To produce a functional diaphragm, the morphogenesis of the muscle, muscle connective tissue, and tendons derived from the different embryonic sources must all coordinate with each other and with the nerves and vasculature that innervate it. CDH arises when there is an error in any part of this process, leading to a weakened or incomplete diaphragm that permits abdominal contents to herniate into the thoracic cavity.

It is unclear which tissue of the developing diaphragm is responsible for the defect; for example, immunofluorescent studies suggest that mutations are predominantly expressed in nonmuscle cells of the PPFs. Additionally, failure of diaphragm development may be a result of defects in the proliferation and/or survival of myogenic progenitors, aberrant migration of myogenic cells, or defects in muscle differentiation. Finally, the fact that only small, variable regions of the diaphragm are affected suggests that it could be due to local changes in levels, timing, or site of gene expression during development.

While much is still unknown, newer animal models have helped develop better understanding of this process. One study suggests that the role of the PPFs and a specific subset of PPF-derived muscle connective tissue fibroblasts is critical in the development of CDH. With mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells was found to control diaphragm morphogenesis. In this model, mice with mutated Gata4 strongly expressed in the PPFs universally developed diaphragmatic hernias. Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax. The herniated tissue was shown to physically impede lung development, although mutations in Gata4 also have a primary effect on lung development, further supporting the dual-hit hypothesis. Therefore, this investigation identified a critical role of the PPFs and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic and pulmonary development ( Fig. 22.3 ).

Model of CDH development.

Data support a model whereby CDH arises from early genetic mutations in a subset of PPF-derived muscle connective tissue fibroblasts (A; mutant fibroblasts are yellow, wild-type fibroblasts are green ). Mutant fibroblasts clonally expand and inhibit muscle progenitors from developing in these regions (via decreased proliferation and increased apoptosis of muscle progenitors), resulting in local regions (shown in yellow ) that are amuscular but contain connective tissue fibroblasts and their associated extracellular matrix (B–D). Amuscular regions are thinner and more compliant than surrounding thicker and stiffer muscularized diaphragm and allow herniation of abdominal contents into the thoracic cavity (D, E).

E , Developing aorta, vena cava, and esophagus; NT , neural tube; PPF , pleuroperitoneal fold; so , somite; ST , septum transversum.

Rights reserved ; Reference Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat Genet . 2015;47(5):496–504.

Other studies suggest that the retinoic acid pathway plays a key role in diaphragmatic development and altering various points in this pathway will create defects similar to those seen in CDH. Suppression of retinaldehyde dehydrogenase-2 (RALDH2), a critical enzyme responsible for retinoic acid synthesis, leads to the manifestation of diaphragmatic defects. Additionally, Vitamin A-deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH.22 Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Nitrofen is a diphenyl ether herbicide that readily crosses the placenta and accumulates in the fetus causing cardiopulmonary and diaphragmatic defects. Data suggest this teratogen works by inhibiting the proper synthesis of retinoic acid. Plasma levels of retinoic acid and retinol-binding protein in infants with CDH are lower in concentration compared to controls.

Diaphragmatic defects can be classified by either posterolateral defects, known as “Bochdalek” defects, or as anterior defects, known as “Morgagni” defects ( Fig. 22.4 ). Morgagni hernias typically make up 2%–5% of all congenital diaphragmatic hernias. They result from failure of fusion of the crural and sternal portions of the diaphragm. This can occur on either side at the junction of the septum transversum and thoracic wall where the superior epigastric artery (internal mammary artery, intrathoracically) traverses the diaphragm. These are usually anterior midline defects. Typically, a hernia sac is present and may contain omentum, small intestine, and/or colon, though these hernias can contain liver and/or spleen. Morgagni hernias carry a high incidence of associated anomalies, namely congenital heart disease and Down syndrome. Most children with a Morgagni hernia are asymptomatic and are rarely diagnosed during the neonatal period. Symptoms, if present, typically include respiratory distress in infants, recurring lung infections, or general epigastric discomfort or vomiting due to intermittent obstruction. ^, They can be associated with pentalogy of Cantrell due to a failure in the development of the septum transversum. Pentalogy of Cantrell is a rare cluster of five congenital midline anomalies that includes defects in the abdominal wall (i.e., omphalocele), pericardium, sternum, intrinsic cardiac abnormalities, and a diaphragmatic defect. The cardiac defect is the most severe problem and is the main cause of mortality.

Morgagni versus Bochdalek hernias.

Morgagni hernias are found in the anterior diaphragm while Bochdalek hernia are found typically in the left posterior-lateral diaphragm.

Bochdalek hernias are posterolateral and are the classic congenital diaphragmatic hernia. These defects allow the herniation of abdominal contents into the chest creating the cascade of complications associated with CDH. These defects are typically on the left, but can be found on the right, and can range in size. They are the focus of most CDH research due to their far more profound physiologic compromise compared to Morgagni hernias or diaphragmatic eventrations.

The CDH Study Group (CDHSG) has shown that the size of the diaphragmatic defect is a major factor influencing the outcome of infants with CDH and is a major independent risk factor associated with mortality. To better risk stratify these patients, the CDHSG created an objective grading system to classify the defects identified at the time of operation. These defects are classified from A to D. Defect A is the smallest defect that consists of a mostly intact hemidiaphragm and is often completely intramuscular, though it may involve less than 10% of the chest wall. Defect B is a defect that involves 50%–75% of the hemidiaphragm and less than half of the circumference of the chest wall is affected. Defect C is a defect where approximately 25% of the hemidiaphragm is present but more than half of the chest wall is involved in the defect. Defect D is the largest defect and has minimal or no diaphragm present, affecting most of the chest wall. This condition has been previously referred to as agenesis ( Fig. 22.5 ).

CDHSG diaphragm defect staging system.

A left diaphragmatic defect is shown as viewed from the peritoneal cavity looking toward the hemithorax. Defects are classified as:

Defect A: Smallest defect, usually intramuscular defect with >90% of the hemidiaphragm present; this defect involves <10% of the circumference of the chest wall.

Defect B : 50%–75% hemidiaphragm present; this defect involves <50% of the chest wall.

Defect C : <50% hemidiaphragm present; this defect involves >50% of the chest wall.

Defect D : Largest defect (previously known as agenesis); complete or near-complete absence of the diaphragm with <10% hemidiaphragm present; this defect involves >90% of the chest wall. Surgically, it is an absent posterior rim beyond the spine, absent posterior-lateral rim, and an anterior/anterior-medial rim, which is miniscule. As it is truly unusual to have zero tissue at all, this is the CDHSG member consensus. “D” defects should all require a patch (or muscle flap) for repair.

Rights reserved; Reference Lally KP, Lasky RE, Lally PA, et al. Standardized reporting for congenital diaphragmatic hernia–an international consensus. J Pediatr Surg . 2013(48):2408–2415.

These defects are unique compared to a diaphragmatic eventration, which is an abnormal elevation of the diaphragm, resulting from diminished muscle or nerve function with normal anatomic relationships, leading to a paradoxical motion during respiration and interferes with normal pulmonary mechanics and function. ^, Congenital eventration usually results from the incomplete development of the central tendon or muscular portion of the diaphragm. While commonly left-sided, bilateral congenital eventrations have been described. The diaphragm muscle is typically present but does not move in a coordinated fashion. Large eventrations can interfere with lung development due to the paradoxical motion and decreased thoracic space. Similar to CDH, congenital eventration can result in lung hypoplasia, although this is uncommon and/or less severe ( Fig. 22.6 ).

Fetal MRI.

Fetal MR image of a left-sided CDH at 28 weeks’ gestation. A large CDH with herniation of the small bowel and stomach is found within the left hemithorax ( large arrow ). There is dextroposition of the fetal heart ( small arrow ). There is no evidence of liver herniation.

Courtesy Holcomb G, Murphy, JP, Peter, SD. Holcomb and Ashcraft’s pediatric surgery. In: Harting M, Hollinger, LE, Lally, KP, eds. Congenital Diaphragmatic Hernia and Eventration . 7th ed.: Elsevier; 2020:377–402.

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

Malformations in any of these stages can contribute to the physiology seen with CDH. During the embryonic stage, or organogenesis phases, a mutation can lead to abnormal lung bud formation, abnormal tracheal/esophageal separation, and incomplete formation of the diaphragm. It is the incomplete closure of the pericardial-peritoneal canals, during this embryonic stage, that results in a diaphragmatic hernia. During the pseudoglandular stage, lung development depends on mechanical stimuli. Fetal breathing movements cause stretching of the lung tissue and movement of fluid in and out of the lungs, stimulating epithelial cell proliferation and surfactant secretion. ^, The compression of lung development secondary to the herniation of the abdominal organs stifles this process. In the canalicular and saccular phases, direct mechanical compression limits ongoing branching and alveolar maturation ( Fig. 22.7 ).

Development of the airways and arteries.

The stages of lung development ( blue ) are correlated to the development of the airways ( black ) and the arteries ( red ). On average, an airway of a human lung ends in an alveolar saccule after 23 generations; however, due to the shape of the lung, a range of 18–30 generations has been observed. Preacinar arteries are formed out of a capillary plexus surrounding the growing lung buds (vasculogenesis). Intraacinar arteries grow by angiogenesis.

Adapted from Schittny JC. Development of the lung. Cell Tissue Res . 2017;367(3):427–444.

One of the hallmarks of CDH is pulmonary hypoplasia. Pulmonary hypoplasia is characterized by a decrease in bronchial divisions, bronchioles, and alveoli. These infants have abnormal lung development with fewer bronchial branches and alveoli, retardation of alveolar development, increased interstitial tissue, reduced alveolar air space and gas exchange surface area, and an increased muscularity of the pulmonary vascular bed. The alveoli are thick-walled with intraalveolar septations. These immature alveoli have increased glycogen content leading to thickened secretions that further limits gas exchange.

Historically, it was thought that this herniation of abdominal contents impeded lung development causing lung hypoplasia. Recent studies show that it is likely more complicated than this. The dual-hit hypothesis suggests that (1) the pulmonary abnormalities emerge separately from the diaphragmatic defect and develop after the defect as a result of intrathoracic contents creating pathophysiologic pressures that impede development, and (2) the pulmonary abnormalities are a result of a disruption in early pulmonary embryogenesis that happens simultaneously with diaphragm development. ^, This is supported by several studies. It has been shown that alterations in transcription factors, like Fgf10, lead to abnormal branching and growth of the distal alveolar bud in both lungs. Additionally, animal models of CDH demonstrate pulmonary hypoplasia with decreased levels of total lung DNA and protein and the contralateral lung, exhibiting the structural abnormalities of pulmonary hypoplasia. Further, the lungs of rodents exposed to nitrofen are hypoplastic, even when there is no diaphragmatic defect.

The degree of pulmonary hypoplasia is assessed clinically and ranges from being incompatible with life to a minimal respiratory insult. Infants will typically present with respiratory distress, visible with gasping, tachypnea, poor effort, retractions, and cyanosis. The degree of respiratory distress is variable and can fluctuate to a significant degree, particularly in the first 48–72 hours of life.

Fetal pulmonary vascular development occurs in concordance with associated lung development and follows the pattern of airway and alveolar maturation. The functional unit, the acini, consists of alveoli, alveolar ducts, and respiratory bronchioles. The pulmonary vasculature develops as the acini multiply and evolve during the canalicular stage, while the pulmonary vascular development for the trachea, major bronchi, lobar bronchi, and terminal bronchioles is completed by the end of the pseudoglandular stage. As the alveoli continue to multiply and develop, the pulmonary vasculature propagates in conjunction with distal angiogenesis.

Normal fetal cardiopulmonary circulation transitions to its postnatal state rapidly with a large increase in pulmonary blood flow within hours following birth. Fetal pulmonary blood flow is characterized as a low-flow, high-resistance circuit due to medial and adventitial hypertrophy of the vasculature. Normally, the pulmonary vascular resistance quickly decreases as the distal small pulmonary arteries and arterioles remodel over the first few months of life, resulting in a low-resistance, high-flow postnatal circulation. However, this process is attenuated in CDH newborns, and the fetal circulation persists, resulting in CDH-associated pulmonary hypertension (CDH-PH). Pulmonary hypertension is the primary driver of pathophysiology in CDH and is defined as sustained, supernormal pulmonary arterial pressures leading to dysfunctional pulmonary circulation, suboptimal gas exchange, and/or cardiac function. Clinically, it is a term that describes the syndrome of raised pulmonary artery pressures seen with hypoxemia, cardiac dysfunction, and systemic hypotension.

In CDH, as the pulmonary system development is stunted overall, the pulmonary vasculature development is severely compromised. There is a decrease in density per unit of lung parenchyma as well as an increase in muscularization that extends to the vasculature at the acinar level, decreased angiogenesis, and altered molecular signal responsiveness contributing to pulmonary hypertension. It is suggested that increased levels of ET-1 and receptor expression contribute to these changes. ^{, ,} These changes increase pulmonary blood flow and pulmonary vascular resistance contributing to the overall increased pulmonary arterial pressures.

The World Health Organization (WHO) has classified pulmonary hypertension into five categories: pulmonary arterial hypertension, pulmonary venous hypertension due to left heart disease, pulmonary hypertension due to lung disease and/or hypoxia, chronic thromboembolic pulmonary hypertension, and multifactorial pulmonary hypertension. Broadly, these can be grouped by abnormally constricted pulmonary vasculature due to parenchymal disease (e.g., meconium aspiration, respiratory distress syndrome, or pneumonia), remodeled pulmonary vasculature with normal lung parenchyma (idiopathic), or as seen in CDH, hypoplastic vasculature. The pulmonary hypertension seen in CDH is unique compared to other forms of pulmonary hypertension. In CDH-PH, the pulmonary vasculature is comprised of hypertrophic smooth muscle cells, with decreased angiogenesis, and altered molecular signal responsiveness. This varies from the other forms of pulmonary hypertension, where a disruption in either the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, prostacyclin-cyclic adenosine monophosphate (cAMP) pathway, endothelin signaling pathway, and/or oxidative stress pathways results in the pulmonary vascular pathophysiology. Altered expression or response in these pathways leads to the typical clinical characteristics seen with pulmonary hypertension. The nuanced differences in CDH-PH play an important role in management. The first-line therapy to decrease pulmonary vascular resistance in many forms of pulmonary hypertension is inhaled nitric oxide (iNO) ; however, current evidence suggests that iNO does not decrease ECLS use or improve survival among infants with CDH ( Fig. 22.8 ).

WHO classification.

World Health Organization classification of pulmonary hypertension. CDH is best classified as group 3 (developmental anomalies and lung disease, although it shares some characteristics with groups 1, 2, and 5).

Modified from Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension [published correction appears in J Am Coll Cardiol . 2014;63:746]. J Am Coll Cardiol . 2013;62(suppl):D34–D41. https://doi.org/10.1016/j.jacc.2013.10.029

Recognizing the distinct nature of CDH-PH in comparison to other forms of pulmonary hypertension has paved the way for expanded insights and ongoing research. There is a developing interest in recognizing how these increased postcapillary pulmonary pressures are related to left ventricular disfunction, hypoplasia, and elevated end diastolic pressures. It is this functional interplay between the lungs and the heart that is now thought to be an important driver of the variable hemodynamic phenotypes seen in CDH.

While it is well established that pulmonary hypoplasia and pulmonary hypertension are central features of CDH, more recent evidence suggests cardiac dysfunction plays an equally significant role in the pathophysiology and is an independent predictor of disease severity and adverse outcomes. A multicenter prospective study completed with the CDHSG registry evaluated the ventricular function determined by echocardiograms within the first 48 hours of life. They found that ventricular dysfunction was significantly associated with the infant’s prenatal diagnosis and that ventricular dysfunction was associated with survival : Normal ventricular function– 80% survival, right ventricular dysfunction– 74% survival, left ventricular dysfunction– 57% survival, and both right and left ventricular (biventricular) dysfunction– 51% survival. ECLS was used with increased frequency along this continuum. Echocardiograms show that fetal left heart structures are smaller in CDH infants, causing diastolic dysfunction. The extent of cardiac hypoplasia directly correlates with fetal lung hypoplasia, which is thought to be due to a combination of direct mechanical compression from herniated abdominal contents, mediastinal shift leading to altered ductus venous flow away from the heart, and reduced left ventricular filling due to reduced pulmonary blood flow. ^,

Persistent elevation of pulmonary vascular pressures leads to right ventricular dysfunction, resulting in hypoxemic right-to-left shunting and increased afterload pressures. This condition arises due to continued high pressure in the pulmonary system. This right ventricular dysfunction contributes to dysfunction of the left ventricle by altering the mechanisms of ventricular interdependence with shared muscle fibers, pericardial space, and septum. In combination with displacement of the septum and left ventricular hypoplasia, diastolic function is further impaired. This biventricular dysfunction and reduced cardiac output causes systemic hypotension, acidosis, and hypoxemia, further exacerbating cardiac dysfunction and pulmonary vasoconstriction leading to spiraling clinical deterioration. Furthermore, it is believed that due to inadequate cardiac output, the heart experiences poor perfusion. This systemic tissue hypoxia is linked to mitochondrial DNA damage and subsequent mitochondrial loss, resulting in the suppression of vital mitochondrial-related pathways necessary for energy production and function. Consequently, this cascade of events leads to alterations in myocardial energetics, mechanical impairment, and potentially, ventricular failure. This severe biventricular dysfunction is associated with adverse outcomes, including early death and increased ECLS use.

There is no one genetic mutation associated with CDH, but there is increasing evidence that CDH has intermittent association with genetic aberrations and concomitant anomalies, and it should certainly not be considered an isolated anomaly in many patients. There are more than 70 well-characterized syndromes associated with CDH. In some cases, the diaphragmatic malformation is the predominant defect, as in Fryns and Donnai–Barrow syndromes. ^, One study suggested that Fryns syndrome was the most common association, followed by trisomy 18 (Edward syndrome), trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), Cornelia de Lange syndrome, and Pallister–Killian syndrome. This study reviewed the CDH registry from 1996 to 2020 and found that only 3.4% of all infants in the registry had a reported known syndrome. The overall survival to discharge for syndromic CDH was 34% compared to isolated CDH, which was 76.7%. Simpson–Golabi–Behmel and Beckwith–Wiedemann syndromes are infrequent in CDH; however, they occur much more often than in the general population. These syndromes can be carried by both autosomal and X-linked variants. Identifying the patterns of nonhernia-related anomalies associated with CDH and recognizing genetic syndromes helps determine the prognosis, treatments, counseling, and outcomes. While survival varies depending on the genetic cause, early genetic diagnosis is important and may influence the decision-making of the families and practitioners who care for these infants.

Approximately 60% of CDH cases are isolated. The remainder are associated with anomalies of the cardiovascular (27.5%), urogenital (17.7%), musculoskeletal (15.7%), and central nervous (9.8%) systems. The impact of associated anomalies on prognosis and outcome cannot be overstated. Most infants with immediate neonatal demise have associated anomalies. In contrast, only approximately 10% of infants that survive preoperative stabilization and come to operative repair have major additional anomalies. Although defect size and the degree of CDH-PH are important contributors to overall survival, infants with isolated CDH demonstrate a significant survival advantage when compared to those with major concomitant cardiac, chromosomal, or associated structural anomalies (70%–85% vs. 20%) underscoring the need for a thorough evaluation and characterization of these associations. ^{, ,}

Cardiovascular anomalies have been found to be the most common associated malformation. Common cardiac defects associated with CDH include (in decreasing order of frequency): ventricular septal defects (VSDs), atrial septal defects (ASDs), and other outflow tract anomalies (aortic coarctation, hypoplastic left heart syndrome, and tetralogy of Fallot). Those with a concomitant diagnosis of CDH and congenital heart disease (CHD) have an increase in morbidity, mortality, and the need for ECLS. They also have a lower survival rate compared to those with isolated CDH or an isolated cardiac defect. There is little information on this topic and outcomes of newborns with CDH and major heart defects have not improved over the last decade, making this area a target for innovation and affording an opportunity to develop collaborative strategies involving pediatric surgeons and congenital cardiac surgeons.

CDH is usually diagnosed prenatally based on ultrasound. It is typically detected during the routine scan obtained between 20–24 weeks’ gestation. The diagnosis is based on the presence of mediastinal shift and a fluid-filled stomach next to or behind the heart; however, if the defect is on the right, there may appear to be a homogenous mass (the liver) in the chest at the level of the heart. Ideally, these children are then referred to a tertiary center for further testing, prenatal management, and postnatal care planning. Once at these centers, additional testing is done to rule out associated anomalies and personalize prediction of disease severity and prognosis.

Full prenatal assessment consists of genetic testing and more detailed imaging. While there is no conclusive cytogenetic anomaly that is linked to CDH, genetic testing is still completed to rule out other additional syndromes or mutations and to better characterize the disorder, and in 2%–33% of patients, a causative mutation can be identified. Repeat imaging consists of more detailed ultrasound and MRI.

The first critical measurement is the size of the lungs. This measurement can then be compared to the head to establish the lung-to-head ratio (LHR). This provides an indirect estimate of the side of the lung contralateral to the hernia, normalized for the head circumference. This measurement is usually obtained in the late second trimester and values that are under 1.0 are associated with a poor prognosis and outcome. The caveat to this is that the LHR changes over gestation as the lung area grows more rapidly compared to the head circumference. To correct for this, the observed/expected LHR or o/e LHR was developed. O/E LHR is now the preferred measurement and values less than 25% are considered severe and are an independent predictor of poor postnatal survival. Additionally, MRI can be used to establish the total fetal lung volume, which can then be converted to a percentage of that expected in a normal fetus. This value, observed-to-expected total fetal lung volume (o/e TFLV), is analogous to o/e LHR ( Figs. 22.9 and 22.10 ).

Lung volume in LHR: measurement methods.

Assessing fetal lung volumes has been shown to be one of the best ways to predict neonatal prognosis in cases with congenital diaphragmatic hernia. There are multiple methods to measure fetal lung volume for LHR, including the longest length approach, the anterior posterior approach, and the trace approach.

Fetal CDH ultrasound, LHR.

Fetal ultrasound image of a left CDH at the level of the four-chamber heart. The left lobe of the liver is seen herniated into the left hemithorax at the four-chamber view of the heart. This is the level used to calculate the lung-to-head ratio (LHR), most commonly using the trace method (see yellow + signs defining the area of the right lung). Common errors include not having a clear four-chamber view and/or including “nonlung” areas in the measurement.

Liver position is also evaluated, but it can be difficult to assess the liver with ultrasound imaging since the echogenicity of the liver is similar to the lungs. Prenatal MRI imaging can qualitatively and quantitatively assess the presence of liver in the chest. The amount of liver found in the chest has been found to be a predictive marker for postnatal survival. It can be categorized as a binary variable: liver “up” (in the thorax) or “down” (confined to the abdomen). Most prenatal management algorithms will use a combination of the position of the liver and the o/e LHR to stratify patients into groups. The percentage of liver herniation on fetal MRI correlates with pulmonary morbidity, with >20% liver herniation predicting more profound morbidity and mortality.

Having an accurate diagnosis with well-described features is critical for prenatal planning and care. It allows for early identification of a group who might benefit from early interventions and allows for analysis of risk-adjusted outcomes, costs, and management approaches. Importantly, families can be more prepared with counseling, and resource allocation, establishment of care limits, delivery planning, and postnatal care and interventions can be planned. Additionally, there is new evidence showing that severity-specific management not only results in higher survival rates in high-risk CDH patients, but also potentially reduces complications and cost of care in lower-risk patients.

While no widely agreed-upon approach exists for risk stratification based on diagnostic imaging, genetic testing, and identification of other structural anomalies, it is possible to identify those considered at a higher risk. Prognosis and management in complex patients are not only determined by the severity of their CDH but additionally from their concomitant abnormalities. In contrast, the severity of isolated CDH prenatally is determined by imaging characteristics.

High-risk CDH infants usually present with an o/e LHR value less than 25% or an o/e TFLV of less than 35%; however, those with less than 20% of the liver herniated had a significantly higher survival compared to those who did not. ^, Liver herniation implies a large defect that is associated with a greater degree of lung hypoplasia and the need for a patch repair postnatally. ECLS is used more frequently in those with an o/e-TFLV <35% and in those with more than 20% liver herniation. Additionally, the percent predicted lung volume (PPLV) is a newer measure based on lung volumes and fetal size. PPLV values less than 15% are associated with lower survival rates, longer lengths of stay, and a prolonged ECLS course.71

The ability to identify high-risk infants early in development raises the possibility of a prenatal intervention that could alter the disease course. While there have been many attempts to identify prenatal pharmacologic interventions there are no effective pharmacologic therapies currently, and the only clinical strategy to promote lung growth in severe, high-risk CDH is by fetoscopic endoluminal tracheal occlusion (FETO).72

The idea of performing a fetal repair for left-sided CDH without liver and stomach herniation prior to 24 weeks’ gestation was initially evaluated in the late 1980s.73 These early strategies failed to demonstrate survival benefit due to high risk of intraoperative fetal death due to umbilical vein occlusion, the inability to reverse the CDH-induced lung architecture and pulmonary vasculature, and induced preterm deliveries.73 The concept of tracheal occlusion originated from the observation that infants with congenital high airway obstruction developed hyper plastic lungs. Experimental fetal tracheal occlusion showed that lung growth was stimulated by stretching the lung parenchymal cell. However, it has been noted that long-term tracheal occlusion decreases the number of type 2 pneumocytes and surfactant production. The concept of reversing the occlusion prenatally was introduced and showed that lung maturation continued.73 This was then transitioned into clinical practice with the FETO procedure.

FETO is a minimally invasive procedure that involves the endoluminal insertion of an inflatable balloon into the trachea. These balloons are inserted percutaneously with ultrasound guidance between 24–28 weeks’ gestation and then are deflated and removed at 34 weeks.73 ^, 74 By deflating and removing the balloon at 34 weeks, the need for an ex-utero intrapartum treatment (EXIT) procedure at delivery is avoided, although emergent airway access may be needed at delivery for any patient who undergoes in utero tracheal occlusion and experiences premature labor prior to deocclusion (Fig. 22.11 ).

FETO depiction.

Illustration of ultrasound-guided fetoscopic endoscopic tracheal occlusion procedure. The inserted pictures highlight the detachable balloon, normally used for endovascular occlusion and its position with the trachea.

Rights reserved; Adapted from Danzer E, Rintoul NE, van Meurs KP, Deprest J. Prenatal management of congenital diaphragmatic hernia. Semin Fetal Neonatal Med . 2022;27(6):101406.

Initial observational studies showed that in fetuses with severe left CDH (o/e LHR <25%) with a mean gestational age of 27 weeks, there was 49% survival compared to the 24% survival in the expectantly managed control group.75 FETO increased the chance of a preterm delivery before 34 weeks’ gestation but adverse events and side effects from the procedure itself were less likely.73 A more formal multicenter, prospective, randomized controlled trial (Tracheal Occlusion to Accelerate Lung Growth– TOTAL) was then undertaken.

The TOTAL trial evaluated fetuses with severe and moderate pulmonary hypoplasia. Those with severe hypoplasia had their balloons inserted between 27–29 weeks’ gestation (early FETO) and those with moderate hypoplasia had their balloons inserted between 30–31 weeks’ gestation (late FETO), with balloon removal at 34 weeks.73 ^, 74 ^, 76 The primary outcome was survival to discharge.73 ^, 74 ^, 76 The results showed that for severe hypoplasia, survival to discharge was 40% with FETO and only 15% with expectant management. In those in the moderate pulmonary hypoplasia, survival to discharge was 63% with FETO compared to 50% with expectant management, with the most common complication being premature rupture of membranes and subsequent preterm delivery in the intervention arm.74 ^, 76

Studies show that prenatal FETO progress can now be monitored through MRI metrics, o/e TLV, and percent liver herniation.77 In one study, MRI metrics for fetuses with CDH were calculated for pre- and post-FETO intervention and the percent change was then calculated.77 It was found that a post-FETO increase in o/e TLV by less than 10% had a lower survival rate to hospital discharge and a higher use of ECLS, compared to those who had a 10% or greater change.77

It is important to note FETO is not without risk, including preterm rupture of membranes, preterm delivery, and even neonatal demise.76 Preterm delivery can have devastating consequences in this population, especially when a response to treatment is not guaranteed. The response to treatment (lung growth/expansion during occlusion) is defined as the change in lung volumes from pre- to post-FETO intervention. Studies that have examined this change have found different responses at different time points. Even in nonsurvivors, an increase in lung volume was noted at 2 days, postulated to be from fluid retention rather than actual lung growth. However, at 7 days lung expansion is likely related to actual lung growth, with survivors having better lung growth than those who expired (Fig. 22.12 ). The underlying reason for this variability remains uncertain and renders FETO an intervention where potential benefits and risks must be carefully considered and discussed with prospective families (Fig. 22.13 ).

FETO response distribution.

Observed expected ratios, expressed as percentages of the appropriate normal mean for gestation, of the contralateral lung volumes of fetuses with isolated diaphragmatic hernia before FETO, 2 days after FETO and 7 days after FETO. The horizontal line at 100% of the observed-to-expected ratio represents the mean and the interrupted lines the 95% confidence interval of the ratio in normal fetuses. The black dots represent those infants that died and open dots represent survivors. The red line depicts the trajectory of those with poor lung volumes that did not survive, and the green line shows the dynamic volume changes seen in survivors.

Rights reserved; Adapted from Peralta CF, Jani JC, Van Schoubroeck D, Nicolaides KH, Deprest JA. Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome. Am J Obstet Gynecol . 2008;198(1):60.e1–60.e5.

Lung volume change secondary to FETO.

Reconstructed 3D ultrasound lung volumes of a fetus with isolated diaphragmatic hernia that died after birth (top) and a fetus that survived (bottom), measured before FETO at 27 weeks’ gestation, 2 days after FETO and 7 days after FETO.

Rights reserved; Reference Peralta CF, Jani JC, Van Schoubroeck D, Nicolaides KH, Deprest JA. Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome. Am J Obstet Gynecol . 2008;198(1):60.e1–60.e5.