Congenital Diaphragmatic Hernia and Eventration

Diaphragm Development and CDH Pathogenesis

The development of the human diaphragm is a complex, multicellular, multitissue interaction that remains incompletely understood. Precursors to the diaphragm begin to form during the fourth week of gestation. Historically, the diaphragm was thought to develop from the fusion of four embryonic components: anteriorly by the septum transversum, dorsolaterally by the pleuroperitoneal folds (PPFs), dorsally by the crura from the esophageal mesentery, and posteriorly by the body wall mesoderm ( Fig. 24.1 ). According to this theory, as the embryo begins to form, the septum transversum migrates dorsally and separates the pleuropericardial cavity from the peritoneal cavity. At this point, the pleural and peritoneal cavities still communicate. The septum transversum interacts with the PPF and mesodermal tissue surrounding the developing esophagus and other foregut structures, resulting in the formation of primitive diaphragmatic structures. Bound by pericardial, pleural, and peritoneal folds, the paired PPFs now separate the pleuropericardial and peritoneal cavities. Eventually, the septum transversum develops into the central tendon. As the PPF develops during the sixth week of gestation, concurrently, the pleuroperitoneal membranes close and separate the pleural and abdominal cavities by the eighth week of gestation. Typically, the right side closes before the left. Ultimately, the phrenic axons and myogenic cells destined for neuromuscularization migrate to the PPF and form the mature diaphragm. The muscularization of the primitive diaphragm is a separate but inter-related process.

Another theory for CDH development is a failure of muscularization of the future diaphragm prior to complete closure of the canal ( Fig. 24.2 ). Inadequate closure of the pleuroperitoneal canal allows the abdominal viscera to enter the thoracic cavity when they return from the extraembryonic coelom to herniate into the chest with the liver. As a result of the limited intrathoracic space, due to the visceral herniation, pulmonary hypoplasia develops.

Although traditional theories suggest that the lung hypoplasia is secondary to the diaphragmatic malformation, others have postulated that the primary disturbance may be abnormal lung development that causes the diaphragmatic defect. According to this theory, disturbances in lung bud formation subsequently impair the posthepatic mesenchymal plate (PHMP) development and result in failure of diaphragm fusion/muscularization.

More recently, the role of the PPF and, specifically, a subset of PPF-derived muscle connective tissue fibroblasts, in the development of CDH has been further elucidated. Through the use of mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells has been found to control diaphragm morphogenesis ( Fig. 24.3 ). In this model, mice with mutated Gata4 , strongly expressed in the PPFs, universally developed diaphragmatic hernias. Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax. The herniated tissue was shown to physically impede lung development (though mutations in Gata4 also have a primary effect on lung development). Therefore, this investigation identified a critical role of the PPF and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic development.

The nitrofen rodent model has led to improved understanding of abnormal pulmonary development in CDH. Nitrofen (2,4-dichloro-phenyl- p -nitrophenyl ether) is an environmental teratogen. If a specific dose is administered at a specific time during gestation, it can cause pulmonary, cardiac, skeletal, and diaphragmatic abnormalities, analogous to the human condition. Diaphragmatic defects resulting from the administration of nitrofen in mice are very similar to the diaphragmatic defects seen in babies with severe CDH in regard to size, location, and herniation of abdominal viscera. The side of the CDH depends on the time of nitrofen exposure during gestation. In nitrofen-exposed fetal mice, a defect is clearly seen in the posterolateral portions of the PPF. In addition, nitrofen exposure appears to affect muscularization of the PPF (see Fig. 24.2 ). Finally, the offspring will exhibit features of pulmonary vasculopathy including increased muscularization and pulmonary vessel hyporesponsiveness, as well as pulmonary hypoplasia, including reduced airway branching, decreased alveolarization, and surfactant deficiency, all leading to respiratory failure at birth.

Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects. Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development. Vitamin A–deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH. Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.

Lung Development and Pulmonary Hypoplasia

Lung development is recognized as a complex programmed event regulated by genetic signals, transcription factors, growth factors, and hormones. These events control the temporal and spatial interactions between epithelium and endothelium. Early transcription signals, such as thyroid transcription factor-1 and hepatocyte nuclear factor-3β, regulate pulmonary development from the primitive foregut mesenchyme. Other pathways of pulmonary development include sonic hedgehog, transforming growth factor-β, Notch-delta pathway, and Wingless-Int. In addition, glucocorticoids, thyroid hormone, and retinoic acid have all been shown to regulate pulmonary organogenesis.

Fetal lung development is divided into five overlapping stages. (1) The embryonic stage begins during the third week of gestation as a caudal diverticulum from the laryngotracheal groove. The primary lung buds and trachea form from this diverticulum by the fourth week, and lobar structures are seen by the sixth week. (2) The pseudoglandular stage occurs between the 5th and 17th weeks of gestation with the formation of formal lung buds as well as the main and terminal bronchi. (3) During the canalicular stage, the pulmonary vessels, respiratory bronchioles, and alveolar ducts develop between weeks 16 and 25 with the appearance of type 1 pneumocytes and type 2 pneumocyte precursors. At this stage, functional gas exchange is possible. (4) The saccular stage continues from 24 weeks to term with the maturation of alveolar sacs. Airway dimensions and surfactant synthesis capabilities continue to mature as well. (5) Finally, the alveolar stage begins after birth with a continued increase and development of functional alveoli.

Concomitantly, fetal pulmonary vascular development occurs in concordance with the associated lung development and follows the pattern of airway and alveolar maturation. A functional unit known as the acinus consists of the alveolus, alveolar ducts, and respiratory bronchioles. The pulmonary vasculature develops as these acinar units multiply and evolve during the canalicular stage. The preacinar structures consist of the trachea, major bronchi, lobar bronchi, and terminal bronchioles. The pulmonary vascular development for the preacinus is typically completed by end of the pseudoglandular stage. In theory, any impedance to normal pulmonary development will concurrently hinder pulmonary vascular development (and the converse is likely also true).

Pulmonary hypoplasia is characterized by a decrease in bronchial divisions, bronchioles, and alveoli. The alveoli and terminal saccules exhibit abnormal septations that impair the air–capillary interface limiting gas exchange. At birth, the alveoli are thick-walled with intra-alveolar septations. These immature alveoli have increased glycogen content leading to thickened secretions that further limit gas exchange. Animal models of CDH have demonstrated pulmonary hypoplasia with decreased levels of total lung DNA and protein. In addition, the pulmonary vasculature has a diminished capacity for vasoreactivity, with abnormally thick-walled arteries and arterioles. Interestingly, the contralateral lung also exhibits the structural abnormalities of pulmonary hypoplasia.

Preclinical treatments for pulmonary hypoplasia present interesting areas of research for nonsurgical therapies of infants with CDH. Previous therapies, including prenatal steroids and surfactant, have been shown to have no clinical benefit and are currently not recommended. Although multiple avenues of investigation are ongoing, several areas with potential include the retinoic acid pathway involving vitamin A, tracheal occlusion for pulmonary growth, and cell therapy approaches.

Pulmonary Vascular Development and CDH-Associated Pulmonary Hypertension

Normal fetal cardiopulmonary circulation transitions to its postnatal state rapidly with a 10-fold increase in pulmonary blood flow within hours following birth. Fetal pulmonary blood flow is characterized as a low-flow, high-resistance circuit due to medial and adventitial hypertrophy of the vasculature. Normally, the pulmonary vascular resistance (PVR) quickly decreases as the distal small pulmonary arteries and arterioles remodel over the first few months of life, resulting in a low-resistance, high-flow postnatal circulation. However, this process appears to be arrested in CDH newborns, and the fetal circulation persists resulting in CDH-PH. In fact, the abnormal fetal pulmonary circulation in CDH fetuses appears to originate and progress in early gestation. The pulmonary arteries exhibit a decrease in density per unit of lung parenchyma as well as an increase in muscularization that extends to the vasculature at the acinar level. In fetal lamb models of surgically created CDH as well as human fetuses with CDH, there is a relative decrease in lung parenchyma. This impaired lung growth and development has been speculated to be related to impaired vascular development. As a result, CDH-PH appears to develop in utero, which may cause a reduction in pulmonary artery growth, proper alveolar development, and normal lung growth. However, in contrast to a congenital pulmonary airway malformation (CPAM), another congenital malformation associated with pulmonary hypoplasia and severe pulmonary compression, pre- and postnatal pulmonary vascular pathology and remodeling was found to be worse in infants with CDH versus CPAM in one study, suggesting a multifactorial origin for CDH-PH. Finally, the timing of diaphragmatic and pulmonary development further supports the “two-hit hypothesis” of CDH development, wherein both defective early pulmonary development and subsequent defective diaphragmatic development contribute to the ultimate pulmonary pathogenesis.

In a retrospective study, CDH infants who developed normal pulmonary artery pressures during the first 3 weeks of life were found to have a 100% survival rate. In this same study, an intermediate reduction in elevated pulmonary pressures after birth were seen in 34% of infants with a 75% survival. Mortality was 100% in CDH infants who had persistent, suprasystemic pulmonary pressures despite maximal therapy. Although contemporary outcomes for infants with pulmonary hypertension have improved, these data underscore the importance of CDH-PH.

Prenatal Diagnosis

Accurate prenatal diagnosis and prognostication of disease severity is an important adjunct to prenatal counseling, patient triage, and identification of high-risk infants with CDH. In obtaining an accurate diagnosis, it is important to differentiate CDH from other intrathoracic anomalies in which normal anatomy is otherwise undisturbed. These include CPAMs, bronchogenic cysts, bronchial atresia, or bronchopulmonary sequestrations, as well as mediastinal lesions, including enteric, neuroenteric, or thymic cysts. Diaphragm eventration must also be included in the differential diagnoses. Although it can be challenging to differentiate eventration from CDH, eventration carries a favorable prognosis with a different management algorithm. Eventrations are typically isolated lesions, but can be complicated with pleural and/or pericardial effusions.

Approximately 50–70% of infants with CDH are identified during pregnancy, and the frequency of prenatal detection has substantially improved in the past two decades. The diagnosis of CDH is most often first made between the 18th and 22nd weeks of pregnancy on ultrasound (US) screening exams ( Fig. 24.4 ). Fetal US features include polyhydramnios, intrathoracic fluid-filled bowel loops, an echogenic chest mass, mediastinal shift, and/or an intrathoracic stomach. Left-sided CDHs are more frequently detected prenatally and feature mediastinal/cardiac shift to the right as well as herniation of the stomach, intestines, and/or spleen. The liver may herniate, but its echogenicity is often similar to the lung and may be more difficult to differentiate. In right-sided CDH, the right lobe of the liver is herniated, with a left-sided mediastinal shift.

US of the fetal chest is best performed in the axial plane. The lung-to-head ratio (LHR) is a prenatal US assessment ratio, utilizing the contralateral lung area to the head circumference, which predicts CDH severity. Using the lung tracing method, fetal lung circumference is used to determine the LHR and is measured at the level of the four-chambered view of the heart (see Fig. 24.4 ). The fetal diaphragm can be seen as early as the first trimester as a thin hypoechogenic line in the sagittal view. Measurements of fetal lung circumference are most accurate after the first trimester, when the majority of the dynamic growth of the fetal thorax has stabilized, and the head-to-thorax ratio is less variable and generally remains 1:3.

Although independent sonographic features of CDH have not been shown to be accurate predictors of postnatal severity, severe or advanced CDH can be identified by an intrathoracic liver (“liver up”), mediastinal shift to the contralateral thoracic cavity, or hydrops fetalis.

Two distinct US measurements have been utilized to risk stratify infants with CDH: (1) observed-to-expected (O/E) LHR (O/E normalizes for variation by gestational age) and (2) liver herniation into the hemithorax. A recent meta-analysis provides an up-to-date review of survival prediction with LHR and liver herniation. O/E LHR serves as one of the best US predictors of postnatal survival, with 25% serving as a reasonable discriminative threshold. The gestational age differential in thoracic growth compared with head growth can be ameliorated by using the LHR as a function of observed or measured to the expected or age-based norms of the same lung. Infants with O/E LHR <25% have predicted survival ranging from 12.5–30%, while survival for O/E LHR >35% ranges from 65–88%. Most studies that were evaluated also demonstrated significantly improved prognoses if the liver was not in the chest. Although fetal US is a highly reliable, inexpensive, readily accessible modality for prenatal prediction of prognosis in CDH, its inconsistent utilization and inter-rater/inter-institutional variability has limited the generalizability of the technique.

If diaphragm pathology is suspected on fetal US, fetal magnetic resonance imaging (MRI) may add additional prognostic value ( Fig. 24.5 ). MRI offers improved tissue characterization and spatial resolution when compared with US. Moreover, MRI can further clarify liver position due to discernibly different signal intensities on MRI compared with US, accounting for the higher water content of fetal lungs on T2-weighted images. The percentage of liver herniation on fetal MRI correlates with pulmonary morbidity, with >20% liver herniation predicting more profound morbidity. In addition, fetal MRI is an excellent modality for morphologic and volumetric measurements of the fetal lung (total fetal lung volume [TFLV]). It is especially advantageous in patients with oligohydramnios and maternal obesity. Eight studies included in the recently published meta-analysis showed a statistically significant difference between the mean O/E TFLV of survivors compared with nonsurvivors with CDH. Survival rates with O/E TFLV <25% ranged from 0–25%, whereas for O/E TFLV >35%, survival ranged from 75–89%.

Clinical Presentation

Newborns with CDH typically present with respiratory distress. Clinical scenarios at birth range from immediate, profound respiratory distress with concomitant respiratory acidosis and hemodynamic instability, to an initial stable period with delayed respiratory distress, to an asymptomatic newborn. Initial signs associated with respiratory distress include tachypnea, chest wall retractions, grunting, cyanosis, and/or pallor. On physical examination, infants will often have a scaphoid abdomen and may have a subtle increase in thoracic diameter. The point of maximal cardiac impulse is often displaced, a physical finding with mediastinal shift. Bowel sounds may be auscultated within the thoracic cavity with a decrease in breath sounds bilaterally. Chest excursion may be reduced, suggesting a lower tidal volume.

The diagnosis of CDH is typically confirmed by a chest radiograph demonstrating intestinal loops within the hemithorax, cephalad displacement of the stomach/orogastric tube, and a mediastinal shift toward the contralateral hemithorax ( Fig. 24.6 ). The abdominal cavity may have minimal to no gas, particularly initially. Right-sided CDH can be challenging to diagnose ( Fig. 24.7 ). Salient features, such as intestinal and gastric herniation, may not be prominent, and the herniated right lobe of the liver can be mistaken for a right diaphragmatic elevation or eventration. Occasionally, features of lung compression may be the only radiographic sign, which can cause confusion with CPAMs, pulmonary sequestrations, bronchopulmonary cysts, neurogenic cysts, or cystic teratomas.

Although most infants with CDH will be diagnosed within the first 24 hours of life, as many as 20% may present outside the neonatal period. These patients present with mild respiratory symptoms, chronic pulmonary infections, pleural effusions, pneumonias, feeding intolerance, or gastrointestinal pathology. As CDH is invariably associated with abnormal intestinal rotation and fixation, some children can present with intestinal obstruction or volvulus. Occasionally, CDH may be completely asymptomatic and is discovered only incidentally. Patients who present later in life have an excellent prognosis due to milder or absent associated complications, such as pulmonary hypoplasia and CDH-PH.

Prenatal Care

The prenatal diagnosis of CDH continues to improve with the increased use and refinement of fetal US examination and advanced fetal MRI. After initial screening, an advanced US helps to determine discordant size and dates, associated anomalies (cardiovascular, neurologic, other), as well as signs of fetal compromise (i.e., hydrops fetalis). Further, an accurate LHR can estimate the probable severity, allowing informed counseling and consideration for appropriate prenatal monitoring and/or intervention. Once diagnosed, chromosomal screening via amniocentesis for karyotyping and chromosome microarray analysis is recommended. Optimally, the mother and fetus should be referred to a tertiary perinatal center with protocolized fetal MRI and advanced maternal fetal medicine (a fetal center), neonatal, surgical, and critical care capabilities, including HFOV, ECMO, and pulmonary hypertension therapeutic expertise. A prenatal diagnosis enables informed counseling for the mother and family including treatment options and prognosis.