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Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic
ORIGINAL ARTICLE
Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic Rodrigo Ruano, MD, PhD; Denise B. Klinkner, MD, MEd; Karthik Balakrishnan, MD, MPH; Victoria A. Novoa y Novoa, MD; Norman Davies, MD; Dean D. Potter, MD; William A. Carey, MD; Christopher E. Colby, MD; Amy B. Kolbe, MD; Katherine W. Arendt, MD; Leal Segura, MD; Hans P. Sviggum, MD; Maureen A. Lemens, RN; Abimbola Famuyide, MD; and Andre Terzic, MD, PhD Abstract Objective: To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH). Patients and Methods: Two cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks’ gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters. Results: Diagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support. Conclusion: The successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia. Trial Registration: clinicaltrials.gov Identifier: G170062. ª 2018 Mayo Foundation for Medical Education and Research
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egenerative medicine is an evolving field that seeks to restore organ health. To date, the primary focus has been on establishing regenerative solutions applicable postnatally.1,2 The realization that fetal therapy for certain defined clinical conditions may improve postnatal outcomes, mainly based on restoring fetal organ structure and
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function, has provided the impetus to expand the scope of regenerative medicine to prenatal interventions.3-5 A case in point is congenital diaphragmatic hernia (CDH) with severe pulmonary hypoplasia, a life-threatening anomaly that affects 1 in 3000 live births and is associated with a poor survival rate.6 Developmental defects of the diaphragm
Mayo Clin Proc. n June 2018;93(6):693-700 n https://doi.org/10.1016/j.mayocp.2018.02.026 www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research
For editorial comment, see page 673
Affiliations are at the end of this article.
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TABLE. Prenatal and Postnatal Multidisciplinary Management Protocol for Patients Undergoing Fetal Endoscopic Tracheal Occlusion at Mayo Clinic Prenatal fetal imaging
Prenatal consultations
Pre-FETO evaluation
Variable
Fetal ultrasonography for anatomic evaluation and lung measurements Fetal magnetic resonance imaging for lung measurements Fetal echocardiography Fetal karyotype/chromosomal microarray
Pre-FETO family care conference Pre-FETO simulation and briefing FETO procedure
NA NA Ultrasound and fetoscopic guidance
Post-FETO evaluation
Fetal ultrasonography for lung measurements every week Fetal ultrasonography for fetal growth every 3-4 wk Fetal echocardiography at 34 wk Fetal magnetic resonance imaging for lung measurements at 34 wk
Preeballoon removal simulation and briefing Fetal endoluminal tracheal balloon removal at around 34 wk
NA Ultrasound and fetoscopic guidance Ex utero intrapartum treatment (EXIT) procedure
Maternal-fetal surgeon Pediatric surgeon Pediatric cardiologist Neonatologist Geneticist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric otorhinolaryngologist Social worker Maternal-fetal medicine nurse practitioner Maternal-fetal medicine nurse All specialties All specialties Maternal-fetal surgeon Pediatric surgeon Pediatric otorhinolaryngologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Maternal-fetal surgeon Pediatric surgeon Pediatric cardiologist Neonatologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric otorhinolaryngologist Maternal-fetal medicine nurse practitioner Maternal-fetal medicine nurse All specialties Maternal-fetal surgeon Pediatric surgeon Pediatric otorhinolaryngologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric surgeon Neonatologist Pediatric otorhinolaryngologist Pediatric cardiologist
Postnatal follow-up
NA
FETO ¼ fetal endoscopic tracheal occlusion; NA ¼ not applicable.
cause abdominal viscera to herniate into the chest, compromising lung development.6 High morbidity and mortality are primarily due to pulmonary hypoplasia, a decrease in size and volume of the lungs associated with elevated neonatal respiratory distress, pulmonary arterial hypertension, and neonatal mortality.7-9 Fetoscopic tracheal occlusion (FETO) has been proposed for isolated severe CDH.10 The procedure is performed percutaneously with ultrasound-guided uterine access and fetoscopic deployment of a detachable tracheal 694
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balloon at 26 to 30 weeks of gestation.11,12 Preclinical and clinical studies have found that the occluded trachea optimizes parenchymal growth, improving pulmonary hypoplasia and vascular remodeling.13 In fact, collective experience has suggested that fetuses with severe isolated CDH have higher survival rates after FETO than those treated only postnatally.11,14 The growing body of evidence provides the basis for advancing the use of FETO as a genuine regenerative therapy for restoring fetal lung growth.
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The objective of this study is to share our initial experience with a FETO-based care program at Mayo Clinic as a prototype regenerative surgery intervention in utero. To execute this project, a complementary multidisciplinary team, including specialists in fetal regenerative medicine and surgery, pediatric anesthesiology, pediatric surgery, pediatric otolaryngology, neonatology, obstetric anesthesiology, and maternal-fetal medicine, was activated. PATIENTS AND METHODS The Institutional Review Board at Mayo Clinic in Rochester, Minnesota, approved the present study (IRB 16-008720) that was declared at clinicaltrials.gov (Identifier: G170062). Inclusion criteria for FETO were (1) singleton pregnancy, (2) isolated left-sided diaphragmatic hernia (no associated structural or chromosomal abnormality), (3) severe pulmonary hypoplasia (observed-to-expected lung area to head circumference ratio [o/e-LHR], <25%) with liver herniation, (4) gestational age less than 29 weeks and 6 days at the time of intervention, and (5) cervical length greater than 15 mm. Specific exclusion criteria were mothers not able to consent in full and maternal coexisting disease (arterial hypertension, diabetes, preeclampsia, history of premature delivery). The Table presents the prenatal and postnatal multidisciplinary management protocol for patients undergoing FETO at Mayo Clinic. FETO was offered between 26 weeks and 29 weeks, per Mayo Clinic Fetal Diagnostic and Therapeutic Center protocol. Figure 1 illustrates the FETO procedure. Before the procedure, cefazolin, gentamicin, and metronidazole were administered intravenously (IV) for infection prophylaxis. Local maternal anesthesia was provided by injecting 10 mL of 1% lidocaine to maternal skin. Maternal sedation was provided with IV propofol (up to 130 mg/kg per minute) and intermittent IV fentanyl totaling 100 mg. Fetal anesthesia was provided by intramuscular injection of fentanyl (5-10 mg/kg), vecuronium (200 mg/kg), and atropine (20 mg/kg) under ultrasound guidance. Under ultrasound guidance, the fetus was gently positioned to have the fetal mouth facing the ultrasound probe by transabdominal manipulations. An 11F catheter (Cook Medical) was inserted through Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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FIGURE 1. Key steps in the fetoscopic tracheal occlusion procedure. A, Percutaneous introduction of fetoscope into the amniotic cavity and towards the fetal mouth under ultrasound guidance. B, Advancement of the detachable balloon into the fetal trachea. C, Inflation of fetal endoluminal tracheal balloon through the microcatheter. D, Detachment of fetal endoluminal balloon positioned in trachea.
the abdominal wall under ultrasound guidance into the uterus directly over the fetal mouth. A 1.3-mm fetoscope was placed into the sheath and advanced until the fetal mouth was seen. The mouth and tongue were identified, and the scope was advanced inside the fetal trachea (Figure 2A and B). The balloon was inflated with 0.8 mL of sterile water and detached (Figure 2C). After confirming the correct position of the balloon inside the fetal trachea with ultrasound (Figure 2D), the scope was then removed. Fetal well-being was monitored every 2 weeks with ultrasonography once the patient was discharged from the hospital. Fetal lung size was estimated by measuring the o/eLHR. The lung to head ratio was calculated using the longest axis method; lung area was calculated by multiplication of the longest diameter of the lung by its longest perpendicular diameter.15 Then the area of the lung was divided by the head circumference. The o/eLHR values were calculated using established nomograms.16 Magnesium sulfate (6 g loading dose, 2 g/h continuously) was initiated near the end of the procedure after optimal balloon placement was noted and the scope was removed, and it was continued for postoperative tocolysis with a gradual decrease over the course of 24 hours after surgery. If the patient presented with contractions after this period, magnesium
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and removal, gestational age at delivery, and postnatal outcome. RESULTS
FIGURE 2. Fetoscopic tracheal occlusion procedure. A, Fetoscopic view of the fetal mouth. IL ¼ inferior lip of the fetus; P ¼ fetal palate; To ¼ fetal tongue. B, Fetoscopic view of the fetal trachea (T). C, Fetoscopic view of the fetal endotracheal balloon (red arrow). D, Parasagittal ultrasound image of fetal chest identifying the balloon inside the fetal trachea (red arrows).
sulfate was re-introduced until contractions ceased. Once magnesium sulfate was discontinued, prophylactic tocolysis was maintained with nifedipine, 10 mg 3 times a day, for the duration of the pregnancy. Postoperatively, prophylactic cefazolin was continued for 24 hours. Removal of the balloon was planned at 34 weeks preferentially through direct visualization of the balloon through fetoscopic procedure. We also simulated urgent/emergent removal of the balloon by ex utero intrapartum therapy (EXIT procedure) as well as ultrasound-guided puncture of the balloon. The EXIT procedure is a modification of cesarean delivery that consists of delivering the head and partially the chest of the fetus while maintaining fetal-placental circulation as the tracheal occlusion balloon is removed and the neonatal airway is controlled, usually with endotracheal intubation. The following information was evaluated: gestational age at procedure, o/e-LHR growth, maternal and obstetric complications, technical aspects of the balloon placement 696
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Case 1 A 26-year-old patient (gravida 4, para 1; 1 previous spontaneous vaginal delivery) was referred to our center at 20 weeks of gestation with a diagnosis of left-sided CDH. The 20-week ultrasound examination revealed an isolated severe form of left-sided CDH; fetal echocardiography confirmed dextroposition of the heart with situs solitus of the atria and no other abnormalities. At 23 weeks, fetal magnetic resonance imaging (MRI) revealed left CDH with herniation of the stomach, bowel, left lobe of the liver, and spleen. The MRI estimated a total lung volume of 10.2 mL (observed-to-expected total lung volume ratio of 34%, with the expected total lung volume calculated using the Rypens formula).17 Amniocentesis was performed and results were within normal limits. At 28 weeks and 5 days, the o/e-LHR was 20.3%. FETO was performed at 28 weeks and 6 days without any complications. Figure 1 depicts key steps of the procedure. First, percutaneous introduction of the fetoscope into the amniotic cavity under ultrasound guidance (Figure 1A), followed by placement of the detachable balloon into the fetal trachea (Figure 1B-D). Both the mother and the fetus tolerated the procedure well. At 30 weeks and 3 days, ultrasound imaging showed good fetal pulmonary response to the FETO procedure with an o/e LHR of 34.6%. Polyhydramnios was noted, which persisted until delivery. At 33 weeks and 4 days, a large chorioamniotic separation throughout the uterus was diagnosed on routine ultrasonography. Magnetic resonance imaging confirmed severe chorioamniotic separation. The patient was admitted to the hospital, and betamethasone was administered. She remained asymptomatic. Because of the extremely large chorioamniotic separation, a fetoscopic procedure to remove the balloon became technically challenging because of the difficulty of perforating the floating membrane. The decision was made to perform ultrasound-guided puncture of the balloon. The balloon was successfully punctured under ultrasound guidance at 35 weeks and
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4 days using a 22-gauge needle (Figure 3). Follow-up ultrasonography showed no evidence of the balloon inside the fetal trachea. The patient was discharged from the hospital 2 days after the balloon puncture procedure. By 36 weeks and 5 days, the o/e-LHR had increased to 62.7%. At 38 weeks and 6 days, 10 weeks after tracheal balloon placement and 3 weeks after balloon puncture, the patient underwent spontaneous labor. A liveborn female weighing 3810 g with an Apgar score of 3 at 1 minute and 7 at 5 minutes was delivered vaginally. Both mother and baby were in stable condition at the conclusion of the procedure. The infant was orotracheally intubated after delivery because of the known diagnosis of left CDH and was transferred to the neonatal intensive care unit. The neonate had development of mild systemic hypotension and pulmonary hypertension, which was treated with 3 days of dopamine support as well as hydrocortisone. On serial echocardiography, pulmonary hypertension improved from suprasystemic pressures with moderate right ventricular enlargement to mild septal flattening preoperatively. A large left-sided anterior diaphragmatic defect was diagnosed intraoperatively, which was repaired using a GORE-TEX mesh (W.L. Gore & Associates) 6 days after delivery. Interestingly, our first patient had a large left anterior defect mimicking left lateral-posterior CDHs. Usually, the anterior diaphragmatic defects have better prognosis with different findings on fetal ultrasonography and MRI than our patient had. She was extubated 3 days after the surgery, and continuous positive airway pressure was discontinued 8 days later. A small atrial septal defect was also diagnosed; however, no medical management was required. Thirty-three days after delivery, she was discharged home on room air. At 3 months of age, she is on room air with no respiratory symptoms and is gaining weight appropriately with no early signs of developmental concerns.
Case 2 A 23-year-old patient (gravida 3, para 2) was referred to our center at 22 weeks of gestation with a diagnosis of left-sided CDH. Her previous obstetric history included 2 Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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FIGURE 3. Case 1. Axial ultrasound imaging of fetal neck showing the 22-gauge needle (red arrows) puncturing the fetal endotracheal balloon at 35 weeks and 4 days. FT ¼ fetal thyroid gland; Nt ¼ needle tip; Nv ¼ fetal neck vessels (carotid artery and jugular vein).
uncomplicated pregnancies that resulted in vaginal deliveries at term. Fetal ultrasonography at 22 weeks revealed an isolated severe form of left-sided CDH, with o/e LHR of 23%. Amniotic fluid was within normal limits, and the placenta was located anteriorly. Fetal echocardiography at the same time revealed dextroposition of the heart and no other abnormalities. Magnetic resonance imaging at 24 weeks established that the hernia contained a distended stomach, nondilated bowel, left hepatic lobe, and spleen. The total lung volume was calculated at 14.1 mL with an observed-to-expected total fetal lung volume of 47% (using Rypens formula).17 At 28 weeks and 2 days of gestation, FETO was performed successfully (Figure 1). However, the initial balloon was placed too far distal, resulting in right mainstem bronchial occlusion. Because the balloon was not optimally positioned and the airway developed minor bleeding when attempting the balloon removal, the decision was made to insert a second balloon with the aim of achieving the optimal tracheal occlusion. Accordingly, a successful tracheal balloon placement was accomplished during the same procedure. Both the mother and fetus were stable at the conclusion of the procedure. Prophylactic antibiotics and tocolysis were initiated according to the protocol. On postoperative day 2, chorioamniotic separation measuring 7.3 1.3 cm located at the uterine
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Observed/expected lung to head ratio according to gestational age
Observed/expected lung to head ratio (%)
70.0 59.6
60.0
62.7 52.4
52.3
50.0
51.2
49.9
40.0 29.9
30.0
34.6
29.4
23.0 20.0
20.3 Patient 1 Patient 2
10.0 0.0 22.0
24.0
26.0
28.0 30.0 32.0 Gestational age (wk)
34.0
36.0
FIGURE 4. Trend of lung growth in both fetuses after fetoscopic tracheal occlusion procedure.
puncture site was observed. One balloon was noted at the fetal trachea; the other was located in the proximal aspect of the right bronchus. The patient was managed conservatively, monitored as an inpatient because of the risk of membrane rupture, and discharged from the hospital on postoperative day 6. At 30 weeks and 1 day gestation, the patient complained of irregular uterine contractions. She was hospitalized and magnesium sulfate was initiated for tocolysis and fetal neuroprotection per protocol. The contractions ceased, and she was discharged home after 1 day. At 32 weeks and 2 days, 4 weeks after tracheal balloon placement, she presented with preterm premature rupture of membranes. Ultrasonography at admission revealed polyhydramnios (amniotic fluid index, 28 cm; maximum vertical pocket, 10.6 cm) and an o/e-LHR of 52.4%. There were no signs of maternal or fetal distress; however, the patient had vaginal bleeding and cervical change, so after 1 dose of betamethasone, the decision was made to proceed with delivery by EXIT procedure because of the presence of 2 balloons inside the fetal trachea and right bronchus. The EXIT procedure was performed at 32 weeks and 3 days with a pediatric 698
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otolaryngologist performing rigid bronchoscopy and tracheal balloon removal before delivery. One balloon was identified in the midtrachea and the other in the right mainstem bronchus. Both were punctured and removed without difficulty. The infant had mild tracheomegaly and proximal right bronchomegaly. A 3.5 micro-cuffed tube was used for intubation after allowing pulmonary fluid to drain. A live-born 2720-g male with an Apgar score of 6 at 1 minute and 8 at 5 minutes was delivered. He was transferred to neonatal intensive care unit. The mother was discharged home after 3 days. The neonate had a large posterior left diaphragmatic hernia repaired 5 days after delivery with a GORE-TEX mesh patch. He had development of mild systemic pulmonary hypertension (right ventricular systolic pressure of 54 mm Hg), which necessitated 3 days of dopamine support. Interval airway endoscopy before extubation revealed mild tracheomalacia and bronchomalacia. Seventeen days after CDH repair, he was successfully extubated. Forty-one days after delivery, he was safely discharged home with 1/8 L supplemental oxygen at the corrected gestational age of 38 weeks and 1 day. At 3 months of age, he is on room air and is feeding, growing, and gaining weight well. He has no respiratory symptoms apart from an intermittent brassy cough suggestive of mild tracheomalacia. Regenerative Outcome Regenerative outcome was demonstrated by substantial fetal lung growth and reversal of severe pulmonary hypoplasia. Specifically, lung growth essentially doubled in one fetus and increased by a third in the other fetus, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2 (Figure 4). DISCUSSION This article reports our initial successful experience with the implementation of a multidisciplinary FETO program as part of the build-out of a fetal regenerative medicine service at Mayo Clinic.18 We demonstrated the feasibility and safety of FETO in our patients, along with substantial fetal lung growth after FETO in line with clinically
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demonstrable regenerative outcomes following execution of an in utero intervention. Critical in the success of implementing FETO care is the deployment of a multidisciplinary team proficient in addressing in tandem the concomitant needs of mother and fetus.10,11,18 A well-coordinated group, orchestrated by a fetal regenerative specialist, includes maternal fetal medicine specialists, pediatric surgeons, otolaryngologists, neonatologists, anesthesiologists, and radiologists to provide adequate prenatal and postnatal care and achieve optimal prenatal, perinatal, and postnatal results. Moreover, it is vital to perform FETO in an advanced medical center that provides necessary resources, infrastructure, and expertise for intense management a newborn with an obstructed airway. Given the complexity and novelty of the techniques involved with fetal intervention in CDH and the logistics required to organize a trained, dedicated, and efficient transdisciplinary team led by a surgeon with experience in FETO, this report ultimately offers an example of how to deploy a shared prenatal regenerative service. Previous studies reported expansion of fetal lung and improvement of pulmonary vascularization after FETO in severe CDH, which directly correlates with better postnatal outcomes suggestive of a regenerative outcome within the favorable prenatal period for organ repair.5,14 Also, as previously suggested, o/eLHR provides an important prediction of survival in patients with CDH.19,20 Our results demonstrate substantial increase of o/e-LHR in both fetuses after FETO (an increase of 42.4 percentage points in case 1 and 29.4 percentage points in case 2). Balloon removal remains one of the limitations of the procedure, and the method for removal depends on operator preference and clinical conditions. Usually it is preferred to remove the balloon in utero via fetoscopy. Percutaneous ultrasound-guided needle puncture can be another option when used by an experienced practitioner. We describe a situation in which the fetoscopic removal of the balloon was technically impossible because it was not possible to introduce a trocar and a fetoscope inside a large chorion-amniotic separation. Therefore, percutaneous ultrasound-guided puncture of the balloon was considered a safe option. A recent Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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study suggested that in utero balloon removal, either by fetoscopy or ultrasound-guided puncture, does not cause immediate rupture of membranes or premature labor.21 Balloon removal can also be facilitated by establishing airway control on placental circulation to remove the balloon via an EXIT delivery procedure. This may be particularly helpful in an urgent scenario in which delivery of the fetus with the occluded trachea is imminent or in patients in whom balloon location in the more distal trachea or bronchus precludes safe needle puncture. Intervening with FETO between 26 and 30 weeks has been reported to increase fetal pulmonary size and vascularity and neonatal survival.5,12,14,22 Our study confirms these findings, intervening at 28.3 and 28.9 weeks. Prevention of preterm labor is also fundamental to the success of the surgery.11 A European cohort with 210 patients had a mean interval from balloon placement to delivery of 8.2 weeks. The gestational age at delivery ranged from 25.7 to 41.0 weeks (median, 35.3 weeks) and was before 34 weeks in 65 (30.9%) cases.19 A randomized controlled trial with 41 patients reported that despite the high incidence of prematurity (50.0%) and preterm premature rupture of the membranes (35.0%), FETO was associated with better perinatal outcome for infant survival at 6 months (50% [10 of 20 patients] vs 4.8% [1 of 21]).14 Similarly, a European cohort that included 210 cases estimated that in fetuses with left-sided CDH treated with FETO, the survival rate increased from 24.1% to 49.1%, and overall, 48% of infants were discharged from the hospital alive. They also reported a median delivery gestational age of 35.3 weeks, with 31% of the total cases delivered before 34 weeks.19 Our results provide further support to the validity of FETO-based care with our patients at Mayo Clinic delivered at 32.4 and 38.9 weeks, and both of them discharged from the hospital less than 45 days after delivery. CONCLUSION This article documents that FETO promotes fetal lung growth and reverse severe pulmonary hypoplasia in the setting of severe CDH. Our study provides a novel concept of using FETO-induced fetal lung growth as a regenerative outcome end point. This practical
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clinical end point may be useful to evaluate outcomes and, more generally, success of novel therapies. Our clinical experience thus provides a blueprint for future roll-out of fetal regenerative services focusing on improving prenatal care of a spectrum of congenital conditions including, beyond CDH, spina bifida, lower urinary tract obstruction, and severe cardiac anomalies. ACKNOWLEDGMENTS We thank Ms Jan H. Case for her work in preparing the illustrations and Mr Mark A. Wentworth for supporting the IDE application. Abbreviations and Acronyms: CDH = congenital diaphragmatic hernia; EXIT = ex utero intrapartum therapy; FETO = fetoscopic tracheal occlusion; IV = intravenous; o/e-LHR = observed-to-expected lung area to head circumference ratio; MRI = magnetic resonance imaging Affiliations: From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology (R.R., V.A.N.N., N.D., M.A.L., A.F.), Center for Regenerative Medicine (R.R., A.T.), Division of Pediatric Surgery, Department of Surgery (D.B.K., D.D.P.), Department of Otorhinolaryngology (K.B.), Division of Neonatal Medicine, Department of Pediatric and Adolescent Medicine (W.A.C., C.E.C.), Department of Radiology (A.B.K.), and Department of Anesthesiology and Perioperative Medicine (K.W.A., L.S., H.P.S.), Mayo Clinic, Rochester, MN. Grant Support: This work was supported by grant RMM 102516008 from the State of Minnesota. Dr Ruano is a recipient of the Regenerative Medicine Minnesota Clinical Trial grant: “Fetoscopic Regenerative Therapy for Severe Pulmonary Hypoplasia e A Feasibility Pre-Randomized Control Trial Study.” Potential Competing Interests: The authors report no competing interests. Correspondence: Address to Rodrigo Ruano, MD, PhD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (ruano.rodrigo@mayo. edu).
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4. Ruano R, Sananes N, Wilson C, et al. Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity. Ultrasound Obstet Gynecol. 2016;48(4):476-482. 5. Ruano R, da Silva MM, Campos JA, et al. Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia. Obstet Gynecol. 2012;119(1): 93-101. 6. Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia: epidemiology and outcome. Clin Perinatol. 1996;23(4):671-688. 7. Britto IS, Sananes N, Olutoye OO, et al. Standardization of sonographic lung-to-head ratio measurements in isolated congenital diaphragmatic hernia: impact on the reproducibility and efficacy to predict outcomes. J Ultrasound Med. 2015; 34(10):1721-1727. 8. Ruano R, Aubry MC, Barthe B, Mitanchez D, Dumez YB, Benachi A. Predicting perinatal outcome in isolated congenital diaphragmatic hernia using fetal pulmonary artery diameters. J Pediatr Surg. 2008;43(4):606-611. 9. Ruano R, Martinovic J, Aubry MC, Dumez Y, Benachi A. Predicting pulmonary hypoplasia using the sonographic fetal lung volume to body weight ratiodhow precise and accurate is it? Ultrasound Obstet Gynecol. 2006;28(7):958-962. 10. Deprest J, Gratacos E, Nicolaides KH; FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results [published correction appears in Ultrasound Obstet Gynecol. 2004;24(5):594]. Ultrasound Obstet Gynecol. 2004;24(2):121-126. 11. Belfort MA, Olutoye OO, Cass DL, et al. Feasibility and outcomes of fetoscopic tracheal occlusion for severe left diaphragmatic hernia. Obstet Gynecol. 2017;129(1):20-29. 12. Ruano R, Duarte SA, Pimenta EJ, et al. Comparison between fetal endoscopic tracheal occlusion using a 1.0-mm fetoscope and prenatal expectant management in severe congenital diaphragmatic hernia. Fetal Diagn Ther. 2011;29(1):64-70. 13. Khan PA, Cloutier M, Piedboeuf B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am J Med Genet C Semin Med Genet. 2007;145C(2):125-138. 14. Ruano R, Yoshisaki CT, Da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. 2012;39(1):20-27. 15. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31(1):148-151. 16. Jani JC, Peralta CF, Nicolaides KH. Lung-to-head ratio: a need to unify the technique. Ultrasound Obstet Gynecol. 2012;39(1):2-6. 17. Rypens F, Metens T, Rocourt N, et al. Fetal lung volume: estimation at MR imagingdinitial results. Radiology. 2001;219(1): 236-241. 18. Deprest J, Jani J, Cannie M, et al. Prenatal intervention for isolated congenital diaphragmatic hernia [published correction appears in Curr Opin Obstet Gynecol. 2006;18(3):354]. Curr Opin Obstet Gynecol. 2006;18(2):203-215. 19. Jani JC, Nicolaides KH, Gratacós E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009;34(3):304-310. 20. Jani J, Nicolaides KH, Benachi A, et al. Timing of lung size assessment in the prediction of survival in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol. 2008;31(1):37-40. 21. Jiménez JA, Eixarch E, DeKoninck P, et al. Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia. Am J Obstet Gynecol. 2017;217(1):78.e1-78.e11. 22. Deprest JA, Flemmer AW, Gratacos E, Nicolaides KH. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2009;14(1):8-13.
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Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic Rodrigo Ruano, MD, PhD; Denise B. Klinkner, MD, MEd; Karthik Balakrishnan, MD, MPH; Victoria A. Novoa y Novoa, MD; Norman Davies, MD; Dean D. Potter, MD; William A. Carey, MD; Christopher E. Colby, MD; Amy B. Kolbe, MD; Katherine W. Arendt, MD; Leal Segura, MD; Hans P. Sviggum, MD; Maureen A. Lemens, RN; Abimbola Famuyide, MD; and Andre Terzic, MD, PhD Abstract Objective: To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH). Patients and Methods: Two cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks’ gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters. Results: Diagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support. Conclusion: The successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia. Trial Registration: clinicaltrials.gov Identifier: G170062. ª 2018 Mayo Foundation for Medical Education and Research
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egenerative medicine is an evolving field that seeks to restore organ health. To date, the primary focus has been on establishing regenerative solutions applicable postnatally.1,2 The realization that fetal therapy for certain defined clinical conditions may improve postnatal outcomes, mainly based on restoring fetal organ structure and
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function, has provided the impetus to expand the scope of regenerative medicine to prenatal interventions.3-5 A case in point is congenital diaphragmatic hernia (CDH) with severe pulmonary hypoplasia, a life-threatening anomaly that affects 1 in 3000 live births and is associated with a poor survival rate.6 Developmental defects of the diaphragm
Mayo Clin Proc. n June 2018;93(6):693-700 n https://doi.org/10.1016/j.mayocp.2018.02.026 www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research
For editorial comment, see page 673
Affiliations are at the end of this article.
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TABLE. Prenatal and Postnatal Multidisciplinary Management Protocol for Patients Undergoing Fetal Endoscopic Tracheal Occlusion at Mayo Clinic Prenatal fetal imaging
Prenatal consultations
Pre-FETO evaluation
Variable
Fetal ultrasonography for anatomic evaluation and lung measurements Fetal magnetic resonance imaging for lung measurements Fetal echocardiography Fetal karyotype/chromosomal microarray
Pre-FETO family care conference Pre-FETO simulation and briefing FETO procedure
NA NA Ultrasound and fetoscopic guidance
Post-FETO evaluation
Fetal ultrasonography for lung measurements every week Fetal ultrasonography for fetal growth every 3-4 wk Fetal echocardiography at 34 wk Fetal magnetic resonance imaging for lung measurements at 34 wk
Preeballoon removal simulation and briefing Fetal endoluminal tracheal balloon removal at around 34 wk
NA Ultrasound and fetoscopic guidance Ex utero intrapartum treatment (EXIT) procedure
Maternal-fetal surgeon Pediatric surgeon Pediatric cardiologist Neonatologist Geneticist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric otorhinolaryngologist Social worker Maternal-fetal medicine nurse practitioner Maternal-fetal medicine nurse All specialties All specialties Maternal-fetal surgeon Pediatric surgeon Pediatric otorhinolaryngologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Maternal-fetal surgeon Pediatric surgeon Pediatric cardiologist Neonatologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric otorhinolaryngologist Maternal-fetal medicine nurse practitioner Maternal-fetal medicine nurse All specialties Maternal-fetal surgeon Pediatric surgeon Pediatric otorhinolaryngologist Maternal anesthesiologist Pediatric/fetal anesthesiologist Pediatric surgeon Neonatologist Pediatric otorhinolaryngologist Pediatric cardiologist
Postnatal follow-up
NA
FETO ¼ fetal endoscopic tracheal occlusion; NA ¼ not applicable.
cause abdominal viscera to herniate into the chest, compromising lung development.6 High morbidity and mortality are primarily due to pulmonary hypoplasia, a decrease in size and volume of the lungs associated with elevated neonatal respiratory distress, pulmonary arterial hypertension, and neonatal mortality.7-9 Fetoscopic tracheal occlusion (FETO) has been proposed for isolated severe CDH.10 The procedure is performed percutaneously with ultrasound-guided uterine access and fetoscopic deployment of a detachable tracheal 694
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balloon at 26 to 30 weeks of gestation.11,12 Preclinical and clinical studies have found that the occluded trachea optimizes parenchymal growth, improving pulmonary hypoplasia and vascular remodeling.13 In fact, collective experience has suggested that fetuses with severe isolated CDH have higher survival rates after FETO than those treated only postnatally.11,14 The growing body of evidence provides the basis for advancing the use of FETO as a genuine regenerative therapy for restoring fetal lung growth.
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The objective of this study is to share our initial experience with a FETO-based care program at Mayo Clinic as a prototype regenerative surgery intervention in utero. To execute this project, a complementary multidisciplinary team, including specialists in fetal regenerative medicine and surgery, pediatric anesthesiology, pediatric surgery, pediatric otolaryngology, neonatology, obstetric anesthesiology, and maternal-fetal medicine, was activated. PATIENTS AND METHODS The Institutional Review Board at Mayo Clinic in Rochester, Minnesota, approved the present study (IRB 16-008720) that was declared at clinicaltrials.gov (Identifier: G170062). Inclusion criteria for FETO were (1) singleton pregnancy, (2) isolated left-sided diaphragmatic hernia (no associated structural or chromosomal abnormality), (3) severe pulmonary hypoplasia (observed-to-expected lung area to head circumference ratio [o/e-LHR], <25%) with liver herniation, (4) gestational age less than 29 weeks and 6 days at the time of intervention, and (5) cervical length greater than 15 mm. Specific exclusion criteria were mothers not able to consent in full and maternal coexisting disease (arterial hypertension, diabetes, preeclampsia, history of premature delivery). The Table presents the prenatal and postnatal multidisciplinary management protocol for patients undergoing FETO at Mayo Clinic. FETO was offered between 26 weeks and 29 weeks, per Mayo Clinic Fetal Diagnostic and Therapeutic Center protocol. Figure 1 illustrates the FETO procedure. Before the procedure, cefazolin, gentamicin, and metronidazole were administered intravenously (IV) for infection prophylaxis. Local maternal anesthesia was provided by injecting 10 mL of 1% lidocaine to maternal skin. Maternal sedation was provided with IV propofol (up to 130 mg/kg per minute) and intermittent IV fentanyl totaling 100 mg. Fetal anesthesia was provided by intramuscular injection of fentanyl (5-10 mg/kg), vecuronium (200 mg/kg), and atropine (20 mg/kg) under ultrasound guidance. Under ultrasound guidance, the fetus was gently positioned to have the fetal mouth facing the ultrasound probe by transabdominal manipulations. An 11F catheter (Cook Medical) was inserted through Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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FIGURE 1. Key steps in the fetoscopic tracheal occlusion procedure. A, Percutaneous introduction of fetoscope into the amniotic cavity and towards the fetal mouth under ultrasound guidance. B, Advancement of the detachable balloon into the fetal trachea. C, Inflation of fetal endoluminal tracheal balloon through the microcatheter. D, Detachment of fetal endoluminal balloon positioned in trachea.
the abdominal wall under ultrasound guidance into the uterus directly over the fetal mouth. A 1.3-mm fetoscope was placed into the sheath and advanced until the fetal mouth was seen. The mouth and tongue were identified, and the scope was advanced inside the fetal trachea (Figure 2A and B). The balloon was inflated with 0.8 mL of sterile water and detached (Figure 2C). After confirming the correct position of the balloon inside the fetal trachea with ultrasound (Figure 2D), the scope was then removed. Fetal well-being was monitored every 2 weeks with ultrasonography once the patient was discharged from the hospital. Fetal lung size was estimated by measuring the o/eLHR. The lung to head ratio was calculated using the longest axis method; lung area was calculated by multiplication of the longest diameter of the lung by its longest perpendicular diameter.15 Then the area of the lung was divided by the head circumference. The o/eLHR values were calculated using established nomograms.16 Magnesium sulfate (6 g loading dose, 2 g/h continuously) was initiated near the end of the procedure after optimal balloon placement was noted and the scope was removed, and it was continued for postoperative tocolysis with a gradual decrease over the course of 24 hours after surgery. If the patient presented with contractions after this period, magnesium
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and removal, gestational age at delivery, and postnatal outcome. RESULTS
FIGURE 2. Fetoscopic tracheal occlusion procedure. A, Fetoscopic view of the fetal mouth. IL ¼ inferior lip of the fetus; P ¼ fetal palate; To ¼ fetal tongue. B, Fetoscopic view of the fetal trachea (T). C, Fetoscopic view of the fetal endotracheal balloon (red arrow). D, Parasagittal ultrasound image of fetal chest identifying the balloon inside the fetal trachea (red arrows).
sulfate was re-introduced until contractions ceased. Once magnesium sulfate was discontinued, prophylactic tocolysis was maintained with nifedipine, 10 mg 3 times a day, for the duration of the pregnancy. Postoperatively, prophylactic cefazolin was continued for 24 hours. Removal of the balloon was planned at 34 weeks preferentially through direct visualization of the balloon through fetoscopic procedure. We also simulated urgent/emergent removal of the balloon by ex utero intrapartum therapy (EXIT procedure) as well as ultrasound-guided puncture of the balloon. The EXIT procedure is a modification of cesarean delivery that consists of delivering the head and partially the chest of the fetus while maintaining fetal-placental circulation as the tracheal occlusion balloon is removed and the neonatal airway is controlled, usually with endotracheal intubation. The following information was evaluated: gestational age at procedure, o/e-LHR growth, maternal and obstetric complications, technical aspects of the balloon placement 696
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Case 1 A 26-year-old patient (gravida 4, para 1; 1 previous spontaneous vaginal delivery) was referred to our center at 20 weeks of gestation with a diagnosis of left-sided CDH. The 20-week ultrasound examination revealed an isolated severe form of left-sided CDH; fetal echocardiography confirmed dextroposition of the heart with situs solitus of the atria and no other abnormalities. At 23 weeks, fetal magnetic resonance imaging (MRI) revealed left CDH with herniation of the stomach, bowel, left lobe of the liver, and spleen. The MRI estimated a total lung volume of 10.2 mL (observed-to-expected total lung volume ratio of 34%, with the expected total lung volume calculated using the Rypens formula).17 Amniocentesis was performed and results were within normal limits. At 28 weeks and 5 days, the o/e-LHR was 20.3%. FETO was performed at 28 weeks and 6 days without any complications. Figure 1 depicts key steps of the procedure. First, percutaneous introduction of the fetoscope into the amniotic cavity under ultrasound guidance (Figure 1A), followed by placement of the detachable balloon into the fetal trachea (Figure 1B-D). Both the mother and the fetus tolerated the procedure well. At 30 weeks and 3 days, ultrasound imaging showed good fetal pulmonary response to the FETO procedure with an o/e LHR of 34.6%. Polyhydramnios was noted, which persisted until delivery. At 33 weeks and 4 days, a large chorioamniotic separation throughout the uterus was diagnosed on routine ultrasonography. Magnetic resonance imaging confirmed severe chorioamniotic separation. The patient was admitted to the hospital, and betamethasone was administered. She remained asymptomatic. Because of the extremely large chorioamniotic separation, a fetoscopic procedure to remove the balloon became technically challenging because of the difficulty of perforating the floating membrane. The decision was made to perform ultrasound-guided puncture of the balloon. The balloon was successfully punctured under ultrasound guidance at 35 weeks and
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4 days using a 22-gauge needle (Figure 3). Follow-up ultrasonography showed no evidence of the balloon inside the fetal trachea. The patient was discharged from the hospital 2 days after the balloon puncture procedure. By 36 weeks and 5 days, the o/e-LHR had increased to 62.7%. At 38 weeks and 6 days, 10 weeks after tracheal balloon placement and 3 weeks after balloon puncture, the patient underwent spontaneous labor. A liveborn female weighing 3810 g with an Apgar score of 3 at 1 minute and 7 at 5 minutes was delivered vaginally. Both mother and baby were in stable condition at the conclusion of the procedure. The infant was orotracheally intubated after delivery because of the known diagnosis of left CDH and was transferred to the neonatal intensive care unit. The neonate had development of mild systemic hypotension and pulmonary hypertension, which was treated with 3 days of dopamine support as well as hydrocortisone. On serial echocardiography, pulmonary hypertension improved from suprasystemic pressures with moderate right ventricular enlargement to mild septal flattening preoperatively. A large left-sided anterior diaphragmatic defect was diagnosed intraoperatively, which was repaired using a GORE-TEX mesh (W.L. Gore & Associates) 6 days after delivery. Interestingly, our first patient had a large left anterior defect mimicking left lateral-posterior CDHs. Usually, the anterior diaphragmatic defects have better prognosis with different findings on fetal ultrasonography and MRI than our patient had. She was extubated 3 days after the surgery, and continuous positive airway pressure was discontinued 8 days later. A small atrial septal defect was also diagnosed; however, no medical management was required. Thirty-three days after delivery, she was discharged home on room air. At 3 months of age, she is on room air with no respiratory symptoms and is gaining weight appropriately with no early signs of developmental concerns.
Case 2 A 23-year-old patient (gravida 3, para 2) was referred to our center at 22 weeks of gestation with a diagnosis of left-sided CDH. Her previous obstetric history included 2 Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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FIGURE 3. Case 1. Axial ultrasound imaging of fetal neck showing the 22-gauge needle (red arrows) puncturing the fetal endotracheal balloon at 35 weeks and 4 days. FT ¼ fetal thyroid gland; Nt ¼ needle tip; Nv ¼ fetal neck vessels (carotid artery and jugular vein).
uncomplicated pregnancies that resulted in vaginal deliveries at term. Fetal ultrasonography at 22 weeks revealed an isolated severe form of left-sided CDH, with o/e LHR of 23%. Amniotic fluid was within normal limits, and the placenta was located anteriorly. Fetal echocardiography at the same time revealed dextroposition of the heart and no other abnormalities. Magnetic resonance imaging at 24 weeks established that the hernia contained a distended stomach, nondilated bowel, left hepatic lobe, and spleen. The total lung volume was calculated at 14.1 mL with an observed-to-expected total fetal lung volume of 47% (using Rypens formula).17 At 28 weeks and 2 days of gestation, FETO was performed successfully (Figure 1). However, the initial balloon was placed too far distal, resulting in right mainstem bronchial occlusion. Because the balloon was not optimally positioned and the airway developed minor bleeding when attempting the balloon removal, the decision was made to insert a second balloon with the aim of achieving the optimal tracheal occlusion. Accordingly, a successful tracheal balloon placement was accomplished during the same procedure. Both the mother and fetus were stable at the conclusion of the procedure. Prophylactic antibiotics and tocolysis were initiated according to the protocol. On postoperative day 2, chorioamniotic separation measuring 7.3 1.3 cm located at the uterine
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Observed/expected lung to head ratio according to gestational age
Observed/expected lung to head ratio (%)
70.0 59.6
60.0
62.7 52.4
52.3
50.0
51.2
49.9
40.0 29.9
30.0
34.6
29.4
23.0 20.0
20.3 Patient 1 Patient 2
10.0 0.0 22.0
24.0
26.0
28.0 30.0 32.0 Gestational age (wk)
34.0
36.0
FIGURE 4. Trend of lung growth in both fetuses after fetoscopic tracheal occlusion procedure.
puncture site was observed. One balloon was noted at the fetal trachea; the other was located in the proximal aspect of the right bronchus. The patient was managed conservatively, monitored as an inpatient because of the risk of membrane rupture, and discharged from the hospital on postoperative day 6. At 30 weeks and 1 day gestation, the patient complained of irregular uterine contractions. She was hospitalized and magnesium sulfate was initiated for tocolysis and fetal neuroprotection per protocol. The contractions ceased, and she was discharged home after 1 day. At 32 weeks and 2 days, 4 weeks after tracheal balloon placement, she presented with preterm premature rupture of membranes. Ultrasonography at admission revealed polyhydramnios (amniotic fluid index, 28 cm; maximum vertical pocket, 10.6 cm) and an o/e-LHR of 52.4%. There were no signs of maternal or fetal distress; however, the patient had vaginal bleeding and cervical change, so after 1 dose of betamethasone, the decision was made to proceed with delivery by EXIT procedure because of the presence of 2 balloons inside the fetal trachea and right bronchus. The EXIT procedure was performed at 32 weeks and 3 days with a pediatric 698
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otolaryngologist performing rigid bronchoscopy and tracheal balloon removal before delivery. One balloon was identified in the midtrachea and the other in the right mainstem bronchus. Both were punctured and removed without difficulty. The infant had mild tracheomegaly and proximal right bronchomegaly. A 3.5 micro-cuffed tube was used for intubation after allowing pulmonary fluid to drain. A live-born 2720-g male with an Apgar score of 6 at 1 minute and 8 at 5 minutes was delivered. He was transferred to neonatal intensive care unit. The mother was discharged home after 3 days. The neonate had a large posterior left diaphragmatic hernia repaired 5 days after delivery with a GORE-TEX mesh patch. He had development of mild systemic pulmonary hypertension (right ventricular systolic pressure of 54 mm Hg), which necessitated 3 days of dopamine support. Interval airway endoscopy before extubation revealed mild tracheomalacia and bronchomalacia. Seventeen days after CDH repair, he was successfully extubated. Forty-one days after delivery, he was safely discharged home with 1/8 L supplemental oxygen at the corrected gestational age of 38 weeks and 1 day. At 3 months of age, he is on room air and is feeding, growing, and gaining weight well. He has no respiratory symptoms apart from an intermittent brassy cough suggestive of mild tracheomalacia. Regenerative Outcome Regenerative outcome was demonstrated by substantial fetal lung growth and reversal of severe pulmonary hypoplasia. Specifically, lung growth essentially doubled in one fetus and increased by a third in the other fetus, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2 (Figure 4). DISCUSSION This article reports our initial successful experience with the implementation of a multidisciplinary FETO program as part of the build-out of a fetal regenerative medicine service at Mayo Clinic.18 We demonstrated the feasibility and safety of FETO in our patients, along with substantial fetal lung growth after FETO in line with clinically
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demonstrable regenerative outcomes following execution of an in utero intervention. Critical in the success of implementing FETO care is the deployment of a multidisciplinary team proficient in addressing in tandem the concomitant needs of mother and fetus.10,11,18 A well-coordinated group, orchestrated by a fetal regenerative specialist, includes maternal fetal medicine specialists, pediatric surgeons, otolaryngologists, neonatologists, anesthesiologists, and radiologists to provide adequate prenatal and postnatal care and achieve optimal prenatal, perinatal, and postnatal results. Moreover, it is vital to perform FETO in an advanced medical center that provides necessary resources, infrastructure, and expertise for intense management a newborn with an obstructed airway. Given the complexity and novelty of the techniques involved with fetal intervention in CDH and the logistics required to organize a trained, dedicated, and efficient transdisciplinary team led by a surgeon with experience in FETO, this report ultimately offers an example of how to deploy a shared prenatal regenerative service. Previous studies reported expansion of fetal lung and improvement of pulmonary vascularization after FETO in severe CDH, which directly correlates with better postnatal outcomes suggestive of a regenerative outcome within the favorable prenatal period for organ repair.5,14 Also, as previously suggested, o/eLHR provides an important prediction of survival in patients with CDH.19,20 Our results demonstrate substantial increase of o/e-LHR in both fetuses after FETO (an increase of 42.4 percentage points in case 1 and 29.4 percentage points in case 2). Balloon removal remains one of the limitations of the procedure, and the method for removal depends on operator preference and clinical conditions. Usually it is preferred to remove the balloon in utero via fetoscopy. Percutaneous ultrasound-guided needle puncture can be another option when used by an experienced practitioner. We describe a situation in which the fetoscopic removal of the balloon was technically impossible because it was not possible to introduce a trocar and a fetoscope inside a large chorion-amniotic separation. Therefore, percutaneous ultrasound-guided puncture of the balloon was considered a safe option. A recent Mayo Clin Proc. n June 2018;93(6):693-700 www.mayoclinicproceedings.org
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study suggested that in utero balloon removal, either by fetoscopy or ultrasound-guided puncture, does not cause immediate rupture of membranes or premature labor.21 Balloon removal can also be facilitated by establishing airway control on placental circulation to remove the balloon via an EXIT delivery procedure. This may be particularly helpful in an urgent scenario in which delivery of the fetus with the occluded trachea is imminent or in patients in whom balloon location in the more distal trachea or bronchus precludes safe needle puncture. Intervening with FETO between 26 and 30 weeks has been reported to increase fetal pulmonary size and vascularity and neonatal survival.5,12,14,22 Our study confirms these findings, intervening at 28.3 and 28.9 weeks. Prevention of preterm labor is also fundamental to the success of the surgery.11 A European cohort with 210 patients had a mean interval from balloon placement to delivery of 8.2 weeks. The gestational age at delivery ranged from 25.7 to 41.0 weeks (median, 35.3 weeks) and was before 34 weeks in 65 (30.9%) cases.19 A randomized controlled trial with 41 patients reported that despite the high incidence of prematurity (50.0%) and preterm premature rupture of the membranes (35.0%), FETO was associated with better perinatal outcome for infant survival at 6 months (50% [10 of 20 patients] vs 4.8% [1 of 21]).14 Similarly, a European cohort that included 210 cases estimated that in fetuses with left-sided CDH treated with FETO, the survival rate increased from 24.1% to 49.1%, and overall, 48% of infants were discharged from the hospital alive. They also reported a median delivery gestational age of 35.3 weeks, with 31% of the total cases delivered before 34 weeks.19 Our results provide further support to the validity of FETO-based care with our patients at Mayo Clinic delivered at 32.4 and 38.9 weeks, and both of them discharged from the hospital less than 45 days after delivery. CONCLUSION This article documents that FETO promotes fetal lung growth and reverse severe pulmonary hypoplasia in the setting of severe CDH. Our study provides a novel concept of using FETO-induced fetal lung growth as a regenerative outcome end point. This practical
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clinical end point may be useful to evaluate outcomes and, more generally, success of novel therapies. Our clinical experience thus provides a blueprint for future roll-out of fetal regenerative services focusing on improving prenatal care of a spectrum of congenital conditions including, beyond CDH, spina bifida, lower urinary tract obstruction, and severe cardiac anomalies. ACKNOWLEDGMENTS We thank Ms Jan H. Case for her work in preparing the illustrations and Mr Mark A. Wentworth for supporting the IDE application. Abbreviations and Acronyms: CDH = congenital diaphragmatic hernia; EXIT = ex utero intrapartum therapy; FETO = fetoscopic tracheal occlusion; IV = intravenous; o/e-LHR = observed-to-expected lung area to head circumference ratio; MRI = magnetic resonance imaging Affiliations: From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology (R.R., V.A.N.N., N.D., M.A.L., A.F.), Center for Regenerative Medicine (R.R., A.T.), Division of Pediatric Surgery, Department of Surgery (D.B.K., D.D.P.), Department of Otorhinolaryngology (K.B.), Division of Neonatal Medicine, Department of Pediatric and Adolescent Medicine (W.A.C., C.E.C.), Department of Radiology (A.B.K.), and Department of Anesthesiology and Perioperative Medicine (K.W.A., L.S., H.P.S.), Mayo Clinic, Rochester, MN. Grant Support: This work was supported by grant RMM 102516008 from the State of Minnesota. Dr Ruano is a recipient of the Regenerative Medicine Minnesota Clinical Trial grant: “Fetoscopic Regenerative Therapy for Severe Pulmonary Hypoplasia e A Feasibility Pre-Randomized Control Trial Study.” Potential Competing Interests: The authors report no competing interests. Correspondence: Address to Rodrigo Ruano, MD, PhD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (ruano.rodrigo@mayo. edu).
REFERENCES 1. Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: the “R3” regenerative medicine paradigm. Clin Transl Sci. 2008; 1(2):168-171. 2. Terzic A, Nelson TJ. Regenerative medicine primer. Mayo Clin Proc. 2013;88(7):766-775. 3. Belfort MA, Whitehead WE, Shamshirsaz AA, et al. Fetoscopic open neural tube defect repair: development and refinement of a two-port, carbon dioxide insufflation technique. Obstet Gynecol. 2017;129(4):734-743.
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4. Ruano R, Sananes N, Wilson C, et al. Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity. Ultrasound Obstet Gynecol. 2016;48(4):476-482. 5. Ruano R, da Silva MM, Campos JA, et al. Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia. Obstet Gynecol. 2012;119(1): 93-101. 6. Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia: epidemiology and outcome. Clin Perinatol. 1996;23(4):671-688. 7. Britto IS, Sananes N, Olutoye OO, et al. Standardization of sonographic lung-to-head ratio measurements in isolated congenital diaphragmatic hernia: impact on the reproducibility and efficacy to predict outcomes. J Ultrasound Med. 2015; 34(10):1721-1727. 8. Ruano R, Aubry MC, Barthe B, Mitanchez D, Dumez YB, Benachi A. Predicting perinatal outcome in isolated congenital diaphragmatic hernia using fetal pulmonary artery diameters. J Pediatr Surg. 2008;43(4):606-611. 9. Ruano R, Martinovic J, Aubry MC, Dumez Y, Benachi A. Predicting pulmonary hypoplasia using the sonographic fetal lung volume to body weight ratiodhow precise and accurate is it? Ultrasound Obstet Gynecol. 2006;28(7):958-962. 10. Deprest J, Gratacos E, Nicolaides KH; FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results [published correction appears in Ultrasound Obstet Gynecol. 2004;24(5):594]. Ultrasound Obstet Gynecol. 2004;24(2):121-126. 11. Belfort MA, Olutoye OO, Cass DL, et al. Feasibility and outcomes of fetoscopic tracheal occlusion for severe left diaphragmatic hernia. Obstet Gynecol. 2017;129(1):20-29. 12. Ruano R, Duarte SA, Pimenta EJ, et al. Comparison between fetal endoscopic tracheal occlusion using a 1.0-mm fetoscope and prenatal expectant management in severe congenital diaphragmatic hernia. Fetal Diagn Ther. 2011;29(1):64-70. 13. Khan PA, Cloutier M, Piedboeuf B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am J Med Genet C Semin Med Genet. 2007;145C(2):125-138. 14. Ruano R, Yoshisaki CT, Da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. 2012;39(1):20-27. 15. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31(1):148-151. 16. Jani JC, Peralta CF, Nicolaides KH. Lung-to-head ratio: a need to unify the technique. Ultrasound Obstet Gynecol. 2012;39(1):2-6. 17. Rypens F, Metens T, Rocourt N, et al. Fetal lung volume: estimation at MR imagingdinitial results. Radiology. 2001;219(1): 236-241. 18. Deprest J, Jani J, Cannie M, et al. Prenatal intervention for isolated congenital diaphragmatic hernia [published correction appears in Curr Opin Obstet Gynecol. 2006;18(3):354]. Curr Opin Obstet Gynecol. 2006;18(2):203-215. 19. Jani JC, Nicolaides KH, Gratacós E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009;34(3):304-310. 20. Jani J, Nicolaides KH, Benachi A, et al. Timing of lung size assessment in the prediction of survival in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol. 2008;31(1):37-40. 21. Jiménez JA, Eixarch E, DeKoninck P, et al. Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia. Am J Obstet Gynecol. 2017;217(1):78.e1-78.e11. 22. Deprest JA, Flemmer AW, Gratacos E, Nicolaides KH. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2009;14(1):8-13.
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