2005 Wiley-Liss, Inc.

American Journal of Medical Genetics 140A:151 155 (2006)

Research Review

Cystic Adenomatoid Malformation of the Lung: Review of Genetics, Prenatal Diagnosis, and In Utero Treatment
R. Douglas Wilson,* Holly L. Hedrick, Kenneth W. Liechty, Alan W. Flake, Mark P. Johnson, Michael Bebbington, and N. Scott Adzick
Childrens Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Received 10 May 2005; Accepted 6 September 2005

Prenatal identication of lung abnormalities has increased with prenatal surveillance. Treatment usually requires serial ultrasound observation but in rare situations in utero therapy may be required for fetal survival. We review the genetics, prenatal evaluation, and treatment of lung abnormalities with congenital cystic adenomatoid malformation (CCAM). Other lung lesions, bronchopulmonary sequestration (BPS), hybrid lesions involving both malformations, congenital lobar emphysema (CLE), are briey included as differential diagnosis options. Outcome of fetuses identied to have CCAM lung abnormalities resulting in fetal hydrops and

having in utero therapy (thoracoamniotic shunting, fetal thoracotomy, EXIT delivery) are discussed. In the appropriate situation, this maternal fetal surgery approach for CCAM is life-saving for the affected fetus with acceptable maternal morbidity risks in the present and future pregnancies. 2005 Wiley-Liss, Inc.

Key words: cystic adenomatoid malformation of the lung; prenatal diagnosis; in utero treatment; thoracoamniotic shunting; EXIT

INTRODUCTION

Cystic adenomatoid malformations (CCAM) are relatively rare developmental abnormalities of the lung. They are generally characterized as benign hamartomatous or dysplastic lung tumors characterized by overgrowth of terminal bronchioles. The exact incidence of CCAM is unknown [Bianchi et al., 2000a; Sanders et al., 2002a]. The development of the vertebrate lung has been subdivided into ve distinct periods based on: the anatomical changes that occur in lung architecture: embryonic (37 weeks), pseudoglandular (7 17 weeks), canalicular (1729 weeks), saccular (24 36 weeks), and alveolar (36 weeks to maturity). The CCAM develops during the pseudoglandular period (717 weeks). Initially the tracheobronchial tubules are formed from the pulmonary diverticulum that forms at the medial tracheolaryngeal sulcus in the ventral wall of the foregut. Branching of the trachea produces two lobar bronchi on the left and three on the right side, dening the lobar anatomy of the human lung. The esophagus and trachea separate, bronchial tubules subdivide to form the bronchial pulmonary segments, and the splanchnic mesenchyme undergoes differentiation and organization to form blood vessels, lymphatics, and other support-

ing structures. In the pseudoglandular period (7 17 weeks) there is rapid expansion of the conducting airways and peripheral lung tubules, which continue to branch and bud to form acinar tubules. The expansion of these small tubules in the periphery of the lung produces a glandular appearance. The peripheral lung mesenchyme thins and becomes increasingly vascularized. Neuroendocrine bodies, nerves, and organized smooth muscle are observed in the developing areas. Cartilage rings form around the segmental bronchi. The pleura and peritoneal cavity closes, the diaphragm thickens and becomes increasingly muscularized [Gilbert-Barness and Debich-Spicer, 2004; Whitsett et al., 2004]. CCAM is usually unilateral and usually involves only one lobe of the lung. Cystic structures arise from an overgrowth of the terminal bronchioles with a reduction in the number of alveoli. Five pathological types have been described: (1) type 0acinar

*Correspondence to: R. Douglas Wilson, M.D., The Center for Fetal Diagnosis and Treatment, The Childrens Hospital of Philadelphia, 34th Street and Civic Center Boulevard, 5th Floor, Wood Center, Philadelphia, PA 19104-4399. E-mail: wilsonrd@email.chop.edu DOI 10.1002/ajmg.a.31031

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dysplasia, (2) type Imultiple large cysts or a single dominate cyst, (3) type IImultiple evenly spaced cysts, (4) type IIIbulky rm mass, (5) type IV peripheral cyst type. Prenatally, the more useful characterization is to identify CCAMs as either cystic or solid as these provide more useful categories for determining options and prognosis [Gilbert-Barness, 1997; Gilbert-Barness and Debich-Spicer, 2004]. The majority of fetuses with CCAM detected antenatally have a good outcome but appropriate identication and ongoing surveillance is required due to the unpredictability of growth patterns for CCAM lesions [Bianchi et al., 2000a; Saunder et al., 2002a].
GENETICS

Two recent review articles [Whitsett et al., 2004; Groenman et al., 2005] have looked at the genetic and molecular basis inuencing lung formation and abnormal lung development. CCAM is characterized by abnormal airway patterning during lung branching morphogenesis and is formed by abnormal branching of the immature bronchioles. One of the potential genes of inuence for this development disorder is HOXB5, as its expression is maintained at a level typical for early lung development [Volpe et al., 2003]. The different types of CCAM identify arrested development taking place at different stages in lung development. Arrest in the pseudoglandular phase of lung development CCAM pathology (type IIII) involves the bronchial type of epithelium while a later arrest in weeks 2236 result in an alveolar acinar type CCAM pathology (type IV) of epithelium. This latter pathology could be explained as a distal development and maturation disorder rather than a developmental arrest [Morotti et al., 1999]. Overexpression of Fgf7 gene using the SP-C promoter in mice results in a lung with CCAM-like lesions [Simonet et al., 1995]. This observation raises the possibility that disruption of an Fgf7-dependent interactions between the epithelium and mesenchyme may be involved in the pathogenesis of CCAM in humans. CCAM-like lesions occur in transgenic mice that overexpress keratinocyte growth factor (KGF) [Simonet et al., 1995]), but Liechty et al. [1999] found no differences in the expression of KGF protein or KGF mRNA in CCAM and normal lung. In contrast, fetal CCAMs that grew rapidly, progressed to hydrops and required in utero resection showed increased platelet derived growth factor (PDGF-B) gene expression and PDGF-BB protein production compared with normal fetal lung or term CCAM specimens [Liechty et al., 1999].
PRENATAL DIAGNOSIS AND ASSESSMENT

General statements can be made about the prenatal natural history for CCAMs [Adzick et al., 1998, 2003; Bianchi et al., 2000a; Sanders et al., 2002a].

Diagnosis in fetal life is generally worse than diagnosis in postnatal life. The CCAM is usually highly unpredictable in its growth potential between 18 and 26 weeks of gestation. If hydrops develops secondarily to the CCAM location and growth, there is a high risk for fetal or neonatal death depending on gestation age at onset of hydrops. Ultrasound in its routine obstetrical use in the second trimester, allows more fetuses with a lung malformation to be identied and the differential diagnosis includes CCAM, bronchopulmonary sequestration (BPS), bronchogenic or neuroenteric cysts, and diaphragmatic hernia [Goldstein, 2000; Sanders et al., 2002a,b]. These lesions have different natural histories and prognosis so the correct diagnosis of the lung abnormality is very important [Adzick, 2003]. Ultrasound and MRI are used to identify the location of the lung abnormality, characterize the abnormality by its appearance, evaluate the blood supply and venous drainage by Doppler ultrasound, and determine any changes in thoracic position of other lung lobes, mediastinum, and the cardiac structures [Hubbard et al., 1999; Goldstein, 2000]. Ultrasound will usually characterize the lesions as macrocystic or microcystic. The macrocystic category has large variable size cysts (210 cm) with thin intervening echogenic areas. These multiple cysts are interconnected, but at times only a single cyst can be seen. The microcystic category has a dened echogenic area in the fetal lung with no cystic spaces being identied. A CCAM categorization between the macrocystic and microcystic denition is sometimes used where the cyst spaces are present but small to moderate sized (<2 cm) with adjacent echogenic tissue areas. CCAM has both its arterial and venous blood ow from the pulmonary system. BPS specically has arterial ow from the systemic aorta, but some lung lesions show a hybrid status with blood ow from both the pulmonary and aortic systems [Cass et al., 1997; Goldstein, 2000]. The development of an ultrasound-derived CCAM volume to head circumference ratio (CVR) has allowed a gestational aged corrected volume ratio to be used prognostically when CCAM lesions are identied [Crombleholme et al., 2002; Adzick, 2003]. The CCAM volume (cc) is sonographically measured by using the formula for an ellipse (length height width 0.52). A CVR is obtained by dividing the CCAM volume (cc) by the head circumference (cm) to correct for differences in the fetal gestational age. CCAM lesions that are predicted to be high-risk have a CVR greater than 1.6 or lesions with a signicant macrocystic component. Surveillance of a CCAM is dictated by these features with high risk lung lesions being followed two to three times per week, while smaller lung lesions may be followed on a weekly basis (<1.2) or twice per week (1.21.6) depending on the gestational age and CVR ratio at initial evaluation [Adzick et al., 1998, 2003; Adzick

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and Kitano, 2003]. The fastest growth in the CVR appears to occur between 20 and 25 weeks with a peak in the mean CVR occurring at 25 weeks gestation [Crombleholme et al., 2002]. There is a plateau in CCAM growth beginning at 25 weeks gestation with a decrease in the CVR after 25 weeks gestation reecting continued fetal growth. Actual regression in CCAM size was observed after 29 weeks gestation reecting in a further decrease in the CVR. Other ultrasound features that should be followed are cardiac function especially if there is a signicant shift of the mediastinum and heart. Additional ultrasound evaluations should include amniotic uid volume, umbilical artery Doppler ow patterns, ductus venosus Doppler ow patterns, and placental thickness. There is no known association of CCAM with chromosome abnormalities, but additional structural abnormalities in the renal (renal agenesis) and gastrointestinal (diaphragmatic hernia and bowel atresia) systems should be assessed [Sanders et al., 2002a]. Other lung lesions that need to be considered in the prenatal evaluation differential diagnosis include BPS, congenital lobar emphysema (CLE), and peripheral bronchial atresia (PBA) [Goldstein, 2000; Sanders et al., 2002b; Gilbert-Barness and DebichSpicer, 2004]. BPS can be either an intralobar lesion resulting from early ectopic lung budding prior to pleural development or extralobar with later lung budding with a separate pleural covering [Bianchi et al., 2000b; Sanders et al., 2002b]. These BPS masses are usually benign pulmonary tissue lacking tracheobronchial connection with a separate vascular supply that usually arises from the thoracic or abdominal aorta. The incidence is estimated at 1 per 1,000 births with intralobar having an equal male to female ratio and extralobar having a male to female ratio of one to four. Intralobar lesions are present in 75% and are usually located at either the right or left base. Approximately 10% have associated anomalies including diaphragmatic hernia, tracheoesophageal stula, congenital heart defects, foregut duplication, and aneuploidy. Venous drainage for the intralobar BPS is usually via the pulmonary veins. The extralobar lesions are present in 25% with 10% located below the diaphragm. The majority of extralobar lesions are at the left base and with an increased association of anomalies estimated at 50%. Venous drainage is usually via the subdiaphragmatic veins. Pleural effusions are associated with BPS lesions. Other lung lesions include CLE which are not commonly diagnosed in fetal life. CLE is a lobar overination without destruction of the alveolar septae and are usually in the upper (left greater than right) or middle lobes [Gilbert-Barness and DebichSpicer, 2004]. CLE is enclosed in a normal pleural envelope and has an ultrasound appearance similar to a microcystic CCAM. There is a cartilage deciency in the bronchus wall. Another lung lesion, PBA, has a

prenatal ultrasound appearance similar to CCAM or BPS but is postnatally stable, asymptomatic, and pathology shows hyperinated segments of lung with uid trapping [Adzick, 2005].
IN UTERO THERAPY

The majority of fetuses with prenatal identication of a CCAM have a decreased CCAM size in the third trimester and undergo normal vaginal delivery with postnatal resection at 58 weeks of life, (no respiratory symptoms at birth; resection of lesion due to risks of infections, pneumothorax, and malignant degeneration), but some fetuses require more extensive evaluation and treatment in utero [Adzick et al., 1998; Bianchi et al., 2000a; Adzick, 2003; Adzick and Kitano, 2003]. The current approach to in utero management of large CCAMs requires evaluation by fetal ultrasound, fetal echocardiogram, ultrafast MRI, and fetal karyotype [Adzick and Kitano, 2003]. When associated anomalies or chromosomal anomalies are identied, that fetus would not be a candidate for any in utero treatments. Counseling and expectant management of the pregnancy would be recommended. When a fetus with an isolated CCAM is complicated by hydrops, the next triage decision is dependent on gestational age. If the fetus is less than 32 weeks and no dominant cyst is available for drainage, an open maternal-fetal surgery is considered for fetal thoracotomy/lobectomy. Expectant management in this situation has a predicted 100% lethal outcome. If the fetus is less than 32 weeks gestation and has a single or multiple large CCAM cysts, then fetal thoracoamniotic shunting is an appropriate approach. Other details of this shunting therapy will be provided later in this article. If the fetus is greater than 32 weeks gestation, the plan would be for delivery with or without an EXIT procedure (exutero intrapartum treatment). One of the signicant aspects of this triage decision is that fetuses need to be 34 weeks gestation or have a weight of 2,000 g to have additional pulmonary support by extracorporeal membrane oxygenation (ECMO) if required, due to pulmonary hypertension or pulmonary hypoplasia. Open maternal-fetal therapy has been reviewed in a number of previous publications and detailed description of the surgical techniques will not be included in this article [Harrison and Adzick, 2001]. The Childrens Hospital of Philadelphias experience includes 14 cases of open maternal-fetal therapy used for large CCAM lesions from a total from 107 maternal-fetal open procedures. Survival for these 14 cases from surgery to discharge from the Neonatal Intensive Care Unit is 50%. Gestational age at the time of these surgeries ranges from 21 to 29 weeks gestation. In the survivors, there is resolution of the hydrops in 12 weeks with movement of the mediastinum back to the midline in 3 weeks. There is rapid residual lung growth. The mean time to

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delivery following the in utero maternal-fetal surgery was 8 weeks. To date the follow-up of these children have shown normal developmental outcome. In the non-survivor group, some fetal losses have been intraoperative usually after developing profound bradycardia after delivery of the CCAM mass from the chest. It is hypothesized that the CCAM delivery from the thorax and abrupt removal of cardiac compression results in a pathophysiology response similar to correction of a pericardial tamponade with fetal hemodynamic collapse and reactive bradycardia. As a result of this experience, specic changes have been made to delay surgery until 2324 weeks gestation so that intravenous access can be obtained in the fetus to allow intraoperative blood gas and hematocrit evaluation as well as volume expansion with blood. The fetus is pretreated with intravenous atropine. Fetal echocardiography is used on a routine continuous basis for all maternal-fetal surgery cases, but it has more signicant value in the CCAM cases as direct monitoring of the fetal myocardial performance can be obtained and appropriate adjustments of uid volumes and medications can be utilized. Other fetal losses have been secondary to preterm labor, intrauterine death at 24 hr, and maternal mirror syndrome requiring early delivery with neonatal death. The ultrasound-guided intrauterine use of thoracoamniotic shunting for macrocystic CCAMs has previously been reviewed with our rst ten cases being published [Wilson et al., 2004]. There are now a total of 23 pregnancies that have undergone this therapy. There was no difference in the CCAM location with 11 right sided and 12 left sided lesions. There was some gender difference with 17 males and 6 females but no statistical signicance. Fetal hydrops was present in 18 fetuses and polyhydramnios in 11 pregnancies with 9 fetuses having both hydrops and polyhydramnios. The gestational age at evaluation, shunt placement, and delivery was 22.3, 21.4, and 36.3 weeks, respectively. The mean interval of shunt to delivery was 11.8 weeks. The preshunt evaluation found the mean CCAM volume was 70.8 cc (range of 19.6263 cc) and the mean CVR was 2.4. Following thoracoamniotic shunting, the mean CCAM volume decreased to 22.7 cc and the mean CVR to 0.7. Overall reduction in volume and CCAM ratio was approximately 70%. The prenatal outcome for these 23 shunted fetuses was 22 live born and 1 intrauterine death, but there were 5 subsequent neonatal deaths. Overall survival was 74% (17/23). Evaluations of the perinatal mortality showed that the gestational age at shunt insertion was similar for both the surviving and non-surviving neonates. The main difference between the two outcomes was the shunt to delivery interval, survivors with 76.8 days (range 12 119 days) compared to non-survivors with 19.7 days (range 348 days). Although gender differences of the overall population did not meet signicance, all six perinatal losses were male.

In clinical scenarios where the CVR continues to be large in the third trimester and it is anticipated that signicant respiratory distress may be present at birth, the EXIT delivery is considered using placental bypass during the fetal thoracotomy and lobectomy. [Hedrick, 2003; Hedrick et al., 2005] At the time of the EXIT delivery, only head and neck are initially delivered through the hysterotomy. The intrauterine volume is maintained with lower fetal body and continuous amnio infusion of warmed Ringers lactate to prevent cord compression. Uterine relaxation is maintained by high concentration inhalational anesthetics with additional tocolysis, if necessary. These maneuvers preserve the utero-placental circulation and continue gas exchange between maternal, placental, and fetal compartments. Hedrick et al. [2005] reported on nine fetuses who had undergone resection of lung lesions during the EXIT delivery. The mean gestational age at EXIT delivery was 35.4 weeks. All lung masses maintained large sizes late into gestation with a mean CVR of 2.5 at presentation and 2.2 at EXIT. Some of the nine fetuses demonstrated hydropic changes and/or polyhydramnios and had prenatal intervention including thoracocentesis, thoracoamniotic shunt placement, amnio reduction, and/or maternal betamethasone administration. Overall survival after EXIT lung mass resection was 89%. The average time on placental bypass was 65 min. Postnatal complications included reoperation for air leak (n 1), reoperation for bleeding (n 1), and death from sepsis and prematurity (n 1). Extracorporeal oxygenation (ECMO) was used in four neonates for persistent pulmonary hypertension. Maternal prenatal complications included polyhydramnios (n 5), preterm labor (n 4), and chorioamnionitis (n 1). One mother required perioperative blood transfusion. Conclusions from this clinical experience indicates that the EXIT delivery allows for controlled resection of large fetal lung masses at delivery, avoiding acute respiratory decompensation related to mediastinal shift, air trapping, and compression of normal lung.
SUMMARY

This review of CCAMs has discussed the possible gene interaction with CCAM pathology may involve the HOXB-5 gene, FGF-7 gene, and PDGFB gene. Prenatal diagnosis techniques such as ultrasound and MRI are able to differentiate the different types of lung pathology that can be present in the fetus and with functional echocardiography, direct appropriate therapies to the prenatal diagnosis. In utero evaluation and treatment can vary from serial observation in utero with normal delivery and resection at 58 weeks of newborn life to in utero techniques, which include open maternal-fetal therapy with fetal thoracotomy and lobectomy, thoracoamniotic shunting of macrocystic CCAMs and third trimester EXIT

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delivery with fetal thoracotomy, and lobectomy on maternal placental bypass. The survival for in utero indicated treatments of open maternal-fetal therapy, thoracoamniotic shunting, and EXIT delivery are 50%, 75%, and 89%, respectively. The information provided in this review allows evidence-based outcomes to be discussed with families. In the appropriate situation, these maternal-fetal surgeries for CCAM pathology are life saving for the affected fetus at risk for hydrops or severe respiratory dysfunction while allowing acceptable maternal risk in the present and future pregnancies. This type of fetal therapy requires the energy, dedication, and expertise of a multi-disciplinary team with both maternal and fetal risk/benet considerations.
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