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Congenital pulmonary airway malformation: Prenatal diagnosis and management

Congenital pulmonary airway malformation: Prenatal diagnosis and management
Literature review current through: Jan 2024.
This topic last updated: Jun 16, 2023.

INTRODUCTION — Congenital lung masses include congenital pulmonary airway malformation (CPAM, previously known as congenital cystic adenomatoid malformation [CCAM]), bronchopulmonary sequestration (BPS, also called lung or pulmonary sequestration), congenital lobar overinflation, bronchogenic cyst, and bronchial atresia. Hybrid lesions are common, which suggests that these masses represent a spectrum of abnormalities (figure 1). The abnormalities in this spectrum are characterized by abnormal development of the pulmonary airways, parenchyma, and/or vasculature, likely secondary to obstruction. The level, degree, and timing of obstruction determine the resulting pathology [1-3].

The prenatal course of CPAM depends on the size of the mass, amount of mediastinal shift, fetal hemodynamics, and associated anomalies. In the absence of hydrops, the prognosis is good, with reported live birth rates ≥95 percent.

Several interventions have been developed for managing hydropic fetuses remote from term, with the goal of improving fetal hemodynamics, preventing lung hypoplasia, and improving survival.

Postnatally, surgical excision in the neonatal period is curative and the prognosis for survival is excellent. In the absence of surgery, the most common postnatal complication of CPAM is recurrent pulmonary infection; there is also a weak association with malignancy.

This topic will focus on prenatal diagnosis and management of CPAM. Prenatal diagnosis and management of BPS and hybrid BPS/CPAM lesions are reviewed separately (see "Bronchopulmonary sequestration: Prenatal diagnosis and management"). Postnatal management and outcome of CPAM are also reviewed separately. (See "Congenital pulmonary airway malformation".)

EPIDEMIOLOGY — Congenital pulmonary airway malformation (CPAM) is one of the most common lung lesions diagnosed prenatally (59 percent of prenatal lung lesions [4]), although the birth prevalence is quite low, between 0.87 and 1.92/10,000 live births [5]. It is usually sporadic and isolated and has no familial recurrence [4]. (See "Congenital pulmonary airway malformation", section on 'Epidemiology'.)

CLASSIFICATION — Prenatally, CPAM is classified as microcystic (74 percent) or macrocystic (26 percent) [4] based on imaging characteristics [6]. Prenatal percentages are different from postnatal percentages, probably because macrocystic lesions are more likely to be symptomatic postnatally, resulting in a higher reported incidence of macrocystic lesions in postnatal series [4].

Stocker's more refined classification system is useful prognostically, but not practical prenatally since tissue is not available for histologic analysis [7]. There are five subtypes of malformations (0-tracheobronchial, 1-bronchial, 2-bronchiolar, 3-alveolar duct, 4-acinar) based on cyst size and histopathology; immunohistochemistry and proteomics suggest they occur at different stages of lung development [5]. A brief synopsis of characteristics of the five types is available in the table (table 1) and described in more detail separately. (See "Congenital pulmonary airway malformation", section on 'Pathology'.)

PRENATAL DIAGNOSIS

Imaging modality — Ultrasound is the primary modality for imaging the fetal chest and detecting fetal chest masses [8]. However, sonographic assessment of lung parenchyma can be limited due to maternal obesity, oligohydramnios, overlying ribs, and fetal lie. Magnetic resonance imaging (MRI) is less limited by these factors, thus MRI can be a useful adjunct for confirming the presence of a mass, further characterizing normal and abnormal anatomy, and assessing residual lung volume, which is useful for counseling and obstetric management [9-13]. (See 'Role of magnetic resonance imaging' below.)

Appearance of normal lung

Ultrasound images – On axial images, the normal fetal chest is oval or round, with the heart in the anterior half of the left chest and bordered by lung parenchyma (image 1). Inferiorly, the diaphragms are dome-shaped and hypoechoic. Lung parenchyma appears homogeneous and slightly hyperechogenic compared with the fetal liver, and its echogenicity increases with gestational age [14]. The fetal airway is not well delineated on ultrasound.

Fetal lung volume increases with gestational age with the right lung typically measuring 56 percent of total lung volume. Three-dimensional and four-dimensional ultrasound imaging appear to be more useful than two-dimensional ultrasound for estimating lung volume [15].

Magnetic resonance images – On MRI, the normal fetal lung has a homogeneously moderate high signal on T2-weighted (T2w) chest (image 2) [14]. The T2 signal increases with gestational age as increasing numbers of alveoli and production of alveolar fluid develop and decreases in signal with T1-weighted (T1w) [16]. When normal lung is compressed by either a lung mass or an extraparenchymal lesion, it appears slightly hypointense compared with noncompressed normal lung [14].

The liver, mediastinal structures, and lung parenchyma are easily differentiated by MRI. Compared with adjacent lung, the liver has a lower signal on T2w and higher signal on T1w. The fetal airway can be seen well due to fluid within the larynx, trachea, and bronchi. The thymus is homogeneous and has a higher signal than the heart, which appears as a dark flow void on single slice fast spin echo sequences (SSPSE) and high signal on steady state free precession sequences (SSFP).

CPAM

Diagnosis — The prenatal diagnosis of CPAM is most commonly based on ultrasound findings first detected in the second trimester. It can be classified as macrocystic, microcystic, or mixed [4] based on the ultrasound appearance [6].

Macrocystic CPAM is characterized by anechoic cysts >5 mm in diameter, often surrounded by hyperechogenic lung parenchyma (image 3) (type I), which is bright on T2w MRI due to the large amount of fluid within the lesion.

Microcystic CPAM is characterized by a solid-appearing homogeneous mass that is hyperechogenic compared with adjacent normal lung parenchyma, and composed of microcystic lesions <5 mm in diameter (image 4) (type III). As gestational age increases, microcystic lesions become more difficult to visualize due to increased echogenicity of surrounding normal lung [16]. Shadowing from overlying ribs also makes assessment of the mass more difficult in the third trimester. Microcysts also are characteristically T2 bright on MRI.

Mixed CPAM lesions contain both solid and cystic components (image 5) (type II).

On color and power Doppler, the arterial supply and venous drainage are from the pulmonary circulation. If a systemic feeding vessel is noted, the lesion is considered a bronchopulmonary sequestration (BPS) if it is solid and a hybrid BPS/CPAM lesion if it is both cystic and solid. (See 'Differential diagnosis' below.)

There have been a few cases of CPAM with decreased echogenicity/T2w hypointense signal [17], which can be related to immature parenchymal development and increased mesenchymal tissue or CPAM regression. (See 'Role of magnetic resonance imaging' below.)

Additional findings include:

CPAM can have a connection to the tracheobronchial tree. Bronchial atresia has been noted pathologically in up to 70 percent of cases [18].

CPAMs develop in the right and left lungs with equal frequency [19]; bilateral lung involvement is rare [20]. Only one lobe is involved in 85 to 95 percent of cases and the lower lobe is the most common site, but any lobe can be affected [6,21].

Large or rapidly growing lesions can cause mediastinal shift to the contralateral side, possibly with cardiac rotation. Particular attention should be paid to mediastinal shift since a severe shift resulting in compression of the inferior vena cava (IVC) and heart can lead to hydrops (image 6). (See 'Hydrops with abnormal fetal echocardiography' below.)

The esophagus can become compressed and obstructed, resulting in proximal dilation, a small stomach, and polyhydramnios. The ipsilateral diaphragm may be flattened.

Postdiagnostic imaging evaluation

Assessment for associated anomalies – Because 10 to 20 percent of fetuses with CPAM have associated congenital abnormalities, a comprehensive fetal survey should be performed. The most common associated anomalies are cardiovascular and urogenital, but others have been described, including tracheoesophageal fistula, cleft lip and palate, and diaphragmatic, central nervous system, bony, and other pulmonary abnormalities [22-25]. (See "Congenital pulmonary airway malformation", section on 'Neonatal period'.)

Fetal echocardiography is recommended initially to rule out congenital cardiac anomalies [26]. It is also performed to assess cardiac function in cases with, or at high risk for, hydrops [27]. Echocardiographic assessment includes the size of heart chambers, evaluation for valvar regurgitation, measurement of contractility and ventricular function, and Doppler examination of the IVC, ductus venosus, and umbilical vein [27]. A cardiovascular profile score can help plan management and predict outcome [27,28]; this point system score takes into account hydrops, heart size, cardiac function, and findings on Doppler velocimetry of the ductus venosus, umbilical vein, and umbilical artery. (See 'Poor prognostic factors' below.)

Quantitative measurements – Quantitative evaluation helps predict the prenatal and postnatal course of the disease. The following prenatal ultrasound measurements have been described. Their significance as prognostic factors is discussed below. (See 'Quantitative measurements' below.)

CPAM volume ratio (CVR) – Obtained by calculating the volume of the lung mass using the formula for the volume of a prolate ellipse (0.52 x each of three orthogonal measurements) and normalizing it by gestational age. To normalize by gestational age, the lung mass volume should be divided by the head circumference [29]:

CVR = height x anteroposterior diameter x transverse diameter x 0.52 (constant)/head circumference.

Mass-to-thorax ratio (MTR) – The ratio between the transverse diameter of the mass and the transverse diameter of the thorax. It is measured on an axial image of the chest, where the four-chamber view of the heart is present.

Lesion to lung volume ratio (LLV) – The sum of all measurements of the mass is multiplied by the section thickness to obtain a volume in cubic centimeters and is divided by the observed normal total fetal lung volume (TFLV), which is the volume of normal lung excluding the volume of the lung mass.

Observed/expected normal fetal lung volume (O/E-NFLV) – The observed lung volume is the sum of all measurements of the fetal lung excluding the lung mass multiplied by the section thickness to obtain a volume in cubic centimeters. This is then divided by the mean expected TFLV for the gestational age.

Observed to expected lung area-to-head circumference ratio (observed/expected LHR) – This ratio is used to predict outcomes of fetuses with congenital diaphragmatic hernia, and its use has been assessed in the evaluation of fetuses with CPAM, though with less sensitivity [30]. It is described in detail separately. (See "Congenital diaphragmatic hernia: Prenatal issues", section on 'Lung area to head circumference ratio'.)

Cardiomediastinal shift angle (CMSA) – A transverse image of the fetal chest with the four chamber view of the heart is obtained and a reference line is drawn from the center of the vertebral body to the sternum [31]. Normally, this line lies at a 45-degree angle to the interventricular septum and intersects the atrial septum. When this does not occur because of mediastinal shift, a second index line is drawn from the center of the vertebral body to cross through the displaced atrial septum and on to the chest. The angle between the reference and index lines is the CMSA.

Role of magnetic resonance imaging — MRI is a useful adjunct for supporting the diagnosis and increasing specificity [9,21,32]. It can be used to confirm the presence and size of the mass, particularly when it is difficult to see by ultrasound because the mass involves the entire lung or hydrops or bilateral lesions are present [14,33]. It can also be used to measure lung volume and detect associated fetal abnormalities. This additional information can be useful for counselling, determining frequency of follow-up examinations, and preparation for delivery and perinatal care. (See 'Poor prognostic factors' below.)

The fetal MRI-derived volume ratio (LMVR) is analogous to the ultrasound-derived CVR. The volume in cubic centimeters is obtained by multiplying the sum of all measurements of the mass by the section thickness. The volume is then divided by the head circumference in centimeters to derive the LMVR.

The optimal timing of fetal MRI to assess suspected CPAM is unclear. In the late third trimester, the T2w signal of normal lung increases, which may diminish differentiation between a type III CPAM and normal parenchyma. As on ultrasound, the lung lesion on MRI may demonstrate a macrocystic, microcystic, or mixed appearance, which are of high signal on T2w compared with normal lung parenchyma. Careful assessments of vascularity and whether the T2w signal is high or low can help in the differential diagnosis. Normal pulmonary vascularity coursing through a mass suggests congenital lobar overinflation, while a feeding vessel from the aorta is consistent with a BPS or hybrid lesion. Rarely, a CPAM can be low signal on T2w and hypoechoic on ultrasound [17]. These CPAMs have a more immature parenchymal development with increased mesenchymal tissue, similar to myofibroblastic tumors, or may be resolving CPAMs as the lesion decreases in size and collapses. Polyhydramnios is often associated with these unusual, low-signal, hypoechoic lesions.

In one series in which two fetal MRIs were performed early (20 to 26 weeks of gestation) and late (>32 weeks of gestation), the type of malformation was concordant with postnatal diagnosis in 19 of 26 cases (73 percent) with early MRI versus 22 of 26 cases (85 percent) with late MRI [34]. The authors suggested that the addition of a later MRI may improve clinical management and could delay or reduce postnatal imaging.

DIFFERENTIAL DIAGNOSIS — The prenatal differential diagnosis of CPAM includes:

Bronchopulmonary sequestration (BPS) – BPS is a homogeneous echogenic mass of the lung parenchyma with well-defined borders, most frequently left-sided but bilateral cases have been described [35]. In contrast to CPAM, BPS does not communicate with the tracheobronchial tree. Another difference from CPAM is that BPS has anomalous systemic feeding and draining vessels that can often be identified by color and power Doppler imaging, whereas blood flow to CPAM is through the normal pulmonary vasculature [12,36].

Hybrid lesions containing features of both CPAM and BPS are the second most common lung lesion (38 percent) [4] and, by imaging, contain mixed cystic and solid components with anomalous feeding systemic vessels. These lesions have a better prognosis than CPAM alone. (See "Bronchopulmonary sequestration: Prenatal diagnosis and management" and "Bronchopulmonary sequestration".)

Congenital lobar overinflation (CLO)/congenital lobar emphysema (CLE)/bronchial atresia – Criteria for CLO/CLE/bronchial atresia include hyperlucent lung postnatally, normal lung architecture, and absence of macroscopic cysts. CLO/CLE/bronchial atresia may involve one or more lobes or segments of one or both lungs [37]. Prenatally, the diagnosis can be difficult to differentiate from microcystic CPAM and BPS. The presence of normal pulmonary vascularity excludes BPS and the lack of cysts excludes CPAM. Diagnosis is confirmed by postnatal computed tomography with intravenous contrast [33]. (See "Congenital lobar emphysema".)

Bronchogenic cyst Bronchogenic macrocysts arise from abnormal budding of the ventral foregut along the tracheobronchial tree. The thin-walled cystic lesions are covered by respiratory epithelium [38]. They are typically isolated lesions located in the cervical, paratracheal, subcarinal, hilar or mediastinal area, or within the region of the carina, and surrounded by normal lung parenchyma [39,40]. The diagnosis should be suspected when an isolated macrocyst appears to arise from the wall of the trachea or proximal airways [40]. Fifteen percent of cases are intraparenchymal rather than adjacent to the tracheobronchial tree. In these cases, it may be difficult to differentiate a bronchogenic cyst from a macrocystic CPAM prenatally. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Bronchogenic cyst'.)

Diaphragmatic hernia Herniated bowel loops in the hemithorax can mimic a multicystic, heterogeneous lung mass. Mediastinal and cardiac deviation may be the only hint that a congenital diaphragmatic hernia is present in cases when the stomach remains infradiaphragmatic. When the stomach is herniated into the hemithorax, nonvisualization of fluid-filled stomach (stomach bubble) within the abdomen is helpful for making the diagnosis [21,36]. Peristalsis of bowel loops in the thorax can sometimes be seen by ultrasound [21]. Deviation of the umbilical portion of the portal vein suggests liver herniation into the thorax. In subtle and uncertain cases, use of the umbilical vein ratio can help in the ultrasound diagnosis since almost all congenital diaphragmatic hernias have an abnormal ratio [41].

Magnetic resonance imaging (MRI) is particularly useful in assessing the amount of liver herniation and delineation of meconium filled small and large bowel in the chest. Meconium is dark on T2 and bright on T1, while liver is higher signal on T1-weighted (T1w) and intermediate signal on T2-weighted (T2w), and thus easily differentiated from adjacent lung. (See "Congenital diaphragmatic hernia: Prenatal issues" and "Congenital diaphragmatic hernia in the neonate".)

Congenital high airway obstruction (CHAOS) CHAOS secondary to laryngeal or tracheal atresia should be included in the differential diagnosis when the diagnosis of bilateral large CPAMs is being considered [14,36]. Aberrant pulmonary budding off the foregut is present in CHAOS and most CHAOS lesions also have a connection with the esophagus. Both lungs appear symmetrically enlarged and echogenic by ultrasound due to fluid trapping. The diaphragms are flattened and everted. Compression of the heart and great vessels may result in heart failure and hydrops [42]. Compression of the esophagus may lead to polyhydramnios.

MRI demonstrates abnormally large high signal lungs on T2w images. Identification of dilated fluid-filled trachea and bronchi confirms the diagnosis. When suspected, a thorough examination should be performed and genetic testing offered to look for other congenital structural and chromosomal abnormalities as CHAOS can be associated with trisomy 9, trisomy 16, and chromosome 5p deletion [43]. Prognosis is poor [36].

Neurenteric/enteric cysts These cysts are formed by failure of the gastrointestinal track to separate from the primitive neural crest. Neurenteric cysts are typically associated with vertebral anomalies and are located in the posterior mediastinum. Enteric or duplication cysts are seen in adjacent to bowel and have no communication with the neural track.

Mediastinal cystic teratoma These tumors can be cystic and/or solid and are located in the anterior mediastinum. They have increased vascularity, which can be noted on Doppler imaging [44].

Rare fetal pulmonary neoplasms – Rare neoplasms, such as the pleuropulmonary blastoma (PPB), congenital peribronchial myofibroblastic tumor, and the fetal lung interstitial tumor (FLIT), should also be considered in differential diagnosis. These tumors can be cystic and/or solid and mimic a CPAM. While the majority of these tumors are discovered postnatally, prenatal diagnoses have been reported [45-48].

CPAM and PPB can be difficult to differentiate by imaging. In a systematic review, a lesion identified as CPAM by imaging was actually a PPB in 4 percent of cases [49]. There was no evidence to suggest that a CPAM evolves into a PPB. The presence of pleural effusions raises the chances of PPB since effusions are more commonly associated with PPB than with CPAM [50]. A germline mutation in the DICER1 gene [51] has been found in two-thirds of PPB cases [52]. The identification of this germ-line mutation could also be useful in differential diagnosis when the family history is positive for tumors associated with PPB, such as thyroid cancer [50].

Presentation later in gestation in combination with a solid appearance with radiating curved bands of high signal within and along the periphery of the lesion suggest FLIT and might help differentiate CPAM from this tumor [53].

PRENATAL COURSE

Overview — The prenatal course of CPAM depends more on the gestational age, size of the mass, amount of mediastinal shift, fetal hemodynamics, and associated anomalies than on the type of lesion (macrocystic versus microcystic) [6,14,38].

Growth velocity across gestation – Longitudinal studies of fetal CPAM have reported that most have rapid progressive growth from approximately weeks 20 to 26 of gestation, peaking at approximately 25 weeks [29,54], and then growth plateaus and often regresses [55]. Macrocystic lesions grow less rapidly than microcystic/solid lesions. CPAM growth at 20 to 26 weeks is often relatively greater than overall fetal growth, increasing the risk for mediastinal shift and development of hydrops during this time. Therefore, CPAM should be followed closely from 20 to 26 weeks, with weekly scans in cases where mediastinal shift is increasing. (See 'Follow-up imaging' below.)

Regression – Fifteen percent of the masses decrease in size during the late second and the third trimesters; the majority have a relative decrease in size due to normal fetal thoracic growth, but a few increase in size [6,54]. As the size decreases, echogenicity can become similar to that of surrounding normal lung due to both increase in normal lung echogenicity and decrease in echogenicity of the CPAM. On T2-weighted magnetic resonance imaging (MRI), as the lesions regress, their signal intensity may become less than a normal lung.

Prenatal resolution/persistence and postnatal findings – The mass appears to resolve by ultrasound before delivery in 50 percent of cases [56], usually in cases with a microcystic/solid appearance and a low CPAM volume ratio (CVR) [57]. On postnatal imaging, 60 percent of these cases show no abnormality. When postnatal imaging is normal, CPAM may not have been the underlying cause for the anomaly seen prenatally, instead it may have been a transient bronchial tree obstruction with retention of fluid [56] or a lesion that outgrew its blood supply or underwent spontaneous torsion [57]. The remaining 40 percent show a residual lesion that was no longer recognized prenatally due to the normal increase in lung echogenicity late in pregnancy, which makes differentiating normal from abnormal lungs difficult [29]. Computed tomography or MRI may be needed to demonstrate these residual lesions postnatally.

In the 50 percent of cases that do not appear to resolve before delivery, postnatal imaging confirms persistence of the mass in over 95 percent of cases.

Development of hydrops — Fetuses with large masses can develop hydrops secondary to impaired venous return due to displacement and compression of the heart, vena cava, or ductus venosus, which can be associated with poor heart function [4,27,58,59]. Hydrops can also be caused by compression of lymphatic structures (cisterna chyli or thoracic duct), which generally is not associated with poor heart function (see 'Hydrops with abnormal fetal echocardiography' below). If hydrops has not developed by approximately 28 weeks, it is unlikely to develop since CPAM growth plateaus by the end of the second trimester and the fetal thorax continues to increase [29,55]. Hydrops has not been described after mass growth plateaus.

An additional complication of fetal hydrops is the association with maternal mirror syndrome (generalized maternal edema, often with pulmonary involvement, that "mirrors" the edema of the hydropic fetus and placenta). (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)

Poor prognostic factors

Hydrops with abnormal fetal echocardiography — Hydrops associated with poor heart function is associated with a high risk for perinatal death, so early intervention should be considered [27]. When hydrops is not associated with poor heart function, its presence is not a direct predictor of demise; live birth rates are ≥95 percent without intervention [30,32,56,59-61]. Cases of spontaneous resolution of early hydrops (pleural effusion and/or ascites) without intervention have been reported, but these cases are extremely rare [21] and tend to be diagnosed around the time when the relative growth of the CPAM plateaus, so that mediastinal shift decreases without iatrogenic intervention.

In a study including 24 fetuses with lung masses at high risk for hydrops, only 13 percent of hydropic fetuses with an abnormal echocardiogram survived in the absence of fetal surgery [27]. On the other hand, 100 percent of hydropic fetuses with a normal echocardiogram survived. Thus, in an hydropic fetus with a large lung mass, abnormal echocardiography appears to be a good predictor of poor outcome and should be considered an indication for urgent intervention.

Quantitative measurements — The initial ultrasound can help predict if the lesion will regress, stabilize, or continue to grow, depending on the gestational age at the time of the examination and severity of mass effect. The use of quantitative measures such as CVR, mass-to-thorax ratio (MTR), lung mass volume ratio (LMVR), lesion to lung volume ratio (LLV), observed to expected normal fetal lung volume ratio (O/E-NFLV), observed to expected lung area-to-head circumference ratio (O/E-LHR), or cardiomediastinal shift angle (CMSA) can aid in risk stratification and help direct perinatal management and counseling [30,59,61]. Measurement of these ratios is described above (See 'Postdiagnostic imaging evaluation' above.) and interpretation is discussed below.

CVR – CVR >1.6 is generally considered predictive of risk for hydrops, respiratory distress at birth, and probable need for early surgery [29,61], whereas CVR <0.91 at presentation predicts a favorable outcome, so follow-up prenatal examinations can be less frequent [30]. In a series of 58 fetuses with CPAM, the rate of subsequent development of hydrops for CVR ≤1.6 and >1.6 was 7 out of 42 (17 percent) and 12 out of 16 (75 percent), respectively, and survival was 40 out of 42 (94 percent) versus 9 out of 16 (56 percent) after fetal intervention, respectively [29]. The predictive value of CVR was enhanced by excluding fetuses with CVR ≤1.6 and a dominant cyst because some of these cysts rapidly enlarged from fluid accumulation while solid masses grew more slowly. When only fetuses with CVR ≤1.6 and no dominant cysts were considered, hydrops developed in only 1 out of 36 (2.8 percent).

Thresholds lower than >1.6 have also been suggested since they are more predictive of important adverse outcomes other than hydrops [58,62]. For example, a CVR >1.1 is highly predictive of requiring urgent surgical intervention at birth and thus would be an indication for planned delivery at a hospital with personnel and other resources for neonatal stabilization and early surgical intervention [58]. In one retrospective study of fetal lung lesions, a predelivery CVR >1 in nonhydropic fetuses was predictive of respiratory symptoms at birth (sensitivity, specificity, positive and negative predictive values: 75, 98, 75, and 98 percent) and perinatal resection (sensitivity, specificity, positive and negative predictive values: 100, 98, 75, and 100 percent) [63].

MTR – MTR <0.51 suggests the fetus is at low risk for developing complications [30].

LMVR – In a 10-year retrospective series including 128 fetuses with congenital lung masses, a cutoff of >2 was associated with worse perinatal outcome with 84 percent sensitivity and 99 percent specificity; a value >1.3 was associated with neonatal respiratory distress at delivery (89 versus 7 percent with LMVR <1.3) [59]. LMVR >2 was also associated with hydrops (42 versus 2 percent with LMVR <2) and heart failure (32 versus 2 percent with LMVR <2).

O/E-NFLV – O/E-NFLV of <75 percent predicts a worse postnatal course with 57 percent sensitivity and 80 percent specificity [59]. The predictive value improves after 26 weeks of gestation.

LLV – Fetuses that died had significantly larger LLV (10.5 versus 8) in one study [59].

Observed/expected LHR – This ratio is commonly used to predict outcome of fetuses with congenital diaphragmatic hernia, who typically have hypoplastic lung on the contralateral side. The use of O/E-LHR ratio in the assessment of outcome in the fetus with CPAM is less predictive of outcome, possibly due to more normal lung development on the contralateral side in the third trimester. In CPAM, a cutoff of 45 percent has a sensitivity of 73 percent and specificity of 68 percent for prediction of adverse outcome (perinatal death, pregnancy termination, hydrops, need for prenatal intervention [eg, pleural drainage and/or thoracocentesis], or need for postnatal respiratory assistance), with positive and negative predictive values of 0.52 and 0.84, respectively. Using a cutoff of 25 percent (which is associated with poorer prognosis in congenital diaphragmatic hernias) had low sensitivity (6 percent) but a positive predictive value of 1 and specificity of 100 percent [30]. (See "Congenital diaphragmatic hernia: Prenatal issues", section on 'Lung area to head circumference ratio'.)

Cardiomediastinal shift angle (CMSA) – Each 10-degree increase in CMSA increases the odds of an adverse perinatal outcome and hydrops [31]. The ability of CMSA to predict adverse perinatal outcome is optimized at a cutoff of 34.3 degrees (sensitivity 72 percent, specificity 85 percent), where its performance is comparable to the CVR. CMSA appears to be an alternative to CVR for evaluating CPAM lesions and predicting those that will have poor perinatal outcomes and thus can be useful when the CVR is difficult to measure or equivocal.

PREGNANCY MANAGEMENT — In addition to routine prenatal care, we suggest the following.

Genetic counseling — The incidence of chromosomal abnormalities is not increased above baseline in fetuses with congenital pulmonary airway malformation (CPAM) alone; this should be considered when weighing the risks and benefits of invasive procedures for genetic studies. Microarray can be offered for further evaluation, and should be offered in cases with associated anomalies, as the frequency of genetic abnormalities is increased in fetuses with additional anomalies and/or nonimmune hydrops [36]. A case has been reported of an isolated CPAM associated with mosaic Klinefelter syndrome [64].

The genetic background of CPAM is not known, and associations with different genes have been suggested, including TTF-1 [24], FABP-7 [24], FGF-7, FGF-9, FGF-10, Hoxb-5, and SOX2 [65]. Abnormal Hoxb-5 expression during human lung branching morphogenesis has been implicated in the development of CPAM [66]. Genetic assessment has shown a higher than expected number of mutations in cancer genes [67,68] and genetic analysis of resected tissue in a different cohort showed a clear association between CPAM type 1 and mucinous adenocarcinoma with KRAS point mutations [69].

The American College of Medical Genetics and Genomics practice guidelines have recommended that exome and genome sequencing be considered as a first- or second-tier test for pediatric patients with congenital anomalies [70].

Parental counseling — Parental counseling includes:

The differential diagnosis of prenatally suspected CPAM. (See 'Differential diagnosis' above.)

The possible course of the CPAM during pregnancy, including the possible growth patterns of the mass and risk for development of hydrops. CPAM volume ratio (CVR) >1.6 is generally considered predictive of risk for hydrops, respiratory distress at birth, and probable need for early surgery. Hydrops associated with poor cardiac function is associated with a high risk for perinatal death. (See 'Prenatal course' above.)

The majority of cases are managed conservatively, but the potential need for, and the options for, prenatal intervention (eg, betamethasone, cyst drainage, or thoracoamniotic shunting). (See 'Second-line therapy: Invasive procedures' below.)

Choosing an appropriate site for planned delivery, with consideration of the need for resources for newborn resuscitation and surgery. (See 'Delivery' below.)

Postnatal issues (clinical manifestations, postnatal evaluation, postnatal management, potential complications (eg, infection, risk of malignancy), prognosis of associated anomalies, and range of outcomes). (See "Congenital pulmonary airway malformation".)

Follow-up imaging — Serial prenatal ultrasound examinations are recommended every one to four weeks to assess change in size of the lung mass, change in CVR, and development of polyhydramnios and hydrops [6,29]. The frequency within this range depends on the gestational age and CVR. Closer follow-up should be performed in those patients at high risk of developing hydrops (eg, CVR ≥1.6, age <26 weeks), whereas the interval between studies can be lengthened if the CPAM is very small (CVR <0.91) [30], or growth has plateaued or is regressing, especially after 30 weeks of gestation [71]. When incipient hydrops is suspected because of fluid in one fetal compartment, assessment every two to three days may be reasonable. (See 'Poor prognostic factors' above.)

MANAGEMENT OF THE HYDROPIC FETUS

Delivery versus in utero treatment — Hydrops is considered a high-risk scenario, thus requiring close observation with frequent cardiac assessment. Hydrops associated with heart failure is particularly prognostic for poor fetal outcome and therefore an indication for fetal intervention or delivery, depending on the gestational age [6,8,14,27,38]. No trials have compared the outcomes of delivery versus intervention. A reasonable approach is:

For hydropic fetuses over 32 to 34 weeks of gestation, early delivery is probably the best option, with immediate postnatal resection [6]. Ex utero intrapartum therapy (EXIT) has been used to stabilize fetuses with large lesions expected to have difficulty breathing at birth [72,73]. (See 'Delivery' below.)

For hydropic fetuses between 20 and 32 weeks of gestation, the morbidity and mortality of preterm birth is a major concern so interventions to improve fetal hemodynamics and prevent lung hypoplasia have been investigated and appear to improve survival [74,75]. For example, small case series show good survival (>90 percent) if hydrops resolves after maternal glucocorticoid therapy [76] and a systematic review found that prenatal drainage or resection improved survival of hydropic fetuses with primary hydrothoraces and/or congenital cystic lung lesions compared with hydropic controls who did not undergo these interventions (odds ratio 9, 95% CI 3-101) [77]. These options are discussed below. (See 'Options for in utero treatment' below.)

Options for in utero treatment

First-line therapy: Maternal betamethasone administration — Steroids are the only medical option in the management of CPAM and have become the first-line therapy before 32 weeks in hydropic fetuses or fetuses determined to be at risk for developing hydrops because of CPAM volume ratio (CVR) >1.6 (image 7). The therapeutic mechanism for resolution of hydrops is unknown, but it may be related to steroid-induced accelerated lung maturation or mass involution.

Initial dosing – A single standard course is administered to the mother: two doses of betamethasone 12 mg intramuscularly 24 hours apart.

Ultrasound follow-up is performed weekly to evaluate the course of hydrops. The response to treatment is variable; fetuses with microcystic lesions appear to respond better than those with macrocystic lesions [76,78-80]. In three studies, including a total of 31 patients with microcystic disease and mean CVR of 2.5 treated with steroids, hydrops was present at steroid administration in 20 patients (65 percent), hydrops resolved in 16 of these 20 patients (80 percent), and 27 of the 31 patients (87 percent) survived [76,78,79]. In one of these studies, resolution of hydrops was noted in two cases as soon as five and nine days after steroid administration, but took two to five weeks in five cases, 13 weeks in one case, and did not resolve in the remaining two cases [76].

Although these results are better than generally reported in historic controls, some studies without administration of steroids have reported resolution of hydrops in 50 percent of fetuses and a 63 percent survival rate [29,54]. It is possible that fetal thoracic growth and/or CPAM regression rather than steroids accounted for the resolution of hydrops, particularly in those cases in which improvement did not occur for many weeks.

Repeated steroid dosing – Some fetuses who fail to respond to a single course of betamethasone will respond to additional courses, although not all fetuses respond to repeated courses of therapy. In retrospective studies, a substantial proportion of fetuses who did not respond to a first course of steroids stabilized or improved (eg, reduction in lesion size, resolving hydrops) after receiving two to three courses of therapy [81,82]. The median interval between the first and second course of steroids was approximately two weeks (range one to six weeks).

Based on these findings, it is reasonable to administer one or two additional courses of betamethasone to fetuses with persistent elevated CVRs, lesion growth, or hydrops. The steroids are administered at intervals of at least one week following the previous steroid treatment. The use of additional courses of steroids versus invasive intervention depends on gestational age and severity of heart failure.

Second-line therapy: Invasive procedures — For fetuses <32 weeks with hydrops or at risk for developing hydrops because of CPAM volume ratio (CVR) >1.6 who do not respond to steroids, invasive intervention is the next option. The choice of the best invasive approach depends on the type of lesion (macrocystic versus microcystic). Patients being considered for cyst drainage should be managed by maternal-fetal medicine specialists with experience in invasive fetal procedures.

If not already evaluated, fetal microarray may be performed prior to initiating fetal therapy, given the increased risk for a genetic abnormality in hydropic fetuses (which may affect decision-making) and the cost and risk of invasive interventions [83].

Choice of procedure — Macrocystic CPAM can be managed with a drainage procedure [49,84]. A microcystic solid appearing CPAM is not amenable to shunting or cyst aspiration but can be managed by resection or ablation.

Drainage procedures

Cyst aspiration – Aspiration can decompress a large macrocyst and reverse the mediastinal shift [49]. Fluid reaccumulation limits its usefulness, but some fetuses will improve after one or two aspirations [29].

Thoracentesis – While large effusions are rare in CPAM, thoracentesis has been described [43]. It is used as a temporizing maneuver to provide prognostic information when considering placement of a thoracoamniotic shunt [6,32,45,77]. Rapid reaccumulation of fluid limits its usefulness.

Thoracoamniotic shunt – If the lesion is macrocystic with a dominant cyst and no large solid component, thoracoamniotic shunting may be a more definitive in utero solution than aspiration. Survival rates of 60 to 70 percent have been reported [44,85] and can be as high as 90 percent in nonhydropic fetuses [86]. However, the procedure results in a mild deformity of the chest wall in the majority of cases [87]. Prognostic factors associated with neonatal survival include resolution of hydrops after in utero therapy, reduction in mass volume, unilateral rather than bilateral effusion, and later gestational age at delivery [85].

Complications include displacement or malfunction of the catheter, preterm prelabor rupture of membranes, and preterm labor [32]. Rarely, fetal hemorrhage, procedure-related abruption, and thrombus occlusion of the catheter have been reported. An internally displaced catheter has been associated with trauma to the fetal chest wall (especially if the procedure is performed before 20 weeks) and with refractory tension pneumothorax postnatally [44,88].

A long-term assessment (median of 11 years) of patients with congenital lung malformations treated with fetal thoracoamniotic shunt placement demonstrated preserved respiratory capacity and exercise tolerance [87].

Alcohol ablation – Alcohol ablation is used for large cystic lesions as well as microcystic lesions. For large lesions, ethanol is instilled and then withdrawn after five minutes. For microcystic lesions small volumes of ethanol are instilled at multiple locations and cannot be withdrawn. Complications from ethanol spillage can result in chest wall anomalies.

Open resection — Open fetal surgery with resection of solid or mixed solid/cystic CPAM with a large solid component has been reported to be successful in approximately 50 percent of cases but has risk to both the mother and the fetus. The surgical team needs to optimize maternal anesthesia, uterine relaxation, hysterotomy technique, fetal exposure, and intraoperative fetal monitoring, as well as be experienced in reapproximation of the fetal membranes and uterine incision. Close postoperative follow-up is critical for early detection and treatment of maternal and fetal complications.

Following resection, hydrops resolves over one to two weeks with reversal of the mediastinal shift over three weeks [44]. In one study, surgical resection of the mass (fetal lobectomy) was performed in 13 hydropic fetuses at 21 to 29 weeks of gestation [6]. Hydrops resolved in eight fetuses (61 percent), with good subsequent in utero lung growth and neonatal survival. There were four intraoperative or postprocedure fetal deaths, and one newborn delivered one week after the procedure died within 48 hours of birth of pulmonary hypoplasia. A smaller series reported survival in only two of seven fetuses [29].

Maternal-fetal surgery requiring hysterotomy is associated with an increased risk of serious complications in the current pregnancy (preterm labor, preterm prelabor rupture of membranes, uterine dehiscence or rupture) [44], as well as an increased risk of uterine rupture or dehiscence in subsequent pregnancies [89].

Investigational procedures

Percutaneous laser ablation – A few case reports have described percutaneous laser ablation of solid CPAM [44,90-94]. Mass size decreased in one series, with complete resolution of fetal hydrops in four of seven cases, but only two fetuses survived [90]. Additional studies are needed to determine whether this a valid therapeutic option.

Percutaneous sclerotherapy – Percutaneous injection of ethanolamine oleate or polidocanol into a large solid CPAM under ultrasound guidance is another option. One study attempted fetal sclerotherapy in three patients under 26 weeks of gestation with CPAM and hydrops, severe mediastinal shift, and polyhydramnios, with resolution of the mass effect and hydrops in all cases [95]. In another series of eight patients and hydrops who underwent sclerotherapy, four fetuses died and four survived to term and underwent postnatal resection [96].

Percutaneous administration of a sclerosing agent can also be used for cystic lesions [97]. In macrocystic cases, the sclerosing agent is instilled and then withdrawn after five minutes. In microcystic lesions, small volumes of the sclerosing agent are instilled at multiple locations but cannot be withdrawn. Spillage of the sclerosing agent can result in chest wall anomalies.

DELIVERY

Planning — Birth planning should be in conjunction with the pediatric staff (neonatology, pediatric surgery) [98].

Small CPAM – If the lung mass has resolved or is small with no mediastinal shift or hydrops, CPAM itself is not an indication for early delivery or cesarean birth [44,99,100]. Neonatal respiratory problems would be unlikely.

Large CPAM – For fetuses with large masses that cause mediastinal shift and/or hydrops, birth should be planned for a tertiary care center with an intensive care nursery capable of resuscitating a neonate with respiratory problems (including extracorporeal membrane oxygenation [ECMO] capability) and with available pediatric surgeons experienced in care of these infants [32,48]. When a large mass is present, immediate thoracotomy in the delivery room may need to be performed to relieve lung compression.

Intermediate CPAM – In masses that are intermediate in size, a CPAM volume ratio (CVR) >1 predicts increased risk of neonatal respiratory problems and thus the need for substantial newborn support in the delivery room [101].

Ex utero intrapartum therapy (EXIT) procedure — EXIT has been used to improve outcome of exceptionally large lung lesions [48]. If a large CPAM connects to the bronchial airway, the neonates initial respirations can fill the CPAM with air but it will not decompress, which can result in an expanding intrathoracic mass that can compress the heart and behave like a tension pneumothorax.

In EXIT, the fetus is partially delivered and intubated without clamping the umbilical cord. Uteroplacental blood flow and gas exchange are maintained by using inhalational agents to provide uterine relaxation and amnioinfusion to maintain uterine volume and to avoid uterine collapse that could result in placental separation and/or cord compression. This provides time for cannulation for ECMO and chest decompression before delivery of the fetus and allows for delayed removal of the CPAM. In rare instances, the lung mass can be excised before completing delivery.

Overall fetal/newborn survival of 90 percent has been reported [44]. However, the risk of maternal bleeding is increased, and 13 percent of mothers need transfusion [102,103].

POSTNATAL MANAGEMENT — Postnatal management of symptomatic CPAM is surgical resection, with timing dependent on severity of symptoms [49]. The treatment for asymptomatic CPAM remains controversial. Postnatal presentation, evaluation, complications, and management are discussed separately. (See "Congenital pulmonary airway malformation".)

SUMMARY AND RECOMMENDATIONS

Anatomy – Prenatally, congenital pulmonary airway malformation (CPAM) is classified as microcystic (74 percent) or macrocystic (26 percent), although mixed lesions also occur. (See 'Epidemiology' above.)

Prenatal diagnosis – Prenatal diagnosis is most commonly based on ultrasound findings first detected in the second trimester. (See 'Prenatal diagnosis' above.)

Macrocystic CPAM is characterized by the presence of anechoic cysts >5 mm in diameter, often surrounded by hyperechogenic lung parenchyma (image 3) (type I).

Microcystic CPAM is characterized by the presence of a solid-appearing homogeneous mass that is hyperechogenic compared with adjacent normal lung parenchyma, and composed of microcystic lesions <5 mm in diameter (image 4) (type III). As gestational age increases, microcystic lesions can become more difficult to visualize due to increased echogenicity of surrounding normal lung [16]. Increased shadowing from overlying ribs also makes assessment of the mass more difficult in the third trimester.

Mixed CPAM lesions contain both solid and cystic components (image 5) (type II).

On color and power Doppler, the arterial supply and venous drainage are from the pulmonary circulation. If a systemic feeding vessel is noted, the lesion is considered a bronchopulmonary sequestration (BPS) if solid and a hybrid BPS/CPAM lesion if cystic and solid.

Postdiagnostic evaluation – Initial evaluation should include assessment for other congenital anomalies. Genetic background of CPAM is not known, but associations with different genes has been suggested, including some associated with increased cancer risk. Microarray can be offered for further evaluation, and should be offered in cases with associated anomalies, as the frequency of genetic abnormalities is increased in fetuses with additional anomalies and/or nonimmune hydrops. The American College of Medical Genetics and Genomics practice guidelines recommend exome and genome sequencing as second-tier tests for pediatric patients with congenital anomalies. (See 'Postdiagnostic imaging evaluation' above.)

Echocardiography is useful to assess for congenital heart disease and outcome if hydrops develops. Magnetic resonance imaging (MRI) is used to better delineate abnormal and normal anatomy when the entire lung is involved by the mass, in the presence of hydrops or bilateral lesions, and when the diagnosis is uncertain. (See 'Role of magnetic resonance imaging' above.)

We suggest serial prenatal ultrasound examinations every one to four weeks to assess change in size of the lung mass, change in CPAM volume ratio (CVR), and development of polyhydramnios and hydrops. The frequency within this range depends on the gestational age and CVR. Closer follow-up should be performed in those patients at high risk of developing hydrops (eg, CVR ≥1.6, age <26 weeks), whereas the interval between studies can be lengthened if the CPAM is very small (CVR <0.91) [30], or growth has plateaued or is regressing, especially after 30 weeks of gestation. (See 'Follow-up imaging' above.)

Prenatal course – Most CPAMs demonstrate rapid progressive growth from approximately weeks 20 to 26 of gestation, peaking at approximately 25 weeks, and then growth plateaus and often regresses. Fetuses with large masses can develop hydrops, which has a poor prognosis in the absence of intervention. If hydrops has not developed by 28 weeks, it is unlikely to develop and the prognosis is excellent, with reported live birth rates ≥95 percent. Prenatal course can be predicted by quantitative measurements, such as the CVR, mass-to-thorax ratio (MTR), lung mass volume ratio (LMVR), observed/expected lung-to-head ratio (LHR), and cardiomediastinal shift angle (CMSA). (See 'Prenatal course' above.)

Management of hydrops

For hydropic fetuses over 32 to 34 weeks of gestation, we suggest delivery with immediate postnatal resection rather than in utero treatment (Grade 2C). (See 'Management of the hydropic fetus' above.).

For hydropic fetuses 20 to 32 weeks, we recommend maternal administration of betamethasone (12 mg intramuscularly, two doses 24 hours apart) rather than delivery or expectant management (Grade 1C). Better responses have been noted with microcystic compared with macrocystic CPAM. Some fetuses who fail to respond to a single course of betamethasone respond to additional courses. (See 'First-line therapy: Maternal betamethasone administration' above.)

Interventional procedures such as cyst drainage and placement of a thoracoamniotic shunt are invasive options for refractory cases of macrocystic CPAM with hydrops remote from term. These procedures are not options for microcystic CPAM.

Open resection is the most invasive option, and can be used for solid or mixed solid/cystic CPAM with a large solid component with refractory hydrops remote from term, but has risk to both the mother and the fetus. (See 'Second-line therapy: Invasive procedures' above.)

Delivery – Delivery planning should be in conjunction with the pediatric staff (neonatology, pediatric surgery). If the lung mass has resolved or is small with no mediastinal shift or hydrops, CPAM itself is not an indication for early delivery or cesarean birth. Neonatal respiratory problems would be unlikely.

For fetuses with large masses that cause mediastinal shift and/or hydrops, delivery should be planned for a tertiary care center with an intensive care nursery capable of resuscitation of a neonate with respiratory difficulties, including capability of extracorporeal membrane oxygenation (ECMO), and with pediatric surgeons experienced in care of these infants.

For masses that are not large or small, a CVR >1 can help predict the risk of neonatal respiratory problems and, in turn, the most appropriate site for delivery. (See 'Delivery' above.)

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Topic 14207 Version 35.0

References

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