Ex Utero Intrapartum Treatment (EXIT) Procedures Advances in prenatal diagnostic imaging have afforded opportunities to refine our understanding of the natural history of fetal conditions, in particular tumors or malformations involving the fetal airway. Lesions that compromise the fetal airway constitute an immediate threat to the newborn, with the risk of hypoxia, ischemic brain injury, and/or death. The ex-utero intrapartum treatment (EXIT) procedure provides a delivery strategy that converts potentially catastrophic event into a controlled procedure. For Medical Professionals IntroductionIn the past, numerous case reports described intubation and bronchoscopy before severing the umbilical cord in patients with such lesions (1-7). Skarsgard et al., described “operating on placental support” (referred to as the OOPS procedure) in the treatment of a fetus with anticipated airway obstruction (8). In this approach, intra-partum laryngoscopy or bronchoscopy during cesarean section or vaginal delivery before placental separation, did not assure that uteroplacental circulation would be maintained (9). In the OOPS procedure, no attempt was made to prevent normal uterine contraction during the procedure, and in some cases, the fetus was removed from the uterus entirely to instrument the airway resulting in rapid loss of uterine volume. In both of these instances, cessation of uteroplacental circulation would be expected (9). In contrast, the central principles of the EXIT procedure are controlled uterine hypotonia and maintenance of uterine artery perfusion pressure to preserve uteroplacental gas exchange (10). The EXIT procedure was initially described for reversal of tracheal occlusion in fetuses with severe congenital diaphragmatic hernia (CDH) (9). These cases required neck exploration for the removal of the tracheal surgical clips, with maintenance of uteroplacental gas exchange until the fetal airway was secured by endotracheal intubation. Experience with the EXIT technique demonstrated fetal and maternal hemodynamic stability and soon led to expanded indications for its use. Indications for EXIT-to Airway have broadened to include giant fetal neck masses (11), fetal mediastinal masses (12), fetal lung masses(13), congenital high airway obstruction syndrome (CHAOS) (14) and micrognathia (15) among others. In addition, the EXIT strategy has been successfully employed in a number of non-airway conditions which benefit from preserved uteroplacental gas exchange such as EXIT-to-Resection for sacrococcygeal teratoma (16), EXIT-to- ECMO or cardiopulmonary bypass for severe congenital diaphragmatic hernia (17) and hypoplastic left heart syndrome with intact atrial septum (18), respectively. Differential Diagnosis of Fetal Airway Obstruction Amendable to EXIT Strategy Causes of fetal airway compromise may be thought of as resulting from obstruction due to extrinsic compression of the airway or obstruction that is intrinsic to the airway itself. Extrinsic Airway ObstructionAny cause of extrinsic airway obstruction, from the lips to the main-stem bronchi, may result in problems during fetal development, and difficulties in establishing an airway at delivery and newborn resuscitation. Extrinsic airway obstructions may be in an oral, cervical, or thoracic location with the more frequent causes being cervical teratomas, lymphatic vascular malformations, epignathus and micrognathia. EXIT-to-Airway to Reverse Tracheal OcclusionThe principles that underlie the EXIT procedure were first developed to reverse tracheal occlusion performed to treat the most severe forms of congenital diaphragmatic hernia (9,19). Tracheal occlusion results in accumulation of fluid within the fetal airway raising intratracheal pressure which in turn drives lung development. This was first applied as extrinsic compression using open fetal surgery to apply surgical clips across the trachea to completely occlude the airway and accelerate lung growth (19,20). This open fetal surgical approach was quickly supplanted by fetoscopic endoluminal tracheal occlusion (FETO) in which a detachable balloon is placed within the trachea to occlude it with subsequent fetoscopic removal after it has induced lung growth (21). In about a third of cases the balloon can by punctured by ultrasound guided needle obviating the need for a second fetoscopic procedure. A small percentage of cases may go into labor before either of these procedures can be performed. All FETO centers must have an experienced team on standby for the rare instance in which this scenario occurs. An EXIT procedure can be performed to allow rigid bronchoscopy to puncture the balloon and retrieve the collapsed balloon and attached valve mechanism during delivery. In cases of precipitous delivery, before the team arrives to perform bronchoscopy, the baby can be intubated with an ETT as small as 2.5 Fr and the inner stylet of the needle designed for fetoscopic balloon puncture can be passed via the ETT to decompress the balloon. In these cases, the collapsed balloon and valve mechanism may be retained and pushed distally in the lung by positive pressure ventilation. Oral Conditions Oropharyngeal Teratoma: Epignathus Epignathus is a rare oropharyngeal teratoma arising from the sphenoid bone, or hard palate, with an estimated incidence of 1:35,000 to 1:200,000 (22). It usually presents as a large mass protruding through the mouth and obstructing the upper airway. Immediate removal is often necessary at the time of delivery to allow an airway to be established by orotracheal intubation. A large epignathus tumor may present in the second trimester with polyhydramnios and airway obstruction. If pharyngeal obstruction is complete, the ensuing polyhydramnios may require serial amnioreductions to minimize the risks of premature labor and delivery (24). Imaging with ultrasound and ultrafast magnetic resonance imaging (MRI) can provide important information about the mass. Management of the fetus with epignathus is dictated by the degree of airway obstruction, gestational age at presentation, and any other physiologic impact that the mass may have on the fetus. Some masses are small and do not completely obstruct the fetal airway and therefore can be managed by conventional delivery and, if needed, intubation. By contrast, an epignathus which grows very rapidly to large exophytic proportions may completely obstruct the fetal airway, dislocate the mandible, and may even cause fetal hydrops from the increased blood flow through the tumor, resulting in a high output cardiac failure. All such cases warrant urgent consultation at a fetal care center. Treatment involves resection of the mass, which, despite its large size, usually arises from a narrow base on the fetal palate. Depending on gestation and severity, this might theoretically warrant consideration of open fetal surgery to resect the mass or, if the single systemic arterial feeding vessel can be localized, interstitial ablation of that feeding vessel can be considered. After 28 weeks of gestation, ex-utero intrapartum treatment (EXIT) procedure to resect the mass and secure the airway prior to delivery should be considered (24). Congenital Epulis (Neumann's Tumor) Epulis, also known as a gingival granular cell tumor of the newborn, is an oral mass (or masses), which protrudes through the mouth and may obstruct the airway (25,26). Embryologically, the tumor arises from the gingival mucosa. Congenital epulis has a female preponderance of 8: 1 and, although most are very small and clinically incidental, tumors vary in size from a few millimeters to as large as 7.5 cm. Epulis has often been reported to regress spontaneously after birth, suggesting that its growth may depend somewhat on hormonal stimulation during pregnancy (27). If an epulis is large, the diagnosis can often be made prenatally, allowing the planning of delivery in collaboration with a Pediatric Surgeon or Pediatric Otolaryngologist-led airway team in case an emergency resection or tracheostomy in the newborn is necessary. Interventions at birth, may be necessary, depending on the size and likelihood of airway obstruction. Epulis often originates from a narrow base and can often be easily resected before establishing an airway in the controlled environment of an EXIT-to-airway delivery (24). Mandibular Hypoplasia: Micrognathia/Retrognathia Micrognathia or retrognathia may be isolated or syndromal and, in severe cases, may lead to upper airway obstruction. Pierre Robin sequence (PRS) may cause upper airway obstruction, and is associated with micro-retrognathia and glossoptosis. PRS occurs in 1 :8500 to 14,000 births, being characterized by a small mandible accompanied by a U-shaped cleft palate (28). Approximately 40% of PRS cases occur in isolation and 60% present as part of a syndrome. Other conditions associated with micrognathia include Stickler or velocardiofacial syndromes (29). Severe micrognathia can also be part of a group of rare conditions known as arthrogryposis multiplex congenita, characterized by multiple non-progressive joint contractures, glossoptosis, retrognathia, cleft palate, poor fetal swallowing, breech presentation and preterm birth (30). Not all cases of micrognathia will cause critical compromise of the airway. The severity of micrognathia can be assessed on sagittal images of the fetal head using the jaw index (31), which is calculated by the ratio of the anterior-posterior mandibular length divided by the biparietal diameter (BPD) x 100. If the jaw index is <5th percentile, associated with either glossoptosis or evidence of an upper gastrointestinal obstruction as indicated by an absent stomach bubble and polyhydramnios, an EXIT-to-Airway delivery strategy should be considered (15). Critical airway obstruction is more likely to be present when there is associated upper gastrointestinal tract obstruction, i.e. polyhydramnios or the absence of fluid in the stomach on prenatal ultrasound (32). Such severe cases of micrognathia or retrognathia require EXIT-to-Airway and uniformly require tracheostomy until jaw distraction achieves sufficient mandibular growth to allow tracheal decannulation. Cervical Conditions Congenital Giant Cervical Teratoma All three germ layers are represented in teratomas and these can arise in the abdomen, sacrum, chest, neck, or cranium. In the newborn, the incidence is about 1 :40,000 (33). Yolk sac components may be a histological forerunner with malignant potential in any teratoma, but are rarely found in cervical teratomas diagnosed prenatally (34). There is neither a male nor female predilection . Ectopic embryological components may include bone, teeth, hair, neural or thyroid tissue. More than 20% of all fetal tumors occur in the face or neck region [ 34 ]. Fetal teratomas are most commonly sacrococcygeal (60-80%), however 5-13% are cervical and these carry a significant risk of airway obstruction [33-36]. Cervical teratomas can be massive, some measuring > 12 cm in diameter, and may extend from the mastoid process and body of the mandible across to the clavicle and sternal notch in some cases causing superior vena cava syndrome (11,37). Mandibular hypoplasia and facial nerve palsy may occur in large cervical teratomas resulting from pressure on the developing bone and nerve, respectively. Polyhydramnios and/or an absent stomach bubble are found in about 40% of cases, due to mass effect compressing the esophagus (38,39). Differentiating a lymphatic vascular malformation from a cervical teratoma can be difficult on prenatal ultrasound (37). But cervical teratomas are usually solid, with some cystic areas, and well-defined borders; they may have internal calcifications and are usually positioned in the anterior neck. In contrast, lymphatic vascular malformations are usually multiloculated cystic structures with less solid components and tend to be more laterally located in the neck. Biochemical markers are usually unhelpful, since maternal serum alpha-fetoprotein is elevated in <30% of cervical teratomas (40). The natural history of cervical teratomas is not well defined, but the majority are benign. In one case series, “benign” metastases occurred in 14% of cervical teratomas in the form of immature neuroglial elements found in regional lymph nodes, whereas only 1.4% had yolk sac components (34). Fortunately, many infants remain disease-free long after resection, even with metastatic spread to regional lymph nodes (41). Tumor growth may continue up until term, and usually an EXIT-to-Airway delivery is planned at about 34-36 weeks of gestation due to the risk of prematurity and attended by Pediatric Surgeon and/or Pediatric Otolaryngologist for airway management (42,43). Cervical Lymphatic Vascular Malformation Lymphatic vascular malformations of the neck are often evident at birth as a soft tissue mass and may have both lymphatic and vascular endothelial components. At about 5-6 weeks of development, dilation of primordial lymphatic channels or hypoplasia of the lymphatic vessels are thought to cause these malformations. Lymphatic vascular malformations may also occur in the axillae, thorax, and lower extremities, although less frequently than in the neck (44). Often these benign tumors grow ·to be very large, causing significant fetal airway compromise (Figure 6). Lymphatic vascular malformations have been estimated to occur in 1 :1775 live births (45). But in spontaneous abortions, the incidence may be as high as 1 :300 (44). The mortality and spontaneous abortion rate associated with lymphatic vascular malformations diagnosed <20 weeks of gestation is as high as 60-70%. They have associated chromosomal anomalies or other genetic syndromes or structural anomalies, and non-immune hydrops is frequent (45,46). Lymphatic malformations may be associated with Turner syndrome (45,X), trisomies 21 and 18, Noonan or Fryn’s syndrome, fetal alcohol syndrome, oligohydramnios, a single umbilical artery and/or hydrops fetalis (47-51). The natural history of cervical lymphatic vascular malformations will vary widely depending on the gestational age at diagnosis. The etiology of early versus late-appearing lymphatic vascular malformations may be different, as those appearing early tend to have a more cystic, diffuse appearance and are often located in the posterior triangle of the neck, as opposed to isolated cervical malformations that may not become apparent until the late third trimester (47). When a lymphatic vascular malformation of the neck is predominantly macrocystic and posterioe, what has previously been referred to as a cystic hygroma, often does not cause any significant airway obstruction. It is the giant lymphatic vascular malformations that are lateral or anterior in the neck that may impinge on the fetal airway and, in such cases, Pediatric Surgeon or Pediatric Otolaryngologist should be in attendance at delivery, in case an emergent airway is necessary. In some cases, the size of the lymphatic vascular malformation may be deceptive and even large lesions may not impair the fetal airway. Even in this setting however, rapid enlargement may occur in immediate postnatal setting in the neonate rapidly progressing to airway compromise. Sometimes, differentiation between a cervical teratoma and cervical lymphatic vascular malformation may be challenging antenatally, and, if there is thought to be any potential for airway compromise, referral to an appropriate center for an EXIT-to-Airway delivery strategy should be considered. Goiter and Other Neck Masses Congenital goiter is occasionally seen in mothers taking propylthiouracil for hyperthyroidism due to Grave’s disease. Fetal thyroid size should be monitored serially on ultrasound in such cases and, if a goiter is suspected, this can be corrected with intra-amniotic thyroxine administration. In the rare cases where goiters have been reported to cause some degree of upper airway obstruction at birth, simple intubation has been successful. Other neck masses such as branchial cleft cysts are anterolateral and generally appear as unilocular cysts. These have not been reported to cause significant airway obstruction at birth. Thoracic Conditions Some thoracic masses may be sufficiently large to cause obstruction of the intrathoracic fetal airway. Depending on the location, their potential for obstruction is quite variable and will inform decisions regarding the need for prenatal or postnatal intervention and delivery planning. An EXIT delivery may need to be considered in some of these cases. Bronchogenic Cyst/Foregut Duplication Cyst A bronchogenic is cyst arising from the trachea or mainstem bronchi which can rarely completely obstruct the trachea or a mainstem bronchus, causing “hyperinflation” of the lung distal to the obstruction (52). These can be relatively easy to see on ultrasound and MRI since they are usually fluid-filled. These lesions may be amenable to simple antenatal ultrasound-guided aspiration and decompression. However, the fluid tends to be quite viscous and recurrence of the cyst even if successfully aspirated is typically observed. If antenatal decompression is not possible or unsuccessful, then an EXIT-to-Resection delivery strategy may need to be considered. Depending on the location of the bronchogenic cyst, complete obstruction of the distal trachea or one bronchus can result in CHAOS-like hyperinflation of one or both lungs. In this setting, EXIT-to-Resection may facilitate newborn resuscitation and stabilization. Thoracic Teratomas Although rare, tracheal obstruction may be seen with a congenital teratoma of the thorax. Non-immune hydrops may occur, either because of cardiac tamponade or high output failure. Mediastinal teratomas due to their size and location can compress the trachea from the innominate artery to the mainstem bronchi which may make airway control impossible without resection. An EXIT-to-Resection via median sternotomy allows the airway to be secured prior to delivery (12). Depending on the severity and duration of airway compromise tracheomalacia may further complicate the postnatal course. Pericardial teratomas are usually confined to the pericardial sac but can become extremely large or have associated large pericardial effusions which can exert mass effect on the intrathoracic airway (53). Depending upon the rate of growth and size these lesions tend to have more of an effect on cardiac function often resulting in non-immune hydrops. Congenital Pulmonary Airway Malformations (CPAMs) CPAMs are classified as macrocystic or microcystic on prenatal ultrasound. These may contain a range of histologies in the spectrum of the staging system described by Stocker for what were called congenital cystic adenomatoid malformations (CCAMs) and are now referred to as congenital pulmonary airway malformations (CPAMs). These lesions are usually diagnosed initially at the time of the 18-20-week ultrasound and rarely prior to this gestation. CPAMs often grow until about 26-28 weeks of gestation, when most CPAMs will begin to plateau or regress in size. The most frequently occurring lesions are microcystic and the outcome for the vast majority of these is excellent. The prognosis worsens rapidly if hydrops develops, which is more likely to occur if the CPAM is large at initial presentation. A CPAM volume ratio (CVR)> 1.6 at presentation has been shown to be at significantly increased risk of hydrops and a poor outcome and this can be used to stratify the frequency of evaluation (54). Once diagnosed, close ultrasound monitoring is important, especially if lesions are either macrocystic or large. Recently it has been shown that a course of intramuscular maternal betamethasone may arrest the growth of many large microcystic CPAMs, with reversal of hydrops (55). By contrast, large macrocystic CPAMs, especially if hydropic, are most effectively treated by ultrasound-guided fetal thoraco-amniotic shunting, with excellent results (56). CPAMS that are large and cause significant mediastinal shift or cross the midline may compress the intrathoracic trachea and may be considered for EXIT-to-Resection. Hedrick et al reported a small series of CPAMs causing intrathoracic airway compromise managed by EXIT-to-Resection in which 8/9 surived with 4 requiring ECMO support due to the severity of underlying pulmonary hypoplasia and pulmonary hypertension (13). The need for EXIT-to-Resection for CPAM has been questioned as objective criteria for the degree of intrathoracic airway compromise to warrant EXIT-to-Resection have not been established. We currently use evidence on fetal MRI of complete effacement of the intrathoracic trachea by compression by CPAM close to the time of delivery as an indication to consider EXIT-to-Resection. Intrinsic Airway Obstruction Congenital High Airway Obstruction Syndrome (CHAOS) CHAOS is due to complete obstruction of the upper fetal airway. An ultrasound frequently shows enlarged echogenic lungs with a dilated tracheobronchial tree and inverted or flattened diaphragms, a “compressed” heart, and ascites. To date, no fetus diagnosed prenatally with CHAOS has survived without a fetal or perinatal intervention (14,57). The airway obstruction in CHAOS is complete obstruction caused by laryngeal atresia, laryngeal web or cyst or tracheal atresia that causes complete upper airway obstruction and prevents the normal egress of lung fluid. As this fluid accumulates in the tracheobronchial tree, both lungs become distended, echogenic and diffusely enlarged (14,57-59). Unilateral bronchial atresia can also result in CHAOS physiology, but rather than both lungs being enlarged, one lung is hyperinflated with dilated bronchi and the mediastinum is severely shifted with ipsilateral diaphragmatic inversion, ascites and contralateral lung hypoplasia. Postnatally, laryngeal atresia may be classified into three types -type I: supra and infra glottic atresia; type II: infra-glottic atresia only; and type III: where the atresia is located directly at the glottis. This classification adds little clinically in the antenatal period, however. Embryologically, laryngeal atresia probably results from failure of recanalization of the larynx, whereas tracheal atresia probably results from unequal partitioning of the foregut into the esophagus and trachea. Fraser’s syndrome, an autosomal recessive disorder, has most widely been associated with CHAOS this involves renal agenesis, tracheal or laryngeal atresia, syndactyly or polydactyly, and microphthalmia (60). CHAOS has also been reported in association with short-rib polydactyly syndrome, cri-du-chat syndrome, velocardiofacial syndrome, Shprintzen-Goldberg omphalocele syndrome, and the VATER/VACTERL association (Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects). Some chromosomal anomalies (22q11.2 deletion, chromosome 5p deletion, 47,XXX, partial trisomy 9 and partial trisomy 16q) have also been reported (61). However, most cases of laryngeal and tracheal atresia resulting in CHAOS are isolated and sporadic, without any known risk of recurrence. The true incidence of CHAOS is unknown; partly because many of these fetuses die in utero (60,61). With proper diagnosis and delivery planning, survival is possible. Historically, the first long-term suivivor with CHAOS was described by Crombleholme in 2000, when the fetus was delivered by EXIT and a tracheostomy established prior to clamping the umbilical cord (14). CHAOS may not develop or hydrops may resolve in a fetus with either tracheal or bronchial atresia in which a fistula develops to the proximal trachea or esophagus in which case the airway obstruction may go undiagnosed until delivery (14,62). On antenatal ultrasound, CHAOS must be distinguished from bilateral microcystic CCAMs of the lung, especially if there is associated hydrops. Only about 2% of CCAMs are bilateral (54,60); compressed normal lung tissue can usually be appreciated on imaging in a fetus with a bilateral CCAM and the diaphragms are not usually everted. The predominant manifestation of hydrops in CHAOS is massive ascites and eversion of the lungs due to distension of the lungs, whereas, in CCAM, the edema initially is usually in an upper body distribution, only a segment of the lungs is hyperechoic and the trachea and mainstem bronchi are not dilated. EXIT Procedures for Non-Airway Related Indications The first use of EXIT procedure for a non-airway related indication was performed for severe congenital diaphragmatic hernia with an associated Tetrology of Fallot (10). The rationale was that this diagnosis had an extremely high rate of needing ECMO support and it would eliminate the stressful neonatal resuscitation to transition to postnatal life. A small series of EXIT-to-ECMO for CDH was subsequently reported by Kunasaki et al which supported the use of EXIT-to-ECMO (17). However, this same group published a follow up series which showed no benefit (63). Another small prospective study of uniformly severe left CDH ( which would have met criteria for FETO) self-selected either conventional management vs EXIT-to-ECMO (64). Of 8 patients electing conventional therapy only 1 of 8 survived, only 4 made it out of the delivery room and 3 of the 4 who did make it out of the delivery room required ECMO support. In those treated by EXIT-to ECMO 4 of 8 survived with 3 of 4 non-survivors having autopsy pulmonary findings incompatible with life. There were no maternal deaths or complications, but all mothers required a surgical delivery under general anesthesia. This series was too small to reach definitive conclusions, however it was thought that EXIT-to ECMO is an unproven therapeutic option, which may be considered in the most severe cases in which the baby is to be treated at a freestanding Children’s Hospital with no delivery capacity. Centers with delivery capability may achieve the same level of support with ECMO standby in the delivery suite obviating the maternal risks of EXIT procedure. EXIT-to-Cath LabIn hypoplastic left heart syndrome (HLHS) a subset of fetuses have either a highly restrictive foramen ovale or an intact atrial septum which prevents mixing at the atrial level following delivery (18). These babies typically become bradycardic and arrest within 20 to 30 minutes of birth. A delivery strategy aimed at minimizing the time to catheterization laboratory to perform an atrial septostomy have ranged from Cesarean section in the hybrid catheterization laboratory to actual EXIT procedure in the catheterization laboratory to obtain venous access via the femoral vein prior to delivery to expedite the atrial septostomy or cardiopulmonary bypass for atrial septectomy. Selection of fetuses with HLHS with sufficiently restrictive atrial septum to warrant such an approach is based on the pulmonary venous waveform with a ratio >3:1 (65). This identifies cases with critically restrictive atrial septums that would be expected to become bradycardic within 20-30 minutes of delivery. EXIT-to-Cardiopulmonary BypassIn a case of HLHS with an intact atrial septum that had undergone a failed attempt at in utero atrial stent placement which became dislodged and resulting in pulmonary venous hypertension and pulmonary lymphangectasia an EXIT-to-Cardiopulmonary Bypass was planned as simple atrial septostomy would be insufficient (66). The EXIT procedure was performed and the baby was intubated with the ETT sutured to the gums after which a median sternotomy was performed and baby placed on cardiopulmonary bypass by aortic and right atrial cannulation prior to clamping the cord for delivery. On an adjacent operating table the baby then underwent atrial septectomy prior to coming off bypass. EXIT-to-PacemakerIn cases of congenital complete heart block, a slow ventricular response rate occurs due to immune mediated injury to the conduction system and myocardium. This immune mediated injury from transplacental passage of maternal SSA antibodies in mothers with underlying lupus erythematosus leads to heart block and heart failure (67). The transition to postnatal life exposes the compromised heart to increased systemic vascular resistance and can exacerbate heart failure in the time it takes to successfully pace the newborn heart to achieve a higher cardiac output. In a case of congenital complete heart block with a ventricular response rate of 45 beats/minute with early signs of hydrops it was thought that the baby would not tolerate the transition to postnatal life. An EXIT procedure was performed for placement of an epicardial pacemaker which captured and paced the heart at 75 beats/minute to increase the cardiac output prior to clamping the cord for delivery. This allowed a more seamless transition to postnatal life with the newborn heart rate adjusted to augment the cardiac output as needed to prevent development of acidosis. EXIT-to-Resection for Sacrococcygeal TeratomaIn high risk sacrococcygeal teratoma (SCT) (see chapter 82) a rapidly enlarging highly vascular tumor puts the fetus into a high output state resulting in progressively increasing combined ventricular output, polyhydramnios, placentomegaly, and hydrops resulting in death or severe preterm delivery (68). Open fetal surgery to partially resect the exophytic portion of the SCT has been successful in a handful of cases (69-71). But it has proven extremely difficult to keep the mother pregnant after open fetal surgery and prevent maternal mirror syndrome. Crombleholme and colleagues, applied the EXIT strategy to the problems of trying to get as far out in pregnancy as possible by putting a “telephone tree” in place for emergent EXIT-to-Resection for high risk SCTs. Conventional management by classical Cesarean section in these high-risk cases has resulted in hemorrhage into the tumor and arrest at the time of delivery with no survivors despite attempts at resuscitation, tourniquet of the base of the tumor and even emergent resection of the exophytic component. In 9 cases in which EXIT-to-Resection had been applied there were 8 survivors delivered between 26 and 29 weeks’ gestation. The only non-survivor whose high output state was initially palliated by ultrasound guided intravascular laser photocoagulation of feeding arterial collaterals extended the gestation to 29 weeks’. The baby succumbed to severe laryngeal stenosis with tracheal hypoplasia with the airway too small for tracheostomy tube placement at the time of EXIT (72). EXIT-to-SeparationIn parasitic conjoined twins, the twins share a single heart and there is heart failure due to the excessive load on the heart which results in the death of both twins following delivery. In these cases it is possible to separate the twins with the goal of a single survivor. EXIT-to-Separation has been employed successfully to better define the conjoined anatomy prior to cord clamping which may precipitate acute hemodynamic decompensation or to perform the separation surgery itself (73). EXIT Strategy Planning and Simulation In most centers there may be little experience with EXIT procedures or fetal surgery in general. Even in fetal surgery centers with experience with EXIT procedure there is always benefit to advance planning and, when possible, in situ simulation to better define the roles of all participants and anticipate needs for the procedure ranging from sterile equipment required, to fetal medications, and sequence of events during the EXIT procedure. Of paramount importance is the maintenance of communication between the surgical, nursing and anesthesia teams. We usually have an Obstetrical Anesthesiologist for the mother, and a Pediatric Anesthesiologist for the baby. The surgical team is usually led by either a Fetal or Pediatric Surgeon or a Maternal Fetal Medicine specialist. It is the responsibility of the EXIT procedure leader to coordinate the surgical specialists rotating in to assist with various portions of the procedure. In addition, it is the responsibility of the lead to integrate the information from the Pediatric Cardiologist on any changes in echocardiographic findings, status of uterine tone and any evidence of placental dysfunction, abruption or bleeding and communicate with Anesthesia regarding the adequacy of uterine relaxation and the anticipation of the timing of return of uterine tone near the conclusion of the EXIT procedure. The EXIT procedure leader should delegate the responsibility of starting an IV in the fetus and applying the Nelcor pulse oximeter as well as responsibility for initiation and sequence of the airway algorithm. While these tasks can be done by the Fetal and Pediatric Surgeon or Pediatric Otolaryngologist, it is ideal to have the EXIT procedure leader not tied up in specific procedures so there is no risk of losing situational awareness. If the EXIT is for airway access, then the airway algorithm in figure 15 should be followed. If a Pediatric Otolaryngologist is initially involved this may require switching out for the Pediatric Surgeon later in the algorithm. In other EXIT indications, the role and positioning around the operating table of other specialists, i.e. the Pediatric Cardiologist, Cardiac Surgeon, assistant Pediatric Surgeon and scrub assistants should be worked out in advance. It may be necessary to have one scrub team for the mother and another scrub team for the baby. Anesthesia in EXIT Procedures Maternal Anesthetic ConsiderationsMaternal safety is always the foremost concern and the risk of maternal complications must be weighed against potential benefits for the fetus. A detailed preoperative anesthetic evaluation must be performed to rule out the presence of maternal comorbidities that may increase anesthetic risk. Maternal preoperative laboratory testing should include a complete blood cell count and type and cross-match. In addition, leukocyte reduced, irradiated O negative blood, cross-matched to the mother, should be readily available for the fetus. Relevant information on prenatal imaging for the anesthesiologist includes placental location, fetal airway anatomy, baseline fetal heart rate and function, presence of fetal hydrops, results of fetal karyotyping, and estimated fetal weight for drug dosing. Unlike most Cesarean sections, EXIT procedures are performed under general anesthesia. Pre-operatively, a lumbar epidural catheter may be placed for postoperative analgesia. The patient is positioned supine on the operating table, with left uterine displacement. After adequate preoxygenation, a rapid-sequence induction is performed to facilitate endotracheal intubation. In addition to standard ASA monitors, a second large-bore intravenous access is obtained and an arterial line is inserted for close hemodynamic monitoring. General anesthesia is maintained with either volatile agents or intravenous anesthetic agents, such as propofol and remifentanil infusions. To ensure adequate uteroplacental blood flow, maternal hemodynamics are closely monitored and supported with phenylephrine and ephedrine, if necessary. Continuous fetal echocardiography is performed to monitor fetal heart rate, ventricular function, and ductal patency. Fetal bradycardia (fetal heart rate < 100 bpm) is a sign of fetal distress that warrants immediate attention. As with any fetal surgical procedure, the EXIT procedure involves the treatment of two patients: the mother and her baby. For this reason, we usually have one anesthesiologist for the mother and another for the baby. There are a number of maternal and fetal anesthesia considerations that must be managed. The physiology of pregnancy contributes to a number of maternal and fetal anesthetic risks (75). The mother is at increased risk for aspiration pneumonitis due to pregnancy-related reduction of lower esophageal sphincter pressure, the increased pressure of the gravid uterus on the stomach, and increased gastric acid production. The cardiovascular system is also affected during pregnancy. A decrease in the preload during supine positioning can cause maternal hypotension, decreased uterine artery perfusion, and thus fetal hypoxia. It is therefore important to position the mother with a left uterine displacement to maximize venous return to the heart and preserve an adequate maternal cardiac output. In pregnancy there is an expanded blood volume, but a lower hematocrit and an increase in peripheral venous capacity. Pregnancy also affects pulmonary function, with a decrease in functional residual capacity that puts the mother at an increased risk for hypoxia. Fetal Anesthetic ConsiderationsSupport of the fetus during the EXIT procedure depends entirely on the preservation of uteroplacental gas exchange. Both uterine and umbilical artery blood flow influence fetal oxygenation. Uterine artery blood flow is affected by maternal systemic blood pressure and myometrial tone. Volatile anesthetics used during the EXIT procedure not only decrease myometrial tone but also tend to decrease both maternal blood pressure and placental blood flow. This can result in a decrease in fetal oxygenation (76). Maintenance of maternal blood pressure within 10% of baseline is critical for adequate fetal oxygenation during the EXIT procedure. Maintenance of maternal blood pressure is achieved using ephedrine to counterbalance the hypotensive effects of the high concentrations of inhalational agents used in EXIT procedures. Ephedrine acts selectively on peripheral vascular resistance and sparing placental circulation (76). Uteroplacental gas exchange is also dependent on umbilical artery blood flow, which is influenced by fetal cardiac output and placental vascular resistance. Preservation of fetal cardiac output is thus important in maintaining fetal oxygenation. The cardiovascular physiology of the fetus is different from that of full-term neonates in that the cardiac output is more dependent on heart rate rather than on stroke volume. In addition, high vagal tone and low baroreceptor sensitivity cause the fetus to respond to stress with a decrease in heart rate. The fetus primarily relies on increased heart rate to increase cardiac output and blood flow redistribution in response to stress (77). This preserves oxygenation for the brain at the expense of the rest of the body. In addition to the peculiar characteristics of fetal physiology, inhalational anesthetics also cause a direct fetal myocardial depression, vasodilatation, and changes in arteriovenous shunting, all of which can lead to fetal hemodynamic instability (78). These physiologic differences and responses to anesthetic agents require continuous fetal monitoring to ensure uncompromised uteroplacental gas exchange and fetal wellbeing. The traditional inhalational anesthetic regime used during the EXIT procedure passes through two different stages. Anesthesia is at first maintained with 0.5 MAC (minimal alveolar concentration) of desflurane or sevoflurane in oxygen, and is then increased to 2 MAC before maternal incision. It is subsequently increased as needed before hysterotomy to achieve the desired relaxation of uterine tone. Often a tocolytic is given, such as magnesium sulfate, at the beginning of the procedure to augment the uterine relaxation. However, use of high doses of volatile agents has been associated with significant fetal cardiac dysfunction (78). Alternatively, supplementing volatile agents with intravenous anesthetic agents (propofol and remifentanil infusions) has allowed lowering the dose of volatile agents required for uterine relaxation, thereby minimizing fetal cardiac dysfunction (79). Subsequently, a hemostatic hysterotomy is performed using a specialized absorbable uterine stapler (Medtronic, Dublin, IR) (80). The hysterotomy site is dictated by the location of the placenta and the lower uterine segment is used if at all possible. Maintaining uterine volume is critical during an EXIT procedure to prevent cord compression and placental abruption (81). To maintain uterine volume and prevent hypothermia, warm (40oC) lactated Ringers solution is continuously infused by Level I Rapid Infusor (Avanos Medical, Alpharetta, GA) into the uterine cavity and then the fetal head, arms, and upper torso are partially delivered through the hysterotomy. Fetal anesthesia is provided primarily through the transplacental passage of the volatile anesthetics. However, this takes about an hour to reach 70% of the maternal levels. As such, before fetal incision, a cocktail is administered intramuscularly to supplement anesthesia and provide for postoperative analgesia (81). An intramuscular fetal cocktail of fentanyl (20 mcg/kg), vecuronium (0.2 mg/kg) or rocuronium (2 mg/kg), and atropine (20 mcg/kg) is administered into the fetal shoulder to ensure adequate immobilization and fetal analgesia. In addition to continuous fetal echocardiography, a pulse oximeter probe is placed on a fetal hand to monitor fetal oxygen saturation. The normal range for fetal oxygen saturation is 30–70%. Regardless of the indication for the EXIT procedure, the fetal airway should be secured first, should the EXIT procedure have to be abandoned early secondary to placental abruption, excessive uterine tone compromising uteroplacental gas exchange or evidence of prolonged fetal distress. A number of tocolytic agents can be used as an adjunct to inhalational agents, including indomethacin, terbutaline, or nitroglycerine. Indomethacin may also prevent prostaglandin-mediated increases in placental resistance independent of its effects on uterine tone (82). Maintenance of uterine volume is also important to prevent uterine contraction and placental abruption. This is accomplished by preventing the fetus from completely delivering by holding the baby in a partially delivered position both in and out of the uterus and by the use of amnioinfusion with warm Ringer’s lactate solution administered via a rapid infuser to prevent cord compression. The second critical stage of the anesthetic technique comes just before clamping of the cord and ending the EXIT procedure. During this stage, coordination between the surgical and anesthesia teams is crucial to prevent uterine atony and excessive maternal bleeding. The volatile anesthetic is decreased to 0.5 MAC or turned off entirely to allow uterine tone to return to normal. This is followed by administration of oxytocin 20 units in 500 mL of normal saline intravenously as a bolus followed by 10 units in a 1000-mL drip titrated to enhance uterine contraction. If required, further measures are taken to decrease the risk of uterine atony. These measures include uterine massage and administration of 0.25 mg Methergine and 250 µg carboprost (F2-alpha prostaglandin) via intramuscular or intravenous injection. Failure of uterine tone to return may indicate the need to activate the massive transfusion protocol and place a Bakri balloon to help tamponade the uterine hemorrhage (83). While we are not aware of any EXIT procedure related uterine atony requiring hysterectomy this should be consented as an extremely rare but possible complication of EXIT procedure. EXIT Procedure & Techniques Intraoperative Maternal and Fetal MonitoringClose maternal and fetal monitoring during the EXIT procedure aim at the anticipation and early recognition and management of problems as they arise. Maternal monitoring includes invasive arterial blood pressure monitoring (arterial line) to recognize possible maternal hypotension that will jeopardize uterine perfusion and fetal oxygen transport, continuous electrocardiography, pulse oximetry, and end-tidal CO2 monitoring (84). Continuous fetal monitoring is of paramount importance during the EXIT procedure. Fetal arterial saturation is monitored by a reflectance pulse oximeter placed on the fetal hand and wrapped with Coban to decrease ambient operating room light exposure. Normal fetal arterial saturation can range from 30% to 70%, although values greater than 40% represent adequate fetal oxygenation (85). Continuous intraoperative fetal echocardiography is also used to monitor fetal cardiovascular function (78). The use of fetal echocardiography helps to identify subtle changes such as decreased filling, decreased myocardial contractility, ductal constriction, and atrioventricular valve incompetence early before cardiac compromise leads to fetal bradycardia. These are all signs of fetal cardiac compromise that require prompt treatment. Fetal arterial or venous blood gases may be obtained through umbilical vessel puncture during periods of fetal distress to guide therapy. In most EXIT procedure intravenous access is essential to allow administration of fluids, blood, or medications for inotropic support when needed. EXIT Procedure Surgical TechniqueThe decision to enter the abdomen through a low transverse skin incision or through a midline fascial incision is based on the placental location, predicted site of hysterotomy, and the indication for performing the EXIT procedure. The incision of choice is usually a low transverse abdominal incision unless anterior position of the placenta necessitates a posterior hysterotomy. In the latter case, a midline laparotomy is required to tilt the uterus out of the abdomen. After laparotomy, the uterus is examined for adequacy of myometrial relaxation, and concentration of inhalational agents is adjusted as necessary. Before fashioning the hysterotomy, precise sonographic mapping of the placental edge is crucial to avoid placental injury and hemorrhage. A sterile intraoperative ultrasound is used to map the placental borders. This is performed while considering the position of the fetal head and neck to avoid excessive fetal manipulation after hysterotomy. Special considerations are important in cases of severe polyhydramnios or anhydramnios. In polyhydramnios, ammnioreduction is necessary to avoid underestimation of the proximity of the placental edge to the hysterotomy. In cases in which there is oligohydramnios or anhydramnios, often secondary to ruptured membranes or placental dysfunction, use of a T fasteners (Avanos Medical, Alpharetta, Georgia) to retract the myometrium facilitates the safe placement of myometrial stay sutures to create an avascular point of entry for the uterine stapler. In addition, to allow room to manipulate the fetus into a favorable position, it is sometimes necessary to decompress any accompanying fetal ascites or cystic masses. This can be achieved by using a 20- or 22-gauge spinal needle under US guidance. In some instances, the use of amnioinfusion and fetal version before hysterotomy facilitates the exposure. During EXIT procedures, hysterotomy is performed using a specially designed uterine stapler (Medtronic, Dublin, IR) to decrease the incidence of bleeding. Following hysterotomy, maintenance of uterine volume is one of the most important steps in an EXIT procedure (78,80,81). This is done to decrease the likelihood of uterine contraction and placental abruption, thus maintaining continuous maternal-fetal oxygen transfer. Ringer’s lactate solution heated to body temperature is infused by a Level I rapid infusion device (Level I H-1200, Smith Medical Inc, Minneapolis, Minnesota) after the hysterotomy to maintain the uterine volume and prevent cord compression. One member of the operative team is assigned responsibility for holding the fetus only partially delivered to preserve uterine volume. Limited exposure of the fetus during the EXIT procedure also helps in maintaining uterine volume and fetal temperature. In cases of fetal airway compromise, only the head, neck, and shoulders are exposed while keeping the remainder of the fetus and the cord intrauterine. Airway Management AlgorithmThe most important aspect of fetal airway management during an EXIT procedure is preparedness of the team for every contingency. In that one can never assume that the fetus will only require direct laryngoscopy and intubation we have developed an airway algorithm (81). In addition to the basic instruments and set-up, the following items should be available on a separate sterile airway table managed by a second scrub nurse: direct laryngoscopy supplies with Miller O and 00 blades, armored endotracheal tubes (ETT) appropriate for the size of the fetus, endotracheal tube exchangers, 2.5 and 3.0 Fr feeding tubes for surfactant administration, 2.5 or 3.0 rigid bronchoscope, a flexible bronchoscope, and a major neck tray for formal tracheostomy or mass resection and major chest tray for median sternotomy and retrograde intubation. Direct laryngoscopy and endotracheal intubation should be the first option for securing a fetal airway during EXIT procedures. In cases in which there is distortion of the normal anatomy, flexible and/or rigid bronchoscopy may be necessary to visualize and diagnose abnormal airway anatomy. The glottis is sometimes displaced cephalad above the level of the soft palate; in such cases, flexible bronchoscopy via the nares may be helpful. In other cases, mass effect may shift the glottis severely laterally from its normal midline position. An armored endotracheal tube can be placed over the flexible bronchoscope or rigid lens and can be used to place the ETT beyond the level of obstruction. In the case of large neck masses, traction by an assistant may lift the mass off the airway. This may permit an armored ETT to be passed beyond the level of obstruction. If there is severe compression by tumor, operative release of the bilateral strap muscles may allow elevation of the mass off the airway and passage of an armored ETT beyond the area of airway obstruction. Airway control is sometimes impossible even after all these maneuvers have been attempted. In this instance, retrograde intubation becomes the next option in which a tracheotomy is performed through limited neck dissection. An ETT exchanger is passed ·retrograde until seen in the oropharynx. The ETT is passed antegrade over the ETT exchanger and the tracheotomy repaired. In these cases, reflection of the mass off the airway or complete resection of the mass to facilitate formal surgical tracheostomy may be necessary. Proper positioning of the tracheostomy is extremely important, especially in cases of giant neck masses in which the trachea is often pulled out of the chest by neck hyperextension. It is not uncommon to find the carina at the level of the thoracic inlet due to the opisthotonic fetal position induced by the neck mass. Pitfalls in Performing an EXIT Procedure A number of pitfalls in performing an EXIT procedure have been described (86). Failure to adequately relax the uterus will result in compromised uteroplacental gas exchange leading to fetal hypoxia and respiratory acidosis. Uterine tone must be assessed continuously during an EXIT procedure to allow immediate action to correct excessive uterine tone. This may require increase in volatile agent or the addition of intravenous nitroglycerine. Polyhydramnios is common in many conditions for which an EXIT procedure may be indicated and will flatten the placenta making detection of the placental edge difficult to determine sonographically. This can lead to hysterotomy made through the placenta which causes significant maternal and fetal hemorrhage and may precipitate placental abruption. Reducing the amniotic fluid to near normal levels allows the placenta to plump back up making it much easier to determine the edge sonographically. If the hystertomy is started though the placental edge in error, the best course is to continue to staple across it completely to control the bleeding. Not using a uterine stapler for EXIT procedures is inadvisable as it is likely to result in excessive maternal blood loss. Fetal position during the EXIT procedure is important and may require version to have the fetal head and neck positioned near the planned hystertomy. This is especially challenging in cases of emergency EXIT procedures following spontaneous rupture of membranes. This can be addressed once the hystertomy is completed and a Level I Rapid Infusion catheter is placed to help perform an internal version to facilitate delivery of the head and neck. The Level I intravenous fluid can be heated to 40o C to keep the baby warm and avoid hypothermia during the procedure. Continuous fetal echocardiography is an essential means of fetal monitoring during the EXIT procedure which can detect evolving fetal cardiac dysfunction well before fetal bradycardia is observed. The small 7Hz probe, rather than the larger Obstetrical linear array probe should be used due to its smaller profile given the limited access to the fetal chest wall. Echocardiographic findings such as evolving atrioventricular valve incompetence, changes in contractility, or altered ductal flow patterns can be harbingers of fetal stress which can be addressed before they progress to bradycardia. The most common cause of fetal bradycardia however, is cord compression, which can be immediately addressed by shifting fetal position and turning up the infusion rate of the Level I. It is important for the safe conduct of an EXIT procedure to delegate the responsibility of maintaining the fetus only partially delivered while continuously assessing the uterine tone and the size of the placenta and look for indications of bleeding. In cases of placental abruption, there may be no external indication of hemorrhage as the blood may accumulate between the uterine wall and the detaching placenta. This is both maternal and fetal blood loss and indicates that uteroplacental gas exchange has ceased and the EXIT procedure must be terminated and the baby delivered. If the placenta is fundal in location an increase in the size of the placenta may be difficult to see, but difficulty keeping the baby in the uterus or blood welling up into the field should alert the team that abruption is occurring and the EXIT must be ended. Immediate attention to securing the fetal airway, if not already done, hand ventilation with 100% FiO2, turning off inhalational agents, and administering Oxytocin should all be effected. Because there is no guarantee how much time you have during an EXIT procedure having an adjacent Operating room set up to continue operating is advisable for most indications for EXIT procedures. An important step in every EXIT procedure regardless of the indication is the transition anticipating delivery. If this occurs too rapidly there may not be sufficient time for uterine tone to return and uterine arteries to clamp down. Turning off the inhalational agents and uterine massage will help improve uterine tone and hand ventilation of the baby with 100% FiO2 will induce the fetal umbilical arteries to clamp down minimizing maternal and fetal blood loss, respectively. If the uterine tone does not respond to these maneuvers, the cord should be clamped and the baby delivered. Continued uterine massage during delivery of placenta with infusion of methegine, carboplast and misoprostil should be administered. If unresponsive to these agents and uterine massage, the massive transfusion protocol should be activated and placement of a Bakri balloon should be employed to tamponade hemorrhage. Hysterectomy would be a last resort for bleeding complications following an EXIT procedure. Summary The EXIT procedure has enabled performing lifesaving procedures on fetuses at risk for severe airway compromise and hypoxia after birth. The indications for EXIT procedure have evolved and now include securing the airway in fetuses at risk for airway obstruction, resection of fetal lung and thoracic masses, and ECMO cannulation, while still on placental support. Ideally, patients requiring an EXIT procedure should be referred to an experienced fetal treatment center for optimal planning and management of the delivery and neonatal resuscitation. 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