One of the key elements in developing fetal intervention for CDH has been identifying what factors will identify those fetuses at the greatest risk for a poor outcome. The factors most consistently associated with a poor outcome on prenatal US are (1) the presence of liver herniation into the chest and (2) a low lung-to-head ratio (LHR). In general, survival has been near 100% in fetuses with CDH that do not have liver herniation on prenatal US and 56% in fetuses with CDH and liver herniation into the chest. ^, The LHR is calculated as the area of the contralateral lung at the level of the cardiac atria divided by the head circumference. This LHR value has been shown to statistically correlate with survival: 100% survival with an LHR >1.35, 60% survival with an LHR between 0.6% and 1.35%, and 0% survival with an LHR <0.6.

While the LHR has been a reliable predictor of outcomes in our experience, five other institutions have suggested the LHR does not account for discrepant growth rates between the head and lung during gestation and therefore may not be reliable at certain gestational ages. ^, To account for this, the observed to expected LHR (OE LHR) has been developed. The OE LHR is represented as a percentage of what the expected LHR would be in a normal fetus of the same gestational age. For left-sided defects, an OE LHR <25% is associated with a 20% survival, whereas an OE LHR >45% correlates with 90% survival. ^, Alternatively, some researchers have suggested that the quantitative lung index (QLI, where QLI = lung area/(head circumference/10)2) is the best way in which to normalize LHR against gestational changes and most accurately predict both survival and the need for prenatal intervention.

Magnetic resonance imaging (MRI) for volumetric measurement of the lungs is a promising prognostic modality for CDH. MRI can be used to calculate the percent predicted lung volume (PPLV). Results for PPLV have varied. In one study, a PPLV >20% was associated with 100% survival, whereas survival was only 40% when PPLV was <15%. In another study, a PPLV <25% was associated with a 13% survival and a PPLV >35% correlated with 83% survival. MRI can also be used to determine the percentage of liver herniation, although the method has not been standardized.

CDH and its effect on fetal lung development has been studied in animal models. ^, In the fetal lamb model, compression of the lungs, either with an intrathoracic balloon or by creation of a diaphragmatic hernia, results in uniformly fatal pulmonary hypoplasia. In fact, pulmonary hypoplasia is the biggest predictor of mortality and morbidity in CDH-affected fetuses, closely followed by persistent pulmonary hypertension. However, in utero correction of the compressing lesion leads to sufficient lung growth and development, which improves postnatal survival.

This concept of early, in utero correction of CDH has been studied and applied in humans. ^, Fetal surgery for CDH initially involved open repair of the diaphragmatic defect. The first successful case was reported in 1990, which demonstrated the feasibility of open fetal repair using a two-step approach involving creation of an abdominal silo to accommodate the reduced viscera and prevent compression of the umbilical vessels. This initial success was followed by a prospective trial at UCSF comparing open fetal surgery to postnatal repair in severe cases of prenatally diagnosed CDH. However, in this study, there was no difference in survival or in the need for extracorporeal membranous oxygenation (ECMO) between fetal repair and postnatal repair. ^, Concordant with this effort, investigators at UCSF observed that fetuses with congenital high airway obstruction syndrome (CHAOS) had pulmonary hyperplasia. Also, fetal tracheal occlusion had been shown to cause pulmonary hyperplasia. In this condition, the lung parenchyma creates fluid that is “exhaled” by the fetus. Occluding the trachea causes a buildup of this fluid and subsequent pulmonary hyperplasia. ^, The inability to improve outcomes with open fetal repair for severe cases of CDH led to an interest in this physiologic process.

The first eight patients were treated with open hysterotomy and tracheal occlusion using a metallic clip. This approach proved to be problematic for several reasons. First, the open hysterotomy led to significant prematurity due to premature labor. Second, the use of clips was associated with tracheal stenosis and also required a stringent delivery plan—which was later described as the ex utero intrapartum treatment (EXIT) procedure—whereby the fetus was exposed through a hysterotomy and maintained on uteroplacental circulation while the clip was removed and a patent airway established prior to delivering the baby. ^, However, outcomes with this approach were poor, with only a 15% survival rate.

Ongoing advancements led to fetoscopic balloon placement for tracheal occlusion ( Fig. 9.1 ). This technique has the advantages of being less invasive and with a lower risk of tracheal stenosis. Also, the balloon is much easier to remove, although early techniques still necessitated an EXIT procedure. Results in the first eight cases were favorable, with a 75% survival rate compared with a 38% survival rate in historical, case-matched controls managed with postnatal repair. These early results led to the development of Fetoscopic Endoluminal Tracheal Occlusion (FETO), first described in a fetal lamb model. ^, Single center studies have demonstrated promise with FETO with overall survival of 47.1% and improvement between pre-balloon removal O/E LHR and pre-FETO O/E LHR was significantly higher in survivors compared to neonates who died (40.8% vs. 21.2%, respectively; p <.05). A subsequent National Institutes of Health (NIH)-funded, prospective, randomized trial compared FETO to standard postnatal care for fetuses diagnosed with severe left-sided CDH (liver up and LHR <1.4) and no other detectable anomalies. However, results of the trial showed no difference in survival between the tracheal occlusion group and the standard postnatal care group (73% vs. 77%, respectively). Unexpectedly, the survival in the postnatal repair group was considerably greater when compared with historical controls. Although this study did not demonstrate a difference in survival between the prenatal intervention group and the postnatal group, the results of this trial demonstrated the tremendous importance of proper randomized controlled trials for novel fetal surgical procedures.

This schematic diagram shows the method of fetoscopic tracheal occlusion. A fetoscope is placed into the fetal mouth, the airway is identified, and a balloon is inserted into the trachea by using both fetoscopic and ultrasonographic visualization.

Further data regarding fetal tracheal occlusion have suggested that temporary, short-term reversible tracheal occlusion may be preferable to a longer duration of occlusion. Animal models of fetal tracheal occlusion have shown that long-term tracheal occlusion can be deleterious to type II pneumocytes (the cells that secrete surfactant) and that this adverse effect is not seen with a shorter duration of tracheal occlusion. To test the hypothesis that temporary fetal tracheal occlusion is better, Deprest et al. studied patients undergoing FETO who also had the balloon removed prenatally to limit the duration of occlusion. In this group of patients, improved lung growth was evident on fetal MRI and was also associated with improved postnatal survival. Although reversal of the tracheal occlusion requires a second maternal and fetal intervention for balloon removal, it obviates the need for an EXIT procedure at birth. These favorable findings with temporary tracheal occlusion led to its application in Europe. The European FETO consortium reported a 48% survival rate among 210 cases of severe CDH treated with temporary fetal tracheal occlusion, with improvement in survival with both left and right CDH.

More recent studies have yielded even more promising findings. Of particular importance was the international randomized Tracheal Occlusion to Accelerate Lung growth (TOTAL) trial, which focused on the efficacy of fetal intervention in CDH-related pulmonary hypoplasia. In arm 1 of the trial, fetuses at 27–29 weeks’ gestation with severe pulmonary hypoplasia and left-sided CDH (OE LHR <25%) were randomly assigned to FETO, with reversal at 34 weeks, versus expectant management. Survival to discharge was 40% in the FETO group compared to 15% in the expectant group, though the incidence of PPROM (preterm, prelabor rupture of membranes) and preterm birth were higher with FETO. The second arm focused on moderate left-sided CDH (OE LHR 25%–34.9% or 35%–44.9% with liver herniation), with FETO at 30–31 weeks to reduce the risk of preterm labor. The survival-to-discharge rates were not significantly different (63% FETO vs. 50% expectant), though on analysis of pooled data the severity of pulmonary hypoplasia did not appear to have an effect, and the sample size was too small to determine if the timing of intervention had a role. However, the risk of preterm delivery was higher with earlier intervention.

A recent meta-analysis on FETO found that FETO reduced 1-month mortality (OR 0.56) and 6-month mortality (OR 0.56), and that the effects on pulmonary hypertension and ECMO requirements were dependent on the severity of CDH, though the quality of evidence was low to moderate, given that most of the data resulted from the TOTAL trial. Preterm labor was also increased with FETO, but not the rate of extreme preterm birth (<32 weeks).

A prior U.S. study with Food and Drug Administration oversight recommended percutaneous placement of a fetoscopic tracheal balloon between 26 and 28 weeks of gestation, with removal of the balloon via a second percutaneous fetoscopic procedure between 32 and 34 weeks. Following the results of the TOTAL trial, FETO should be considered for fetuses at 27–29 weeks’ gestation with severe pulmonary hypoplasia and OE LHR < 25%. Several groups are currently offering reversible fetal tracheal balloon occlusion for fetuses with liver herniation in the chest and an LHR of <1.0, as these babies continue to have a very high mortality. Given the uncertain benefit of FETO with moderate pulmonary hypoplasia, potential intervention in this group should include an informed discussion between the surgical team and family on a case-by-case basis.

Alternative fetal treatments such as transamniotic stem cell therapy (TRASCET), stem cell extracellular vesicles, and intraamniotic micro-RNA delivery have been shown to have some benefit in rodent models of pulmonary hypoplasia. Promotion of lung growth with instillation of perfluorooctylbromide augments lung growth without suppression of surfactant protein synthesis and has been suggested as promising prental therapy as an alternative to FETO. Ongoing advancements in prenatal treatment of CDH will need to address optimal timing of FETO therapy, efficacy in moderate CDH, and additional less-invasive fetal treatment options.

CPAMs are pulmonary lesions with a broad range of clinical presentations. This new terminology includes congenital cystic adenomatoid malformations (CCAMs) and bronchopulmonary sequestrations (BPS). CCAMs are much more likely than BPS to cause nonimmune fetal hydrops. CCAMs are characterized by an overgrowth of respiratory bronchioles with the formation of cysts of various sizes. ^, Most fetuses diagnosed with a CCAM develop normally and can be followed with serial US studies. MRI can also be a useful diagnostic tool if clear images are not obtainable by US. These asymptomatic patients then undergo standard, postnatal resection. A small percentage of patients with the prenatal diagnosis of CCAM will develop nonimmune hydrops. ^,

Various measurements have been developed to predict which fetuses are at risk for developing hydrops. The most accepted measurement is the CCAM volume ratio (CVR), defined as the product of the three longest measurements of the lesion on US multiplied by the constant 0.52, and then divided by the head circumference. A CVR of 1.6 has been identified as a cutoff for an increased likelihood of developing hydrops. When the CVR is <1.6, there is only a 2% risk of developing hydrops. When the CVR is >1.6, there is an 80% chance of developing hydrops. For fetuses who have already developed hydrops, an irregular echocardiogram may be the most accurate indicator of the need for fetal intervention and possible demise.

CCAMs that are predominantly microcystic have a more predictable course than the macrocystic ones. Microcystic or solid CCAMs undergo steady growth that tends to plateau at 26–28 weeks of gestation. At this point, fetal growth exceeds that of the CCAM. For this reason, patients with microcystic or solid CCAMs should be followed closely for up to 26–28 weeks of gestation, at which point the interval between US examinations can be lengthened if the pregnancy has been otherwise uncomplicated. In contrast, macrocystic CCAMs undergo abrupt enlargement due to rapid fluid accumulation in a dominant cyst. Therefore, macrocystic CCAMs require close follow-up with serial US throughout the pregnancy. ^,

If a fetus develops hydrops at a viable gestational age, early delivery should be considered. Hydropic fetuses who are not yet viable outside the uterus and have a dominant macrocystic lesion are appropriate candidates for a thoracoamniotic shunt. Needle drainage alone has not been found to be effective therapy as rapid reaccumulation of fluid in the cyst necessitates repeat intervention. In the largest single-center experience with thoracoamniotic shunts, shunting led to a mean 51% volume reduction in the size of the lesion and a 70% survival rate. Other institutions have reported similar survival rates. Despite shunting, these babies can still have significant respiratory distress at birth and should be delivered at a tertiary referral center.

A recent study investigating long-term outcomes after thoracoamniotic shunt in 31 patients who underwent fetal intervention for high-risk congenital lung malformations reported a fetal survival rate of 90%. Of the 16 patients that delivered at their center, 94% survived to hospital discharge and 93% reported normal lung function at a median follow-up of 10.7 years. Sixty percent of this cohort had some degree of chest-wall deformity from fetal intervention, but none required surgical management of the deformity. While small, this study suggests overall favorable long-term outcomes after thoracoamniotic shunt, though larger case-controlled studies are needed.

Open fetal thoracotomy and CCAM resection is an option in the previable fetus with a microcystic or solid lesion. This is performed through an open hysterotomy. A thoracotomy is made through the fifth intercostal space, and the lobe containing the CCAM is identified and exteriorized through the incision ( Fig. 9.2 ). The pulmonary hilar structures are then mass ligated using an Endoloop or endoscopic stapler. The thoracotomy is then closed in layers. ^,

These photographs depict an infant with a large left upper lobe congenital cystic adenomatoid malformation (CCAM) undergoing in utero left lobectomy. (A) The infant’s left arm is visualized. Note the maternal hysterotomy and the left fetal thoracotomy (with retractors inserted) through the fifth intercostal space. (B) The left upper lobe containing the CCAM has been identified and exteriorized through the thoracotomy incision. The pulmonary hilar structures were mass ligated using an endoloop. (C) The fetal thoracotomy incision ( arrow ) has been closed. (D) The left upper lobe specimen containing the CCAM is seen.

In a group of 120 patients with the prenatal diagnosis of CPAM from UCSF and Children’s Hospital of Philadelphia (CHOP), 79 had no evidence of hydrops. Of these, 76 were followed expectantly and all survived. Three fetuses without evidence of hydrops and with large dominant cysts underwent thoracoamniotic shunting—all three fetuses survived. Twenty-five hydropic fetuses were followed with no intervention. All mothers delivered prematurely, and all fetuses died perinatally. Sixteen fetuses with hydrops underwent intervention: 13 underwent open fetal surgery while 3 underwent thoracoamniotic shunting. Two of the 3 survived in the group that underwent shunt insertion, and 8 of 13 survived in the open fetal surgery group.

Despite positive results with open fetal resection in the hydropic fetus, there has been a shift away from this therapy due to the efficacy of maternal steroids. This finding was discovered serendipitously at UCSF during the preparation of several hydropic fetuses for open fetal surgery. In these cases, maternal steroids were administered to enhance fetal lung maturity. Preoperative US studies showed resolution of the hydrops, and those fetuses survived to delivery and beyond. Thirteen patients with microcystic CCAMs, 9 of which were complicated by hydrops, had an overall survival rate of 85% with resolution of the hydrops in 7 of 9 fetuses. CHOP has reported a series of 11 patients, 5 of whom had hydrops, and all survived after receiving steroids. A recent review reported that in high risk patients with CPAM and hydrops, a single cycle of steroids resulted in a resolution of hydrops in 70% of fetuses, with a survival rate of 83.8%.

Currently, we recommend maternal betamethasone for fetuses with nonimmune hydrops or a CVR >1.6. Steroids can be redosed, but repeated administration of maternal steroids beyond three to five courses can result in untoward effects such as reduced birth weight. It is widely accepted that steroids are most effective for predominantly microcystic or solid lesions as this is the component of the malformation that responds to steroids. Macrocystic lesions are less likely to respond. Fetal intervention should be considered in cases where hydrops does not respond to steroid administration.

Investigations into other minimally invasive interventions have occurred in recent years and yielded some promising results. Perhaps most notably, US-guided fetal laser ablation of the feeding artery (FLAFA) may help resolve hydrops in fetuses with large lung masses and sequestrations, but additional research is required to augment this approach and reduce complications. Interestingly, for BPS patients with pleural effusions, laser ablation of the feeding vessel may result in more favorable outcomes than pleuroamniotic shunting and result in a decreased need for subsequent postnatal intervention. FLAFA may produce similarly positive outcomes for fetuses with large hybrid lung lesions in addition to hydrops and/or pleural effusions. A recent case report also described radio-frequency ablation of a large CPAM with hydrops in a 21-week-old fetus, with subsequent resolution of hydrops. Other investigative techniques include CPAM sclerotherapy with ethanolamine oleate, with mixed results in the literature requiring further study. ^, For mainstem bronchial atresia (MBA), fetal pneumonectomy may resolve hydrops and reduce contralateral lung growth, but this approach is presently still correlated with prematurity and its associated complications.

SCT is another rare tumor that is being diagnosed prenatally with increasing frequency, allowing for observation of the natural history of the disease and appropriate perinatal management. As with CCAM, fetuses with SCT are susceptible to IUFD. SCTs can grow to a large size in relation to the fetus and can cause high-output cardiac failure and nonimmune hydrops through vascular shunting. Rarely, tumors can hemorrhage internally or externally, resulting in fetal anemia, hypovolemia, and IUFD. Other potential problems for a fetus with a large SCT are dystocia and preterm labor. Delivery can be particularly difficult when the diagnosis has not been made prenatally. A traumatic delivery can result in tumor rupture and/or hemorrhage. Thus, prenatal diagnosis and careful obstetric planning are critical in the management of these fetuses.

The tumor volume to fetal weight ratio (TFR) is an important prognostic indicator. Tumor volume is calculated using the greatest length, width, and height of the tumor as measured by US or MRI. Fetal weight can be calculated by US as well. In the initial report of 10 fetuses with SCT, a TFR >0.12 was associated with an 80% incidence of hydrops and a 60% mortality, whereas a TFR <0.12 was associated with 100% survival. The group at UCSF presented their experience in 37 fetuses with SCT and confirmed that a TFR <0.12 was a favorable prognostic finding up to 24 weeks. Between 24 and 32 weeks, a TFR of <0.11 was associated with better outcomes. In addition, they also found that cystic SCTs had a more favorable prognosis than solid ones.

The fetus with SCT has a high risk for mortality, especially when associated with nonimmune fetal hydrops. The group at CHOP has previously published their experience with 30 fetuses with SCT. There were 14 survivors, and 4 pregnancies were terminated. Fifteen fetuses had solid tumors. Of those, 4 developed signs of hydrops and underwent fetal debulking operations. Three of the 4 survived. In the published UCSF experience with 65 prenatally diagnosed SCTs, the overall survival was 44%. Nineteen of these pregnancies were complicated by fetal hydrops, of which 8 underwent a fetal intervention and 3 survived. In the 11 patients with hydrops who did not undergo fetal intervention, there was only 1 survivor. Overall, 15 patients with SCT have undergone fetal intervention at UCSF (excluding patients who had cyst aspiration to facilitate delivery): 6 underwent open resection, 5 underwent RFA, 1 underwent alcohol ablation, 1 had therapeutic cyst aspiration to relieve urinary tract obstruction, 1 had RFA followed by EXIT-to-resection, and 1 had EXIT-to-resection alone. Overall survival was 33%. Although 10 patients survived to delivery, the mean gestational age was 28.1 weeks and there was a 50% neonatal mortality rate.

The most common approach for fetal SCT resection is a maternal hysterotomy with resection or debulking of the tumor ( Fig. 9.3 ). A predominantly cystic lesion may be amenable to percutaneous drainage or placement of a shunt, but fetal drainage may not be necessary given the favorable prognosis for cystic SCTs. On the other hand, immediate decompression of an SCT may be needed just prior to delivery to prevent dystocia or to facilitate cesarean delivery. Indeed, case studies have demonstrated the potential efficacy of US-guided percutaneous drainage when conducted immediately before labor induction and vaginal delivery. Tumor debulking using percutaneous coagulation techniques, such as with RFA or laser coagulation, to decrease the vascular shunt are alternatives to open resection that may warrant further investigation. ^, Several studies thus far have reported success with these kinds of minimally invasive techniques, although associated fetal complications can be considerable and mortality rates remain high. One group found that vascular laser ablation may increase fetal survival and treat hydrops, and that selective vascular ablation could be more effective than interstitial ablation. A recent systemic review of the literature for intrafetal0 laser therapy (IFL) suggested that it is a safe and feasible therapy for various fetal conditions, including 11 cases of SCT, where complete cessation of blood flow was achieved in 4 patients (36.4%). Minimally invasive interventions greatly reduce the maternal morbidity seen with open procedures, but the risk of fetal demise is higher, likely due to hemorrhage into the tumor. ^, Early delivery before 32 weeks of gestation has also been associated with positive outcomes for high-risk SCT without fulminant hydrops, likely because of avoiding the complications that increase with gestation.

Due to a tumor volume to fetal weight ratio (TFR) that was >0.12, it was decided to perform a fetal resection for this fetus with a large sacrococcygeal teratoma (SCT). Initially, the maternal laparotomy was made and the uterus exposed (A). Using ultrasound, the location of the SCT was identified and maternal hysterotomy was performed. The large SCT is seen ( asterisk ). The red rubber catheter has been placed in the anus (B). The tumor resection was initiated using the electrocautery (C). In D, the tumor has been resected and the incision closed. The baby was returned to the uterus and had an uneventful birth.

Twin–twin transfusion syndrome (TTTS) is the most common complication of monochorionic twin pregnancies with an incidence of about 10%–20%. In such twin pregnancies, the two fetuses share a single placenta with normal vascular connections (arterial-to-venous, venous-to-arterial, and arterial-arterial) between the fetuses. TTTS occurs when these connections lead to unbalanced blood flow from one twin to the other. As a result of the transfusion of blood from the donor twin to the recipient twin through this unbalanced flow, hemodynamic compromise can occur in either or both twins. The donor twin suffers from a low flow state manifesting initially as oligohydramnios and possibly resulting in high-output cardiac failure or ischemia to the brain and kidneys. Conversely, the recipient twin has fluid overload (polyhydramnios) and may develop congestive heart failure and hydrops. The hallmark of TTTS is oligohydramnios in the donor twin and polyhydramnios in the recipient twin, both of which must be present to make the diagnosis. Often there is size discordance between the twins, with the donor being smaller than the recipient. Quintero described five stages of TTTS ( Table 9.2 ). Components include assessment of bladder filling; Doppler assessment of the umbilical artery, ductus venosus, and umbilical vein; and presence of hydrops or fetal demise. Advanced stages of the disease are evidenced by progressive discordance in fluid volumes, bladder filling, and cardiovascular manifestations. The donor twin experiences hypovolemia, resulting in oliguria and oligohydramnios with minimal to no bladder filling and an appearance of being “stuck” to the uterine wall due to lack of fluid. In contrast, the increased preload experienced by the recipient twin leads to release of atrial natriuretic peptide and brain natriuretic peptide, which stimulates diuresis and leads to polyhydramnios. The recipient twin can subsequently develop cardiac dysfunction and hydrops. If left untreated, TTTS carries an 80%–90% mortality rate for both twins. In addition, in monochorionic twins, if one twin dies, the other is at risk for neurologic injury due to a sump phenomenon in the placenta that leads to temporary hypotension and ischemia in the surviving twin.

Clinicians have attempted a variety of treatments aimed at achieving improved outcome in one or both twins. Historically, high-volume amnioreduction in the polyhydramniotic sac was the primary therapy. Because polyhydramnios can incite labor, the initial aim of amnioreduction is to reduce uterine volume to decrease the risk of preterm labor. In a review of the International Amnioreduction Registry, high-volume amnioreduction resulted in a survival rate in at least one twin of almost 60%.

Several groups have used fetoscopic guidance to laser ablate the intertwin vascular connections, and this approach has largely replaced amnioreduction. This procedure can be done either nonselectively by ablating all intertwin connections, or selectively by ablating only the arteriovenous connections with flow in the causative direction. Fetoscopic laser ablation is performed using a 3-mm fetoscope with a side channel for irrigation and insertion of a laser. Use of reflectance spectrometry may increase the accuracy of laser ablation by helping to distinguish donor from recipient placental vessels.

Two large prospective trials have compared amnioreduction to laser ablation of intertwin vessels. A European trial enrolled 70 women in the amnioreduction arm and 72 women in the laser ablation arm. The trial was stopped early after interim analysis showed a clear survival advantage for laser therapy: 76% versus 51% single survivor and 36% versus 26% for dual survivors. A North American trial was also stopped early after randomizing 42 mothers (20 in the amnioreduction arm and 22 in the laser ablation cohort) because of reluctance among referring physicians to send patients to participating centers for randomization due to a strong bias for laser ablation. There was no survival benefit to either intervention in this study, which was underpowered because of its early termination. A Cochrane review and meta-analysis also favored laser ablation for TTTS with an overall survival of 66% for laser ablation compared with 48% for amnioreduction. When laser ablation is not available or not possible for technical reasons, amnioreduction is an appropriate alternative. Whether or not every case of TTTS requires intervention is controversial. The natural history of stage I TTTS is that up to 75% of patients remain stable or regress with expectant management; therefore, laser ablation is only offered in those cases that are stage II or higher. The presence of an arterial-arterial anastomosis may be protective by serving as a bidirectional valve that allows for equilibration between the twins. Of 639 placentas evaluated, only 5% of those with an arterial-arterial anastomosis had true TTTS. However, early detection and close monitoring of all monochorionic pregnancies at risk for TTTS or intrauterine fetal death may contribute to positive neonatal outcomes. ^,

Despite the current status of laser ablation as the standard of care for TTTS, many women worldwide still do not have adequate access to this treatment. However, there is evidence that outcomes are unaffected for patients with TTTS who must undergo long-distance air travel in order to reach a tertiary facility capable of conducting safe, high-quality RFA.

Other TTTS interventions have been explored in recent years including endoscopic equatorial laser therapy and adjunctive medical therapy. Equatorial laser therapy differs from selective laser coagulation in that the ablation occurs across the entire vascular equator instead of only at selected vessels. Outcomes thus far with this technique in terms of fetal survival do not differ significantly from selective laser coagulation. Possibly the most researched adjunctive medical therapy at this point is the calcium blocker nifedipine, which may help target cardiomyopathy and improve fetal survival when maternally administered prior to laser ablation. ^,

Indeed, fetal myocardial function is one of the most important factors to consider with TTTS, as monochorionic twin pregnancies are at a significantly elevated risk for congenital heart defects and heart failure. In a recent study, about 10% of recipient twins presented with pulmonary stenosis and pulmonary atresia (PS/PA), and the bulk of these PS/PA cases arose in Quintero stages III and IV. Interestingly, laser ablation has been shown to be followed by reduced isovolumetric relaxation time (IRT), which may indicate improved diastolic function. Because impaired cardiac activity is characteristic of recipient twins in TTTS pregnancies even in early stages, The Children’s Hospital of Pennsylvania and the Cincinnati modification of the Quintero system incorporate additional cardiovascular parameters for the prediction of neonatal outcomes. Clinically, myocardial performance is not yet widely used for early prediction of TTTS.

Twin reversed arterial perfusion sequence (TRAP) is a disease of monochorionic twins with an incidence approaching 2.6% of monozygotic twins, and 1 in every 9500 to 11,000 pregnancies. TRAP occurs when one normal twin acts as a “pump” for an acardiac, acephalic twin. This occurs because of early formation of arterial-arterial anastomoses that results in retrograde flow from the umbilical arteries of the “pump” twin into the umbilical arteries of the acardiac twin. In the most common morphology, the acephalic, acardiac twin’s upper body does not develop, but the lower extremities develop normally. In rare cases, the acardiac fetus has morphologies ranging from an amorphous mass to recognizable body shapes.

The normal twin is put at risk for high-output heart failure and hydrops as it has to maintain blood flow throughout the entire placenta as well as to the acardiac twin. The vascular flow in the acardiac twin is characteristically reversed. The natural history of TRAP is greater than a 50% mortality in the pump twin due to hydrops. ^, The risk of hydrops increases as the mass of the acardiac twin increases relative to the normal twin. Generally, intervention is needed when there is evidence of hydrops in the pump twin, or when the estimated fetal weight of the acardiac twin is 50% or more relative to the twin functioning as the pump.

Multiple approaches have been used to separate the vascular connections in TRAP pregnancies: open hysterotomy and delivery, fetoscopic ligation, bipolar cautery, harmonic scalpel division, thermal coagulation, and laser coagulation. RFA is commonly used to coagulate the umbilical cord insertion site on the acardiac twin’s abdomen. ^, RFA was originally designed for ablation of solid tumors, but its small size and effective coagulation has been ideal for the treatment of TRAP. One study described 29 patients who underwent RFA between 18 and 24 weeks of gestation. Survival was 92% overall. A recent report suggests that RFA may be effective beginning at 12 weeks of gestation. The therapeutic use of interfetal laser in the TRAP sequence has also been recently studied and shown to have a neonatal survival rate comparable with intrafetal RFA; however, the incidence of PROM before 32 weeks gestation was significantly higher.

Nearly 50% of all monochorionic twin gestations will be complicated. Although TTTS is the most common complication, it occurs in only 10%–20% of all monochorionic twin pregnancies. Thus, the clinician should be aware of other complications that can be confused with TTTS.

Unequal placental sharing occurs because there is no predetermined organization for each umbilical cord insertion to ensure that each twin has an equal share of the placenta. When one of the twins has an eccentric cord insertion, their growth can be adversely affected when their demand exceeds what their share of the placenta can provide. This results in intrauterine growth restriction (IUGR) and eventual growth discordance between the twins (defined as discordant weights >20%). In fact, the growth-restricted twin can develop oligohydramnios raising the suspicion for TTTS, but the distinction is that the normal twin will have normal amniotic fluid volume. The growth-restricted twin can become distressed leading to preterm labor and extreme prematurity, which can also adversely affect the normal twin. Another scenario is IUFD. When this occurs, there can be transient shunting with hypotension in the surviving twin that can lead to permanent neurologic injury in 20%–40% of cases.

Monochorionic pregnancies require close monitoring to ensure there is no evidence of TTTS and that growth is appropriate. In cases with severe IUGR, selective RFA of the growth-restricted twin has been offered to protect the normal twin. One study reports survival of the normal twin to be 87% without any adverse neurologic outcomes. However, one factor to consider is that up to 20% of monochorionic diamniotic pregnancies treated with selective RFA may be complicated by CMS, and 30% may develop iatrogenic PROM. ^,

The corollary to unequal sharing is polyhydramnios affecting a recipient-like twin (PART). In this condition, one of the twins has polyhydramnios, which can raise a concern for TTTS. However, the other twin does not have oligohydramnios and therefore does not meet criteria for TTTS. Pregnancies affected by PART require close surveillance. Currently, there is no fetal intervention recommended for PART, but underlying causes for the polyhydramnios should be sought and treated as needed.

The North American Fetal Therapy Network has outlined the following recommendations for optimal monitoring of uncomplicated monochorionic pregnancies in order to ensure early detection of any complications and secure positive outcomes. First, chorionicity (the number of chorions in the placenta that supply the developing fetuses) should be determined as early as possible, and antenatal screening with US should be initiated at 16 weeks. Anatomical survey and fetal echocardiogram should be conducted between 18 and 22 weeks of gestation, and serial US examinations should be repeated biweekly. Each US should include each fetus’s maximum vertical amniotic fluid pocket and bladder status, with the option of middle cerebral artery peak systolic velocity. Fetal growth should be examined every 4 weeks via serial US, and individual twin identities should be upheld throughout pregnancy and delivery. Lastly, delivery should be considered between 36 0/7 weeks and 37 6/7 weeks.

Currently, less-invasive methods for the treatment of MMC are being pursued to minimize fetal and maternal morbidity. One promising area may be fetoscopic coverage of the defect for temporary intrauterine protection, followed by definitive closure postnatally. The fetoscopic MMC repair technique was initially reported in 2003 by Farmer et al., although outcomes of the study suggested that endoscopic repair was unfavorable at that time compared with hysterotomy in terms of fetal morbidity and mortality. However, fetoscopic methods have been refined in the last 20 years, despite a temporary cessation of minimally invasive repairs in the United States during the MOMS trial.

Currently, investigators have not reached a consensus as to whether fetoscopic MMC repair results in superior neonatal, obstetric, and neurodevelopmental outcomes when compared with maternal laparotomy and hysterotomy. Supporters of the minimally invasive technique argue that fetoscopy could decrease the obstetric complications typically seen with open repairs and lower fetal mortality. Reduction in maternal morbidity includes the potential for future vaginal delivery and a decrease in long-term obstetric risks. However, others believe that intrauterine endoscopy is still too significantly associated with PROM, amniotic fluid leakage, prematurity, and longer operative times to be feasibly implemented on a widespread scale as the technique currently stands. A lack of neurodevelopmental data leaves a question mark when considering the long-term neurologic and cognitive effects of fetoscopic repair.

Aside from PROM and correlated prematurity, perhaps the biggest hurdle to overcome before fetoscopy can become a widely practiced MMC repair approach is the issue of a water-tight defect closure, considered important for ensuring protection from amniotic fluid and cerebrospinal fluid (CSF) leakage. ^, The lack of a water-tight seal may prevent effective reversal of the hindbrain herniation, and can necessitate subsequent postnatal repair. ^, One possible method by which a sufficient seal may be consistently obtained is through the application of a patch over the defect, as opposed to the layered-closure approach. Multiple studies thus far have indicated that fetoscopic patching with amniotic membrane, Gore-polytetrafluoroethylene, Duragen, and silastic patches, among others, is an effective means of closure. ^{, ,} Advancement of various surgical glues and bioengineering techniques will likely contribute further to the feasibility of water-tight intrauterine endoscopic MMC closure in the future.

Currently, the data to support a fetoscopic approach remains mixed. Due to small samples and lack of information regarding long-term neurodevelopmental outcomes, fetoscopic fetal MMC repair is recommended in an IRB-approved investigational setting at an institution with an appropriate level of expertise, resources, and research oversight. A novel fetoscopic based trial utilizing cryopreserved human umbilical cord as a patch is currently underway at the University of Texas Health Science Center at Houston (UT–Houston).

The group at the UT Houston sought alternative methods of closure utilizing cryopreserved human umbilical cord (HUC) as a skin patch for the fetal MMC repair when primary closure is not possible (e.g., in large defects such as myeloschisis without a sac). HUC has been used in ovine MMC models with regeneration of the epidermal, dermal, and subcutaneous tissue layers; reversal of hindbrain herniation; and preserved neurologic function. ^, Experimental lamb fetuses that underwent HUC repair were compared with two unrepaired lambs. HUC patch animals demonstrated improved neurologic outcome, superior nociception, increased bladder control, and reversal of hindbrain herniation. Excellent results from HUC patch repair in animals in promoting healing of the repaired site in the fetal lamb and reversal of hindbrain herniation prompted investigative studies in humans.

Based on these preclinical studies, in utero spina bifida repair was performed using HUC as a skin patch for large defects. In the two initial cases, myeloschisis-type lesions were repaired with primary dural closure with subsequently mobilization of circumferential skin flaps. An HUC patch was used to provide skin-level, tension-free closure utilizing 6–0 Monocryl suture. The approach demonstrated watertight closure, reversal of the hindbrain herniation, and minimal tethering at birth. Although the HUC patches demonstrated in-growth and healing at the skin edges, there was failure of complete epithelialization of the patch during the pregnancy. Both patients delivered during the 37th week of gestation (approximately 12–13 weeks in utero from the time of repair). With postnatal wound care, complete epithelialization was achieved approximately 3–4 weeks postnatally. These findings have been consistent with subsequent cases at this center. As a result of these positive findings, researchers at UT–Houston are conducting a clinical trial for the utilization of HUC for repair of spina bifida with a fetoscopic approach (Clinical Trials ID NCT04243889). The application of a cryopreserved HUC patch is a novel method for spina bifida repair.

Lastly, cell-based therapies are becoming important to fetal MMC repair. Investigators are now testing various stem cell techniques in animal models, and results thus far have been promising. Researchers at the University of California, Davis (UCD) have conducted cell-based MMC studies utilizing placenta-derived mesenchymal stem cells (PMSCs) to repair surgically created MMC in ovine models. They have conducted 9 years of preclinical research, testing different stem cell types and repair scaffolds, culminating in the discovery that treatment with early gestation PMSCs seeded on a clinical grade extracellular matrix (ECM) during in utero repair of MMC functionally cures paralysis in a rigorous fetal ovine model in over 50 lambs, resulting in 75% improvement over standard in utero repair ( Fig. 9.5 ). The team is currently conducting an FDA-approved first-in-human clinical trial, the CuRe trial (Clinical Trials ID NCT04652908). There are innovative studies at both Boston Children’s Hospital and CHOP that have demonstrated that techniques such as transamniotic stem cell therapy (TRASCET) and sponges with basic fibroblast growth factor (bFGF) can initiate total or incomplete coverage of the MMC defect in animal models.

Photograph of twin lambs from the same gestation. Lamb # 1 treated with ECM only had minimal hindlimb joint movements, whereas lamb # 2 treated with PMSC-ECM ambulated independently and cleared an obstacle.

The positive results from the MOMS trial have resulted in greater accessibility and proliferation of fetal surgery for MMC in the United States despite limited data of long-term outcomes. Whereas 97 fetal surgeries were performed during the MOMS trial over a 7-year period, the CHOP group performed 100 cases in the subsequent 4 years after the trial. According to data from the North American Fetal Therapy Network (NAFTNet), over 15 centers have performed fetal surgery for MMC. This widespread adoption has prompted the development of guidelines for practice and counseling. In a Committee Opinion by the American College of Obstetrics and Gynecology and Society of Maternal Fetal Medicine with endorsement from NAFNet, the authors concluded that open maternal-fetal surgery for MMC repair is a major procedure for the woman and her affected fetus. Although there is demonstrated potential for fetal and child benefit, there are significant maternal implications and complications that may occur acutely, postoperatively, for the duration of the pregnancy, and in subsequent pregnancies. Maternal-fetal surgery for MMC repair should only be offered to carefully selected patients at facilities with the appropriate level of personnel and resources necessary to care for both patients.