Review
Prenatal management of the fetus with isolated congenital diaphragmatic hernia in the era of the TOTAL trial

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Summary

Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial (www.totaltrial.eu) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue.

Introduction

The prevalence of congenital diaphragmatic hernia (CDH) ranges between one and four per 10,000 births, which makes this condition officially a rare disease. Based on 2008 birth rates in the EU-27, this would mean between 542 and 2168 children in EU-27 [1]. CDH is the denominator for posterior lateral (Bochdalek 95%) and anterior (Morgagni defects). Eighty-six percent of Bochdalek defects are left-sided, 13% right-sided, and up to 2% bilateral. CDH is further classified as either isolated, syndromic or associated with other anomalies. In its isolated form, CDH leads to two neonatal problems: (1) the anatomical yet surgically correctable diaphragmatic defect; and (2) the coinciding pulmonary hypoplasia. The latter is the result of disturbed lung development, which starts in the embryonic period. As pregnancy continues, viscera herniate into the chest, and compete for space with the developing lungs. CDH lungs have fewer airway branches, smaller cross-sectional area of pulmonary vessels, structural vascular remodelling, and vasoconstriction with altered vasoreactivity [2]. The degree of lung development is individually quite variable; whether this is related to the size of the defect, or primarily determined by an initial underlying problem or a combination of both, remains uncertain. The in-utero death rate is around 2%, usually without demonstrable direct cause. At birth, the immediate problems are respiratory insufficiency and persistent pulmonary hypertension (PHT). Once the newborn is stabilized, the defect is corrected, which may for large defects require the use of a patch (reviewed in [3]). When the condition is not isolated, the prognosis is usually poor, as the above problems are combined with those caused by the other associated anomalies. In isolated cases, the condition is lethal in up to 30%, despite prenatal referral to a high volume center offering standardized neonatal care [4], [5], [6]. Survivors may suffer from additional morbidities, mainly chronic lung disease and/or persistent PHT, gastroesophageal reflux and feeding problems, and thoracic deformations [7]. Most babies eventually lead a life very close to normal provided they are managed in a multidisciplinary follow-up program [8], [9].

In the western world, >60% of cases are diagnosed at the latest by the second trimester screening ultrasound. As for any suspected congenital birth defect, its diagnosis should prompt referral to a tertiary center for confirmation of, or differential diagnosis, further documentation of severity and exclusion of associated problems (Box 1). This will be followed by multidisciplinary counseling of parents by specialists with experience in managing the condition. Additional diagnostic steps include genetic testing, and where applicable advanced imaging, which today will include magnetic resonance. The overall goal is to define the individual prognosis, so that parents, based on factual information regarding their fetus, can choose further management, which includes expectant management with prenatal referral to a high volume center for carefully timed delivery, termination of pregnancy, or fetal intervention for selected patients.

Section snippets

Microarray analysis

In recent years, genetic testing for prenatal diagnosis has moved beyond conventional karyotyping. The Leuven Centre for Human Genetics moved early to introduce chromosomal microarray analysis for prenatal diagnosis in the presence of ultrasound anomalies [12], which by now is the first-tier diagnostic test for routine prenatal diagnosis in Belgium [13]. We demonstrated the added value of chromosomal microarrays for the investigation of apparently isolated CDH, both retrospectively using a

Prenatal imaging for assessment of severity

Next to ruling out additional anomalies, ultrasound and magnetic resonance imaging are used to assess severity. This topic is reviewed in depth by Benachi et al. [27]. In essence, two-dimensional ultrasound enables assessment of lung size and identification of position of the liver. Both parameters have been named to be predictive of outcome, though it remains unknown whether they act independently. Other less studied factors are position of the stomach, polyhydramnios, gestation at diagnosis

Fetal therapy

The ability to prenatally identify a future non-survivor prompts the search for an intervention that can avoid that outcome. As CDH is a developmental problem, the ideal therapeutic window of opportunity is the prenatal period. Historically this was first done by in-utero anatomical repair [57]. Today the only clinically applied intervention is fetal endoluminal tracheal occlusion (FETO; Fig. 3). TO for alleviation of pulmonary hypoplasia was to our knowledge first proposed by Jay Wilson and

Future perspectives in genetics and non-surgical strategies

The current clinical experience with fetal surgery yields less than desirable survival rates. Nor can the side-effects of FETO be ignored (up to 25% membrane rupture and preterm delivery rate) (Fig. 6). Due to its technical complexity and logistic demands, fetal surgery is neither universally applicable nor available. Therefore alternative, less invasive and/or more potent and/or easy methods for forced lung growth should be explored. Pharmacological or cell-based strategies are attractive

Acknowledgements

J.D.P. is a fundamental clinical researcher supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO; 1.801207). E.G. and J.D. steer an Erasmus Joint Doctoral program of the Universities of Barcelona, Leuven and Lund, which is sponsored by the European Commission (2013-0040). The TOTAL trial was initially set up within the framework of the “Eurostec” FP-6 program (EuroSTEC, LSHC-CT-2006-037409) on perinatal tissue engineering for congenital birth defects, sponsored by the European

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