Clinical and research developments in congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH) is a lethal human birth defect occuring in 1 : 2 500 births. An infant with CDH is born every 24–36 hours in the UK. Hypoplastic lung development is the leading contributor to the 40–50% mortality of CDH (1). Efforts to improve survival have focused on fetal intervention, advances in intensive care, in utero diagnosis and delivery at specialist centres (1–3). High frequency oscillatory ventilation, permissive hypercapnia, inhaled nitric oxide and ECMO have been employed with variable outcome (4–6). Preoperative stabilisation and delayed surgical repair is currently performed at most centres (7,8). The impact of abnormal lung development on affected infants has stimulated research on the developmental biology of CDH. Traditionally lung hypoplasia has been viewed as a consequence of in utero compression of the fetal lungs by herniated viscera prolapsing through a defect in the diaphragm. Based on this ‘compression theory’ fetal surgery was pioneered to repair CDH and rescue lung growth in ‘high risk’ cases. It has shown no survival benefits. New insights into mechanisms regulating fetal lung growth and maturation are providing alternative less invasive antenatal strategies. Prompted by the observation that humans with congenital larnygeal atresia have enlarged hyperplastic lungs fetoscopic tracheal occlusion (FETENDO-PLUG) is being evaluated in human trials for the ‘high risk’ CDH fetus With liver herniation (3). Pharmacological strategies to ameliorate pulmonary hypoplasia in CDH are under investigation. Human studies have shown that the lungs of babies with severe CDH resemble the immature lungs of premature newborns with respiratory distress syndrome (RDS). Prenatal hormonal therapy regimens adapted from RDS protocols have demonstrated striking improvements in lung maturation in experimental CDH models. An international multicentre trial of corticosteroid therapy is now underway in prenatally diagnosed CDH patients (9). Closure of the human diaphragm at 8 weeks gestation limits detailed embryological investigation of CDH to teratogenic models. The ‘compression theory’ of pulmonary hypoplasia has been challenged by studies of primordial lung development prior to diaphragmatic hernia (10). Disruption of stereotyped airway branching correlates with and precedes CDH indicating an intrinsic defect of lung development in CDH. Organotypic culture sytems are providing invaluable research tools to manipulate lung hypoplasia and investigate the role of growth factors and cell signalling pathways. Genetic studies in murine models and the fruitfly Drosophila melanogaster have elucidated the molecular control of respiratory organogenesis. Testing fibroblast growth factors (FGFs), epidermal growth factor (EGF) and heparin on normal and hypoplastic lung primordia has demonstrated profound differences in embryonic growth and pulmonary morphogenesis that indicate intrinsic defects in mitagenic regulatory pathways fundamental to CDH (11–13). What are the future therapeutic implications for clinicians treating CDH? Selection of patients for fetal surgery will require more accurate prognostic indicators of poor perinatal outcome. Fetal surgery at present may be ‘too little too late’ to correct an established embryopathy in pulmonary development. Antenatal corticosteroid therapy is the subject of a multicentre trial. Fetoscopic delivery of targeted growth factors to enhance airway development in CDH will require careful appraisal. The concept of a pharmacological agent or medical ‘PLUG’ to reverse pulmonary hypoplasia is a goal for the future. Postnatal therapies to reduce barotrauma will salvage those newborns with the less severe degrees of pulmonary hypoplasia. Finally prevention of the birth defect by preconceptual prophylaxis (as in the case of neural tube defects) may represent the ultimate solution for this highly lethal human anomaly (14).