- What Is a Diaphragmatic Hernia?
About 1,600 babies are born with congenital diaphragmatic hernia every year in the United States. The condition occurs when the diaphragm — the muscle that separates the chest from the abdomen and assists in breathing — forms incorrectly during fetal development. This important structure helps keep the contents of the chest (lungs and heart) separate from the contents of the abdomen (stomach, liver and intestines).
When a diaphragmatic hernia occurs, contents of the abdomen move into the chest through the opening. This limits the space in which the lungs can grow and reduces blood flow to the area, resulting in underdeveloped lungs, possible high blood pressure, asthma, feeding disorders and developmental delays.
In severe cases, the insufficient lung development can be significant enough to affect the newborn’s survival. Early detection and diagnosis of a congenital diaphragmatic hernia are critical to promote the best outcome possible. The physicians of Fetal Care Center Dallas are at the forefront of treatment and care for this condition. We are highly skilled to evaluate the severity of your baby’s condition and make treatment recommendations using the most advanced available resources.
- How We Treat a Diaphragmatic Hernia
Your pregnancy will be closely monitored by the Fetal Care Center Dallas team to help us determine if it will be necessary to deliver your baby early, or if you and your baby may be candidates for fetal intervention.
If your baby is diagnosed with a complex diaphragmatic hernia, treatment before birth may be recommended to allow the lungs to grow enough so your baby is capable of surviving and thriving once delivered. Fetoscopic endoluminal tracheal occlusion (FETO) is an advanced fetal surgery procedure performed by our surgeons to help improve outcomes in babies with a severe form of the disorder.
Normally, a fetus’s lungs produce fluid that escapes through the trachea, or windpipe. Blocking the trachea prevents this fluid from escaping, which can increase pressure in the trachea and stimulate lung growth. The FETO procedure serves as an artificial way to block the trachea and promote development of your baby’s lungs.
ECMO and Breathing Support
After delivery, treatment for babies with severely compromised or fragile lungs may include the use of extracorporeal membrane oxygenation (ECMO), a temporary heart-lung bypass technique used to oxygenate the blood and allow the lungs to rest and grow. In some cases, the baby may have a diaphragmatic hernia repair procedure while on ECMO.
For babies with large defects or who completely lack a diaphragm, the hole may be closed with a mesh patch or muscle flap. In cases where the abdominal wall cannot be easily closed during surgery, a mesh or vacuum closure may be temporarily placed and left intact as your child grows.
In the most severe cases of diaphragmatic hernia, a specialized delivery referred to as an EXIT-to-ECMO procedure may be necessary before advanced therapies such as ECMO can be initiated. The EXIT-to-ECMO procedure was pioneered by Dr. Timothy Crombleholme and his colleagues to allow a seamless transition from prenatal to postnatal life without prematurely tasking a newborn’s underdeveloped lungs and pulmonary system.
For Healthcare Providers
- CDH Introduction
Congenital diaphragmatic hernia (CDH), a defect in the diaphragm, is thought to be due to failure of the pleuroperitoneal canal to close by 9 to 10 weeks of gestation and results in varying degrees of pulmonary hypoplasia from compression of the developing lungs by the herniated viscera (Harrison et al., 1993b). The traditional view that the diaphragm forms by fusion of the septum transversum, the esophageal mesentery, the pleuroperitoneal folds, and ingrowth of musculature from the lateral body wall, is now being questioned (Pober, 2008). In model organisms, recent work suggests that a non-muscular diaphragmatic anlage first develops, and that the diaphragmatic musculature derives from muscle precursors that migrate through the pleuroperitoneal folds at approximately day 37 of gestation (Babiuk and Greer, 2002; Pober, 2008).
During the development of the diaphragm, the peritoneal cavity is quite small and the midgut is normally present in the umbilical cord as physiologic herniation of the cord. If closure and muscularization of the pleuroperitoneal canal has not occurred by 9 or 10 weeks of gestation, when the midgut returns to the abdomen to undergo its normal 270-degree rotation, the viscera may herniate into the thorax through the posterolateral diaphragmatic defect because of limited intra-abdominal space (Areechon et al., 1963). If herniation occurs before the closure of the pleuroperitoneal canal there is no hernia sac. However, if pleuroperitoneal membrane has formed but is not muscularized, a hernia sac will be present and is observed in 10% to 15% of cases (Areechon et al., 1963). Occasionally, a “transient” herniation may occur later in gestation, with little effect on pulmonary development (Adzick et al., 1985a; Stringer et al., 1995).
The clinical course of an infant with isolated CDH depends entirely on the degree of pulmonary hypoplasia and severity of pulmonary hypertension. The degree of pulmonary hypoplasia depends on the timing of herniation during development, the volume of viscera herniated, and duration of herniation, that is, whether or not the viscera slide in and out of the thorax (Harrison et al., 1993a; Stringer et al., 1995).
An appreciation of the pathophysiology of CDH requires an understanding of the normal growth and development of the tracheobronchial tree and pulmonary vasculature. Reid (1977) has described four overlapping stages of normal histologic development: embryonic (from conception to 5 weeks); pseudoglandular (5–16 weeks); canalicular (16–24 weeks); and terminal sac or alveolar (24 weeks to postnatal life). The bronchial tree is almost completely developed by 16 weeks of gestation, at which time the adult complement of airways is established. However, alveoli continue to develop after birth, increasing in number until about 8 years of age (Boyden, 1977).
The severity of pulmonary developmental abnormalities depends on the time and the extent to which the herniated viscera compress the adjacent lung. A large intrathoracic mass effect that develops during the formation of the conducting airways (pseudoglandular stage) will reduce the number of bronchial divisions, decreasing the thoracic volume available for lung development (Geggel and Reid, 1984). The herniation of viscera in CDH usually occurs during the pseudoglandular stage of lung development (5–16 weeks) (Reid et al., 1977). In fetuses with CDH, the major bronchial buds are already present, but the number of bronchial branches is pruned and greatly reduced (Companale et al., 1955). The number of alveoli per acinus may be normal, but the absolute number of alveoli is decreased because of the reduced number of bronchial divisions. These morphologic changes are more pronounced in the lung ipsilateral to the diaphragmatic hernia, but the contralateral lung is similarly affected by compression from the shifted mediastinum (Figure 37-1) (Harrison et al., 1980a, 1980b, 1981, 1990, 1993a; O’Rourke et al., 1984; Adzick et al., 1985b; Hasegawa et al., 1990). Persistent mass lesions during later stages of lung development (canalicular or alveolar stages) will result in a reduction not only in airway size, but in the number and size of saccules, alveoli, and preacinar and intraacinar vessels (Areechon et al., 1963). Concomitant with these changes in the fetal tracheobronchial tree is an increase in the thickness of the arterial media and extension of muscle peripherally into the small preacinar arteries (Levin et al., 1978). The pulmonary hypoplasia that is associated with CDH is one of the major determinants of morbidity and mortality (Figure 37-1). Some have suggested a “two-hit” theory in which pulmonary underdevelopment occurs first but is then made worse by subsequent mechanical compression (Keijzer et al., 2000). In addition, the pulmonary vasculature is abnormal with overmuscularized vessels. In addition to the increased muscularization of the preacinar arteries, Geggel et al. have demonstrated that there is a reduction in size of the pulmonary vascular bed in CDH (Geggel et al., 1985). These changes in the pulmonary vascular bed are the histologic correlates of pulmonary hypertension seen in experimental models of CDH and newborns with pulmonary hypoplasia.
There is evidence that mutations in specific genes that are involved in diaphragmatic development and/or the vitamin A pathway may play a role in the etiology of CDH and pulmonary hypoplasia (Ackerman and Pober, 2007). Key genes that are mutated in teratogenic mouse models of CDH include the transcription factors Fog2, couptf2, wt1, slit3, and GATA4, and molecules involved in cell migration and signaling such as slit3 (Bielinska et al., 2007). It is not clear that this teratogenic model from which these mutations have been identified apply to human CDH. Interestingly, in the human, these genes map to areas that have been consistently shown to have chromosome abnormalities that are associated with CDH. There has also been one case in a human mutation in FOG2 in which there was pulmonary hypoplasia and a diaphragmatic abnormality consistent with eventration, but no CDH (Ackerman et al., 2005).
- Incidence of CDH
Approximately 85% to 90% of diaphragmatic hernias occur on the left side, 10% to 15% are on the right side, and a few are bilateral. In 60% of cases, the diaphragmatic hernia is either isolated or associated with malformations that are due to hemodynamic or mechanical consequences of the CDH. In 40% of cases the CDH is nonisolated or part of a syndrome. All studies have shown that infants with syndromic (or “complex”) CDH have higher mortality (Pober, 2007). The incidence of CDH has been estimated at between 1 in 3000 and 1 in 5000 livebirths (Puri and Gorman, 1984). These estimates ignore the significant numbers of intrauterine fetal death, stillbirths, and neonatal deaths that occur before transfer to a tertiary care facility. An accurate incidence of CDH is more likely around 1 in 2200 births (Fitzgerald, 1979; Harrison et al., 1979; Reynolds et al., 1984; Puri, 1989). In years past, the postnatal survival rate of infants with CDH was traditionally quoted as 50% (Adzick et al., 1981), but this figure represents survival in a favorably selected group of patients who survive not only to term, but also transfer to a referral center for further treatment (Harrison et al., 1979, 1990, 1993a, 1994; O’Rourke et al., 1984; Adzick et al., 1985a). The most severely affected neonates die before they are transferred to a tertiary care center. Harrison has referred to this discrepancy as the “hidden mortality” of CDH (Harrison et al., 1979). A more recent meta-analysis found that the average mortality for prenatally diagnosed cases was 75%, for cases ascertained as part of a population-based study it was 48%, and for cases transferred to a tertiary facility it was 45% (Skari et al., 2000). The survival rate in tertiary centers has improved with rates now reported between 70 and 92% (Putnam et al 2016, Freddy et al 2009, Mah et al 2009, Burgos et al 2017, Barriere et al 2018).
The cause of CDH is unknown but it has been reported in association with maternal ingestion of thalidomide, Bendectin, quinine, and antiepileptic drugs (Hobolth, 1962; Kup, 1967; Hill, 1974; Greenwood et al., 1976; Tubinsky et al., 1983). Associated anomalies are seen in 25% to 57% of all cases of CDH, but this figure rises to 95% in stillborn infants (Crane et al., 1979; Tubinsky et al., 1983; Puri, 1984). The associated anomalies may include congenital heart defects, hydronephrosis or renal agenesis, intestinal atresias, extralobar sequestrations, and neurologic defects, including hydrocephalus, anencephaly, and spina bifida (Crane et al., 1979; Tubinsky et al., 1983). CDH has been described as a finding in Fryns, Beckwith–Wiedemann, and Pierre–Robin syndromes as well as in congenital choanal atresia (Thorburn et al., 1970; Evans et al., 1971; Harrison et al., 1991). Chromosomal anomalies are diagnosed in 10% to 20% of cases of CDH diagnosed prenatally. The most common diagnoses include trisomies 21, 18, and 13 (Lesk et al., 1959; Crane et al., 1979; Tubinsky et al., 1983).
- Sonographic Findings
Approximately 60% to 90% of cases of CDH are detected prenatally by sonography or MRI depending on the center reporting ascertainment (Pober, 2008). The diagnosis of CDH should be suspected if the stomach bubble is not observed in its normal intra-abdominal location. The fetal chest should be viewed in the true transverse plane, and landmarks such as the inferior margin of the scapula should be used to identify the abdominal viscera in the chest (Lesk et al., 1959). Abdominal viscera that are seen cephalad to the inferior margin of the scapula or at the same level of the four-chamber view of the heart are herniated, confirming a diagnosis of CDH (Figures 2 to 4). The herniated abdominal viscera associated with a left-sided CDH may be the easiest to detect. The fluid-filled stomach and small bowel contrast strikingly with the more echogenic fetal lung.
The position of the fetal liver is one of the most significant and reproducible independent prognostic factors, with liver herniation predictive of poor outcome (Harrison et al., 1990; Cannie et al., 2006; Hedrick et al., 2007; DePrest et al., 2009). One of the most reliable prenatal predictors of postnatal survival is the presence or absence of liver hernation into the chest. A systematic review of 710 fetuses in which ultrasound or MRI was used to determine liver herniation found a significantly higher survival rate in fetuses without liver herniation (74%) compared to those with liver herniation (45%) (Mullasary et al 2010). Ultrafast fetal MRI may be the most accurate modality to demonstrate liver herniation (Quinn et al 1998, Worley et al 2009, Hubbard et al 1998, Bebbington et al 2014). Kinking of the sinus venosus is a reliable sign of left-sided CDH with herniated left lobe of the liver (Figure 5). In a retrospective review of 16 fetuses with left CDH, Boostaylor et al. (1995) found that bowing of the umbilical segment of the portal vein (the portal sinuses) to the left of midline and coursing of portal vessels to the lateral segment of the left hepatic lobe toward or above the diaphragmatic ridge are the best predictors for liver herniation into the left chest. Another subtle finding is an echodense space between the left border of the heart and the stomach, which is due to interposed herniation of the left lobe of the liver. Sonographic or MRI delineation of the diaphragm is not always possible. Even identifying the diaphragm cannot exclude CDH because only a portion of the diaphragm may be missing.
The location of the gallbladder may also be helpful in diagnosing CDH because it may be herniated in the right chest in right-sided CDH or displaced to the midline or left upper quadrant with left-sided CDH. A large-volume herniation will result in mediastinal shift with polyhydramnios. Mediastinal shift is thought to interfere with swallowing, thus resulting in polyhydramnios (Harrison et al., 1991). Since the stomach may be rotated 180 degrees counterclockwise from its normal anatomic position up into the chest, it is more likely that there is partial gastric outlet obstruction due to kinking at the gastroduodenal junction. The stomach position is also a good indicator of liver hernation if observed in a posterior or midthoracic location (Boostaylor et al., 1995). CDH has been also reported in association with concomitant bronchopulmonary sequestration cystic adenomatoid malformation, and teratomas. These may be noted as echogenic masses seen in association with the CDH.
The extent of pulmonary hypoplasia is the most important determinant of survival in CDH. Hasegawa et al. (1990) have proposed using a ratio of the cross-sectional area of the lung to thorax (L:T ratio) in sonographic transverse section of the fetal chest at the level of the four-chamber view of the heart to assess the likelihood of pulmonary hypoplasia. They found, in a small series of eight fetuses with CDH, that the L:T ratio was below 2 SD from the mean ratio obtained in 156 normal controls. There was also an inverse correlation between the L:T ratio in the fetus and in the postnatal A-aDO2 (alveolar-to-alveolar oxygen difference) values (Hasegawa et al., 1990).
Metkus et al. (1996) reported the use of the right-lung area to head circumference ratio (LHR) as a sonographic predictor of survival in fetal diaphragmatic hernia. The LHR is the two-dimensional area of the right lung taken at the level of the four-chamber view of the heart. This is divided by the head circumference. In a retrospective review of 55 fetuses diagnosed with left-sided CDH, the LHR was found to be predictive at its extremes. At low values (i.e., small right lung), fetuses with LHRs <0.6 did not survive with postnatal therapy. But in fetuses with LHRs >1.35, survival was 100% with conventional postnatal therapies, including ECMO (Cannie et al., 2006; DePrest et al., 2006). The survival of fetuses with LHRs between 0.6 and 1.35 was 61%. At an NIH symposium, Harrison et al. (2003) provided additional data in the group of fetuses with values between 0.6 and 1.35. Survival with an LHR <1.0 was only 11%. The accuracy of the LHR described by Metkus et al. (1996) was validated in two sub-sequent prospective studies (Flake et al., 2000). The LHR has not been widely adopted due to the difficulty in accurately and reproducibly obtaining the LHR.
There now have been three different techniques reported for obtaining lung:head circumference ratio and a fourth modification in which the observed LHR is normalized to an expected LHR. Only two of these methods have been validated in prospective studies. In the technique first reported by the University of California San Francisco (UCSF) group, the largest transverse width of the right lung is obtained from the cross-sectional view of fetal chest at the level of the four-chamber view of the heart. This transverse measurement is taken parallel to the sternum from the right side of the Ao to the edge of the lung at the right chest wall. The anterior-posterior (AP) measurement is obtained perpendicular to this measurement. A second technique obtains the longest transverse measurement at the level of the four-chamber view of the heart independent of the orientation of the sternum. The third technique captures the image of the cross-sectional view of the chest at the level of the four-chamber view and traces the outline of the right lung to obtain the area and divides by the head circumference. Each of these techniques yields slightly different results that may alter the perceived prognosis. These techniques are not only highly user-dependent, but the prognosis based on these results may not translate from one center that sees a high volume of fetuses with CDH to one that sees only a few cases each year. Case in point, Crombleholme et al. (2009) have reported the Cincinnati Children’s experience with LHR, finding a survival of 100% when LHR was >1.0 and 50% with LHR <1.0. These findings are in contrast to older reports of prognosis based on LHR that indicates the institutional-specific nature of the utility of LHR in predicting survival. The accuracy of the LHR in predicting outcome has been challenged by the Columbia group (Arkovitz et al., 2007), who reported that the LHR in their series was not predictive of outcome. Methodical problems with LHR acquisition may be an issue, but this does point to concern regarding how easily translatable use of LHR is from one center to another.
Between 12 and 32 weeks’ gestation, normal lung area increases four times more than head circumference (DePrest et al., 2009). For this reason, Jani et al. (2007) proposed referencing LHR to gestational age by expressing the observed LHR as a ratio to the expected mean LHR for that gestational age. In a study from the CDH antenatal registry of 354 fetuses with isolated left and right CDH between 18 and 38 weeks, Jani et al. found that observed/expected LHR (O/E LHR) predicted postnatal survival. The O/E LHR tended to be more accurate at 32 to 33 weeks than at 22 to 23 weeks’ gestation. The O/E LHR was also found to correlate with short-term morbidity indicated (Jani et al., 2007, 2009).
A novel approach was reported by Mahieu-Caputo et al. (2001) using the thoracic volume minus the mediastinal volume to yield an estimate of what the lung volume would be expected to be if there was no CDH and dividing the actual lung volume by this estimate to yield the percent predicted lung volume (PPLV). Mahieu-Caputo et al. (2001) found that the observed/expected fetal lung volume ratio was significantly lower in CDH patients who died with a mean of 26% compared to those who survived with a mean of 46%. This same group reported a larger experience from a 4-year prospective multicenter study of 77 fetuses with isolated CDH diagnosed between 20 and 33 weeks’ gestation (Gorincour et al., 2005). They found that the observed/expected lung volume was significantly lower in fetuses with CDH that died (23%) compared to those that survived (36%). When the observed to expected fetal lung volume ratio was below 25%, there was a significant decrease in postnatal survival to 19% versus 40.3%. While these survival rates are lower than usually reported in the United States, they still support the utility of this prognostic technique.
Using this same technique that she termed PPLV, Barnewolt et al. (2007) reported their preliminary experience in Boston with 14 patients with CDH in which there was a clear break point at a PPLV of 15%. Fetuses with PPLV more than 20% had 100% survival while those with PPLV <15% had a 40% survival and all required prolonged ECMO. However, Crombleholme et al. (2009), in reporting the Cincinnati Children’s experience with PPLV with 28 patients, found that PPLV was not as predictive of outcome as LHR (Crombleholme et al., 2009). In this series, three of the four deaths occurred in patients with PPLV more than 15%. In contrast, survival with LHR >1.0 was 100% and all deaths occurred in patients with LHR <1.0.
Fetal MRI has been also applied to directly measure total lung volumes to predict outcome in CDH. Hubbard et al. (1997) found that fetal lung volumes obtained by MRI at midgestation did not accurately predict postnatal outcome. Kilian et al. (2006) reported a series of fetal MRI-derived lung volumes at 34 to 35 weeks’ gestation. They noted that most of the growth in lung volume occurs in late gestation, as reflected in the later sharp upward sweep of lung volume normograms. They reasoned that in the presence of a large CDH there would not be the normal increase in lung growth. In a series of 38 cases of CDH, both right-sided and left-sided, they correlated lung volume with survival and the need for ECMO. They found that the mean lung volume of survivors was 35 cc, while mean lung volume of nonsurvivors was 9 cc. The mean lung volume of those infants requiring ECMO was 18 cc, while 25 cc was the mean lung volume of those that did not require ECMO.
Most prenatal prognostic measurements are based on the size of the lungs, the volume of the herniated viscera, degree of liver herniation but cannot measure lung function as an indicator of the severity of pulmonary hypoplasia. Vuletin et al., were the first to report a prenatal measurement that predicted how severe the pulmonary hypertension would be at three weeks after delivery (Vuletin et al 2009). At the time of 34 weeks’ gestation MRI, measurement of the branch pulmonary artery diameter and the descending Ao allows calculation of the modified McGoon index. Vuletin et al. (2009) have shown that the modified McGoon <1.0 and the prenatal pulmonary hypertensive index (PPHI, branch pulmonary arteries divided by the cerebellum to normalize for age) correlates with severe postnatal pulmonary hyper-tension at 3 weeks of age.
Cystic diseases of the chest, such as type I congenital cystic adenomatoid malformation (CCAM) of the lung, bronchogenic cysts, neurenteric cysts, and cystic mediastinal teratoma, may also be mistaken for the herniated bowel of CDH (Harrison et al., 1991). The demonstration of normal upper gastrointestinal anatomy helps to distinguish cystic thoracic masses from CDH. Peristalsis of bowel loops within the chest may also help distinguish these two diagnoses. In right-sided lesions the liver is often the only organ herniated. This may be more difficult to identify, due to the similar echodensities of the fetal liver and lung. It may also be difficult to distinguish herniation of the liver into the chest from a type III CCAM.
- Antenatal Natural History
It is still thought, although controversial, that prenatal detection of CDH improves outcome by allowing transport of the mother to an appropriate facility, planned delivery, immediate resuscitation, and sophisticated postnatal intervention with “gentilation” strategies, high-frequency ventilation and/or ECMO. Older reviews of prenatally diagnosed CDH, however, consistently showed a 76% to 80% mortality rate despite this optimized approach to management (Adzick et al., 1981; O’Rourke et al., 1984; Reynolds et al., 1984; Harrison et al., 1990, 1993a, 1993b, 1994; Puri and Gorman, 1984). More recent experience with prenatally diagnosed CDH has shown that there is a difference in survival between cases that were diagnosed prenatally and delivered in the appropriate setting versus those that were not and were “out born”. there is a 10% incidence of intrauterine fetal demise in isolated left sided CDH mostly observed in the later third trimester (Harrison et al 1994). We recommend a planned induction of labor at a tertiary center with experience with CDH and ECMO capability to avoid the need for transporting a critically ill newborn with CDH.
There has been a trend toward improved survival even among the most severely affected fetuses with CDH in which there is liver herniation and LHR <1.0. In the NIH study reported by Harrison et al. (1997), the survival in fetuses regardless of treatment was 30%. Although the numbers were small, this is an improvement from 11% previously reported by this group. Similarly, the CHOP group has reported 40% survival in this high-risk category. Contemporary survival for isolated left sided CDH with an LHR of >1.0 in experienced centers should approach 100%. The improvement in survival in general for CDH has shifted innovative strategies of management to only those patients with LHR <1.0 and liver herniation or an O/E LHR <25% and liver herniation. These innovative strategies include reversible tracheal balloon occlusion (DePrest, 2007; DePrest et al., 2009), EXIT-to-ECMO (Kunisaki et al., 2007), aggressive management of pulmonary hypertension with off-label use of inhaled nitric oxide and inhaled prostacyclin (Lim, 2007). In our experience, aggressive management of pulmonary hypertension in CDH has resulted in 100% survival in isolated CDH with LHR >1.0. Even with LHR <1.0, the we have observed a 50% survival and have reduced the need for ECMO to only 8% in patients not sufficiently severe for EXIT-to-ECMO.
- Management of Pregnancy
The evaluation of the fetus with suspected CDH should include a detailed ultrasound examination to confirm the diagnosis and detect possible associated anomalies. If possible, measurement of LHR and observed to expected LHR (O/E LHR) should be obtained. Prenatal karyotyping is indicated in all cases of CDH because of the high incidence of associated chromosomal anomalies (16–37% of cases) (Adzick et al., 1981; Puri, 1984; Sharland et al., 1992). Even if termination of the pregnancy is not an option because of gestational age or parental choice, the diagnosis of a chromosomal anomaly may influence the management of labor and the plan for neonatal resuscitation. Microarray analysis is now a standard recommendation for all cases of prenatally diagnosed CDH due to limitations in completely ascertaining all anomalies in utero (Pober, 2008, Vora et al 2016).
The most common chromosome abnormalities associated with CDH are trisomy 18, and tetrasomy 12p (Pallister–Killian syndrome), and trisomy 21. Other chromosome rearrangements that have been reported in association with multiple cases of CDH include del(15)(q26.1-q26.2), del (8)(p23.1), del (4)(p16), partial and full trisomy 22, del (1)(q41-q42.12), and rearrangement of 8q23 (Holder et al., 2007; Pober, 2008).
CDH is found in at least a dozen single-gene disorders, including Cornelia de Lange syndrome, craniofrontonasal syndrome, Donnai–Barrow syndrome, multiple vertebral segmentation defects, Simpson–Golabi–Behmel syndrome, Denys–Drash syndrome, and Frasier syndrome. Although a diagnosis of Fryns syndrome is commonly made, there is likely to be etiologic heterogeneity with Fryns, and no gene that causes this condition has been identified to date (Pober, 2008). If the CDH is suggested to be syndromic, consultation with a medical geneticist is advised.
Fetal echocardiography is also recommended in all cases because of the 16% incidence of associated congenital heart disease (Sharland et al., 1992).
The diagnosis of CDH at less than 25 weeks of gestation with long-standing large-volume herniation (indicated by mediastinal shift and dilated intrathoracic stomach, herniated liver, LHR <1.0, O/ELHR<25% and associated polyhydramnios) indicates a fetus at risk for severe pulmonary hypoplasia and a poor outcome. The severity of pulmonary hypoplasia and CDH seems to correlate with the timing, duration, and volume of herniation. A few mildly affected fetuses will have minimal developmental effects on the lungs because of herniation late during gestation, small-volume hernia, minimal mediastinal shift, and greater lung volume as indicated by an L:T ratio >0.5 or LHR >1.4 (Hasegawa et al., 1990; Metkus et al., 1996; Stringer et al., 1995). These fetuses should be followed closely by serial ultrasound examinations and delivered at term in an ECMO center staffed with pediatric surgeons and neonatologists, expert in management of infants with CDH.
The majority of fetuses with prenatally diagnosed CDH are detected early in gestation (less than 25 weeks), with a large-volume herniation with mediastinal shift and intrathoracic stomach, polyhydramnios, low L:T ratio (<0.5), and low LHR (<1) O/E LHR (<25%). The management of the fetus depends on the gestational age at diagnosis. If the fetus is less than 24 weeks, then the parents may choose to terminate the pregnancy, continue the pregnancy with conventional postnatal care at term, or consider fetoscopic tracheal balloon occlusion procedure in utero. There is no currently FDA-approved device for fetal tracheal balloon occlusion in the United States and it is only available under the use of an investigational device exemption (IDE). Tracheal occlusion is being offered in Canada and Europe. Several centers in the United States including the Fetal Care Center of Dallas, CHOP, UCSF, Cincinnati Children’s, Texas Children’s, Johns Hopkins and UT Houston, are offering this therapy on an FDA-approved IDE as part of support for the tracheal occlusion to accelerate lung growth (TOTAL) trial.
Deprest et al began randomizing patients with left sided CDH to fetoscopic tracheal balloon occlusion (FETO) versus conventional postnatal therapy in the TOTAL trial. This trial has a severe and a moderate arm. In the severe trial, the O/E LHR must be <25% and the endpoint is survival. In the moderate trial the O/E LHR must be >25<45% and the endpoint is morbidity. The European Ethics Committees (equivalent to IRBs in the US) thought that the preliminary data for the TOTAL trial was sufficiently compelling that they must offer FETO clinically outside the TOTAL trial. This created a “back door” in which patients were offered randomization to FETO or postnatal management in the TOTAL trial or they could elect to be treated with FETO outside the trial. As a consequence very few patients agreed to randomization.
Deprest approached centers in North America to participate in the TOTAL trial because the balloon was not FDA approved and would require an investigational device exemption (IDE) which would prevent the “back door” issue limiting access to FETO to centers collaborating in the North American FETO Consortium and to patients who were willing to be randomized to get access to FETO. Currently, centers in the United States must go through a qualifying period in which 5 cases of FETO must be performed to demonstrate that they can safely perform FETO before they can randomize patients in the TOTAL trial.
Congenital Diaphragmatic Hernia Composite Prognostic Index (CDH-CPI)
There are a number of prognostic variables which have been shown to be of prognostic importance including, liver position, associated congenital heart disease, chromosomal abnormalities, genetic syndromes, lung volumes (total lung volume (TLV) and percent predicted lung volumes (PPLV), pulmonary hypertension (McGoon index, prenatal pulmonary hypertensive index (PPHI), pulmonary arterial response to maternal oxygenation, presence or absence of a sac to name but a few. However, sometimes these variables are not always consistent or may be discordant with other prognostic findings. To address the problem we developed the CDH composite prognostic index which incorporates many of these variables in a single index (Le et al 2012). Working with a biostatistician we developed a 10 point scale based on 4 parameters: genetic, cardiac, sac, lung volumes. A point is deducted for genetic or significant cardiac abnormalities (except for ventricular septal defect or atrial septal defect). A point is added for the presence of a hernia sac as well as for favorable LHR, PPLV, and TLV (see table). The CDH-CPI, was found to correlate with both survival and the need for ECMO ( ref). In cases whith a 10/10 score a 100% survival can be anticipated. In cases with a score of 9/10 a 90% survival was observed. The survival dropped precipitously when the score was only 6/10 with a 35% survival.
Table and Figure for CDH-CPI
Cesarean delivery is not indicated for CDH. There are no data to support elective preterm delivery. However, elective induction at 37 weeks allows a planned delivery in the appropriate center with suitable resources for the care of a fetus with severe pulmonary hypoplasia. There has been controversy as to whether CDH fetuses are surfactant deficient with reports on both sides of the argument. Recently however, Benachi (2007) from France reported definitive results in autopsy specimens in fetuses with CDH near term, as demonstrated by the presence of type II pneumocytes both bronchoalveolar lavage and histology that were no different from normal-term control fetuses. There is, however, another reason to administer prenatal steroids within 48 hours up to 7 days prior to delivery. Davey et al. (2007) have demonstrated in a sheep model of CDH that steroid administration close to the time of delivery can reverse the extensive muscularization of the preacinar capillary bed responsible for pulmonary.
- Fetal Intervention
Compensatory lung growth and development are possible after repair of CDH, but weeks or months may be required to achieve this. Postnatal support by ECMO is usually limited to 2 to 6 weeks, which may be an inadequate period of support for the most severely affected infants (O’Rourke et al., 1984). It has been demonstrated experimentally that reduction and repair of the hernia in utero allows the lungs adequate time for compensatory growth (Harrison et al., 1980a, 1980b, 1981; Adzick et al., 1985b). In a series of experiments in fetal sheep and rhesus monkeys, the techniques of open fetal surgery and perioperative tocolytic therapy were established before clinical trials of open fetal surgery for CDH were undertaken (Harrison et al., 1980a, 1980b, 1981, 1991; Adzick et al., 1985b; Adzick and Harrison, 1994).
Although the survival rate with in utero repair of CDH in initial clinical trials was not encouraging (Harrison et al., 1990, 1993a, 1993b), the dramatic results observed in surviving infants prompted an NIH-sponsored trial (Harrison et al., 1997). The results of this trial, limited to diaphragmatic hernia without herniation of the left lobe of the liver, showed no survival benefit of fetal surgery over postnatal treatment. As a result, there is currently no indication for complete repair of diaphragmatic hernia without herniation of the left lobe of the liver. However, cases of diaphragmatic hernia associated with herniation of the left lobe of the liver remain the most severely affected cases, with profound pulmonary hypoplasia. Ironically, although considered an exclusion criterion for complete repair of diaphragmatic hernia, it is now one of the selection criterions for fetal tracheal occlusion (FETO; Deprest et al., 2009).
It was recognized long ago that occlusion of the fetal trachea results in markedly enlarged and hyperplastic lungs (Carmel et al., 1965; Lanman et al., 1971; Alcorn et al., 1976). This observation was applied to the problem of diaphragmatic hernia. Throughout gestation the fetal lung produces fluid that exits the trachea during normal breathing movements. External drainage of this fluid, bypassing the glottic mechanism, results in retarded lung growth and pulmonary hypoplasia (Carmel et al., 1965; Lanman et al., 1971; Alcorn et al., 1976). Conversely, tracheal occlusion results in accelerated lung growth and pulmonary hyperplasia (Carmel et al., 1965; Alcorn et al., 1976; Moessinger et al., 1990; Hedrick et al., 1993; Hooper et al., 1993; DeFiore et al., 1994; Bealer et al., 1995; Luks et al., 1995; Beierle et al., 1996). In the fetal lamb model of diaphragmatic hernia, tracheal obstruction accelerates lung growth, pushing the viscera back into the abdomen resulting in larger lungs with significant functional improvement at birth as compared with controls (Hedrick et al., 1993; Wilson et al., 1993; DeFiore et al., 1994; Bealer et al., 1995; Luks et al., 1995; Beierle et al., 1996). The results of experimental work were so impressive that this strategy was employed by Harrison in fetuses with herniation of the left lobe of the liver (Harrison et al., 1997).
Despite an excellent biologic response with complete tracheal occlusion, there was only one survivor in the initial series of patients treated by tracheal occlusion. We had similar problems when the procedure was performed at 28 weeks of gestation (Figure 7). Survival increased to 40% in fetuses with a predicted mortality rate in excess of 90% when fetal tracheal clip application was performed at 26 weeks of gestation (Flake et al., 2000).
Due to difficulties with open fetal surgery for tracheal clip application as well as fetoscopic tracheal clip application, the UCSF group adopted the tracheal occlusion by detachable endoluminal balloon placement originally developed by Deprest (Deprest et al 2004).
The results with fetoscopic balloon tracheal occlusion were evaluated by the UCSF group in an NIH-sponsored randomized trial that compared fetoscopic tracheal occlusion to conventional postnatal therapy in fetuses with isolated left-sided CDH with liver herniation and LHR <1.4 (Harrison et al., 2003). The investigators’ preliminary data suggested an anticipated survival with conventional therapy of 50% and with fetoscopic tracheal occlusion of 75%. A crucial aspect of the trial was that patients from both arms of the trial were born and treated postnatally at UCSF. The trial was stopped after randomization of only 24 patients because of an unexpectedly high survival rate with standard care. Eight of the 11 fetuses (73%) randomized to tracheal occlusion survived and 10 of 13 fetuses (77%) randomized to standard care survived to 90 days of age. There was a significant difference in gestational age at delivery for FETO (30.8 weeks) compared to conventional therapy (37 weeks). This trial demonstrated a significant improvement in survival compared to historical controls in the same center. However, the inclusion of fetuses with LHR > 1 < 1.4 biased the study toward the less severe end of the spectrum with insufficient power to analyze the effects in the subset of patients with LHR <1.0.
The tracheal occlusion procedure is done using maternal percutaneous access under local or regional anesthesia with a single 3.3 mm port and a balloon to occlude the trachea (DePrest et al., 2009). The balloon is inserted at 27 to 30 weeks and removed at 34 weeks. If patients deliver prior to 34 weeks they require emergency peripartum balloon removal, which requires the availability of trained clinicians at all times. The Eurofoetus group reports in their experience of more than 210 cases a survival rate with tracheal occlusion of 49% (DePrest et al., 2009). However, these studies have been criticized due to lack of contemporary controls. Nonetheless, no maternal complications have been reported, but iatrogenic preterm rupture of the membranes has occurred in 20% of cases. Long-term follow-up study of infants is in progress. DePrest and his Eurofoetus colleagues have achieved survival of 83% with tracheal occlusion at 26 to 28 weeks’ gestation followed by reversal of tracheal occlusion performed either by popping the balloon by an ultrasound-guided needle or by a second fetoscopic procedure. In the United States, several centers, including the Fetal Care Center of Dallas, are currently offering FETO under IRB approved protocol and IDE from the FDA.
The only other fetal surgery offered for high-risk CDH is EXIT-to-ECMO. In preliminary results reported by Kunisaki et al. (2007), fetuses with liver herniation and PPLV or <20% are offered EXIT-to-ECMO, with a 65% survival. Similar results have been observed at Cincinnati Children’s and Vanderbilt. This therapeutic innovation remains unproven but may hold promise in these high-risk CDH cases given survival with conventional treatment in this category is significantly lower.
- Treatment of the Newborn
All fetuses with CDH are at high risk for severe pulmonary hypoplasia and are optimally managed by delivery in a perinatal center with neonatal and pediatric surgical expertise in CDH immediately available, preferably in a center capable of performing ECMO (Harrison et al., 1990; Marwan and Crombleholme, 2006). The resuscitation of a newborn includes immediate endotracheal intubation, “gentilation” limited, positive-pressure ventilation with PIPs <25 cm H2O. The infant should have a sump-style nasogastric tube inserted in the delivery room to perform continuous suction to avoid dilation of the intrathoracic bowel from the infant swallowing air. In the delivery room the infant should have umbilical arterial and umbilical venous catheters placed to monitor arterial blood gases and provide venous access. In the face of liver herniation, however, umbilical venous lines rarely successfully traverse the kink in the ductus venosus. Preductal and postductal transcutaneous oxygen saturation monitors can help to continuously monitor right-to-left shunting across the ductus arteriosus.
Judicious volume resuscitation is important, and many infants with diaphragmatic hernia require vasopressor support with dopamine, milrinone, or epinephrine. The need for pressor support in CDH newborns is almost universal and may be related to a relative cortisol deficiency as described by Kamath (Kamath et al 2015). We routinely draw cortisol levels and empirically administer hydrocortisone at stress dosing. This often restores blood pressure or makes the baby more responsive to pressor support. Occasionally vasopressor refractory hypotension may require the use of steroids or even vasopressin.
The use of inhaled nitric oxide in CDH has met with mixed results. Inhaled nitric oxide has not clearly been shown to benefit newborns with diaphragmatic hernia. However, inhaled nitric oxide has been beneficial in preventing the need for ECMO during the postoperative period (Frostell et al., 1993; Dillon et al., 1995). We routinely evaluate the cardiac function echocardiographically to assess the severity of elevated right sided pressures due to pulmonary hypertension and assess the function of the ventricles in dealing with this increased afterload. The severity of pulmonary hypertension can be inferred by the degree of right ventricular dilation, the bowing of the interventricular septum, or measured from the envelope of the tricuspid regurgitant jet. The shunting from right to left at the ductus arteriosus can also indicate systemic or suprasystemic right sided pressures.
Pulmonary hypertension has both “fixed” and a “dynamic” components. The “fixed” component is due to pruning of the pulmonary vascular bed caused by the compression of the lungs during the pseudoglandular stage of development. This “fixed” component is not responsive to pharmacologic agents and must rely on lung growth and remodeling to improve over weeks or months. In contrast, the “dynamic” component is due to excessive muscularization and reactivity of the pulmonary vascular bed. This component may be responsive to pharmacologic agents such as inhaled nitric oxide (iNO), Flolan, or endothelin-1 receptor blockers. It is important to obtain an echocardiogram prior to starting these agents to rule out left sided ventricular dysfunction and elevated left atrial pressure. In this setting, iNO is contraindicated as it may increase blood flow to the lungs and right atrium predisposing to pulmonary hemorrhage.
The response to vasodilator therapy should be assessed both clinically and echocardiographically. Many newborns may not respond to iNO and consideration should be given to other agents which may work by alternative pathways or alternative delivery mechanisms. For example, effective use of iNO depends on well recruited lungs for effective delivery. If recruitment is variable in the lungs then IV sildenafil may be useful. Similarly, if there is no response to iNO in well recruited lungs, consideration should be given to inhaled Flolan which operates by an alternate intracellular mechanism. Some babies may respond to iNO and not to inhaled Flolan and vice versa. Other agents such as endothelin-1 receptor blocking agents (Bosentan) are more useful in the chronic setting as they are oral agents which may have variable absorption in a sick newborn and requires close monitoring of liver function tests. In some circumstances other agents may be useful as adjuncts in the treatment of pulmonary hypertension. Acute premature closure of the ductus arteriosus in the CDH baby with pulmonary hypertension may cause an acute hemodynamic decompensation and will respond to PGE1 infusion to keep the ductus arteriosus open allowing the right ventricle a “pop off” relieving the right sided pressures.
An aggressive approach for pulmonary hypertension including inhaled nitric oxide combined with inhaled prostacyclin has yet to be proven to affect outcome, but preliminary results with this approach have been promising, and results in 90% overall survival in CDH and 100% survival in cases with LHR >1.0. (Crombleholme et al., 2009)
- Surgical Treatment
It was once believed that immediate operation to decompress the chest was necessary. However, in recent years, it has been recognized that this is not the case. The more important variable is the degree of underlying pulmonary hypoplasia. Emergency surgical repair may, in fact, be detrimental to the infant’s tenuous pulmonary and hemodynamic status after birth and relative pulmonary artery hypertension (Hazebrock et al., 1989; Langer et al., 1989). It is better to delay repair until the infant has stabilized.
We recently demonstrated that attempting CDH repair prior to fall in pulmonary hypertension that normally occurs in days to weeks after birth can result in acute hemodynamic or respiratory decompensation (Deeney et al 2017). We normally wait until the echocardiographically estimated pulmonary pressures have fallen to below 80% of systemic pressures. Not only did this prevent acute post-operative decompensation it also appears to improve survival.
If the infant deteriorates during this so-called “honeymoon” period, ECMO can be initiated. The infant can undergo repair of CDH while on ECMO and be weaned from the circuit postoperatively (Connors et al., 1990). An alternate strategy is to perform early repair on ECMO to facilitate remodeling of the hypoplastic lung following repair of the diaphragmatic defect. The rationale here is that relieving compression of the lung is beneficial for pulmonary hypertension. The risk of this approach is postoperative bleeding while anticoagulated on ECMO prior to a time when ECMO decannulation would be possible.
Repair of CDH is usually performed via a left-upper-quadrant transverse or subcostal incision, which allows exposure of the defect and reduction of the herniated viscera. The diaphragm can occasionally undergo primary repair, but in severe cases, the defect is large or there may be complete diaphragmatic aplasia, both of which require a prosthetic patch. Because reherniation may occur in 4 to 50% of cases with gortex patch repair, there is growing interest in the use of the transversus abdominus muscle flap as a patch. Because the tissue is autologous there is decreased risk of infection, and because it grows with the infant, it is believed to prevent dehiscence and reherniation. A chest tube may be inserted after repair of CDH. If used, the chest tube is placed only to water seal, and no suction is applied. We have routinely used the transversus abdominus muscle flap to repair CDH for the last 20 years with only one case of recurrent herniation during that time in well over 200 cases. Not only does the transversus abdominus flap appear to prevent re-herniation, it is autologous and if infection were to occur can be successfully cleared with intravenous antibiotics. In contrast, gortex patches usually require remove to clear the infection.
- Long-Term Outcome
The long-term outcome of infants with isolated CDH who survive the neonatal period depends on the severity of pulmonary hypoplasia, and the degree of bronchopulmonary dysplasia resulting from long-term ventilatory support (Bales and Anderson, 1979). In addition, extrapulmonary complications are noted more commonly in survivors of CDH (Glass et al., 1989; Lund et al., 1994). There is a high incidence of neurologic problems in children with CDH, independent of exposure to ECMO. Other complications such as reactive airway disease, sensorineural hearing loss due to prolonged need for antibiotics and/or furosemide (Lasix), seizures, and developmental delay, may be seen in up to 20% to 30% of patients (Lund et al., 1994). Long-term follow-up evaluation and early intervention are indicated in this group of high-risk patients.
Failure to thrive has been noted in many survivors of diaphragmatic hernia (Cunniff et al., 1990; Atkinson and Poon, 1992; Van Meers et al., 1993; D’Agostino et al., 1995). Many infants with isolated diaphragmatic hernia have feeding difficulties that may require gavage feedings and may contribute to failure to thrive. The causes of failure to thrive may be multifactorial, but Nobuhora et al. (1996) noted that 30% of infants remained below the fifth percentile despite optimization of caloric intake; 68% of the patients in this group were ECMO survivors. Van Meers et al. (1993) also noted a high percentage (50%) of CDH survivors supported with ECMO who had failure to thrive. The incidence of FTT in the CDH registry is 85%. We consider nutrition one of the most important aspects of care for infants with CDH. If the baby is not growing then neither are the lungs, and neither is the pulmonary vasculature which can lead to chronic pulmonary hypertension. We routinely aim to provide 125-130 kcal/kg/day in nutritional support either by, fortifying formula, supplemental gavage feeding by NGT or G tube, or by supplemental TPN.
Gastroesophageal reflux may affect as many as 50% to 62% of diaphragmatic hernia survivors (Koot et al., 1993; Kieffer et al., 1995). While some have reported good response to medical therapy (Stolar et al., 1990), the need for antireflux surgery varied from 9.6% to 14.8% (Nagaya et al., 1994; Kieffer et al., 1995).
Musculoskeletal deformities, such as pectus excavatum and scoliosis, may also develop in survivors of diaphragmatic hernia. The cause of these deformities may be the asymmetric lung size, the diaphragmatic repair, or the increased work of breathing some patients may have. In the series reported by Nobuhora et al. (1996), the incidence of pectus excavatum was 21% and scoliosis was 10.5%.
The most worrisome finding is the incidence of neurodevelopmental delays, which may be present in up to 40% of survivors with CDH. While in general the risk of neurodevelopmental delay is thought to be proportional to the severity of the infant’s NICU course, this has not been proven.
- Genetics and Recurrence Risk
In recent years, there have been multiple lines of evidence that suggest that many cases of CDH may have a genetic etiology. These include: (1) recurring chromosome abnormalities in unrelated individuals that reveal CDH “hot spots”; (2) single gene disorders in which the causative gene is known and provides insight into pathways that are critical for diaphragmatic development; (3) multiple families in which CDH recurs (Pober, 2008).
For all fetuses in which a CDH is detected, a complete family history should be obtained and the parents should be examined. The first consideration should be whether the CDH is isolated or nonisolated. Anomalies such as pulmonary hypoplasia, bowel malrotation, patent ductus arteriosus, dextraposition of the heart, tricuspid or mitral valve regurgitation, or undescended testicles are considered to be mechanical or hemodynamic consequences of the CDH, so if present, they do not preclude a diagnosis of isolated CDH (Pober, 2008). A truly isolated CDH carries a multifactorial recurrence risk of at most 2% (Pollock and Hall, 1979; Norio et al., 1984).
All fetuses with CDH should have a minimum of a metaphase karyotype, and ideally, an array cGH study. If a chromosome abnormality is detected, the prognosis and recurrence risk will be those of the specific abnormality.
If associated anomalies are detected the prospective parents should meet with a medical geneticist. The single-gene disorders in which CDH is a major feature are listed in Table 37-1. If the geneticist suspects one of the conditions listed, DNA diagnosis is possible on amniocytes. Special note should be made of Fryns’ syndrome, an autosomal recessive condition that is commonly considered for fetuses with CDH (Moerman et al., 1988; Bamforth et al., 1989; Cunniff et al., 1990). The gene responsible for this condition is not known. For a diagnosis of Fryns syndrome to be made, Lin et al. (2005) propose that at least four of the following six findings are present: diaphragmatic defect, pulmonary hypoplasia, specific facial dysmorphic features, distal digital hypoplasia, and affected sibling, or “other anomalies” (typically, septal or conotruncal cardiac defects, renal cystic dysplasia, or agenesis of the corpus callosum). If a single-gene disorder is diagnosed, either by molecular testing or by physical examination of the neonate, the recurrence risk and prognosis are that of the condition.
In cases of perinatal loss, every attempt should be made to have autopsy studies performed to document the presence of additional anomalies not detected on sonographic examination. A follow-up meeting with a clinical geneticist is useful to summarize autopsy results and discuss possible genetic diagnoses. A fibroblast cell line should be established as a source of DNA for molecular studies. If karyotype and CGH analysis were not performed earlier, they should be done on cultured cells.
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Figure 1. Autopsy photograph demonstrating the shift of the heart to the right side of the chest and bilateral lung hypoplasia due to diaphragmatic hernia.
Figure 2 A. Coronal image of a fetus with a left congenital diaphragmatic hernia demonstrating the stomach in the left chest and the heart deviated into the right chest.
B. An axial image demonstrating the four-chamber view of the heart and adjacent herniated loops of bowel. (Reprinted, with permission, from Morin L, Crombleholme TM, Dalton ME. Prenatal diagnosis and management of fetal thoracic lesions. Semin Perinatol. 1994;18:228-253.)
Figure 3 A. Sagittal image of a fetus with a right congenital diaphragmatic hernia demonstrating the liver above the diaphragm.
B. An axial image demonstrating a right congenital diaphragmatic hernia with the liver filling the right fetal thorax and the heart deviated against the left chest wall.
Figure 4. Fetal MRI demonstrating a right diaphragmatic hernia; note the liver, gallbladder, and small intestine filling the right thorax and the stomach below the diaphragm.
Figure 5 A. Color flow Doppler images demonstrating normal course of sinus venosus on left.
B. ‘‘Kinked” sinus venosus on right in CDH.
Figure 6. Algorithm for the management of prenatally diagnosed CDH.
Figure 7. Intraoperative view of a fetus at 26 weeks of gestation undergoing fetal tracheal clip application. The fetal arms are retracted down through the hysterotomy and the head is extended within the uterus. The fetal neck is opened above the sternal notch to expose the fetal trachea.