2014 cirugía fetal

Clinical Expert Series

Fetal Surgery Principles, Indications, and Evidence Katharine D. Wenstrom,

MD,

and Stephen R. Carr,

MD

Since the first human fetal surgery was reported in 1965, several different fetal surgical procedures have been developed and perfected, resulting in significantly improved outcomes for many fetuses. The currently accepted list of fetal conditions for which antenatal surgery is considered include lower urinary tract obstruction, twin–twin transfusion syndrome, myelomeningocele, congenital diaphragmatic hernia, neck masses occluding the trachea, and tumors such as congenital cystic adenomatoid malformation or sacrococcygeal teratoma when associated with developing fetal hydrops. Until recently, it has been difficult to determine the true benefits of several fetal surgeries because outcomes were reported as uncontrolled case series.

However, several prospective randomized trials have been attempted and others are ongoing, supporting a more evidence-based approach to antenatal intervention. Problems that have yet to be completely overcome include the inability to identify ideal fetal candidates for antenatal intervention, to determine the optimal timing of intervention, and to prevent preterm birth after fetal surgery. Confronting a fetal abnormality raises unique and complex issues for the family.

For this reason, in addition to a maternal-fetal medicine specialist experienced in prenatal diagnosis, a pediatric surgeon, an experienced operating room team including a knowledgeable anesthesiologist, and a neonatologist, the family considering fetal surgery should have access to psychosocial support and a bioethicist.

(Obstet Gynecol 2014;124:817–35) DOI: 10.1097/AOG.0000000000000476

BACKGROUND Brief History of Fetal Surgery Although the first documented nonhuman fetal surgery was reported by Cohnstein and Zuntz in 1884,1 it was not until the 1940s that techniques were developed that allowed the (rat) fetus to be removed from the uterus, treated surgically, successfully returned to From the Women & Infants Hospital of Rhode Island, Warren G. Alpert Medical School of Brown University, Providence, Rhode Island.

Dr. Rouse, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.

Continuing medical education for this article is available at http://links.lww. com/AOG/A553.

Corresponding author: Katharine D. Wenstrom, MD, Women & Infants Hospital of Rhode Island, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 101 Dudley Street, Providence, RI 02905; e-mail: kwenstrom@wihri.org.

Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published

by Lippincott Williams & Wilkins.

ISSN: 0029-7844/14

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the uterus, and the pregnancy to continue.2 The human fetus, however, did not become a patient until 1963, when Liley devised a technique for fetal transfusion.3 At the time, before ultrasonographic fetal diagnosis was possible, the only condition suitable for fetal therapy was erythroblastosis fetalis, because it could be predicted using only the obstetric history and maternal blood tests and was lethal without intervention. Liley’s technique required radiographs and large-bore Touhy needles; radio-opaque contrast medium was blindly injected into the amniotic fluid, the fetus was given time to swallow it, and the location of the fetus within the uterus was then determined by X-ray. A 17-gauge Touhy needle was then guided through the maternal abdomen and uterus and into the presumed location of the fetal abdominal cavity, and red cells were injected; it was assumed that the red cells would eventually be absorbed by the subdiaphragmatic lymphatics. Although lymphatic absorption of red cells was suboptimal at best, and limited in the setting of fetal hydrops, the main drawback of this technique was the potential for damaging

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fetal organs by blindly injecting contrast medium into fetal tissues or blindly inserting a 17-gauge needle into the enlarged fetal liver or spleen or kidney, lung, or pericardium.4 Then, in 1965, Adamson and colleagues5 reported the first human fetal surgery, in which the fetal breech was delivered through a hysterotomy and a catheter sewn into the fetal peritoneal cavity, through which blood could be infused. The first four reported cases did not result in living newborns for the same reasons that fetal surgeries today are sometimes unsuccessful; the development of intra-amniotic infection and preterm labor resulted in preterm delivery and fetal or neonatal death. The presumption that the fetuses would have died anyway from erythroblastosis justified the therapeutic attempts and, in retrospect, illustrated one of the currently acknowledged tenets of fetal surgery: the fetal condition must be serious and life-threatening, and the outcome without intervention should be morbid or lethal.

Ironically, because current fetal surgical techniques have been enabled by and are completely dependent on real-time ultrasound technology, it was the development of obstetric ultrasonography that sidelined efforts to perfect fetal surgery. Diagnostic ultrasonography was developed in the late 1950s and applied to obstetrics in the 1960s; the use of realtime ultrasonography for obstetric evaluation was first described in 1968.6 When it became possible to perform a fetal transfusion relatively noninvasively using ultrasound guidance,7,8 efforts to access the fetus through fetal surgery ceased. Simultaneously, pediatric surgical techniques advanced rapidly, so that most fetal abnormalities could be corrected after birth. In an early review of fetal surgery, Adamson stated that “it appears unlikely that even in the distant future fetal surgery will become a field of major concern to the clinician since most abnormalities requiring surgical correction can be dealt with after birth.�9 Presciently, he noted that the only likely exceptions to this conclusion were hydrocephalus, fetal neoplasms, and diaphragmatic hernia.

The burgeoning use of obstetric ultrasonography in the 1970s and the increasing ability to provide accurate prenatal diagnoses eventually re-energized efforts to establish safe and effective techniques for fetal surgery. In 1982, Harrison, summarizing the first meeting of the group that would become the International Fetal Medicine and Surgery Society, noted that diaphragmatic hernia, hydronephrosis, and hydrocephalus were defects that might be amenable to prenatal therapy because they were simple structural defects that nevertheless prevented normal fetal development.10 That same year Harrison and his

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group made the first report of an open fetal surgery performed at 21 weeks of gestation for congenital hydronephrosis.11 The necessity of perfecting surgical techniques in animal models was recognized early, and Harrison’s group first developed the surgical procedure using fetal lambs.12 Importantly, because primates are a better model for human fetuses, in part because they are more susceptible to preterm labor than other experimental animals, this group then refined their anesthetic and surgical techniques in a monkey model.13 Although the surgery was a success in that the pregnancy continued for another 14 weeks, at birth it was clear that the fetal kidneys had been irrevocably damaged. The newborn had features of oligohydramnios deformation sequence and died of pulmonary hypoplasia. Nearly simultaneously, Clewell and his team14 performed the first open fetal surgery for ventriculoamniotic shunt placement in a 22-week fetus with presumed isolated hydrocephalus. This procedure was also deemed successful in that the fetal ventricles remained decompressed and the pregnancy was stable until 32 weeks, when sudden ventricular enlargement prompted delivery. Unfortunately, the fetus was discovered to have X-linked hydrocephalus and had a poor cognitive outcome. These cases illustrated one of the most challenging aspects of fetal surgery: the difficulty of accurately diagnosing the fetal condition and determining the prognosis to identify those fetuses most likely to benefit from prenatal intervention.

Prenatal surgical procedures for other malformations were subsequently reported; some were perfected over time and some were abandoned, but all were complicated by the lack of effective tocolytic therapies and the overwhelming risk of preterm birth. Excision or debulking of pulmonary masses or sacrococcygeal teratomas in the setting of impending or full-blown fetal hydrops proved to be life-saving in some cases,15,16 whereas ventricular shunting for hydrocephalus was abandoned largely because it was not possible to determine which fetuses would benefit from the intervention.17 Importantly, as neonatal care of preterm newborns has improved, and with the advent of betamethasone, magnesium sulfate for neuroprotection, and surfactant, elective preterm delivery has become preferable to fetal intervention in many cases.

Although great progress has been made in the past 30 years, efforts to perfect prenatal surgery for a variety of fetal anomalies continue to be complicated by the challenge of selecting appropriate candidates for surgery and the inability to prevent preterm delivery. The reader is referred to several previous excellent reviews of maternal-fetal surgery, including the comprehensive

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technical brief by Hartmann et al, a review of the fundamental issues of fetal surgery by Chescheir, and a history of the leaders of fetal surgery by Bruner.18–20 Importantly, accumulated experience has served to confirm the basic requirements for fetal surgery proposed by the fledgling International Fetal Medicine and Surgery Society in 1982 (Box 1).10 Although these requirements were originally developed to guide the development of new fetal surgeries, it can be argued that they apply to any fetal surgery being considered today. Among these, the importance of having a multidisciplinary team involved in the prenatal evaluation, the surgical therapy, and the postnatal care cannot be overemphasized. Because confronting a fetal abnormality raises unique and complex issues for the family, in addition to a maternal-medicine specialist experienced in prenatal diagnosis, a pediatric surgeon, an experienced operating room team including a knowledgeable anesthesiologist, and a neonatologist, the family should have access to psychosocial support and a bioethicist.21 This report summarizes data regarding maternalfetal surgical procedures that have been tested and perfected and are currently considered standard of care in experienced hands. It is beyond the scope of

Box 1. Basic Requirements for Fetal Surgery 1. The anatomic malformations suitable for in utero treatment are simple structural defects that interfere with organ development but that might allow normal fetal development to proceed if corrected.

2. The fetus should be a singleton with no additional structural or genetic anomalies.

3. The natural history of the defect and fetal disease must be known, with intervention justified only if there is reasonable probability of benefit.

4. Before consideration of surgery, careful serial assessment of anatomy and organ function must be performed to exclude fetuses affected mildly enough that they could wait for postnatal therapy, as well as fetuses so severely affected that they cannot be saved.

5. The family must be counseled about risk and benefits and should agree to treatment including longterm follow-up.

6. A multidisciplinary team including a maternalmedicine specialist experienced in prenatal diagnosis, a pediatric surgeon, and a neonatologist should agree on the plan for treatment.

7. There should be access to a level III high-risk obstetric unit and intensive care nursery and to bioethical and psychosocial consultation.

Data from Harrison MR, Filly RA, Golbus MS, Berkowitz RL, Callen PW, Canty TG, et al. Occasional notes: fetal treatment 1982. N Engl J Med 1982;307:1651–2.

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this review to include a discussion of all fetal procedures currently undergoing development.

CONDITIONS TREATED WITH CLOSED SURGICAL THERAPIES Technique “Closed” fetal surgeries are procedures performed by inserting needles, catheters, or trocars through the uterine wall without the need for a hysterotomy, although for some procedures the uterus is first exposed using mini-laparotomy. Some of these procedures (such as bladder shunt placement) can be performed under local anesthesia or sedation. Others, such as laser photocoagulation of placental vessels, need to be performed under regional anesthesia (spinal or epidural) if the uterus is exposed by mini-laparotomy first. All closed procedures are performed under direct ultrasound guidance and usually involve only one uterine puncture, approximately 2.4 mm, to allow the insertion of a trocar through which a shunt or semi-rigid endoscope can be passed.

Intrauterine Fetal Transfusion As noted, the advent of real-time ultrasound technology allowed dramatic advancements in the technique for fetal blood transfusion. In 1983, Daffos reported using ultrasound guidance to obtain fetal blood samples from the umbilical vein, and in 1986, Grannum et al reported performing four ultrasoundguided fetal red blood cell transfusions directly into the umbilical vein.22,23 This intravascular technique was quickly adopted, and subsequent case control studies confirmed the superiority of this approach.

One study that compared the outcomes of 75 fetuses treated with intraperitoneal transfusion with the outcomes of 44 fetuses treated with umbilical vein transfusion confirmed that the intravascular technique resulted in a statistically significant increase in survival (91% compared with 66%; P,.005), fewer complications (10% compared with 38%; P5.003), and more advanced gestational age at delivery (34.1 compared with 30.7 weeks; P5.01).24 The technique for intravascular fetal transfusion has been perfected over time and has long been considered standard of care for anemic fetuses.25 Although initially the decision to perform a transfusion was based on maternal antibody titers and amniotic fluid bilirubin levels (which reflect the degree of fetal hemolysis), in 2000, Mari et al26 reported that the peak systolic velocity of blood flow through the middle cerebral artery had 100% sensitivity to detect a fetal hemoglobin level less than 0.65 multiples of the median with a 0% false-negative rate and a 12% false-positive rate, and amniocentesis was

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no longer needed to identify anemic fetuses. Although the use of Rh immune globulin has drastically reduced the incidence of RhD disease, isoimmunization to other red cell antigens makes fetal intrauterine transfusion the most common fetal therapy performed today.

CLOSED SURGICAL THERAPIES Lower Urinary Tract Obstruction Lower urinary tract obstruction results from obstruction of the urethra. Although some degree of obstruction is identified in up to 1% of all fetuses, most blockages are minor and not associated with morbidity.27 Complete unrelenting obstruction, however, has severe and well-documented consequences, including bladder dilation, hydrouretronephrosis, renal dysplasia, and, as a result of anhydramnios, pulmonary hypoplasia; 45% of cases of severe obstruction end in neonatal death.28 The ultimate effect of the urethral obstruction is a function of degree and timing: the more severe the obstruction and the earlier the onset, the greater the potential for the known consequences.

If complete obstruction occurs before the glomeruli are fully formed, renal dysplasia results. In a sheep model, ligation of the urethra at 90 days (comparable to 160 days or 25 weeks in a human fetus) resulted in the development of renal fibrosis, whereas ligation at 60 days (106 days or 17 weeks) resulted in renal cystic dysplasia.29 Improvements in ultrasonography have enhanced our ability to diagnose lower urinary tract obstruction at earlier gestational ages, but our ability to discriminate between the recognized etiologies of lower urinary tract obstruction remains limited. Although lower urinary tract obstruction can result from urethral atresia, the most common etiology is posterior urethral valves, occurring in approximately 1 out of 1,250 almost exclusively male fetuses.30 In this disorder, a membrane in the portion of the urethra surrounded by the prostate results in varying degrees of urethral obstruction.31 Lower urinary tract obstruction typically manifests early in gestation with bladder dilation, followed by renal pelviceal dilation and then development of echogenic renal cortex. High-grade bladder obstruction typically results in bladder distention soon after the onset of fetal urine production at 8–10 weeks, but the diagnosis is usually not made until an anatomic survey is performed at 18–20 weeks of pregnancy.

There have been numerous attempts to determine prognosis in lower urinary tract obstruction. Among the potentially predictive factors that have been studied are gestational age at diagnosis, appearance of the renal parenchyma, and oligohydramnios.

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Morris et al32 concluded that severe oligohydramnios and the development of renal cortical cysts are the most reliable predictors of poor outcome. Prediction of outcome based on fetal renal function as measured by fetal urinary electrolytes has also been attempted.

Glick’s criteria,33 which originally included fetal urinary sodium and chloride concentrations and hourly urine output, with b2 microglobulin, calcium, total protein, and osmolality added by other investigators, are commonly used in this setting, but a recent meta-analysis revealed that there are no individual analytes or thresholds that demonstrate good clinical utility in predicting poor renal outcome.34 In that meta-analysis, only elevated fetal urinary calcium or elevated fetal urinary sodium showed predictive potential.

Antenatal intervention for lower urinary tract obstruction, first described in 1982, has yet to live up to its early promise, most likely because of our incomplete understanding of prognostic factors and the precise timing and natural history of the insults resulting from lower urinary tract obstruction. Antenatal intervention most commonly entails placement of a vesico-amnionic shunt or ablation of the obstruction using fetal cystoscopy, both intended to relieve the lower urinary tract obstruction and thus prevent some or all of the sequelae. Vesico-amnionic shunting, which is associated with relatively low morbidity for the mother, is accomplished using ultrasound guidance to insert a narrow trocar through the maternal abdomen and uterus and into the fetal bladder, through which a double pigtail catheter is placed so that one end is in the fetal bladder and the other exits out the fetal abdomen. This procedure can be performed under local anesthesia and results in only minor trauma to the uterus. Ablation of the urethral obstruction is accomplished by performing fetal cystoscopy; an endoscope is advanced through a trocar inserted into the fetal bladder, the urethra is visually inspected, and the obstruction is relieved by using a laser or hydroablation to remove the tissue blocking the urethra or by inserting a stent into the urethra under direct visualization. This procedure usually requires general anesthesia, so it entails more risk for the mother.

A recent meta-analysis by Morris et al35 evaluated the efficacy of antenatal intervention for lower urinary tract obstruction. Twenty studies were identified, with 369 fetuses included in the evaluation. A total of 261 of the 369 fetuses underwent antenatal intervention; 226 underwent vesico-amnionic shunt, 9 had an open procedure, and 26 had fetal cystoscopy. Of the 26 fetuses evaluated with cystoscopy, only 14 ultimately

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had cystoscopically guided therapy, either posterior urethral valve ablation by laser or hydroablation or urethral stent placement. The remainder had vesicoamnionic shunts placed after cystoscopy demonstrated no fixable lesion or the cystoscopically directed intervention was not successful. Intervention improved overall perinatal survival compared with no intervention (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.14–6.82), but once terminations and fetal demises were removed from the data set, the only group that demonstrated benefit from intervention was the subgroup with poor prognosis (OR 9.36, 95% CI 1.41–62.05). There was no significant improvement in the rate of survival with normal postnatal renal function in the group with good prognosis (OR 2.98, 95% CI 0.45–19.62). No comparison of the group with good prognosis and the subgroup with poor prognosis could be made, because no fetuses in the group with poor prognosis survived with normal renal function. The authors concluded that prenatal intervention for lower urinary tract obstruction is associated with increased perinatal survival (particularly in the subgroup with poor prognosis), but that intervention is associated with increased incidence of impaired postnatal renal function.

Despite the relative ease (compared with fetal cystoscopy) of shunt placement, vesico-amnionic shunt placement is associated with significant fetal morbidity.

Initial reports documented 4% mortality and 44% complication rates.36 A more recent series illustrated the associated morbidities: two of nine catheters had to be re-inserted; only six of nine fetuses survived (there was one termination and two deaths attributable to pulmonary hypoplasia) and three of the six survivors had some degree of renal impairment (two had endstage renal disease and one had mild impairment).37 Fetal cystoscopy, the other modality used to address lower urinary tract obstruction, offers improved sensitivity in detecting posterior urethral valves compared with ultrasonography (87–100% detection using cystoscopy compared with 45% using ultrasonography).38,39 It also offers the theoretical advantage of preserving normal fetal bladder cycling, which is essential for normal postnatal bladder function. The most comprehensive analysis of the effect of fetal cystoscopy on postnatal outcomes is the metaanalysis of four eligible studies including 63 patients that was performed by Morris et al38 in 2011.

Although cystoscopy was associated with an increase in perinatal survival compared with no treatment (OR 20.51, 95% CI 3.87–108.69), it offered no improvement in perinatal survival over vesico-amnionic shunt (OR 1.49, 95% CI 0.13–16.97).

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Although most authorities agree that fetal intervention should be based on an understanding of the natural history of the disorder being treated, there are little data in this regard for lower urinary tract obstruction. One of the only studies to address longterm outcome relative to age at diagnosis is the study

by Ylinen et al,40 in which a cohort of 46 Finnish neonates, 23 of whom had antenatal diagnoses and 23 had postnatal diagnoses, were followed for a mean of 12.5 years. These investigators found no significant difference between the cohort with antenatal diagnoses and the cohort with postnatal diagnoses with respect to poor renal function (complete renal failure or end-stage renal disease, mean glomerular filtration rate, age of advancing to end-stage renal disease, initial or highest creatinine, presence of vesicoureteral reflux, or incidence of renal dysplasia). The authors acknowledged that it is still not clear whether the real damage associated with lower urinary tract obstruction is caused by the disturbed urodynamics resulting from antenatal obstruction or whether the renal dysplasia develops as a result of the same insult that caused the obstruction, and thus co-exists with but is not caused by the lower urinary tract obstruction. Until the etiology of lower urinary tract obstruction–associated renal dysplasia is clarified, it will not be possible to accurately identify appropriate candidates for antenatal intervention.

The almost inescapable conclusion arising from these data is that we have not as yet demonstrated the efficacy of intrauterine intervention for lower urinary tract obstruction. The literature is problematic because it consists of small case series with widely differing selection criteria for intervention. Although meta-analyses overcome some of these limitations, a prospective randomized trial is needed. The percutaneous shunting in low urinary tract obstruction (PLUTO) trial41 proposed to randomize 150 fetuses with lower urinary tract obstruction to either vesico-amnionic shunt or conservative noninterventional care. It began in 2009 but closed because of slow enrollment after enlisting only 31 patients.

Although the trial did not reach recruitment goals, it found that shunted fetuses had better survival than nonshunted fetuses (relative risk [RR] 3.30, 95% CI 1.02–9.62; P5.03). The study reached no conclusions regarding the benefit (or lack thereof) of vesicoamnionic shunting on long-term renal function.

The much-needed high-quality data that we hoped to see from the PLUTO trial, data that we could use to inform our choice of interventions, remain elusive.

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Placental Laser Photocoagulation for Twin–Twin Transfusion Syndrome Unbalanced placental vascular anastomoses across a monochorionic, diamnionic placenta underlie the pathophysiology of twin–twin transfusion syndrome (Fig. 1) and can present in four ways: arterio-venous, veno-arterial, arterio-arterial, and veno-venous.

Arterio-venous and veno-arterial anastamoses result when a placental surface feeder vessel from each twin perfuses a common cotyledon, and arterioarterial and veno-venous anastamoses are connections on the surface of the placenta that have the potential for either unidirectional or bidirectional blood flow. Computer modeling suggests that severe twin–twin transfusion syndrome results from unidirectional blood flow primarily through arteriovenous anastamoses, from donor placental arteries to recipient placental veins,42 but the initiating event remains unknown. The best estimate of the incidence of twin–twin transfusion syndrome is that it affects 9% to 15% of monochorionic twin pregnancies,43,44 but our understanding remains incomplete of why twin–twin transfusion syndrome occurs in a minority of monochorionic twins when placental anastamoses are nearly ubiquitous in these pregnancies.

Placental injection studies suggest that twin–twin transfusion syndrome is more likely in placentas with fewer anastamoses and without arterio-arterial anastamoses. 45,46

Fig. 1. Schematic depiction of twin–twin transfusion syndrome demonstrating vascular anastomoses between monochorionic and diamnionic twins. Image courtesy of Francois Luks, MD. Used with permission.

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The imbalance in circulating blood volume that results from these anastomoses leads to cardiovascular responses that eventually become maladaptive.

Although the donor twin usually maintains normal cardiac function, hypervolemia in the recipient twin results in increased preload, leading to right ventricular hypertrophy, and eventually hypertension and cardiomyopathy. The increased systemic pressure may also result in increased right ventricular afterload and diminished right heart output, contributing to pulmonic stenosis.47 Eventually, fetal death results; the mortality rate for untreated progressive twin–twin transfusion syndrome is approximately 90%.48 The goal of intervention is to restore more equitable blood flow between the twins and thus to halt or reverse cardiac decompensation in the recipient.

Therapies attempted for twin–twin transfusion syndrome have included selective fetal reduction, septostomy of the dividing membrane, amnioreduction, and laser photocoagulation of the surface placental anastomoses; all except selective reduction have been tested in randomized trials. Septostomy allows the amniotic fluid volume in each sac to equilibrate, reversing the oligohydramnios or anhydramnios typically seen in the sac of the donor twin, and amnioreduction is based on the theory that reducing the amniotic fluid volume alters the hydrostatic pressure on the placental surface vessels and enables more equal blood flow between the two areas of the placenta supporting each twin. Studies of septostomy indicate no survival advantage with this technique and an association with complications such as preterm rupture of the membranes and the unintentional creation of a monoamniotic cavity. Amnioreduction has been reported to result in survival rates of 18% to 83%, but it is also associated with complications such as preterm rupture of the membranes, infection, placental abruption, preterm delivery, and neurologic complications in 5% to 58% of survivors.49 Laser photocoagulation is associated with similar obstetric complications but with survival rates of 55% to 69% and neurologic abnormalities in 5% to 11% of survivors. A Cochrane review found that laser ablation of placental vessels was associated with less perinatal death (RR 0.59, 95% CI 0.40– 0.87) and less neonatal death (RR 0.29, 95% CI 0.14–0.61) than amnioreduction.50 Currently, the therapy of choice is a laser photocoagulation procedure, in which a laser is introduced endoscopically into the uterus and used to ablate surface placental vessel anastomoses under ultrasound guidance. This procedure can be performed under local anesthesia.

However, some groups perform a mini-laparotomy

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first to gain better access to the uterine surface, and thus greater control of the laser, and this requires regional anesthesia.

Determining the threshold for intervening in twin–twin transfusion syndrome is problematic, in part because of the unpredictable nature of the progression of the disorder. In an attempt to standardize nomenclature for this condition, Quintero51 proposed classifying the progression of twin–twin transfusion syndrome into five stages based on the degree of fetal compromise (Table 1). Although a few programs offer intervention for stage I twin–twin transfusion syndrome, most programs consider only Quintero stage II or higher twin–twin transfusion syndrome to be sufficient justification for undertaking the risks of in utero intervention. Because twin–twin transfusion syndrome does not always progress linearly through all the stages, and because a proportion of cases of early stage twin–twin transfusion syndrome regress spontaneously, some programs require persistent Quintero stage II on more than one occasion more than 24 hours apart to justify those risks. The gestational age beyond which laser photocoagulation should not be offered also differs between programs, with some centers not offering this therapy after 24 weeks and others not offering it after 25 or 26 weeks. For these and other reasons, interpreting data from case series is problematic. The results of two large randomized trials have been reported, but both were interrupted before completion. In a trial sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, pregnancies presenting before 22 weeks and complicated by stage II or higher twin–twin transfusion syndrome first underwent an amnioreduction and were then randomized to laser photocoagulation or aggressive serial amnioreduction.52

Table 1. Staging of Twin–Twin Transfusion Syndrome Stage I

II III

IV V

Ultrasonographic Findings Maximum vertical amnionic fluid pocket smaller than 2 cm in donor sac; maximum vertical amnionic fluid pocket larger than 8 cm in recipient sac Nonvisualization of bladder in donor twin Absent or reversed umbilical artery end-diastolic flow, reversed ductus venosus a-wave flow, or pulsatile umbilical vein flow Hydrops in one or both twins Death of one or both twins

Data from Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–5.

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This trial was halted after enrollment of 42 of 146 planned participants, in part because an interim analysis indicated increased mortality in recipient twins after laser photocoagulation. The Eurofetus trial randomized pregnancies presenting between 15 weeks and 26 weeks complicated by stage I or higher twin–twin transfusion syndrome (recipient twin with maximum vertical amnionic fluid pocket 8 cm or larger up to 20 weeks and 10 cm or larger at more than 20 weeks, with a distended bladder; donor twin with maximum vertical amnionic fluid pocket 2 cm or smaller) to laser photocoagulation or serial amnioreduction.53 This trial was stopped after enrollment of 142 of 172 planned participants after an interim analysis indicated that laser ablation resulted in better survival rates at 28 days of life (at least one twin alive at 28 days: 76% compared with 56%, P5.009; RR of death of both fetuses: 0.63, 95% CI 0.25–0.93) and at 6 months of life (P5.002), as well as fewer neurologic abnormalities in survivors (no neurologic complications at 6 months of age: 52% compared with 31%; P5.003). The Brown University program, which offers laser photocoagulation only to patients with persistent stage II or higher twin–twin transfusion syndrome, has reported fetal outcomes identical to those of other programs while taking only approximately 50% of all evaluated patients to the operating suite.54 There is a randomized trial underway under the auspices of the North American Fetal Treatment Network to determine whether the risks of stage I twin–twin transfusion syndrome warrant the risks of in utero intervention.

A number of different strategies have been proposed to maximize the clinical effect of laser ablation.

The most recent contribution to this literature is a randomized controlled trial of 274 women randomized to either standard laser coagulation or coagulation of the entire vascular equator. That study found that laser coagulation of the entire vascular equator was associated with a significant reduction in twin anemia polycythemia sequence (OR 0.16, 95% CI 0.05–0.49) and reduced recurrence of twin–twin transfusion syndrome (OR 0.21, 95% CI 0.04–0.98), but no difference in perinatal mortality and severe neonatal morbidity.55

Thoraco-Amniotic Shunting Fetal pleural effusions occur in every 1 out of 10,000– 15,000 pregnancies. Effusions can be primary or isolated, meaning that they are not associated with other fetal anomalies, or secondary, meaning that they occur in association with or as the result of a variety of fetal abnormalities. The majority of isolated effusions

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result from the abnormal drainage of lymph fluid directly into the pleural space rather than into the mediastinal lymph nodes; although this would be called a chylothorax in the neonatal period, the standard criteria for defining chylothorax cannot be applied to fetuses because they are not feeding (thus, triglyceride levels are not elevated) and fetal lymphocyte counts are normally high. Secondary effusions can occur as part of hydrops or as the result of intrathoracic malformations such as congenital cystic adenomatoid malformations or bronchopulmonary sequestrations, congenital infections including herpes simplex or parvovirus B19, or genetic abnormalities such as trisomy 21 or Noonan syndrome.56 Associated fetal malformations that may adversely affect pregnancy outcomes have been reported in 25% to 75% of cases. In 2011, Ruano et al57 published their observations of 56 untreated cases evaluated at their center between 2005 and 2009. Fourteen had isolated pleural effusion, 19 had pleural effusion and associated structural anomalies, and 23 had pleural effusion with an abnormal karyotype. None of the fetuses with associated structural anomalies and only 13% of fetuses with karyotypic abnormalities survived the neonatal period. Because the prognosis of a secondary effusion appears to be determined by its cause rather than by the effusion itself, typically only fetuses with isolated or primary effusions or survivable lesions such as congenital cystic adenomatoid malformation or pulmonary sequestration are considered candidates for prenatal shunting.

The rationale for shunting is that, if an effusion becomes severe, the increased hydrostatic pressure within the fetal thorax can compress developing lung tissue, resulting in pulmonary hypoplasia, or can compress the fetal heart, leading to cardiac decompensation or nonimmune hydrops. Because of the threat of fetal compromise and the ease with which intrathoracic fluid can be accessed, isolated pleural effusions offer tempting targets for practitioners adept with ultrasonography and needles. However, as with all fetal surgeries, the natural history of the condition should be understood and the efficacy of the intervention should be proven before shunt placement is considered.

The natural history of untreated isolated fetal pleural effusion has been assessed by several groups.

In the study by Ruano57 that examined 56 fetuses with pleural effusion, 63% of untreated fetuses with isolated effusion survived, as did 50% of fetuses with isolated effusion and hydrops. Rustico et al56 summarized the outcomes of 54 cases of unshunted isolated pleural effusion from the published literature. Seventy-three percent of fetuses with untreated isolated pleural effu-

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sion without hydrops survived, as did 35% of fetuses with hydrops. Unfortunately, these series do not include data regarding gestational age at delivery, so it is unclear whether survival was achieved by iatrogenic preterm birth, which might have had additional consequences. In a review of 204 published cases of isolated pleural effusion by Aubard in 1998, spontaneous regression occurred in 22%; regression was most likely in cases identified in the second trimester and in those with unilateral effusions.58 The unpredictable outcome manifest in these series suggests that we do not yet have a full understanding of the natural history of this disorder.

For this reason and others, there is no strong consensus in the literature about indications for intervention in fetuses with pleural effusion. A guideline issued by the National Institute for Health and Clinical Excellence states that invasive fetal therapy for fetal hydrothorax should be restricted to fetuses with primary or isolated effusions resulting in hydrops.59 However, other experienced clinicians have suggested that criteria for intervention should include the following: fetal hydrops with the pleural effusion as the likely etiology; isolated pleural effusion without hydrops occupying more than 50% of the thoracic cavity, causing the mediastinum to shift or rapidly increasing in size or associated with polyhydramnios; or isolated effusion without associated anomalies.60 Confirming that an effusion is isolated requires a careful and complete fetal evaluation that generally includes a detailed examination of fetal anatomy including a fetal echocardiogram, a fetal karyotype, maternal blood type and antibody status, Kleihauer-Bettke testing, and virology testing, including toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, and parvovirus B19.

Interventions for draining the fetal chest and obliterating the potential intrathoracic space include thoracentesis, thoracoamniotic shunt placement, and pleurodesis. All are performed under ultrasound guidance and have known fetal and maternal risks.

A recent report of a single center experience cites these risks as shunt failure in 22% of cases, premature rupture of membranes (PROM) in up to 33% of cases, and intrauterine fetal death directly attributable to the procedure itself in 7% of cases.61 Pleurodesis, or creating inflammation that obliterates the pleural space by injecting an irritant, has the additional risk of inhibiting shunt placement as a second-line therapy by causing the formation of intrathoracic bands.

There have been no published randomized trials directly comparing pregnancy outcomes in treated compared with untreated fetal pleural effusions, so we

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are left to compare case series and collections of case series, most of which evaluated hydropic and nonhyropic fetuses separately. The 2007 report of Rustico56 included data from 203 published cases of antenatally treated isolated fetal pleural effusion, which indicated a survival rate of 77% to 82% in nonhydropic fetuses and 50% to 62% in hydropic fetuses treated with thoracentesis or thoracoamniotic shunting. The survival rate was 60% in the pleurodesis group, with no difference between hydropic and nonhydropic fetuses, but the numbers were quite small.

Duerloo et al62 reviewed 108 hydropic fetuses with pleural effusion culled from the published literature, treated with thoracentesis, thoracoamniotic shunting, or pleurodesis. They found very similar survival rates of 60% to 80% regardless of intervention. Pellegrini et al63 summarized their large single-center experience and reported an 85% survival rate in shunted nonhydropic fetuses and a 47% survival rate in shunted hydropic fetuses, for an overall survival rate of 52%. In 2012, Yang et al64 published the largest series of pleurodesis for fetal pleural effusion. Of 49 fetuses with bilateral pleural effusions attributed to chylothorax, 4 had spontaneous resolution (8.2%) and 14 (31.1%) did not survive to birth (10 [22.2%] had an intrauterine fetal death and 4 [8.9%] terminated after unsatisfactory results after pleurodesis). After successful pleurodesis procedures, the rate of long-term survival was 14.8% (4/27) for hydropic fetuses and was 66.7% (12/18) for nonhydropic fetuses.

Our understanding of the natural history of fetal pleural effusions remains imperfect. Natural history observational studies suggest that untreated fetal pleural effusions are associated with 63% to 73% survival in nonhydropic cases and 35% to 50% in hydropic cases.56 However, in most published series, in utero intervention appears to be associated with a survival rate of 60% to 85% for isolated nonhydropic fetal pleural effusions and 50% to 60% for hydropic fetuses. As noted previously, in most series it is unclear if survival with or without antenatal treatment was achieved by elective preterm delivery, so the effect of antenatal treatment on the prolongation of pregnancy is unknown. At present, the available data suggest that intervening in cases of isolated nonhydropic pleural effusion offers, at most, a small increase in survival.

CONDITIONS TREATED WITH OPEN SURGICAL THERAPIES Technique “Open� fetal surgery refers to the fact that a hysterotomy is performed to gain access to the fetus, and creating the hysterotomy might be considered the

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most challenging part of the surgery. The uterine incision must be placed well away from the placental edge, which is located intraoperatively using ultrasonography, but must also allow ready access to the fetus. Once the optimal site is chosen, two fullthickness stay sutures are placed through the uterus and into the amniotic cavity at one edge of the planned incision site, fixing the membranes to the uterine wall, and the uterine cavity is entered with a trocar. A uterine stapling device with absorbable staples is then inserted through the opening created by the trocar, engaged, and fired along the planned incision line; the staples fix the membranes to the uterine wall so that they can be incorporated into the closure, thus preventing membrane separation.

The edge of the incision corresponding to the trocar site, which is not covered by staples, is then rendered hemostatic with a running lock stitch of absorbable suture. One serious complication that can occur during this part of the procedure is bleeding between the membranes and the uterus, leading to a subchorionic hematoma, which could potentially dissect the membranes away from the uterine wall. Recognizing this problem early allows sutures to be placed to tamponade the bleeding vessels. Ideally, the fetus is positioned directly beneath the incision site with only minimal manipulation, and a catheter for the infusion of warm saline is placed into the uterus to maintain amniotic fluid volume and prevent umbilical cord compression and fetal cooling. The fetal heart rate is monitored ultrasonographically throughout the procedure, with fetal resuscitation in the form of position change, increased amnioinfusion, or maternal measures provided as needed.

OPEN SURGICAL THERAPIES Myelominingocele Neural tube defects, including anencephaly, encephalocele, and myelominingocele, are the most common congenital structural defects worldwide. Before folic acid supplementation, neural tube defects affected 1–2 per 1,000 pregnancies The fortification of cereal and grain products in the United States (begun in 1996, mandatory by January 1998) has been associated with a 31% decrease in the incidence of neural tube defects.65 Myelominingocele is the result of incomplete closure of the neural tube, resulting in defective vertebrae that permit the neural placode, meninges, or both to herniate out of the spinal canal, allowing the open dura mater to fuse laterally to the dermis and the open pia pater to fuse to the epidermis.66 The spinal cord is damaged at the site of and distal to the defect and, as a consequence, survivors with meningomyelocele

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generally live with some degree of bladder and bowel dysfunction, limited or no independent ambulation, and ventriculomegaly requiring a ventriculoperitoneal shunt.

Serial observations of affected fetuses and postmortem and animal studies indicate that the neurologic damage occurs both as the result of abnormal neurulation and as a consequence of prenatal exposure of the neural elements to amniotic fluid and trauma attributable to fetal movement. This theory is supported by the observation that only half of affected fetuses have ventriculomegaly before 24 weeks, but more than 90% have developed ventriculomegaly by term.67 This theory also provides the rationale for trying to close the defect during midgestation. Because additional neurologic damage can occur after birth as the result of ventriculoperitoneal shunt malfunction, replacement of the ventriculoperitoneal shunt, and infection, any treatment that reduces the need for ventriculoperitoneal shunting would also improve outcome.

The first reported fetal surgery for meningomyelocele used a laparoscopic approach68 but, because of disappointing outcomes, this technique was abandoned in favor of open repair using hysterotomy.69 Subsequently, several nonrandomized case series reported retrospectively and at least two prospective cohort studies have been published, totaling more than 270 cases worldwide,70 in which outcomes after prenatal surgery were compared with those of similar patients undergoing postnatal repair. However, patients (and their fetuses) who were offered antenatal surgery were frequently different from those who had postnatal repair, and rapidly changing standards of postnatal care for meningomyelocele made historical controls unacceptable. Although most studies described reversal of hindbrain herniation and significantly lower rates of postnatal shunt placement in fetuses treated prenatally, including one study in which the fetal participants were stratified by lesion level, neurologic follow-up was generally limited. No study found that prenatal meningomyelocele repair improved postnatal urologic function, and data regarding ultimate bowel and leg function were limited. Although nonrandom patient selection, multiple potential sources of bias, and lack of long-term follow-up of both the child and the mother made it difficult to determine the potential benefits of this procedure using existing reports, most experts agreed there was enough encouraging data to warrant a randomized trial.

The Management of Myelomeningocele Study trial was an ambitious trial of prenatal compared with postnatal myelomeningocele repair that was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the

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National Institutes of Health and was conducted at the University of California in San Francisco, the Children’s Hospital of Philadelphia, and Vanderbilt University.71 The study is notable for several reasons.

It was the first multicenter, prospective, randomized controlled trial of maternal-fetal surgery for myelomeningocele, and it required that all three centers develop a multispecialty team of clinicians who could evaluate all clinical and psychosocial aspects of potential patients and provide standardized prenatal, surgical, and perioperative care. Surgeons at all three centers had to develop and adhere to a strict protocol covering every aspect of the surgery and perioperative treatment. It also required the three major centers performing this surgery to agree not to offer it outside the trial for the duration of the study (amounting to a nationwide moratorium on myelomeningocele surgery), which turned out to be 7 years. Although the criteria for entry into the trial were stringent, there was no requirement that fetal leg motion still be present, a criterion for previous published series that made it difficult to assess the surgery’s effect on future mobility. The surgery was offered to patients at 19.0 weeks to 25.0 weeks of gestation with confirmed euploid fetuses having myelomeningocele located between T1 and S1, with evidence of hindbrain herniation. Women randomized to prenatal surgery had to stay in the vicinity of their assigned center from the time of the initial surgery until delivery at 37 weeks; those assigned to postnatal surgery were required to return to their center at 37 weeks for delivery, with the newborn’s postnatal repair performed by the same team that performed the prenatal repairs. Importantly, all children in the study underwent physical and neurologic examinations and developmental testing at 12 months and 30 months of age by trained independent pediatricians and psychologists who were unaware of the child’s surgical assignment.

The first primary outcome of the study, evaluated at 12 months of age, was a composite of fetal or neonatal death or the need for a cerebrospinal shunt.

The second primary outcome, assessed at 30 months of age, was a composite score of the Mental Development Index of the Bayley Scales of Infant Development II and the child’s motor function with adjustment for lesion level (determined by an independent group of radiologists). Secondary maternal, fetal, and neonatal outcomes included surgical and obstetric complications and neonatal morbidity.

Infant outcomes included the status of the Chiari II malformation, the timing of the first shunt, locomotion, the Psychomotor Development Index of the Bayley Scales, scores on the Peabody Developmental

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Table 2. Management of Myelomeningocele Study Trial Neonatal Outcomes* Outcome Primary outcome Components of primary outcome Death Shunt criteria met Shunt placed without criteria met Shunt placement Any hindbrain herniation Degrees of herniation None Mild Moderate Severe

Prenatal Surgery (n578)

Postnatal Surgery (n580)

RR (95% CI)

P

53 (68)

78 (98)

0.70 (0.58–0.84)†

,.001 ,.001

2 (3) 51 (65) 0 31 (40) 45/70 (64)

0 74 (92) 4 (5) 66 (82) 66/69 (96)

0.48 (0.36–0.64) 0.67 (0.56–0.81)‡

,.001 ,.001 ,.001

25/70 28/70 13/70 4/70

3/69 20/69 31/69 15/69

(36) (40) (19) (6)

(4) (29) (45) (22)

RR, relative risk; CI, confidence interval.

Data are n (%) or n/N (%) unless otherwise specified. * Percentages may not total 100 because of rounding. † The relative risk for the composite primary outcome is reported with a 97.7% confidence interval. ‡ The between-group comparison was performed with the use of the Cochran-Armitage test for trend.

Data from Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK, Johnson MP, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993–1004. Copyright Ó 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Motor Scales, and the degree of functional impairment and disability.

Power analysis determined that 100 patients per group were required. One thousand eighty-seven women underwent screening, but ultimately only 183 were enrolled during the first 7 years of the study. The Data and Safely Monitoring Committee recommended that the study be terminated early, after an interim analysis of the first 134 patients enrolled revealed that outcomes were better in the prenatal surgery group (Table 2). Specifically, compared with neonates who underwent postnatal surgery, fetuses treated with prenatal surgery were significantly less likely to experience fetal or neonatal death or meet criteria for shunt placement and were significantly less likely to have any kind of hindbrain herniation. The hindbrain herniation they did have was less severe. At 30 months, the children in both groups had similar scores on the Bayley Mental Development Index and similar Wee FIM (a measure of pediatric functional independence) cognitive scores.

However, those who underwent prenatal surgery were significantly more likely to have motor function one or two or more levels better than predicted by the level of the lesion and had significantly better Bayley Psychomotor Development Index and Peabody Developmental Motor Scales scores. Compared with the postnatal group, twice as many children in the prenatal surgery group were walking independently and fewer were not walking at all. These outcomes were especially surprising considering that, although the women in the two

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groups were similar in almost every way, the fetuses of women randomized to prenatal surgery actually had more severe lesions (27% at the L1 to L2 level compared with 12% in the postnatal group). In addition, the majority of the antenatal treatment group delivered preterm; 13% delivered before 30 weeks, 33% delivered at 30 to 34 weeks, and 33% delivered at 35 to 36 weeks.

The Management of Myelomeningocele Study trial also revealed significant adverse consequences of antenatal surgery. In addition to preterm delivery, women who underwent prenatal surgery were significantly more likely to develop pulmonary edema, placental abruption, oligohydramnios, spontaneous rupture of the membranes, or spontaneous labor, and more likely to require a blood transfusion than those whose child underwent postnatal repair. At the time of the cesarean delivery, 25% of women who had prenatal surgery had a very thin hysterotomy site, 9% had an area of dehiscence within the site, and 1% had a complete dehiscence. In addition, more children in the prenatal surgery group required surgery for tethered cord (8% compared with 1%).

Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia complicates 1 in every 2,000–3,000 births.72 Although the precise etiology remains uncertain, data from animal models suggest that an abnormality of nonmuscular mesenchymal cell differentiation leads to failure of the pleuroperitoneal folds to fuse during weeks 4 to 10.73

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Regardless of the etiology, intrusion of abdominal contents into the thoracic cavity during the critical period for development of bronchi and pulmonary arteries (up to week 16) leads to diminished branching of bronchioles, decreased overall arterial crosssectional area, and increased muscularization of the pulmonary arterial system.74 This abnormal pulmonary development results in pulmonary hypoplasia and pulmonary hypertension, the major causes of morbidity in neonates with congenital diaphragmatic hernia.

There are three types of congenital diaphragmatic hernia. The majority (95%) are the Bochdalek type, or defects of the postero-lateral diaphragm, most of which are left-sided. Other more rare types include the Morgagni type (parasternal defect) and defects of the central tendon.75 Prenatal diagnosis of congenital diaphragmatic hernia relies on several classic ultrasound findings, including abdominal organs (stomach, intestines, liver) seen in the thoracic cavity, displacement of the heart to the hemithorax contralateral to the defect, cardiac axis shift, and polyhydramnios.

Approximately two thirds of cases of isolated congenital diaphragmatic hernia are identified in the second and third trimesters,76 with higher detection rates reported by specialty centers. In approximately 26–58% of congenital diaphragmatic hernia cases, the hernia is accompanied by additional unrelated anomalies or occurs as part of a genetic syndrome.77 Because the survival rate for these cases is very poor regardless of the type and timing of intervention, they are usually not considered for antenatal fetal therapy.

Over the past 30 years, the overall survival of neonates with isolated congenital diaphragmatic hernia has increased from 50% to 70% to 80%.78 Although the diagnosis and treatment of antenatally diagnosed congenital diaphragmatic hernia have evolved during this time, the improved survival is primarily attributable to significant advances in postnatal care, including the use of extracorporeal membrane oxygenation, nitric oxide, and other modalities.

This has made it more challenging to demonstrate the efficacy of in utero intervention. In view of current satisfactory survival rates with postnatal care at a tertiary center, most investigators now offer prenatal intervention to only the severest cases with the worst prognosis and lowest life expectancy. Early work utilizing hysterotomy and fetal thoracotomy for diaphragmatic hernia repair was promising, but clinical trials showed no increase in survival over standard postnatal care,79 and this approach was abandoned.

In the 1990s, experimental work in a sheep model of congenital diaphragmatic hernia demonstrated that

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tracheal occlusion could accelerate fetal lung growth, prevent pulmonary hypoplasia, and restore normal physiologic lung function.80 The presumed mechanism is that obstruction of the normal efflux of fetal lung fluid leads to an increase in transpulmonic pressure, resulting in large, fluid-filled lungs. Early human trials of tracheal occlusion also utilized hysterotomy and an open fetal technique.81,82 These trials demonstrated greater than predicted survival in treated fetuses (33% compared with 13%, respectively), but the results were difficult to interpret because they were not randomized and the majority of cases resulted in preterm birth.

To minimize the risks of preterm labor and premature rupture of membranes, the fetal surgery community developed minimally invasive techniques to achieve reversible tracheal occlusion.83 In the first randomized controlled trial of percutaneous fetal tracheal occlusion, fetuses with severe left-side congenital diaphragmatic hernia were randomly assigned to either in utero tracheal occlusion (two cases of a tracheal clip, six cases of endotracheal balloon) or standard care.84 All study pregnancies were delivered by ex utero intrapartum treatment (EXIT, discussed below). Enrollment was stopped at 24 cases because of an unexpectedly high survival rate in the postnatal treatment group, and there was no demonstrated benefit associated with in utero intervention; a high rate of preterm delivery in the prenatal intervention group likely influenced this outcome. In a more recent trial,85 patients with severe congenital diaphragmatic hernia were randomized to either fetoscopic endotracheal occlusion (n520) or standard postnatal management (n521). Fifty percent of fetuses in the fetoscopic endotracheal occlusion group survived to 6 months of age, whereas 6-month survival was only 4.8% in the postnatal treatment group.

The discrepant outcomes of these two trials likely result from differences in the study participants.

Although both studies included only cases of “severe� congenital diaphragmatic hernia, the thresholds used to define severe congenital diaphragmatic hernia differed. Congenital diaphragmatic hernia severity has been estimated by the lung-to-head ratio, in which the area of the lung contralateral to the congenital diaphragmatic hernia is divided by the head circumference. Although increasing lung-to-head ratio is generally associated with improved survival, a wide range of outcomes after antenatal intervention has been reported. This disparity likely results from variations in measurement techniques, as well as a spectrum of gestational ages at the time of the surgery, and inclusion of both left congenital diaphragmatic hernia and right

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congenital diaphragmatic hernia and both liver-up and liver-down cases. Recent studies and conventional wisdom suggest that the liver-up position is associated with a decreased chance of survival,86,87 but it remains uncertain whether liver position is truly an independent predictor.88 Based on findings that the lung-to-head ratio increases with gestational age, Jani et al89 proposed an observed-to-expected lung-to-head ratio that is truly gestational age–independent. The observed-to-expected lung-to-head ratio has the advantage of being applicable to both left-sided and rightsided congenital diaphragmatic hernias, and logistic regression demonstrated that it predicted survival independent of the position of the liver above or below the level of the diaphragm. Magnetic resonance imaging–based calculations likely offer increased accuracy in determining fetal lung volumes, and a magnetic resonance imaging–based observed-to-expected fetal lung volume of 30% appears to be a threshold above which survival improves and below which survival decreases.90 A consensus on the timing of in utero intervention has evolved. Maximal benefit for lung development requires that the tracheal occlusion be performed as early as possible, but evidence suggests that tracheal occlusion before 26 weeks increases the risk of tracheal damage91; therefore, current practice is to occlude the fetal trachea at 26–28 weeks. Greater benefit is derived from occluding the trachea as long as possible, but the increased risk of preterm delivery and the potential of neonatal death from an occluded trachea have led to a consensus to remove the occlusive balloon at 34 weeks. This can be performed either by percutaneous balloon deflation (by needling) under ultrasound guidance or by endoscopic removal.

Alternatively, a planned EXIT procedure can be performed.

Improvement in the survival of neonates who receive standard postnatal surgery and support demands that in utero intervention be offered only in those cases in which standard postnatal treatment will likely not be successful. Improved methods for identifying those fetuses at greatest risk are making it possible to accomplish that, but, as with in utero intervention for bladder outlet obstruction, proof of efficacy remains elusive, and in utero intervention must be considered experimental. An indication that we are on the right path comes from a secondary analysis of the fetoscopic endotracheal occlusion registry of 210 consecutive procedures. This analysis showed that fetuses with congenital diaphragmatic hernia with poor prognosis (observed-to-expected lung-to-head ratio of less than 25% in left-side defects

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and less than 45% in right-side defects) treated antenatally have experienced morbidities similar to those fetuses with moderate congenital diaphragmatic hernia managed expectantly.92

Fetal Tumors Fortunately, fetal tumors are rare, occurring in 4–8 per 100,000 births.93 Although the widespread use of antenatal ultrasonography has led to the antenatal diagnosis of many fetal tumors, most are best treated after delivery. Certain fetal tumors, however, can disrupt fetal development or lead to fetal death by causing the development of hydrops. The most common tumor in this category is sacrococcygeal teratoma, with an incidence of 1 out of 35,000 to 40,000 births.94 Sacrococcygeal teratomas are derived from abnormal growth of the pluripotent cells in the Hensen node, and thus contain tissues of endodermal, mesodermal, and ectodermal origin with both solid and cystic components. They usually appear as a mass of mixed echogenicity extending from the sacrum or growing from the sacrum into the pelvis. Because they are often highly vascular, contain arterio-venous shunts, and may grow rapidly, sacrococcygeal teratomas can lead to fetal compromise through vascular steal phenomena, leading to high-output fetal cardiac failure.

Tumor tissue may also be fragile, with spontaneous bleeding occurring when the enlarging tumor is compressed against the uterine wall or during labor or delivery. Fetuses with sacrococcygeal teratomas can have additional anomalies, mostly occurring as the consequence of deformation by the sacrococcygeal teratoma, which can affect prognosis. These include rectal stenosis or atresia, hydrocolpos, urinary tract obstruction and related renal anomalies, pulmonary hypoplasia resulting from oligohydramnios, and hip dislocation or club foot.95 Several studies have attempted to delineate the natural course of untreated sacrococcygeal teratomas and to identify factors that indicate poor prognosis.

Early case series of sacrococcygeal teratoma were likely negatively skewed by the fact that many prenatal cases were discovered during a work-up for hydramnios or other pregnancy complications. More recent series including cases identified during routine targeted ultrasound examination suggest that the majority of fetuses with incidentally diagnosed sacrococcygeal teratomas survive to delivery without intervention and do well after neonatal surgery.96 However, a small proportion of fetuses with sacrococcygeal teratomas have fast-growing, highly vascular tumors and are at risk of prenatal death as the result of heart failure or bleeding, making hydrops the

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strongest predictor of an adverse outcome.97 Other reported predictors include a ratio of tumor volume to fetal weight of 0.12 or more, tumors with mostly solid rather than cystic elements, rapid tumor growth, impaired fetal cardiac function or cardiomegaly, and the development of complications such as hydramnios or the mirror syndrome (maternal features of preeclampsia mirroring fetal hydrops).96,98,99 The development of hydrops at a gestational age at which neonatal survival is likely usually prompts delivery, whereas impending hydrops in an immature fetus raises the possibility of fetal therapy. Current interventions include open fetal surgical debulking, shunt placement in large cystic lesions, and radiofrequency ablation, with a wide range of reported survival rates; the high rate of adverse outcomes reported by fetal treatment centers may reflect the increased severity of referred cases. Hedrick et al95 reported a series of 30 cases of sacrococcygeal teratomas managed at one center in which the criteria for open fetal surgical treatment included sacrococcygeal teratomas in a singleton euploid fetus without other anomalies and impending high-output cardiac failure at less than 30 weeks of gestation. Of the 26 ongoing pregnancies, only four fetuses met the criteria for open fetal surgery and underwent antenatal surgical debulking, and three of these survived. Ten fetuses had other interventions (amnioreduction, amnioinfusion, or cyst aspiration), and nine survived. However, of the remaining 12 pregnancies, five resulted in fetal death before intervention (three were hydropic, one had partial tumor rupture and pericardial and pleural effusions, and one had no autopsy), three resulted in death after preterm delivery performed for antenatal tumor rupture and hemorrhage, two died of tumor rupture during neonatal surgery, and one died as the result of pulmonary hypoplasia. Thus, the overall survival rate for sacrococcygeal teratomas in this series was only 46% (12/26).

In contrast, Lee et al100 reported a series of 32 fetuses with sacrococcygeal teratomas treated at one center; eight were treated antenatally with radiofrequency ablation, shunt placement, or cyst aspiration, and the overall survival rate was 91% (although 10 fetuses were lost to follow-up). The criteria for radiofrequency ablation in this series included a rapidly growing, highly vascular mass and cardiomegaly.

Although eight fetuses were treated with radiofrequency ablation, it was successful in only one fetus; the other seven were delivered preterm at 25 to 31 weeks, and five survived. Makin et al101 published a series of 29 cases treated over an 11-year period, which included 17 fetuses not requiring antenatal ther-

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apy and delivered at a mean gestational age of 38 weeks; 16 of these survived. Of the other 12 fetuses, seven had hydrops, two had hydramnios (one with cardiomegaly), one had fetal bladder obstruction, two had a cyst so large it would obstruct delivery, and all underwent antenatal therapies including laser vessel ablation (n54), alcohol sclerosis (n53), cyst drainage (n52), amniodrainage (n52), and vesicoamniotic shunt (n51). The five fetuses without hydrops survived, but six of the seven hydropic fetuses died. The overall survival rate in this series was 76%.

The literature on sacrococcygeal teratomas suggests that therapy to try to reverse full-blown fetal hydrops is frequently unsuccessful, yet our ability to identify impending cardiac decompensation and thus candidates for possible antenatal intervention is imperfect. Importantly, prenatal therapy is not possible in many cases because the impending decompensation includes hydramnios, placentomegaly, and preterm labor. One report suggests that a policy of preterm delivery for fetuses with impending hydrops before 32 weeks is a reasonable strategy; of nine fetuses delivered at 26–31 weeks for evolving hydrops, rapid tumor growth, nonreassuring fetal status, or preterm labor, four survived.102 The literature on fetal thoracic masses such as congenital cystic adenomatoid malformation or pulmonary sequestration is very similar to that on sacrococcygeal teratomas. Most of these thoracic masses are well-tolerated by the fetus and successfully treated after birth, whereas others can lead to antenatal cardiac decompensation and hydrops. As with sacrococcygeal teratomas, the prognosis for fetuses with hydrops in this setting is dismal. Impending cardiac decompensation at an early gestational age is an indication for fetal therapy, usually in the form of open surgery for mass resection or the placement of a thoraco-amniotic shunt. A review of the outcomes of a series of fetuses with congenital cystic adenomatoid malformation or pulmonary sequestration from one of the world’s largest fetal treatment centers confirms that, for nonhydropic fetuses, survival without antenatal surgery is excellent (98% survival for 125 cases of congenital cystic adenomatoid malformation; 100% survival for 23 cases of pulmonary sequestration).103 The survival rate for the 48 ongoing hydropic pregnancies complicated by fetal congenital cystic adenomatoid malformation was zero for the 14 patients who elected no intervention and 57% for the 23 patients who had open fetal surgery; other treatments included percutaneous intervention (one of five survived) and EXIT to immediate postnatal surgery (one of three survived). Interestingly, in this series three patients

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elected to have maternal steroid treatment followed by delivery at 21–24 weeks, and all survived, suggesting that early delivery in the presence of hydrops is also a viable treatment option for thoracic mass lesions.

Conditions Treated With the Ex Utero Intrapartum Treatment Procedure The EXIT procedure was developed for the delivery of fetuses with congenital diaphragmatic hernia treated with antenatal tracheal clipping, to allow time to remove the clip and establish an airway before the fetus was separated from the placenta.104 It has since been applied to cases of airway obstruction from a variety of other causes. In this procedure, the patient (and fetus) undergoes general anesthesia with neuromuscular blockade, a hysterotomy is created with a stapling devise using absorbable sutures, and the fetal head and shoulders are delivered through the incision. While the placenta is still providing gas exchange, fetal intubation by laryngoscopy or rigid bronchoscopy, tracheostomy, or even tumor resection can be performed to establish an airway. Bleeding is controlled by the staples on the edge of the incision and by coordination between the surgeon and anesthesiologist regarding the timing of decreasing the inhaled anesthetic and the administration of oxytocin. To prevent the collapse of the uterine cavity and possible placental separation or umbilical cord compression, warm saline can be infused into the uterus.

In addition to facilitating the removal of tracheal clips, the EXIT procedure has now been used successfully for fetuses with congenital high airway obstruction syndrome (the absence or blockage of the larynx or trachea)105 and a variety of anomalies including neck masses that compress the trachea, oral tumors, dysgnathia complex, and persistent mediastinal compression associated with lung masses.106– 110 In one review of 52 cases in which the EXIT procedure was performed for tracheal clip or balloon removal in fetuses with congenital diaphragmatic hernia or for neck masses, the average operating time was 45625 minutes and the average blood loss was 9706510 mL.111 However, this review also noted that successful completion of the procedure without fetal or maternal compromise has been reported after 150 minutes before delivery.

SUMMARY Developing the fetal surgical procedures described in this review required the contributions of a large number of physician scientists over many, many years. First, pediatricians and neonatologists identified

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structural congenital anomalies that are lethal or highly morbid because they prevent normal development. Geneticists, embryologists, and pathologists then worked to determine the etiologies of these malformations and to predict the developmental outcome if the defects could be corrected or ameliorated before birth. Maternal-fetal medicine specialists and radiologists developed imaging techniques to accurately diagnose these defects prenatally. Pediatric surgeons then worked to adapt neonatal surgical procedures to the antenatal period and to perfect those techniques using animal models. Anesthesiologists, surgeons, and maternal-fetal medicine specialists worked together to safely apply those surgical procedures to human fetuses while minimizing maternal risk.

Maternal-fetal medicine specialists cared for postsurgical patients and developed protocols to minimize complications, including the risk of preterm birth. Neonatologists cared for the former fetal patients, who were likely to have been born preterm, and devised a variety of supportive therapies. Social workers and bioethicists provided parental support throughout. Once these steps had been accomplished, the procedures began to be tested in small series, allowing colleagues to exchange ideas and suggest procedural modifications. Eventually, the data regarding some surgeries seemed promising enough that they could be evaluated in prospective randomized trials, a task that required the collaboration of hundreds of practitioners at multiple centers because the fetal defects being treated are rare.

The surgical procedures described in this review are the result of all these efforts, expended over many, many years by a wide variety of specialists, and are thus remarkable in many ways. It is therefore with a spirit of optimism, not criticism, that we must acknowledge that in nearly every case the procedures have not yet been perfected. The primary problems continue to be accurately identifying which fetuses will die or be severely injured without intervention, but still will have the capacity to recover relatively normal function if fetal surgery is performed, and prevention of preterm delivery after fetal intervention.

Advances in neonatal care, which have resulted in the survival of neonates who surely would have died even 15–20 years ago, have made the perfection of some fetal procedures less urgent. However, there are still some anomalies, especially those leading to permanent renal or neurologic damage, that will continue to be devastating regardless of neonatal care, and it is for these anomalies that prenatal surgery holds the most promise.

The tremendous resources required to perform fetal surgery, including the considerable investment in

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training that is required of a fetal surgeon, together with the relative rarity of most of the conditions for which fetal surgery is attempted, demand that the number of fetal surgery centers be limited so that each can care for enough patients to justify their cost and maintain the skills of the fetal interventionists. At present there is no consensus on how many procedures each center or provider should perform each year to maintain their skills or, for that matter, how many procedures should be performed before a surgeon is considered qualified.

The societies of the various specialists involved in fetal surgery must collaborate on criteria for initial and ongoing certification of fetal surgery centers and fetal surgeons so that the considerable progress that has been achieved so far can continue, and maternal and fetal patients can continue to receive the safest and most effective therapies.

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