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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 eal membrane oxygenation (ECMO), significant mortality and
of the diaphragm with an incidence of approximately one per morbidity rates remain in CDH patients.
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 Aetiology and Pathogenesis
the lungs. Maldevelopment of the terminal bronchioles, alveoli
Normally, the diaphragm starts to develop at approximately 4
and pulmonary vessels is the result,2,3 and severe respiratory
weeks of gestation and is fully formed by the twelfth week of
failure occurs soon after birth because of pulmonary hypoplasia
gestation.4 In infants with CDH, one of the components of the
and the presence of pulmonary hypertension. Despite recent
diaphragm does not form properly creating a defect that allows
advances in treatment, such as ‘gentle ventilation’, the use of
abdominal viscera to enter into the thoracic cavity. CDH can be
high-frequency oscillation ventilation (HFOV) and extracorpor-
classified based on the anatomical position of the defect into
posterolateral, anterior and central defects. The posterolateral
Key Points
defect (Bochdalek hernia) occurs in 70–75% of the cases, ante-
1 Aetiology and pathogenesis of congenital diaphragmatic
rior defects (Morgagni hernia) in 23–28% and central defects in
hernia (CDH) are poorly understood. However, several genetic
only 2–7% of the cases. The posterolateral defect most often
and environmental factors appear to play a role in the devel-
occurs on the left side (85%) but can occur on the right side
opment of CDH.
(13%) or even bilaterally (2%).5
2 Best treatment strategies for CDH remain uncertain, and
The pathogenesis of CDH is complex and remains poorly
therapeutic strategies vary widely among centres. Multi-
understood. Nitrofen experiments in mice and rats have dem-
centre, randomised, controlled trials should be encouraged
onstrated that pulmonary hypoplasia in CDH occurs prior to
to investigate this issue and recruit a sufficient number of
diaphragm development.6,7 This observation led to the so- called
CDH patients.
‘dual-hit hypothesis’.8 This hypothesis contends that pulmonary
3 Long-term morbidities are a major cause of concern in CDH
hypoplasia in CDH occurs as the result of two developmental
survivors. Therefore, a close follow-up and long-term care of
insults. The first insult affects both lungs and is occurring before
these patients are important.
the diaphragm has fully developed in a background of genetic
and environmental factors. The second event affects only the
Correspondence: Professor Dominic A Fitzgerald, Department of
ipsilateral lung and is the result of interference with efficient
Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag
fetal breathing movements caused by compression of this lung
4001, Westmead, NSW 2145, Australia. Fax: +61 2 9845 3396; email:
dominic.fitzgerald@health.nsw.gov.au
by the herniated abdominal organs.
Retinoids are thought to play a significant role in the
Conflict of interest: The authors declare that there are no conflicts of pathogenesis of CDH. There are a number of animal studies that
interest.
have linked perturbations of retinoid signalling to CDH.9–11
Accepted for publication 05 January 2014. Further, two clinical studies have demonstrated that retinol and

Journal of Paediatrics and Child Health (2014) 1

© 2014 The Authors
Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Congenital diaphragmatic hernia
Table 1 Congenital abnormalities associated with CDH
Genetic syndromes
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
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, cardio-
vascular 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 ultrasonogra-
phy 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, abnor-
mal cardiac axis or mediastinal shift.22 The presence of abdomi-
nal 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 Journal of Paediatrics and Child Health (2014)
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L Leeuwen and DA Fitzgerald
Chromosomal abnormalities Congenital anomalies
Trisomy 13 Pulmonary
Trisomy 18 Cardiovascular
Trisomy 21 Central nervous system
Turner syndrome Gastrointestinal
Genitourinary
Musculoskeletal
Prenatal diagnosis is important as it allows for patient educa-
tion, 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 hernia-
tion, 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 scaph-
oid 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 man-
agement of CDH. Parents should be informed about the sever-
ity 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 oppor-
tunity for informed decision-making regarding termination of
pregnancy and antenatal therapy options as well as under-
standing of the events that will follow post-natally. To date,
the standard antenatal care for CDH is expectant manage-
ment with ultrasound surveillance for prenatal complications.
© 2014 The Authors
L Leeuwen and DA Fitzgerald
a b
Fig. 1 (a) Pre-operative chest radiograph of a
newborn infant with a left-sided congenital dia-
phragmatic 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 occlu-
sion 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 <1.0. Outcomes of FETO procedures have varied consid-
erably. Some studies reported higher survival rates after a FETO
procedure,28,29 but others have failed to show an improved sur-
vival rate.30 FETO is not offered as a standard intervention in
Australia.
Post-natal management
The post-natal management of CDH has evolved in recent
decades and now includes gentle ventilation with permissive
hypercapnia, delayed surgical repair after stabilisation, with the
use of inhaled nitric oxide (iNO), HFOV and ECMO as rescue
therapies. However, little is known about the best therapy strat-
egy for children with CDH, and studies have shown contradic-
tory results.
In the delivery room, infants with severe CDH are immedi-
ately intubated. Bag mask ventilation should be avoided in CDH
infants because it can lead to abdominal and intestinal disten-
sion with increased respiratory distress. Surgical repair of the
diaphragm defect is undertaken after cardio-respiratory func-
tions are stable, usually in the first week of life. After successful
repair, the chest radiograph considerably improves (Fig. 1b).
Surgical repair can be accomplished by open and minimally
invasive techniques. The method of closure (primary or patch
repair) depends on the size of the diaphragm defect. Small
defects are repaired primarily, whereas large defects require a
patch in order to repair the defect. Minimally invasive
approaches as well as patch repair have been associated with
increased recurrence rates of CDH.31
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)
Congenital diaphragmatic hernia
The ventilation strategy for CDH is based on the principle of
gentle ventilation, which incorporates controlling the peak
inflation pressure by limiting the pressure of ventilation while
tolerating an oxygen saturation of 85% and a rise of the arterial
pressure of CO2 (permissive hypercapnia) and stimulating
spontaneous ventilation.32 This approach achieves adequate
oxygenation while it avoids injury to the lungs from positive
pressure.
HFOV is also increasingly used as a ventilation mode because
it allows adequate oxygenation and CO2 elimination at low
ventilation pressures thereby decreasing iatrogenic pulmonary
barotrauma.33 At the moment, HFOV is mainly used as rescue
therapy when conventional ventilation fails. HFOV has been
shown to be effective in improving oxygenation and ventilation
of neonates with CDH.34 Some studies have also reported that
HFOV improves survival;35,36 however, discrepancies exist.34,37
Additionally, ECMO may be useful in the treatment of
patients with severe CDH. The criteria for ECMO indication in
CDH patients are widely variable among centres. Whereas some
centres use ECMO liberally, others reserve it as a rescue therapy.
The survival rate for children treated with ECMO is approxi-
mately 50%.38 The beneficial effects of ECMO in children
with CDH remain controversial.39 Some studies have shown
increased survival rates with ECMO therapy.40,41 However, other
studies have demonstrated no improved survival,42 and ECMO
has been associated with adverse long-term outcomes such as
impaired neurodevelopmental outcomes, increased respiratory
morbidity and growth failure.43–45
Pulmonary hypertension is common among CDH infants and
is a major cause of mortality.46,47 The optimal treatment of CDH-
associated pulmonary hypertension remains one of the major
therapy challenges. Currently, iNO is the most commonly used
acute treatment for pulmonary hypertension in CDH infants.
However, the beneficial effects of iNO on improvements in
oxygenation and survival are questionable.48 Sildenafil is
another treatment option for persistent pulmonary hyperten-
sion in infants with CDH, which appears to be more effective
than iNO.49 However, further studies are necessary to clarify the
efficacy and safety of sildenafil.
3
Congenital diaphragmatic hernia L Leeuwen and DA Fitzgerald

Survival
Table 2 Recommended schedule of follow-up assessments for chil-
Mortality rates for CDH patients have varied considerably in the dren with CDH
literature. Single institution-based studies report significantly
Age Follow-up assessments
improved survival rates in recent years with survival rates now 3 months Growth
approaching 90%.50,51 However, population-based studies have Respiratory status
found no recent changes in survival rates with an overall mor- 6 months Growth
tality rate remaining high between 42% and 68%.52,53 These Respiratory status
differences are most likely because of the presence of ‘hidden Echocardiography
mortality’.54 The term ‘hidden mortality’ accounts for intra- Hearing evaluation
uterine deaths because of CDH and CDH patients who die before 12 months Growth
arriving at the reporting institution and who, therefore, are not Respiratory status
reported by institution-based studies. This difference in meas- Echocardiography
uring mortality among CDH patients makes it hard to accurately Hearing evaluation
evaluate the influence of the recent advances in treatment on Neurodevelopmental evaluation
survival outcomes; therefore, recently reported increases in sur- 2 years Growth
vival rates should be interpreted with caution. Respiratory status
Echocardiography†
Hearing evaluation
Long-Term Morbidities 3 years Growth
Respiratory status
The long-term outcomes and quality of life of survivors with Echocardiography†
CDH have become an increasingly important issue. CDH Hearing evaluation
patients appear to be at risk for many long-term sequelae Neurodevelopmental evaluation
including pulmonary disease, gastro-intestinal morbidity, poor 5 years Growth
growth, neurological impairment, hearing loss and muscu- Respiratory status
loskeletal abnormalities.55 Additionally, lower quality of life Lung function test
levels have been reported in CDH survivors.56 The high preva- Echocardiography
lence of long-term morbidities among CDH survivors empha- Hearing evaluation
sises the importance of close follow-up and long-term care. 8 years Growth
Table 2 summarises our recommended follow-up schedule for Respiratory status
CDH patients. Lung function test
Echocardiography†
Exercise test
Pulmonary morbidity Scoliosis and chest wall deformity screening
12 years Growth
There is a high incidence of chronic lung disease in CDH survi-
Respiratory status
vors. Pulmonary hypertension in CDH infants can persist during
Lung function test
the first months of life, which is associated with early death.47
Echocardiography†
Initially, neonates with CDH have restrictive lung defects
Hearing evaluation
because of pulmonary hypoplasia. Patients who remain
Exercise test
intubated and mechanically ventilated subsequently develop Scoliosis and chest wall deformity screening
partially reversible lower airway obstruction that suggests the 16 years Growth
presence of airway reactivity.57 Lung function appears to gradu- Respiratory status
ally improve to normal or near-normal lung function during Lung function test
childhood.58 However, a recent study showed that airflow Echocardiography†
obstruction and diffusion capacity deteriorated mildly from Hearing evaluation
childhood into adulthood in survivors of CDH, which demon- Exercise test
strates the importance of long-term follow-up of lung function Scoliosis and chest wall deformity screening
in these children.59
†If evidence of structural heart disease or pulmonary hypertension on
previous echocardiography. CDH, congenital diaphragmatic hernia.
Gastrointestinal morbidity
Gastro-oesophageal reflux (GOR) is present in 45–89% of
infants with CDH.60,61 The pathogenesis of GOR in CDH is not
clearly understood. However, possible aetiologies include abnor- Growth failure and nutritional morbidity
mal hiatal anatomy at the gastro-oesophageal junction, lack of
an angle of His, herniation of the stomach into the chest and Poor growth occurs in many CDH patients, with failure to
presence of oesophageal dilation or ectasia. Further, the inci- thrive being present in up to 69% of CDH survivors at the age
dence of GOR correlates with the defect size and the need for of 1 year.62 The cause for poor growth in CDH patients is mul-
patch repair.55 tifactorial, including increased catabolic stress in the neonatal

4 Journal of Paediatrics and Child Health (2014)

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Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
L Leeuwen and DA Fitzgerald
period, GOR and persistent pulmonary impairment.63 Contrib-
uting to poor growth, oral aversion is reported to be present in
approximately 25% of CDH infants.63
Neurological impairment
Adverse neurodevelopmental outcomes have been identified as
one of the most significant morbidities among CDH survivors.
Neurodevelopmental delays and behavioural disorders occur
in a large number of CDH survivors. However, incidence rates
of impaired neurodevelopmental outcomes in CDH patients
during the first years of life have varied considerably in litera-
ture ranging from 12% to 77%.64,65 Infants requiring ECMO
appear to have the highest risk for adverse neurodevelopmental
outcomes.43,45 Further, an increased risk of sensorineural
hearing loss has been described in CDH survivors with reported
prevalence rates varying between 0% and 100%.65,66
Chest wall deformities
Deformities of the chest wall are commonly described in chil-
dren with CDH. Pectus deformities and progressive asymmetry
of the chest wall have been reported in 21–48% of CDH survi-
vors.67,68 The close relationship between the development of the
lung, diaphragm and thoracic cage is the reason that deformities
of the chest wall are more common in patients with CDH.69
Additionally, scoliosis has been found in 10–27% of these CDH
patients.67,68 The aetiology of scoliosis is probably multifactorial.
However, the pull of a tense diaphragm on its spinal insertion
could produce scoliosis with convexity towards the defect.69
Most of these morbidities are mild and do not require surgical
intervention.
Conclusions
CDH remains a challenging condition with an aetiology and
pathogenesis that are poorly understood. However, both genetic
and environmental factors appear to play a significant role in
the development of CDH. Despite recent advances in treatment,
much remains unknown about the best management for chil-
dren with CDH, and there is a paucity of studies among patients
with CDH. In the future, multicentre studies should be imple-
mented to conduct appropriately sized trials. Additionally, mor-
tality and morbidity rates remain high in CDH patients. CDH
survivors have a high risk of long-term morbidities and a lower
quality of life level. Therefore, a close follow-up by a multidis-
ciplinary team, including respiratory paediatrician, paediatric
surgeon, neonatologist/general paediatrician, nurse practitioner
and dietician, is important as problems can be recognised, diag-
nosed and appropriate care instituted at an earlier stage.
Multiple Choice Questions
Pulmonary hypoplasia in CDH occurs
A. Ipsilaterally
B. Contralaterally
C. Bilaterally
D. Pulmonary hypoplasia does not occur in CDH
C. Although the ipsilateral lung is more affected than the
contralateral lung, pulmonary hypoplasia in CDH occurs bilat-
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)
Congenital diaphragmatic hernia
erally. The dual-hit hypothesis tries to explain pulmonary
hypoplasia in CDH as the result of two developmental insults.
The first insult occurs before the diaphragm has fully devel-
oped in a background of genetic and environmental factors.
This first event is responsible for the occurrence of pulmonary
hypoplasia in both lungs. 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. This second event is the
reason for more severe pulmonary hypoplasia in the ipsilateral
lung.
Which of the following statements is true?
A. Environmental factors do not play a role in the development
of CDH.
B. Most cases of CDH are detected prenatally.
C. After delivery, CDH infants should immediately be ventilated
using a bag mask.
D. Minimal invasive surgery and patch repair are not associated
with increased recurrence rates of diaphragmatic hernias.
E. Right-sided hernia is easily detectable on ultrasound.
A. Incorrect: Both genetic and environmental factors are
thought to play a role in the development of CDH.
B. Correct: CDH is diagnosed prenatally by ultrasonography in
approximately 60% of cases.
C. Incorrect: Bag mask ventilation in CDH infants should be
avoided because it can lead to abdominal and intestinal disten-
sion with increased respiratory distress. Therefore, infants with
severe CDH and respiratory distress should be immediately
intubated after delivery.
D. Incorrect: Minimal invasive surgery and patch repair are
associated with increased recurrence rates of diaphragmatic
hernias.
E. Incorrect: The liver has an echogenicity similar to the lungs.
In right-sided CDH, the liver is usually the only herniated
abdominal organ which makes it hard to detect right-sided CDH
on ultrasonography. Therefore, the diagnosis of right-sided CDH
is more frequently missed than left-sided CDH.
Which of the following statements is false?
A. Right-sided hernia is the most uncommon type of hernia.
B. CDH is associated with trisomy 21, CHARGE syndrome and
genitourinary anomalies.
C. Poor growth, feeding problems and gastro-oesophageal
reflux are long-term morbidities occurring in CDH survivors.
D. Cardiovascular anomalies are the second most common con-
genital anomalies in CDH patients.
E. ECMO is associated with impaired neurodevelopmental out-
comes in CDH survivors.
A. Incorrect: Bilateral hernia is the most uncommon type of
hernia (2%), followed by right-sided hernia (13%). Left-sided
hernia is the most common type of diaphragmatic hernia
(85%).
B. Correct: Trisomy 21, CHARGE syndrome and genitourinary
anomalies are all associated with CDH (see Table 1).
C. Correct: CDH survivors are at risk of many long-term mor-
bidities. Poor growth, feeding problems and gastro-oesophageal
reflux are just a few long-term sequelae that can occur in CDH
survivors.
D. Correct: Cardiovascular anomalies are the second most
common group of congenital anomalies present in CDH infants,
5
Congenital diaphragmatic hernia
occurring in 11–15% of CDH patients without a recognisable
syndrome. The most common group of congenital anomalies is
pulmonary anomalies.
E. Correct: ECMO has been associated with many adverse long-
term outcomes including impaired neurodevelopmental out-
comes being one of the most significant adverse outcomes.
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