PAEDIATRIC RESPIRATORY REVIEWS (2002) 3, 339±348 doi: 10.1016/S1526±0542(02)00262-2, available online at http://www.idealibrary.com on

SERIES: THORACIC SURGERY

Congenital diaphragmatic hernia

Nicola P. Smith, Edwin C. Jesudason and Paul D. Losty*

Institute of Child Health, University of Liverpool, Alder Hey Children's Hospital, Eaton Road, Liverpool, L12 2AP, UK

KEYWORDS Summary Congenital diaphragmatic hernia (CDH) is a lethal human birth defect. congenital Hypoplastic development is the leading contributor to its 30±50% mortality rate. diaphragmatic hernia, Efforts to improve survival have focused on , advances in intensive care and lung hypoplasia, elective delivery at specialist centres following in utero diagnosis. antenatal diagnosis, The impact of abnormal lung development on affected infants has stimulated research animal models into the developmental biology of CDH. Traditionally lung hypoplasia has been viewed as a secondary consequence of in utero compression of the fetal lung. Experimental evidence is emerging for a primary defect in lung development in CDH. Culture systems are providing research tools for the study of lung hypoplasia and the investigation of the role of growth factors and signalling pathways. Similarities between the of premature newborns and infants with CDH may indicate a role for antenatal . Further advances in postnatal therapy including permissive hypercapnia and liquid ventilation hold promise. Improvements in our basic scienti®c understanding of lung development may hold the key to future developments in CDH care. ß 2002 Published by Elsevier Science Ltd.

INTRODUCTION and thalidomide have been reported.7,8 Approximately 80% are left-sided defects and the majority occur as an Congenital diaphragmatic hernia (CDH) is an idiopathic isolated anomaly. CDH may, however, also occur as part of birth malformation comprising the Bochdalek diaphrag- a syndromic genopathy. Genetic associations include triso- matic defect, herniation of abdominal viscera into the mies 13 and 18 as well as syndromes including Fryn's thoracic cavity and pulmonary hypoplasia. An incidence (MIM229850), Cof®n-Siris (MIM135900) and Denys-Drash of approximately 1:2500 births1,2 results in a new case (MIMÃ194070). Survival is poor among infants with asso- every 24±36 h in the UK. Despite current advances in ciated abnormalities. Mortality may be as high as 93%, many neonatal care around 30±50% of affected infants die, largely succumbing in the antenatal period.9 due to respiratory insuf®ciency secondary to pulmonary hypoplasia.3±5 This review discusses contemporary clinical management and highlights recent research developments ANTENATAL DIAGNOSIS in CDH. Diagnosis of CDH is increasingly reported on antenatal The aetiology of CDH remains largely unclear. The ultrasound scans ± either by routine anomaly scans at majority are sporadic ± only 2% occurring with a familial around 20 weeks gestation, or following clinical suspicion association.6 Although in most instances CDH is idiopathic, of maternal polyhydramnios. CDH is con®rmed by visual- rare association with teratogens such as phenometrazine ising the stomach or loops of bowel within the thoracic cavity ± ideally level with the ``four-chamber'' view of the fetal heart, along with mediastinal shift away from * Correspondence to: Paul D. Losty, Senior Lecturer and the side of the lesion. Antenatal diagnosis should prompt Honorary Consultant Paediatric Surgeon. Tel.: ‡44-(0)-151-252-5250; Fax: ‡44-(0)-151-228-2024; a careful search for cardiac and neural tube defects. E-mail: [email protected] Despite the increasing use of ultrasound, reports have

1526±0542/02/$ ± see front matter ß 2002 Published by Elsevier Science Ltd. 340 N. P. SMITH ET AL.

suggested isolated CDH is antenatally diagnosed in only approximately 50% of cases.10±14 Early diagnosis provides an opportunity for parental counselling by a team of clinicians ideally including an obstetrician, neonatologist and paediatric surgeon.

PROGNOSTIC INDICATORS One important aspect of counselling is the issue of prog- nosis. Should associated anomalies be found on the ante- natal scan this will alter the projected outcome and each should be considered individually. For isolated CDH de®ning accurate antenatal prognostic indicators has proved challenging. Features including early diagnosis (<25 weeks), polyhydramnios and the presence of an intrathoracic stomach bubble have all been suggested to equate with poor prognosis. None has been found to be consistently reliable.10,15±17 Given that the major determi- nant of outcome is the degree of pulmonary hypoplasia, an estimation of fetal lung growth would seem a logical indicator. Estimation of volume by ultrasound using a ratio of right lung diameter to head circumference (to normalise for overall fetal growth) known as the lung:head ratio (LHR), has been shown to be of use in predicting those at extreme ends of the scale with a value of <0.6 being correlated with 100% mortality.18,19 For the CDH fetus with an LHR in the mid-range it has proved less helpful. Fetal magnetic resonance imaging (MRI) has been sug- Figure 1 Plain radiograph of a human newborn with congenital gested as a tool to give a three-dimensional estimation of diaphragmatic hernia (CDH). Note the presence of gas-filled lung growth. Initial reports are encouraging and results from intestinal loops (B) and stomach (S) displacing the heart (H), mediastinum and endotracheal tube (T). Vertebral anomalies are larger studies are needed.20 Currently, a combination of also apparent (V), indicating the global embryopathy in CDH. LHR along with the presence of liver in the thoracic cavity (so-called ``liver-up'' cases) is used by fetal surgical centres considering antenatal intervention.21,22 will help differentiate CDH from lesions such as cystade- 23,24 PLAN FOR DELIVERY nomatoid malformations. Antenatal counselling also provides an opportunity to MANAGEMENT formulate a plan for delivery. Ideally elective delivery should occur at an obstetric centre with easy access to paediatric At birth, or following diagnosis, the infant should be surgical expertise to avoid long distances in the postnatal intubated and a large bore NG tube passed. Both inter- transfer of the infant. is usually reserved ventions are designed to prevent any dilatation of the for obstetric indications. intrathoracic bowel, which would cause further respiratory embarrassment. Early postnatal management is aimed at POSTNATAL DIAGNOSIS providing adequate tissue oxygenation whilst avoiding high ventilatory pressures, that cause damage to the neonatal Should an antenatal diagnosis not be made, postnatal lungs through barotrauma. Traditionally this is achieved diagnosis most commonly occurs in the ®rst few minutes through routine use of sedation, with or without paralysis of life. Signs of respiratory distress, a scaphoid abdomen and to prevent the infant ``®ghting'' the ventilator. Peak inspira- mediastinal shift away from the side of the lesion all suggest tory pressure and positive end expiratory pressures the diagnosis. X-ray appearances including an absent dia- (PEEPs) are adjusted to maximise oxygenation and prevent phragmatic outline, along with loops of bowel in the chest the development of acidosis. Minimal handling and main- should con®rm the diagnosis (Fig. 1). If necessary, the tenance of normal pH are applied to minimise aggravating position of the tip of a nasogastric (NG) tube within the pulmonary hypertension, which inevitably accompanies thorax, along with an upper gastrointestinal (GI) contrast pulmonary hypoplasia. Failure of conventional ventilation study or postnatal ultrasound scan (in experienced hands) to provide adequate oxygenation may require the addition CONGENITAL DIAPHRAGMATIC HERNIA 341 of inhaled nitric oxide, high frequency oscillatory ventilation care.40,41 This report failed to show any consistent or extracorporeal membrane oxygenation (ECMO). improvement in outcome with the use of ECMO. The results of a multicentre trial in the UK, whilst demonstrating INHALED NITRIC OXIDE bene®ts in infants with respiratory failure, failed to support the use of ECMO in CDH.42 This study has been criticised Initial attempts to treat pulmonary hypertension in the however for excessively stringent entry criteria necessitat- newborn involved the use of systemic vasodilators such ing near unsalvageable respiratory failure before inclusion of as tolazoline or prostaglandins. However, signi®cant side- infants with CDH. A 2002 Cochrane Review on ECMO effects, in particular systemic hypotension, made their use showed a signi®cant survival advantage for all infants with unacceptable.25±27 Inhaled nitric oxide presented an attrac- respiratory failure. The advantage was least signi®cant for tive alternative. Inhalational delivery and rapid metabolism CDH patients.43,44 Despite a lack of clear evidence for its mean that systemic side effects are minimised. Initial trials in use, ECMO is likely to remain a treatment modality for the infants with persistent pulmonary hypertension of the new- infant with CDH. born were very encouraging, some demonstrating a uni- 28±30 versal increase in SaO2. Studies in infants with CDH PERMISSIVE HYPERCAPNIA have shown a more variable response with many infants manifesting no bene®t. A recent meta-analysis and An alternative approach, ®rst suggested by Wung et al. in Cochrane review showed an improvement in perinatal 1985 from New York is permissive hypercapnia.45 This outcome only in infants with persistent pulmonary hyper- avoids the use of sedation, allowing the infant to breathe tension who do not have CDH.31,32 spontaneously on the ventilator. Peak inspiratory pressures are strictly limited, to avoid the effects of barotrauma on the HIGH FREQUENCY OSCILLATORY hypoplastic lung, whilst PEEP is used to maximise alveolar recruitment. This technique permits arterial carbon dioxide VENTILATION levels to rise as necessary, whilst reserving sodium bicar- The use of high frequency oscillatory ventilation (HFOV) bonate infusions to treat severe metabolic acidosis. The aim has been widely adopted. This follows the concept that is to keep preductal pH > 7:2 with an arterial oxygen altering the mode of ventilation by increasing the ventilator pressure of >65 kPa and an oxygen saturation of >90% rate to 100±150 breaths/min with gas exchange occurring whilst not allowing peak inspiratory pressure to exceed through bulk diffusion rather than mass ¯ow may improve 30 cmH2O. Impressive results (84% survival) have been gas exchange whilst decreasing barotrauma. Despite the reported using this technique,46±48 making this an impor- outcome of an early multicentre randomised trial in North tant advance in postnatal therapy for infants with CDH.46 America suggesting no bene®ts in preterm neonates with respiratory failure,33 several anecdotal reports continue to EXOGENOUS SURFACTANT 34,35 report improvements in CDH. A recent Italian study THERAPY reported on the outcome of 44 infants treated over a 10 year period showing an increase in survival from 67% to It is now widely accepted that the use of exogenous 94% by employing HFOV in the preoperative management surfactant therapy to improve ventilation in premature of CDH.36 Surgical repair has also been undertaken whilst infants is effective.49,50 The bene®ts in CDH are less clear. maintaining the infant on high frequency ventilation.36 Researchers have used a variety of methods to evaluate the surfactant status (measurements of phospholipid, phospha- EXTRACORPOREAL MEMBRANE tidylcholine and surfactant proteins) in experimental CDH OXYGENATION models. Lungs from the CDH lamb model have been shown to be de®cient in phospholipid and phosphatidyl- ECMO, introduced in the late 1970s, involves placing the choline.51,54 Similarly, lungs from the nitrofen rat CDH infant on cardiopulmonary support to allow a period of model are de®cient in phospholipid and surfactant pro- ``lung rest'' and reduction in pulmonary vascular resistance teins.52,53,55 Work in human infants has been inconclusive. whilst providing the infant with oxygenated blood via an Studies addressing the levels of phospholipid and surfac- arti®cial circuit. ECMO is an accepted treatment modality tant-related proteins in amniotic ¯uid and bronchoalveolar for the management of respiratory failure in newborns. In lavage ¯uid have failed to demonstrate any difference the UK its use is restricted to designated paediatric ECMO between CDH patients and age-matched controls.56,57 centres. The effects of exogenous surfactant therapy are not Evidence to support the use of ECMO in CDH is universally successful. Although in rats an early increase in con¯icting. Early favourable reports were ¯awed by the pulmonary compliance was seen, this bene®t was short- use of historical controls.37±39 A North American study lived and no ongoing improvement was demonstrated.55 In addressed the relative outcomes from two centres, one humans, early work involving the administration of surfac- offering ECMO, the other offering conventional respiratory tant prior to the ®rst breath (prophylactic administration) 342 N. P. SMITH ET AL.

was encouraging by showing improvements in ventilatory requirement for immunosuppression and its potential parameters.58 This experience was also mirrored in the sequelae in neonates together with problems of donor lamb CDH model, where maximal bene®t from exogenous availability and size match75,76 essentially limit the wide- surfactant was seen with prophylactic delivery.59,60 How- spread clinical application of this technique. ever, a small randomised trial of surfactant therapy in human infants with CDH has failed to demonstrate any SURGERY FOR CDH sustained bene®ts.61 Larger multicentre randomised trials are needed. Surgical repair of CDH has varied little in operative tech- nique from the original reports. Operation is usually via a ANTENATAL STEROID THERAPY subcostal incision, although a thoracotomy may rarely be considered for right-sided lesions. Gentle reduction of Antenatal steroids improve lung maturation of pre-term abdominal viscera from the thoraxis followed by identi- infants.62 In CDH animal models, antenatal glucocorticoids ®cation and excision of any hernia sac (found in 10%).2 have been shown to improve morphological maturity and Diaphragmatic closure is achieved by approximating freed reduce hypermuscularisation of the pulmonary vascula- native tissue with non-absorbable sutures. The anterior rim ture.63±66 Anecdotal bene®ts have been reported in a small is frequently well formed, whilst the posterior rim is often number of cases (D. Tibboel, pers. comm.).67,68 A multi- more sparse or even absent. Where insuf®cient natural centre trial (by the CDH Study Group) is currently eval- tissue exists, prosthetic material e.g. GoretexTM (W.L. Gore uating antenatal glucocorticoid therapy in humans with and Associates, Flagstaff, AZ) may be utilised to complete prenatally diagnosed CDH.67 closure.77,78 Other innovative techniques include the crea- tion of a muscle ¯ap from either the latissimus dorsi or 79,80 LIQUID VENTILATION rectus abdominus to close the diaphragmatic defect. Similarly if primary abdominal closure is dif®cult or com- Liquid ventilation using hyperbarically oxygenated ¯uid was plicated by unacceptably high ventilatory pressures, a pros- brie¯y investigated for use in astronauts and divers during thetic patch may be incorporated into the abdominal wall.81 the 1950s. Theoretical advantages of liquid ventilation Patients on ECMO present a technical challenge. The use of include the fact that, unlike gases, liquids spread uniformly anticoagulation to maintain the ECMO circuit precludes in lung tissue, whilst decreasing the air±¯uid interfaces and aggressive dissection of native diaphragmatic tissue. In such surface tension in alveoli. Initial efforts to use electrolyte cases prosthetic patch closure is common.77 solutions were unsuccessful due to poor gas solubility. An interesting recent development has been the deploy- However, the discovery of ¯uorocarbons has regenerated ment of laparoscopy to repair diaphragmatic defects.82±86 liquid ventilation as a potential therapy in CDH. Advantages Although the technique has been described with some of per¯uorocarbon include a greater solubility for respira- success in adults and older children,84,87±89 its application in tory gases than blood, elimination by vaporisation (mini- the high-risk CDH infant must be interpreted with caution. mising metabolic derangements) and a terminal bromide molecule, which makes it radio-opaque. Initial studies in LONG-TERM OUTCOME animal and human subjects showed encouraging results, 69,70 90 with an increase in PaO2 and pulmonary compliance. Long-term follow up of survivors is required. Apart from Added bene®ts of liquid ventilation may include stimulation neurological sequelae resulting from chronic neonatal of lung growth. A signi®cant increase in lung volume and hypoxia, a high proportion of patients have chronic respira- improvement in ventilatory mechanics in CDH neonates tory insuf®ciency secondary to pulmonary hypoplasia and deemed to have a dismal prognosis at entry to the trial has the consequences of iatrogenic lung injury.91,92 Gastro- been reported.71 Liquid ventilation may offer promise for oesophageal re¯uxand its attendant complications are improving survival in infants with CDH. Phase three clinical perhaps related to diaphragmatic malfunction and may trials are underway to further evaluate this therapy. entail anti-re¯uxsurgery. 93,94 Deformity of the spine and/or chest wall following CDH repair may similarly 95 LUNG TRANSPLANTATION require surgical treatment. In particular, results of long- term follow-up studies following CDH patch repair indicate Lung transplantation is an established clinical treatment for the need for close scrutiny, since nearly half will suffer from paediatric patients with end-stage chronic respiratory insuf- patch failure and recurrent herniation.96 The continuing ®ciency.72 Despite cumulative experience in the very young evolution of treatments for CDH means that true long- patient under the age of 1 year,73 lung transplantation has term follow-up is destined only to identify the inadequacies only been performed in a single infant with CDH.74 The of previous therapies. The ®rst substantial series reporting concept of a temporary lung allograft, remaining in situ until survival after CDH repair date from the 1940s.97 Whilst the contralateral native lung has developed suf®ciently to signi®cant impairments of lung function are not observed support postnatal life is an attractive proposition. The in school age survivors, it is highly plausible that with CONGENITAL DIAPHRAGMATIC HERNIA 343 continued improvements in neonatal respiratory care, mor- bidity from this birth defect will substantially increase.98,99

FETAL SURGERY FOR CDH Failure of conventional postnatal therapies to signi®cantly alter the prognosis of infants with CDH prompted pae- diatric surgeons to consider repair of the hernia antenatally. It was postulated that fetal diaphragmatic hernia repair would remove the compressive forces on the developing lung and permit lung growth to improve on the dismal survival of CDH. To address this hypothesis, surgeons created a surgical model of diaphragmatic hernia in fetal lambs and simulated antenatal closure of the defect with improved survival at birth.100 This led to the development of experimental fetal surgery for humans with CDH. Initial ®ndings from the San Francisco group, operating on without liver herniation, demonstrated no survival bene®t over standard postnatal therapy ± suggesting the risks of Figure 2 Photomicrographs of unsectioned rat lung primordia antenatal surgery were not justi®ed in this group.101,102 harvested at day 13.5 and prior to established diaphragmatic Fetal surgery continues to provoke signi®cant interest for hernia. (a) Normal control lung rudiments. (b) Nitrofen-exposed the high-risk CDH fetus with liver herniation. The seminal lung rudiments with normal bronchial anatomy (>6 buds). observation that infants with laryngeal atresia develop (c) Nitrofen-exposed lung rudiments with reduced lobar bronchi enlarged hyperplastic lungs103,104 led to the deployment (<6 buds). of the ``PLUG'' (Plug the Lung Until it Grows) technique ± surgical occlusion of the fetal trachea in an attempt to nant rodents as a single oral dose at a speci®c point in stimulate hypoplastic lung growth.105,106 Early studies of gestation to produce CDH with severe lung hypoplasia in a fetal tracheal occlusion performed by open fetal surgery proportion of the litter.116±119 Associated malformations in have been superseded by a fetoscopic approach ± the the nitrofen Sprague-Dawley rat model closely mimic ``'' (FETal ENDOscopy) procedure ± to override the incidence and spectrum of those seen in human the problems of preterm labour.107,108 The fetal trachea is CDH.120±126 Since nitrofen is administered during early clipped at 24±26 weeks gestation109 and the occlusion is left organogenesis it provides (unlike the surgically created in place until an EXIT (EX-utero Intrapartum Treatment) lamb CDH model) the opportunity to examine the embry- procedure is performed by Caesarean section at elective ology of CDH and associated lung hypoplasia. delivery.110 FETENDO surgery is currently being investi- Development of an organotypic culture system along gated in a National Institutes of Health trial for the high-risk with detailed morphometric measurements of lungs in ``liver-up'' CDH fetus (M. Harrison, pers. comm.). organ culture has facilitated comparison of pulmonary growth between nitrofen-treated rat embryos and BASIC SCIENCE ± LUNG untreated controls (Fig. 2).127 Such observations have DEVELOPMENT IN CDH revealed that disruption of stereotyped airway branching correlates with and precedes CDH, indicating an intrinsic In recent years there has been an increased appreciation defect of lung development in CDH.127 These observations that CDH is more than just a ``hole in the diaphragm''. The were further con®rmed by D. Tibboel's group, who pos- recognition of associated anomalies in 30±50% of CDH tulated the ``dual-hit'' hypothesis.128 Lung culture systems newborns implies that the key features of CDH may are now providing invaluable research tools for manipulat- represent a global embryopathy.9,111±113 This proposal ing lung hypoplasia and investigating the role of growth suggests that lung hypoplasia arises during the embryonic factor and cell signalling pathways. period and before the fetal diaphragmatic hernia develops. Closure of the human diaphragm at 8 weeks gestation GROWTH FACTORS precludes any detailed investigation of lung development prior to the effect of herniated viscera. The use of terato- Mammalian lung development requires the interaction of genic models has allowed detailed embryological investiga- the ®broblast growth factor (FGF) family, cognate recep- tion to occur. tors (FGFRs) and heparan sulphate (HS) proteoglycans. A number of chemicals have been shown to induce This has been elucidated from studies in mice and the CDH in rodents.114,115 One of these, nitrofen (2,4- fruit¯y, Drosophila melanogaster.129 Branchless and breath- dichloro-40-nitro diphenyl ether), is administered to preg- less are Drosophila mutants lacking FGF and its receptor 344 N. P. SMITH ET AL.

display CDH together with left lung agenesis and signi®cant right lung hypoplasia.135 Experimental studies into the possible restorative role of vitamin A in hypoplastic CDH lungs have had interesting results. Strikingly Thebaud and colleagues have shown that prenatal treatment with vitamin A in the nitrofen model of CDH reduces the incidence of CDH at term, as well as demonstrating improvements in lung growth and matura- tion in perinates.136,137

TRANSGENIC MODELS The ability to manipulate the expression of speci®c genes in transgenic mice has provided a powerful means of dissect- ing the genetic regulation of development and investigating the molecular events underpinning many malformations. Figure 3 Photomicrographs of normal and nitrofen-treated Several mutant phenotypes have been described in which (hypoplastic) lung primordia in culture. The nitrofen treated lungs diaphragmatic hernia may feature. Whilst the inactivation of are smaller and demonstrate an abnormal response to fibroblast several genes may predispose to CDH, gene targeting growth factor 1 (FGF1) and FGF2. (a) No FGF. (b) FGF1 ‡ 1 mg/ typically does not ensure CDH in knockout offspring. This ml heparin. (c) FGF2 alone. suggests a complexinteraction of multifactorial events in the genesis of CDH. For example, homozygous inactivation (FGFR), respectively.129 Sugarless and sulphateless mutants of WT-1 (the gene found to be deleted in familial cases of lack HS. All these Drosophila mutants share abrogated Wilm's tumour) yields CDH with overgrown, underdeve- airway branching.130 loped lungs and renal malformations in rodents,138 whilst Utilising this knowledge, we studied the effects of exo- deletion of both murine retinoic-acid receptors (RARs) genous growth factors on embryonic lung development. yields a high incidence of cranial, vertebral, limb, cardiac, Testing the effects of FGF1Æ heparin, we noted stimulated foregut and pulmonary malformations with a low incidence branching morphogenesis of normal lung primordia in vitro. of CDH.135,139 Although transgenic studies are useful, In contrast, whilst nitrofen-exposed lung primordia were information gathered needs to be translated to the human unexpectedly inhibited by FGF1, they also exhibited strik- situation with caution. Scientists in Scandinavia assessed the ingly abnormal responses to FGF2Æ heparin (Fig. 3). Most incidence of WT-1 mutations in a population of human notably, FGF2 produced massive dilatation of the epithelial infants with CDH. They found no signi®cant abnormalities, lumen of nitrofen lungs, whilst having only minor transient indicating that although WT-1 deletion may give rise to effects on normal lungs.131,132 CDH in rodents, it is not an important factor in the genesis Whilst con®rming a role for the FGF pathway in embry- of the human phenotype.140 onic lung development, this work suggested that FGF1 alone is unlikely to rescue hypoplastic lung growth in vivo. FUTURE DIRECTIONS The abnormal responsiveness of nitrofen-exposed lungs to FGFs further indicate they are intrinsically abnormal prior to What are the future therapeutic implications for clinicians visceral herniation. It has been postulated that disturbance treating CDH? Selection of patients for fetal surgery will of the FGF/FGFR/HS network (or its downstream intracel- require more accurate prognostic indicators of poor peri- lular targets) may comprise at least part of such a signalling natal outcome. Fetal surgery at present may be ``too little defect.132 Clarifying the exact nature of such a lesion too late'' to correct an established embryopathy in pul- presents a formidable task. monary development. Antenatal therapy is the subject of a multicentre trial. Fetoscopic delivery of VITAMIN A targeted growth factors to enhance airway development in CDH will require careful appraisal. The concept of a Vitamin A is important in lung development. In 1953, pharmacological agent or medical ``PLUG'' to reverse Wilson and colleagues noted a high incidence of CDH pulmonary hypoplasia is a goal for the future. Postnatal in the pups of vitamin A de®cient rats.133 Interestingly it has therapies to reduce barotrauma will salvage those new- been noted that human infants with CDH have signi®cantly borns with the less severe degrees of pulmonary hypo- reduced levels of retinol and retinol-binding protein com- plasia. Finally the prevention of the birth defect by pared to age-matched controls.134 A strain of transgenic preconceptual prophylaxis (as in the case of neural tube mice in which both copies of the retinoic acid receptor defects) may represent the ultimate solution for this highly (vitamin A binding receptor) gene have been deleted lethal human anomaly. CONGENITAL DIAPHRAGMATIC HERNIA 345

REFERENCES 24. Heij HA, Ekkelkamp S, Vos A. Diagnosis of congenital cystic adenomatoid malformation of the lung in newborn infants and 1. Bajaj P, Tayal A, Logani KB, Bhan S. Congenital diaphragmatic children. Thorax 1990; 45: 122±125. hernia: a retrospective autopsy study. Indian Pediatr 1991; 28: 25. Bloss RS, Turmen T, Beardmore HE, Aranda JV. Tolazoline therapy 495±500. for persistent pulmonary hypertension after congenital diaphrag- 2. Clark RH, Hardin WD, Hirschl RB et al. Current surgical manage- matic hernia repair. J Pediatr 1980; 9: 984±988. ment of congenital diaphragmatic hernia: a report from the 26. Stevens DC, Schreiner RL, Bill MJ et al. An analysis of tolazoline Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg therapy in the critically ill neonate. J Pediatr Surg 1980; 15: 964±970. 1998; 33: 1004±1009. 27. Wilson RG, George RJ, McCormick WJ, Raine PA. Duodenal 3. Ladd WE, Gross RE. Congenital diaphragmatic hernia. NEngl J Med perforation associated with tolazoline. Arch Dis Child Fetal Neonatal 1940; 223: 917±923. Ed 1985; 60: 878±879. 4. Beresford MW, Shaw NJ. Outcome of congenital diaphragmatic 28. Finer NN, Etches PC, Kamstra B et al. Inhaled nitric oxide in infants hernia. Pediatr Pulmonol 2000; 30: 249±256. referred for extracorporeal membrane oxygenation. Dose re- 5. Skari H, Bjornland K, Haugen G, Egeland T, Emblem R. Congenital sponse. J Pediatr 1994; 124: 302±308. diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr 29. Kinsella JP, Neish SR, Dunbar D et al. Clinical responses to Surg 2000; 35: 1187±1197. prolonged treatment of persistent pulmonary hypertension of the 6. Tibboel D, Gaag AV. Etiologic and genetic factors in congenital newborn with low doses of inhaled nitric oxide. J Pediatr 1993; 123: diaphragmatic hernia. Clin Perinatol 1996; 23: 689±699. 103±108. 7. Hobolth N. Drugs and congenital abnormalities. Lancet 1962; ii: 30. Roberts JD, Polaner DM, Lang P, Zapol W. Inhaled nitric oxide in 1333±1334. persistent pulmonary hypertension of the newborn. Lancet 1992; 8. Powell PD, Johnstone JM. Phenometrazine and fetal abnormalities. 340: 818±819. BMJ 1962; ii: 1327. 31. Oliviera CA, Troster EJ, Pereira CR. Inhaled nitric oxide in the 9. Witters I, Legius E, Moerman P et al. Associated malformations and management of persistent pulmonary hypertension of the newborn: chromosomal anomalies in 42 cases of prenatally diagnosed a meta-analysis. Rev Hosp Clin Fac Med Sao Paulo 2000; 55: 145±154. diaphragmatic hernia. Am J Med Genet 2001; 103: 278±282. 32. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants 10. Adzick NS, Vacanti JP, Lillehei CW et al. Fetal diaphragmatic hernia: born at or near term (Cochrane Review). Cochrane Database Syst ultrasound diagnosis and clinical outcome in 28 cases. J Pediatr Surg Rev 2001; 4: CD000399. 1989; 24: 654±657. 33. The HIFI Study Group. High-frequency oscillatory ventilation com- 11. Thilaganathan B. Routine ultrasound for the prenatal diagnosis of pared with conventional mechanical ventilation in the treatment of congenital diaphragmatic hernia: the `isms'. Ultrasound Obstet Gynecol respiratory failure in preterm infants. NEngl J Med 1989; 320: 88±93. 2002; 19: 327±328. 34. Bohn DJ. Ventilatory management and blood gas changes in 12. Detti L, Mari G, Ferguson JE. Color Doppler ultrasonography of the congenital diaphragmatic hernia. In: Puri P (ed.). Modern Problems in superior mesenteric artery for prenatal ultrasonographic diagnosis of Pediatrics. Basel: Karger, 1989; pp. 76±89. a left-sided congenital diaphragmatic hernia. J Ultrasound Med 2001; 35. Miguet D, Claris O, Lapillone A et al. Peroperative stabilisation using 20: 689±692. high frequency oscillatory ventilation in the management of 13. Dillon E, Renwick M, Wright C. Congenital diaphragmatic herniation: congenital diaphragmatic hernia. Crit Care Med 1994; 22: 877±882. antenatal detection and outcome. Br J Radiol 2000; 73: 360±365. 36. Cacciari A, Ruggeri G, Mordenti M et al. High-frequency oscillatory 14. Garne E, Haeusler M, Barisic I et al. Congenital diaphragmatic hernia: ventilation versus mechanical ventilation in congenital diaphragmatic evaluation of prenatal diagnosis in 20 European regions. Ultrasound hernia. Eur J Pediatr Surg 2001; 11: 3±7. Obstet Gynecol 2002; 19: 329±333. 37. Atkinson JB, Ford EG, Humphries B et al. The impact of 15. Adzick NS, Harrison MR, Glick PL et al. Diaphragmatic hernia in the extracorporeal membrane support in the treatment of congenital fetus: prenatal outcome and diagnosis in 94 cases. J Pediatr Surg diaphragmatic hernia. J Pediatr Surg 1991; 26: 791±793. 1985; 20: 357±362. 38. Finer NN, Etches DC, Hallgren R et al. Neonatal congenital 16. Nakayama DK, Harrison MR, Chinn DH et al. Prenatal diagnosis and diaphragmatic hernia and extracorporeal membrane oxygenation. natural history of the fetus with a congenital diaphragmatic hernia: Can Med Assoc J 1992; 146: 501±508. initial clinical experience. J Pediatr Surg 1985; 20: 18±124. 39. Johnston PW, Bashner B, Liberman R et al. Clinical use of extra- 17. Burge DM, Atwell JB, Freeman NV. Could the stomach site help corporeal membrane oxygenation in the treatment of persistent predict outcome in babies with left sided diaphragmatic hernia pulmonary hypertension following surgical repair of congenital diagnosed antenatally? J Pediatr Surg 1989; 24: 567±569. diaphragmatic hernia. J Pediatr Surg 1988; 23: 908±912. 18. Lipshutz GS, Albanese CT, Feldstein VA et al. Prospective analysis of 40. Azarow K, Messineo A, Pearl R et al. Congenital diaphragmatic lung-to-head ratio predicts survival for patients with prenatally hernia ± a tale of two cities: the Toronto experience. J Pediatr Surg diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997; 32: 1997; 32: 395±400. 1634±1636. 41. Wilson J, Lund DP, Lillehei CW et al. Congenital diaphragmatic 19. Sbragia L, Paek BW, Filly RA et al. Congenital diaphragmatic hernia hernia ± a tale of two cities: the Boston experience. J Pediatr Surg without herniation of the liver: does the lung-to-head ratio predict 1997; 32: 401±405. survival? J Ultrasound Med 2000; 19: 845±848. 42. UK Collaborative ECMO Trial Group. UK collaborative randomised 20. Paek BW, Coakley FV, Lu Y et al. Congenital diaphragmatic hernia: trial of neonatal extracorporeal membrane oxygenation. Lancet prenatal evaluation with MR lung volumetry ± preliminary 1996; 348: 75±82. experience. Radiology 2001; 220: 63±67. 43. Elbourne D, Field D, Mugford M. Extracorporeal membrane 21. Albanese CT, Lopoo J, Goldstein RB et al. Fetal liver position and oxygenation for severe respiratory failure in newborn infants. perinatal outcome for congenital diaphragmatic hernia. Prenat Diagn Cochrane Database Syst. Rev. 2002; CD001340. 1998; 18: 1138±1142. 44. Al-Shanafey S, Giacomantonio M, Henteleff H. Congenital diaphrag- 22. Mychaliska GB, Bullard KM, Harrison MR. In utero management matic hernia: experience without extracorporeal membrane of congenital diaphragmatic hernia. Clin Perinatol 1996; 23: 823± oxygenation. Pediatr Surg Int 2002; 18: 28±31. 841. 45. Wung JT, James LS, Kilchevsky E, James E. Management of infants 23. May DA, Barth RA, Yeager S et al. Perinatal and postnatal chest with severe respiratory failure and persistence of the fetal sonography. Radiol Clin North Am 1993; 31: 499±516. circulation, without hyperventilation. Pediatrics 1985; 76: 488±494. 346 N. P. SMITH ET AL.

46. Boloker J, Bateman DA, Wung JT, Stolar CJ. Congenital diaphrag- 66. Losty PD, Suen HC, Manganaro TF, Donahoe PK, Schnitzer JJ. matic hernia in 120 infants treated consecutively with permissive Prenatal hormonal therapy improves pulmonary compliance in the hypercapnea/spontaneous respiration/elective repair. J Pediatr Surg nitrofen-induced CDH rat model. J Pediatr Surg 1995; 30: 420±426. 2002; 37: 357±366. 67. Van Tuyl M, Hosgor M, Tibboel D. Tracheal ligation and 47. Wung JT, Sahni R, Mof®tt ST, Lipsitz E, Stolar CJ. Congenital corticosteroids in congenital diaphragmatic hernia: for better for diaphragmatic hernia: survival treated with very delayed surgery, worse? Pediatric Res 2001; 50: 441±444. spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30: 68. Ford W, Kirby C, Wilkinson C, Furness M, Slater A. Antenatal 406±409. and favourable outcomes in fetuses with `poor 48. Mof®tt ST, Schulze KF, Sahni R et al. Preoperative cardiorespiratory prognosis' diaphragmatic hernia. Pediatr Surg Int 2002; 18: 244±246. trends in infants with congenital diaphragmatic hernia. J Pediatr Surg 69. Major D, Cadenas M, Cloutier R et al. Combined gas ventilation and 1995; 30: 604±611. per¯uorocarbon tracheal instillation as an alternative treatment for 49. Jobe A. Pulmonary surfactant therapy. NEngl J Med 1993; 328: 861± lethal congenital diaphragmatic hernia in lambs. J Pediatr Surg 1995; 868. 30: 1178±1182. 50. Yost CC, Soll RF. Early versus delayed selective surfactant treatment 70. Pranikoff T, Gauger P, Hirschl RB. Partial liquid ventilation in for neonatal respiratory distress syndrome. Cochrane Database Syst newborn patients with congenital diaphragmatic hernia. J Pediatr Surg Rev 2000; CD001456. 1996; 31: 613±618. 51. Glick PL, Stannard VA, Leach CL et al. Pathophysiology of congenital 71. Fauza DO, Hirschl RB, Wilson J. Continuous intrapulmonary diaphragmatic hernia II: the fetal lamb CDH model is surfactant distension with per¯uorocarbon accelerates lung growth in infants de®cient. J Pediatr Surg 1992; 27: 382±387. with congenital diaphragmatic hernia: initial experience. J Pediatr Surg 52. Mysore MR, Margraf LR, Jaramillo MA et al. Surfactant protein A is 2001; 36: 1237±1240. decreased in the rat model of congenital diaphragmatic hernia. Am J 72. Parisi F. Advances in pediatric transplantation: heart and lung. Respir Crit Care Med 1998; 157: 654±657. Transplant Proc 2001; 33: 1725±1726. 53. Suen HC, Catlin EA, Ryan DP, Wain JC, Donahoe PK. Biochemical 73. Huddelston CB, Mendeloff EN. Lung transplantation in infants. Semin immaturity of lungs in congenital diaphragmatic hernia. J Pediatr Surg Thorac Cardiovasc Surg Pediatr Card Surg Annu 2001; 4: 115±122. 1993; 28: 471±475. 74. Van Meurs KP, Rhine WD, Benitz WE et al. Lobar lung 54. Hedrick HL, Kaban JM, Pacheco BA et al. Prenatal glucocorticoids transplantation as a treatment for congenital diaphragmatic hernia. improve pulmonary morphometrics in fetal sheep with congenital J Pediatr Surg 1994; 29: 1557±1560. diaphragmatic hernia. J Pediatr Surg 1997; 32: 217±221 (Discussion 75. Jennings RW, Lorenz HP, Duncan BW et al. Adult-to-neonate lung 221±222). transplantation: anatomic considerations. J Pediatr Surg 1992; 27: 55. Scetters EC, Ijsselstijn H, Tenbrinck R et al. Evaluation of lung 1285±1290. function before and after surfactant application during arti®cial 76. Cromblehome TM, Adzick NS, Hardy K et al. Pulmonary lobar ventilation in newborn rats with congenital diaphragmatic hernia. transplantation in neonatal swine: a model for treatment of J Pediatr Surg 1994; 29: 820±824. congenital diaphragmatic hernia. J Pediatr Surg 1990; 25: 11±18. 56. Ijsselstijn H, Zimmermann LJ, Bunt JE, de Jongste JC, Tibboel D. 77. Connors RH, Tracy TJ, Bailey PV et al. Congenital diaphragmatic Prospective evaluation of surfactant composition in bronchoalveolar hernia on ECMO. J Pediatr Surg 1990; 25: 1043±1046. lavage ¯uid of infants with congenital diaphragmatic hernia and of 78. de Kort LM, BaxKM. Prosthetic patches used to close congenital age-matched controls. Crit Care Med 1998; 27: 1219±1221. diaphragmatic defects behave well: a long-term follow-up study. Eur 57. Sullivan K, Hawgood SB, Flake AW, Harrison MR, Adzick NS. J Pediatr Surg 1996; 6: 136±138. Amniotic ¯uid phospholipid analysis in the fetus with congenital 79. Bianchi A, Doig CA, Cohen SJ. The reverse latissimus dorsi ¯ap for diaphragmatic hernia. J Pediatr Surg 1994; 29: 1020±1023. congenital diaphragmatic hernia repair. J Pediatr Surg 1983; 18: 58. Glick PL, Leach CL, Besner GE et al. Pathophysiology of congenital 560±563. diaphragmatic hernia III: exogenous surfactant therapy for the high 80. Simpson JS, Gassage JD. Use of abdominal wall muscle ¯ap in repair risk infant with CDH. J Pediatr Surg 1992; 27: 866±869. of large congenital diaphragmatic hernia. J Pediatr Surg 1971; 6: 59. WilcoxDT, Glick PL, Karamanoukian H et al. Pathophysiology of 42±44. congenital diaphragmatic hernia V: effect of exogenous surfactant 81. Michalevicz D, Chaimoff C. Use of Silastic sheet for widening the therapy on gas exchange and lung mechanics in the lamb congenital abdominal cavity in the surgical treatment of diaphragmatic hernia. diaphragmatic hernia model. J Pediatr 1994; 124: 289±293. J Pediatr Surg 1989; 24: 265±266. 60. O'Toole SJ, Karamanoukian H, Morin FC et al. Surfactant decreases 82. Shah AV, Shah AA. Laparoscopic approach to surgical management pulmonary vascular resistance and increases pulmonary blood ¯ow of congenital diaphragmatic hernia in the newborn. J Pediatr Surg in the fetal lamb model of congenital diaphragmatic hernia. J Pediatr 2002; 37: 548±550. Surg 1996; 31: 507±511. 83. Lima M, Lauro V, Domini M et al. Laparoscopic surgery of 61. Lotze A, Knight GR, Anderson KD et al. Surfactant (beractant) therapy diaphragmatic diseases in children: our experience with ®ve cases. for infants with congenital diaphragmatic hernia on ECMO: evidence Eur J Pediatr Surg 2001; 11: 377±381. of persistent surfactant de®ciency. J Pediatr Surg 1994; 29: 407±412. 84. Frantzides CT, Carlson MA, Pappas C, Gatsoulis N. Laparoscopic 62. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of repair of a congenital diaphragmatic hernia in an adult. J the randomised trials, 1972 to 1994. Am J Obstet Gynecol 1995; 173: Laparoendosc Adv Surg Tech A 2000; 10: 287±290. 322±355. 85. Taskin M, Zengin K, Unal E, Eren D, Korman U. Laparoscopic repair 63. Losty PD, Pacheco BA, Manganaro TF et al. Prenatal hormonal of congenital diaphragmatic hernias. Surg Endosc 2002; 16: 869. therapy improves pulmonary morphology in rats with congenital 86. Thoman DS, Hui T, Phillips EH. Laparoscopic diaphragmatic hernia diaphragmatic hernia. J Surg Res 1996; 65: 45±52. repair. Surg Endosc 2002; 16: 1345±1349. 64. Taira Y, Miyazaki E, Ohshiro K, Yamataka T, Puri P. Administration of 87. van der Zee DC, BaxNM. Laparoscopic repair of a congenital antenatal glucocorticoids prevents pulmonary artery structural diaphragmatic hernia in a 6-month-old child. Surg Endosc 1995; 9: changes in nitrofen-induced congenital diaphragmatic hernia in rats. 1001±1003. J Pediatr Surg 1998; 33: 1052±1056. 88. Rice GD, O'Boyle CJ, Watson DI, Devitt PG. Laparoscopic repair of 65. Ijsselstijn H, Pacheco BA, Albert A et al. Prenatal hormones alter Bochdalek hernia in an adult. Aust NZ J Surg 2001; 71: 443±445. antioxidant enzymes and lung histology in rats with congenital 89. Campos LI, Sipes EK. Laparoscopic repair of diaphragmatic hernia. diaphragmatic hernia. Am J Physiol 1997; 272: L1059±L1065. J Laparoendosc Surg 1991; 1: 369±373. CONGENITAL DIAPHRAGMATIC HERNIA 347

90. Lund DP, Mitchell J, Kharasch V et al. Congenital diaphragmatic 113. Sweed Y, Puri P. Congenital diaphragmatic hernia: in¯uence of hernia: the hidden morbidity. J Pediatr Surg 1994; 29: 258±262. associated malformations on survival. Arch Dis Child 1993; 69: 68± 91. Bos AP, Hussain SM, Hazebrook FW et al. Radiographic evidence of 70. bronchopulmonary dysplasia in high-risk congenital diaphragmatic 114. Kang YJ, Zolna L, Manson JM. Strain differences in response of hernia survivors. Pediatr Pulmonol 1993; 15: 231±234. Sprague-Dawley and Long Evans Hooded rats to the teratogen 92. Ijsselstijn H, Tibboel D, Hop WJ et al. Long term pulmonary nitrofen. Teratology 1986; 34: 213±223. sequelae in children with congenital diaphragmatic hernia. Am J 115. Taleporos P, Salgo MP, Oster G. Teratogenic action of bis(dichloro- Respir Crit Care Med 1997; 155: 174±180. acetyl)diamine on rats: patterns of malformations produced in high 93. Kieffer J, Sapin E, Berg A et al. Gastroesophageal re¯uxafter repair incidence at time-limited periods of development. Teratology 1978; of congenital diaphragmatic hernia. J Pediatr Surg 1995; 30: 1330± 18: 5±15. 1333. 116. Kluth D, Keijzer R, Hertl M, Tibboel D. Embryology of congenital 94. Koot VC, Bergmeijer JH, Bos AP, Molenaar JC. Incidence and diaphragmatic hernia. Semin Pediatr Surg 1996; 5: 224±233. management of gastroesophageal re¯uxafter repair of congenital 117. Kluth D, Kangah R, Reich P et al. Nitrofen-induced diaphragmatic diaphragmatic hernia. J Pediatr Surg 1993; 28: 48±52. hernias in rats: an animal model. J Pediatr Surg 1990; 25: 850±854. 95. Vanamo K, Peltonon J, Rintala R et al. Chest wall and spinal 118. Kluth D, Losty PD, Schnitzer JJ et al. Toward understanding the deformities in adults with congenital diaphragmatic defects. J Pediatr developmental anatomy of congenital diaphragmatic hernia. Clin Surg 1996; 31: 851±854. Perinatol 1996; 23: 456±462. 96. Moss RL, Chen CM, Harrison MR. Prosthetic patch durability in 119. Kluth D, Tenbrick R, von Ekesparre M et al. The natural history of congenital diaphragmatic hernia: a long-term follow-up study. congenital diaphragmatic hernia and pulmonary hypoplasia in the J Pediatr Surg 2001; 36: 152±154. embryo. J Pediatr Surg 1993; 28: 456±462. 97. Irish MS, Holm BA, Glick PL. Congenital diaphragmatic hernia. A 120. Kim WG, Suh JW, Chi JG. Nitrofen-induced congenital malforma- historical review. Clin Perinatol 1996; 23: 625±653. tions of the heart and great vessels in rats: an animal model. J Pediatr 98. Marven SS, Smith CM, Claxton D et al. Pulmonary function, exercise Surg 1999; 34: 1782±1786. performance and growth in survivors of congenital diaphragmatic 121. Losty PD, Connell MG, Freese R et al. Cardiovascular malformations hernia. Arch Dis Child Fetal Neonatal Ed 1998; 78: 137±142. in experimental congenital diaphragmatic hernia. J Pediatr Surg 1999; 99. Stolar CJ. What do survivors of congenital diaphragmatic hernia 3: 1203±1207. look like when they grow up? Semin Pediatr Surg 1996; 5: 275± 122. Migliazza L, Otten C, Xia H et al. Cardiovascular malformations in 279. congenital diaphragmatic hernia: human and experimental studies. 100. Harrison MR, Bressack MA, Churg AM, de Lorimier AA. Correction J Pediatr Surg 1999; 34: 1352±1358. of congenital diaphragmatic hernia in utero II: simulated correction 123. Migliazza L, Xia H, Alvarez JI et al. Heart hypoplasia in experimental permits fetal lung growth with survival at birth. Surgery 1980; 88: congenital diaphragmatic hernia. J Pediatr Surg 1999; 34: 706±710. 260±268. 124. Migliazza L, Xia H, Diez-Pardo JA, Tovar JA. Skeletal malformations 101. Harrison MR, Adzick NS, Bullard KM et al. Correction of congenital associated with congenital diaphragmatic hernia: experimental and diaphragmatic hernia in utero VII: a prospective trial. J Pediatr Surg human studies. J Pediatr Surg 1999; 34: 1624±1629. 1997; 32: 1637±1642. 125. Tovar JA, Alfonso LF, Aldazabal P et al. The kidney in the fetal rat 102. Harrison MR, Adzick NS, Flake AW et al. Correction of congenital model of congenital diaphragmatic hernia induced by nitrofen. diaphragmatic hernia in utero VI: hard-earned lessons. J Pediatr Surg J Pediatr Surg 1992; 27: 1356±1360. 1993; 28: 1411±1417 (Discussion 1417±1418). 126. Xia H, Migliazza L, Diez-Pardo JA, Tovar JA. The tracheobronchial 103. Hedrick M, Estes J, Sullivan K et al. Plug the lung until it grows tree is abnormal in experimental congenital diaphragmatic hernia. (PLUG): a new method to treat congenital diaphragmatic hernia Pediatr Surg Int 1999; 15: 184±187. in utero. J Pediatr Surg 1994; 29: 612±617. 127. Jesudason EC, Connell MG, Fernig DG, Lloyd DA, Losty PD. Early 104. Beierle EA, Langham MR Jr, Cassin S. In utero lung growth of fetal lung malformations in congenital diaphragmatic hernia. J Pediatr Surg sheep with diaphragmatic hernia and tracheal stenosis. J Pediatr Surg 2000; 35: 124±127. 1996; 31: 141±146 (Discussion 146±147). 128. Keizer R, Lui J, Deimling J et al. Dual-hit hypothesis explains 105. Bealer JF, Skarsgard ED, Hedrick M et al. The ``PLUG'' odyssey: pulmonary hypoplasia in the nitrofen model of congenital diaphrag- adventures in experimental tracheal occlusion. J Pediatr Surg 1995; matic hernia. Am J Pathol 2000; 156: 1299±1306. 20: 361±364 (Discussion 364±365). 129. Metzger RJ, Krasnow MA. Genetic control of branching morpho- 106. Luks FI, Gilchrist BF, Jackson BT, Piasecki GJ. Endoscopic tracheal genesis. Science 1999; 284: 1634±1639. obstruction with an expanding device in the fetal lamb model: 130. Lin X, Buff EM, Perrimno N, Micheloson AM. Heparan sulphate preliminary considerations. Fetal Diagn Ther 1996; 11: 67±71. proteoglycans are essential for FGF receptor signalling during 107. Albanese CT, Jennings RW, Filly RA et al. Endoscopic tracheal Drosophila embryonic development. Development 1999; 126: occlusion: evolution of techniques. Pediatr Endosurg Innov Tech 1998; 3715±3723. 2: 17±53. 131. Jesudason EC, Connell MG, Fernig DG, Lloyd DA, Losty PD. 108. Skarsgard ED, Meuli M, Vandeiwall KJ et al. Fetal endoscopic tracheal Heparin and in vitro experimental lung hypoplasia. Pediatr Surg Int occlusion (FETENDO ``PLUG'') for congenital diaphragmatic hernia. 2000; 16: 247±251. J Pediatr Surg 1996; 31: 1335±1338. 132. Jesudason EC, Fernig DG, Lloyd DA, Losty PD. In vitro effects of 109. Vanderwall KJ, Bruch SW, Meuli M et al. Fetal endoscopic growth factors on lung hypoplasia in a congenital diaphragmatic (`Fetendo') tracheal clip. J Pediatr Surg 1996; 31: 1101±1103. hernia (CDH) model. J Pediatr Surg 2000; 35: 914±922. 110. Mychaliska GB, Bealer JF, Graf JL et al. Operating on placental 133. Wilson J, Roth CB, Waekany J. An analysis of the syndromes of support: the ExUtero Intrapartum Treatment (EXIT) procedure. J malformation induced by maternal vitamin A de®ciency: effects of Pediatr Surg 1997; 32: 227±230. restoration of vitamin A at various times during gestation. Am J Anat 111. Benjamin DR, Juul S, Siebert JR. Congenital posterolateral diaphrag- 1953; 92: 189±217. matic hernia: associated malformations. J Pediatr Surg 1988; 23: 899± 134. Major D, Cadenas M, Fournier L et al. Retinol status of newborn 903. infants with congenital diaphragmatic hernia. Pediatr Surg Int 1998; 112. Jones PM. Congenital diaphragmatic hernia: in¯uence of associated 13: 547±549. malformations on survival. Arch Dis Child Fetal Neonatal Ed 1994; 70: 135. Mendelsohn C, Lohnes D, Decimo D et al. Function of the retinoic F159 (Comment). acid receptors (RARs) during development (II). Multiple abnor- 348 N. P. SMITH ET AL.

malities at various stages of organogenesis in RAR double mutants. 138. Kreidberg JA, Sariola H, Loring JM et al. WT-1 is required for early Development 1994; 120: 2749±2771. kidney development. Cell 1993; 74: 679±691. 136. Thebaud B, Tibboel D, Rambaud C et al. Vitamin A decreases the 139. Lohnes D, Mark M, Mendelsohn C et al. Function of the retinoic acid incidence and severity of nitrofen-induced congenital diaphragmatic receptors (RAR's) during development (I). Craniofacial and skeletal hernia in rats. Am J Physiol 1999; 277: L423±L429. abnormalities in RAR double mutants. Development 1994; 120: 137. Thebaud B, Barlier-Mur AM, Chailley-Heu B et al. Restoring effects 2723±2748. of vitamin A on surfactant synthesis in nitrofen-induced congenital 140. Nordenskjold A, Tapper-Persson M, Anvret M. No evidence of diaphragmatic hernia in rats. Am J Respir Crit Care Med 2001; 164: WT1 gene mutations in children with congenital diaphragmatic 1083±1089. hernia. J Pediatr Surg 1996; 31: 925±927.