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doi:10.1111/jpc.12508
REVIEW ARTICLE
Congenital diaphragmatic hernia Lisette Leeuwen1,2 and Dominic A Fitzgerald1,3 1 Department of Respiratory Medicine, The Children’s Hospital at Westmead, and 3Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia and 2Medical School, University of Groningen, Groningen, The Netherlands
Abstract: Congenital diaphragmatic hernia is an uncommon congenital anomaly of the diaphragm with pulmonary hypoplasia and persistent pulmonary hypertension as serious consequences. Despite recent advances in therapy, congenital diaphragmatic hernia remains a challenging condition. Best treatment strategies are still largely unknown, and practice strategies vary widely among different centres. Additionally, as congenital diaphragmatic hernia is a relatively uncommon condition, it is difficult to recruit sufficient numbers of patients for clinical trials. In recent years, survival rates of congenital diaphragmatic hernia patients appear to have increased. With the progressively improved survival rates, the long-term prognosis and quality of life of patients have become an increasingly important issue. Survivors have been shown to be at risk for many long-term morbidities, which highlights the importance of long-term follow-up of these children. The aim of this review is to give an overview of the current knowledge regarding congenital diaphragmatic hernia. Key words:
congenital diaphragmatic hernia; long-term outcome; pathogenesis; survival; treatment.
Congenital diaphragmatic hernia (CDH) is a congenital anomaly of the diaphragm with an incidence of approximately one per 2500 births.1 During embryonic development, the diaphragm defect forms and abdominal organs herniate through the defect into the thoracic cavity, impeding the normal development of the lungs. Maldevelopment of the terminal bronchioles, alveoli and pulmonary vessels is the result,2,3 and severe respiratory failure occurs soon after birth because of pulmonary hypoplasia and the presence of pulmonary hypertension. Despite recent advances in treatment, such as ‘gentle ventilation’, the use of high-frequency oscillation ventilation (HFOV) and extracorporKey Points 1 Aetiology and pathogenesis of congenital diaphragmatic hernia (CDH) are poorly understood. However, several genetic and environmental factors appear to play a role in the development of CDH. 2 Best treatment strategies for CDH remain uncertain, and therapeutic strategies vary widely among centres. Multicentre, randomised, controlled trials should be encouraged to investigate this issue and recruit a sufficient number of CDH patients. 3 Long-term morbidities are a major cause of concern in CDH survivors. Therefore, a close follow-up and long-term care of these patients are important. Correspondence: Professor Dominic A Fitzgerald, Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Fax: +61 2 9845 3396; email: dominic.fi[email protected] Conflict of interest: The authors declare that there are no conflicts of interest. Accepted for publication 05 January 2014.
eal membrane oxygenation (ECMO), significant mortality and morbidity rates remain in CDH patients.
Aetiology and Pathogenesis Normally, the diaphragm starts to develop at approximately 4 weeks of gestation and is fully formed by the twelfth week of gestation.4 In infants with CDH, one of the components of the diaphragm does not form properly creating a defect that allows abdominal viscera to enter into the thoracic cavity. CDH can be classified based on the anatomical position of the defect into posterolateral, anterior and central defects. The posterolateral defect (Bochdalek hernia) occurs in 70–75% of the cases, anterior defects (Morgagni hernia) in 23–28% and central defects in only 2–7% of the cases. The posterolateral defect most often occurs on the left side (85%) but can occur on the right side (13%) or even bilaterally (2%).5 The pathogenesis of CDH is complex and remains poorly understood. Nitrofen experiments in mice and rats have demonstrated that pulmonary hypoplasia in CDH occurs prior to diaphragm development.6,7 This observation led to the so- called ‘dual-hit hypothesis’.8 This hypothesis contends that pulmonary hypoplasia in CDH occurs as the result of two developmental insults. The first insult affects both lungs and is occurring before the diaphragm has fully developed in a background of genetic and environmental factors. The second event affects only the ipsilateral lung and is the result of interference with efficient fetal breathing movements caused by compression of this lung by the herniated abdominal organs. Retinoids are thought to play a significant role in the pathogenesis of CDH. There are a number of animal studies that have linked perturbations of retinoid signalling to CDH.9–11 Further, two clinical studies have demonstrated that retinol and
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
1
Congenital diaphragmatic hernia
L Leeuwen and DA Fitzgerald
Table 1 Congenital abnormalities associated with CDH Genetic syndromes
Chromosomal abnormalities
Congenital anomalies
Beckwith–Wiedemann syndrome CHARGE syndrome Cornelia de Lange syndrome Craniofrontonasal syndrome Denys–Drash syndrome Donnai-Barrow syndrome Fryns syndrome Pallister–Killian syndrome Simpson–Golabi–Behmel syndrome Thoracoabdominal syndrome Wolf–Hirschorn syndrome
Trisomy 13 Trisomy 18 Trisomy 21 Turner syndrome
Pulmonary Cardiovascular Central nervous system Gastrointestinal Genitourinary Musculoskeletal
Derived from Pober et al.,17 Enns et al.18 and Holder et al.19 CDH, congenital diaphragmatic hernia.
retinol-binding-protein plasma levels are significantly decreased in cord blood of newborns with CDH when compared with newborns without CDH.12,13 Additionally, several studies have presented evidence for an increased risk for the development of CDH by prenatal exposure to various maternal factors such as alcohol, smoking, periconceptional low intake of retinol, obesity and antimicrobial drugs.14–16 However, these results are based upon relatively small patient cohorts; therefore, the contributing effect of these factors remain uncertain. There is also growing evidence supporting genetic causation of CDH. The incidence of associated congenital abnormalities in CDH is approximately 40%.17 Associated genetic syndromes, chromosome abnormalities and congenital anomalies are shown in Table 1.17–19 Apart from pulmonary anomalies, cardiovascular anomalies are the most common group of congenital anomalies present in CDH infants, occurring in 11–15% of CDH patients without a recognisable syndrome.20 Although many candidate genes including COUP-TFII, FOG2, GATA4, WT1 and members of the retinoic acid signalling pathway have been proposed,5,19 no specific causal gene defect has been identified in humans to date.
Diagnosis The diagnosis of CDH can be made prenatally by ultrasonography or is made post-natally when clinical symptoms occur soon after birth. In approximately 60% of the cases, CDH is diagnosed prenatally by ultrasonography.21 The prenatal diagnosis of CDH with ultrasound is made by detecting direct signs, such as the presence of abdominal organs within the thoracic cavity, or indirect signs, such as the presence of polyhydramnios, abnormal cardiac axis or mediastinal shift.22 The presence of abdominal organs in the thoracic cavity is the hallmark in the diagnosis of CDH, and the diagnosis should be suspected when the stomach is not observed in its normal intra-abdominal location. In right-sided CDH, the liver is usually the only herniated abdominal organ which has similar echogenicity to the lung; therefore, the diagnosis of right-sided CDH is more frequently missed.22 2
Prenatal diagnosis is important as it allows for patient education, identification of those cases at risk for the worst outcome, and the opportunity for prenatal intervention and planned delivery in an experienced centre. Several prenatal factors have been proposed to determine post-natal outcomes, including associated congenital anomalies, the presence of liver herniation, sonographic measurement of the lung-to-head ratio (measurement to estimate the degree of pulmonary hypoplasia) and assessment of fetal lung volume by magnetic resonance imaging.23 However, there is no consensus about the usefulness of these prenatal predictors; thus, predicting outcomes for CDH infants and counselling parents remain challenging. Although most infants with CDH are diagnosed prenatally, approximately 40% of the cases are missed. These undiagnosed infants present post-natally with acute respiratory distress. Physical examination may reveal a barrel-shaped chest, a scaphoid abdomen, absence of breathing sounds at the ipsilateral side, shifted cardiac sounds and bowel sounds in the chest.24 Chest and abdominal X rays are usually diagnostic and will show an opacified hemithorax with mass effect and contralateral shift of the mediastinum with stomach and gas-filled loops of bowel in the chest (Fig. 1a).25 Milder forms of CDH may present with mild respiratory or gastrointestinal symptoms after several months or even years.26
Management Antenatal management Counselling is an essential component in the antenatal management of CDH. Parents should be informed about the severity of CDH, the expected pre- and post-natal events, and the risk of poor outcomes including death and several long-term morbidities. Optimal prenatal counselling will allow the opportunity for informed decision-making regarding termination of pregnancy and antenatal therapy options as well as understanding of the events that will follow post-natally. To date, the standard antenatal care for CDH is expectant management with ultrasound surveillance for prenatal complications.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
L Leeuwen and DA Fitzgerald
Congenital diaphragmatic hernia
a
b
Fig. 1 (a) Pre-operative chest radiograph of a newborn infant with a left-sided congenital diaphragmatic hernia (CDH). (b) Post-operative chest radiograph of the same infant several weeks after surgery. The post-operative chest radiograph is considerably improved but shows evidence of left lung hypoplasia with some bulging of the right lung across the midline. Images courtesy of Dr. Neil Caplin.
Importantly, infants with CDH should be delivered at a tertiary perinatal centre at or close by to where they will undergo surgical intervention. In recent years, there has been an increase in the use of fetal surgery as an experimental treatment approach. Fetal tracheal occlusion (FETO) therapy is based on the principle that occlusion of the trachea prevents egress of lung fluid, which increases airway pressure and accelerates lung growth.27 FETO can be considered in patients with a high risk of poor outcomes based on the presence of liver herniation and a lung-to-head ratio
doi:10.1111/jpc.12508
REVIEW ARTICLE
Congenital diaphragmatic hernia Lisette Leeuwen1,2 and Dominic A Fitzgerald1,3 1 Department of Respiratory Medicine, The Children’s Hospital at Westmead, and 3Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia and 2Medical School, University of Groningen, Groningen, The Netherlands
Abstract: Congenital diaphragmatic hernia is an uncommon congenital anomaly of the diaphragm with pulmonary hypoplasia and persistent pulmonary hypertension as serious consequences. Despite recent advances in therapy, congenital diaphragmatic hernia remains a challenging condition. Best treatment strategies are still largely unknown, and practice strategies vary widely among different centres. Additionally, as congenital diaphragmatic hernia is a relatively uncommon condition, it is difficult to recruit sufficient numbers of patients for clinical trials. In recent years, survival rates of congenital diaphragmatic hernia patients appear to have increased. With the progressively improved survival rates, the long-term prognosis and quality of life of patients have become an increasingly important issue. Survivors have been shown to be at risk for many long-term morbidities, which highlights the importance of long-term follow-up of these children. The aim of this review is to give an overview of the current knowledge regarding congenital diaphragmatic hernia. Key words:
congenital diaphragmatic hernia; long-term outcome; pathogenesis; survival; treatment.
Congenital diaphragmatic hernia (CDH) is a congenital anomaly of the diaphragm with an incidence of approximately one per 2500 births.1 During embryonic development, the diaphragm defect forms and abdominal organs herniate through the defect into the thoracic cavity, impeding the normal development of the lungs. Maldevelopment of the terminal bronchioles, alveoli and pulmonary vessels is the result,2,3 and severe respiratory failure occurs soon after birth because of pulmonary hypoplasia and the presence of pulmonary hypertension. Despite recent advances in treatment, such as ‘gentle ventilation’, the use of high-frequency oscillation ventilation (HFOV) and extracorporKey Points 1 Aetiology and pathogenesis of congenital diaphragmatic hernia (CDH) are poorly understood. However, several genetic and environmental factors appear to play a role in the development of CDH. 2 Best treatment strategies for CDH remain uncertain, and therapeutic strategies vary widely among centres. Multicentre, randomised, controlled trials should be encouraged to investigate this issue and recruit a sufficient number of CDH patients. 3 Long-term morbidities are a major cause of concern in CDH survivors. Therefore, a close follow-up and long-term care of these patients are important. Correspondence: Professor Dominic A Fitzgerald, Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Fax: +61 2 9845 3396; email: dominic.fi[email protected] Conflict of interest: The authors declare that there are no conflicts of interest. Accepted for publication 05 January 2014.
eal membrane oxygenation (ECMO), significant mortality and morbidity rates remain in CDH patients.
Aetiology and Pathogenesis Normally, the diaphragm starts to develop at approximately 4 weeks of gestation and is fully formed by the twelfth week of gestation.4 In infants with CDH, one of the components of the diaphragm does not form properly creating a defect that allows abdominal viscera to enter into the thoracic cavity. CDH can be classified based on the anatomical position of the defect into posterolateral, anterior and central defects. The posterolateral defect (Bochdalek hernia) occurs in 70–75% of the cases, anterior defects (Morgagni hernia) in 23–28% and central defects in only 2–7% of the cases. The posterolateral defect most often occurs on the left side (85%) but can occur on the right side (13%) or even bilaterally (2%).5 The pathogenesis of CDH is complex and remains poorly understood. Nitrofen experiments in mice and rats have demonstrated that pulmonary hypoplasia in CDH occurs prior to diaphragm development.6,7 This observation led to the so- called ‘dual-hit hypothesis’.8 This hypothesis contends that pulmonary hypoplasia in CDH occurs as the result of two developmental insults. The first insult affects both lungs and is occurring before the diaphragm has fully developed in a background of genetic and environmental factors. The second event affects only the ipsilateral lung and is the result of interference with efficient fetal breathing movements caused by compression of this lung by the herniated abdominal organs. Retinoids are thought to play a significant role in the pathogenesis of CDH. There are a number of animal studies that have linked perturbations of retinoid signalling to CDH.9–11 Further, two clinical studies have demonstrated that retinol and
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
1
Congenital diaphragmatic hernia
L Leeuwen and DA Fitzgerald
Table 1 Congenital abnormalities associated with CDH Genetic syndromes
Chromosomal abnormalities
Congenital anomalies
Beckwith–Wiedemann syndrome CHARGE syndrome Cornelia de Lange syndrome Craniofrontonasal syndrome Denys–Drash syndrome Donnai-Barrow syndrome Fryns syndrome Pallister–Killian syndrome Simpson–Golabi–Behmel syndrome Thoracoabdominal syndrome Wolf–Hirschorn syndrome
Trisomy 13 Trisomy 18 Trisomy 21 Turner syndrome
Pulmonary Cardiovascular Central nervous system Gastrointestinal Genitourinary Musculoskeletal
Derived from Pober et al.,17 Enns et al.18 and Holder et al.19 CDH, congenital diaphragmatic hernia.
retinol-binding-protein plasma levels are significantly decreased in cord blood of newborns with CDH when compared with newborns without CDH.12,13 Additionally, several studies have presented evidence for an increased risk for the development of CDH by prenatal exposure to various maternal factors such as alcohol, smoking, periconceptional low intake of retinol, obesity and antimicrobial drugs.14–16 However, these results are based upon relatively small patient cohorts; therefore, the contributing effect of these factors remain uncertain. There is also growing evidence supporting genetic causation of CDH. The incidence of associated congenital abnormalities in CDH is approximately 40%.17 Associated genetic syndromes, chromosome abnormalities and congenital anomalies are shown in Table 1.17–19 Apart from pulmonary anomalies, cardiovascular anomalies are the most common group of congenital anomalies present in CDH infants, occurring in 11–15% of CDH patients without a recognisable syndrome.20 Although many candidate genes including COUP-TFII, FOG2, GATA4, WT1 and members of the retinoic acid signalling pathway have been proposed,5,19 no specific causal gene defect has been identified in humans to date.
Diagnosis The diagnosis of CDH can be made prenatally by ultrasonography or is made post-natally when clinical symptoms occur soon after birth. In approximately 60% of the cases, CDH is diagnosed prenatally by ultrasonography.21 The prenatal diagnosis of CDH with ultrasound is made by detecting direct signs, such as the presence of abdominal organs within the thoracic cavity, or indirect signs, such as the presence of polyhydramnios, abnormal cardiac axis or mediastinal shift.22 The presence of abdominal organs in the thoracic cavity is the hallmark in the diagnosis of CDH, and the diagnosis should be suspected when the stomach is not observed in its normal intra-abdominal location. In right-sided CDH, the liver is usually the only herniated abdominal organ which has similar echogenicity to the lung; therefore, the diagnosis of right-sided CDH is more frequently missed.22 2
Prenatal diagnosis is important as it allows for patient education, identification of those cases at risk for the worst outcome, and the opportunity for prenatal intervention and planned delivery in an experienced centre. Several prenatal factors have been proposed to determine post-natal outcomes, including associated congenital anomalies, the presence of liver herniation, sonographic measurement of the lung-to-head ratio (measurement to estimate the degree of pulmonary hypoplasia) and assessment of fetal lung volume by magnetic resonance imaging.23 However, there is no consensus about the usefulness of these prenatal predictors; thus, predicting outcomes for CDH infants and counselling parents remain challenging. Although most infants with CDH are diagnosed prenatally, approximately 40% of the cases are missed. These undiagnosed infants present post-natally with acute respiratory distress. Physical examination may reveal a barrel-shaped chest, a scaphoid abdomen, absence of breathing sounds at the ipsilateral side, shifted cardiac sounds and bowel sounds in the chest.24 Chest and abdominal X rays are usually diagnostic and will show an opacified hemithorax with mass effect and contralateral shift of the mediastinum with stomach and gas-filled loops of bowel in the chest (Fig. 1a).25 Milder forms of CDH may present with mild respiratory or gastrointestinal symptoms after several months or even years.26
Management Antenatal management Counselling is an essential component in the antenatal management of CDH. Parents should be informed about the severity of CDH, the expected pre- and post-natal events, and the risk of poor outcomes including death and several long-term morbidities. Optimal prenatal counselling will allow the opportunity for informed decision-making regarding termination of pregnancy and antenatal therapy options as well as understanding of the events that will follow post-natally. To date, the standard antenatal care for CDH is expectant management with ultrasound surveillance for prenatal complications.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
L Leeuwen and DA Fitzgerald
Congenital diaphragmatic hernia
a
b
Fig. 1 (a) Pre-operative chest radiograph of a newborn infant with a left-sided congenital diaphragmatic hernia (CDH). (b) Post-operative chest radiograph of the same infant several weeks after surgery. The post-operative chest radiograph is considerably improved but shows evidence of left lung hypoplasia with some bulging of the right lung across the midline. Images courtesy of Dr. Neil Caplin.
Importantly, infants with CDH should be delivered at a tertiary perinatal centre at or close by to where they will undergo surgical intervention. In recent years, there has been an increase in the use of fetal surgery as an experimental treatment approach. Fetal tracheal occlusion (FETO) therapy is based on the principle that occlusion of the trachea prevents egress of lung fluid, which increases airway pressure and accelerates lung growth.27 FETO can be considered in patients with a high risk of poor outcomes based on the presence of liver herniation and a lung-to-head ratio
