Obstetrics & Gynecology:
Fetal Pulmonary Response After Fetoscopic Tracheal Occlusion for Severe Isolated Congenital Diaphragmatic Hernia
Ruano, Rodrigo MD, PhD; da Silva, Marcos Marques MD; Campos, Juliana Alvares Duarte Bonini DDS, PhD; Papanna, Ramesha MD; Moise, Kenneth Jr MD; Tannuri, Uenis MD, PhD; Zugaib, Marcelo MD, PhD
From the Obstetrics Department and Pediatric Surgery, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil; Texas Children's Fetal Center and the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; and the Social Department, Faculdade de Odontologia, Universidade Estadual Paulista, Araraquara, Brazil.
The present study is funded by the CNPq (Conselho Nacional de Desenvolvimento de Pesquisa e Tecnologia do Brasil).
Presented at the International Fetal Medicine and Surgery Society Meeting, September 25–30, 2010, Tokyo, Japan, and at the 20th World Congress on Ultrasound in Obstetrics and Gynecology, October 10–14, 2010, Prague, Czech Republic.
Corresponding author: Rodrigo Ruano, MD, PhD, Universidade de São Paulo, Faculdade de Medicina, Obstetrics Department, São Paulo, Brazil, Rua Dionisio da Costa, 63, ap 121, Sao Paulo, SP, Brazil, 04117-110; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.
LEVEL OF EVIDENCE: II
Congenital diaphragmatic hernia can be accurately diagnosed by second-trimester ultrasonographic examination.1,2 Despite all efforts, neonatal morbidity and mortality rates for cases diagnosed prenatally remain high, especially in fetuses with extremely reduced lung volumes, liver herniation, and decreased pulmonary vascularization.3,4 Neonatal death in severe congenital diaphragmatic hernia cases occurs as a result of severe pulmonary hypoplasia and pulmonary arterial hypertension.5–10 Fetal endoscopic tracheal occlusion has been shown to stimulate fetal lung growth in both animal models and humans with congenital diaphragmatic hernia.11,12 Our previous studies have demonstrated that fetal endoscopic tracheal occlusion can improve neonatal survival in severe cases of congenital diaphragmatic hernia.13 However, predicting neonatal survival after tracheal occlusion remains a challenge.13–15 Jani et al12 reported that a preoperative lung-to-head ratio of less than 0.7 was associated with a poor neonatal outcome after fetal endoscopic tracheal occlusion. Both three-dimensional ultrasonography and magnetic resonance imaging used to measure lung volumes in the immediate postoperative period have also shown promise in predicting neonatal outcome after the fetal endoscopic tracheal occlusion procedure.16–18 Fetal pulmonary vascular status can also be evaluated by three-dimensional power Doppler ultrasonography, which has the advantage of evaluating the entire pulmonary vascularity.10 In fetuses with congenital diaphragmatic hernia without prenatal treatment, fetal pulmonary vascular indices are associated with severe pulmonary arterial hypertension and neonatal death.10 However, the assessment of these vascular indices has not been studied to date to determine if they can aid in the prediction of neonatal survival after fetal endoscopic tracheal occlusion.
The first objective of the current study was to estimate serial measurements of the observed-to-expected lung-to-head ratio, the observed-to-expected total lung volume ratio, and the contralateral pulmonary vascularization index in a group of fetuses with congenital diaphragmatic hernia that were not treated with fetal endoscopic tracheal occlusion and compare these results with a group of fetuses undergoing fetal endoscopic tracheal occlusion. A second objective was to determine if neonatal survivors after fetal endoscopic tracheal occlusion exhibited a different pattern of pulmonary response as compared with nonsurvivors.
MATERIALS AND METHODS
Between January 2006 and December 2010, a prospective study was conducted in a single fetal medicine unit in São Paulo, Brazil. The inclusion criteria for consideration of a fetal endoscopic tracheal occlusion procedure were: 1) singleton pregnancy; 2) gestational age at diagnosis of fetal congenital diaphragmatic hernia between 24 and 30 weeks; 3) the presence of severe congenital diaphragmatic hernia defined as an observed-to-expected lung-to-head ratio less than 25% with the liver parenchyma herniated into the thoracic cavity; 4) no other detectable anomalies (normal fetal echocardiogram with normal fetal karyotype); and 5) absence of maternal contradictions to general anesthesia. After extensive counseling, patients who met the inclusion criteria and agreed to participate signed written informed consent for both fetal intervention and study participation. The protocol was approved by the local ethics committee of the University of São Paulo, Brazil (CAPPesq 108707).
A total of 72 patients underwent serial pulmonary measurements. The first 34 patients were previously reported in our pilot controlled study, in which 16 fetuses underwent the fetal endoscopic tracheal occlusion procedure, whereas 18 fetuses with similar characteristics underwent routine prenatal management. Prenatal management was randomly assigned for prenatal expectant management by a computer program with a ratio of 1:1.13 The last 38 cases were part of a randomized controlled trial, in which the randomization process was generated by a computer program in a ratio of 1:1 either but following the CONSORT guidelines (clinicaltrials.gov #NCT01302977).19 (Ruano R, Yoshizaki CT, Silva MM, Ceccon MEJ, Grasi MS, Tannuri U, Zugaib M. A randomized controlled trial of fetoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. In Press.) Because the inclusion criteria were the same for both studies, the studied sample characteristics were very similar (Table 1).
Fetal endoscopic tracheal occlusion was performed between 26 and 30 weeks (average 27.5± 1.0 weeks) gestation following a well-established protocol under maternal epidural anesthesia as previously described13 (see Video 1, available online at http://links.lww.com/AOG/A270). Fetal anesthesia was conducted by injecting fentanyl (15 micrograms/kg of estimated fetal weight determined by ultrasonography) and pancuronium (2 mg/kg) under ultrasonographic guidance into the fetal deltoid muscle using a 22-gauge needle. A special designed, slightly curved operating sheath with a diameter of 2.7 mm with two separate channels and obturators (the upper with a working channel of 1.3 mm and the lower with a 1.2-mm channel to accommodate a 1-mm fetoscope) was used.20 This sheath was introduced into the amniotic cavity while guided by conventional two-dimensional ultrasonography. Once inside the amniotic cavity, the trocars were withdrawn and the fetoscope inserted. The cannula with the fetoscope was advanced through the fetal mouth, over the tongue, to the pharynx, then to the larynx, over the epiglottis, and finally through the vocal cords to the trachea. After identifying the carina, a catheter loaded with a detachable balloon was positioned just above it. The balloon was inflated with 0.8 mL of physiological saline solution and detached from the catheter; its position inside the fetal trachea was confirmed by ultrasonography. Prophylactic tocolysis and antibiotics were administered to the patients during the procedure and for 24 hours after completing the intervention. The mean duration of the procedure was 24.6±8.3 minutes (range 10–40 minutes).
For the evaluation of the pulmonary indices, a Voluson 730 ultrasound machine was used. The observed-to-expected lung-to-head ratio was calculated by measuring the ratio between the contralateral lung area (at the level of the four-chamber heart view) and the head circumference compared with the expected value for gestational age using two-dimensional ultrasonography.21,22
Fetal lung volumes were estimated by a previously described technique.23 A thoracic volumetric block was acquired in a transverse section of the fetal thorax at the level of the four-chamber view of the fetal heart with its apex proximal to the transducer. Maximal resolution was optimized and a sweep angle from 60° to 85° was established. Each lung was measured in a transverse section using VOCAL software (three-dimensional Sonoview) by rotating the image 30°. The total fetal lung volume was then calculated by summing the ipsilateral and contralateral lung volumes and then dividing this value by the expected total lung volumes in an effort to correct for changes in gestational age, as previously described.24
The contralateral pulmonary vascularization index was calculated as previously reported.10 Using the same pre-established settings (angio mode: cent; smooth: 4/5; frequency: low; quality: 16; density: 6; enhance: 16; balance: G>150; filter: 2; actual power: 2 dB; pulse repetition frequency: 0.9) for all cases and throughout gestational age, power Doppler was applied to image the pulmonary vasculature. The three-dimensional volumetric block of the fetal thorax was acquired with maximal resolution and with varying the sweep angle between 40° and 85° depending on the gestational age. A transverse section of the fetal thorax at the level of the four-chamber heart view with the pulmonary vessels proximal to the transducer was used for this measurement. The contralateral lung volume was measured using VOCAL software (rotation of 30°) also in a transverse section image of the three-orthogonal multiplanar imaging. A Doppler histogram was used to determine the vascularization index from on-board computer algorithms, which calculate the color-voxel-to-total-voxel ratio. This percentage of color flow Doppler within the lung is indicative of the vessels that are present as compared with the background nonvascular parenchyma. Because it has been previously demonstrated that fetal pulmonary vascularization index does not vary throughout gestation,10 an observed-to-expected ratio was unnecessary for this parameter.
All fetuses in the fetal endoscopic tracheal occlusion group were delivered by ex utero intrapartum therapy to allow for the controlled removal of the tracheal balloon at a planned gestational age of 38 weeks using a grasping forceps. The balloon was identified in all cases up to 6 weeks after fetal endoscopic tracheal occlusion but could only be seen on prenatal ultrasonography in 25 of 35 fetuses (71.4%) after that. In the control group (prenatal expectantly managed cases), cesarean delivery was scheduled at 38 weeks. Antenatal steroids were not given to any cases in the present series. All newborns were treated with the same protocol.25 Briefly, the neonates were intubated in the delivery room and immediately admitted to the intensive care unit. The protocol design was as follows: immediate ventilator support was initiated followed by high-frequency oscillatory ventilation when necessary and delayed congenital diaphragmatic hernia repair. The treatment protocol did not include extracorporeal membrane oxygenation, either preoperatively or postoperatively because this therapy was not available at our institution. Inhaled nitric oxide was administered in cases of persistent pulmonary hypertension verified by a preductal compared with postductal saturation difference of greater than 10% confirmed by echocardiography. Hemodynamic support was achieved with volume expansion, dobutamine (10–20 micrograms/kg/min) and norepinephrine when necessary (0.5–2 micrograms/kg/min). Congenital diaphragmatic hernia repair was only performed after preoperative respiratory and hemodynamic stabilization. Stabilization was defined by the following criteria: 1) normal hemodynamic variables (mean blood pressure greater than 40 mm Hg with a urine output greater than 2 mL/kg/h) without the need for inotropic agents; 2) absence of persistent pulmonary hypertension after discontinuation of inhaled nitrous oxide; and 3) successful weaning to conventional mechanical ventilation with moderate values of peak inspiratory pressure (15–20 cm H2O) and adequate oxygenation achieved with FiO2 0.4 or less.
The data were analyzed using the Student's t, analysis of variance, and the post hoc Sidak tests26 and chi-square and Fisher's exact tests for all three lung parameters measured at four different time intervals (before and 2, 4, and 6 weeks after fetal intervention) for comparison between fetal endoscopic tracheal occlusion and no fetal endoscopic tracheal occlusion (all cases) and for comparison of neonatal survivors and nonsurvivors among fetuses that underwent fetal endoscopic tracheal occlusion. Receiver operating characteristic curves were also calculated to evaluate the accuracy of each variable at all four time intervals for the prediction of neonatal survival among the 35 fetuses that underwent fetal endoscopic tracheal occlusion by comparing the areas under the curve (AUC) according to the DeLong et al and Hanley and McNeil tests.27,28 Best thresholds (points with the highest sensitivity and lowest rate of false positivity) were established. In addition, the relative ratio and its 95% confidence intervals (CIs) were calculated. Factor analysis and regression analysis were performed to evaluate combinations of variables at all intervals (before and after fetal endoscopic tracheal occlusion). Receiver operating characteristic curves were generated from the regression factor analysis to evaluate the combinations of observed-to-expected lung-to-head ratio, observed-to-expected total fetal lung volume ratio, and contralateral pulmonary vascularization index; lung-to-head ratio and contralateral pulmonary vascularization index; and observed-to-expected total fetal lung volume ratio and contralateral pulmonary vascularization index at all time intervals. P<.05 was considered statistically significant.
Maternal and fetal demographics were similar in both groups (Table 1). The incidence of preterm premature rupture of the membranes was slightly higher in the fetal endoscopic tracheal occlusion group (34% compared with 22%); however, this difference did not reach statistical significance. Other complications including maternal blood transfusion, maternal infection, and abruption were similar in both groups.
The mean interval between fetal endoscopic tracheal occlusion and delivery was 8.0±2.6 weeks (range 2–12 weeks). Patients in the fetal endoscopic tracheal occlusion group delivered on average 2 weeks earlier than the no fetal endoscopic tracheal occlusion group (P<.01); however, mean newborn weight was similar in both groups. The overall survival rate was 19 of 35 (54.3%) cases in the fetal endoscopic tracheal occlusion group compared with two of 37 (5.4%) cases in the no fetal endoscopic tracheal occlusion group (P<.01). Severe pulmonary artery hypertension was diagnosed in 17 of 35 (48.6%) newborns in the fetal endoscopic tracheal occlusion group and in 32 of 37 (86.5%) in the no fetal endoscopic tracheal occlusion group (P<.01). Postnatal surgical repair of the diaphragm defect was performed in 31 neonates after ventilatory and hemodynamic stabilization: in 65.7% of cases in the fetal endoscopic tracheal occlusion group compared with 21.6% in the no fetal endoscopic tracheal occlusion group (P<.01).
When comparing serial pulmonary measurements, the observed-to-expected lung-to-head ratio, observed-to-expected total fetal lung volume ratio, and contralateral pulmonary vascularization index were statistically unchanged throughout gestation in the no fetal endoscopic tracheal occlusion group (0.3%, 0.1%, 0.0%, P=.99), whereas in the fetal endoscopic tracheal occlusion group, all parameters increased progressively up to 4 weeks after fetal intervention (56.2%, 37.9%, 98.6%, P<.01) (Fig. 1A–C). For all three fetal pulmonary parameters in the fetal endoscopic tracheal occlusion group, there was no statistical difference between 4 and 6 weeks after the procedure (P<.05). Comparing the fetal endoscopic tracheal occlusion and the no fetal endoscopic tracheal occlusion group, all three parameters were significantly increased at 2, 4, and 6 weeks after fetal endoscopic tracheal occlusion when compared with the no fetal endoscopic tracheal occlusion group (P<.01).
Among the 35 fetuses that underwent fetal endoscopic tracheal occlusion, the comparison between survivors and nonsurvivors is shown in Table 2. Gestational age at fetal endoscopic tracheal occlusion, interval to delivery, and gestational age at delivery were similar in the two groups.
There was a statistical increase in the observed-to-expected lung-to-head ratio with advancing gestational age in both survivors and nonsurvivors (P<.01); however, this difference was only significant between these groups at 4 weeks and 6 weeks after fetal endoscopic tracheal occlusion (P<.01; Fig. 2A). The observed-to-expected total fetal lung volume ratio similarly increased in both groups after fetal endoscopic tracheal occlusion; however, this increase was statistically more pronounced in the survivors as compared with nonsurvivors at 2, 4, and 6 weeks after fetal endoscopic tracheal occlusion (P<.01; Fig. 2B). Vascularization index increased in both groups but a statistical difference in the increase was noted at 2, 4, and 6 weeks in the survivors over the nonsurvivors (P<.01; Fig. 2C). The receiver operating characteristic analysis showed that the baseline observed-to-expected total lung volume ratio (AUC 0.88, relative risk 5.3, 95% CI 1.4–19.7) was the best predictor of survival after the fetal endoscopic tracheal occlusion procedure when compared with observed-to-expected lung-to-head ratio (AUC 0.78, relative risk 5.1, 95% CI 5.1–14.9) and contralateral pulmonary vascularization index (AUC 0.66, relative risk 2.2, 95% CI 0.9–4.9, P<.01). However, 4 weeks after fetal endoscopic tracheal occlusion procedures, the contralateral pulmonary vascularization index (AUC 0.98, relative risk 9.9, 95% CI 1.5–66.9) was associated with the greatest accuracy for predicting neonatal survival when compared with the observed-to-expected lung-to-head ratio (AUC 0.85, relative risk 7.8, 95% CI 1.4–22.8) and observed-to-expected total fetal lung volume ratio (AUC 0.93, relative risk 8.1, 95% CI 2.1–17.5, P<.01). The receiver operating characteristic analysis provided the best cutoffs for the observed-to-expected lung-to-head ratio, observed-to-expected total fetal lung volume ratio, and contralateral pulmonary vascularization index that were associated with increased chance of survival rates, which were 0.26% or greater, 0.35% or greater, and 25% or greater, respectively.
Considering dual combinations including one parameter that measures the lung size and another the pulmonary vascularity, the best predictor for neonatal survival was found to be “observed-to-expected total fetal lung volume ratio + contralateral pulmonary vascularization index” measured at 4 weeks after fetal endoscopic tracheal occlusion (AUC 0.98, relative risk 16.6, 95% CI 2.5–112.3) when compared with the “observed-to-expected lung-to-head ratio+contralateral pulmonary vascularization index” (AUC 0.92, relative risk 8.7, 95% CI 2.3–32.7; P<.01).
A subsequent analysis of fetal pulmonary response and neonatal outcome was undertaken by considering the best thresholds for preoperative pulmonary values that had been determined through receiver operating characteristic curve analysis (Table 3). This analysis confirmed that observed-to-expected lung-to-head ratio 0.17 or less and observed-to-expected total fetal lung volume ratio 0.23 or less at 4 weeks after fetal endoscopic tracheal occlusion were significantly associated with an insufficient fetal lung response and subsequent neonatal death (P<.01).
Our study confirms that fetal endoscopic tracheal occlusion improves survival in fetuses with isolated severe congenital diaphragmatic hernia by promoting the increase in fetal lung size and pulmonary vasculature. In the present study, the survival rate among fetuses with severe isolated congenital diaphragmatic hernia increased from 5% without fetal intervention to 55% after fetal endoscopic tracheal occlusion in our center by improving the pulmonary response (increase in lung size and vascularity) after fetal tracheal occlusion. Besides, among those fetuses that underwent fetal endoscopic tracheal occlusion procedure, the fetal pulmonary response after tracheal occlusion can also be used to predict postnatal outcome.
Previous studies have reported information on the follow-up of fetal pulmonary growth up to 4 weeks after fetal endoscopic tracheal occlusion.18,29 Peralta et al18 followed pulmonary growth in 30 fetuses with isolated severe congenital diaphragmatic hernia that underwent fetal endoscopic tracheal occlusion using three-dimensional ultrasonography for 7 days after the procedure. The authors demonstrated that the lung response 2 and 7 days after tracheal occlusion was useful in predicting neonatal survival. However, there was no evaluation of the fetal pulmonary response after fetal endoscopic tracheal occlusion when compared with those fetuses that did not undergo to tracheal occlusion procedures. Recently, Cannie et al29 provided evidence that lung volumes estimated by magnetic resonance imaging before and 3.3 weeks after fetal endoscopic tracheal occlusion were independent predictors of neonatal survival in a controlled study.
In our study, fetal pulmonary size and vascularity were evaluated up to 6 weeks after fetal endoscopic tracheal occlusion by using two-dimensional and three-dimensional ultrasonography. Our findings demonstrated that the fetal lung size and vascularity increased to a maximum by 4 weeks after fetal endoscopic tracheal occlusion and then a slight reduction occurred but without statistical significance. This information suggests that 4 weeks of tracheal occlusion may be sufficient for the peak response in fetal lung growth and may represent the optimal time to remove the balloon (“unplugging”). Experimental research in a sheep model for congenital diaphragmatic hernia has revealed that tracheal occlusion should be reversed to permit recovery of type II pneumocytes.11,30–34 However, there are no experimental data (in animal models) to date in the literature that provide information on the optimal duration length of tracheal occlusion. In humans, the general guidelines for fetal endoscopic tracheal occlusion include placement between 26 and 30 weeks of gestation with removal 6 weeks later.35 Data in humans as to the optimal length of tracheal occlusion for the treatment of congenital diaphragmatic hernia are lacking as well. Fetuses undergoing the release of tracheal occlusion at least 24 hours before delivery exhibit an improved neonatal outcome.29 Although our data are suggestive that 4 weeks may be the proper duration for fetal endoscopic tracheal occlusion, additional human trials will be needed to determine the correct length of time required.
Our study also provides unique information regarding the fetal pulmonary vascular response after fetal endoscopic tracheal occlusion. Experimental research in rabbit models for congenital diaphragmatic hernia has shown that tracheal occlusion reverses the detrimental effects of the muscularization of pulmonary arteries caused by pulmonary hypoplasia.36–39 A previous study at our institution demonstrated that the contralateral pulmonary vascularization index estimated by three-dimensional-power Doppler was the best predictor of neonatal outcome in those cases with isolated congenital diaphragmatic hernia not treated with fetal intervention.40 Contralateral pulmonary vascularization index also correlated with the postnatal diagnosis of severe pulmonary artery hypertension, the main cause of neonatal death and morbidity.10 The current investigation indicates that contralateral pulmonary vascularization index in conjunction with a measure of lung size (observed-to-expected total fetal lung volume ratio) was the best overall predictor of neonatal survival. These data confirm that fetal endoscopic tracheal occlusion improves fetal lung growth and vascularity in the majority of fetuses with congenital diaphragmatic hernia, which is related to postnatal outcome.
Our study also demonstrates that fetuses with extremely severe pulmonary hypoplasia (observed-to-expected lung-to-head ratio 0.17 or less and observed-to-expected total fetal lung volume ratio 0.23 or less) before fetal endoscopic tracheal occlusion exhibit a diminished pulmonary response to tracheal occlusion with an associated worse neonatal prognosis. For these cases, fetal endoscopic tracheal occlusion performed between 26 and 30 weeks of gestation may not be beneficial and additional fetal therapies should be evaluated. Early fetal endoscopic tracheal occlusion, performed between 22 and 24 weeks of gestation, needs to be studied to verify if fetal pulmonary response and neonatal outcome will be improved. Our study also suggests that fetal lung parameters should be followed after fetal endoscopic tracheal occlusion because they are useful to predict postnatal outcome. In cases of poor pulmonary response, a stormy neonatal course can be expected. In such cases, immediate access to extracorporeal membrane oxygenation soon after birth may be warranted.
In conclusion, the present study demonstrates that minimal changes in pulmonary size and vascularity occur with advancing gestational age in fetuses with severe congenital diaphragmatic hernia. When fetal endoscopic tracheal occlusion is performed between 26 and 30 weeks of gestation, improvement in fetal pulmonary growth and vascularization occurs. These effects are less pronounced in fetuses with extremely severe congenital diaphragmatic hernia. In these cases, fetal endoscopic tracheal occlusion may not be effective in the treatment of a congenital diaphragmatic hernia.
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