eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Pulmonary Hypoplasia

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Coauthor(s): Girija Natarajan, MD, Assistant Professor, Division of Neonatology, Children's Hospital of Michigan & Wayne State University; Ibrahim Abdulhamid, MD, Assistant Professor of Pediatrics, Wayne State University; Director of Pediatric Pulmonary Medicine, Clinical Director of Pediatric Sleep Laboratory, Children's Hospital of Michigan
Contributor Information and Disclosures

Updated: Mar 5, 2009

Introduction

Background

Pulmonary hypoplasia or aplasia is part of the spectrum of malformations characterized by incomplete development of lung tissue.

Pathophysiology

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 factors affect the volume and composition of the amniotic fluid, including the following:

• Volume and pressure
  • The volume of liquid in the lung is determined by the net rate at which liquid is secreted across the pulmonary epithelium (4-5 mL/kg/h) and the rate at which it flows from the trachea into the fetal pharynx. The pressure in the fetal trachea is normally about 2 mm Hg higher than in the amniotic fluid, thus preventing outflow of fetal lung fluid.
  • Any alteration in the critical volume and pressure relationships of amniotic fluid in the trachea and lung during the canalicular stage of fetal lung development at 15-28 weeks' gestation can induce hypoplasia.
• Composition of lung fluid
  • Lung development is regulated by several transcription factors, such as thyroid transcription factor 1 (TTF-1) family, hepatocyte nuclear family, and peptide growth factors.
  • The presence of growth factors in amniotic fluid indicates that lung development is not solely a pressure phenomenon. Signals from these growth factors are integrated with environmental influences, such as lung fluid volume and hyperoxia, to cause cellular proliferation and differentiation. A key component is the branching morphogenesis that occurs as a result of an interaction between the endodermal and mesenchymal components. Growth factors are produced by mesenchymal tissue and are present in amniotic fluid. Therefore, the expression of a number of growth factors and their receptors, all of which affect fetal lung development, is temporally and spatially regulated.
• Role of the kidney in lung growth
  • Lung development starts during the midtrimester with branching morphogenesis and is completed postnatally with the development of alveoli. Fetal urine is an important component of amniotic fluid during late gestation and contributes to lung growth. During fetal development, the kidney is also a major source of proline. Proline aids in the formation of collagen and mesenchyme in the lung, thus explaining the severe pulmonary hypoplasia in renal agenesis and dysplasias.
  • Pathologically, the hypoplastic lung has reduced lung weight, alveolar number, fewer generations of airways, and hypoplasia of the corresponding pulmonary arteries. Epithelial differentiation is delayed, and surfactant deficiency is associated.
  • 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.
    • Studies have revealed the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH, with implications of retinoids in the development of the diaphragm and the lung.¹
    • A nitrofen-induced CDH model demonstrates that lung hypoplasia may precede the diaphragmatic defect, leading to a dual-hit hypothesis.
    • Studies have demonstrated that prenatal treatment with retinoic acid in the nitrofen model of CDH stimulated alveologenesis in hypoplastic lungs² by increasing type 1 alveolar cell proliferation.³
  • Studies using nitrofen-induced hypoplastic lung explants indicate a possible role for interleukin-6 (IL-6) in catch-up growth.⁴
  • The role of other mesenchymal growth factors such as overexpression of fibroblast growth factor-10 (FGF10) in cystic adenomatoid malformation (CAM) development has been studied.⁵

Frequency

United States

The true incidence is unknown, but the etiologies (in order of frequency) include prolonged rupture of membranes, fetal renal dysplasias and obstruction, and fetal neuromuscular diseases. In cases of premature rupture of membranes at 15-28 weeks' gestation, the reported incidence of pulmonary hypoplasia ranges from 9-28% (13% in most studies). Lung hypoplasia also occurs in association with diaphragmatic hernia and congenital cystic lung lesions such as CAMs. The occurrence of CDH is estimated at 0.08-0.45 cases per 1000 births.

International

In Canada, the estimated incidence of CAM is 1 per 25,000-35,000 pregnancies.

Mortality/Morbidity

In different studies, mortality rates of 71-95% have been reported during the perinatal period in patients with pulmonary hypoplasia.

The following conditions increase the risk of mortality:

• Premature rupture of membranes at less than 25 weeks' gestation
• Severe oligohydramnios (amniotic fluid index <4) for more than 2 weeks
• Earlier delivery

To avoid mortality from severe lung hypoplasia in association with diaphragmatic hernia or CAM, fetal surgical intervention has been attempted. The survival rate of CDH is 55-65%. A review of 11 centers reported an overall survival rate of 79%, with infants with isolated CDH having a survival of 85%.⁶  Most studies report a mortality rate of 25-30% in neonates with CAM. However, in other cystic lung lesions, most are clinically asymptomatic and may not need aggressive management.⁷

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.

Race

No racial predilection has been noted.

Sex

No sex predilection has been noted.

Clinical

History

In patients with pulmonary hypoplasia, the clinical profile and the time of presentation vary depending on the extent of hypoplasia and other anomalies.

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.

Physical

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.

Pneumothorax, spontaneous or associated with mechanical ventilation, may occur. 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 lung hypoplasia caused by the associated renal defects.

When the etiology of the hypoplasia is a neuromuscular disease, the patient may have myopathic facies, with a V-shaped mouth, muscle weakness, and growth retardation.

Abdominal masses, such as cystic renal diseases and an enlarged bladder, must be sought. Associated anomalies of the cardiovascular, GI (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.

Causes

Pulmonary hypoplasia may be primary, but it is usually secondary, manifested by small fetal thoracic volume caused by compression in the hemithorax due to structures such as abdominal contents in congenital diaphragmatic hernia (CDH) or congenital anomalies such as congenital adenomatoid malformation (CAM) or cysts.

• The cause of primary pulmonary hypoplasia has not been identified. However, experimental models suggest deficiencies in certain transcription factors (eg, TTF-1, GATA factors, hepatocyte nuclear factor HNF3b10) or growth factors (eg, epidermal growth factor and its receptor, EGFR; mitogen-activated protein [MAP] kinase, connective tissue growth factor or CTGF⁸ ) can result in disordered lung growth.
• Causes of secondary pulmonary hypoplasia include the following:
• Small fetal thoracic volume
• CDH
• CAM
• Sequestration
• Pleural effusions with fetal hydrops
• Malformations of the thorax (eg, asphyxiating thoracic dystrophy)
• Achondroplasia
• Thanatophoric dwarfism
• Osteogenesis imperfecta
• Thoracic neuroblastomas
• Hydrothorax
• Eventration of the diaphragm
• Abdominal mass lesions
• Prolonged oligohydramnios
• Fetal renal agenesis
• Urinary tract obstruction
• Bilateral renal dysplasia
• Bilateral cystic kidneys
• Prolonged rupture of membranes
• Early rupture of membranes
• More severe oligohydramnios (amniotic fluid index <4)
• Longer latent period before delivery
• Decreased fetal breathing
• CNS lesions
• Lesions of the spinal cord, brain stem, and phrenic nerve
• Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)
• Arthrogryposis multiplex congenital
• Maternal depressant drugs
• Congenital heart diseases with poor pulmonary blood flow
• Tetralogy of Fallot
• Hypoplastic right heart
• Pulmonary artery hypoplasia
• Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
• Trisomies 18,13, and 21
• The role of retinoic acid and antioxidants in pulmonary hypoplasia has been extensively studied. Despite encouraging in vitro work, supplementation with vitamin A has not reduced pulmonary hypoplasia.
• Pressure appears to affect fetal lung growth. Specifically, airway distension may affect various developmental and signaling pathways such as receptor tyrosine kinase growth factors, homeobox genes, transcription factors, retinoid signaling, and oxidation reduction. Experimentally, tracheal occlusion in fetal animals induces lung growth. These encouraging observations in various animal models have led to application to human fetuses with CDH. A US trial was stopped early because the data monitoring board found no difference in the survival rate compared with standard therapy. However, a European trial is currently continuing with promising preliminary results.⁹
• The detrimental effect of compression of the lung by other tissue such as herniation of abdominal viscera in the thorax in CHD is further suggested by a case report of bilateral CDH with gastroschisis.¹⁰ Their newborn was born without pulmonary hypertension and had a favorable outcome.

• Search for CME/CE on This Topic »

• Pulmonary Hypoplasia (Radiology)
• Meckel-Gruber Syndrome (Pediatrics: Genetics and Metabolic Disease)
• Respiratory Distress Syndrome (Pediatrics: Cardiac Disease and Critical Care Medicine)
• Potter Syndrome (Pediatrics: General Medicine)

• A Day Too Long: Rethinking Physician Work Hours
• Neonatal Autosomal Recessive Polycystic Kidney Disease