Continuing Education Activity

Pulmonary hypoplasia is a relatively uncommon medical condition characterized by incomplete development of the lungs that can affect the overall development of the child. It can be either primary (idiopathic) or secondary to other congenital anomalies and usually leads to severe respiratory insufficiency in the fetus. This activity describes the pathogenesis, clinical, radiological features and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Describe the pathophysiology of hypoplastic lung disease.
• Outline the typical presentation of patients with hypoplastic lung disease.
• Summarize the typical imaging findings associated with pulmonary hypoplasia.
• Explain the importance of collaboration and communication among the interprofessional team to enhance the delivery of care for patients affected by hypoplastic lung disease.

Introduction

Pulmonary hypoplasia is a rare congenital anomaly characterized by incomplete development of the lung tissue. There are impaired gaseous exchange and respiratory insufficiency due to a decrease in the number of airways and alveoli.[1] 

Primary forms of idiopathic lung hypoplasia are rare, with the vast majority of cases occurring due to other developmental fetal abnormalities. In 1912, Schneider classified abnormal development of lung into three types, modified by Boyden in 1955 as:

• Type 1 (Agenesis): The complete absence of pulmonary parenchyma, bronchus, and vessels.
• Type 2 (Aplasia): The complete absence of pulmonary parenchyma but the presence of a rudimentary bronchus on the affected side.
• Type 3 (Hypoplasia): The presence of variable amounts of pulmonary parenchyma with a decrease in the number of lung cells, airways, and alveoli.[2]

The extent of hypoplastic pulmonary tissue depends on the timing of the insult during the stages of fetal lung maturation. The maturation arrest happens during the pseudo glandular stage between 5 to 17 weeks of gestation. During this stage, lung development depends on mechanical stimuli. An imbalance of the pressure between the extraluminal space and intraluminal airway results in compression of the lung(s) tissue and resultant hypoplastic lung tissue. The clinical course ranges from fatal respiratory insufficiency in neonates (severe form) to chronic lung disease with recurrent respiratory infections (mild form) in adulthood.[3]

Etiology

The etiology of primary pulmonary hypoplasia is not entirely understood. It is multifactorial in origin with genetic, environmental, maternal, and nutritional factors all thought to be contributing. Examples of primary pulmonary hypoplasia include congenital acinar dysplasia and hypoplastic lung in genetic disorders like trisomy 21. Secondary causes of pulmonary hypoplasia are due to fetal lung compression secondary to underlying anomalies affecting the thoracic cavity or amniotic fluid volume.

Intrathoracic or intra-abdominal space-occupying lesions like congenital diaphragmatic hernia (CDH), congenital cystic adenomatoid malformations are frequently referred to in the current literature as congenital pulmonary airway malformation (CPAM) or chest wall deformities like skeletal dysplasias interfere with fetal lung development before 16 weeks of gestation. In contrast, oligohydramnios secondary to lack of functional renal parenchyma (renal agenesis, Potter syndrome), urinary outflow tract abnormalities, or prolonged premature rupture of membranes (PPROM) affect lung development after 16 weeks of gestation.[4] 

Premature rupture of membranes has also been associated with increased risk of hypoplasia secondary to oligohydramnios, with gestational age less than 25 weeks and oligohydramnios with a pocket less than 1 cm as independent risk factors for fatal pulmonary hypoplasia.

Epidemiology

The exact incidence is unknown. In the general population, the incidence of pulmonary hypoplasia is 1.4 per 1000 in all births and 0.9 to 1.1 per 1000 live births.[5][6] However, estimates suggest that these numbers are falsely underestimated given infants with less severe disease survive the neonatal period and are determined to have respiratory symptoms later in life. In a prospective study conducted by Winn et al. in the United States, the incidence of pulmonary hypoplasia was 12.9% (21 of 163 births) in patients with mid-trimester rupture of membranes between 15 to 28 weeks of gestation. 

Mortality was as high as 95.2% ( 20/21) in the hypoplasia group compared with 48.2% (68/141) in patients without pulmonary hypoplasia.[7] A recent retrospective analysis conducted in Spain found the mortality rate to be 47% within the first 60 days of life and 75% of the deaths on the first day of life.[8]

Pathophysiology

During the fourth week of intra-uterine life, the laryngotracheal groove arises from the wall of the primitive pharynx. The groove elongates into the splanchnopleuric mesoderm to form the respiratory diverticulum. The distal end becomes bifid to form two lung buds. Each lung bud then undergoes the repeated process of branching and elongation such that the conducting airways develop by the 16 weeks of organogenesis. Acini development then takes place to form the gaseous exchange system during the canalicular (16 to 26 weeks) and terminal sac (26 weeks to birth) stages of lung development with continued maturation till childhood. The mechanical forces play an essential role in fetal lung development during the pseudo glandular stage of organogenesis. The spontaneous contractions of airways and fetal breathing movements regulate fluid movement in and out of the lung.[3] 

Oligohydramnios decreases the distensibility of the lungs by reducing the fluid around the potential airspaces. Severe hypoplasia is associated with a reduction in alveolar size and number with a proportional decrease in the pulmonary vasculature.[9] Factors such as early gestational age at rupture of membranes, a latency period of more than six days, and amniotic fluid index (AFI) less than 1 to 2 cm (single deepest cord-free pocket of amniotic fluid) are independent risk factors for pulmonary hypoplasia in neonates with premature rupture of membranes. Pulmonary hypoplasia is an important non-renal feature of Potter syndrome. In Potter syndrome, there is oligohydramnios due to renal agenesis or outflow tract abnormality with a decrease in fetal urine excretion into the amniotic space. The oligohydramnios leads to prolonged fetal lung compression with subsequent hypoplasia.[10] 

Mechanical compression may be due to intra-thoracic or extrathoracic lesions, including congenital diaphragmatic hernia, eventration of the diaphragm, ascites, pleural effusion, cystic malformations of the lung. A regular fetal breathing pattern is imperative for adequate lung maturation. Brainstem anomalies like iniencephaly, neuromuscular problems such as spinal muscular atrophy, or congenital myotonic dystrophy cause ineffective fetal breathing movements and reduction in fetal lung volume. Restrictive chest wall defects, as seen in congenital thoracic dystrophy or short rib polydactyly syndrome, cause impairment in the typical breathing pattern.

The hypoplastic lung could be a part of an abnormally formed right lung as in the Scimitar syndrome. Primary hypoplasia is still widely understudied, but many believe that the underlying cause may be secondary to abnormalities with growth factors like the fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor, or the transcription factors like TTF-1 (thyroid transcription factor 1), and FGFs (fibroblast growth factors) 7 and 10. These factors are responsible for normal lung development, and genetic mutation in any of these factors can result in pulmonary hypoplasia. Abnormalities in the fetal breathing activity, thoracic cavity, or amniotic fluid volume can lead to primary pulmonary hypoplasia. Alternatively, it could be related to the delayed development of the lungs or some degree of functional lung compression with no apparent structural defect.[11]

Histopathology

Several pathological criteria are present for diagnosing pulmonary hypoplasia, but there is no particular gold standard. The most commonly used measure is the lung weight to body weight ratio (LW: BW). The typical ratio is 0.012 for more than 28 weeks of gestation and 0.015 for younger fetuses. The pitfall of the criteria is that it is affected by pulmonary congestion or pulmonary edema.[12] 

The second method for detecting hypoplasia is the radial alveolar count, which was initially proposed by Emery and Mithal. The radial alveolar count (RAC) is defined as the number of alveoli crossing a line drawn from a respiratory bronchiole center to the nearest and definitive connective tissue septum. Askenazi and Perlman did a modification with the counting of the alveolar septae instead of the alveoli. They suggested that radial alveolar count (RAC) <75 % of the mean or LW: BW of less than or equal to 0.012 to be used for diagnosing pulmonary hypoplasia.[13]

History and Physical

The presentation of pulmonary hypoplasia encompasses a broad spectrum that is dependent upon the extent of hypoplasia, as well as other abnormalities associated with the underlying cause. In most cases, it is lethal. Sub-lethal cases present in early infancy as mild to severe respiratory insufficiency, depending on the extent of involvement. Prenatal care may illustrate decreased fetal movement, premature rupture of membranes fluid, and oligohydramnios. The severe cases may be associated with pulmonary hypertension with persistent fetal circulation, bronchopulmonary dysplasia, or alveolar hemorrhage. The mild forms of pulmonary hypoplasia remain undiagnosed until adulthood when they present as an incidental finding on chest radiograph or as recurrent respiratory infections. Isolated exercise desaturation may sometimes be the only clinical feature.

In cases of unilateral hypoplasia, there is an asymmetric appearance of the thoracic cage with restricted chest wall expansion and reduced breath sounds on the affected side. There is herniation of contralateral organs to the affected hemithorax. Bilateral pulmonary hypoplasia typically presents with bell-shaped thoracic cage deformity. The majority of these patients are often tachypneic and in respiratory distress with a shallow breathing pattern. Secondary pulmonary hypoplasia may have associated with congenital anomalies, and sometimes the anomaly is the index for suspicion of pulmonary hypoplasia.

There may be coexisting defects in the cardiovascular, gastrointestinal, genitourinary, and skeletal system. Congenital diaphragmatic hernias present with a scaphoid abdomen and respiratory insufficiency at birth. There are associated congenital heart defects, neural tube defects, or renal anomalies along with the hernia. Potter syndrome presents with many characteristic physical findings at birth. The non-renal features of Potter syndrome, including facial abnormalities, hypertelorism, large floppy ears, flat nose, spade-like hands, and flexion contractures, are seen in conjunction with hypoplastic lungs due to oligohydramnios.

Evaluation

Routine laboratory investigations have a limited role. The cases of oligohydramnios warrant an evaluation of the renal profile like serum creatinine, blood urea nitrogen, and electrolytes. In patients with unilateral lung hypoplasia, plain chest radiography will typically demonstrate an opaque hemithorax with rib crowding and ipsilateral mediastinal shift. There is compensatory hyperinflation of the contralateral lung. The chest radiograph shows a pneumothorax or pneumomediastinum in cases of air leaks.

Computed tomography (CT) of the chest can be done for confirmation of pulmonary hypoplasia and to differentiate from other conditions like Swyer James syndrome or atelectasis. Radiological features on CT include absent or rudimentary bronchus and underlying pulmonary vasculature with collapsed lung on the same side. Ventilation-perfusion scanning shows the absence of ventilation and perfusion in the affected area with more significant impairment in perfusion, leading to a mismatched perfusion defect.

ECG is useful to differentiate between dextrocardia and dextroversion in cases of right lung hypoplasia. There is right axis deviation, positive QRS complex in aVR, and inversion of all waves in Lead-I. Two-dimensional echocardiography (2D Echo) can rule out congenital cardiac anomalies.  

Biometric indices like lung area, thoracic circumference (TC), thoracic circumference to abdominal circumference (TC: AC) ratio have been used during 2D sonography to assess the fetal risk for pulmonary hypoplasia. Volumetric assessment by magnetic resonance imaging (MRI) or 3D ultrasonography has shown some promise. However, unreliable positive and negative predictive value precludes their routine use for diagnosis.[14] 

Pulmonary function testing done in late childhood or adulthood reveals restrictive or obstructive lung defects with a reduction in the diffusion capacity.[15] Pathological criteria for diagnosing pulmonary hypoplasia include lung weight less than 60% of the predicted lung volume, radial alveolar count (RAC) of less than 4.1%, or less than 75% of the standard value, and lung weight to body weight. For infants younger than 28 weeks, the ratio is 0.015. For infants older than 28 weeks gestation, the ratio is 0.012.

Alternative methods for diagnosing pulmonary hypoplasia include alveolar count per unit volume, airway branching count, and lung DNA content of less than 100 mg/kg body weight. Microscopically, there is a decrease in the number of lung cells, fewer branching of bronchi, immature epithelial cells, reduced and thickened pulmonary vessels, and low surfactant concentration. The providers utilize many of the criteria mentioned above in the diagnosis of pulmonary hypoplasia, but there is not a strict diagnostic criterion established.[1][4]

Treatment / Management

Treatment begins in the antenatal period. In cases of preterm premature rupture of membranes, corticosteroids are used for fetal lung maturation in fetuses more than 24 weeks of gestation. The lecithin to sphingomyelin ratio of more than 2 in the amniotic fluid signifies a low risk of fetal distress in the newborn. A combination of antibiotics, corticosteroids, and tocolytics are frequently administered.[16] 

A study conducted by Locatelli et al. in 49 patients with premature rupture of membranes at <26 weeks of gestation demonstrated that serial amnioinfusions reduce perinatal complications and prolong pregnancy.[17] The AMIPROM pilot study (amnio-infusion in preterm premature rupture of membranes) conducted on 56 patients found no statistically significant differences in fetal or maternal outcomes. More extensive studies are needed to ascertain its benefits.[18]

An amniopatch is an alternative that consists of an intraamniotic injection of platelets and cryoprecipitate.[19] In the immediate post-partum period, the infants may require respiratory support, which can be utilized in the form of supplemental oxygen to mechanical ventilation to extracorporeal membrane oxygenation. Limited data exist suggesting the possible benefit of inhaled nitric oxide, but more extensive studies are needed before results show a definitive advantage.[20] 

In regards to congenital diaphragmatic hernias, fetal endoscopic tracheal occlusion minimizes pulmonary arterial hypertension and hypoplasia so that the fetus remains viable to undergo maturation. The major limiting factor is that tracheal occlusion leads to a reduction in the number of type 2 pneumocytes and hence reduced surfactant proteins. The tracheal balloon is deflated shortly before delivery to help restore the surfactant expression.[21] 

Surgical repair of congenital repair is best delayed for 48-72 hours after birth to allow time for cardiopulmonary stability.[22] Timing for surgical repair in a patient on ECMO is highly variable, but a delayed approach reduces operative morbidity and increases survival.[23] 

Survivors of pulmonary hypoplasia tend to have chronic lung disease. Management in adults is conservative with bronchodilators for airway symptoms, antibiotics for respiratory infection, chest physiotherapy, and prophylactic vaccinations. Localized bronchiectasis associated with recurrent respiratory infections can be surgically resected.

Differential Diagnosis

The differential diagnosis for unilateral low lung volume on thoracic imaging include:

1. Scimitar syndrome: Hypoplasia of the right lung with anomalous venous drainage of the right lung to the inferior vena cava.
2. Congenital pulmonary airway malformation: Cystic structure arising from the trachea or bronchi with mediastinal shift to the opposite side.
3. Bronchopulmonary sequestration: Absent connection of the sequestrated segment to the tracheobronchial tree and blood supply is from the systemic artery instead of the pulmonary circulation. The mediastinal shift is to the affected side.
4. Congenital lobar emphysema: Hyperinflation of the involved pulmonary lobe with mediastinal shift to the contralateral lung.
5. Swyer James or Macleod syndrome: Post-infectious bronchiolitis leading to hyperlucent lung.
6. Persistent pulmonary hypertension of the newborn (PPHN).

Prognosis

Primary pulmonary hypoplasia is extremely rare but is lethal in most cases. Most of the cases are secondary, with significant morbidity in survivors. Perinatal mortality is as high as 70% (55-100%) in most cases.[1] 

Patients with unilateral pulmonary hypoplasia can typically experience healthy growth, development, and survivability in the absence of associated lesions. Patients with secondary hypoplasia demonstrate a wide variety of phenotypes secondary to the underlying cause. Of cases with a congenital diaphragmatic hernia, mortality is up to 50% in the perinatal period. The significant deterrents for survival in CDH include pulmonary hypoplasia and severe pulmonary hypertension, with the outcome being more grave in the right-sided congenital diaphragmatic hernia. Other indices for prognosis include associated neurological, gastrointestinal, musculoskeletal, and nutritional comorbidities. Infants who survive often experience chronic lung conditions like low exercise capacity and heightened susceptibility to infection.[24]

Complications

Complications in neonates with pulmonary hypoplasia include acute respiratory failure, tracheomalacia, persistent pulmonary hypertension, and pneumothorax. Pneumothorax could be either spontaneous or secondary to mechanical ventilation. Long term complications in survivors of pulmonary hypoplasia include growth retardation, chronic lung disease, recurrent respiratory infections, low exercise capacity, and chest wall deformity like scoliosis.

Deterrence and Patient Education

Patients require long term follow up and care for pulmonary hypoplasia and related conditions. A multi-disciplinary approach to patient care involving pediatricians, pulmonologists, intensivists, cardiovascular surgeons, and nephrologists is required. Education should begin in the prenatal period regarding natural history, expected complications, and prognosis, which could help the caregivers in decision making.

Enhancing Healthcare Team Outcomes

Pulmonary hypoplasia is a rare disease that has varied presentations. Diagnosis and management begin prenatally and extend into the postnatal period. Prenatal counseling should effectively be conducted upon the initial diagnosis of the illness and repeated at every subsequent visit. The prenatal counseling would facilitate the caregivers to make ethically informed decisions and build an understanding of the family's needs.

While the neonatologist will be inherently involved in the care of patients with pulmonary hypoplasia, it is essential to consult with an interprofessional team of specialists that include obstetrician, cardiothoracic surgery, nephrology, and pulmonary care. The nurses and respiratory therapists are also vital members of the interprofessional group as they will monitor the patient's vitals and assist with the education of the patient and family.

Radiology will play an essential role in supporting the interpretation of imaging studies, while pathology will assist with tissue evaluation. The pharmacy will also play an interval role in determining the dosage and correct form of additional medications that may have assistance with management. The outcome depends on the cause of the hypoplastic lungs and associated fetal anomalies.[25] [Level 3]