Current controversies in perinatal care: fetal versus neonatal surgery

Clin Perinatol 31 (2004) 629 – 648

Current controversies in perinatal care: fetal versus neonatal surgery Marjorie J. Arca, MDa,b,*, Steven Teich, MDc,d a

Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA Division of Pediatric Surgery, Children’s Hospital of Wisconsin, 9000 West Wisconsin Ave., Milwaukee, WI 53226, USA c The Ohio State University College of Medicine and Public Health, 370 West 9th Ave., Columbus, OH 43210, USA d Division of Pediatric Surgery, Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA b

The goal of in utero surgical intervention is to save a fetus from death or lifelong malformation. Fetal surgery should minimize the risk to the mother’s life and her future fertility. Fetal surgery has been made possible by recent advances in fetal imaging, such as three-dimensional rendering of fetal ultrasound [1] and rapid-acquisition MRI [2]. These modalities accurately determine fetal anomalies as early as the first trimester. Recent advances in maternal anesthesia, tocolysis, and technical aspects of surgery have also diminished the risks to the fetus and the mother. Over the past decade, prenatal surgical interventions have been performed in fetuses with the following anomalies: sacrococcygeal teratoma, congenital cystic adenomatoid malformation or bronchopulmonary sequestration of the lung, congenital diaphragmatic hernia, myelomeningocele, and lower urinary tract obstruction. Despite the rapid increase in cumulative experience in fetal surgery, skepticism remains regarding its role. The fundamental questions are: (1) What is the benefit of the fetal intervention to the fetus? (2) Does the intervention justify the risk to the mother and the fetus? (3) Does the intervention provide better results than postnatal therapy? This article focuses on the state of the fetal therapies for the five disease states listed above and rationalizes the role of fetal therapy for each anomaly.

* Corresponding author. Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: [email protected] (M.J. Arca). 0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2004.03.016

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Sacrococcygeal teratoma Natural history Sacrococcygeal teratomas (SCTs) are the most common tumor of the newborn, occurring in 1:35,000 to 1:40,000 live births [3]. The male-to-female ratio is 1:4. The tumor arises around the late second or the early third week of gestation. The tumor is derived from pluripotent cells of Hensen’s node, which is a caudal cell mass in the embryonic disc, located anterior to the coccyx. SCTs include ectodermal, mesodermal, and endodermal components. SCTs are accurately diagnosed on prenatal ultrasound as an intra-abdominal or a caudal mass that is seen as early as 13 weeks gestation. It must be differentiated from other types of caudal masses such as myelomeningocele, rectal duplication cyst, and neuroectodermal cyst. Fetal MRI may more accurately assess pelvic extension of the tumor [2]. Eighty percent of children with SCTs have tumors that are clinically apparent at birth [3]. Most infants born with SCT have an excellent prognosis with early surgical resection. Prompt excision is necessary because the risk of malignancy increases with delayed excision. The American Academy of Pediatrics Surgical Section uses a clinical classification scheme based on the amount of caudal and presacral components of the tumor (Table 1) [4]. Most infants with SCT present as American Academy of Pediatrics Surgical Section (AAPSS) type I and II at birth and undergo early resection [5]. Infants with mostly presacral tumors (type IV) may present later in life with symptoms such as constipation and urinary retention; these children have a higher likelihood of malignant degeneration [5]. Over 90% of tumors diagnosed 2 months after birth are malignant [6]. At least 80% of SCTs are histologically benign [7,8]. Grade 0 tumors have only mature elements. Grade 1 tumors have a small amount of immature neuroectodermal elements. Grade 2 tumors have moderate amounts of immature elements. Grade 3 tumors have a large amount of immature embryonal cells with frank malignant yolk sac or endodermal sinus components. SCTs are sensitive to cist-platinum based therapies. In SCT, infant morbidity arises from tumor hemorrhage, tumor rupture, or dystocia during labor and delivery. Planned cesarean section delivery is recommended for infants with SCTs > 5 cm in size to circumvent these problems [9]. A

Table 1 American Academy of Pediatrics Surgical Section anatomic classification of sacrococcygeal teratomas Class

Tumor description

I II III IV

Primarily external with minimal (if any) presacral component Primarily external, some presacral component Primarily presacral, small external component Completely presacral, with some extension into pelvis or abdomen

Data from Altman RP, Randolph JG, Lilly JR. Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey—1973. J Pediatr Surg 1974;9:389 – 98.

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large SCT may also lead to preterm labor and cause postnatal problems related to prematurity. Infants born with SCT undergo surgery within the first week after delivery. The incision is determined by the location of the lesion. Tumors whose major components are outside the abdomen may be approached solely through the perineum; combined abdominal/perinea incisions are used for type II and III tumors. The coccyx is removed. Surgical resection is curative in most benign tumors. Long-term survival rate of neonates is 92% to 95% [7,8]. Most mortality relates to hemorrhage during the operation and the presence of other anomalies. Prenatally diagnosed sacrococcygeal teratoma The natural history of SCTs is derived from patients who were diagnosed after birth. Several fundamental differences apply between infants who had postnatal diagnosis of SCT and those who were prenatally diagnosed [11]. The data derived from a survey of members of the International Fetal Medicine and Surgery Society show that fetuses with prenatally diagnosed SCTs have a mortality rate of 68% [12], with their prognosis depending on the size and physiology of the tumor. In contrast, postnatally diagnosed SCTs carry a low mortality; the location and histologic grade of the tumor determine the prognosis of postnatal SCTs. Prenatally diagnosed SCTs tend to mature with time; postnatally diagnosed SCTs usually undergo malignant degeneration. Perinatologists believe that full-term babies who are born with SCTs are self-selected in utero for good outcomes given their ability to survive to their due date. The most reliable ultrasonographic factors in determining outcomes of fetuses with SCT are the presence of hydrops fetalis or placentomegaly [12,13]. The presence of one or both of these findings signifies fatal pathophysiologic consequences developing from high-output cardiac failure. Cardiac failure may result from anemia due to bleeding into the tumor or, more commonly, due to the high blood flow into the low-resistance tumor vessels. The tumor may act as a high-grade arteriovenous shunt, which leads to high-output cardiac failure [14]. Hydrops fetalis and placentomegaly have been shown to correlate with fetal demise, which usually follows within days of the ultrasonographic findings [13]. If a fetus with SCT becomes hydropic or if placentomegaly develops, the mother becomes at risk for developing ‘‘mirror syndrome,’’ or Ballantine syndrome [10]. The mother develops symptoms suggestive of preeclampsia such as vomiting, hypertension, edema, or proteinuria. It is thought that the placenta releases vasoactive factors, which effect such changes in the mother. Treatment is delivery of the infant. Fetal interventions for sacrococcygeal teratoma Several fetal interventions have been described for SCT. They include aspiration of the fluid in the cystic component of the tumor [15], laser ablation of the tumor vessels [16], thermocoagulation of the tumor neck [17], radiofrequency ablation

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of the tumor or its vessels [18], and in utero debulking or excision of the tumor. Kay [15] described two fetuses with predominantly cystic SCTs who underwent needle aspiration of the fluid within the tumor. This maneuver enabled the nearterm vaginal delivery of the infants and successful postnatal tumor resection. Several investigators have used different modalities to ablate the vasculature of tumors with more solid components. In 1996, Hecker [16] reported the use of the Nd-YAG laser to ablate the subcutaneous tumor vessels in a fetus under endoscopic guidance in a 20-week estimated gestational age (EGA) fetus. The tumor size stabilized for 3 weeks and then increased in size, prompting another laser treatment. The infant was delivered at 37 weeks; the tumor was excised on the day of birth. In 2002, Lam [17] used an insulated electric wire to thermocoagulate vessels within the tumor neck in two fetuses. Blood flow to the tumor was decreased; however, one of the fetuses died 2 days after intervention, and another had necrosis of the anus, vagina, sciatic nerve, and bladder. Paek [18] reported on four fetuses that underwent ultrasound-guided radiofrequency ablation of fetal SCT. In the first case, the tumor was ablated, which caused tumor hemorrhage and fetal demise. Two of the fetuses had ablation of the feeding vessels only. At birth, areas of perineal skin necrosis were noted. The fourth fetus in the report underwent ablation of the feeding vessels. An MRI performed after the intervention showed marked periventricular leukomalacia, and the pregnancy was terminated. Of the eight in utero operations performed for SCTs, there are three long-term survivors. The first successful operation was reported in 1997 [19]. The pregnancy was complicated by polyhydramnios, placentomegaly, and mirror syndrome. At 25 weeks gestation, the mother underwent a hysterotomy. The tumor was removed from the baby. Premature labor resulted in delivery at 29 weeks. Residual tissue and coccyx were removed 2 months after birth. The baby did well until 16 months of age, when pulmonary metastases of a yolk sac tumor were detected and successfully treated with chemotherapy. In 2000, Graf [20] reported on four patients who underwent open fetal surgery. The survivor underwent tumor removal at 23 weeks EGA. She was born at 28 weeks; the tumor was resected 1 month after birth. At the time of this report, the child is a healthy 3-year-old. One of the fetuses died during surgery, another died due to lung immaturity 6 hours after birth, and the last baby died of an air embolus during postnatal tumor resection. Chiba [21] reported on a fetus with a large pelvic SCT that caused bilateral hydronephrosis, rectal atresia, and oligohydramnios. At 27 weeks, the fetus underwent tumor debulking bilateral ureterostomies and pull-through anorectoplasty. The baby was delivered 3 weeks later but died on the third day of life due to an atrial perforation of a transfemoral venous line. Graf [10] mentioned another survivor of in utero tumor removal in a recent review of fetal SCTs. Role of fetal intervention in sacrococcygeal teratoma Fetal surgery for SCT continues to be an evolving therapy. Like any other in utero operations, its biggest complications are premature labor and preterm

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delivery. Its use is reserved for a select group of pregnancies where maternal and fetal outcomes are compromised by the tumor. High-risk SCTs are those complicated by high-output cardiac failure, hydrops fetalis, placentomegaly, and mirror syndrome. If none of these is present, then serial ultrasonography should be performed. However, if any of these is found in a pregnancy that is < 30 weeks gestation, fetal intervention is recommended. If the fetus is > 30 weeks gestation, emergency cesarean section is indicated. Vaginal delivery may be considered if the tumor is <5 cm in size; otherwise, a planned cesarean section may reduce the chances of dystocia, tumor rupture, or uncontrolled hemorrhage.

Thoracic lesions: congenital cystic adenomatoid malformation and bronchopulmonary sequestration Natural history of congenital cystic adenomatoid malformation and bronchopulmonary sequestration Congenital cystic adenomatoid malformation (CCAM) and bronchopulmonary sequestration (BPS) are the most commonly diagnosed fetal intrathoracic masses. A CCAM is a discrete mass within a lobe of the lung that consists of terminal bronchioles that have formed cysts. CCAMs are usually unilateral and unilobular. Their blood supply originates from the pulmonary vasculature. They retain their communication with the airways and, therefore, may cause air trapping and progressive respiratory compromise. Adzick [22] has classified CCAMs as ‘‘macrocystic’’ or ‘‘microcystic’’ based on gross morphology and characteristics on ultrasound examination. Macrocystic lesions contain cysts that are >5 mm in diameter and appear cystic on ultrasound. Microcystic lesions have cysts that are <5 mm in diameter; they have a solid and bulky sonographic signal. Typically microcystic lesions have a poorer prognosis compared with the macrocystic lesions; these more solid-type CCAMs exert detrimental effects by compression of normal lung or mediastinal structures. Large CCAMs can cause mediastinal displacement, hydrops fetalis, and subsequent fetal death. Additionally, they can cause enough volume compression of the developing lung to result in pulmonary hypoplasia and persistent pulmonary hypertension. Eighty percent of lung lesions prenatally diagnosed are CCAMs. One third of patients with CCAMs present with dyspnea, cyanosis, and respiratory insufficiency around the time of birth. The rest of the patients may present in later life with symptoms of pulmonary infections such as recurrent or persistent pneumonia, lung abscess, or reactive airway disease. CCAMs may also present as incidental cystic changes on chest radiographs [23]. BS is a form of malformation whereby lung tissue is not connected to the natural airways [23]. Bronchopulmonary sequestrations are managed by surgical removal. Sequestrations usually derive their arterial supply from the systemic circulation. Seventy-five percent of sequestrations have their own investing viscera pleura and are outside the normal lung lobes (ie, extralobar). Most ex-

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tralobar sequestrations have systemic venous drainage. Twenty-five percent of sequestrations are within a lobe (ie, intralobar); typically, intralobar sequestrations drain into the normal pulmonary venous system. Intralobar sequestrations are difficult to diagnose with prenatal screening. Extralobar sequestrations may be seen on prenatal ultrasound. Doppler imaging may identify the anomalous arterial blood supply to the lesion. Postnatally, extralobar sequestrations may cause physiologic problems such as respiratory distress, hemorrhage, feeding intolerance, and high-output heart failure. Ten to fifteen percent of extralobar sequestrations are associated with other anomalies such as a congenital diaphragmatic hernia. Intralobar sequestrations manifest later in childhood or in adult life; symptomatically, they present as recurrent pneumonias, lung abscess or hemoptysis. About 15% to 20% of CCAMs get smaller, and approximately two thirds of BPS lesions diminish in size before birth. However, postnatal radiologic studies usually document residual lung abnormalities persisting months after birth [24]. Prenatally diagnosed thoracic lesions Fetal lung development is a sequential process that is time dependent [25]. Bronchial development occurs primarily during weeks 5 to 16 (pseudoglandular phase). During the canalicular phase (weeks 16 –24), the lumina of the bronchi and bronchioles become larger, and the lung tissue becomes highly vascular. By 24 weeks, each terminal bronchiole has given rise to two or more respiratory bronchioles. The terminal sac period, which occurs from 24 weeks to birth, is characterized by further development of terminal sacs, thinning of the epithelium of the terminal sacs, and bulging of the capillaries into the thinned terminal sac epithelium. During the alveolar period, which occurs during the late fetal period and extends into early adulthood, alveoli form and mature. The process of fetal lung development is influenced by other factors. Adequate intrathoracic space is necessary. Fetal breathing movement is conducive to the proper growth of lung parenchyma. Adequate amniotic fluid volume is also critical to fetal lung growth [26]. Harrison demonstrated the effects of thoracic masses on the developing lung in the animal model [27,28]. Balloons were placed in the thoracic cage of fetal sheep to mimic the compressive effects of the masses on the lung. Pulmonary hypoplasia resulted when the lungs were compressed during the third trimester. The rationale for fetal intervention is to allow pulmonary development that allows survival at birth. Thoracic lesions may exert mass effect on the tissues of the chest and mediastinum, causing several problems in utero. Esophageal compression leads to polyhydramnios [24]. Pulmonary hypoplasia may result from compressive effects of large lung lesions. Tension hydrothorax, which may accompany BPS, may also cause pulmonary hypoplasia. However, it is when the mass compresses of the heart and great vessels that it can cause subsequent cardiac failure, hydrops fetalis, and imminent fetal loss. Hydrops has been considered to be the most

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sensitive predictor of fetal or newborn death. In 1998, Adzick [29] reported on 25 fetuses with large CCAM lesions and hydrops; all died before or shortly after birth. Therefore, when considering the course of action for a fetus with a thoracic mass, one must balance the natural history of these lesions (ie, that the mass may shrink in size) with the possible development of hydrops. Hydrops may lead to placentomegaly and maternal mirror syndrome. Adzick’s group feels that maternal mirror syndrome is a contraindication to fetal surgery [26] because reversal of the mirror syndrome does not occur simply by removing of the abnormal lung tissue. Often, premature delivery of the baby or termination of the pregnancy is necessary. The prognosis of fetuses with CCAM is best predicted by the overall size of the lesion rather than the histology. Crombleholme [22] designed the cystic adenomatoid malformation volume ratio (CVR) as a prognostic tool to select fetuses at high risk for developing hydrops fetalis [22]. The CVR is obtained by dividing the CCAM volume (length  width  height  0.52) by the head circumference of the fetus. A CVR >1.6 is correlated with an 80% risk of developing hydrops fetalis. Maximal growth of a CCAM lesion is reached by 28 weeks [30]. Twice weekly ultrasound is recommended for fetuses <28 weeks with a CVR >1.6 to monitor the development of hydrops. For a CVR >1.6, once weekly ultrasound surveillance is adequate. Although ultrasound has been the cornerstone imaging modality of prenatal lung lesions, diagnostic errors may occur. An ultrafast MRI may be able to differentiate CCAM from BPS. In addition, MRI may definitively exclude other lesions, such as diaphragmatic hernias, bronchogenic cysts, lobar emphysema, or mediastinal teratoma, from the differential diagnosis [2]. Fetal interventions for thoracic lesions There are four techniques of fetal intervention described in the literature for thoracic masses. Fetal thoracentesis has been used to treat cystic intrathoracic lesions and hydrothorax [31]. Ultrasound guidance is used to direct a spinal needle to decompress a cystic CCAM or to drain a hydrothorax [26,30]. Failure of the lung to re-expand signifies presence of pulmonary hypoplasia. The use of fetal thoracentesis is limited because fluid reaccumulates within 48 hours [32]. However, Adzick [29] has reported successful management of thoracic fluid in a hydropic fetus with extralobar pulmonary sequestration using serial thoracentesis. Thoracoamniotic shunts have been used successfully to drain unilocular cystic lesions or fluid within the pleural space. Unlike thoracentesis, shunts provide a more definitive drainage of fluid from the thoracic space. In 1997, Dommergues [33] reported on 33 fetuses with prenatally diagnosed CCAM lesions. Of these, 12 fetuses had hydrops or polyhydramnios. Nine fetuses underwent thoracoamniotic shunt placement; four fetuses survived. Becmeur [34] reported on the use of shunt in a fetus with BPS. A thoracoamniotic shunt was used to drain thoracic fluid. The baby was born without problems and survived the perinatal period. Adzick [29] summarized the experience with thoracoamniotic shunts at the fetal

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centers in University of California, San Francisco (UCSF) and Children’s Hospital of Philadelphia (CHOP). A shunt was placed in six patients with CCAMs and in two patients with BPS. CCAM patients with single, large predominant cysts were selected for this therapy. Three fetuses had hydrops when the shunts were placed. Two of the fetuses survived after delivery; one required high-frequency oscillatory ventilation (HFOV), and another needed extra-corporeal membrane oxygenation (ECMO). Three nonhydropic fetuses underwent placement of thoracoamniotic shunts. One required HFOV, and another required ECMO. However, all three were survivors. The two fetuses with BPS who underwent shunting survived after delivery; removal of the abnormal lobe was performed after birth. Complications of shunts include dislodgement, migration, or clogging, with an overall failure rate of 26% [26,29,33 –36]. Percutaneous laser ablation of a solid CCAM has been attempted. In one instance, the fetus was found to be hydropic at 23 weeks EGA [36] An Nd:YAG laser was used on the abnormal lung tissue, resulting in minimal shrinkage. The hydrops worsened, and the fetus died. In another instance, a fetus with hydrops and a large right-sided CCAM underwent multiple yttrium aluminum garnet laser therapy using ultrasound guidance. The fetus underwent three total treatments within 4 weeks. The baby was born with a severely caved-in chest and multiple rib fractures. Definitive removal of the lung lesion has been attempted in several fetuses. Adzick [29] reported on the combined data from UCSF and CHOP. There were 175 fetal lung lesions; 134 were CCAM, and 41 were extralobar BPS. Thirteen CCAM lesions were associated with fetal hydrops. Fetal lung lobectomy was performed in fetuses between 21 and 29 weeks. Hydrops resolved in eight fetuses, all of whom survived to term. Three fetuses died intraoperatively; irretrievable hemodynamic collapse ensued after the abnormal lobe was evacuated from the thorax. One fetus died 8 hours postoperatively; autopsy did not reveal the immediate cause of death. One infant died hours after premature delivery. This case was complicated by maternal mirror syndrome. Removal of the abnormal lobe resulted in the resolution of hydrops. However, placentomegaly and symptoms of the mirror syndrome were not reversed, necessitating a precipitous delivery. None of the fetuses with BPS were treated with prenatal lobectomy. Role of fetal intervention for thoracic lesions Large thoracic lesions may cause fatality by exerting mass effects on the mediastinum and great vessels leading to hydrops fetalis and by compressing the developing lung, causing pulmonary hypoplasia. However, CCAM and BPS have been known to diminish in size and may simply need removal postnatally. The development of hydrops is a significant clue that the fetus, and potentially the mother, may be heading for trouble. In a fetus with CCAM, use of the CVR justifies more frequent ultrasonographic imaging. If a fetus develops hydrops, management is dictated by gestational age. If a fetus is >32 weeks, early delivery and subsequent removal of the lesion are

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recommended. In a hydropic fetus of 32 weeks, fetal intervention may be considered. Options include thoracoamniotic shunting for a predominantly cystic mass or fetal lung resection. Placentomegaly and maternal mirror syndrome are considered contraindications for fetal therapy. Simply removing the lesion does not reverse the physiologic effects on the mother; precipitous delivery, leading to poor fetal outcome, often results. The neonatal outcome for infants with hydrops and large fetal lung lesions has been poor. A recent strategy for the delivery of these babies is the ex utero intrapartum therapy (EXIT) procedure [37]. The baby is delivered via cesarean section, using a uterine stapling device for the hysterotomy. Only the head and the shoulders are removed from the hysterotomy, preserving uterine fluid. Amnioinfusion is used to maintain umbilical cord volume. Tocolytics are administered to prevent uterine contraction. With the placenta intact and delivering oxygenated blood to the baby through the umbilical vein, endotracheal intubation, thoracotomy, and resection of abnormal lung tissue are accomplished. Five fetuses underwent this sequence of procedures at CHOP. Four of the five fetuses survived. Two of the fetuses needed veno-arterial ECMO after the procedure. One fetus needed re-exploration for bleeding; he subsequently succumbed to sepsis and consumptive coagulopathy.

Congenital diaphragmatic hernia Natural history Congenital diaphragmatic hernia (CDH) occurs in 1 in 2400 live births. The defect in the diaphragm of the developing fetus allows the abdominal viscera to migrate into the thorax during critical stages of lung development. Normal lung development is impeded, resulting in a reduction of bronchopulmonary divisions and in the number of alveolar units. Bilateral pulmonary hypoplasia ensues, resulting in inadequate gas exchange. There is significant pulmonary hypertension associated with this condition; the pulmonary arterioles have medial hypertrophy, resulting in highly reactive vessels sensitive to hypoxia, acidosis, and hypercarbia [38]. Operative reduction of the hernia has no significant immediate beneficial effect on oxygenation or ventilation. The goal of immediate postnatal management is to oxygenate and ventilate the baby adequately without inducing barotrauma. If the ventilatory management cannot accomplish these goals, the infant may be placed on ECMO to break the cycle of persistent fetal circulation. Reported outcomes for neonates with CDH vary widely. Tertiary referral centers with extracorporeal membrane oxygenation (ECMO) capability report a 65% to 76% survival rate in infants born with CDH [38,39]. To determine the outcome of the disease in a prospective fashion Harrison et al [40] followed 83 fetuses diagnosed antenatally with left-sided CDH before 24 weeks gestation. There was

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an overall mortality of 58%; 8% died in utero, and 12% died in the immediate perinatal period. Thirty seven percent died despite ECMO support. Of the 35 surviving patients, 22 required ECMO. Nine of these surviving infants have chronic disease attributable to their CDH. Altogether, only 25% of these infants had good quality of life.

Prenatally diagnosed congenital diaphragmatic hernia The timing and the amount of herniated abdominal viscera seem to determine the postnatal severity of the pulmonary hypoplasia. Two indicators have been used to stratify the fetuses into ‘‘good’’ versus ‘‘bad’’ prognosis. One factor is whether the liver has herniated into the chest through the diaphragmatic defect (‘‘liver up’’ or ‘‘liver down’’) [41]. A retrospective review of 48 patients with prenatally diagnosed CDH found a 93% survival in the liver down group compared with 43% in the liver up group [42]. Another index used is the lung/heart ratio (LHR). The LHR is determined by obtaining a transverse axial image at the level of the four-chambered view of the heart at 24 to 26 weeks. Two measurements of the right lung are taken: the longest length (mm) and the length perpendicular to this (mm). LHR is the product of these two measurements divided by the head circumference (mm). LHR >1.4 is associated with no mortality, whereas LHR <1.0 approaches 90% mortality. For LHR between 1 and 1.4, mortality is about 60% [43 –45].

Fetal interventions for congenital diaphragmatic hernia In fetal sheep, open repair of CDH in utero allowed the fetal lung to grow. The first attempted in utero repair was patch closure of the diaphragm. Reduction of the intrathoracic liver tended to kink the inferior vena cava, leading to fetal demise. A prospective clinical trial on CDH repair of liver down fetuses showed no difference in the survival rate between in the four fetuses in the fetal surgery group (75%) and the seven fetuses in the conventional/postnatal treatment group (86%) [41]. Other outcome variables, such as duration of ventilator support, need for ECMO, length of hospital stay, and hospital charges, were not statistically significant between the groups. The prenatally treated group had a higher likelihood of being born prematurely compared with the conventional group. Subsequent approaches to fetal surgery for CDH are based on the observation in fetal lambs that tracheal occlusion decreases the degree of pulmonary hypoplasia seen in CDH. In fetal lambs, tracheal occlusion increases fetal lung size, which translated to better oxygenation and improved lung compliance postnatally [46] Three approaches were attempted in the human fetus: open tracheal clipping, application of a tracheal clip using the fetal endoscopic (FETENDO clip) approach, or tracheal balloon occlusion. Experience with open tracheal occlusion in 15 fetuses diagnosed with isolated CDH before 25 weeks with fetal liver herniation and LHR <1 had a 33% survival rate [47]. Despite in utero lung growth, aggressive

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ventilatory support was needed postnatally because of capillary leak and poor lung compliance. Of the five surviving patients, three had significant neurologic injury. Fetal endoscopic therapy is attractive because it avoids a hysterotomy, which may lead to less pre-term labor. Experience with the FETENDO clip was documented in a retrospective review comparing the outcome of fetal isolated CDH treated with three different methods: (1) standard postnatal therapy (n = 13); (2) open tracheal occlusion (n = 13); and (3) FETENDO clip (n = 8) [48]. Reported survival rates are 38%, 15%, and 75%, respectively. This report was criticized because there were patients in each group who had LHR >1; five of the eight patients who underwent FETENDO clip placement had LHR of 1 or greater. The standard postnatal therapy group had a lower survival rate than is reported in the literature. The FETENDO clip was not successful in four patients, and conversion to open tracheal occlusion was necessary. These patients were analyzed under the ‘‘open tracheal occlusion group,’’ If these patients had been categorized as FETENDO patients, then FETENDO survival rate would be 50%. A randomized control trial evaluating the role of fetoscopic tracheal balloon occlusion was undertaken [49]. Twenty-four women carrying fetuses between 22 and 27 weeks gestation that had liver herniation and low lung/head ratio (< 1.4) were randomly assigned to fetal endoscopic tracheal occlusion or standard postnatal care. Seventy-three percent (8/11) fetuses in the tracheal-occlusion group and 77% (10/13) fetuses in the standard care group survived to 90 days. Preterm delivery was more common in the tracheal occlusion group. There was no difference in the neonatal morbidity between the two groups. The study was stopped because the data safety monitoring board concluded that further recruitment would not result in significant differences in the outcome measures of morbidity and mortality between the two groups. Role of fetal surgery for congenital diaphragmatic hernia The main impetus for prenatal therapy for CDH is to prevent or reverse pulmonary hypoplasia and to restore adequate lung growth for survival. Crucial to this endeavor is the identification of fetuses who may benefit from fetal intervention. The presence of liver herniation and the LHR are two criteria that had been used to delineate which fetuses may be helped with heroic measures such as fetal intervention. However, given the most recent data, it is unclear what fetal intervention that may be. The studies on CDH continue to reinforce that fetal intervention, whether open or endoscopic, continues to be associated with premature delivery, which is detrimental to the fetus.

Myelomeningocele Natural history Myelomeningocele (MMC) is defined as the protrusion of spinal cord and meninges from the spinal canal caused by a defect in the overlying vertebral

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arches, muscle, and skin. It occurs in 1 in 2000 births. It is considered the most common nonlethal malformation in the spectrum of neural tube defects. One of the most important advances in dealing with MMC is the realization that folic acid supplementation before conception and during the first trimester of pregnancy may prevent the majority of MMC [50]. Neurulation, which is the migration of mesodermal tissue around the developing spinal cord to form the vertebral arches, muscles, and connective tissue, occurs between 18 to 27 days of gestation. Folate supplementation is needed before this time. However, about 30% of neural tube defects are considered to be resistant to folate supplementation [50]. Seventy to eighty-five percent of MMC develop hydrocephalus [51]. Additionally, MMC is associated with type II Chiari malformation, a constellation of symptoms that includes the caudal displacement of cerebellum, vermis, elongation of the medulla and the IV ventricle, herniation of midbrain structures through foramen magnus, platybasia, polygyria, and small posterior fossa. The compression of hindbrain contributes to the progression of hydrocephalus. The severity of the associated neurologic deficits depends on the location of the lesion along the neural axis. MMC leads to neurologic injury below the level of the lesion with lower extremity weakness, sexual dysfunction, and incontinence of bowel and bladder function. A ‘‘two-hit hypothesis’’ is offered to explain the neurologic defects [52]. This presumes an initial error in embryogenesis whereby the neural tube fails to close, resulting in a flat neural placode instead of a neural tube. There is subsequent exposure of the cord to an unfavorable uterine environment. Late in gestation, amniotic fluid has increased concentration and urea and meconium, both of which are shown to be harmful to the cord in vitro. In the third trimester, mechanical contractions of the uterus may also damage the cord. Vaginal delivery itself may cause damage to the open neural placode. Cerebrospinal fluid accumulates into the ventral subarachnoid space, pushing the cord dorsally and stretching the nerve roots, which may case nerve damage. Prenatally diagnosed myelomeningocele When an elevated level of alpha-fetoprotein is detected in the maternal serum, the question of a fetal neural tube defect arises. Ultrasonographic imaging of the fetus within the first trimester can usually show the presence of MMC. At 16 to 17 weeks gestation, fetuses with MMC show ultrasound evidence of leg motion [53]. However, most babies born with MMC have unrecoverable loss of lower extremity strength and movement. Myelinization begins between 15 to 24 weeks gestation and continues into the postnatal period. These findings imply that the damage to developing neurons occurs during gestation. Prenatal repair of MMC is directed toward preventing the harmful effects of in utero development to the exposed cord. Fetal interventions for myelomeningocele The first report of in utero coverage of MMC was described in 1997; Bruner [54] described the endoscopic repair of MMC in two fetuses. The technique described consisted of evacuating amniotic fluid, replacing the fluid with carbon

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dioxide, and placing a maternal split-thickness skin graft over the developing neural placode. The skin graft and a layer of oxidized cellulose were attached with fibrin glue. One of the two patients reported was delivered with a planned cesarean section at 35 weeks gestation. The other fetus died as a consequence of premature delivery due to chorioamnionitis. The same group reported again on these cases and two additional cases of endoscopic repair [55]. There was a 50% mortality rate. One of the survivors was born at 28 weeks due to preterm labor. VP shunts were placed in both survivors, and one of the survivors needed a better closure of the MMC at the third day of life. The same group later reported on the repair of MMC using a hysterotomy [56]; a subsequent report [57] addressed the complications of open MMC repair, which includes preterm labor requiring tocolytics and uterine dehiscence. Several reports have documented the anatomic and functional outcomes of fetal MMC repair. An unexpected finding on patients with fetal MMC repair is the decreased incidence of hindbrain herniation or Chiari II changes. Sutton [58] reported on 10 fetuses with documented pre-operative Chiari II changes that subsequently underwent fetal closure of MMC. All nine survivors showed marked improvement in hindbrain herniation and a larger posterior fossa at 6 weeks of life. However, some anatomic changes, such as breaking of the tectum and a vertical tentorium, were present. Tulipan [59] reported similar results in nine patients who had undergone fetal MMC repair. He assessed the severity of hindbrain herniation using a grading system from 0 to 6. He reported that, prenatally, all nine fetuses had hindbrain herniation with a mean grade of 4.3 ± 1.6; postnatally, the average grade of herniation in these patients was 0.9 ± 0.9, with three fetuses showing no evidence of hindbrain herniation. Tulipan [60] compared a cohort of 104 patients who underwent intrauterine MMC repair with 189 historical controls to evaluate the effect of intrauterine MMC repair on the incidence of shunt dependent hydrocephalus. A decrease in the incidence of shunt-dependent hydrocephalus occurred in the fetal intervention group when the lesion was below L2 and when the intervention occurred before 25 weeks gestational age. Short-term urologic function of 16 patients (2 – 12 months of age) who underwent intrauterine MMC repair was evaluated and compared with historical control subjects. Urodynamic findings were found to be comparable to patients who had postnatal closure of the spinal defect [61]. Early reports were promising regarding improvement in the levels of sensorimotor function after prenatal MMC repair. However, overall results have shown that the sensorimotor function has been within one or two vertebral levels of the MMC lesion [62]; lower extremity function is not improved with in utero MMC repair [63]. Role of fetal surgery for myelomeningocele MMC is not a fatal anomaly; yet, the morbidity and mortality of prenatal intervention are real. Although the anatomic results of decreased incidence of

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Chiari II changes and decreased shunt dependent hydrocephalus are promising, the lack of functional improvement is somewhat disappointing. Long-term results are important to determine whether this surgical option is beneficial. Fetal surgery for MMC can be performed only through a clinical trial sponsored by the NICHD. The Management of Myelomeningocoele Study is designed as a randomized clinical trial of fetal versus postnatal repair. The operation will only be performed in one of three centers—Children’s Hospital of Philadelphia, University of California in San Francisco, and Vanderbilt University.

Lower urinary tract obstruction Natural history The effects of lower urinary tract obstruction (LUTO) vary depending on the onset, severity, and duration of the obstruction [64]. The two most devastating consequences of LUTO are pulmonary hypoplasia and renal dysplasia. Amniotic fluid levels are maintained by fetal urine by week 16 of fetal development. When LUTO occurs early during fetal development, oligohydramnios ensues. In animal models of obstructive uropathy, pulmonary hypoplasia results when oligohydramnios occur during the pseudoglandular phase of lung development [65]. The hypothetical mechanisms by which oligohydramnios cause pulmonary hypoplasia include restriction of fetal breathing movements, decreased fetal lung fluid volume, and limited intrauterine space, all of which impede thoracic growth. In the fetal lamb model, ureteral obstruction during the second trimester results in renal dysplasia; this is likely because this period is characterized by rapid kidney development [66]. LUTO leads to increased intrarenal parenchymal pressure, renal scarring, and irreversible renal damage. In contrast, ureteral obstruction during the third trimester gives rise to hydronephrosis with conservation of renal function. Oligohydramnios may also cause joint contractures of the limbs [67] and characteristic ‘‘Potter’’ facies. Facial features consist of wide-set eyes; flattened palpebral fissures; prominent epicanthus; flattened nasal bridge; micrognathia; and large, low-set ears deficient in cartilage [68]. Prenatally diagnosed lower urinary tract obstruction Although anomalies of the fetal urinary tract occur in about 1% of all pregnancies, only about 1 in 500 has clinical significance [64]. LUTO is diagnosed when a fetus has findings of bladder distention and hydronephrosis on antenatal ultrasound. More common etiologies of LUTO include anterior or posterior valves, meatal stenosis, ureterocele, or urethral atresia. With the current imaging modalities, abnormalities of the fetal urinary tract may be discovered by the gestational week 12 to 14 [69]. Ultrasonography evaluates the parenchymal structure, size relative to gestational age, and echo-

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genicity of fetal kidneys. Hyperechogenicity and small kidneys portend poor renal function; the presence of renal cysts is associated with irreversible scarring. The collecting system and ureters are evaluated for the presence or absence of dilation. The fetal bladder is examined for increased wall thickness and bladder dilation. A thickened bladder wall signifies prolonged bladder distention. Renal function is analyzed by examining the fetal urine obtained by vesicocentesis [70]. The fetal urine is usually collected three or more times 48 to 72 hours apart. These sequential samples are assessed for sodium, chloride, osmolality, b2-microglobulin, and total protein. A trend of decreasing hypertonicity and normalization of electrolyte and protein values is seen in fetuses that may benefit from fetal intervention. Fetal interventions for lower urinary tract obstruction The most common fetal intervention for LUTO is the placement of a double pigtail catheter with one end within the bladder and another within the amniotic cavity. The fetal urine is diverted from the bladder to the amniotic cavity. The intervention is performed between 19 and 21 weeks. An ultrasound is performed at 24 to 48 hours. A weekly ultrasound is performed to assess the catheter location and the improvement of dilation of the bladder, ureter, and collecting system. Complications of LUTO include chorioamnionitis, premature rupture of membranes, trauma to the fetus, intraplacental bleeding, and urinary ascites. There is a reported 40% incidence of catheter dislodgement [71]. Recently, fetoscopic procedures to drain the distended bladder have been described. MacMahon [72] has created a cystostomy in a 17-week fetus using an argon laser. By the infant’s birth at 33 weeks, the two openings had healed over. The infant had normal pulmonary and renal function. The efficacy of the intervention is uncertain. Fetal cystoscopy using a transabdominal bladder entry and ablation of urethral valves has also been reported by several authors [73 – 75]. Although this procedure is feasible, the authors noted difficulty in visualization of the site of obstruction. Welsh [75] reported on the 13 fetuses where cystoscopy was performed for the evaluation and management of obstructive uropathy. The bladder wall, bladder neck, and upper urethra were visualized in the majority of the patients. Of the 10 patients who were thought to have posterior urethral valves, six patients had technically successful therapeutic attempts with hydroablation or glidewire insertion. Only two patients had acceptable renal function at follow-up. In 1997, Coplen [76] reported on the five largest series of vesicoamniotic shunts placed in fetuses. He reported an overall 47% survival rate and 45% shuntrelated complications. He also reported that the failure to restore amniotic fluid volume correlated with 100% mortality. Vesico-amniotic shunting in poor prognosis fetuses resulted in 87% renal failure; outcomes of renal function were not altered, but fetal survival increased. Freedman [77] reported on the outcomes of 55 fetuses with LUTO. The etiology of LUTO included posterior urethral valves (n = 13), urethral atresia (n = 11),

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prune belly (n = 9), and miscellaneous (n = 22). Thirty-three fetuses had good prognosis; 22 of these had shunts, and 14 lived. Eleven of these ‘‘good prognosis’’ fetuses had no shunt placed, and about half of these fetuses still lived. Of the 22 poor prognosis fetuses, six had vesicoamniotic shunts, and three survived. The remaining 16 poor prognosis fetuses that had no shunts died. In this series, there was an overall survival of 40% and a shunted survival of 61%. Twenty-three percent of the survivors had a serum creatinine >1.0 at 1 year of age. Patients with the diagnosis of prune belly syndrome fared best. Holmes [78] reviewed the data on 14 fetuses with posterior urethral valves that underwent fetal intervention at UCSF from 1981 to 1999. All fetuses had favorable fetal urinary electrolytes. There was a 43% fetal and newborn mortality rate. Of the remaining eight patients (mean follow-up 11.6 years), five had chronic renal disease. Five patients needed urinary procedures such as diversion or augmentation. Role of fetal surgery for lower urinary tract obstruction Careful patient selection is imperative. Fetuses with an XY karyotype have better prognosis with fetal therapy. Female fetuses with LUTO usually have complex cloacal anomalies, and they usually do not respond well to vesicoamniotic shunts. Ultrasonographic criteria in favorable fetuses include isolated bladder distention, bilateral hydronephrosis, and oligohydramnios. Careful search to rule out other life-threatening conditions is also performed by ultrasonography. A favorable trend in fetal urine function as evidenced by normalization of electrolytes, and protein values during serial vesical collection is mandatory. If the trend of urine values is suboptimal, parents should be counseled that placement of a vesicoamniotic shunt may ensure the delivery of a live baby with a high risk of needing renal replacement therapy.

Summary Fetal surgery has become a viable option for many parents whose unborn infants have congenital anomalies. However, this approach is best suited to specific circumstances and specific babies. Careful prenatal care and early diagnosis ensure that this option is available to those who can benefit from the intervention.

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