Hypoplastic left heart syndrome with mitral regurgitation: a new marker of poor fetal outcome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect and one of the commonly diagnosed congenital heart defects (CHD) during prenatal life. Data collected from the Polish Nationwide Registry of Fetal Cardiac Pathology in the years 2004 to 2018 shows that HLHS accounted for 2.96% of the 9,542 CHDs diagnosed prenatally and published in the Registry^(1,2). Worldwide, HLHS constitutes 3% of all infants born with CHDs⁽³⁾. The potential survival of a neonate with HLHS depends on several factors, including a patent ductus arteriosus and good communication at the level of both atria. Therefore, post-birth management includes the administration of prostaglandin E1 (PGE1) to maintain ductus arteriosus patency. Newborns with HLHS have several treatment options, including the Norwood procedure, heart transplantation, or palliative care. One such option is hybrid treatment, dedicated especially for neonates with low birth weight and those born prematurely. Treatment is important because neonates demonstrate quite high pulmonary vascular resistance at birth. The problem is that after birth pulmonary resistance decreases, leading to increased blood flow through the pulmonary vessels and affecting systemic circulation. If the ductus arteriosus is not properly managed and closes, a reduction in systemic circulation is observed, quickly resulting in cardiovascular insufficiency. In general, the prognosis in HLHS is poor, with only two-thirds of children surviving up to five years of age. Moreover, approximately 33% of neonates die before undergoing any palliative surgical care, and 12.7% of neonates with a single ventricle have a greater risk for cardiac arrest, while 62.3% do not survive⁽³⁾. Recent advances in prenatal screening and diagnostic technologies have enabled healthcare providers to identify HLHS in fetuses and plan postnatal management in newborns. The aim of this study was to develop a new ultrasound marker for better prediction of fetal outcomes in cases of HLHS. HLHS may be accompanied by functional changes affecting the tricuspid and mitral valves. The mitral valve may be hypoplastic, with thickened leaflets that are barely movable, or it may have short chordae tendineae. Sometimes, HLHS is characterized by tricuspid valve insufficiency (regurgitation), despite normal anatomy. The presence of tricuspid insufficiency is a sign of disfunction of the right ventricle. Since both mitral and tricuspid valve disfunctions may affect fetal and neonatal health, the presence of HLHS combined with regurgitation of the mitral and tricuspid valves may indicate a poor prognosis, leading to heart and pulmonary failure. Between 1999 and 2003, Respondek-Liberska M. analyzed 35 fetuses with prenatally diagnosed HLHS at the Prenatal Cardiology Department, showing that around 17% of newborns survived⁽⁵⁾. Prenatal echocardiography makes it possible to assess the severity of congenital heart defects and plan appropriate management and treatment for newborns, including a multidisciplinary team of obstetricians, neonatologists, cardiologists, and surgeons. Additional cardiovascular and extracardiac anomalies that accompany HLHS include ventricular septal defect, atrial septal defect, right aortic arch, single umbilical artery, persistent left superior vena cava, and agenesis of ductus venosus⁽⁶⁾. A recently proposed ultrasound marker for fetal outcomes in fetuses with HLHS is the longitudinal assessment of right ventricular function. Dysfunction of the right ventricle is associated with a poor prognosis in patients with HLHS. Ultrasound markers of right ventricular function include fractional area change (FAC) of the right ventricle and the tricuspid valve annular systolic excursion Z-score value (TAPSE)⁽⁷⁾. As a result, prenatal diagnosis of HLHS plays a key role in managing the condition, as early detection allows for proper medical planning and surgical intervention. Unfortunately, the fetal outcome may change if additional cardiac issues are found⁽⁸⁾.

This was a single-center analysis of a group of fetuses who underwent fetal ultrasound examinations at our tertiary center between 2016 and 2023. Data on HLHS were collected from the database of our unit (Fetal Pathology of the Medical University of Lodz) and the Polish Nationwide Registry of Fetal Cardiac Pathology (www.orpkp.pl) covering the years 2004 to 2023. The analysis included 80 fetuses with HLHS. Gestational age (GA) was calculated based on ultrasound biometry, involving the measurement of key parameters such as biparietal diameter, abdominal circumference, head circumference, femur length. The gestational age of the studied fetuses (n = 80) ranged from 16.3 to 39.5 weeks (average 29.3). All available ultrasound and echocardiographic examinations from multiple visits, up to three per fetus, were analyzed. All the anomalies and irregularities accompanying HLHS, which were the focus of this study, were detected during the second and third trimesters of pregnancy based on 2D ultrasound evaluation, where a disproportion between the left and right parts of the heart was visible, and color Doppler was used to observe the flow of blood through the structures of the left heart, including the left ventricle, aorta, aortic valve, and mitral valve. The measurements performed did not affect clinical management. The focus was solely on the analysis and interpretation of the collected data. This was a retrospective analysis of ultrasound and echocardiographic examinations retrieved from the facility's medical system. As a result, approval from the Ethics Committee was not required. All patients provided consent for the scientific analysis of their data at our center. The inclusion criteria included fetuses with HLHS combined with mitral and/or tricuspid regurgitation. In some cases, additional findings such as cardiomegaly, pericardial effusion, restrictive foramen ovale and/or abnormal flow through the foramen ovale were observed. In all cases, HLHS was characterized by a hypoplastic left ventricle. In the group of fetuses with HLHS combined with tricuspid and mitral valve regurgitation, there was one fetus with aortic arch hypoplasia. In cases with HLHS and mitral valve regurgitation, one fetus presented with mitral valve stenosis, and three cases involved aortic valve atresia. Also, a group of fetuses with HLHS but without mitral and/or tricuspid regurgitation was taken into consideration and presented in Fig. 1.

Fig. 1.

Prenatal and postnatal follow-up of respective HLHS groups

Eighty fetuses with HLHS were included in this study. Gestational age, calculated based on ultrasound biometry, ranged from 16.3 to 39.5 weeks (29.3 ± 6 weeks on average). The distribution of gestational age was normal according to the Shapiro-Wilk test (p = 0.056). The analyzed group of fetuses with HLHS (n = 80) was divided into four subgroups. The first subgroup included fetuses with HLHS without tricuspid (TR) or mitral regurgitation (MR) (n = 55, 69%) and without other abnormalities – the number of deaths was n = 8 (15%) and survivors n = 47 (85%). The second subgroup included fetuses with HLHS with tricuspid regurgitation (TR) (n = 16) but without other abnormalities – the number of deaths was n = 0 (0%) and survivors n = 16 (100%). The third subgroup included fetuses with HLHS and both tricuspid (TR) and mitral regurgitation (MR) (n = 4) but without other abnormalities – the number of deaths was n = 3 (75%) and survivors n = 1 (25%). The fourth subgroup included fetuses with HLHS and mitral regurgitation (MR) (n = 5) but without other abnormalities – the number of deaths was n = 1 (20%) and survivors n = 4 (80%) (Fig. 1). In the group of fetuses with HLHS combined with MR and TR (4 cases), the first case presented with a restrictive foramen and cardiomegaly; the second case showed abnormal flow through the foramen ovale; the third case had no other abnormalities; and the fourth case demonstrated pericardial effusion and cardiomegaly. In all four cases, both tricuspid and mitral regurgitation were classified as mild. Three fetuses with HLHS combined with TR and MR underwent the Norwood operation, while one had a stent implemented in the PDA in the second month of life due to bleeding to the central nervous system.

In the group of fetuses with HLHS with both TR and MR, the mortality rate was 75% (3/4) compared with the group of fetuses with HLHS with TR, where the mortality rate was 0% (0/16) and the survival rate was 100% (16/16). Among the fetuses with HLHS with both TR and MR who died, there was one case with aortic arch hypoplasia and one case with aortic stenosis. The incidence of death was significantly higher in the group of fetuses with HLHS with both tricuspid and mitral regurgitation than in the group with tricuspid regurgitation alone (Yates's chi-squared test p = 0.003; Fisher's test p = 0.0035). (Fig. 2, Fig. 3). There was no significant difference in the frequency of deaths between the group of fetuses with HLHS with tricuspid regurgitation and the group with HLHS with mitral regurgitation (Yates's chi-squared test p = 0.528; Fisher's test p = 0.24); however, this could be attributed to the small number of fetuses with HLHS with mitral regurgitation.

Fig. 2.

Graph illustrating interaction between fetuses with HLHS with TR and fetuses with HLHS with TR and MR

Fig. 3.

Graph illustrating the number of neonatal deaths in cases with prenatally diagnosed HLHS with TR (on the left) and with TR and MR (on the right)

The presence of mitral regurgitation in fetuses with HLHS seems to be an additional ultrasound marker for poor neonatal outcome. The findings of this study have significant implications for prenatal counselling and postnatal management. Prenatal evaluation is key to detecting fetal abnormalities, including those affecting the heart. With advancements in technology, ultrasonographic prenatal diagnosis is expanding to provide the best possible care during pregnancy⁽⁹⁾. According to the classification elaborated by Respondek-Liberska and Słodki, HLHS is a congenital heart defect that can be treated but is often associated with many complications HLHS may be classified as a severe urgent defect or a severe planned defect depending on the presence of a restrictive foramen ovale or wide atrial communication, respectively^(10,11). It is a common finding that HLHS is accompanied by tricuspid regurgitation. However, according to our analysis, the fatality rate in such cases is very low despite the fact that TR is a known additional risk factor for poor prognosis⁽¹²⁾. Mitral regurgitation is a very rare finding in fetuses and newborns, but still such cases are diagnosed prenatally and must be addressed appropriately⁽¹³⁾. The widespread use of fetal echocardiographic monitoring^(14,15,16), which is a first-line method for detecting HLHS, has made early diagnosis possible. Mitral regurgitation detected during prenatal echocardiographic examination in one of the cases with HLHS diagnosed at the Department of Prenatal Cardiology at the Institute of the Polish Mother's Memorial Hospital in Lodz is presented in Fig. 4. Advancements in prenatal echocardiography and postnatal care have contributed to survival rates for HLHS reaching 60–65%⁽¹⁷⁾. HLHS may be accompanied by abnormalities such as tricuspid regurgitation, restrictive foramen ovale, aortic valve atresia/stenosis, mitral valve atresia/stenosis, and pericardial effusion, which were also observed in some patients in this study. However, to date, the literature has not described any cases of HLHS combined with MR, nor has it presented any articles combination.

Fig. 4.

Fetus with HLHS with mitral regurgitation with a blood flow of 98.96 cm/s. Ultrasound image from the Prenatal Cardiology Department at the Institute of the Polish Mother's Memorial Hospital

In the present study, tricuspid regurgitation was observed in 25% of patients with HLHS. Some studies have shown that TR is not a risk factor for early mortality^{(18,19,20,21)}, whereas other studies have demonstrated that TR may be a factor contributing to early mortality^(22,23). In the study by Barber et al., 100 patients with HLHS and TR observed during echocardiographic examinations were analyzed. Of these, 37% had mild TR, 13% had moderate TR, and 3% had severe TR on their preoperative Doppler echocardiograms. The analysis showed that patients diagnosed with moderate or severe TR had a worse survival rate compared with patients without TR⁽²⁴⁾. To sum up, TR is considered a significant risk factor for poor outcomes, especially in newborns with HLHS who develop TR at an earlier age. Despite these findings, our study showed that all patients with HLHS and TR had a survival rate of 100%, suggesting that early and continuous prenatal echocardiographic monitoring makes it possible to develop an optimal management plan for newborns with HLHS and facilitates cooperation among obstetricians, neonatologists, cardiac surgeons, and pediatric cardiologists. When it comes to MR in HLHS, the situation is quite different. In 3 out of 4 cases with HLHS and TR and MR, the survival rate was 25%, compared to cases with HLHS and TR, where the survival rate was 100%. This is a significant difference, which led to poor outcomes in newborns diagnosed with HLHS.

Due to the fact that no information about HLHS with MR is described in the literature, the authors proposed the following pathomechanism. The presence of mitral regurgitation leads to an overwhelming influx of blood into the left atrium. The overburdened left atrium undergoes remodeling and hypertrophy, with an increase in the strength of muscle contractions. With time, the left atrium becomes ineffective in generating a larger total stroke volume, which progresses to left ventricle disfunction. When the left atrium is not able to generate appropriate pressure, the left ventricle is underfilled with blood, causing more blood to accumulate in the left atrium. This results in the overloading of the pulmonary veins with blood and leads to reverse blood flow to the lungs, which become congested. As a result, pulmonary hypertension is observed, accompanied by left ventricle failure⁽²⁵⁾. This is consistent with the post-mortem examination results of one case from this study. In that case, the autopsy results of a newborn with HLHS demonstrated pulmonary hypertension, atelectasis, and heart failure. These three abnormalities were the main findings leading directly to the poor neonatal outcome.

In one study on patients with HLHS, the function of the tricuspid valve and right ventricle was evaluated, concluding that after hybrid palliation for HLHS, patients with significant TR and/or RV dysfunction were at greater risk of death⁽²⁶⁾. The combination of HLHS and TR can result in inadequate oxygenation of blood and overall decreased cardiac output. The severity of TR affects the prognosis for the fetus and/or neonate in different ways. Factors that must be taken into consideration include the degree of underdevelopment of the left side of the heart and the presence of additional cardiac abnormalities, such as a restrictive atrial septum^(27,28,29). Other factors that may affect the outcome in HLHS include race, ethnicity, socioeconomic status, and geography⁽³⁰⁾.

In general, major fetal congenital heart defects are related with a higher risk of pregnancy loss. According to a recent publication on a large cohort, in fetuses with HLHS, the risk of pregnancy loss was 10.7%. However, that study focused only on isolated HLHS⁽³¹⁾. Our study involved HLHS with and without MR and/or TR, which constitute additional risk factors for poor fetal and neonatal outcomes. It is worth noting that some conditions may progress to HLHS by the time of birth. A good example is critical aortic stenosis, which must also be taken into consideration for differentiation purposes⁽³²⁾. Another important issue which must be analyzed during ultrasound examination is the observation of the foramen ovale. In HLHS, it is important to measure the diameter of the foramen ovale. In general, the foramen ovale is considered restrictive when its diameter is below 2.5 mm in fetuses with normal heart study and normal heart anatomy, whereas in fetuses with HLHS, the diameter of the foramen ovale below 4.0 mm is considered restrictive. If Doppler evaluation shows that the maximal blood flow velocity from the right to the left through the foramen ovale is higher than 40 cm/s, it is considered restrictive. According to available studies, HLHS accompanied by a restrictive foramen ovale has the highest mortality rate⁽³³⁾. Another crucial factor to consider during echocardiographic examination is the presence of coronary artery abnormalities, which also occur in patients with HLHS and increase the risk of death⁽³⁴⁾. In HLHS, the left heart is underdeveloped, which affects fetal hemodynamics. Parameters such as flow velocity, pressure, and wall shear stress are completely different than those in fetuses with normal heart structure and anatomy⁽³³⁾.

Managing fetuses with HLHS combined with mitral and/or tricuspid regurgitation typically requires a multidisciplinary approach, including cooperation between fetal medicine specialists, pediatric cardiologists, and cardiothoracic surgeons. The goal is to optimize prenatal care, plan for appropriate interventions, and provide comprehensive support to parents facing the challenges associated with the diagnosis.

The social aspect is also significant, as each case of a fetus with HLHS requires close collaboration between the medical team and the parents to provide guidance, support, and information throughout both the prenatal and postnatal periods. Emotional support for parents facing such a diagnosis is also crucial. According to an interview study, mothers of surviving children with HLHS had feelings of their guilt for the development of the condition in their fetuses. Some mothers also felt that the decisions regarding the pregnancy were mainly theirs, despite that fact that they had received support from their relatives. It is therefore essential for parents to recognize that they are not alone and that there are resources to support them. Receiving a diagnosis of HLHS during pregnancy or after birth can be emotionally overwhelming for parents⁽³⁶⁾. In response to these challenges, many hospitals and support organizations offer counselling, support groups, and resources to assist families in managing the social and emotional aspects of caring for women with fetuses diagnosed with HLHS and, eventually, neonates, even in cases with poor outcomes.

In addition to the existing literature, our study identified another important risk factor in patients with HLHS: mitral and/or tricuspid valve re-gurgitation.

Our study has shown that the presence of mitral regurgitation in fetuses with HLHS may be a risk factor leading to poor neonatal outcomes. A key strength of the study is that it presents retrospective results from a relatively large population of fetuses, particularly given the fact that MR is a very rare finding, especially in patients with HLHS. To date, HLHS with MR has not been discussed in the literature, that is why our analysis may contribute to the adoption of early echocardiographic screening in every fetus, with a focus on the monitoring of both atrioventricular valves. Our findings are thus unique and not found even in the current specialized literature.

The prognosis and outcomes can be challenging in cases of complex congenital heart defects such as HLHS with accompanying mitral and tricuspid valve regurgitation. Close monitoring by a specialized medical team is crucial to determine the best course of action for the neonate⁽³⁷⁾. However, our study has shown that the outcome for fetuses with HLHS associated with MR and TR is very poor.

The are several important clinical implications arising from our study. The aim of this analysis was to demonstrate the impact of mitral regurgitation on the outcome in patients diagnosed with HLHS. According to the study, MR is a strong risk factor for very poor neonatal outcomes due to heart failure. This was not observed in our cases of HLHS with tricuspid regurgitation. Therefore, the presence of MR in fetuses with HLHS should be considered an alarming sign of poor outcome. Such cases should be carefully analyzed by a group of specialists, including prenatal cardiologists, pediatric cardiologists, interventional cardiologists, cardiac surgeons, obstetricians, and neonatologists. These data are of great importance and have significant implications for prenatal counselling and postnatal management.

A limitation of our study is the small number of fetuses with HLHS and MR. The number of cases could have been larger, however, the authors decided to analyze only those cases with complete prenatal and postnatal examinations, including follow-up. In some cases, MR was observed in only one ultrasound examination. Therefore, the study included only those cases in which MR was consistently observed across all examinations during fetal echocardiographic monitoring. This limited the number of patients studied. It must be noted that while fetal echocardiography is highly valuable in diagnosing congenital heart defects, it may not detect all abnormalities. Moreover, this study lacks geographical and demographic diversity to increase the representativeness and generalizability of the results. Therefore, further studies with larger, more diverse cohorts should be performed in the future to strengthen these findings.

The presence of hypoplastic left heart syndrome with tricuspid and mitral regurgitation is significantly associated with neonatal mortality, even when treatment and/or surgery is performed. The presence of mitral regurgitation in fetuses with hypoplastic left heart syndrome seems to be an additional ultrasound marker indicating poor neonatal outcomes. Our study has important implications for prenatal counselling and postnatal management.