Congenital Diaphragmatic Hernia and Eventration Flashcards
Where is the most common location of the defect in a patient with congenital diaphragmatic hernia (CDH)?
A. Right-side posterolateral
B. Left-side posterolateral
C. Right-side anterolateral
D. Left-side anterolateral
E. Retrosternal
ANSWER: B
COMMENTS: The most common type of CDH is the Bochdalek hernia, which is located in the posterolateral portion of the diaphragm. This results from a failure of fusion of the lumbar and costal muscle groups in this location. This accounts for 80% of CDHs.
A Morgagni hernia is an anteromedial defect that is usually retrosternal or parasternal and is far more rare. This usually does not present until later in life, while CDH is generally diagnosed in utero on ultrasound.
At the time of birth, a plain radiograph will identify herniated intestinal contents within the chest or the nasogastric tube terminating within the chest.
There is associated hypoplasia of the lung on the affected side, which often results in respiratory distress.
Although the lung hypoplasia plays a role in the pathogenesis of respiratory compromise, the major cause is pulmonary hypertension due to pulmonary vasoconstriction.
Management begins with cardiorespiratory stabilization of the infant at birth.
Interventions may include nitric oxide, high-frequency ventilation, and extracorporeal membrane oxygenation (ECMO) followed by surgical correction.
Survival rates for CDH range between 60% and 90%. Outcomes have improved over the last decade with the introduction of gentle ventilation strategies.
Repair can be performed via either a subcostal abdominal approach or a thoracotomy.
Open and thoracoscopic and laparoscopic methods have been described; however, there are higher hernia recurrence rates at 1 year with open approaches.
What are the different types of congenital diaphragmatic defects?
- Congenital diaphragmatic hernia (CDH), characterized by a defect that is postero-lateral (Bochdalek hernia) or anterior (Morgagni hernia).
- Diaphragmatic eventration, characterized by an abnormal elevation of one or both intact hemidiaphragms.
How does the diaphragm form?
Four structures give rise to the diaphragm between week 4 and 8 of gestation:
– septum transversum (forms the tendinous part of the diaphragm);
– pleuroperitoneal folds;
– thoracic body wall mesenchyme (both from the muscular part of the
diaphragm);
– esophageal mesentery (forms the crura).
Bochdalek CDH occurs when a pleuroperitoneal fold fails to close the pleuroperitoneal canal.
Morgagni CDH is characterized by a retrosternal herniation through the sternocostal triangle.
What causes CDH to occur?
The etiology is poorly understood, but CDH seems to be due to a combination of genetic, developmental, and environmental factors.
What is the prevalence of CDH?
2.3 in 10,000 livebirths.
What anomalies can be associated with CDH?
50% of babies with CDH have at least one associated anomaly.
10–35% have chromosomal abnormalities (trisomy 13, 18, and 21). Most common anomalies are: • congenital heart disease (15%) • defects of the urogenital system (5%) • musculo-skeletal system (5%) • central nervous system (5%).
What are the main syndromes associated with CDH?
Bochdalek CDH
• Pallister-Killian syndrome (mosaic tetrasomy 12p): central nervous system anomalies, short limbs, coarse facial features, and intellectual impairment.
• Fryns syndrome: facial dysmorphism, clefts, hypertelorism, genitourinary, and cardiovascular anomalies.
Morgagni CDH can be part of the pentalogy of Cantrell, characterized by:
• midline supraumbilical abdominal wall defect (exomphalos)
• lower sternum anomaly
• Morgagni hernia
• congenital intracardiac anomalies
• ectopia cordis.
What are the main determinants of morbidity and mortality in babies with CDH?
- Pulmonary hypoplasia (decreased number of alveoli and thickened mesenchyme)
- Pulmonary hypertension, due to fetal vascular remodeling (decreased number of vessels and increased muscularization of distal pulmonary vessels).
How is CDH prenatally diagnosed and worked-up?
Around 60–70% of cases are diagnosed prenatally at the anatomy scan (18– 20 weeks of gestation), that may show: • polyhydramnios • absence of an intra-abdominal stomach • intra-thoracic abdominal organs • mediastinal shift.
Additional prenatal evaluations include:
• detailed fetal ultrasound scan
• fetal echocardiography
• amniocentesis.
In some centers, a prenatal magnetic resonance imaging is also performed.
What are the prenatal markers to evaluate prognosis of a fetus with CDH?
- Lung-to-head ratio (LHR), expressed as observed/expected LHR, as it correlates to the degree of pulmonary hypoplasia and to predicted survival
- Liver or stomach herniation
- Associated anomalies, such as congenital heart defects
- Chromosomal anomalies (fetal karyotype or microarray).
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The fact that absolute values of LHR and TFLV can change with gestational age has been addressed by reporting them as observed-to-expected ratios, which tend to remain stable during fetal life.
There are several different algorithms for calculating these values. For example, LHR is calculated by dividing the area of the lung contralateral to the diaphragmatic defect, measured at the level of the four-chamber view, by the head circumference.
However, the lung area can be calculated by the longest diameter method or the tracing method.
Similarly, there are different algorithms for calculating MRI-generated lung volumes. It has also been shown that a learning curve may exist for accurately measuring these parameters. Since these values have become quite important in counseling patients, it behooves each institution to perform quality assurance analyses that examine the correlation of these measurements with one another, as well as with overall prognosis.
Additional measurements that have been proposed include those that can be obtained on ultrasound (quantitative lung index [QLI], three-dimensional ultrasound-generated lung volumes) and those that can be obtained on MRI (percent predicted lung volume [PPLV], lung/liver signal intensity ratio [LLSIR]). These parameters have not found wide usage, as they do not seem to increase the prognostic accuracy.
Stomach herniation and liver herniation have also been found to adversely affect prognosis. Recently, stomach herniation has been de-emphasized as it may simply be a surrogate for liver herniation.
While liver herniation has traditionally been reported as a binary variable, more recent studies show that the amount of liver herniation may be more significant, with herniated total volume above 21% associated with increased mortality.
Finally, several studies have reported the potential for fetal echocardiographic findings, such as small-diameter pulmonary arteries, to predict outcomes.
While some correlations have been found, these measurements did not seem to add much to LHR, TFLV, or liver herniation.
[Sherif]
After prenatal diagnosis, what is the current prenatal management of fetuses with CDH?
It is expectant, with ultrasound surveillance for fetal growth and development, parental counseling, and maternal steroids only if at risk of preterm delivery.
When and where should a baby with prenatally diagnosed CDH be delivered?
Scheduled full term delivery in a tertiary center at early term (37–38 weeks).
What treatment can be offered prenatally?
Surgical repair in utero was proven to be associated with increased fetal demise.
Currently, the only available prenatal intervention for fetuses with predicted severe pulmonary hypoplasia is the fetoscopic endo-tracheal occlusion (FETO), which entails the intra-tracheal deployment of a small balloon under fetoscopy at 26–28 weeks of gestation.
The balloon avoids the egression of the pulmonary fluid and keeps the lungs expanded.
At around 34 weeks of gestation, the balloon is removed.
Experimentally, FETO has been reported to improve lung growth and it is currently being evaluated by a randomized controlled trial (TOTAL trial).
Nonetheless, FETO is associated with the risk of premature rupture of membranes and preterm birth.
Correlation of the observed/expected lung-to-head ratio (O/E LHR) with the degree of pulmonary hypoplasia and predicted survival?
O/E LHR (%)
<15: Extreme (0% survival)
15–25: Severe (20% survival)
26–45: Moderate (30-60% survival)
> 45: Mild (>75% survival)
What is the postnatal management of a newborn with CDH?
- Immediate intubation with sedation for assisted ventilation to all neonates with prenatal/postnatal diagnosis CDH. No mask ventilation as it distends the herniated stomach/intestine [1]. Deep sedation and neuromuscular blockade should be avoided.
- Intravenous access+arterial line (preferably into the right radial artery), with a restrictive fluid management in the first 24 hours of life (40 ml/kg/day) [2].
- Nasogastric tube placement for gastrointestinal decompression.
- Thorough physical exam looking for associated anomalies.
- Chest x-ray (two views).
- Echocardiography in the first 48 hours of life (to be repeated at 2–3 weeks of life) to assess cardiac anatomy, severity of pulmonary hypertension, presence/ direction of ductal and intracardiac shunting, and left and right ventricular function.
• Parenteral feeding [2].
Use of surfactant is not recommended in term CDH neonates.
What are the postnatal markers of prognosis?
Several clinical prediction models have been developed, and contain variables such as:
• Birth weight
• Apgar score
• Blood gases, such as highest PaO2, lowest PaCO2, and best oxygenation index (BOI) on day 1 that is calculated as follows:
BOI (d1) = FiO2% x MAP (cmH2O) / PaO2 (kPa)
(where MAP is the mean arterial pressure)
• Pulmonary hypertension
• Chromosomal and major cardiac anomalies.
What is the recommended ventilation strategy?
CDH neonates are managed with gentle ventilation (“gentilation”), which allows permissive hypercapnia and aims to provide adequate tissue oxygenation, while avoiding barotrauma. The recommended initial ventilator settings are:
– peak inspiratory pressure (PIP): <25 cm H20;
– positive end-expiratory pressure (PEEP): 2–5 cm H20 with a frequency of
40–60/min
Oxygen is administered with the goal of a preductal SaO2 > 85% and arterial pCO2 45–60 mmHg (permissive hypercapnia) [4].
If conventional ventilation fails, high frequency oscillatory or jet ventilation are used.
What hemodynamic support can be provided in case of poor systemic perfusion and/or pulmonary hypertension?
Poor perfusion and low systemic blood pressure can be managed with crystal- loid infusion (not exceeding 20 mL/kg), inotropes (dopamine or epinephrine), and hydrocortisone. If poor perfusion continues, the cardiac function should be assessed by echocardiography and central venous saturation.
Pulmonary hypertension can be managed by various therapies, such as:
– Oxygen.
– Inhaled nitric oxide (iNO) should be considered for patients with severe
suprasystemic pulmonary arterial hypertension, preserved left ventricular function, and adequate lung recruitment. However, in case of no clinical or echocardiographic improvement, iNO should be discontinued.
– Sildenafil is a phosphodiesterase-5 inhibitor that can be considered in case of refractory pulmonary hypertension with no response to iNO or when wean- ing from iNO.
– Milrinone is a phosphodiesterase-3 inhibitor that can be considered in case of cardiac dysfunction associated to refractory pulmonary hypertension as it can improve ventricular function and blood gas parameters.
– Prostacyclin, a potent vasodilator, and its analogues (e.g. treprostinil) can be used in case of refractory pulmonary hypertension. Prostaglandin E1 can be used to maintain ductus arteriosus patency and reduce right ventricular afterload.
– Extracorporeal membrane oxygenation (ECMO).
What is the role of ECMO in babies with CDH?
ECMO functions as a heart-lung bypass, with the rationale to provide rest to the hypoplastic lungs, allowing them to grow and avoiding ventilation-induced barotrauma.
However, the indication for and use of ECMO are center-dependent and available evidence shows that survival for neonates with CDH is not affected by the use of ECMO.
Possible candidates for ECMO are:
- CDH babies with refractory hypoxemia (preductal SaO2<85%, postductal SaO2<70%)
- oxygenation index ≥40 for at least 3h
- persistent acidosis (lactate>5mmol/L; pH<7.2),
- persistent hypercapnia (pCO2 > 70 mmHg, with FiO2 100%) and/or
- hypotension resistant to fluid and inotrope therapy [2].
Relative contraindications include:
- weight <2 kg
- gestational age <34 weeks
- intraventricular hemorrhage (grade ≥ 2), or
- bleeding disorders [2].
When is the optimal timing for CDH repair?
- CDH is not considered a surgical emergency and preoperative stabilization before surgery is essential.
- Most surgeons would not perform CDH repair during the first day of life, as some babies may be in a “honeymoon period” of clinical stability before developing a pulmonary hypertensive crisis.
- Nonetheless, timing for CDH repair remains controversial, as it does not influence survival after adjusting for disease severity.
What are the possible surgical approaches for CDH repair?
Diaphragmatic repair can be performed from the abdomen (laparotomy or laparoscopy) or from the chest (thoracotomy or thoracoscopy) (Table 4.2).
The most commonly used approach is laparotomy [5].
What are the main steps of CDH surgery?
(1) Gentle and cautious reduction of the hernia contents back into the abdomen. Division of the umbilical vein and falciform ligament allows the liver rota- tion and reduction (especially in right-sided CDH with liver herniation, where hepatic veins and inferior vena cava are at risk of kinking).
(2) Assessment of hernia defect for size (Fig. 4.2) [6], presence of sac (in 20% of cases), and diaphragmatic tissue available for repair (the pericostal rim might not be present and needs to be developed to allow repair).
(3) Surgical repair with non-absorbable sutures:
a. Small defects—primary repair with interrupted non-absorbable sutures on the edge of the diaphragm
b. If muscle edges can be approximated, avoid a tight closure (high recurrence risk)
c. Large defects—repair with a natural or synthetic patch (the commonest is GoreTex , made of polytetrafluoroethylene) or autologous muscle flap (the commonest is the transversus abdominis).
The placement of a chest tube is not recommended.
How should a neonate with CDH be managed after surgery?
– gradually de-escalate mechanical ventilation
– no evidence for postoperative paralysis
– enteral feeding can be started when postoperative ileus is resolved, and
antireflux therapy should be started.
What are the main surgical complications?
Short-term
• Infection/sepsis
• Bleeding (mainly neonates treated with ECMO at the time of surgery)
• Early recurrence (2%, higher risk in defects size C and D, and cases repaired with minimally invasive surgery) [6]
• Chylothorax (5%, higher risk following patch repair and in neonates treated on ECMO)
• Pleural effusion (common, rarely requiring a drain as it will resolve with lung expansion)
• Abdominal compartment syndrome.
Long-term
• CDH recurrence (7–15%, higher risk after patch repair, in right-sided CDH, and in infants treated with ECMO)
• Adhesive small bowel obstruction (20%, higher risk after patch repair; the majority requires surgery)
What long-term morbidities can affect children born with CDH?
Respiratory
– Long-term pulmonary dysfunction (50%, secondary to pulmonary hypo- plasia and prolonged ventilation).
Digestive
– Gastro-esophageal reflux (10–20% require fundoplication)
– Failure to thrive (1/3 of survivors<5 percentile at one year of age, 20% requiring tube feeds).
Musculo-skeletal
– Chest wall or spinal deformities (1/3 of survivors has scoliosis, pectus excavatum, chest asymmetry).
Neurodevelopmental
– Impairment affects 25% survivors (neuromuscular hypotonia, hearing and visual impairment, neurobehavioral issues, and learning difficulties).
To address CDH morbidities, a dedicated multidisciplinary (surgery, neonatology, pulmonology, gastroenterology, nutrition, neurology, audiology, orthopedics) follow-up is recommended.
Causes of diaphragmatic eventration?
Congenital: Due to poor muscularization (continuum with CDH with a sac)
Acquired: Phrenic nerve injury from traumatic birth or cardiac surgery.
Herniation of abdominal viscera occurs at which age of fetal life to develop diaphragmatic hernia?
A. 7-8 weeks
B. 9-10 weeks
C. 11-12 weeks
D. 13-14 weeks
E. 15-16 weeks
C. 11-12 weeks
Procedure for repair of diaphragmatic hernia includes all, except:
A. Primary repair of non-absorbable suture.
B. Diaphragm sutured to body wall.
C. Plication of diaphragm.
D. Use of prosthetic material to repair defect.
E. Use of prêrenal fascia.
E. Use of prêrenal fascia.
Long term problems after repair of diaphragmatic hernia include all, except:
A. Gastroesophageal reflux
B. Failure to thrive
C. Hyperinflation of lung
D. Respiratory insufficiency
E. Recurrence
C. Hyperinflation of lung
Chest X-ray findings in congenital diaphragmatic hernia include all, except:
A. Loops of intestine
B. Gastric bubble
C. Nasogastric tube position in chest
D. Shifting of mediastinum to same side
E. Invisible complete dome of diaphragm
D. Shifting of mediastinum to same side
What is the “hidden mortality” of CDH?
In both Europe and the United States, the prevalence of CDH is estimated to be 2.3–2.4 per 10,000 live births, and has demonstrated a small but significant increase over time.
A significant proportion of fetuses with CDH are either terminated or stillborn, often associated with other congenital anomalies.
The overall incidence of CDH is likely underestimated, as around 25–35% of fetuses that are prenatally diagnosed with CDH result in pregnancy termination, in utero demise, or death shortly after birth.
Thus, many infants with prenatally diagnosed CDH may never be seen or accounted for in a tertiary referral center.
Presumed to be the most severe of all CDH infants, these patients contribute to the “hidden mortality” of CDH.
[H&A]
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CDH is estimated to occur in 1:2,000 to 1:4,000 live births. A significant hidden mortality exists due to pregnancy termination.
CDH is still associated with 20%–30% mortality, one of the highest rates among the spectrum of common congenital anomalies treated by pediatric surgeons in high-resource settings.
[Sherif]
What is the epidemiology of CDH patients?
CDH affects male infants more commonly, and the majority of posterolateral CDH are left sided (80%), with right sided (19%) and bilateral (1%) accounting for the rest.
Ninety percent of all CDH cases are located at the posterolateral or “Bochdalek” location, and the remainder are located anteriorly, termed “Morgagni” hernias, along with defects of the central septum transversum.
Bilateral diaphragmatic hernias are more commonly associated with other congenital anomalies, and portend a much worse prognosis.
Recent epidemiologic studies have identified no association of CDH with maternal age.
Why should CDH not be considered an isolated anomaly?
Increasing evidence demonstrates CDH to have an intermittent association with genetic aberrations and concomitant anomalies, and it should certainly not be considered an isolated anomaly in many patients.
Approximately 40% of CDH cases are nonisolated, having at least one additional anomaly.
In up to one-third of patients with CDH, a causative genetic variation is detected.
CDH has been associated with genomic aberrations on almost every chromosomal arm, and recurrences have prompted investigation into the locations of CDH-causing genes.
The identification of a genetic association for an individual CDH patient provides important information about prognosis, management, and recurrence risk.
Therefore, all cases of CDH warrant prenatal counseling with a discussion of options for chromosomal analysis, along with a postnatal chromosomal microarray and genetics consultation.
CDH has also been associated with over 70 syndromes.
In some cases, the diaphragmatic malformation is the predominant defect, as in Fryns and Donnai–Barrow syndromes.
In other syndromes such as Simpson–Golabi–Behmel and Beckwith–Wiedemann syndromes, CDH only occurs in a small percentage, but still greater 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 help determine the prognosis, treatments, counseling, and outcomes.
Which anomalies are associated with CDH?
Although approximately 60% of CDH cases are isolated, the others are associated with anomalies of the cardiovascular (27.5%), urogenital (17.7%), musculoskeletal (15.7%), and central nervous (9.8%) (CNS) 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 who 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 with those with major concomitant cardiac, chromosomal, or associated structural anomalies (70–85% vs as low as 20%, depending on specific anomaly or anomalies).
Due to the inferior outcomes of CDH when combined with significant anomalies, detailed and accurate prenatal diagnosis influences the prenatal counseling, delivery plan, perinatal management, and postnatal treatment of CDH.
Postnatally diagnosed infants with CDH have significantly fewer associated anomalies and lower mortality, on average, than infants with a prenatal diagnosis, likely reflecting a decreased disease severity.
However, this difference may be the result of lethal chromosomal anomalies leading to in utero demise, or may reflect parental decisions for termination in high-risk infants with anomalies that portend significant morbidity.
Major congenital heart disease is a significant contributor to morbidity and mortality in newborns with CDH.
Common cardiac defects associated with CDH include (in decreasing order of frequency):
1) ventricular septal defects (VSDs),
2) atrial septal defects (ASDs), and
3) other outflow tract anomalies (aortic coarctation, hypoplastic left heart syndrome, tetralogy of Fallot).
In a review of 4268 infants with CDH, there was an 18% association with congenital heart disease.
Major cardiac lesions (excluding patent foramen ovale, atrial septal defects, patient ductus arteriosus [PDA]) were found in 8%, and these infants had a much worse prognosis with an overall survival of 36% compared with infants with minor anomalies (67%) and those without cardiac defects (73%).
Why has the financial burden of caring for CDH survivors increased?
The financial burden of caring for the increased number of complex survivors of CDH has continued to rise.
Data from the Kids’ Inpatient Database in 2011 projected the annual national costs of caring for infants with CDH to range between $264 and $400 million based on 60% overall survival.
A significant contributor to this high cost over time is the utilization of ECMO, which was associated with a 2.4fold increase in expenditures from 1997 to 2006.
Patients requiring ECMO support had the highest median cost and accounted for 28.5% of the total national costs for CDH.22
The magnitude of interhospital cost variation was recently assessed utilizing the Pediatric Health System database in 2014–2015.
CDH cost a median of $154,730 but represented one of the diagnoses with the greatest cost variation at the hospital level (range $129,764–$173,712) compared with other pediatric surgical diagnoses, suggesting practice variation is an important driver of health care spending.
How does the diaphragm develop based on traditional embryology?
The development of the human diaphragm is a complex, multicellular, multitissue interaction that remains incompletely understood.
4th week AOG: Precursors to the diaphragm begin to form during the fourth week of gestation.
Historically, the diaphragm was thought to develop from the fusion of four embryonic components:
1) anteriorly by the septum transversum,
2) dorsolaterally by the pleuroperitoneal folds (PPFs),
3) dorsally by the crura from the esophageal mesentery, and
4) posteriorly by the body wall mesoderm.
According to this theory, as the embryo begins to form, the septum transversum migrates dorsally and separates the pleuropericardial cavity from the peritoneal cavity.
At this point, the pleural and peritoneal cavities still communicate. The septum transversum interacts with the PPF and mesodermal tissue surrounding the developing esophagus and other foregut structures, resulting in the formation of primitive diaphragmatic structures.
Bound by pericardial, pleural, and peritoneal folds, the paired PPFs now separate the pleuropericardial and peritoneal cavities.
Eventually, the septum transversum develops into the central tendon.
6th week AOG: As the PPF develops during the sixth week of gestation, concurrently, the pleuroperitoneal membranes close and separate the pleural and abdominal cavities by the eighth week of gestation.
Typically, the right side closes before the left.
Ultimately, the phrenic axons and myogenic cells destined for neuromuscularization migrate to the PPF and form the mature diaphragm.
The muscularization of the primitive diaphragm is a separate but inter-related process.
What are theories for the pathogenesis of CDH?
1) Failure of muscularization.
Another theory for CDH development is a failure of muscularization of the future diaphragm prior to complete closure of the canal.
Inadequate closure of the pleuroperitoneal canal allows the abdominal viscera to enter the thoracic cavity when they return from the extraembryonic coelom to herniate into the chest with the liver.
As a result of the limited intrathoracic space, due to the visceral herniation, pulmonary hypoplasia develops.
2) Abnormal lung development.
Although traditional theories suggest that the lung hypoplasia is secondary to the diaphragmatic malformation, others have postulated that the primary disturbance may be abnormal lung development that causes the diaphragmatic defect.
According to this theory, disturbances in lung bud formation subsequently impair the posthepatic mesenchymal plate (PHMP) development and result in failure of diaphragm fusion/muscularization.
3) Early genetic mutations in a subset of PPF-derived muscle connective tissue
More recently, the role of the PPF and, specifically, a subset of PPF-derived muscle connective tissue fibroblasts, in the development of CDH has been further elucidated.
Through the use of mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells has been found to control diaphragm morphogenesis. In this model, mice with mutated Gata4, strongly expressed in the PPFs, universally developed diaphragmatic hernias.
Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax.
The herniated tissue was shown to physically impede lung development (though mutations in Gata4 also have a primary effect on lung development).
Therefore, this investigation identified a critical role of the PPF and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic development.
The nitrofen rodent model has led to improved understanding of abnormal pulmonary development in CDH.
Nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) is an environmental teratogen. If a specific dose is administered at a specific time during gestation, it can cause pulmonary, cardiac, skeletal, and diaphragmatic abnormalities, analogous to the human condition.
Diaphragmatic defects resulting from the administration of nitrofen in mice are very similar to the diaphragmatic defects seen in babies with severe CDH in regard to size, location, and herniation of abdominal viscera. The side of the CDH depends on the time of nitrofen exposure during gestation.
In nitrofen-exposed fetal mice, a defect is clearly seen in the posterolateral portions of the PPF. In addition, nitrofen exposure appears to affect muscularization of the PPF. Finally, the offspring will exhibit features of pulmonary vasculopathy including increased muscularization and pulmonary vessel hyporesponsiveness, as well as pulmonary hypoplasia, including reduced airway branching, decreased alveolarization, and surfactant deficiency, all leading to respiratory failure at birth.
Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects.
Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development.
Vitamin A–deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH.
Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats.
Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.
What is the embryology of fetal lung development?
Fetal lung development is divided into five overlapping stages.
1) Embryonic (3 - 6 weeks AOG): 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) Pseudoglandular (5 - 17 weeks AOG): 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) Canalicular (16 - 25 weeks AOG): 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) Saccular (24weeks - term) 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) Alveolar (after birth): Finally, the alveolar stage begins after birth with a continued increase and development of functional alveoli.
Concomitantly, fetal pulmonary vascular development occurs in concordance with the associated lung development and follows the pattern of airway and alveolar maturation.
A functional unit known as the acinus consists of the alveolus, alveolar ducts, and respiratory bronchioles.
The pulmonary vasculature develops as these acinar units multiply and evolve during the canalicular stage.
The preacinar structures consist of the trachea, major bronchi, lobar bronchi, and terminal bronchioles.
The pulmonary vascular development for the preacinus is typically completed by end of the pseudoglandular stage.
In theory, any impedance to normal pulmonary development will concurrently hinder pulmonary vascular development (and the converse is likely also true).
What is pulmonary hypoplasia?
Pulmonary hypoplasia is characterized by a decrease in bronchial divisions, bronchioles, and alveoli.
The alveoli and terminal saccules exhibit abnormal septations that impair the air–capillary interface limiting gas exchange.
At birth, the alveoli are thick-walled with intra-alveolar septations. These immature alveoli have increased glycogen content leading to thickened secretions that further limit gas exchange.
Animal models of CDH have demonstrated pulmonary hypoplasia with decreased levels of total lung DNA and protein.
In addition, the pulmonary vasculature has a diminished capacity for vasoreactivity, with abnormally thick-walled arteries and arterioles.
Interestingly, the contralateral lung also exhibits the structural abnormalities of pulmonary hypoplasia.
Preclinical treatments for pulmonary hypoplasia present interesting areas of research for nonsurgical therapies of infants with CDH.
Previous therapies, including prenatal steroids and surfactant, have been shown to have no clinical benefit and are currently not recommended. Although multiple avenues of investigation are ongoing, several areas with potential include the retinoic acid pathway involving vitamin A, tracheal occlusion for pulmonary growth, and cell therapy approaches.
How does CDH-associated pulmonary hypertension occur?
Normal fetal cardiopulmonary circulation transitions to its postnatal state rapidly with a 10-fold increase in pulmonary blood flow within hours following birth.
Fetal pulmonary blood flow is characterized as a low-flow, high-resistance circuit due to medial and adventitial hypertrophy of the vasculature.
Normally, the pulmonary vascular resistance (PVR) quickly decreases as the distal small pulmonary arteries and arterioles remodel over the first few months of life, resulting in a low-resistance, high-flow postnatal circulation.
However, this process appears to be arrested in CDH newborns, and the fetal circulation persists resulting in CDH-PH.
In fact, the abnormal fetal pulmonary circulation in CDH fetuses appears to originate and progress in early gestation.
The pulmonary arteries exhibit a decrease in density per unit of lung parenchyma as well as an increase in muscularization that extends to the vasculature at the acinar level.
In fetal lamb models of surgically created CDH as well as human fetuses with CDH, there is a relative decrease in lung parenchyma. This impaired lung growth and development has been speculated to be related to impaired vascular development.
As a result, CDH-PH appears to develop in utero, which may cause a reduction in pulmonary artery growth, proper alveolar development, and normal lung growth.
However, in contrast to a congenital pulmonary airway malformation (CPAM), another congenital malformation associated with pulmonary hypoplasia and severe pulmonary compression, pre- and postnatal pulmonary vascular pathology and remodeling was found to be worse in infants with CDH versus CPAM in one study, suggesting a multifactorial origin for CDH-PH.
Finally, the timing of diaphragmatic and pulmonary development further supports the “two-hit hypothesis” of CDH development, wherein both defective early pulmonary development and subsequent defective diaphragmatic development contribute to the ultimate pulmonary pathogenesis.
In a retrospective study, CDH infants who developed normal pulmonary artery pressures during the first 3 weeks of life were found to have a 100% survival rate. In this same study, an intermediate reduction in elevated pulmonary pressures after birth were seen in 34% of infants with a 75% survival.
Mortality was 100% in CDH infants who had persistent, suprasystemic pulmonary pressures despite maximal therapy.
Although contemporary outcomes for infants with pulmonary hypertension have improved, these data underscore the importance of CDH-PH.
What is the role of MRI in the prenatal diagnosis of CDH?
If diaphragm pathology is suspected on fetal US, fetal magnetic resonance imaging (MRI) may add additional prognostic value.
MRI offers improved tissue characterization and spatial resolution when compared with US.
Moreover, MRI can further clarify liver position due to discernibly different signal intensities on MRI compared with US, accounting for the higher water content of fetal lungs on T2-weighted images.
The percentage of liver herniation on fetal MRI correlates with pulmonary morbidity, with >20% liver herniation predicting more profound morbidity.
In addition, fetal MRI is an excellent modality for morphologic and volumetric measurements of the fetal lung (total fetal lung volume [TFLV]).
It is especially advantageous in patients with oligohydramnios and maternal obesity.
Eight studies included in the recently published meta-analysis showed a statistically significant difference between the mean O/E TFLV of survivors compared with nonsurvivors with CDH.
Survival rates with O/E TFLV <25% ranged from 0–25%, whereas for O/E TFLV >35%, survival ranged from 75–89%.
[H&A]
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Excellent imaging of the fetal lungs is often obtained on MRI, as the high water content of the lungs renders them quite bright on T2 sequences.
While a fetal MRI is not essential to the evaluation, it does provide several pieces of important information, including a full anatomic evaluation of the fetus, accurate diagnosis of liver herniation and quantification of such herniation, if present, and calculation of total fetal lung volume (TFLV).
In addition to LHR, the latter has also been found to have prognostic significance.
[Sherif]
Among CDH patients requiring patch repair, what factor is most strongly associated with morbidity and mortality?
Irrespective of the operative approach, repair of large diaphragmatic defects remains a challenge, usually requiring diaphragmatic replacement with a prosthetic patch or autologous tissue.
In large studies, around 50% of infants undergoing CDH repair require diaphragmatic replacement with a patch.
Comparative studies between patch and primary repairs have consistently shown increased morbidity and mortality in the patch groups, most likely due to the large defect size and the associated severity of the pulmonary hypoplasia.
In many studies, patch repair has been utilized as a surrogate for defect size and disease severity (i.e., larger defects = increased severity of disease).
The CDHSG staging system has clearly shown that defect size is the factor that has the strongest association with morbidity and mortality.
What are guidelines for follow-up for CDH patients?
Although many survive to discharge, infants with CDH carry many sequelae and ongoing health needs that require longterm medical care.
Disease-specific morbidities offer the opportunity for multiple specialties to align together and provide long-term follow-up and care for patients with CDH as well as opportunities for research.
Pulmonary, neurologic, gastrointestinal, and musculoskeletal complications outlined in the text that follows are best served by a multidisciplinary team of surgical, medical, and developmental specialists with experience in caring for patients with CDH.
In response to many single institution reports and increasing knowledge of long-term needs, the standard follow-up care algorithm for infants with CDH is being formulated, and its components are offered below.
What are the types of hiatal hernia?
Type I, or sliding, hiatal hernias can be seen in patients with gastroesophageal reflux disease (GERD), but are rarely actually described on contrast imaging of the upper gastrointestinal tract in children.
The most common etiology of a paraesophageal hernia in the pediatric population is a failed Nissen fundoplication.
Types II, III, and IV congenital hiatal hernias, all considered paraesophageal hernias, are quite rare. These hernias are associated with GERD in approximately 50% of cases and other congenital anomalies in one-third of cases. The esophagus is often dilated.
Diagnosis is often delayed due to lack of familiarity with this type of hernia on the part of pediatric clinicians.
In contrast to Morgagni hernias, excision of the sac in this type of hernia is essential to delineation of hiatal anatomy and adequate repair.
In infants, I prefer an open approach as the procedure is technically challenging. Laparoscopic repair is ideal in older children.
Outcomes are generally quite favorable, unless severe chronic comorbidities exist.
Sherif
