Fetal Surgery In Utero
Number: 0449
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses fetal surgery In utero.
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Medical Necessity
Aetna considers the following interventions medically necessary:
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In utero fetal surgery for any of the following indications:
- Ablation of anastomotic vessels in acardiac twins; or
- Fetal endoscopic tracheal occlusion (FETO) for severe (i.e., observed‑to‑expected lung‑to‑head ratio (O/E LHR) less than 25%) congenital diaphragmatic hernia (CDH); or
- Insertion of pleuro-amniotic shunt for fetal pleural effusion; or
- Laser ablation or occlusion of anastomotic vessels in early, severe (stages II to IV) twin-twin transfusion syndrome (see Appendix for staging classification); or
- Removal of sacrococcygeal teratoma; or
- Repair of myelomeningocele; or
- Resection of malformed pulmonary tissue, or placement of a thoraco-amniotic shunt as a treatment of either of the following:
- Congenital cystic adenomatoid malformation; or
- Extralobar pulmonary sequestration; or
- Thoracoamniotic shunt for pleural effusions; or
- Twin reversed arterial perfusion (TRAP); or
- Vesico-amniotic shunting as a treatment of urinary tract obstruction;
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Serial amnioreduction for twin-to-twin transfusion syndrome when criteria are met:
- Women after 26 weeks of gestation; and
- Evidence of abnormal blood flow documented by Doppler studies in one or both fetuses; and
- Evidence of polyhydramnios in the recipient fetus; and
- Donor fetus is oligohydramniotic.
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Experimental, Investigational, or Unproven
The following interventions are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
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The following applications of in utero fetal surgery because its effectiveness for these indications has not been established:
- Fetal aortic valvuloplasty
- Fetoscopic laser ablation for type 2 vasa previa
- Shunting for the treatment of fetal cerebral ventriculomegaly
- Treatment of amniotic band syndrome
- Treatment of aqueductal stenosis (i.e., hydrocephalus)
- Treatment of cleft lip and/or cleft palate
- Treatment of congenital heart disease (e.g. mitral valve dysplasia)
- Treatment of fetal hydronephrosis
- Treatment of gastroschisis;
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In utero stem cell transplantation, in utero gene therapy, and other applications of in utero surgery.
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Related Policies
Background
Fetal surgery in utero refers to a group of specialized interventions performed during pregnancy to diagnose, treat, or mitigate congenital anomalies before birth, with the goal of improving fetal survival or postnatal outcomes. Procedures range from minimally invasive fetoscopic techniques (using endoscopes and small instruments introduced through the maternal abdomen and uterus) to open fetal surgery, in which a maternal laparotomy and hysterotomy are performed while maintaining uteroplacental circulation. Conditions commonly addressed include open spina bifida (myelomeningocele), twin–twin transfusion syndrome, congenital diaphragmatic hernia, lower urinary tract obstruction, and select cardiac or thoracic anomalies. Advances in imaging, anesthesia, and maternal–fetal medicine have allowed these procedures to be performed at highly specialized centers with multidisciplinary teams, balancing potential fetal benefit against maternal and pregnancy-related risks. Fetal surgery is typically guided by strict selection criteria and standardized perioperative management protocols based on accumulated clinical trial data and observational evidence (ACOG, 2017; Adzick et al., 2011; Moldenhauer and Flake, 2024).
Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia (CDH) is a serious congenital anomaly characterized by the incomplete formation of the diaphragm, which allows abdominal organs to herniate into the thoracic cavity. This condition leads to pulmonary hypoplasia, abnormal pulmonary vascular development, and persistent pulmonary hypertension, all of which are significant contributors to morbidity and mortality (Lally et al., 2007; Zani et al., 2022). CDH is diagnosed in approximately 1 in 3,000 live births, with reported rates ranging from 2 to 4 per 10,000 live births across various studies (Kuchnowska et al., 2024). The defect is most frequently observed on the left side (Bochdalek type) and can occur either as an isolated condition or in conjunction with congenital heart disease or genetic abnormalities, both of which can adversely affect prognosis (Zani et al., 2022). Recent advancements in prenatal imaging have improved risk stratification through assessments of lung size, such as the observed-to-expected lung-to-head ratio (O/E LHR) and liver position, which are closely associated with survival rates and the need for extracorporeal membrane oxygenation (ECMO) (Lally et al., 2007; Kuchnowska et al., 2024). Postnatal management emphasizes stabilizing cardiopulmonary function through lung-protective ventilation, aggressive treatment of pulmonary hypertension, delayed surgical repair until stabilization is achieved, and selective use of ECMO in severe cases, with outcomes largely influenced by the severity of the underlying disease (Lally et al., 2007; Zani et al., 2022).
Deprest et al. (2021a) noted that observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) is associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side; however, data from randomized trials are lacking. In an open-label trial conducted at centers experienced in FETO and other types of prenatal surgery, these researchers randomly assigned women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to either FETO at 27 to 29 weeks of gestation or expectant care in a 1:1 ratio. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit (NICU). These investigators used a group-sequential design with five pre-specified interim analyses for superiority, with a maximum sample size of 116 women. The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat (ITT) analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, compared with 15% (6 of 40) in the expectant care group (relative risk [RR], 2.67; 95% confidence interval [CI]: 1.22 to 6.11; 2-sided p = 0.009). Survival to six months of age was identical to survival to discharge (RR, 2.67; 95% CI: 1.22 to 6.11). The incidence of preterm, pre-labor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% versus 11%; RR, 4.51; 95% CI: 1.83 to 11.9), as was the incidence of preterm birth (PTB) (75% versus 29%; RR, 2.59; 95% CI: 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred due to failed balloon removal. In an analysis that included 11 additional subjects with data available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (RR, 2.65; 95% CI: 1.21 to 6.09). The authors concluded that in fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to six months of age; however, FETO increased the risks of preterm, pre-labor rupture of membranes and preterm birth (PTB).
The authors stated that this study had several drawbacks. A long time period was needed to complete the trial, during which the protocols for postnatal care of congenital diaphragmatic hernia may have changed; however, this would not have differentially affected outcomes between the two treatment groups. Furthermore, management teams were aware of group assignments, but this was unlikely to have affected outcomes. These researchers had information only on short-term outcomes; further study is needed to examine longer-term outcomes after FETO compared with expectant care for severe congenital diaphragmatic hernia. Although these investigators did not find an increased incidence of adverse outcomes associated with PTB in the FETO group, this study was not powered for these outcomes or for uncommon fetal or maternal complications. Because the trial involved experienced fetal surgery units, the findings should not be generalized to centers without extensive experience in fetoscopy and FETO or to centers that could not ensure the availability of a team capable of performing safe and effective balloon retrieval.
In an editorial that accompanied the aforementioned studies by Deprest et al. (2021a and 2021b), Foss (2021) stated that the findings of these studies advanced the understanding of the efficacy of FETO and may help inform counseling for parents and decision-making. However, no infant outcomes beyond six months of age were evaluated in either report, and the size of the cohorts limited statistical power to examine the effect of FETO on several maternal and infant conditions, including bronchopulmonary dysplasia (BPD), the risk of which might be reduced by accelerating lung growth. Furthermore, enrollment in the TOTAL trial did not include prospective genetic screening. Congenital diaphragmatic hernia reduces reproductive fitness, so pathogenic genomic variants in heterogeneous gene loci or pathways may be rare or novel; they may concurrently disrupt diaphragm and lung growth, pulmonary vascular development, or brain maturation; and they may affect infant outcomes independently of strategies for clinical care. The editorialist noted that future studies to examine the effect of FETO on longer-term pulmonary and neurodevelopmental outcomes in infants and to integrate prospective, unbiased genetic screening into patient selection will be important. In addition, both analyses in the TOTAL trial raised several technical questions regarding FETO that warrant further study. For example, can both the integrity of the fetal tracheal balloon and the placement technique be improved to reduce the frequency of spontaneous balloon deflation, which occurred eight times in the trial, and to lower the risk of preterm, pre-labor rupture of membranes and the risk of PTB? Can strategies for reliable, non-invasive balloon deflation be developed? Can prenatal and postnatal lung growth be examined with magnetic resonance imaging (MRI)-based techniques to allow quantitative assessment of the effect of FETO? Perinatal counseling for parents of fetuses with isolated congenital diaphragmatic hernia on the left side and probable severe pulmonary hypoplasia should balance the significant FETO-associated survival benefit in fetuses with severe pulmonary hypoplasia with the variability in fetal ultrasound-based prediction of pulmonary hypoplasia, the increased risks of PTB and preterm, pre-labor rupture of membranes, and uncertainties regarding longer-term outcomes in infants. If parents choose FETO, they should seek an experienced center, ideally one involved in collaborative research to reduce risks associated with FETO and to track short-term and long-term maternal, fetal, and infant outcomes. The lack of a significant survival benefit with FETO in fetuses with moderate pulmonary hypoplasia should prompt providers to encourage participation in additional randomized trials of FETO efficacy and outcomes and to avoid offering FETO outside such trials. The editorialist concluded that the current reports serve as a critical basis for future studies to improve outcomes in pregnancies complicated by fetal congenital diaphragmatic hernia and in infants.
Deprest et al. (2021b) conducted a multicenter, open-label randomized controlled trial (TOTAL trial) to evaluate whether fetoscopic endoluminal tracheal occlusion (FETO) improves survival compared with expectant prenatal care in singleton pregnancies with severe isolated left-sided congenital diaphragmatic hernia. Women were randomized 1:1 to FETO at 27–29 weeks’ gestation or expectant care, with both groups receiving standardized postnatal management; the planned maximum sample size was 116, and the primary endpoint was infant survival to discharge from the neonatal intensive care unit. Enrollment was stopped at a prespecified interim analysis for efficacy, and the primary analysis included 80 women (40 per group). Survival to NICU discharge occurred in 40% of infants in the FETO group compared with 15% in the expectant care group (relative risk 2.67; 95% CI, 1.22–6.11), with survival to 6 months identical to survival to discharge. FETO was associated with higher rates of preterm, prelabor rupture of membranes (47% vs 11%) and preterm birth (75% vs 29%). No maternal complications related to the procedure were reported, and other neonatal outcomes were described without formal hypothesis testing. The authors noted that the trial was not powered to assess secondary outcomes or uncommon maternal or fetal complications, that only short-term outcomes were available, and that results should not be generalized to centers without extensive experience in fetoscopy and balloon retrieval. The authors concluded that FETO increased survival to hospital discharge and to 6 months of age in fetuses with severe left-sided congenital diaphragmatic hernia, while increasing the risk of prematurity, and emphasized that the procedure should be performed in specialized centers with appropriate expertise.
Chen et al. (2023) conducted a systematic review and meta‑analysis to evaluate the clinical effects of fetal endoscopic tracheal occlusion (FETO) compared with expectant management in fetuses with congenital diaphragmatic hernia (CDH), with outcomes analyzed by disease severity (severe vs moderate CDH). The objective was to assess whether FETO is beneficial overall and whether its effects differ by CDH severity. The authors included 20 studies (4 randomized controlled trials and 16 observational cohort studies) comprising 1187 fetuses, of whom 639 underwent FETO. The primary endpoints were mortality at 1, 6, and 12 months after birth, rates of pulmonary hypertension, use of extracorporeal membrane oxygenation (ECMO), and prematurity. Pooled analyses showed that FETO was associated with reduced 1‑month mortality (OR 0.56; 95% CI, 0.34–0.93) and 6‑month mortality (OR 0.34; 95% CI, 0.18–0.65), while no clear reduction was demonstrated for 12‑month mortality. Subgroup analyses indicated that FETO was associated with reduced rates of pulmonary hypertension and ECMO use in severe CDH, but not in moderate CDH, whereas mortality reduction was observed in both severity groups. FETO was associated with increased risk of preterm prelabor rupture of membranes and preterm birth before 37 weeks, but was not associated with preterm birth before 32 weeks, placental abruption, or chorioamnionitis. Reported limitations included heterogeneity across studies, predominance of observational data, variation in FETO timing and technique, and limited evidence for moderate CDH. The authors concluded that FETO is associated with reduced mortality, pulmonary hypertension, and ECMO use in severe CDH, and reduced mortality alone in moderate CDH, and emphasized that FETO should be considered primarily for severe CDH with counseling regarding the increased risk of late prematurity but not extreme prematurity, while further evaluation is warranted for moderate CDH.
Kuchnowska et al. (2024) conducted a narrative review examining the prenatal evaluation of pulmonary hypoplasia as a key determinant of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH), with the objective of summarizing and appraising available imaging‑based risk‑stratification methods and their clinical utility. The authors reviewed ultrasound‑based and adjunct imaging approaches used to predict disease severity and postnatal outcomes, highlighting ultrasound as the primary modality due to its availability, safety, and reproducibility, while noting important limitations related to gestational‑age dependency and variable validation across proposed indices. They emphasized that the observed‑to‑expected lung‑to‑head ratio (o/e LHR), together with assessment of liver herniation, remains the most widely used and clinically accepted framework for distinguishing severe CDH, predicting survival and extracorporeal membrane oxygenation (ECMO) requirement, and performed comparative discussion showing these measures form the basis for contemporary patient selection for fetoscopic endoluminal tracheal occlusion (FETO). The review also evaluated emerging parameters—including lung‑to‑thorax ratios, quantitative lung indices (QLI‑R/L), and quantitative assessment of liver herniation—which may refine prognostication or monitoring of lung growth but currently remain adjunctive due to measurement variability, limited accessibility, or insufficient evidence. Overall, the authors concluded that early prenatal diagnosis and use of validated, reproducible imaging markers are essential for counseling, perinatal planning, and selection of candidates for prenatal and postnatal interventions in CDH.
Fetal Lower Urinary Tract Obstruction (LUTO)
Fetal lower urinary tract obstruction (LUTO) is a rare but severe congenital condition, most commonly caused by posterior urethral valves (PUV) in male fetuses, leading to impaired urine outflow, bladder distension, hydronephrosis, and reduced amniotic fluid volume. Prolonged obstruction can result in pulmonary hypoplasia due to oligohydramnios and progressive renal dysplasia. In selected cases with early, severe obstruction and evidence suggesting potentially salvageable renal function, prenatal (in‑utero) interventions may be considered to decompress the urinary tract and restore amniotic fluid. The most widely used fetal interventions include vesicoamniotic shunt placement, which diverts urine from the fetal bladder into the amniotic cavity, and fetoscopic cystoscopy with ablation of posterior urethral valves, performed in specialized centers. These procedures aim to mitigate secondary pulmonary and renal damage rather than definitively correct the underlying anomaly, and postnatal urologic management remains necessary. Patient selection is based on gestational age, ultrasound findings, fetal urine biochemistry, and multidisciplinary assessment (Crombleholme et al., 1990; Haeri, 2015; Nasrallah and Smith, 2024; Morris et al., 2013).
Haeri (2015) conducted a narrative clinical review to provide obstetric and maternal–fetal medicine providers with a practical overview of the presentation, evaluation, and management of fetal lower urinary tract obstruction (LUTO), a condition associated with substantial fetal morbidity and mortality. The review described diagnostic principles including prenatal ultrasound findings, assessment of amniotic fluid volume, genetic evaluation, and the use of serial vesicocenteses with fetal urine biochemistry to aid prognostication and selection for intervention. Management options discussed included expectant management, pregnancy termination, and prenatal interventions such as vesico‑amniotic shunting, fetal cystoscopy, and fetal vesicostomy. Vesico‑amniotic shunting and fetal cystoscopy were presented as minimally invasive options primarily aimed at restoring amniotic fluid volume and decompressing the urinary tract in selected cases with severe obstruction, favorable prognostic indicators, and oligohydramnios. Fetal vesicostomy via open fetal surgery was identified as another potential treatment option; however, despite promising neonatal results, its use is limited by associated maternal and perinatal morbidity, lack of large‑scale data, and the absence of improvement in bladder function. The author emphasized that, overall, there remains a paucity of high‑quality evidence supporting fetal intervention, even in cases with favorable prognostic profiles. Outcome data summarized from a review by Morris and Kilby indicated that vesico‑amniotic shunting was associated with improved perinatal survival compared with no treatment (OR 3.86; 95% CI 2.00–7.45), but with persistent risk of poor long‑term postnatal renal function, while fetal cystoscopy also appeared to improve perinatal survival (OR 20.51; 95% CI 3.87–106.89) without demonstrating superiority over shunting. The review concluded that although prenatal intervention may improve perinatal survival, survivors may experience increased childhood morbidity related to chronic renal dysfunction, and that large‑scale studies are needed to validate the efficacy of prenatal treatments in preventing pulmonary hypoplasia and preserving renal function, a limitation that should be clearly communicated during counseling.
Mustafa et al. (2024) conducted an international three‑round Delphi consensus study to establish expert agreement on the diagnosis, prognosis, management, and reporting outcomes for fetal lower urinary tract obstruction (LUTO), and to develop a core outcome set (COS). An expert panel of 168 invited stakeholders, including maternal–fetal medicine specialists, pediatric urologists, nephrologists, neonatologists, and patient representatives, participated, with 99 completing round one and 80 (80.8%) completing all rounds. Consensus recommendations addressed diagnostic criteria (e.g., first‑trimester suspicion using a longitudinal bladder diameter ≥7 mm and optimal diagnosis at ≥16 weeks’ gestation), prognostic assessment (favoring imaging features of renal dysplasia such as cortical cysts and loss of corticomedullary differentiation, with vesicocentesis used primarily for prognosis and counseling rather than intervention selection), and management strategies. The primary aim of fetal intervention was agreed to be improvement in perinatal survival rather than renal function, with vesicoamniotic shunting endorsed as the first‑line fetal therapy, while serial amnioinfusion was recommended only within research protocols. The panel agreed that existing prognostic scoring or staging systems should not be used clinically and emphasized amniotic fluid volume before 24 weeks as the best prenatal predictor of survival. The study also defined a standardized COS encompassing antenatal, procedural, neonatal, and long‑term outcomes to improve consistency in future research. Limitations included reliance on expert opinion rather than prospective data and underrepresentation of some geographic regions. The authors concluded that the consensus‑based diagnostic criteria, management pathway, and COS should be integrated into clinical practice and future studies to standardize care and outcome reporting in fetal LUTO.
Twin Reversed Arterial Perfusion (TRAP)
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 is hypothesized that in the presence of artery-to-artery anastomoses in a monozygotic placenta, blood is perfused from the hemodynamically advantaged twin ("donor" or "pump" twin) to the other twin ("recipient" twin) through reversed arterial flow (Quintero et al., 1994; van Allen et al., 1984). Inadequate perfusion of the recipient twin leads to a characteristic and invariably lethal set of anomalies, including 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 management approach is the interruption of the vascular anastomosis between the donor and recipient twin, accomplished using endoscopic laser coagulation in pregnancies at 24 weeks gestation or ligation of the umbilical cord using endoscopic or sonographic guidance at a later gestational age (Arias et al., 1998). In a 1998 study of seven pregnancies treated with laser therapy, the death rate in the normal twin was 13.6%, compared to an expected death rate of 50% in the pump twin when the pregnancy is managed expectantly.
Another approach involves 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 were delivered, and 12 of the 13 infants are alive and well. One infant was delivered at 24.4 weeks gestation and subsequently died from complications of prematurity. The average gestational age at delivery was reported as 36.2 weeks.
Expectant management is another approach for acardiac twins. 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 previously 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 of which were managed expectantly. Of the 10 cases identified, 9 women delivered a healthy pump twin, with only 1 neonatal death. The mean gestational age at delivery was 34.2 weeks, and the mean weights of the pump and acardiac twins were 2,279 g and 1,372 g, respectively.
Twin-Twin Transfusion Syndrome (TTTS)
Twin-twin transfusion syndrome (TTTS) is the most common complication of monochorionic pregnancies, affecting between 5% and 15% of such pregnancies and accounting for 15% to 77% of perinatal mortality in twins. TTTS is believed to occur due to uncompensated arteriovenous anastomoses in a monochorionic placenta, which leads to greater net blood flow 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 amniocentesis of the recipient twin's amniotic sac is the most frequently used (ACOG, 2005). This therapy is thought to work by favorably changing intraamniotic pressure and, consequently, placental intravascular pressure, allowing for the redistribution of placental blood flow and normalization of amniotic fluid volumes in each sac. More aggressive therapies, typically considered only for very early, severe cases, include abolishing the placental anastomoses through endoscopic laser coagulation or selective feticide via umbilical cord occlusion (ACOG, 2005). Clinical studies have shown that in very early (less than 26 weeks gestation), severe cases of TTTS, selective laser coagulation, when compared to serial amniocentesis, results in improved survival rates for at least one twin, reduced neurologic morbidity in survivors, and improved gestational age at the time of delivery (Senat et al., 2004).
Rossi and D'Addario (2008) reviewed the current controversy surrounding laser therapy (LT) versus serial amnioreduction (SA) for TTTS. A search in PubMed from 1997 to 2007 was conducted, with inclusion criteria of diamniotic monochorionic pregnancy, TTTS diagnosed with standard parameters, and well-defined peri- and neonatal outcomes. Triplets and studies focusing on topics other than perinatal outcomes were excluded. A meta-analysis was performed using a fixed-effect model (heterogeneity less than 25%). A total of 10 articles provided 611 cases of TTTS (LT: 70%; SA: 30%) and included four studies comparing the two treatments (395 cases: LT, 58%; SA, 42%). Fetuses undergoing LT were more likely to survive than those 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 demonstrated 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 rate of nearly 100%. The two main therapies include SA and fetoscopic laser coagulation for the vascular anastomoses. The authors stated that comparisons of the two treatments showed better outcomes, with higher survival rates and fewer neurological defects in cases treated with laser coagulation.
Roberts et al. (2014) conducted a Cochrane systematic review to evaluate interventions for the treatment of TTTS, including serial amnioreduction, based on randomized and quasi‑randomized trials. The review included three studies involving 253 women with monochorionic twin pregnancies and 506 fetuses, comparing amnioreduction with endoscopic laser coagulation or septostomy. Serial amnioreduction was described as the repeated removal of excessive amniotic fluid from the recipient sac by amniocentesis, originally introduced to manage hydramnios and reduce the risks of preterm labor or prelabor rupture of membranes, and potentially to modify disease progression. The authors reported that cohort data cited survival rates after serial amnioreduction ranging from approximately 37% to 60%, with neurological morbidity reported in 17% to 33% of survivors, and procedure‑related complications occurring in around 10% of cases, most commonly fetal death within 48 hours of the procedure or spontaneous abortion. In randomized comparisons, amnioreduction showed no clear differences in overall perinatal mortality when compared with laser coagulation or septostomy, but fewer children were alive without long‑term neurological abnormality at six‑year follow‑up compared with laser therapy. The authors emphasized that serial amnioreduction does not require specialized equipment and can be performed in most fetal medicine units, and concluded that while endoscopic laser coagulation should be considered to improve neurodevelopmental outcomes, amnioreduction remains an appropriate treatment option when laser expertise is unavailable or when TTTS is diagnosed later in pregnancy, such as beyond 26 weeks’ gestation.
"Amnioreduction can be retained as a treatment option for those situations where the expertise for laser coagulation is not available, pending transfer to a unit where such treatment can be obtained or when the condition is diagnosed after 26 weeks of pregnancy" (Roberts et al., 2014)
The Society for Maternal-Fetal Medicine (SMFM) (2024) issued Consult Series #72 to provide evidence-based clinical guidance on the diagnosis, surveillance, and management of twin–twin transfusion syndrome (TTTS) and twin anemia–polycythemia sequence (TAPS) in monochorionic twin pregnancies, updating and replacing prior SMFM guidance. This document is a consensus guideline synthesizing data from randomized trials, observational studies, registries, and expert opinion rather than a primary research study. SMFM emphasized routine first-trimester determination of chorionicity and serial ultrasound surveillance beginning at 16 weeks’ gestation for all monochorionic-diamniotic twins. For TTTS, SMFM recommended fetoscopic laser surgery as the standard treatment for stage II–IV disease between 16 and 26 weeks’ gestation and expectant management with close surveillance for asymptomatic stage I disease, with individualized consideration for early or late presentations. SMFM noted that serial amnioreduction, previously a mainstay of TTTS management, is inferior to laser therapy in survival outcomes and does not address the underlying placental anastomoses; therefore, its role is limited to select circumstances, such as late gestational presentations that do not qualify for laser therapy or as a temporizing measure for severe maternal symptoms from polyhydramnios when timely referral to a fetal care center is not feasible. SMFM further highlighted that therapeutic amnioreduction before fetal care center consultation is generally discouraged because of a reported complication rate of approximately 15% within 48 hours and the potential to preclude subsequent laser therapy. For TAPS, SMFM recommended incorporation of middle cerebral artery Doppler peak systolic velocity measurements into monochorionic twin surveillance beginning at 16 weeks, outlined diagnostic and staging criteria, and advised referral to specialized fetal care centers for advanced disease. Limitations acknowledged by SMFM included reliance on predominantly retrospective data, heterogeneity in diagnostic criteria and management strategies, and limited high-quality comparative evidence for some interventions. Overall, SMFM concluded that standardized surveillance, timely referral, and individualized management—favoring fetoscopic laser surgery over serial amnioreduction when appropriate—may reduce morbidity and mortality in monochorionic twin pregnancies.
"Therapeutic amnioreduction before consultation at the fetal care center is generally not recommended because registry data indicate a 15% complication rate within 48 hours of amnioreduction for TTTS." "For TTTS presenting beyond 26 weeks (gestational ages for which amnioreduction, expectant management, or medically indicated delivery are usually considered), laser surgery may be a viable option for select cases of severe disease presenting up to the very early third trimester to reduce risks of fetal and perinatal death or severe prematurity. In some instances, there may be geographic, financial, or patient-driven delays to timely fetal care center referral. In these situations, an individualized approach is advised, and therapeutic amnioreduction may be deemed necessary as a temporizing measure because of severe maternal symptomatology from polyhydramnios. Otherwise, amnioreduction for the management of TTTS is largely restricted to late disease presentations that do not qualify for fetoscopic laser surgery or delivery" (SMFM, 2024).
Fetal Aortic Valvuloplasty
A recent American Heart Association Scientific Statement (Donofrio et al., 2014) assigned a IIb classification (procedure/treatment may be considered; additional studies with broad objectives needed; additional registry data would be helpful) to fetal aortic valvuloplasty (FAV) for evolving hypoplastic left heart syndrome (HLHS), based on a B level of evidence (recommendations usefulness/efficacy less well-established; greater conflicting evidence from a single randomized trial or non-randomized studies). The authors stated that "Because fetal aortic stenosis (AS) with evolving HLHS is relatively uncommon and probably more often than not goes undetected prenatally, clinical experience with fetal intervention for this lesion is limited. Given the morbidity and mortality associated with palliative surgery for HLHS, aortic valve dilation may be considered in fetuses with AS in whom the selection criteria are met. Before the procedure, extensive family counseling should detail the risks of the procedure to the mother and fetus and lay out the expected clinical course for those who undergo intervention compared to those who choose more standard management. Although it is important to appreciate the potential benefits and promise of fetal cardiac catheter intervention for critical AS evolving into HLHS by possibly creating a postnatal 2-ventricle system, the long-term benefits and outcomes of this procedure are unknown. Although outcomes for HLHS after the Fontan operation and the limitations of this strategy are relatively clear, the fetus undergoing a cardiac catheter intervention for AS may be at future risk for multiple operations, valve replacements, ventricular dysfunction, and possibly pulmonary hypertension within the context of a borderline-size small left ventricle. Families should be counseled about these concerns and about the lack of data on long-term outcomes. Comparative analysis of these alternative strategies through careful investigational efforts is warranted."
Freud et al. (2014) stated that FAV can be performed for severe mid-gestation aortic stenosis in an attempt to prevent progression to HLHS. A subset of patients has achieved a biventricular (BV) circulation after FAV. The postnatal outcomes and survival of the BV patients, in comparison with those managed as HLHS, have not been reported. This study included 100 patients who underwent FAV for severe mid-gestation aortic stenosis with evolving HLHS from March 2000 to January 2013. Patients were categorized based on postnatal management as BV or HLHS. Clinical records were reviewed. A total of 88 fetuses were live-born, and 38 had a BV circulation (31 from birth, 7 converted after initial univentricular [UV] palliation). Left-sided structures, namely aortic and mitral valve sizes and left ventricular volume, were significantly larger in the BV group at the time of birth (p < 0.01). After a median follow-up of 5.4 years, freedom from cardiac death among all BV patients was 96 ± 4% at 5 years and 84 ± 12% at 10 years, which was better than HLHS patients (log-rank p = 0.04). There was no cardiac mortality in patients with a BV circulation from birth. All but 1 of the BV patients required postnatal intervention; 42% underwent aortic or mitral valve replacement. On the most recent echocardiogram (ECG), the median left ventricular end-diastolic volume z-score was +1.7 (range of -1.3 to +8.2), and 80% had a normal ejection fraction (EF). The authors concluded that short- and intermediate-term survival among patients who underwent FAV and achieved a BV circulation postnatally is encouraging. However, morbidity still exists, and ongoing assessment is warranted.
In an editorial that accompanied the aforementioned study by Freud et al., Rychik (2014) stated that "Despite abundant enthusiasm for this approach, much more work is necessary, with many more questions to be answered before we know the optimal strategy for management of HLHS in the rapidly advancing era of fetal diagnosis and treatment."
Mellander and Gardiner (2014) noted that the update course in fetal cardiology held by the Fetal Working Group of the Association for European Pediatric and Congenital Cardiology in Istanbul in May 2012 included a session on fetal cardiac therapy. In the introductory overview to this symposium, these investigators examined the level of evidence supporting or refuting proposed fetal cardiac therapies, including trans-placental treatment of fetal tachyarrhythmias, steroid treatment in fetal atrioventricular block, and FAV. The authors concluded that the evidence for the safety and effectiveness of currently available fetal cardiac therapies is low, with no therapy based on a randomized controlled trial (RCT). Trans-placental treatment of fetal tachycardia is generally accepted as effective and safe, based on extensive and widespread clinical experience; however, there is no consensus on which drugs are the most effective in different electrophysiological situations. Randomized studies may be able to resolve this, but this is complicated because tachyarrhythmias are relatively rare conditions, the fetus is not accessible for direct treatment, and it is the healthy mother who accepts treatment she does not need on behalf of her fetus. The indications for steroid treatment in fetal atrioventricular block and for FAV are even more controversial. The authors stated that although randomized trials would be desirable, the practical issues of recruiting sufficient sample sizes and controlling for variation in practice across multiple sites should not be underestimated. They stated that multi-center registries, analyzed free of bias, may be an alternative way to improve the evidence base of fetal cardiac therapy.
Moon-Grady et al. (2015) described the initial report of the International Fetal Cardiac Intervention Registry (IFCIR), which collected data for maternal/fetal dyads and newborns who were referred and evaluated as possible candidates for fetal cardiac intervention. Exploratory analysis of the data was performed to compare outcomes of the intervention group versus those of patients who met criteria but who had no intervention or had an unsuccessful one. Fetal survival to live birth was 80.0% in the intervention group and 85.2% in the non-intervention group; survival to discharge was 57.5% and 59.3%, respectively. In the subgroup of fetuses with aortic stenoses and evolving HLHS, 42.9% of live-born infants were discharged with a BV circulation after successful fetal intervention versus 19.4% of those who had no fetal intervention or where the intervention was unsuccessful. When fetal deaths were counted as intervention failures, the percentage of patients discharged with a BV circulation after successful intervention was 31.3% versus 18.5% with no intervention. The authors concluded that present postnatal data suggested potential benefit to fetal therapy among pregnancies considered for possible intervention and support proposals for additional work.
An accompanying commentary (Donofrio, 2015) identified the limitations of this registry data in reaching conclusions and drawing definitive recommendations: "There are inherent limitations of using registry data to draw overarching conclusions and make definitive recommendations. First and foremost, the lack of randomization precludes a true control group to determine whether those who receive intervention have outcomes similar to those who do not. Although this issue is addressed by using fetuses with unsuccessful interventions as control subjects, this is not ideal and not truly representative of the affected population. Second, there is no uniformly accepted strategy for determining postnatal surgical care for these patients, including accepted criteria for biventricular repair. It is important to note that postnatal management is essential to treating newborns with aortic stenoses and a borderline left ventricle. Key factors, including access to specialized interventional catheterization procedures and innovative surgical techniques, must be considered. Different care strategies from individual practices may introduce center bias, making it difficult to ascertain whether fetal intervention or specialized postnatal care determines success. Also, although most practitioners believe it is more beneficial for a patient to have biventricular repair than single-ventricle palliation, the long-term benefits of strategies that begin with fetal intervention remain unknown. Comparative analysis of long-term outcomes of fetal intervention as an alternate strategy through detailed follow-up is imperative. Finally, alterations in brain development and brain injury in fetuses with aortic stenosis versus those with HLHS will need to be addressed. Data suggest that lack of antegrade aortic flow may have an impact on brain maturation in the third trimester. Careful assessment of brain development and injury in fetuses with aortic stenosis post-fetal intervention will need to be investigated."
Marantz and Grinenco (2015) stated that FAV is intended to alter the natural history of aortic stenosis evolving to HLHS. These investigators reviewed the most recently reported data and advances on this procedure. The highlights of the latest experience were the advances in further understanding of the prenatal and postnatal natural history of this disease, the way in which FAV impacts it, the identification of new predictors of BV outcome, and the report of postnatal survival of intervened patients. These researchers noted that recently reported short-term and middle-term results are encouraging. Experimental research on procedural aspects is ongoing, with no definite results; multi-center studies are also ongoing. The authors concluded that in recent years, there have been advances in the understanding of the prenatal and postnatal processes of aortic stenosis evolving to HLHS and the effects of FAV, as well as the need for adequate postnatal therapeutic strategies for these patients. Procedural aspects are being studied with animal models but still need far more experience before human application. Moreover, long-term results are still to be discovered, and multi-center studies may provide a new perspective. The authors stated that continuing research is mandatory so that ultimately fetal heart intervention finds its place among the therapeutic resources for congenital heart disease (CHD).
In a systematic review and meta-analysis, Araujo Junior and colleagues (2016) evaluated perinatal outcomes and intrauterine complications following fetal interventions for congenital heart defects (CHDs). A systematic review and meta-analysis were performed following an electronic search of the PubMed and SCOPUS databases (last searched August 2015). Perinatal outcomes included fetal death, live birth, preterm birth less than 37 weeks, and neonatal death. Intrauterine complications included bradycardia requiring treatment and hemopericardium requiring drainage. The estimated proportions were reported as mean with 95% confidence intervals (CIs). The electronic search retrieved 2,279 records, and 29 studies (11 retrospective cohort and 18 case reports) were considered eligible. The number of studies and proportions (95% CI) of neonatal death were 3 and 65% (95% CI: 26 to 88) for FAV; 1 and 25% (95% CI: 10 to 49) for pulmonary valvuloplasty; 1 and 14% (95% CI: 6 to 28) for septoplasty; and 24 and 29% (95% CI: 18 to 41) for pericardiocentesis and/or pericardio-amniotic shunt. The number of studies and proportion (95% CI) for bradycardia requiring treatment was 2 and 52% (95% CI: 16 to 87) following FAV; 1 and 44% (95% CI: 23 to 67) for pulmonary valvuloplasty; and 1 and 27% (95% CI: 15 to 43) for septoplasty. The authors concluded that the current evidence on the effectiveness of prenatal interventions for CHDs comes mostly from case reports and a few larger series; none of the studies was randomized. They stated that although their results are encouraging in terms of perinatal survival, they should be interpreted with caution when compared with procedures performed after birth.
Gardiner et al. (2016) described the natural history of fetal aortic stenosis and tested previously published criteria designed to identify cases of evolving HLHS with the potential for a BV outcome following FAV. These investigators reported the natural history of 107 fetuses in continuing pregnancies that did not undergo FAV from a retrospective multi-center study in Europe of 214 fetuses with aortic stenosis (2005 to 2012). They examined longitudinal changes in z-scores of aortic and mitral valve and left ventricular dimensions, and documented the direction of flow across the foramen ovale and aortic arch, and mitral valve inflow pattern and any changes to determine those fetuses satisfying the Boston criteria for emerging HLHS and to estimate the proportion of these that would also have been considered ideal FAV candidates. These researchers applied the threshold score where a score of 1 was awarded to fetuses for each z-score meeting the following: left ventricular length and width greater than 0; mitral valve width greater than -2; and aortic valve width greater than -3.5, and also where the pressure gradient across either the mitral or aortic valve was greater than 20 mmHg, and compared the predicted circulation with known survival and final postnatal circulation (BV; postnatal UV or conversion from BV to UV). In the 107 ongoing pregnancies, there were 8 spontaneous fetal deaths, resulting in 99 live-born children; 5 were lost during follow-up; 5 had comfort care, and 4 had mild aortic stenosis not requiring intervention. There was an intention-to-treat in the remaining 85, but 5 of them died before surgery before the circulation could be determined. Thus, a total of 80 underwent postnatal procedures with 44 BV, 29 UV, and 7 BV-UV outcomes; 70/85 children (82%) with an intention-to-treat had greater than or equal to 30-day survival. Survival was superior in BV circulation at a median of 6 years (p = 0.041). Aortic valve size was significantly smaller at presentation in fetuses with UV outcomes (p = 0.004), but its growth velocity was similar in both circulatory outcomes. In contrast, the mitral valve (p = 0.008) and left ventricular inlet length (p = 0.0042) and width (p = 0.0017) were significantly reduced by term in fetuses with UV compared to BV outcomes. Fetal data from 70 treated neonates, recorded before 30 completed gestational weeks, was evaluated for emerging HLHS; 44 had moderate or severe left ventricular depression, and 38 of these had retrograde flow in the aortic arch, with a further 2 having left-to-right flow at the atrial level and a-wave reversal in the pulmonary veins. Thus, 40 of the 70 satisfied the criteria associated with emerging HLHS, and a BV circulation was documented in 13 (33%); 12 of the 40 fetuses (30%) had a threshold score of 4 or 5, with a BV circulation in 5 (42%) of them without fetal intervention. The authors concluded that their natural history cohort of children diagnosed with aortic stenosis with known outcomes showed that a substantial proportion of fetuses meeting the criteria for emerging HLHS, with or without favorable selection criteria for FAV, had a sustained BV circulation without fetal intervention. They stated that these findings indicated that further work is needed to refine selection criteria to offer appropriate therapy to fetuses with aortic stenosis.
Freud and Tworetzky (2016) discussed the rationale, patient selection, technical aspects, and outcomes of percutaneous, ultrasound-guided fetal cardiac intervention (FCI) for structural congenital heart disease. These investigators stated that FCI is most commonly performed for three forms of congenital heart disease: severe aortic stenosis with evolving HLHS, pulmonary atresia with intact ventricular septum and evolving hypoplastic right heart syndrome, and HLHS with intact or highly restrictive atrial septum. For severe aortic stenosis and pulmonary atresia with intact ventricular septum, the goal of intervention is to alter the natural history such that a biventricular circulation may be achieved postnatally. A growing number of patients have achieved a biventricular circulation; however, patient selection and postnatal management strategy are essential for success. HLHS with intact or highly restrictive atrial septum is one of the most lethal forms of congenital heart disease, and the goal of FCI is to improve survival. Although the creation of an atrial communication in utero is technically feasible and may permit greater stability in the immediate postnatal period, significant improvements in survival have not yet been reported. The authors concluded that FCI is an evolving form of treatment for congenital heart disease that holds promise for select patients; critical evaluation of both short- and long-term outcomes is needed.
Yuan and Humuruola (2016) stated that fetal cardiac interventions for congenital heart diseases may alleviate heart dysfunction, prevent them from evolving into hypoplastic left heart syndrome, achieve biventricular outcomes, and improve fetal survival. Candidates for clinical fetal cardiac interventions are now restricted to cases of critical aortic valve stenosis with evolving HLHS, pulmonary atresia with an intact ventricular septum and evolving hypoplastic right heart syndrome, and HLHS with an intact or highly restrictive atrial septum, as well as fetal heart block. The therapeutic options are advocated as prenatal aortic valvuloplasty, pulmonary valvuloplasty, creation of inter-atrial communication, and fetal cardiac pacing. Experimental research on fetal cardiac intervention involves technical modifications of catheter-based cardiac clinical interventions and open fetal cardiac bypass that cannot be applied in human fetuses for the time being. Clinical fetal cardiac interventions are plausible for mid-gestation fetuses with the above-mentioned congenital heart defects. The technical success, biventricular outcome, and fetal survival are continuously being improved in the context of a sophisticated multidisciplinary team, equipment, techniques, and postnatal care. Experimental research is laying the foundations and may open new fields for catheter-based clinical techniques. The authors stated that attempts to make substantial improvements in fetal cardiac bypass outcomes are underway with regard to technical modifications and candidate selection. In spite of the reproducibility of experimental fetal cardiac bypass, fetal hypoxia and demise subsequent to cytokine-mediated injury and placental dysfunction following bypass significantly impede the technical application in human fetuses. They noted that future directions of fetal cardiac interventions are a combination of non-surgical cardiac therapy with minimally invasive surgical techniques (e.g., robot-guided fetal cardiac intervention, fetoscopic fetal cardiac surgery, and open cardiac surgery); more advantageous techniques and better outcomes are anticipated.
Laraja and associates (2017) characterized neurodevelopmental outcomes after fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome and examined the risk factors for adverse neurodevelopment. Questionnaires were mailed to families of children who underwent fetal aortic valvuloplasty from 2000 to 2012, and medical records were reviewed retrospectively. The primary outcome was the General Adaptive Composite score of the Adaptive Behavior Assessment System Questionnaire-Second Edition. Other questionnaires included the Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, and Pediatric Quality of Life Inventory. Among 69 eligible subjects, 52 (75%) completed questionnaires at a median age of 5.5 years (range of 1.3 to 12 years); 30 (58%) had biventricular status circulation. The General Adaptive Composite mean score (92 ± 17) was lower than population norms (p < 0.001) and similar to published reports in patients with hypoplastic left heart syndrome without fetal intervention; scores in the univentricular versus biventricular group were 97 ± 19 versus 89 ± 14, respectively (p = 0.10). On multivariable analysis, independent predictors of a lower General Adaptive Composite score were total hospital duration of stay in the first year of life (p = 0.001) and, when forced into the model, biventricular status (p = 0.02). For all other neurodevelopmental questionnaires (Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, Pediatric Quality of Life Inventory), most subscale scores for patients with biventricular and univentricular status were similar. The authors concluded that the children who underwent fetal aortic valvuloplasty have neurodevelopmental delay, similar to patients with hypoplastic left heart syndrome without fetal intervention. Achievement of biventricular circulation was not associated with better outcomes. These investigators inferred that innate patient factors and morbidity during infancy have the greatest effect on neurodevelopmental outcomes.
Fetoscopic Laser Ablation for Type 2 Vasa Previa
Chmait and colleagues (2010) stated that vasa previa is associated with increased perinatal morbidity and mortality due to fetal exsanguination at the time of membrane rupture. These investigators reported their experience in the treatment of type II vasa previa via in-utero laser ablation in the third trimester. Two cases of type II vasa previa were identified via endovaginal ultrasound in the second trimester and treated via third-trimester fetoscopic laser ablation. In case 1, fetoscopic laser ablation of the vasa previa was performed without complication at 28 3/7 weeks' gestation as a prophylactic measure. The patient delivered at 33 3/7 weeks' gestation after rupture of membranes without sequelae and with a good perinatal outcome. In case 2, expectant management of twins with a vasa previa was planned. However, significant cervical shortening and funneling were documented at 30 5/7 weeks, and the risk of membrane rupture was deemed relatively high. As a therapeutic alternative to outright preterm delivery, the patient underwent uncomplicated laser ablation of the vasa previa. Delivery occurred at 34 3/7 weeks after rupture of membranes, and the twins did well. The authors suggested that type II vasa previa could be definitively treated in utero by laser photocoagulation in the third trimester. Ablation of the vasa previa may be performed prophylactically or as a therapeutic measure to delay delivery if symptoms of preterm labor and/or cervical shortening develop.
Johnston and associates (2014) noted that unrecognized vasa previa carries a significant risk of fetal mortality. Advances in ultrasound have improved the detection of vasa previa and led to a dramatic reduction in fetal morbidity and mortality. However, current management strategies require prolonged hospitalized surveillance, preterm delivery prior to the onset of labor or rupture of membranes, and a Cesarean delivery. Fetoscopic laser ablation of type II vasa previa allows for the possibility of term vaginal delivery. These researchers presented a patient who underwent successful laser photocoagulation of a type II vasa previa at 32 5/7 weeks' gestation. She subsequently delivered vaginally at term without complications. The authors concluded that the potential benefits of definitive in-utero treatment of non-type I vasa previa, such as vaginal delivery at term, must be weighed against the procedure-related risks of operative fetoscopy.
In a “Letter to the Editor,” Ibirogba and associates (2019) noted that to date, there have been 5 reported cases of fetoscopic laser ablation for the treatment of type II vasa previa between 22 and 33 weeks of gestation. Treatment was indicated due to the presence of premature contractions or progressive cervical shortening in 2 patients. Fetoscopic laser ablation is carried out under maternal local anesthesia with sedation or epidural anesthesia. Occasionally, the fetal head is externally pushed aside for better access. Traversing blood vessels are tracked to the placental edge, where they are ablated using a 600-μm Nd:YAG or diode laser fiber with a power setting of 25 to 45 Watts. In the 5 reported cases, operative time ranged between 30 and 35 minutes, and no perioperative complications have been reported. These investigators stated that from a review of the literature, the initial experience suggested that fetoscopic laser ablation for type II vasa previa appeared to be safe and feasible; however, the benefits of this procedure are still unclear, and further investigation is needed. Four of the 5 patients progressed to preterm premature rupture of membranes (PPROM) after the procedure, with preterm delivery before 35 weeks (i.e., earlier than the gestational age at planned Cesarean delivery), although it should be noted that 2 of these patients were treated to prevent fetal hemorrhage secondary to premature contractions or progressive cervical shortening. Pregnancy was prolonged by an average of 31 days; thus, women with type II vasa previa who may undergo an unnecessarily early Cesarean delivery due to concerns of imminent PPROM (e.g., short cervix or preterm contractions) may benefit from this procedure to avoid fetal bleeding and exsanguination. In stable patients (without preterm contractions or vaginal bleeding), fetoscopic laser ablation could be offered at 34 to 36 weeks of gestation as an alternative to elective Cesarean delivery, given the probability of spontaneous resolution of vasa previa during the late second trimester. Moreover, these researchers stated that future clinical trials are needed to test this hypothesis.
In a retrospective, descriptive study, Chmait and colleagues (2020) examined the feasibility and reported perinatal outcomes of type II vasa previa patients treated via fetoscopic laser ablation. This trial included women with vasa previa treated with laser at the authors’ center between 2006 and 2019. After 2010, laser ablation of vasa previa was only offered after 31 gestational weeks. Continuous variables were expressed as means ± SD. A total of 33 patients were examined for laser ablation of suspected vasa previa; 15 were not candidates (7 had type I vasa previa and 8 had no vasa previa), and the 18 remaining had type II vasa previa; 10 (56%) elected to undergo in utero laser ablation of the vasa previa vessel(s), which was successful in all patients. The mean gestational age at the time of the procedure was 28.8 ± 5.4 weeks, and the total operative time was 48.1 ± 21.3 minutes; there were no perioperative complications. The number of vessels lasered was distributed as follows: 1 (2 cases), 2 (5 cases), and 3 (3 cases). All patients except for 1 were subsequently managed as outpatients. The mean gestational age at delivery was 35.5 ± 3.2 weeks, and vaginal delivery occurred in 5 cases. The 5 patients with singletons who underwent laser ablation for primary diagnosis of type II vasa previa after the protocol change in 2010 had the following outcomes: mean gestational age of surgery was 32.5 ± 0.8 weeks, mean gestational age at delivery was 38.1 ± 1.4 weeks, vaginal delivery occurred in all cases, mean birth weight was 2,965 ± 596 g, and none was admitted to the NICU. The authors concluded that this cohort represented the largest number of vasa previa cases treated via in-utero laser reported to date. Laser occlusion of type II vasa previa was technically achievable in all cases and resulted in favorable outcomes.
In Utero Shunting for the Treatment of Fetal Cerebral Ventriculomegaly
Pisapia and colleagues (2017) stated that fetal ventriculomegaly (VM) refers to the enlargement of the cerebral ventricles in utero. It is associated with the post-natal diagnosis of hydrocephalus. Fetal VM is clinically diagnosed on ultrasound (US) and is defined as an atrial diameter greater than 10 mm. Because of the anatomic detailed seen with advanced imaging, VM is often further characterized by fetal MRI. Fetal VM is a heterogeneous condition with various etiologies and a wide range of neurodevelopmental outcomes. These outcomes are heavily dependent on the presence or absence of associated anomalies and the direct cause of the ventriculomegaly rather than on the absolute degree of VM. The authors discussed diagnosis, work-up, counseling, and management strategies as they relate to fetal VM. They described imaging-based research efforts aimed at using pre-natal data to predict post-natal outcome. They also reviewed the early experience with fetal therapy such as in utero shunting, as well as the advances in pre-natal diagnosis and fetal surgery that may begin to address the limitations of previous therapeutic efforts.
In Utero Stem Cell Therapy / Gene Therapy
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 an improved understanding of the biological barriers to engraftment in the fetus, as well as the development of effective clinical strategies based on the hematopoietic biology of individual disorders (Hayashi and Flake, 2001).
There is considerable scientific and clinical interest in the potential use of hematopoietic stem cells before birth to treat congenital diseases. In theory, stem cell transplantation in utero offers several possible advantages. First, intervention in utero allows for the "correction" of a disorder before clinical manifestations develop. Second, because the fetal immune system has not yet matured, 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 without the risk of rejection.
Current evidence for in-utero stem cell transplantation comes from animal models and a small number of reported cases of in utero transplantations of unmodified bone marrow progenitor cells in human fetuses involving disorders such 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 the success of in-utero stem cell transplantation in X-linked severe combined immunodeficiency syndrome, there is no proven clear advantage over postnatal stem cell transplantation for this indication. Regarding other potential uses, in utero stem cell transplantation has thus far been unsuccessful in target disorders such as hemoglobinopathies, where there is no 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 treating 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.
Dugas and associates (2020) noted that myelomeningocele (MMC) is a congenital spinal cord defect that results in bladder incontinence, bowel dysfunction, and paraplegia. A randomized trial (human study) showed that in-utero surgical repair of the MMC defect improved lower limb motor function; however, functional recovery remained incomplete. Stem cell therapy has recently generated significant interest in the field of prenatal repair of MMC. In a systematic review, these researchers provided an overview of the current application of stem cells in different animal models of MMC. Publications were retrieved from PubMed and Cochrane Library databases, yielding 22 studies for inclusion in this review, which experimented with five different types of stem cells: human embryonic stem cells, neural stem cells, induced pluripotent stem cells, human amniotic fluid stem cells, and mesenchymal stem cells (MSCs). Rodents and ovine were the two major species used for animal model studies. The source, aims, and main results were analyzed. The authors concluded that stem cell therapy appears to be a promising candidate for prenatal repair of MMC, especially MSCs. They stated that further examinations in ovine and rodent models, reporting clinical and functional results, are needed before application in humans.
In a systematic review, Kunpalin and colleagues (2021) examined the safety and effectiveness of in-utero stem cell application in preclinical models with MMC. These investigators searched Medline, Embase, Web of Science, Scopus, and CENTRAL for publications on stem cell therapy in animal fetuses with MMC until May 2020. Publication quality was evaluated using the SYRCLE's tool. Meta-analyses were pooled if studies were conducted in the same animal model, providing similar types of stem cells and outcome measurements. Narrative synthesis was carried out for studies that could not be pooled. A total of 19 studies were included in narrative synthesis, and 7 studies were included in quantitative synthesis, with most using MSCs and primarily involving ovine and rodent models. Both intra-amniotic injection of allogeneic amniotic fluid (AF)-MSCs in a rat MMC model and the application of human placental (P)-MSCs to the spinal cord during fetal surgery in an MMC ovine model did not compromise fetal survival rates at term (rat model, relative risk [RR] 1.03, 95% CI: 0.92 to 1.16; ovine model, RR 0.94, 95% CI: 0.78 to 1.13). A single intra-amniotic injection of allogeneic AF-MSCs into a rat MMC model was associated with a higher rate of complete defect coverage compared to saline injection (RR 16.35, 95% CI: 3.27 to 81.79). The incorporation of human P-MSCs as a therapeutic adjunct to fetal surgery in the ovine MMC model significantly improved the sheep locomotor rating scale after birth (mean difference [MD] 5.18, 95% CI: 3.36 to 6.99). The authors concluded that stem cell therapy during the prenatal period in preclinical animal models was safe and effective. Moreover, these researchers stated that although their findings were encouraging for clinical translation, several concerns needed to be addressed. Further work on neurological functional outcomes (beyond 24 hours) after birth and the response of the fetal immune system to allogeneic stem cell transplantation should also be considered. Additionally, an optimal stem cell source and an appropriate delivery device should be established before moving forward to clinical trials.
In-utero gene therapy (i.e., the genetic modification of somatic cells in utero) has been proposed as most appropriate for disorders that result in irreversible illness or death in the pre- or postnatal period. Examples may include Gaucher’s disease, Krabbe’s disease, and Hurler’s disease. Currently, evidence is limited to animal models that certain genetic conditions can be corrected in utero using gene therapy with viral vectors. In addition to the need for evidence of the effectiveness of gene therapy in utero in humans, it has been argued that two key issues need to be addressed before such an intervention is considered: there must be a clear advantage over postnatal gene therapy, and 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 intrauterine growth restriction (IUGR). Various interventions, such as the use of vasodilators/low-dose aspirin, intravenous glucose infusion, and 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 outcomes 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 were performed without complications. Four patients continued to deteriorate rapidly, with no change in amniotic fluid volume and an increase in uterine artery pulsatility index (PI). In the remaining six 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; however, practical issues regarding its introduction into clinical practice are more challenging. 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 intrauterine intervention. Additionally, 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 intrauterine 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 endeavors has been variable but overall shows promise for the 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. Prenatal 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 postnatal outcomes. 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 prenatal 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 biventricular circulation postnatally, 15 from birth. Larger left heart structures and higher left ventricular pressure at the time of intervention were associated with biventricular outcomes. A multivariable 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 multivariable threshold score at the time of intervention are very unlikely to achieve biventricular circulation postnatally.
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 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 postnatal cardiac interventions than patients with AS (p = 0.007). Mitral annular early diastolic tissue velocity (E') was lower in patients with FAV compared to those with AS and controls in the neonatal period and over follow-up (p < 0.001). Septal E' was similar among all three 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 for the 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 various 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; three 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 five. Prenatal intervention was performed on three fetuses: balloon aortic valvuloplasty (n = 2) and balloon atrial septostomy (n = 1). Of the three, one died in utero, and neither survivor underwent a two-ventricle repair. Five patients required immediate postnatal 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 outcomes. Despite the presence of a dilated left ventricle, postnatal 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, as it may also increase the 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 the potential for biventricular repair strategies after birth.
Adzick (2010) stated that myelomeningocele (MMC) is a common birth defect associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of children with spina bifida. Postnatal surgery aims to cover the exposed spinal cord, prevent infection, and treat hydrocephalus with a ventricular shunt. In-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 suggest that fetal surgery results in the reversal of hind-brain herniation (the Chiari II malformation), a decrease in shunt-dependent hydrocephalus, and possibly improvement in leg function; however, these findings might be explained by selection bias and changing management indications. A prospective, randomized study (the MOMS trial) is currently being conducted by three 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 the operative and perinatal aspects of fetal endoscopic tracheal occlusion (FETO) in congenital diaphragmatic hernia (CDH). It was a multi-center study of singleton pregnancies with CDH treated by FETO. The entry criteria for FETO were severe CDH based on sonographic evidence of intra-thoracic herniation of the liver and a low lung area to head circumference ratio (LHR) defined as the observed to 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 CDH, 34 with right-sided CDH, 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 weeks (range of 23.0 to 33.3 weeks). The first eight cases were done under general anesthesia, but subsequently, either regional or local anesthesia was used. The median duration of FETO was 10 minutes (range of 3 to 93 minutes). 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 days (median of 30 days) after FETO, with 35 (16.7%) cases occurring within 3 weeks of the procedure. Removal of the balloon was performed prenatally either by fetoscopy or ultrasound-guided puncture, intrapartum by ex-utero intrapartum treatment, or postnatally either by tracheoscopy or percutaneous puncture. Delivery occurred at 25.7 to 41.0 weeks (median of 35.3 weeks), with 65 (30.9%) cases delivered before 34 weeks. 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 balloon removal. Significant prediction of survival was provided by the o/e LHR and gestational age at delivery. Based on the relationship between survival and o/e LHR in expectantly managed fetuses with CDH, as reported in the antenatal 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 randomized controlled trial (RCT).
Gastroschisis is associated with inflammatory changes in the exposed bowel that lead to intestinal dysmotility following postnatal repair. In a retrospective study, Heinig et al. (2008) followed a case series of fetuses with isolated gastroschisis to evaluate whether small-bowel dilatation may be indicative of 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 second and third trimesters 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 greater than 25 mm in the third trimester of pregnancy was associated with an increased risk of short-term prenatal complications such as fetal distress or intrauterine 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 third trimester may allow for the identification of fetuses with an 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 whether outcomes differ in infants with gastroschisis when comparing a prenatal diagnosis with a diagnosis only at birth, with the intention of developing a prenatal 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 were studied retrospectively. The infants in the prenatal subset were delivered at the authors' tertiary center, and 18 survived. There were 2 pregnancy terminations, 3 intrauterine deaths at 19, 33, and 36 weeks, respectively, and 1 neonatal death. All 9 infants in the postnatal subset survived—8 were out-born, and 1 was delivered at the authors' tertiary center. Prenatal bowel dilatation did not correlate with outcome. Between the prenatal and postnatal subsets, no significant difference in the outcome of live-born infants was established. For 4 infants with intestinal atresia, a significant difference was demonstrated for the 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 the 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 the neonatal outcome of live-born infants following a prenatal 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 prenatal diagnosis to the outcome of infants with gastroschisis may be in the prevention of unnecessary intrauterine death and detection of intestinal complications. A proposed surveillance protocol for fetuses with gastroschisis, focused on intrauterine 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 abnormal cardiotocography registration, may improve outcomes. 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 included 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 contraindications to surgery, including previous hysterotomy in the active uterine segment. The trial was stopped for the efficacy of prenatal 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 aforementioned 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 three 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 three 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 overestimate the likely benefit for one's own fetus and to underestimate the associated risks. Counseling should involve not only precise quantitative statements comparing outcomes of prenatal versus postnatal surgery based on 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 outcomes 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.
- aortic balloon valvuloplasty for critical aortic stenosis with a small left ventricle or with a normal size left ventricle but poor function;
- atrial septostomy for highly restrictive or intact atrial septum in hypoplastic left heart syndrome; and
- 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, and 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 cases. Prenatal 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 postnatal 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 a normal or enlarged left ventricle secondary to primary mitral valve disease. Increased left heart size and pulmonary vein Doppler patterns are predictive of postnatal outcomes. Despite the presence of a dilated left ventricle, postnatal management with staged single ventricle palliation may be the most effective strategy.
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 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. Overall, the procedure resulted in a functional limb in 50% (7/14) of cases. There were 3 cases with intraoperative 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 the 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 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 their fetal medicine unit over 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 normal neonates at term, 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 favorable outcomes. 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 weeks (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). The median gestational age at delivery was 37.4 weeks (range of 23.7 to 41.4 weeks), and the median interval between the procedure and delivery was 18.2 weeks (range of 1.1 to 25.7 weeks). The median birth weight was 2,720 g (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 days (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 for 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 in 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 continues to grow due to the oxygenated blood from the co-twin. These investigators reported a case of monochorionic, diamniotic twin pregnancy after IVF-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. A reversed a-wave in the ductus venosus was observed, and the acardiac twin showed subcutaneous edema. On November 24, 2011, a successful interstitial ultrasound-guided laser coagulation was performed at 16 weeks of gestation; a 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 delivery, a stage 2 intraventricular hemorrhage and jaundice were observed in the neonate. Phototherapy was administered, and the mother and 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 at the authors’ institution. The essence of the treatment of TRAP sequence is the cessation of 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 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.
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 the 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 among 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.
Ruano et al. (2013) evaluated the effect of early fetoscopic tracheal occlusion (FETO) (22 to 24 weeks' gestation) on pulmonary response and neonatal survival in cases of extremely severe isolated congenital diaphragmatic hernia (CDH). This was a multi-center study involving fetuses with extremely severe CDH (lung-to-head ratio less than 0.70, liver herniation into the thoracic cavity, and no other detectable anomalies). Between August 2010 and December 2011, a total of 8 fetuses underwent early FETO. Data were compared with 9 fetuses that underwent standard FETO and 10 without fetoscopic procedure from January 2006 to July 2010. FETO was performed under maternal epidural anesthesia, supplemented with fetal intramuscular anesthesia. Fetal lung size and vascularity were evaluated by ultrasound before and every 2 weeks after FETO. Postnatal therapy was equivalent for both treated fetuses and controls. The primary outcome was infant survival to 180 days, and the secondary outcome was fetal pulmonary response. Maternal and fetal demographic characteristics and obstetric complications were similar in the 3 groups (p > 0.05). The infant survival rate was significantly higher in the early FETO group (62.5%) compared with the standard group (11.1%) and with controls (0%) (p < 0.01). Early FETO resulted in a significant improvement in fetal lung size and pulmonary vascularity when compared with standard FETO (p < 0.01). The authors concluded that early FETO may improve infant survival by further increases in lung size and pulmonary vascularity in cases with extremely severe pulmonary hypoplasia in isolated CDH. They stated that the findings of this study support formal testing of the hypothesis with a randomized controlled trial.
Ruano et al. (2014) reviewed the indications, technical aspects, preliminary results, risks, and clinical implications of FETO for severe CDH performed outside the United States and its potential future directions in this country and globally. Congenital diaphragmatic hernia occurs in approximately 1 in 2,500 live births and results in high neonatal morbidity and mortality, largely associated with the severity of pulmonary hypoplasia and pulmonary arterial hypertension. With the advent of prenatal imaging, CDH can be diagnosed before birth, and in utero treatment is now available in some centers. The prognosis of CDH can be evaluated by assessing fetal lung size, the degree of liver herniation, and the fetal pulmonary vasculature in isolated forms of CDH. These parameters help classify fetuses as having mild, moderate, severe, or extremely severe isolated CDH. Severe and extremely severe diaphragmatic hernias have poor outcomes and thus are candidates for innovative therapies such as FETO. Fetal endoscopic tracheal occlusion is usually performed between 26 and 30 weeks' gestation. In utero, an endoscope is passed through the fetal mouth and down to the carina; the balloon is deployed just above the carina. After the procedure, ultrasound surveillance every 2 weeks ensures the balloon's structural integrity and measures the fetal pulmonary response. At approximately 34 weeks' gestation, the balloon is deflated and removed. Fetal endoscopic tracheal occlusion is thought to improve outcomes by decreasing mortality and allowing more rapid neonatal stabilization. Ultimately, the goal of FETO is to minimize pulmonary hypoplasia and pulmonary arterial hypertension. Following delivery, neonates still require diaphragm repair.
Sizarov and Boudjemline (2017) noted that efficient use of fetal echocardiography has enabled early detection of congenital heart disease and its often irreversible complications, such as ventricular hypoplasia in cases of severe stenosis of the semilunar valves. Experience over the past 25 years has proved that balloon dilatation of the severely stenotic or atretic valve in fetuses as early as the 23rd week of gestation is technically feasible with a learning curve. Reported results regarding the ultimate bi-ventricular circulation outcome after fetal valve intervention are at best controversial, with the desired improvements in the quality of life (QOL) and cost-benefits of postnatal treatment being as yet unconfirmed. Despite acute hemodynamic success with a relatively low rate of fetal complications, the number of suitable candidates for fetal valve intervention remains low. High valvular tissue plasticity in the fetus and difficulties in assessing the point of no return of myocardial damage often make the success of fetal valve intervention short-lived and unpredictable. The authors concluded that future refinements of the equipment, imaging, and biodegradable tissue regeneration materials will lead to better results of fetal valve interventions beyond their technical success.
Swanson et al. (2025) stated that in utero hematopoietic cell transplantation (IUHCT) uses tolerogenic fetal immunologic development to facilitate the engraftment of donor cells. Non-hematopoietic donor-derived cells have been described in both in utero and postnatal models of hematopoietic cell transplantation (HCT). However, while epithelial routing has been reported, long-term engraftment following IUHCT has not been well studied. These researchers employed intra-amniotic (IA) or intra-vascular (IV) IUHCT to examine routing and engraftment within the pulmonary tissues and gastrointestinal (GI) tract. High donor-cell viability was observed in the amniotic fluid 24 hours following IA injection (mean of 89.1%). At 24 and 72 hours, donor cells were present within the lumens of GI and pulmonary tissues and in the parenchyma of the liver, suggesting that donor cells routed effectively to epithelial surfaces and hematogenous targets following IA injection. However, following IA delivery, long-term engraftment was not observed in peripheral blood, and there was no evidence of donor-derived cells in any target tissue, including lung, bowel, or liver. Following IV injection, mean peripheral blood chimerism at terminal harvest was 23.86% (SEM 12.44; range of 0.00 to 98.90). Following IV delivery, donor-derived cells were noted in the bowel, liver, and lung, but not in the epithelium, suggesting these cells were circulating or tissue-resident leukocytes. The authors concluded that despite the routing of donor cells to multiple fetal sites, the IA injection was an extremely inefficient method for long-term engraftment in the hematopoietic niche, in organ parenchyma, or on epithelial surfaces. On the contrary, despite IV IUHCT being able to consistently produce hematopoietic engraftment, epithelial engraftment was not observed, suggesting a limited role for IV IUHCT in epithelial disorders.
Percutaneous versus Open Fetal Surgical Intervention for Sacrococcygeal Teratomas
Menchaca et al. (2023) noted that sacro-coccygeal teratomas (SCTs) may require in-utero surgery for survival. Open surgical intervention (OSI) was first described; however, increasing reports of percutaneous intervention (PI) with variable indications and outcomes exist. These investigators examined the literature for all published cases of fetal SCT intervention and compared OSI to PI cohorts. Inclusion criteria were as follows: data available per individual fetus including gestational age at intervention, type of intervention, primary indication, survival, gestational age at birth, and complications. Complications were grouped into categories: placenta/membrane, procedural, or hemorrhagic. Failure was defined as little/no improvement or recurrence of the primary indication. χ2 analysis was carried out for solid tumor PI versus OSI to examine significant trends in these intervention groups. A meta-analysis was not feasible due to small numbers and heterogeneity. A total of 27 studies met inclusion criteria. In the PI group, 38 fetuses underwent intervention for solid tumors, 21 for cystic tumors, and 3 for solid and cystic tumor components. Among fetuses with solid tumors, OSI was associated with lower need for multiple interventions (0% versus 31.6%, p = 0.01), and higher survival to discharge (50% versus 39.5%, p = 0.02). A fetal intervention was carried out in the absence of hydrops/early hydrops in 45% of fetuses receiving PI, compared to 21% receiving OSI. Failure to resolve the primary indication was higher in the PI group (55.9% versus 11.1% OSI, p = 0.02). The overall complication rates were high in both groups (90% OSI, 87% PI), although bleeding was unique to the PI group (26.5%). Pre-emptive cyst drainage, for purely cystic tumors, was universally successful and associated with a low complication risk (18.2%). The authors concluded that for solid tumors, OSI appeared to be superior with regard to survival to discharge, fewer interventions, and lower failure rates. Percutaneous interventions to drain a cyst may facilitate delivery or pre-empt future complications, although consideration should be given to long-term oncologic outcomes.
Thoracoamniotic Shunt for Fetal Pleural Effusions
Peranteau and co-workers (2015) stated that hydrops and pulmonary hypoplasia are associated with significant morbidity and mortality in the setting of a congenital lung lesion or pleural effusion (PE). These researchers reviewed their experience using in-utero thoraco-amniotic shunt (TAS) to manage fetuses with these diagnoses. They performed a retrospective review of fetuses diagnosed with a congenital lung lesion or PE who underwent TAS placement from 1998 to 2013. A total of 97 shunts were placed in 75 fetuses. The average gestational age (± SD) at shunt placement and birth was 25 ± 3 and 34 ± 5 weeks, respectively. Shunt placement resulted in a 55 ± 21% decrease in macro-cystic lung lesion volume and complete or partial drainage of the PE in 29% and 71% of fetuses, respectively. Sixty-nine percent of fetuses presented with hydrops, which resolved following shunt placement in 83%. Survival was 68%, which correlated with gestational age at birth, percentage reduction in lesion size, unilateral PEs, and hydrops resolution. Surviving infants had prolonged neonatal intensive care unit (NICU) courses and often needed either surgical resection or tube thoracostomy in the perinatal period. The authors concluded that TAS provided a therapeutic option for select fetuses with large macro-cystic lung lesions or PEs at risk for hydrops and/or pulmonary hypoplasia; survival following shunting depended on gestational age at birth, reduction in mass size, and hydrops resolution.
In a retrospective, single-center study, Suyama and colleagues (2018) examined the role of lung size and abnormal Doppler findings in the umbilical artery (UA) in determining the outcomes of fetuses with primary fetal hydrothorax (FHT) associated with hydrops who underwent TAS. These researchers included cases of primary FHT with hydrops who underwent TAS at the authors’ hospital between 2004 and 2016. They evaluated the relationship between mortality until 28 days after birth and ultrasound findings, including absent or reversed end-diastolic velocity (AREDV) in the UA and the lung-to-thorax transverse area ratio (LTR), before and after TAS. A total of 41 cases of primary FHT with hydrops underwent TAS. The median (range) gestational age at TAS was 28.5 (19.3 to 33.8) weeks. Bilateral PE was observed in 39 cases (95.1%). Among the 41 cases, 19 (46.4%) survived, 11 (26.8%) died in utero, and 11 (26.8%) died in the neonatal period. AREDV in the UA before and after TAS was not associated with mortality (p = 0.32 and 0.47, respectively). The odds ratio (OR) for mortality in LTR 0.2 to 0.3 before TAS was 0.62 (versus LTR of less than 0.2, p = 0.45), and that in LTR 0.2 to 0.3 and greater than 0.3 after TAS were 0.27 and 0.06, respectively (versus LTR less than 0.2, p for trend < 0.01). The authors concluded that a larger LTR following TAS was significantly associated with a better prognosis in hydropic primary FHT. The fetal lung size after the procedure may be a prognostic factor for primary FHT.
Hidaka and associates (2018) stated that although the efficacy of TAS for FHT is well recognized, the co-existence of hydrops fetalis is still a clinical challenge. The preoperative determinants of shunting efficacy are not fully understood. In this study, these investigators examined the perinatal and postnatal outcomes of hydrops fetalis with PE treated by TAS using a double-basket catheter and discussed the preoperative factors predictive of patients who will benefit from TAS. These researchers conducted a retrospective study in hydropic fetuses with PE treated by TAS between 2007 and 2015. They extracted information regarding postnatal survival and pre-therapeutic ultrasound findings, including skin edema thickness, PE pocket size, and Doppler readings. A total of 12 subjects underwent TAS at a median gestational age of 29 + 5 weeks (range of 25 + 5 to 33 + 2 weeks). Skin edema disappeared or regressed in 7 cases; 3 experienced early neonatal death, and the other 9 ultimately survived after a live birth at a median gestational age of 33 + 4 weeks (range of 29 + 1 to 38 + 2 weeks). All surviving children, except for 1, had a pre-therapeutic PE pocket greater than the precordial edema thickness. All 3 children who died had precordial edema thickness equal to or greater than the size of the PE pocket. The authors achieved a high survival rate (75%) using the double-basket technique. These investigators noted that a greater pre-therapeutic width of skin edema compared with the PE pocket was possibly suggestive of a treatment-resistant condition and subsequent poor postnatal outcome.
Dorsi and co-workers (2018) stated that congenital chylothorax is a rare disease, and prognostic factors are key elements in properly informing parents. These investigators determined the prenatal factors associated with neonatal survival in a cohort of live-born infants with congenital chylothorax. An observational monocentric cohort study including all live-born neonates consecutively admitted for congenital chylothorax was conducted. Neonatal mortality was 32% (16/50). Prematurity (or birth weight), persistence of hydrops at birth, and the absence of TAS procedure were significantly associated with mortality, whereas prenatal diagnosis of PE, side of PE, hydrops fetalis, and amnio-drainage were not. In cases of prenatal diagnosis of hydrops fetalis, the reversal in utero of hydrops fetalis was significantly associated with survival (p = 0.001). In cases of TAS, the interval between TAS intervention and delivery was significantly longer for patients who survived (p = 0.03). The authors concluded that TAS and reversal of hydrops significantly improved survival, whereas prematurity worsened the outcome of live-born infants with congenital chylothorax. These researchers stated that these findings also suggested that the interval between TAS and birth appeared to be crucial; the longer the interval, the more likely was the reversal of ante-natal hydrops and neonatal survival.
Chon and colleagues (2019) noted that congenital PE is a rare condition with an incidence of approximately 1 per 15,000 pregnancies. The development of secondary hydrops is a poor prognostic indicator, and such cases can be managed with a TAS. These investigators described postnatal outcomes in survivors after TAS placement for congenital PEs. They carried out a retrospective review of all cases with fetal PEs treated between 2006 and 2016. Patients with dominant unilateral or bilateral PEs complicated by secondary hydrops fetalis received TAS placement. The results were reported as median (range). A total of 29 patients with PE and secondary hydrops underwent TAS placement. The gestational age at the initial TAS placement was 27.6 (20.3 to 36.9) weeks. Before delivery, hydrops resolved in 17 (58.6%) patients. The delivery gestational age was 35.7 (25.4 to 41.0) weeks, and the overall survival (OS) rate was 72.4%. Among the 21 survivors, 19 (90.5%) required admission to the NICU for 15 (5 to 64) days. All 21 survivors had postnatal resolution of the PEs. All 21 children were long-term survivors, with a median age of survivorship of 3 years and 3 months (9 months to 7 years and 6 months) at the time of the last reported follow-up. The authors concluded that TAS in fetuses with dominant PE(s) and secondary hydrops resulted in a 72% survival rate. Nearly all survivors required admission to the NICU; however, a majority did not have significant long-term morbidity.
Comparative Analysis of Bladder Pattern of Patients who Underwent In Utero Versus Post-Natal Myelomeningocele Repair
Parizi and colleagues (2020) stated that In utero myelomeningocele closure is a valid alternative to post-natal repair with unclear benefits to bladder function. These researchers compared bladder status in patients who underwent fetal myelomeningocele surgery versus post-natal repair. They retrospectively reviewed their data-base, with group 1 consisting of in utero surgery and group 2 consisting of post-natal repair. Group 3 was a subgroup of group 2, including patients initially presenting at age less than 12 months. These investigators recorded medical history, radiological investigation with renal US, voiding cystourethrography, urodynamic evaluation and clinical outcome of the bladder pattern following treatment. They identified 88 patients in group 1, 86 in group 2 and 38 in group 3. The incidence of urinary tract infection (UTI) was higher in the post-natal period (45% versus 20%). Hydronephrosis occurred in 20.7%, 22.6% and 28.9% of patients in groups 1, 2 and 3, respectively. Vesicoureteral reflux was diagnosed in 15% in all groups. Urodynamic data showed a higher prevalence of detrusor over-activity in group 1 and no difference in other urodynamic parameters. The high risk bladder pattern at initial evaluation occurred in 56%, 50% and 46% of patients in groups 1, 2 and 3, respectively. There was a trend to decrease the percentages of the high risk bladder pattern and to increase the normal pattern following treatment in all groups. The authors concluded that in utero repair did not improve urological parameters compared to repair in the post-natal period.
Risks and Benefits of Fetal Surgery for Congenital Cardiac Defects
Diniz et at. (2023) stated that CHDs constitute the most prevalent congenital pathology, and they are a consequence of structural and functional abnormalities during fetal development. The etiology of CHD entails the interaction of genetic and environmental factors. Fetal cardiac surgery aims at preventing natural pathways of CHD in utero, mitigating progression to more complex abnormalities. In a systematic review, these investigators examined the risks and benefits of fetal interventions in the 2 most prevalent CHDs, pulmonary stenosis and pulmonary atresia with an intact ventricular septum, but also critical aortic stenosis and hypoplastic left heart syndrome. Original and relevant articles were selected by meta-aggregation to perform a qualitative analysis of fetal cardiac interventions for pulmonary stenosis and critical aortic stenosis. The Joanna Briggs Institute's Qualitative Assessment and Review Instrument (or JBI-QARI) was used for data quality appraisal. Of 61 potential articles, 13 were selected, and 9 were finally included. The present review demonstrated that fetal cardiac surgery increases right ventricular growth and hemodynamic flow in pulmonary stenosis, whereas in critical aortic stenosis it enables growth of the left ventricle and increases left ventricular pressure. However, it has a high complication rate, along with considerable morbidity and mortality. The authors concluded that the benefits of fetal cardiac surgery for pulmonary stenosis and critical aortic stenosis are well-described in the literature; however, there is a significant risk of complications that can be reduced by the surgeon's technical expertise and well-structured hospital facilities.
Appendix
Classification of Twin-Twin Transfusion Syndrome (TTTS). The 5 stages (I to V) of TTTS are based on findings from 2D ultrasound and Doppler velocimetry of the umbilical artery (UA), umbilical vein (UV), and ductus venosus (DV).
Stage I
- Oligohydramnios and polyhydramnios sequence
- The bladder of the donor twin is visible
- Doppler indices (UA, UV, DV) in both twins are normal
Stage II
- Oligohydramnios and polyhydramnios sequence
- Bladder of the donor is not visualized
- Doppler indices (UA, UV, DV) in both twins are normal
Stage III
- Oligohydramnios and polyhydramnios sequence
- Abnormal Doppler indices: At least 1 of the following is present in either twin: absent or reversed end-diastolic velocity in the UA, reversed flow in a-wave of the DV, or pulsatile flow in the UV
Stage IV
- Oligohydramnios and polyhydramnios sequence
- One or both fetuses show(s) signs of hydrops
Stage V
- Oligohydramnios and polyhydramnios sequence
- One or both fetuses is/are dead
Adapted from Quintero et al. (1999); Papanna et al. (2021)
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