The natural history of congenital diaphragmatic hernia and pulmonary hypoplasia in the embryo

Abstract

Up to now, descriptions of the natural history of congenital diaphragmatic hernia (CDH) associated with pulmonary hypoplasia (PH) are based exclusively on observations made in the fetal period. However, nothing is known about the events that take place in an embryo with CDH. Recently, an animal model of CDH and PH has been established in rat embryos to study the embryology and natural history of this lesion. We exposed 36 pregnant Sprague-Dawley rats to a single dose of 100 mg nitrofen on day 11 of pregnancy. A total of 356 staged embryos and fetuses from day 13 to day 21 were studied by light and scanning electronmicroscopy. The litters of 9 untreated rats (124 normal age-matched embryos and fetuses) served as controls. The abnormal development of the diaphragmatic anlage was first seen in embryos aged 13 to 14 days. A defect appeared in the dorsal part of the diaphragm, normally on the right side. The liver grew through this defect early on. Gut was found in an intrathoracic position only in the very late stages (day 21 22 ) and newborns. Compared to controls, lungs of nitrofen-embryos with CDH were smaller, depending on the size of liver found in the thoracic cavity. Histologically, compression of lung was absent at these stages. Most authors speculate that CDH results because the pleuroperitoneal canals fail to close at the end of the embryonic period (ie, week 8 to 10 in human development) leading to a defect in the dorsolateral region of the diaphragm. However, contradictory to this assumption, our findings indicate that diaphragmatic defects develop in early embryonic life. They are easy to identify even in rat embryos as early as 14 days. The early ingrowth of liver into the thoracic cavity through these defects is the crucial step in the pathogenesis of PH in CDH, because it is the liver and not the gut that reduces the thoracic cavity in the embryo. Normal lung growth will be hampered in early embryonic stages according to the size of the liver mass inside the thoracic cavity. Recent reports suggest that the presence of liver in the fetal thoracic cavity affects the outcome of a fetus with CDH. This observation is in accordance with our findings, suggesting that the major events of pathogenesis take place in the embryo and not in the fetus, as often assumed.