Pediatric Pulmonary Hypoplasia
Pulmonary hypoplasia (PH) or aplasia is a rare condition that is characterized by incomplete development of lung tissue, which can be unilateral or bilateral. It results in a reduction in the number of lung cells, airways, and alveoli that results in impaired gas exchange. See the image below.
Pulmonary hypoplasia (PH) may be primary or secondary. Primary PH is extremely rare and routinely lethal. The severity of the lesion in secondary PH depends on the timing of the insult in relation to the stage of lung development. This typically occurs 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 underdeveloped bronchi. 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. The diagnosis can result in a spectrum of respiratory complications ranging from transient respiratory distress, chronic respiratory failure, bronchopulmonary dysplasia to neonatal death in very severe cases. Strict diagnostic criteria are not established for pulmonary hypoplasia; various parameters such as lung weight, lung weight to body weight ratio, total lung volume, mean radial alveolar count and lung DNA assessment have been used to classify pulmonary hypoplasia. [1, 2]
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 studies have demonstrated that gestation age at rupture of membranes (15-28 weeks gestation), latency period (duration between rupture of membranes and birth) and the amniotic fluid index (AFI of less than 1 cm or 5 cm) can influence the development of pulmonary hypoplasia. 
Maintenance of fetal lung volume plays a major role in normal lung development. Normal transpulmonary pressure of about 2.5mm Hg allows the fetal lung to actively secrete fluid into the lumen.  The effect of stretch of the lung parenchyma induces and promotes lung development. Studies in sheep have demonstrated that tracheal ligation and therefore increased lung distension, accelerates lung growth whereas chronic tracheal fluid drainage has the opposite effect.  Cohen and colleagues have found that in-utero overexpression of the cystic fibrosis transmembrane conductance regulator (CFTR) increased liquid secretion into the lung, accelerating lung growth in a rat model. 
Oligohydramnios is considered to be an independent risk factor for the development of pulmonary hypoplasia. This is likely due to reduced distending forces on the lung. Studies have demonstrated that severe oligohydramnios decreased lung cell size, alters cell shape and may also negatively affect Type I cell differentiation which ultimately induces pulmonary hypoplasia.
It has been postulated that the Rho-ROCK pathway can affect the growth of the lung epithelium. Embryonic mouse models have demonstrated that ROCK protein inhibitor decreases the number of terminal lung buds. There are currently several groups studying the role of the Rho/ROCK pathway which has potential therapeutic implications in the reversal of lung hypoplasia. [7, 8]
Several growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), promote cell proliferation and differentiation. Transforming growth factor family proteins like TGFß1 can oppose these effects.
Embryologically, lungs arise from the foregut. Thyroid transcription factor 1 (TTF-1) is thought to be the earliest embryologic marker associated with cells committed to pulmonary development. FGF signaling is thought to be essential in the formation of TTF-1 expressing cells and this is thought to occur even before the pseudoglandular stage of lung development. Sonic hedgehog (SHH) signaling is further responsible for branching morphogenesis and mesenchymal proliferation. Disruption of any of these pathway may result in primary pulmonary hypoplasia. [9, 10, 11, 12]
FGF7 and FGF10 promote epithelial proliferation and formation of the bronchial tree. Overexpression of FGF10 can also stimulate the formation of cysts in the rat lung.  EGF promotes lung branching and Type II alveolar cell proliferation. PDGF plays a crucial role in alveolarization. VEGF promotes angiogenesis and the differentiation of embryonic mesenchymal cells into endothelial cells. Bone morphogenetic protein was thought to oppose lung growth; however recent data suggests that in the presence of mesenchymal cells, BMP4 is a potent inducer of tracheal branching. [14, 15, 16, 17] Aberrant expression of these growth factor proteins in the amniotic fluid during pregnancy have been implicated in abnormal lung development. Interestingly, higher concentrations of VEGF are seen in the amniotic fluid in the second and third trimester and may be a molecular marker for hypoxia which requires further investigation. 
The pathogenesis of PH associated with congenital diaphragmatic hernia (CDH) remains unclear. Several mechanisms have been suggested. The nitrofen model of CDH is widely accepted. Nitrofen is a human carcinogen and the retinoid acid signaling pathway is essential for the normal development of the diaphragm. Perturbation of this pathway with compounds such as nitrofen, can induce CDH and PH. Esumi and colleagues demonstrated that that administration of insulin-like growth factor 2 (IGF2) to nitrofen-induced hypoplastic lungs lead to alveolar maturation. [18, 13, 19, 20, 21, 22] Furthermore, recent data suggests that prenatal treatment with retinoic acid results in increased levels of placental IGF2 and promotes both placental and fetal lung growth in nitrofen induced CDH. 
Interestingly, erythropoietin (EPO) is a direct target of retinoic acid. A recent study has demonstrated decreased levels of EPO mRNA in the liver and kidney of rats which may explain modifications in the pulmonary vasculature in CDH. 
A recent study has also suggested a possible role of interleukin 6 (IL-6) in inducing catch-up growth particularly in nitrofen pre-treated explant fetal rat lungs. 
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.
The true incidence of pulmonary hypoplasia is unknown. The reported incidence is between 9 to 11 per 100,00 live birth which is an underestimation, as infants with lesser degrees of hypoplasia likely survive in the neonatal period.  Incidence also varies by etiology. Most cases are secondary to congenital anomalies (such as congenital diaphragmatic hernia and cystic adenomatous malformations) or complications related to pregnancy that inhibit lung development. These include, but are not limited to, renal and urinary tract anomalies, amniotic fluid aberrations, diaphragmatic hernia, hydrops fetalis, skeletal and neuromuscular disease and conditions like pleural effusions, chylothorax and intrathoracic masses that cause compression of the fetal thorax. 
The incidence of neonatal pulmonary hypoplasia in mid trimester (18-26 weeks gestation) preterm rupture of membranes ranges from 9-28%, with variability attributed to differing diagnostic criteria for pulmonary hypoplasia.
International incidence of pulmonary hypoplasia is not known. In Canada, the estimated incidence of CAM is 1 case per 25,000-35,000 pregnancies. According to the CDH study group the incidence of CDH is 1 in every 2000-4000 births and accounts for 8% of all congenital anomalies. In Europe, the occurrence of CDH ranges from 1.7 to 5.7 cases per 10,000 live births, depending on study population and remains largely unchanged. [8, 25] However, there is no direct correlation between these predisposing lesions to the incidence of 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)
Presence of genetic anomalies
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 CDH and CAM at high volume centers; mortality can be as high as 45% at peripheral care centers. However, in other cystic lung lesions, most are clinically asymptomatic and may not need aggressive management. 
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.
There is a recent retrospective study from Barcelona that studied 60 cases of pulmonary hypoplasia between 1995 to 2014, that found a mortality rate of 47% in the first 60 days of life and upto 75% in the first day of life. 
No racial predilection has been noted.
No sex predilection has been noted.
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Thyroid transcription factor-1 (TTF-1) 
Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) 
Insulinlike growth factors (IGF-1 and IGF-2) and their receptors (IGF-1R and IGF-2R) 
Epidermal growth factors and its receptor family (eg, ErbB receptors) 
Hepatocyte nuclear factor (HNF3ß10)
Mitogen-activated protein kinases
Connective tissue growth factor 
Small Fetal Thoracic Volume
Decreased Fetal Breathing Movements
Congenital Heart Diseases With Poor Pulmonary Blood Flow
Fetal renal agenesis
Central nervous system (CNS) lesions
Cystic adenomatoid malformation (CAM)
Urinary tract obstruction
Lesions of the spinal cord, brain stem, and phrenic nerve
Hypoplastic right heart
Bilateral renal dysplasia
Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)
Pulmonary artery hypoplasia
Pleural effusions with fetal hydrops, hydrothorax
Bilateral cystic kidneys
Arthrogryposis multiplex congenital secondary to fetal akinesia
Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
Prolonged rupture of membranes (PROM)
Maternal depressant drugs
Trisomies 18 and 21
Malformations of the thorax (eg, asphyxiating thoracic dystrophy)
Diaphragmatic anomalies (eg, abdominal wall defects, eventration of the diaphragm)
Abdominal masses causing compression
Terry W Chin, MD, PhD Associate Clinical Professor, Department of Pediatrics, University of California, Irvine, School of Medicine; Associate Director, Cystic Fibrosis Center, Attending Staff Physician, Department of Pediatric Pulmonology, Allergy, and Immunology, Memorial Miller Children’s Hospital
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 Federation for Clinical Research, American Thoracic Society, California Society of Allergy, Asthma and Immunology, California Thoracic Society, Clinical Immunology Society, Los Angeles Pediatric Society, Western Society for Pediatric Research
Disclosure: Nothing to disclose.
Nandini Kataria, MD Fellow in Pediatric Pulmonology, Miller Children’s and Women’s Hospital Long Beach, University of California, Irvine, School of Medicine
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush Children’s Hospital, Rush University Medical Center
Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland
Disclosure: Nothing to disclose.
Susanna A McColley, MD Professor 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, American Thoracic Society
Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from Genentech for consulting; Partner received consulting fee from Boston Scientific for consulting; Received honoraria from Gilead for speaking and teaching; Received consulting fee from Caremark for consulting; Received honoraria from Vertex Pharmaceuticals for speaking and teaching.
Khanh Van Lai, MD Fellow in Pediatric Pulmonology, Miller Children’s Hospital, University of California, Irvine, School of Medicine
Khanh Van Lai, MD is a member of the following medical societies: American Thoracic Society
Disclosure: Nothing to disclose.
Bich-Trang Hoa, MD Fellow in Pediatric Pulmonology, Miller Children’s Hospital, University of California, Irvine, School of Medicine
Disclosure: Nothing to disclose.
The current authors would like to acknowledge the contributions of the following to this article:
Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester School of Medicine and Dentistry; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center;
Girija Natarajan, MD, Assistant Professor, Division of Neonatology, Children’s Hospital of Michigan, Wayne State University School of Medicine; and
Ibrahim Abdulhamid, MD, Associate Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Pulmonary Medicine, Clinical Director of Pediatric Sleep Laboratory, Children’s Hospital of Michigan
Disclosure: Nothing to disclose.
Pediatric Pulmonary Hypoplasia
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