Aetna considers serial amnioreduction for twin-to-twin transfusion syndrome medically necessary when criteria are met:
Fetal surgery in-utero has been attempted for various congenital anomalies including congenital diaphragmatic hernia (CDH), spina bifida and urinary tract abnormalities.
Congenital diaphragmatic hernia is a defect in the diaphragm of a developing fetus, which results in abdominal viscera protrusion into the chest, displacing the lungs and heart in the thoracic cavity. Congenital diaphragmatic hernias are usually repaired after delivery; however, 2 primary methods for treating CDH in-utero have emerged in an attempt to overcome pulmonary hypoplasia and persistent pulmonary hypertension in infants who are more severely affected: (i) surgical repair of the herniated diaphragm, and (ii) ligation of the fetal trachea, with subsequent stimulation of lung growth.
Surgical treatment of spina bifida usually occurs within 24 hours of birth; however, in- utero repair has been used as a method to decrease nerve damage and improve outcomes at birth. Lower urinary tract obstruction has a significant impact on neonatal and child health. Pulmonary hyperplasia and renal impairment could be direct or indirect consequences of this condition leading to significant morbidity and mortality. Vesico-amniotic fetal shunting, open fetal surgery and more recently endoscopic fetal surgery for this condition are available as possible options of fetal intervention. Vesico-amniotic shunting has the advantage of bypassing the obstruction, however it is often associated with complications. Open fetal surgery is not usually recommended because of the complications and high fetal loss rate. Endoscopic surgery to visualize and treat the cause of lower urinary tract obstruction has been tried. Fetal endoscopic surgery is in its infancy and endoscopic procedures are limited to a few groups.
Twin-twin transfusion syndrome is the most common complication of monochorionic pregnancies affecting between 5 and 15 % of such pregnancies and accounts for 15 to 77 % of perinatal mortality in twins. Twin-twin transfusion syndrome is believed to occur as the result of uncompensated arteriovenous anastomoses in a monochorionic placenta, which lead to greater net blood flow going to one twin at the expense of the other. No single therapy is associated with a uniformly improved outcome for the involved twins and success is primarily related to gestational age and severity at diagnosis. A variety of therapies have been attempted, but serial therapeutic amniocenteses of the recipient twin's amniotic sac is most frequently used (ACOG, 2005). This therapy is believed to work by favorably changing intraamniotic pressure and, thus, placental intravascular pressure, allowing redistribution of placental blood flow and normalization of amniotic fluid volumes in each sac. More aggressive therapies, which usually are considered only for very early, severe cases, include abolishing the placental anastomoses by endoscopic laser coagulation or selective feticide by umbilical cord occlusion (ACOG, 2005). Clinical studies have shown that, in very early (less than 26 weeks gestation), severe cases of twin-twin transfusion syndrome, selective laser coagulation, when compared to serial amniocentesis, results in improved survival rates in at least one twin, less neurologic morbidity in survivors, and improved gestational age at time of delivery (Senat et al, 2004).
Rossi and D'Addario (2008) reviewed current controversy on laser therapy (LT) versus serial amnioreduction (SA) performed for twin-twin transfusion syndrome (TTTS). A search in PubMed from 1997 to 2007 was performed. Inclusion criteria were diamniotic monochorionic pregnancy, TTTS diagnosed with standard parameters, and peri- and neo-natal outcomes well-defined. Triplets and investigations on other topics of TTTS rather than perinatal outcomes were excluded. A meta-analysis was performed by fixed-effect model (heterogeneity less than 25 %). A total of 10 articles provided 611 cases of TTTS (LT: 70 %; SA: 30 %) and included 4 studies comparing the 2 treatments (395 cases: LT, 58 %; SA, 42 %). Fetuses undergoing LT were more likely to survive than fetuses undergoing SA (overall survival rate: p < 0.0001; odds ratio [OR], 2.04; 95 % confidence interval [CI]: 1.52 to 2.76; neonatal death: p < 0.0001; OR, 0.24; 95 % CI: 0.15 to 0.40; neurologic morbidity: p < 0.0001; OR, 0.20; 95 % CI: 0.12 to 0.33). The authors concluded that this meta-analysis showed that LT is associated with better outcomes than SA.
Szaflik et al (2013) noted that TTTS occurs in 15 % of monochorionic twin pregnancies. Untreated, TTTS has been reported to have a mortality of nearly 100 %. Two main therapies include SA and fetoscopic laser coagulation for the vascular anastomoses. The authors stated that comparison of the 2 treatments showed better outcomes with higher survival rates and minor neurological defects in cases treated with laser coagulation.
An UpToDate review on “Management of twin-twin transfusion syndrome” (Moise and Johnson, 2013) states that “The clinical threshold to begin serial amnioreductions is subjective. Serial amniocentesis to remove excess amniotic fluid in the recipient twin's amniotic cavity results in higher survival rates than expectant management, but not as high as laser photocoagulation. Disadvantages of amnioreduction are that multiple procedures are usually required and complications from the procedure may preclude subsequent treatment by laser photocoagulation of the vascular communications. No more than 5 liters of amniotic fluid should be removed at the time of amnioreduction, and we suggest removing lesser amounts in severe TTTS …. For women with severe (Quintero stage II-IV) TTTS under 26 weeks of gestation, we suggest laser ablation of placental anastomoses rather than serial amnioreduction …. For women with TTTS after 26 weeks of gestation, we suggest serial amnioreduction or septostomy rather than laser therapy (Grade 2C). The upper gestational age limit is due to Food and Drug Administration restrictions on the use of current fetoscopes, as well as technical issues that make laser therapy difficult in the third trimester”.
Twin reversed-arterial-perfusion (TRAP) sequence is a serious complication of monozygotic twin pregnancies, affecting 1% of monozygotic twins, or 1 in 35,000 births (James, 1997). It has been hypothesized that in the presence of artery-to-artery anastomoses in a monozygotic placenta, blood is perfused by the hemodynamically advantaged twin (“donor” or "pump" twin) to the other twin ("recipient" twin) by means of reversed arterial flow (Quintero et al, 1994; van Allen et al, 1984). Inadequate perfusion of the recipient twin is responsible for the development of a characteristic and invariably lethal set of anomalies, including the acardius fetal malformation (acardiac twins) and acephalus. Typically, the pump twin is structurally normal, but it is at risk for in-utero cardiac failure and without treatment dies in 50 to 75 % of cases, particularly if the recipient twin weighs more than half as much as the pump twin (Quintero et al, 1994).
Acardiac twinning is usually recognized by early fetal echocardiography. One approach to management is interruption of the vascular anastomosis between the donor and recipient twin. This is accomplished using endoscopic laser coagulation in pregnancies 24 weeks gestation or ligation of the umbilical cord using endoscopic or sonographic guidance at a greater gestational age (Arias et al, 1998). In a 1998 study of 7 pregnancies treated with laser therapy, the rate of death in the normal twin was 13.6 %, compared to an expected death rate reported in the literature of 50 % in the pump twin when the pregnancy is managed expectantly.
Another approach is the use of radiofrequency ablation to obliterate the blood supply of the acardiac twin. Tsao et al (2002) reported on the results of selective reduction of the abnormal twin in 13 consecutive cases of monochorionic twin gestation with TRAP sequence. The radiofrequency ablation needle was percutaneously inserted through the maternal abdominal wall into the intrauterine fetal abdomen at the level of the cord insertion site of the acardiac twin. The investigators reported that all 13 pump fetuses had been delivered, and that 12 of 13 infants are alive and well. One infant was delivered at 24.4 weeks gestation and subsequently died from complications of prematurity. The investigators reported that the average gestational age at delivery was 36.2 weeks.
Another approach to acardiac twins is expectant management. Although death rates of 50 % in the pump twin have been reported with expectant management of acardiac twins, Sullivan et al (2003) found that outcomes in expectantly managed cases may be better than reported due to increased antenatal diagnosis. Sullivan et al ascertained all cases of antenatally diagnosed acardiac twins delivered in the Salt Lake community between 1994 and 2001. All were managed expectantly. Of the 10 cases were identified, 9 women delivered a healthy pump twin. There was 1 neonatal death. The mean gestational age at delivery was 34.2 weeks. The mean weights of the pump and acardiac twins were 2,279 g and 1,372 g, respectively.
Other congenital anomalies that are amenable to in-utero treatment include myelomeningocele, cystadenomatoid malformation of the lung and saccrococygeal teratoma, shunts for uropathies and thoracic fluids.
In-utero hematopoietic stem cell transplantation is a promising approach for the treatment of a potentially large number of fetuses affected by congenital hematological disorders. Expansion of clinical application will depend on improved understanding of the biological barriers to engraftment in the fetus as well as on the development of effective clinical strategies based on the hematopoietic biology of individual disorders (Hayashi and Flake, 2001).
Findings of recent studies indicated that the effectiveness of in-utero approach in treating CDH has not been established. Downard and Wilson (2003) noted that antenatal maternal steroid administration and fetal surgery are not proven interventions for CDH. Adzick and Kitano (2003) stated that fetuses diagnosed with left CDH before 26 weeks' gestation with associated liver herniation and a low right lung to head circumference ratio have a reduced prognosis with conventional therapy after birth, but in-utero therapeutic approaches have yet to show a comparative survival benefit. Adzik and Kitano stated that a prospective randomized trial is required to critically evaluate the efficacy of fetal tracheal occlusion for severe diaphragmatic hernia. Heerma et al (2003) reported on comparative autopsy in 16 cases of congenital diaphragmatic hernia with fetal intervention (12 cases tracheal occlusion; 4 cases hernia repair) with 19 cases of congenital diaphragmatic hernia without fetal intervention. The investigators concluded that tracheal occlusion did not prevent development of lung pathology associated with pulmonary hypoplasia.
A prospective randomized controlled trial (RCT) of fetal tracheal occlusion for CDH found no differences in outcomes between subjects assigned to fetal endoscopic tracheal occlusion or standard care (Harrison et al, 2003). Enrollment was stopped after 24 women carrying fetuses with severe CDH had been enrolled because of the unexpectedly high survival rate with standard care and the conclusion of the data safety monitoring board that further recruitment would not result in significant differences between the groups. Eight of 11 fetuses (73 % in the tracheal-occlusion group and 10 of 13 (77 %) in the group that received standard care survived to 90 days of age. The authors concluded that tracheal occlusion did not improve survival or morbidity rates in this cohort of fetuses with CDH. In an accompanying editorial, Wenstrom (2003) argued that there are several reasons why antenatal tracheal occlusion may not result in a better outcome than conventional therapy. Wenstrom reasoned that, with new diagnostic technologies, congenital diaphragmatic defects of varying degrees of severity, from mild to severe, are now routinely identified antenatally, and affected neonates receive care at tertiary centers that offer highly specialized treatments for respiratory disease, including extracorporeal membrane oxygenation, high-frequency oscillatory ventilation, inhaled nitric oxide, exogenous surfactant, and others. As a result, the current survival rate for all cases of isolated CDH -- from mild to severe -- approaches 70 % without fetal surgery, and neonates who do not require extracorporeal life support (approximately 50 % of those with isolated CDH) have a survival rate of at least 80 %. Wenstrom argued that another reason why antenatal intervention may not result in a better outcome than conventional therapy is that any potential benefit may be negated by the substantial fetal morbidity associated with the surgical procedure itself. Most pregnancies subjected to antenatal fetal surgery end in preterm delivery. Wenstrom noted that, in the study by Harrison et al, premature rupture of the membranes and preterm delivery occurred in 100 % of those receiving antenatal treatment. The mean age at delivery was 30.8 weeks in the treated group, an age at which morbidity related to prematurity is likely. In addition, because birth occurred, on average, just 6 weeks after the procedure, appropriate catch-up lung growth may not yet have occurred. Wenstrom concluded that “[t]he study by Harrison et al also illustrates the critical importance of randomized clinical trials in evaluating new therapies – even heroic procedures performed in only a small fraction of neonates – before they are adopted as part of standard practice.”
In a RCT, Keller et al (2004) concluded fetal tracheal occlusion for severe CDH resulted in modest improvements in neonatal pulmonary function that, according to the investigators, were of questionable clinical significance.
There is considerable scientific and clinical interest in the potential use of hematopoietic stem cells before birth to treat congenital disease. In theory, stem cell transplantation in utero offers a number of possible advantages. First, intervention in utero will permit "correction" of a disorder before clinical manifestations have developed. Second, because the fetal immune system has not yet developed, it will not reject foreign cells. Unlike bone marrow transplantation after birth, there is no need to match donor cells. The fetus will become "tolerant" to the foreign cells allowing for further treatment after birth, again without the risk of rejection.
Current evidence for in-utero stem cell transplantation comes from animal models and from a small number reported cases of in utero transplantations of unmodified bone marrow progenitor cells in human fetuses involving such disorders as X-linked severe combined immune deficiency and hemoglobinopathies (e.g.,alpha thalassemia, sickle cell anemia and beta thalassemia). Although there is some evidence for success of in- utero stem cell transplantation in X-linked severe combined immunodeficiency syndrome, there is no proven clear advantage over post-natal stem cell transplantation for this indication. Regarding other potential uses, thus far, in utero stem cell transplantation has been unsuccessful in target disorders such as hemoglobinopathies where there is not a selective advantage for donor cells (Muench and Barcena, 2004; Flake, 2004).
Nijagal et al (2012) stated that in utero hematopoietic cell transplantation is a promising strategy for the treatment of common hematopoietic disorders and for inducing immune tolerance in the fetus. Although the effectiveness of in utero hematopoietic cell transplantation has been demonstrated in multiple small and large animal models, the clinical application of this technique in humans has had limited success.
In-utero gene therapy (i.e., the genetic modification of somatic cells in utero) has been propsed as most appropriate in disorders which result in irreversible illness or death in the pre- or post-natal period. Examples may include Gaucher’s disease, Krabbe’s disease, Hurler’s disease, etc. Currently evidence is limited to animal models that certain genetic conditions can be corrected in-utero using gene therapy using virus vectors. In addition to the need for evidence of the effectiveness of gene therapy in- utero in humans, it has been argued that 2 key issues need to be addressed before such an intervention is considered; that there must be a clear advantage over post-natal gene therapy; and that there must be an advantage over therapy with unmodified cells.
Strumper et al (2005) noted that chronically compromised uterine perfusion may lead to placental insufficiency and subsequent intra-uterine growth restriction (IUGR). Various interventions such as the use of vasodilators/low-dose aspirin, intravenous glucose infusion, as well as hemodilution are often of limited effectiveness. The use of local anesthetics has been demonstrated to improve placental blood flow in pre-eclamptic women. In a pilot study (n = 10), these researchers examined whether epidural administration of local anesthetics might improve outcome in IUGR independent of the underlying cause. Women presenting with oligohydramnios and IUGR were included in the study. In addition to the standard protocol (magnesium, glucose, betamethasone), each patient received an epidural catheter (T10/T12) with continuous infusion of bupivacaine 0.175 % at a rate of 5 ml/hour. Uteroplacental circulation was monitored by Doppler sonography and the amount of amniotic fluid was estimated daily. Epidural insertion and infusion was performed without complications. Four patients continued to deteriorate rapidly, amniotic fluid volume did not change and uterine artery pulsatility index (PI) tended to increase. In the remaining 6 patients the clinical status stabilized, amniotic fluid volume tended to increase and uterine artery PI tended to decrease during treatment. This improvement was associated with a prolonged interval to cesarean section and increased infant birth weight. The authors concluded that even if the underlying cause of IUGR is not pre-eclampsia, epidural infusion of local anesthetic might improve placental blood flow and be beneficial in a subgroup of patients. They stated that a clinical trial to test this hypothesis appears warranted.
Gardiner (2008) noted that the concept of fetal therapy is well-established for many disorders diagnosed before birth; but practical issues regarding its introduction into clinical practice are more difficult. Cardiac malformations are common, with major lesions affecting about 3.5 per 1,000 pregnancies; however, only a small proportion of these is likely to benefit from an intra-uterine intervention. In addition, there are no good animal models of human cardiac disease and knowledge of the underlying mechanisms is at best sketchy. This combination of factors has resulted in slow progress in developing effective therapies for the intra-uterine management of cardiac disease. The author stated that recent research and clinical developments have included percutaneous valvuloplasty for severe aortic and pulmonary stenosis, perforation of the closed or restrictive inter-atrial septum and pacing for complete heart block. Progress in these endeavours has been variable; but overall shows promise for treatment of the human fetus.
McElhinney et al (2009) stated that aortic stenosis in the mid-gestation fetus with a normal-sized or dilated left ventricle predictably progresses to hypoplastic left heart syndrome when associated with certain physiological findings. Pre-natal balloon aortic valvuloplasty may improve left heart growth and function, possibly preventing evolution to hypoplastic left heart syndrome. Between March 2000 and October 2008, 70 fetuses underwent attempted aortic valvuloplasty for critical aortic stenosis with evolving hypoplastic left heart syndrome. These investigators analyzed this experience to determine factors associated with procedural and post-natal outcome. The median gestational age at intervention was 23 weeks. The procedure was technically successful in 52 fetuses (74 %). Relative to 21 untreated comparison fetuses, subsequent pre-natal growth of the aortic and mitral valves, but not the left ventricle, was improved after intervention. Nine pregnancies (13 %) did not reach a viable term or preterm birth. Seventeen patients had a biventricular circulation post-natally, 15 from birth. Larger left heart structures and higher left ventricular pressure at the time of intervention were associated with biventricular outcome. A multi-variable threshold scoring system was able to discriminate fetuses with a biventricular outcome with 100 % sensitivity and modest positive-predictive value. The authors concluded that technically successful aortic valvuloplasty alters left heart valvar growth in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome and, in a subset of cases, appeared to contribute to a biventricular outcome after birth. Fetal aortic valvuloplasty carries a risk of fetal demise. Fetuses undergoing in-utero aortic valvuloplasty with an unfavorable multi-variable threshold score at the time of intervention are very unlikely to achieve a biventricular circulation post-natally.
Friedman et al (2011) noted that fetal aortic balloon valvuloplasty (FAV) has shown promise in altering in-utero progression of aortic stenosis to hypoplastic left heart syndrome. In patients who achieve a biventricular circulation after FAV, left ventricular (LV) compliance may be impaired. Echocardiographic indexes of diastolic function were compared between patients with biventricular circulation after FAV, congenital aortic stenosis (AS), and age-matched controls. In the neonatal period, patients with FAV had similar LV, aortic, and mitral valve dimensions but more evidence of endocardial fibroelastosis than patients with AS. Patients with FAV underwent more post-natal cardiac interventions than patients with AS (p = 0.007). Mitral annular early diastolic tissue velocity (E') was lower in patients with FAV and those with AS and controls in the neonatal period and over follow-up (p < 0.001). Septal E' was similar among all 3 groups in the neonatal period. In follow-up patients, with FAV had lower septal E' than patients with AS or controls (p < 0.001). Early mitral inflow velocity/E' was higher in patients with FAV as neonates and at follow-up (p < 0.001). Mitral inflow pulse-wave Doppler-derived indexes of diastolic function were similar between groups. The authors concluded that echocardiographic evidence of LV diastolic dysfunction is common in patients with biventricular circulation after FAV and persists in short-term follow-up. LV diastolic dysfunction in this unique population may have important implications on long-term risk of left atrial and subsequent pulmonary hypertension.
Rogers et al (2011) stated that mitral valve dysplasia syndrome is a unique form of left-sided heart disease characterized by aortic outflow hypoplasia, dilated left ventricle, dysplastic/incompetent mitral valve, and a restrictive/intact atrial septum. Patients with this constellation of abnormalities have been managed in a variety of ways with overall poor outcomes. These investigators performed a retrospective review of all patients with mitral valve dysplasia syndrome to identify fetal echocardiographic markers predictive of outcomes. Mitral valve dysplasia syndrome was identified in 10 fetuses. Fetal left heart dilation and abnormal pulmonary venous flow were associated with increased mortality. Seven fetuses had abnormal pulmonary venous Doppler patterns; 3 had a unique "double-reversal" flow pattern. Severe fetal left heart dilation (left heart/right heart area ratio greater than 1.5) was present in 5. Pre-natal intervention was performed on 3 fetuses: balloon aortic valvuloplasty (n = 2) and balloon atrial septostomy (n = 1). Of the 3, 1 died in-utero and neither survivor underwent a 2-ventricle repair. Five patients required an immediate post-natal intervention to open the atrial septum. The overall mortality was 50 %. The authors concluded that mitral valve dysplasia syndrome is a unique form of congenital heart disease with severe aortic stenosis but normal or enlarged left ventricle secondary to primary mitral valve disease. Increased left heart size and pulmonary vein Doppler patterns are predictive of post-natal outcome. Despite the presence of a dilated left ventricle, post-natal management with staged single ventricle palliation may be the most effective strategy.
An assessment prepared for the Agency for Healthcare Research and Quality (AHRQ) (Walsh, et al., 2011) evaluated the evidence for prenatal aortic valvuloplasty for aortic stenosis. Eight prospective case series were identified on balloon dilation for critical aortic stenosis. One center in the United Kingdom, two centers in Germany, two in Brazil, and one in the U.S. performed this procedure. The 2011 technology assessment concluded that it is difficult to determine whether the procedure changes long-term outcomes, since it appears that it may also increase risk of fetal loss. They concluded that, overall, the literature was considered to be very early in development. An earlier assessment by the National Institute for Health and Clinical Excellence (NICE, 2006) reached similar conclusions.
A phase I/II clinical trial “Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome” is underway to examine whether in-utero balloon aortic valvuloplasty may improve fetal growth of left heart structures and thus improve potential for biventricular repair strategies after birth.
Adzick (2010) stated that myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the post-natal surgical management of the child with spina bifida. Post-natal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. I n-utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. It is estimated that about 400 fetal operations have now been performed for MMC worldwide. Despite this large experience, the technique remains of unproven benefit. Preliminary results suggested that fetal surgery results in reversal of hind-brain herniation (the Chiari II malformation), a decrease in shunt-dependent hydrocephalus, and possibly improvement in leg function, but these findings might be explained by selection bias and changing management indications. A prospective, randomized study (the MOMS trial) is currently being conducted by 3 centers in the United States, and is estimated to be completed in 2010. The author stated that further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in-utero intervention.
Jani and colleagues (2009) examined operative and peri-natal aspects of fetal endoscopic tracheal occlusion (FETO) in CDH. It was a multi-center study of singleton pregnancies with CDH treated by FETO. The entry criteria for FETO were severe CDH on the basis of sonographic evidence of intra-thoracic herniation of the liver and low lung area to head circumference ratio (LHR) defined as the observed to the expected normal mean for gestation (o/e LHR) equivalent to an LHR of 1 or less. Fetal endoscopic tracheal occlusion was carried out in 210 cases, including 175 cases with left-sided, 34 right-sided and one with bilateral CDH. In 188 cases, the CDH was isolated and in 22 there was an associated defect. Fetal endoscopic tracheal occlusion was performed at a median gestational age of 27.1 (range of 23.0 to 33.3) weeks. The first 8 cases were done under general anesthesia, but subsequently either regional or local anesthesia was used. The median duration of FETO was 10 (range of 3 to 93) mins. Successful placement of the balloon at the first procedure was achieved in 203 (96.7 %) cases. Spontaneous preterm prelabor rupture of membranes (PPROM) occurred in 99 (47.1 %) cases at 3 to 83 (median of 30) days after FETO and within 3 weeks of the procedure in 35 (16.7 %) cases. Removal of the balloon was pre-natal either by fetoscopy or ultrasound-guided puncture, intra-partum by ex-utero intra-partum treatment, or post-natal either by tracheoscopy or percutaneous puncture. Delivery was at 25.7 to 41.0 (median of 35.3) weeks and before 34 weeks in 65 (30.9 %) cases. In 204 (97.1 %) cases, the babies were live born and 98 (48.0 %) were discharged from the hospital alive. There were 10 deaths directly related to difficulties with removal of the balloon. Significant prediction of survival was provided by the o/e LHR and gestational age at delivery. On the basis of the relationship between survival and o/e LHR in expectantly managed fetuses with CDH, as reported in the ante-natal CDH registry, these researchers estimated that in fetuses with left CDH treated with FETO the survival rate increased from 24.1 % to 49.1 %, and in right CDH survival increased from 0 % to 35.3 % (p < 0.001). The authors concluded that FETO in severe CDH is associated with a high incidence of PPROM and preterm delivery but a substantial improvement in survival. They also stated that these findings need to be tested in a RCT.
Gastroschisis is associated with inflammatory changes in the exposed bowel that leads to intestinal dysmotility following post-natal repair. In a retrospective study, Heinig et al (2008) followed a case-series of fetuses with isolated gastroschisis to evaluate if small-bowel dilatation may be indicative for emerging obstetric complications. The secondary objective of the study was to establish preliminary normative curves for the external diameter and wall thickness of eventerated fetal small bowel in gastroschisis during the 2nd and 3rd trimester of pregnancy. A total of 14 fetuses with isolated gastroschisis were followed at a single center. Repeated ultrasound examinations for fetal surveillance with measurement of fetal small-bowel diameter and wall thickness over the course of pregnancy until delivery were performed. Longitudinal data analysis showed significantly increasing bowel diameter and wall thickness of eventerated small bowel with advancing gestation. Dilatation of small bowel more than 25 mm in the 3rd trimester of pregnancy was associated with an increased risk of short-term pre-natal complications as fetal distress or intra-uterine fetal death (positive predictive value 100 %; 95 % confidence interval [CI]: 29.2 % to 100 %, negative predictive value 100 %; 95 % CI: 71.5 % to 100%). The authors concluded that dilatation of the extra-abdominal fetal small bowel in the 3rd trimester may allow identifying fetuses with increased risk of fetal distress requiring closer monitoring of fetal well-being or delivery in a short interval to prevent impending fetal death.
Cohen-Overbeek et al (2008) studied in infants with gastroschisis whether outcome is different when comparing a pre-natal diagnosis with a diagnosis only at birth with the intention to develop a pre-natal surveillance protocol. Intestinal atresia established after birth and preterm versus term delivery were studied as risk factors. A total of 24 fetuses and 9 infants diagnosed with gastroschisis and were studied retrospectively. The infants of the pre-natal subset were delivered at the authors' tertiary center and 18 survived. There were 2 pregnancy terminations, 3 intra-uterine deaths at 19, 33 and 36 weeks, respectively, and 1 neonatal death. All 9 infants in the post-natal subset survived -- 8 were out-born and 1 was delivered at the authors' tertiary center. Pre-natal bowel dilatation did not correlate with outcome. Between the pre-natal and post-natal subset, no significant difference in outcome of live-born infants was established. For 4 infants with intestinal atresia a significant difference was demonstrated for induction of preterm labor (p < 0.05), duration of parenteral nutrition (p < 0.01), number of additional surgical procedures (p < 0.001) and length of hospital stay (p < 0.01). The 15 infants born prior to 37 weeks of gestation spent a significantly longer period in hospital compared to those delivered at term. When the cases with bowel atresia were excluded this difference was no longer present. Five of the 33 cases were diagnosed with associated anomalies which mainly involved the urinary tract. The authors concluded that neonatal outcome of live born infants following a pre-natal diagnosis of gastroschisis is not different from a diagnosis at birth. The presence of intestinal atresia is the most important prognostic factor for morbidity. The supplemental value of pre-natal diagnosis to the outcome of infants with gastroschisis may be in the prevention of unnecessary intra-uterine death and detection of intestinal complications. A proposed surveillance protocol for fetuses with gastroschisis focused on intra-uterine signs of pending distress such as a dilated stomach, intra-abdominal bowel dilatation with peristalsis, notches in the umbilical artery Doppler signal, development of polyhydramnios and an abnormal cardiotocography registration may improve outcome. Currently, in-utero repair of gastroschisis is being studied in the sheep model (Stephenson et al, 2010). Thus, this approach is not ready for clinical use.
Adzick et al (2011) compared outcomes of in-utero repair for myelomeningocele with standard postnatal repair. These investigators randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function. Inclusion criteria were a singleton pregnancy, myelomeningocele with the upper boundary located between T1 and S1, evidence of hind-brain herniation, a gestational age of 19.0 to 25.9 weeks at randomization, a normal karyotype, U.S. residency, and maternal age of at least 18 years. Major exclusion criteria were a fetal anomaly unrelated to myelomeningocele, severe kyphosis, risk of preterm birth (including short cervix and previous preterm birth), placental abruption, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 35 or more, and contraindication to surgery, including previous hysterotomy in the active uterine segment. The trial was stopped for efficacy of pre-natal surgery after the recruitment of 183 of a planned 200 patients. This report was based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68 % of the infants in the prenatal-surgery group and in 98 % of those in the postnatal-surgery group (relative risk, 0.70; 97.7 % CI: 0.58 to 0.84; p < 0.001). Actual rates of shunt placement were 40 % in the prenatal-surgery group and 82 % in the postnatal-surgery group (relative risk, 0.48; 97.7 % CI: 0.36 to 0.64; p < 0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (p = 0.007) and in improvement in several secondary outcomes, including hind-brain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery. The authors concluded that prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks.
In an editorial that accompanied the afore-mentioned study, Simpson and Greene (2010) stated that "[t]o what extent can these results be generalized? Caution is necessary here. For the decade of this trial, all cases nationwide were funneled to the 3 study centers, which by now should have developed near-optimal prowess. With the trial complete, other U.S. centers are likely to initiate their own programs, diluting experience and necessitating individual center-specific learning curves. Fetal results may not be as good as those in MOMS, and maternal complications could be increased. In addition, most women who expressed interest in the trial were either ineligible or declined to participate, with only 15 % participation of those who were screened. This percentage may or may not increase as access extends beyond the 3 centers. Earlier diagnosis of myelomeningocele and the performance of open fetal surgery earlier than that performed in MOMS might further improve outcomes, but the potential benefits of even earlier intervention must be weighed against the greater likelihood of maternal complications and possibly increased difficulty of fetal repair. More work is also needed to determine whether baseline characteristics could predict which fetuses would be more or less likely to benefit from prenatal surgery. But surely the greatest benefit would derive from a less traumatic approach. Our job as physicians is to communicate options and available data to patients as lucidly as possible while assiduously adhering to the principles of non-directive genetic counseling. For many women, the 20 % absolute improvement in ambulation at the age of 3 years and the decreased need for shunting may be perceived as sufficient to justify the increased risk of maternal complications, but it should be recognized that outcomes after prenatal surgery were less than perfect in MOMS. Couples who do not elect to terminate a pregnancy unavoidably feel pressured “to do everything possible” and hence may be inclined to interpret even marginal benefit favorably. It is also human nature to over-estimate the likely benefit for one's own fetus and to under-estimate the associated risks. Counseling should involve not only precise quantitative statements comparing outcomes of prenatal versus postnatal surgery on the basis of this report but also the provision of information on center-specific experience. The degree to which intrauterine repair will transform outcomes for fetuses with myelomeningocele remains unclear. The study by Adzick et al is a major step in the right direction, but the still suboptimal rates of poor neonatal outcome and high maternal risk necessitate the use of less invasive approaches if such procedures are to be widely implemented".
Guidance from the National Institute for Health and Clinical Excellence (NICE, 2006) concluded that current evidence on the safety and efficacy of pleuro-amniotic shunts to drain fetal pleural effusions appears adequate. The guidance noted, however, that there are uncertainties about the natural history of fetal pleural effusion and about patient selection. Therefore, this procedure should not be used without special arrangements for consent and for audit or research.
Bacha (2011) stated that fetal cardiac interventions performed by interventional cardiologists are currently in a clinical experimental phase. The 3 most frequent interventions are: (i) aortic balloon valvuloplasty for critical aortic stenosis with a small left ventricle or with a normal size left ventricle but poor function; (ii) atrial septostomy for highly restrictive or intact atrial septum in hypoplastic left heart syndrome; and (iii) pulmonary valvuloplasty for pulmonary atresia and hypoplastic right ventricle.
Rogers et al (2011) stated that mitral valve dysplasia syndrome is a unique form of left-sided heart disease characterized by aortic outflow hypoplasia, dilated left ventricle, dysplastic/incompetent mitral valve, and a restrictive/intact atrial septum. Patients with this constellation of abnormalities have been managed in a variety of ways with overall poor outcomes. These investigators performed a retrospective review of all patients with mitral valve dysplasia syndrome to identify fetal echocardiographic markers predictive of outcomes. Mitral valve dysplasia syndrome was identified in 10 fetuses. Fetal left heart dilation and abnormal pulmonary venous flow were associated with increased mortality; 7 fetuses had abnormal pulmonary venous Doppler patterns; 3 had a unique "double-reversal" flow pattern. Severe fetal left heart dilation (left heart/right heart area ratio greater than 1.5) was present in 5. Pre-natal intervention was performed on 3 fetuses: balloon aortic valvuloplasty (n = 2) and balloon atrial septostomy (n = 1). Of the 3, 1 died in utero and neither survivor underwent a 2-ventricle repair. Five patients required an immediate post-natal intervention to open the atrial septum. The overall mortality was 50 %. The authors concluded that mitral valve dysplasia syndrome is a unique form of congenital heart disease with severe aortic stenosis but normal or enlarged left ventricle secondary to primary mitral valve disease. Increased left heart size and pulmonary vein Doppler patterns are predictive of postnatal outcome. Despite the presence of a dilated left ventricle, post-natal management with staged single ventricle palliation may be the most effective strategy.
An UpToDate review on “Amniotic band sequence” (Bodamer, 2013) states that “Amniotic band sequence refers to a highly variable spectrum of congenital anomalies that occur in association with amniotic bands. It is called a sequence because the pattern of congenital anomalies results from a single defect that can be produced by a variety of different etiologies. In contrast, a syndrome refers to a pattern of congenital anomalies that are known, or at least assumed, to result from only a single etiology …. There is no in utero treatment. Postnatally, surgical correction and limb prostheses may be needed”.
Javadian et al (2013) presented 2 successful cases of fetoscopic release of amniotic bands with umbilical cord involvement, and provided a review of the literature on fetal intervention for amniotic band syndrome (ABS). These 2 case reviews, as well as a review of the literature were performed. A total of 14 patients with an ABS underwent fetoscopic intervention between 1965 and 2012. Two of the authors, independently completed literature searches in PubMed, Ovid and MEDLINE for articles related to ABS. STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines were followed. Among 14 published cases of ABS, 57 % and 7 % of cases were complicated by PPROM and spontaneous preterm birth (SPTB), respectively. Over all, the procedure resulted in a functional limb in 50 % (7/14) of cases. There were 3 cases with intra-operative complications including intra-amniotic bleeding, uterine wall bleeding, and inability to complete the cases due to ineffective equipment. The authors concluded that fetoscopic release of amniotic bands with minimally invasive surgery may allow for preservation of life and/or limb function, in cases of ABS. They stated that the acceptable functional outcome in 50 % of the cases is reassuring, although more experience and further studies are needed in order to hone in on the appropriate selection criteria that will justify the risk of this invasive in-utero therapy for ABS.
Ville et al (1994) stated that in monozygotic twin pregnancies with reversed arterial perfusion (TRAP) sequence, the donor twin is at high-risk of perinatal death. These investigators described the use of endoscopic surgery in the management of this condition. In 4 cases of TRAP sequence presenting at 17, 20, 26 and 28 weeks' gestation, respectively, an endoscope was introduced into the uterus under local anesthesia and a Nd-YAG laser was used to coagulate the umbilical cord vessels of the acardiac twin. Laser coagulation was successful in arresting blood flow to the acardiac fetus in the cases treated at 17 and 20 weeks, and healthy infants were delivered at term. In the pregnancies treated at 26 and 28 weeks, the umbilical cords were very edematous and laser coagulation failed to arrest blood flow; healthy infants were delivered after spontaneous labor at 29 weeks. The authors concluded that these findings suggested that, during mid-gestation, endoscopic laser coagulation of the umbilical cord vessels of the acardiac twin is an effective method of treating TRAP sequence. In later pregnancy, alternative methods of treatment are needed.
Weisz et al (2004) described their management of pregnancies complicated by TRAP sequence. This was a retrospective study involving all cases of TRAP sequence referred to our fetal medicine unit in a 3-year period (2000 to 2002). Patients were routinely managed by repeat sonographic surveillance with sonographic anatomical evaluation and detailed echocardiography. Cases with signs of impending cardiac failure were treated by in-utero YAG-laser coagulation of the umbilical vessels of the acardiac twin. A total of 6 cases were studied; 3 patients in whom there were no signs of deterioration in the status of the pump twin, and in whom the acardiac twin was smaller than the pump twin, were managed conservatively. However, 1 of these with monoamniotic twins ended in intrauterine fetal death of the pump twin. The other 2 cases presented with spontaneous cessation of blood flow in the umbilical artery of the acardiac twin. Both delivered at term normal neonates whose follow-up revealed no signs of neurological sequelae. One case of quadruplet pregnancy (with TRAP sequence and 2 dichorionic twins) was treated by selective termination of the monochorionic twins. Two cases with signs of impending cardiac failure were treated by in-utero YAG-laser occlusion of the vessels in the acardiac mass. Both interventions had a favorable outcome. The authors concluded that conservative treatment is suitable for milder cases of TRAP sequence in which the pump twin is the larger one. Cases in which the acardiac twin is larger have a poorer prognosis and should be treated by invasive intervention and cord occlusion.
In a prospective, multi-center study, Hecher et al (2006) evaluated the feasibility and outcome of fetoscopic laser coagulation in pregnancies with TRAP sequence. Percutaneous fetoscopic laser coagulation of placental anastomoses (n = 18) or the umbilical cord of the acardiac twin (n = 42) was performed in 60 consecutive pregnancies at a median gestational age of 18.3 (range of 14.3 to 24.7) weeks under local or loco-regional anesthesia. Vascular coagulation with arrest of blood flow was achieved in 82 % (49/60) of cases by laser alone and in a further 15 % (9/60) by laser coagulation in combination with bipolar forceps. The overall survival rate of the pump twin was 80 % (48/60). Median gestational age at delivery was 37.4 (range of 23.7 to 41.4) weeks and the median interval between the procedure and delivery was 18.2 (range of 1.1 to 25.7) weeks. Median birth weight was 2,720 (range of 540 to 3,840) g. Preterm premature rupture of membranes before 34 weeks' gestation occurred in 18 % (11/60) at a median of 62 (range of 1 to 102) days after the procedure. However, only 2 (3 %) women delivered within 28 days of the procedure. The authors concluded that fetoscopic laser coagulation of placental vascular anastomoses or the umbilical cord of the acardiac twin is an effective treatment of TRAP sequence, with a survival rate of 80 %, and 67 % of pregnancies with surviving pump twins going beyond 36 weeks' gestation without further complications.
Wegrzyn et al (2012) noted that TRAP sequence complicates about 1 % of all monochorionic twin pregnancies and about 1 to 35.000 of all pregnancies. It involves an acardiac twin whose structural defects are incompatible with life, and an otherwise normal "pump" co-twin. As the blood flow in the acardiac twin is reversed, it keeps on growing owing to the oxygenated blood from the co-twin. These investigators reported a case of monochorionic, diamniotic twin pregnancy after ICS/-ET complicated with TRAP sequence, diagnosed at 11 weeks of pregnancy. The unusual finding in this case was the residual heart in the so called acardiac twin. Gradually the normal twin developed signs of hemodynamic compromise. Reversed a-wave in ductus venosus was observed. The acardiac twin showed subcutaneous edema. On November 24, 2011 a successful interstitial ultrasound-guided laser coagulation was performed at 16 weeks of gestation; 17-G needle and 0.6 mm laser fiber were used. The needle was introduced into the pelvic region of the acardiac twin through the abdominal wall. A series of laser bursts lasting 5 to 10 seconds were fired, until cessation of blood flow in the pelvic vessels and umbilical cord of the acardiac twin was confirmed using color Doppler. The course of the intervention was uneventful. Routine steroid therapy was administered at 27 weeks of gestation. At 32 weeks the patient was hospitalized and oral antibiotics were administered due to premature rupture of the membranes and suspicion of intrauterine growth retardation of the pump twin. The patient delivered spontaneously at completed 33 weeks of pregnancy (weight 1,805 g, Apgar 10). After the delivery, a stage 2 intra-ventricular hemorrhage and jaundice were observed in the neonate. Phototherapy was administered and the mother and the child were eventually discharged from the hospital, both in good general condition. Since then, 2 more successful interstitial laser coagulations in TRAP sequence were performed in the authors’ institution. The essence of the treatment of TRAP sequence is cessation of the blood flow from the pump to the acardiac twin. Fetoscopic cord ligature or coagulation, and laser or radiofrequency ablations of the acardiac twin vessels, are the possible methods of intervention. The interstitial laser coagulation of the acardiac twin is less invasive than fetoscopic umbilical cord coagulation, as the outer diameter of the 17-G needle is much smaller. A meticulous comparison of these methods would require a randomized study but at 16 weeks of MCDA twin pregnancy interstitial laser coagulation seems to be the method of choice.
An UpToDate review on “Diagnosis and management of twin reversed arterial perfusion (TRAP) sequence” (Holland et al, 2014) states that “In utero therapy -- For continuing pregnancies with one or more poor prognostic criteria, antenatal intervention, delivery, and expectant management are options. As the acardiac twin is nonviable, treatment for TRAP sequence is focused on improving the outcome for the pump twin. Historically, intervention in pregnancies with TRAP sequence was limited to amnioreduction to reduce hydramnios or relief for the pump twin by selective delivery of the acardiac twin via hysterotomy or administration of sclerosing agents (e.g., alcohol) into the umbilical cord of the acardiac twin. For pregnancies between 18 and 27 weeks of gestation, current treatment modalities target occlusion of the umbilical cord of the acardiac twin and include laser ablation, bipolar cord coagulation, and radiofrequency ablation (RFA), which are performed with local anesthesia and conscious sedation. Fetoscopic cord ligation is an alternative, but is less common”.
Lissauer et al (2007) noted that fetal lower urinary tract obstruction (LUTO) affects 2.2 per 10,000 births. It is a consequence of a range of pathological processes, most commonly posterior urethral valves (64 %) or urethral atresia (39 %). It is a condition of high mortality and morbidity associated with progressive renal dysfunction and oligohydramnios, and hence fetal pulmonary hypoplasia. Accurate detection is possible via ultrasound, but the underlying pathology is often unknown. In future, magnetic resonance imaging (MRI) may be increasingly used alongside ultrasound in the diagnosis and assessment of fetuses with LUTO. Fetal urine analysis may provide improvements in prenatal determination of renal prognosis, but the optimum criteria to be used remain unclear. It is now possible to decompress the obstruction in utero via percutaneous vesico-amniotic shunting or cystoscopic techniques. In appropriately selected fetuses intervention may improve perinatal survival, but long-term renal morbidity amongst survivors remains problematic.
Ethun and associates (2013) examined the outcomes of patients with LUTO treated with vesico-amniotic shunt (VAS) to improve the quality of prenatal consultation and therapy. The medical records of all patients diagnosed with LUTO at the authors’ center between January 2004 and March 2012 were reviewed retrospectively. Of 14 male fetuses with LUTO, all with characteristic ultrasound findings, 11 underwent intervention. One patient received vesicocentesis alone, while 10 had VAS. Two fetuses additionally underwent cystoscopy (1 with attempted valve ablation), and 2 had peritoneo-amniotic shunts. Of 16 total VAS, 13 were placed successfully, 8 dislodged (median of 7 days), and 1 obstructed (84 days). Two fetuses suffered in utero demise, and 2 have unknown outcomes. Lower urinary tract obstruction was confirmed in 6 of 8 live-born fetuses. One patient died in the neonatal period, while 7 survived. All 6 available at follow-up (median of 3.7 years), had significant genitourinary morbidity. Five patients had chronic kidney disease, but only 1 has required dialysis and transplant; 3 had respiratory insufficiency, and 1 required a tracheostomy. The authors concluded that despite significant perinatal and long-term morbidity, VAS offers patients faced with a poor prognosis an improved chance of survival. Moreover, they stated that these results underscore the need for further research into the diagnosis and treatment of LUTO.
Furthermore, an UpToDate review on “Overview of antenatal hydronephrosis” (Baskin and Ozcan, 2014) states that “Fetal surgery -- Although there have been several prospective and retrospective studies of antenatal surgery in fetuses with sonographic findings consistent with lower urinary tract obstruction, there is no good evidence that this intervention improves renal outcome. These procedures increase the amount of amniotic fluid, thus potentially improving lung development and survival rate. However, there remains a high rate of chronic renal disease in the survivors, necessitating renal replacement therapy in almost two-thirds of the cases”.
|CPT Codes / HCPCS Codes / ICD-9 Codes|
|CPT codes covered if selection criteria are met:|
|59001||Amniocentesis; therapeutic amniotic fluid reduction (includes ultrasound guidance)|
|59072||Fetal umbilical cord occlusion, including ultrasound guidance|
|59076||Fetal shunt placement, including ultrasound guidance|
|Other CPT codes related to the CPB:|
|59074||Fetal fluid drainage (eg, vesicocentesis, thoracocentesis, paracentesis), including ultrasound guidance|
|59897||Unlisted fetal invasive procedure, including ultrasound guidance|
|HCPCS codes covered if selection criteria are met:|
|S2401||Repair, urinary tract obstruction in the fetus, procedure performed in utero|
|S2402||Repair, congenital cystic adenomatoid malformation in the fetus, procedure performed in utero|
|S2403||Repair, extralobar pulmonary sequestration in the fetus, performed in utero|
|S2404||Repair, myelomeningocele in the fetus, procedure performed in utero|
|S2405||Repair of sacrococcygeal teratoma in the fetus, procedure performed in utero|
|S2409||Repair, congenital malformation of fetus, procedure performed in utero, not otherwise classified|
|S2411||Fetoscopic laser therapy for treatment of twin-to-twin transfusion syndrome|
|HCPCS codes not covered for indications listed in the CPB:|
|S2400||Repair, congenital diaphragmatic hernia in the fetus using temporary tracheal occlusion, procedure performed in utero|
|ICD-9 codes covered if selection criteria are met:|
|238.0||Neoplasm of uncertain behavior of bone and articular cartilage|
|511.9||Unspecified pleural effusion|
|653.73||Other fetal abnormality causing disproportion, antepartum|
|678.03||Fetal hematologic conditions, antepartum condition or complication [severe twin-twin transfusion syndrome]|
|678.13||Fetal conjoined twins, antepartum condition or complication [twin reversed arterial perfusion (TRAP)]|
|741.00 - 741.93||Spina bifida|
|748.4||Congenital cystic lung|
|748.5||Agenesis, hypoplasia, and dysplasia of lung|
|748.8||Other specified anomalies of respiratory system|
|753.20 - 753.29||Obstructive defects of renal pelvis and ureter [not covered for fetal hydronephrosis]|
|753.6||Atresia and stenosis of urethra and bladder neck|
|759.4||Conjoined twins [twin reversed arterial perfusion (TRAP)]|
|759.89||Other specified congenital anomalies [acardia] [twin reversed arterial perfusion (TRAP)]|
|762.3||Placental transfusion syndrome|
|ICD-9 codes not covered for indications listed in the CPB:|
|655.03||Known or suspected fetal central nervous system malformation in fetus affecting management of the mother, antepartum condition or complication [acqueductal stenosis hydrocephalus]|
|655.13||Known or suspected chromosomal abnormality in fetus affecting management of the mother, antepartum condition or complication|
|655.93||Unspecified known or suspected fetal abnormality affecting management of the mother, antepartum condition or complication|
|742.59||Other specified anomalies of spinal cord|
|745.0 - 746.9||Bulbus cordis anomalies and anomalies of cardiac septal closure and other congenital anomalies of the heart|
|749.0 - 749.25||Cleft palate and cleft lip|
|756.6||Anomalies of diaphragm|
|762.8||Other specified abnormalities of chorion and amnion [amniotic band syndrome]|
|Other ICD-9 codes related to the CPB:|
|653.73||Other fetal abnormality causing disproportion, antepartum condition or complication|
|655.83||Other known or suspected abnormality, not elsewhere classified, affecting management of the mother, antepartum condition or complication|