Pulmonary Hypoplasia

Overview

Definition

Pulmonary hypoplasia is the insufficient or defective development of one or both lungs, resulting in underdeveloped or undeveloped pulmonary parenchyma with decreased alveoli and airway branches.

• Classified as:
  • Type I (agenesis): complete absence of lung parenchyma, bronchus, and vessels
  • Type II (aplasia): the complete absence of pulmonary parenchyma with rudimentary bronchus
  • Type III (hypoplasia): some degree of pulmonary parenchymal development with decreased number of airways and alveoli
• Severity depends on the underlying cause and its timing in relation to fetal lung development.
• Can be unilateral or bilateral

Epidemiology

• Rare condition overall, with high rate of neonatal mortality and chronic morbidity for survivors
• Exact incidence is unknown but estimated to be 1.4 per 1000 births.
• Mortality and degree of morbidity related to gestational age when impacted:
  • Often lethal
  • Mortality rate of 47% in the 1st 60 days of life in affected babies born alive
  • Mild to severe respiratory symptoms for children who survive the immediate neonatal period
  • Can be a cause of more mild and chronic respiratory symptoms, sometimes discovered later, even into adulthood

Etiology

• Impairment of lung development, especially before 22 weeks of gestational age
• Causes involve multiple factors: 
  • Genetic
  • Environmental
  • Maternal
  • Nutritional
• Primary hypoplasia:
  • Rare and fatal (e.g., congenital acinar dysplasia)
  • Not well understood but are thought to be genetic mutation in growth and transcription factors, which are key to lung development
• Secondary hypoplasia:
  • Majority of cases
  • Due to other fetal developmental abnormalities
  • Conditions that lead to reduced space of the thoracic cavity during fetal development:
    • Congenital diaphragmatic hernia (CDH)
    • Fetal hydrops (pleural effusion)
    • Mediastinal mass
    • Congenital cystic adenomatoid malformations or CCAM (now referred to as congenital pulmonary airway malformation (CPAM))
    • Abdominal tumors
    • Skeletal abnormalities (thoracic dystrophy or Jeune syndrome, skeletal dysplasia, chest wall tumors)
  • Conditions associated with oligohydramnios before 28th week of gestation:
    • Renal agenesis
    • Urinary outflow tract obstructive lesions
    • Prolonged, preterm membrane rupture
    • Bilateral cystic kidneys
  • Disorders of impaired breathing:
    • Phrenic nerve abnormality
    • Neuromuscular or CNS disorders
  • Chromosomal abnormalities:
    • Trisomy 21 (Down syndrome)
    • Trisomy 13 (Patau syndrome)
    • Trisomy 18 (Edwards’ syndrome)
  • Congenital heart disease with pulmonary blood flow impairment:
    • Tetralogy of Fallot
    • Pulmonary artery hypoplasia
    • Hypoplastic right heart

Pathophysiology

Fetal lung development

• 4th week of gestation:
  • Laryngotracheal groove forms from the wall of the primitive pharynx → the groove elongates, with distal end bifurcating into tracheal buds and then bronchial buds
  • Process of elongation and branching of buds continues as conducting airways up to 16 weeks of gestation.
• From 16 weeks to birth, the gaseous exchange system (acini) develops:
  • 16–26 weeks: canalicular stage
  • 26–40 weeks: terminal sac stage
• Normal development of the fetal lung depends on: 
  • Normal thoracic cavity space
  • Mechanical forces that require adequate amniotic fluid:
    • Spontaneous contraction of developing airways
    • Fetal breathing movements

Abnormal fetal lung development

Multiple aspects of the impairment of fetal lung growth can lead to hypoplasia.

• Oligohydramnios:
  • Lack of amniotic fluid → lack of lung distensibility and arterial branching → decreased surface area for gas exchange
  • Can be secondary to:
    • Premature rupture of membranes at early gestational age
    • Renal dysgenesis or agenesis (at 16 weeks of gestational age, fetal urine becomes the main source of amniotic fluid)
  • Potter sequence, or Potter syndrome (historic term), encompasses features resulting from oligohydramnios and causing mechanical compression: 
    • Pulmonary hypoplasia
    • Limb deformities
    • Potter facies (flattened nose, recessed chin, epicanthal folds, low-set ears)
• Reduced thoracic space:
  • Intrathoracic lesions:
    • CPAM
    • Pleural effusion
  • Extrathoracic lesions:
    • CDH
    • Ascites
    • Eventration of diaphragm 
• Impairment in fetal breathing, which is important for lung maturation:
  • Neuromuscular:
    • Spinal muscular atrophy
    • Congenital myotonic dystrophy
  • Restrictive:
    • Congenital thoracic dystrophy
    • Short rib polydactyly syndrome
  • Brain stem impairment of normal breathing patterns

Clinical Presentation

Antenatal

• Decreased fetal movement during pregnancy
• Oligohydramnios
• Ultrasound detection of anatomic malformations or masses
• Ultrasound detection of other congenital abnormalities
• Prenatal diagnosis of associated chromosomal abnormalities 

Postnatal

• Often lethal
• Babies who survive the immediate neonatal period may have:
  • Mild to severe respiratory distress
  • Bell-shaped thoracic cavity in bilateral pulmonary hypoplasia
  • Asymmetrical ventilation and decreased ventilation on the affected side, if unilateral
  • Imaging showing:
    • Space-occupying lesion such as CPAM
    • Interthoracic abdominal contents on the affected side
  • Bronchopulmonary dysplasia
  • Alveolar hemorrhage
  • Pneumothorax
  • Renal mass or enlarged bladder
  • Classic Potter syndrome features:
    • Potter facies
    • Pulmonary hypoplasia
    • Limb deformities
• If mild at birth, later development of:
  • Recurrent pulmonary infections
  • Exercise intolerance

Complications

• Immediate neonatal period:
  • Acute respiratory failure
  • Pneumothorax
  • Tracheomalacia
  • Pulmonary hypertension
• Long term:
  • Chronic lung disease
  • Respiratory infections
  • Limited exercise capacity
  • Poor growth
  • Scoliosis

Mnemonic for Potter sequence

• P: pulmonary hypoplasia (leads to respiratory insufficiency)
• O: oligohydramnios (can be the cause or an associated finding)
• T: twisted face (e.g., beaked nose, low-set ears, prominent epicanthal folds)
• T: twisted skin
• E: extremity defects (limb malformations)
• R: renal failure (in utero)

Diagnosis

Antenatal

• Fetal ultrasonography to look for:
  • Oligohydramnios
  • Decreased fetal movement
  • Growth restriction or anatomic abnormalities
  • Hydrops
  • Intrathoracic masses
  • Ratio of thoracic circumference to abdominal circumference: < 0.6
  • Lung weight:body weight (LW:BW) ratio: 
    • 0.015 if < 28 weeks
    • 0.012 if > 28 weeks
  • Radial alveolar count:
    • Defined as number of alveoli that cross a line drawn from a respiratory bronchiole to the nearest connective tissue septum
    • < 75% of the standard value
• MRI:
  • Abnormal anatomy
  • Volumetric assessment 
• Chromosomal analysis showing abnormalities associated with pulmonary hypoplasia: 
  • Trisomy 21 (Down syndrome)
  • Trisomy 13 (Patau syndrome)
  • Trisomy 18 (Edwards’ syndrome)

Postnatal

• Initial physical exam:
  • Check level of respiratory distress.
  • Scaphoid abdomen seen with CDH
  • Decreased or absent lung sounds on the affected side
  • Potter syndrome features (flattened facies, limb malformations)
  • Other physical findings typical for other underlying chromosomal abnormalities:
    • Trisomy 21: hypotonia, murmur, epicanthal folds, simian crease
    • Trisomy 13: cleft lip and/or palate, hypotonia, microphthalmia
    • Trisomy 18: microcephaly, clenched fists, convex sole of foot (rocker bottom)
    • 22q deletion: craniosynostosis, polydactyly
• Chest X-ray:
  • Bilateral pulmonary hypoplasia is shown by bell-shaped chest and elevation of the diaphragm.
  • Unilateral pulmonary hypoplasia shows:
    • Opaque hemithorax
    • Rib crowding
    • Ipsilateral mediastinal shift
    • Hyperinflated contralateral lung in unilateral pulmonary hypoplasia
• CT: to confirm hypoplasia and rule out other causes of respiratory distress
• Electrocardiography
• Chromosomal analysis in some cases, and counseling for parents
• Pulmonary function tests for older children and adults

Management

Antenatal

• Steroids to help with fetal lung maturation in fetuses 24–34 weeks of gestational age
• Tocolytics and antibiotics in the case of premature rupture of membranes
• Amnio-infusion and amniopatch can be attempted.
• Fetal endoscopic tracheal occlusion may improve outcomes for CDH (under investigation):
  • Occlusion blocks the airway, allowing fluid buildup and lung growth.
  • Pulmonary artery hypertension and pulmonary hypoplasia can be minimized.
  • Occlusion (tracheal balloon) is removed before birth and timed to allow for type 2 pneumocyte development and adequate surfactant production.

Postnatal

• Immediate respiratory support as needed; may include:
  • Supplemental oxygen
  • Surfactant administration
  • Endotracheal intubation and mechanical ventilation
  • ECMO
• Inhaled NO for pulmonary hypertension
• Surgical correction in cases of CDH and other congenital defects
• Address other complications (e.g., cardiac, gastrointestinal)

Prognosis

• Primary pulmonary hypoplasia is rare and usually lethal.
• Overall prognosis depends on: 
  • Underlying cause
  • Associated conditions
  • Degree of hypoplasia
• Poor prognostic factors:
  • CDH has a 50% mortality rate, with worse prognosis in:
    • Right-sided lesion
    • Associated pulmonary hypertension
  • Presence of genetic abnormalities
  • Severe oligohydramnios for > 2 weeks
  • Rupture of membranes, especially at < 25 weeks of gestation
• Other factors to consider:
  • Infants with unilateral pulmonary hypoplasia can do well if there are no associated lesions or genetic anomalies.
  • Some infants delivered many weeks after premature rupture of membranes can have good outcomes, with improved lung function over time.
  • Pulmonary hypertension may resolve with good support and management.
• Survivors may have:
  • Chronic lung disease
  • Limited exercise tolerance
  • Increased risk of pulmonary infection

Clinical Relevance

• Congenital diaphragmatic hernia: a congenital defect in the fetal diaphragm that allows herniation of abdominal contents into the thorax, leading to pulmonary hypoplasia on the affected side: The types of hernia are posterolateral Bochdalek (left-sided Bochdalek in 85% of cases), anterior Morgagni, paraesophageal, and hiatal. Mild cases can be repaired in the first days of life with a good long-term prognosis. More severe cases require high levels of support, with long-term respiratory, neurodevelopmental, and growth issues and can be lethal.
• Congenital pulmonary airway malformation (CPAM): previously known as congenital cystic adenomatoid malformation (CCAM): Rare hamartomatous cystic and adenomatous lesions in the lung can occur in either side of the lung (unilobar or multilobar). If large enough, these lesions can lead to pulmonary hypoplasia and hydrops. Affected children can be asymptomatic at birth or can present with infections. Other risks include spontaneous pneumothorax and, rarely, malignancy. Management may involve resection before 1 year of age or close observation, depending on the size and other risk factors.
• Oligohydramnios: amniotic fluid volume reduced for gestational age: Diagnosis is by ultrasonography: amniotic fluid index of ≤ 5 cm. The different etiologies include maternal (e.g., medications, preeclampsia), placental (e.g., abruption), fetal (e.g., chromosomal abnormalities), and/or idiopathic. First-trimester oligohydramnios carries a poor prognosis. For subsequent trimesters, a fetal structural survey is performed, determining fetal abnormalities, along with serial ultrasound monitoring. Short-term improvement can be achieved with amnio-infusion.
• Trisomy 21, or Down syndrome: a genetic syndrome caused by the presence of an extra chromosome 21; associated with advanced maternal age: This syndrome may be suspected on fetal ultrasonography and on prenatal screening (typically low alpha-fetoprotein, estriol) and confirmed with genetic testing. Classic features include hypotonia, short neck, epicanthal folds, cardiac defects, and simian crease. There is an increased incidence of pulmonary hypoplasia.
• Trisomy 18 (Edwards’ syndrome): the 2nd most common trisomy. This genetic syndrome is caused by the presence of 3 copies of chromosome 18, with predominance in girls. Characteristic features include intrauterine growth restriction, cardiac defects, clenched fists with overlapping fingers, and rocker bottom feet. Other findings can include diaphragmatic eventration and lung hypoplasia. Diagnosis is made by karyotype analysis. No treatment is available, and many patients do not survive beyond 1 year of life.
• Trisomy 13 (Patau syndrome): the 3rd most common trisomy: This genetic syndrome is caused by the presence of 3 copies of the 13th chromosome. Clinical features include brain and spinal cord malformations, cardiac defects, eye defects, cleft lip/palate, and hypotonia. This syndrome is also associated with pulmonary hypoplasia. Diagnosis is made by karyotype analysis. No treatment is available, and most patients do not survive beyond 1 year of life.