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Ultrasound Guided Fetal Intervention

Prenatal diagnosis has become increasingly sophisticated, and technological advances have enhanced not only our diagnostic abilities but also our understanding of the natural history of lesions detected in the prenatal period. Invasive therapies have developed as a consequence of our expanded understanding of the natural history and pathophysiology of structural anomalies. Today, there are many fetal interventions for a broad range of conditions that provide families with more alternatives, including ultrasound-guided procedures. 

For Medical Professionals

The most common indications for intrauterine transfusion (IUT) for severe anemia are due to Rh(D) alloimmunization, non-Rh(D) alloimmunization, parvovirus B19, and homozygous alpha thalassemia (Moise 2018). The use of prophylactic Rh(D) immune globulin (Rhogam) has dramatically reduced the need for IUT. The indications for treatment vary from center to center but include severe anemia as indicated by fetal middle cerebral artery peak systolic velocity of >1.5 MoM which would be an indication for fetal blood sampling. A fetal hemoglobin > 2 standard deviations below the mean for the gestational age of the fetus would indicate at least moderate anemia. There may be better outcomes if IUT is performed prior to the development of severe anemia.

Due to technical factors, IUT is only recommended between 18 and 35 weeks gestation. Earlier than 18 weeks has proven challenging due to the small size of the target structures while delivery after 35 weeks may be safer than an another IUT.

Safe options for the approach to IUT include intravascular (IV) and intra-peritoneal (IP) transfusions. The IP approach may provide slower absorption over time than IV transfusion. But IP transfusion is contraindicated if there is ascites present which may limit red blood cell absorption from the peritoneal cavity. Harmon et al., compared outcomes with IUT in hydropic and non-hydropic fetuses matched for severity, placental location, and gestational age at first transfusion and found that the IV approach nearly doubled the survival rate in the hydropic fetuses and increased survival in the non-hydropic fetuses 13% over those treated by IP approach (Harmon et al).

An intravascular approach can be performed by intra-cardiac injection, umbilical vein injection at the placental cord insertion, or in the intrahepatic portion of the umbilical vein. Because of the risks and complications associated with the intra-cardiac approach, it is rarely used (Westgren et al 1988).

Most centers in the US use the placental cord insertion as it provides a stationary target and the umbilical vein puncture has a lower rate of fetal bradycardia compared to the umbilical artery. Free-floating loops of the cord may be used when access to the placental cord insertion is blocked by the fetal position. European centers more commonly use the intrahepatic portion of the umbilical vein as there is a lower incidence of fetal bradycardia and any bleeding that occurs from the puncture site can be reabsorbed from the peritoneal cavity (Nicolaides et al 1988, 1990).

Moise et. al., have recommended using gestational age-appropriate hemoglobin level targets due to the hemodynamic stress of IUT, particularly in fetuses < 24 weeks’ (Moise etal 1990). In fetuses, <24 weeks’ a hemoglobin target of < 25% or <4 fold increase in the pre-IUT value (Forestier et al 1991) with a second transfusion within 24 hours to bring the hemoglobin within the normal range. Later in gestation, the hematocrit target is 40 to 50% (Moise 2015). Because viscosity increases with polycythemia and may cause serious complications, hematocrits over 50% should be avoided (Dildy et al 19991, Drew et al 1997).

Moise has suggested subsequent transfusions in 10 days, 14 days, and 21 days after the first, second, and third transfusions, respectively (Moise et al 2018). Because the IUT will suppress fetal hematopoiesis and the adult donor RBCs are not at risk for hemolysis, after 3 transfusions most of the circulating RBCs are from the adult donor. An estimate of 1% fall per day in hematocrit allows an estimate of when a subsequent IUT may be necessary (Moise 2018).

There are several methods to estimate the volume of blood to be transfused. Madelbrot et. al., proposed using volume transfused in ml= volume of fetoplacental unit (ml) X (final-initial hematocrit) divided by the hematocrit of the transfused blood, usually assumed to be ~75%. Another formula uses a series of coefficients for increasing the hematocrit by a specific amount. In order to increase the hematocrit of an 800gm fetus from 20 to 37%, one would multiply 0.037 by 800 to obtain a volume of 30ml (Gianina et al 1998).

Expected survival in treating severe anemia due to alloimmunization with IUT will vary from center to center but rates ranging from 83 to 90% have been reported (Lindenburg et al 2013, Schumacher et al 1996). The survival will be affected by the number of cases of hydropic fetuses in the treated cohort and the frequency of presentation prior to 20 weeks’ gestation (Lindenburg et al 2013, Poissonier et al 2003, Yinon et al 2010).

Lindenburg et al reported the results of the long-term follow-up after intrauterine transfusion (LOTUS study) which evaluated the incidence and risk factors for neurodevelopmental impairment following IUT for hemolytic disease of the fetus and newborn in 291 cases (Lindenburg et al 2012). In this cohort of 291 children, alloimmunization was due to Rh(D) in 85% and 26% of cases were hydropic when treatment started. The mean gestational age at first transfusion was 26 weeks and the mean number of transfusions was 3.

The incidence of severe neurodevelopmental delay was not significantly different from the general population (3.1% vs2.3%), but the incidence of cerebral palsy was higher than observed in the general population (2.1% vs 0.2 to 0.2 depending on gestational age. In general however, 94% of survivors treated by IUT would be expected to have a normal neurologic outcome (Moise et al 2012). In multivariate regression analysis only severe hydrops was found to be independently associated with neurodevelopmental impairment (Moise et al 2012).

It is not uncommon on routine third trimester ultrasound to diagnose cystic masses in the female fetal abdomen. Ovarian cysts are one of the most common cystic abdominal masses in the fetus and the newborn. They are typically small follicular cysts due to maternal hormonal stimulation and are rarely clinically significant and usually regress spontaneously (Kirkinen and Jouppila, 1985). The prenatal diagnosis of an ovarian cyst should be considered in any female fetus with a cystic mass. Although they can be mistaken for mesenteric cysts, duplication cysts, adrenal cysts, urachal cysts, renal cysts or choledochal cysts, ovarian cysts are usually simple abdominal cysts that have a peak incidence during the third trimester and usually disappear shortly after delivery.

The importance of diagnosing a fetal ovarian cyst is distinguishing them from other etiologies which may require postnatal intervention such as choledochal cysts, duplication cysts, and mesenteric cysts. Occasionally, these cysts require surgery for complications due to size, rupture, or torsion (Kurjak et al., 1984; Kirkinen and Jouppila, 1985). Ovarian cysts which expand rapidly (> 1cm/week in diameter), are noted to wander about the abdomen, or are >5 cm in diameter are at particularly increased risk for torsion and infarction and can result in complications which require laparotomy after delivery. Once an ovarian cyst becomes symptomatic, salvage of the ovary is less likely.

Other cystic structures can usually be distinguished from ovarian cysts by a combination of ultrasound and MRI. Duplication cysts are characterized by an echogenic inner stripe which is unique to enteric duplications and is due to the enteric epithelial lining. Duplication cysts are intimately associated with the bowel wall and can occur anywhere from the esophagus to the rectum. Choledochal cysts are fixed in the right upper quadrant and are distinguished by their intimate association with the hepatic artery and portal vein which is typically on the back wall of the choledochal cyst. Similarly, renal cysts are intimately associated with the renal parenchyma. Mesenteric cysts may be difficult to distinguish from ovarian cysts but the presence of multiple septae would favor a diagnosis of a mesenteric cyst.

Ovarian cysts tend to be anechoic unilocular cysts and only develop a complex inner structure after undergoing torsion and hemorrhage. If first observed after undergoing torsion it may not be possible to distinguish a torsed ovarian cyst from an ovarian teratoma. An ovarian cyst with a diameter of > 2 cm is considered abnormal. A finding which is thought to be pathognomonic of ovarian cyst is the presence of the “daughter cyst” sign in which a small round anechoic structure is seen within the cyst (Lee et al 2000, Quarello et al 2003). In a series of cystic lesions in neonates, infants and children 8 of 11 ovarian cysts had a “daughter cyst” sign (16).

Ovarian cyst aspiration can be both diagnostic and therapeutic. Cyst tap revealing high levels of prostaglandin F21, progesterone, and testosterone in the fluid confirms the diagnosis of ovarian cyst. Valenti et al. were the first to perform cyst decompression in utero, in 1975. A large (7 by 9 cm) ovarian cyst was aspirated to prevent intrapartum cyst rupture. Landrum et al. (1986) reported fetal ovarian cyst aspiration ostensibly to prevent pulmonary hypoplasia. While pulmonary hypoplasia from an abdominal mass is unlikely, aspiration to prevent in utero rupture or torsion and to preserve ovarian tissue is a more appropriate indication for treatment. Holzgreve et al. (1993) have reported their experience with 13 cases of fetal ovarian cysts.

This group recommends ovarian cyst decompression if the cyst is large, rapidly increasing in size, or observed to be a “wandering mass” as cysts exhibiting these features are more likely to undergo torsion. Giorlandino et al. (1990) have reported a case of ovarian cyst treated by cyst aspiration and sclerosis with tetracycline. While this treatment was successful, the use of tetracycline as a sclerosing agent in the fetus is not advised.

This group has subsequently reported success in four cases of simple cyst aspiration (Giorlandino et al., 1993). Similarly, D’Addario (1990) aspirated ovarian cysts in two fetuses, but neonatal surgery was still needed. Crombleholme et al. have suggested criteria for intervention in fetal ovarian cysts with diameters of >4 cm, increasing 1 cm per week in size, or as Holzgreve suggested, noted to wander about the abdomen (Crombleholme et al., 1997). Although fetal ovarian cyst decompression seems a relatively benign procedure with the potential for ovarian preservation, the indications for fetal intervention are not uniformly accepted.

Cameron et al were the first to report ultrasound-guided amnioinfusion to treat oligohydramnios secondary to fetal renal agenesis (Cameron et al 1984). The 10 amnioinfusions were performed with the baby delivering at 33 weeks’ gestation. Despite allowing lung development, the baby died on the day of life 23 and had significant cerebral pathology on postmortem examination.

More recently, Bienstock et al successfully treated a fetus with bilateral renal agenesis with serial amnioinfusion resulting in delivery at 32 weeks gestation. The baby not only survived but went on to successful kidney transplantation. There have been numerous anectdotal reports of amnioinfusion to treat fetal renal failure, however, repeated needle puncture of the amnion, often two to three times a week to maintain amniotic fluid dynamics, inevitably results in preterm premature rupture of membranes predisposing to chorioamnionitis.

Dr. Crombleholme developed the amnioport concept to eliminate the need for repeated needle puncture of the amnion allowing the port to be accessed percutaneously without violating the amnion (Polzin et al). We reported outcomes in 8 mothers who underwent amnioport placement. Amniotic fluid was restored in all 8 patients. There were two deaths, one due to unrecognized laryngeal atresia and the other due to PPROM with persistent in oligohydramnios and pulmonary hypoplasia.

Three with fetal renal failure due to an underlying diagnosis of fetal bladder outlet obstruction caused by posterior urethral valves survived infancy and went on to successful renal transplantation at 12, 22, and 24 months, respectively. The remaining three infants with renal parenchymal malformations died on day of life 1, 9, and 94, respectively.

Amnioinfusion for fetal renal failure is an unproven therapy which may or may not improve survival or neonatal outcomes. This fetal intervention commits the family to a course of neonatal continuous peritoneal dialysis with the hope of getting the baby to renal transplantation. We emphasize that this is an extraordinary undertaking for any family and we routinely have families meet with Neonatology, Pediatric Nephrology, Pediatric Urology, Transplanation, and a Psychologist to be sure that famliles have been adequately counseled about the hazards of taking this course.

We limit amnioport placement to healthy mothers, who are less than 22 weeks’ gestation who have not had longstanding anhydramnnios. The family must be willing to relocate to Hartford for postnatal care. When the baby is stable on peritoneal dialysis they may be transitioned to a hospital closer to home. The family must live in a community with advanced Neonatal care and Pediatric Nephrology that can accommodate neonatal dialysis even in premature infants.

Bronchopulmonary sequestrations (BPS) and hybrid congenital pulmonary airway malformations (CPAM) are characterized by a systemic vascular blood supply. These nonfunctional lung masses may grow significantly causing mass effect in the fetal chest and hydrops with a high attendant mortality (Witlox et al 2011, Khalek et al 2013, Davenport et al 2004, Raychaudhuri et al 2011, Bunkuki et al 2000, Baud et al 2013). Occlusion of the vascular supply to the BPS has been reported using ultrasound-guided interstitial laser photocoagulation (Ruano et al 2012).

A total of 25 cases of interstitial laser photocoagulation have been reported: 17 for BPS and 8 for CPAM (Cavoretto et al 2008, Davenport et al 2004, Baud et al 2013, Fortunato et al1997, Bruner et al 2000, Ong et al 2006, Oepkes et al 2007, Ruano 2007, Witlox et al 2009, Rammos et al 2010). These procedures were performed under fetal anesthesia (fentanyl 15 micrograms/kg) and paralysis (pancuronium 2 mg/kg). Either a 400 or 600 micron laser endostate was passed through an 18 gauge needle placed into the vessel within the BPS or CPAM. In these cases a Nd-YAG laser (15 to 50 Watts) was used. Persistence or recurrence of blood flow to the BPS occurred in 13 (52%) and a second procedure was performed in 7 (28%). There were three fetal deaths (12%), four neonatal deaths (16%) and 18 live births (72%).

The survival rate for interstitial laser was significantly better when used for BPS in which 16 of 17 survived (94%) versus in CPAMs in which only 2 of 8 survived (25%). It should be noted that in the case of CPAM, the interstitial treatment was of the mass itself and not just coagulation of the systemic feeding vessel. This treatment of CPAMs was uniformly unsuccessful and in at least one case destroyed the entire chest wall and the baby died of pulmonary hypoplasia (Bruner et al 2000). In BPS, interstitial laser was often indicated to treat the BPS which had resulted in tension hydrothorax from torsion of the extralobar BPS. Once the systemic feeding vessel had been photocoagulated the needle could be withdrawn into the pleural effusion to aspirate the hydrothorax. In this approach, thoraco-amniotic shunting may be avoided as ablation of the systemic feeding vessel prevents recurrence of fetal hydrothorax and the effusion does not recur.

Interstitial laser photocoagulation has also been applied in the treatment of 9 cases of hydropic sacrococcygeal teratoma (SCT) (VanMieghem et al 2014, Makin et al 2004, Hecher et al 1996, Ruano et al 2009, Ding et al 2010). The rationale for interstitial laser treatment of SCT is that the hyper-vascular SCT results in arterio-venous shunting through the mass with cardiac overload from high output failure resulting in hydrops and placental steal.

Photocoagulation of vessels feeding the SCT will temporarily reduce blood flow to the tumor, however re-treatment will be necessary as other collateral vessels will become parasitized by the SCT and the high output state will recur. Two cases developed PPROM and all 8 delivered prior to 32 weeks’ gestation. Fetal demise (n=4) and neonatal demise (n=2) occurred in 6 of the 10 treated SCTs with an overall survival of only 4 of 10.

Temporizing treatment of the SCT by repeated ultrasound guided interstitial laser photocoaguation may reverse the hydrops caused by high output cardiac failure if the arteriovenous shunting through the SCT can be reduced. Even if additional shunting occurs through subsequent formation of new arteriovenous shunts this approach may buy significant amount of time and allow the pregnancy to get further along. Most SCTs get into trouble with hydrops between 23 and 27 weeks’ and any additional time in utero may reduce complications related to prematurity.

Twin reversed arterial perfusion sequence (TRAP) is one of the most common indication for the use of ultrasound guided intrafetal radiofrequency ablation (RFA). Other indications include selective reduction in the setting of monochorionic twins in which a lethal anomaly in one twin threatens the life or the neurologic integrity of the normal co-twin or in twin-twin transfusion syndrome (TTTS) in which the monochorionic twins are poor candidates for selective fetoscopic laser treatment such as in “double barrel” placental cord insertion which does not have a clear vascular equator or a hydropic recipient with severe biventricular dysfunction and pulmonic valve atresia in which survival is extremely poor. In these cases, RFA may offer a less invasive approach to treatment with better co-twin survival.

There have been numerous techniques reported to treat TRAP sequence from injecting thrombogenic coils or alcohol soaked silk to fetoscopic cord ligation or bipoloar cautery. But no approach has been as successful as ultrasound guided intrafetal RFA. This procedure is quite minimally invasive and usually performed with a 17gauge Super Slim Leveen needle on an outpatient basis. This approach was first reported in a small series by Lee et al, with a 91% survival rate (Lee 2004).

We reported a series of 26 cases of TRAP treated with RFA with a 95% survival rate and an average gestational age at delivery of 36 weeks’(Livingston). We subsequently have reported a series of 54 cases of TRAP sequence (all with an acardius to pump twin ratio >0.7, evidence of increased combined ventricular output, or polyhydramnios in the pump twin) treated by RFA with a 97.3% survival and an average gestational age at delivery of 36.5 weeks’.

The results with RFA for TRAP sequence have not been replicated when this technique has been applied to the treatment of TTTS or in monochorionic twins with an anomalous co-twin. In these cases the survival rates of the co-twin has ranged from 70 to 80% . The reason for this poorer outcome is not known, but may be related to the higher blood flow in the cords of these twins compared to that in cord of the acardius in TRAP sequence. In TRAP sequence the blood flow in the umbilical artery is reversed and sluggish which may make it more susceptible to coagulation by RFA. In contrast, the higher blood flow in TTTS twins or monochorionic twins with an anomalous co-twin the blood flow in the umbilical cord is higher and this will dissipate the heat generated by RFA and make coagulation less efficient.

Radiofrequency ablation (RFA) has been used to devascularize SCTs with devastating results because the thermal energy cannot be precisely controlled and in at least one case resulted in ischemic necrosis of rectum, bladder, vagina, sciatic nerve, and is now considered a contraindicated for the treatment of SCT.

Fetal Shunting Procedures

A new era in invasive fetal therapy began in the early 1980s, when several independent groups introduced shunting procedures for hydrocephalus and hydronephrosis (Clewell et al., 1982; Frigoletto et al., 1982; Golbus et al., 1982). These first few cases represented an extension of invasive fetal therapy from simple intrauterine blood transfusion for a medical illness to the first attempts at in utero treatment of structural anomalies.

During this period, hydronephrosis and hydrocephalus were being recognized more frequently with ultrasound examination. The prenatal natural history of these lesions was established by serial sonographic observation of untreated cases (Chervenak et al., 1984; Glick et al., 1984a,b; Clewell et al., 1985; Nakayama et al., 1986; Crombleholme et al., 1988b; Cendron et al., 1994). Fetuses with high-grade obstructive uropathy followed to term were often born with advanced hydronephrosis, type IV cystic dysplasia, and pulmonary hypoplasia that were incompatible with life (Potter, 1976; Crombleholme et al., 1988b; Cendron et al., 1994). In the case of obstructive hydrocephalus, it was known that shunting during the newborn period improved neurologic outcome, and it was reasoned that decompression in utero might avert progressive brain damage (Lawrence and Coates, 1962; Lorber, 1969; Young et al., 1973). However, the poor outcomes observed with shunting for hydrocephalus resulted in a moratorium on the use of shunts in the treatment of obstructive hydrocephalus (Clewell, 1991). In other conditions, work in appropriate animal models helped to define the pathophysiology of these lesions and establish the theoretical basis for intervention (Adzick et al., 1970; Harrison et al., 1982d, 1983; Glick et al., 1983, 1984a, 1984b).

The first case of a fetus with obstructive uropathy treated in utero by vesicoamniotic shunting was reported by Golbus et al. in 1982. Advances soon followed in diagnosis, technique, shunt design, and patient selection (Rodeck et al., 1988; Crombleholme et al., 1988a, 1991a; Harrison and Filly, 1991; Crombleholme, 1994; Johnson et al., 1995). The enthusiasm for treating fetal obstructive uropathy has continued unabated during the past two decades. The procedure became widely implemented before stringent selection criteria for treatment were developed and the therapeutic efficacy of the procedure was established. The widespread use of vesicoamniotic shunts also had the effects of shifting cases away from the centers studying vesicoamniotic shunts to better define their role in the management of fetal obstructive uropathy.

The lack of a prospective randomized trial makes it difficult to address the efficacy of prenatal decompression of fetal obstructive uropathy. One of the few series that attempted to address this question, was a retrospective analysis reported by Crombleholme et al. (1991a). In fetuses predicted to have either good or poor prognoses by fetal urine electrolyte and ultrasound criteria, survival was greater among those who underwent decompression in utero, as opposed to those who did not undergo decompression.

In the group of fetuses predicted to have a poor prognosis by selection criteria, 10 were treated; three of these pregnancies were electively terminated, 4 neonates died from pulmonary hypoplasia or renal dysplasia, and 3 survived. All three survivors had restoration of normal amniotic fluid (AF) levels and no pulmonary complications, but two of the three subsequently developed renal failure requiring renal transplantation. Among the 14 patients with no intervention, there were no survivors (11 terminations and 3 neonatal deaths from pulmonary hypoplasia). In the entire series, uncorrected oligohydramnios was associated with a 100% neonatal mortality rate. Normal or restored AF volume was associated with a 94% survival rate (Crombleholme et al., 1991a).

Although in utero decompression seems to prevent neonatal death from pulmonary hypoplasia, the effect on renal function is less clear. The severity of renal dysplasia at birth depends on the timing and severity of obstruction before birth (Harrison et al., 1981a,b, 1982a,c, 1987, 1990; Manning et al., 1986; Crombleholme et al., 1988b, 1991a). Experimental work suggests that relief of obstruction during the most active phase of nephrogenesis (20–30 weeks of gestation) may obviate further damage and allow normal nephrogenesis to proceed (Adzick et al., 1970; Beck, 1971; Harrison et al., 1982a, 1987; Glick et al., 1984a,b; Gonzalez et al., 1985; Salinas-Madrigal et al., 1988; Peters et al., 1991).

The development of postnatal renal failure in two infants who were not treated because AF volume remained normal raises the question of whether to treat fetuses with obstruction before oligohydramnios develops. Because renal development or maldevelopment is complete at birth, relief of obstruction in infancy or childhood may not prevent the progression to end-stage renal failure (Warshaw et al., 1982). Müller et al. (1993) reported on a group of fetuses with obstructive uropathy, a favorable prognostic profile, and normal AF in whom renal insufficiency developed by 1 year of age. The only feature that distinguished this group of fetuses was a urinary level of β2-microglobulin greater than 2 mg per liter suggesting that elevated fetal urinary levels of β2-microglobulin may identify fetuses at increased risk for ongoing renal damage from obstruction, even if AF is normal.

Other investigators have not found β2-microglobulin levels to be as useful, although levels greater than 10 mg per liter can be a predictor of poor outcome in fetuses over 20 weeks of gestation (Freedman et al., 1997). It remains an open question whether or not in utero decompression could prevent long-term renal insufficiency in these patients. The Harrison vesicoamniotic shunt has a luminal diameter of only 1 mm and is ~12 cm in length. High intra-vesicle pressures must be generated to force fetal urine through this shunt. In most cases of severe bladder outlet obstruction, the ureterovesicle junctions are incompetent. Therefore, intra-vesicle pressures are transmitted ot the kidneys causing ongoing injury to the developing kidneys.

The maternal morbidity associated with vesico-amniotic shunting has been reported to be minimal, but chorioamnionitis related to the procedure has been reported (Glick et al., 1985; Crombleholme et al., 1991a). In addition, there have been reports of shunt-induced abdominal wall defects with herniation of bowel through trochar stab wounds and maternal ascites from leakage of AF through the uterine wall into the maternal peritoneal cavity (Manning et al., 1986; Robichaux et al., 1991; Ronderos-Dumit et al., 1991).

There has only been one prospective randomized trial examining the efficacy of vesico-amniotic shunts compared to conservative management called the percutaneous vescioamniotic shunting vs conservative management for fetal lower urinary tract obstruction (PLUTO) trial (Morris et al 2013). This trial was stopped early due to poor recruitment. Despite this, there appears to be a survival benefit among those undergoing vescio-amniotic shunting.

This effect was significant when analysis was based on treatment received. However, the chances of survival with normal long-term postnatal renal function was low and were observed only in two pateints undergoing vesico-amniotic shunting. All deaths in the conservatively managed group wer due to pulmonary hypoplasia. The findings of the PLUTO trial suggest that while vesico-amniotic shunting may improve survival by restoring amniotic fluid dynamics it may do nothing to improve renal outcomes.

The utility of vesicoamniotic shunts is limited by the brief duration of decompression, the risk of infection, the risk of catheter obstruction or dislodgment, fetal injury during placement, and potentially inadequate decompression of the fetal urinary tract (Glick et al., 1985; Crombleholme et al., 1988a, 1991a; Estes and Harrison, 1993).

These factors make vesicoamniotic shunts less effective when placed early in gestation for long-term decompression of the urinary tract and are the impetus for development of open fetal surgical and fetoscopic techniques to treat obstructive uropathy in utero (Crombleholme et al., 1988a; Estes and Harrison, 1993; Crombleholme and Lim, in press).

Thoracentesis should be considered a diagnostic maneuver to obtain pleural fluid for differential cell count and culture and to establish whether the effusion is primary or secondary. The primary role of fetal thoracentesis is obtaining fluid for cell count and differential. A lymphocyte count of >90% (some authors have used >80%) is consistent with a diagnosis of primary fetal hydrothorax or chylothorax. Cells counts less than this cut off are considered secondary fetal hydrothorax and may be part of generalized non-immune hydrops or manifestation of a viral infection.

The presence of atypical lymphocytes is sometimes a clue to the presence of viral infection. The importance of distinguishing primary from secondary fetal hydrothorax is that primary fetal hydrothorax is far more likely to respond to thoraco-amniotic shunting. In some cases after thoracentesis alone, the pleural effusion may not recur and in this setting is therapeutic. But even repeated thoracentesis provides inadequate decompression of the fetal chest.

There have been several reports of thoracentesis for fetal hydrothorax (FHT), performed with either complete resolution or a good outcome despite reaccumulation (Petres et al., 1982; Kurjak et al., 1985; Benacerraf et al., 1989). Others have had disappointing results with repeated thoracentesis for FHT, because of rapid reaccumulation of the effusion and neonatal death from respiratory insufficiency (Longaker et al., 1989; Nicolaides and Azar, 1990). Spontaneous resolution of FHT may occur in as many as 10% of cases, and resolution following thoracentesis may or may not be related to the procedure. Thoracentesis alone cannot adequately decompress the fetal chest to allow pulmonary expansion and prevent pulmonary hypoplasia (Laberge et al., 1991).

Thoracoamniotic shunting for FHT, first reported by Rodeck et al. in 1988, provides continuous decompression of the fetal chest, allowing lung expansion. If instituted early enough, this allows compensatory lung growth and prevents neonatal death from pulmonary hypoplasia.

Nicolaides and Azar (1990) reported 48 cases of thoracoamniotic shunting, but there was no attempt to distinguish isolated primary FHT from secondary FHT. Despite intervention, mortality was high. Four of the deaths were due to termination of pregnancy when a chromosomal abnormality was diagnosed. In addition, there were 12 neonatal deaths despite thoracoamniotic shunt placement, but these fetuses seemed to have severe hydrops and secondary FHT. Two fetuses that died in utero also seemed to have had secondary FHT and severe hydrops. If the cases that appear to be secondary FHT are eliminated, the survival of isolated primary FHT treated with thoracoamniotic shunting is 38 of 41 (92%) cases (Nicolaides and Azar, 1990; Moran et al., 1994).

A similar survival rate with thoracoamniotic shunting was found by Hagay et al. (1993) in their review of fetal pleural effusions. This is a striking improvement when compared with a survival of only 50% in untreated FHT.

The indications for thoracoamniotic shunting are not well defined. Most authors consider the presence of FHT-induced hydrops or polyhydramnios as indications for shunting (Rodeck et al., 1988; Longaker et al., 1989; Nicolaides and Azar, 1990). In addition, we recommend thoracoamniotic shunting for primary FHT with evidence of effusion under tension even in the absence of hydrops (Moran et al., 1994). Because spontaneous resolution has been observed even in severe cases of FHT, we reserve thoracoamniotic shunting for cases in which tension hydrothorax recurs after two thoracenteses.

The limited experience with thoracoamniotic shunting suggests that it is extremely effective in decompressing effusion and improving survival. The risks to mother and fetus of thoracentesis and shunt placement have been minimal and are far outweighed by the potential benefits. Few complications have been reported for either fetal thoracentesis or thoracoamniotic shunts.

Procedure-related fetal death is rare, due to hemorrhage from an intercostal artery laceration or torsion of the umbilical cord (Longaker et al., 1989). Migration of the shunt under the fetal skin has also been reported, but required no intervention when the infant was born (Rodeck et al., 1988). There have been no maternal complications reported with either thoracentesis or thoracoamniotic shunting. However, it should be recognized that these procedures have the potential for significant complications, including infection, bleeding, premature rupture of membranes, preterm labor, and injury to the fetus (Moran et al., 1994).

There are currently two FDA-approved devices available for shunt placement in a broad range of applications including bladder outlet obstruction, pleural effusions, and cyst decompressions in congenital pulmonary airway malformation (CPAM). The Harrison catheter (Cook, Inc., IN) is available in a complete shunt insertion kit that includes not only the polyurethane shunt but also the trocar for insertion, the guide wire over which the double pigtail catheter is threaded and the pusher that deploys the shunt. The advantages of the Harrison catheter include the ease of insertion and the complete kit it comes with. The disadvantage of the Harrison catheter is that it is more easily dislodged.

The alternative catheter is the Rocket or KCH catheter. The Rocket catheter requires a reusable trocar insertion device that is larger and somewhat more difficult to use compared to the Harrison catheter set and the pigtail ends are at 90 degrees to each other so that the external coil sits flush on the fetal skin. The advantage of the Rocket catheter is that it is less likely to be dislodged. The larger size of the Rocket trocar may make this less appealing for chest shunt insertion due to increased difficulty inserting the shunt and increased risk of laceration of the intercostal artery, especially in fetuses at less than 25 weeks’ gestation. The Rocket KCH catheter has been removed from the market and is currently unavailable.

In 1987, Nicolaides et al. reported the first case of CPAM treated by shunt insertion in utero. Decompression of a large type I CCAM in a 20-week-old fetus by percutaneous placement of a thoracoamniotic shunt was subsequently reported by Clark in 1987. This procedure resulted in resolution of both mediastinal shift and hydrops and successful delivery at 37 weeks of gestation. Postnatally, the infant underwent uneventful resection of the CCAM. Wilson et al. (2006) reviewed the CHOP experience with thoracoamniotic shunts for cystic CCAMs demonstrating an average acute 70% reduction in CCAM volume with a 74% survival with thoracoamniotic shunting in the presence of hydrops, polyhydramnios or fetuses at increased risk for developing pulmonary hypoplasia.

This experience is consistent with other reports of CCAMs with a dominant cyst that responded to thoracoamniotic shunt placement (Adzick, 2003, Wilson et al., 2004, 2006). There are however potential procedure-related complications including catheter dislodgment, catheter occlusion from thrombus, fetal hemorrhage, placental abruption, premature rupture of membranes or preterm delivery, and chest wall deformity (Dommergues et al., 1997; Mann et al., 2007; Merchant et al., in press). More commonly, it is the type III CCAM or microcystic lesions, which becomes enlarged, resulting in hydrops and intrauterine fetal death; in these cases, open fetal surgery and resection are indicated. However, in the rare instances in which there is a single large cyst in CCAM responsible for hydrops, thoracoamniotic shunting appears to be an appropriate treatment option.

Fetal Cardiac Interventions

Structural cardiac defects, such as pulmonic atresia with an intact ventricular septum (PAIVS) or severe aortic stenosis (AS), may result in obstruction to blood flow, which in turn alters the development of the heart chambers as well as the pulmonic and systemic vasculature in utero (Vlahakes et al., 1981). The major morbidity from these congenital heart defects often results from the secondary alterations in heart development caused by the primary defect (i.e., hypoplasia of the right ventricle in PAIVS or hypoplastic left heart syndrome [HLHS] in AS). In theory, relief of the anatomic obstruction in utero may allow more normal cardiac development, thereby eliminating the need for corrective surgery postnatally.

AS diagnosed prenatally is frequently associated with intrauterine fetal death or neonatal death in fetuses that survive to term. Maxwell et al. (1991) reported a series of 28 fetuses diagnosed prenatally with AS either alone or associated with endocardial fibroblastosis. Only 12 mothers continued the pregnancy to term, and in 2 there was an intrauterine fetal death. None of the 10 neonates survived despite balloon valvuloplasty in 4 of them.

Maxwell et al. also noted that in four fetuses the left ventricle failed to grow, resulting in hypoplastic left heart, which would make the neonate unsuitable for postnatal aortic valve reconstruction. This grim natural history for fetuses with prenatally detected AS, as well as poor outcomes with Norwood procedure in their institution, prompted Maxwell et al. (1991) to attempt the first in utero aortic balloon valvuloplasty.

This procedure was performed by direct percutaneous puncture of the left ventricle under ultrasound guidance. A J-wire is passed through the stenotic valve, and the balloon catheter is passed over the wire and inflated. All three fetuses treated with this procedure survived to term; two died as neonates and one was doing well to a follow-up of 3 years of age (Maxwell et al., 1991). Two other fetuses were treated unsuccessfully by this technique by another group (Chouri et al., 1994).

More recently, the group at Boston Children’s Hospital reintroduced fetal balloon valvuloplasty in an effort to prevent progression of AS to HLHS (Mäkikallio et al., 2006). In their initial experience with 43 fetuses diagnosed with AS, they retrospectively identified a subset of patients that all progressed to HLHS postnatally. These fetuses all had AS associated with normal LV length, reversed flow in the transverse aortic arch or foramen ovale, and a monophasic mitral inflow pattern.

Several centers soon followed with reports of attempts at fetal aortic valvuloplasty. Although most centers’ experience is quite small, there appears to be a steep learning curve judging from the largest series reported thus far (Tworetzky and Marshall, 2004; Matsui and Gardiner, 2007). “Technical success,” as defined as increased flow across the aortic valve, has been achieved in 75% of cases but only 1/3 of technically successful procedures achieve an eventual biventricular circulation postnatally (Matsui and Gardiner, 2007). This contrast between technical success and postnatal success suggests that current selection criteria do not accurately select fetuses that are likely to respond to balloon valvuloplasty.

As experience has grown with mid-gestation fetal AS with evolving HLHS it has become possible to refine selection criteria for fetal cardiac intervention (McElhinny et al 2010). The goal of fetal aortic valvuloplasty is to alter left heart physiology and growth sufficiently to allow postnatal survival with biventricular circulation. The Boston group developed a scoring system based on prenatal echocardiographic assessment that allows exclusion of patients that had no chance of biventricular outcome (McElhinney et al 2009). Despite refinement in selection criteria and increased experience only ~30% of successful fetal cardiac interventions have biventricular circulation from birth. In virtually all cases, postnatal interventions are required to achieve biventricular outcome.

Wright et al. (1994) have performed radiofrequency pulmonic valvotomy in a fetus with PAIVS. In the most severe forms of PAIVS, the primary valvular lesion causes secondary alteration in the intracardiac flow pattern, resulting in a hypoplastic right ventricle (Casteneda et al., 1994). In these instances, only palliative pulmonary valvotomy and systemic to pulmonary artery shunting can be performed. However, if flow can be reestablished across the pulmonic valve in utero, restoration of intracardiac blood flow may allow subsequent growth of the right ventricle and pulmonary outflow tract.

The indications for fetal balloon valvuloplasty in PAIVS include a cardiovascular profile score of less than 7, decreased biventricular cardiac output, severe pulmonary stenosis and/or elevated RV pressure and/or hydrops (Matsui and Gardiner, 2007). In a 26-week-old fetus with PAIVS, no growth was observed in the right ventricle during 6 weeks of in utero observation. By direct puncture of the right ventricle, a pulmonary valvotomy was performed using a radiofrequency ablation catheter. Although only a minute hole with insignificant flow resulted, this procedure and those reported by Maxwell and Chouri et al. have established the feasibility of in utero treatment of structural heart disease. Although there have been technical successes, the outcomes have not been different from the natural history of PAIVS often due to growth failure of the pulmonic valve annulus (Matsui and Gardiner, 2007; Gardiner, 2008).

These procedures are certainly not without risk. One of Maxwell’s patients died within hours of the procedure and pieces of balloon and guide wire were left within the fetal heart. All three centers have noted pericardial effusions at the conclusion of the procedure that required evacuation. In the series reported by Marshall et al. (2005), in 20 of 26 patients with technically successful procedures, 12 had at least mild regurgitation at the procedure.

In a report from the same group, 45% of 83 fetuses experienced hemodynamic instability (Mizrahi-Arnaud et al., 2007) that was associated with transventricular approach and the development of large hemopericardium. In 31 of the 37, resuscitation medications were used and—in all 37—the hemodynamic stability was restored. However, there were 5 fetal deaths (5 of 63, 8%) within 24 hours of the procedure (Mizrahi-Arnaud et al., 2007). Despite the risk of these procedures, the unfavorable outcomes for the fetuses with these structural heart defects argue in favor of continued efforts at developing safe and effective invasive fetal therapies.

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