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Fax +41 61 306 12 34E-Mail [email protected]

Invited Review

Fetal Diagn Ther 2011;29:617

DOI: 10.1159/000322844

Fetal Surgery for Congenital DiaphragmaticHernia Is Back from Never Gone

Jan A. Depresta Kypros Nicolaidesb Eduard Gratacosc

aDivision Woman and Child, University Hospitals KU Leuven, Leuven, Belgium; bKings College Hospital,

Harris Birthright Centre for Fetal Medicine, London, UK; cHospital Clinic-Idibaps, University of Barcelona and

CIBER-ER, Barcelona, Spain

Introduction

Congenital diaphragmatic hernia (CDH) is a congeni-tal birth defect which occurs in 1/3,000 to 1/5,000 livebirths [1]. This number includes what has been called thehidden mortality, such as stillbirths or neonatal deathbefore transfer to a tertiary care centre, so that a more ac-curately estimated incidence of CDH is believed to be 1in 2,200 live births [2, 3]. Eurostat counted 5,420,900 livebirths in the European Union (EU-27) in 2008. As a con-sequence, this means that in absolute numbers at leastevery 4 h one new case is born alive [4]! According to ameta-analysis, up to 40% of cases have associated prob-lems [5]. These can occur in the absence or presence ofidentified syndromes or other genetic problems. Theirpresence is an independent predictor of neonatal death.The majority thus are apparently isolated. The surgicaldefect is typically left sided, but 10% are right sided and2% are bilateral. Though CDH is a surgically correctable

defect, neonates may not make it to the operation becauseof the pulmonary underdevelopment that is invariablypresent. It affects both airways and vessels, leading tovariable degrees of ventilatory insufficiency and/or pul-monary hypertension (PHT). Pulmonary hypoplasia ismore prominent on the side of the lesion, but both lungsare affected.

Key Words

Congenital diaphragmatic hernia Fetal intervention

Endoscopic tracheal occlusion, fetal Fetoscopy

Pulmonary hypoplasia

Abstract

Over half of the cases of congenital diaphragmatic hernia are

picked up prenatally. Prenatal assessment aims to rule out

associated anomalies and to make an individual prognosis.

Prediction of outcome is based on measurements of lung

size and vasculature as well as on liver herniation. A subset

of fetuses likely to die in the postnatal period is eligible for a

fetal intervention that can promote lung growth. Two ran-

domized trials have shown that fetal surgery using open an-

atomical repair or tracheal occlusion via hysterostomy has

no benefit. Since then, a percutaneous fetoscopic technique

has been introduced, which has been shown to be safe and

seems to improve survival when compared to historical con-

trols. Rupture of the fetal membranes and early delivery, nev-ertheless, remain an issue, but are less likely as compared to

earlier experience. Improved outcomes are confirmed in two

other studies published in this issue of Fetal Diagnosis and

Therapy. This paper summarizes the experimental and clini-

cal history of fetal surgery for congenital diaphragmatic her-

nia. It stresses the need for another randomized trial. This

trial started in Europe and patients should be asked whether

they would like to participate. Copyright 2011 S. Karger AG, Basel

Received: October 28, 2010

Accepted after revision: November 16, 2010

Published online: February 3, 2011

Jan Deprest, MD, PhDDivision Woman and Child, Department WomenUniversity Hospitals LeuvenBE3000 Leuven (Belgium)Tel. +32 1634 4215, Fax +32 1634 4205, E-Mail jan.deprest @ uzleuven.be

2011 S. Karger AG, Basel10153837/11/02910006$38.00/0

Accessible online at:www.karger.com/fdt

The authors founded the FETO Task Force.
http://dx.doi.org/10.1159%2F000322844http://dx.doi.org/10.1159%2F000322844

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Fetal Surgery for CDH Fetal Diagn Ther 2011;29:617 7

In case of prenatal diagnosis, in utero transfer is there-fore recommended to ensure optimal neonatal manage-ment. Since the 1990s postnatal management has shiftedfrom emergency repair, aggressive ventilation and hyper-oxygenation to gentle ventilation followed by delayed sur-gery, together with measures for control of PHT [6]. Gen-

tilation with permissive hypercapnia and minimal seda-tion must avoid baro- and volutrauma of the lung. Overthe course of years other novel neonatal strategies, such asthe use of inhaled nitric oxide and prostaglandins (forPHT), high-frequency oscillatory ventilation, extracorpo-real membrane oxygenation and even liquid ventilation(for ventilator insufficiency) have been embraced, withthe hope to improve survival; however, this was in vain [7].It is extremely difficult to compare results from differentcentres, as case load, case mix and neonatal managementmay be significantly different. It seems, however, fair tosay that mortality rates for prenatally diagnosed, isolated

left-sided CDH are still as high as 30% in tertiary centres[8]. As postnatal strategies may fall short, prenatal therapyhas been suggested as early as 1963 to treat (nearly) lethalpulmonary hypoplasia [9]. CDH has always been high onthe fetal surgery agenda, but its story followed certainlycycles of hope and despair. Over the last decade, we haveseen a renewed interest because of a coinciding improve-ment in prenatal diagnostic tools, as well as the introduc-tion of (yet another) prenatal intervention.

A Special Issue on CDH

It is a great pleasure to see that Fetal Diagnosis andTherapydevotes a special issue to recent progress in thefield of CDH. Since the focus of the readership of Fetal Di-agnosis and Therapyis in essence clinical, the stress is onclinical applied research. This issue contains informationrelevant to all physicians dealing with CDH in fetuses ornewborns. It looks at the different aspects of making amore precise prenatal diagnosis of CDH. Indeed, parentsexpect caregivers not only to make the diagnosis in goodtime but also to provide them with comprehensive infor-

mation on the impact of the condition after birth. In real-ity they expect clinicians to predict the outcome of theirbaby; in other words, they expect an individualized prog-nosis (fig. 1). Such an individualized management requiresin utero referral to a specialized multidisciplinary team ata tertiary care centre, familiar with the pre- and postnatalmanagement of the disease. In view of the increasing spec-trum of prenatal options, physicians less familiar with thiscondition should refrain from making statements about

the potential prognosis, in order not to compromise futureoptions [10]. As will be explained below, CDH is no longera black box. In this issue both evaluation of airway devel-opment as well as pulmonary vasculature is being re-

viewed [11, 12]. This means that the prenatal decision-making process can now be objectivized.

This issue of Fetal Diagnosis and Therapywill also dealwith fetal surgery for highly selected patients. Severalgroups have enthusiastically explored the potential of fetaltherapy over the last 20 years. Between 1980 and 1989, 61clinical papers on CDH were published in English, whichalso mentioned (the potential of) fetal therapy. This in-creased to 205 by 1999, and by another 40% to 286 by Oc-tober 2010 [13]. In recent years, it has become apparentthat fetal intervention can be offered through minimallyinvasive access and is safe for the mother. Fetal Diagnosisand Therapy now publishes 2 additional clinical serieswith percutaneous fetoscopic endoluminal tracheal oc-

clusion (FETO), suggesting an increased survival rate af-ter fetal surgery [1417]. Though the published experienceseems to demonstrate variable degrees of benefit of fetaltherapy, one should remember this remains an experi-mental procedure, in the sense that it is not a therapy withproven efficacy (as is the case for many other fetal thera-pies). Simplification of the antenatal intervention by thedevelopment of minimally invasive instruments and theuse of local anaesthesia may make the procedure appeartrivial. A new hammer, however, should not make every-thing look like a nail. FETO should only be offered withina precise trial protocol by an experienced multidisci-plinary team in accordance with the criteria for fetal sur-gery defined by the International Fetal Medicine and Sur-gery Society [18]. Actually, the time has come to offer thisfetal procedure within a randomized trial, testing the hy-pothesis whether FETO truly improves outcome as com-pared to expectant management during pregnancy [19].In order to update the interested reader who is less famil-iar with fetal surgery, we describe below the odyssey offetal surgery for this condition. It may show us that per-ceived advances in fetal therapy have to be substantiatedby hard evidence prior to a change in clinical practice.

The History of Experimental Fetal Surgery for CDH

Different experimental models were designed to repro-duce the pathophysiology of CDH. In rodents, the dia-phragmatic defect and pulmonary hypoplasia are typical-ly induced by a teratogen or dietary changes [20]. The lit-erature on nitrofen-exposed rodents is huge, and several

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Deprest /Nicolaides /GratacosFetal Diagn Ther 2011;29:6178

good reviews are available [21]. Today, transgenic modelsare also available. In rabbits and sheep, the defect is typi-cally created surgically, though space occupation by a bal-

loon also provokes pulmonary hypoplasia [22]. De Lori-mier et al. [23] were the first to surgically induce a dia-phragmatic defect in lambs in order to reproduce problemswith lung development. However, it was late in pregnancyso that the effects were minimal. Kent et al. [24] then cre-ated it in the late second trimester, with subsequent PHT,right-to-left shunting, hypoxia, hypercarbia, acidaemia,and a decreased total lung-to-body weight ratio. Adzick etal. [25] created the defect as early as at 65 days, which inlambs is in the pseudoglandular phase. This resulted inparenchymal and vascular changes similar to those seenat autopsy of babies with CDH. The functional impact ofthese morphological changes was later demonstrated bythe groups from Boston and Buffalo [26, 27].

The concept of a prenatal surgical intervention wasalready raised in 1963 by Areechon and Eid [9]. They sug-gested that timely repair could lead to sufficient paren-chymal growth. Harrison et al. [28] proved the principleof this concept by deflation of a previously inf lated intra-thoracic balloon. This increased lung weight, air capacityand cross-sectional area of the pulmonary vascular bedwith improvement in pulmonary compliance. The samegroup also demonstrated the efficacy of in utero anatom-

ical diaphragmatic repair. In the late 1980s and early1990s, this approach was applied clinically, first in theUSA [29] and then briefly in Paris [30]. For fetuses with-out liver herniation, a two-step repair consisting of clo-sure of the diaphragm and enlargement of the abdomenyielded compensatory lung growth [31]. A formal NIH-sponsored clinical trial in humans showed that in the liv-er-down group an unexpectedly high survival rate ob-tained in the expectantly managed group, without a fur-

ther increase in those treated by fetal surgery [32].Additionally, the fetal surgery group had a high rate ofneurological morbidity. Fetuses with liver herniated into

the thorax are theoretically better candidates for fetal in-tervention since their survival is lower. However, whendoing an anatomical repair in this group, reduction of theliver is required. This acutely kinks the umbilical venousreturn, leading to fetal death [33]. These observations puta (temporary) end to open fetal surgery programs basedon anatomical repair.

A completely different approach was based on the re-discovery of observations made in 1965 by Carmel et al.[34]. During fetal life the lungs are important contribu-tors to amniotic fluid volume. Lung-liquid volume andintratracheal pressure are maintained within precise lim-its by opening and closing of the larynx [35]. The prenatalairway pressure is determined by the balance of forcesgenerating the elastic recoil of the lungs and the thoracicwall. The fetal chest wall is relatively stiff, whereas thelungs are more compliant, creating a negative intrapleu-ral pressure of 0.20.7 Torr [36]. The intratracheal pres-sure varies with fetal breathing movements: in their ab-sence, pressure under the glottis is 1.82.0 Torr above thatof the amniotic fluid cavity [37, 38]. In other words, dur-ing fetal apnoea there is a net transpulmonary pressureof about 2.7 Torr, which stents the airways and promotes

lung growth [39]. Fetal breathing leads to the opening ofthe vocal cords, and levels the airway pressure to that ofthe amniotic cavity. Chronic drainage of lung liquid leadsto pulmonary hypoplasia, while its entrapment causes in-creased lung growth despite moderate effects on intratra-cheal pressure [4042].

Better insight into the role stretch plays in fetal airwaydevelopment started a convoluted journey consisting ofmany experimental and clinical manipulations of fetal

0

10

20

30

40

50

60

70

80

90

100

Surv

ivalrate(%)

Extreme

Liver in thorax (up)

Liver in abdomen (down)

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lung liquid. To our knowledge, DiFiore and Wilson [26]first suggested the use of fetal tracheal ligation to reverselethal pulmonary hypoplasia due to CDH. Tracheal oc-clusion (TO) is also referred to as the PLUG (plug the lunguntil it grows) strategy [43]. Clips were first used becausean endoluminal foam plug induced tracheal side effects

or was not completely occlusive [44]. Groups from Leu-ven, Paris, San Francisco, Calif., Philadelphia, Pa. andProvidence, R.I. independently explored endoluminalocclusion techniques, leading to a true odyssey of de-vices, ranging from cuffs and polymeric foam to mag-netic valves, umbrellas and vascular occlusive balloons[4548]. The varying occlusion methods have differentocclusive performance, clinical acceptability, accommo-dation of tracheal growth, reversibility at birth or in ute-ro, and local side effects. As early as in 1995, we used adetachable endoluminal balloon which we could insert inlambs by fetoscopy. This balloon system is currently still

in clinical use and prevailed over the other methods for avariety of reasons. First, balloon occlusion allows for tra-cheal growth. Second, it avoids neck dissection and ex-ternal clipping, thereby preventing its inherent morbidity[49]. Third, percutaneous access is feasible in over 95% ofcases [15]. Finally, experimentally tracheal side effectswere limited to mild local tracheal changes, consisting ofloss of epithelial folding, squamous metaplasia and focaldefects without damage to the cartilage [50].

The eventual effect of TO is dependent on timing, du-ration and reversal of the occlusion. The literature on thistopic has been summarized elsewhere by Khan et al. [51]and Nelson et al. [52]. Briefly, TO increases DNA synthesis,which peaks after 2 days and is largely complete by 4 days[53]. Thereafter, growth falls back to control rates [54]. TOfor 1 week induces pulmonary hyperplasia, but effects aremore important after 3 weeks of obstruction [55, 56]. Ges-tational age at occlusion is another important determinant[57]. Lung growth is primarily driven by the volume oflung liquid rather than by tracheal pressure. As a conse-quence, the rate of lung growth is greater late in gestation,because of the higher lung liquid secretion in older fetuses,together with higher chest wall compliance [53, 58, 59].

However, growth rate is not the only concern: lung sizewhich can eventually be achieved at birth is as critical.Therefore, earlier intervention may lead to larger lung sizethan late TO. Lipsett et al. [60] demonstrated the beneficialeffect of early TO (101 days of pregnancy in sheep; cana-licular phase; term = 145 days) over late TO (129 days; sac-cular phase). Sustained TO may increase lung mass andtemporarily improve gas exchange [26], but TO lungs aredepleted of alveolar type II cells [61] and surfactant [62]

and there is PHT after birth. Our group proposed thatthese effects should be limited by reversal of TO beforebirth (plug-unplug sequence) [63]. One of the most com-prehensive experiments in fetal lambs was that by Nelsonet al. [64]. A cyclical occlusion protocol with a 47-hour oc-clusion and 1-hour release performed between 110 and 138

days provided ideal lung growth. Unfortunately, this inter-mittently active occlusion device has yet to be produced forclinical use. Temporary TO also leads to more normalmuscularization of pulmonary arterioles. However, thefunctional impact is not very obvious [65, 66].

The above is mainly a summary of ovine experiments,but rabbits with CDH have also been used to study airwayand vascular changes by TO. Rabbits have a pulmonarydevelopment that largely mimics that of the human lung.Alveolization occurs prior to birth so that at term, rabbitlungs are in the terminal air sac stage. Rabbits have a rel-atively short gestational period (term = 31 days) and a

large litter size so that they are practical for fetal surgicalexperiments. The pseudoglandular phase stretches pro-portionally far in pregnancy so that fetal surgery on areasonably sized animal can be done. We demonstratedthat surgical induction of CDH at day 23 of gestationleads to progressive and severe pulmonary hypoplasiaand vascular changes [6769]. TO reverses this process inpart, in particular late in pregnancy, and steroids mayhave a beneficial effect [70, 71]. In utero, a reversal has notbeen described in this animal. Nitrofen rats have alsobeen used to study the effect of TO [72, 73]. These ani-mals, however, have a different lung development andsurgery is more difficult. Very sophisticated experimentshave made it possible to unravel gene expression follow-ing TO in these animals, while pharmacologic agents thatmay induce lung growth, with or without TO, are beingtested as well. For instance, osmotic active agents maytrigger lung growth as demonstrated in rats [74] as wellas sheep. Perfluorocarbons may be used as well. Theyhave a high density and viscosity and in fetal rabbits withnormal lungs, we together with others have shown thatperfluorooctyl bromide can trigger lung growth [75, 76].Perfluorooctyl bromide-treated animals also had im-

proved neonatal lung mechanics and normal type IIpneumocyte density [76].

Prenatal Diagnosis and Prediction of Outcome

One of the criteria for fetal surgery is that an accuratediagnosis can be made and the natural history of the con-dition can be predicted. Wide availability of high-resolu-

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tion ultrasound and increasing access to prenatal screen-ing have made it possible in western countries to diagnose2 cases out of 3 antenatally [77]. Following diagnosis, ad-ditional imaging methods and genetic studies allow to ruleout the vast majority of associated anomalies, which havea proven negative effect on postnatal outcome. Karyotyp-ing is an essential step in the work-up of the fetus withCDH, but its resolution may fall short of excluding under-lying genetic problems. Modern techniques are, therefore,increasingly being used, also to better understand the ae-tiopathogenesis of CDH [78, 79]. In this issue, Brady et al.[80] review these new approaches that are slowly intro-duced into the clinic. They recently designed a purpose-designed array, targeting genes previously linked to CDH,and applied it to fetuses with apparently isolated CDH [81].They hypothesized that even in those isolated cases, theremight be underlying genetic causes resulting from copynumber variants. Indeed, in nearly 4% of the samples a ge-nomic imbalance was detected, and 2 out of 3 located ongenes earlier tied to CDH. This underscores the need forfurther investigation of the genetic basis of this condition,including in cases phenotypically presenting as isolated

CDH. Today, genome-wide comparative hybridization istechnically feasible and we are integrating it into our as-sessment of anomalies like CDH [82]. However, the inter-pretation of the detected copy number variations (particu-larly those that exhibit reduced penetrance or with variableexpression), incidental findings not clearly related to theanomaly involved or unclassified variants remains diffi-cult. Therefore, these novel techniques have to be usedwith caution within research protocols [83].

Apart from genetic analyses, structural evaluation isused to rule out associated anomalies which include indescending order cardiac defects (52%), genitourinary(23%), gastrointestinal (14%) and central nervous systemanomalies (10%) [5]. In this issue of Fetal Diagnosis andTherapy, Claus et al. [12] review the different imagingmethods that provide anatomical assessment of the fetuspresumably with CDH. Though ultrasound remains thebasis of prenatal diagnosis, fetal MRI may play an in-creasingly important role. However, its added value maybe difficult to prove. When after scrutinous assessmentthe condition seems isolated, parents will ask for an esti-mation of the chances of survival. This may help themwith further decision making. This includes terminationof pregnancy, which in most countries is legally and eth-ically acceptable. Therefore, survival chances and mor-bidities should be predicted on the basis of objectiveinformation. In other words, prenatal prediction ofoutcome has become an issue for any fetal medicine spe-cialist, even if there were no fetal surgery option. In thisissue, both the assessment of the developing airways aswell as of the pulmonary vasculature and knowledge

about the factor liver herniation will be reviewed [12].Briefly, the best-studied prognostic method in use to-day is the lung-to-head ratio (LHR), which involves stan-dardized 2-dimensional ultrasound measurement of thecontralateral lung at the level of the four-chamber view ofthe heart, as demonstrated by the antenatal CDH registry[84, 85]. When expressed as a proportion of what canbe expected in a normal fetus (observed/expected LHR),this measuring method is independent of gestational age

Chin suture T-bar

Sonogram

Trocar

Tracheal screw

a b c

Fig. 2.Clinical TO techniques using a foam plug (a), an external clip (b) [44], and the same but applied by fe-toscopy (c) [101]. Reproduced with permission.

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(fig. 1) [86]. This is also the sole method tested for predic-tion of (early neonatal) morbidity [87].

Bilateral lung volumetry, as compared to 2-dimen-sional measurement of the contralateral lung area, cer-tainly has the potential to improve prediction, but thisremains to be demonstrated [8890]. Again, here vol-

umes also need to be expressed as a function of what isexpected in a normal control. The most accurate methodis to match cases with normal lung development and withequal estimated fetal weight, though gestational age alsoworks fairly well [91]. There is a debate on whether lungvolumetry should be done by 3-dimensional ultrasoundor fetal magnetic resonance. In our own experience, thelatter seemed superior because of its higher resolution al-lowing more often a reliable measurement of the ipsilat-eral (smaller) lung [92]. Liver-up has already early onbeen recognized as a poor prognostic factor, and this hasbeen confirmed in two meta-analyses [93, 94]. Hernia-

tion of the liver into the thorax is observed in about 50%of left-sided cases, whereas it is nearly a constant in theright-sided cases. Logically, the predictive value could beimproved if the amount of liver herniation is quantifiedmore precisely. This was already done by several groups,but standardization is lacking [95]. Also, it remains to bedemonstrated whether lung volume and (amount of) liv-er hernation are independent predictors, as suggested inour recent study [96]. From a pragmatic viewpoint, in Eu-rope we currently use a combination of both variables forprenatal counselling.

Another tool is the assessment of the pulmonary cir-culation, which one might hope may be predictive ofPHT. This is the second most important cause of deathin CDH. Over the course of time, measurements of thenumber of branches, vessel diameters, flow velocimetryor volume, and reactivity to maternal oxygen inhalationhave been made. This is described in detail in the contri-bution of Cruz-Martinez et al. [97]. Vascular and airwaydevelopment are interconnected so that there is certainlya relationship between vascular assessment and measure-ments of lung size [98100]. However, several studieshave already pointed to the independent nature of these

measurements.

Early Clinical Experience with TO

The tale of clinical TO started, as for most fetal surgi-cal procedures, at the University of California, San Fran-cisco (UCSF). Following the failure of foam plugs to oc-clude the trachea, TO was achieved by laparotomy, hys-

terotomy, neck dissection and tracheal clipping (fig. 2)[44]. Soon, a clinical series was published by the group ofthe Childrens Hospital of Philadelphia. All fetuses hadsevere pulmonary hypoplasia prior to TO. The lung re-sponse was variable and overall survival rate was 33%.Four out of the 5 survivors had serious neurological mor-

bidity [101]. The UCSF later reported a 75% survival rate,which they related to the use of endoscopic uterine access(fig. 3). For clarity, this meant initially uterine exposureby laparotomy, multiple cannulation and endoscopic tra-cheal dissection and clipping [49, 102]. The use of TO alsomade it possible to operate on fetuses with liver hernia-tion. Later, the UCSF group moved to a single 4.5-mmport inserted into the uterus following laparotomy anduse of a balloon [102, 103]. The first percutaneous endo-luminal occlusion was reported by Quintero et al. [104].Unfortunately, the device fai led to occlude and the babydied in the postnatal period. In Europe, the so-called Fe-

tal Endoscopic Tracheal Occlusion Task Force pro-posed an operation through a 3.3-mm percutaneous ac-cess with the use of an endoluminal balloon (fig. 3) [14].This programme had barely started when the results ofthe single-centre NIH-sponsored randomized controlledtrial (RCT) became available [105]. The survival rate afterFETO was over 75% as was hoped. But as in the previousRCT, there was an unexpectedly high survival rate in theexpectantly managed group. Given that there was no ap-parent benefit from fetal surgery, the European FETOconsortium considered stopping their trial. However, at acloser look, the patients in American RCT did not meetthe severity criteria the FETO task force used, i.e. fetuseswith an LHR !1.0 (around 2629 weeks: observed/ex-pected LHR 2527%) and liver herniation (severe pulmo-nary hypoplasia).

Current Percutaneous FETO Technique

Ideally, we strived to perform FETO at 2628 weeks.FETO was done under general anaesthesia at f irst, but wesoon moved to regional and local anaesthesia with fetal

sedation and immobilization. The first balloons were re-moved via an ex utero intrapartum treatment procedure,but we soon tried to establish whenever it is clinically pos-sible to reverse the occlusion in utero, either by ultra-sound-guided puncture or fetoscopy. This allowed forvaginal delivery and early return of the patient to the re-ferring unit, but the most important argument was thatin sheep it improved pulmonary maturation [63].

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Additionally, it was hoped that the lesser invasiveness,as a result of the use of locoregional or local anaesthesia,the percutaneous approach and the smaller diameter ofinstruments, would reduce the membrane rupture rateobserved by the UCSF group (table 1). After an initial re-port in 2004 [14], we recently came up with data on ourentire experience of 210 consecutive cases [15].

In the European setting, the majority of patients arenot staying at the FETO centre after occlusion or for de-livery. Our data, therefore, report on the outcomes irre-spective of the location of management of the fetus orneonate. The most frequently used technique for reversalof occlusion was fetoscopy (50%). Ultrasound-guidedpuncture accounted for 19% of cases. Hence, in a third ofcases, the airways were managed around the time of de-livery. In 21%, this was done while the fetus was still onthe umbilical cord, and in 7% it was done postnatally.There were difficulties with balloon removal in 10 cases,when this happened in unprepared circumstances. Thismay have led or contributed to neonatal death [14, 106]and is the reason why we want to avoid at all cost an un-

planned balloon removal. Therefore, we now plan elec-tive removal at 34 weeks and insist that patients stay closeto the FETO centre in the occlusion phase, since it is theonly place that has sufficient experience and can organizea 24/7 service for the management of fetal airways.

In 210 consecutive cases, preterm prelabour rupture ofmembranes within 3 weeks of FETO occurred in 16.7%cases. The rupture rate prior to 34 weeks was 25%. Whenamniorrhexis occurred, labour did not necessarily start

so that an expectant management was possible. Deliverytook place at a median of 35.3 weeks, but it was before 34weeks in 30.9% cases. On the basis of data from the ante-natal CDH registry, FETO would increase survival rate insevere cases with left-sided CDH from 24.1 to 49.1% andin right-sided CDH from 0 to 35.3% (p ! 0.001) [84].Short-term morbidity in survivors is also better than ex-pected: it is close to that of cases with moderate pulmo-nary hypoplasia, who are managed expectantly duringpregnancy [107]. Most newborns require surgical patch-ing of the diaphragm, indicating the rather large size ofthe defect in this selected group.

A number of predictors of survival were identified,but many of these are interconnected. One is the ob-served/expected LHR prior to the procedure [15, 108].This would suggest that smaller lungs, having a smallerairway epithelial surface, might have a reduced ability toproduce lung liquid, hence rising airway pressure to alesser extent. A second predictor is the gestational age atdelivery. Logically this follows the high occurrence ofpreterm prelabour rupture of membranes, which itself is

also a predictor, in turn related to operation time. Thesecond intervention (balloon removal) might also in-crease the risk for early delivery. However, we observedat the same time a higher survival rate in fetuses in whomthe balloon was removed more than 24 h prior to birth[8]. Therefore, a balance has to be made between the ad-vantages of elective and timely balloon removal and therisk of early delivery by the second intervention or lettingthe pregnancy progress and be confronted with an acute

Perfusion scope

Ultrasound

Balloon

inatedBalloon

detached

a b

Fig. 3.Clinical TO techniques using a balloon. aVia laparotomy and hysterostomy [49]. bPercutaneous [122].Reproduced with permission.

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need for balloon removal. One could also move FETO tolater in gestation, which would reduce the risk of pretermbirth, but clinical data show that this yields a lesser lung

response [109]. For this reason, we offer late TO only tomoderate cases in the setting of a trial [10, 11].There are few demonstrable clinical side effects of the

balloon on the developing trachea, except in very early oc-clusions and when complications arise at the time of bal-loon removal [110]. Neonates and infants do however havelarger tracheal dimensions referred to as tracheomegaly.This does not seem to have an obvious clinical impact,except for a barking cough on effort [111]. Over time, the

widening seems to become less important [112]. This is inline with the observations from animal experiments, butserious side effects can obviously not be excluded [113].

We are aware of other experience [114, 115], and alsoUS-based programmes at UCSF [116] (NIH trial iden-tifier: NCT00768703), St. Lukes at Denver, Colo.(NCT00881660) and the Hasbro Hospital in Providence,R.I. (NCT00966823). In this issue of Fetal Diagnosis andTherapy, two larger case series from Brazil are also pub-lished. The reported outcomes of the study by Ruano etal. [16] and Peralta et al. [117] are quasi duplicates of whatwe reported (table 1).

Table 1.Fetal surgery for CDH trends in clinical experience

Harrison et al. (2003) [105]n = 11

FETO consortium (2009)n = 210

South American series (2010)n = 16 [16], n = 12 [123]

Criteria for surgery (left) LHR

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The Tracheal Occlusion to Accelerate Lung Growth

(TOTAL) Trial and FETO in the Future

The fact that the FETO procedure, just as laser photo-coagulation for transfusion syndrome is increasingly be-ing used, underscores the acceptability of a minimally

invasive fetal surgical procedure, both by physicians andpatients. This success may also become the Achilles heelof the procedure. The above history of fetal surgery forthis condition has demonstrated that things are not al-ways what they seem. Therefore, it is more than time toconduct, in controlled circumstances, this randomizedtrial comparing expectant management during pregnan-cy and fetal intervention, followed by standardized neo-natal care. Controlled means that there is rigorous ad-herence to selection criteria, surgical technique and skills,availability of emergency airway management, postnatalmanagement, follow-up of patients and precise as well

as comprehensive reporting. We may be the first to beblamed for not having started a randomized trial earlier,which was for a variety of reasons [19]. Meanwhile, in Eu-rope, we finally moved to a randomized trial comparingexpectant management during pregnancy to late (3032 weeks) FETO in cases of moderate hypoplasia(NCT00763737), and more recently, FETO at 2730weeks for severe cases (NCT01240057).

Soon we will be joining centres in London, Paris andToronto which have a considerable fetoscopic turnover aswell as a case load of CDH fetuses, and also have trainingfor the FETO procedure. Though difficult, it is hoped thatother North American centres will also join the list ofseveral European centres endorsing this trial. We decidedto adopt a pragmatic approach, with few centres doingFETO, yet with more tertiary care centres offering stan-dardized postnatal care, either in expectantly managedcases or after balloon removal. The balloon is removed at34 weeks. Postnatal management of this multicentre trialis standardized by a consensus protocol made up by lead-ing European neonatal centres directed by Tibboel andSchaible [118, 119]. The same neonatal experts report inthis issue on their outcomes using a nearly identical pro-

tocol [120]. Given different background survival rates (inexpectantly managed cases) in some areas, there might beroom for additional trials. We would, however, plead foragreement between investigators to have at least compa-rable study designs and outcome measures to allow fu-ture comparison.

Conclusion

Currently, the diagnosis of CDH should prompt refer-ral of the patient to a tertiary care centre used to managethis condition. There a comprehensive evaluation, in-cluding imaging and (high-resolution) genetic studies,

should be carried out. The primary purpose of this eval-uation is to rule out associated anomalies and to assessthe severity of pulmonary hypoplasia in order to offerparents an individualized prognosis. The latter can bedone on the basis of the dimensions of the lung, its vas-cularization and liver position. Further multidisciplinaryconsultation should address the neonatal issues as well aslater morbidities. Based on this complete evaluation andafter extensive counselling, patients should make an in-formed choice out of the available management optionswhich also include fetal therapy for more severe cases andin a number of centres spread over the world. In Europe,

all elements are available to formally evaluate FETO forsevere and moderate CDH. Over the last 5 years, we havebuilt up sufficient experience to consider FETO as a safeand clinically acceptable procedure. What needs to bedone now is to assess whether the procedure is truly ben-eficial, and therefore we have designed 2 randomized tri-als. Fetal medicine specialists have earlier shown (intwin-to-twin transfusion syndrome) that RCTs can workin fetal surgery [121]. These trials are the only way to con-trol the history of FETO, which in the absence of level Ievidence of superiority will start to live its own life withever-ongoing debates between advocates and opponents.We, therefore, strongly urge that patients who are open totrial participation should be referred to FETO centres foradditional evaluation and counselling about the logisticsof fetal surgery and eventually trial participation.

Acknowledgments

The European Commission funded the EuroSTEC pro-gramme (LSHC-CT-2006-037409) which includes the organiza-tion of a randomized trial for this condition. The Fonds voorWetenschappelijk Onderzoek Vlaanderen (FWO; 1.8.012.07.N.02)

and the Instituut voor Wetenschap en Technologie (IWT/070715)fund the fetal therapy programme in Leuven (Belgium). We thankthe centres and colleagues of the antenatal CDH registry and theFETO consortium for making this story happen.

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