Pediatric Pulmonary Hypoplasia

For lung development to proceed normally, physical space in the fetal thorax must be adequate, and amniotic fluid must be brought into the lung by fetal breathing movements, leading to distension of the developing lung. Several studies have demonstrated that gestation age at rupture of membranes (15-28 weeks gestation), latency period (duration between rupture of membranes and birth) and the amniotic fluid index (AFI of less than 1 cm or 5 cm) can influence the development of pulmonary hypoplasia.[3]

Fetal lung fluid and oligohydramnios

Maintenance of fetal lung volume plays a major role in normal lung development. Normal transpulmonary pressure of about 2.5mm Hg allows the fetal lung to actively secrete fluid into the lumen.[4] The effect of stretch of the lung parenchyma induces and promotes lung development. Studies in sheep have demonstrated that tracheal ligation and therefore increased lung distension, accelerates lung growth whereas chronic tracheal fluid drainage has the opposite effect.[5] Cohen and colleagues have found that in-utero overexpression of the cystic fibrosis transmembrane conductance regulator (CFTR) increased liquid secretion into the lung, accelerating lung growth in a rat model.[6]

Oligohydramnios is considered to be an independent risk factor for the development of pulmonary hypoplasia. This is likely due to reduced distending forces on the lung. Studies have demonstrated that severe oligohydramnios decreased lung cell size, alters cell shape and may also negatively affect Type I cell differentiation which ultimately induces pulmonary hypoplasia.

It has been postulated that the Rho-ROCK pathway can affect the growth of the lung epithelium. Embryonic mouse models have demonstrated that ROCK protein inhibitor decreases the number of terminal lung buds. There are currently several groups studying the role of the Rho/ROCK pathway which has potential therapeutic implications in the reversal of lung hypoplasia.[7, 8]

Role of growth factors

Several growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), promote cell proliferation and differentiation. Transforming growth factor family proteins like TGFß1 can oppose these effects.

Embryologically, lungs arise from the foregut. Thyroid transcription factor 1 (TTF-1) is thought to be the earliest embryologic marker associated with cells committed to pulmonary development. FGF signaling is thought to be essential in the formation of TTF-1 expressing cells and this is thought to occur even before the pseudoglandular stage of lung development. Sonic hedgehog (SHH) signaling is further responsible for branching morphogenesis and mesenchymal proliferation. Disruption of any of these pathway may result in primary pulmonary hypoplasia.[9, 10, 11, 12]   

FGF7 and FGF10 promote epithelial proliferation and formation of the bronchial tree. Overexpression of FGF10 can also stimulate the formation of cysts in the rat lung.[13] EGF promotes lung branching and Type II alveolar cell proliferation. PDGF plays a crucial role in alveolarization. VEGF promotes angiogenesis and the differentiation of embryonic mesenchymal cells into endothelial cells. Bone morphogenetic protein was thought to oppose lung growth; however recent data suggests that in the presence of mesenchymal cells, BMP4 is a potent inducer of tracheal branching.[14, 15, 16, 17] Aberrant expression of these growth factor proteins in the amniotic fluid during pregnancy have been implicated in abnormal lung development. Interestingly, higher concentrations of VEGF are seen in the amniotic fluid in the second and third trimester and may be a molecular marker for hypoxia which requires further investigation.[15]

Congenital diaphragmatic hernia

The pathogenesis of PH associated with congenital diaphragmatic hernia (CDH) remains unclear. Several mechanisms have been suggested. The nitrofen model of CDH is widely accepted. Nitrofen is a human carcinogen and the retinoid acid signaling pathway is essential for the normal development of the diaphragm. Perturbation of this pathway with compounds such as nitrofen, can induce CDH and PH. Esumi and colleagues demonstrated that that administration of insulin-like growth factor 2 (IGF2) to nitrofen-induced hypoplastic lungs lead to alveolar maturation.[18, 13, 19, 20, 21, 22] Furthermore, data suggest that prenatal treatment with retinoic acid results in increased levels of placental IGF2 and promotes both placental and fetal lung growth in nitrofen induced CDH.[23]

Interestingly, erythropoietin (EPO) is a direct target of retinoic acid. A study has demonstrated decreased levels of EPO mRNA in the liver and kidney of rats which may explain modifications in the pulmonary vasculature in CDH.[22]

A study has also suggested a possible role of interleukin 6 (IL-6) in inducing catch-up growth particularly in nitrofen pre-treated explant fetal rat lungs.[24]

In cases of congenital diaphragmatic hernia (CDH) associated with pulmonary hypoplasia, hypertrophy of the contralateral lung has been demonstrated, with associated pulmonary artery hypertension. The hypoxemia in pulmonary hypoplasia stems from hypoventilation and right-to-left extrapulmonary shunting.

The causes of primary pulmonary hypoplasia have not been identified. Sonic hedgehog (Shh) appears to play a role in pulmonary branching morphogenesis. Shh knockout transgenic mice had severely hypoplastic lungs with loss of cartilaginous rings.[9, 11]  Experimental models suggest deficiencies in certain factors and/or their receptors can result in abnormal lung growth (see Table 1). These findings suggest that primary pulmonary hypoplasia likely results from disruptions in signaling during embryologic phase of lung development but needs further study.

Causes of secondary pulmonary hypoplasia include conditions that can result in small fetal thoracic volume, prolonged oligohydramnios, decreased fetal breathing movements, and congenital heart disease with poor pulmonary blood flow (see Table 2). Condition such as congenital diaphragmatic hernia, large pleural effusions and congenital pulmonary malformations also lead to the development of pulmonary hypoplasia due to mass effect.[1]

 

Table 1. Factors and/or Their Receptors Possibly Involved with Abnormal Lung Growth (Open Table in a new window)

 

Table 2. Causes of Secondary Pulmonary Hypoplasia (Open Table in a new window)

United States statistics

The true incidence of pulmonary hypoplasia is unknown. The reported incidence is between 9 to 11 per 100,00 live birth which is an underestimation, as infants with lesser degrees of hypoplasia likely survive in the neonatal period.[1] Incidence also varies by etiology. Most cases are secondary to congenital anomalies (such as congenital diaphragmatic hernia and cystic adenomatous malformations) or complications related to pregnancy that inhibit lung development. These include, but are not limited to, renal and urinary tract anomalies, amniotic fluid aberrations, diaphragmatic hernia, hydrops fetalis, skeletal and neuromuscular disease and conditions like pleural effusions, chylothorax and intrathoracic masses that cause compression of the fetal thorax.[2]  

The incidence of neonatal pulmonary hypoplasia in mid trimester (18-26 weeks gestation) preterm rupture of membranes ranges from 9-28%, with variability attributed to differing diagnostic criteria for pulmonary hypoplasia.

International statistics

International incidence of pulmonary hypoplasia is not known. In Canada, the estimated incidence of CAM is 1 case per 25,000-35,000 pregnancies. According to the CDH study group the incidence of CDH is 1 in every 2000-4000 births and accounts for 8% of all congenital anomalies. In Europe, the occurrence of CDH ranges from 1.7 to 5.7 cases per 10,000 live births, depending on study population and remains largely unchanged.[8, 26] However, there is no direct correlation between these predisposing lesions to the incidence of pulmonary hypoplasia.

Race- and sex-related demographics

No racial predilection has been noted.

No sex predilection has been noted.

Mortality has traditionally been very high. In a retrospective study of 76 premature infants less than 35 weeks’ gestation, 20 had prolonged rupture of membrane of more than 5 days and were clinically diagnosed with pulmonary hypoplasia. Of those 20 infants with pulmonary hypoplasia, 18 died. In another retrospective study of 117 infants of less than 37 weeks’ gestation who had prolonged rupture of membrane of more than 99 hours, 11 died and were considered to have pulmonary hypoplasia. The median age of death was 20 hours (range, 12-48 h), mostly commonly from respiratory failure.

While antepartum amnioinfusions for treatment of oligohydramnios have significantly reduced the risk of pulmonary hypoplasia, longitudinal follow-up studies are lacking on the long-term outcomes of these children.

Of children with pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH), the postnatal survival rate of CDH at tertiary centers has improved, with reported rates of 70-92%.[27]  However, the survival rates do not account for the cases of CDH that are stillborn, died outside a tertiary center, or died as a result of spontaneous or therapeutic abortion.

CDH survivors have a high incidence of respiratory, nutritional, musculoskeletal, neurological, and gastrointestinal morbidities.[27]  In a prospective study of 41 CDH survivors, abnormal muscle tone was found in 90% at age 6 months and 51% at age 24 months. While almost half (49%) had normal scores for neurocognitive and language skills, 17% had mildly delayed and 15% had severe delayed scores. Likewise, in psychomotor testing, while 46% had normal scores, 23% and 31% scored as mildly delayed and severely delayed, respectively. Autism was present in 7%. Studies of brain maturation using MRI show delayed structural brain development and other abnormalities that may lead to long-term neurologic complications.[28]

In a retrospective follow-up study of 55 children survivors with scimitar syndrome followed at one center, a high rate of respiratory complications was observed. All (100%) of the children had right lung hypoplasia of varying degrees of severity. The median duration of follow-up was 7.2 years. Pulmonary infections were reported in 38%, and 43% of children reported wheezing episodes during the last 12 months of follow-up. A restrictive pattern of lung function was observed in the majority of patients, likely related to right-sided lung hypoplasia. Lower total lung capacity values were seen in children with the infantile form of scimitar syndrome, possibly reflective of the severity of pulmonary hypoplasia in these children.[29]

Right-sided hypoplasia, typically secondary to right sided CDH, seems to carry a higher mortality. This is likely due to higher risk of recurrent herniation, increased risk of pulmonary complications, requiring pulmonary vasodilator therapy and tracheostomy. However, no differences in neurodevelopmental outcomes was found.[30, 31]

A minimum lung volume of 45% compared with age-matched control subjects has been shown to be a predictor of survival in neonates with diaphragmatic hernia treated with extracorporeal membrane oxygenation (ECMO). Similarly, a functional residual capacity of 12.3 mL/kg, about one half the normal capacity, has been thought to be a predictor of survival in pulmonary hypoplasia with CDH.

Morbidity/mortality

In different studies, mortality rates associated with PH are reported to be as high as 71-95% in the perinatal period.[1, 2]  

The following conditions increase the risk of mortality[26] :

• Earlier gestational age at rupture of membranes, particularly at less than 25 weeks of gestation

• Severe oligohydramnios (amniotic fluid index < 4) for more than 2 weeks

• Earlier delivery (decreased latency period)

• Right-sided lesion

• Presence of genetic anomalies

To avoid mortality from severe lung hypoplasia in association with CDH or CAM, fetal surgical intervention has been attempted. Most studies report a mortality rate of 25-30% in neonates with CDH and CAM at high volume centers; mortality can be as high as 45% at peripheral care centers. However, in other cystic lung lesions, most are clinically asymptomatic and may not need aggressive management.[32]  A retrospective cohort study by Cuestas et al showed that mortality was significantly higher in neonates with PH who had CDH than in those with PH secondary to renal dysplasia.[33]

Risk factors for a poor outcome include the presence of hydrops fetalis, with a mortality rate as high as 80-90%. Other indicators include the type of CAM and its size. All of these factors reflect the degree of pulmonary compromise with lesions that result in varying degrees of pulmonary hypoplasia.

A retrospective study from Barcelona that studied 60 cases of pulmonary hypoplasia between 1995 and 2014 found a mortality rate of 47% in the first 60 days of life and up to 75% in the first day of life.[34]

Complications

Complications in pediatric pulmonary hypoplasia are as follows:

• Mortality due to acute respiratory failure in the neonatal period

• Chronic respiratory failure or insufficiency

• Pneumothorax, either spontaneous or as a result of ventilatory support

• Persistent pulmonary hypertension caused by a reduced pulmonary vascular bed and worsened by hypoxia or a coexisting left-to-right intracardiac shunt

• Chronic lung disease of infancy caused by prolonged ventilatory support

• Airway abnormalities, including tracheobronchial compression and tracheomalacia caused by the displaced aorta and enlarged left pulmonary artery

• Restrictive lung disease due to reduced total lung capacity

• Recurrent respiratory infections

• Recurrent wheezing episodes

• Reduced exercise tolerance

• Scoliosis in adolescent years due to abnormal thoracic cage development

• Nutritional, musculoskeletal, neurological, and gastrointestinal comorbidities

• Delayed growth and development

There is wide variation in the clinical presentation of pulmonary hypoplasia, depending on the extent of hypoplasia and other associated anomalies.[16]

The history may include poor fetal movement or amniotic fluid leakage and oligohydramnios. The neonate may be asymptomatic or may present with severe respiratory distress or apnea that requires extensive ventilatory support. In older children, dyspnea and cyanosis may be present upon exertion, or a history of repeated respiratory infections may be noted.

The external chest may appear normal or may be small and bell shaped, with or without scoliosis. A mediastinal shift is observed toward the involved side, and dullness upon percussion is heard over the displaced heart. In right-sided hypoplasia, the heart is displaced to the right, which may lead to a mistaken diagnosis of dextrocardia. Breath sounds may be decreased or absent on the side of hypoplasia, especially over the bases and axilla.

Some infants may present with otherwise asymptomatic tachypnea, and other may have severe respiratory distress at birth requiring ventilatory support. Pneumothorax, either spontaneous or associated with mechanical ventilation, may occur.

Infants with secondary pulmonary hypoplasia may have associated congenital anomalies or features suggestive of neuromuscular diseases. Such patients may have myopathic facies, with a V-shaped mouth, muscle weakness, and growth restriction. Multiple genetic syndromes associated with primary pulmonary hypoplasia are reported in the literature such as Scimitar syndrome, trisomy 21, and Pena-Shokeir syndrome (fetal akinesia).[35, 36]  

Compression deformities due to prolonged oligohydramnios, contractures, and arthrogryposis may be present. The Potter facies (hypertelorism, epicanthus, retrognathia, depressed nasal bridge, low set ears) suggest the possibility of lung hypoplasia caused by the associated renal defects.

Abdominal masses, such as cystic renal diseases and an enlarged bladder, must be sought. Associated anomalies of the cardiovascular, gastrointestinal (eg, tracheoesophageal fistula, imperforate anus, communicating bronchopulmonary foregut malformation), and genitourinary systems, as well as skeletal anomalies of the vertebrae, thoracic cage, and upper limbs, may be found upon examination.[37]

If the cause of the pulmonary hypoplasia is renal pathology, serum creatinine, blood urea, and electrolytes levels should be measured to assess renal function.

There is no gold standard for the prenatal prediction of pulmonary hypoplasia or for postnatal diagnosis.

Radiographs

Chest radiographic findings vary. The ribs may appear crowded with a low thoracic-to-abdominal ratio, and the chest wall is classically bell-shaped; however, lung fields are clear unless there is also coexisting respiratory distress syndrome. Pneumothorax or other forms of air leak are frequently present. Films may also show features of the neonate's underlying condition. In severe cases, there may be mediastinal shift with a homogenous density on the involved hypoplastic side and compensatory herniation of the contralateral lung across the mediastinum. Rib deformities may be observed. See the images below.

Two and three dimensional ultrasonography

Thoracic circumference (TC), thoracic circumference to abdominal circumference (TC:AC) ratio and lung area (LA) are frequently used measurements to assess prenatal risk for pulmonary hypoplasia.[1] TC and LA are gestational-age dependent whereas TC:AC ratio is not affected by gestational age. All of these measurements have a high specificity (between 40-100%) but none have a high enough sensitivity to be used reliably in clinical practice. However, in fetuses with CDH, the observed to expected lung-to-head ratio (LHR) measured by two-dimensional ultrasound remains the best predictor of pulmonary hypoplasia.[38]

Three-dimensional ultrasound techniques, which include pulmonary volume measurement, appears to have a high sensitivity 92% and specific 84% and appears to be a reliable technique to predict pulmonary hypoplasia.[39, 40] Barros and Colleagues found that lung volumes measurements using 3D ultrasound has a high sensitivity (83.3%) and specificity (100%) for predicting lethal pulmonary hypoplasia in infant with skeletal anomalies.[41]

Targeted fetal ultrasonography may demonstrate renal malformations, oligohydramnios, and decreased fetal movements in fetal neuromuscular diseases. While this is readily available at most centers, diagnosing disease requires expertise and can be limited by the presence of maternal obesity, low AFI and fetal malposition.[42]

Autopsy studies have shown that pulmonary hypoplasia is associated with a reduction in a number of pulmonary vessels and with increased arterial smooth muscle thickness, which may lead to increased pulmonary vascular resistance and decreased pulmonary arterial compliance. Pulmonary vasculature remodeling and pulmonary hypertension is particularly common in CDH and results in high mortality.[43] Given abnormalities in the vasculature, Doppler ultrasonography has been studied as way to predict pulmonary hypoplasia. Determination of pulmonary artery blood velocity waveforms is one tool used to diagnose pulmonary hypoplasia, however as a single test is unreliable. Pulsatile index of the ductus arteriosus for predicting PH had a sensitivity of only 37% and specificity of 2% which is again, not clinically reliable.[44]

.

Diaphragmatic hernia (see first 3 images below), associated skeletal anomalies (see fourth image below), scimitar syndrome, and sequestration may be identified.

Chest CT scanning may show loss of lung volume and abnormal or absent normal airway branching to the affected lung (see images below).

Other imaging studies

Echocardiography may be used to identify associated cardiac anomalies. The frequency of cardiovascular malformations associated with isolated CDH is 11-15%.[45] The most common anomalies include atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects.

Angiography is indicated to confirm the diagnosis of any aberrant pulmonary vessels, to rule out scimitar syndrome, and to confirm reduced pulmonary vascular bed.

MRI or magnetic resonance angiography (MRA) may also be used to identify the smaller pulmonary arterial supply to the affected lung and the presence of other abnormal vascular anatomy (see image below).

Fetal MRI during the second and third trimester has been attracting increasing attention; however, universally accepted standardized values for the prediction of pulmonary hypoplasia are not available. Different techniques, including MRI volumetry, assessment of signal intensities, and MRI spectroscopy of the fetal lung, have been used clinically to identify abnormal fetal lung growth.[46]

Both MRI and ultrasonography appear to be useful in determining the degree of pulmonary hypoplasia.[47]  The American College of Radiology and Society of Pediatric Radiology joint guidance on the performance of MRI during pregnancy endorses the use of MRI at any stage of pregnancy for further evaluation of any anomaly found on ultrasonography. Specific indications include volumetric assessment of fetal lung parenchyma for secondary hypoplasia in at-risk fetuses.[48]

Particularly in CDH, MRI based total fetal lung volume (FLV) and fetal body volume (FBV) measurements are useful in predicting post-natal survival. More recent studies are also demonstrating that MRI based FLV:FBV ratio measurements are not only able to predict neonatal mortality but also able to predict ECMO requirement with high accuracy.[49]  Additionally, the use of lung-to-liver signal intensity ratio on T2-weighted images to predict fetal pulmonary hypoplasia has been proposed.[50]

Lung scintigraphy has been used to evaluate the degree of pulmonary hypoplasia in infants with CDH. One study suggested that lung scintigraphy is useful to predict long-term pulmonary morbidity and poor nutritional status in survivors of CDH.[51]

Obtaining an ECG and/or echocardiogram is important to distinguish between dextrocardia and dextroposition caused by pulmonary hypoplasia. In dextrocardia, ECG findings include an inverted P wave and T in lead 1, with negative QRS deflection and a reverse pattern between aVR and aVL. A mirror image progression is observed from V1 to a right-sided V6 lead. A tall R in lead V1 or an RS ratio equal to or greater than 1 also suggests dextrocardia.

The frequency of cardiovascular malformations associated with isolated CDH is 11-15%.[45] The most anomalies include atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects.

Bronchoscopy or bronchography is indicated because the reduced size of a bronchus and its branches confirms the diagnosis (see image below).

Pulmonary function testing is difficult to obtain in the young age, however it may a useful tool in monitoring the course of the disease to assess lung maturation and development. A recent study has demonstrated that lung function remains abnormal in the first three years of life in children with congenital diaphragmatic hernia. This study revealed normalization of total lung capacity, however with increasing residual volumes likely due to pulmonary overinflation. They hypothesized that the pulmonary hyperinflation was not due to normal alveolarization that occurs in the first three years of life, but is likely due to overdistended, simplified air spaces that was functionally different from those seen in normally grown lungs.[52]  Another study reported normalization of all lung function parameters after surgery by age 24 months.[53] As expected, lung function significantly correlated with increase in age, height, and, especially, weight.

On autopsy, in pulmonary hypoplasia, the overall lung size is reduced, cell numbers are decreased, branches of airways may be narrower and fewer, alveolar differentiation may be reduced, and a surfactant deficiency may be present.

Histopathologic descriptions of pulmonary hypoplasia may have limited value since some may appear similar to normal lung. However, in other cases there may be a reduction in a number of pulmonary vessels (and smaller pulmonary arterioles) and increased arterial smooth muscle thickness, indicating the presence of pulmonary hypertension.

The diagnosis of pulmonary hypoplasia is made if the lung weight–to–body weight ratio is less than 0.015 in infants born before 28 weeks of gestation and less than 0.012 in infants born after 28 weeks of gestation, in conjunction with a mean radial alveolar count (RAC) of less than 4%. The RAC provides a simple objective measurement of the "relative paucity of alveoli" or "crowding of bronchial structures, which is unaffected by the state of expansion of the lungs.

In addition, in infants with severe risk factors (renal anomalies, diaphragmatic hernia), lung hypoplasia may be diagnosed by a lung volume–to–body weight ratio less than the 10th percentile when assessed on age-specific reference values.[54]

In fetuses with pulmonary hypoplasia, interventions can be done prenatally and treatment goals should be established for postnatal care. Prenatal interventions are performed with the goal of delaying preterm labor and allowing for lungs to mature.

Preterm rupture of membranes without signs of fetal distress or intrauterine infection is treated conservatively with or without tocolytics, antibiotics, and steroids in various combinations. Antenatal corticosteroids enhance fetal lung maturation in pregnancies less than 34 weeks of gestation. If gestational age is uncertain, lung maturity can be determined by aspiration of amniotic fluid from the vaginal vault. The lamellar body counts are a direct measurement of surfactant production by type II pneumocytes. If this initial screen shows neither clearly mature nor immature fetal lung, then the lecithin/sphingomyelin (L/S) ratio can be determined from amniotic fluid. The risk of respiratory distress is very low when the L/S ratio is greater than 2.0.

Amnioinfusions and amniopatch techniques have shown promising results in the treatments of preterm labor. Amnioinfusion consists of instilling isotonic fluid into the amniotic cavity. Amniopatch consists of intraamniotic injection of platelets and cryoprecipitate with the goal of sealing amniotic fluid leak. Small cases series have reported that both techniques reduce perinatal complications and prolong pregnancy particularly in severe oligohydramnios.[55, 56]

After delivery, the infant needs respiratory support, which can range from supplying supplemental oxygen to mechanical ventilation, including high-frequency ventilation and extracorporeal membrane oxygenation (ECMO). Ventilatory strategies that have veered toward the use of gentle volume recruitment, permissive hypercapnia, especially in cases of congenital diaphragmatic hernia (CDH), have led to increased survival and improved outcomes.[57] Fetal MRI based lung volume assessment may be useful in predicting the severity of pulmonary hypoplasia and may also predict the need for ECMO. Weidner and colleagues demonstrated lower FLV:FBV ratios in infants who required ECMO.[58] While the timing of CDH repair for infant on ECMO remains controversial, there are studies that show that surgical repair of CDH while on ECMO, can be done safely and is associated with good survival and there may be increased mortality associated with delayed repair.[59, 60] Pulmonary hypertension contributes to significant mortality in patient with CDH and this particular subset of patients may have additional benefit from early ECMO support.

There is conflicting data regarding the efficacy of iNO to manage pulmonary HTN secondary to CDH. Randomized controlled trials of inhaled nitric oxide (iNO) treatment for infants with CDH have shown marginal, if any, efficacy. Poor left ventricular function and/or left ventricular hypoplasia may account for some of the poor response to iNO. Infants with severe respiratory failure secondary to pulmonary hypoplasia and documented persistent pulmonary hypertension of the newborn may benefit from iNO, but the data are limited.[61]  Aggressive ventilation in these infants causes overexpansion of lungs with compresses intra-alveolar capillaries which further aggravates pulmonary hypertension. If this is the case, hemodynamics should be optimized prior to initiating nitric oxide. More recently there are smaller population studies that show that nitric oxide may be beneficial as adjunct therapy in combination with Sildenafil and dopamine infusions to improve survival, but larger studies are needed.[62]

Low lung compliance associated with CDH is thought to be secondary to surfactant deficiency, although there is very limited and conflicting data regarding this theory. One study shows that infants with CDH had lower rates of synthesis of surfactant protein B (SP-B) and less SP-B in tracheal aspirates compared with age-matched controls without lung disease.[63] While surfactant is not contraindicated, it does not seem to provide additional survival benefit in infants with CDH.

Of note, overexpansion of hypoplastic lungs compresses intra-alveolar capillaries and aggravates pulmonary hypertension. Partial liquid ventilation has also been used; however, data are lacking to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome.[64]

Dialysis for support of renal function is provided in some cases, but it should be started only after careful consideration. Patients with severe chronic renal impairment with pulmonary hypoplasia have a poor prognosis; the ultimate outcome is difficult to improve, even with optimal renal and respiratory support.

Some studies suggest that strict infection control may improve the outcome of neonates with CDH without the need for ECMO.[65]

Medical management of cystic adenomatoid malformations (CCAM) and prognosis is dependent on the size of the lesion. Microcysts < 5cm will regress on their own while, macrocysts are progressive, can cause mass effect and results in hydrops fetalis. The presence of hydrops fetalis in CCAM is indicative of poor fetal outcome and will typically require prenatal interventions in order to prevent pulmonary hypoplasia.[66]  Spontaneous improvement and possible resolution may occur over months to years in many of these lesions.[67] Their management must be individualized, with very large lesions resulting in lung hypoplasia or fetal hydrops required possible fetal surgery.[68] In most cases of fetal lung lesions, continued observation with possible postnatal therapy occurs if respiratory distress or failure to thrive develops.[69]

Multiple studies have proven the importance of the retinoic acid signaling pathway in lung development as mentioned above. In keeping with this, the role of retinoic acid supplementation and antioxidants in pulmonary hypoplasia has been extensively studied. There is some promising human data that demonstrated decrease in incidence of bronchopulmonary dysplasia in extremely low birth infants who received vitamin A supplementation.[70] There are also several animal models that show an increase in VEGF expression and increased lung alveolarization in response to vitamin A supplementation. Despite encouraging in vitro work, supplementation with vitamin A failed to reverse oligohydramnios-induced pulmonary hypoplasia in fetal rats.

A multidisciplinary team with expertise in fetal surgery should be involved, when feasible, in all cases of severe pulmonary hypoplasia. A major indication for fetal surgery is the presence of hydrops and a gestation of less than 32 weeks. In general cases that require surgical intervention are large cystic lung malformations and congenital diaphragmatic hernias.

Cystic lung malformations

Thoracocentesis or thoracoamniotic shunts can allow for drainage of fluid from the congenital CAM, but the fluid usually rapidly re-accumulates. Thoracoamniotic shunts may be offered in pregnancies complicated by hydrops secondary to the presence of a large or multiple communicating macrocysts or severe pleural effusions. Shunt placement has been reported to decrease congenital CAM mass volumes by an average of 50%, and as much as 80% in some cases.[56]

In cases of significant mass effect due to congenital CAMs (or other solid lung mases) recommendations for delivery can range from an ex utero intrapartum treatment (EXIT) procedure with tumor resection while still on placental bypass, to elective cesarean delivery and immediate pediatric surgical evaluation and resection, to delivery with on-site pediatric surgical services. In cases in which masses plateau earlier in their growth phase, and presents a nonsignificant risk of pulmonary hypoplasia or hemodynamic compromise, surgery can be planned as an outpatient at age 4-6 week.[66]  Therefore, the management of the congenital cystic lung abnormalities needs to consider the spontaneous improvement and possible resolution that occurs over months to years in many of these lesions.[67] Up to 15% of prenatally diagnosed congenital CAMs regress and may sonographically "disappear" by becoming isoechoic within the surrounding normal lung tissue. However, these lesions can still be identified on postnatal CT scan with contrast.

The risks of subsequent malignant degeneration of congenital CAMs are poorly understood. After removal by lobectomy, the remaining normal ipsilateral lung demonstrates compensatory lung growth, and in general these children have no residual respiratory problems.[66]

Thoracocentesis or thoracoamniotic shunts can allow for drainage of fluid from the congenital CAM, but the fluid usually rapidly reaccumulates. Thoracoamniotic shunts may be offered in pregnancies complicated by hydrops secondary to the presence of a large or multiple communicating macrocysts or severe pleural effusions. Shunt placement has been reported to decrease congenital CAM mass volumes by an average of 50%, and as much as 80% in some cases.[66]

Intrauterine vesicoamniotic shunts and endoscopic ablation of posterior urethral valves are other techniques that are currently used in fetuses with urinary tract obstruction and pulmonary hypoplasia. With careful case selection, pulmonary hypoplasia is prevented, and postnatal renal and respiratory function is improved.[71]

Congenital diaphragmatic hernia

In experimental animals, percutaneous fetal endoluminal tracheal occlusion (FETO) induces lung growth and morphologic maturation. FETO with a clip may lead to accelerated lung growth and prevent pulmonary hypoplasia. FETO is currently being studied at some centers across Europe, as a way to improve survival in cases of pulmonary hypoplasia associated with severe CDH.[72] There are variations in the technique but most centers prefer the non-invasive technique, where a balloon, inserted into the tracheal lumen at 22-28 weeks' gestation.[73] Balloon occlusion creates a transpulmonic pressures, prevent fluid egress of fluid from the fetal lung which stimulate lung growth. It has been suggested that later insertion of the balloon beyond 29 weeks does not results in significant lung growth.[74]   A recent study from Texas has reported improved postnatal outcomes in infants with severe CDH.[75] This procedure was found to be minimally invasive, may reverse pulmonary hypoplasia changes, and may improve survival rate in these highly selected cases. In addition, the airways can be restored before birth.

The optimal time of surgery for CDH repair varies from center to center. Surgical repair typically involves primary or patch closure of the diaphragm through an open abdominal approach. Successes have been reported with an endoscopic approach; however, it is associated with an increased incidence of hernia recurrence.[76] The decision is made based on the severity of the lesion, hemodynamics of the patient and the center's preferences. Intraoperative considerations include the length of operative time, as thoracoscopic repair is associated with substantially longer operative times, leading to concerns for intraoperative instability, carbon dioxide retention, and pulmonary vasospasm for patients with moderate-to-severe pulmonary hypertension.[77]  There are some studies that suggest that early intervention in patients on ECMO, reduced the total duration of ECMO, reduced surgical complications and increased survival. However, this data may be skewed toward patients who may have been too sick to be weaned off ECMO prior to surgery and further studies are needed.[78]  

 

These patients should be followed by a pediatric pulmonologist after birth so that appropriate diagnostic tests can be performed and routinely followed. If early surgery is not performed during infancy, close follow-up of these patients is needed. As indicated above, some cystic lung abnormalities can spontaneously resolve over months to years. Newborns who have been referred for a cystic lesion observed by fetal ultrasonography may have complete resolution on postnatal chest CT. Also, the occurrence of pneumonia or repeated respiratory infections may suggest surgical intervention is needed in a patient who has been conservatively managed.

Consult a pediatric surgeon for CDH, CAM, or any other lesion that requires surgery. Also, consult a pediatric surgeon in cases that involve pulmonary hypertension or respiratory failure that requires ECMO.

Consult a nephrologist and a urologist if a renal obstructive, cystic, or agenetic lesion is the cause of the pulmonary hypoplasia.

Consult a cardiologist and cardiothoracic surgeon if the patient has a causative or coexisting cardiac lesion, such as anomalous pulmonary venous connection.

Consult a neurologist in cases of congenital neuromuscular diseases.

Preterm rupture of membranes and an imminent preterm delivery is managed with tocolytics to control contractions and to prevent delivery, as indicated. Maternal steroids to accelerate lung maturity of the fetus are indicated in preterm labor.

The most common tocolytic agents used for the treatment of preterm labor are magnesium sulphate (MgSO4), indomethacin, and nifedipine. In the past, beta-mimetic agents, such as terbutaline or ritodrine, were the agents of choice, but in recent years their use has been significantly curtailed due to maternal and fetal side effects, such as maternal tachycardia, hyperglycemia, and palpitations. The use of these agents can lead to pulmonary edema, myocardial ischemia, and cardiac arrhythmia. The tocolytic agents currently used to treat preterm labor appear to be equally efficacious in delaying delivery for at least 48 hours. Although MgSO4 is associated with more maternal toxicity, indomethacin is associated with more fetal and neonatal toxicity. For more information, see Preterm Labor.

Class Summary

These agents are used to induce or accelerate lung maturity in a preterm newborn at less than 32 weeks' gestation or when lung immaturity is known by amniotic fluid assay. Long-acting steroids (eg, dexamethasone, betamethasone) are recommended by a National Institutes of Health (NIH) Consensus Conference panel for all pregnancies at 24-34 weeks' gestation at risk of preterm delivery, in patients with preterm rupture of membranes at less than 30-32 weeks' gestation, and in complicated pregnancies with anticipated delivery before 34 weeks' gestation unless the corticosteroid will have an adverse effect on the mother.

Dexamethasone (Decadron)

Decreases frequency of respiratory distress syndrome, surfactant therapy, and serious intraventricular hemorrhage. Optimal benefit occurs within 24 h and lasts for 7 d.

Betamethasone (Celestone Soluspan)

Decreases frequency of respiratory distress syndrome, surfactant therapy, and serious intraventricular hemorrhage. Optimal benefit occurs within 24 h and lasts for 7 d.

Class Summary

These agents are administered at birth to newborns to improve lung mechanics and oxygenation when treating airspace disease. Following inhaled administration, surface tension is reduced, and alveoli are stabilized, thus decreasing the work of breathing and increasing lung compliance.

Beractant (Survanta)

A semisynthetic bovine lung extract that contains phospholipids, fatty acids, and surfactant-associated proteins B (7 mcg/mL) and C (203 mcg/mL).

Calfactant (Infasurf)

A natural calf lung extract that contains phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL).

Since chronic lung disease is common in survivors of pulmonary hypoplasia, these infants and children have an increased risk of fatality and serious morbidity from upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs). Antiviral and antibiotics should be administered based on clinical symptoms and signs.

Children may be given bronchodilators and/or inhaled corticosteroids for the treatment of wheezing episodes and/or reactive airway disease.

Respiratory syncytial virus (RSV) prophylaxis should be considered during RSV season in infants younger than two years who have been treated with oxygen or medication for chronic lung disease within 6 months of the start of RSV season. Palivizumab is a humanized monoclonal antibody (IgG) directed against the fusion protein of RSV and has been shown to reduce the risk of hospitalization from RSV infection in high-risk pediatric patients by 55%. RSV season in most parts of the United States is from October to March. The dose is 15 mg/kg via intramuscular injection monthly throughout RSV season.

Children with pulmonary hypoplasia should receive the influenza vaccine at the start of every influenza season, which in the United States, while varying from season to season, begins as early as October. The influenza season peaks in January or February and continues as late as May.

Children with chronic lung disease are considered at high risk for invasive pneumococcal disease. If younger than two years, they should be administered the 13-valent pneumococcal conjugate vaccine (PCV13) 4-dose series at ages two, four, and six months, with a booster dose at 12-15 months. If aged 24 months to five years, they should receive 1 or 2 doses of PCV13 if they have not already completed the 4-dose series. Anyone over the age of two, with chronic lung disease, should also receive 1 dose of PCV23.

Various aerosolized medications such as bronchodilators and corticosteroids should be considered if symptoms suggest reactive airway disease or obstructive airway disease.

Persistent pulmonary arterial hypertension can be treated with various pulmonary vasodilators such as inhaled nitric oxide and sildenafil, and endothelin receptor inhibitors such as bosentan.