Congenital anomalies that do poorly postnatally despite aggressive medical and surgical management have been a source of constant frustration for clinicians. Weary of these poor outcomes, clinicians begged the question: can treatment of the fetus lead to better postnatal outcomes in specific congenital anomalies? In 1982, the first therapeutic human fetal surgical intervention was performed for bilateral ureteropelvic junction obstruction.34 Although the fetus did not survive, this attempt ushered in a new era of prenatal care and established the field of fetal surgery. Needle-based interventions were first reported in 1983 with the application of percutaneous umbilical blood sampling, which also permitted access for fetal transfusion.22 Since then the application of percutaneous techniques in the treatment of the fetus has broadened. Ultrasound-guided percutaneous procedures are performed through small skin incisions on the mother’s abdominal wall. Percutaneous approaches require real-time ultrasound to visualize the fetal and maternal anatomy and guide the appropriate instruments.92 Cystic masses, ascites, pleural fluid, or other fluid collections can be aspirated as a diagnostic or therapeutic maneuver. Shunts can be inserted for more definitive drainage of fluid into the amniotic space. Other devices such as radio frequency ablation (RFA) probes can also be deployed to treat various twin gestational anomalies. The needles used to place these catheters, as well as the RFA device, are approximately 1.5 to 2 mm in diameter, minimizing morbidity to the mother and irritation of the uterus.53 Ex-utero intrapartum therapy (EXIT) allows for a fetal intervention to be conducted while maintaining uteroplacental circulation to support the fetus followed by immediate delivery. EXIT procedures are most commonly indicated for airway issues, but have been described for extracorporeal membranous oxygenation, separation of conjoined twins, and resection of fetal neoplasms.41 An EXIT procedure is performed similarly to the open fetal procedure described above. However, at the conclusion of the case, with an established airway, the fetus is delivered. Since uterine relaxation is critical during any fetal intervention, the EXIT procedure carries a significant risk for maternal hemorrhage at the time of delivery, and coordination between the anesthesiologist and the surgeon is critical. These principles are covered further in the next section. For the less invasive percutaneous and fetoscopic procedures, anesthesia can be administered using epidural, spinal, or local anesthesia depending on the mother’s preference and anticipated length of the procedure. Special consideration for spinal anesthesia should be undertaken when an emergency cesarean section is desired by the patient for fetal distress. Spinal anesthesia can cause hypotension, which negatively impacts uteroplacental blood flow; therefore, with spinal anesthesia normotension is maintained with a phenylephrine infusion. Both phenylephrine and ephedrine are effective vasopressors that maintain maternal blood pressure while minimizing the effect on umbilical cord blood flow.45,87 Additional conscious sedation can be provided intravenously using propofol or inhaled nitrous oxide. Nitrous oxide also has the added benefit of uterine relaxation. For open fetal procedures, including EXITs, deep maternal general anesthesia is required to ensure adequate uterine relaxation.23 Volatile inhaled anesthetics are used at high concentrations (usually 2.0 minimal alveolar concentration), but the subsequent relaxation of the myometrium can lead to a drop in placental blood flow.23 Therefore, maternal blood pressure is augmented in these cases with either ephedrine or phenylephrine to allow uterine relaxation without compromised fetal blood flow. The surgeon should be vigilant about repeated assessment of uterine tone. When the uterus is open, amniotic fluid volume is maintained with warm, isotonic crystalloid solution to prevent compression of the umbilical cord. The transplacental passage of anesthetic from mother to fetus leads to myocardial depression, which is significant because fetal cardiac output is primarily determined by heart rate.7 Moreover, the fetal response to stress is bradycardia. These hemodynamic changes place the fetus at substantial risk for fetal demise. Other environmental factors such as hypothermia and umbilical cord compression can also contribute to demise. Therefore, continuous fetal monitoring should be undertaken. Continuous monitoring of fetal heart rate via transcutaneous pulse oximetry and intraoperative fetal echocardiography is recommended. Additional measures include fetal venous access, amnioinfusion, and continuous monitoring of amniotic fluid temperature. Despite significant advances in neonatal respiratory support, children born with congenital diaphragmatic hernia (CDH) in the United States have a survival rate of only 60% to 70%. When CDH is diagnosed prenatally, survival may be as low as 25%, owing to the hidden mortality from intrauterine fetal demise (IUFD) and stillborns who are not included in conventional postnatal survival data.67 The poor outcomes associated with this congenital anomaly, which can be diagnosed in utero, have made CDH a primary target for effective prenatal intervention, and this entity was one of the primary driving forces in the genesis of fetal surgery at the University of California, San Francisco. Given the risks of fetal interventions, it is widely accepted that they should only be considered in those cases in which a poor prognosis is expected. For CDH the factors on prenatal ultrasound that are most consistently associated with a worse outcome are (1) the presence of liver herniation into the chest and (2) a low lung-to-head ratio (LHR), which is calculated as the area of the contralateral lung at the level of the cardiac atria divided by the head circumference. In one study, survival was 100% in fetuses without liver herniation on prenatal ultrasound, whereas survival dropped to 56% when liver herniation was present.4 LHR has also been shown to directly correlate with survival: 100% survival with an LHR greater than 1.35, 61% survival with an LHR between 0.6 and 1.35, and 0% survival with an LHR less than 0.6.4 Despite data supporting the LHR, others have suggested that use of the LHR does not account for discrepant growth rates between the head and lung during gestation and therefore may only apply to certain gestational ages.46 To account for this, the observed to expected LHR (O : E LHR) has been proposed wherein the LHR is represented as a percent of what the expected LHR would be in a normal fetus of the same gestational age. For left-sided defects, an O : E LHR less than 25% is associated with an 18% survival, whereas an O : E LHR greater than 45% correlates with 89% survival.20,46 Newer techniques for measuring lung volume using magnetic resonance imaging (MRI) have been described.47 The best studied application of fetal MRI lung volumes is the percent-predicted lung volume (PPLV). Similar to the LHR, however, results from various centers have not been consistent. In one study, a PPLV greater than 20% was associated with 100% survival, whereas survival was only 40% when PPLV was less than 15%.16 In another study, a PPLV less than 25% was associated with a 13% survival and a PPLV greater than 35% correlated with 83% survival.93 The earliest studies investigating the feasibility of in utero correction of CDH focused on the effect of compression on fetal lung development in animal models.1 Two fetal lamb models were used: (1) compression of the lungs using an intrathoracic balloon and (2) a mechanically created diaphragmatic hernia. Both proved to be uniformly fatal owing to pulmonary hypoplasia. However, in utero correction, either release of the balloon compression or closure of the defect, resulted in sufficient lung growth and development, which ultimately improved postnatal survival and created much enthusiasm about the application of this concept in high-risk human fetuses with CDH.1 In utero correction of CDH initially involved open repair of the diaphragmatic defect through an open hysterotomy.35 The first successful case was reported by investigators at the University of California, San Francisco (UCSF) in 1990 using a two-step approach that involved creation of an abdominal silo to accommodate the reduced viscera and prevent compression of the umbilical vessels.35 The group at UCSF further studied this approach in a prospective trial comparing open fetal repair to postnatal repair in severe cases of prenatally diagnosed CDH. However, no difference in survival or need for extracorporeal membrane oxygenation (ECMO) was found, primarily because of the morbidity of the prenatal repair and subsequent preterm labor.36 At this time, pulmonary hyperplasia was observed in patients treated at UCSF with congenital high airway obstruction syndrome (CHAOS).40 When the trachea is occluded, either intentionally or as seen in CHAOS, fluid secreted by the lung parenchyma that is normally “exhaled” by the fetus builds up, leading to pulmonary hyperplasia.25 This was not an entirely novel concept, yet the investigators at UCSF were the first to apply this strategy of tracheal occlusion to the prenatal treatment of CDH.37 The first eight patients were treated with open hysterotomy and tracheal occlusion with a metallic clip.37 However, this approach had several problems that resulted in only a 15% survival rate.37 First, there was still the morbidity associated with an open hysterotomy and significant prematurity from preterm labor. Second, occlusion of the trachea using metallic clips resulted in tracheal stenosis. Last, delivery of an infant with an occluded airway required a stringent delivery plan—which ultimately became known as the EXIT procedure (Figure 14-1).41 Despite the initially disappointing results, investigators were still optimistic that tracheal occlusion and pulmonary hyperplasia held promise for treating high-risk CDH patients. Ongoing advancements in fetal surgery led to less invasive means for fetal tracheal occlusion, including fetoscopic balloon tracheal occlusion (Figure 14-2). The theoretic advantages of fetoscopic balloon occlusion included elimination of the hysterotomy, lower risk of tracheal stenosis, and ease of balloon removal—although an EXIT procedure is still required. The ultimate advantage was a 75% survival rate with fetoscopic balloon occlusion in the first eight patients compared with a 38% survival rate in historical, case-matched controls managed with postnatal repair.38 To corroborate these findings, an National Institutes of Health—funded, prospective randomized trial comparing fetoscopic balloon occlusion to standard postnatal care for fetuses diagnosed with severe left-sided CDH (liver up and LHR <1.4) and no other detectable anomalies was opened at UCSF. In this study, there was no difference in survival between the tracheal occlusion group and the postnatal care group (73% versus 77%, respectively).39 Further data regarding fetal tracheal occlusion have indicated that temporary, short-term reversible tracheal occlusion is preferable to indefinite occlusion that is released at the time of delivery. The rationale behind this is that animal models of fetal tracheal occlusion have demonstrated that long-term tracheal occlusion can be deleterious to type II pneumocytes, resulting in surfactant deficiency; however, this adverse effect is not seen with a shorter duration of tracheal occlusion.82 Deprest and colleagues have studied the effect of temporary tracheal occlusion, measuring lung hyperplasia with MRI and reporting improved postnatal survival as high as 93%.11 The downside is that temporary tracheal occlusion requires a second prenatal intervention for fetoscopic balloon retrieval; however, this obviates the need for an EXIT procedure.41 The most recent report from the European FETO consortium has reported a 48% survival rate among 210 cases of severe CDH treated with temporary fetal tracheal occlusion compared to an 11% survival in historical controls.11 Currently, the Eurofetus group is sponsoring a prospective trial aimed at determining the ideal time and duration for tracheal occlusion.48 In North America, only a handful of centers are offering fetoscopic tracheal occlusion on an investigational basis. Currently, UCSF is offering temporary fetal tracheal balloon occlusion for left-sided defects with liver herniation and an LHR less than 1.0.49 This study is being conducted with an investigational device exemption from the Food and Drug Administration and involves percutaneous placement of a fetoscopic tracheal balloon between 26 and 28 weeks’ gestation, with removal of the balloon via a second percutaneous fetoscopic procedure between 32 and 34 weeks. Congenital pulmonary airway malformations (CPAMs) are pulmonary lesions with a broad range of clinical presentations. This broad category includes what are felt to be neoplastic lesions such as congenital cystic adenomatoid malformations (CCAMs) and bronchopulmonary sequestrations (BPS) as well as nonneoplastic lesions associated with bronchial atresia and subsequent pulmonary hyperinflation that can mimic CCAMs. However, CCAMs are characterized by an overgrowth of respiratory bronchioles with the formation of cysts that can vary in size.44 They are much more likely than sequestrations to cause nonimmune fetal hydrops, yet distinguishing CCAMs from BPS prenatally oftentimes cannot be done, and most fetuses diagnosed with a CPAM develop normally and are best treated with standard, postnatal resection.44 Similar to CDH, various prognostic factors have been described for CPAMs; the most widely accepted measurement is the cyst volume ratio (CVR), defined as the product of the three longest measurements of the lesion on ultrasound multiplied by the constant 0.52, and then divided by the head circumference. A CVR greater than 1.6 has been found to predict a greater risk, up to 80%, for the development of nonimmune fetal hydrops, whereas a CVR less than 1.6 carries only a 2% risk of developing hydrops.17 The morphology of the lesion is also an important consideration in determining risk. Microcystic lesions have a more predictable course, with steady growth that tends to plateau at 26 to 28 weeks’ gestation, at which point fetal growth exceeds that of the CPAM. For this reason, patients with microcystic or solid CPAMs should be followed closely up to 26 to 28 weeks’ gestation, at which point the interval between ultrasound examinations can be lengthened if the pregnancy has been otherwise uncomplicated. In contrast, macrocystic CPAMs can undergo abrupt enlargement caused by rapid fluid accumulation in a dominant cyst regardless of the CVR. Therefore, macrocystic CPAMs require close follow-up with serial ultrasound throughout the duration of the pregnancy.63 The development of hydrops at a viable gestational age should prompt early delivery. Aspiration or thoracoamniotic shunting is reserved for fetuses with a dominant, macrocystic lesion and hydrops at a gestational age that precludes early delivery.97 Needle drainage alone is not typically a durable therapy as fluid rapidly reaccumulates within the cyst, making a thoracoamniotic shunt a better option. In fact, several series have shown that thoracoamniotic shunting results in as much as a 50% to 70% volume reduction in the size of the lesion and up to a 74% survival rate.97 Thoracoamniotic shunting is not without complications, which can include shunt migration, shunt occlusion, hemorrhage, membrane separation, placental abruption, and/or preterm labor.61 Furthermore, despite shunting, these babies can still have significant respiratory distress at birth and should be delivered at a tertiary referral center. Open fetal thoracotomy for resection of the CPAM has historically been an option in the previable fetus with a microcystic or solid lesion and nonimmune fetal hydrops. Through an open hysterotomy, a thoracotomy is made through the fifth intercostal space, and the lobe containing the CPAM is identified and resected (Figure 14-3).2 In a group of 120 patients with the prenatal diagnosis of CPAM from UCSF and Children’s Hospital of Philadelphia (CHOP), 25 hydropic fetuses were followed with no intervention, and all mothers delivered prematurely and all fetuses died perinatally. There were 16 fetuses with hydrops who underwent intervention: 13 underwent open fetal surgery, and three underwent thoracoamniotic shunting. Two of the three survived in the group that underwent shunt insertion, and eight of 13 survived in the open fetal surgery group. Although the results of open fetal resection for moribund fetuses with CPAMs were promising, this therapy has essentially been replaced by the serendipitous discovery of steroid-induced regression of microcystic CPAMs.90 At UCSF, during preparation of several hydropic fetuses for open fetal surgery, maternal steroids were administered to enhance fetal lung maturity in anticipation of preterm labor. Preoperative ultrasound studies showed resolution of the hydrops, and resection was deferred. Thirteen patients with microcystic CPAMs, nine of which were complicated by hydrops, had an overall survival rate of 85% with resolution of hydrops in seven of nine fetuses.21 A series of 11 patients has also been reported at CHOP, five of whom had hydrops, and all survived after receiving steroids.69 Current practice is to initiate maternal betamethasone for nonimmune hydrops or a CVR greater than 1.6 whether or not hydrops is present primarily for microcystic lesions. Predominantly macrocystic lesions are not routinely treated with steroids, as they are unlikely to respond. Maternal steroids can be redosed, but care should be taken because repeated courses of maternal steroids beyond three to five courses can result in untoward effects such as reduced birth weight.29 The tumor volume to fetal weight ratio (TFR) has been developed as an important prognostic indicator for fetuses with SCT.78 Tumor volume is calculated using the greatest length, width, and height of the tumor as measured by ultrasound or MRI, and fetal weight is calculated by ultrasound using the Hadlock formula. Originally TFR was applied to 10 fetuses with SCT, and a TFR greater than 0.12 was associated with an 80% incidence of fetal hydrops and 60% mortality. However, a TFR less than 0.12 was associated with 100% survival.78 A recent experience in 37 fetuses with SCT confirmed that a TFR less than 0.12 was a favorable prognostic finding. Tumor morphology was also considered, and researchers found that cystic SCTs carried a more favorable prognosis than solid ones.86 The fetus with SCT is at high risk for IUFD especially when associated with fetal hydrops. In the CHOP experience of 30 fetuses with SCT, there were only 14 survivors.96 Four out of 15 patients with solid tumors developed fetal hydrops and underwent open fetal debulking operations, and three survived.96 In 65 prenatally diagnosed SCTs, the overall survival was 44%.86 There were 19 cases complicated by fetal hydrops and eight underwent a fetal intervention with a 38% survival. There was only a single survivor in the other 11 patients with hydrops who did not have a fetal intervention. At UCSF the cumulative experience is now with 15 patients who have undergone fetal intervention (excluding patients who had cyst aspiration to facilitate delivery): six underwent open fetal resection, five underwent RFA, one underwent alcohol ablation, one had therapeutic cyst aspiration to relieve urinary tract obstruction, one had RFA followed by EXIT-to-resection, and one had EXIT-to-resection alone. The overall survival following fetal therapy has been 33%. Of the 10 patients who survived to delivery after fetal intervention, the mean gestational age was 28 weeks, and there was still a 50% neonatal mortality rate.86 Despite the poor outcomes with open fetal debulking of SCT in the setting of hydrops, the therapeutic options are limited and expectant management carries an overwhelming risk of IUFD. More recently, fetal echocardiographic data have been applied to identify those patients who have early signs of heart failure in order to intervene before the late stages of heart failure manifest as hydrops. A cardiothoracic ratio greater than 0.5, a combined ventricular output greater than 550 mL/min/kg, any tricuspid or mitral valve regurgitation, and a mitral valve z-score greater than 2 were all associated with a poor outcome.10 The most common approach to treat fetal SCT is an open fetal resection through a maternal hysterotomy (Figure 14-4). The goal of this procedure is not to achieve complete resection, but to debulk enough of the tumor to reduce the vascular shunting. This usually requires re-excision postnatally in those who survive. Sacrococcygeal teratomas can be malignant and can recur later with malignant transformation; therefore, surveillance after resection with digital rectal examination, serial alpha-fetoprotein, and MRI as indicated is necessary.
Surgical Treatment of the Fetus
Fetal Access
Percutaneous
Exit Procedure
Anesthetic Considerations
Anomalies Amenable to Fetal Surgery
Congenital Diaphragmatic Hernia
Prognostic Criteria
Fetal Interventions
Neoplasms
Congenital Pulmonary Airway Malformations
Sacrococcygeal Teratoma
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Surgical Treatment of the Fetus
