The Impact of Fetal Echocardiography on the Prognosis of Congenital Heart Disease

Abstract

Congenital heart disease (CHD) represents the group of the most common malformations detected both prenatally and after birth. Although progress in the management and treatments of CHD, it still remains a significant cause of neonatal morbidity and mortality. However, the recent improvement in the diagnosis and therapy of CHD represents one of the most important successes of cardiac surgery and medical treatment. Accordingly, in the last twenty years, the number of patients with CHD who have reached adulthood has increased significantly and even surpass the number of affected pediatric patients, due to the extraordinary progress in the diagnostic, clinical, and surgical technologies. In particular, the ultrasound study of the fetal heart allows a diagnosis of CHD in the prenatal period, significantly improves perinatal outcomes in infants with critical CHD, and enables a reduction in stillbirth.

1. Introduction

Congenital heart disease (CHD) is the most common malformation detected prenatally and at birth. Generally, estimated incidence is approximately 10/1000 of live births and is significantly higher in premature infants and in stillborn [1]. Although remarkable progress has been made in the diagnosis and treatment of this condition, it still remains a significant cause of neonatal morbidity and mortality. Congenital malformations of the heart are a broad spectrum of defects varying from mild lesions that produce only minimal or no symptoms and might be incidentally detected in adult life to severe anomalies that cause premature death. There are many factors that increase the risk of having a child with CHD. The etiology of CHD can be separated into genetic and non-genetic forms. Epidemiological studies have suggested that a genetic or environmental cause can be identified in approximately 30% of CHD cases [2]. Approximately 17% of CHD occurs in association with a well-defined syndrome such as trisomies 13, 15, 18, 21 and Turner syndrome [3]. Some environmental factors have been identified as responsible for CHD such as congenital rubella infection or teratogenic drugs [2]. However, the majority of cases remain unexplained, probably due to some combination of genetic and environmental factors [4].

The main classification of CHD includes:

• Left-to-right shunt leading to an increased pulmonary flow

• Reduced pulmonary blood flow

• Transposition of the great arteries

• Left and right heart obstruction

• Duct dependent pulmonary or systemic circulation

In this chapter, we will discuss in detail the importance of fetal echocardiography and the fundamental impact of early detection and interventions during fetal life on postnatal outcomes. We will also discuss the importance of adequate counseling in order to allow parents to understand the condition, to support them in the most difficult decision to interrupt or keep pregnancy, to offer extensive information on available therapeutic options, and prevision of data on outcome and quality of life.

2. Fetal echocardiography, impact on the prognosis

Fetal echocardiography is born in the late 80s, when the improvement of ultrasound technology has made possible to focus attention on the characteristics of the fetal heart. Huhta JC, one of the pioneers of this method, raised the question if, without the possibility of treating in utero CHD, is it useful or advisable to make the diagnosis in advance, before birth [5]. It is clearly demonstrated that a team consisting of an expert gynecologist and a pediatric cardiologist can make diagnosis of a number of congenital heart defects in the fetal stage with very high degree of accuracy [6]. The prenatal diagnosis of CHD in the last 30 years has reached a high degree of diagnostic accuracy allowing to identify of almost all forms of CHD during fetal life; this is true in most expert centers since the interpretation of fetal echocardiography requires advanced skills. Accordingly, a suspected cardiac abnormality should then always be referred to a fetal cardiology specialist in a tertiary level center for further evaluation. Prenatal diagnosis rates for CHD increased from 23.0% in 1983–1988 to 47.3% in 1995–2000 [6]. Similarly, termination rates increased from 9.9% (between 1983 and 1989) to 14.7% (between 1989 and 2000) [6]. The spectrum of CHD observed before birth appears similar to the spectrum of CHD postnatally detected [6]. Early diagnosis of CHD during fetal echocardiography can influence the prognosis because it can permit the parents and clinicians to treat the defect. In this chapter, we will address pregnancy and delivery management, issues related to voluntary interruption of pregnancy, and fetal interventions.

3. Pregnancy and delivery management

Prenatal diagnosis has an impact on morbidity and mortality for most severe conditions because it allows an appropriate referral and planning of delivery and immediate assistance in expert centers resulting in improving short-term outcomes. However, its influence on long-term outcomes are still not clarified. In particular, prenatal diagnosis of conditions that constitute a neonatal emergency, such as duct dependent lesions, allows for manage the delivery in a tertiary care center. This strategy improves survival significantly and reduces preoperative morbidity and risk of neurological compromission [7]. CHD patients diagnosed postnatally that were born at non-tertiary centers, without specialist neonatal or cardiac services, presented later and required much higher levels of cardio-respiratory support during transfer from geographically distant locations [8]. Of note, clinical instability in postnatally diagnosed infants with CHD is an established risk factor for morbidity and mortality [8]. Moreover, it has also been proven that prenatally diagnosed infants undergo significantly earlier surgery [8].

4. Voluntary interruption of pregnancy

It has been documented that a parallel increase in pregnancy interruption occurred with fetal CHD diagnosis [9]. Thus, early diagnosis of CHD permits parents to make the difficult choice of eventual interruption of pregnancy. The rates of prenatal diagnosis of CHD were 47,3% in France, 49% in USA, and 52,8% in Australia [10]. In our center, our 21 years’ experience is in accord with the one of Khoshnood [6]: the spectrum of prenatally diagnosis CHD is getting similar to the one observed after birth. This is due to the great number of detected cases. Other than hypoplastic left heart syndrome (HLHS), pregnancy termination was exceptional. Early neonatal mortality in patients with severe CHD decreased to less than 1/3 in the period 1995–2000 [6]. The curve of survival shows a slightly worse survival for neonates with the prenatal diagnosis but this is likely to be related to the composition of the population and selection bias since fetal echocardiography is performed only when there is a high index of suspicion for more severe CHD [11].

4.1 Fetal cardiac intervention

Several fetal studies reported that structural heart disease, in particular aortic stenosis, evolves in utero, hindering the growth of the left ventricle [12]. Fetal cardiac intervention (FCI) is a novel and advanced technique that allows in utero treatment of a subset of congenital heart disease. Fetal cardiac intervention with valvuloplasty, is based on the principle that intervention will modify the natural history of the disease process [13]. To prove an eventual favorable impact of FCI, we must first gain a full understanding of the unaltered progression of heart disease in utero. Referral centers that have performed the most procedures have shown that in utero valvuloplasty can be performed successfully, with limited risk to the mother and encouraging outcomes for fetuses, especially in those with aortic stenosis at risk of evolving to HLHS [14].

Fetal intervention is technically feasible only in a small specific subset of congenital heart defects.

The three most commonly performed FCI are [15]:

1. Fetal aortic stenosis with risk factors for evolving into hypoplastic left heart syndrome (HLHS).

2. HLHS with intact or restrictive atrial septum.

3. Pulmonary atresia/stenosis with intact ventricular septum, with concern for worsening right ventricular (RV) hypoplasia.

   • Fetal aortic stenosis. In Linz center between October 2000 and February 2020, 115 fetal aortic valvuloplasties (FAV) were undertaken in 95 fetuses. All patients but one had at least one technically successful procedure. An overall success rate of 82.4% (14/17 procedures) was reported by Tulzer et al. [16]. Similarly, Pickard et al. reported in a period from 2000 to 2017 that fetal aortic valvuloplasty was technically successful in 84% of 143 fetuses, while fetal demise was observed in 8%. Biventricular circulation was achieved in 50% of the remaining 111 live-born infants with successful fetal aortic valvuloplasty, while only 16% of the 19 patients with unsuccessful valvuloplasty achieved biventricular circulation [17].

   • HLHS with intact or restrictive atrial septum. The incidence of intact atrial septum in HLHS is approximately 6%, with restrictive atrial septum occurring in up to 22% [18]. Survival for patients with HLHS and intact atrial septum remains poor, with a 1-year survival rate of ∼ 30% [19]. The rationale for FCI in HLHS with intact or restrictive atrial septum is to avoid 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. Postnatal management involves atrial septostomy, the Rashkind procedure, to open the atrial septum and enhance atrial mixing. Some selected centers performing this type of FCI, have attempted to maintain patency of the atrial septal defect until the time of delivery, with an atrial septal stent. In the largest cohort of patients undergoing FCI on the atrial septum (n = 47) from the International Fetal Cardiac Intervention Registry, technical success was reported in 77% of cases, with 65% success in atrial stent placement [20].

   • Pulmonary atresia/stenosis with an intact ventricular septum. Even lesions like pulmonary atresia with intact ventricular septum and severe pulmonary stenosis can progress to significant right ventricular dysplasia and evolve to unfavorable univentricular circulation at birth which will require complex and multiple interventions in the follow-up. These fetuses are potential candidates for pulmonary balloon valvuloplasty in utero. Fetal cardiac intervention offers the potential for improved right ventricle and tricuspid valve growth, less damage to the myocardium, potential for biventricular circulation, and improved morbidity and mortality [21].

The International Fetal Cardiac Intervention Registry (IFCIR) has published data from multiple institutions that provide FCI for PA/IVS [22]. In this study, 16 patients enrolled underwent FCI with 11 successful procedures. The procedure success rate was 11/16 (69%). Of the 11 technically successful cases, five (45%) had postnatal biventricular repair [22]. The group at the Children’s Hospital Heart Center in Linz has published a large cohort of patients at a single center [23]. They performed 35 FCI on 25 maternal-fetal pairs for either PA/IVS (n = 15) or critical pulmonary valve stenosis (n = 8). They report either partial or successful FCI in 21/23 maternal-fetal pairs. In the successful intervention group, 15 had a predicted biventricular surgery (70%), three a one and a half ventricle surgery and three an indeterminate outcome. No patients that had a successful FCI were predicted to have a single ventricle outcome [23]. A study performed at Boston Children’s Hospital describes their experience [24]. FCI was performed in ten fetuses with PA/IVS. The first four procedures were technically unsuccessful and the following six procedures were successful. Compared with control fetuses (n = 15) with PA/IVS who did not undergo prenatal intervention and had univentricular outcomes after birth, the tricuspid valve annulus, right ventricle length, and PV annulus grew significantly more from midgestation to late gestation in the six fetuses who underwent successful interventions. Nine fetuses were liveborn; one fetus was terminated after an unsuccessful attempt at FCI. All nine patients required postnatal interventions. Of the six successful FCIs, five had a predicted biventricular outcome (83%) and one had a predicted single-ventricle outcome [24].

FCI also includes transplacental drug therapy, such as maternal antiarrhythmic drugs in case of fetal arrhythmias and steroids [25].

4.2 Termination of pregnancy

FCI techniques have made possible to improve the success rates of cardiac interventions in utero, obtaining better postnatal outcomes. However, it is inevitable to consider the consequences of a diagnosis of CHD in the prenatal period, leading to a set of complex emotional states in parents who move away from the concept of “healthy condition” of their future child. Discussion with parents on the long-term prognosis constitutes a fundamental element of adequate counseling. Appropriate counseling is ideally composed of an interdisciplinary team: obstetrician, pediatrician, pediatric cardiologist, and heart surgeon [26]. Counseling to parents following the diagnosis of congenital heart disease should take into account: the severity of CHD, the association with extracardiac malformations, and the presence of an associated genetic syndrome. All of these factors influence the parents’ decision regarding pregnancy continuation or interruption.

In recent decades, the study of the heart in the prenatal period through fetal echocardiography, associated with a marked improvement in ultrasound technologies, and a greater competence of the operators, has significantly increased detection of the prenatal CHD. The incidence cardiac anomalies diagnosed at prenatal ultrasound screening differs from that observed at birth, due to intrauterine fetal demise and the recourse to termination of pregnancy (TOP). Indeed, in countries where prenatal evaluation is considered as standard of care, the incidence of CHD births is even lower [27]. As mentioned before, the main advantages of an early diagnosis of cardiac malformation are the possibility of adequate preparation for childbirth and neonatal care and early interventions in utero. However, it is inevitable to consider the consequences of a diagnosis of cardiac malformation have in the prenatal period, leading to a set of complex emotional states in parents who have to move away from the concept of “healthy condition” of their future child and eventually undertake the difficult choice of TOP [6]. Annually in the European Union, it has been estimated that 36000 children are live-born with CHD [28]. Increasing prenatal detection may lead to a reduced birth incidence of severe complex CHD through a high rate of TOP, even if this trend is not universal [29]. In the EUROCAT registry, a total of 31% of prenatally diagnosed nonchromosomal CHD resulted in TOP [28]. The parent’s choice to TOP is conditioned by several factors as listed below [30, 31, 32]:

1. ethical and/or religious reasons;

2. current legislation;

3. severity of cardiac malformation;

4. impact of heart disease on quality of life;

5. possibly associated extracardiac malformations;

6. underlying genetic condition;

7. complexity of cardiac surgery;

8. prediction of survival to adulthood and long-term quality of life;

Additional components that influence the couple’s decision-making process include the socioeconomic status, the age of the parents, and the overall family context (caregivers) [33]. It is also reported in the literature that the “pressure” regarding the choice to terminate a pregnancy following multidisciplinary counseling is greater when listening to gynecologists than to pediatric cardiologists and cardiac surgeons [34]. A French study reports an interesting analysis of isolated CHD fetuses; concluding that more than half of the choices for termination of pregnancy were based on the “complexity” of heart disease as HLHS, univentricular heart, pulmonary valve atresia, aortic stenosis [6]. It is, therefore, essential to transfer adequate and precise counseling to the couple without limiting the decision-making process. Thus, considering the information that is offered to parents by pediatric cardiologists and cardiac surgeons regarding the diagnosis of hypoplastic left heart syndrome, it is not surprising that the choice for TOP will increase in this condition because this CHD has a poor post-natal outcome with an impact on the quality of life of the newborn, given the multistage palliative surgery and the surgical risks associated with each intervention [35]. After these considerations, we should if fetal echocardiography should be performed ignoring the consequence of such acts [36]. This debate is still ongoing today, asking questions about the impact that prenatal ultrasound diagnosis can have on the future of humanity [37, 38].

4.3 Fetal counseling

Since the prenatal diagnosis of fetal malformation has improved and it’s now possible to detect or suspect a fetal malformation from the mid-gestation, it has been necessary to improve the counseling, paying attention to the ethical and psychological aspects related to this issue [39, 40, 41, 42]. This is an important issue raised by the large and growing scientific literature on this argument [39, 40, 41, 42]. As a consequence of these observations, many authors [43, 44] suggest that is necessary that counseling is performed by a multidisciplinary team comprising the obstetrician, the cardiologist, the surgeon, and the psychologist, in order to provide a fully comprehensive information to the parents. The passage from paternalistic medicine to defensive medicine, which recognizes the patient’s right to have full information, incites the doctor to tell the truth, even in the case of the inauspicious diagnosis of a life-threatening illness. During counseling, at the communicative level, the challenge is not “whether to tell the truth, but rather, how to tell it”. Since CHD is a significant cause of morbidity and mortality in the newborns, its diagnosis may lead to a huge crisis in the affected families, considering the perceived implications of having an abnormality of such vital an organ. The severity of the crisis depends not only on the nature of the abnormality, but also upon its perceived seriousness and whether the defect is correctable. During the pregnancy, parents idealize the newborn and give him/her qualities, feelings, and capacities that they wish. The birth of a baby with a malformation is a sorrow including the death of the imagined child.

The majority of the diagnosis of fetal congenital heart disease occurs after the 18th week of gestation, when the mother already feels the first fetal movements, and the baby is part of her body [45]. During counseling, parents need to know if there is a possibility of repair and what is the risk of the procedures, and how will be the child’s quality of life. Some authors analyzed the mother’s desire for more information on prenatal diagnosis of fetal abnormality [46]. Some mothers preferred to have increased information upfront in order to “wrap their head around the disease,” while other mothers felt that too much information upfront increased anxiety and would rather “cross that bridge when they came to it.”

The explanation should possibly be given with both parents present, allowing each to provide support to the other, considering that the impact may be different on either parent, since each may perceive the abnormality differently.

4.4 Genetic counseling

The etiology of congenital heart disease is currently the focus of intense research.

The ideal genetic counseling for cardiovascular malformations includes a thorough understanding of the anatomy, management, and outcome of the particular defect, identification of other affected family members, and careful pedigree analysis for prediction of familial risks, identification of associated malformations or syndromes, and options for prenatal diagnosis [2]. Preferably, genetic counseling should be provided both by a clinical geneticist with adequate knowledge about cardiac defects and outcomes and by a pediatric cardiologist who has good knowledge and skills in genetic issues.

In the past, genetic counseling for isolated congenital cardiovascular malformations (i.e., without extracardiac malformations or syndromic diagnosis) was transmitted as an advice, with the use of overall recurrence risk for first-degree relatives of 2–5%. These malformations were reputed to be multifactorial, but recent studies suggest that specific genetic influences may be more important than previously recognized, and that certain malformations are more likely to have a stronger genetic component [47, 48].

A common genetic defect or pathogenetic mechanism may cause several apparently different forms of congenital cardiovascular malformations, as, for example, in case of chromosome 22q deletion, that cause a variety of conotruncal malformations and aortic arch anomalies [49, 50].

5. Conclusions

The prenatal diagnosis of CHD in the last 30 years has reached a high degree of diagnostic accuracy allowing identification of almost all the main forms of CHD during fetal life, in expert centers. In particular, prenatal diagnosis of conditions that constitute a neonatal emergency, such as duct dependent lesions, allows to manage the delivery in a tertiary care center. This strategy improves survival significantly, and reduces preoperative morbidity, and the risk of neurological compromise. While some CHD may have a successful surgical correction in postnatal life, a small selective subset of these defects can progress during intrauterine life and be susceptible to early interventions in the uterus. Fetal cardiac interventions might prevent in utero worsening from a simple, potentially correctable lesion to a complex cardiac condition in selective patients. FCIs are most commonly and successfully performed in the setting of 1) fetal aortic stenosis with risk for evolving to hypoplastic left heart syndrome, 2) HLHS with intact or restrictive atrial septum 3) pulmonary atresia/stenosis with intact ventricular septum, with specific features associated with risk for worsening right ventricular hypoplasia. FCI also includes transplacental therapy, including maternal antiarrhythmic drugs in case of fetal arrhythmias and steroids. FCI is a procedure that has maternal and/or fetal risks, which must be well explained to parents at the time of counseling, to be sure that they fully understand the possible complications.

Moreover, fetal early diagnosis allows to program earlier clinical management and surgery after birth, improving outcomes. The improvement in the diagnosis and treatment of these conditions, due to extraordinary advances in imaging and cardiac surgical and interventional technologies in the last twenty years, has led to a significant increase in survival rate in patients with CHD, and accordingly, the number of patients with CHD who have reached adulthood has increased significantly and even surpass the number of affected kids.