Fetal Endoscopic Tracheal Occlusion Research Articles

Myocardial effects of fetal endoscopic tracheal occlusion in lambs with CDH.

Fetal endoscopic tracheal occlusion in congenital diaphragmatic hernia (CDH) may reduce pulmonary hypertension and ameliorate postnatal cardiac output. The effects of sustained early (ETO) and late (LTO) tracheal occlusion on left ventricular (LV) cells in the lamb model have not been described. CDH was created in lambs at 70 days' gestation (term = 145 days). ETO (85 days) or LTO (105 days) was sustained till term. After cesarean section (140 days) fetuses were euthanized and hearts harvested. LV myocardial cells were studied by histological and immunofluorescence (TGF-beta 1, endothelin-1) assays in CDH, ETO, LTO, and the control group (two subjects per group). Small intramyocardial arteries were evaluated by traditional histology. LV myocardial histology in CDH and LTO was similar. ETO-induced LV myocardial cell enlargement and increased endothelin-1 and TGF-beta 1 staining; a weaker immunofluorescence signal was observed in LTO compared with ETO. Myocardial vascular wall thickness was greater in CDH than in controls. ETO was associated with a vascular wall thickness within the range of controls. With only two fetuses in each group, only an explorative evaluation was possible. The time point at which TO is performed seems to have an effect on cardiac morphology. Functional studies as well as confirmation in clinical samples are mandatory.

59: Fetal endoscopic tracheal occlusion for severe isolated left-sided congenital diaphragmatic hernia: a USA tertiary care center experience

59: Fetal endoscopic tracheal occlusion for severe isolated left-sided congenital diaphragmatic hernia: a USA tertiary care center experience

Patterns of fetal lung growth in fetuses with isolated left-sided congenital diaphragmatic hernia

Objective: To evaluate right lung growth pattern in fetuses with isolated left-sided congenital diaphragmatic hernia (iL-CDH) and to analyze the pattern according to postnatal outcome. Methods: Lung-to-head ratio (LHR) and observed-to-expected LHR (O/E LHR) were obtained in 58 cases. Correlation and regression analysis for the total number of measurements, general linear models for those cases with a least three serial measurements and linear mixed effect models were used to analyze the influence of gestational age on the right lung size. Cases expectantly managed and those with fetal endoscopic tracheal occlusion were analyzed separately. Results: LHR, but not O/E LHR, increased significantly with gestational age (GA) (r = 0.43, p = 0.003 and r = −0.13, p = 0.30, respectively). According to neonatal mortality, in those fetuses that died, LHR remained unchanged and O/E LHR decreased significantly with GA (r = 0.07, p = 0.65 and r = −0.37, p = 0.02, respectively). In those cases with at least three serial measurements, the same two patterns were found. Similarly, in cases with expectant management, surviving fetuses showed a significantly higher weekly increase in LHR (p = 0.01) and a trend to a lower weekly decrease in O/E LHR (p = 0.17) than in those that died. Conclusions: Patterns of right lung growth in iL-CDH differ according to postnatal survival. Serial measurements, but not a single one, might increase the prediction of neonatal death.

OC14.05: Impact of fetal endoscopic tracheal occlusion on postnatal outcome according to the severity of congenital diaphragmatic hernia

OC14.05: Impact of fetal endoscopic tracheal occlusion on postnatal outcome according to the severity of congenital diaphragmatic hernia

Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: A systematic review.

We aimed to systematically review all published pre-clinical research on prenatal medical treatment of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Background The neonatal mortality due to isolated CDH remains high. Whether fetal endoscopic tracheal occlusion (FETO) reduces mortality is still to be demonstrated. Therefore more potent preferentially medical therapy would be welcomed. Methods We searched MEDLINE (Pubmed), Embase and the Web of Science including all studies from the earliest date (1951) to December 2013. Article quality was assessed using the modified CAMRADES checklist. Inclusion criteria were those animal studies addressing prenatal medical interventions and principal variables were confirmation of a diaphragmatic defect, lung to body weight ratio (LBWR), formal airway morphometry or DNA/protein content. Results In total 983 articles were identified. Following abstract review, 96 articles were assessed by two authors in agreement with a third for eligibility. Of these, 43 were included in the final analysis. The median number of study quality checklist items (maximum 10) scored was 4 (IQ range: 2-5). Thirty (69.8%) of studies were in the nitrofen rat. The majority were treated with vitamins or glucocorticoids. Single studies reported some improvement in lung morphology with alternative therapies. It was impossible to identify a pattern in animal model selection or creation, mode, time point or duration of treatment and readouts. Only one study reported a sample size calculation. Conclusion Comparison in pre-clinical studies in CDH is challenging due to methodological variation. Agreed standardized methods need to be applied in future investigation of new medical therapies.

Phospholipid profile of amniotic fluid in ovine model of congenital diaphragmatic hernia (CDH): the effect of fetal tracheal occlusion.

Fetal endoscopic tracheal occlusion has been proposed as a prenatal intervention to ameliorate congenital diaphragmatic hernia (CDH) prognosis. Tracheal occlusion (TO) prevents pulmonary fluid egress, leading to tissue expansion, reversal of lung hypoplasia, and potential maturation. Fetal lung maturity strongly correlates with amniotic fluid (AF) phospholipidic composition. In this preliminary study, we characterized the AF phospholipidic profile in CDH-induced, TO-treated, and healthy fetal lambs to define the prenatal treatment benefits of TO on lung maturity. CDH induction was performed at 70 days of gestation, TO was carried out at 102 days of gestation, and caesarean section was carried out at 136 days of gestation. AF samples, taken at 102-136 days of gestation, were evaluated using mass spectrometry. The analysis focused on phosphatidylcholines (PCs) and sphingomyelins (SMs). The most abundant phosphatidylcholine species retrieved in healthy AF was POPC [PC(18:1/16:0)], while the level of DPPC [PC(16:0/16:0)] was extremely low at both gestational ages. CDH induction caused a decrease in POPC and many other PCs. A substantial return of some PCs, in particular POPC, PC(34:2) and PC(18:0/16:0), to a more physiological level was prompted by TO. SMs were unaltered. The AF phospholipidic profile could provide prenatal prognostic markers of CDH and possible indices of lung maturation after fetal treatment.

Long-term neurologic outcomes after common fetal interventions

Fetal interventions have clearly decreased mortality, but the neurological outcomes of survivors are of critical concern. Here we consolidated available data on long-term neurological outcomes after common fetal interventions to guide counseling, management, and future research. Published studies assessing long-term neurological outcomes after common fetal interventions from 1990 through 2014 were collected. We included all studies with a cohort of more than 5 patients and with follow-up of 1 year or longer. We divided procedures into those performed for singletons and for multiples. Singleton procedures included amnioinfusion for preterm premature rupture of membranes, intrauterine transfusion for red cell alloimmunization-associated anemia, intrauterine transfusion for parvovirus-associated anemia, vesicoamniotic shunts, thoracoamniotic shunts, ventriculoamniotic shunts, fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia, and open fetal cases by myelomeningocele and others. Multiple procedures included those done for monochorionic twins including serial amnioreduction, selective fetoscopic laser photocoagulation, and selective termination. Of 1341 studies identified, 28 met the inclusion criteria. We combined available literature for all procedures. Studies varied in their length of follow-up and method of assessing neurological status. Neurological outcome after intervention varied by procedure but was normal in 40-93%, mildly impaired in 3-33%, and severely impaired in 1-40%. Follow-up to school age was rare with the exception of procedures for monochorionic twins. Fetal treatments have been successful in achieving survival in previously hopeless cases, but success should also be determined by the outcomes of survivors. Except for monochorionic twins, there is a dearth of reported long-term outcomes. Standardized reporting of long-term neurological sequelae is imperative so that meaningful analysis and study comparisons can be made.

Experimental fetal endoscopic tracheal occlusion in rhesus and cynomolgus monkeys: nonhuman primate models

ABSTRACTObjective: The monkey model is the best model to investigate some physiological response to the fetal transitory tracheal occlusion but it has never been described in Macaca monkeys. The aim of this study was to evaluate the feasibility of fetal endoscopic tracheal occlusion (FETO) in a non-human primate model.Methods: Pregnant rhesus monkeys and cynomolgus were tested as a potential experimental model for FETO in the third trimester of pregnancy, by performing fetal tracheoscopies with and without tracheal occlusion.Results: A total of 22 pregnancies were followed in 16 monkeys and underwent fetal surgery. Percutaneous endoscopic access to the uterine cavity was possible in 20 cases (91%). Of these 20 pregnant monkeys, fetal tracheoscopy could be achieved in 15 cases (75%). In rhesus monkeys, the time between the onset of endoscopy and tracheal penetration decreases as operator experience increases. Neither maternal morbidity nor mortality was related to surgery. Two fetal losses were possibly due to the procedure.Conclusion: FETO is feasible in the non-human primate, which closely reflects procedures in humans. The non-human primate model for FETO, specially the rhesus monkeys, may be useful for future studies concerning the mechanisms related to the lung growth after transitory fetal tracheal occlusion.

Right-sided congenital diaphragmatic hernia: the challenge remains.

Fetal surgery is without a doubt one of the greatest achievements in fetal medicine over the last three decades, addressing a number of lethal or otherwise debilitating congenital conditions and pregnancy complications. Fetal endotracheal occlusion (FETO) for the treatment of pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH), although always ‘high on the fetal surgery agenda’, has seen many waves of ‘hope and despair’ (Deprest JA et al., Fetal surgery for congenital diaphragmatic hernia is back from never gone, Fetal Diagn Ther 2011;29:6–17). Indeed, despite sound physiological theories and animal experiments suggesting its potential benefits, randomised controlled trials comparing FETO to expectant management have not consistently shown the expected success (Harrison MR et al., A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia, N Engl J Med 2003;349:1916– 24). Notwithstanding the low incidence of CDH, a continued challenge surrounding FETO has been the difficulty in accurately determining fetal prognostic factors which may prompt intervention. These concerns appear to be greater in right-sided CDH (RCDH), given that its incidence is 70–80% lower than leftsided defects, and that liver herniation, a major prognostic factor in contralateral cases, is almost universally present (Hedrick HL et al., Right congenital diaphragmatic hernia: prenatal assessment and outcome, J Pediatr Surg 2004;39:319– 23). In their study, DeKoninck et al. correctly point out that most CDH studies address isolated left-sided defects, and that perhaps RCDH may be a different pathology altogether, worthy of its own evaluation. To describe the specific characteristics and outcomes of RCDH, they conducted a retrospective review of cases with isolated RCDH and liver herniation subjected to FETO at two centres over 10 years, and find that fetuses with a lung-to-head ratio ≤45% have a tendency towards increased survival at 42% relative to 17% among expectantly managed cases (P = 0.09), without a significant increase in preterm birth. Akin to left-sided defects, they re-iterate that initial lung size predicts survival following FETO in right-sided defects. These results, although not statistically significant, point to the value that FETO may have in severe RCDH. Or do they? The issue with retrospectively analysing rare pathologies using observational data that is collected outside the realm of a controlled trial, in addition to not offering a power calculation, is that facing non-statistically significant results such as those provided in this study, one cannot attribute the differences, or lack thereof, between subjects and controls either to a lack of statistical power or to the absence of a true relationship between intervention and outcome. The nuanced interpretation in conclusions such as ‘Though the current data do not show benefit, in poor prognosis cases FETO may seem to be justifiable’ needs to be therefore regarded with the utmost caution. Indeed, the same way in which a trend towards positive outcomes, such as increased survival, may prompt intervention, the risk of rendering a non-statistically significant negative outcome such as preterm birth significant, increases. All in all, it would seem from these results that at best, FETO

OP34.10: Impact of fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia in a developing country

<scp>OP</scp>34.10: Impact of fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia in a developing country

FETO effects on tracheal diameter

In order to ameliorate pulmonary hypoplasia in congenital diaphragmatic hernia (CDH), an approach has been taken using fetal endoscopic tracheal occlusion (FETO). The rationale is that a balloon prevents liquid from escaping from the lungs in utero, resulting in increased airway pressure, increased lung volumes, and maturation of pulmonary vessels. A side effect of FETO is tracheomegaly. The question of whether tracheomegaly truly is more common in infants treated with FETO, compared with children without such treatment, was addressed by Zani et al in this issue of The Journal.

Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia

In the present study, we review the indications, technical aspects, preliminary results, risks, and clinical implications of fetal endoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia (CDH) performed outside the United States and its potential future directions in this country and globally. Congenital diaphragmatic hernia occurs in approximately 1 in 2500 live births and results in high neonatal morbidity and mortality, largely associated with the severity of pulmonary hypoplasia and pulmonary arterial hypertension. With the advent of prenatal imaging, CDH can be diagnosed before birth, and in utero treatment is now available in some centers. The prognosis of CDH can be evaluated by assessing the fetal lung size, the degree of liver herniation, and the fetal pulmonary vasculature in isolated forms of CDH. These parameters help classify fetuses as having mild, moderate, severe, or extremely severe isolated CDH. Severe and extremely severe diaphragmatic hernias have poor outcomes and thus are candidates for innovative therapies such as FETO. Fetal endoscopic tracheal occlusion is usually performed between 26 and 30 weeks' gestation. In utero, an endoscope is passed through the fetal mouth and down to the carina; the balloon is deployed just above the carina. After the procedure, ultrasound surveillance every 2 weeks ensures the balloon's structural integrity and measures the fetal pulmonary response. At approximately 34 weeks' gestation, the balloon is deflated and removed. Fetal endoscopic tracheal occlusion is thought to improve outcomes by decreasing mortality and allowing more rapid neonatal stabilization. Ultimately, the goal of FETO is to minimize pulmonary hypoplasia and pulmonary arterial hypertension. Following delivery, neonates still require diaphragm repair.

Development and use of a high-fidelity simulator for fetal endotracheal balloon occlusion (FETO) insertion and removal

Objectives The objective of this article is to describe the development of an anatomically accurate simulator in order to aid the training of a perinatal team in the insertion and removal of a fetal endoscopic tracheal occlusion (FETO) balloon in the management of prenatally diagnosed congenital diaphragmatic hernia. Methods An experienced perinatal team collaborated with a medical sculptor to design a fetal model for the FETO procedure. Measurements derived from 28-week fetal magnetic resonance imaging were used in the development of an anatomically precise simulated airway within a silicone rubber preterm fetal model. Clinician feedback was then used to guide multiple iterations of the model with serial improvements in the anatomic accuracy of the simulator airway. Results An appropriately sized preterm fetal mannequin with a high-fidelity airway was developed. The team used this model to develop surgical skills with balloon insertion, and removal, and to prepare the team for an integrated response to unanticipated delivery with the FETO balloon still in situ. Conclusions This fetal mannequin aided in the ability of a fetal therapy unit to offer the FETO procedure at their center for the first time. This model may be of benefit to other perinatal centers planning to offer this procedure.

Left Heart Structures in Human Neonates with Congenital Diaphragmatic Hernia and the Effect of Fetal Endoscopic Tracheal Occlusion

Background: Small left heart structures are observed in fetuses with left-sided congenital diaphragmatic hernia (CDH). Fetoscopic tracheal occlusion (FETO) in mid-gestation promotes lung growth in fetuses with CDH, however cardiac effects of FETO are poorly described. We studied the effects of FETO on cardiac structure size at birth, hypothesizing that left heart structures would be larger in neonates who had undergone fetal intervention. Methods/Results: We performed retrospective measurements of atrioventricular and semilunar valve and pulmonary artery diameters, ventricular lengths, left ventricular end-diastolic volume indexed (LVEDVi) to body surface area. 35 patients were studied (9 FETO, 26 controls). All fetuses had liver herniation and a lung-to-head ratio <1 at fetal presentation. At birth the intervention group had larger LVEDVi (16.8 vs. 12.76 ml/m², p < 0.05), LV length Z-score (-2.05 vs. -4, p < 0.01), LV:RV length ratio (1.43 vs. 1.04, p < 0.05), LPA diameter Z-score (+1.71 vs. -1.04, p < 0.05), and better growth of aortic valve (-2.18 FETO, -3.3 controls, p < 0.01). There was a trend toward higher LV output in the FETO group. Conclusions: Left heart structures and LPA were larger postnatally in patients with CDH who underwent FETO than in those who did not. Hemodynamic alterations are introduced with tracheal occlusion that are associated with alterations in ventricular loading and may influence growth.

Cardiac function pre and post fetal endoscopic tracheal occlusion (FETO) in fetuses with congenital malformations of the thorax

Objective: Evaluation of pre- and post-procedure cardiac function in fetuses with severe CDH or congenital thoracic anomalies (CCAM, hydrothorax) causing mediastinal shift and cardiac compression who underwent FETO to improve survival and to reduce morbidity.

Outcome of CDH infants following fetoscopic tracheal occlusion — influence of premature delivery

PurposeTo evaluate the mortality and morbidity of infants with congenital diaphragmatic hernia who had undergone fetal endoscopic tracheal occlusion (FETO) and whether this was influenced by premature birth. MethodsThe gestational age at delivery, lung–head ratio (LHR) pre and post FETO, neonatal outcomes, and respiratory, gastro-intestinal, neurological, surgical, and musculoskeletal problems at follow up of consecutive infants who had undergone FETO were determined. Elective reversal of FETO was planned at 34weeks of gestation. ResultsThe survival rate of the 61 FETO infants was 48%, with 84% delivered prematurely. Thirty-one delivered <35weeks of gestation. Their survival rate was 18%. Twenty-three of 24 infants who had emergency balloon removal were born <35weeks of gestation. Survival was related to gestational age at delivery (OR 0.55, 95% CI 0.420, 0.77, p<0.001) and the duration of FETO (OR 0.73, 95% CI 0.59, 0.91, p<0.005). Infants born prior to 35weeks of gestation compared to those born at≥35weeks required a longer duration of ventilation (median 45days versus 12days, p<0.001), and a greater proportion had surgery for gastro-oesophageal reflux (50% versus 9%, p=0.011). ConclusionThese results emphasize the need to reduce premature delivery following FETO.

An Evidence-Based Review of the Current Treatment of Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia is a rare but severe condition affecting 1 in 2000 to 3000 newborns with a survival rate of 67%. Although regular antenatal screening allows prenatal diagnosis in many cases, traditionally treatment has been based on postnatal surgical repair. Recent literature has pointed out the survival benefits of initial stabilization and the use of gentle ventilation strategies prior to definitive treatment, shifting the trend from immediate to delayed surgical repair. Advances in fetal intervention have allowed the introduction of fetal endoscopic tracheal occlusion as a method to hasten lung development before birth in order to minimize postnatal morbidity. Despite appropriate treatment, the long-term outcomes of these patients are plagued with numerous complications, associated with the primary pathology and also aggressive therapeutic measures. International centers of excellence have recently come together in an effort to standardize the care of such patients in hopes of maximizing their outcomes.

Hernia diafragmática congénita: criterios pronósticos y estado actual del tratamiento prenatal. Guía clínica

Congenital diaphragmatic hernia (CDH) is a severe congenital birth defect, which is commonly associated with genetic abnormalities and malformations in other systems. Once the diagnosis is made, there should be a thorough evaluation to confirm that the malformation is isolated, as well as an assessment of prognostic factors, essentially lung size and liver herniation. With these parameters an individualized and relatively accurate prognosis can be offered to parents. Management options include termination of pregnancy, conservative prenatal management and post-natal treatment, or fetal therapy. Fetal therapy consists of fetal endoscopic tracheal occlusion (FETO) and is offered in a small number of centers worldwide. Available evidence suggests that prenatal treatment might increase the chances of survival by 35-40% compared with baseline survival. Several randomized trials are now underway to assess the impact of therapy on very severe and moderate cases of CDH.

Fetal Pulmonary Response After Fetoscopic Tracheal Occlusion for Severe Isolated Congenital Diaphragmatic Hernia

To estimate the response in lung growth and vascularity after fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia in the prediction of neonatal survival. Between January 2006 and December 2010, fetal lung parameters (observed-to-expected lung-to-head ratio; observed-to-expected lung volume; and contralateral lung vascularization index) were evaluated before fetal tracheal occlusion and were evaluated longitudinally every 2 weeks in 72 fetuses with severe isolated congenital diaphragmatic hernia. Thirty-five fetuses underwent fetal endoscopic tracheal occlusion and 37 cases did not. Survival rate was significantly higher in the fetal endoscopic tracheal occlusion group (54.3%) than in the no fetal endoscopic tracheal occlusion group (5.4%, P<.01). Fetal endoscopic tracheal occlusion resulted in a significant improvement in fetal lung size and pulmonary vascularity when compared with fetuses that did not go to the fetal intervention (increase of the observed-to-expected lung-to-head ratio, observed-to-expected total lung volume, and contralateral pulmonary vascularization index 56.2% compared with 0.3%, 37.9% compared with 0.1%, and 98.6% compared with 0.0%, respectively; P<.01). Receiver operating characteristic curves indicated that the observed-to-expected total fetal lung volume was the single best predictor of neonatal survival before fetal endoscopic tracheal occlusion (cutoff 0.23, area under the curve [AUC] 0.88, relative risk 5.3, 95% confidence interval [CI] 1.4-19.7). However, the contralateral lung vascularization index at 4 weeks after fetal endoscopic tracheal occlusion was more accurate in the prediction of neonatal outcome (cutoff 24.0%, AUC 0.98, relative risk 9.9, 95% CI 1.5-66.9) with the combination of observed-to-expected lung volumes and contralateral lung vascularization index at 4 weeks being the best predictor of outcome (AUC 0.98, relative risk 16.6, 95% CI 2.5-112.3). Fetal endoscopic tracheal occlusion improves survival rate by increasing the lung size and pulmonary vascularity in fetuses with severe congenital diaphragmatic hernia. The pulmonary response after fetal endoscopic tracheal occlusion can be used to predict neonatal survival.

A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia

Severe pulmonary hypoplasia and pulmonary arterial hypertension are associated with reduced survival in congenital diaphragmatic hernia (CDH). We aimed to determine whether fetal endoscopic tracheal occlusion (FETO) improves survival in cases of severe isolated CDH. Between May 2008 and July 2010, patients whose fetuses had severe isolated CDH (lung-to-head ratio < 1.0, liver herniation into the thoracic cavity and no other detectable anomalies) were assigned randomly to FETO or to no fetal intervention (controls). FETO was performed under maternal epidural anesthesia supplemented with fetal intramuscular anesthesia. Tracheal balloon placement was achieved with ultrasound guidance and fetoscopy between 26 and 30 weeks of gestation. All cases that underwent FETO were delivered by the EXIT procedure. Postnatal therapy was the same for both treated fetuses and controls. The primary outcome was survival to 6 months of age. Other maternal and neonatal outcomes were also evaluated. Twenty patients were enrolled randomly to FETO and 21 patients to standard postnatal management. The mean gestational age at randomization was similar in both groups (P = 0.83). Delivery occurred at 35.6 ± 2.4 weeks in the FETO group and at 37.4 ± 1.9 weeks in the controls (P < 0.01). In the intention-to-treat analysis, 10/20 (50.0%) infants in the FETO group survived, while 1/21 (4.8%) controls survived (relative risk (RR), 10.5 (95% CI, 1.5-74.7), P < 0.01). In the received-treatment analysis, 10/19 (52.6%) infants in the FETO group and 1/19 (5.3%) controls survived (RR, 10.0 (95% CI, 1.4-70.6) P < 0.01). FETO improves neonatal survival in cases with isolated severe CDH.