Fetal Surgery for Prenatally Diagnosed Malformations - CAM 40110
Fetal surgery is used for specific congenital abnormalities that are associated with a poor postnatal prognosis. Prenatal surgery typically involves opening the gravid uterus (with a Cesarean surgical incision), surgically correcting the abnormality and returning the fetus to the uterus and restoring uterine closure. Minimally invasive procedures through single or multiple fetoscopic port incisions are also being developed.
Due to a number of factors, including the rarity of the conditions and the small number of centers specializing in fetal interventions, the evidence on fetal surgery is limited. Fetal surgery for many congenital conditions, including congenital diaphragmatic hernia (CDH) and heart defects, has not been shown to improve health outcomes in comparison with postnatal treatment. The available evidence is insufficient to demonstrate that fetal tracheal occlusion for CDH and fetal intervention for evolving hypoplastic left heart syndrome (HLHS) and critical pulmonary stenosis or pulmonary atresia provides improve health outcomes. For these and other applications of fetal surgery that are currently considered investigational, additional studies are needed to identify appropriate candidates and to evaluate longer term outcomes compared with postnatal management.
For conditions leading to fetal hydrops (certain cases of congenital cystic adenomatoid malformation, bronchopulmonary sequestration or sacrococcygeal teratoma), for which mortality approaches 100 percent, fetal surgery may be considered medically necessary. For bilateral urinary tract obstruction, evidence from retrospective and prospective cohort studies summarized in the 2011 Agency for Healthcare Research and Quality technology assessment on fetal surgery suggests that vesicoamniotic shunting improves survival, at least in the short term. A recent, small, randomized controlled trial evaluating the use of vesicoamniotic shunting found limited benefit from the procedure when data were analyzed by intention-to-treat analysis. However, the study's significant limitations, including low enrollment leading to early cessation of the study and significant crossover between treatment and control groups, make it difficult to generalize its finding of no significant benefit from treatment. As such, vesicoamniotic shunting for bilateral urinary tract obstruction may also be considered medically necessary to minimize the effects of this condition on kidney and lung development. Additional studies for these surgeries are needed to better define the appropriate surgical candidates, the most effective timing of the interventions and the long-term health outcomes in surviving children.
Data from the MOMS trial show that prenatal repair of myelomeningocele reduces the need for shunting in the first 12 months after delivery and improves a composite measure of mental and motor function, with adjustment for lesion level, at 30 months of age. Prenatal surgery also improves the degree of hindbrain herniation and the likelihood of being able to walk independently when compared with postnatal surgery. The long-term impact on function needs to be evaluated, and benefits must be balanced against risks to mother and child. Thus, fetal surgery may be considered medically necessary following informed decision-making for cases of prenatal myelomeningocele that meet the criteria of the MOMS study.
Most fetal anatomic malformations are best managed after birth. However, advances in methods of prenatal diagnosis, particularly prenatal ultrasound, have led to a new understanding of the natural history and physiologic outcomes of certain congenital anomalies. Fetal surgery is the logical extension of these diagnostic advances, related in part to technical advancement in anesthesia, tocolysis and hysterotomy.
This policy will pertain to fetal surgery performed for the following clinical conditions.
Fetal Urinary Tract Obstruction
Although few cases of prenatally diagnosed urinary tract obstruction require prenatal intervention, bilateral obstruction can lead to distention of the urinary bladder and is often associated with serious disease, such as pulmonary hypoplasia secondary to oligohydramnios. Therefore, fetuses with bilateral obstruction, oligohydramnios, adequate renal function reserve and no other lethal or chromosomal abnormalities may be candidates for fetal surgery. The most common surgical approach is decompression through percutaneous placement of a shunt or stent. Vesicoamniotic shunting bypasses the obstructed urinary tract, permitting fetal urine to flow into the amniotic space. The goals of shunting are to protect the kidneys from increased pressure in the collecting system and to assure adequate amniotic fluid volume for lung development.
Congenital Diaphragmatic Hernia
CDH results from abnormal development of the diaphragm, which permits abdominal viscera to enter the chest, frequently resulting in hypoplasia of the lungs. CDH can vary widely in severity, depending on the size of the hernia and the timing of herniation. For example, late herniation after 25 weeks of gestation may be adequately managed postnatally. In contrast, liver herniation into the chest before 25 weeks of gestation is associated with a poor prognosis, and these fetuses have been considered candidates for fetal surgery. Temporary tracheal occlusion using a balloon is being evaluated for the treatment of CDH. Occluding the trachea of a fetus prevents the normal efflux of fetal lung fluid, which results in a buildup of secretions in the pulmonary tree and increases the size of the lungs, gradually pushing abdominal viscera out of the chest cavity and back into the abdominal cavity. It is believed that this, in turn, will promote better lung maturation. Advances in imaging have resulted in the ability to detect less severe lesions, which has resulted in a decrease in mortality rates for defects detected during pregnancy. Due to these changes over time, concurrent controls are needed to adequately compare pre- and postnatal approaches.
Congenital Cystic Adenomatoid Malformation (Congenital Pulmonary Airway Malformation) or Bronchopulmonary Sequestration
Congenital cystic adenomatoid malformation (CCAM), also referred to as congenital pulmonary airway malformations, and bronchopulmonary sequestration (BPS) are the two most common congenital cystic lung lesions and share the characteristic of a segment of lung being replaced by abnormally developing tissue. CCAMs can have connections to the pulmonary tree and contain air, while BPS does not connect to the airway and has blood flow from the aorta rather than the pulmonary circulation. In more severe cases, the malformations can compress adjacent normal lung tissue and distort thoracic structure. CCAM lesions typically increase in size in mid-trimester and then in the third trimester either involute or compress the fetal thorax, resulting in hydrops in the infant and sometimes mirror syndrome (a severe form of pre-eclampsia) in the mother. Mortality is close to 100 percent when lesions are associated with fetal hydrops (abnormal accumulation of fluid in two or more fetal compartments). These patients may be candidates for prenatal surgical resection of a large mass or placement of a thoracoamniotic shunt to decompress the lesion.
Sacrococcygeal teratoma (SCT) is both a neoplasm with autonomous growth and a malformation made up of multiple tissues foreign to the region of origin and lacking organ specificity. It is the most common tumor of the newborn and generally carries a good prognosis in infants born at term. However, in utero fetal mortality approaches 100 percent with large or vascular tumors, which may become larger than the rest of the fetus. In this small subset, SCT is associated with fetal hydrops, which is related to high output heart failure secondary to arteriovenous shunting. In some cases, mothers of fetuses with hydrops can develop mirror syndrome.
Myelomeningocele is a neural tube defect in which the spinal cord forms abnormally and is left open, exposing the meninges and neural tube to the intrauterine environment. Myelomeningocele is the most common cause of spina bifida, and, depending on the location, results in varying degrees of neurologic impairment to the legs and bowel and bladder function, brain malformation (i.e., hindbrain herniation), cognitive impairment and disorders of cerebrospinal fluid circulation, i.e., hydrocephalus requiring placement of a ventriculoperitoneal shunt. Traditional treatment consists of surgical repair after term delivery, primarily to prevent infection and further neurologic dysfunction. Fetal surgical repair to cover the exposed spinal canal has been proposed as a means of preventing the deleterious exposure to the intrauterine environment with the hope of improving neurologic function and decreasing the incidence of other problems related to the condition.
In utero interventions are being investigated for several potentially lethal congenital heart disorders, including critical aortic stenosis with evolving HLHS, HLHS with intact atrial septum and critical pulmonary stenosis or pulmonary atresia.1 Critical pulmonary stenosis or atresia with intact ventricular septum is characterized by a very narrow pulmonary valve without a connection between the right and left ventricles. Pulmonary atresia with intact ventricular septum can evolve into right ventricular hypoplasia. Fetal pulmonary valvuloplasty may result in biventricular circulation. Critical aortic stenosis with impending HLHS is a very narrow aortic valve that develops early during gestation that may result in HLHS, a complex spectrum of cardiac anomalies characterized by hypoplasia of the left ventricle and aorta, with atretic, stenotic or hypoplastic atrial and mitral valves. In utero aortic balloon valvuloplasty relieves aortic stenosis with the goal of preserving left ventricular growth and halting the progression to HLHS. HLHS with intact trial septum is a variant of HLHS that occurs in about 22 percent of all HLHS cases in which blood flow across the foramen ovale is restricted, leading to left atrial hypertension and damage to the pulmonary vasculature, parenchyma and lymphatics. For HLHS with intact atrial septum, fetal balloon atrial septostomy is designed to reduce the left atrial restriction.
Vesico-amniotic shunting as a treatment of urinary tract obstruction may be considered MEDICALLY NECESSARY in fetuses meeting all four of these conditions:
- Evidence of hydronephrosis due to bilateral urinary tract obstruction.
- Progressive oligohydramnios.
- Adequate renal function.
- No other lethal abnormalities or chromosomal defects.
Open in utero resection of malformed pulmonary tissue or placement of a thoraco-amniotic shunt may be considered MEDICALLY NECESSARY under all three of these conditions:
- Congenital cystic adenomatoid malformation or bronchopulmonary sequestration is identified.
- The fetus is at 32 weeks' gestation or less.
- There is evidence of fetal hydrops, placentomegaly and/or the beginnings of severe pre-eclampsia (i.e., the maternal mirror syndrome) in the mother.
In utero removal of sacrococcygeal teratoma may be considered MEDICALLY NECESSARY under both of these conditions:
- The fetus is at 32 weeks' gestation or less.
- There is evidence of fetal hydrops, placentomegaly and/or beginnings of severe pre-eclampsia (i.e., the maternal mirror syndrome) in the mother.
In utero repair of myelomeningocele may be considered MEDICALLY NECESSARY under both of these conditions
- The fetus is at less than 26 weeks' gestation.
- Myelomeningocele is present with an upper boundary located between T1 and S1 with evidence of hindbrain herniation.
In utero repair of myelomeningocele is considered INVESTIGATIONAL in any of these situations:
- Fetal anomaly unrelated to myelomeningocele.
- Severe kyphosis.
- Risk of preterm birth (e.g., short cervix or previous preterm birth).
- Maternal body mass index of 35 or more
Other applications of fetal surgery are INVESTIGATIONAL including, but not limited to, temporary tracheal occlusion as a treatment of congenital diaphragmatic hernia, treatment of congenital defects.
Amnioreduction and fetoscopic laser therapy as a treatment of twin-twin transfusion are not addressed in this policy.
After 32 weeks' gestation, fetal lung maturity is adequate to permit cesarean section and management of congenital cystic adenomatoid malformation, bronchopulmonary sequestration or sacrococcygeal teratoma postnatally.
In utero surgery should be restricted to centers experienced in treating these conditions and staffed by surgeons adequately trained in fetal surgery techniques.
Because of the differing benefits and risks of in utero versus postnatal surgeries, parents should make an informed choice between procedures.
BlueCard/National Account Issues
Fetal surgery is a specialized technique that requires a multidisciplinary approach and may require referral to an out-of-network facility.
This evidence review was originally based on 1998 and 1999 TEC Assessments2,3 and has been updated periodically with literature searches of the MEDLINE database. The most recent update was with a review of the literature through Oct. 27, 2014.
The evidence related to the use of fetal surgery is limited by the rarity of the conditions treated and the extremely specialized nature of the procedures, although randomized controlled trials (RCTs) have been conducted for several conditions. The literature related to fetal surgery has been summarized in several systematic reviews. In addition to the 1998 and 1999 TEC Assessments, the Agency for Healthcare Research and Quality (AHRQ) published a technology assessment on fetal surgery in April 2011.4
Fetal Urinary Tract Obstruction
The 2011 AHRQ assessment identified 26 publications representing 25 unduplicated reports on fetal interventions for obstructive uropathy. From the 3 prospective cohorts and 8 retrospective cohorts identified, 24 fetuses had placements of shunts, 11 had other treatments for posterior urethral valves, 14 had no fetal intervention and 13 pregnancies were terminated due to poor prognosis. Overall, 53% to 66% of infants who had shunt placement survived short-term. However, more than half of otherwise normal infants who have only isolated bladder outlet tract obstruction and do not have multiple anomalies or syndromes, do not recover normal renal function in childhood, and the majority require dialysis and renal transplantation. In addition, a proportion of affected infants have clusters of syndromic features that are not readily diagnosed prenatally, increasing morbidity among survivors. For example, in a follow-up of 18 male children who had survived prenatal vesicoamniotic shunting (follow-up range, 1 – 14 years), one-third required dialysis or transplantation, and one-half exhibited respiratory, growth and development or musculoskeletal abnormalities. Despite this, parents and physicians reported the children to be neurodevelopmentally normal, with most having acceptable renal and bladder function and satisfactory self-reported quality of life.5 There is a need to better identify appropriate surgical candidates and clarify health outcomes in children who do and do not receive fetal intervention to inform decision-making. At the time of the AHRQ assessment, 1 publication described the protocol for the multicenter randomized PLUTO trial of percutaneous shunting for lower urinary tract obstruction (LUTO) that was designed to assess whether intrauterine vesicoamniotic shunting improved pre- and perinatal health outcomes better than conservative, noninterventional care.6
Randomized Controlled Trials
Since publication of the 2011 AHRQ assessment, Morris et al. (2013) published the results of the PLUTO trial.7 This unblinded RCT included 31 women with male singleton pregnancies, complicated by an isolated LUTO, recruited from centers in the United Kingdom, Ireland and the Netherlands. Inclusion criteria were an ultrasound diagnosis of LUTO (diagnosed on the basis of the visualization of an enlarged bladder and dilated proximal urethra, bilateral or unilateral hydronephrosis and cystic parenchymal renal disease) about whom the treating physician was uncertain as to the optimum management. Women pregnant with fetuses with other major structural or chromosomal abnormalities were excluded. Women were randomly allocated to either prenatal intervention, consisting of placement of a vesicoamniotic shunt, or control, consisting of usual care. The primary outcome measure was survival to 28 days after birth, with secondary outcomes of survival at 1 and 2 years and renal function at 28 days, 1 year and 2 years (measured by serum creatinine, renal ultrasound appearance and evidence of renal impairment based on need for medical treatment, dialysis or transplantation). The original planned sample size for the trial of 75 pregnancies in each study group was based on calculations from a meta-analysis reported by the study authors in 20108 and was designed to detect a relative risk (RR) of survival with vesicoamniotic shunting of 1.55 with 80% power. The study was terminated early due to poor enrollment. Concurrent with the RCT, study authors enrolled eligible subjects who elected not to participate due to patient or physician preference in an observational registry. There was a high degree of crossover between groups: 3 of 16 women randomized to receive vesicoamniotic shunting did not receive it, and 2 of 15 women randomized to the control group received a vesicoamniotic shunt.
Analyses were conducted on an intention-to-treat basis and a per-protocol basis. For the study's primary outcome of 28-day survival, there was no significant difference between the groups: of the 16 pregnancies randomly assigned to vesicoamniotic shunting, 8 neonates survived to 28 days, compared with 4 from the 15 pregnancies assigned to the control group (RR = 1.88; 95% confidence interval [CI], 0.71 to 4.96; p = 0.27). Analysis based on treatment received showed a stronger association between shunting and survival (RR = 3.2; 95% CI, 1.06 to 9.62; p = 0.03). The authors conducted a Bayesian analysis, combining data from their trial with elicited priors from experts, and found an 86% probability that vesicoamniotic shunting increased survival at 28 days. Overall, the authors concluded that “survival seemed higher in the fetuses receiving vesicoamniotic shunting, but the size and direction of the effect remained uncertain.” While strengths of this study included its randomized controlled design and tracking of longer (2-year) outcomes, it was limited by the inability to reach enrollment targets and the significant crossover between treatment and control groups. As such, it is difficult to conclude that the lack of significant association between shunting and survival was not due to underpowering.
Morris et al. reported on secondary outcomes in a complete health technology assessment of the PLUTO trial and the associated registry for patients who elected not to participate in the randomized trial portion.9 Secondary outcomes included cost-effectiveness of vesicoamniotic shunting compared with conservative management; effect of vesicoamniotic shunting on short-term morbidity; survival and development of chronic renal failure at 1 year of age; identifying prognostic markers of outcome; determining clinicians’ prior beliefs about the effectiveness of vesicoamniotic shunting; and assessing influences on women’s decision making with respect to opting for termination of pregnancy, randomization and the acceptability of the intervention. For the secondary outcomes of the randomized portion of the trial, there were no statistically significant differences in mortality from 28 days to 1 year, although the point estimate for the RR was in the direction of benefit (RR = 2.19; 95% CI, 0.69 to 6.94). Of those infants who survived to 1 year, 2 had no evidence of renal impairment (vesicoamniotic shunt arm), while 4 in the vesicoamniotic shunt arm and 2 in the conservative arm required medical management for renal impairment. One infant in the conservative arm had end-stage renal failure at 1 year.
Forty-five women entered the concurrent registry; of those, 78% had conservative management. Women who were in the registry cohort differed from those randomized: registry patients who had conservative management were more likely to have a normal (> 5th percentile) amniotic fluid volume at diagnosis than those who received vesicoamniotic shunting (p = 0.07) or randomized (p = 0.05). Women in the registry arm were more likely to be diagnosed at 24 or more weeks among these women than among those in the randomized group (p = 0.003).
Section Summary: Fetal Urinary Tract Obstruction
Evidence from retrospective and prospective cohort studies summarized in the 2011 AHRQ technology assessment on fetal surgery suggests that vesicoamniotic shunting as a therapy for bilateral urinary tract obstruction improves survival, at least in the short term. A subsequent small RCT found limited benefit from the procedure; however, the study's limitations make it difficult to confidently conclude that vesicoamniotic shunting is associated with no clinical benefit.
Congenital Diaphragmatic Hernia
Tracheal Obstruction for Congenital Diaphragmatic Hernia
In 1999, the TEC Assessment3 concluded that temporary tracheal obstruction met the TEC criteria as a treatment of congenital diaphragmatic hernia (CDH), based in part on a 2000 case series.10 However, in 2003, Harrison et al., the same authors who reported on the 2000 case series, reported the results of a randomized trial of fetoscopic tracheal occlusion compared with standard postnatal care.11 Enrollment was stopped at 24 women due to the unexpectedly high 90-day infant survival rate with standard care and, thus, the safety monitoring board concluded that further recruitment would not result in a significant difference between the groups. In addition, the fetal surgery group had higher rates of premature birth and lower birth weights. The survival rate in the standard treatment group was 73%, considerably higher than the estimated survival rate of 37% based on historical controls. The survival of infants with a lung-to-head ratio (LHR) greater than 1.0 was 100% in both groups. In contrast, in other publications, survival has been reported to be approximately 10% for children with isolated CDH who have left-sided lesions, liver herniation and an LHR of less than 1.0 during mid-gestation.12 In this subgroup, temporary placement of a detachable balloon to occlude the trachea resulted in a survival rate of 55% (35 cases) compared with 8% survival in a group of contemporary controls treated by postnatal therapy. Based on the results of the Harrison randomized trial, the policy statement was revised to indicate that tracheal occlusion is considered investigational.
Evidence for tracheal obstruction for CDH includes the 2011 AHRQ assessment, which identified 25 publications with 21 unduplicated populations from 10 U.S. sites, 9 European sites, 3 multinational sites and 5 other countries (total N = 335 cases). The single RCT was by Harrison11 (previously described), with follow-up reported by Cortes et al. in 2005.13 Growth failure occurred in 56% of controls and 86% of infants who had occlusion. No neurodevelopmental differences were observed between groups with follow-up at 1 or 2 years of age. This randomized study reinforces the importance of a concomitant control group, because survival for CDH with postnatal repair also improved over time. Also noted were results of the Fetal Endoscopic Tracheal Occlusion Task Group in Europe, which used a control group of 86 fetuses with left-sided CDH and liver herniation, managed expectantly and liveborn after 30 weeks of gestation. In this control group, the survival rate increased from 0% for LHR of 0.4 to 0.7 to approximately 15% survival for LHR of 0.8 to 0.9, to 65% survival for LHR of 1.0 to 1.5 and to 83% survival for LHR of 1.6 or more.
Since the 2001 AHRQ assessment, several studies have addressed fetal endoscopic tracheal occlusion (FETO) in CDH. In 2011, Ruano et al. published a small nonrandomized controlled study that evaluated the feasibility of percutaneous FETO with a 1-mm fetoscope.14 Thirty-five women were enrolled from 2006 to 2008, of whom 17 were intended for fetal intervention and 16 underwent successful fetal tracheal occlusion. Nine (539%) of 17 fetal intervention infants and 1 (6%) of 18 control group infants survived to 28 days, and the authors concluded the intervention was feasible.
In a subsequent study , Ruano et al. (2012) reported a small randomized trial that compared percutaneous FETO with postnatal management in 41 patients whose fetuses had severe CDH (LHR <1.0 and at least one-third of the fetal liver herniated into the thoracic cavity).15 All fetuses in the FETO group were delivered by ex-utero intrapartum therapy to remove the tracheal balloon; controls were delivered by Cesarean section at a maximum gestational age of 38 weeks. The primary outcome (survival to 6 months of age by intention-to-treat analysis) was 50% (10/20) in the fetal surgery group and 5% (1/21) in controls (RR = 10.5). Mean delivery was about 2 weeks earlier in the fetal surgery group that in controls (35.6 weeks vs. 37.4 weeks). There was a trend for a higher frequency of premature delivery (< 37 weeks, 50% for FETO vs. 28.6% for controls) and extreme premature delivery (<32 weeks, 15% for FETO vs. 0% for controls) in the FETO group. For the 10 survivors in the FETO group, mean age at hospital discharge was 34.7 days.
In 2014, Rocha et al. published a retrospective case-control study that compared left heart structure size in patients with CDH who underwent FETO with those managed conservatively.16 Based on observational data that infants born with CDH have small left heart structures, possibly due to direct compression by herniated abdominal organs and/or abnormal orientation of the inferior vena cava and foramen ovale, the authors postulated that increased lung size associated with FETO may lead to increased left heart structure size in patients with CDH. The study included 9 cases with left-sided CHD and an LHR of 1 or less who underwent FETO who were compared to 25 similar controls who did not undergo fetal intervention. Mortality did not differ significantly between groups (67% in the fetal intervention group vs. 52% in the control group, p = NS). At birth, the intervention group had larger left ventricular (LV) enddiastolic volume (indexed to body surface area) (16.8 mL/m2 vs. 12.76 mL/m2, p < 0.05), LV length z score (-2.05 vs. -4, p < 0.01), left ventricular:right ventricular length ratio (1.43 vs. 1.04, p < 0.05), left pulmonary artery diameter z score (+1.71 vs. -1.04, p < 0.05) and better growth of the aortic valve (-2.18 vs. -3.3, p < 0.01). The authors noted that FETO may have benefits in postnatal cardiac output and pulmonary hypertension but that the potential benefits of fetal treatment for CDH are still currently under investigation in several trials and must be weighed against the risks of prematurity and risk to the mother.
In 2014, Shan et al. published a systematic review and meta-analysis of RCTs evaluating FETO for CDH.17 The authors included 3 studies identified as RCTs, including Harrison et al. (2003), Ruano et al. (2011) and Ruano et al. (2012). In pooled analysis, patients treated with FETO had higher survival rates than patients treated with standard therapy (27/48 vs. 12/52; OR for survival with fetal treatment, 5.95; 95% CI, 2.11 to 16.78; p<0.000). Patients treated with FETO had an earlier average gestational age at delivery than patients treated with standard therapy (mean difference, -3.43 weeks; 95% CI, -6.82 to -0.04; p < 0.05). However, the pooled estimates are difficult to interpret because Ruano et al. (2011) categorized by its authors as an RCT, was a controlled but nonrandomized.
Section Summary: Congenital Diaphragmatic Hernia
Although early (before 2003) noncomparative studies suggested benefit from FETO for the treatment of CDH, the most direct evidence on the effectiveness of this procedure comes from 2 RCTs from 2003 and 2012 that report conflicting findings. The 2012 RCT demonstrated promising findings of improved survival at 6 months postdelivery in patients treated with FETO. However, given the inconclusive results in the randomized trial by Harrison et al., additional study is needed to determine the survival benefit with greater certainty. Longer follow-up is also needed to evaluate morbidity (e.g., neurologic and pulmonary outcomes) in survivors.
Congenital Cystic Adenomatoid Malformation and Bronchopulmonary Sequestration
The 2011 AHRQ assessment identified 17 publications describing 6 distinct cohorts and 4 case series from 7 academic centers in the United States, South America, Europe and Asia. Of 401 infants believed to have congenital cystic adenomatoid malformations (CCAMs), 54 had thoracoamniotic shunting and 3 had open procedures, with the goal of decompressing the lung lesion. An additional 13 fetuses with bronchopulmonary sequestration were described. In the cohorts, 44% to 100% of infants who had thoracoamniotic shunts survived to birth or through neonatal hospitalization; there was an overall survival rate of 54% in the literature. For fetuses with hydrops, survival was 20% to 30% following surgical treatment compared with 5.7% for untreated hydrops. Because some infants with large CCAMs respond to in utero medical treatment with steroids, failure to respond to steroids may be an entry criterion for future surgical interventions.
In 2014, White et al. reported outcomes after the use of a transabdominal, transuterine percutaneous thoracoabdominal shunt creation technique in 5 fetuses with nonimmune hydrops due to fetal thoracic abnormalities.18 The study was a retrospective review of fetal thoracic abnormality cases treated with percutaneous shunt creation by a combination of interventional radiology and maternal-fetal medicine team at a single institution from 2007 to 2012. Eligible fetuses had to have a thoracic abnormality, no infection, an absence of lethal genetic abnormalities and have a normal karyotype. All fetuses with type I congenital pulmonary airway malformation (CPAM) received betamethasone to attempt to decrease the CPAM size. Seven shunts were placed in 5 patients. There was 1 case of fetal distress requiring induction of labor at 31 weeks, 2 days of gestation. After delivery, all shunts were in place in the thoracic cavity. Three infants underwent uncomplicated surgical resection of type I CPAMs and were discharged home. Two infants with chylothoraces had bilateral chest tubes placed after delivery and were discharged home after the chylothoraces resolved.
At the time of the 1999 TEC Assessment, the published literature only included 4 cases of fetal surgery for sacrococcygeal teratoma (SCT). However, in utero surgery resulted in prenatal resolution of hydrops, healthy long-term survival and normal development in some children. These results were impressive given the near-certain fetal mortality when fetal hydrops is left untreated. For example, in a 2004 report of 4 cases of open surgical resection of SCT, Hedrick et al. reported 1 neonatal death and 3 survivals with a follow-up range of 20 months to 6 years.19 Complications other than the fetal death included 1 embolic event, 1 chronic lung disease and 1 tumor recurrence. The 2011 AHRQ assessment identified 7 retrospective cohorts and case series from 3 academic fetal surgery groups in the United States and the United Kingdom. The 17 fetuses treated with open surgery were compared with 94 cases with other interventions or no intervention; however, the expectant management cases were less severe. Other ablation methods included alcohol sclerosis (all 3 cases died), radiofrequency ablation (RFA; 4/7 survived) and laser ablation (all 4 died). For open surgical procedures, survival rates were 33% to 75%. All fetal and neonatal deaths occurred among patients with hydrops or prodromal cardiovascular changes related to developing hydrops. Challenges in this area are the early and reliable detection of development of hydrops and the timing of the fetal intervention.4
In 2014, Van Mieghem et al. reported a case series of 5 fetuses with SCT treated with fetal interventions, along with a systematic review on fetal therapies for solid SCTs.20 Cases included in the case series were women presenting between 17 5/7 and 26 4/7 weeks of gestation with fetuses found to have large SCT with evidence of fetal heart failure. Treatment was conducted with fetoscopic laser ablation (n = 1), RFA (n = 2) or interstitial laser ablation with or without vascular coiling (n=2). Two intrauterine fetal deaths occurred; the remaining 3 cases resulted in preterm labor within 10 days of surgery. Of those surviving to delivery, 1 death occurred and 2 infants survived without procedure-related complications but with complications of prematurity. In the authors’ literature review, 21 case reports, case series and cohort studies were identified, which were generally assessed to be of poor to fair quality. Twenty-nine cases of minimally invasive procedures, with embolization of the SCT vasculature by a variety of therapies, for fetal SCT treatment were identified; they were associated with an overall survival rate of 44%. Twelve cases of open fetal surgery for SCT were identified, with survival of 55%. The authors noted that, absent treatment, fetal mortality with large fetal vascular SCTs approaches 100%, providing a rationale for fetal intervention.
As noted in the 2011 AHRQ assessment, more than 200 fetuses with myelomeningocele have undergone open surgical repair in the United States.4 All 25 reports on open surgery identified in the AHRQ assessment were based on 4 series of patients from 4 academic medical centers in the United States. Two studies had concurrent comparisons.21,22 One of these analyzed the first 29 cases of open myelomeningocele repair at Vanderbilt University Medical Center, finding significant reductions in the need for postnatal shunt placement (51% vs. 91%) and reduced hindbrain herniation (38% vs. 95%). However, both prospective studies found that in utero repair was associated with higher rates of oligohydramnios (48% vs. 4%), lower gestational ages (33 weeks vs. 37 weeks) and no difference in lower extremity function.
Randomized Controlled Trials
In 2011, results of the National Institutes of Health‒sponsored Management of Myelomeningocele Study (MOMS), comparing prenatal repair to standard postnatal repair, were published.23 This RCT began in 2003 and enrolled pregnant women ages 18 years or older whose fetuses had myelomeningocele. Women assigned to have prenatal surgery were scheduled for surgery within 1 to 3 days after they were randomized and stayed near the MOMS center until they delivered by Cesarean section. Women in the postnatal group traveled back to their assigned MOMS center to deliver, also by Cesarean section, around the 37th week of gestation. Follow-up on the children was performed at 1 year and 2.5 years of age to evaluate motor function, developmental progress and bladder, kidney and brain development. There was a voluntary moratorium in the United States on conducting in utero repair of myelomeningocele outside of this trial.4
The inclusion criteria for MOMS were singleton pregnancy, myelomeningocele with the upper boundary located between T1 and S1, evidence of hindbrain herniation, gestational age of 19.0 to 25.9 weeks at randomization, normal karyotype, U.S. residency and maternal age at least 18 years. Major exclusion criteria were fetal anomaly unrelated to myelomeningocele, severe kyphosis, risk of preterm birth, placental abruption, body mass index (BMI) of 35 kg/m2 or greater and contraindication to surgery, including previous hysterotomy in the active uterine segment. Surgeons had performed at least 15 procedures before this randomized study. Primary outcomes were a composite of fetal or neonatal death or the need for a cerebrospinal fluid shunt (shunt placement or meeting criteria for shunt) at 12 months and a composite score of the Mental Development Index of the Bayley Scales of Infant Development II and the child’s motor function at 30 months adjusted by level of lesion. Secondary outcomes were surgical and pregnancy complications and neonatal morbidity and mortality. Women were randomized to treatment group in 1:1 ratio.
Recruitment, planned to include 200 subjects, was stopped at 183 subjects when a clear advantage of prenatal intervention was apparent. The 2013 report included 158 woman randomized before July 1, 2009. Outcomes up to 30 months were based on 138 women randomized before Dec. 1, 2007. Groups were similar other than that there were more female fetuses and the lesion level was more severe in the prenatal surgery group. Two perinatal deaths occurred in each treatment group. Both deaths in the prenatal surgery group occurred on the fifth postoperative day, a still birth at 26 weeks and a neonatal death due to prematurity at 23 weeks of gestation. Two neonates in the postnatal surgery group died with severe symptoms of the Chiari II malformation. Fetal or neonatal death or the need for shunt occurred in 68% of infants in the prenatal-surgery group and in 98% of the postnatal-surgery group (RR = 0.70; 97.7% CI, 0.58 to 0.84; p < 0.001). Shunts were placed in 40% of the prenatal surgery and in 82% of postnatal surgery groups (p < 0.001). At 12 months, 4% of infants in the prenatal surgery group had no evidence of hindbrain herniation versus 36% in the postnatal surgery group. There was 1 death in each group between 12 and 30 months (coxsackie septicemia in a child who received prenatal surgery and complications of chemotherapy for choroid plexus carcinoma in a child who received postnatal surgery).
The composite of score of Bayley Scales and motor function adjusted by lesion level at 30 months was significantly better in the prenatal surgery group: mean (SD) of 148.6 (57.5) in the prenatal surgery group (n = 64) and 122.6 (57.2) in the postnatal surgery group (n = 70) (p = 0.007).
Maternal morbidity and complications related to prenatal surgery included oligohydramnios, chorioamniotic separation, placental abruption and spontaneous membrane rupture. At delivery, an area of dehiscence or a very thin prenatal uterine surgery scar was seen in one-third of mothers who had prenatal fetal surgery. The average gestational age of babies in the prenatal surgery group was 34.1 weeks, and 13% were delivered before 30 weeks of gestation. One-fifth of infants in the prenatal surgery group had evidence of respiratory distress syndrome, which was likely related to prematurity. The trialists observed that “in the case of infants with low lumbar and sacral sessions, in whom less impairment in lower-limb function may be predicted, the normalization of hindbrain position and the minimization of the need for postnatal placement of cerebral spinal shunt may be the primary indication for surgery.” They cautioned that the potential benefits of fetal surgery must be balanced against the risks of premature delivery and maternal morbidity and that continued assessment is required to learn if early benefits of prenatal surgery and effects of fetal surgery on bowel and bladder continence, sexual function and mental capacity are sustained. They warned that trial results should not be generalized to centers with less experience or to patients who do not meet eligibility criteria.
A 2004 report by Bruner et al. described minimum 12-month follow-up of 116 fetuses after intrauterine repair of spina bifida (myelomeningocele or myeloschisis).24 Sixty-one (54%) fetuses required ventriculoperitoneal shunt placement for hydrocephalus. Statistical analysis revealed that fetuses were less likely to require ventriculoperitoneal shunt placement when surgery was performed at 25 weeks or earlier, when ventricular size was less than 14 mm at the time of surgery, and when the defects were located at L4 or below. Johnson et al. reported on the results of a series of 50 fetuses who underwent open fetal closure of a myelomeningocele between 20 and 24 weeks of gestation.25 Fetal selection criteria included the presence of hindbrain herniation and sonographic evidence of intact neurologic function (i.e., movement of the lower extremities, absence of clubfoot deformities). Perinatal survival was 94%, with a mean age at delivery of 34 weeks. All fetuses demonstrated reversal of hindbrain herniation; 43% required ventriculoperitoneal shunting compared with 68% to 100% in historical controls, depending on the location of the myelomeningocele. Another study reporting leg function at longer follow-up showed no difference between patients treated with fetal surgery at 20 to 28 weeks and traditional surgery.21
In 3 articles, investigators at the University of Pennsylvania reported outcomes of myelomeningocele repair in 54 patients treated before the voluntary moratorium.26,27,28 At median follow-up of 66 months (range, 36 – 113 months), 37 (69%) of 54 walked independently, 13 (24%) of 54 were assisted walkers and 4 (7%) of 54 were wheelchair dependent. The strongest factors predicting a lower likelihood to walk independently were higher level lesion (> L4) and the development of clubfoot deformity after fetal intervention. Most independent ambulators, and all children who required assistive devices to walk experienced significant deficits in lower-extremity coordination.27 Thirty children returned at 5 years of age for neurocognitive examination. In this highly selected group, most children had average preschool neurodevelopmental scores, and children who did not require shunt placement were more likely to have better scores.28 A survey of 48 families focused on hindbrain herniation‒associated brainstem dysfunction (e.g., apnea, neurogenic dysphagia, gastroesophageal reflux disease, neuro-ophthalmologic disturbances).26 Half of the children required shunting. At a median age of 72 months, 15 nonshunted and 10 shunted children were free of hindbrain herniation symptoms. There were no hindbrain herniation‒related deaths, and no children developed severe persistent cyanotic apnea. Most children had no or only mild brainstem dysfunction. The authors concluded that reversal of hindbrain herniation after fetal surgery may reduce the incidence and severity of brainstem dysfunction.
Investigators at a German center retrospectively analyzed expectantly managed patients who received surgical intervention within 2 days of birth at their institution and compared them with outcomes after fetal surgery from other centers, including those previously discussed and to data from historical controls.29 Patients were born between 1979 and 2009 and had reached a mean (SD) age of 13.3 (8.9) years. Gestational age at birth in the expectantly managed group was 37.8 weeks, significantly higher than in the prenatal surgery patients. In the expectantly managed group, shunt placement was required in 69.8% at mean (SD) age of 16.0 (10.7) days, which was less than for historical controls and comparable to data reported on patients who received fetal surgery. The authors suggested that inconsistency in clinical criteria for shunting used in studies might contribute to differences in this outcome. Among their expectantly managed patients, 56.4% were assisted walkers and 64.1% attended regular classes, both comparable with historical controls. Noting the discrepancy in the rate of assisted walkers and wheelchair users between expectantly managed patients/historical controls and patients who received surgery, the authors observed that the mean age of the study population was 21.7 years for historical controls, 13.3 years for their population and only 67.0 months after fetal surgery. They cited earlier studies reporting mobility decreases from early childhood to the early teens including 1 reporting that “the percentage of patients ambulating the majority of time decreased from 76% at 0-5 years to 46% at 20-25 years, with a flattening beyond 10 years.”30
Following publication of the MOMS results, Moldenhauer et al. assessed outcomes for a cohort of patients treated at single institution with fetal myelomeningocele repair from 2011 to 2014.31 A total of 587 patients were referred for potential fetal myelomeningocele repair during the study period, of whom 348 (59.3%) underwent onsite evaluations and 209 (35.6%) were excluded due to noncandidacy for the procedure (BMI >35 kg/m2, additional fetal anomalies, genetic diagnosis in the fetus, gestational age > 26 weeks, pre-existing maternal medical condition, multiple pregnancy, no hindbrain herniation on magnetic resonance imaging). A total of 139 (23.7%) patients were considered potential candidates for fetal myelomeningocele repair, of whom 101 underwent open fetal surgery, 13 had postnatal management and 25 underwent pregnancy termination. Average gestational age at the time of fetal surgery was 23.4 weeks. Fetal resuscitation (need for intraoperative cardiac compressions and/or administration of atropine, epinephrine or blood products via the umbilical vein) was successfully performed in 5 cases. Preterm premature rupture of membranes (PPROM) occurred in 31 (32.3%) of 96 patients and preterm labor occurred in 36 (37.5%) of 96 patients. Sixteen patients had PPROM with preterm labor. The perinatal loss rate was 6.1% (6/98), which included 2 intrauterine demises, 1 diagnosed at the conclusion of fetal myelomeningocele repair and 1 on postoperative day 1, and 4 neonatal deaths. Maternal complications included clinical chorioamnionitis (n = 4), persistent oligohydramnios (n = 6), pre-eclampsia/gestational hypertension (n = 1) and placental abruption (n = 2). For the 83 patients liveborn at the authors’ institution, hindbrain herniation was reversed in 71.1%, and the functional level improved compared with prenatal sonographic bony lesion level in 44 (55%) of 80 neonates assessed. The authors concluded that their experience with fetal myelomeningocele repair was similar to that reported in the MOMS trial.
Bennett et al. compared outcomes for a cohort of patients treated with fetal myelomeningocele repair in the post-MOMS era to those treated at the same institution during MOMS.32 Outcomes were evaluated for 43 patients treated with fetal myelomeningocele repair from 2011 to 2013 and compared to those for 78 patients treated as part of MOMS. During the study time period, the repair technique was modified so that no uterine trocar was used, and uterine entry, manipulation and closure were modified to reduce amniotic membrane separation. Although the mean gestational age at delivery was similar for the post-MOMS and the MOMS cohort (34.4 weeks vs. 34.1 weeks, respectively), a greater proportion of post-MOMS cohort subjects were born after 37 weeks of gestation (39% vs. 21%, p = 0.03). Post-MOMS cohort subjects had lower incidences of premature rupture of membranes (22% vs. 46%, p = 0.011) and chorioamnion separation (0% vs. 26%, p < 0.001). These results suggested that fetal myelomeningocele repair outcomes in practice can be comparable to or better than those obtained in the MOMS study.
Section Summary: Myelomeningocele
The most direct evidence related to fetal myelomeningocele repair comes from the MOMS study, an RCT that demonstrated significant benefits across multiple outcomes for fetal repair. Single-arm studies have supported these findings. Therefore, fetal myelomeningocele may be considered medically necessary following informed decision making for cases that meet the criteria of the MOMS trial.
The 2011 AHRQ technology assessment included the following evidence on fetal surgery for cardiac malformations::
- Two case series (total N = 10) were identified on fetal surgery for pulmonary atresia and intact ventricular septum. The literature was described as scant, reflecting the early formative period of development of procedures for this rare condition.
- Eight prospective case series (total N = 90) were identified on balloon dilation for critical aortic stenosis. One center in the United Kingdom, 2 centers in Germany, 2 in Brazil and 1 in the United States performed this procedure. Seventy patients were from Boston. The 2011 assessment concluded that it is difficult to determine whether the procedure changes long-term outcomes, because it appears to increase the risk of fetal loss but potentially prevents neonatal deaths. However, it did appear that technical success improves over time within a dedicated team and center. For example, the North American center improved its success rate from 25% to 90% over several years. The literature was considered to be very early in development.
- Three case series from 1 U.S. institution (total N = 24 patients) addressed the in utero creation of an atrial septal defect for an intact atrial septum. There were no reports of this procedure performed outside of the United States. The procedure appears to have technical success; however, mortality remains high, and no controlled trials were available to compare outcomes in patients treated prenatally and postnatally.
The AHRQ report concluded that, overall, procedures for severe fetal cardiac anomalies are in an early stage. Preliminary work is being reported in a few highly specialized centers that are establishing the groundwork for feasibility and future directions for outcomes research in this area. The authors concluded that the most pressing challenge is the ability to identify the “right” patient whose care would be compromised by waiting for postnatal repair.
McElhinney et al. analyzed their group's experience with 70 prenatal balloon aortic valvuloplasties attempted in mid-gestational fetuses between March 2000 and October 2008 for critical aortic stenosis with evolving hypoplastic left heart syndrome (HLHS) to identify factors associated with procedural and postnatal outcomes.33 Median gestational age was 23.2 weeks (range, 20 – 31 weeks). Technical success was achieved in 52 fetuses. Compared with 21 untreated fetuses, subsequent prenatal growth of the aortic and mitral valves, but not the left ventricle, was improved after intervention. Nine pregnancies did not reach viable term or preterm birth. Seventeen patients had a biventricular circulation postnatally, 15 of them from birth. Two of these patients had no neonatal intervention. Sixteen were alive at a median age of 2.1 years (range, 4 months to 7 years). The other patient died of unrelated causes. Guidelines for assessing the potential for a biventricular circulation changed during the study period and became more selective. Larger left heart structures and higher LV pressure at the time of intervention were associated with biventricular outcome. The authors concluded that further investigation is required before it is possible to predict whether fetal intervention will improve left heart growth and postnatal survival with a biventricular circulation, and “the potential benefits of fetal intervention must be weighed against the risk of technical failure, fetal demise, aortic regurgitation and potential long-term adverse events that have yet to be identified.”
In 2013, Marantz et al. reported results from a case series of 5 prenatal balloon aortic valvuloplasties for fetuses with aortic stenosis and risk of progression to HLHS.34 The procedure was technically successful in all cases with no maternal complications or fetal demise. One pregnancy was terminated after the procedure; of the remaining cases, 1 progressed to HLHS and 3 did not. Rates of longer term survival and complications were not provided. The authors conclude that fetal aortic valvuloplasty is safe and feasible.
Pedra et al. reported a case series of 22 fetal cardiac interventions for several cardiac conditions in 21 fetuses in Brazil.35 Fetal cardiac intervention was considered for the following echocardiographic findings in patients with isolated cardiac defects (i.e., no other structural abnormality or marker for chromosomal abnormality): (1) critical aortic stenosis with evolving HLHS (n = 9); (2) critical aortic stenosis, massive mitral regurgitation, giant left atrium and hydrops (n = 4); (3) HLHS with intact interatrial septum or small patent foramen ovale (n = 4); and (4) pulmonary atresia with intact ventricular septum or critical pulmonary stenosis with impending hypoplastic right heart syndrome (n = 4). Fetal interventions included atrial septostomy, aortic valvuloplasty, pulmonary valvuloplasty or a combination of aortic septostomy and aortic valvuloplasty in 1 case. Technical success was achieved in 20 (91%) of 22 procedures, with 1 failed aortic and 1 failed pulmonary valvuloplasty. There was 1 fetal death, but no maternal complications. Longer term outcomes were generally poor, even among those with successful interventions. Among the 20 with successful fetal interventions, 8 eventually achieved biventricular circulation, with 1 “probable” biventricular circulation, and 12 deaths.
Chaturvedi et al. reported outcomes from a series of 10 fetuses who underwent active perinatal management for HLHS with restrictive or intact atrial septum at a single institution from 2000 to 2012.36 Four of the fetuses underwent percutaneous stenting of the atrial septum. No maternal complications occurred. At follow-up, 2 children were alive at 16 and 20 months. Two neonatal deaths occurred in fetuses with the highest left atrial hypertension before intervention and recurrence in utero of left atrial hypertension secondary to stent stenosis.
Kalish et al. reported outcomes for 9 fetuses with HLHS with intact atrial septum who underwent prenatal atrial septal stent placement.37 Atrial septal stent placement was attempted in 9 fetuses, with successful stent deployment in 5, of which 4 demonstrated flow across the stent at the time of intervention. In the remaining 4 cases, stent placement was technically unsuccessful, but in 75% of cases, atrial balloon septoplasty during the same procedure was successful. One fetal death occurred, along with 4 neonatal deaths, 2 of which had undergone stenting. No maternal complications were reported.
Section Summary: Cardiac Malformations
Evidence related to fetal interventions for congenital heart defects, particularly for evolving HLHS and critical pulmonary stenosis/pulmonary atresia, is limited to small case series. Although postnatal repair/correction of these severe cardiac defects is associated with very high morbidity and mortality, further studies are needed to demonstrate that health outcomes are improved with fetal interventions. Randomized trials are unlikely to be conducted, but comparative studies with concurrent controls would provide further insight into the net benefit of and appropriate patient populations for fetal cardiac interventions.
The use of fetal surgery for other defects is expanding; recent case reports include prenatal correction of cleft lip and palate and decompression of the fetal trachea.38,39
A review of 187 maternal-fetal surgeries performed at the University of California San Francisco Fetal Treatment Center found significant short-term maternal morbidity but no maternal deaths.40 Postsurgical complications included increased rates of Cesarean birth, treatment in intensive care, prolonged hospitalization and blood transfusion.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
|NCT No.||Trial Name||Planned Enrollment||Completion Date|
Lower urinary tract obstruction
Randomized Controlled Trial of Fetal Cystoscopy Versus Vesico-amniotic Shunting in Severe Lower Urinary Tract Obstructions
Congenital diaphragmatic hernia
"Early" Versus "Standard" Fetal Endoscopic Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia - a Randomized Controlled Trial
A Prospective Study of the Effectiveness of Fetal Endotracheal Occlusion (FETO) in the Management of Severe and Extremely Severe Congenital Diaphragmatic Hernia
Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left Sided and Isolated Congenital Diaphragm Hernia and Severe Pulmonary Hypoplasia.
Percutaneous Endoscopic Tracheal Plug/Unplug for Congenital Diaphragmatic Hernia
Prenatal Surgical Repair of Fetal Myelomeningocele
Minimally Invasive Fetal Neural Tube Defect Repair S
Evolving hypoplastic left heart syndrome
Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome
NCT: national clinical trial.
Summary of Evidence
Due to a number of factors, including the rarity of the conditions and the small number of centers specializing in fetal interventions, the evidence on fetal surgery is limited. Fetal surgery for many congenital conditions, including congenital diaphragmatic hernia (CDH) and heart defects, has not been shown to improve health outcomes compared with postnatal treatment. The available evidence is insufficient to demonstrate that fetal tracheal occlusion for CDH and fetal intervention for evolving hypoplastic left heart syndrome (HLHS) and critical pulmonary stenosis or pulmonary atresia provides improved health outcomes. For these and other applications of fetal surgery that are currently considered investigational, additional studies are needed to identify appropriate candidates and to evaluate longer term outcomes compared with postnatal management.
For conditions leading to fetal hydrops (certain cases of congenital cystic adenomatoid malformation, bronchopulmonary sequestration or sacrococcygeal teratoma), for which mortality approaches 100%, fetal surgery may be considered medically necessary. For bilateral urinary tract obstruction, evidence from retrospective and prospective cohort studies summarized in the 2011 Agency for Healthcare Research and Quality technology assessment on fetal surgery suggests that vesicoamniotic shunting improves survival, at least in the short term. A recent small, randomized controlled trial evaluating the use of vesicoamniotic shunting found limited benefit from the procedure when data were analyzed by intention-to-treat analysis. However, the study's significant limitations, including low enrollment leading to early cessation of the study and significant crossover between treatment and control groups, make it difficult to draw firm conclusions from its findings. As such, vesicoamniotic shunting for bilateral urinary tract obstruction may also be considered medically necessary to minimize the effects of this condition on kidney and lung development. Additional studies for these surgeries are needed to better define the appropriate surgical candidates, the most effective timing of the interventions and the long-term health outcomes in surviving children.
Data from the MOMS trial showed that prenatal repair of myelomeningocele reduces the need for shunting in the first 12 months after delivery and improves a composite measure of mental and motor function, with adjustment for lesion level, at 30 months of age. Prenatal surgery also improves the degree of hindbrain herniation and the likelihood of being able to walk independently when compared with postnatal surgery. The long-term impact on function needs to be evaluated, and benefits must be balanced against risks to mother and child. Thus, fetal surgery may be considered medically necessary following informed decision making for cases of prenatal myelomeningocele that meet the criteria of the MOMS trial.
Practice Guidelines and Position Statements
American College of Obstetricians and Gynecologists and American Academy of Pediatrics
ACOG’s Committee on Ethics and AAP's Committee on Bioethics issued a committee opinion on maternal-fetal intervention and fetal care centers in 2011.41 The opinion recommended that:
- Fetal intervention cannot be performed without the explicit informed consent of the pregnant woman.
- Distinctions should be made to prospective parents between which protocols are standard or evidence-based therapies and which are innovative or experimental interventions.
- The informed consent process should involve thorough discussion of the risks and benefits for both the fetus and the pregnant woman.
- Safeguards should be in place to protect women considering fetal research.
- Access to support services such as social services, palliative care and perinatal hospice services, genetic counseling and ethics consultation should be provided, when appropriate.
- The organization and governance of centers providing fetal interventions should involve a diverse group of professionals, including members without direct ties to the center involved.
- Cooperation between fetal care centers should be encouraged to establish collaborative research networks and to support multicenter trials to accumulate more robust short- and long-term maternal and fetal outcome data on all categories of fetal intervention. In addition, the establishment of centers of excellence for those procedures that are particularly challenging and rare may help to optimize fetal and maternal outcomes.
International Fetal Medicine and Surgery Society
A consensus, endorsed by the IFMSS, proposed the following criteria for fetal surgery12:
- “Accurate diagnosis and staging possible, with exclusion of associated anomalies
- Natural history of the disease is documented, and prognosis established
- Currently no effective postnatal therapy
- In utero surgery proven feasible in animal models, reversing deleterious effects of the condition
- Interventions performed in specialized multidisciplinary fetal treatment centers within strict protocol and approval of the local Ethics Committee and with informed consent of the mother or parents.”
National Institute of Child Health and Human Development
The National Institute of Child Health and Human Development convened the fetal myelomeningocele Maternal-Fetal Management Task Force with representatives from the American Academy of Pediatrics (AAP), American College of Obstetricians and Gynecologists (ACOG), American Institute of Ultrasound in Medicine, American Pediatric Surgical Association, American Society of Anesthesiologists, American Society of Pediatric Neurosurgeons, International Fetal Medicine and Surgery Society (IFMSS), American Association of Neurological Surgeons/Congress of Neurological Surgeons, North American Fetal Therapy Network, Society for Maternal-Fetal Medicine, Society of Pediatric Anesthesia and Spina Bifida Association. The Task Force provided recommendations about optimal practice criteria for maternal-fetal surgery for myelomeningocele repair.42 Recommendations are related to 6 key considerations for teams providing in utero myelomeningocele repair:
- Defining a fetal therapy center
- Perioperative management for fetal myelomeningocele repair
- Long-term care
- Reporting and monitoring
- Access and regionalization.
In general, the authors emphasized the need for access to multidisciplinary teams for prenatal, perinatal and follow-up care, and recommended that in utero myelomeningocele repair be performed under strict adherence to the MOMS trial protocol in terms of preoperative evaluation, intraoperative procedure and immediate postoperative care.
American College of Obstetricians and Gynecologists
In 2013, ACOG issued a committee opinion on maternal-fetal surgery for myelomeningocele.43 This opinion states, “Maternal-fetal surgery is a major procedure for the woman and her fetus, and it has significant implications and complications that occur acutely, postoperatively, for the duration of the pregnancy, and in subsequent pregnancies. Therefore, it should only be offered at facilities with the expertise, multidisciplinary teams, services and facilities to provide the intensive care required for these patients.”
U.S. Preventive Services Task Force Recommendations
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- Blue Cross and Blue Shield Technology Evaluation Center. Fetal surgery for prenatally diagnosed malformations. Technology Assessment. 1998;Vol 13, Tab 22.
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- Walsh WF, Chescheir NC, Gillam-Krakauer M, et al. Maternal-fetal surgical procedures. Comparative Effectiveness Technical Briefs, No. 5. Rockville (MD): Agency for Healthcare Research and Quality (US) 2011 Apr. Report No. 10(11)-EHC059-EF. http://www.ncbi.nlm.nih.gov/books/NBK54520/pdf/TOC.pdf. Accessed October, 2011.
- Biard JM, Johnson MP, Carr MC, et al. Long-term outcomes in children treated by prenatal vesicoamniotic shunting for lower urinary tract obstruction. Obstet Gynecol. Sep 2005;106(3):503-508. PMID 16135579
- Kilby M, Khan K, Morris K, et al. PLUTO trial protocol: percutaneous shunting for lower urinary tract obstruction randomised controlled trial. BJOG. Jul 2007;114(7):904-905, e901-904. PMID 17567421
- Morris RK, Malin GL, Quinlan-Jones E, et al. Percutaneous vesicoamniotic shunting versus conservative management for fetal lower urinary tract obstruction (PLUTO): a randomised trial. The Lancet. 2013;382(9903):1496-1506.
- Morris RK, Malin GL, Khan KS, et al. Systematic review of the effectiveness of antenatal intervention for the treatment of congenital lower urinary tract obstruction. BJOG. Mar 2010;117(4):382-390. PMID 20374578
- Morris RK, Malin GL, Quinlan-Jones E, et al. The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controlled trial: evaluation of the effectiveness, cost-effectiveness and acceptability of percutaneous vesicoamniotic shunting for lower urinary tract obstruction. Health Technol Assess. Dec 2013;17(59):1-232. PMID 24331029
- Flake AW, Crombleholme TM, Johnson MP, et al. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol. Nov 2000;183(5):1059-1066. PMID 11084541
- Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med. Nov 13 2003;349(20):1916-1924. PMID 14614166
- Deprest J, Jani J, Lewi L, et al. Fetoscopic surgery: encouraged by clinical experience and boosted by instrument innovation. Semin Fetal Neonatal Med. Dec 2006;11(6):398-412. PMID 17056307
- Cortes RA, Keller RL, Townsend T, et al. Survival of severe congenital diaphragmatic hernia has morbid consequences. J Pediatr Surg. Jan 2005;40(1):36-45; discussion 45-36. PMID 15868556
- Ruano R, Duarte SA, Pimenta EJdA, et al. Comparison between fetal endoscopic tracheal occlusion using a 1.0-mm fetoscope and prenatal expectant management in severe congenital diaphragmatic hernia. Fetal Diag Ther. 2011;29(1):64-70.
- Ruano R, Yoshisaki CT, da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. Jan 2012;39(1):20-27. PMID 22170862
- Rocha LA, Byrne FA, Keller RL, et al. Left heart structures in human neonates with congenital diaphragmatic hernia and the effect of fetal endoscopic tracheal occlusion. Fetal Diagn Ther. 2014;35(1):36-43. PMID 24356206
- Shan W, Wu Y, Huang G, et al. Foetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia--a systemic review and meta-analysis of randomized controlled trials. J Pak Med Assoc. Jun 2014;64(6):686-689. PMID 25252491
- White SB, Tutton SM, Rilling WS, et al. Percutaneous in utero thoracoamniotic shunt creation for fetal thoracic abnormalities leading to nonimmune hydrops. J Vasc Interv Radiol. Jun 2014;25(6):889-894. PMID 24702750
- Hedrick HL, Flake AW, Crombleholme TM, et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg. Mar 2004;39(3):430-438; discussion 430-438. PMID 15017565
- Van Mieghem T, Al-Ibrahim A, Deprest J, et al. Minimally invasive therapy for fetal sacrococcygeal teratoma: case series and systematic review of the literature. Ultrasound Obstet Gynecol. Jun 2014;43(6):611-619. PMID 24488859
- Tubbs RS, Chambers MR, Smyth MD, et al. Late gestational intrauterine myelomeningocele repair does not improve lower extremity function. Pediatr Neurosurg. Mar 2003;38(3):128-132. PMID 12601237
- Bruner JP, Tulipan N, Paschall RL, et al. Fetal surgery for myelomeningocele and the incidence of shuntdependent hydrocephalus. JAMA. Nov 17 1999;282(19):1819-1825. PMID 10573272
- Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. Feb 9 2011;364(11):993-1004. PMID 21306277
- Bruner JP, Tulipan N, Reed G, et al. Intrauterine repair of spina bifida: preoperative predictors of shuntdependent hydrocephalus. Am J Obstet Gynecol. May 2004;190(5):1305-1312. PMID 15167834
- Johnson MP, Sutton LN, Rintoul N, et al. Fetal myelomeningocele repair: short-term clinical outcomes. Am J Obstet Gynecol. Aug 2003;189(2):482-487. PMID 14520222
- Danzer E, Finkel RS, Rintoul NE, et al. Reversal of hindbrain herniation after maternal-fetal surgery for myelomeningocele subsequently impacts on brain stem function. Neuropediatrics. Dec 2008;39(6):359-362. PMID 19569004
- Danzer E, Gerdes M, Bebbington MW, et al. Lower extremity neuromotor function and short-term ambulatory potential following in utero myelomeningocele surgery. Fetal Diagn Ther. 2009;25(1):47-53. PMID 19174610
- Danzer E, Gerdes M, Bebbington MW, et al. Preschool neurodevelopmental outcome of children following fetal myelomeningocele closure. Am J Obstet Gynecol. May 2010;202(5):450 e451-459. PMID 20347433
- Mayer S, Weisser M, Till H, et al. Congenital myelomeningocele - do we have to change our management? Cerebrospinal Fluid Res. 2010;7:17. PMID 20946644
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- Moldenhauer JS, Soni S, Rintoul NE, et al. Fetal myelomeningocele repair: the post-MOMS experience at the Children's Hospital of Philadelphia. Fetal Diagn Ther. Aug 15 2014. PMID 25138132
- Bennett KA, Carroll MA, Shannon CN, et al. Reducing perinatal complications and preterm delivery for patients undergoing in utero closure of fetal myelomeningocele: further modifications to the multidisciplinary surgical technique. J Neurosurg Pediatr. Jul 2014;14(1):108-114. PMID 24784979
- McElhinney DB, Marshall AC, Wilkins-Haug LE, et al. Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. Circulation. Oct 13 2009;120(15):1482-1490. PMID 19786635
- Marantz P, Aiello H, Grinenco S, et al. Foetal aortic valvuloplasty: experience of five cases. Cardiology in the Young. 2013;23(05):675-681.
- Pedra SR, Peralta CF, Crema L, et al. Fetal interventions for congenital heart disease in Brazil. Pediatr Cardiol. Mar 2014;35(3):399-405. PMID 24030590
- Chaturvedi RR, Ryan G, Seed M, et al. Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension. Int J Cardiol. Oct 3 2013;168(3):2029-2036. PMID 23481911
- Kalish BT, Tworetzky W, Benson CB, et al. Technical challenges of atrial septal stent placement in fetuses with hypoplastic left heart syndrome and intact atrial septum. Catheter Cardiovasc Interv. Jul 1 2014;84(1):77-85. PMID 23804575
- Papadopulos NA, Papadopoulos MA, Kovacs L, et al. Foetal surgery and cleft lip and palate: current status and new perspectives. Br J Plast Surg. Jul 2005;58(5):593-607. PMID 15992528
- Kohl T, Hering R, Bauriedel G, et al. Fetoscopic and ultrasound-guided decompression of the fetal trachea in a human fetus with Fraser syndrome and congenital high airway obstruction syndrome (CHAOS) from laryngeal atresia. Ultrasound Obstet Gynecol. Jan 2006;27(1):84-88; discussion 88. PMID 16308883
- Golombeck K, Ball RH, Lee H, et al. Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol. Mar 2006;194(3):834-839. PMID 16522421
- American College of Obstetricians and Gynecologists Committee on Ethics and the American Academy of Pediatrics Committee on Bioethics. Committee opinion no. 501: Maternal-fetal intervention and fetal care centers. Obstet Gynecol. Aug 2011;118(2 Pt 1):405-410. PMID 21775875
- Cohen AR, Couto J, Cummings JJ, et al. Position statement on fetal myelomeningocele repair. Am J Obstet Gynecol. Feb 2014;210(2):107-111. PMID 24055581
- American College of Obstetricians and Gynecologists. ACOG Committee opinion no. 550: maternal-fetal surgery for myelomeningocele. Obstet Gynecol. Jan 2013;121(1):218-219. PMID 23262964
|CPT||59076||Fetal shunt placement, including ultrasound guidance|
|59897||Unlisted fetal invasive procedure, including ultrasound guidance|
|Correction of fetal defect|
|ICD-9 Diagnosis||653.73||Other fetal abnormality causing disproportion, antepartum condition or complication (includes myelomeningocele)|
|655.8||Other known or suspected fetal abnormality, not elsewhere classified (includes fetal urinary tract obstruction, fetal diaphragmatic hernia, and fetal cystic adenomatoid malformation)|
|656.7||Other fetal and placental problems affecting the management of mother (includes placentomegaly)|
|658.0||Oligohydramnios (known of suspected fetal abnormality affecting management of mother)|
|V28.1||Screening for raised alpha-fetoprotein levels in amniotic fluid (ie, prenatal diagnosis of spina bifida)|
|HCPCS||S2400||Repair, congenitally diaphragmatic hernia in the fetus using temporary tracheal occlusion, procedure performed in utero|
|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, procedure 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|
|ICD-10-CM (effective 10.01.15)||O3.7xx0||Maternal care for disproportion due to other fetal deformities|
|O35.0xx0-O35.9xx9||Maternal care for known or suspected fetal abnormality and damage; code range|
|O41.000-O41.939||Other disorders of amniotic fluid and membranes; code range|
|O43.011-O43.199||Placental disorders; code range|
|Q05.0-Q05.9||Spina bifida; code range|
|Z36||Encounter for antenatal screening of mother|
|ICD-10-PCS (effective 10/01/15)||
|Obstetrics, repair, nervous system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, cardiovascular system in products of conception, code depending on approach use of device or no device|
|Obstetrics, repair, lymphatics and hemic in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, eye in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, ear, nose and sinus in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, respiratory system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, mouth and throat in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, gastrointestinal system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, hepatobiliary and pancreas in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, endocrine system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, skin in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, musculoskeletal system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, urinary system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, female reproductive system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, male reproductive system in products of conception, code depending on approach and use of device or no device|
|Obstetrics, repair, other body system in products of conception, code depending on approach and use of device or no device|
|Type of Service||Obstetric/Gynecology|
|Place of Service||Inpatient|
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.
"Current Procedural Terminology © American Medical Association. All Rights Reserved"
History From 2014 Forward
Annual review. No change to policy intent.
Annual review. No change to policy intent.
Annual review. No change to policy intent.
Annual review. No change to policy intent.
Annual review. No change to policy intent
Annual review, no change to policy intent.
Annual review, no change to policy intent. Updating rationale and references.
Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.
Annual review. Updated rationale and references. No change to policy intnet.