Seminars in Fetal & Neonatal Medicine 15 (2010) 58–67 Contents lists available at ScienceDirect Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/sinyFetal surgery is a clinical realityJan A. Deprest a, *, Roland Devlieger a, Kasemsri Srisupundit a, Veronika Beck a, Inga Sandaite b,Silvia Rusconi a, Filip Claus b, Gunnar Naulaers a, Marc Van de Velde c, Paul Brady d, Koen Devriendt d,Joris Vermeesch d, Jaan Toelen e, Marianne Carlon e, Zeger Debyser e, Luc De Catte a, Liesbeth Lewi aa Division Woman and Child, University Hospital Gasthuisberg, Leuven, Belgiumb Division Medical Imaging, University Hospital Gasthuisberg, Leuven, Belgiumc Division Anesthesiology and Critical Care Medicine, University Hospital Gasthuisberg, Leuven, Belgiumd Centre of Medical Genetics, University Hospital Gasthuisberg, Leuven, Belgiume Laboratory for Molecular Medicine, Virology and Gene Therapy, Faculty of Medicine, Leuven, Belgium s u m m a r yKeywords: An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable toCongenital diaphragmatic hernia fetal surgical intervention. We discuss the current clinical status and recent advances in endoscopic andFetal pain open surgical interventions. In Europe, fetoscopic interventions are widely embraced, whereas theFetal surgery uptake of open fetal surgery is much less. The indications for each access modality are different, henceFetoscopy they cannot substitute each other. Although the stage of technical experimentation is over, mostMonochorionic twins interventions remain investigational. Today there is level I evidence that fetoscopic laser surgery for twin-to-twin transfusion syndrome is the preferred therapy, but this operation actually takes place on the placenta. In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele. Overall maternal safety is high, but rupture of the membranes and preterm delivery remain a problem. The increasing application of fetal surgery and its mediagenicity has triggered the interest to embark on fetal surgical therapy, although the complexity as well as the overall rare indications are a limitation to sufﬁcient experience on an individual basis. We plead for increased exchange between high volume units and collaborative studies; there may also be a case for self-regulation. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience. Ó 2009 Elsevier Ltd. All rights reserved.1. Introduction to fetal therapy, a subsequent further referral to a highly specialized unit may be required, as many therapies cannot be offered locally As ultrasound screening programmes become more widely with a reasonably sufﬁcient experience.implemented and qualitatively improved, an increasing number of This issue of Seminars in Fetal and Neonatal Medicine describesanomalies will be diagnosed prior to birth. When fetal malforma- the area of expertise of one of the world’s largest centers in fetaltions, genetic diseases or conditions acquired in utero are assessment and therapy. The Children’s Hospital of Philadelphiasuspected, those patients should be referred to fetal care centers. (CHOP) is a ‘quaternary’ care unit, i.e. it typically accepts patientsThese have the necessary equipment and the required skills for from secondary but mainly tertiary referring hospitals offeringmore accurate prenatal evaluation, and are located in institutions review for an invasive procedure. As such, this issue has become anwith multidisciplinary teams familiar with the perinatal manage- interesting collection of reviews on modern fetal therapy. Fetalment of those conditions. They will make a prognostic evaluation therapy has recently received much attention, in part thanks toand deﬁne all potential options open to the family. When it comes groups like CHOP who have pushed at the frontiers of knowledge. Historically fetal surgery was mainly an American pediatric surgery enterprise, pioneered by Michael Harrison at the University of California at San Francisco (UCSF). Being also an important * Corresponding author. Address: Division Woman and Child, Department postnatal pediatric surgery training center, the seed of fetal surgeryWomen, University Hospitals Leuven, B-3000 Leuven, Belgium. Tel.: þ32 16344215;fax: þ32 16344205. spread as his trainees dispersed over North America. Thus, UCSF E-mail address: firstname.lastname@example.org (J.A. Deprest). probably trained the vast majority of clinicians at some stage in1744-165X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.siny.2009.10.002
J.A. Deprest et al. / Seminars in Fetal & Neonatal Medicine 15 (2010) 58–67 59their fetal surgery career, with Scott Adzick as one of the earliest but there are no ofﬁcially endorsed wider initiatives. For instance,and most prominent research fellows. in the EU healthcare is still a responsibility of the individual (national) European member states. Therefore any effort to regulate2. Conditions for fetal surgery and centers offering it quality of care but also optimal access for patients will ultimately be at a national level, because the EU itself is not empowered to do so. Programmes such as those from CHOP and UCSF have inspiredmany others, including ourselves, to explore the avenues of fetal 3. In-utero endoscopy: differences in approach betweentherapy. Also, the mediagenicity of fetal surgery is currently Europe and the USAtempting an increasing number of hospitals and clinicians to opencenters for comprehensive fetal care throughout the world. As fetal The growing availability of video-endoscopic surgery in themedicine specialists, we intuitively applaud this increased interest 1990s and miniaturization of cameras as well as ﬁberendoscopesfor the fetal patient, but there are certainly downsides to this. introduced the concept of endoscopic fetal surgery. A ﬁrm boost to First, most prenatal conditions can await therapy until after fetoscopic surgery was given by the European Commission whenbirth, but there are rare conditions that require prenatal interven- the ‘Eurofoetus’ research and development project was granted.tion to save the life of the fetus, or prevent permanent organ It funded a consortium of selected European fetal medicine unitsdamage. This can be achieved by correcting the malformation, by and one endoscopic instrument-maker to design new endoscopesarresting the progression of the disease, or by treating some of the and instruments.3 We, at our institution, were able to developimmediately life-threatening effects of the condition, delaying safely our novel operating skills in an ovine model by optimalmore deﬁnitive repair until after birth. By deﬁnition we are dealing cross-fertilization of a pediatric surgeon, Francois Luks, and thewith uncommon conditions, and very few patients may opt for fetal primary author, a gynaecologic endoscopic surgeon.4 According totherapy. This inherently means that there is a case-load limitation, the IFMSS guidelines, we then moved to clinical application, byand this is even so for any center offering advanced fetal diagnosis. doing Europe’s ﬁrst successful umbilical cord ligation, unaware of Second, most therapies described herein require access to the an almost simultaneously performed successful procedure doneuterus and/or fetus, hence are invasive. They carry a substantial risk by Ruben Quintero and colleagues at Wayne State Universityand/or may fail, so that the claimed beneﬁts of the intervention (Detroit).5 At that time, the scene was set for minimal access to themust be weighed against the inherent risk for complications. This fetal patient. Given the general assumption that fetoscopy signiﬁ-balance was worded more than 25 years ago by the International cantly reduces the risk for ruptured membranes and pretermFetal Medicine and Surgery Society (IFMSS) (Box 1).1 A small group labour, a number of teams started reconsidering fetal surgery.of pioneers in the ﬁeld of fetal intervention drafted guidelines for Remarkably, the revival of fetoscopy initially focused on surgerynovel interventions, designed to save the life or the organ function, of the placenta and umbilical cord in complicated monochorionicbut which are in the early phase without any proven beneﬁt. At that twin pregnancies, and to a lesser extent the fetal membranestime, these interventions typically required maternal laparotomy, (Table 1).6 This indication was initially not on the shortlist of fetaland partial exteriorization of the fetus through a stapled hyster- surgery targets. The placenta not being the usual habitat of theotomy. Even as today the fetus can be minimally invasively pediatric surgeon prompted the need for involvement of fetalaccessed, these consensus guidelines have remained a reference, medicine specialists. Although this may initially have caused someand in our opinion, should remain so. Where fetal intervention has friction, the full participation of obstetricians has probably lowerednot been formally evaluated, we believe the fetus should not be the threshold for fetal surgical intervention. Another boost tooperated except within a formal trial, in a select number of centers fetoscopy was that complications of monochorionic twinning arethat fully comply with these guidelines. Who and where that would much more common than any other typical indication for fetalbe is certainly a matter of debate, and it is nearly impossible to surgery. In Europe, the Eurofoetus project climaxed with thejudge in an evidence-based way. In an effort to offer maximal successful execution of a randomized trial on laser coagulation forquality and also make further clinical research viable, it will have to twin-to-twin transfusion syndrome (TTTS). Whereas this operationbe agreed upon by the fetal medicine community. In North America was originally pioneered in the USA by Julian DeLia, its widerthis could be in organizations such as NAFTNeT,2 whereas for other clinical implementation in the USA was much slower at theareas of the world this is much less clear. Initiatives such as Euro- ‘traditional’ fetal surgery centers. By contrast, Ruben Quintero, whofoetus are focused around one disease or instrument development, is an obstetrician by training, initially did most of these operations in the USA and as such advanced much the knowledge about this condition just as Kypros Ncolaides, Yves Ville and Kurt Hecher did Box 1. Criteria for fetal surgeryf in Europe. In fact, the successful Eurofoetus trial removed many questions about maternal safety as well as feasibility of fetoscopic 1. Accurate diagnosis and staging possible, with exclusion surgery, hence has been pivotal for the wide clinical acceptance of of associated anomalies. fetoscopy. Another factor that may have contributed to an initially 2. Natural history of the disease is documented, and slower uptake of fetoscopy in the USA may be the delay in regu- prognosis established. latory approval of novel surgical instrumentation. Though these 3. Currently no effective postnatal therapy. 4. In-utero surgery proven feasible in animal models, regulations are obviously there to protect the patient from both an reversing deleterious effects of the condition. overzealous industrial and potentially also medical community, it is 5. Interventions performed in specialized multidisciplinary at times difﬁcult to understand from a European perspective why fetal treatment centers within strict protocols and subsequent subtle variations of the same instrument (an endo- approval of the local ethics committee with informed scope) have to go through such a long regulatory process. As consent of the mother or parents. a side-effect, this may even feed already present suspicions that the technique is controversial and unsafe. There are fewer regulatory issues in Europe, without – as far as we know today – compromising patient safety. Regulatory issues have to our knowledge also partly contributed to limited clinical activity in yet f Adapted from Harrison et al.1 another potential indication for fetal surgery, i.e. congenital
60 J.A. Deprest et al. / Seminars in Fetal & Neonatal Medicine 15 (2010) 58–67Table 1Indications and rationale for in-utero surgery on the fetus, placenta, cord or membranesa Pathophysiology Rationale for in-utero therapy Surgery on the fetus: 1. Congenital diaphragmatic hernia Pulmonary hypoplasia and pulmonary hypertension Timely reversal of pulmonary hypoplasia and prevention of pulmonary hypertension 2. Lower urinary tract obstruction Progressive renal damage by obstruction Urinary diversion prevents obstructive uropathy and Pulmonary hypoplasia by oligohydramnios restores amniotic ﬂuid volume 3. Sacrococcygeal teratoma High output cardiac failure by arteriovenous Cessation of steal phenomenon shunting Reversal of cardiac failure; Fetal anemia by tumor growth and/or Prevention of polyhydramnios bleeding within a tumor 4. Thoracic space-occupying lesions Pulmonary hypoplasia (space-occupying mass) Prevention of pulmonary hypoplasia and cardiac failure Hydrops by impaired venous return (mediastinal compression) 5. Neural tube defects Damage to exposed neural tube;cerebrospinal Covering exposed spinal cord, cessation of leakage ﬂuid leak, leading to Chiari malformation and preventing hydrocephaly and reversing cerebellar herniation hydrocephalus 6. Cardiac malformations Critcal lesions causing irreversible hypoplasia or damage Prevention of hypoplasia or arrest of progression of damage Surgery on the placenta, cord or membranes: 7. Chorioangioma High output cardiac failure by arteriovenous shunting Prevention of cardiac failure and hydrops fetoplacentalis and polyhydramnios 8. Amniotic bands Progressive constrictions causing irreversible neurological Prevention of limb deformities and function loss or vascular damage 9. Abnormal monochorionic twinning: Twin-to-twin transfusion Intertwin transfusion leads to oligopolyhydramnios sequence, Bichorionization stops intertwin transfusion, reverses hemodynamic changes; obstetric complications (preterm labor cardiac failure, preventing neurological damage, and rupture of the membranes) delaying delivery (amniodrainage) Fetus acardiacus and discordant Discordant anomalies: where one fetus can be a threat to the Fetocide to improve chances of the other fetus; avoidance of anomalies other, or to avoid termination of entire pregnancy termination of entire pregnancy a Adapted from Deprest et al.6diaphragmatic hernia. Although all the pioneering work has been function in selected fetuses.11–13 This is described in detail bydone in the USA, by the teams of UCSF, Boston, CHOP, and Buffalo, Adzick.14 The National Institutes of Health (NIH) decided to sponsorthis clinical indication is currently much more explored in Europe the Management Of Myelomeningocele Study (MOMS) randomizedthan in the USA. Conversely, Europe has failed to embrace open trial, which involves three centers (San Francisco, Nashville andfetal surgery to the same degree as in the USA. This has traditionally Philadelphia) (www.spinabiﬁdamoms.org). The primary outcomebeen explained by concerns about maternal safety and side-effects, is death or the need for shunting by the age of 1 year. The set-up ofas well as the risk for preterm delivery. The latter is in reality not this trial may have a number of major beneﬁts. First, it maya valid objection, as outcomes from open fetal surgery in larger unequivocally demonstrate whether we should operate on a fetusseries compare favorably to what has been published a decade for this condition (or not). Second, it is conceptually interesting asearlier and remained the general perception (Table 2).7,8 Despite the trial explores the role of fetal surgery in a condition that is notthat, open fetal surgery is rarely done in Europe, with the exceptionof operations on placental support.9,10 This is in our opinion not Table 2scientiﬁcally supported, therefore at the least open to criticism – as Obstetrical and short-term outcomes in the Children’s Hospital of Philadelphiawe will touch on at the end of this contribution. This issue of (CHOP)7 and Vanderbilt University8 series on myelomeningocele repairSeminars covers nearly the entire range of fetal intervention. In this CHOP (n ¼ 51) Vanderbilt (n ¼ 178)article we summarize each of these, with work from CHOP as well Gestation at surgery 23þ0 (20þ0 to 25þ4) (19–30); later 26 weeksas others. (weeks) þ4 þ4 a Gestation at delivery 34 (25 to 37) 33þ5 (25–38) (weeks)4. Myelomeningocele Chiari malformation graded as either (moderate/severe) Although myelomeningocele (MMC) may be a non-lethal Before surgery 14%/86%congenital defect, it does lead to signiﬁcant lifelong morbidity and After surgery 100%/0% 7%/0%burden. This condition should now be detected as early as the ﬁrst, Postnatal shunt 46% (21 weeks) 46% (12 weeks)or at the latest in the second, trimester. Also its extent or location, (postnatal age)which are the most important prognostic factors, can be easily Perinatal losses 3/51 (6%) (prematurity) 5/178 (2.8%) (not speciﬁed) Length of hospital stay 4 days 3.3 days (3–7)determined. In view of the prognosis, many pregnancies are Oligohydramnios 25% early on;terminated, and at this point there is not much hope for an 30% readmission rateimproved postnatal management strategy eventually altering Delivery 30 weeks 5/47 (10.6%)b 11.8% boutcome. All hope is therefore focused on prenatal intervention to Delivery 32 weeks (40/47) 85% (not speciﬁed) Maternal complications None reported, including 9 (5.1%) mild pulmonaryimprove outcome. Experimental work in animal models has shown dehiscence or rupture; edema;that this is possible. Early clinical evidence from both Vanderbilt 1 amniotic ﬂuid leak 1 bowel obstruction;University and CHOP (Table 2) underscored this hypothesis.7,8 In through hystertomy 4 (2.2%) dehiscence,their experience timely prenatal microsurgical layered repair asymptomatic in 3reversed hindbrain herniation, decreased the need for shunting, a Includes all patients. bimproved leg and bladder function, as well as later cognitive Denominator is survivors only.
J.A. Deprest et al. / Seminars in Fetal Neonatal Medicine 15 (2010) 58–67 61lethal, hence does not even appear in the initial shortlist (Box 1 and Late cases without hydrops are delivered in optimal conditions,Table 1). The inherent side-effect is that an occasional preterm with attendants prepared for the management of respiratorydelivery may lead to neonatal death in a condition that is in essence distress. In cases of hydrops their outcome is poorer, and the CHOPnon-lethal, and unlikely to cause preterm birth per se.7 Third, it has group proposes resection while on placental circulation (EXIT-to-prevented an unfettered promulgation of this type of operation. CCAM resection).10 Macrocystic masses can be punctured orFourth, it shows that centers of excellence, although they might shunted and both procedures are minimally invasive. The CHOPhave competing interests, can collaborate effectively. In that experience group is probably the largest, with 23 shunted cases atrespect, the assignment of patients to geographical areas was a mean of 21–22 weeks. Shunting reduced CCAM volume by aninteresting. Some other additional interesting aspects of this trial average of 70% and it can also reverse hydrops. Survival rate wasare that it is overseen and outcomes are evaluated by independent 74% and other smaller series conﬁrm this.25,26 In another chapter,assessors, and that investigators are blinded to the outcomes for the Adzick discusses the use of open fetal surgery for CCAM.27 Fetalduration of the trial. Also some safety and standardization lobectomy for more solid masses has been shown to be bothprecautions are taken, such as deﬁning an upper limit of maternal feasible and effective. Adzick reports on 24 cases operated betweenbody mass index, in an effort to minimize maternal risks. Due to 21 and 31 weeks. Half of them survived and developed normally.28a less than expected recruitment rate of the 200 patients, the trial is Overall, the ideal fetal intervention remains a matter of debate.only expected to be completed in 2010 but the results should be Interestingly, prenatal steroids were shown to resolve hydropsworth waiting for. fetalis and it would seem logical to try this treatment ﬁrst.29,30 The MOMS trial has also closed the backdoor: major fetal care Along the same lines, shunts are also used for signiﬁcantcenters have agreed that no fetal surgery outside of the trial would thoracic effusions, which may have a wide etiologic range, in anbe offered within the USA for the duration of the trial. This certainly effort to prevent pulmonary hypoplasia. Bebbington et al. reviewedis the ideal scenario for an effective trial. In other countries where the CHOP experience (n ¼ 27), with an overall survival rate of 70%.termination of pregnancy is less available (or not at all), patients It is important to realize that the need for insertion of a secondmay be more tempted to offers for fetal surgery. It is important that shunt because of dislodgment shunt is as high as one in three. Thisthis form of experimental fetal surgery should also there be con- may increase the risk for preterm membrane rupture, leadingducted using the same stringent selection criteria and follow-up. potentially to pretem delivery, which is the most important nega- As an unanticipated side-effect, this study apparently tempo- tive prognostic factor.31 In reality, neither appropriate case selec-rized the clinical development of minimally invasive techniques to tion nor optimal fetal intervention are truly known. Shunting isperform this operation in the USA. However, one already needs to only one of a multitude of interventions including also single asthink a step further. The potential of endoscopic coverage of the well as serial thoracentesis, combinations and pleurodesis usingdefect is currently explored by several teams, experimentally and a variety of products. In a recent review by Deurlo and Devlieger allalso clinically.15,16 So far this is a multiple port procedure, with these were shown to be equally effective.32potentially a higher risk for membrane rupture and early delivery, LUTO is a descriptive term for a heterogeneous group ofhence neonatal death. It is also technically different from a layered conditions, of which posterior urethral valves is by far the mostrepair and does therefore not avoid the requirement of a shunt. common. The typical ultrasound ‘key hole sign’ can, however, also be caused by conditions such as stenosis of the urethral meatus,5. In-utero shunting anterior valves, urethral atresia, ectopic insertion of a ureter or even (peri)vesical tumors. Female fetuses very often have more complex Shunts are devices that surgically connect two spaces, so that cloacal malformations. Any obstructive lesion will cause compen-ﬂuid can freely drain from one to another. Their size and satory hypertrophy of the bladder wall smooth muscle, vesico-introduction method compare very much to what operators do ureteral reﬂux and loss of normal renal function. Resultingwhen performing fetoscopy. In this respect, it was surprising to see oligohydramnios will further cause pulmonary hypoplasia,how people who were widely using these devices 10 years earlier ultimately making the condition lethal. One of the potentialwere often criticizing the use of fetoscopy, though the use of shunts solutions, irrespective of the cause, is to create urinary diversion,was at least as debatable. Apart from that, it should be remembered which will salvage renal function when this was within reasonablethat these are only devices, so that their merits are completely limits prior to the procedure. The exact way to determine renaldependent on the indication for its use. For instance, they have been function ahead of time, and predict ultimate outcome, remains tohistorically used for draining isolated hydrocephaly. Later on, be demonstrated.17,33,34 Landmark work comes from Johnson anda moratorium on this indication was agreed on because prenatal Biard at CHOP, who were able to determine the long-term outcomeshunting did not alter outcome. Their further use in cases of urinary of in-utero-treated patients. They concluded that the actual type oftract obstruction and thoracic pathology is reviewed by Mann et al.17 urinary obstruction diagnosed postnatally was predictive of Congenital cystic adenomatoid malformation of the lung long-term renal outcome. In essence, posterior urethral valves do(CCAM) is an overgrowth of terminal bronchioles which act as much better, whereas babies with urethral atresias or the ‘prunea space-occupying lesion. If large enough, it causes pulmonary belly’ phenotype do less well.35 Second, despite favorable prenatalhypoplasia and mediastinal shift, with subsequent hydrops fetalis estimation of kidney function, up to half of survivors may end upand polyhydramnios. Growth, which is maximal around 28 weeks, with chronic renal insufﬁciency.36,37 This underscores the urgentcan be followed by longitudinal measurement of the lesion. need for better anatomical and functional prenatal evaluationCrombleholme et al. proposed to use the proportion of the mass of methods than we currently have. Also it means that urinarythe lesion divided by the head circumference (CCAM volume ratio: diversion is a salvage solution, not guaranteeing rescue of organCVR) to plan follow-up and/or predict fetal demise.18 After function.28 weeks the majority will decrease in size. Planned delivery and Two future strategies should change this. Kilby et al. proposedneonatal resection will be sufﬁcient, with excellent long-term a randomized trial of the value of fetal intervention (http://www.outcomes.19–22 Only a small subset cause fetal problems, with fetal pluto.bham.ac.uk) with currently available means. Also we needhydrops being the best predictor of death. When CVR is 1.6, risk to explore the possibility of better anatomical evaluation, e.g. usingfor hydrops is 80% (range: 15–75%). In this group intervention in-utero endoscopy. At present the equipment available is less thanseems justiﬁed.23,24 For only a minority this will be fetal surgery. ideal. Even in the hands of the pioneers it was not possible to
62 J.A. Deprest et al. / Seminars in Fetal Neonatal Medicine 15 (2010) 58–67distinguish between urethral valves and atresia.38 Their size is still experience at San Francisco.64 Removal of the balloon was prenataltoo large and it is difﬁcult to direct the endoscope to the bladder either by fetoscopy or ultrasound-guided puncture, intrapartum byneck, being the area of interest. However, the advantage of fetal EXIT (ex-utero intrapartum therapy) or postnatal either bycystoscopy is that it can be extended to a therapeutic procedure. tracheoscopy or percutaneous puncture. Delivery took place atBoth fetoscopic antegrade catheterization, hydro- or laser ablation a median of 35.3 weeks. Again, it was before 34 weeks in 30.9%of urethral valves have been described.38–40 cases. In 204 (97.1%) cases the babies were live born and 98 (48.0%) were discharged from the hospital alive. On the basis of the6. Congenital diaphragmatic hernia relationship between survival and O/E LHR in expectantly managed fetuses with CDH, as reported in the antenatal CDH registry, In this issue Hedrick reviews the issue of prenatal assessment we estimated that in fetuses with left CDH treated with FETO theand therapy for isolated congenital diaphragmatic hernia (CDH).41 survival rate increased from 24.1% to 49.1% and in right CDHCDH is a surgically correctable defect, but the essential problem is survival increased from 0% to 35.3% (P 0.001).65 Operationthe coexisting pulmonary hypoplasia. This causes ventilatory time was dependent on surgeon experience. It also predictedinsufﬁciency and pulmonary hypertension (PHT) in the neonatal the occurrence of PPROM. The strongest predictors of outcomeperiod. Prenatal referral, high case load and advanced neonatal care were O/E LHR prior to the procedure, PPROM and gestational age atimprove survival but the condition is still lethal in around 30% of delivery.cases (Table 3).42–49 Prenatal prediction of poor outcome creates In earlier work in smaller series, we showed that increase ina clinical need to counsel parents on prenatal options, including lung area or volume after FETO is an independent predictor oftermination of pregnancy or prenatal intervention to trigger lung survival.66 Short-term morbidity in survivors is comparable to whatgrowth. Fetal imaging techniques are used to measure lung size and is expected in fetuses with moderate hypoplasia managedvascular development or reactivity. The best validated prediction postnatally.67 Whereas a later FETO would theoretically reduce themethod today is the use of the lung-to-head ratio (LHR), which risk for preterm birth, it needs to be balanced against a lesser lunginvolves standardized two-dimensional ultrasound measurement response. This was demonstrated experimentally and clinically, soof the contralateral lung on a cross-section through the chest.50 that it seems that later occlusion would be reserved for milderWhen expressed as a proportion to what is normally expected cases.68,69 These observations were the basis for the start of[observed/expected (O/E) LHR] prediction is independent of a randomized trial in Europe, currently looking at the value of FETOgestational age and technique used.51 When O/E LHR 15% the in moderate hypoplasia, but soon also for severe cases. This will befetus has extreme pulmonary hypoplasia and virtually no chance of a multicenter trial, which has required the drafting of a consensussurvival. Fetuses with O/E LHR ¼ 15–25% have severe pulmonary protocol for postnatal management by Tibboel et al., which in itselfhypoplasia and their predicted survival is around 15%. Above that, is already an achievement.70survival increases to 60% or more (Figure 1).52 MRI volumetry isvery likely to become more accurate, hence better predictive.53–55 It 7. Interventions in monochorionic twinsalso allows quantiﬁcation of the degree of liver herniation.56Measurement of pulmonary vessels, their resistance and reactivity Monochorionic (MC) twins account for 70% of monozygousare currently evaluated as predictors of PHT.57–59 twins and 20% of all twins. Compared with dichorionic twins, they Fetal tracheal occlusion (TO) entraps lung liquid, leading to are at increased risk for fetal loss, preterm delivery and perinatalstretch-induced growth of airways and vessels. The experimental mortality and morbidity. A number of complications are amenablebackground on effects of TO was recently summarized elsewhere.60 to fetal intervention either on the cord or placenta. As these are allOur clinical experience with percutaneous fetoscopic endoluminal possible through minimal access, these interventions becametracheal occlusion (FETO) started in 2004, prompting abandonment quickly accepted. As a result the general knowledge about MC twinsof other occlusion methods (Figure 2).61,62 We recently reported the has increased greatly. Herein we summarize brieﬂy the currententire experience (n ¼ 210) of the FETO consortium (Leuven, state of affairs; more extensive reviews can be found elsewhere.71,72Barcelona and London).63 FETO was offered to severe cases, and TTTS complicates 9% of MC twin pregnancies.73 It is an ultra-occassionally in a number of cases with associated anomalies. FETO sound diagnosis based on the following criteria: polyuric poly-was performed at a median gestation of 27.1 (range: 23.0–33.3) hydramnios in the sac of the recipient twin (deﬁned as deepestweeks. The median duration of FETO was 10 (range: 3–93) min. vertical pocket of 8 cm prior to 20 weeks and 10 cm between 20Spontaneous prelabor rupture of membranes (PROM) prior to 37 and 26 weeks; in the USA 8 cm is the single cut-off parameter)weeks (preterm PROM, or PPROM) occurred in 47.1% cases at combined with oligouric oligohydramnios in the donor sac (deep-a median of 30 days after FETO. A more informative number is that est vertical pocket 2 cm). The immediate threat to pregnancy ispreterm PROM occurred within 3 weeks in 16.7% cases. Although polyhydramnios-induced PPROM and preterm delivery. In view ofstill clinically highly relevant, this is much less than in the earlier the poor survival rates with expectant management, there is little disagreement that therapy should be offered. For years therapy therefore consisted in repetitive amniodrainages with a totalTable 3 survival rate of 61%, gestational age at delivery around 28 weeksRecent series on postnatal outcome of isolated congenital diaphragmatic hernia and morbidity of around 20%.74 As the condition is caused by Publication No. of cases TOP rate Survival rate speciﬁc patterns of anastomoses which run at the placental surface, Stege et al. (2003)42 185 NA 70% the logical therapy consists of fetoscopic identiﬁcation and ablation Gallot et al. (2007)43 314 7% 63% of all visible anastomoses. This should be done as sparingly as Sartoris et al. (2006)45,a 244 NA 70% possible without being at the expense of leaving anastomoses, Hedrick et al. (2007)46 89 NA 66% which cause recurrence, intrauterine fetal death or fetal anemia.75– Datin-Dorriere et al. (2008)47 ` 99 20% 63% 78 Mettauer et al. (2009)48,a 147 – 77% Fetoscopic laser is performed percutaneously under local or loco- Grushka et al. (2009)49,a 121 – 81% regional anesthesia and requires only a short hospital stay. ATOP, termination of pregnancy; NA, not available. randomized trial demonstrated better results with laser than a Some units report survival rates after transfer of the neonate, and therefore do amnioreduction, both in terms of gestational age at delivery (33.3not include the hidden mortality. vs 29.0 weeks), survival till 6 months (76% vs 51%; relative
J.A. Deprest et al. / Seminars in Fetal Neonatal Medicine 15 (2010) 58–67 63 100 90 extreme severe moderate mild 80 Survival rate (%) 70 60 50 40 30 20 10 0 15 15-25 26-35 36-45 ≥46 O/E LHR (%) liver in thorax (‘up’) liver in abdomen (‘down’) irrespective of liver positionFigure 1. Survival rates of fetuses with isolated left-sided congenital diaphragmatic hernia, depending on measurement of the observed/expected lung:head ratio (O/E LHR)measurements and liver position as in the antenatal congenital diaphragmatic hernia registry. Reproduced with permission from Deprest et al.50risk ¼ 1.49) and neurologic outcome.3 IUFD after laser can be pre- to the experience from leading centers in Boston (USA), Londondicted preoperative by abnormal Doppler.79 Preoperative short- (UK) and Linz (Austria). The potential of these interventions hasened cervix is predictive for premature delivery.80 Postoperative revived interest such that even a new society was proposed.99 Keypatients should be watched for anemia, persisting transfusion limitations at this moment are appropriate and timely selection ofsyndrome and cardiac problems.81,82 Brain lesions are the main patients and the lack of purpose-designed instruments.concern, but some can be detected by ultrasound in 80% of cases, Tran has described feto-maternal anesthetic techniques. Onlyand magnetic resonance imaging identiﬁes another 20%.83 a limited number of procedures today require general anesthesia.100 A number of discussions are ongoing regarding this condition. This provides perfect feto-maternal anesthesia as well as uterineThe ﬁrst considers whether the current staging system, based on relaxation. The vast majority of fetal interventions are being donethe presence of ﬂuid discrepancy (stages I–II) and haemodynamic under local anesthesia, usually with intravenous maternal sedation.impact without (stage III) or with (stage IV) hydrops should be Loco-regional anesthesia is also used and particularly useful in thechanged. Survival is indeed stage dependent.84,85 Assessment of viable period, as one can proceed immediately with urgentcardiac function is now being suggested to be incorporated into abdominal delivery in cases of fetal distress. During the previablea staging system because it would better reﬂect the pathophysi- period, in-utero resuscitation is the only option, and requiresology of the condition.86–90 However, it is unclear whether that will excellent teamwork between anaesthesiologists and the fetalchange therapy at all. Also the place for invasive therapy for stage I surgeon. This chapter also touches on the newly developing ﬁeld ofdisease is currently at stake, and a trial has been announced. fetal pain relief. The requirement for pain relief in the neonatal MC twins are more prone to structural anomalies, more than 80% period informs those caring for the antenatal patient, as allbeing discordant. Patients may prefer selective fetocide in such anatomical and functional features required for pain sensation arecases. Another anomaly is twin reversed arterial perfusion sequence present in the gestational age period during which the fetal surgeon(acardiac fetus). The normal ‘pump’ twin perfuses the anomalous works.101 As a consequence, ways to manage fetal pain and theparasitic mass, leading to congestive heart failure and hydrops in stress response during invasive fetal interventions are required.10250%. Fetal death puts the healthy one at risk, due to feto-fetal As a side-effect it may also reduce fetal movements, which can behemorrhage over the anastomoses. In those cases controlled feto- helpful for some procedures or diagnostic assessment.103cide can be done by obliteration of arterial and venous ﬂow, mostoften with ultrasound-guided bipolar cord coagulation with 9. Future challenges and innovations by transcontinentalinstruments comparable in size to those used for TTTS. Cord occlu- communicationsion has a 78–84% survival rate.91,92 Pre- and perinatal losses of thehealthy twin are mainly due to cord entanglement through iatro- An important chapter in this issue is that by Roybal et al. on thegenic rupture of the intertwine membrane or early delivery future non-surgical approach, using stem cell and gene therapy.104following PPROM, also responsible for 7% developmental problems Surgery is always an invasive solution, typically only partly solvingin survivors. An effect of operator experience was demonstrated, the problem. Similarly, we would like to draw attention to anothershowing decrease in PPROM and morbidity after 40 procedures. cellular approach, which is the use of tissue engineering in theAlternative energy sources such as laser, monopolar or radio- perinatal period. The amniotic ﬂuid is an evident source of rapidlyfrequency energy may be used through 14–18 G needles.93–95 They expanding fetal cells, wherein multipotent mesenchymal stem cellswork effectively in TRAP where low ﬂow conditions are present, have been demonstrated.105,106 As amniocentesis is typically part ofwhere all energy modalities show comparable outcomes.96,97 The the initial assessment, these cells are readily available. Severalexperience for other indications is less so that some centers will not groups are currently exploring the potential of these stem cells asoffer those when there are two pumping hearts.98 well as other tissue engineering techniques. It might be possible to engineer homologous ‘biological’ grafts while the fetal patient8. Other indications and fetal pain relief awaits postnatal therapy during further pregnancy. One example is diaphragmatic reconstruction. Rather than using a synthetic graft, Because of space constraints, the percutaneous interventions which does not grow with the infant and is basically non-func-such as fetal valvuloplasty or cardiac septostomy will not be dis- tional, one could aim at a more functional diaphragmaticcussed. For advances in this exciting ﬁeld of fetal medicine, we refer replacement.107
64 J.A. Deprest et al. / Seminars in Fetal Neonatal Medicine 15 (2010) 58–67Figure 2. Left: fetoscopic images of balloon insertion. The catheter, loaded with the balloon, is inserted; the balloon is inﬂated between carina and vocal cords and then detached.Middle, lower: ultrasound image of the balloon in place. Middle, upper two images: balloon is being retrieved by fetoscopic extraction, using a 1 mm forceps. Right: schematicdrawing of cannula insertion towards the mouth (upper corner). Reproduced with permission from Gucciardo et al.62 One of the initial assumptions with the introduction of operative As mentioned earlier, open fetal surgery is rarely done infetoscopy was that minimization of uterine and membrane trauma Europe. To us, the dogmatic denial of open fetal surgery reﬂectswould obviate the problem of iatrogenic preterm prelabor rupture rather an attitude of the physician than one of the patient. In ourof the membranes (iPPROM). Unfortunately this has not material- view such denial is not justiﬁed. Moreover, if the NIH-sponsoredized so far and we actually referred to it as the Achilles’ heel of ‘MOMS’ trial demonstrates decreased morbidity in fetuses withfetoscopic surgery.5 Many researchers have spent time in trying to MMC undergoing surgical repair, open fetal surgery will inevitablysolve this problem. Strategies explored are: (i) prevention, by using have to be placed on the European agenda once more. Along thethe most appropriate access method, the use of smaller and fewer same lines, we have to permanently question the indications orinstruments, or sealing the defect on the way out of the uterus; criteria for intervention. Dogmatism indeed prevents overzealous(ii) treatment: using membrane sealing agents to arrest amnior- application of invasive therapy, but it may arrest innovation.rhexis in the absence of infection.108 As to the former, we are Flexibility and reconsideration can force breakthroughs. Debatescurrently investigating the use of an acellular collagen matrix to be between opponents and proponents are only apparent conﬂicts,inserted through the cannula. It acts as a sponge, which, after and these days they focus around indications such as CDH.41 Bothabsorption of body ﬂuids, can increase in diameter so that it sides agree that the clinical problem of CDH fetuses is far fromover-sizes the initial defect as well as locking the membranes solved. It is therefore important that scientists from differentagainst the uterine wall, while being held in place by the ‘schools’ liaise, always questioning themselves and workingcontracting myometrium.109 It is hoped that the matrix allows cells together on this and other obstacles for fetal surgery. If thisto invade and trigger or stimulate a true membrane wound-healing happens at the level of the most senior research groups, it is moreprocess. As membranes heal poorly spontaneously, adjuncts may likely to succeed, rather than by an exclusive attitude which forceshave to be used, e.g. platelets.110,111 The EU-sponsored EuroSTEC every new researcher or team to ﬁrst reinvent the wheel. Weproject pursues additional strategies (www.euroSTEC.eu), such as therefore might have to lobby for the concept of transcontinentalthe use of purpose-designed membrane-derived matrices, funding for collaborative research between centers of excellence oneventually seeded with cells, which might improve in growth.112,113 both sides of the ocean – and further.For the latter, therapeutic sealing clinically is done by the injection The practice of fetal surgery today ﬂoats on a permanentof platelets, which are programmed to adhere to (epithelial) conﬂict between what is optimal quality and how this can bemembrane defects.114 Clinical trials will have to show that these guaranteed, versus that of sufﬁcient numbers of patients as well asstrategies are effective at all. fetal care centers.115 Again it needs to balance between the drive
J.A. Deprest et al. / Seminars in Fetal Neonatal Medicine 15 (2010) 58–67 65for innovation and alternative approaches questioning the dogmas at the Children’s Hospital of Philadelphia possible. This grant and itsof the past. We need a balance of appropriate regulation and content were independent from the assignment to this paper.concern for patient protection, versus sufﬁcient space for enthu-siastic new scientists and clinicians who may be the pioneers of Referencesthe future. It is our personal belief that such balance is best madewithin a few leading centers, which have the necessary means and 1. Harrison MR, Filly RA, Golbus MS, et al. Fetal treatment. N Engl J Medcase load, as well as sufﬁcient senior people, who are prepared to 1982;307:1651–2.guide their young researchers along paths that seem today far 2. Johnson MP. The North American Fetal Therapy Network (NAFTNet): a new approach to collaborative research in fetal diagnosis and therapy. Semin Fetalfrom the beaten track. 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Fetal compared to open fetal surgery, but the problem of Diagn Ther 2006;21:185–93. 17. Mann S, Johnson P, Wilson RD. Fetal thoracic and bladder shunts. Semin Fetal iatrogenic PPROM remains. There is a clinical need for Neonatal Med 2010;15:28–33. methods to address this problem. 18. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic adenomatoid malfor- There is a need for formal trials to determine the place of mation volume ratio predicts outcome in prenatally diagnosed cystic adeno- fetal surgery for most indications. matoid malformation of the lung. J Pediatr Surg 2002;37:331–8. Given the rarity of diseases, collaborative studies are 19. Calvert JK, Boyd PA, Chamberlain PC, et al. Outcome of antenatally suspected congenital cystic adenomatoid malformation of the lung: 10 years’ experience required. 1991–2001. Arch Dis Child Fetal Neonatal Ed 2006;91:F26–8. Long-term outcomes for most conditions remain 20. Kamata S, Usui N, Kamiyama M, et al. Long-term outcome in patients with unknown. prenatally diagnosed cystic lung disease: special reference to ventilation and The future lies in non-surgical treatment of diseases, perfusion scan in the affected lung. J Pediatr Surg 2006;41:2023–7. and will be based on the use of cells or engineered 21. Kunisaki SM, Barnewolt CE, Estroff JA, et al. Large fetal congenital cystic adenomatoid malformations: growth trends and patient survival. J Pediatr tissues and gene therapy. Surg 2007;42:404–10. 22. Ierullo AM, Ganapathy R, Crowley S, et al. Neonatal outcome of antenatally diagnosed congenital cystic adenomatoid malformations. Ultrasound Obstet Gynecol 2005;26:150–3. 23. Davenport M, Warne SA, Cacciaguerra S, et al. Current outcome of antenallyAcknowledgements diagnosed cystic lung disease. J Pediatr Surg 2004;39:549–56. 24. Wilson RD, Hedrick HL, Liechty KW, et al. Cystic adenomatoid malformation of The clinical fellows (Leonardo Gucciardo, Tim Van Mieghem, the lung: review of genetics, prenatal diagnosis, and in utero treatment. Am J Med Genet A 2006;140:151–5.Philip De Koninck) are thanked for their contribution to our fetal 25. Wilson RD, Baxter JK, Johnson MP, et al. Thoracoamniotic shunts: fetalsurgery programme. treatment of pleural effusions and congenital cystic adenomatoid malforma- tions. Fetal Diagn Ther 2004;19:413–20.Conﬂict of interest statement 26. Knox EM, Kilby MD, Martin WL, Khan KS. In utero pulmonary drainage in the management of primary hydrothorax and congenital cysti lung lesion: None declared. a systematic review. Ultrasound Obstet Gynecol 2006;28:726–34. 27. Adzick NS. Open fetal surgery for life-threatening fetal anomalies. Semin FetalFunding sources Neonatal Med 2010;15:1–8. Our research has been funded by the European Commission 28. Adzick NS. Management of fetal lung lesions. Clin Perinatol 2003;30:481–92.(EuroSTEC, 6th Framework LSHC-CT-2006-037409, Marie Curie 29. Tsao K, Hawgood S, Vu L, et al. Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr SurgProgramme MEST CT2005 019707), the Fonds voor Weten- 2003;38:508–10.schappelijk Onderzoek Vlaanderen (FWO; 1.8.012.07.N.02) and the 30. Peranteau WH, Wilson RD, Liechty KW, et al. Effect of maternal betametha-Instituut voor Wetenschap en Technologie (IWT/070715). The sone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007;22:365–71.University of Pennsylvania, the FWO and the University Hospitals 31. Bebbington M, Rosner M, Wilson RD, Mann S, Johnson M. Perinatal outcomesLeuven are thanked for supporting a grant making a research period with fetal chest shunts. Am J Obstet Gynecol 2008;192:S138.
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