Recent advances in the treatment of complex congenital diaphragmatic hernia-a narrative review

Abstract

Background and objective: Congenital diaphragmatic hernia (CDH) is an anomaly of the cardiopulmonary system maturation process that results from both a global embryopathy and concomitant mechanical compression of the cardiopulmonary system from the abdominal contents during fetal maturation. This results in pulmonary hypertension, pulmonary hypoplasia, and cardiac dysfunction, requiring intense critical care management. The patients with highest risk CDH are the most challenging, resource-intensive, and bear most of the mortality. Advances at the basic, translational, and clinical research levels are leading to novel therapies and management strategies for complex, high-risk CDH. Our objective is to review novel approaches in thinking and management for the most complex and high-risk CDH patients. These include patients with prenatal and postnatal indicators of high-risk defects, those receiving extracorporeal life support (ECLS), and those with concomitant anomalies such as complex cardiac and/or chromosomal abnormalities.

Methods: PubMed was searched in late 2022 and early 2023 to identify relevant evidence. Search terms included congenital diaphragmatic hernia (CDH)", "extracorporeal life support (ECLS)", "pulmonary hypertension", "dual-hit hypothesis", "risk reduction", "cardiac/chromosomal anomalies", and "novel therapies". We included trials, multicenter studies (prospective and retrospective), single-center reports, and review articles/expert opinion.

Key content and findings: CDH is a congenital anomaly of the cardiopulmonary and diaphragmatic systems that represents a spectrum of disease. High-risk or complex patients are defined by prenatal/postnatal risk stratification, receipt of ECLS, and/or having concomitant anomalies, representing the severe end of that spectrum. Overall survival of high-risk CDH is about 50% and comprises the vast majority of mortality, mandating special emphasis. The development of risk-stratification processes, best practices or guidelines of management, and novel therapies is critical to optimize the care of these infants.

Conclusions: CDH patients with high-risk disease remain a challenging subset of CDH patients. Increasing opportunities for survival are being realized with novel, investigational approaches.

Keywords: CDH repair; Congenital diaphragmatic hernia (CDH); diaphragm repair; outcomes.

Figure 1

CDHSG diaphragm defect staging system. Defect A is the smallest defect that consists of a mostly intact hemidiaphragm and is completely intramuscular and does not extend to the chest wall. Defect B is a defect that involves 50–75% of the hemidiaphragm and less than half of chest wall is affected. Defect C is a defect where approximately 25% of the hemidiaphragm is present but more than half of the chest wall is involved in the defect. Defect D is the largest defect and has minimal or no diaphragm present and affects most of the chest wall. This condition is often referred to as agenesis. Permissions granted (Lally KP, Lasky RE, Lally PA, et al. Standardized reporting for congenital diaphragmatic hernia--an international consensus. J Pediatr Surg 2013;48:2408-15.). CDHSG, the Congenital Diaphragmatic Hernia Study Group.

Figure 2

The dual-hit hypothesis. The dual-hit hypothesis is another theory that attributes lung hypoplasia as the primary cause of CDH development with herniation of the abdominal contents as a secondary hit, exacerbating the growth impairment of an already underdeveloped lung. Images created with BioRender. CDH, congenital diaphragmatic hernia.

Figure 3

Effects of PGE1 on pulmonary hypertension on the heart. PGE1 is administered to maintain ductal patency in congenital heart disease allowing improved pulmonary and systemic blood flow. This approach can also be beneficial in infants with CDH who experience supra-systemic right ventricular pressures. A patent PDA can reduce the afterload on the right heart by serving as a “pressure relief valve”. Images created with BioRender. PGE1, prostaglandin E1; CDH, congenital diaphragmatic hernia; PDA, patent ductus arteriosus.

Figure 4

Effects of AFSC-EVs on lung epithelial and mesenchymal cells. The presence of AFSC-EVs RNA in the mRNA regulatory network involved in lung development indicated that this EV-based therapy can promote fetal lung growth and restore the regeneration of the epithelial and mesenchymal cells. Images created with BioRender. AFSC-EVs, amniotic fluid stem cell extracellular vesicles.