Abstract
Fetal cardiac intervention consists of a novel and evolving technique for the intrauterine treatment of a subset of patients with congenital heart diseases, which aims to improve hemodynamics, reduce secondary damage, and achieve better postnatal outcomes. Nevertheless, the risks and benefits of this therapy remains subject to controversy. This review describes the rationale, selection criteria, and technical features for the most frequently performed fetal cardiac interventions. In addition, we provide a comprehensive overview of the medical literature, exploring the clinical implications of each therapy.
Keywords
Introduction
The advent of improved fetal diagnosis and interventional techniques has increased enthusiasm for intrauterine interventions for a wide variety of congenital disorders, including congenital heart diseases (CHDs), congenital diaphragmatic hernia, spina bifida, and tumours. As a result, a variety of interventions have been proposed with the aim of improving postnatal outcomes in affected individuals.1,2
Congenital heart disease impacts roughly nine out of every 1,000 live births, with a rising prevalence worldwide. 3 In this context, fetal cardiac intervention (FCI) emerged to treat an abnormality at the developmental stage so that the process of cardiac growth, which is complex and relies on the volume and direction of circulating blood as well as genetic determinants, can continue. As most cardiac interventions are palliative, major abnormalities are still present at birth. Nevertheless, tangible benefits following successful fetal intervention include improved hemodynamics and reduction in secondary damage leading to better postnatal outcome.4,5
Although the vast majority of patients with CHD can be diagnosed accurately in midgestation, 6 it is only in a small subset of patients with CHD that the fetal intervention is technically feasible and a strong rationale for fetal intervention can be proposed. 7 Fetal cardiac intervention is based on a dynamic conception of the natural history of CHD, most of which progress prenatally. This happens in cases of severe obstruction of the semilunar valves and in those with interatrial flow restriction. Thus, the ventricle affected by outflow obstruction can evolve into a situation of extreme hypoplasia, which prevents biventricular circulation (BC) and would require adopting palliative surgical strategies that may lead to univentricular circulation.
The stenosed semilunar valve reduces the flow through the corresponding ventricular chamber and induces wall hypertrophy and stiffness, and it is ventricular function and growth that is most negatively affected with progression toward hypoplasia. In contrast, rapidly stenosing valves, especially early in gestation, usually result in dilation and poor systolic function of the respective ventricle. Rarely, valve growth failure might secondarily occur because of primary myocardial disease, in which initial ventricular dysfunction and dilation evolves into hypoplastic left or right heart syndrome 8 (Figure 1).
Schematic illustration showing that the semilunar valve stenosis induces wall hypertrophy and stiffness.
The first fetal heart valvuloplasty was described in 1991. 9 However, initial fetal cardiac valvuloplasty and/or septoplasty interventions resulted in high rates of fetal death, technical failure, and postnatal mortality. These may be explained by inadequate patient selection, technical modifications, and the need for improvement of surgical skills. 10
Fetal cardiac diseases that are potential candidates for FCI fit into one of two categories: diseases that worsen during midgestation and/or late gestation, such that there is a progression in disease process from the time of midgestation diagnosis to birth; or diseases that carry a high risk of demise in utero and/or are life threatening at birth. In these circumstances FCI may offer a chance to improve in utero and neonatal survival. 7
In cases of semilunar valve stenosis, or atresia, fetal valvuloplasty aims to achieve a biventricular, rather than univentricular circulation. Opening and stenting a restrictive atrial foramen ovale may preserve the pulmonary function in cases of hypoplastic left heart syndrome (HLHS), thereby increasing the chances of successful postnatal surgery. 4
Chronic maternal hyperoxygenation was proposed to stimulate the growth of left-sided fetal heart structures by increasing pulmonary venous return to the left atrium, thereby increasing preload to the left heart. This involves chronic administration of oxygen to a mother for several hours a day during the third trimester. This intervention requires the evaluation of both maternal and fetal safety, and a robust investigation of preliminary claims that it may prevent the need for postnatal surgery in lesions such as coarctation of the aorta and the borderline-sized left heart. 11
This article reviews three lesions for which ultrasound-guided, percutaneous, catheter-based FCI has been performed, and should be considered: (1) fetal aortic stenosis with evolving HLHS; (2) HLHS with intact or restrictive atrial septum; and (3) pulmonary atresia with intact ventricular septum (PAIVS), with concern for worsening right ventricular (RV) hypoplasia. Each of these conditions presents unique challenges and risks to fetal health, making them suitable candidates for FCI intervention. We investigate the surgical techniques currently used and address the inclusion criteria for performing FCI, emphasizing the importance of patient selection in optimizing results and minimizing the risks associated with the intervention. By selecting appropriate candidates based on specific criteria, healthcare providers may ensure that FCI is offered to those who identify themselves as most likely to benefit from the procedure. Furthermore, our review discusses outcomes associated with FCI for each CHD mentioned above.
Fetal Aortic Stenosis With Evolving Hypoplastic Left Heart Syndrome
Overview
Hypoplastic left heart syndrome encompasses a range of conditions characterized by an intact ventricular septum and underdeveloped left heart structures incapable of sustaining systemic circulation. Some variations of HLHS feature atresia of the mitral and/or aortic valves, whereas in others, there exists a discernible left ventricle (LV) cavity with hypoplastic yet patent mitral and aortic valves. 7
Natural history studies have demonstrated that severe aortic stenosis in midgestation of the fetus initially leads to LV dilation as the ventricle attempts to overcome significant afterload. As pregnancy advances, the LV gradually experiences dysfunction, leading to eventual growth arrest of left-sided structures. By the time of birth, the left side of the heart is incapable of supporting the systemic circulation, and the result is HLHS. 12
The goal of fetal intervention for this disease is to relieve the severe aortic stenosis that triggers these hemodynamic alterations, thereby avoiding evolution to HLHS and enabling a BC postnatally 12 (Figure 2).
Ultrasound images of fetal critical aortic stenosis. (A) B-mode image showing a narrow left ventricular outflow tract. (B) Color Doppler image showing minimal flow in the left ventricular outflow tract.
In fetuses with valvar aortic stenosis, the ongoing LV pressure load and lack of blood flow through the left heart during gestation leads to worsening endocardial and myocardial fibrosis, and growth arrest of left heart structures. The recognition that fetal aortic stenosis is a progressive disease led to initial interest in FCI to avoid in utero progression of aortic stenosis to HLHS. The concept behind fetal aortic balloon valvuloplasty is to reduce left ventricular pressure and enhance left heart flow, both of which are thought to foster left heart development and mitigate adverse left ventricular remodeling and fibrosis. The ultimate aim is to augment the probability of establishing a left ventricle capable of sustaining systemic circulation at birth. 7
Inclusion Criteria
Selecting fetal candidates for aortic valvuloplasty involves two primary assessments: (1) the presence of features strongly indicative of HLHS progression without FCI and (2) the possibility of FCI restoring left heart function and subsequently sustaining systemic circulation.
Criteria indicative of probable development of HLHS include LV systolic dysfunction at a moderate or higher level, retrograde flow in the aortic arch, altered flow in the foramen ovale (either bidirectional or left-to-right), and monophasic inflow of the mitral valve. The factors associated with higher likelihood of LV recovery to support systemic circulation after birth have been established and include LV pressure >46 mm Hg, larger ascending aorta z-score and indices of more normal diastolic function.13,14 When analyzing surgical decision making from 13 European countries, Kovacevik et al15 reported a high probability of agreement between a multidisciplinary team and these fetal centers. As a result, the inclusion criteria for FCI in fetal aortic stenosis may be deemed well defined.
Technique of Fetal Aortic Valvuloplasty
Fetal aortic balloon valvuloplasty for fetal aortic stenosis with evolving HLHS is currently performed percutaneously under ultrasound guidance and is considered the most predominant FCI currently utilized.
Performing this intervention requires maternal conscious sedation and epidural anesthesia. The use of intramuscular fetal anesthesia and muscle relaxants aims to alleviate fetal pain and promote correct fetal positioning. Once the fetus is optimally positioned, an 18- or 19-gauge needle is introduced percutaneously into the fetal chest and through the LV myocardial wall, with the needle bore directed toward the LV outflow tract. A guidewire is then passed through the stenotic aortic valve. Over this guidewire, a deflated coronary angioplasty balloon is moved into position at the level of the aortic valve annulus. Once the balloon position is confirmed, the balloon is inflated up to maximal diameter of approximately 3.3 mm 7 (Figure 3 and Video S1). The technical success of the procedure is defined by an enhancement in anterograde flow through the aortic valve and/or the emergence of new aortic regurgitation. The technical methods are employed, and their resultant outcomes are summarized in Table 1. 10
Fetal aortic valvuloplasty ultrasound image sequence. (A) Apical left ventricle entry with transcutaneous needle puncture (cannula). (B) Cannula course parallel to the left ventricle outflow track. (C) Guidewire advanced through the cannula at the aortic valve. (D) Balloon inflation at the aortic valve. *: cannula and stylet needle. Dashed circle: aortic valve with critical aortic stenosis. Long arrow: guidewire through the cannula. Short arrow: inflated balloon.
Fetal Cardiac Interventions—Objectives, Procedure, and Related Complications.
Abbreviation: HLHS, heart left hypoplastic syndrome.
Complication rates were based on Araujo Júnior et al. 10
Outcomes
About half of the fetuses undergoing prenatal aortic valvuloplasty demonstrated both bradycardia and RV dysfunction of diverse severity. Fetal hemodynamic instability occurs almost exclusively in fetuses undergoing ventricular puncture and may become evident either before the balloon is introduced into the ventricle, during dilation, or even after removal of equipment from the fetal heart. 15 Fetal aortic valvuloplasty carries a risk of fetal demise of about 10%. 16 Based on existing evidence from three studies comprising 198 procedures, aortic valvuloplasty demonstrates a live-birth rate of 65%, accompanied by a neonatal mortality rate of 16%. 10 We provide reported outcomes in Table 2 with their 95% confidence intervals.
Main Perinatal Outcomes of Fetal Cardiac Interventions.
Abbreviation: HLHS, heart left hypoplastic syndrome.
Perinatal outcomes rates were based on Araujo Júnior et al. 10
Critical aortic stenosis accompanied by a restrictive interatrial septum may cause fetal congestive heart failure and hydrops, ultimately resulting in fetal death if untreated. 17 In this situation, Tulzer et al18 assessed the potential benefits of FCI, and found that valvuloplasty may restore fetal cardiac output, holding the promise of resolving hydrops.
Moreover, a recent cohort study illustrated an elevated probability of technical success in FCI associated with a more recent time frame. This observation underscores the impact of the learning curve on surgical outcomes,19 which may justify notably high rates of technical success in proficient centers and minimal risk to the mother with FCI.20
Of note, 16.7% of deaths occurred within 48 h after fetal aortic valvuloplasty, and a later gestational age at intervention was associated with increased odds of live birth. However, delaying the procedure may result in missing the opportunity to prevent progression to HLHS.20 Consequently, it is essential to investigate different timing for performing FCI with the aim of preventing HLHS and minimizing the procedural risks.
Long-term outcomes should also be analyzed in those patients who underwent FCI in comparison with a prenatally expectant group. In this context, Laraja et al 21 explored neurodevelopmental outcomes in both groups of patients, and no significant difference was observed between these groups. The study authors concluded that children diagnosed with aortic stenosis during pregnancy have a neurodevelopmental delay, irrespective of fetal aortic valvuloplasty performance.
Percutaneous ultrasound-guided FCI appears to be safe for the mother and does not influence the mode of delivery. No invasive procedure is without risk, and this question needs to be explored. 22 Rebizant et al 23 investigated 113 pregnant women who underwent intrauterine treatment, and there were no cases of premature rupture of ovular membranes, wound infection, or chorioamnionits related to the procedure. Nonetheless, one case of placental abruption, without need of blood transfusion, was reported.
Pulmonary Atresia With Intact Ventricular Septum
Overview
Pulmonary atresia with intact ventricular septum is a rare congenital heart defect. It involves pulmonary valve (PV) atresia, along with diverse degrees of hypoplasia in the RV and tricuspid valve (TV). The left ventricle is generally not affected. This condition is typically difficult to manage because of its wide spectrum of RV morphologic features. 20
Right ventricular and TV size are highly correlated and can range from the low end of normal to severely hypoplastic. The primary factors influencing postnatal outcomes, which span from achieving BC via pulmonary valve perforation and dilation to resorting to single ventricle palliation with Fontan circulation in the most severe instances, are RV size and compliance, along with TV size. 7
Similar to fetal aortic stenosis, pulmonary atresia follows a progressive course during gestation. The rationale to perform FCI for PAIVS and evolving hypoplastic rigth heart syndrome (HRHS) is to alter the natural history and permit a biventricular outcome after birth. This may be achieved by dilating the atretic PV in utero to facilitate right heart growth throughout the remainder of gestation. PAIVS, however, is a more heterogeneous disease than aortic stenosis with evolving HLHS and the outcomes are often based on the degree of RV and TV hypoplasia. For example, fetuses with PAIVS and severely hypoplastic right ventricles, which may be associated with fibromuscular atresia of the RV outflow and a RV-dependent coronary circulation, are not elegible for FCI. 12
In utero identification of PAIVS typically involves detecting pulmonary atresia coupled with left-to-right flow through the ductus arteriosus and evidence of RV hypertrophy, frequently evaluated quantitatively through the presence of tricuspid regurgitation. 24
Inclusion Criteria
Although generally considered for patients who are expected to have a palliative procedure in the neonatal period, fetal pulmonary valvuloplasty (FPV) lacks clearly defined criteria within the context of PAIVS. 25
Only a small subset of fetuses with PAIVS should be considered candidates for FCI, because even in very small right ventricles, as long as the TV is of an appropriate size, continued RV growth can occur through staged surgical palliation after birth resulting in successful biventricular repair. In contrast to aortic valvuloplasty, size criteria of the right-sided structures as predictors of a BC outcome after fetal pulmonary valve intervention are lacking. Nonetheless, in cases of severe tricuspid regurgitation, and hydrops in whom impending fetal demise is anticipated, prenatal intervention might be lifesaving to the fetus. 8
The degree of RV hypoplasia correlates with the z-score of the TV, and, similar to postnatal studies, the fetal TV z-score may predict eventual postnatal outcome. 12 Midgestation fetuses with TV z-score equal to or greater than 2.5 generally go on to have BC with postnatal therapy, while those with TV z-score lower than 4 already have severe right heart hypoplasia that is unlikely to be recoverable to support pulmonary circulation after fetal pulmonary balloon valvuloplasty. 7
Technique of FPV
Fetal cardiac intervention for PAIVS and evolving HRHS is more challenging than FCI for aortic stenosis with HLHS because of the complex geometry of the RV as well as the presence of hypertrophy. A 19-gauge cannula is used, and the initial trajectory is toward the RV outflow tract. The atretic valve is perforated with the stylet or a 22-gauge Chiba needle, and a 0.014-inch guide wire and coronary angioplasty balloon are positioned across the annulus for dilation. In successful interventions, color Doppler imaging demonstrates antegrade flow through the PV along with evidence of pulmonary regurgitation. 12 Table 1 outlines the technical aspects of the procedures performed and their associated results.
Outcomes
Hogan et al 25 reported nine fetal deaths (15.5%) in those patients undergoing FCI, contrasting with none in expectant management. Nevertheless, 43 patients (91%) were discharged alive, compared with nine (75%) in the control group. Among liveborn infants, successful FCI resulted in achieving BC more frequently, occurring in 87% of neonates, compared with 43% (9 out of 21) in those without FCI or with unsuccessful attempts. However, these outcomes should be evaluated with caution due to the lack in uniformity regarding inclusion criteria. In 2022, Luo et al 26 reported the outcomes of seven patients who underwent FPV. Of these, four fetuses had persistent bradycardia requiring treatment, and five were successfully delivered. In comparison with data prior to FPV, a progressive improvement in the TV annulus diameter/mitral valve annulus diameter and the right ventricle diameter/left ventricle diameter of all fetuses occurred. Nonetheless, individual variations in the development of the right ventricle were identified.
Hypoplastic Left Heart Syndrome With Intact or Highly Restrictive Atrial Septum
Overview
Hypoplastic left heart syndrome with intact restrictive atrial septum (IAS) is one of the most lethal forms of CHD,27 and approximately 5.7% of 316 infants with HLHS have IAS. 28 Unlike fetal aortic stenosis or PAIVS, in which there is in utero progression of the cardiac disease, the rationales for FCI in HLHS with intact or restrictive atrial septum are: to prevent severe neonatal hypoxia and death; and to prevent worsening of the lung disease that frequently occurs as a result of chronic in utero pulmonary venous hypertension. 7
Although neonatal survival in infants with HLHS continues to improve, one of the strongest risk factors for early mortality is an intact or highly restrictive atrial septum. 15 The incidence of IAS in HLHS is approximately 6%, with restrictive atrial septum occurring in up to 22%. Survival for patients with HLHS and IAS remains poor, with a one-year survival rate of approximatelly 30%. 7
The goal of creating an atrial communication in utero is to decompress the left atrium and prevent further damage to the pulmonary vasculature and developing lungs and to enable the patient to be more stable at birth. 12 There are two primary problems associated with this condition: (1) profound hypoxemia after birth due to restricted outflow from the pulmonary veins, which results in little effective pulmonary blood flow; and (2) chronic pulmonary venous hypertension in utero due to restriction to left atrial outflow, which results in pulmonary venous thickening and perioperative morbidity and mortality. Thus, even if postnatal opening of the atrial septum is rapid and effective, damage to the pulmonary vasculature may contribute to further mortality in the first few weeks or months of life. 15
If left atrial decompression can be achieved sufficiently early in gestation, adverse pulmonary venous remodeling may also be prevented. It follows logically that this intervention should be performed as early as possible during fetal life. Unfortunately, experience has shown that, mainly because of the small size of the left atrium, there are technical limitations to achieving an opening between the atria, and more importantly, one that remains open. Ballooning alone does not result in an atrial septal defect that remains open long enough. For all these reasons, atrial septal stenting is now preferred in some centers, and the procedure is performed during early-to-mid third trimester. 16
Nonetheless, stent placement also presents technical challenges. One of the main difficulties lies in the uncertainty associated with ultrasound visualization of the septum and stent. This lack of clarity can complicate the process, as precise positioning of the stent is essential to prevent embolization and ensure the effectiveness of the intervention. Additionally, position of the fetus adds another layer of complexity to the procedure. Ensuring precise stent positioning is crucial to prevent embolization, yet achieving this level of accuracy is challenging due to the resolution limitations of transabdominal ultrasound. 29
Inclusion Criteria
The feasibility of fetal atrial septal intervention is constrained by factors such as the timing of diagnosis, fetal positioning, and the capacity to establish a nonrestrictive interatrial communication. Consequently, numerous patients are ineligible for this potentially advantageous approach. 26 In general, IAS or an atrial septal defect equal to or lower than 1 mm, prominent pulmonary vein flow reversal, and forward-to-reverse pulmonary vein velocity time integral ratio less than 5 are reported as eligibility criteria for FCI. 27 A retrograde velocity-time integral ratio of less than 3 and maternal hyperoxygenation after 28 weeks with less than 10% reactivity are also described. 30
Technique
Septal intervention is conducted by guiding the placement of a 6F sheath into the right atrium using echocardiography. Subsequently, the central portion of the septum is perforated with a 22-gauge Chiba needle. Once septal access is established, a guide wire is preferably inserted into the left lower pulmonary vein to ensure an optimal angle and stable wire position. In certain specialized centers, a 3-mm balloon may be then advanced over the wire and inflated across the atrial septum (referred to as static balloon atrial septoplasty) to create a small atrial opening. In cases where the septum is thin and mobile, a balloon septostomy is the preferred approach, and the septum is dilated sequentially using cutting balloons. 31 In cases of stent placement, an 18-gauge needle punctures the right atrium, followed by perforation of the atrial septum. Subsequently, a 0.014 wire is inserted into a left pulmonary vein. Finally, a coronary artery stent is deployed within the atrial septum to address the condition 32 (Figure 4).
(A) Schematic image of a septostomy with placement of a stent in the interatrial septum with access to the free wall of the right atrium. (B) Ultrasound image showing the stent in the interatrial septum. (C) Color Doppler showing the right–left flow by means of stent. LA, left atrium; LV, left ventricle; RA right atrium; RV, right ventricle.
Outcomes
Despite fetal intervention in HLHS with IAS being associated with comparable results regarding live birth, neonatal death, and survival at hospital discharge, there was a lower rate of postnatal atrial restrictive septum in patients undergoing FCI.33,34 Mustafa et al 33 performed a single-arm meta-analysis and indirectly compared FCI with expectant management. In this study, there was 10% of fetal demise in those patients submitted to septal intervention, and 54.7% underwent Norwood procedure. In contrast, 3.6% had fetal demise and 69.8% were submitted to Norwood surgery in expectant group. Postnatal restrictive septum was observed in 46.6% of the newborns in FCI group compared to 60% in expectant management.
Although elevated LA pressure, pulmonary vein dilation, and magnetic resonance imaging-estimated lung perfusion improved after stent implantation, it is important to highlight that stent stenosis may occur in fetuses submitted to stent placement. 35
Maternal Complications
The evidence regarding any maternal complications related to FCI is limited and demands further investigation. In a retrospective study comprising 53 patients, postoperative pain was the most commom complication, affecting 32% of the entire cohort. Additionally, 26% of these patients reported postoperative nausea and vomiting, and only two cases of threatened premature labor were described.22
Conclusion
Fetal cardiac intervention represents a promising frontier in prenatal medicine, offering potential benefits in managing CHDs and improving postnatal outcomes. Candidates for fetal intervention are primarily those with CHDs that worsen during pregnancy or carry a high risk of mortality. Specific lesions targeted by FCI include fetal aortic stenosis, HLHS, and pulmonary atresia. As techniques evolve and safety profiles improve, FCI holds the potential to further advance prenatal care and contribute to better outcomes for infants with CHDs. However, continued research, refinement of techniques, and careful patient selection are necessary to maximize the efficacy and safety of these interventions. Furthermore, while FCI also seems to be safe for the mother and may have no impact on mode of delivery, thorough exploration of this aspect remains imperative to safeguard the well-being of both mother and fetus.
Supplemental Material
Footnotes
Abbreviations and Acronyms
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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References
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