Introduction
As fetal echocardiography has advanced over the past several decades, our understanding of the natural history of congenital heart disease in utero has progressed. For select lesions that evolve in utero and lead to significant morbidity and/or mortality by the time of birth, relatively simple anatomic modifications may alter the natural history and improve prognosis. This understanding, along with improvements in interventional obstetric and catheterization techniques, has led to minimally invasive percutaneous fetal cardiac interventions. Since the first report of fetal cardiac intervention by Maxwell et al. in London in 1991, the field has developed considerably. However, fetal cardiac intervention is not curative and represents the first step toward a management strategy that must be pursued in the postnatal setting.
This chapter focuses on three forms of structural congenital heart disease for which fetal cardiac intervention is performed: severe aortic stenosis (AS) with evolving hypoplastic left heart syndrome (HLHS); pulmonary atresia with intact ventricular septum (PA/IVS) and evolving hypoplastic right heart syndrome (HRHS); and established HLHS with intact or highly restrictive atrial septum (IAS). Fetal aortic and pulmonary valvuloplasty are performed for severe AS with evolving HLHS and PA/IVS with HRHS, respectively, to promote a biventricular circulation. The goal is to prevent the life-long morbidity and mortality that accompanies staged reconstruction for functionally univentricular heart (see also Chapters 71 and 73 ). In contrast, fetal atrial septoplasty (perforation/balloon dilation), often with atrial septal stent placement, is performed for established HLHS with IAS or highly restrictive atrial septum to improve survival of an otherwise nearly lethal disease. Staged reconstruction remains necessary for such patients postnatally.
Patient selection for fetal cardiac intervention technical aspects of the procedures, and postnatal outcomes and management are discussed. Maternal considerations of fetal cardiac intervention have been central to the development of the field, with no major adverse events reported to date. Although maternal issues remain paramount to consider as new therapies evolve, they are beyond the scope of this chapter.
Severe Midgestation Aortic Stenosis With Evolving Hypoplastic Left Heart Syndrome
Fetal aortic valvuloplasty for severe midgestation AS with evolving HLHS is the most commonly performed fetal cardiac intervention. Although early surgical survival has improved for infants with HLHS, staged univentricular palliation to a Fontan circulation carries significant life-long morbidity and mortality. A subset of patients with HLHS have a common pathophysiologic etiology in utero; namely, severe valvar AS with left ventricular (LV) dilation and dysfunction. Natural history studies have demonstrated that severe AS in the midgestation fetus initially leads to LV dilation as the ventricle attempts to overcome significant afterload ( Fig. 10.1 ). As gestation progresses, the LV becomes dysfunctional and ultimately growth arrest of left-sided structures ensues. By the time of birth, the left side of the heart is incapable of supporting the systemic circulation, resulting in HLHS.
The first attempt at fetal aortic valvuloplasty was reported by Maxwell et al. in 1991. Over the next decade, multiple centers attempted to perform the procedure; however, due to selection of severe cases in the third trimester and technical difficulties, the experience was largely unsuccessful. In 2000, investigators at Boston Children’s Hospital and Brigham and Women’s Hospital embarked on a program to perform fetal aortic valvuloplasty among second trimester fetuses that met specific physiologic criteria of fetal AS with evolving HLHS. With technical modifications to the procedure, greater success was able to be achieved. The experience has since been replicated at other centers worldwide.
Makikallio and colleagues outlined specific pathophysiologic features of fetuses with severe midgestation AS that reliably predicted evolution to HLHS. These features included LV systolic dysfunction, retrograde flow in the transverse aortic arch ( Fig. 10.2 ), monophasic mitral inflow, and left-to-right flow across the foramen ovale, which have since been validated in a distinct cohort. The goal of fetal intervention for this disease is to relieve the severe AS that triggers these hemodynamic alterations in the second trimester, thereby avoiding evolution to HLHS and enabling a biventricular circulation postnatally.
Patient Selection
When selecting candidates for fetal aortic valvuloplasty, the first consideration is whether the fetus has evidence of severe valvar AS and pathophysiologic features that are highly suggestive of evolution to HLHS. These features are the hemodynamic findings outlined previously, namely, LV systolic dysfunction, retrograde flow in the transverse aortic arch, monophasic mitral inflow, and left-to-right flow across the foramen ovale. This is particularly important because a small subset of patients with midgestation AS may not present with these features and may achieve a biventricular circulation with postnatal aortic valvuloplasty alone.
The second consideration is whether the left heart is salvageable. Some fetuses present with disease that is too far advanced. For example, if the LV is already hypoplastic at the time of presentation, then recovery is unlikely. Based on fetal aortic valvuloplasty performed in 70 fetuses, McElhinney et al. devised a scoring system to help predict which patients would be likely to have a biventricular circulation postnatally. The scoring system included LV long-axis z -score greater than 0, LV short-axis z -score greater than 0, aortic annulus z -score greater than −3.5, mitral valve annulus z -score greater than −2, and AS (or mitral regurgitation) maximum systolic gradient ≥20 mm Hg. The presence of four or more of these features had 100% sensitivity and 38% positive predictive value for identifying patients with a biventricular outcome. In addition, certain patients may present with a normal or dilated LV, but extensive scar tissue, or endocardial fibroelastosis is present. Endocardial fibroelastosis is associated with abnormal LV geometry and more severe diastolic dysfunction, which also limits the ability to salvage the LV. For this reason, the Boston group recently reanalyzed their experience of 123 fetuses. In addition to the size of left-heart structures (particularly the ascending aorta and mitral valve) and the estimate of LV pressure, the mitral valve inflow time, which is a marker of diastolic dysfunction, was retained in the model to estimate likelihood of biventricular outcome from birth ( Fig. 10.3 ).
Finally, and perhaps most importantly, the mother must be a suitable candidate for fetal cardiac intervention. Since the fetus may or may not be of a viable gestational age and carries a significant anomaly, fetal cardiac intervention should not be performed unless there is minimal risk to the mother. All mothers should be thoroughly assessed by maternal-fetal medicine specialists prior to offering fetal cardiac intervention.
Technical Aspects
Because the safety of the mother is paramount, fetal cardiac intervention should be performed in an obstetric operating room with maternal epidural anesthesia. Once the epidural is placed, the fetal position is determined, and version is often performed to move the fetus into a favorable position. As seen in Fig. 10.4 , the fetus is ideally positioned such that the left chest is anterior and there is a straightforward pathway to the LV outflow tract. Once the fetus is optimally positioned, an intramuscular injection of analgesic (fentanyl), paralytic agent (pancuronium), and atropine is given.
Laparotomy is reserved only for select cases in which optimal fetal positioning is unable be achieved with external version or imaging is limited. Under ultrasound guidance, a 19-gauge cannula and stylet needle are advanced through the maternal abdomen, uterine wall, and fetal chest wall, and the LV apex is punctured ( Fig. 10.5 , ). After stylet removal and evidence of blood return confirming intracardiac cannula position, a 0.014-inch guidewire is manipulated across the LV outflow tract into the ascending aorta. A coronary angioplasty balloon is advanced over the wire, positioned across the aortic valve annulus, and inflated, typically at least two times, to 100% to 120% of the size of the aortic annulus ( ).
Technical success is confirmed by color Doppler demonstrating a broader jet of antegrade flow across the aortic valve and/or the presence of aortic regurgitation ( ). After cannula removal, the fetus is monitored for at least 30 minutes in the operating room. The most common complications, which occur in up to 40% of fetuses, are bradycardia, ventricular dysfunction, and hemopericardium. Bradycardia and dysfunction are treated with intracardiac epinephrine and atropine, typically with brisk response. If the hemopericardium is small and hemodynamically insignificant, then no intervention is performed. If the hemopericardium is moderate to large and/or there is associated hemodynamic instability, then pericardiocentesis is performed.
In 2017 the Boston group reported technical success in 101 of 123 patients (83%) who underwent fetal aortic valvuloplasty from 23.9 to 32 weeks. Greater success, up to 94%, was noted in the latter half of the experience, as would be expected after an initial learning curve. An 11% risk of fetal demise (14 of 123) was also reported, mostly from the early experience from 2000 to 2008. Most of these deaths occurred within 24 hours of the procedure. The use of laparotomy has also substantially decreased with greater experience with fetal cardiac intervention. Importantly, no significant maternal morbidity has been noted.
Postnatal Outcome and Management
Technically successful fetal aortic valvuloplasty has been shown to alter the hemodynamics ; myocardial performance as determined by both tissue Doppler imaging and strain mechanics ; and growth of left-sided heart structures in utero. In 2014 the Boston group reported the postnatal outcomes of the first 100 patients who underwent fetal aortic valvuloplasty. Most importantly, technically successful intervention resulted in larger left-sided heart structures at the time of birth ( Fig. 10.6 ). Among live-born patients ( n = 88), 31 were managed as biventricular from birth and seven were converted to a biventricular circulation after various stages of single ventricle palliation. Of the technically successful interventions, 45% resulted in a biventricular outcome postnatally.
Compared with patients managed as HLHS, freedom from cardiac death was better among patients with a biventricular circulation at midterm follow-up ( Fig. 10.7 ). However, biventricular patients had substantial cardiac morbidity, often owing to residual AS or borderline left heart structures. Nearly all patients required postnatal cardiac catheterization and/or surgery. Valve replacements were among the most common procedures performed, and 18% of patients required both aortic and mitral valve replacements at midterm follow-up. Resection of endocardial fibroelastosis was also performed at the time of cardiac surgery for other indications in 86% of patients. Not surprisingly, in addition to the borderline size of the left heart structures, diastolic dysfunction and pathologic LV remodeling may complicate postnatal management. The borderline left heart structures and diastolic dysfunction resulted in approximately one-third of this population demonstrating pulmonary hypertension, typically in the mild range, at latest follow-up.
As with other patients with borderline left ventricles, there is no precise formula that will dictate management in the neonatal period. However, because the etiologic lesion in this subgroup of patients appears to be the aortic valve, an attempt at postnatal aortic valvuloplasty is reasonable to consider if there is residual obstruction. If there is concern regarding the development of severe aortic regurgitation then a surgical valvotomy may be preferred, depending on institutional preference. Subsequent hemodynamics will provide critical data as to whether the LV may support the systemic circulation. If the left heart remains inadequate, Emani and colleagues have demonstrated that staged LV recruitment, involving aortic and mitral valvuloplasties, resection of endocardial fibroelastosis, and restriction of the atrial septum, may preserve a biventricular outcome. For patients who proceed down the single ventricle pathway early in life, conversion to a biventricular circulation is possible with reasonable outcome if the LV end-diastolic pressure is relatively low (<13 mm Hg).
Postnatal management of patients following successful fetal aortic valvuloplasty is complex and heterogeneous, which is often due to differences in myocardial response. Although some patients may require only a postnatal aortic valvuloplasty to achieve a biventricular circulation, others may require initial staged single ventricle palliation with ongoing LV rehabilitation. Long-term follow-up of this population and of patients managed as HLHS is critical to assess which superior management strategy is better over time. Whether it is preferable to have a biventricular circulation with a rehabilitated LV or to proceed with staged reconstruction with a systemic right ventricle remains to be seen.
Pulmonary Atresia With Intact Ventricular Septum and Evolving Hypoplastic Right Heart Syndrome (See Also Chapter 43 )
Similar to fetal aortic valvuloplasty, the rationale to perform fetal pulmonary valvuloplasty for PA/IVS and evolving HRHS is to alter the natural history and permit a biventricular outcome after birth. Fetal pulmonary valvuloplasty involves perforating and dilating the atretic pulmonary valve to facilitate right heart growth throughout the remainder of gestation. However, PA/IVS is a more heterogeneous disease than severe AS with evolving HLHS, and the wide spectrum of management and outcomes is often based on the degree of right ventricular and tricuspid valve hypoplasia. For example, fetuses with PA/IVS and severely hypoplastic right ventricles, which may be associated with fibromuscular atresia of the right ventricular outflow and/or a right ventricular–dependent coronary circulation, are not candidates for fetal cardiac intervention. As neonates, such patients typically undergo staged reconstruction as in other forms of a functionally univentricular heart. On the other end of the spectrum are fetuses with only mildly hypoplastic right ventricles in whom postnatal pulmonary valvuloplasty alone is often sufficient to achieve a biventricular circulation.
Candidates for fetal pulmonary valvuloplasty fall in the middle of the spectrum and would be expected to be managed with at least one palliative procedure in the neonatal period. Such patients are considered to have an intermediate circulation, and whether a biventricular circulation is ultimately achieved is dependent on postnatal management strategy. Ideally, fetal cardiac intervention would enable such patients to achieve a biventricular circulation in the neonatal period.
Patient Selection
PA/IVS is diagnosed in utero by the presence of pulmonary atresia with left-to-right flow through the ductus arteriosus and right ventricular hypertrophy with elevated right ventricular pressure, which often can be assessed quantitatively by the presence of tricuspid regurgitation. The degree of right ventricular hypoplasia correlates with the z -score of the tricuspid valve, and similar to postnatal studies, the fetal tricuspid valve z -score may predict eventual postnatal outcome. Fetal cardiac intervention is considered for patients with moderate right ventricular hypoplasia who are anticipated to require a palliative procedure in the neonatal period. More specifically, criteria for fetal cardiac intervention include the following: (1) membranous atresia of the pulmonary valve with an intact (or highly restrictive) ventricular septum; and (2) tricuspid valve z -score less than −2 with an identifiable but small right ventricle that may be a target for cannula access ( Fig. 10.8 ). However, rigorous selection criteria have not yet been defined.
Technical Aspects
Fetal pulmonary valvuloplasty is more challenging due to the complex geometry of the right ventricle and the presence of hypertrophy. A 19-gauge cannula is used, and the initial trajectory toward the right ventricular outflow tract is critical because there is less room for repositioning within the right ventricular cavity. The atretic valve is perforated with the stylet or a 22-gauge Chiba needle, and a 0.014-inch guidewire and coronary angioplasty balloon are positioned across the annulus for dilation ( ). Technically successful interventions are characterized by color Doppler imaging demonstrating antegrade flow across the pulmonary valve and pulmonary regurgitation. Complications such as bradycardia, ventricular dysfunction, and hemopericardium may occur, as detailed previously. In 2008 the group in Boston reported four technically unsuccessful fetal cardiac interventions, followed by six technically successful cases among fetuses 21 to 28 weeks, highlighting the steep learning curve for such a procedure. No fetal demise occurred. This experience has also been replicated at other centers worldwide for PA/IVS and/or critical pulmonary stenosis. In a report from the International Fetal Cardiac Intervention Registry in 2015, 16 cases of fetal pulmonary valvuloplasty were performed. Eleven were technically successful; three periprocedural demises and one late fetal demise were reported.
Postnatal Outcome and Management
Fetal pulmonary valvuloplasty may alter the natural history of PA/IVS in utero, as demonstrated by subsequent right heart growth during gestation. Among the five live-born patients with technically successful fetal cardiac intervention in Boston, four were able to achieve a biventricular circulation with varying degrees of postnatal intervention. Similarly, from the registry data, five of seven live-born patients who underwent technically successful fetal cardiac intervention were discharged with a biventricular circulation.
Similar to AS with evolving HLHS, fetal cardiac intervention for PA/IVS should be viewed as the first step toward right ventricular rehabilitation in select patients. In conjunction with aggressive postnatal management, such a strategy may permit a biventricular circulation. If the right ventricle is adequate in size at the time of birth, then postnatal pulmonary valvuloplasty alone may be sufficient. However, if the right ventricle remains borderline, then right ventricular outflow tract augmentation may be necessary, with or without central shunt placement. As the right ventricle remodels over the first couple of months to year of life, then the central shunt (and atrial septal defect) may be closed to permit a staged approach to a biventricular outcome. However, the limiting factor to the performance of fetal pulmonary valvuloplasty appears to be the lack of consensus regarding appropriate candidates.
Established Hypoplastic Left Heart Syndrome With Intact or Highly Restrictive Atrial Septum
HLHS with IAS is one of the most lethal forms of congenital heart disease. Although fetal aortic valvuloplasty is performed to prevent evolution to HLHS, fetal atrial septoplasty is performed in patients with established HLHS and IAS to improve survival. In this defect, there is minimal or no egress from the left heart. This leads to left atrial and pulmonary venous hypertension with downstream adverse effects on the pulmonary vasculature and developing lungs. Unlike the newborn, the fetus tolerates this circulation because pulmonary blood flow is low and systemic oxygen delivery is not dependent on atrial level shunting. However, at birth, an IAS leads to lack of oxygenated blood from the pulmonary veins entering the systemic circulation, as well as significant pulmonary edema. Cyanosis, acidosis, respiratory failure, and death rapidly ensue.
If HLHS with IAS is diagnosed prenatally, most tertiary care centers proceed with a timed delivery, often via cesarean section, such that the neonate may have a catheter-based or surgical intervention to decompress the left atrium immediately after birth. However, despite this postnatal strategy, survival remains dismal. Therefore fetal atrial septoplasty (dilation/perforation of the atrial septum)—and eventually atrial septal stent placement—evolved. The goal of the procedure is to create a durable atrial communication in utero to (1) decompress the left atrium and prevent further damage to the pulmonary vasculature and developing lungs and (2) enable the patient to be more stable at birth.
Patient Selection
Fetuses with established HLHS and an intact or highly restrictive atrial septum (≤1 mm atrial communication) may be considered for fetal cardiac intervention if left atrial hypertension is present and there is concern that the patient will require an emergent postnatal procedure for left atrial decompression. The degree of atrial septal restriction and left atrial hypertension is assessed by the ratio of forward to reverse flow in the pulmonary veins by pulse wave Doppler evaluation ( Fig. 10.9 ). Candidacy for this procedure is primarily based on high-risk physiology as opposed to discrete anatomic features; however, fetuses with a hypoplastic left atrium and exceptionally thick atrial septum may not be candidates for technical reasons.
