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Prenatal intervention for congenital diaphragmatic hernia
Seminars in Pediatric Surgery (2007) 16, 101-108
Prenatal intervention for congenital diaphragmatic hernia Yoshihiro Kitano, MD From the Division of General Surgery, Saitama Children’s Medical Center, Saitama, Japan. KEYWORDS Congenital diaphragmatic hernia; Tracheal occlusion; Fetal surgery; Prenatal diagnosis; Gentle ventilation
Advances in prenatal ultrasound have revealed the poor natural history of fetal congenital diaphragmatic hernia (CDH) and its hidden mortality during gestation and immediately after birth. Attempts to improve this poor outcome led to the development of prenatal surgical intervention for severe CDH by Harrison and his colleagues at the University of California San Francisco. Prenatal surgical intervention for CDH has seen four phases: open fetal surgical repair, open surgical tracheal occlusion, endoscopic external tracheal occlusion, and endoscopic endoluminal tracheal occlusion. After extensive work in the laboratory, prenatal intervention has been applied in humans since 1984. With the most recent techniques, maternal risk is significantly reduced as is the incidence of preterm labor. In the meantime, the survival rate of fetuses with CDH without fetal intervention has improved mainly due to the minimization of iatrogenic lung injury by gentle ventilation, first described in 1985. However, the morbidity of the survivors with severe CDH remains high. Prenatal intervention for CDH will be justified if improvement in survival or morbidity can be demonstrated when compared to planned delivery and postnatal management with gentle ventilation strategy. © 2007 Elsevier Inc. All rights reserved.
Congenital diaphragmatic hernia (CDH) remains one of the most challenging diagnoses for pediatric surgeons and neonatologists. It is well known that the pulmonary hypoplasia and concomitant pulmonary hypertension, resulting from inadequate space in the thoracic cavity during lung development, have a major impact on postnatal mortality and respiratory morbidity in patients with CDH. Pulmonary hypoplasia in CDH is characterized by a decrease in lung weight and reduction in the number of bronchial divisions, respiratory bronchioles, and alveoli. The pulmonary vascular bed is also hypoplastic, and increased muscularization is observed in arterioles, which contributes to the pulmonary hypertension. The degree of pulmonary hypoplasia is related to the timing of herniation and the volume occupied in the chest by abdominal viscera.1 In late-presenting diaphragmatic hernia, despite similar radiological findings, the
Address reprint requests and correspondence: Yoshihiro Kitano, MD, Division of General Surgery, Saitama Children’s Medical Center, 2100 Iwatsuki-ku, Saitama 339-8551, Japan. E-mail: [email protected].
1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.01.005
outcomes are excellent because of normal pulmonary development.2 There have been two trends in the management of prenatally diagnosed CDH: the development of prenatal intervention and improvements in postnatal care. Both approaches have made significant progress, while the clinical role of the former remains controversial. The purpose of this article is to review the recent issues related to prenatal tracheal occlusion (TO) compared with postnatal care with gentle ventilation. Since prenatal intervention is currently not considered for those fetuses with other associated anomalies, only prenatally diagnosed, isolated CDH will be discussed in this chapter.
Prenatal diagnosis of CDH and recognition of hidden mortality The diagnosis of CDH is relatively easy to make by screening ultrasound examination. The prenatal diagnosis of leftsided CDH is made by seeing a fluid-filled stomach or
102 bowel with or without the liver in the left chest cavity and rightward mediastinal shift. Right-sided CDH may be more difficult to diagnose because the liver, which has a similar sonographic appearance as the lung, can be the single organ herniated into the chest. Although there is considerable variation in detection rates between regions depending on the prenatal screening programs, the overall prenatal detection rate is 59% in European countries.3 As prenatal diagnosis of CDH became common in the 1980s, the natural history of fetal CDH was recognized to be very different from that of neonatal CDH. Improvements in fetal diagnosis led to a recognition of increasing numbers of CDH cases with severe pulmonary hypoplasia. These were the subgroup of patients who would not have survived the immediate postnatal period without planned delivery. This issue was addressed in a prospective analysis, which provided invaluable data on the mortality rate of fetal CDH without associated anomalies.4 The study included 83 cases with isolated CDH diagnosed before 24 weeks gestation, referred for consideration of fetal therapy between 1989 and 1993. Forty-eight patients (including 7 cases of third trimester intrauterine demise) died, resulting in an overall 58% mortality rate. Twenty-two of 35 survivors required extracorporeal membrane oxygenation (ECMO), of which 9 patients had significant morbidity. This study clearly documented that patients diagnosed with an isolated CDH in utero suffer substantial mortality and morbidity, despite accurate prenatal diagnosis and sophisticated neonatal care including maternal transport, planned delivery, and immediate resuscitation at institutions with ECMO capability (but, presumably not gentle ventilation).
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 aspect of the liver to the apex of the chest by the distance from the diaphragm remnant to the apex of the chest.5 They found that the mean liver/diaphragm ratio was significantly higher in the survivors compared with the non-survivors, but no clear cut-off had been determined. This observation was reproduced in Japan.9 The LHR is a sonographic measurement of right lung size standardized to head circumference in left-sided CDH, and has been validated retrospectively7 and prospectively.15 Although excellent correlation between LHR and survival are reported,8 other centers have been unable to reproduce its prognostic value.16,17 The reason for this discrepancy could be related to two factors. First, the measurement of LHR is observer-dependent and, from our experience, the difference of 0.2 to 0.3 is not uncommon. Secondly, improvements in postnatal care are lowering the cut-off values of LHR, and its prognostic value is changing. For instance, the prognostic value of LHR in the liver-down CDH has been refuted8,18 as opposed to the previous reports.19 From the perspective of majority of clinicians, the prognostic role of LHR is controversial. Recently, efforts have been made to predict survival by other morphological assessments, such as three-dimensional measurement of lung volume by fetal MRI5,20 or threedimensional sonography21,22 and measurement of pulmonary artery diameters.23 Physiological assessment of fetal lung function is ideal but limited at present to that of pulmonary vascular function. The pulmonary arterial pulsatility index with or without maternal oxygen supplementation24,25 and acceleration time/ejection time ratio26 are reported as physiological assessments of fetal pulmonary hypoplasia. The prognostic value of these new measurements must be validated in a further study.
Prenatal prediction of survival in fetal CDH The ability to predict which fetuses are destined for a poor outcome is a prerequisite for any fetal intervention. Although a number of prenatal predictors of survival have been proposed, few have been confirmed in more than a single center. The most widely accepted prognostic indicators for fetal CDH are the position of the liver (“liver-up ” versus “liver-down”) and sonographic measurement of the right lung area-to-head circumference (LHR). Liver herniation is a well-known prognostic factor of CDH.5-7 The current survival rate for liver-up CDH is estimated to be around 50%.6-9 The true incidence of liver herniation is unknown, but up to 75% of CDH patients are reported to have some portion of the liver in the chest.10 Although Doppler ultrasonography has been the most common tool to determine the liver position, it can be examinerdependent,11,12 and we believe that MRI is a more objective modality.9,13,14 The degree of liver herniation can vary and affects the outcome. There is only one study assessing the degree of liver herniation by measuring a left liver/diaphragm ratio, which is calculated by dividing the distance from superior
Development of prenatal intervention Since the recognition of the poor natural history of prenatally diagnosed CDH, prenatal intervention was extensively studied first in the laboratory and then in human trials. Until recently, it was generally accepted that a fetus with liver-up CDH and LHR ⬍1.0 had a very little chance of survival, and prenatal interventions were aimed to improve survival in this subset of patients. The initial prenatal intervention was in utero repair, first attempted in 1984.27 This was an open fetal operation requiring maternal laparotomy, hysterotomy, and fetal laparotomy/thoracotomy. The first successful case using this procedure was reported in 1990,28 and a prospective randomized study in fetuses with liver-down CDH was performed. Successful repair was possible in fetuses with liverdown CDH, but the mortality and morbidity with this procedure was not different from postnatal conventional management.29 In liver-up CDH, the open procedure was not feasible because reduction of the liver obstructed the umbilical vein, the lifeline of the fetus.30,31 This procedure
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was therefore abandoned, and fetuses without liver herniation were excluded from future prenatal intervention. A completely different approach arose from the clinical observation that tracheal atresia results in lung hyperplasia even with bilateral renal agenesis.32 Combined with known physiological data on lung fluid dynamics and fetal lung growth,33-35 therapeutic tracheal occlusion (TO) was suggested as a potential method to overcome lethal pulmonary hypoplasia associated with CDH.36,37 The technique as well as the effects of this procedure was extensively studied in various animal models in the 1990s. Briefly, the following observations were established. 1. TO accelerates fetal lung growth in normal and CDH animal models with pulmonary hypoplasia.36-40 2. The accelerated lung growth is the result of increased cell division and increased number of alveoli accompanied by an appropriate increase in capillary vessels.36,38,40,41 3. The accelerated lung growth is associated with remodeling of pulmonary arterioles which is likely to ameliorate pulmonary hypertension.42-46 4. Prolonged TO reduces the number of type II cells, resulting in surfactant depletion, which may partly be reversed by early release of TO.47-52 5. The lung growth response to TO is affected by multiple factors including timing (stage of lung development), length of TO, and drugs that affect lung fluid production, such as terbutaline and steroids.39,53-58 6. The mechanism of accelerated lung growth is not fully understood, but it is related to increased lung tissue stretch, which turns on mechano-transduction pathways resulting in lung growth.59-63 A pressure difference (intratracheal pressure–amniotic pressure) of 4-5 mmHg is observed in fetal sheep after complete tracheal obstruction, and no lung growth is achieved with minor lung fluid leakage.59 Achieving watertight, prolonged, and damage-less occlusion of the growing fetal trachea was a challenge.64 Various methods were tried, and it was concluded that external application of vascular clips was superior to an internal plug, which caused tracheomalacia when watertight occlusion was achieved. The first clinical application of TO was reported in 1998.65 Initially, TO was performed by open fetal surgery. Maternal laparotomy and hysterotomy was followed by fetal neck dissection and application of metal clips to fetal trachea. The results of open TO were rather discouraging as discussed below.65,66 The main reason limiting the success of the procedure was assumed to be the maternal hysterotomy, and a less invasive approach was investigated. Videoand ultrasound-assisted fetal endoscopy (FETENDO) served this purpose.67 Although “FETENDO-clip” avoided maternal hysterotomy, it was a complex procedure requiring 3 to 4 cannulas, endoscopic dissection of fetal trachea, and maternal general anesthesia. With evolution of the technique, the procedure-related risks of prenatal intervention
103 decreased. In a retrospective analysis of 187 cases of fetal surgery, Golombeck and coworkers reported that FETENDO was less invasive compared with open fetal surgery comparing cesarean delivery as delivery mode (58.8% versus 94.8%), requirement for intensive care unit stay (1.4% versus 26.4%), length of hospital stay (7.9 days versus 11.9 days), and requirement for blood transfusions (2.9% versus 12.6%).68 However, there were no significant differences in the incidence of premature rupture of membranes (44.1% versus 51.9%), pulmonary edema (25.0% versus 27.8%), placental abruption (5.9% versus 8.9%), preterm delivery (26.5% versus 32.9%), or interval from the procedure to delivery (6.0 weeks versus 4.9 weeks) between FETENDO and open fetal surgery. Interestingly, chorion– amnion membrane separation was seen more often with FETENDO (64.7% versus 20.3%). These complications were significantly less in percutaneous ultrasound-guided procedures. As a result, this technique was also abandoned due to the high rate of preterm delivery and irreversible damage to the laryngeal nerve and trachea. The concept of internal obstruction using a detachable balloon originally designed for aneurysm treatment was revived. This approach was shown effective without tracheal damage in fetal lambs.69,70 It was performed with (FETENDO-balloon) or without (FETO) maternal laparotomy. It is now feasible to perform with a single 10-Fr cannula and a 1.2-mm fetoscope without maternal laparotomy under regional anesthesia.71,72 The whole procedure is accomplished within 20 minutes in experienced hands and does not require large doses of tocolytics. Furthermore, in order to avoid the need for an EXIT procedure and to overcome the drawback of long-term TO, that is, differentiation of type II pneumocytes into type I pneumocytes resulting in surfactant deficiency, a strategy was developed to deflate the balloon at 34 weeks by puncturing it under sonographic guidance. Table 1 summarizes the evolution of endoscopic TO procedures.
Survival and morbidity of fetuses treated with TO: American reports TO was first performed in humans by open fetal surgery with a survival of 15% (n ⫽ 13) and 33% (n ⫽ 15), in two series.65,66 Although the main reason for this poor outcome was attributed to the invasive technique leading to premature delivery, Flake and coworkers reported two intriguing observations. First, lung growth response to TO was variable. Some fetal lungs did not grow significantly despite complete tracheal obstruction confirmed at birth. Second, pulmonary function of the newborns treated with TO was abnormal even when dramatic lung growth was observed in utero. The survivors required intensive management after birth with significant long-term morbidity, including neurologic injury in 60%. An NIH-sponsored prospective randomized trial comparing endoscopic TO and standard postnatal treatment was
104 Table 1
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 Evolution of endoscopic tracheal occlusion Reports from U.S.A.
Reports from Europe
Technique
FETENDO-clip
FETENDO-balloon
FETO
Device for TO Number of cannulas Size of the cannula Laparotomy Anesthesia Length of procedure EXIT
Vascular clip 3 5 mm Yes General 2.5-6 hrs Yes
Detachable balloon 1 5 mm Yes General 2-2.5 hrs Yes
Detachable balloon 1 3.3 mm no Spinal-epidural 20 min (5-54 min) no
carried out between 1999 and 2001.73 The inclusion criteria for this study were the presence of isolated left-sided liver-up CDH with an LHR ⬍1.4 (measured at between 22 and 27 weeks gestation). The procedures included were FETENDO-clip (n ⫽ 2) and FETENDO-balloon (n ⫽ 9). In this study, 13 cases were treated by standard postnatal care and 11 by TO with the survival of 77% and 73%, respectively. The study was closed prematurely due to the conclusion that further recruitment would not result in significant differences in survival between the two groups. The unexpectedly high survival in the standard postnatal care group shows the recent improvements in postnatal care. Of note, all postnatal care was provided by UCSF in this trial as opposed to previous reports in which postnatal care was given by each referral center. Premature rupture of membranes leading to premature delivery was inevitable in the TO group (the mean age at delivery was 30.8 weeks). Although this was a drawback of prenatal intervention, an argument was made that the same survival achieved in the more premature babies of the TO group indicates the potential benefit of TO. There was a question why an LHR ⬍1.4 was chosen because it had been known that a fetus with an LHR of 1.0 to 1.4 does not always die.15 It could be argued that the comparable survival was the result of inclusion of too many patients with potentially good prognosis. However, the survival was comparable even if the fetuses with an LHR ⬍1.06 were compared; 11 cases in postnatal group and 7 cases in TO group had an LHR ⬍1.06 with the survival of 73% and 71%, respectively. Despite the comparable survival in both groups, the clinical significance of TO would not be lost if less morbidity could be shown in the survivors. For example, if TO could improve neonatal lung function and decrease the ECMO need, the morbidity of TO and ECMO should be compared. However, ECMO was required in only one of 13 patients in the postnatal care group. The rates of respiratory and gastrointestinal complications at discharge were not different. The morbidity of the survivors (9 cases in the postnatal care group and 7 cases in the TO group) after 1 to 2 years is also reported.74 Both groups suffered from various problems including chronic lung disease, gastro-esophageal reflux, hernia recurrence, growth retardation, and auditory deficit.
There was no difference in any morbidity between the two groups. Neonatal pulmonary functions of the survivors was reported by Keller and coworkers.75 While some parameters, such as respiratory system compliance, peak expiratory flow, and alveolar–arterial oxygen difference, were better in the TO group than in the standard care group, there was no difference in the oxygenation index and minute ventilation. Although this comparison has a limitation because the gestational age of the two groups (30.8 ⫾ 2.0 weeks versus 37.4 ⫾ 1.0 weeks) is significantly different, the authors concluded that the benefit of TO in neonatal pulmonary function was of questionable clinical significance. An autopsy study of the patients who underwent TO revealed that the radial alveolar count was low, even in those cases who showed increasing LHR after TO.76 Instead, each alveolus was enlarged. The medial thickness of arterioles was also not different. These results should be cautiously interpreted because the survivors are not studied. However, it should be appreciated that the increase in LHR after TO does not necessarily indicate accelerated lung growth. The mere distention of the existed lung air space can cause marked increase in LHR. These reports from UCSF and CHOP suggest that the clinical benefit of TO remains questionable. Most importantly, the morbidity of the survivors does not seem to be improved by TO.
Survival and morbidity of fetuses treated with TO: European reports The European perinatologists (The FETO task group) organized a multicenter prospective study on FETO. In their initial report, they offered FETO to a subset with liver herniation and an LHR ⬍1.0, measured between 26 and 28 weeks.77 The selection criteria were intended to identify a more severe subset than those studied in the UCSF trial. The laterality of the defect was not considered and there were 15 left-sided CDH and 6 right-sided CDH included, which was somewhat confusing because the LHR in right-sided CDH was not well validated. They reported a survival of 48%,
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which is significantly better than the survival of 8% in a comparable group who declined fetal intervention. The airway was restored either perinatally (n ⫽ 12) or prenatally (n ⫽ 9), and the survival was higher with prenatal balloon retrieval compared with postnatal retrieval (67% versus 33%), although this did not reach statistical significance. There were no serious maternal complications or direct fetal adverse effects in their initial experience with 24 FETO.71 Tocolysis used to be a major concern after open fetal surgery, but the only tocolysis given perioperatively for FETO was nifedipine, 20 mg twice a day for a few days. None of their patients required additional tocolysis after the procedure. Premature rupture of membranes occurred in 33.3% of patients before 32 weeks, but has been improving over time. As a result, the mean gestational age at delivery was 33.5 weeks, later than that reported in the UCSF trial (30.8 weeks). With increasing experience, it has further improved to 37 weeks in their last 20 cases.78 Thus, maternal morbidity, if not fetal morbidity, has been significantly decreased by FETO, potentially justifying its application in selected candidates. The study is still ongoing, and in their latest report it was suggested that preoperative LHR is predictive of the postnatal survival after FETO.84 In their 28 consecutive cases of left-sided liver-up CDH with an LHR of ⬍1.0, 16 (57%) survived. Twelve deaths were all caused by respiratory insufficiency. The survival rate of fetuses that underwent FETO was 17% for those with an LHR of 0.4 to 0.5, 62% for those with an LHR of 0.6 to 0.7, and 78% for those with an LHR of 0.8 to 0.9. The survival rate of 78% in those with an LHR of 0.8 to 0.9 was higher than the survival rate of those with an LHR of 1.0 to 1.3 treated postnatally (65%). Hence, it is claimed that FETO may improve the outcome in those fetuses with an LHR of 0.6 to 1.3 (instead of ⬍1.0). Information on the morbidity of the survivors from European Series is limited, but promising compared to the results reported from UCSF. The 12 survivors (6-35 months) have no apparent developmental problems.19 Four of them were oxygen-dependent after discharge but are currently off oxygen. In addition, not a single case required ECMO in patients with an LHR of 0.7 to 0.9 (n ⫽ 22).78 A group from Germany independently reported their early experience with deliberately delayed FETO.79 Kohl and coworkers elected to perform FETO later in gestation between 29 to 32 weeks to minimize the adverse effects of premature delivery and to reserve ECMO as a treatment option postnatally. Eight fetuses with comparably severe CDH (details shown in Table 2) underwent FETO, and 6 of 8 patients survived. Two patients died before ECMO and 5 of the 6 survivors required ECMO. The control patients were treated by the same team with a survival rate of 33% (2/6). Their approach is appealing, but the results are inconsistent with previous reports. The FETO task group, in their early experience, found that FETO performed at 31 and 32 weeks did not prevent respiratory failure at birth, and the timing of FETO was advanced to the second trimester.77
105 Flake and coworkers also found that early TO (25-26 weeks) results in more consistent lung growth than late TO (27-28 weeks).66 There is no question that FETO has significantly reduced maternal risks and has almost overcome preterm delivery, the Achilles heel of fetal surgery, and the preliminary results are encouraging. However, the following limitations need to be appreciated to prevent premature widespread application of FETO. First, control cases were collected from multiple centers since 1995. This may not reflect the recent improvements in postnatal care. In a future randomized study, all postnatal care should be given at the same centers that care the babies treated by FETO. Second, the details of longterm outcome and morbidity of the survivors are yet to be reported. Third, there remains some concern regarding the efficacy of tracheal obstruction by balloons80 because the increase of LHR from 0.7 (range, 0.4-0.9) to 1.8 (range, 1.1-2.9),77 or from 0.7-1.0 to 1.0-3.579 is not as dramatic as the increase reported by others.66 Clinical reports on fetal TO for CDH are summarized in Table 2.
Recent improvement in postnatal care Perhaps the most important factor that has improved postnatal care of CDH is the introduction of gentle ventilation, or avoidance of ventilator-induced lung injury to the immature and hypoplastic lung. The role of mechanical ventilation in CDH is discussed in the article by Logan and coworkers.81 With slow but steady acceptance of gentle ventilation, the survival of fetal CDH has improved. Some centers reported a survival as high as 90% with this approach,82,83 but this is not always reproduced across all institutions probably due to different levels of postnatal care and case selection bias. Thus, the true survival rate with gentle ventilation strategy is not yet established. Since the management of a patient with severe CDH is like walking the ridge with steep cliffs on both sides, any small accident could lead to a bad outcome. Infection control including the management of central venous lines, aggressive establishment of enteral nutrition, and experience in managing the sickest babies may make a significant difference. The natural history of fetal CDH including both morbidity and mortality in the era of planned delivery and gentle ventilation must be reestablished in selected centers capable of NO inhalation, HFOV, and ECMO in order to accurately evaluate fetal intervention.
Future Despite significant improvements in postnatal care, there remains a small subset of patients whose lung is too small to survive, and more importantly, the morbidity of the survivors is significant. To prove the role of prenatal intervention in the management of fetal CDH, it should prove to save a
Not improved Morbidity of the survivors
—
Not improved
Without apparent developmental problems, all off oxygen
75% (left 3, right 3) 2/6⫽33% (left only), treated at the same institution — 57% 3/27⫽11% 73% 10/13⫽77%, treated at the same institution 33% (left 3, right 2) 0/7⫽0%, treated at the same institution Open 15%, FETENDO-clip 75% 5/13⫽38%
28 FETENDO-clip 2, FETENDO-balloon 9 15 (left 13, right 2)
Number of patients Survival (%) Control
Open 13, FETENDO-clip 8
— No FETO (25–29 wks) Left, liver-up, LHR ⬍1.0 1999-2001 Yes FETENDO-clip vs FETENDO-balloon Left, liver-up, LHR ⬍1.4 1994-1997 No Open vs FETENDO-clip Left, liver-up, LHR ⬍ 1.4 Study period Randomized study TO methods Inclusion criteria
1995-1999 No Open Left, liver-up, LHR ⬍1.0, or right, Liver-up, left lung not visualized
Deprest (2006) Harrison (2003) Flake (2000) Harrison (1998) Author (year)
Summary of prenatal tracheal occlusion for CDH in humans Table 2
— No Late FETO (29–32 wks) Left, liver-up, LHR ⬍0.9, MRI lung volume ⬍14 ml, or right, liver-up, LHR ⬍1.0, MRI lung volume ⬍14 ml 8 (left 5, right 3)
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007
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small subset with fatal pulmonary hypoplasia or improve the morbidity of the survivors. It may be difficult to show the former because of improving postnatal care and current limitation of FETO to treat the severest subset with LHR ⬍0.5.84 The latter is very important because it is conceivable that more parents would choose termination without an improvement in postnatal morbidity. This trend will inevitably be enhanced by continued advances in prenatal imaging; many fetuses with liver-up CDH could be diagnosed at 20 weeks in the near future. Therefore, the morbidity (or quality of life) of the survivors of FETO, such as the need for home oxygenation or ventilation therapy, hearing loss, growth retardation, and mental development, needs to be addressed in detail. If the results are encouraging, a randomized controlled study comparing the morbidity, rather than the survival, may be practical. Considering the fact that FETO can be performed with a 4-mm incision within 20 minutes under local-regional anesthesia by an experienced team, it may become reasonable to offer this procedure to a mother carrying a fetus with severe CDH in selected centers. The expected role of prenatal intervention for CDH has shifted from improving survival to improving morbidity related with pulmonary hypoplasia. We can expect prenatal intervention to further improve in the future. Optimal timing and duration of TO in human CDH remains unproven.66,72,79 Refinement of the procedure, such as ultrasound-guided occlusion of fetal trachea,85 intratracheal delivery of a rapidly polymerizing hydrogel cephalad to balloons to prevent balloon dislodgement,80 and enhancement of lung fluid osmolarity,86 are being investigated. Combination of FETO with other modalities such as surfactant and corticosteroids may prove effective.87 Therapeutic gene therapy88 and vitamin-A administration89,90 are being studied in the laboratory.
References 1. Harrison MR. The fetus with a diaphragmatic hernia: pathophysiology, natural history, and surgical management. In: Harrison MR, Golbus MS, Filly RA, eds. The Unborn Patients: Prenatal Diagnosis and Treatment (ed 2), Chap 28. Philadelphia, PA: Saunders, 1991: 295-313. 2. Congenital Diaphragmatic Hernia Study Group. Late presenting congenital diaphragmatic hernia. J Pediatr Surg 2005;40:1839-43. 3. Garne E, Haeusler M, Barisic I, et al. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329-33. 4. Harrison MR, Adzick NS, Estes JM, et al. A prospective study of the outcome for fetuses with diaphragmatic hernia. J Am Med Assoc 1994;271:382-4. 5. Walsh DS, Hubbard AM, Olutoye OO, et al. Assessment of fetal lung volumes and liver herniation with magnetic resonance imaging in congenital diaphragmatic hernia. Am J Obstet Gynecol 2000;183: 1067-9. 6. Albanese CT, Lopoo J, Goldstein RB, et al. Fetal liver position and perinatal outcome for congenital diaphragmatic hernia. Prenat Diagn 1998;18:1138-42. 7. Metkus AP, Filly RA, Stringer MD, et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-51.
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8. Jani J, Keller RL, Benachi A, et al. Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:18-22. 9. Kitano Y, Nakagawa S, Kuroda T, et al. Liver position in fetal congenital diaphragmatic hernia retains a prognostic value in the era of lung-protective strategy. J Pediatr Surg 2005;40:1827-32. 10. Doyle NM, Lally KP. The CDH Study Group and advances in the clinical care of the patient with congenital diaphragmatic hernia. Semin Perinatol 2004;28:174-84. 11. Lewis DA, Reickert C, Bowerman R, et al. Prenatal ultrasonography frequently fails to diagnose congenital diaphragmatic hernia. J Pediatr Surg 1997;32:352-6. 12. Bootstaylor BS, Filly RA, Harrison MR, et al. Prenatal sonographic predictors of liver herniation in congenital diaphragmatic hernia. J Ultrasound Med 1995;14:515-20. 13. Hubbard AM, Adzick NS, Crombleholme TM, et al. Left-sided congenital diaphragmatic hernia: value of prenatal MR imaging in preparation for fetal surgery. Radiology 1997;203:636-40. 14. Kilian AK, Busing KA, Schaible T, et al. Fetal magnetic resonance imaging Diagnostics in congenital diaphragmatic hernia. Radiologe 2006;46:128-32. 15. Lipshutz GS, Albanese CT, Feldstein VA, et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997;32: 1634-6. 16. Arkivitz M, Devine P, Russo M, et al. Fetal lung to head ratio (LHR) is not related to outcome for antenatal diagnosed congenital diaphragmatic hernia (CDH). J Pediatr Surg 2007;42:107-11. 17. Heling KS, Wauer RR, Hammer H, et al. Reliability of the lung-tohead ratio in predicting outcome and neonatal ventilation parameters in fetuses with congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2005;25:112-8. 18. Sbragia L, Paek BW, Filly RA, et al. Congenital diaphragmatic hernia without herniation of the liver: does the lung-to-head ratio predict survival? J Ultrasound Med 2000;19:845-8. 19. Jani J, Gratacos E, Greenough A, et al. Percutaneous fetal endoscopic tracheal occlusion (FETO) for severe left-sided congenital diaphragmatic hernia. Clin Obstet Gynecol 2005;48:910-22. 20. Gorincour G, Bouvenot J, Mourot MG, et al. Prenatal prognosis of congenital diaphragmatic hernia using magnetic resonance imaging measurement of fetal lung volume. Ultrasound Obstet Gynecol 2005; 26:738-44. 21. Ruano R, Martinovic J, Dommergues M, et al. Accuracy of fetal lung volume assessed by three-dimensional sonography. Ultrasound Obstet Gynecol 2005;26:725-30. 22. Jani J, Peralta CF, Van Schoubroeck D, et al. Relationship between lung-to-head ratio and lung volume in normal fetuses and fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:545-50. 23. Sokol J, Shimizu N, Bohn D, et al. Fetal pulmonary artery diameter measurements as a predictor of morbidity in antenatally diagnosed congenital diaphragmatic hernia: a prospective study. Am J Obstet Gynecol 2006;195:470-7. 24. Chaoui R, Kalache K, Tennstedt C, et al. Pulmonary arterial Doppler velocimetry in fetuses with lung hypoplasia. Eur J Obstet Gynecol Reprod Biol 1999;84:179-85. 25. Broth RE, Wood DC, Rasanen J, et al. Prenatal prediction of lethal pulmonary hypoplasia: the hyperoxygenation test for pulmonary artery reactivity. Am J Obstet Gynecol 2002;187:940-5. 26. Fuke S, Kanzaki T, Mu J, et al. Antenatal prediction of pulmonary hypoplasia by acceleration time/ejection time ratio of fetal pulmonary arteries by Doppler blood flow velocimetry. Am J Obstet Gynecol 2003;188:228-33. 27. Harrison MR, Langer JC, Adzick NS, et al. Correction of congenital diaphragmatic hernia in utero. V. Initial clinical experience. J Pediatr Surg 1990;25:47-55. 28. Harrison MR, Adzick NS, Longaker MT, et al. Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 1990;322:1582-4.
107 29. Harrison MR, Adzick NS, Bullard KM, et al. Correction of congenital diaphragmatic hernia in utero VII: a prospective trial. J Pediatr Surg 1997;32:1637-42. 30. MacGillivray TE, Jennings RW, Rudolph AM, et al. Vascular changes with in utero correction of diaphragmatic hernia. J Pediatr Surg 1994;29:992-6. 31. Harrison MR, Adzick NS, Flake AW, et al. Correction of congenital diaphragmatic hernia in utero. VI. Hard-earned lessons. J Pediatr Surg 1993;28:1411-7. 32. Wigglesworth JS, Desai R, Hislop AA. Fetal lung growth in congenital laryngeal atresia. Pediatr Pathol 1987;7:515-25. 33. Alcorn D, Adamson TM, Lambert TF, et al. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat 1977;123:649-60. 34. Carmel JA, Friedman F, Adams FH. Fetal tracheal ligation and lung development. Am J Dis Child 1965;109:452-6. 35. Adzick NS, Harrison MR, Glick PL, et al. Experimental pulmonary hypoplasia and oligohydramnios: relative contributions of lung fluid and fetal breathing movements. J Pediatr Surg 1984;19:658-65. 36. DiFiore JW, Fauza DO, Slavin R, et al. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:248-56. 37. Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993;28:1433-9. 38. Kitano Y, Davies P, von Allmen D, et al. Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia. J Appl Physiol 1999;87:769-75. 39. De Paepe ME, Johnson BD, Papadakis K, et al. Lung growth response after tracheal occlusion in fetal rabbits is gestational agedependent. Am J Respir Cell Mol Biol 1999;21:65-76. 40. Hedrick MH, Estes JM, Sullivan KM, et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 1994;29:612-7. 41. Lipsett J, Cool JC, Runciman SI, et al. Effect of antenatal tracheal occlusion on lung development in the sheep model of congenital diaphragmatic hernia: a morphometric analysis of pulmonary structure and maturity. Pediatr Pulmonol 1998;25:257-69. 42. Roubliova XI, Verbeken EK, Wu J, et al. Effect of tracheal occlusion on peripheric pulmonary vessel muscularization in a fetal rabbit model for congenital diaphragmatic hernia. Am J Obstet Gynecol 2004;191:830-6. 43. Kanai M, Kitano Y, von Allmen D, et al. Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia: tracheal occlusion reverses the arterial structural abnormality. J Pediatr Surg 2001;36:839-45. 44. Luks FI, Wild YK, Piasecki GJ, et al. Short-term tracheal occlusion corrects pulmonary vascular anomalies in the fetal lamb with diaphragmatic hernia. Surgery 2000;128:266-72. 45. Sylvester KG, Rasanen J, Kitano Y, et al. Tracheal occlusion reverses the high impedance to flow in the fetal pulmonary circulation and normalizes its physiological response to oxygen at full term. J Pediatr Surg 1998;33:1071-4. 46. DiFiore JW, Fauza DO, Slavin R, et al. Experimental fetal tracheal ligation and congenital diaphragmatic hernia: a pulmonary vascular morphometric analysis. J Pediatr Surg 1995;30:917-23. 47. De Paepe ME, Papadakis K, Johnson BD, et al. Fate of the type II pneumocyte following tracheal occlusion in utero: a time-course study in fetal sheep. Virchows Arch 1998;432:7-16. 48. Benachi A, Chailley-Heu B, Delezoide AL, et al. Lung growth and maturation after tracheal occlusion in diaphragmatic hernia. Am J Respir Crit Care Med 1998;157:921-7. 49. Piedboeuf B, Laberge JM, Ghitulescu G, et al. Deleterious effect of tracheal obstruction on type II pneumocytes in fetal sheep. Pediatr Res 1997;41:473-9.
108 50. O’Toole SJ, Karamanoukian HL, Irish MS, et al. Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment. J Pediatr Surg 1997;32:407-10. 51. Bin Saddiq W, Piedboeuf B, Laberge JM, et al. The effects of tracheal occlusion and release on type II pneumocytes in fetal lambs. J Pediatr Surg 1997;32:834-8. 52. O’Toole SJ, Sharma A, Karamanoukian HL, et al. Tracheal ligation does not correct the surfactant deficiency associated with congenital diaphragmatic hernia. J Pediatr Surg 1996;31:546-50. 53. Kitano Y, von Allmen D, Kanai M, et al. Epinephrine inhibits tracheal occlusion induced lung growth in fetal sheep. Fetal Diagn Ther 2003;18:333-7. 54. Wu J, Ge X, Verbeken EK, et al. Pulmonary effects of in utero tracheal occlusion are dependent on gestational age in a rabbit model of diaphragmatic hernia. J Pediatr Surg 2002;37:11-7. 55. Kitano Y, Kanai M, Davies P, et al. Lung growth induced by prenatal tracheal occlusion and its modifying factors: a study in the rat model of congenital diaphragmatic hernia. J Pediatr Surg 2001;36:251-9. 56. Keramidaris E, Hooper SB, Harding R. Effect of gestational age on the increase in fetal lung growth following tracheal obstruction. Exp Lung Res 1996;22:283-98. 57. Probyn ME, Wallace MJ, Hooper SB. Effect of increased lung expansion on lung growth and development near midgestation in fetal sheep. Pediatr Res 2000;47:806-12. 58. Boland RE, Nardo L, Hooper SB. Cortisol pretreatment enhances the lung growth response to tracheal obstruction in fetal sheep. Am J Physiol 1997;273:L1126-31. 59. Kitano Y, Von Allmen D, Kanai M, et al. Fetal lung growth after short-term tracheal occlusion is linearly related to intratracheal pressure. J Appl Physiol 2001;90:493-500. 60. Nardo L, Maritz G, Harding R, et al. Changes in lung structure and cellular division induced by tracheal obstruction in fetal sheep. Exp Lung Res 2000;26:105-19. 61. Islam S, Donahoe PK, Schnitzer JJ. Tracheal ligation increases mitogen-activated protein kinase activity and attenuates surfactant protein B mRNA in fetal sheep lungs. J Surg Res 1999;84:19-23. 62. Liu M, Liu J, Buch S, et al. Antisense oligonucleotides for PDGF-B and its receptor inhibit mechanical strain-induced fetal lung cell growth. Am J Physiol 1995;269:L178-84. 63. Banes AJ, Tsuzaki M, Yamamoto J, et al. Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals. Biochem Cell Biol 1995;73:349-65. 64. Bealer JF, Skarsgard ED, Hedrick MH, et al. The ‘PLUG’ odyssey: adventures in experimental fetal tracheal occlusion. J Pediatr Surg 1995;30:361-4. 65. Harrison MR, Mychaliska GB, Albanese CT, et al. Correction of congenital diaphragmatic hernia in utero. IX. Fetuses with poor prognosis (liver herniation and low lung-to-head ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33: 1017-22. 66. Flake AW, Crombleholme TM, Johnson MP, et al. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000; 183:1059-66. 67. Harrison MR, Mychaliska GB, Albanese CT, et al. Correction of congenital diaphragmatic hernia in utero IX: fetuses with poor prognosis (liver herniation and low lung-to-head ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33: 1017-22. 68. Golombeck K, Ball RH, Lee H, et al. Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol 2006;194:834-9. 69. Deprest JA, Evrard VA, Van Ballaer PP, et al. Tracheoscopic endoluminal plugging using an inflatable device in the fetal lamb model. Eur J Obstet Gynecol Reprod Biol 1998;81:165-9. 70. Flageole H, Evrard VA, Vandenberghe K, et al. Tracheoscopic endotracheal occlusion in the ovine model: technique and pulmonary effects. J Pediatr Surg 1997;32:1328-31.
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 71. Deprest J, Jani J, Van Schoubroeck D, et al. Current consequences of prenatal diagnosis of congenital diaphragmatic hernia. J Pediatr Surg 2006;41:423-30. 72. Deprest J, Jani J, Gratacos E, et al. Fetal intervention for congenital diaphragmatic hernia: the European experience. Semin Perinatol 2005;29:94-103. 73. Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916-24. 74. Cortes RA, Keller RL, Townsend T, et al. Survival of severe congenital diaphragmatic hernia has morbid consequences. J Pediatr Surg 2005;40:36-45; discussion 45-6. 75. Keller RL, Hawgood S, Neuhaus JM, et al. Infant pulmonary function in a randomized trial of fetal tracheal occlusion for severe congenital diaphragmatic hernia. Pediatr Res 2004;56:818-25. 76. Heerema AE, Rabban JT, Sydorak RM, et al. Lung pathology in patients with congenital diaphragmatic hernia treated with fetal surgical intervention, including tracheal occlusion. Pediatr Dev Pathol 2003;6:536-46. 77. Deprest J, Gratacos E, Nicolaides KH. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Obstet Gynecol Surv 2005;60:85-6. 78. Deprest J, Jani J, Gratacos E, et al. Reply. J Pediatr Surg 2006;41: 1345-6. 79. Kohl T, Gembruch U, Filsinger B, et al. Encouraging early clinical experience with deliberately delayed temporary fetoscopic tracheal occlusion for the prenatal treatment of life-threatening right and left congenital diaphragmatic hernias. Fetal Diagn Ther 2006;21:314-8. 80. Chang R, Komura M, Andreoli S, et al. Rapidly polymerizing hydrogel prevents balloon dislodgement in a model of fetal tracheal occlusion. J Pediatr Surg 2004;39:557-60. 81. Logan JW, Cotten CM, Goldberg RN, et al. Mechanical ventilation strategies in the management of congenital diaphragmatic hernia. Semin Pediatr Surg (in press). 82. Bagolan P, Casaccia G, Crescenzi F, et al. Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg 2004;39:313-8. 83. Kays DW, Langham MR Jr, Ledbetter DJ, et al. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340-8. 84. Jani JC, Nicolaides KH, Gratacos E, et al. Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO). Am J Obstet Gynecol 2006;195:1646-50. 85. David AL, Weisz B, Gregory L, et al. Ultrasound-guided injection and occlusion of the trachea in fetal sheep. Ultrasound Obstet Gynecol 2006;28:82-8. 86. Kunisaki SM, Chang RW, Andreoli S, et al. Hyperoncotic enhancement of fetal pulmonary growth after tracheal occlusion: an alveolar and capillary morphometric analysis. J Pediatr Surg 2006; 41:1214-8. 87. Davey MG, Danzer E, Schwarz U, et al. Prenatal glucocorticoids and exogenous surfactant therapy improve respiratory function in lambs with severe diaphragmatic hernia following fetal tracheal occlusion. Pediatr Res 2006;60:131-5. 88. Larson JE, Cohen JC. Improvement of pulmonary hypoplasia associated with congenital diaphragmatic hernia by in utero CFTR gene therapy. Am J Physiol Lung Cell Mol Physiol 2006;291:L410. 89. Montedonico S, Nakazawa N, Puri P. Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants. Pediatr Surg Int 2006;22:2-8. 90. Lewis NA, Holm BA, Swartz D, et al. Antenatal vitamin A decreases ventilation-induced lung injury in the lamb model of congenital diaphragmatic hernia. Asian J Surg 2006;29:193-7.
Prenatal intervention for congenital diaphragmatic hernia Yoshihiro Kitano, MD From the Division of General Surgery, Saitama Children’s Medical Center, Saitama, Japan. KEYWORDS Congenital diaphragmatic hernia; Tracheal occlusion; Fetal surgery; Prenatal diagnosis; Gentle ventilation
Advances in prenatal ultrasound have revealed the poor natural history of fetal congenital diaphragmatic hernia (CDH) and its hidden mortality during gestation and immediately after birth. Attempts to improve this poor outcome led to the development of prenatal surgical intervention for severe CDH by Harrison and his colleagues at the University of California San Francisco. Prenatal surgical intervention for CDH has seen four phases: open fetal surgical repair, open surgical tracheal occlusion, endoscopic external tracheal occlusion, and endoscopic endoluminal tracheal occlusion. After extensive work in the laboratory, prenatal intervention has been applied in humans since 1984. With the most recent techniques, maternal risk is significantly reduced as is the incidence of preterm labor. In the meantime, the survival rate of fetuses with CDH without fetal intervention has improved mainly due to the minimization of iatrogenic lung injury by gentle ventilation, first described in 1985. However, the morbidity of the survivors with severe CDH remains high. Prenatal intervention for CDH will be justified if improvement in survival or morbidity can be demonstrated when compared to planned delivery and postnatal management with gentle ventilation strategy. © 2007 Elsevier Inc. All rights reserved.
Congenital diaphragmatic hernia (CDH) remains one of the most challenging diagnoses for pediatric surgeons and neonatologists. It is well known that the pulmonary hypoplasia and concomitant pulmonary hypertension, resulting from inadequate space in the thoracic cavity during lung development, have a major impact on postnatal mortality and respiratory morbidity in patients with CDH. Pulmonary hypoplasia in CDH is characterized by a decrease in lung weight and reduction in the number of bronchial divisions, respiratory bronchioles, and alveoli. The pulmonary vascular bed is also hypoplastic, and increased muscularization is observed in arterioles, which contributes to the pulmonary hypertension. The degree of pulmonary hypoplasia is related to the timing of herniation and the volume occupied in the chest by abdominal viscera.1 In late-presenting diaphragmatic hernia, despite similar radiological findings, the
Address reprint requests and correspondence: Yoshihiro Kitano, MD, Division of General Surgery, Saitama Children’s Medical Center, 2100 Iwatsuki-ku, Saitama 339-8551, Japan. E-mail: [email protected].
1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.01.005
outcomes are excellent because of normal pulmonary development.2 There have been two trends in the management of prenatally diagnosed CDH: the development of prenatal intervention and improvements in postnatal care. Both approaches have made significant progress, while the clinical role of the former remains controversial. The purpose of this article is to review the recent issues related to prenatal tracheal occlusion (TO) compared with postnatal care with gentle ventilation. Since prenatal intervention is currently not considered for those fetuses with other associated anomalies, only prenatally diagnosed, isolated CDH will be discussed in this chapter.
Prenatal diagnosis of CDH and recognition of hidden mortality The diagnosis of CDH is relatively easy to make by screening ultrasound examination. The prenatal diagnosis of leftsided CDH is made by seeing a fluid-filled stomach or
102 bowel with or without the liver in the left chest cavity and rightward mediastinal shift. Right-sided CDH may be more difficult to diagnose because the liver, which has a similar sonographic appearance as the lung, can be the single organ herniated into the chest. Although there is considerable variation in detection rates between regions depending on the prenatal screening programs, the overall prenatal detection rate is 59% in European countries.3 As prenatal diagnosis of CDH became common in the 1980s, the natural history of fetal CDH was recognized to be very different from that of neonatal CDH. Improvements in fetal diagnosis led to a recognition of increasing numbers of CDH cases with severe pulmonary hypoplasia. These were the subgroup of patients who would not have survived the immediate postnatal period without planned delivery. This issue was addressed in a prospective analysis, which provided invaluable data on the mortality rate of fetal CDH without associated anomalies.4 The study included 83 cases with isolated CDH diagnosed before 24 weeks gestation, referred for consideration of fetal therapy between 1989 and 1993. Forty-eight patients (including 7 cases of third trimester intrauterine demise) died, resulting in an overall 58% mortality rate. Twenty-two of 35 survivors required extracorporeal membrane oxygenation (ECMO), of which 9 patients had significant morbidity. This study clearly documented that patients diagnosed with an isolated CDH in utero suffer substantial mortality and morbidity, despite accurate prenatal diagnosis and sophisticated neonatal care including maternal transport, planned delivery, and immediate resuscitation at institutions with ECMO capability (but, presumably not gentle ventilation).
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 aspect of the liver to the apex of the chest by the distance from the diaphragm remnant to the apex of the chest.5 They found that the mean liver/diaphragm ratio was significantly higher in the survivors compared with the non-survivors, but no clear cut-off had been determined. This observation was reproduced in Japan.9 The LHR is a sonographic measurement of right lung size standardized to head circumference in left-sided CDH, and has been validated retrospectively7 and prospectively.15 Although excellent correlation between LHR and survival are reported,8 other centers have been unable to reproduce its prognostic value.16,17 The reason for this discrepancy could be related to two factors. First, the measurement of LHR is observer-dependent and, from our experience, the difference of 0.2 to 0.3 is not uncommon. Secondly, improvements in postnatal care are lowering the cut-off values of LHR, and its prognostic value is changing. For instance, the prognostic value of LHR in the liver-down CDH has been refuted8,18 as opposed to the previous reports.19 From the perspective of majority of clinicians, the prognostic role of LHR is controversial. Recently, efforts have been made to predict survival by other morphological assessments, such as three-dimensional measurement of lung volume by fetal MRI5,20 or threedimensional sonography21,22 and measurement of pulmonary artery diameters.23 Physiological assessment of fetal lung function is ideal but limited at present to that of pulmonary vascular function. The pulmonary arterial pulsatility index with or without maternal oxygen supplementation24,25 and acceleration time/ejection time ratio26 are reported as physiological assessments of fetal pulmonary hypoplasia. The prognostic value of these new measurements must be validated in a further study.
Prenatal prediction of survival in fetal CDH The ability to predict which fetuses are destined for a poor outcome is a prerequisite for any fetal intervention. Although a number of prenatal predictors of survival have been proposed, few have been confirmed in more than a single center. The most widely accepted prognostic indicators for fetal CDH are the position of the liver (“liver-up ” versus “liver-down”) and sonographic measurement of the right lung area-to-head circumference (LHR). Liver herniation is a well-known prognostic factor of CDH.5-7 The current survival rate for liver-up CDH is estimated to be around 50%.6-9 The true incidence of liver herniation is unknown, but up to 75% of CDH patients are reported to have some portion of the liver in the chest.10 Although Doppler ultrasonography has been the most common tool to determine the liver position, it can be examinerdependent,11,12 and we believe that MRI is a more objective modality.9,13,14 The degree of liver herniation can vary and affects the outcome. There is only one study assessing the degree of liver herniation by measuring a left liver/diaphragm ratio, which is calculated by dividing the distance from superior
Development of prenatal intervention Since the recognition of the poor natural history of prenatally diagnosed CDH, prenatal intervention was extensively studied first in the laboratory and then in human trials. Until recently, it was generally accepted that a fetus with liver-up CDH and LHR ⬍1.0 had a very little chance of survival, and prenatal interventions were aimed to improve survival in this subset of patients. The initial prenatal intervention was in utero repair, first attempted in 1984.27 This was an open fetal operation requiring maternal laparotomy, hysterotomy, and fetal laparotomy/thoracotomy. The first successful case using this procedure was reported in 1990,28 and a prospective randomized study in fetuses with liver-down CDH was performed. Successful repair was possible in fetuses with liverdown CDH, but the mortality and morbidity with this procedure was not different from postnatal conventional management.29 In liver-up CDH, the open procedure was not feasible because reduction of the liver obstructed the umbilical vein, the lifeline of the fetus.30,31 This procedure
Kitano
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was therefore abandoned, and fetuses without liver herniation were excluded from future prenatal intervention. A completely different approach arose from the clinical observation that tracheal atresia results in lung hyperplasia even with bilateral renal agenesis.32 Combined with known physiological data on lung fluid dynamics and fetal lung growth,33-35 therapeutic tracheal occlusion (TO) was suggested as a potential method to overcome lethal pulmonary hypoplasia associated with CDH.36,37 The technique as well as the effects of this procedure was extensively studied in various animal models in the 1990s. Briefly, the following observations were established. 1. TO accelerates fetal lung growth in normal and CDH animal models with pulmonary hypoplasia.36-40 2. The accelerated lung growth is the result of increased cell division and increased number of alveoli accompanied by an appropriate increase in capillary vessels.36,38,40,41 3. The accelerated lung growth is associated with remodeling of pulmonary arterioles which is likely to ameliorate pulmonary hypertension.42-46 4. Prolonged TO reduces the number of type II cells, resulting in surfactant depletion, which may partly be reversed by early release of TO.47-52 5. The lung growth response to TO is affected by multiple factors including timing (stage of lung development), length of TO, and drugs that affect lung fluid production, such as terbutaline and steroids.39,53-58 6. The mechanism of accelerated lung growth is not fully understood, but it is related to increased lung tissue stretch, which turns on mechano-transduction pathways resulting in lung growth.59-63 A pressure difference (intratracheal pressure–amniotic pressure) of 4-5 mmHg is observed in fetal sheep after complete tracheal obstruction, and no lung growth is achieved with minor lung fluid leakage.59 Achieving watertight, prolonged, and damage-less occlusion of the growing fetal trachea was a challenge.64 Various methods were tried, and it was concluded that external application of vascular clips was superior to an internal plug, which caused tracheomalacia when watertight occlusion was achieved. The first clinical application of TO was reported in 1998.65 Initially, TO was performed by open fetal surgery. Maternal laparotomy and hysterotomy was followed by fetal neck dissection and application of metal clips to fetal trachea. The results of open TO were rather discouraging as discussed below.65,66 The main reason limiting the success of the procedure was assumed to be the maternal hysterotomy, and a less invasive approach was investigated. Videoand ultrasound-assisted fetal endoscopy (FETENDO) served this purpose.67 Although “FETENDO-clip” avoided maternal hysterotomy, it was a complex procedure requiring 3 to 4 cannulas, endoscopic dissection of fetal trachea, and maternal general anesthesia. With evolution of the technique, the procedure-related risks of prenatal intervention
103 decreased. In a retrospective analysis of 187 cases of fetal surgery, Golombeck and coworkers reported that FETENDO was less invasive compared with open fetal surgery comparing cesarean delivery as delivery mode (58.8% versus 94.8%), requirement for intensive care unit stay (1.4% versus 26.4%), length of hospital stay (7.9 days versus 11.9 days), and requirement for blood transfusions (2.9% versus 12.6%).68 However, there were no significant differences in the incidence of premature rupture of membranes (44.1% versus 51.9%), pulmonary edema (25.0% versus 27.8%), placental abruption (5.9% versus 8.9%), preterm delivery (26.5% versus 32.9%), or interval from the procedure to delivery (6.0 weeks versus 4.9 weeks) between FETENDO and open fetal surgery. Interestingly, chorion– amnion membrane separation was seen more often with FETENDO (64.7% versus 20.3%). These complications were significantly less in percutaneous ultrasound-guided procedures. As a result, this technique was also abandoned due to the high rate of preterm delivery and irreversible damage to the laryngeal nerve and trachea. The concept of internal obstruction using a detachable balloon originally designed for aneurysm treatment was revived. This approach was shown effective without tracheal damage in fetal lambs.69,70 It was performed with (FETENDO-balloon) or without (FETO) maternal laparotomy. It is now feasible to perform with a single 10-Fr cannula and a 1.2-mm fetoscope without maternal laparotomy under regional anesthesia.71,72 The whole procedure is accomplished within 20 minutes in experienced hands and does not require large doses of tocolytics. Furthermore, in order to avoid the need for an EXIT procedure and to overcome the drawback of long-term TO, that is, differentiation of type II pneumocytes into type I pneumocytes resulting in surfactant deficiency, a strategy was developed to deflate the balloon at 34 weeks by puncturing it under sonographic guidance. Table 1 summarizes the evolution of endoscopic TO procedures.
Survival and morbidity of fetuses treated with TO: American reports TO was first performed in humans by open fetal surgery with a survival of 15% (n ⫽ 13) and 33% (n ⫽ 15), in two series.65,66 Although the main reason for this poor outcome was attributed to the invasive technique leading to premature delivery, Flake and coworkers reported two intriguing observations. First, lung growth response to TO was variable. Some fetal lungs did not grow significantly despite complete tracheal obstruction confirmed at birth. Second, pulmonary function of the newborns treated with TO was abnormal even when dramatic lung growth was observed in utero. The survivors required intensive management after birth with significant long-term morbidity, including neurologic injury in 60%. An NIH-sponsored prospective randomized trial comparing endoscopic TO and standard postnatal treatment was
104 Table 1
Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 Evolution of endoscopic tracheal occlusion Reports from U.S.A.
Reports from Europe
Technique
FETENDO-clip
FETENDO-balloon
FETO
Device for TO Number of cannulas Size of the cannula Laparotomy Anesthesia Length of procedure EXIT
Vascular clip 3 5 mm Yes General 2.5-6 hrs Yes
Detachable balloon 1 5 mm Yes General 2-2.5 hrs Yes
Detachable balloon 1 3.3 mm no Spinal-epidural 20 min (5-54 min) no
carried out between 1999 and 2001.73 The inclusion criteria for this study were the presence of isolated left-sided liver-up CDH with an LHR ⬍1.4 (measured at between 22 and 27 weeks gestation). The procedures included were FETENDO-clip (n ⫽ 2) and FETENDO-balloon (n ⫽ 9). In this study, 13 cases were treated by standard postnatal care and 11 by TO with the survival of 77% and 73%, respectively. The study was closed prematurely due to the conclusion that further recruitment would not result in significant differences in survival between the two groups. The unexpectedly high survival in the standard postnatal care group shows the recent improvements in postnatal care. Of note, all postnatal care was provided by UCSF in this trial as opposed to previous reports in which postnatal care was given by each referral center. Premature rupture of membranes leading to premature delivery was inevitable in the TO group (the mean age at delivery was 30.8 weeks). Although this was a drawback of prenatal intervention, an argument was made that the same survival achieved in the more premature babies of the TO group indicates the potential benefit of TO. There was a question why an LHR ⬍1.4 was chosen because it had been known that a fetus with an LHR of 1.0 to 1.4 does not always die.15 It could be argued that the comparable survival was the result of inclusion of too many patients with potentially good prognosis. However, the survival was comparable even if the fetuses with an LHR ⬍1.06 were compared; 11 cases in postnatal group and 7 cases in TO group had an LHR ⬍1.06 with the survival of 73% and 71%, respectively. Despite the comparable survival in both groups, the clinical significance of TO would not be lost if less morbidity could be shown in the survivors. For example, if TO could improve neonatal lung function and decrease the ECMO need, the morbidity of TO and ECMO should be compared. However, ECMO was required in only one of 13 patients in the postnatal care group. The rates of respiratory and gastrointestinal complications at discharge were not different. The morbidity of the survivors (9 cases in the postnatal care group and 7 cases in the TO group) after 1 to 2 years is also reported.74 Both groups suffered from various problems including chronic lung disease, gastro-esophageal reflux, hernia recurrence, growth retardation, and auditory deficit.
There was no difference in any morbidity between the two groups. Neonatal pulmonary functions of the survivors was reported by Keller and coworkers.75 While some parameters, such as respiratory system compliance, peak expiratory flow, and alveolar–arterial oxygen difference, were better in the TO group than in the standard care group, there was no difference in the oxygenation index and minute ventilation. Although this comparison has a limitation because the gestational age of the two groups (30.8 ⫾ 2.0 weeks versus 37.4 ⫾ 1.0 weeks) is significantly different, the authors concluded that the benefit of TO in neonatal pulmonary function was of questionable clinical significance. An autopsy study of the patients who underwent TO revealed that the radial alveolar count was low, even in those cases who showed increasing LHR after TO.76 Instead, each alveolus was enlarged. The medial thickness of arterioles was also not different. These results should be cautiously interpreted because the survivors are not studied. However, it should be appreciated that the increase in LHR after TO does not necessarily indicate accelerated lung growth. The mere distention of the existed lung air space can cause marked increase in LHR. These reports from UCSF and CHOP suggest that the clinical benefit of TO remains questionable. Most importantly, the morbidity of the survivors does not seem to be improved by TO.
Survival and morbidity of fetuses treated with TO: European reports The European perinatologists (The FETO task group) organized a multicenter prospective study on FETO. In their initial report, they offered FETO to a subset with liver herniation and an LHR ⬍1.0, measured between 26 and 28 weeks.77 The selection criteria were intended to identify a more severe subset than those studied in the UCSF trial. The laterality of the defect was not considered and there were 15 left-sided CDH and 6 right-sided CDH included, which was somewhat confusing because the LHR in right-sided CDH was not well validated. They reported a survival of 48%,
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which is significantly better than the survival of 8% in a comparable group who declined fetal intervention. The airway was restored either perinatally (n ⫽ 12) or prenatally (n ⫽ 9), and the survival was higher with prenatal balloon retrieval compared with postnatal retrieval (67% versus 33%), although this did not reach statistical significance. There were no serious maternal complications or direct fetal adverse effects in their initial experience with 24 FETO.71 Tocolysis used to be a major concern after open fetal surgery, but the only tocolysis given perioperatively for FETO was nifedipine, 20 mg twice a day for a few days. None of their patients required additional tocolysis after the procedure. Premature rupture of membranes occurred in 33.3% of patients before 32 weeks, but has been improving over time. As a result, the mean gestational age at delivery was 33.5 weeks, later than that reported in the UCSF trial (30.8 weeks). With increasing experience, it has further improved to 37 weeks in their last 20 cases.78 Thus, maternal morbidity, if not fetal morbidity, has been significantly decreased by FETO, potentially justifying its application in selected candidates. The study is still ongoing, and in their latest report it was suggested that preoperative LHR is predictive of the postnatal survival after FETO.84 In their 28 consecutive cases of left-sided liver-up CDH with an LHR of ⬍1.0, 16 (57%) survived. Twelve deaths were all caused by respiratory insufficiency. The survival rate of fetuses that underwent FETO was 17% for those with an LHR of 0.4 to 0.5, 62% for those with an LHR of 0.6 to 0.7, and 78% for those with an LHR of 0.8 to 0.9. The survival rate of 78% in those with an LHR of 0.8 to 0.9 was higher than the survival rate of those with an LHR of 1.0 to 1.3 treated postnatally (65%). Hence, it is claimed that FETO may improve the outcome in those fetuses with an LHR of 0.6 to 1.3 (instead of ⬍1.0). Information on the morbidity of the survivors from European Series is limited, but promising compared to the results reported from UCSF. The 12 survivors (6-35 months) have no apparent developmental problems.19 Four of them were oxygen-dependent after discharge but are currently off oxygen. In addition, not a single case required ECMO in patients with an LHR of 0.7 to 0.9 (n ⫽ 22).78 A group from Germany independently reported their early experience with deliberately delayed FETO.79 Kohl and coworkers elected to perform FETO later in gestation between 29 to 32 weeks to minimize the adverse effects of premature delivery and to reserve ECMO as a treatment option postnatally. Eight fetuses with comparably severe CDH (details shown in Table 2) underwent FETO, and 6 of 8 patients survived. Two patients died before ECMO and 5 of the 6 survivors required ECMO. The control patients were treated by the same team with a survival rate of 33% (2/6). Their approach is appealing, but the results are inconsistent with previous reports. The FETO task group, in their early experience, found that FETO performed at 31 and 32 weeks did not prevent respiratory failure at birth, and the timing of FETO was advanced to the second trimester.77
105 Flake and coworkers also found that early TO (25-26 weeks) results in more consistent lung growth than late TO (27-28 weeks).66 There is no question that FETO has significantly reduced maternal risks and has almost overcome preterm delivery, the Achilles heel of fetal surgery, and the preliminary results are encouraging. However, the following limitations need to be appreciated to prevent premature widespread application of FETO. First, control cases were collected from multiple centers since 1995. This may not reflect the recent improvements in postnatal care. In a future randomized study, all postnatal care should be given at the same centers that care the babies treated by FETO. Second, the details of longterm outcome and morbidity of the survivors are yet to be reported. Third, there remains some concern regarding the efficacy of tracheal obstruction by balloons80 because the increase of LHR from 0.7 (range, 0.4-0.9) to 1.8 (range, 1.1-2.9),77 or from 0.7-1.0 to 1.0-3.579 is not as dramatic as the increase reported by others.66 Clinical reports on fetal TO for CDH are summarized in Table 2.
Recent improvement in postnatal care Perhaps the most important factor that has improved postnatal care of CDH is the introduction of gentle ventilation, or avoidance of ventilator-induced lung injury to the immature and hypoplastic lung. The role of mechanical ventilation in CDH is discussed in the article by Logan and coworkers.81 With slow but steady acceptance of gentle ventilation, the survival of fetal CDH has improved. Some centers reported a survival as high as 90% with this approach,82,83 but this is not always reproduced across all institutions probably due to different levels of postnatal care and case selection bias. Thus, the true survival rate with gentle ventilation strategy is not yet established. Since the management of a patient with severe CDH is like walking the ridge with steep cliffs on both sides, any small accident could lead to a bad outcome. Infection control including the management of central venous lines, aggressive establishment of enteral nutrition, and experience in managing the sickest babies may make a significant difference. The natural history of fetal CDH including both morbidity and mortality in the era of planned delivery and gentle ventilation must be reestablished in selected centers capable of NO inhalation, HFOV, and ECMO in order to accurately evaluate fetal intervention.
Future Despite significant improvements in postnatal care, there remains a small subset of patients whose lung is too small to survive, and more importantly, the morbidity of the survivors is significant. To prove the role of prenatal intervention in the management of fetal CDH, it should prove to save a
Not improved Morbidity of the survivors
—
Not improved
Without apparent developmental problems, all off oxygen
75% (left 3, right 3) 2/6⫽33% (left only), treated at the same institution — 57% 3/27⫽11% 73% 10/13⫽77%, treated at the same institution 33% (left 3, right 2) 0/7⫽0%, treated at the same institution Open 15%, FETENDO-clip 75% 5/13⫽38%
28 FETENDO-clip 2, FETENDO-balloon 9 15 (left 13, right 2)
Number of patients Survival (%) Control
Open 13, FETENDO-clip 8
— No FETO (25–29 wks) Left, liver-up, LHR ⬍1.0 1999-2001 Yes FETENDO-clip vs FETENDO-balloon Left, liver-up, LHR ⬍1.4 1994-1997 No Open vs FETENDO-clip Left, liver-up, LHR ⬍ 1.4 Study period Randomized study TO methods Inclusion criteria
1995-1999 No Open Left, liver-up, LHR ⬍1.0, or right, Liver-up, left lung not visualized
Deprest (2006) Harrison (2003) Flake (2000) Harrison (1998) Author (year)
Summary of prenatal tracheal occlusion for CDH in humans Table 2
— No Late FETO (29–32 wks) Left, liver-up, LHR ⬍0.9, MRI lung volume ⬍14 ml, or right, liver-up, LHR ⬍1.0, MRI lung volume ⬍14 ml 8 (left 5, right 3)
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small subset with fatal pulmonary hypoplasia or improve the morbidity of the survivors. It may be difficult to show the former because of improving postnatal care and current limitation of FETO to treat the severest subset with LHR ⬍0.5.84 The latter is very important because it is conceivable that more parents would choose termination without an improvement in postnatal morbidity. This trend will inevitably be enhanced by continued advances in prenatal imaging; many fetuses with liver-up CDH could be diagnosed at 20 weeks in the near future. Therefore, the morbidity (or quality of life) of the survivors of FETO, such as the need for home oxygenation or ventilation therapy, hearing loss, growth retardation, and mental development, needs to be addressed in detail. If the results are encouraging, a randomized controlled study comparing the morbidity, rather than the survival, may be practical. Considering the fact that FETO can be performed with a 4-mm incision within 20 minutes under local-regional anesthesia by an experienced team, it may become reasonable to offer this procedure to a mother carrying a fetus with severe CDH in selected centers. The expected role of prenatal intervention for CDH has shifted from improving survival to improving morbidity related with pulmonary hypoplasia. We can expect prenatal intervention to further improve in the future. Optimal timing and duration of TO in human CDH remains unproven.66,72,79 Refinement of the procedure, such as ultrasound-guided occlusion of fetal trachea,85 intratracheal delivery of a rapidly polymerizing hydrogel cephalad to balloons to prevent balloon dislodgement,80 and enhancement of lung fluid osmolarity,86 are being investigated. Combination of FETO with other modalities such as surfactant and corticosteroids may prove effective.87 Therapeutic gene therapy88 and vitamin-A administration89,90 are being studied in the laboratory.
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108 50. O’Toole SJ, Karamanoukian HL, Irish MS, et al. Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment. J Pediatr Surg 1997;32:407-10. 51. Bin Saddiq W, Piedboeuf B, Laberge JM, et al. The effects of tracheal occlusion and release on type II pneumocytes in fetal lambs. J Pediatr Surg 1997;32:834-8. 52. O’Toole SJ, Sharma A, Karamanoukian HL, et al. Tracheal ligation does not correct the surfactant deficiency associated with congenital diaphragmatic hernia. J Pediatr Surg 1996;31:546-50. 53. Kitano Y, von Allmen D, Kanai M, et al. Epinephrine inhibits tracheal occlusion induced lung growth in fetal sheep. Fetal Diagn Ther 2003;18:333-7. 54. Wu J, Ge X, Verbeken EK, et al. Pulmonary effects of in utero tracheal occlusion are dependent on gestational age in a rabbit model of diaphragmatic hernia. J Pediatr Surg 2002;37:11-7. 55. Kitano Y, Kanai M, Davies P, et al. Lung growth induced by prenatal tracheal occlusion and its modifying factors: a study in the rat model of congenital diaphragmatic hernia. J Pediatr Surg 2001;36:251-9. 56. Keramidaris E, Hooper SB, Harding R. Effect of gestational age on the increase in fetal lung growth following tracheal obstruction. Exp Lung Res 1996;22:283-98. 57. Probyn ME, Wallace MJ, Hooper SB. Effect of increased lung expansion on lung growth and development near midgestation in fetal sheep. Pediatr Res 2000;47:806-12. 58. Boland RE, Nardo L, Hooper SB. Cortisol pretreatment enhances the lung growth response to tracheal obstruction in fetal sheep. Am J Physiol 1997;273:L1126-31. 59. Kitano Y, Von Allmen D, Kanai M, et al. Fetal lung growth after short-term tracheal occlusion is linearly related to intratracheal pressure. J Appl Physiol 2001;90:493-500. 60. Nardo L, Maritz G, Harding R, et al. Changes in lung structure and cellular division induced by tracheal obstruction in fetal sheep. Exp Lung Res 2000;26:105-19. 61. Islam S, Donahoe PK, Schnitzer JJ. Tracheal ligation increases mitogen-activated protein kinase activity and attenuates surfactant protein B mRNA in fetal sheep lungs. J Surg Res 1999;84:19-23. 62. Liu M, Liu J, Buch S, et al. Antisense oligonucleotides for PDGF-B and its receptor inhibit mechanical strain-induced fetal lung cell growth. Am J Physiol 1995;269:L178-84. 63. Banes AJ, Tsuzaki M, Yamamoto J, et al. Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals. Biochem Cell Biol 1995;73:349-65. 64. Bealer JF, Skarsgard ED, Hedrick MH, et al. The ‘PLUG’ odyssey: adventures in experimental fetal tracheal occlusion. J Pediatr Surg 1995;30:361-4. 65. Harrison MR, Mychaliska GB, Albanese CT, et al. Correction of congenital diaphragmatic hernia in utero. IX. Fetuses with poor prognosis (liver herniation and low lung-to-head ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33: 1017-22. 66. Flake AW, Crombleholme TM, Johnson MP, et al. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000; 183:1059-66. 67. Harrison MR, Mychaliska GB, Albanese CT, et al. Correction of congenital diaphragmatic hernia in utero IX: fetuses with poor prognosis (liver herniation and low lung-to-head ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33: 1017-22. 68. Golombeck K, Ball RH, Lee H, et al. Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol 2006;194:834-9. 69. Deprest JA, Evrard VA, Van Ballaer PP, et al. Tracheoscopic endoluminal plugging using an inflatable device in the fetal lamb model. Eur J Obstet Gynecol Reprod Biol 1998;81:165-9. 70. Flageole H, Evrard VA, Vandenberghe K, et al. Tracheoscopic endotracheal occlusion in the ovine model: technique and pulmonary effects. J Pediatr Surg 1997;32:1328-31.
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