improved from 8 to 12 years of age (P < .001). In non-ECMO patients, the mean WFH improved from 5 to 8 years of age and from 8 to 12 years of age (P = .03 and P = .02, respectively). The prevalence of wasting remained high in both groups (Fig 3 C).

    FIGURE 4

    WFH in patients with CDH treated with and without ECMO until 12 years of age. Estimated marginal means with error bars representing 95% confidence intervals were plotted, and the presentation of data is based on a general linear model, with time point, ECMO, and their interaction effect as independent variables. The solid line represents the ECMO patients; the dashed line represents the non-ECMO patients. a The data indicate a significant difference between ECMO and non-ECMO patients.

    Associations Between Growth Measurements and Clinical Variables

    Associations between HFA, DTH, and WFH z scores and clinical variables are shown in Supplemental Table 5. HFA was negatively associated with the duration of PICU stay and positively associated with gestational age. DTH was negatively associated with the duration of PICU stay and patch repair. There were significant interaction effects between time point and ECMO, which showed that ECMO had a negative association with HFA and DTH from 1 to 8 years of age. Tube feeding at follow-up had a positive association with HFA, DTH, and WFH. There was a significant interaction effect between time point and tube feeding on WFH, which showed the highest positive association between tube feeding and WFH at 6 months of age. WFH had a negative association with ECMO, patch repair, and the use of calorie-enriched feeds at follow-up.

    Pilot Study: Indirect Calorimetry

    At the median age of 8.2 years (IQR: 4.4–12.1), 11 patients underwent indirect calorimetry (Supplemental Table 6). REE was profoundly increased in 4 (36%) patients. Seven (64%) patients had a disturbed eating pattern (they could only eat small portions, and it took them longer to eat compared with their peers).

    Discussion

    In this longitudinal study, we observed growth impairments in patients with CDH. High prevalence rates of wasting and stunting were found, especially in ECMO-treated patients. Furthermore, from 6 months to 1 year of age, the mean WFH z score declined, which was followed by a decline in the mean HFA z score until 5 years of age. We assume that the decline in growth during infancy might be explained by inadequate nutritional intake to meet energy needs, and this possible cause should be explored as an initial step. In patients with CDH, feeding difficulties and increased resting and active energy expenditure due to respiratory morbidity contribute to impaired growth. Although results seemed more favorable after correcting for TH, the mean DTH was still less than normal at 12 years of age in both groups.

    Recently, Terui et al10 retrospectively evaluated growth in 174 patients with CDH at 1.5, 3, and 6 years of age. They found wasting and/or stunting in 19.5% of patients at 1.5 years of age. Weight improved from 1.5 to 3 years of age, although stunting remained in 13.5% of patients at 6 years of age. Similar to what we found, chronic malnutrition seemed to develop via acute malnutrition. It is difficult to compare the prevalence rates of Terui et al10 with our prevalence rates because they used different definitions for wasting and stunting than we did. In addition, we had a higher number of ECMO-treated patients (6% vs 25%). We assume that feeding difficulties and increased energy expenditure occur especially in ECMO-treated patients who are the most critically ill and have the most hypoplastic lungs. Therefore, this subgroup of patients is more prone to persistent growth problems. Interestingly, we observed a catch-up of height in ECMO-treated patients from 8 to 12 years of age, which is reassuring. This catch-up growth may be explained by the improvement of clinical problems over time, including lower rates of respiratory infections, hospitalizations, and feeding difficulties. Nevertheless, future studies should evaluate whether this catch-up growth is sustained into adolescence and adulthood.

    Terui et al10 also summarized the results of previous longitudinal studies that retrospectively evaluated growth in patients with CDH until 1 to 2 years of age.5,6,9,11 Some studies reported catch-up growth from the age of 6 months to 1 year6,9; others reported such growth from the ages of 1 to 2 years.5,11 However, it is difficult to compare our results with these studies because of differences in study populations, which included the selection of less severe9 or more severe5 patients with CDH and retrospective study designs with potential selection bias due to relatively high numbers of patients lost to follow-up. In addition, nutritional management strategies differed among centers.

    Multiple factors are thought to be involved in growth problems in patients with CDH, including feeding problems and an increased metabolism due to the increased work of breathing.11 Previous studies identified different variables associated with impaired growth, including lower birth weight,6,10 prematurity,6 ECMO treatment,3,11 patch repair,10 use of inhaled nitric oxide,10 lower protein intake during PICU stay,6 longer duration of mechanical ventilation9,10 and hospital stay,10 need for supplemental oxygen at discharge,6,10,11 and use of GERD therapy at discharge.6 In our study, HFA and DTH were negatively associated with ECMO and the duration of PICU stay. WFH was negatively associated with ECMO, patch repair, and the use of calorie-enriched feeds. ECMO treatment, patch repair, and a longer PICU stay are indicators of more severe CDH, which can explain the negative association between these clinical variables and growth. In addition, during PICU stay, critically ill neonates are subjected to factors that may generate a poor growth status, including mechanical ventilation, surgery, feeding interruptions, and prolonged hospitalization.2123 A recent trial found that not starting parenteral nutrition at up to 1 week in the PICU was superior to an early start of parenteral nutrition.24 This means that one has to be cautious in administering parenteral feeding in the first week of PICU stay. Nevertheless, nutritional support is important for recovery and growth after the acute phase of critical illness. Growth and nutritional assessments and interventions should therefore be considered in the different phases of disease during PICU stay.25

    Malnutrition has been associated with negative effects on long-term outcomes in different groups such as premature infants and children in developing countries. It is associated with immune dysfunction,26 impaired neurodevelopment,7,8 behavioral problems,27 lower educational achievement,28 and lower economic status in adulthood.28 In patients with CDH, lower weight and smaller head circumference at 2 years of age were associated with increased risk of borderline or delayed neurologic outcomes at this age.29 Therefore, we think malnutrition should ideally be prevented, and, if present, should be treated at an early stage. Tube feeding had a positive association with HFA, DTH, and WFH z scores. More liberal and longer use of tube feeding could be considered in patients with impaired growth. However, initiating oral feeding in an early phase is important to avoid feeding difficulties and oral aversion.30 Therefore, a tailor-made approach for each patient with CDH managed by a multidisciplinary nutritional support team is recommended. In addition to the American Academy of Pediatrics guideline recommendations of long-term follow-up,4 we propose a risk stratification flowchart that can be used during follow-up to identify patients who need dietary consultation and intervention (Fig 5, Table 3). This flowchart is based on the Screening Tool for Risk on Nutritional status and Growth (STRONGkids).31,32

    FIGURE 5

    Flowchart for dietary consultation and intervention in patients with CDH. a Use HFA if DTH is not available. b Modified nutritional risk screening tool STRONGkids for patients with CDH (see Table 3).31

    TABLE 3

    Modified Nutritional Risk Screening Tool STRONGkids for Patients With CDH31

    An increased REE and feeding difficulties may contribute to impaired growth. In a pilot study with REE measurements, we found an increased measured REE in 4 (36%) patients and a disturbed eating pattern in 7 (64%). These results emphasize the importance of care by a multidisciplinary nutritional support team. Dietary consultation with REE measurement could serve as a first step to identify possible causes of poor growth. All children with REE measurements were older than 3 years of age. REE may be even higher in the first 2 years of life because of an increased rate of breathing after correction of the defect. Indeed, Haliburton et al33 reported that 10 (59%) of 17 patients were hypermetabolic at the median age of 32 days. Longitudinal studies including more patients should be performed to assess metabolic needs in patients with CDH over time.

    This is the largest prospective cohort study following growth of patients with CDH up to 12 years of age. Other study strengths are the high follow-up rate of 96% and the use of z scores for growth by using recently established reference values for Dutch children.16 In addition, this is the first study to report DTH z scores in patients with CDH. Because adjusting for TH improved height z scores, it seems important to calculate DTH z scores when evaluating growth parameters in patients with CDH.

    Our study has some limitations. The birth weight of most patients was estimated. Therefore, we used growth measurements at 6 months of age as the reference point in the general linear model analyses. Secondly, as this is a longitudinal study, not all children had yet reached the age of 12 years. Although general linear models can account for missing data values, the limited number of children assessed at 12 years of age may have contributed to not finding a significant difference in the mean HFA z scores between ECMO and non-ECMO patients (type II error). Ongoing assessment of growth into adolescence is therefore recommended. In addition, management of CDH changed during the study period, which could have influenced our results. However, we did not find a significant association between HFA, DTH, and WFH z scores and the change in treatment protocol. In our pilot study, nutritional assessments were performed in a limited number of patients, but our results support previous findings.33 In addition, our study highlights the importance of early initiation of nutritional assessment and intervention by a multidisciplinary nutritional team.

    Conclusions

    We found impaired growth in patients with CDH, especially in those who had received ECMO treatment. A decline in weight gain was followed by a decline in linear growth suggestive of inadequate nutritional intake to meet energy needs during infancy. This study shows the importance for early risk stratification for poor growth to identify patients with a high risk, such as those who required ECMO treatment. Early risk stratification should be combined with nutritional assessments and interventions, as well as long-term follow-up of growth. Further studies are needed to determine the relation between growth problems and functional outcomes, both physical and neuropsychological.

    Acknowledgment

    We thank Ko Hagoort for editorial comments.

    Footnotes

      • Accepted April 26, 2017.
    • Address correspondence to Hanneke IJsselstijn, MD, PhD, Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children’s Hospital, Room SK-1280, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands. E-mail: h.ijsselstijn{at}erasmusmc.nl
    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: This study was partially supported by the Swart-van Essen Foundation.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

    References