Pediatric Pulmonary Hypoplasia

Updated: May 20, 2014
  • Author: Terry W Chin, MD, PhD; Chief Editor: Michael R Bye, MD  more...
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Overview

Background

Pulmonary hypoplasia or aplasia is part of the spectrum of malformations characterized by incomplete development of lung tissue. It is a condition characterized by a reduction in the number of lung cells, airways, and alveoli that results in a lower organ size and weight. Pulmonary hypoplasia can be either unilateral or bilateral. See the image below.

Chest radiograph of a newborn with primary pulmona Chest radiograph of a newborn with primary pulmonary hypoplasia of the right lung showing shift of the mediastinum to the right hemithorax.

The severity of the lesion depends on the timing of the insult in relation to the stage of lung development, prior to or after the pseudoglandular stage at 6-16 weeks of gestation. In pulmonary hypoplasia, the lung consists of incompletely developed lung parenchyma connected to bronchi that may be underdeveloped, depending on the timing of the insult. Besides disturbances of the bronchopulmonary vasculature, there is a high incidence, approximately 50-85%, of associated congenital anomalies such as cardiac, gastrointestinal, genitourinary, and skeletal malformations. Postnatal diagnosis of pulmonary hypoplasia can be made with specific criteria such as clinical and radiologic criteria, or pathologic criteria such as lung weight or lung weight–to–body weight ratio, mean radial alveolar count, and DNA estimation for growth assessment at autopsy. [1, 2]

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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, reduced mean radial alveolar count, unusually numerous bronchioles, and fewer generations of proximal conducting airways. There may be 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. [3] A nitrofen (a human carcinogen)–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 lungs [4] by increasing type 1 alveolar cell proliferation. [5]

Studies using nitrofen-induced hypoplastic lung explants indicate a possible role for interleukin-6 (IL-6) in catch-up growth. [6]

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. [7]

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Epidemiology

Frequency

United States

As the diagnosis of pulmonary hypoplasia is made by pathologic examination, the true incidence is unknown.

Etiologies (in order of frequency) include prolonged rupture of membranes, fetal renal dysplasias and obstruction, and fetal neuromuscular diseases.

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

Lung hypoplasia also occurs in association with diaphragmatic hernia and congenital cystic lung lesions such as cystic adenomatoid malformations (CAMs). The occurrence of CDH is estimated at 0.08-0.45 case per 1000 births.

International

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

In Europe, the occurrence of CDH ranges from 1.7 to 5.7 cases per 10,000 live births, depending on study population. [8]

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:

  • 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)

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 CAM. However, in other cystic lung lesions, most are clinically asymptomatic and may not need aggressive management. [9]

Survival in patients with pulmonary hypoplasia secondary to CDH has improved in recent years. The survival rate of CDH is presently 60-70%. [8] A review of 11 centers reported an overall survival rate of 79%, with infants with isolated CDH having a survival rate of 85%. [10]

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. [11]

Race

No racial predilection has been noted.

Sex

No sex predilection has been noted.

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