Open fetal surgery for life-threatening fetal malformations

Open Fetal Surgery for Life-threatening Fetal Malformations Yoshihiro Kitano, Alan W. Flake, Timothy M. Crombleholme, Mark P. Johnson, and N. Scott Adzick

After more than two decades of experimental and clinical work, fetal surgery has become an accepted treatment modality for selected fetuses with life-threatening anomalies. Color Doppler ultrasound and ultrafast fetal magnetic resonance imaging have enhanced the accuracy of prenatal evaluation traditionally made by ultrasound alone. Fetal lung masses associated with hydrops are nearly 100% fatal. These lesions can be resected in utero if they are predominantly solid or multicystic, Thoracoamniotic shunting may be effective in the setting of a single large predominant cyst. Fetuses diagnosed with left congenital diaphragmatic hernia before 26 weeks' gestation with liver herniation and a sonographic right lung to head circumference ratio (LHR) of less than one may benefit from fetal tracheal occlusion. Fetal sacrococcygeal teratoma complicated with placentomegaly, hydrops, or progressive high output heart failure may benefit from in utero resection of the tumor. Although preterm labor still remains the Achilles heel of open fetal surgery, effective tocolysis may, in the future, expand the scope of fetal surgery.

Copyright 9 1999 by W.B. Saunders Company " ~ / ~ i t h the advent of prenatal diagnosis, pediV V atric surgeons and neonatologists were challenged with a whole new patient population. This was the subset of fetuses with life-threatening malformations who had not survived in the past without prenatal diagnosis, maternal transport, and planned delivery. Although prenatal diagnosis improved perinatal care, improvement in overall morbidity and mortality rates did not readily follow because some fetuses, detected by prenatal diagnosis, were already too sick to treat successfully after birth. This frustrating situation led to the development of fetal surgery. In the 1980s, the natural history of several potentially correctable lesions was determined by serial sonographic observation and postnatal follow-up of human fetuses, and selection criteria for intervention were developed. The pathophysiology of these lesions was delineated in animal models and anesthetic, tocolytic, and surgical techniques for hysterotomy and fetal surgery were refined. Based on this investment in

basic and clinical research, open fetal surgery is now being offered in highly selected circumstances when the fetal prognosis is otherwise extremely poor. This article summarizes the current status of open fetal surgery for fetuses with life-threatening anomalies and gives specific recommendations for their prenatal and perinatal management. Specifically, the natural history, pathophysiology, prenatal diagnosis, surgical management, and related experimental studies for congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration (BPS), congenital diaphragmatic hernia (CDH), and sacrococcygeal teratoma (SCT) will be discussed after a general description of current perioperative management in open fetal surgery.

From the Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, PA. Address reprint requests to N. ScottAdzick, MD, The Centerfor Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104-4399; e-mail: [email protected] Copyright 9 1999 by W.B. Saunders Company 0146-0005/99/2306-0003510. 00/0

As is the case with any other invasive treatment, the risks and benefits of fetal surgery must be weighed for each patient. For the fetus, the risk of the procedure is small when compared with the potential benefit of salvage, The risks and benefits for the mother are more difficult to assess. Most fetal malformations do not directly

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Perioperative Management o f Open Fetal Surgery Preoperative Evaluation and Care

Seminars in Perinatology, Vol 23, No 6 (December), 1999: pp 448461

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threaten the mother's health, yet she must bear significant potential risk and discomfort from the procedure. Maternal safety is the paramount issue. Fortunately, there have been no maternal deaths, no compromise in future fertility, and few postoperative maternal complications. But there has been considerable morbidity related primarily to preterm labor and its treatment. This risk to the mother must be weighed against the risk of f e e l loss or the burden of raising a child with a severe malformation. Patients referred to a f e e l treatment center are evaluated by a multidisciplinary team. The evaluation includes (1) detailed ultrasonography to confirm the diagnosis and detect any other anatomic abnormalities, (9) ultra.fast f e e l magnetic resonance imaging (MRI) in selected cases for additional anatomic information, (3) a fetal echocardiogram to rule out congenital heart disease and assess f e e l cardiac function, and (4) usually amniocentesis or umbilical blood sampling for f e e l karyotyping. In general, the following conditions are considered contraindications for open feel surgery: chromosomal anomaly, multiple gestation, other significant anatomical anomalies, a history of heavy cigarette smoking or other maternal risk factors, and the presence of the maternal mirror syndrome (discussed later). Finally, an informed consent conference is held with the family, including the pediatric surgeon, perinatologist, anesthesiologist, social worker, and nurse coordinator to discuss the f e e l surgical procedure, expected results, maternal and f e e l risks, and potential benefits and alternatives to f e e l surgery.

Postoperative Care Achievement of total uterine relaxation during surgery is achieved by deep inhalational anesthesia and is facilitated postoperatively by adequate analgesia via an epidural catheter. The tocolytic regimen includes an indomethacin rectal suppository (50 mg) preoperatively and every 4 to 6 hours postoperatively for 48 hours. Daily f e e l echocardiography is performed to detect adverse feel effects of indomethacin including d u c e l constriction, tricuspid regurgitation, and oligohydramnios. During closure of the hysterotomy the patient is given a 6 g loading dose of magnesium sulfate (MgSO4) followed by a continuous infusion at 2 to 4 g / h depending on the

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degree of uterine irritability. The MgSO 4 infusion is maintained for 48 to 72 hours postoperatively while monitoring serum magnesium levels and observing for clinical signs of magnesium toxicity. By the second postoperative day the indomethacin and magnesium can usually be stopped and the patient is converted to a pump that delivers terbutaline subcutaneously. Feel heart rate and uterine activity are recorded externally by tocodynamometer, and daily ultrasound is performed as the patient is hospitalized (usually 5 to 7 days). Feel movement (an indirect assessment of f e e l well being), anatomic evaluation, and amniotic fluid index are carefully assessed by an experienced sonographer. The resolution of placentomegaly and f e e l hydrops, if present before surgery, will be observed over the next 1 to 3 weeks. Because the midgestation hysterotomy is not in the lower uterine segment, all patients who undergo open f e e l surgery require cesarean delivery for all future deliveries to avoid uterine rupture during labor. The fetuses who underwent the tracheal clip procedure must have the clips removed before delivery. To provide time for neck dissection, clip removal, bronchoscopy, and intubation, the ex utero intrapartum treatment procedure was developed. ~,2 Uteroplacene l gas exchange is maintained during the ex utero intrapartum treatment procedure by keeping the uterus relaxed through the use of inhalational agents and uterine volume is mainmined by exposing only the f e e l head and neck for clip removal.

Complications Specific to Open Fetal Surgery The current tocolytic regimen is inadequate to uniformly prevent preterm labor after f e e l surgery. For the first 27 cases of open f e e l surgery at the Children's Hospital of Philadelphia (CHOP), the mean duration from surgery to delivery was 8 weeks and the mean gesetional age at delivery was 32.5 weeks. Preterm labor remains the Achilles heel of f e e l surgery and can obscure its benefits. Noncardiogenic interstitial pulmonary edema is a serious potential complication in mothers who undergo f e e l surgery. This complication developed in 15 (23%) of 65 f e e l surgery patients at the University of California, San Fran-

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cisco (UCSF). 3 In addition to known risk factors such as tocolytic agents (magnesium sulfate and terbutaline) and generous intravenous hydration, it is speculated that disruption of the myometrium and membranes provokes the release o f various vasoactive agents (such as prostaglandins and thromboplastins), resulting in increased maternal vascular permeability and pulm o n a r y "capillary leak." Because accumulation of interstitial fluid is d e t e r m i n e d by the balance between osmotic and hydrostatic pressure in the capillary bed and interstitium, we serially measure colloid osmotic pressure after open fetal surgery. We f o u n d that maternal colloid osmotic pressure decreases significantly after open fetal surgery and reaches its nadir early o n postoperative day 2, corresponding with t h e risk period for maternal p u l m o n a r y edema. 4 Whereas the decrease in maternal colloid osmotic pressure lowers the threshold for pulmonary edema, aggressive fluid restriction can compromise the maternal-placental-fetal circulation and induce p r e t e r m labor. We use a regimen o f judicious postoperative intravenous fluid administration and empiric furosemide diuresis, which has dramatically reduced the incidence o f this complication. Amniotic fluid leak can develop either from the hysterotomy site in the a b d o m e n (rare) or via the vagina because o f m e m b r a n e rupture. In the f o r m e r case, surgical repair is required, but we have not experienced this complication for several years with o u r c u r r e n t hysterotomy closure technique: a r u n n i n g layer of absorbable m o n o f i l a m e n t suture to the myometrium and membranes, interrupted full thickness stay sutures o f heavy absorbable m o n o f i l a m e n t sutures, and an omental patch. Chorioamniotic separation is a recently recognized complication that can lead to amniotic band formation and membrane rupture. The UCSF group described 5 cases o f this complication in more than 40 cases o f o p e n fetal surgery. 5 T h r e e of these fetuses had umbilical c o r d compromise by a band of amniotic m e m b r a n e leading to 1 fetal death. Awareness o f this potentially lethal complication and its evaluation by serial ultrasound and fetal monitoring is r e c o m m e n d e d because emergent delivery may be required when this situation develops.

Fetal Lung Lesions CCAM is a benign cystic lung mass that is usually restricted to 1 lobe o f the lung. It is histologically characterized by an overgrowth o f terminal respiratory bronchioles that form cysts of various sizes and by a lack of normal alveoli. Many pathologists consider CCAM a hamartoma, a developmental abnormality with excess of I or several tissue components. Most CCAMs communicate with the normal bronchial tree and derive their bIood supply from the pulmonary circulation. BPS is a nonfunctioning lung mass that arises as an aberrant o u t p o u c h i n g from the developing foregnt with systemic vascular supply. BPS lesions are classified into extralobar and intralobar forms. The extralobar form consists of pulm o n a r y tissue that is enveloped in its own pleura, without communication with the normal tracheobronchial tree. It may occur above or below the diaphragm. T h e intralobar form is f o u n d within the normal lung tissue, with or without communications with the normal bronchial tree.

Natural History T h e natural history and clinical spectrum of prenatally diagnosed lung lesions is quite variable and appears to d e p e n d on the size and secondary physiological derangements caused by these tumors. Approximately 20% of fetal CCAM lesions decrease in size and two thirds of BPS lesions shrink dramatically before birth. 6,7 Initial impressions concerning the prognosis of a large lung mass with mediastinal shift should be temp e r e d with the understanding that it can shrink in size or even "disappear" by ultrasound. Winters et al s reported 7 children with prenatally diagnosed CCAM that disappeared during prenatal sonographic follow-up. Postnatal chest c o m p u t e d tomography scans revealed persistent abnormalities in all cases, emphasizing the importance of postnatal imaging studies in these patients. In face of the variable natural history o f these lesions, how can we select the fetuses who would benefit from fetal intervention? Presently, the development of fetal hydrops is considered the only criteria because it is nearly always a predictor o f fetal death. In a recent review by Adzick et al, 6 all 25 fetuses who had large CCAMs associated with hydrops died before or shortly after

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birth when they were followed-up expectantly. Although the resolution of fetal hydrops associated with a large CCAM has been reported, 9-11 this is a rare circumstance. In search for a better parameter to predict which fetuses are at risk for the development of hydrops, we are evaluating sonographically determined CCAM volume. CCAM volume is determined by using the formula for a prolate ellipse, and the CCAM volume ratio (CVR) is obtained by dividing the CCAM volume by the head circumference to correct for differences in fetal size. In a retrospective review of 20 fetal CCAMs with regard to CVR and the developm e n t of hydrops, 5 fetuses who developed hydrops had significantly larger CVR compared with the 15 nonhydropic fetuses. 12 Most of the fetuses with high CVR values were already hydropic and the CVR could not be used to predict hydrops. However, none of the fetuses with a CVR of less than 1.2 developed hydrops. The CVR of 1.2 is derived from 2 standard deviations from the mean of the nonhydropic CCAM group at presentation. This parameter is now being evaluated in a prospective study. Investigations in our laboratory have helped define the biological characteristics of fetal CCAMs that show rapid growth resulting in fetal hydrops. Liechty et aP 3 and Cass et al TM reported that large CCAM specimens requiring fetal resection show increased cell proliferation, decreased apoptosis, and increased mesenchymal platelet-derived growth factor-B gene expression and protein production compared with either normal fetal lung tissue or much smaller CCAMs that were resected after birth.

Pathophysiology Huge fetal lung lesions have reproducible pathophysiological effects on the developing fetus. Polyhydramnios likely results from esophageal compression by the thoracic mass and decreased fetal swallowing of amniotic fluid. This concept is supported by the frequent absence of fluid in the stomach of fetuses with large thoracic tumors and marked mediastinal shift, and the reappearance of stomach fluid and the restoration of normal amniotic fluid volume after effective fetal treatment. Hydrops is secondary to obstruction of the great vessels and cardiac compression from large tumors causing an extreme

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mediastinal shift. Fetal BPS can also cause fetal hydrops, either directly from the mass effect or from a tension hydrothorax that is the result of fluid or lymphatic secretion from the mass. Much of our knowledge concerning the pathophysiology of a huge chest mass stems from work in laboratory animals. 15,16 We have developed experimental models that simulate an enlarging intrathoracic mass and result in pulmonary hypoplasia and death at term due to respiratory insufficiency. Gradual enlargement of an intrathoracic implanted balloon led to a dramatic increase in central venous pressure followed by the development of hydrops in fetal sheep. When the balloon was deflated to simulate resection of the mass, central venous pressure decreased to normal values and hydrops resolved. We have also showed that fetal pulmonary resection is straightforward. The development of fetal hydrops and placentomegaly associated with large lung masses can lead to the maternal "mirror syndrome," a potentially devastating maternal illness in which the mother's condition begins to mirror that of the sick fetus. She develops progressive symptoms of preeclampsia including vomiting, hypertension, peripheral edema, proteinuria, and pulmonary edema. The pathophysiology of this condition is unclear, but it may result from the release of vasoactive factors from the edematous placenta. We have learned that this syndrome can quickly develop and that its reversal cannot be accomplished by treatment of the fetal anomaly alone. Therefore, the presence of placentomegaly and the maternal mirror syndrome is considered a contraindication to open fetal surgery. 6 Earlier fetal intervention before the related m a t e m a l preeclamptic state develops is recommended.

Prenatal Diagnosis The prenatal diagnosis of CCAM and BPS is made primarily by ultrasound. CCAM lesions may be solid a n d / o r cystic. Adzick et a117 have classified prenatally diagnosed CCAM into 2 categories based on gross anatomy and ultrasound findings. Macrocystic CCAM lesions contain single or multiple cysts that are 5 mm in diameter or larger and appear cystic on prenatal ultrasound (Fig 1A). Microcystic lesions are more solid, contain cysts smaller than 5 m m in diam-

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Figure 1. Fetal ultrasonography showing a (A) macrocystic cystic and (B) microcystic solid CCAM. eter, and appear echogenic on prenatal ultrasound (Fig 1B). BPS lesions usually appear as a well-defined echodense, h o m o g e n e o u s mass. A systemic arterial supply from the aorta detected by Doppler ultrasound is the p a t h o g n o m o n i c feature for BPS. However, if this Doppler finding is not detected, then an echodense microcystic CCAM and a BPS can have the same sonographic characteristics. Furthermore, we have described "hybrid" cystic lung lesions that display clinicopathologic features of both CCAM and BPS, which suggests a shared embryonic basis for some of these lung lesions, a8 It is also important to distinguish exceedingly rare bilateral lung lesions from congenital high airway obstruction syndrome that presents with bilateral large echodense lungs, the absence of mediastinal shift, and hydrops. 19

should p r o m p t consideration of fetal surgery (Fig 2). Fetal thoracentesis is limited by the rapid reaccumulation o f cyst fluid and does not appear to alter the long-term outlook of these fetuses. Thoracoamniotic shunting is effective in cases with a large p r e d o m i n a n t cyst as long as there is not a large solid c o m p o n e n t to the CCAM. 6,11 Multicystic or predominantly solid CCAM lesions do not lend themselves to catheter decompression and require resection. Fetal lobectomy (Fig 3) is a reasonable therapeutic choice for those cases. Ipsilateral hypoplastic lung tissue should be saved whenever possible because we have learned that significant compensatory lung growth can occur. Fetuses without hydrops usually survive intrauterine life and can be managed postnatally in the setting of maternal transport, planned delivery, and immediate postnatal evaluation and treatment at a facility with extracorporeal m e m b r a n e oxygenation (ECMO) capability. T h e combined experience from C H O P and UCSF was recently reviewed by Adzick et al. 6 One h u n d r e d and seventy five fetal lung lesions diagnosed by antenatal ultrasound were included (134 CCAMs and 41 extralobar BPS). Fetal lobectomy was p e r f o r m e d at 21 to 29 weeks' gestation in 13 hydropic fetuses with 8 fetuses (62%) continuing gestation with subseq u e n t hydrops resolution, impressive lung growth, and neonatal survival. T h e mean postoperative pregnancy duration was 8 weeks (range, from 2 to 13 weeks). T h e r e were 5 fetal deaths: 3 were intraoperative or postoperative fetal deaths in 21-week gestation fetuses with p r o f o u n d hydrops, 1 was an intraoperative fetal

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Surgical Management The presence or evolution of hydrops in association with isolated CCAM before lung maturity

Figure 2. Algorithm for the fetus with a prenatally diagnosed CCAM.

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Figure 3. Exposure of CCAM (arrow) through fetal thoracotomy. The hilar structures are being carefully ligated. demise caused by uncontrollable uterine contractions, and the other death was caused by uncontrolled preterm labor in a mother who already had the maternal mirror syndrome. Six fetuses with a large solitary cyst underwent thoracoamniotic shunting and 5 survived. Three of these 6 fetuses were hydropic and 2 of the 3 survived. All 25 hydropic fetuses managed expectandy died before or shortly after birth. In contrast, 10 of 16 hydropic fetuses (63%) that underwent fetal CCAM resection or shunting survived. Our updated experience (as of April 1999) has shown that 17 of 25 hydropic fetuses (68%) survived after fetal therapy. This series shows that in highly selected cases fetal CCAM treatment is reasonably safe, technically feasible, reverses hydrops, and allows sufficient lung growth to permit survival. Of 41 extralobar BPS cases, 28 dramatically regressed before birth and were asymptomatic after birth. Of the remaining 13 cases, 2 underwent therapeutic abortion, 7 symptomatic lesions were resected successfully after birth, 1 hydropic fetus died, and 3 fetuses with BPS complicated by tension hydrothorax with secondary hydrops were successfully treated by either fetal

serial thoracenteses or thoracoamniotic shunting followed by postnatal resection. Seventy-six fetuses with CCAM lesions that were not associated with hydrops survived with expectant management including maternal transport and planned delivery near or at term. Many of the babies with large lesions required substantial ventilatory support and 4 needed ECMO. Because CCAM is associated with infection and malignant degeneration, ~~ we recommend elective resection even in asymptomatic infants.

Congenital Diaphragmatic Hernia CDH is a simple anatomic defect with a devastating physiological consequence: pulmonary hypoplasia. CDH occurs in 1 in 2,200 to 3,500 live births. 2a The defect arises on the right side in 10% of cases and bilaterally in 2%. Nearly all cases are sporadic with the rare exception of familial CDH usually associated with diaphragmatic agenesis. 24 Associated anomalies, such as congenital heart defects, chromosomal anomalies (trisomy 21, 18, and 13), neurological defects (hydrocephalus, anencephaly, and spina

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bifida), and o t h e r anomalies of the urinary tract a n d gastrointestinal systems, are seen in 25% to 57% o f cases of prenatally d i a g n o s e d CDH a n d 95% of stillborns. 25,2a Natural

History

Retrospective studies of C D H vary widely in their postnatal mortality rate and are each flawed by what Harrison et a127 have referred to as a "hidd e n mortality." This h i d d e n mortality arises f r o m deaths occurring in utero or in the delivery r o o m before transfer to a tertiary center. This issue was addressed in a prospective analysis by Harrison et al, 2s which provided invaluable data on the mortality rate of fetal C D H without associated anomalies. T h e study included 83 cases referred to UCSF between 1989 and 1993 for consideration of fetal therapy with isolated C D H diagnosed before 24 weeks' gestation. Fortyeight patients (including 7 cases of inexplicable third trimester intrauterine demise) died resulting in an overall 58% mortality rate. Twenty-two o f 35 survivors required ECMO, of which 9 patients had significant morbidity. This study clearly d o c u m e n t e d that patients b o r n with an isolated CDH suffer substantial mortality and morbidity despite accurate prenatal diagnosis a n d sophisticated neonatal care including maternal transport, p l a n n e d delivery, and immediate resuscitation at institutions with ECMO capability. But, at the same time, this study also showed that 42% of prenatally diagnosed patients are treatable with m o r e conventional postnatal approaches. An accurate prenatal m a r k e r was n e e d e d to predict postnatal o u t c o m e to appropriately select patients for fetal surgery who would do poorly with conventional postnatal therapies. Various prognostic factors for p o o r o u t c o m e have b e e n p r o p o s e d such as early gestational diagnosis, severe mediastinal shift, polyhydramnios, a small lung-thorax transverse area ratio, left heart u n d e r d e v e l o p m e n t , and the presence of stomach in the chest. However, n o n e of these features have b e e n uniformly predictive of outcome. 29 Liver herniation is a n o t h e r i m p o r t a n t prognostic factor. 3~ Although color flow Doppler ultrasound can visualize bowing of the ductus venosus to the left o f the midline or coursing of the portal branches or hepatic veins to the lat-

eral s e g m e n t of the left lobe above the level of the diaphragm, ultrasound has not always accurately showed liver herniation in the fetus with left-sided CDH. Ultrafast fetal MRI with the rapid HASTE technique is a powerful tool to accurately show liver herniation. 32 A n o t h e r advantage of ultrafast fetal MRI may be its ability to directly measure fetal lung volumes, s3 T h e absence of liver herniation indicates a g o o d prognosis with a survival of 93%, whereas liver herniation is associated with 43% survival. Because the extent of liver herniation does not completely correlate with LHR, the presence of liver herniation alone does not warrant consideration for fetal intervention. Currently, the most reliable prenatal predictor o f postnatal o u t c o m e for left C D H is the LHR, defined as the two dimensional right lung area measured at the level of the f o u r - c h a m b e r view of the heart divided by the h e a d circumference to normalize for gestafional age. 3~ T h e L H R m e a s u r e d at 24 to 26 weeks' gestation has now b e e n retrospectively and prospectively assessed in 2 centers (UCSF and C H O P ) and is a useful predictor of postnatal outcome. 3~ In the prospective study r e p o r t e d by Lipshutz et al, ~4 no patient with a L H R of less than 1 survived, whereas all patients with a L H R greater than 1.4 survived. L H R values between 1 and 1.4 were associated with 38% survival. 34 We have independently confirmed their results with an 89% survival with a LHR of greater than 1.6 (eight ninths, 1 death f r o m termination), 56% survival with a LHR of 1 to 1.6, and 11% survival with a L H R of less than 1. T h e L H R is the first m a r k e r that has predicted the severity of lung hypoplasia in left CDH based on ultrasound a p p e a r a n c e before 26 weeks. It remains uncertain if L H R is as accurate in predicting o u t c o m e in right CDH or in patients diagnosed after 26 weeks.

Pathophysiology T h e presence of herniated viscera in the chest seriously hinders the d e v e l o p m e n t of the fetal lungs. All c o m p o n e n t s of the respiratory unit including the bronchi, alveoli, arteries, and capillary b e d are reduced. In addition, there is an a b n o r m a l muscularization of the preacinar pulm o n a r y arterioles which, in c o m b i n a t i o n with a r e d u c e d capillary bed, predisposes to severe neonatal p u l m o n a r y hypertension. Polyhydramnios

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may arise from gastric outlet obstruction because of the displacement of the stomach into the chest. The severity of pulmonary hypoplasia is directly related to the timing of herniation and the volume of herniated viscera. 35,36 The spectrum of CDH varies from neonates with early severe herniation and such extreme pulmonary hypoplasia that they are unsalvageable to patients with relatively mild hypoplasia, who can be managed successfully by standard postnatal care. Cases with herniation only late in gestation have minimal pulmonary hypoplasia and a near uniform postnatal survival, a6

Surgical Management The original approach of complete in utero CDH repair a5 proved technically impossible when liver herniation was present because acute reduction of the liver compromised umbilical venous flow, resulting in fetal bradycardia and arrest. 37 This was disappointing as the most severely affected fetuses with CDH have liver herniation. Although the procedure was feasible in fetuses without liver herniation, a prospective clinical trial comparing fetal CDH repair to postnatal therapy showed no difference in survival: 75% in the fetal surgery group and 86% in the postnatal therapy group survived, ss There was also no difference between the two groups in duration of ventilatory support, requirement for ECMO, length of hospital stay, or hospital charges. The authors concluded that in utero repair does not improve survival over standard postnatal treatment in the subgroup of CDH fetuses without liver herniation, primarily because survival in this subgroup is favorable without prenatal intervention. The disappointing experience with complete CDH repair in utero in cases with liver herniation led to the development of fetal tracheal occlusion for severely affected CDH fetuses. It has been recognized for many years that the dynamics of fetal lung fluid affect lung growth. Increased fetal lung fluid egress results in pulmonary hypoplasia, whereas decreased fetal lung fluid egress results in large fluid-filled lungs. In 1993, Wilson et al a9 reported that experimental pulmonary hypoplasia can be prevented by tracheal ligation with a nephrectomized fetal lamb and suggested its potential usefulness in the treatment of fetal CDH. Di-

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Fiore et al 4~ and Hedrick et a141 each confirmed this concept in a fetal lamb model of CDH. Prenatal tracheal occlusion was shown in the fetal CDH lamb model to induce lung growth with the reduction of herniated viscera and dramatic improvement in lung compliance and gas exchange. The results of these experiments, now replicated in several laboratories, were so compelling that fetal tracheal occlusion has been applied successfully in h u m a n fetuses with severe CDH. There are currendy two approaches to occlude the fetal trachea: open fetal surgery and a video-fetoscopic technique (Fetendo Clip). Open tracheal clipping is performed through a small hysterotomy exposing only the upper extremities and leaving the fetal head inside the uterus. The fetal trachea is meticulously dissected through a small transverse cervical incision. Great care is taken to avoid injury to the recurrent laryngeal nerves. The occlusion of the trachea is accomplished by applying 2 large hemoclips (Fig 4). Fetendo Clip was pioneered by the UCSF group to obviate a hysterotomy that may contribute to preterm labor. A recent retrospective review from UCSF compared the outcome of fetal isolated CDH treated with 3 methods: (1) Standard postnatal therapy, (2) Open tracheal occlusion, and (3) Fetendo Clip. 42 The survival rate reported for each group was 38%, 15%, and 75%, respectively, favoring the Fetendo Clip. However, the authors treated fetuses with a LHR up to 1.4, and 5 of 8 fetuses in the Fetendo group had a LHR between 1 and 1.4. This subset of patients may have survived with conventional postnatal therapy, making the interpretation of this study difficult. In addition, all 4 Fetendo cases that had to be converted to an open procedure and died are included in the open surgery group. If these cases were included in the Fetendo group, the survival rate for the Fetendo group would have been 50%. The current Fetendo Clip technique has had complications including a long operative time, bilateral recurrent laryngeal nerve damage, and amniotic fluid leak. The latter may be related to the requirement for 4 endoscopic ports, which may predispose to m e m b r a n e rupture. Finally, experimental evidence that the fetoscopic approach minimizes preterm labor is inconclusive. 4s,44 Because of these limitations we favor the open surgical approach for tracheal clip application.

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1 Figure 4. Exposure and application of fetal tracheal clips (arrow). Only the lower neck and upper extremities are exposed. The trachea is dissected through a lower horizontal neck incision and clips are applied. T h e r e are a n u m b e r of problems to be solved regarding fetal tracheal occlusion. First, one o f the u n e x p e c t e d consequences of fetal tracheal occlusion is induction of surfactant deficiency related to decreased type II pneumocytes. 45 Although the short-term and long-term clinical significance of this effect is unknown, experimental work has showed that type II pneumocyte numbers r e b o u n d with release of tracheal o c c l u s i o n . 46,47 In addition, o u r clinical experience has shown the effect to be transient and responsive to surfactant replacement therapy. Second, the enlarged lungs are likely to be "polyalveolar," a term first applied by Hislop and Reid 48 to a newborn with an enlarged lobe in which several segments had about 5 times the normal alveolar n u m b e r and showed clinical features of lobar emphysema. 48 T h e term describes the lung with an increased n u m b e r of alveoli per acinus. Because the development of airway branching in the h u m a n fetus is believed to be complete by the end o f pseudoglandular stage (16 weeks), increase in airway branching is unlikely to be induced by tracheal occlusion, which is p e r f o r m e d later in gestation. Thus, it is likely that the portion of lung that grows in response to tracheal occlusion is distal to terminal bronchiole, resulting in polyalveolar lung. The longterm function of polyalveolar lung is not known. H o w e v e r , increase of alveolar n u m b e r without increase o f airway branching is known to occur in compensatory lung growth after p n e u m o n e c tomy 4~ and in the patient with CDH ~~ and uni-

lateral pulmonary aplasia. 51 Emphysema does not always accompany the polyalveolar l u n g in these cases. We speculate that fetal tracheal occlusion may accelerate the same process and are optimistic about the long-term function of the enlarged lungs. Davey et a152 r e p o r t e d that in a fetal s h e e p model of p u l m o n a r y hypoplasia induced by lung fluid drainage, subsequent fetal tracheal occlusion resulted in the actual survival of the neonatal lamb with almost normal pulmonary function after birth. Harrison et a142 reported that the oxygen r e q u i r e m e n t after birth was low in h u m a n CDH survivors after tracheal occlusion. As a result, 7 o f 8 survivors did not require ECMO. These results indirectly suggest that the enlarged lungs do function after birth. The third problem is variable lung growth response to tracheal occlusion, which is a phen o m e n o n specific to humans. We have shown that the growth response of h u m a n fetal CDH lungs to tracheal occlusion is gestation dependent, ie, fetuses occluded late in gestation (26 to 30 weeks) do not respond to tracheal occlusion as consistently as those who u n d e r g o occlusion at 24 to 26 weeks. On the o t h e r hand, some fetal lungs may respond so quickly as to cause cardiac compression and hydrops within a week after tracheal occlusion. 5~ The features responsible for this biological variability in response to tracheal occlusion are poorly understood, O u r current algorithm for the m a n a g e m e n t of fetuses with CDH is shown in Figure 5. The selection criteria for the o p e n fetal surgical tra-

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1 Clipping

Figure 5. Algorithm for the fetus with a prenatally diagnosed CDH.

cheal clip procedure are (1) isolated CDH with normal karyotype, (2) diagnosis before 26 weeks, (3) presence of liver herniation, and (4) an LHR of less than 1. To exclude associated anomalies and to estimate the degree of lung hypoplasia, all potential candidates undergo chromosomal studies, detailed ultrasound, echocardiography, and ultrafast fetal MRI. Because of our impression that fetal lungs grow more consistently after tracheal occlusion earlier in gestation, we perform this procedure at 24 to 26 weeks' gestation. An intraluminal tracheal "plug," which can be placed by a fetoscope, is being developed by our group and others. 54-57 An ideal intraluminal plug could be placed endoscopically by using a single port, would consistently obstruct the growing fetal trachea for more than 4 weeks, would not damage the trachea, and could be reversed in utero if necessary or at the time of birth. In theory, the reversibility of the device would be important both to stop rapid lung growth that may result in fetal hydrops and to minimize the potentially detrimental effect of prolonged tracheal occlusion on lung maturation. We are investigating the efficacy of a detachable silicone or latex balloon, an expandable tracheal occlusion device, and an injectable cross-linked hydrogel in fetal animal models.

Saeroeoeeygeal Teratoma SCT is the most c o m m o n tumor of the newborn with an incidence of 1 in 35,000 to 40,000 live births. The occurrence of chromosomal abnor-

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malities or associated congenital anomalies are rare. SCT is uniformly attached to the coccyx and has been classified by the relative amounts of intrapelvic and external tumor by using the AAPSS (American Academy of Pediatrics, Surgical Section) classification. 5s Type I is primarily external and has only a small presacral component. Type II is predominantly external but has a significant intrapelvic portion. Type III is partially external but is predominantly intrapelvic with abdominal extension. Type IV is located entirely within the pelvis and abdomen. The value of this classification relates to the ease of surgical resection and prenatal detection as well as the likelihood of malignancy. Type I is easy to detect and resect with a low incidence of malignancy. In contrast, type IV tumors are difficult to diagnose, not amenable to fetal resection and are frequently malignant when first diagnosed because of prolonged delay in recognition. Fortunately, the majority of tumors are type I or II. Abdominal or pelvic extension of the tumor is also important to determine in terms of the feasibility of fetal surgery. As a result of acoustic shadowing by the fetal pelvic bones, ultrasound cannot always define the most cephalad extent of SCT. Ultrafast fetal MRI is superior in delineating the intrapelvic extent of the tumor. .~'.~

Natural History and Histology The majority of newborns with SCT do well after early surgical resection, although rarely the tumor undergoes malignant transformation. In contrast, the prognosis of SCT diagnosed before birth has a mortality rate of 30% to 50%. 60-62 A rapid phase of tumor growth frequently precedes the development of placentomegaly and hydrops, which is a sign of impending fetal demise. The histological classification of fetal SCT may change dramatically in utero. Graf et a163 reported histological maturation in fetal SCT between the initial debulking procedure (4 in utero and 1 postnatal at 32 weeks) and subsequent definitive resection. It is unclear whether this was the result of tumor maturation induced by preterm debulking or the natural in utero maturation of fetal SCT.

Pathophysiology The high mortality rate of fetal SCT is attributed to a variety of mechanisms (Fig 6). The mass

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Mass Effect

• Polyhydranmios

/

\

Dystocia

PretermLabor

Tumor Vascular

"Steal"

1

High Output Cardiac Failure

l

Tumor Rupture

Hemorrhage

Lung Immaturity

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Placentomcgaly Hydrops

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Figure 6. Pathophysiology of fetal SCT. A variety of mechanisms can cause fetal death. effect from the SCT can result in premature delivery a n d / o r dystocia. Premature delivery is t h o u g h t to be due to associated polyhydramnios inducing uterine irritability and premature rupture of the membranes. Dystocia in unsuspected cases is frequently associated with traumatic tum o r rupture and h e m o r r h a g e during delivery, which is usually lethal. T h e hemodynamic effects o f SCT can be ascribed mainly to a large blood flow to the t u m o r and, in part, to anemia caused by h e m o r r h a g e into the tumor. The f o r m e r results in high o u t p u t cardiac failure because o f arteriovenous shunting in the t u m o r and the latter c o m p o u n d s the high o u t p u t state. A large

t u m o r creates a vascular "steal" from the placenta and the fetus, which has b e e n docum e n t e d by echocardiographic and Doppler ub trasound measurements. Actual reversal of diastolic flow in the umbilical arteries can be observed as the lower resistance in the tumor "steals" blood flow from the placenta. Abnormalities also occur in left and right ventricular end-diastolic diameters, placental thickness, dia m e t e r of the inferior vena cava, c o m b i n e d ventricular output, descending aortic flow, and umbilical venous flow. 64 T h e end stage of placentomegaly and fetal hydrops can lead to the maternal mirror syndrome. As in cases with CCAM, fetal intervention before the related maternal preeclamptic state develops is recommended.65, 66

Surgical Management We r e p o r t e d the first successful fetal surgical resection of SCT. 66 In this case, fetal SCT was first detected at 20 weeks' gestation. T h e tumor grew rapidly thereafter to b e c o m e the size of the fetus accompanied by the development o f polyhydramnios, placentomegaly, and maternal tachycardia and proteinuria. At 26 weeks' gestation, o p e n surgical resection of the t u m o r led to the reversal of fetal hydrops and placentomegaly by 10 days after surgery, A 1.33 kg baby girl, who did well postnatally, was delivered at 29 weeks' gestation. This case revealed that resection of a large t u m o r can reverse the pathophysiology of high o u t p u t cardiac failure and that early inter-

Figure 7. Exposure of (A) fetal SCT and (B) resection with a surgical stapler.

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effective p h a r m a c o l o g i c a l c o n t r o l o f u t e r i n e c o n t r a c t i o n s w o u l d b e a m a j o r b r e a k t h r o u g h in this field.

References

1 ) .......

I r~l~Sency

Figure 8. Algorithm for the ferns with a prenatally diagnosed SCT.

v e n t i o n offers t h e b e s t h o p e f o r fetal survival o n c e h i g h o u t p u t c a r d i a c f a i l u r e is d o c u m e n t e d . I f signs o f h i g h o u t p u t c a r d i a c f a i l u r e a r e a b s e n t , t h e fetus m a y b e f o l l o w e d by serial s o n o g r a p h y . I f p l a c e n t o m e g a l y o r h y d r o p s d e v e l o p s a f t e r pulm o n a r y m a t u r a t i o n , t h e fetus s h o u l d b e delive r e d by e m e r g e n t c a e s a r i a n s e c t i o n . O p e n fetal s u r g e r y (Fig 7) is c o n s i d e r e d in fetuses less t h a n 32 w e e k s ' g e s t a t i o n w h e n t h e t u m o r is a n a t o m i cally a m e n a b l e to r e s e c t i o n . I n t h e p r e s e n c e o f t h e m a t e r n a l m i r r o r s y n d r o m e , t h e f a m i l y is c o u n s e l e d t h a t t h e b e s t a l t e r n a t i v e is d e l i v e r y to prevent life-threatening maternal complications (Fig 8). T h e efficacy o f a r a d i o f r e q u e n c y t h e r m a l abl a t i o n t e c h n i q u e to o c c l u d e f e e d i n g a r t e r i e s o f fetal SCT is b e i n g e v a l u a t e d in t h e l a b o r a t o r y . 67 A l t h o u g h l a s e r t h e r a p y h a s b e e n t r i e d in a h u m a n case o f fetal C C A M 68 a n d SCT, 69 we b e l i e v e f u r t h e r e v a l u a t i o n o f its efficacy a n d safety m u s t b e d o n e in t h e l a b o r a t o r y b e f o r e c l i n i c a l a p p l i c a t i o n . It m a y b e c o m e p o s s i b l e in t h e n e a r fut u r e to r e v e r s e h y d r o p s c a u s e d by fetal SCT by u s i n g m i n i m a l l y invasive t e c h n i q u e s .

Conelusions M o s t fetuses with a n a n t e n a t a l d i a g n o s i s o f c o n g e n i t a l a n o m a l y c a n b e t r e a t e d at a n a p p r o p r i a t e c e n t e r with m a t e r n a l t r a n s p o r t , p l a n n e d delivery, a n d p r o m p t t h e r a p y a f t e r b i r t h . F e t a l surg e r y is c u r r e n t l y r e s e r v e d f o r a s m a l l s u b g r o u p o f p a t i e n t s with e x t r e m e l y p o o r p r o g n o s i s a n d t h e initial results a r e e n c o u r a g i n g . P r e t e r m l a b o r a f t e r fetal s u r g e r y r e m a i n s a m a j o r o b s t a c l e , a n d

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