Pediatric Pulmonary Hypoplasia 

  • Author: Terry W Chin, MD, PhD; Chief Editor: Michael R Bye, MD   more...
 
Updated: Mar 5, 2009
 

Background

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

Chest radiograph of a newborn with primary pulmonaChest 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 and the presence of other anatomic anomalies. The hypoplastic lung consists of a carina, a malformed bronchial stump, and absent or poorly differentiated distal lung tissue. In more than 50% of these cases, coexisting cardiac, GI, genitourinary, and skeletal malformations are present, as well as variations in the bronchopulmonary vasculature. To define pulmonary hypoplasia, some investigators have devised specific criteria that are based on reduced lung weight, volume, DNA content, and radial alveolar count.

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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, 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 lungs[2] 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]
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Epidemiology

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.

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Contributor Information and Disclosures
Author

Terry W Chin, MD, PhD  Associate Director, Pediatric Allergy/Immunology/Pulmonology, Miller Children's Hospital, Long Beach Memorial Medical Center; Associate Professor, Department of Pediatrics, University of California, Irvine, School of Medicine

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Girija Natarajan, MD  Assistant Professor, Division of Neonatology, Children's Hospital of Michigan & Wayne State University

Girija Natarajan, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

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

Ibrahim Abdulhamid, MD is a member of the following medical societies: American Academy of Pediatrics, American Academy of Sleep Medicine, and American Thoracic Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Susanna A McColley, MD  Associate Professor, Department of Pediatrics, Northwestern University, The Feinberg School of Medicine; Director of Cystic Fibrosis Center, Head, Division of Pulmonary Medicine, Children's Memorial Medical Center of Chicago

Susanna A McColley, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Sleep Disorders Association, and American Thoracic Society

Disclosure: Genentech Honoraria Speaking and teaching; Genentech Honoraria Consulting; Boston Scientific Consulting fee Consulting; Gilead Honoraria Speaking and teaching; Caremark Consulting fee Consulting; Vertex Pharmaceuticals Honoraria Speaking and teaching

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Heidi Connolly, MD  Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary E Cataletto, MD  Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital

Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians

Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Michael R Bye, MD  Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

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Chest radiograph of a newborn with primary pulmonary hypoplasia of the right lung showing shift of the mediastinum to the right hemithorax.
CT scan of the same patient (a newborn with primary pulmonary hypoplasia of the right lung) showing absence of the right lung. Note branching of the left lower lobe bronchus (horizontal arrow) and absence of airways in the right side (vertical arrow).
A posteroanterior radiograph of a 3-month-old infant with primary pulmonary hypoplasia of the right lung.
Lateral view of the same patient (a 3-month-old infant with primary pulmonary hypoplasia of the right lung) showing one dome of the diaphragm.
Bronchogram of the same patient (a 3-month-old infant with primary pulmonary hypoplasia of the right lung) showing absence of the airways in the right side and presence of the left main bronchus and its branches.
A chest radiograph of a 14-year-old child with primary pulmonary hypoplasia of the right side causing secondary scoliosis.
A chest radiograph of a newborn with achondroplasia and small chest causing hypoplasia of both lungs.
A chest radiograph of a newborn with diaphragmatic hernia in the right hemithorax shortly after birth.
CT scan of the same child (a newborn with diaphragmatic hernia in the right hemithorax shortly after birth) showing the presence of abdominal contents in the right hemithorax. Note the presence of the left lower bronchus and its main branches (horizontal arrow) and absence of the right lower lobe bronchus. The liver in the right hemithorax is indicated by the upper arrow.
A chest radiograph of a 10-month-old child after repair of a right diaphragmatic hernia showing loss of lung volume in the right hemithorax.
MRI of the same patient (a 10-month-old child after repair of a right diaphragmatic hernia) showing loss of right lung volume and smaller right pulmonary artery than the left pulmonary artery (arrow).
 
 
 
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