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Seminars in Fetal & Neonatal Medicine 15 (2010) 3439

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Seminars in Fetal & Neonatal Medicine


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Ex-utero intrapartum therapy


Kenneth W. Liechty*
Center for Fetal Diagnosis and Treatment, Childrens Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA

s u m m a r y
Keywords: Congenital cystic adenomatoid malformation Congenital diaphragmatic hernia Congenital high airway obstruction Ex-utero intrapartum therapy Mediastinal mass Neck mass Placental support

The ex-utero intrapartum therapy (EXIT) procedure was designed to secure the airway at delivery in fetuses who had undergone tracheal occlusion for severe congenital diaphragmatic hernia. The EXIT was then adapted for deliveries where the airway may be difcult to secure, such as large neck masses or congenital high airway obstruction. Subsequently, use of EXIT has been extended to fetal anomalies where resuscitation may be compromised, including large thoracic masses, severe congenital diaphragmatic hernia, or pulmonary agenesis. The key to EXIT is preservation of uteroplacental blood ow and gas exchange, using inhalational agents to provide uterine relaxation, and maintenance of uterine volume by amnioinfusion and only partial exposure of the fetus. This provides time for procedures such as laryngoscopy, bronchoscopy, vascular access, resection of neck or lung masses, or cannulation for extracorporeal membrane circulation, in order to convert an emergent crisis to a controlled situation. 2009 Published by Elsevier Ltd.

1. Introduction The extensive use of prenatal ultrasound has resulted in the increased identication of a number of fetal malformations that have a direct impact on the perinatal management of the fetus and the subsequent outcome. The ex-utero intrapartum therapy (EXIT) procedure was initially described for the reversal of tracheal occlusion at the time of delivery in fetuses with severe congenital diaphragmatic hernia (CDH) that had undergone in-utero tracheal occlusion.1 The EXIT procedure uses maintenance of uteroplacental blood ow, or placental bypass, to provide time to reverse the tracheal occlusion by removal of the clip, to establish an airway, and to administer surfactant and resuscitative drugs. The additional time provided by the EXIT procedure was subsequently adapted for the delivery of patients where neonatal airway compromise was suspected, including fetal neck masses and fetuses with congenital high airway obstruction (CHAOS).2,3 The use of the EXIT procedure was then further expanded to include any fetal anomaly where neonatal resuscitation may be compromised, including large thoracic lesions, CDH, unilateral pulmonary agenesis, and cardiac lesions.47 The EXIT procedure provides time to secure the airway, obtain vascular access, administer surfactant and other resuscitation medications, resect cervical or thoracic masses, and for extracorporeal membrane circulation (ECMO) cannulation.27 The time provided by the EXIT procedure converts an emergent crisis into a controlled situation.

2. Prenatal evaluation In order to identify fetuses that may potential benet from the use of the EXIT procedure, early and accurate diagnosis is essential. The prenatal evaluation includes high resolution fetal ultrasonography, ultrafast fetal magnetic resonance imaging, fetal echocardiography, and karyotype analysis. In addition, the early involvement of a multidisciplinary team, including pediatric surgeons, high risk obstetricians, radiologists, anesthesiologists, neonatologists, cardiologists, operating room personnel, and social work, are equally important in planning the delivery procedure and facilitating parental understanding of the potential risks and benets of the proposed procedure.

3. Elements of the EXIT procedure The EXIT procedure is signicantly different from previous reports of intrapartum laryngoscopy or bronchoscopy in which the fetus was delivered either by cesarean section or vaginal delivery and the cord was not clamped.8,9 In these cases there was no attempt to prevent uterine contraction, and in most of these cases the fetus was removed from the uterus, resulting in uterine contraction, placental separation, and cessation of uteroplacental gas exchange.10 In the EXIT procedure, high concentrations of inhalational anesthetics and additional tocolytics, if necessary, are used to provide uterine relaxation and preserve placental perfusion. In addition, only the head and upper torso are delivered and amniotic uid volume is replaced by amnioinfusion; both maneuvers preserve uterine volume, preventing uterine contraction, and

* Tel.: 1 215 590 4511; fax: 1 215 590 3324. E-mail address: Liechty@email.cho.edu 1744-165X/$ see front matter 2009 Published by Elsevier Ltd. doi:10.1016/j.siny.2009.05.007

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EXIT Indications  Suspected airway compromise - large neck masses - CHAOS  Resuscitation compromise - large thoracic lesions - CDH - unilateral pulmonary agenesis - cardiac lesion

preserve placental blood ow. During the EXIT procedure fetal well-being is continuously monitored by pulse oximetry and echocardiography. Fig. 1 shows an EXIT procedure for a fetus with a large cervical teratoma. Many of the elements of the EXIT are demonstrated. Note that only partial delivery of the fetus is performed to maintain uterine volume. The use of the fetal pulse oximeter is also seen. In this case the fetus is undergoing rigid bronchoscopy to dene and establish an airway.

Fig. 1. Ex-utero intrapartum therapy delivery of a fetus with a large cervical teratoma. Rigid bronchoscopy is being performed to identify and secure the airway. The small arrow indicates the pulse oximeter being applied to the hand. The large arrow indicates the partial exposure of the fetus and maintenance of uterine volume.

Key Elements for the EXIT  Uterine relaxation - inhalational agents - tocolytic agents  Maintain uterine volume - amnioinfusion - partial delivery  Fetal monitoring - pulseoximetry - echogardiography  Maternal monitoring - ECG - arterial line - pulseoximetry - end tidal CO2

The details of the mechanics of the EXIT procedure have been extensively described in the literature.17 In brief, a multidisciplinary team is used and consists of two or three pediatric surgeons, an obstetrician, a neonatologist, an anesthesiologist, and two scrub nurses. The mother is positioned with left uterine displacement to maintain inferior vena cava blood ow, and pneumatic compression boots are applied. Maternal monitoring consists of invasive arterial blood pressure monitoring, continuous electrocardiography and pulse oximetry, and end-tidal CO2 monitoring. Anesthesia is induced with a rapid sequence technique using thiopental, succinylcholine, and fentanyl given intravenously followed by tracheal intubation. Anesthesia is maintained with desurane at 0.31.9% expired in a balance of oxygen, as measured by end-tidal mass spectrometry. The dose of inhalation agent is titrated to uterine relaxation to preserve uteroplacental circulation and fetal gas exchange.11 A low transverse maternal laparotomy incision is used to expose the uterus and sterile intraoperative ultrasound is used to map the position of the placenta and to monitor the fetal heart during the procedure. If polyhydramnios is present, amnioreduction is performed to decompress the uterus and avoid underestimation of the proximity of the placental edge to

the hysterotomy. Decompression of fetal ascites or large cystic masses may be performed at this time to facilitate manipulation of the fetus. While one assistant stabilizes fetal position, full-thickness uterine stay sutures are placed under ultrasound guidance. A transverse lower uterine segment hysterotomy is performed except when contraindicated because of placental location or concern about the ability to adequately position the fetus. The hysterotomy is then performed using a uterine stapling device to provide hemostasis.12 The fetal head and upper torso are then delivered through the hysterotomy. To maintain uterine volume, the lower body is left in the uterus and amniotic uid is maintained using a Level 1 uid warming device and the infusion of Ringers lactate. Although the fetus is anesthetized during the EXIT procedure from placental transfer of maternally administered anesthesia, this is supplemented by vecuronium, fentanyl, and atropine administered intramuscularly. Fetal heart rate and hemoglobin saturation are continuously monitored by a pulse oximeter attached to the fetal hand13 and by continuous echocardiography. If fetal distress occurs during the case, the position of the umbilical cord, uterine volume, and maternal bleeding are reassessed. In cases where prolonged operative times are expected or where there may be a need for fetal volume loading, as in the case of large thoracic masses, then fetal venous access is obtained with a peripheral intravenous line. The procedure on the fetus is then initiated. The procedures that can be performed during EXIT range from direct laryngoscopy, rigid bronchoscopy, and even tracheostomy to secure the fetal airway, to resections of neck masses and thoracic masses, to the placement of ECMO cannulas. Following establishment of the airway and if indicated by gestation age, surfactant is administered using a 4 French feeding tube fed through the endotracheal tube or bronchoscope to deliver it to the distal tracheobronchial tree, and ventilation is initiated. Prior to clamping of the umbilical cord and delivery of the baby, communication between the surgical and anesthesia teams is essential to prevent uterine atony and excessive maternal hemorrhage. The inhalational agent is decreased and a Pitocin bolus followed by a continuous infusion is administered and titrated to uterine tone, and the umbilical cord is then clamped and divided and the newborn taken to a separate operating room for further resuscitation, including possible placement on ECMO.

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After maternal skin closure the inhalational agent is discontinued and glycopyrrolate and neostigmine are given intravenously, and the mother is extubated when spontaneously ventilating and has protective airway reexes. 4. Uses of the EXIT procedure The EXIT procedure has been used extensively in controlling the airway. In the largest series in the literature,6 the use of the EXIT was reported in the management of 43 fetuses referred to the Center for Fetal Diagnosis and Treatment at the Childrens Hospital of Philadelphia (CHOP) from 1996 to 2002. The most common use of the EXIT procedure in this series, as well as the most common indication in the literature, is to secure the airway in the delivery of fetuses with large neck masses or CHAOS. The next most common indication was the reversal of tracheal occlusion in fetuses with congenital diaphragmatic hernia that had undergone in-utero tracheal clip application, however, this approach to tracheal occlusion is no longer being offered. Other indications included cases where neonatal resuscitation may be compromised, such as large CCAMs or thoracic masses, CDH, unilateral pulmonary agenesis, and conjoined twins. Our current recommendation for specic indications that may benet from the use of the EXIT procedure are outlined below. 4.1. Airway obstruction There is no more striking example of a fetal anomaly that directly impacts the perinatal management of a fetus than the diagnosis of fetal airway obstruction. Airway obstruction at birth is life-threatening and associated with a high mortality.7,8,14 Delays in obtaining an airway and inability to ventilate the neonate can result in hypoxia and acidosis, and if the delay is >5 min anoxic brain injury may occur.15 Fetal airway obstruction can be the direct result of intrinsic defects in the larynx or trachea, and is classied under CHAOS.3 Fetal airway obstruction can also be the indirect result of a giant fetal neck mass such as a cervical teratoma or lymphangioma compressing the trachea extrinsically.14 In each of these cases, the establishment of an accurate prenatal diagnosis of fetal airway obstruction permits the formulation of a delivery plan and use of the EXIT procedure, to optimize the outcome of the fetus. This is particularly important in fetuses with an isolated anomaly that would otherwise have a good outcome, but die as the result of an inability to secure the airway at the time of delivery.8 4.1.1. Neck masses The EXIT procedure has been used in the delivery of 19 patients with fetal neck masses referred to CHOP.6 The average gestational age at EXIT was 36.1 weeks and the average time on placental bypass was 28.9 min. There were 10 teratomas, seven lymphangiomas, one foregut duplication involving the tongue, and one goiter. Using direct laryngoscopy or rigid brochoscopy, an airway was established in 68% (13/19) of these patients (Fig. 1). In six patients the airway was unable to be obtained despite rigid brochoscopy. Three of these neonates required formal surgical tracheostomy at the time of the EXIT procedure. Two of these neonates underwent retrograde endotracheal intubation through a temporary tracheostomy after partial mass resection. The temporary tracheostomy allowed the retrograde passage of a feeding tube from the tracheal to the oropharynx. The endotracheal tube was then attached to the feeding tube and passed antegrade to the proper position. The temporary tracheotomy was then closed with ne absorbable sutures. The sixth case involved a 26 week gestation fetus with a giant cervical lymphangioma with extensive involvement of the

face. This fetus could not be intubated during the EXIT and the family had given strict directives before surgery to not perform a tracheostomy if orotracheal intubation was not possible. Overall, an airway was established in 18 of 19 neonates. The long-term survival was 89% (16/18). The two mortalities in this group were in neonates with giant cervical teratomas who died shortly after the EXIT procedure due to respiratory insufciency. On postmortem examination it was determined that the mass effect from the giant cervical teratoma had pulled the carina into the neck and wedged the lungs into the apices of the chest resulting in fatal pulmonary hypoplasia.16 4.1.2. Congenital high airway obstruction syndrome CHAOS is a rare clinical condition diagnosed prenatally where near complete or complete intrinsic obstruction of the fetal airway prevents the egress of lung uid from the tracheobronchial tree.3 There are multiple etiologies of CHAOS including: laryngeal atresia, laryngeal web, tracheal atresia, and laryngeal cyst. This obstruction results in bilateral enlarged and echogenic lungs, dilated airways, and attened or everted diaphragms and is associated with fetal ascites and non-immune hydrops.17 Most cases of CHAOS occur as sporadic, isolated malformations without a known risk of recurrence. However, a wide range of anomalies can be seen in association with laryngeal atresia, including: absent radius, anophthalmia, bronchotracheal stula, cardiac anomalies, esophageal atresia, genitourinary anomalies, hydrocephalus, imperforate anus, syndactyly, uterine anomalies, and vertebral anomalies.18 Malformations of the esophagus and trachea, including tracheoesophageal stula, allow decompression of the obstructed tracheobronchial tree and affected fetuses do not develop the typical manifestations of CHAOS including hydrops. In addition, CHAOS may be the initial presentation of the Fraser syndrome.19 Because of these associated anomalies, a detailed prenatal work-up is essential to establish the diagnosis and exclude other anomalies. In a review of the natural history of CHAOS, we reported that the prenatal prognosis of CHAOS may be less dismal than previously thought.20 In some cases, fetal hydrops may completely resolve in the third trimester as a result of decompression through a tracheolaryngeal or tracheoesophageal stula. Since the prenatal natural history of CHAOS is not completely understood, once diagnosed, a fetus with CHAOS should have frequent surveillance for the remaining period of gestation. Fetuses with CHAOS should be delivered using the EXIT procedure to provide time to perform bronchoscopy and to secure the airway, which usually requires a tracheostomy. The successful use of the EXIT procedure has been reported in the delivery of several fetuses with CHAOS,6,21 and with excellent long-term survival. 4.2. Thoracic masses The prenatal history of fetal lung lesions is variable, with some lesions undergoing rapid growth resulting in non-immune fetal hydrops and in-utero fetal demise, whereas other lesions spontaneously regress and disappear on fetal ultrasound during the third trimester.2224 This period of variable growth ranges from 18 to 28 weeks of gestation. Large fetal lung lesions exert a mass effect that results in mediastinal shift. This shift can interfere with fetal swallowing of amniotic uid resulting in polyhydramnios,25 and can also compress the contralateral lung resulting in pulmonary hypoplasia.26 In severe cases, it can lead to vena caval obstruction, cardiac compression, and fetal hydrops.25,26 Because of the variable natural history, and to stratify the risk of developing fetal hydrops, we developed the CCAM volume ratio, or

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CVR.27 The CVR uses the formula for an ellipsoid (width height length 0.523) to determine the volume and then divides this by the head circumference to standardize between differences in gestation age. This is then used to follow mass growth. CVR >1.6 at presentation correlated with the development of fetal hydrops, the need for fetal intervention, and the need for ventilatory support and ECMO, as well as the length of postnatal hospital stay and survival. Because of this correlation, fetuses with CVR >1.6 are followed biweekly for signs of impending fetal hydrops, including ascites, skin or scalp edema, pleural effusions, and placentomegaly. Impending fetal hydrops is an indication for fetal intervention, which may include open fetal surgery to resect the mass, the placement of a thoracoamniotic shunt in cases where there are dominant cysts, or early delivery using the EXIT procedure. Fetuses that have a persistent large lung mass that is present late in gestation with an elevated CVR, extensive mediastinal shift, or impending hydrops, are at risk for a difcult resuscitation and subsequent poor outcome. In this select group of patients, the use of the EXIT procedure to deliver these patients can improve outcomes. There are several key elements in the use of the EXIT procedure for fetal lung lesions. In elective cases lung maturity should be veried by amniocentesis. If polyhydramnios is present, amnioreduction should be performed to allow accurate mapping of the placental edge to prevent bleeding complications. Prior to performing the thoracotomy, intravenous access should be obtained and the fetus volume loaded under echocardiographic guidance to decrease the risk of fetal cardiovascular collapse once the mass is removed. ECMO should also be on standby if needed for support.
Fig. 2. Fetus undergoing an ex-utero intrapartum therapy (EXIT) procedure with a large type 1 congenital cystic adenomatoid malformation in the right chest. The large dominant cyst was decompressed in utero with a thoracoamniotic shunt (white arrow). This fetus had residual mass effect from the lesion and was at risk for air trapping in this cyst at birth, so resection of the lesion was performed during the EXIT procedure. In preparation for resection an airway has been established but without ventilation. Venous access has also been obtained to volume load the neonate prior to resection based on the echocardiogram. Partial exposure of the fetus is demonstrated with the black arrow indicating the cut edge of the uterus.

Key EXIT Elements in Thoracic Lesions  Lung maturity - elective cases - amniocentesis  Polyhydramnios - amnioreduction  Fetal Echogardiography - assess volume load  ECMO on standby

Fig. 2 demonstrates a fetus undergoing the EXIT procedure. This fetus has a large type 1 CCAM in the right chest. The large dominant cyst underwent decompression in utero with a thoracoamniotic shunt. This fetus had residual mass effect from the lesion and was at risk for air trapping in this large cyst at birth, so resection of the lesion was performed during the EXIT procedure. We have reported the resection of nine fetal lung lesions during the EXIT procedure in patients referred to the CHOP.4 The mean gestational age at EXIT procedure was 35.4 weeks (range: 2739) and mean birth weight was 3.2 kg (range: 1.54.0). All lung masses maintained large sizes late into gestation with mean CVR of 2.5 at presentation and 2.2 at EXIT procedure. The average time on placental bypass was 65 min (range: 5082). As a result of continuous fetal echocardiography, six of the fetuses received supplemental uids, blood transfusion, or additional medications during the EXIT procedure. Nitric oxide was initiated early for pulmonary hypertension in four cases with three of these subsequently requiring ECMO. Venoarterial ECMO was initiated in a total of four neonates, within 1 h (n 2), 20 h, and 8 days of life for high mean airway pressures. The mean ECMO duration was 369.5 h

(range: 313505) and nitric oxide was re-initiated in three cases to facilitate weaning from ECMO. All four of these patients survived. The overall survival of patients in this series undergoing lung mass resection during the EXIT procedure was 89% (8/9). The mean number of ventilator days was 34 (range: 3103) and the mean length of hospital stay was 60 days (range: 11175). The one death in the series occurred in a 27 week gestation fetus who underwent re-operation for bleeding. This fetus did achieve transient oxygen saturations above 90%, but died secondary to overwhelming sepsis and consumptive coagulopathy within 12 h of delivery. In addition to fetal lung lesions, the use of the EXIT procedure has been expanded to other space-occupying thoracic lesions. Fig. 3 demonstrates a fetus with a large mediastinal mass that compressed the airway in the chest, raising the concern for an inability to secure the airway at birth. During the EXIT procedure, this fetus underwent resection of a large mediastinal teratoma through a median sternotomy. Upon exploration, the airway was distorted and compressed by the mass, and following resection the airway was secured. 4.3. EXIT to ECMO Congenital diaphragmatic hernia (CDH) and the associated pulmonary hypoplasia remain a signicant clinical problem. We have reported our experience with 89 fetuses with CDH referred to

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4.4. Miscellaneous Other extensions of the EXIT procedure include unilateral pulmonary agenesis6 and conjoined twins.7,29 In the case of the unilateral pulmonary agenesis, which is associated with bronchial stenosis to the solitary lung, the EXIT procedure was used to secure the airway successfully. In the thoracoomphalopagus conjoined twins, one twin had a rudimentary heart and there was extensive vascular communication with the normal twin and progressive decline in the normal twins cardiac function. The EXIT procedure was used to minimize the stress on the normal twins heart and to secure the airways of both twins. 5. Complications The most serious complication of the EXIT procedure is related to the strategies used to provide uterine relaxation and maintain uteroplacental blood ow. High concentrations of inhalational anesthetic agents provide uterine relaxation which may potentially increase the risk of maternal bleeding due to uterine atony, and which in severe cases may increase the risk for hysterectomy to control bleeding. It is essential that communication occur between the surgeons and the anesthesiologists prior to the time of umbilical cord clamping to ensure prompt restoration of uterine tone. In our experience, there has been no need for emergent hysterectomy, and the mean blood loss with the EXIT procedure has been equivalent to that observed with standard cesarean sections.2 An additional maternal risk is uterine rupture during labor in subsequent pregnancies if a classical uterine incision is required for the EXIT. The low anterior transverse uterine incision is always preferred as it allows the possibility of future vaginal births but may be contraindicated by placental position. Prior to the EXIT procedure the mother should be counseled that cesarean delivery may be required for all future pregnancies. There is also potential for fetal complications during the EXIT procedure. These are primarily related to failure to preserve uteroplacental gas exchange due to cord compression, placental abruption, or loss of uterine relaxation. 6. Conclusions The EXIT procedure should be considered in cases where there is a question about the ability to obtain an airway at the time of delivery. In addition, the EXIT procedure should also be considered in cases where neonatal resuscitation may be compromised. Uteroplacental blood ow is preserved by maintaining uterine relaxation using deep inhalational anesthesia, and by maintaining uterine volume using a strategy of only partial delivery of the fetus and amnioinfusion. The EXIT approach allows time for multiple procedures to be performed, ranging from bronchoscopy to mass resection, to the placement of ECMO cannulas, thus converting a potentially fatal neonatal emergency to a controlled situation with improved outcomes.

Fig. 3. Fetus undergoing resection of a large mediastinal mass during an ex-utero intrapartum therapy procedure. The head of the fetus is at the bottom of the gure and the cut edge of the uterus is indicated by the black arrow. The mediastinal teratoma is clearly seen through the median sternotomy in the fetus.

CHOP.28 There were 20 fetuses that had a lung/head circumference ratio (LHR) <1 at 2325 weeks of gestation. Survival in this group was 35%, and 75% of the patients required ECMO. The remaining 69 fetuses with LHR >1 had a survival rate of 75% and an ECMO rate of 49%. In this report we also examined the position of the fetal liver in relation to survival and the need for ECMO. In 49 fetuses the liver was intrathoracic (55%) and the survival was 45% with an 80% ECMO rate. In the 40 fetuses with the liver in the abdomen, the survival was 93%, with only a 25% ECMO rate. Because of the poor survival rates in the low LHR group, the use of the EXIT procedure has been extended to this patient population, using the time provided by the EXIT to place ECMO cannulas and initiate ECMO support prior to clamping the umbilical cord. The rationale for this approach is that the avoidance of neonatal hypoxia, hypercapnea, hemodynamic instability, and extended neonatal resuscitation, can improve outcomes. Kunisaki and co-workers reported their experience with the EXIT in the management of fetuses with CDH.5 The fetuses selected for the EXIT to ECMO strategy had intrathoracic liver and an LHR <1.4. Eleven fetuses were placed on ECMO support during the EXIT procedure and there was a 64% survival rate reported. The EXIT to ECMO strategy has also been reported in fetuses with CDH and severe congenital heart disease, a combination which has an extremely poor prognosis.5,6 In addition, this strategy may be useful in patients with congenital heart malformations, such as hypoplastic left heart syndrome (HLHS) with a restrictive atrial septum. This would allow the neonate to be stabilized on ECMO prior to going to the catheterization laboratory. The role of EXIT to ECMO remains controversial. It is difcult to assess the actual need for ECMO in the rst few minutes of ventilation especially while the fetus is still on placental support. The studies referenced above cite a 64% survival with EXIT to ECMO. Based on liver position, this represents a potential improvement from 45%. By contrast, the LHR used in this study was <1.4, and survival rates of 75% for LHR >1 have been reported.6 This study highlights the controversial nature of this extension of the EXIT procedure and the need for more information to develop standardized patient inclusion criteria.

Practice points  The EXIT is not a cesarean section  Uterine volume is maintained to preserve uteroplacental blood ow  The EXIT provides time for multiple procedures  The EXIT converts an emergent crisis to a controlled situation

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Research directions  Identication of other situations where neonatal resuscitation may be compromised  Identify standardized criteria for the use of the EXIT to ECMO approach  Identify criteria for the EXIT approach to early delivery of compromised fetuses

Conict of interest statement None declared. Funding sources None. References


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10. McNamara H, Johnson N. The effect of uterine contractions on fetal oxygen saturation. Br J Obstet Gynaecol 1995;102:6447. 11. Embrey MP, Garret WJ, Pryer DL. Inhibitory action of halothane on contractility of human pregnant uterus. Lancet 1958;2:10934. 12. Bond SJ, Harrison MR, Slotnick RN, Anderson J, Flake AW, Adzick NS. Cesarean delivery and hysterotomy using an absorbable stapling device. Obstet Gynecol 1989;74:258. 13. Dassel AC, Graaff R, Aarnoudse JG, et al. Reectance pulse oximetry in fetal lambs. Pediatr Res 1992;31:2669. 14. Kelly MF, Berenholz L, Rizzo KA, et al. Approach for oxygenation of the newborn with airway obstruction due to a cervical mass. Ann Otol Rhinol Laryngol 1990;99:17982. 15. Dawes G. Fetal and neonatal physiology. Chicago: Year Book; 1968. 16. Liechty KW, Hedrick HL, Hubbard AM, et al. Severe pulmonary hypoplasia associated with giant cervical teratomas. J Pediatr Surg 2006;41:2303. 17. Kalache KD, Chaoui R, Tennstedt C, et al. Prenatal diagnosis of laryngeal atresia in two cases of congenital high airway obstruction syndrome (CHAOS). Prenat Diagn 1997;17:57781. 18. Feldman E, Shalev E, Weiner E, et al. Microphthalmic-prenatal ultrasound diagnosis: a case report. Prenat Diagn 1995;5:2057. 19. Schauer GM, Dunn LK, Godmilow L, et al. Prenatal diagnosis of Fraser syndrome at 18.5 weeks gestation, with autopsy ndings at 19 weeks. Am J Med Genet 1990;37:58391. 20. Lim FY, Crombleholme TM, Hedrick HL, et al. Congenital high airway obstruction syndrome: natural history and management. J Pediatr Surg 2003;38:9405. 21. Crombleholme TM, Sylvester K, Flake AW, et al. Salvage of a fetus with congenital high airway obstruction syndrome by ex utero intrapartum treatment (EXIT) procedure. Fetal Diagn Ther 2000;15:2802. 22. Adzick NS, Harrison MR, Crombleholme TM, et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998;179:8849. 23. MacGillivray TE, Adzick NS, Harrison MR, et al. Disappearing fetal lung lesions. J Pediatr Surg 1993;28:13215. 24. Winters WD, Effmann EL, Nghiam HV, et al. Disappearing fetal lung masses: importance of postnatal imaging studies. Pediatr Radiol 1997;27:5359. 25. Thorper-Beeston JG, Nicolaides KH. Cystic adenomatoid malformation of the lung: prenatal diagnosis and outcome. Prenat Diagn 1994;14:67788. 26. Adzick NS. Management of fetal lung lesions. Clin Perinatol 2003;30: 48192. 27. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformations of the lung. J Pediatr Surg 2002;37:3318. 28. Hedrick HL, Danzer E, Merchant A, et al. Liver position and lung-to-head ratio for prediction of extracorporal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia. Am J Obstet Gynecol 2007;197:422.e14. 29. Mackenzie TC, Crombleholme TM, Johnson MP, et al. The natural history of prenatally diagnosed conjoined twins. J Pediatr Surg 2002;37:3039.

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