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Long-term medical and psychosocial outcomes in congenital diaphragmatic hernia survivors
  1. Jason K Tan1,
  2. Georgia Banton2,
  3. Corrado Minutillo1,
  4. Graham L Hall2,3,
  5. Andrew Wilson3,4,
  6. Conor Murray5,
  7. Elizabeth A Nathan6,
  8. Maureen Verheggen4,
  9. James Ramsay7,
  10. Naeem Samnakay8,
  11. Jan Dickinson9
  1. 1 Neonatal Intensive Care Unit, Perth Children’s Hospital, Perth, Western Australia, Australia
  2. 2 Children’s Lung Health, Telethon Kids Institute, Perth, Western Australia, Australia
  3. 3 School of Physiotherapy and Exercise Science, Curtin University – Perth City Campus, Perth, Western Australia, Australia
  4. 4 Department of Respiratory Medicine, Perth Children’s Hospital, Perth, Western Australia, Australia
  5. 5 Department of Radiology, Perth Children’s Hospital, Perth, Western Australia, Australia
  6. 6 Division of Obstetrics and Gynaecology, University of Western Australia Faculty of Medicine Dentistry and Health Sciences, Crawley, Australia
  7. 7 Department of Cardiology, Perth Children’s Hospital, Perth, Western Australia, Australia
  8. 8 Division of Surgery, University of Western Australia Faculty of Health and Medical Sciences, Perth, Western Australia, Australia
  9. 9 Division of Obstetrics and Gynaecology, University of Western Australia Faculty of Health and Medical Sciences, Perth, Western Australia, Australia
  1. Correspondence to Dr. Jason K Tan, Neonatal Intensive Care Unit, Perth Children’s Hospital, Perth, Western Australia 6009, Australia; Jason.Tan{at}health.wa.gov.au

Abstract

Objective Survival rates for congenital diaphragmatic hernia (CDH) are increasing. The long-term outcomes of CDH survivors were compared with a healthy control group to assess the morbidity for guidance of antenatal counselling and long-term follow-up programmes.

Participants and design Participants born with CDH in Western Australia 1993–2008 were eligible with matched controls from the general population. Participants had comprehensive lung function tests, echocardiogram, low-dose chest CT scan and completed a Strengths and Difficulties Questionnaire (SDQ) and quality of life (QOL) questionnaire.

Results 34 matched case–control pairs were recruited. Demographic data between groups were similar. Cases were smaller at follow-up (weight Z-score of −0.2vs0.3; p=0.03; height Z-score of −0.3vs0.6; p=0.01). Cases had lower mean Z-scores for forced expiratory volume in 1 s (FEV1) (−1.49 vs −0.01; p=0.004), FEV1/forced vital capacity (−1.92 vs −1.2; p=0.009) and forced expiratory flow at 25-75% (FEF25-75) (−1.18vs0.23; p=0.007). Cases had significantly worse respiratory mechanics using forced oscillation technique. Subpleural triangles architectural distortion, linear opacities and scoliosis on chest CT were significantly higher in cases. Prosthetic patch requirement was associated with worse lung mechanics and peak cough flow. Cases had significantly higher rates of gastro-oesophageal reflux disease (GORD) and GORD medication usage. Developmental delay was significantly higher in cases. More cases had a total difficulties score in the high to very high range (25% vs 0%, p=0.03) on the SDQ and reported lower objective QOL scores (70.2 vs 79.8, p=0.02).

Conclusion Survivors of CDH may have significant adverse long-term medical and psychosocial issues that would be better recognised and managed in a multidisciplinary clinic.

  • congenital diaphragmatic hernia
  • long-term outcomes

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What is already known on this topic?

  • Children and young adults born with a congenital diaphragmatic hernia (CDH) are at risk of pulmonary, gastrointestinal and cardiovascular complications.

  • The impact on long-term outcomes outside these health domains is poorly understood.

What this study adds?

  • CDH survivors have altered airway and peripheral lung mechanics assessed by forced oscillation technique.

  • The novel use of chest CT scan confirms the presence of gas trapping and parenchymal changes.

  • CDH survivors have similar psychosocial issues and quality of life to controls.

Introduction

Congenital diaphragmatic hernia (CDH) were first described by Morgagni and Bochdelek in the 1800s, with the first successful neonatal operation in 1946.1 Advances in neonatal intensive care have resulted in survival rates as high as 80%2 3; however, long-term sequelae such as reduced lung function,4–6 gastro-oesophageal reflux disease (GORD) and poor growth are commonly reported.7 8 Only a few long-term studies report on cardiovascular, quality of life (QOL), psychosocial and neurodevelopmental outcomes,9–12 with even fewer studies adopting a multidisciplinary approach to reporting sequelae.

This prospective study compares a well-defined population-based cohort of children and adolescents born with CDH with a healthy control group with the following aims: first, to document the respiratory and cardiovascular structure and function of children and adolescents born with CDH; second, to investigate the effects of CDH on growth and general health, and third, to document any longer term effects on QOL and psychosocial development.

Methods

All infants born with a CDH in the state of Western Australia between 1993 and 2008 inclusive were identified from the Maternal Fetal Medicine Service Database at King Edward Memorial Hospital for Women and the Neonatal Database of the Princess Margaret Hospital for Children. These were the only tertiary obstetric and children’s hospitals in WA during this period, enabling complete case ascertainment. Children over 5 years of age with a CDH repaired in the neonatal period were eligible for inclusion. A minimum age of 5 years was chosen to better assess longer term outcomes. The control group was recruited from the general population with advertisements placed in hospitals, local recreation clubs and newspapers. For one of the preterm cases, their control was their twin. Cases and controls were matched on a 1:1 ratio for gestational age, gender and age at review. Controls were excluded if they had a chronic illness or persistent asthma requiring regular systemic medication.

A paediatrician/paediatric fellow assessed each participant prior to the other assessments and questionnaires. Growth parameters were converted to a Z-score using the WHO 2007 growth reference ranges.13 A general medical, respiratory, gastrointestinal and school performance questionnaire was completed.

The Comprehensive Quality of Life – School Children Questionnaire, Fifth Edition, for children 11–18 years of age and scoring guide was used.14 The QOL questionnaire was completed by children 11 years and over and was chosen to allow self-reporting. Seven domains are reported: material well-being, health, productivity, intimacy, safety, place in community and emotional well-being. An objective and subjective score was calculated for each domain and converted to an overall objective and subjective score (% scale maximum [%SM]).

Behavioural and emotional conditions were screened using the Strengths and Difficulties Questionnaire (SDQ). An overall score was calculated for the five measured scales (emotional symptoms, conduct problems, hyperactivity problems, peer problems and prosocial behaviour) and reported as normal, borderline, high or very high.15 16 The risk of a psychiatric disorder (conduct-oppositional disorders, hyperactivity-inattention disorders, anxiety-depressive disorders and any psychiatric disorder) was reported as ‘unlikely’, ‘possible’ and ‘probable’, which correlates with a diagnosis of a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) psychiatric disorder in approximately 2%, 11% and 53%, respectively.15 16 A clinical psychologist referral was offered if the score was in the probable range.

A comprehensive panel of lung function tests were performed: spirometry, body plethysmography, gas transfer of the lung (TLCO) using the single breath carbon monoxide test, sniff nasal inspiratory pressure (SNIP), peak cough flow (PCF) tests (Medisoft, MGC Diagnostics, Belgium) and forced oscillation technique (FOT; I2M Chess Medical, Ghent, Belgium). Lung function outcomes were derived from acceptable and repeatable tests obtained in accordance to American Thoracic Society/European Respiratory Society standards.17–20 All respiratory measures except SNIP and PCF were converted to a Z-score based on published norms.17 21 The SNIP and PCF were converted to %predicted based on established reference values in healthy children.22 23 The lower limit of normal equating to a Z-score <−1.64 and an upper limit of normal equating to a Z-score >+1.64 was used to define abnormal lung function. A clinical/physiological difference between groups was defined as a difference in Z-score of 0.5 between groups suggested by the Consensus with the Global Lungs Initiative scientific advisory panel (http://www.lungfunction.org), which was supported by an editorial.24 25

A paediatric echocardiographer performed transthoracic echocardiogram with a GE Vivid-q ultrasound machine (General Electric, Boston, Massachusetts, USA) that was reported by a paediatric cardiologist. Echocardiographic standards described by the American Society of Echocardiography (ASE) guidelines, and the ASE guidelines for clinical trials taskforce for echocardiography were used.26 27 Systolic function, global function, pulsed wave Doppler, Doppler tissue imaging, left ventricular diastolic function, right ventricular diastolic function and pulmonary artery pressure estimates were assessed.

Low-dose, spirometry-guided, chest CT scan was performed. The scan was a high pitch (FLASH mode) helical acquisition without intravenous contrast using a tube voltage of 100 kVp and current of 10 mAs on inspiration and 80 kVp and 4 mAs on expiration for an effective dose of 0.2 to 0.3 mSv (dose was age dependent). A paediatric radiologist and pulmonologist blinded to the clinical data consensus reported the CT scans. A score for each hemithorax and a total chest CT score were calculated using a modified Brody score for the presence and severity of lung opacification, nodules, gas trapping, peripheral linear or subpleural triangular densities and calibre and thickness of small airways.28 The diaphragm position was recorded.

Informed consent or assent was obtained from eligible participants and caregivers. The institutional radiation safety officer assessed the radiation dose and approved the use of low dose CT scan. The radiation exposure from the CT scan was emphasised to participants and carers (equivalent to no more than three chest X-rays), and they were given the opportunity to opt out of this part of the study.

Data and statistical analysis

Continuous data summaries were presented as mean and SD or median, IQR and range, according to data normality. Categorical data were summarised by frequency distributions. Comparisons of continuous outcomes between cases and controls were made using the paired t-test or the Wilcoxon signed-rank test, and categorical outcomes were compared using the McNemar test to account for the pair-matching of the subjects. Comparisons between cases with and without a prosthetic patch were made using independent t-tests. SPSS statistical software was used in data analysis (V.22.0). All hypothesis tests were two sided, and p values <0.05 were considered statistically significant.

Results

During the target period, there were 96 live births with a CDH; 37 died leaving 59 eligible survivors. Of these, 36/59 (61%) participated in the study (figure 1). The non-participating survivors were similar to the participating survivors with regards to gestation age (GA), gender and the need for a patch (data not shown). A left-sided CDH occurred in 31/36 (86%) and 9/36 (24%) had a prosthetic patch for closure. Thirty-four of these participants were matched with controls on gestational age, age and gender for analysis.

Figure 1

Flow chart of participants. CDH, congenital diaphragmatic hernia.

Neonatal details of cases

The median duration of mechanical ventilation was 6 days (range 1–80 days), which was significantly higher among cases with a prosthetic patch (median 28 days, range 6–80 days vs median 5 days, range 1–16 days, p<0.001). High frequency oscillation ventilation was used in 12/34 (35%) participants. Echocardiography reports were available for 26/34 (76%) participants, of which 20/34 (59%) had evidence of pulmonary hypertension (two had no pulmonary hypertension, eight had mild, seven had moderate and three had severe). Nitric oxide was used for 9/34 (26%) of participants. Inotropic support was required in 14/34 (41%) of participants.

Demographic and growth data

Gender, gestational age and age at follow-up was similar between groups. At follow-up, cases had significantly lower height and weight Z-scores compared with controls (table 1).

Table 1

Demographic and growth data

Respiratory outcomes

Spirometry

Reproducible spirometry data were available in 24/36 (67%) cases and 27/34 (76%) controls. Cases had evidence of reduced forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) and FEF25-75 but not FVC Z-scores when compared with controls (table 2). The FVC Z-score was 0.61 less in cases compared with controls, which is physiologically relevant.

Table 2

Comparison of lung function between groups

Plethysmography

Reproducible lung volume data were available in 13/36 (36%) cases and 12/34 (35%) controls. The mean Z-score for residual volume (RV), FRC and total lung capacity (TLC) Z-scores were similar between cases and controls (table 2). The RV/TLC ratio Z-score was 0.89 higher in cases compared with controls.

SNIP and PCF

SNIP and PCF data were available in 29/36 (81%) cases and 29/34 (85%) controls (table 2). There was no statistical difference in SNIP between groups; however, %predicted SNIP was 9% lower in cases. Cases had significantly lower PCF compared with controls.

Transfer capacity of the lung

TLCO data were available in 13/36 (36%) cases and 13/34 (38%) controls. TLCO outcomes (alveolar volume, TLCO/VA or TLCO) were similar between groups (table 2). However, the TLCO difference was large between groups (0.81 in cases vs 1.64 in controls).

Forced oscillation technique

FOT testing was completed by all cases and 33/34 (97%) controls (table 3). Cases had worse respiratory mechanics, including area under the reactance curve, respiratory resistance and reactance at 8 Hz Z-scores (Rrs8) compared with controls.

Table 3

Comparison of respiratory mechanics between groups

Prosthetic patch and lung function

There were 9/36 (25%) cases that required a prosthetic patch. The use of a prosthetic patch was significantly associated with impaired lung mechanics and reduced PCF (table 4). Other lung function measures were not presented because of the small numbers in each group.

Table 4

Effect of a prosthetic patch on lung mechanics

Chest CT scan

There were 26 matched pairs for analysis of the CT chest. Subpleural triangles, architectural distortion and linear opacities were significantly higher in cases compared with controls. Gas trapping, atelectasis and evidence of bronchial wall thickening and bronchiectasis were similar between groups (table 5). Scoliosis and pectus excavatum was seen significantly more in cases compared with controls.

Table 5

Comparison of chest CT scan findings between groups

Cardiovascular outcomes

Borderline diastolic dysfunction of the left ventricle was found in four cases, right ventricle in one case and biventricular in one. One case had borderline systolic dysfunction of the left ventricle. There was no evidence of persistent pulmonary hypertension in any of the cases.

Questionnaires

Medical questionnaires

Questionnaire data were available for 32 matched pairs (table 6). Reported rates of asthma diagnosis were similar between groups; however, significantly more cases used asthma medications any time in the past (58% vs 27%, p=0.01). Significantly, more cases reported cough or shortness of breath when they were well or active, reduced activity levels and disrupted sleep. Parental anxiety and disturbance of parental sleep were significantly higher in cases.

Table 6

Long-term medical outcomes

Gastro-oesophageal reflux disease (GORD) and use of GORD medication was significantly more common in cases (table 6). Three cases had fundoplication for severe GORD; all were reported as successful by parents. Poor growth was frequently reported in cases (32% vs 6%, p=0.02).

Parents of cases reported significantly higher rates of developmental delay, teacher-raised concerns and need for a teacher’s aide (table 6). Significantly more cases had a referral to the State Child Development service (29% vs 0%; p=0.008). This was for speech and language in 14/34 (41%), early developmental delay in 10/34 (29%), literacy issues in 7/34 (21%) and autism assessment in 4/34 (12%).

Strengths and difficulties screening questionnaire

SDQ scores were available for 24 matched case–control pairs (table 7). There were more cases that had a ‘total difficulties’ score in the high to very high range (25% vs 0%, p=0.03). Individual scale scores were similar between groups. A similar proportion of cases and controls fell into either the possible or probable category for the three groups of psychiatric disorders; however, there appeared to be a higher proportion in the hyperactivity/concentration disorder group (p=0.07).

Table 7

Psychosocial screening outcomes

Quality of life

All cases and controls over 11 years completed the QOL questionnaire with full information on 11 matched pairs. The safety domain was the only scale with significantly lower %SM score in cases compared with controls (75 vs 91.7, p=0.03). The overall objective axis (%SM score) was lower in cases compared with controls (70.2 vs 79.8, p=0.05).

The subjective scores for all seven domains were similar between the two groups. The %SM score for the overall subjective axis was similar between the two groups (74.4 vs 80.1, p=0.505).

Discussion

We have shown that infants born with a CDH are at high risk of long-term morbidities affecting multiple systems and therefore require a multidisciplinary approach to their follow-up care. The assessment of respiratory mechanics and structural abnormalities of the lungs provides new information on the pathophysiology of the respiratory disease seen in CDH survivors.

Our cohort had evidence of obstructive airways disease and altered respiratory mechanics with increased resistance and reduced reactance. Similar studies have reported rates of obstructive airways disease ranging from 25% to 67%,5 6 29 30 with evidence these changes persist into adulthood.31 32 Impairments in respiratory resistance reflect airway, parenchymal and chest wall mechanics but are likely to be dominated by changes in the resistance of conducting airways, which contribute to the majority of respiratory resistance. The increased Rrs supports the high level of airway obstruction suggested by spirometry. Basek et al 29 are the only other group that used FOT and found increased predicted resistance at 8 Hz in 15 CDH survivors. No other FOT measures were reported, so further comparison with our data was not possible. The altered respiratory reactance seen in survivors of CDH is likely to reflect changes in peripheral lung mechanics, including peripheral airways, chest wall mechanics and parenchymal mechanics.

The aetiology of lung disease in CDH survivors is multifactorial and includes hypoplasia of both lungs; parenchymal lung disease from ventilator-induced lung injury and hyperinflation; diaphragmatic dysfunction; and anatomical changes to the chest wall and spine.5 33 34 The global parenchymal injury (subpleural triangles and linear opacities) seen on the CT scans and the linked changes in peripheral lung mechanics are likely a result of hyperinflation of both lungs that leads to stretching and alteration of the parenchymal architecture.33 While we did not report a difference in lung volumes between groups, there was a difference of 0.89 Z-scores in RV/TLC ratio (table 2) suggesting the presence of air trapping, although this requires further investigation in a larger cohort. Scoliosis was common in our cohort, which may be due to the sensitivity of CT scan. Only three cases had scoliosis identified on clinical examination. Four of the 12 participants with scoliosis have ongoing regular follow-up with an orthopaedic surgeon. The scoliosis and chest wall deformities may be due to the asymmetrical lung development35 and has been associated with restrictive and obstructive lung disease.35 36 The use of CT has helped confirm the aetiology of lung disease seen in CDH survivors.

The use of a prosthetic patch was associated with impaired lung mechanics and diaphragm dysfunction. Other groups report the use of a prosthetic patch and longer mechanical ventilation predicts long-term lung disease.18 30 37 The use of a patch is generally reserved for larger defects, hence expected to predict poorer outcomes.

None of our cohort had pulmonary artery hypertension (PAH) at follow-up, and the mix of mild systolic or diastolic dysfunction was of unknown clinical significance. Similarly, other studies that did not find PAH in CDH survivors, between 1 and 16 years of age, did not find long-term PAH.34 38 39 This may be due to selection bias of less severe cases, because hospitals using extracorporeal membrane oxygenation (ECMO) have reported PAH in 14%–38% of their cohort.40 41

Our study provides contemporary data supporting the view that CDH survivors are at risk of psychosocial issues, particularly attentional difficulties that required community child development service input. Conversely, Michel et al 42 found their cohort fell within the normal range for all SDQ subscales. Other groups have reported similar emotional and behavioural problems such as attention and concentration difficulties and depression to our cohort.43 44 Access to child development services in our cohort was common with other studies reporting early school age neurobehavioural sequelae.12 It is important for follow-up programmes to incorporate screening for psychosocial issues and to continue screening for these conditions through to adulthood.

CDH survivors have multiple medical comorbidities that may impact on their QOL; however, this has not been well described. Studies have found QOL in younger children (parental report) is reduced but improves by adolescence and adulthood.45 46 Our cohort had similar QOL outcomes compared with controls. A possible explanation for the improved QOL with increasing age is that CDH survivors adapt to their physical limitations and compared with their parents underestimate the impact of their physical limitations.43 We did not quantify the impact on the family, but Chen et al found that families of CDH survivors may have lower functional status.47

CDH survivors have complex long-term morbidities, some of which may not be routinely monitored such as scoliosis and psychosocial development in early adulthood. Results from our data and multidisciplinary follow-up clinics in Canada, USA and Europe have helped to standardise follow-up, which is useful given the low incidence of CDH.12 These clinics will assist in early detection and treatment of the multiple comorbidities experienced by CDH survivors.

The role of ECMO for management of CDH is unclear with data from Toronto, Boston and reviews finding no long-term survival benefit with ECMO.48–51 Long-term morbidity after ECMO such as respiratory, gastrointestinal and severe neurodevelopmental problems are as high or higher than our cohort.52 53 Research is needed to identify infants that will benefit most from ECMO and to provide contemporary long-term data after ECMO.

Our study is limited by the small sample size due to the low incidence of CDH, time period for eligibility and geographical limitations, thus the data should be interpreted with this in mind. Although we were unable to contact and recruit the entire cohort, the two groups were similar. There may have been selection bias, with our cohort having less severe disease. ECMO was not available during the study period; however, approximately one-third of our cohort had moderate to severe PAH, which required nitric oxide and HFOV.

Strengths of our study include a matched control group for comparison; a single unit recruitment, thus more uniform management; extensive cardiopulmonary testing including chest CT scans; and a mix of parent and self-reported questionnaires.

Conclusion

CDH survivors have high rates of respiratory, gastrointestinal and psychosocial sequelae with those having prolonged ventilation or a patch for repair being at highest risk. It is important that clinicians adopt a comprehensive follow-up of infants born with a CDH. Given the low incidence of CDH, we recommend units joining local and international CDH registries and setting up multidisciplinary follow-up clinics to observe trends and facilitate audits to improve outcomes.

References

Footnotes

  • Contributors JKGT conceptualised and designed the study, designed the data collection instruments, collected data, coordinated and supervised data collection, drafted the initial manuscript and reviewed and revised the manuscript. GB designed the data collection instruments, collected data, coordinated and supervised data collection and reviewed and revised the manuscript. CM conceptualised and designed the study, designed the data collection instruments, collected data, coordinated and supervised data collection and reviewed and revised the manuscript. GLH and MV designed the study, designed the data collection instruments, reviewed and reported all respiratory function tests and reviewed and revised the manuscript. AW and CM conceptualised and designed the study, designed the data collection instruments, reviewed and reported all chest CT scans and reviewed and revised the manuscript. EAN designed the study, reviewed and conducted all statistical analyses and reviewed and revised the manuscript. JR conceptualised and designed the study, designed the data collection instruments, reviewed and reported all echocardiograms and reviewed and revised the manuscript. NS designed the study, coordinated and supervised data collection and critically reviewed the manuscript for important intellectual content. JD conceptualised and designed the study, coordinated and supervised data collection and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

  • Funding All phases of this study were supported by a research grant from Channel 7 Telethon.

  • Competing interests None declared.

  • Ethics approval The Princess Margaret Hospital Human Research Ethics Committee approved this study (reference 2017EP).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data that are included in the manuscript may be available upon contact with the corresponding author. There are some data that are unpublished. These data were reviewed by the statistician who felt that because of the small numbers no statistical analysis should be performed. These data may be available upon contact with the corresponding author.

  • Patient consent for publication Not required.