Congenital diaphragmatic hernia

Congenital diaphragmatic hernia

PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 323–335 CME ARTICLE Congenital diaphragmatic hernia Paul D. Robinson1,2,* and Dominic A. Fitzgerald1,2 1 D...

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PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 323–335

CME ARTICLE

Congenital diaphragmatic hernia Paul D. Robinson1,2,* and Dominic A. Fitzgerald1,2 1

Department of Respiratory Medicine, The Children’s Hospital at Westmead, University of Sydney, New South Wales, Westmead, Australia; 2The Children’s Hospital at Westmead Clinical School, Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia

EDUCATIONAL AIMS  To appreciate recent advances in the understanding of the pathophysiology of congenital diaphragmatic hernia (CDH).  To appreciate the significant morbidity that accompanies survival beyond the neonatal period in CDH and the need for multidisciplinary follow up.  To appreciate that despite advances in a number of important areas, including foetal surgery and perinatal clinical management, CDH remains a condition with significant mortality.  To appreciate that postnatal diagnosis occurs in a significant number of cases. There is frequent misdiagnosis on the initial chest radiograph for late presenting cases of CDH.

Summary The incidence of congenital diaphragmatic hernia (CDH) may be as high as 1 in 2000. Over the past two decades, antenatal diagnosis rates have increased, the pathophysiology of CDH has become better understood, and advances in clinical care, including foetal surgery, have occurred. However, there remains a paucity of randomised controlled trials to provide evidence-based management guidelines. Reports of improved survival rates appear to be confined to a select subset of CDH infants, surviving to surgical repair, while the overall mortality, at over 60%, appears to be unchanged, largely due to the often forgotten ‘hidden mortality’ of CDH. The significant long-term morbidity in surviving infants has become apparent, and the need for long-term multidisciplinary follow up established. A total of 10% of cases may present later in life, and misdiagnosis on initial chest X-ray may lead to significant morbidity. Crown Copyright ß 2007 Published by Elsevier Ltd. All rights reserved.

The incidence of congenital diaphragmatic hernia (CDH) has been reported as 1 in 3000–5000 live births,1 however, in population studies – including cases resulting in premature terminations, still births and neonatal deaths prior to transfer to tertiary centres – the incidence approaches 1 in * Corresponding author. The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address: [email protected] (P.D. Robinson).

2000.1,2 Over the past two decades, antenatal diagnosis rates have increased, the pathophysiology has become better understood, and advances in clinical care have occurred. The significant long-term morbidity has become apparent, and the need for long-term follow-up established. The International CDH registry, established in 1995, contains over 3000 cases, but there remains a paucity of randomised controlled trials to provide evidence-based management guidelines.

1526-0542/$ – see front matter. Crown Copyright ß 2007 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2007.08.004

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PATHOPHYSIOLOGY Herniation of abdominal contents occurs most often, in over 95% of cases, through the posterior foramen of Bochdalek, posterior and lateral to the spine, with 80% occurring on the left side.3 Less commonly, retrosternal herniation occurs, through the foramen of Morgagni. The exact mechanism of lung hypoplasia in CDH is a matter of debate. The traditional view involved a diaphragmatic defect resulting from failed closure of the pleuroperitoneal canals by the end of the embryonic period (weeks 8–10 of gestation). Herniation of abdominal viscera into the thorax resulted in compression of the developing ipsilateral lung, and to a lesser extent the contralateral lung. This view is supported by surgically reproduced CDH rabbit and lamb models.4 However, the herbicide-induced (nitrofen) model in mice and rats demonstrates lung hypoplasia occurring prior to diaphragm development, in week 5 of gestation, without concomitant mechanical pressure from herniated viscera.4 In the ‘dual hit hypothesis’, a first insult occurs early in development affecting branching morphogenesis of both lungs equally, followed by a second, diaphragmatic insult, affecting the ipsilateral lung at a later stage of development via both mechanical compression by herniated abdominal organs, and decreased foetal breathing movements causing impaired lung fluid regulation.5 Embryological mesenchyme contains precursors of diaphragm, pulmonary airway and vascular smooth muscle. Distal pulmonary mesenchyme secretes important growth factors for lung development, including fibroblast growth factor 10 (FGF-10), which is essential for lung morphogenesis. FGF-10 deficiency produces pulmonary atresia in a mouse model,6 and is documented in nitrofen-induced CDH animal models, with substantial reversibility demonstrated on supplementation.7 FGF-10 producing mesenchymal cells differentiate into airway smooth muscle cells, which play a key role in early lung growth in maintaining intraluminal pressure via airway peristaltic mechanisms, and later in gestation regulating compliance.8 Deficiency of the FGF-10 producing mesenchymal cells may increase the lungs’ vulnerability to compression by herniated viscera. Abnormalities in pulmonary vasculature found in CDH may be explained if this mesenchymal lesion extended to progenitors of pulmonary vascular smooth muscle.9 This recently proposed ‘smooth muscle hypothesis’ provides an interesting potential explanation of CDH pathophysiology. Consequently, the reports of airway hyper-responsiveness in CDH survivors are of interest (see later section). Moreover, a recently reported mutation in the Fog-2 gene, expressed in early mesenchyme, represents the first identified in non-syndromic CDH.10 While a teratogen is central to CDH pathophysiology in the rodent model, no teratogen has been implicated in human CDH. Drugs have been associated, including thalidomide, quinine, and antiepileptic drugs.11,12 CDH has

P. D. ROBINSON, AND D. A. FITZGERALD also been reported in an infant born to a diabetic mother,13 and with both vitamin A toxicity and deficiency.14 The retinoic acid pathway is an important component of the nitrofen-induced CDH pathway.15 A vitamin A deficient diet produces pups with a 25–40% incidence of CDH.16 Vitamin A supplementation decreases the incidence of nitrofen-induced CDH from 54% to 15%,17 and reverses nitrofen-induced lung18 and heart hypoplasia.19 Antenatal administration decreases ventilator-induced lung injury in CDH lambs.20 Decreased serum markers of vitamin A are documented in infants with CDH, compared with controls.21 Animal studies to further define this potential and risk of teratogenicity are necessary before antenatal supplementation in humans can be explored. Antioxidant acceleration effect on lung growth has led to other antioxidants – such as glutathione and vitamins C and E – being explored as potential therapeutic agents. In-utero gene therapy, using the CFTR gene in combination with an adenoviral expression vector, significantly improves lung development in the rat nitrofen model.22 Chloride transport is an important component of lung fluid secretion. Whether this observed effect represents correction of an underlying deficiency or true over-expression remains to be answered and there are concerns regarding safety of CFTR over-expression given the detrimental effect seen in previous mice experiments.23 Whether a CFTR-deficient state exists in CDH infants is also unclear. However, this potentially represents a less invasive in-utero therapy to foetal surgery (discussed in a later section). The importance of abnormal pulmonary vasculature as a determinant of survival has emerged. Foetal hypoxia is the main stimulant for angiogenesis, via activation of target genes including vascular endothelial growth factor (VEGF) by transcription factors.24 The literature is conflicting regarding VEGF in CDH, with decreased levels in lungs of CDH rats,25 but increased expression in infants with CDH.26 Both structural and functional pulmonary vascular abnormalities occur in CDH. Specifically, the small crosssectional area of pulmonary vessels causes a fixed component of high resistance, with additional structural vascular remodelling, and vasoconstriction with altered pulmonary vasoreactivity.27 Decreased pulmonary blood flow causes lung parenchymal hypoplasia,28 which may contribute to compression-induced hypoplasia. Hormonal modulation may be important. Glucocorticoids improve lung maturity and normalise pulmonary vascular wall thickening in animal CDH models, and increased glucocorticoid receptor expression has been demonstrated in CDH infants.29

ANTENATAL DIAGNOSIS Prenatal diagnosis allows patient education, potential identification of those cases at risk for worst outcome, and the opportunity for prenatal intervention. Despite advances in antenatal detection, perinatal mortality remains high.

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Paediatric survival data are not applicable to all cases of prenatally diagnosed CDH, as reported outcomes concern cases surviving pregnancy and the immediate neonatal period. Right-sided and bilateral defects are associated with a worse outcome with a mortality rate of up to 80% and 100%, respectively.30 Prenatal ultrasound detection is only successful in 50% of cases,31,32 with regional variation from 29% to 100%. This increases to 72% if additional anomalies or an abnormal karyotype are detected.31 A significant number are detected after 24 weeks of gestation. The study quality plays a significant role, with obvious features not recognised in one-third of cases, and suboptimal examination found in two-thirds of cases.33 None were missed because the defect was too small. CDH is most commonly diagnosed on ultrasound by the presence of abdominal organs within the thoracic cavity. Indirect signs include polyhydramnios, abnormal cardiac axis and mediastinal shift. Peristalsis of a fluid-filled stomach and small intestine within the thorax may be seen late in gestation. Rightsided CDH may be especially difficult to detect, as the liver has similar echogenicity to the lung, and may be the only organ to have herniated into the chest. Localisation of the gallbladder and other indirect signs may be especially useful in this case. Associated structural anomalies are found in 39% of cases (ranging from 25% to 58% in reported series),34 rising to 95% in those with intrauterine demise.35 Most common are congenital heart defects (patent ductus arteriosus, ventricular septal defects, tetralogy of Fallot, or cardiac hypoplasia), renal (23%), central nervous system (10%), and gastrointestinal (GI) anomalies (14%).36 In cases of foetal demise, central nervous system defects predominate.

GENETICS Isolated CDH is a sporadic condition, with familial cases accounting for less than 2%.37 Familial cases are more likely to be isolated findings and have a higher incidence of bilateral defects. The risk of recurrence is approximately 2%, in the absence of a family history.38 A variety of Mendelian pedigrees, ranging from autosomal recessive to autosomal dominant or X-linked, have been described. CDH may also occur as part of a syndrome,39 with at least 10% of patients with CDH and additional birth defects estimated to have an underlying syndromal diagnosis14 (see Table 1). Fryns syndrome is the most common autosomal recessive syndrome associated with CDH, reported in up to 10% of patients with CDH,40 comprising CDH, pulmonary hypoplasia, craniofacial abnormalities, distal limb hypoplasia and internal malformations.41 The underlying mechanism of pathogenesis of CDH in these syndromes remains unclear . Chromosomal defects occur in 33% of cases with CDH,14 with multiple anomalies more likely to have chro-

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Table 1 Syndromes associated with congenital diaphragmatic hernia14,137 Syndrome Fryns syndrome Beckwith–Wiedemann syndrome Brachman–de Lange syndrome Simpson–Golabi–Behmel syndrome Donnai syndrome Denys–Drash syndrome Perlman syndrome Craniofrontonasal syndrome Spondylocostal dysostosis Marfan syndrome Donnai–Barrow syndrome Gershoni–Baruch syndrome Matthew–Wood syndrome

mosomal abnormalities. Almost every chromosome has been implicated, and potential causative gene locations for CDH are suggested by recurrently reported anomalies.42 Duplication or deletion mutations, producing aneuploidic karyotypes, such as Turners syndrome and trisomy 21,14 are the most commonly reported. Partial trisomies, 22q42 and 11q,43 and chromosome deletions, 1q42.11 to 1q42.3,14 and 15q26.1 to 15q26.2,44 as well as a gene involved in diaphragm formation at distal Xp45 have been reported.46 Karyotype analysis should be performed in every child with CDH and additional malformations not directly caused by the hernia.

POSTNATAL DIAGNOSIS CDH commonly presents with severe immediate cardiorespiratory distress with cyanosis, tachypnoea and tachycardia. On examination, there is a prominent hemithorax with minimal air entry, a displaced apex beat indicating mediastinal shift, and often a scaphoid abdomen. Chest and abdominal X-rays are usually diagnostic (see Fig. 1). However, 10% of CDH may present later in life,47 with a differing clinical picture. A recent retrospective review of the CDH study group database,47 described a mean age at diagnosis of 1 year (32 days to 15 years), no difference, compared with classical neonatal CDH, in sex distribution, side of hernia, birth weight, gestational age at birth, and incidence of major anomalies. The most frequent presentation was respiratory (43%), followed by GI (33%), both respiratory and GI (13%) and asymptomatic (11%). The majority of right-sided lesions present with respiratory symptoms, confirmed elsewhere.48 Blockage of the defect with the liver may prevent subsequent hollow viscera herniation and development of GI symptoms.47 Equal incidence of respiratory and GI symptoms was seen with left-sided lesions.

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INITIAL MANAGEMENT

Figure 1 Neonatal chest X-ray showing left-sided congenital diaphragmatic hernia. The stomach is at the level of the 10th rib. Multiple gas-filled bowel loops are present within the left hemithorax. There is mediastinal shift to the right with compression of the right lung. The mild increase in density within the right lung may indicate oedema or retained fluid. The patient is ventilated and has a long line in situ.

A routine chest X-ray is recommended in all children with unexplained respiratory or GI symptoms.47,48 While the outcome is more favourable, misdiagnosis can result in considerable morbidity. Misinterpretation of initial chest Xray changes occurred in 25%, with pneumothorax or effusion the most common incorrect diagnosis.48 Bowel or liver perforation from incorrect chest drain placement is an important potential consequence. Nasogastric tube insertion, to identify stomach position, and upper GI contrast studies aid correct diagnosis of left-sided lesions. Computed tomography may be useful to identify liver herniation in right-sided CDH.48

DIFFERENTIAL DIAGNOSIS Foetal lung lesions can cause significant mass effect, resulting in non-immune hydrops, and leading to foetal and postnatal infant demise. These include extralobular sequestration, congenital cystic adenomatoid malformation, congenital lobar emphysema, diffuse pulmonary cysts, and more rarely pulmonary agenesis. Distinction between these differential diagnoses antenatally is often difficult, although CDH can be excluded by the presence of normal intraabdominal organs and is more likely when peristalsis is seen within the thorax. Postnatally, computed tomography with contrast aids diagnosis, delineating systemic blood supply in extralobular sequestration. Other postnatal differential diagnoses include pneumothorax, true dextrocardia (primary ciliary dyskinesia, congenital heart disease), and laryngotracheal obstruction.

Earliest post-surgical survival reports included only lessseverely affected infants, who were able to survive the initial few minutes post delivery, to be operated on. This natural selection bias generated impressive survival rates, which have taken considerable time to match, with recent reported survival rates of over 80%.49 However, case selection bias still exists. While advances in initial management of CDH appear to have had a beneficial outcome effect in a selected group of CDH, the overall impact is less impressive.2,50 The ‘hidden mortality’ of CDH, originally described by Harrison,51 comprising intrauterine demise, stillbirths, and death on transfer to a specialist centre, is often not included in studies, underestimating the true mortality of the condition. This subset of children reaching a tertiary surgical centre may represent only 40% of total cases.50 Elective termination rates of up to 33% are reported,2,50 with 50% quoted in some countries.52 Termination is more commonly performed if another major congenital anomaly is present.50 The true overall mortality may be greater than 60%.2 Evidence-based management data are sparse due to limited numbers, introduction of a large number of new therapies, and excessive focus on retrospective studies leading to relatively few randomised controlled trials.53 The international CDH registry has been established to help facilitate the multicentre trials that are necessary to improve this. It has also provided a useful source of observational data. While the benefit of antenatal corticosteroids in anticipated deliveries before 34 weeks of gestation is well established and currently recommended,54 repeated doses of corticosteroids in CDH to further aid foetal lung maturation is based solely on a small case series of multiple doses of betamethasone given biweekly from 24 weeks through to term.55 A small randomised controlled trial and observational data from the CDH registry found no evidence of benefit in survival, length of stay, ventilator days, or oxygen use at 30 days.56 A CDH data registry review showed 14% of infants greater than 34 weeks gestation with prenatally diagnosed CDH receiving corticosteroids. Delivery should be in an experienced centre. There are no controlled trials to support either scheduling deliveries electively or opting for Caesarean section rather than vaginal route. Endotracheal intubation post delivery, and avoidance of bag-and-mask ventilation, avoids distension of the stomach and further compromise of pulmonary function. Placement of a nasogastric tube allows intermittent decompression of the bowel. Gas exchange and acid base balance should be monitored via an arterial catheter. Delayed surgical repair (Fig. 2) has become the preferred approach in many centres,57 allowing stabilisation of haemodynamic and respiratory function prior to surgery, which further compromises functional residual capacity (FRC). Clear evidence of survival benefit is lacking.58 It

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Figure 2 View from the abdominal incision showing repair of diaphragmatic defect being undertaken using interrupted nonabsorbable sutures (courtesy of Dr John Harvey).

allows involvement of other subspecialities, thorough evaluation for associated anomalies, and detailed discussion with parents regarding therapeutic options and outcome. The importance of cardiovascular stability is further demonstrated by changes observed in cerebral haemodynamics during surgery, monitored using near-infrared spectroscopy, suggesting a decrease in cerebral blood volume and oxygenation. Increased right to left shunting and decreased venous return (due to inferior vena cava compression by repositioned abdominal viscera) were suggested aetiologies.59 Laparoscopic repair in selected cases with favourable pre-operative pulmonary (minimal ventilatory support, no clinical evidence of pulmonary hypertension) and anatomical status (stomach intra-abdominally) has been shown to be safe.60 Prosthetic patch repair allows pleuroperitoneal separation in large defects with inadequate muscle availability for primary closure. However, inability of the patch to grow with the child may lead to patch separation and recurrent herniation, reported in up to 40%.61 If separation does not occur, this may lead to restriction of pulmonary function. The herniation recurrence rate is not affected by the type of prosthetic material used.62 Later definitive repair, using a muscle flap, is possible,63 although normal diaphragmatic motion with improved lung function has yet to be conclusively shown. Primary closure results in persistent diaphragmatic dysfunction with decreased amplitude of contraction compared with both the contralateral side and ipsilateral side in controls, but normal spirometry in a small reported cohort.64 Prophylactic surfactant administration is common, yet convincing evidence of primary surfactant deficiency in CDH is lacking, with conflicting data between animal models – that suggest deficiency – and humans. In CDH infants, no difference from controls was found in bronchoalveolar lavage surfactant components65 and surfactant kinetics data are conflicting. Small case series have suggested benefits of exogenous surfactant, however CDH

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registry observational data suggest no benefit regardless of gestational age.66,67 While there is no evidence to support the recommendation of surfactant use in CDH, in significant prematurity its use may be indicated for co-existing true surfactant deficiency. The main goal of ventilation is to achieve adequate gas exchange. Initial ventilation strategies targeted hyperventilation and respiratory alkalosis, based on observation of reversal of right to left shunting in a different population with persistent pulmonary hypertension.68 Fears that subsequent ventilator-induced lung injury (VILI)69 might exacerbate mortality led to adopting permissive hypercapnia with minimisation of inspiratory pressures. ‘Gentle ventilation’ tolerates PaCO2 of 60–65 mmHg with adequate oxygenation defined as preductal oxygen saturations of greater than 85%, allowing minimisation of peak inspiratory pressure to less than 20 cm H2O. This represents the most significant advancement in CDH management, with marked improvements in survival, from 50% to 89%,70 and reduction in complications of barotrauma. High-frequency oscillatory ventilation use has moved from rescue therapy, when conventional ventilation failed, to stabilisation therapy in many centres. As a high pressure lung recruitment strategy in CDH, it is of little benefit,71 while as part of a gentle ventilation strategy, the literature is inconclusive.72,73 Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary bypass used for the treatment of severe but potentially reversible hypoxaemic respiratory failure. Pulmonary hypertension (PH) in CDH, not only varies in severity but is potentially irreversible, and if persistent may lead to progressive right heart failure and death. Overall survival of CDH infants is the lowest among all aetiologies with hypoxic respiratory failure treated with ECMO,74 although improved survival was seen in those with predicted mortality of greater than 80%.75 Decreased inducible nitric oxide synthase in CDH infants, increasing during ECMO treatment, may transiently reduce severity of PH and potentially explain this improved survival in more severe CDH.76 Post-operative use of ECMO declining from 20%, in 1999, to only 5%, in 200577 reflects changing utilisation from rescue therapy to aiding pre-operative stabilisation, minimising VILI. Criteria for use vary widely between institutions. Achievement of good survival outcomes despite low ECMO use further questions its role, suggesting benefit only in a select group of CDH. Identification of selection criteria will help clarify the role of ECMO in CDH. The significant morbidity of the increasing population of ECMO-treated survivors is another associated concern of its widespread use (see later section). The oxygen and carbon dioxide-carrying capacity of perfluorocarbons combined with its physical properties of high density, and low surface tension, confer potential to oxygenate and ventilate diseased lung while minimising barotrauma. Progressive lung growth while on liquid ventilation and ECMO occurs in both lamb models and

328 humans.78 A small, randomised controlled trial demonstrated feasibility of the technique in a near-term ECMO-treated group, with a non-significant trend towards improvement in ECMO duration and survival.79 More severely affected infants may benefit, but larger trials are needed. While inhaled nitric oxide (iNO) has been shown to be effective in persistent pulmonary hypertension of the newborn by reducing the need for ECMO rescue therapy,80 the largest randomised controlled trial to date showed no benefit, with increased ECMO rates in the iNO group.81 This was reiterated by a recent Cochrane review.82 Left ventricular dysfunction has been proposed as the best predictor of iNO responsiveness, with suprasystemic pulmonary vascular resistance after establishment of optimal lung inflation and adequate left ventricular performance (i.e. without ductal-dependent systemic blood flow) the indication for use.83

PREDICTORS OF SURVIVAL Predicting prognosis from prenatal findings, given the wide spectrum of severity in CDH, is paramount for appropriate antenatal counselling. Numerous attempts have been made to correlate prenatal imaging with postnatal outcome, with mixed results. Perinatal outcome, broadly speaking, depends on a number of core factors: the presence of additional anomalies, the gestational stage at herniation, the volume of intra-thoracic organs; and extent of resultant lung hypoplasia and cardiovascular changes. An important role of ultrasound is detection of additional anomalies, identifying cases at highest risk for poor outcome. While most identified associated anomalies have very little impact on survival, chromosomal defects and more serious cardiac defects have more significant impact. In one analysis, co-existing heart defects dropped survival from 70.2% to 41.1%, with univentricular anatomy associated with only 5% survival.84 Numerous ultrasound poor prognostic indicators have been suggested: diagnosis prior to 25 weeks of gestation (controversial significance given conflicting survival rates in literature); intrathoracic stomach bubble (better than 90% survival if stomach below diaphragm85); polyhydramnios (due to compression of the oesophagus from large intrathoracic volume of abdominal organs – conflicting impact in literature with some stating no relationship with outcome86; liver herniation (liver down has better prognosis but as 75% have herniation of at least some portion of the liver, its discriminating power is poor87); hydrops (consistently associated with a poor prognosis); left ventricular hypoplasia; and lung to head ratio (LHR) less than 1.0. LHR appears to be the best prognostic indicator. LHRs of <1.0 and >1.4 are strong predictors of outcome, with reported mortalities of 100% and 100% survival respectively,88,89 independent of gestational age.88 Its utility is less clear between 1.0–1.4, with survival ranging from 38 to 61%.88,89

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Nomograms for three-dimensional ultrasound scans are published and provide accurate estimations of foetal lung volumes.90 While a prospective study has demonstrated its potential role in predicting outcome, its current role remains investigational. Antenatal echocardiography identifies additional cardiac anomalies. Detection of pulmonary hypertension is theoretically not feasible as it most likely develops postnatally with the transition from foetal to neonatal circulation. Proposed antenatal markers of poor outcome include left ventricular hypoplasia,86 and increased pulsatility index in the pulmonary artery.91 Postnatally, cross-sectional main pulmonary artery area/diaphragmatic defect area ratio has been found to correlate with outcome.92 Larger randomised trials are needed to determine its prognostic value. Magnetic resonance imaging has many benefits over conventional ultrasound imaging. It is not limited by maternal obesity or oligohydramnios, with better soft tissue contrast,93 and is effective in confirming the diagnosis and presence of additional anomalies.94 It is more reliable in detecting liver herniation. Comparison of antenatal lung volume, while not predictive of outcome, showed a trend towards increased lung volume in survivors.95 Relative lung volume may be a more accurate prognostic marker, with less than 40% indicating poor postnatal outcome.96 When CDH is suspected, a thorough ultrasound evaluation to confirm the diagnosis, detect additional anomalies, and aid with prognostic considerations should be performed. Foetal echocardiography is suggested to rule out cardiac malformations and assess foetal heart function. Magnetic resonance imaging, if available, may provide additional information affecting prognosis. Prenatal counselling should involve a multidisciplinary team, and ideally be completed before 24 weeks of gestation (20 weeks gestation in some countries), allowing the option of termination.97 Several postnatal prognostic factors have been investigated, including poor aeration on chest X-ray,98 which failed subsequent validation.99 A postnatal predictive equation of mortality developed by the CDH Study Group, based on initial Apgar scores and birth weight,100 yielded disappointing results on validation, suggesting better utility as a comparative tool between centres than as a predictor of mortality.49 The Score for Neonatal Acute Physiology, version II (SNAP-II) has also recently been validated, and found to be most predictive in combination with gestational age.101

MORBIDITY The associated morbidity of CDH is now better appreciated. It is estimated that less than one-third of prenatally diagnosed foetuses will survive without significant morbidity.102 Some morbidity is anatomic and unavoidable. Other morbidity reflects potentially toxic effects of treatment and may be avoidable or eliminated in the future. Optimal care requires a multidisciplinary approach with co-ordinated

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input from a variety of specialities including surgery, neonatology, respiratory, dietetics, cardiology and audiology.

Lung function Lung function represents the most significant source of morbidity in survivors. Infant lung function shows a severe restrictive pattern with low lung compliance post-operatively.103 Hyperinflation of the ipsilateral and/or contralateral lung (indicated by normal or increased FRC, increased resistance,104 and decreased forced vital capacity105), is followed by probable lung growth (suggested by normal FRC, increasing compliance and decrease in resistance104). This is mirrored by significant improvement in both ventilation and perfusion, on scintigraphy, over the first year, in a non-ECMO CDH population.106 Persistent reduction of perfusion to the lung of the affected side, suggests little ability to grow ipsilaterally at the vascular level, supporting the concept of primary vascular hypoplasia in CDH.107 Whether scintigraphy impacts clinical management remains unclear, although an ability to predict future pulmonary morbidity and poor nutritional status has been suggested.106 Frequent respiratory infections occur in 24% of patients with mild to moderate pulmonary hypolplasia.108 Intuitively, this will be an even greater problem in the infants now surviving with more severe hypoplasia. ECMO and patch repair are reported as identifiers of significant pulmonary morbidity.109 Management included tracheostomy in 4% of one series, which will add its own additional morbidity.110 Poor growth of the ipsilateral lung, on scintigraphy, has been shown to occur in those with frequent respiratory infections, and each may negatively impact on the other.111 Despite gradual normalisation of lung function in the first two years, persistent abnormalities are documented throughout childhood, adolescence and into adulthood. Obstructive airways disease was found in 25% at 5 years of age, with 60% prescribed bronchodilators, and 40% inhaled steroids.109 Mild to moderate airway obstruction, high prevalence of bronchodilator responsiveness and decreased inspiratory muscle strength, compared with controls, was found in an adolescent cohort,112 and abnormal spirometry in 52% of adults.113 Near normal exercise capacity and cardiorespiratory response to exertion was found in the adolescent cohort.114 While clinical impact appears minimal, 70% of the adults participated in sports and >80% perceived themselves as ‘healthy’.113 Periods of increased respiratory stress, such as episodes of pneumonia and potential adolescent scoliosis surgery, may have important consequences.

Pulmonary hypertension The significant morbidity of PH beyond the neonatal period has been recognised recently. Its severity is disproportionate to improvements in respiratory status, with significant

329 but subclinical PH detectable into late childhood.83 Potential therapeutic options include phosphodiesterase and endothelin antagonists and nitric oxide. Interestingly, despite poor postnatal impact, nasal cannula delivered nitric oxide produces sustained pulmonary vasodilation.115 Therapeutic treatment of high pulmonary pressures may reduce mortality in a subset of CDH, and facilitate cardiopulmonary recovery after extubation. Echocardiography should be performed in early childhood to screen for pulmonary hypertension.

Hearing impairment Sensorineural hearing impairment is well described in CDH (in almost 60% in one case series116), with a wide range of incidence. It may be progressive.117 Early identification of hearing impairment prevents significant speech and language delay. While underlying aetiology is unknown, risk factors proposed include: duration of respiratory treatment, including ECMO;118 duration of ototoxic medications, such as loop diuretics; and the neuromuscular blocker pancuronium, with indirect effects mediated through impaired renal function.119 Postnatal brain-stem auditory evoked responses (BAER) screening is not sufficient, given frequent reports of progressive hearing loss in patients with initial normal BAER.118 Regular testing until the age of 3 years, and as indicated thereafter, has been recommended.118

Orthopaedics Chest wall asymmetry and pectus deformity are the most commonly described orthopaedic problems. Asymmetry of the chest wall in 48% and significant scoliosis in 27% of one series,120 is likely to be an underestimate, as true incidence cannot be assessed reliably before cessation of growth. Asymmetry and pectus deformity are more common with large diaphragmatic defects, with scoliosis more common with ventilatory impairment and large diaphragmatic defect.120 The majority of deformities are mild120 and surgical intervention is rarely necessary. Early referral and careful follow-up prevents further compromise to an already impaired respiratory system.

Nutrition and growth Growth failure is common and most likely multifactorial, due to increased metabolic demand (increased work of breathing of chronic lung disease), gastroesophageal reflux disease (GORD), and oral aversion. In one study, 50% of patients with repaired CDH were below the 25th percentile, with one-third requiring gastrostomy feeds to improve caloric intake. Predictive factors included ECMO and need for oxygen at discharge.121 Catch-up growth can occur with aggressive management, but failure to thrive remains a problem in a subset.122 Management is difficult, with varying rates of gastrostomy use reflecting lack of consensus in the

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literature. Almost 25% show behaviour consistent with oral aversion.110,121 Prolonged intubation impacts on the swallowing reflex in adults,123 and may be an important contributor in CDH infants.121 Delay of developmental milestones frequently accompanies failure to thrive.124 Early recognition and intervention is essential. Poor growth despite optimisation of caloric intake should undergo further evaluations for GORD, while some recommend commencing all on H2-blockers,121 outgrowing the dose as tolerated.

GORD GORD is reported in up to 89% of survivors,125 although incidence reported depends on diagnostic method used. Recent increases may also reflect the impact of multidisciplinary approach and involvement of speech pathologists. A number of aetiologies have been suggested: distal oesophageal dilatation and impaired motility secondary to partial obstruction by extrinsic mass effect; disruption of the angle of His during development due to malposition of the stomach in the thorax; increased strain on diaphragmatic crura post primary closure predisposing to hiatus hernia; CDH recurrence; and increased intraabdominal pressure post-operatively.126 Further evaluation is necessary if symptoms suggest GORD, or if pulmonary morbidity increases. Pulmonary complications of GORD include recurrent bronchitis, worsening chronic lung disease, and aspiration pneumonia. Antireflux surgery is reserved for patients not responding to maximal medical therapy.121 Oesophagitis in over 50% of adults,124 illustrates the need for long-term follow up.

Neurology CDH infants are at high risk for hypoxic-ischaemic brain injury and other secondary neurologic effects of severe illness. Newborns with more severe pulmonary hypoplasia are at risk of periods of hypoxaemia, acidosis, and poor perfusion. While duration of hypoxaemia and hyperventilation correlates with neurological outcome,127 potential long-term effects of prolonged permissive hypercapnia and often borderline oxygenation are not known. While disease severity significantly contributes to neurological outcome,128 the possible contribution of ECMO and other therapies is of particular concern and remains unclear. In CDH, adverse neurodevelopmental outcome is often attributed to ECMO. Neurologic delay occurred in 67% of ECMO-treated infants compared with 24% of CDH controls, and included cerebral palsy, hearing loss, seizure disorder, cognitive delay and delayed motor skills.128 Abnormal neuroimaging in over 75% of ECMO-treated survivors has led to suggestions of neuroimaging in all ECMO-treated survivors.125 Rationalisation to those more severely affected may help answer its neurodevelopmental impact through longitudinal analysis. Neurodevelopmental

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outcome appears to improve with age, with early delay in motor skills not predictive of future disability.110,125 All studies demonstrate some level of dysfunction.

Recurrent hernia Hernia recurrence figures very widely. More concerning figures of recurrence in up to 22%, increasing to 40% with patch repair, have been reported.125 However, incidence and timing varies in the literature. Patch revision within three years was required in 50% of another cohort with a bimodal distribution of incidence: 14% occurred between 1 and 3 months and 28% between 10 and 36 months.61 Recurrence may present with GI symptoms (bowel obstruction, progressive severe vomiting), pulmonary symptoms or asymptomatically.61 Surveillance with chest X-rays at 2, 6 and 12 months of age has been recommended.61

ANTENATAL SURGERY Foetal intervention, to minimise the degree of pulmonary hypoplasia, has been the focus of research for over 20 years. Attempts at in-utero anatomical repair were abandoned after a small clinical trial failed to show any benefit.129 The procedure excluded those with liver herniation, as attempted reduction caused kinking of the umbilical vein, and subsequent foetal death. Tracheal occlusion (TO) techniques are based on the upper airway’s central role in controlling efflux of lung fluid, produced by lung epithelial cells, maintaining constant pressure, and facilitating tension-induced lung development in the lower airways. Foetal TO prevents egress of lung liquid, increasing levels of lung tissue stretch, triggering lung growth.130 Optimal timing and duration of TO has yet to be determined exactly. The more vigorous lung response to early TO needs to be balanced against the risk of pre-term delivery.131 The optimal time for intervention appears to be from the late canalicular phase, but not maintained until term, allowing recovery of the deleterious effects of excess differentiation of type II into type I alveolar epithelial cells and subsequent surfactant deficiency.132 Prophylactic surfactant at birth does not improve gas exchange or ventilation efficiency in the lamb model.133 Severity of outcome predictors, such as LHR, may lead to timing stratification in the future.134 The initial North American experience was disappointing, with a randomised controlled trial terminated due to unexpected high survival in the standard treatment group (77% survival to 90 days), and expectation that foetal therapy in this design would show no benefit.135 Changes in ventilation strategy, discussed in the prior section, may have contributed to the observed ‘trial effect’. Subsequent European data have been more promising.136 Induced pre-term delivery has fallen with increasing experience, with mean gestational delivery age improving to 34.2 weeks gestation. LHR

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increased from a median 0.7 (range 0.5–0.9) to 1.8 (range 1.1–2.9) 2 weeks after TO. Improved survival in a more severely affected population, with LHR less than 1.0, than the earlier North American study, which included neonates with an LHR less than 1.4, have been achieved, with 50% survival to hospital discharge, versus 8.3% in those declining intervention (excluding those opting for termination).

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CONCLUSION Caution needs to be used when interpreting reports quoting improved survival rates, due to the impact of case selection bias. Improving survival rates from 63% reported in 199857 to 67% reported in 2005,84 are challenged by population-based studies showing static mortality rates2,50 despite the apparent improvement in specific subgroups reported. The absence of large randomised controlled trials makes strong evidence-based recommendations impossible, with most current recommendations based on observational studies, historical data and animal studies. Difficulty exists in separating the apparent effect from that of other co-interventions. Multicentre randomised controlled trials, utilising the framework of the CDH data registry, are needed to provide clarity.

REFERENCES 1. Butler N, Claireaux AE. Congenital diaphragmatic hernia as a cause of perinatal mortality. Lancet 1962; 1: 659–663. 2. Stege G, Fenton A, Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatrics 2003; 112(3 Pt 1): 532– 535. 3. Lally KP. Congenital diaphragmatic hernia. Curr Opin Pediatr 2002; 14: 486–490. 4. Wilcox DT, Irish MS, Holm BA, Glick PL. Animal models in congenital diaphragmatic hernia. Clin Perinatol 1996; 23: 813–822. 5. Keijzer R, Liu J, Deimling J, Tibboel D, Post M. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am J Pathol 2000; 156: 1299–1306. 6. Min H, Danilenko DM, Scully SA, Bolon B, Ring BD, Tarpley JE et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 1998; 12: 3156–3161. 7. Acosta JM, Thebaud B, Castillo C, Mailleux A, Tefft D, Wuenschell C et al. Novel mechanisms in murine nitrofen-induced pulmonary hypoplasia: FGF-10 rescue in culture. Am J Physiol Lung Cell Mol Physiol 2001; 281: L250–L257. 8. Jesudason EC, Smith NP, Connell MG, Spiller DG, White MR, Fernig DG et al. Developing rat lung has a sided pacemaker region for morphogenesis-related airway peristalsis. Am J Respir Cell Mol Biol 2005; 32: 118–127. 9. Jesudason EC. Small lungs and suspect smooth muscle: congenital diaphragmatic hernia and the smooth muscle hypothesis. J Pediatr Surg 2006; 41: 431–435. 10. Ackerman KG, Herron BJ, Vargas SO, Huang H, Tevosian SG, Kochilas L et al. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet 2005; 1: 58–65. 11. Hagen EO. Drugs and congenital abnormalities. Lancet 1963; 1: 501. 12. Sievers G, Schradler-Beielstein H. Drugs and congenital abnormalities. Lancet 1963; 1: 330. 13. Higuchi R, Minami T, Shimoyamada Y, Kamisako H, Koike M, Takigawa H et al. Diaphragmatic hernia in an infant of a diabetic

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

mother: an unusual association in diabetic embryopathy. Pediatr Int 1999; 41: 581–583. Enns GM, Cox VA, Goldstein RB, Gibbs DL, Harrison MR, Golabi M. Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review. Am J Med Genet 1998; 79: 215–225. Gallot D, Marceau G, Coste K et al. Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development? Birth Defects Res A Clin Mol Teratol 2005; 73: 523–531. Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 1953; 92: 189–217. Babiuk RP, Thebaud B, Greer JJ. Reductions in the incidence of nitrofen-induced diaphragmatic hernia by vitamin A and retinoic acid. Am J Physiol Lung Cell Mol Physiol 2004; 286: L970–L973. Gonzalez-Reyes S, Martinez L, Martinez-Calonge W, FernandezDumont V, Tovar JA. Effects of antioxidant vitamins on molecular regulators involved in lung hypoplasia induced by nitrofen. J Pediatr Surg 2006; 41: 1446–1452. Gonzalez-Reyes S, Fernandez-Dumont V, Calonge WM, Martinez L, Tovar JA. Vitamin A improves Pax3 expression that is decreased in the heart of rats with experimental diaphragmatic hernia. J Pediatr Surg 2006; 41: 327–330. Lewis NA, Holm BA, Swartz D, Sokolowski J, Rossman J, Glick PL. Antenatal vitamin A decreases ventilation-induced lung injury in the lamb model of congenital diaphragmatic hernia. Asian J Surg 2006; 29: 193–197. Major D, Cadenas M, Fournier L, Leclerc S, Lefebvre M, Cloutier R. Retinol status of newborn infants with congenital diaphragmatic hernia. Pediatr Surg Int 1998; 13: 547–549. Larson JE, Cohen JC. Improvement of pulmonary hypoplasia associated with congenital diaphragmatic hernia by in utero CFTR gene therapy. Am J Physiol Lung Cell Mol Physiol 2006; 291: L4–L10. Larson JE, Delcarpio JB, Farberman MM, Morrow SL, Cohen JC. CFTR modulates lung secretory cell proliferation and differentiation. Am J Physiol Lung Cell Mol Physiol 2000; 279: L333–L341. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407: 242–248. Okazaki T, Sharma HS, Aikawa M, Yamataka A, Nagai R, Miyano T et al. Pulmonary expression of vascular endothelial growth factor and myosin isoforms in rats with congenital diaphragmatic hernia. J Pediatr Surg 1997; 32: 391–394. Shehata SM, Mooi WJ, Okazaki T, El Banna I, Sharma HS, Tibboel D. Enhanced expression of vascular endothelial growth factor in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension. Thorax 1999; 54: 427–431. Kent GM, Olley PM, Creighton RE, Dobbinson T, Bryan MH, Symchych P et al. Hemodynamic and pulmonary changes following surgical creation of a diaphragmatic hernia in fetal lambs. Surgery 1972; 72: 427–433. Tajchman UW, Tuder RM, Horan M, Parker TA, Abman SH. Persistent eNOS in lung hypoplasia caused by left pulmonary artery ligation in the ovine fetus. Am J Physiol 1997; 272(5 Pt 1): L969–L978. Solari V, Puri P. Glucocorticoid receptor gene expression in the hypoplastic lung of newborns with congenital diaphragmatic hernia. J Pediatr Surg 2002; 37: 715–718. Adzick NS, Harrison MR, Glick PL, Nakayama DK, Manning FA, deLorimier AA. Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 1985; 20: 357–361. Garne E, Haeusler M, Barisic I, Gjergja R, Stoll C, Clementi M. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002; 19: 329–333. Grandjean H, Larroque D, Levi S. The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol 1999; 181: 446–454.

332

33. Lewis DA, Reickert C, Bowerman R, Hirschl RB. Prenatal ultrasonography frequently fails to diagnose congenital diaphragmatic hernia. J Pediatr Surg 1997; 32: 352–356. 34. Skari H, Bjornland K, Haugen G, Egeland T, Emblem R. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg 2000; 35: 1187–1197. 35. Puri P, Gorman F. Lethal nonpulmonary anomalies associated with congenital diaphragmatic hernia: implications for early intrauterine surgery. J Pediatr Surg 1984; 19: 29–32. 36. Skarsgard ED, Harrison MR. Congenital diaphragmatic hernia: the surgeon’s perspective. Pediatr Rev 1999; 20: e71–e78. 37. Tibboel D, Gaag AV. Etiologic and genetic factors in congenital diaphragmatic hernia. Clin Perinatol 1996; 23: 689–699. 38. Norio R, Kaariainen H, Rapola J, Herva R, Kekomaki M. Familial congenital diaphragmatic defects: aspects of etiology, prenatal diagnosis, and treatment. Am J Med Genet 1984; 17: 471–483. 39. Smith DW. Recognizable Patterns of HUman Malformation Genetic, Embryologic and Clinical Aspects. 3 ed. Philadelphia, PA: W.B. Saunders, 1982. 40. Philip N, Gambarelli D, Guys JM, Camboulives J, Ayme S. Epidemiological study of congenital diaphragmatic defects with special reference to aetiology. Eur J Pediatr 1991; 150: 726–729. 41. Slavotinek AM. Fryns syndrome: a review of the phenotype and diagnostic guidelines. Am J Med Genet A 2004; 124: 427–433. 42. Lurie IW. Where to look for the genes related to diaphragmatic hernia? Genet Couns 2003; 14: 75–93. 43. Klaassens M, Scott DA, van Dooren M, Hochstenbach R, Eussen HJ, Cai WW et al. Congenital diaphragmatic hernia associated with duplication of 11q23-qter. Am J Med Genet A 2006; 140: 1580– 1586. 44. Biggio JR Jr, Descartes MD, Carroll AJ, Holt RL. Congenital diaphragmatic hernia: is 15q26.1–26.2 a candidate locus? Am J Med Genet A 2004; 126: 183–185. 45. Nowaczyk MJ, Ramsay JA, Mohide P, Tomkins DJ. Multiple congenital anomalies in a fetus with 45,X/46,X,r(X)(p11.22q12) mosaicism. Am J Med Genet 1998; 77: 306–309. 46. Plaja A, Vendrell T, Sarret E, Toran N, Mediano C. Terminal deletion of Xp in a dysmorphic anencephalic fetus. Prenat Diagn 1994; 14: 410–412. 47. Mei-Zahav M, Solomon M, Trachsel D, Langer JC. Bochdalek diaphragmatic hernia: not only a neonatal disease. Arch Dis Child 2003; 88: 532–535. 48. Baglaj M, Dorobisz U. Late-presenting congenital diaphragmatic hernia in children: a literature review. Pediatr Radiol 2005; 35: 478–488. 49. Downard CD, Jaksic T, Garza JJ, Dzakovic A, Nemes L, Jennings RW et al. Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg 2003; 38: 729–732. 50. Colvin J, Bower C, Dickinson JE, Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics 2005; 116: e356–e363. 51. Harrison MR, Bjordal RI, Langmark F, Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg 1978; 13: 227–230. 52. Harmath A, Hajdu J, Csaba A, Hauzman E, Pete B, Gorbe E et al. Associated malformations in congenital diaphragmatic hernia cases in the last 15 years in a tertiary referral institute. Am J Med Genet A 2006; 140: 2298–2304. 53. Hardin WD Jr, Stylianos S, Lally KP. Evidence-based practice in pediatric surgery. J Pediatr Surg 1999; 34: 908–912. 54. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. JAMA 1995; 273:413– 418. 55. Ford WD, Kirby CP, Wilkinson CS, Furness ME, Slater AJ. Antenatal betamethasone and favourable outcomes in fetuses with ’poor prognosis’ diaphragmatic hernia. Pediatr Surg Int 2002; 18: 244–246.

P. D. ROBINSON, AND D. A. FITZGERALD

56. Lally KP, Bagolan P, Hosie S, Lally PA, Stewart M, Cotten CM et al. Corticosteroids for fetuses with congenital diaphragmatic hernia: can we show benefit? J Pediatr Surg 2006; 41: 668–674. 57. Clark RH, Hardin WD Jr, Hirschl RB, Jaksic T, Lally KP, Langham MR Jr et al. Current surgical management of congenital diaphragmatic hernia: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 1998; 33: 1004–1009. 58. Moyer V, Moya F, Tibboel R, Losty P, Nagaya M, Lally KP. Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants. Cochrane Database Syst Rev 2002; CD001695. 59. Dotta A, Rechichi J, Campi F et al. Effects of surgical repair of congenital diaphragmatic hernia on cerebral hemodynamics evaluated by near-infrared spectroscopy. J Pediatr Surg 2005; 40: 1748– 1752. 60. Yang EY, Allmendinger N, Johnson SM, Chen C, Wilson JM, Fishman SJ. Neonatal thoracoscopic repair of congenital diaphragmatic hernia: selection criteria for successful outcome. J Pediatr Surg 2005; 40: 1369–1375. 61. Moss RL, Chen CM, Harrison MR. Prosthetic patch durability in congenital diaphragmatic hernia: a long-term follow-up study. J Pediatr Surg 2001; 36: 152–154. 62. Grethel EJ, Cortes RA, Wagner AJ et al. Prosthetic patches for congenital diaphragmatic hernia repair: Surgisis vs Gore-Tex. J Pediatr Surg 2006; 41: 29–33. 63. Sydorak RM, Hoffman W, Lee H et al. Reversed latissimus dorsi muscle flap for repair of recurrent congenital diaphragmatic hernia. J Pediatr Surg 2003; 38: 296–300. 64. Arena F, Romeo C, Calabro MP, Antonuccio P, Arena S, Romeo G. Long-term functional evaluation of diaphragmatic motility after repair of congenital diaphragmatic hernia. J Pediatr Surg 2005; 40: 1078–1081. 65. IJsselstijn H, Zimmermann LJ, Bunt JE, de Jongste JC, Tibboel D. Prospective evaluation of surfactant composition in bronchoalveolar lavage fluid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med 1998; 26: 573–580. 66. Lally KP, Lally PA, Langham MR et al. Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia. J Pediatr Surg 2004; 39: 829–833. 67. Van Meurs K. Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia? J Pediatr 2004; 145: 312–316. 68. Drummond WH, Gregory GA, Heymann MA, Phibbs RA. The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension. J Pediatr 1981; 98: 603–611. 69. Wung JT, Sahni R, Moffitt ST, Lipsitz E, Stolar CJ. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30: 406–409. 70. Kays DW, Langham MR Jr, Ledbetter DJ, Talbert JL. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999; 230: 340–348. 71. Paranka MS, Clark RH, Yoder BA, Null DM Jr. Predictors of failure of high-frequency oscillatory ventilation in term infants with severe respiratory failure. Pediatrics 1995; 95: 400–404. 72. Reyes C, Chang LK, Waffarn F, Mir H, Warden MJ, Sills J. Delayed repair of congenital diaphragmatic hernia with early high-frequency oscillatory ventilation during preoperative stabilization. J Pediatr Surg 1998; 33: 1010–1014. 73. Kamata S, Usui N, Ishikawa S et al. Prolonged preoperative stabilization using high-frequency oscillatory ventilation does not improve the outcome in neonates with congenital diaphragmatic hernia. Pediatr Surg Int 1998; 13: 542–546. 74. Conrad SA, Rycus PT, Dalton H. Extracorporeal Life Support Registry Report 2004. ASAIO J 2005; 51: 4–10. 75. Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia? The Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 1999; 34:720–724.

CONGENITAL DIAPHRAGMATIC HERNIA

76. Shehata SM, Sharma HS, Mooi WJ, Tibboel D. Pulmonary hypertension in human newborns with congenital diaphragmatic hernia is associated with decreased vascular expression of nitric-oxide synthase. Cell Biochem Biophys 2006; 44: 147–155. 77. Khan AM, Lally KP. The role of extracorporeal membrane oxygenation in the management of infants with congenital diaphragmatic hernia. Semin Perinatol 2005; 29: 118–122. 78. Fauza DO, Hirschl RB, Wilson JM. Continuous intrapulmonary distension with perfluorocarbon accelerates lung growth in infants with congenital diaphragmatic hernia: initial experience. J Pediatr Surg 2001; 36: 1237–1240. 79. Hirschl RB, Philip WF, Glick L et al. A prospective, randomized pilot trial of perfluorocarbon-induced lung growth in newborns with congenital diaphragmatic hernia. J Pediatr Surg 2003; 38: 283–289. 80. Clark RH, Kueser TJ, Walker MW et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000; 342: 469–474. 81. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics 1997; 99:838–845. 82. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; CD000399. 83. Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 2005; 29: 123–128. 84. Graziano JN. Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 2005; 40: 1045–1049. 85. Hatch EI Jr, Kendall J, Blumhagen J. Stomach position as an in utero predictor of neonatal outcome in left-sided diaphragmatic hernia. J Pediatr Surg 1992; 27: 778–779. 86. Thebaud B, Azancot A, de Lagausie P et al. Congenital diaphragmatic hernia: antenatal prognostic factors. Does cardiac ventricular disproportion in utero predict outcome and pulmonary hypoplasia? Intensive Care Med 1997; 23: 10062–10069. 87. Doyle NM, Lally KP. The CDH Study Group and advances in the clinical care of the patient with congenital diaphragmatic hernia. Semin Perinatol 2004; 28: 174–184. 88. Laudy JA, Van Gucht M, Van Dooren MF, Wladimiroff JW, Tibboel D. Congenital diaphragmatic hernia: an evaluation of the prognostic value of the lung-to-head ratio and other prenatal parameters. Prenat Diagn 2003; 23: 634–639. 89. Lipshutz GS, Albanese CT, Feldstein VA et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997; 32: 1634–1636. 90. Ruano R, Benachi A, Martinovic J et al. Can three-dimensional ultrasound be used for the assessment of the fetal lung volume in cases of congenital diaphragmatic hernia? Fetal Diagn Ther 2004; 19: 87–91. 91. Chaoui R, Kalache K, Tennstedt C, Lenz F, Vogel M. Pulmonary arterial Doppler velocimetry in fetuses with lung hypoplasia. Eur J Obstet Gynecol Reprod Biol 1999; 84: 179–185. 92. Fumino S, Shimotake T, Kume Y, Tsuda T, Aoi S, Kimura O et al. A clinical analysis of prognostic parameters of survival in children with congenital diaphragmatic hernia. Eur J Pediatr Surg 2005; 15: 399–403. 93. Ward VL. MR imaging in the prenatal diagnosis of fetal chest masses: effects on diagnostic accuracy, clinical decision making, parental understanding, and prediction of neonatal respiratory health outcomes. Acad Radiol 2002; 9: 1064–1069. 94. Levine D, Barnewolt CE, Mehta TS, Trop I, Estroff J, Wong G. Fetal thoracic abnormalities: MR imaging. Radiology 2003; 228: 379–388. 95. Walsh DS, Hubbard AM, Olutoye OO et al. Assessment of fetal lung volumes and liver herniation with magnetic resonance imaging in congenital diaphragmatic hernia. Am J Obstet Gynecol 2000; 183: 1067–1069.

333

96. Paek BW, Coakley FV, Lu Y et al. Congenital diaphragmatic hernia: prenatal evaluation with MR lung volumetry–preliminary experience. Radiology 2001; 220: 63–67. 97. Graham G, Devine PC. Antenatal diagnosis of congenital diaphragmatic hernia. Semin Perinatol 2005; 29: 69–76. 98. Donnelly LF, Sakurai M, Klosterman LA, Delong DM, Strife JL. Correlation between findings on chest radiography and survival in neonates with congenital diaphragmatic hernia. AJR Am J Roentgenol 1999; 173: 1589–1593. 99. Holt PD, Arkovitz MS, Berdon WE, Stolar CJ. Newborns with diaphragmatic hernia: initial chest radiography does not have a role in predicting clinical outcome. Pediatr Radiol 2004; 34: 462–464. 100. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. The Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg 2001; 36:141–145. 101. Skarsgard ED, MacNab YC, Qiu Z, Little R, Lee SK. SNAP-II predicts mortality among infants with congenital diaphragmatic hernia. J Perinatol 2005; 25: 315–319. 102. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996; 31: 148–151. 103. Nakayama DK, Motoyama EK, Mutich RL, Koumbourlis AC. Pulmonary function in newborns after repair of congenital diaphragmatic hernia. Pediatr Pulmonol 1991; 11: 49–55. 104. Koumbourlis AC, Wung JT, Stolar CJ. Lung function in infants after repair of congenital diaphragmatic hernia. J Pediatr Surg 2006; 41: 1716–1721. 105. Helms P, Stocks J. Lung function in infants with congenital pulmonary hypoplasia. J Pediatr 1982; 101: 918–922. 106. Okuyama H, Kubota A, Kawahara H, Oue T, Kitayama Y, Yagi M. Correlation between lung scintigraphy and long-term outcome in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2006; 41: 882–886. 107. Geggel RL, Murphy JD, Langleben D, Crone RK, Vacanti JP, Reid LM. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 1985; 107: 457–464. 108. Wischermann A, Holschneider AM, Hubner U. Long-term followup of children with diaphragmatic hernia. Eur J Pediatr Surg 1995; 5: 13–18. 109. Muratore CS, Kharasch V, Lund DP et al. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg 2001; 36: 133–140. 110. Jaillard SM, Pierrat V, Dubois A et al. Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study. Ann Thorac Surg 2003; 75: 250–256. 111. Kamata S, Usui N, Kamiyama M et al. Long-term follow-up of patients with high-risk congenital diaphragmatic hernia. J Pediatr Surg 2005; 40: 1833–1838. 112. Trachsel D, Selvadurai H, Bohn D, Langer JC, Coates AL. Long-term pulmonary morbidity in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2005; 39: 433–439. 113. Vanamo K, Rintala R, Sovijarvi A et al. Long-term pulmonary sequelae in survivors of congenital diaphragmatic defects. J Pediatr Surg 1996; 31: 1096–1099. 114. Trachsel D, Selvadurai H, Adatia I et al. Resting and exercise cardiorespiratory function in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2006; 41: 522–529. 115. Dillon PW, Cilley RE, Hudome SM, Ozkan EN, Krummel TM. Nitric oxide reversal of recurrent pulmonary hypertension and respiratory failure in an infant with CDH after successful ECMO therapy. J Pediatr Surg 1995; 30: 743–744. 116. Robertson CM, Cheung PY, Haluschak MM, Elliott CA, Leonard NJ. High prevalence of sensorineural hearing loss among survivors of neonatal congenital diaphragmatic hernia. Western Canadian ECMO Follow-up Group. Am J Otol 1998; 19: 730–736.

334

117. Robertson CM, Tyebkhan JM, Hagler ME, Cheung PY, Peliowski A, Etches PC. Late-onset, progressive sensorineural hearing loss after severe neonatal respiratory failure. Otol Neurotol 2002; 23: 353–356. 118. Nobuhara KK, Lund DP, Mitchell J, Kharasch V, Wilson JM. Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol 1996; 23: 873–887. 119. Masumoto K, Nagata K, Uesugi T, Yamada T, Taguchi T. Risk factors for sensorineural hearing loss in survivors with severe congenital diaphragmatic hernia. Eur J Pediatr 2007; 166: 607– 612. 120. Vanamo K, Peltonen J, Rintala R, Lindahl H, Jaaskelainen J, Louhimo I. Chest wall and spinal deformities in adults with congenital diaphragmatic defects. J Pediatr Surg 1996; 31: 851–854. 121. Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg 2001; 36: 1171–1176. 122. Cortes RA, Keller RL, Townsend T, Harrison MR, Farmer DL, Lee H et al. Survival of severe congenital diaphragmatic hernia has morbid consequences. J Pediatr Surg 2005; 40: 36–45. 123. de LV, Montravers P, Dureuil B, Desmonts JM. Alteration in swallowing reflex after extubation in intensive care unit patients. Crit Care Med 1995; 23: 486–490. 124. Vanamo K, Rintala RJ, Lindahl H, Louhimo I. Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J Pediatr Surg 1996; 31: 551–554. 125. Van Meurs KP, Robbins ST, Reed VL et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122: 893–899. 126. Kieffer J, Sapin E, Berg A, Beaudoin S, Bargy F, Helardot PG. Gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 1995; 30: 1330–1333. 127. Bifano EM, Pfannenstiel A. Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 1988; 81: 657–661.

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Educational questions Answer true or false to the following statements: 1. Antenatal diagnosis and imaging a. Magnetic resonance imaging can provide useful additional information to antenatal ultrasound b. Advances in antenatal diagnosis have led to a significant improvement in perinatal mortality

P. D. ROBINSON, AND D. A. FITZGERALD

128. McGahren ED, Mallik K, Rodgers BM. Neurological outcome is diminished in survivors of congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation. J Pediatr Surg 1997; 32: 1216–1220. 129. Harrison MR, Adzick NS, Bullard KM et al. Correction of congenital diaphragmatic hernia in utero VII: a prospective trial. J Pediatr Surg 1997; 32: 1637–1642. 130. DiFiore JW, Fauza DO, Slavin R, Peters CA, Fackler JC, Wilson JM. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29: 248–256. 131. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000; 183: 1059–1066. 132. Benachi A, Delezoide AL, Chailley-Heu B, Preece M, Bourbon JR, Ryder T. Ultrastructural evaluation of lung maturation in a sheep model of diaphragmatic hernia and tracheal occlusion. Am J Respir Cell Mol Biol 1999; 20: 805–812. 133. Butter A, Bratu I, Flageole H et al. Fetal tracheal occlusion in lambs with congenital diaphragmatic hernia: role of exogenous surfactant at birth. Pediatr Res 2005; 58: 689–694. 134. Kohl T, Gembruch U, Tchatcheva K, Schaible T. Current consequences of prenatal diagnosis of congenital diaphragmatic hernia by Deprest et al. (J Ped Surg 2006;41:423–430). J Pediatr Surg 2006; 41: 1344–1346. 135. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003; 349: 1916–1924. 136. Deprest J, Jani J, Gratacos E et al. Fetal intervention for congenital diaphragmatic hernia: the European experience. Semin Perinatol 2005; 29: 94–103. 137. Slavotinek AM. The genetics of congenital diaphragmatic hernia. Semin Perinatol 2005; 29: 77–85.

c. Liver herniation is easy to recognise on foetal ultrasound d. Indirect signs of congenital diaphragmatic hernia (CDH) on antenatal ultrasound include polyhydramnios and mediastinal shift e. Detection rate is improved if additional anomalies are present 2. Foetal surgery a. The option of foetal surgery should be offered to all antenatally diagnosed cases of CDH b. In-utero anatomical repair is effective in clinical trials c. Preventing efflux of lung fluid, using tracheal obstruction, can improve lung growth d. Surfactant deficiency is a recognised complication of tracheal obstruction e. Recent experience suggests survival benefit in a more severely affected subset 3. Late presenting CDH a. A total of 20% of CDH presents beyond the neonatal period b. The most common mode of presentation is with respiratory symptoms

CONGENITAL DIAPHRAGMATIC HERNIA

c. Misdiagnosis on initial chest X-ray occurs in 25% of cases d. A chest X-ray is recommended in all children with unexplained respiratory or gastrointestinal symptoms e. Differential diagnosis includes pneumothorax, dextrocardia and laryngeal obstruction 4. Associated anomalies a. The most common associated anomaly is congenital heart disease b. Central nervous system anomalies predominate in cases of foetal demise c. Associated anomalies are rare

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d. Most identified anomalies have very little impact on survival e. Chromosome defects are associated with CDH 5. Prognostic factors for CDH a. Right-sided defects are associated with a poorer prognosis b. Post-natal prognostic equations are well validated c. An antenatal lung to head ratio of <1.0 is associated with a poor prognosis d. Co-existing cardiac defects have a negative effect on prognosis e. Liver herniation is a strong predictor of prognosis