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The availability of high-resolution ultrasound imaging and screening programs has made the unborn child a true patient. When fetal mal- formations, genetic diseases, or in utero acquired conditions are sus- pected, patients are referred to tertiary care units with more specialized skills, technical equipment, experience, and multidisciplinary coun- selors to define potential options. In some cases, intervention before birth may be desirable, which often does not require direct access to the fetus—for example, transplacental administration of pharmaco- logic agents for cardiac arrhythmias or antibiotics in case of fetal infection. Other conditions can be treated only by invasive access to fetus. In utero transfusion of a hydropic fetus to treat the anemia of Rh isoimmunization, first described in 1961, was probably the first successful invasive therapeutic procedure. Today, blood transfusion through the umbilical cord, intrahepatic vein, or (exceptionally) directly into the fetal heart is widely offered, with good fetal and long-term outcome when procedures are done by experienced operators. Some conditions are amenable to surgical correction, and in the majority of cases this is best done after birth. Occasionally, prenatal surgery is required to save the life of the fetus, or to prevent permanent organ damage. This can be achieved by correcting the malformation, by arresting the progression of the disease, or by treating some of the immediately life-threatening effects of the condition, delaying more definitive repair until after birth. Because of the potential complica- tions, risks and benefits of the intervention must be weighed against each other. Table 24-1 summarizes the indications and rationale for in utero surgery on the fetus, placenta, cord, or membranes. A consensus, endorsed by the International Fetal Medicine and Surgery Society (IFMSS), has been reached on the criteria and indica- tions for fetal surgery (Table 24-2). 1 In the 1980s to 1990s, only a few conditions met these criteria, and surgical intervention required maternal laparotomy, partial exteriorization of the fetus through a stapled hysterotomy. These “open” procedures were initially associated with high fetal-maternal morbidity, raising the question for some of the value of claimed benefits. The growing availability of videoendoscopic surgery in the 1990s, combined with earlier experience with fetoscopy, paved the way for the concept of endoscopic fetal surgery. The rationale was that mini- mally invasive access to the amniotic cavity would reduce the fre- quency of preterm labor and diminish maternal morbidity. Investigators at the Centre for Surgical Technologies (CST) in Leuven, Belgium, have helped advance the application of these techniques by first estab- lishing an ovine model for endoscopic fetal surgery. 2 That experience laid the basis for the first successful umbilical cord ligation in Europe, 3 almost simultaneously with, but independently from, a successful pro- cedure done by Quintero a few months earlier. The Leuven group subsequently set up the Eurofoetus consortium supported by the European Commission (E.C.), acting as liaison between selected European fetal medicine units and an endoscopic instrument maker to design new endoscopes and instruments to improve management of specific conditions. 4,5 The later execution of a successful randomized trial on laser coagulation of twin-twin transfusion syndrome (TTTS) prompted in Europe wide clinical acceptance of fetoscopy. Progress in the practice of fetal surgery has been slowed by the paucity of randomized trials, by patient and practitioner reluctance, by availability of local operator expertise, and even by the lack of regu- latory approval of novel surgical instrumentation. For example, open fetal surgery can now be performed with significantly improved out- comes and fewer side effects compared with a decade ago. Despite that, such procedures are rarely done in Europe, with the exception of operations on placental support. 6 In the United States, slow regulatory acceptance of new fetoscopic instruments has contributed to the con- troversy regarding the place of fetoscopic treatment of TTTS, 7,8 together with a historically stronger preference for open procedures, including even for nonethical conditions. Indeed, in utero repair of myelome- ningocele (MMC) is currently being performed in the MOMS trial (see Outcome of Antenatal Neural Tube Defect Repair, later), sponsored by the National Institutes of Health, which tests the hypothesis that antenatal repair will reduce morbidity in survivors compared with postnatal repair. Should the results of the MOMS trial be positive, undoubtedly European centers will have to reconsider the issue of open surgery, just as increasing experience and more encouraging long-term results of fetoscopic procedures from Europe have spurred the spread of minimally invasive procedures throughout the United States. Open Fetal Surgery Open fetal surgery is a complex enterprise that should be undertaken only in centers staffed with skilled personnel. Because of the high inci- dence of preterm labor, prophylactic tocolysis is essential, using for instance indomethacin or nifedipine. Large-bore venous access is established, but fluid administration is conservative and meticulously managed to reduce the risk for pulmonary edema that frequently occurs with certain tocolytics. Open surgical procedures are typically per- formed using general endotracheal anesthesia, taking advantage of the myorelaxant and uterine contraction suppression qualities of haloge- nated anesthetic gases. The uterus is exposed by a large laparotomy and opened with specially designed, resorbable lactomer surgical staples Chapter 24 Invasive Fetal Therapy Jan A. Deprest, MD, PhD, Eduardo Gratacos, MD, PhD, and Liesbeth Lewi, MD, PhD

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  • 1.Chapter 24Invasive Fetal TherapyJan A. Deprest, MD, PhD, Eduardo Gratacos, MD, PhD, and Liesbeth Lewi, MD, PhDThe availability of high-resolution ultrasound imaging and screening cedure done by Quintero a few months earlier. The Leuven groupprograms has made the unborn child a true patient. When fetal mal- subsequently set up the Eurofoetus consortium supported by theformations, genetic diseases, or in utero acquired conditions are sus- European Commission (E.C.), acting as liaison between selectedpected, patients are referred to tertiary care units with more specialized European fetal medicine units and an endoscopic instrument makerskills, technical equipment, experience, and multidisciplinary coun- to design new endoscopes and instruments to improve managementselors to dene potential options. In some cases, intervention beforeof specic conditions.4,5 The later execution of a successful randomizedbirth may be desirable, which often does not require direct access totrial on laser coagulation of twin-twin transfusion syndrome (TTTS)the fetusfor example, transplacental administration of pharmaco-prompted in Europe wide clinical acceptance of fetoscopy.logic agents for cardiac arrhythmias or antibiotics in case of fetal Progress in the practice of fetal surgery has been slowed by theinfection. Other conditions can be treated only by invasive access topaucity of randomized trials, by patient and practitioner reluctance,fetus. In utero transfusion of a hydropic fetus to treat the anemia of by availability of local operator expertise, and even by the lack of regu-Rh isoimmunization, rst described in 1961, was probably the rstlatory approval of novel surgical instrumentation. For example, opensuccessful invasive therapeutic procedure. Today, blood transfusionfetal surgery can now be performed with signicantly improved out-through the umbilical cord, intrahepatic vein, or (exceptionally)comes and fewer side effects compared with a decade ago. Despite that,directly into the fetal heart is widely offered, with good fetal and such procedures are rarely done in Europe, with the exception oflong-term outcome when procedures are done by experiencedoperations on placental support.6 In the United States, slow regulatoryoperators. acceptance of new fetoscopic instruments has contributed to the con-Some conditions are amenable to surgical correction, and in thetroversy regarding the place of fetoscopic treatment of TTTS,7,8 togethermajority of cases this is best done after birth. Occasionally, prenatalwith a historically stronger preference for open procedures, includingsurgery is required to save the life of the fetus, or to prevent permanent even for nonethical conditions. Indeed, in utero repair of myelome-organ damage. This can be achieved by correcting the malformation, ningocele (MMC) is currently being performed in the MOMS trial (seeby arresting the progression of the disease, or by treating some of theOutcome of Antenatal Neural Tube Defect Repair, later), sponsoredimmediately life-threatening effects of the condition, delaying more by the National Institutes of Health, which tests the hypothesis thatdenitive repair until after birth. Because of the potential complica- antenatal repair will reduce morbidity in survivors compared withtions, risks and benets of the intervention must be weighed against postnatal repair. Should the results of the MOMS trial be positive,each other. Table 24-1 summarizes the indications and rationale forundoubtedly European centers will have to reconsider the issue ofin utero surgery on the fetus, placenta, cord, or membranes. open surgery, just as increasing experience and more encouragingA consensus, endorsed by the International Fetal Medicine andlong-term results of fetoscopic procedures from Europe have spurredSurgery Society (IFMSS), has been reached on the criteria and indica-the spread of minimally invasive procedures throughout the Unitedtions for fetal surgery (Table 24-2).1 In the 1980s to 1990s, only a few States.conditions met these criteria, and surgical intervention requiredmaternal laparotomy, partial exteriorization of the fetus through astapled hysterotomy. These open procedures were initially associatedwith high fetal-maternal morbidity, raising the question for some of Open Fetal Surgerythe value of claimed benets.Open fetal surgery is a complex enterprise that should be undertakenThe growing availability of videoendoscopic surgery in the 1990s,only in centers staffed with skilled personnel. Because of the high inci-combined with earlier experience with fetoscopy, paved the way for dence of preterm labor, prophylactic tocolysis is essential, using forthe concept of endoscopic fetal surgery. The rationale was that mini-instance indomethacin or nifedipine. Large-bore venous access ismally invasive access to the amniotic cavity would reduce the fre- established, but uid administration is conservative and meticulouslyquency of preterm labor and diminish maternal morbidity. Investigators managed to reduce the risk for pulmonary edema that frequently occursat the Centre for Surgical Technologies (CST) in Leuven, Belgium,with certain tocolytics. Open surgical procedures are typically per-have helped advance the application of these techniques by rst estab- formed using general endotracheal anesthesia, taking advantage of thelishing an ovine model for endoscopic fetal surgery.2 That experiencemyorelaxant and uterine contraction suppression qualities of haloge-laid the basis for the rst successful umbilical cord ligation in Europe,3 nated anesthetic gases. The uterus is exposed by a large laparotomy andalmost simultaneously with, but independently from, a successful pro-opened with specially designed, resorbable lactomer surgical staples

2. 434CHAPTER 24 Invasive Fetal TherapyTABLE 24-1INDICATIONS AND RATIONALE FOR IN UTERO SURGERY ON THE FETUS, PLACENTA,CORD, OR MEMBRANES Pathophysiology Rationale for In Utero InterventionSurgery on the Fetus1. Congenital diaphragmatic hernia Pulmonary hypoplasia and anatomic substrate Reverse pulmonary hypoplasia and reduce degree of for pulmonary hypertensionpulmonary hypertension; repair of actual defect delayed until after birth2. Lower urinary tract obstruction Progressive renal damage by obstructive Prevention of renal failure and pulmonary hypoplasia uropathyby anatomic correction or urinary deviation Pulmonary hypoplasia by oligohydramnios3. Sacrococcygeal teratoma High-output cardiac failure by arteriovenousReduction of functional impact of the tumor by its shunting and/or bleedingablation or (part of) its vasculature Direct anatomic effects of the tumoral mass Reduction of anatomic effects by draining cysts or bladder Polyhydramnios-related preterm laborAmnioreduction preventing obstetric complications4. Thoracic space-occupying lesionsPulmonary hypoplasia (space-occupying mass) Creating space for lung development Hydrops by impaired venous return Reverse process of cardiac failure (mediastinal compression)5. Neural tube defects Damage to exposed neural tube Prevention of exposure of the spinal cord to amniotic Chronic cerebrospinal uid leak, leading to uid; restoration of CSF pressure, correcting Arnold-Chiari malformation andArnold-Chiari malformation hydrocephalus6. Cardiac malformations Critical lesions causing irreversible hypoplasiaReverse process by anatomic correction of restrictive or damage to developing heart pathologySurgery on the Placenta, Cord, or Membranes7. Chorioangioma High-output cardiac failure by arteriovenousReverse process of cardiac failure and hydrops shuntingfetoplacentalis by ablation or reduction of ow Effects of polyhydramnios8. Amniotic bandsProgressive constrictions causing irreversiblePrevention of amniotic band syndrome leading toneurologic or vascular damagedeformities and function loss9. Abnormal monochorionicIntertwin transfusion leads toArrest intertwin transfusion, prevent or reverse twinning: twin-to-twinoligopolyhydramnios sequence, cardiac failure and/or neurologic damage, including transfusion hemodynamic changes; preterm labor andat the time of in utero death rupture of the membranes; in utero damage Prolongation of gestation to brain, heart, or other organs In utero fetal death may cause damage to co-twin Fetus acardiacus and discordant Cardiac failure of pump twin andSelective feticide: to arrest parasitic relationship, to anomalies consequences of polyhydramniosprevent consequences of in utero fetal death Serious anomaly raises question for To avoid termination of the entire pregnancy termination of pregnancy or selective feticideHistorically, in utero treatment of hydrocephalus was attempted but abandoned. In the late 1990s, indications 5 and 6 were added; 7 to 9 were typicalresults of the introduction of obstetric endoscopy in fetal surgery programs.TABLE 24-2CRITERIA FOR FETAL SURGERY (Premium Poly CS 57, US Surgical, Norwalk, CT) to prevent intraopera- tive maternal hemorrhage. Location of the uterine incision largely1. Accurate diagnosis and staging is possible, with exclusion of depends on placental position, as determined by sterile ultrasound. associated anomaliesThe fetus is partially exposed, and sometimes exteriorized, and2. Natural history of the disease is documented, and prognosis monitored while the procedure is performed, using ultrasound, pulse- established. oximetry, or direct fetal electrocardiography.9 Additional analgesics,3. Currently no effective postnatal therapy.4. In utero surgery proven feasible in animal models, reversingatropine, and pancuronium or vecuronium are given to the fetus to deleterious effects of the condition. suppress the fetal stress response, bradycardia, as well as to immobilize5. Interventions performed in specialized multidisciplinary fetalit. The fetus is kept warm through the use of intrauterine infusion of treatment centers with strict protocols and approval of the Ringers lactate at body temperature, and intrauterine volume and local ethics committee, and with informed consent of thepressure are maintained as close as possible to physiologic levels. After mother or parents.completion of the fetal portion of the procedure, the uterus is closed in two layers with resorbable sutures, amniotic uid volume is restored,Adapted from Harrison MR, Adzick NS: The fetus as a patient: Surgicalconsiderations. Ann Surg 213:279-291; discussion, 277-278, 1991. and intra-amniotic antibiotics are administered. The hysterotomy is covered with an omental ap. Postoperatively, the patient is managed 3. CHAPTER 24 Invasive Fetal Therapy 435in intensive care while receiving aggressive tocolysis with magnesiumber-endoscopes rather than conventional rod lens scopes, and as thesulfate and, when required, additional agents. number of pixels has increased, image quality has improved markedly.Complications of open fetal surgery include preterm contractions,Working length must be sufcient to reach all regions of the intrauter-maternal morbidity from tocolysis, rupture of membranes, and fetal ine space. Amniotic access is facilitated by thin-walled, semiexibledistress. Postoperative uterine contractions are the Achilles heel of disposable, or larger-diameter reusable metal cannulas, so that instru-open fetal surgery, but new tocolytic regimes have improved tocolyticment changes are possible. Once inside the amniotic cavity, the obtura-efcacy while limiting maternal side effects. Amniotic uid leakagetor is replaced by the fetoscope. Technical handbooks provide detailsthrough the hysterotomy site (or, more commonly, vaginally because of use of these instruments and a discussion of distention media.3,4of membrane rupture) can occur. With signicant postoperative oligo- Instrument insertion is facilitated with local or locoregional anesthesia,hydramnios, delivery may be necessary because of fetal distress. Inwhich is injected along the anticipated track of the cannula down torecent case series on myelomeningocele repair, patients left the hospitalthe myometrium.within a few days, a much shorter interval than previously.10,11 DeliveryDespite the minimally invasive nature of fetoscopy, it continues toby cesarean section is mandatory to prevent uterine rupture. be associated with iatrogenic preterm premature rupture of mem- branes (pPROM) (Table 24-3). Initiatives that have been evaluated to treat or prevent this condition12 include attempts to repair defects withThe EXIT Procedure various tissue sealants applied either intracervically or intra-amnioti-The EXIT (ex utero intrapartum treatment) procedure is increasinglycally. These efforts have met with limited success, because fetal mem-used for selected fetal conditions and is an example of open fetal branes have limited ability to heal.13 The use of amniopatch as asurgeryin this instance, to establish functional and reliable fetal treatment modality for symptomatic iatrogenic pPROM was rstairway control while keeping the fetus attached to the uteroplacentaldescribed by Quintero in 1996,14 and since then a number of case seriescirculation by delivering only a portion of the fetus through a hyster-have been published15 for iatrogenic membrane rupture after amnio-otomy incision. EXIT is done under maximal uterine relaxation, so thecentesis, fetoscopy, or chorionic villus sampling.16 Chorionic mem-maternal risks of this procedure are mainly hemorrhagic. Because ofbrane separation, without obvious amniorrhexis, is anotherthe complex interactions necessary between the anesthesia, obstetric,complication that may be treated with amniopatch.17and pediatric personnel, EXIT procedures require signicant advancepreparation and preassignment of the roles for the many physiciansand nurses involved. The indications for EXIT include congenital Fetal Pain Relief during Proceduresairway obstruction from laryngeal atresia, large head and neck tumors, Pain is a subjective experience occurring in response to impendingand malformations of the face and jaw. For more information on EXIT, or actual tissue damage. The subjective experience of pain requiresplease refer to the Online Edition of this chapter.nociception and an emotional reaction. Nociception requires an intact sensory system, whereas an emotional reaction requires some form of consciousness. It is difcult to know the extent to which the fetus experiences pain. However, several indirect methods haveFetoscopysuggested that the fetus at least can feel pain. Anand and colleagues and Fisk and coworkers demonstrated that premature infants andInstrumentationfetuses display several stress responses during invasive procedures.18-20Fetoscopic procedures are minimally invasive interventions that can be These data indicate that the mid-gestational fetus responds to noxiousconsidered a cross between ultrasound-guided and formal surgical stimuli by mounting a distinct stress response as evidenced by an out-procedures. Fetoscopy must be organized so that the surgical team canpouring of catecholamines and other stress hormones as well as hemo-see simultaneously both the ultrasound and the fetoscopic image. dynamic changes. Consequently, management of fetal pain andSpecically designed fetoscopes typically have deported eyepieces to associated stress response in utero during invasive fetal interventionsreduce weight and facilitate precise movements. Nearly all are exible is important.20TABLE 24-3RISK FOR PRETERM PREMATURE RUPTURE OF MEMBRANES (pPROM) AFTERFETOSCOPIC PROCEDURESRisk for pPROM Procedure(At Assessment) Diameter Instrument Reference Amniocentesis1%-1.7%22 ga (0.7 mm) Tabor et al, 1986; Eddlemanet al, 2006 Amniodrainage1% per tap 18 ga (1.2 mm) Umur et al, 2001Mari et al, 2000 Cordocentesis3.7% (