Children's Hospital Colorado

Congenital Diaphragmatic Hernia (CDH)

Congenital Diaphragmatic Hernia (CDH) Medical IllustrationCongenital diaphragmatic hernia (CDH) is a defect in the diaphragm that occurs in approximately 1 in 2500 live births. The diaphragm is a dome-shaped muscular partition that separates the chest from the abdomen. The defect usually occurs early in pregnancy (9-10 weeks), but might occur as early as 5-6 weeks. The cause of CDH is unknown.  The defect in the diaphragm allows abdominal organs to enter the chest cavity thereby affecting fetal lung development. 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. CDH is either part of a genetic syndrome (trisomies 21, 18, and 13) in 10-20% or associated with other organ structure abnormalities (nonisolated) in approximately 40% of cases. CDH often is suspected in the second trimester if a fluid-filled stomach or other abdominal organs are seen within the chest. The position of the fetal liver is one of the most significant and reproducible independent prognostic factors, with liver herniation into the chest being predictive of poor outcome. The extent of pulmonary hypoplasia (incomplete development of the lungs) is the most important determinant of survival in CDH along with the severity of pulmonary hypertension (high blood pressure that affects the arteries in the lungs and the right side of the heart). Because CDH might be mistaken for other chest masses, the fetus should be evaluated in a center capable of performing a detailed fetal ultrasound, specialized ultrasound of the fetal heart (fetal echocardiography) as well as a fetal MRI.

For Patients

A congenital diaphragmatic hernia (CDH), also known as a diaphragm hernia, is a condition that develops when a baby’s diaphragm forms incorrectly at around 9 to 10 weeks gestation. The diaphragm is a muscular structure just below the lungs but above the contents of the abdomen that assists in breathing. It also helps keep the contents of the chest (lungs, heart) separate from the contents of the abdomen (liver, stomach, bowel, etc). CDH occurs when the diaphragm does not form correctly and it creates an opening between the chest cavity and abdominal cavity. This opening can allow the abdominal organs to “herniate” into the chest cavity causing problems for growth and development of the baby. Any abdominal organs can be misplaced in the chest in this situation with the most common being the bowel and stomach.

CDH can be diagnosed through a detailed ultrasound to examine for possible anomalies. Learn more about congenital diaphragmatic hernia treatment options below.

We understand that a CDH diagnosis for your child can be a stressful time for you and your family. The team at the Colorado Fetal Care Center is at the forefront of treatment for CDH, led by Dr. Timothy Crombleholme, a nationally recognized expert and leader in treating this condition. His approach to treatment, along with the help of our experienced team, has resulted in some of the highest CDH survival rates in the country.

A diaphragmatic hernia can cause several complications depending on the size and location of the opening. The most common complication is pulmonary hypoplasia, or underdeveloped lungs. This is a result of the abdominal contents (bowel, stomach, liver) putting pressure on the lungs that does not allow them to grow as they normally would.  Pulmonary hypoplasia can lead to a variety of ailments after birth, including pulmonary hypertension, or high blood pressure in the lungs, respiratory failure, feeding problems and developmental delays. In some cases the pulmonary hypoplasia can be significant enough to effect survival of the newborn.

CDH is rare, occurring in approximately 1 in every 2,500 births in the U.S., meaning about 1,600 cases are diagnosed annually. Of these cases, about 85-90% of the diaphragmatic hernias are located on the left side of the chest cavity, 10-15% on the right side and only 2% of the hernias centralized on the diaphragm.

Approximately 60% of the cases are isolated, with the remaining 40% being associated with other abnormal findings in the fetus (ie brain, heart, etc). CDH can be associated with genetic abnormalities especially when there are multiple abnormal findings.

Ready to learn more?

See below for answers to some of our most frequently asked questions and available treatment options at the Colorado Fetal Care Center.

Initial diagnosis of CDH in a fetus is performed using ultrasound. If it is diagnosed or suspected patients are usually referred to a center that specializes in the evaluation and eventual care of infants with CDH. This evaluation will likely include a more detailed ultrasound in order to best understand the significance of the diagnoses. Fetal Magnetic Resonance Imaging (MRI) and fetal echocardiogram can also be used in order to determine the extent of the CDH, evaluate for other abnormalities, and help determine the best treatment course. In addition, you will likely be offered an amniocentesis to evaluate the genetics of the fetus due to the association between genetic abnormalities and CDH. This is a procedure in which a small needle is guided into the amniotic cavity, under ultrasound guidance, and amniotic fluid is removed for testing.

There are different treatment options for Congenital Diaphragmatic Hernia. Learn about CDH repair & how the CFCC is at the forefront of caring for CDH babies.

Congenital Diaphragmatic Hernia Treatment Options

Congenital diaphragmatic hernia treatment involves providing breathing support while not damaging the lungs, which in some cases may require the use of extracorporeal membrane oxygenation, or ECMO. In cases that are severe, delivery using an EXIT to ECMO strategy may be used. This EXIT to ECMO procedure was pioneered by the Colorado Fetal Care Center Director Dr. Timothy Crombleholme, a nationally recognized expert and leader in treating CDH. The use of a multidisciplinary team is essential to the management of the complex patients. This approach has resulted in some of the highest congenital diaphragmatic hernia survival rates in the country.

While a congenital diaphragmatic hernia diagnosis for your baby feels life-changing, there are treatment options available that may help your child thrive, both before and after birth.

Treatment Option: ECMO

The Colorado Fetal Care Center is one of the nation’s top care centers for CDH care, including surgery in-utero and post-birth. Traditional care for this diagnosis has focused on care after delivery. This care can include infant breathing support, surgical closure of the diaphragmatic hernia, and intensive unit care. For severe cases, post-birth care may include the use of extracorporeal membrane oxygenation (ECMO), which is a machine that performs the function of the lungs while they are growing.

Treatment Option: FETO

The Colorado Fetal Care Center specializes in advanced techniques in caring for fetuses/newborns with CDC. For the most severe cases, Fetoscopic Endoluminal Balloon Tracheal Occlusion (FETO) may be recommended which can accelerate fetal lung growth.

Treatment Option: EXIT to ECMO

In addition, a specialized delivery referred to as an EXIT to ECMO procedure can be used. This procedure was pioneered by Colorado Fetal Care Center Director Dr. Timothy Crombleholme, a recognized expert in treating CDH.

Ready to learn more?

See below for answers to some of our most frequently asked questions, or read about successful surgeries through our patient stories.

What does it mean to be diagnosed with CDH?

CDH occurs when the diaphragm (the muscular structure that separates the chest contents (heart and lungs) from the abdominal contents (bowel, stomach, and liver) does not form correctly and it creates an opening between these two cavities. This opening can allow the abdominal organs to “herniate” into the chest cavity causing problems for growth and development of the baby. Any abdominal organs can be misplaced in the chest in this situation with the most common being the bowel and stomach.

What happens when my child has CDH?

The herniation of the abdominal contents into the chest cavity can cause underdevelopment of the lungs called pulmonary hypoplasia. This underdevelopment can cause significant breathing issues at birth and long term. Children with CDH require specialized care for the potential multiple medical complications of this condition. Care includes assistance with breathing, surgery to repair the CDH, and long term health care.

What if CDH is suspected during pregnancy?

Most cases of CDH can be diagnosed in utero using ultrasound.  If CDH is suspected then a specialist should evaluate the fetus with ultrasound to confirm the diagnosis.  The CFCC using cutting-edge technology combining fetal ultrasound, echocardiography, and fetal magnetic resonance imaging (MRI) to evaluate the severity of disease and therefore make recommendations for prenatal and postnatal care aimed at ensuring the best outcome possible.

What are the different types of CDH?

There are three different types or locations of the CDH based on which part of the diaphragm has the defect. The defect can be described as left-sided, right-sided, or central.

How serious is a CDH?

CDH is a significant diagnosis for your fetus or infant that will require specialized medical care. Consultation and care with experts in the evaluation and management of this diagnosis is important in order to ensure the best outlook possible.

What caused this?

CDH is an abnormality that forms during the embryonic period of development occurring in the 4th to 10th week of gestation. It is likely due to a failure of the pleuroperitoneal folds to close which leaves a deficit in the diaphragm. The diaphragm is a muscular structure that separates the contents of the chest/thorax (heart and lungs) from the abdominal contents (stomach, liver, bowel). It is also an important muscle for breathing.

Could this have been prevented?

There is no known way to prevent CDH from occurring.

Do I have to give up my plans for breastfeeding?

No you do not. Babies with CDH usually do not feed by mouth for the first several days to weeks of life however breast pumping and storing milk can be arranged and given to the baby once feeding can occur. Eventually, feeding at the breast may be possible. Breast milk contains important nutrients for the baby and therefore breast feeding is encouraged.

Do I need to have a C-section?

Not necessarily. Your full evaluation will include recommendations on mode of delivery aimed at optimizing initial outcomes. In some severe cases of CDH a C-section may be recommended.

For Healthcare Professionals

The evaluation of the fetus with suspected congenital diaphragmatic hernia (CDH) should include a detailed ultrasound examination to confirm the diagnosis and detect possible associated anomalies. Approximately 60% to 90% of cases of CDH are detected prenatally by sonography or MRI depending on the center reporting ascertainment. 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. 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. 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.

Congenital Diaphragmatic Hernia Sonogram

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. 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). 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).

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).

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, dextraposision of the heart, tricuspid or mitral valve regurgitation, or undescended 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 multifactoral recurrence risk of at most 2% (Pollack and Hall, 1979; Norio et al., 1984).

If associated anomalies are detected the prospective parents should meet with a medical geneticist. The single-gene disorder in which CDH is a major feature are listed in Table 1. If the geneticist suspects one of the conditions listed, DNA diagnosis is possible on amniocytes. Special note should be made of Fryns’ syndrome (Moerman et al., 1988; Bamforth et al., 1989; Cunniff et al., 1990).

cdh_how_do_we_diagnose_cdh_table_1

A congenital diaphragmatic hernia is thought to be due to failure of the pleuroperitoneal canal to close by 9 to 10 weeks of gestation.

  • Approximately 60% of cases are isolated and 40% are complex or syndromic.
  • Multiple sonographic and MRI techniques have been described to predict lung volume, which is an important predictor of survival. Liver position is also very important with regard to outcome.
  • In the most severe cases of congenital diaphragmatic hernia, therapeutic innovations such as fetal tracheal occlusion with a balloon which is removed prior to delivery or EXIT to ECMO may offer the best hope for survival.
  • All fetuses with a congenital diaphragmatic hernia should be delivered in a tertiary center with specific neonatal and surgical expertise in this condition and ECMO capability.
  • Cesarean section delivery is indicated only for standard obstetrical reasons or for ECMO standby.
  • Approximately a dozen single-gene disorders have a congenital diaphragmatic hernia as a major feature. With increased cytogenetic resolution through array cGH, more syndromic cases are being recognized as being associated with chromosome abnormality. Fetal karyotype is indicated in all cases.
  • Incidence is around 1 in 2200 with 85% to 90% being left sided, 10% to 15% right sides and 2% bilateral.

It was once thought that prenatal detection of CDH might improve 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. Reviews of prenatally diagnosed CDH, however, have consistently shown a 76 to 80% mortality rate despite this optimized approach to management (Adzick et al. 1981; Harrison et al. 1990, 1993a, 1993b, 1994; O’Rourke et al. 1984; Reynolds et al. 1984).

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. 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. These innovative strategies include reversible tracheal balloon occlusion (DePrest et. al 2007; 2008), EXIT-to-ECMO (Kunisaki et al. 2007), and aggressive management of pulmonary hypertension with off-label use of inhaled nitric oxide and inhaled prostacyclin (Lim et al. 2008). This aggressive management of pulmonary hypertension in CDH has resulted in 100% survival in isolated CDH with LHR > 1.0. Even with LHR ≤ the group at Cincinnati Children’s have observed a 50% survival and have reduced the need for ECMO to only 8% in patients not sufficiently severe for EXIT-to-ECMO.

CDHs remain among the most challenging congenital anomalies to manage despite advances in critical care, extracorporeal membrane oxygenation (ECMO) support, anti pulmonary hypertensive therapies, and prenatal tracheal occlusion. Although several prenatal prognostic factors have been reported such as long-to-head ratio (LHR) [1,2] observed to expected LHR [3], percentage predicted lung volumes (PPLV) [4], liver position [5], total lung volume (TLV) [6], and modified McGoon Index [7], no single prognostic variable adequately encompasses the broad range of severity, functional limitation and associated anomalies which may influence the prognosis.

The compelling rationale for an accurate prognostic stratification of CDH severity includes appropriate counseling of parents and likely outcomes. This will help define needs before delivery that may determine the site of delivery, indicate the need for alternative delivery options such as EXIT-to-ECMO, cesarean delivery with ECMO-standby, or in the most severe cases, consideration of fetal tracheal occlusion or comfort care only. Accurate risk stratification can also inform resuscitative efforts postnatally including initiation of more aggressive antipulmonary hypertensive management, or establishing a lower threshold to initiate ECMO support (Le et al., 2012).

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: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 congenital diaphragmatic hernia, 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. 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% (Harrison et al. 2003). The accuracy of the LHR described by Metkus et al. (1996) was validated in two subsequent 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. The 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 4-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 AP measurement is obtained perpendicular to this measurement. A second technique obtains the longest transverse measurement at the level of the 4-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 4-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. 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 (Crombleholme et al. 2009). These findings are in contrast to older reports of prognosis based on LHR which 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.

The graph on the left shows LHR values as a function of gestational age in normal fetusus demonstrating a progressive increase in LHR (Figure 1). The graph on the right demonstrates the effect of normalizing observed to expected LHR, creating a more linear effect as a function of gestational age (Figure 1).

CDH_OH_LHR_Figure-1.png

Between 12 and 32 weeks’ gestation, normal lung area increases four times more than head circumference (DePrest et al. 2008). For this reason, Jani et al. proposed referencing LHR to gestational age by expressing the observed LHR as a ratio to the expected mean LHR for that gestational age (Jani et al. 2007). In a study from the CDH antenatal registry, 3.54 fetuses with isolated left and right CDH between 18 and 38 weeks’, Jani et al. found that observed/predicted LHR predicated postnatal survival (Figure 2). The O/E LHR tended to be more accurate at 32 -33 weeks’ than at 22-23 weeks’ gestation. The O/E LHR was also found to correlate with short-term morbidity indicated (Jani et al. 2007).

CDH_OE_LHR_figure-2.png

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 34-35 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 non-survivors 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.

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. 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 hypertension at 3 weeks of age (Vuletin et al. 2009).

Cystic diseases of the chest, such as type I cystic adenomatoid malformation of the lung (CCAM), 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.

Donnell has developed a system for grading the severity of herniation in CDH.

PPLV

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 observed to expected fetal lung volume. 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 in what she termed the percent predicted lung volume (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.

CDH_PPLV_Figure-3.png

Total Lung Volume

In a study to determine if there is a correlation between late gestational fetal MRI-derived total lung volumes (TLV) and CDH outcomes it was concluded that when stratifying patients by TLV, patients with higher lung volumes had better survival and less need for ECMO support (Fig.5). Patients with a TLV of greater than 40 mL had a 90% survival, whereas patients with TLV of less than 20 mL had a 35% survival. In regard for the need for ECMO support, patients with a TLV of greater than 40mL have a much lower rate of ECMO support (10% need for ECMO) than patients who have TLV of less than 20 mL (86% need for ECMO). With this same type of analysis, there is also a significant difference in the TLV and the length of stay.

This study demonstrates that late gestation fetal MRI-derived TLV may provide useful information for the counseling of patients who have a fetus with an isolated CDH. In this study, a clear association was observed between lower TLVs at 32 to 34 weeks gestation and the need for ECMO support and an increased postnatal mortality. These findings may have clinical benefit, especially in those patients with no previous workup or a workup from an outside facility without the capability of obtaining prognostic measurements such as LHR or PPLV

The value of this data and its analysis is the ability to appropriately counsel expectant mothers in regard to the anticipated duration of the postnatal hospital course and postnatal outcomes (Lee et al. 2011).

cdh_pplv_figure_4.png
cdh_pplv_figure_5.png

In patients with CDH, abnormal persistence of elevated pulmonary vascular resistance in the form of pulmonary arterial hypertension (PAH) is recognized as one of the most important components of the pathophysiology of the disease. The evolution of pulmonary hypertension has been reported to be a critical determinant of the mortality and morbidity in CDH patients [3]. As a result of advances in prenatal imaging, biometric parameters used for risk stratification have been developed and survival rates are better predicted [4,5]. However, prenatal prognostic factors such as lung-to-head ratio (LHR), percent predicted lung volume (PPLV), and total lung volume (TLV) rely entirely on lung size or volume to predict the degree of pulmonary hypoplasia and do not necessarily correlate with the severity of pulmonary hypertension postnatally. In contrast, the prenatal pulmonary hypertension index (PPHI) and the modified McGoon index appear to better reflect the presence of suprasystemic pulmonary hypertension in newborns with CDH at 3 weeks of age postnatally. Diameters of the right pulmonary artery, left pulmonary artery (LPA), aorta, and the length of vermis of the cerebellum are obtained from prenatal magnetic resonance imaging to calculate the PPHI. The Modified McGoon Index (MGI) is obtained where (MGI) [=(diameter of the right pulmonary artery + diameter of left pulmonary artery/diameter of aorta]. PPHI and MGI were compared with LHR, PPLV, and TLV for pulmonary hypertension and survival. The PPHI and MGI had a significant correlation with the presence of pulmonary hypertension at 3 weeks of postnatal life. The PPHI and MGI are significantly lower in the group with systemic or suprasystemic pulmonary arterial pressures at 3 weeks of age. In contrast, lung to head ratio, percent predicted lung volume, and total lung volume could not distinguish CDH newborns that would be subsystemic or suprasystemic at 3 weeks of age. This study found that both PPHI and MGI accurately predict the severity of postnatal PAH in isolated left CDH (Crombleholme et al., 2010).

Presence of Sac in CDH

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). The presence of a hernia sac is a favorable prognostic finding as it limits the degree of visceral herniation and decreases the severity of pulmonary hypoplasia.

Liver Herniation Grading

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 el al., 2006; Hedrick et al., 2007; De Prest et al., 2009). Kinking of the sinus venosus is a reliable sign of left-sided CDH with herniated left lobe of the liver. In a retrospective review of 16 fetuses with left congenital diaphragmatic hernia, 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 is often 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 predictor if observed in a posterior or midthoracic location if the liver is herniated (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.

CDH CPI

Many prenatal prognostic indicators such as LHR, PPLV, TLV, modified McGoon Index, and liver position have each been individually used to predict survival and need to ECMO support [4,7-11]. However, these prognostic indicators measure different aspects of CDH. Lung-to-head ratio, TLV, and PPLV measure lung volume; the modified McGoon Index measures pulmonary arteries; the lack of liver herniation or presence of a sac is indicator of less visceral herniation. In addition, the impact of associated anomalies such as karyotype abnormalities, congenital heart defects, and presence of chest masses such as congenital pulmonary airway malformations and bronchopulmonary sequestrations are not factored into individual prognostic variables.

A composite prognostic index incorporates all known prognostic variables into a single composite index to improve prognostic accuracy. The use of the CDH-CPI may provide useful information for the counseling of parents with a fetus that has been diagnosed with an isolated left-sided CDH. There is a positive correlation between CDH-CPI score and survival. The CDH-CPI has a stronger degree of correlation than each of the individual parameters. This is probably because of the all-encompasing nature of this scoring index, which allows for more comprehensive prenatal counseling.

Of all of the prenatal prognostic studies, LHR is the only validated prenatal predictor of CDH outcome [1,2] but focuses purely on the lung hypoplasia component of the CDH with no significance given to the pulmonary hypertension, presence of genetic syndromes or the attributes of the hernia. Total lung volume [12] and PPLV [4] have shown promise in predicting survival but have only been examined in small case series and suffer from the same limitation as LHR of assessing only the lung hypoplasia component. The limitation of these measurements (LHR, TLV, PPLV) of lung hypoplasia is evident in the example of a fetus who may have a favorable LHR, but in light of a significant genetic syndrome or a significant cardiac defect, survival can potentially be greatly diminished. Significant heart defects can result in a 3-fold increase in mortality in patients with CDH [14]. Liver herniation has also shown to be useful as it not only addresses the attributes of the hernia but also is a surrogate marker for lung hypoplasia. The main advantage of the CDH-CPI is that it takes into account several aspects of the fetus’ overall state of health and severity of the CDH, from the genetic and cardiac perspective and further includes both assessment of the pulmonary hypoplasia and the significant pulmonary hypertension that can be associated with CDHs. This may account for the stronger correlation with survival of the CDH-CPI as compared with the other individual parameters. The CDH-CPI score may allow the surgeon to prenatally predict potential outcomes and appropriately counsel expectant mothers on severity and likely outcomes associated with CDH while potentially predicting the need for ECMO support. Such a tool may enable pediatric surgeons to objectively stratify patient and alter their delivery and postnatal strategy (Le et al., 2012).

TLV

There is data of noted trajectory of growth from the initial diagnosis to the 34 week evaluation that PPLV and TLV is predictive.

Most prognostic criteria are obtained at presentation between 20 and 26 weeks. However, we have found significant benefit to repeating the prognostic evaluation at 34 weeks gestation. As Rypen has noted, significant lung growth should occur. However, in CDH, the severity of the hypoplasia is reflected in limited lung growth. Recent studies suggest that late gestation fetal MRI-derived TLV may provide useful information for the counseling of patients who have a fetus with an isolated CDH. A clear association was observed between lower TLVs at 32 to 34 weeks gestation and the need for ECMO support and an increased postnatal mortality (Crombleholme et al., 2011).

Fetal MRI has been 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.

cdh_sonogram_flowchart

Late Gestation TLV and PPLV

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 hypertension at 3 weeks of age.

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 should be obtained. Prenatal karyotyping is indicated in all cases of CDH because of the high incidence of associated chromosomal anomalies (16 to 37% of cases) (Adzick et al. 1981; Puri et al. 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. Array cGH has also been recommended by some for all cases of prenatally diagnosed CDH due to limitations in completely ascertaining all anomalies in utero (Pober, 2008).

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 (Pober, 2008; Holder et al. 2007).

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, or LHR <1.0 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. 1995; 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 (<1.35). 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 (if available). At the time of publication, no FDA-approved device for fetal tracheal balloon occlusion was available in the United States, and tracheal occlusion is being offered in Europe. Several centers including UCSF and Cincinnati Children’s, are offering this therapy on an FDA-approved investigational device exemption. After 28 weeks of gestation, CDH is managed by conventional postnatal management or EXIT-to-ECMO.

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.

Even in isolated CDH, without cardiac or chromosomal abnormalities, there is a 10% incidence of intrauterine fetal demise during the 3rd trimester. Even in isolated CDH there is a predisposition to prematurity in CDH with an average gestational age at delivery of 36 weeks. This is likely a consequence of polyhydramnios predisposing to preterm labor and delivery. There are no data to support elective preterm delivery. However, elective induction or cesarean section at 38 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.

Compensatory lung growth and development are possible after congenital diaphragmatic hernia treatment and repair, but weeks or months may be required to achieve this. Postnatal support by ECMO is usually limited to two to six weeks, which may be an inadequate period of support for the most severely affected infants. It has been demonstrated experimentally that reduction and repair of the hernia in utero allows the lungs adequate time for compensatory growth. 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 a congenital diaphragmatic hernia were undertaken.

Although the survival rate with in utero repair of a congenital diaphragmatic hernia 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. 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.

It was recognized long ago that occlusion of the fetal trachea results in markedly enlarged and hyperplastic lungs. 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. Conversely, tracheal occlusion results in accelerated lung growth and pulmonary hyperplasia. 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. 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. The group at The Children’s Hospital of Philadelphia had similar problems when the procedure was performed at 28 weeks of gestation. 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 began performing tracheal occlusion by detachable endoluminal balloon placement.

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 fetal tracheal occlusion (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 currently in use in Europe is done using maternal percutaneous access under local or regional anesthesia with a single 3.3mm port and a balloon to occlude the trachea (DePrest et al. 2008). The balloon is inserted at 26 to 28 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 over 150 cases a survival rate with tracheal occlusion of 50-57% (DePrest et al. 2008). 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 of study 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. While no randomized trial comparing fetoscopic tracheal occlusion to conventional care is planned. The Eurofoetus study will soon begin randomizing patients to different gestational ages to determine the best timing of tracheal occlusion. In the United States, no center is currently offering FETO due to the lack of an FDA approved device. The only 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 is significantly lower.

The prenatal natural history of CDH has led to attempts to correct the diaphragmatic defect before birth, with some anecdotal success. It had been recognized in the physiology literature for decades that occlusion of the fetal trachea results in accelerated lung growth. This technique was applied in animal models of CDH, demonstrating that tracheal occlusion can correct the pulmonary hypoplasia associated with CDH (DiFiore et al., 1994; Hedrick et al., 1994). This work was quickly replicated in other laboratories and was pioneered in clinical application by Harrison and the University of California San Francisco (UCSF) group using open fetal surgical techniques to occlude the trachea (Harrison et al., 1996). The survival using an open fetal surgical approach, however, was disappointing, and fetoscopic techniques of tracheal occlusion were developed in hopes of avoiding the problems of preterm labor and complications from tocolytic agents associated with hysterotomy (Adzick et al., 1985b; Harrison et al. 1990; Flake et al., 2000). The fetoscopic techniques used for tracheal occlusion have evolved with growing experience by the UCSF and Eurofetus group.

Experimental and clinical data suggest that fetal endoscopic tracheal occlusion to induce lung growth may improve the outcome of severe congenital diaphragmatic hernia. Harrison and his team performed a randomized, controlled trial comparing fetal tracheal occlusion with standard postnatal care. The team concluded that tracheal occlusion did not improve survival or morbidity rates in this cohort of fetuses with congenital diaphragmatic hernia. (Harrison, MR et al. 2003).

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 the 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.

It was recognized long ago that occlusion of the fetal trachea results in markedly enlarged and hyperplastic lungs. This observation was applied to the problem of diaphragmatic hernia. Throughout gestation the fetal lunch 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. 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 on survivor in the initial series of patients treated by tracheal occlusion. The group at Children’s Hospital Philadelphia had similar problems when the procedure was performed at 28 weeks of gestation. 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 gestation (Flake et al., 2000).

Eurofetus Experience

The Eurofetus group reports that in their experience of more than 210 cases a survival rate with tracheal occlusion of 49% (DePrest et al., 2009). The Eurofetus study will soon begin randomizing patients to different gestational ages to determine the best timing of tracheal occlusion.

TOTAL Trial

The TOTAL Trial investigates the potential advantages of intervention before birth in patients with either moderate or severe lung hypoplasia associated with CDH. This clinical trial that looks into the potential added value of treating babies with isolated CDH and moderate to severe lung hypoplasia prior to birth.

The hope is that treatment before birth makes the lung grow enough to decrease this risk of postnatal demise and prolonged oxygen needs. The study is based on previous experience with babies with severe diaphragmatic hernia, in which postnatal outcome seems to improve by the prenatal placement of a balloon in the wind-pipe (trachea). This balloon stops lung fluid from flowing from the lung towards the amniotic cavity and produces in this way an increase in pulmonary pressure leading to lung growth. In babies with severe CDH, the prenatal therapy increased postnatal survival and decreased the need for prolonged oxygen administration as compared to a group of historical controls of babies with severe CDH that didn’t undergo fetal surgery.

The study is officially called “RANDOMIZED TRIAL OF FETOSCOPIC ENDOLUMINAL TRACHEAL OCCLUSION (FETO) VERSUS EXPECTANT MANAGEMENT DURING PREGNANCY IN FETUSES WITH LEFT SIDED AND ISOLATED CONGENITAL DIAPHRAGMATIC HERNIA AND MODERATE PULMONARY HYPOPLASIA”. The acronym used is ‘TOTAL’ (Tracheal Occlusion To Accelerate Lung growth).

For information regarding the TOTAL trial, visit their website at http://www.totaltrial.eu/?id=12.

No FDA Approval on Balloon

In the United States, no center is currently offering FETO due to lack of an FDA-approved device. The only fetal surgery offered for high-risk CDH is EXIT-to-ECMO. Recently, centers in the United States including Colorado Fetal Care Center, CHOP, UCSF, Texas Children’s and Toronto have obtained an investigational device exemption (IDE) to perform fetoscopic tracheal occlusion in cases of severe CDH with liver herniation and a lung/head ratio (LHR) of <1.0 between 26 and 28 weeks’ gestation.

In the most severe cases of CDH, significant hypoxemia, hypercarbia, barotraumas, hemodynamic instability or death can occur before advanced therapies such as extracorporeal membrane oxygenation (ECMO) can be initiated. The very first EXIT-to-ECMO was preformed by Dr. Timothy Crombleholme and colleagues at CHOP for an infant with severe left CDH, (LHR 0.75) and associated Tetralogy of Fallot. Previous work by Cohen and Crombleholme had shown that chances of survival with CDH and CHD were poor if the LHR was <1.2 and that the chances that the infant would avoid an ECMO run were poor. The rationale for EXIT-to-ECMO in CDH is that it allows a seamless transition from prenatal to postnatal life without asking the newborn lungs and newborn pulmonary arterial bed to function before they are able to do so. EXIT-to-ECMO eliminates the stress to the infant of the newborn resuscitation, eliminates risk of volutrauma or barotrauma by minimizing the ventilator support to “rest settings” only. The infant is never hemodynamically unstable, never hypoxic, never hypertensive and makes a smooth transition to postnatal life allowing days to weeks to undergo vascular remodeling and progressive improvements of pulmonary hypertension. Typically in high risk CDH treatment by ECMO would reduce the herniated viscera and repair the diaphragm as soon as coagulation status of the newborn on ECMO was stable. This decompresses the hypoplastic lungs, allowing them to expand and encourages vascular remodeling to proceed. This does not happen if the lungs are completely atelectatic.

Kunisaki et al reported the first series of CDH patients managed by EXIT-to-ECMO. This was a heterogeneous group of fetuses with CDH, some with congenital heart disease that were by current standards not very severe. They had to have liver herniation, but an LHR < 1.4 and a percent predictive lung volume of 15%. All 14 fetuses had a trial of ventilation while on placental support. Three passed the trial of ventilation with preductal oxygen saturation >90%. The remaining 11 patients were managed by EXIT-to-ECMO, 4 of which also had congenital heart disease. Seven of 11 had VA ECMO 4 had VV ECMO. The survival among the EXIT-to-ECMO group was 64%.

This same group published a follow up report in 2012 describing these their subsequent experience from 2005 to 2010 in which they identified 17 patients requiring ECMO support that had a PPLV < 15%. Only 6 patients (3 had congenital heart disease, 2 ASDs and 1 HLHS) had EXIT-to-ECMO and only 2 out of 6 survived versus 50% in those managed conventionally. This series is very small and half the EXIT-to-ECMO patients had CHD and CDH which confounds the interpretation.

Crombleholme et al reported a prospective series of 19 cases of isolated CDH of an extremely severe group of patients that had large volume of liver herniation, LHR<1.0, O/E LHR<25%, PPLV<15, TLV<18 ml, with normal karyotype and no other associated anomalies. In contrast to the report by Steffan et al, Crombleholme reported a 50% survival for the 8 EXIT-to-ECMO group but only a 20% survival among those who were managed without EXIT. Two of these fetuses died in the delivery room, the remainder ended up on ECMO. Among the EXIT-to-ECMO group 3 of 4 non survivors had postmortem examinations demonstrating pulmonary pathology incompatible with life.

It is noteworthy that the series reported by Crombleholme met the criteria being used by Eurofetus centers for balloon tracheal occlusion. In these patient the survival was 49% versus 20% for those managed conventionally.

While EXIT-to-ECMO remains a therapeutic innovation that is yet to be proven to be superior than conventional therapy, we continue to offer EXIT-to-ECMO in these highly selected patients with CDH in which the families have been counseled regarding all available data.

In addition to EXIT-to-ECMO we also offer delivery with ECMO standby. In our previous experience the survival in this category had been ~35% between conventional delivery and EXIT-to-ECMO. In CDH patients in this high risk category the option for families to consider would be 1) participation in the Tracheal Occlusion to accelerate lung growth trial (when enrollment opens and if they meet criteria) 2) delivery with ECMO standby; and EXIT-to-ECMO.

The team at Boston Children’s examined the use of the ex utero intrapartum treatment (EXIT) to ECMO procedure (EXIT with placement on ECMO) in high-risk infants and reported a survival advantage.

EXIT-to-ECMO

In preliminary results reported by Kunisaki et al. (2007), fetuses with liver herniation and PPLV of <20% are offered EXIT-to-ECMO, with a 65% survival.

Prior to an EXIT procedure, mothers should be counseled about the possibility that future pregnancies would require cesarean delivery.

Every patient with less than 15% predicted lung volume during January 2005 to December 2010 was included. They obtained data on prenatal imaging, size and location of the defect, and survival. Seventeen high-risk infants were identified. All 17 (100%) received ECMO and required a patch. Six children were delivered by EXIT to ECMO, and only 2 (33%) survived. An additional patient was delivered by EXIT to intubation with ECMO on standby and died. Of the 10 children who did not receive EXIT, 5 (50%) survived.

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 (<1.35). 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 (if available). After 28 weeks of gestation, CDH is managed by conventional postnatal management or EXIT-to-ECMO.

All fetuses with CDH are at high risk for severe pulmonary hypoplasia and are optimally managed by delivery in a perinatal center with dedicated neonatal and pediatric surgical expertise in CDH immediately available, with ECMO capability (Harrision et al., 1990; Marwan and Crombleholme, 2006). In our institution we have a CDH Team that manages all patients with CDH from prenatal diagnosis.

8 Pillars of CDH Management

Over a period of 20 years informed by experience with the care of hundreds of infants with CDH we have developed the following principles of management of CDH which have resulted in progressive increases in survival and decreases in requirement for ECMO support.

I. Gentilation

The ventilatory strategy of “permissive hypercapnia” initially developed for the management of extremely premature infants, has also been applied to the management of CDH. It is now widely recognized that either excessive pressure or excessive volume can result in barotrauma or volutrauma respectively. It is also now clear that increasing ventilatory setting to injurious levels does not improve survival and can increase the incidence and severity of chronic lung disease in those who do survive. In addition, it is now recognized that elevated pCO2 is often due to severe pulmonary hypertension which decreases lung perfusion and limits gas exchange which will not respond to increasing ventilatory settings. The concept of “permissive hypercapnia” in CDH management is that the pCO2 is allowed to rise as high as 65 as long as systemic perfusion remains good and there is no production of acid in the periphery. A lower pH to ~7.25 is also tolerated as the rise in pCO2 will drop the pH.

Commonly used limits for both pressure or volume controlled ventilation is a peak inspiratory pressure (PIP) of < 25. There are no defined pressure limits in the use of high frequency oscillatory ventilation, but the minimal mean airway pressure commensurate with good lung expansion with mean airway pressure in the range of 12 to 15 are commonly used. The Delta P is set to achieve good chest wall jiggle and can be increased to address hypercapnia that is out of gentilation range. The frequency of oscillation similarly can be dropped to increase CO2 clearance.

Bi-Vent or APRV is another ventilatory strategy that may be particularly affective in CDH when the compression of the lung may prevent recruitment. This mode of ventilation allows higher mean airway pressure but significantly lower peak inspiratory pressure. Due to the high mean airway pressure this mode of ventilation is better at recruiting atelectatic lung and stent open the trachea and bronchi which may be malacic secondary to compression in utero.

II. Treatment of Pulmonary Hypertension

We now have many more tools to treat pulmonary hypertension in CDH than ever before. The causes of pulmonary hypertension in CDH are related to both the pruning of pulmonary vascular bed (“fixed”) and excessive muscularization of the pulmonary arterial bed (“dynamic”) down to the preacinar capillary bed. The “fixed” component of pulmonary hypertension does not respond to vasodilators and can only be improved through lung growth and remodeling over time. The excessive muscularization of the pulmonary vasculature is the anatomic correlate of the “dynamic” reactive nature of the pulmonary vascular bed which can be responsive to pulmonary arterial vasodilation therapy.

There are multiple agents that can be helpful in managing pulmonary hypertension. Oxygen itself can be a potent vasodilator and is important in the management of CDH. Once adequate pulmonary recruitment has been achieved, inhaled nitric oxide can be initiated which not only will vasodilate the pulmonary vascular bed but this is evidence that it enhances apoptosis of pulmonary vascular smooth muscle cells facilitating pulmonary vascular remodeling. Another very potent pulmonary vascular nasodilator is inhaled epoprostenol or Flolan. Although originally an intravenous medication it causes such profound systemic hypotension its use in CDH is limited. In contrast, inhaled Flolan has little to no effect on systemic blood pressure. Because Flolan works by different mechanism than inhaled iNO and these agents may be complementary in their effects. In addition, intravenous sildenafil can also be used to enhance pulmonary vasodilation. However this agent functions by the same mechanism as inhaled NO. In the use of all of these agents it is important to achieve good lung recruitment otherwise V/Q mismatch will be increased and intrapulmonary shunt will increase and hypoxia will result.

III. Echocardiography

It is near impossible to manage CDH without serial echocardiographic assessment. The echocardiogram can assess the severity of pulmonary hypertension, the estimate RV pressure and determine the degree and direction of shunt at the ductus arteriosus and the atrial levels. The echocardiogram can also assess the function of the RV and LVin the face of severe pulmonary hypertension or less commonly LV dysfunction. The echocardiogram can also be used to assess the pulmonary vascular response to inhaled iNO or iFlolan and in assessment of acute clinical deterioration which can occur for example with premature closure of the ductus arteriosus.

IV. Inotropic Support

It is not uncommon for newborns with CDH to be hypotensive which may initially respond to fluid boluses. However, excess fluid resuscitation must be avoided and after one or two small fluid challenges pressors should be initiated. Our first line choice is dopamine at doses limited to <10 mg/kg/min followed by epinephrine which is both a chronotropic and an inotropic agent. In the face of severe pulmonary hypertension we routinely use milrinome to help support RV function. If there is not the desired response, stress doses of steroids should be started as these fetuses are often relatively hypoadrenal. Vasopressin is initiated in instances of inotrope resistant hypotension despite epinephrine doses of 0.5 mg/kg/min. Serum sodium levels must be followed closely as profound hyponatremia may result with use of vasopressin.

V. Delayed Repair of CDH

Years ago it was thought that repair of CDH was an emergency that should be performed within hours of birth. It was recognized that this adversely affected the baby and often precipitated hemodynamic and ventilatory instability. More recently most centers adopted a strategy of repairing the CDH between 3 and 5 days when the infant appeared to have stabilized. However, this is a subjective assessment and in most cases these infants will have pulmonary pressures that are equivalent to systemic pressure. In this setting even minor noxious stimuli from operative care perpetuate an acute pulmonary hypertensive crisis.

We have taken the approach that the operative repair should only be conducted once the pulmonary arterial pressure estimated by echocardiography is < 80% of systemic. In mild to moderate CDH this may well occur within 3 to 5 days. But in moderate or severe CDH this may take 10 to 14 days or longer. In some very severe cases we have waited up to 56 days to repair the CDH based on severity of pulmonary hypertension. The obvious exception to this are cases in which there is a large USD or very large PDA in which equalization of systemic and pulmonary pressures occurs. Since implementing this criteria for repair we have not had a single case that became unstable after CDH repair requiring escalation of care or initiation of ECMO.

The one exception to this approach is in cases which go on ECMO. In these cases we favor earlier repair to decompress the chest to favor lung recruitment to allow vascular remodeling to proceed which does not happen if the lungs remain atelectatic.

VI. Airway Assessment

We now know that up to 5% to 10% of CDH infants will have some degree of tracheomalacia or bronchomalacia due to compression by herniated viscera in utero. The reason this is important is that collapse of the airway will exacerbate pulmonary hypertension, prevent response to vasodilators, and most importantly will prevent vascular remodeling of pulmonary arterial muscularization preventing a fall in pulmonary arterial blood pressures. If the anticipated improvement in pulmonary arterial hypertension does not occur, bronchoscopy should be performed to exclude the potentially confounding problem of tracheomalacia or bronchomalacia. This can easily be treated by modest levels of positive end expiratory pressure in the range of 6-10 cm H2O. This amount of PEEP required can be determined by the use of a PEEP grid which calculates the TV and compliance at each level of PEEP between 5 and 12 to determine the optimal stenting of the airway. In these cases, adequate PEEP can have a dramatic effect on pulmonary hypertension.

VII. Cardiac Catheterization

It is important to recognize that estimates of pulmonary arterial pressure made by echocardiography are estimates only and determined from the velocity of the tricuspid regurgitant jet. If an infant with CDH has persistence of systemic level of pulmonary hypertension to 3 weeks of age without an obvious source such as tracheomalacia, the baby should be considered for cardiac catheterization. This allows direct measurement of pulmonary artery pressures and can exclude anatomic reasons for persistent pulmonary hypertension such as kinking of pulmonary veins. In addition, response to vasodilators such as O2, iNO, iFlolan and IV Sildenafil can be assessed. In a series of 15 cases of refractory pulmonary hypertension at 3 weeks of age cardiac catheterization changed the management in all 15 cases based on findings at cath.

VIII. Nutrition

In data from the CDH registry, 85% of infants with CDH experience growth failure. We have taken a very aggressive approach to nutrition providing a minimum of 125 kcal/kg/day in enteral nutrition. This is initiated as soon as the gut is available for feeding by transpyloric feeding tube placed at the time of surgical repair . Once the infant has a pattern of sustained growth the transpyloric tube is pulled back to gastric position. Virtually all cases of CDH will have significant gastroesophageal reflux and will require antireflux medications and over half will require antireflux surgery. If the infant does not tolerate gastric feedings we proceed to Nissen fundoplication.

The reason for this aggressive approach to GERD in CDH is not just the high incidence of growth failure. If the infant is not growing neither are the lungs and compensatory lung growth that normally would occur during the first year of life, doesn’t occur or does so at a much reduced rate. In addition, the hypoplastic lungs will not tolerate an aspiration episode should it occur and these infants do not tolerate pneumonia well.

The Colorado Fetal Care Center's Congenital Diaphragmatic Hernia (CDH) team was formed in 2010, with its objective to improve outcomes and care for infants with CDH. The team is comprised of members from multiple disciplines including doctors from newborn intensive care, pediatric surgery, cardiology, cardiac surgery and maternal fetal medicine, X-rays specialists, and pediatric and cardiac anesthesia. This team of specialists provides continuity of care by seeing expectant mother prior to giving birth, while the baby is in the hospital, and after patients have gone home.

Congenital Diaphragmatic Hernia Treatment

There are different severities of congenital diaphragmatic hernia that can be determined before childbirth. For this reason, the CDH team provides comprehensive evaluations while the baby is still in the womb, using MRI and ultrasound to determine the CDH severity before birth and develop individualized care plans for each specific baby. CDH team members attend all deliveries and provide advice and continuity to the primary team throughout the hospitalization. These guidelines for care were developed and provide for earlier removal of central lines and breathing tubes, which resulted in decreased hospital acquired infection and illness, strategies to prevent lung injury while on the ventilator, and the use of the babies own tissue to avoind the need for prosthetic implants.

After discharge patients are seen in a CDH follow up program, which exists as part of the Congenital Diaphragmatic Herni team and uses the core team to provide continuity of care in the outpatient setting. This ensures a smooth transition to the outpatient setting and a close assessment of long and short-term problems including breathing problems, high blood pressure in the lungs (pulmonary hypertension), swallowing problems, reflux and developmental outcomes, screening for long term problems related to congenital diaphragmatic hernia including curvature of the spine (scoliosis) and hearing loss.

Transporting Congenital Diaphragmatic Hernia patients

For infants born at other hospitals, a CDH team member accompanies the newborn transport team for all congenital diaphragmatic hernia transports. The use of specialized respirators, including high frequency oscillation and medicines to relax the blood vessels in the lung while in transport, has allowed for optimal state of the art care to be implemented prior to arrival at the Children’s Hospital Colorado and improved survival and outcomes for infants born at outside institutions.

Congenital Diaphragmatic Hernia Cases and ECMO

Integral to any CDH program is the ability to safely use the heart lung machine (ECMO). The heart lung bypass (ECMO) program at Children’s Hospital Colorado has received recognition as an ECMO center of excellence, an honor bestowed upon only the top programs in the USA. The CDH team meets regularly to discuss the quality of care, difficult cases and guidelines for care. There is close collaboration and discussion with other specialized programs at Children’s Hospital Colorado (pulmonary hypertension, cardiology and the ventilator care program), which has allowed for a holistic approach to CDH and its associated complications.  The multidisciplinary team and continuity of care for CDH at Children’s Hospital Colorado has improved the survival for babies with CDH from 72% to 93%, one of the highest survival rates in the country.

Finally Children’s Hospital Colorado is also a member of the Children’s Hospital Neonatal Consortium, where bimonthly meetings are held by teleconference and treatment approaches, protocols and outcomes are contrasted between member centers. These meetings ensure that we are providing state of the art care and that our outcomes exceed the national standard.

The Colorado Fetal Care Center's CDH Team

A interdisciplinary team approach, in conjunction with regular local and national discussion around the care of infants with CDH, makes Children’s Hospital Colorado a national leader in the care of infants with congenital diaphragmatic hernia.

Timothy Crombleholme, MD

A nationally and internationally recognized expert in the prenatal diagnosis and management of CDH with over 20 years of experience treating over 400 cases of CDH. Dr. Crombleholme has pioneered fetal prognostic indicators such as PPHI, the MGI and the CDH-CPI and developed innovative fetal treatment approaches such as EXIT-to-ECMO.

John Kinsella, MD

A nationally and internationally renowned Neonatologist who pioneered the use of inhaled NO in CDH and is a recognized expert in pulmonary hypertension and the use of high frequency oscillatory ventilation.

Jason Gien, MD

A Neonatologist whose major clinical and research interest is in the care and management of CDH.

Stephen Abman, MD

One of the world’s leading experts in pulmonary hypertension and has pioneered the use of inhaled NO and other treatments for pulmonary hypertension.

Dunbar Ivy, MD

The Chief of Cardiology and is a recognized expert in pulmonary hypertension.

The members of the CDH team collaborate on every aspect of the evaluation and treatment of all CDH patients seen in the Colorado Fetal Care Center. The CDH team collaborates on the hour to hour management of all CDH patients with the Neonatal and Surgical teams.

CDH Management

All patients are managed by the same CDH team protocols including aggressive managements of pulmonary hypertension with inhaled NO and inhaled epoprostenol (Flolan), a “gentilation” strategy using bivent and high frequency oscillatory ventilation. The CFCC advances a very aggressive approach to nutritional management.

The average gestational age at delivery is 36 weeks, but ideally the team would like to get to 38 weeks gestation. There is a 10% risk of intrauterine fetal demise during the third trimester even in cases with no other abnormalities except the CDH. For this reason the team recommends NSTs and BPP beginning at 30 weeks gestation. There is no reason to deliver by Cesarean section except for obstetrical indications. The team routinely recommends that the delivery be planned for 38 weeks either by induction of labor or by Cesarean section.

The team will routinely reassess the prognosis at 34 weeks' gestation by repeating the MRI for total lung volume, PPLV , and the modified McGoon index. If the Prognostic Profile is in the most severe category then EXIT-to-ECMO may be an option. We reserve this option for the most severe cases with PPLV< 15%, TLV < 18 ml with liver up. For patients from great distances or from out of state we work with the referring physician to coordinate and transition care to Denver at a gestational age that depends on the Obstetrical history, cervical status, and risk of preterm labor. Usually this gestational age is between 34 and 36 weeks.

Immediately following delivery, a breathing tube is inserted, and a nasogastric tube is inserted to decompress the stomach and bowel and the infant is started on inhaled nitric oxide as a pulmonary vasodilator. The CDH babies are urgently transported to the NICU and assessed by echocardiography for the severity of pulmonary hypertension and indication for additional vasodilator such as inhaled nitric oxide and/or prostacycline. The combination of "gentliation" along with aggressive management of the pulmonary hypertension is the acute goal of care. ECMO is available as a back up for infants unresponsive to standard CDH medical therapy.

Physicians recommend that an amniocentesis be done for a full karyotype and microarray analysis due to the CDH, SUA, and growth restriction. The baby be examined postnatally by a Geneticist to rule out the small possibility of an associated syndrome which might not be seen on prenatal imaging in CDH. All babies with CDH at Children's Hospital Colorado are managed by the multidisciplinary CDH Team, including Neonatology, Surgeons, and Cardiologists. We use protocols that have markedly increased survival of babies with CDH that include aggressive management of pulmonary hypertension including the use of inhaled nitric oxide and inhaled prostacyclin. We transition to oral sildenafil once the baby is tolerating feedings. We routinely wait until the pulmonary hypertension has improved and is reduced to less than 80% of systemic blood pressure prior to surgical repair of defect. In the absence of liver herniation it is possible that there is enough diaphragmatic tissue to perform a primary repair of the diaphragm. Large diaphragmatic defects require a patch repair either with Gortex or with a transversus abdominus muscle flap. We favor the use of the transversus abdominus muscle flap as it has a lower risk of infection and recurrent herniation.

Once the defect is repaired the next phase of care is focused on growth and nutrition. The CDH Registry data shows that almost 85% of CDH babies have growth failure but we employ an aggressive approach to nutrition as well as the use of Nissen fundoplication to prevent severe gastroesophageal reflux which is often associated with CDH. The CDH babies are at risk for long-term problems including neurodevelopmental delay, visual or auditory problems as well as delayed motor skills. For this reason we recommend that all of these babies be followed in our High Risk Clinic.

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