Fetal intervention in congenital malformations of the respiratory system

Embryology and etiology

In the normal embryological process, the diaphragm is derived from various contributors, including the septum transversum, body wall, dorsal mesentery, and pleuroperitoneal folds, which are meant to fuse. CDH can develop as early as 8 weeks of gestation when one or more of these structures fail to fuse; 90% of CDH presentations are posterolateral, known as Bochdalek hernias, while the anterolateral Morgagni hernias make up the remainder. ^,

The development of CDHs is thought to be influenced by both genetic and environmental factors. Genetic aspects of disease development are highly varied and include aneuploidies, cytogenic abnormalities, and single-gene mutations; common aneuploidies associated with CDH are trisomy 18, 13, and 21. In rare cases, CDH can have inheritance patterns such as X-linked recessive or dominant traits. These can run in families and present with herniation of both sides of the thoracic cavity; a subtype known as familial diaphragmatic agenesis is inherited in an autosomal recessive manner and has a poorer prognosis than typical posterolateral herniations. While a majority of the cases of CDH are isolated, approximately 40% are syndromic in their origin (WAGR [Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability], Denys-Drash, and Wolf-Hirschhorn syndromes). ^, Environmental causative factors are associated with maternal exposure to substances like tobacco and alcohol, advanced maternal age, a history of diabetes, and high maternal BMI.

CDH can be isolated or associated with other anomalies, which can increase mortality and morbidity of the infant. Cardiac anomalies are the most commonly associated with CDHs, with a prevalence of 30% in live births; these heart defects can have a vast spectrum of presentation, with more severe defects having a higher rate of mortality. The development of pulmonary hypertension in the postnatal period is another complication associated with diaphragmatic herniation. CDH causes aberrant airway branching and impaired alveolarization, disrupting the pulmonary vascularization, leading to high pulmonary vascular resistance that persists after delivery.

The bulk of fetuses with congenital diaphragmatic herniations present with the defect on the left side of the thorax, whereas right-sided defects account for approximately 15% of the cases; bilateral presentations account for less than 1%. Right-sided CDH presentations can be associated with hepatopulmonary fusion, in which an unidentifiable plane of separation is seen between the lung and herniated liver. This rare malformation allows the merging of fetal lung and liver, leading to indistinguishable histopathological findings; hepatopulmonary fusion can also provoke pulmonary bronchial and vascular pathologies as well.

Prenatal diagnosis

The diagnosis of CDH is typically made prenatally, as the displacement of abdominal organs into the thoracic cavity can be seen on multiple imaging modalities, including routine ultrasound investigations, typically around a gestational age of 24 weeks. ^,

Although ultrasound is the most common mode of diagnosis, three-dimensional (3D) imaging, fetal MRI, and echocardiography can aid in determining not only the severity but prognosis as well. Ruano et al. showed that 3D sonography and MRI measurements could accurately determine fetal lung volumes and thus can be used to diagnose pulmonary hypoplasia in fetuses with CDH. While the direct measurement of the lung volume is a sound way of predicting neonatal outcomes, Metkus et al. were the first to demonstrate that lung-to-head ratio (LHR) could be used to accurately determine the size of the lung contralateral to the side of the hernial defect.

Prenatal fetal therapy

Fetal endoscopic tracheal occlusion (FETO) is a minimally invasive procedure (no need for a hysterotomy to perform the procedure) that is now one of the surgical options for CDH. It involves the percutaneous placement of instruments under sonographic guidance and fetoscopic placement of a tracheal balloon to improve fetal lung development. Several studies, including a recent randomized controlled trial, have shown that tracheal occlusion reduces perinatal morbidity and mortality rates and decreases the need for ECMO. FETO can promote lung regrowth and pulmonary vascular development in the fetus and may decrease the severity of pulmonary arterial hypertension. ^,

FETO is typically used in fetuses with severe herniation without other major congenital malformations. Before FETO, fetal congenital diaphragmatic herniations were treated via Fetendo tracheal clipping, but this was associated with damage to the fetal vocal cords and trachea; thus, FETO is now the preferred approach.

The gestational timeframe for FETO intervention is typically between 22 and 30 weeks of gestation. In this procedure, a trocar is inserted through the maternal abdominal wall and into the amniotic cavity under ultrasonic guidance. Following this, a fetoscope is inserted into the fetus’ mouth to reach the trachea and advanced until the carina is seen. At that point, the tracheal balloon is deployed. Preferably, the balloon should remain in the trachea until at least the 34th week of gestation when the plug is removed. Until that time, frequent monitoring is needed to ensure deflation or other complications do not occur. The procedure typically lasts an average of 15 minutes and is performed using local maternal anesthesia and fetal intramuscular anesthesia to minimize the risk of complications during the procedure.

The time frame for balloon removal depends on a myriad of factors, including the surgeon’s level of expertise, stability of mother and fetus, and balloon accessibility. However, it is usually removed at 34 weeks’ gestation when a maximal fetal lung response is seen. Multiple methods can be used for the removal, such as fetoscopic retrieval, percutaneous puncture, and removal via the ex utero intrapartum treatment (EXIT procedure). Following removal, the pregnancy can be managed expectantly; however, if removal is not possible during pregnancy, immediate removal after delivery must occur. In a trial performed by Ruano et al., the EXIT procedure was used to remove tracheal balloons in all subjects involved. Once this removal occurred, the umbilical cord was cut, and delivery occurred. Ruano et al. also demonstrated that the maximal fetal pulmonary response is achieved at approximately 34 weeks of gestation. Removing the fetal tracheal balloon at this time frame may allow for a more effective transition of type I alveolar cells to type II cells.

FETO is not without complications, the most prevalent being preterm delivery and premature rupture of the membranes (PROM). These complications are related to the size of the fetoscope used during the procedure, with larger fetoscopes associated with more side effects. Furthermore, the duration of the procedure also increases the risk of premature rupture of membranes, so fetal surgeons should strive to perform FETO in the shortest time possible. While intraamniotic hemorrhage due to trocar insertion is possible, its incidence decreases with surgical expertise.

Attempts to close the CDH in utero via open fetal thoracotomy and maternal hysterotomy have failed so far. Open fetal repair of the diaphragmatic hernia in utero has a higher risk for maternal morbidity and premature delivery and showed no overall improvement in fetal survival. ^, Furthermore, open repair is not possible in fetuses that present with liver herniation as attempts at reduction can damage the umbilical vein.

Future applications of FETO to reduce the prevalence of possible complications include integrating smart balloon technology. This was first described by Sananes et al. who developed the “Smart-TO” composed of latex and a magnetic valve. The application of a magnetic field can open the valve and deflate the balloon, reducing the need for the traditional methods of removing the balloon.