Antenatal Management of Isolated Congenital

Journal of Pediatric Surgery (2012) 47, 282–290

www.elsevier.com/locate/jpedsurg

Journal of Pediatric Surgery Lecture

Antenatal management of isolated congenital diaphragmatic hernia today and tomorrow: ongoing collaborative research and development☆
Jan Deprest a,⁎, Paolo De Coppi b
Division of Woman and Child, Department of Reproduction, Development, and Regeneration, University Hospitals Leuven, 3000 Leuven, Belgium b University College, London, UK
Received 1 November 2011; accepted 10 November 2011
a

Key words:
Congenital diaphragmatic hernia; Fetal intervention; Fetal endoscopic tracheal occlusion; Fetoscopy; Pulmonary hypoplasia

Abstract The diagnosis of congenital diaphragmatic hernia should be made prenatally in virtually all cases where routine maternal ultrasonography is available. At that time, the prognosis can be predicted based on whether it is isolated and assessment of lung size and/or the position of the liver. Prenatal intervention may be offered in those selected fetuses that have a predicted poor outcome. The aim of this procedure is to reverse the key determinant of survival—pulmonary hypoplasia. Percutaneous fetal endoscopic tracheal occlusion by a balloon is a minimally invasive procedure that has been shown safe and yields a 50% survival rate in severe cases. The outcome can be predicted by the gestational age at birth, the lung size before and after balloon placement, and whether the balloon has been removed prenatally. Currently, the added value of prenatal intervention is being investigated in the Tracheal Occlusion To Accelerate Lung Growth trial ((TOTAL); a European and North American collaboration). Future developments may include better prediction of outcome by more complex algorithms reflecting combinations of prenatal predictors, gene expression profiling to reflect lung development and response to tracheal occlusion, and alternative prenatal strategies for salvaging the worst cases. Fetuses with severe hypoplasia usually require postnatal operative repair using prosthetic patches, and tissue engineering offers the potential for ex utero culture. © 2012 Elsevier Inc. All rights reserved.

The prevalence of congenital diaphragmatic hernia (CDH) ranges between 1 and 4 per 10,000 births, and based on 2008 birth rates in the 27 countries of the European Union, anywhere from 542 to 2168 children with CDH
Presented, in part, as the Journal of Pediatric Surgery Lecture at the Annual Meeting of the British Association of Pediatric Surgery; Belfast, Northern Ireland, UK; July 20-22, 2011. ⁎ Corresponding author. Tel.: +32 16344215; fax: +32 16344205. E-mail address: [email protected] (J. Deprest). 0022-3468/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.11.020
☆

would be born each year [1]. About 85% are left-sided CDH, 13% are right-sided CDH, and bilateral lesions and complete agenesis comprise less than 2%. Congenital diaphragmatic hernia can occur in association with other anomalies, and in which case, the mortality is greater than 85%. Isolated CDH, at first glance, is a straightforward surgically correctable defect of the diaphragm, but from the first trimester, abdominal contents have usually herniated into the thorax, interfering with lung development. This causes hypoplasia of both lungs, that is, fewer airway branches and abnormal

Antenatal management of isolated CDH pulmonary vessels, as well as a reduced lung compliance resulting in potentially fatal postnatal ventilatory insufficiency and pulmonary hypertension. Despite optimal tertiary neonatal care, mortality rates of up to 30% are common. Furthermore, survivors may have severe morbidity, such as bronchopulmonary dysplasia, persistent pulmonary hypertension, gastroesophageal reflux, and, less frequently, thoracic deformation [2,3]. Maternal ultrasound screening programs have led to prenatal diagnosis in about 2 of 3 cases and should prompt referral to a tertiary center experienced in assessing this anomaly and managing CDH in the perinatal period [4]. A comprehensive diagnostic and prognostic workup comprises advanced imaging, genetic testing, and multidisciplinary counseling, so that parents can take a well-informed decision [5].

283 that over time, fetal MRI will become the method of choice for anatomical lung assessment, but now, there is no proof for superiority over ultrasound [12]. The lung-to-head ratio (LHR) was first described by Metkus et al [13] in the Journal of Pediatric Surgery and consists of measurement of the contralateral lung (at the level of the 4 chamber view). This is then quoted in relation to the head circumference (as measured in the standard biparietal view). The most accurate method for lung measurement consists of tracing lung contours [14,15]. Major decisions are best based on measurements by experienced operators because the actual measurement of the LHR has a steep learning curve [16]. One cannot rely, however, on the absolute value of LHR in the index case because it is a function of gestational age and changes over time. The lung grows 4 times more than the head over the entire gestational period. The LHR of the index case should now be expressed as a function of what is expected in a gestational-age control (observed [O]/expected [E] LHR). This expected value can be calculated using formulas specific for the measuring technique, as well as the side of the lesion, and embedded in a freely available Web-based calculator (www.totaltrial.eu) [11,17,18]. The prognostic value of the O/E LHR has been validated in 354 fetuses with unilateral isolated CDH, which were evaluated between 18 and 38 weeks' gestation, both in terms of mortality and morbidity (Fig. 1) [20,21]. Predictive value using this index is more accurate in later gestation; however, this is probably true for any prediction method [22]. Prediction of long-term outcome is, at present, not possible.

1. Prenatal evaluation and prediction of outcome
Accurate prediction is crucial because of possible prenatal intervention in the worst cases. Individual prediction is primarily based on estimation of lung size, which is a proxy for pulmonary hypoplasia. This can be done by ultrasound (reviewed in Knox et al [6]) as well as fetal magnetic resonance imaging (MRI) volumetry (reviewed in Mayer et al [7]). Assessment of the pulmonary circulation may predict pulmonary hypertension. Lastly, the presence of liver herniation is also predictive [7,8]. Whether this is an independent predictor and what the exact pathophysiology of the feature means remain unknown. More accurate prediction is possible by combining these elements [9,10]. For a further review on the exact techniques used, we refer to an earlier review by Claus et al [11]. We insist on precise assessment of the contralateral lung size by 2-dimensional ultrasound before selection for fetal surgical trials. It is likely

2. Prenatal intervention for CDH
There are comprehensive reviews available on the history of fetal surgery for CDH [23,24]. Currently,

Fig. 1 Survival rates of fetuses with isolated left-sided CDH, depending on the measurement of the O/E LHR and the position of the liver as in the antenatal CDH registry. Numbers at the bottom refer to the number in each severity group. Adapted from Deprest et al [19], with permission of the authors and the publisher.

284 prenatal intervention consists of percutaneous fetoscopic endoluminal tracheal occlusion (FETO). This is believed to work because it prevents egress of lung fluid, thereby increasing airway pressure and inducing cellular proliferation and an increase in alveolar airspace and better maturation of pulmonary vasculature [25]. In experimental conditions, sustained tracheal occlusion (TO) was shown to reduce the number of type II pneumocytes and, hence, reduce surfactant expression. This can be improved by in utero release of the occlusive device (“plug-unplug sequence”) [26]. Our group first described TO experimentally using endoscopy and an endoluminal balloon, and this opened the door to a percutaneous, clinically acceptable technique [27]. Over time, invasiveness was reduced by moving away from general to local anesthesia with fetal analgesia and immobilization [28]. Appropriate instruments were developed with the support of the European Commission, which we recently reviewed in this journal [29]. The FETO task force proposes for those defined as “severe cases” insertion of the balloon at around 28 weeks and reversal of occlusion at 34 weeks. Although experimental evidence suggests that in utero removal improves lung maturation, there are additional secondary advantages such as the potential for vaginal delivery and neonatal management at the recruiting tertiary center [26]. In utero reversal is achieved either by fetoscopy (50%) or by ultrasound guided puncture (19%), and in 1 large series, this improved survival [29]. In those cases where prenatal removal is not possible, the balloon can be removed at birth while still on placental circulation (21%). The least preferred method is that of postnatal retrieval (7% of the entire experience, including non-FETO centers). Postnatal retrieval should not be underestimated because in the European experience, there have been difficulties with balloon removal in 10 cases. Typically, this happens when delivery occurs at a location without experience or preparation. We now insist that the mother stays close to the FETO center, which has a responsibility to organize a 24/7 service for management of the fetal airway. We have reported outcomes of 210 interventions. On the basis of stratified data from the antenatal CDH registry, FETO increased survival in severe cases with left-sided CDH from 24% to 49% and in right-sided CDH from 0% to 35% (P b .001) [20]. The strongest predictors of survival were O/E LHR before the procedure (odds ratio, 1.49; P = .02) and gestational age at delivery (odds ratio, 1.02; P = .007). The latter is mainly determined by the occurrence of preterm premature rupture of membranes, and this occurred in 17% of cases within 3 weeks of FETO. This is less than in the randomized trial of Harrison et al [30], where premature rupture of membranes less than 34 weeks was less than 25% compared with 100%. Delivery occurred at a median of 35.3 weeks and, again, was later compared with Harrison et al [30], where delivery at less than 34 weeks took place in 100% of their patients compared with 31% in our experience.

J. Deprest, P. De Coppi Interestingly, survival for those delivering at 32 to 33 weeks was equal to those of 34 weeks or greater (60%; left-sided cases only). Short-term morbidity in survivors is also better than expected and close to that of cases with moderate pulmonary hypoplasia that were managed expectantly during pregnancy [31,32]. Early clinical experience has shown few demonstrable adverse effects of the balloon on the developing trachea, except in very early occlusions and complications arising at the time of removal [33]. However, the neonates and infants do have obvious tracheomegaly, but this does not seem to have a clinical impact, except for a barking cough on effort [33,34]. Over time, the widening seems to become less important [34]. Most neonates require surgical patching of the diaphragm, strongly suggesting the larger size of the defect in this selected high-risk group. The use of patch has previously been shown to be a predictor of outcome. High patch rates will increase the number of patch-related complications so that we feel that tissue engineering an autologous patch is also an important research aim [35].

3. Trials on FETO vs expectant management
All the outcomes quoted previously were based on the data from the antenatal CDH registry and compared with expected outcomes in those who had had expectant management during pregnancy [20]. A similar increase in survival after TO (although slight differences in protocols) has been observed in Brazil and Germany [36-38]. Obviously, this claim of improved outcome must now be proven in appropriately designed trials. Thus, in severe cases, we propose insertion of the balloon at 27 to 30 weeks and its removal at 34 weeks (NCT01240057), which is based on our existing experience. A few items are worth mentioning. (1) We have moved

Fig. 2 Graphical display of the number of patients delivering (black bars) and the number of fetuses surviving (gray bars) as a function of gestational age. Modified from Deprest et al [29], with permission from the authors and the publisher.

Antenatal management of isolated CDH slightly the time point of insertion from 26 to 28 weeks to 27 to 30 weeks and believe that this will lessen the risk for early delivery less than 32 weeks (shown to have a negative impact on survival; Fig. 2) without compromising the evidence for a less vigorous lung response if inserted at more than 30 weeks [39]. (2) We chose in utero balloon removal (3) at 34 weeks because this seemed to be associated with a higher survival [29]. Moreover, survival does not increase with gestation at delivery beyond 34 weeks. Timely and elective balloon removal avoids unexpected emergency balloon retrieval. Nevertheless, in the 2 Brazilian series, there was no apparent difference in survival with balloon removal at the time of or before birth. We have also started a trial in fetuses with moderate pulmonary hypoplasia, testing whether FETO decreases bronchopulmonary dysplasia (NCT00763737). In this group, occlusion is done at 30 to 32 weeks. For both trials, our neonatal colleagues from all over Europe have designed a standardized consensus postnatal management protocol

285 (Table 1). Both trials will take place under the acronym TOTAL (Tracheal Occlusion To Accelerate Lung growth [http://www.totaltrial.eu/]). Obviously, these trials can only be successful given sufficient recruitment. The multicenter trials have postnatal treatment centers and FETO centers. The latter are the ones who evaluate patients and, when applicable, treat them prenatally (Table 2). This is for consistency of patient selection and management [16]. We agreed on firm criteria for centers doing FETO, based on current activity in fetoscopy as well as the number of FETO procedures before embarking on the trial (Table 3). We have been and are training centers in Paris and Toronto as well as selected North American Fetal Treatment NETwork (NAFTNET) centers (Philadelphia, Houston, Cincinnati, San Francisco, Baltimore). Wet laboratories are added to on-site training as well as the development of purpose-designed inanimate models. Postnatal management can be done at tertiary care centers, adhering to the standardized postnatal care protocol [42,45]. However, trial

Table 1

Fetal criteria and list of outcome measurements in the TOTAL trial

Isolated left-sided CDH Trial for severe hypoplasia
a

Trial for moderate hypoplasia

Gestational age at randomization : at the latest, 29 wk + 5 d Gestational age at randomization a: at the latest, 31 wks + 5 d Severity Severity O/E LHR b25%, irrespective of liver position O/E LHR 25%-34.9% (included), irrespective of the liver position, or O/E LHR 35%-44.9% (included) with intrathoracic herniation of the liver Primary outcome measurement • Survival (in case of severe hypoplasia) without bronchopulmonary dysplasia [40] (in case of moderate hypoplasia) Secondary postnatal outcome measurements • Survival at discharge from the hospital • Grade of oxygen dependency (grades 0-III) • Occurrence of severe pulmonary hypertension • Need for ECMO support for centers offering it • Number of days in neonatal intensive care unit • Number of days of ventilatory support • Presence of periventricular leukomalacia at ≤2 mo postnatally • Presence of neonatal sepsis • Presence of intraventricular hemorrhage (grades 0-III) • Presence of retinopathy of prematurity (grade ≥III) • Number of days till full enteral feeding • Presence of gastroesophageal reflux (above one third of the esophagus on clinically indicated radiologic study) • Day of surgery • Use of a patch (yes/no) Secondary prenatal outcome measure • Lung volume as serially measured (O/E LHR, O/E total lung volume) • Liver position; in case of liver herniation, the liver-to-thorax volume Secondary longer-term outcome variables • Pulmonary function and volume testing before and after repair, at discharge, and at 1 y of age • Neurodevelopmental milestones at discharge, 12 mo, and 2 y (ages and stages) • Death at 2 y (caused by either primary illness or other causes)
ECMO indicates extracorporeal membrane oxygenation. a Fetal evaluation ideally at 26 weeks or beyond. For consistency, a post hoc determination of severity will be done on archived images, which need to be submitted to the principal investigator.

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Table 2 Summary of the most important items in the postnatal treatment of patient with CDH according on the consensus statement of the CDH-EURO Consortium [41] Treatment in the delivery room • No bag masking • Immediate intubation • Peak pressure b 25 cm H20 • Nasogastric tube • Adapt ventilation to obtain preductal saturation between 85% and 95% • pH N 7.20, lactate 3-5 mmol/L • Conventional ventilation (CMV) or high-frequency oscillation (HFOV) maximum peak pressure 25-28 cm H20 in CMV and mean airway pressure 17 cm H20 in HFOV • Targeting blood pressure: reference value for gestational age • Consider inotropic support • Perform echocardiography • Inhaled nitric oxide (iNO), first choice in case of nonresponse to stop iNO • In the short-term phase: phosphodiesterase inhibitors, endothelin antagonist, tyrosine kinase inhibitors • Only starting if the patient is able to achieve a preductal saturation N85% • Inability to maintain preductal saturation N85% • Respiratory acidosis • Inadequate oxygen delivery (lactate N5mmol/L) • Therapy-resistant hypotension • Fraction of inspired oxygen (Fio2) b0.5 • Mean blood pressure normal of gestational age • Urine output N2 mL kg−1 h−1 • No signs of persistent pulmonary hypertension

J. Deprest, P. De Coppi
Table 3 Excerpt from protocol on criteria for centers participating to the TOTAL trial Postnatal management centers • Multidisciplinary team of perinatologists, obstetric anesthesiologists, and neonatologists with extensive experience with and a written protocol for managing CDH before the study, organized by an on-call schedule for management of these patients • Signed commitment to the consensus guidelines for standardized management (Table 1) • Providing profile by outcome statistics of all consecutive cases managed within the period 2000-2010, using the CDH study group outcome parameters • Post hoc, the case load will be calculated. A minimum of 12 cases per 22 months as determined by the Canadian Neonatal Network is recommended for study participation [43,44]. • Commit to provide data without delay New FETO centers • Eligibility determined by the FETO trial steering committee • Established and active fetoscopy program with N36 fetoscopies/y (3/mo) • Assign multidisciplinary team and principal investigator accredited at the center; with written on-call schedule to deal with short-term airway management and neonatal care • Personal involvement in ≥15 FETO cases and ≥5 cases done by the principal investigator at the new FETO center before enrollment • Adherence to TOTAL trial study protocol, agreement not to offer FETO procedure at other locations than the FETO center facilities • No acceptance of patients evaluated for TOTAL trial at other FETO centers

Treatment on the NICU/PICU

Treatment of pulmonary hypertension

ECMO

Surgical repair

NICU indicates neonatal intensive care unit: PICU, pediatric intensive care unit. Reproduced from Deprest et al [42].

commencement in the United States might still take some time because device exemption has to be given by the Food and Drug Administration for tools used off-label.

4. Current research
4.1. Improved diagnosis and patient selection
Congenital diaphragmatic hernia is most likely caused by disruption of common developmental pathways by several genes spread across the genome [46]. We recently

reviewed the genetic factors underlying CDH, including evidence from genetic and teratogenic animal models of CDH and differential expression analysis [47]. Although all these fetuses with isolated CDH are routinely karyotyped, identification of (novel) submicroscopic imbalances and novel genes and/or therapeutic targets requires the use of high-resolution diagnostic methods. We have custom designed a high-resolution array for comparative genomic hybridization [48], and the next step will be to use exome sequencing techniques in selected familial cases. Given the high probability of a mutation(s) segregating with the CDH phenotype, this approach will likely reveal the underlying gene(s) involved in the pathogenesis of CDH for each family studied. Advanced genetic testing in large populations with (apparently) isolated CDH will lead to a better understanding of the genetics of this condition. A more immediate goal is to gather in a large database prenatal observations using gray scale ultrasound, Doppler studies, and fetal MRI. An application for a validation study based on contemporary data from the NAFTNET group is currently being reviewed. This will help to define

Antenatal management of isolated CDH the natural history of the disease in the 21st century. Combination algorithms may further increase predictive values. The combination of vascular and lung size assessment is, in this, respect the first logical step [10,49-51].

287 fluoroethylene [Gore-Tex, William Gore, Flagstaff, AZ] and polypropylene [Marlex, CR Bard, Covington]) have also been used to allow better tissue in-growth and, perhaps, to provide a more durable closure [63]. AlloDerm. Life Cell, Branchburg, NJ, an acellular tissue matrix, however, appears particularly ineffective [61]. The use of autologous anterior abdominal wall and/or a latissimus dorsi muscle flap may also be a valid alternative with low recurrence rates, but clinical experience has been limited [64]. Advances in stem cell biology and tissue engineering may provide alternatives for diaphragmatic repair. The use of engineered functional skeletal muscle tissue in a patch may prevent infection and dislodgment and may improve functionality, as compared with nonseeded polymers [65]. Tissue engineering is based on 3 fundamental principles: (1) the cells, (2) the supporting 3-dimensional scaffolds, and (3) the bioreactors. Scaffolds are usually made by natural materials that are essentially bioactive but lack mechanical strength. Alternatively, synthetic materials, which lack inherent bioactivity but are mechanically stronger, can be engineered with the desired macrostructure and microstructure, to which bioactive properties can be added to facilitate or enhance cellular growth and organogenesis [66]. Although scaffolds are key tools for tissue engineering and several attempts to generate whole organs such as the liver have been done by developing structures with vascular channels to ensure an adequate network of vascular supply [66], major developments in regenerative medicine have been achieved only after the discovery of stem cells. These cells are unspecialized or undifferentiated cells with the capacity of self-renewal and the power to give rise to multiple different specialized cell types [67]. For skeletal muscle regeneration, the choice of cells suitable for in vitro culture is mainly based on their capability to proliferate and preserve their biological activity [65]. Satellite cells are the unique source of myogenic precursors in postnatal life, but their capacity to expand and differentiate in vitro is limited [68]. Bone marrow–derived cells display a low recruitment into myofibers [69]; if they have any effect on regeneration of skeletal muscle, this is rather through activation of resident satellite cells. Mesangioblasts and pericytes can integrate on a regenerating muscle, but they are still unable to give rise to satellite cells [70]. Only embryonic stem cells have shown the potential to generate satellite cells when appropriately induced [71], but their safety for a clinical use is debatable. Amniotic fluid (AF) may be a safe source of cells with myogenic potential [72]. In contrast with satellite cells, AFderived stem cells could easily be collected at the time of amniocentesis—which, in the case of CDH, is required anyway [35]. These AF-derived stem cells could be expanded and engineered during gestation to produce a muscle patch, allowing postnatal repair of the defect with autologous tissue. Dario Fauza from Boston, MA, has engineered a diaphragmatic tendon graft, and preclinical validation has been obtained [73] and may soon become a clinical reality.

4.2. Overcoming limitations of fetal intervention
At present, it seems that, still, 50% of fetuses cannot be salvaged by FETO. There may be 2 reasons for this. One is iatrogenic loss by mainly, membrane rupture and subsequent preterm delivery. We are working on developing lesser invasive instruments. Another reason is that TO simply does not trigger enough lung growth. Our current knowledge of lung growth has been reviewed recently by Khan et al [25]. One method to increase lung growth is to increase the stretch induced by TO, for example, by using oncotic agents [52,53]. Unraveling the molecular mechanisms driving lung growth may also open other doors. Current microarray technology allows global gene expression analysis that will identify genes and pathways and potential therapeutic targets in CDH. This has already been started in animal models for CDH, such as the nitrofen rat [54] or after TO in a rat model with normal lungs [55].

4.3. Cell-based therapy for CDH and tissue engineering
Fetal surgery candidates are more likely to require a prosthetic patch to close their diaphragmatic defect. This is associated with poor long-term outcomes and is a risk factor for infection and hernia recurrence [31,33]. In a large study conducted by the Congenital Diaphragmatic Hernia Study Group, defect size was the most significant predictor of outcome [34]. Infants with a near-absence of the diaphragm had a survival rate of only 57%; whereas those undergoing primary repair, it was nearly 95%. Use of patch also increases the number of ventilator days and hospital stay and increases the risk of gastroesophageal reflux [56,57]. In the prenatal period, retrospective studies have shown that the need for a patch can be predicted by herniation of the liver as well as the O/E LHR [21,57,58]. In the CDH antenatal registry, prenatal liver herniation occurred in 42% of infants requiring patch repair compared with 17% of those primarily repaired [21]. Currently, several different types of patch material are in use, as well as different operative techniques including thoracoscopic repair, although recurrence seems to be higher with the latter (eg, 12% open vs 33% thoracoscopic [59]). The ideal material has yet to be found, and several series have reported recurrence rates of 40% to 50% [60,61]. The experience in Great Ormond Street Hospital, London, UK [62], has been somewhat better, with a 7% recurrence rate when polyethylene terephthalate (Dacron) patches were used, which was comparable with the 6% rate after primary repair. Other composite meshes (polytetra-

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J. Deprest, P. De Coppi Technologies, Leuven, Belgium); Kypros Nicolaides and Eduard Gratacos (Investigators of the TOTAL trial, Eurostec Programme, Leuven, Barcelona and London); Agostino Pierro (University College, London, UK); Dick Tibboel (Erasmus Pediatric Hospital, Rotterdam, the Netherlands); Diana Bianchi (Department of Genetics, TUFTS University, Boston, MA); Marcus Davey (Children's Hospital of Philadelphia, Philadelphia, PA); and Greg Ryan (Fetal Medicine Unit, Mount Sinai Hospital, Toronto, Ontario, Canada).

4.4. Pulmonary hypoplasia
The same principles may also be applied to ameliorate lung function in severely hypoplastic lungs. We think about the use of stem cells both during fetal development and in the postnatal period. Mesenchymal stem cells, which can be derived from various tissues such as bone marrow, adipose tissue, and AF, can modulate damage caused by their potent immunosuppressive effect [67]. Mesenchymal stem cells have already shown their efficacy in the context of bleomycin-induced fibrosis, bacterial infection, and airway allergy [74]. Potentially, bone marrow–derived stem cells may directly promote regeneration by differentiation into specialized cells within the lung [75]. This has become evident from observations done in sex-mismatched bone marrow transplants, where bone marrow–derived cells were shown to incorporate into the airway epithelium and contribute to tissue repair [76]. Tissue regeneration within the lung probably requires endogenous epithelial progenitor cells. Recently, the presence of multipotent lung stem cells has been shown in distal airway niches [77]. When these cells are injected into damaged mice lungs, they form human bronchioles, alveoli, and pulmonary vessels [78]. We speculate that activation of these cells during fetal development or postnatally may also benefit patients with CDH.

References
[1] Marcu M. The EU-27 population continues to grow. Eurostat 2009. Data in Focus. http://epp.eurostat.ec.europa.eu/cache/ITY_OFFPUB/ KS-QA-09-031/EN/KS-QA-09-031-EN.PDF. Accessed October 28th, 2010. [2] Bagolan P, Morini F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg 2007;16:134-44. [3] Trachsel D, Selvadurai H, Bohn D, et al. Long-term pulmonary morbidity in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2005;39:433-9. [4] Garne E, Haeusler M, Barisic I, et al. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329-33. [5] Deprest J, Jani J, Van Schoubroeck D, et al. Current consequences of prenatal diagnosis of congenital diaphragmatic hernia. J Pediatr Surg 2006;41:423-30. [6] Knox E, Lissauer D, Khan K, et al. Prenatal detection of pulmonary hypoplasia in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis of diagnostic studies. J Matern Fetal Neonatal Med 2010;23:579-88. [7] Mayer S, Klaritsch P, Petersen S, et al. The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and metaanalysis of observational studies. Prenat Diagn 2011. [8] Cannie M, Jani J, Chaffiotte C, et al. Quantification of intrathoracic liver herniation by magnetic resonance imaging and prediction of postnatal survival in fetuses with congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2008;32:627-32. [9] Done E, Allegaert K, Lewi P, et al. Maternal hyperoxygenation test in fetuses undergoing FETO for severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2010. [10] Cruz-Martinez R, Moreno-Alvarez O, Hernandez-Andrade E, et al. Contribution of intrapulmonary artery Doppler to improve prediction of survival in fetuses with congenital diaphragmatic hernia treated with fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2010;35:572-7. [11] Claus F, Sandaite I, Dekoninck P, et al. Prenatal anatomical imaging in fetuses with congenital diaphragmatic hernia. Fetal Diagn Ther 2011;29:88-100. [12] Jani J, Cannie M, Sonigo P, et al. Value of prenatal magnetic resonance imaging in the prediction of postnatal outcome in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2008;32:793-9. [13] Metkus AP, Filly RA, Stringer MD, et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31: 148-51 [discussion 151-142]. [14] Peralta CF, Cavoretto P, Csapo B, et al. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2005;26: 718-24. [15] Jani J, Peralta CF, Benachi A, et al. Assessment of lung area in fetuses with congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2007;30:72-6.

5. Conclusion
In the era of prenatal diagnosis of CDH, patients should receive individualized counseling on expected outcome. Fetoscopic endoluminal tracheal occlusion is an investigational procedure that has the potential for improving prognosis. This is being investigated in an international multicenter trial that became possible because of a consensus document on standardized postnatal management. The potential of fetal therapy has boosted research on prenatal prediction and intervention for this rare condition. Our current research projects now stretch further than surgical intervention and include genetic studies and pharmacologic and cell-based therapies.

Acknowledgments
The clinical studies have been supported by the European Commission (EuroSTEC, 6th Framework, LSHC-CT-2006037409 and endoVV IAPP project 251356). J.D. is a “clinical researcher” from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (1.8.012.07.N.02). Much of this work has been achieved through the active collaboration of many different units and facilities across national boundaries and disciplines. However, our particular thanks go to Jaan Toelen, Paul Brady, Alexander Engels, Silvia Zia, Philip De Koninck, and Jute Richter (University Hospitals Leuven and Centre for Surgical

Antenatal management of isolated CDH
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