Bokhari SFH, Faizan Sattar SM, Mehboob U, Umais M, Ahmad M, Malik A, Bakht D, Iqbal A, Dost W. Advancements in prenatal diagnosis and management of hypoplastic left heart syndrome: A multidisciplinary approach and future directions. World J Cardiol 2025; 17(3): 103668 [DOI: 10.4330/wjc.v17.i3.103668]
Corresponding Author of This Article
Wahidullah Dost, Curative Medicine, Kabul University of Medical Sciences, Karte-e-sakhi Kabul, Kabul 10001, Kābul, Afghanistan. wahidullahdost96@gmail.com
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Syed Faqeer Hussain Bokhari, Syed M Faizan Sattar, Umair Mehboob, Muhammad Umais, Muhammad Ahmad, Ahmad Malik, Danyal Bakht, Asma Iqbal, Department of Medicine and Surgery, King Edward Medical University, Lahore 54000, Punjab, Pakistan
Wahidullah Dost, Curative Medicine, Kabul University of Medical Sciences, Kabul 10001, Kābul, Afghanistan
Author contributions: Bokhari SFH contributed to the conceptualization and design of the study, supervised data collection, critically revised the manuscript, and provided overall guidance throughout the research; Faizan Sattar SM conducted the literature review, participated in data analysis, and contributed significantly to editing the manuscript; Mehboob U assisted in data collection, statistical analysis, and interpretation of findings, and contributed to manuscript preparation and revisions; Umais M provided technical support, contributed to the methodology section, and participated in manuscript proofreading; Faizan Sattar SM and Umais M contributed to drafting the manuscript; Ahmad M assisted in the literature search, organized the data for analysis, and provided input during manuscript revisions; Malik A supported data collection and organization, contributed to writing the results section, and ensured accuracy in reporting; Bakht D contributed to data validation and visualization and provided input on the manuscript’s discussion and conclusion sections; Iqbal A assisted in finalizing the manuscript, ensured adherence to formatting and journal guidelines and reviewed the references for accuracy; Dost W contributed to the review of the manuscript, provided feedback on the discussion section, and ensured clarity in presenting the study’s clinical implications; all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wahidullah Dost, Curative Medicine, Kabul University of Medical Sciences, Karte-e-sakhi Kabul, Kabul 10001, Kābul, Afghanistan. wahidullahdost96@gmail.com
Received: November 28, 2024 Revised: February 12, 2025 Accepted: February 27, 2025 Published online: March 26, 2025 Processing time: 114 Days and 21.1 Hours
Abstract
Hypoplastic left heart syndrome is a severe congenital defect involving underdeveloped left-sided cardiac structures, leading to significant mortality and morbidity. Prenatal diagnosis using fetal ultrasound and echocardiography enables early detection, family counseling, and improved clinical decision-making. Advanced prenatal interventions, such as fetal aortic valvuloplasty and atrial septostomy, show promise but require careful patient selection. A multidisciplinary approach involving obstetricians, neonatologists, and pediatric cardiologists is vital for effective management. Future directions include refining imaging techniques, such as three-dimensional ultrasound, cardiovascular magnetic resonance imaging, and exploring bioengineering solutions, stem cell therapies, and genetic research. These advancements aim to improve therapeutic options and address current limitations, including transplant scarcity and postoperative complications. Although surgical innovations have improved survival rates, challenges remain, including neurological risks and long-term hemodynamic issues. Ongoing research and technological advancements are essential to enhance outcomes and quality of life for hypoplastic left heart syndrome patients.
Core Tip: Congenital heart diseases, including hypoplastic left heart syndrome, are among the most significant fetal malformations due to their high morbidity and mortality rates. Recent advancements in prenatal diagnosis, including fetal echocardiography and imaging techniques, have revolutionized early detection and facilitated informed parental decision-making. Innovative prenatal management strategies, such as fetal aortic valvuloplasty and bioengineering therapies, offer the potential to improve outcomes. Despite advancements, challenges remain in imaging precision, treatment optimization, and genetic understanding of hypoplastic left heart syndrome. A multidisciplinary approach is essential for advancing care and exploring future directions, including stem cell therapy and bioengineered hearts, to enhance survival and quality of life for affected patients.
Citation: Bokhari SFH, Faizan Sattar SM, Mehboob U, Umais M, Ahmad M, Malik A, Bakht D, Iqbal A, Dost W. Advancements in prenatal diagnosis and management of hypoplastic left heart syndrome: A multidisciplinary approach and future directions. World J Cardiol 2025; 17(3): 103668
Congenital heart diseases (CHD) are the most common fetal malformations, for which the prevalence rate is 3.7/1000 live births for all cases and 2.4/1000 for cases confirmed by invasive methods[1]. They are associated with high fetal mortality and morbidity[1]. More importantly, the prevalence is rising, with a maximum rate of 9.4/1000 between 2010-17, owing to advances in screening protocols and detection techniques[2]. Fetal diagnosis of these conditions allows medical practitioners ample time to properly guide the parents about the condition of their offspring, possible surgical intervention and complications, life expectancy after surgical intervention and to screen for co-morbid conditions, as these may complicate the management[3-5]. This may help parents reach a decision to opt for palliative surgical intervention, decline surgery, and choose comfort care, or terminate the pregnancy.
Hypoplastic left heart syndrome (HLHS) refers to the abnormal development of left-sided cardiac structures such as underdevelopment of the left ventricle, aorta, and aortic arch along mitral atresia or stenosis, all of which ultimately result in left ventricular outflow tract obstruction (Figure 1)[6]. Although there is ongoing debate about the status of the ventricular septum, as left-sided structures can be hypoplastic when there is a perforated septum, these lesions have different features compared with instances where the septum is intact. Therefore, it is recommended that only those lesions with an intact septum should be included in the HLHS [7]. It has an incidence of 0.1-0.25/1000 live births[8]. These figures are an underestimation because they do not take into account intra-uterine deaths caused by HLHS, as demonstrated by the study conducted by Allan et al[9], which showed that HLHS can cause up to 5% of spontaneous intra-uterine deaths.
Prenatal diagnosis of HLHS is one of the most significant aspects of the management of the disease, as it is associated with decreased mortality, decreased duration of hospital stay, and low risk of postnatal brain injury[10-13]. The pregnancy termination rate for HLHS after prenatal detection has been reported to be 12%-48%[4]. It is also important to note that the socioeconomic status of the parents influences the likelihood of prenatal diagnosis[5]. This article is a narrative review, chosen specifically to provide a holistic exploration of advancements in the prenatal diagnosis and management of HLHS. Unlike systematic reviews, which address specific research questions through strict methodologies, narrative reviews allow for a broader discussion of multidisciplinary advancements and emerging therapies, offering contextual analysis that systematic reviews may not cover. Recent systematic reviews by Jacquemyn et al[14], Ponzoni et al[15], and Kanngiesser et al[16] have explored specific aspects of HLHS, such as surgical outcomes or imaging modalities, comparison of surgical palliation strategies, prognosis after tricuspid valve repair, or serial assessments of right ventricular deformation[12-17]. However, they do not provide an integrated discussion of prenatal imaging advancements, genetic research, multidisciplinary approaches, and innovative therapies like stem cell treatments and bioengineering solutions. This review aims to bridge these gaps, synthesizing diverse insights to guide future research and clinical strategies.
The methodology offers a structured framework for systematically gathering, analyzing, and integrating data to investigate existing literature on this subject thoroughly. A comprehensive search strategy was implemented, focusing on scholarly databases including PubMed/MEDLINE, Embase, and Google Scholar, covering literature from inception to September 2024. Specific keywords – “HLHS”, “prenatal diagnosis”, “prenatal management”, “multidisciplinary approach”, “fetal interventions”, and “future directions” - were employed to ensure the identification of relevant studies. Studies were included if they focused on HLHS diagnosis and management, were published in peer-reviewed journals, and were available in English. Non-original research and studies lacking relevance or sufficient data were excluded. Two independent reviewers screened titles and abstracts, followed by full-text reviews to ensure eligibility, resolving discrepancies through discussion. Data on study design, population, interventions, and outcomes were extracted using standardized forms, and methodological quality was assessed to maintain rigor. While extensive efforts were made to include a broad range of literature, it is important to acknowledge the limitations arising from the availability and quality of existing research. Despite this, the review reflects a steadfast commitment to academic rigor and aims to provide a scholarly discussion that adheres to high academic standards.
Prenatal detection and screening
Prenatal detection and screening are crucial in facilitating optimal family counseling and comprehensive intra- and extra-uterine management. These measures are associated with a significant reduction in both mortality and morbidity. Additionally, they offer valuable insights into variations in disease incidence and prevalence, thereby enabling policymakers and healthcare specialists to make evidence-based decisions that enhance the overall quality of care.
The most commonly employed tools for detecting prenatal cardiac defects are fetal ultrasound (fUSG) and fetal echocardiography (fECHO). The fUSG utilizes high-frequency sound waves directed toward the target tissue, with the reflected echoes generating detailed images. The International Society of Ultrasound in Obstetrics and Gynecology provides key guidelines for fUSG, recommending that examinations be conducted between 18 weeks and 22 weeks of gestation. However, earlier screening between 11 weeks and 14 weeks can also yield important findings or raise suspicions of cardiac abnormalities[18]. During fUSG, maximum possible high frequency should be used for maximum resolution, keeping in mind the balance between penetration and resolution. Fetal situs and the four-chamber, outflow-tract, and great-vessel views should be used to ensure comprehensive visualization of cardiac structures (Figure 2)[19,20].
In the context of various congenital malformations, which collectively represent a leading cause of infant mortality, fECHO has emerged as a valuable diagnostic tool. It enables medical practitioners to provide families with informed counseling regarding prognosis and available intra- and extra-uterine surgical interventions. Additionally, fECHO facilitates the confirmation and deeper understanding of the natural progression of congenital cardiac anomalies[21]. The fECHO for prenatal screening of congenital cardiac and extra-cardiac abnormalities is performed via two imaging modalities, namely transabdominal and transvaginal ECHO[22]. Although optimal trans-abdominal images are acquired at about 20 weeks of gestation, when the fetus and uterus are larger and thus provide better trans-abdominal windows, advances in ECHO technology now allow accurate diagnostic fECHO to be performed via transabdominal approach as early as 16 to 18 weeks of gestation[22]. However, fetal position, activity, and size along with maternal obesity and retroverted uterus can pose a challenge to optimum scanning[23]. Transvaginal echocardiography (ECHO) is performed via the vaginal canal and can be performed even earlier than a trans-abdominal scan at 10-12 weeks when the heart is just 7-8 mm in length, as it uses a high-resolution 6.5-7.5 MHz probe. Trans-vaginal 4 chamber view is considered best for examining the cardiac structures[24,25]. While discussing the timing of ECHO, it is also worth noting that early ECHO can yield both false positive and false negative results. This is because some cardiac structures may not yet be fully formed. fECHO is performed based on the presence of risk factors, which are explained in Table 1[19,26].
Prenatal fever or viral infection with seroconversion only
-
-
Yes
Abnormal findings obtained from fECHO and ultrasound correlate with genetic abnormalities. For example, atrial septal defect and ventricular septal defect (VSD) on ECHO are strongly associated with genetic abnormalities, especially trisomies (trisomy 13, 18 and 21) and partial trisomy 9. Along with the trisomies, Holt-Oram, Smith-Lemli-Opitz, and Jacobsen syndrome are also associated[27]. Moreover, Turner syndrome is associated with severe cardiac defects and has a high postnatal lethality rate. Tricuspid regurgitation and disproportion identified by fUSG is also associated with chromosomal abnormalities and can be used as a marker[23].
Prenatal diagnosis
The clinical presentation of HLHS closely resembles symptoms associated with other cardiac structural abnormalities that obstruct the left ventricular outflow tract, hindering its ability to sustain systemic circulation and requiring ductal-dependent blood flow ex utero. These conditions include coarctation of the aorta, critical aortic stenosis, and interrupted aortic arch. Additionally, non-structural conditions such as neonatal endocarditis and neonatal sepsis can also mimic the clinical presentation of HLHS[25,28]. The main ECHO findings associated with HLHS include the absence of left ventricular structures, atrial or VSDs, and aortic or mitral valve abnormalities. The development of the left ventricle is closely associated with the normal development of the atrial septum and communication between the left and right atria via the foramen ovale. In HLHS, it has been observed that either there is no foramen ovale, there is an anomalous attachment of septum primum to the left atrial wall, or there is a restriction to flow due to the smaller caliber of foramen ovale[27,29-31]. An unrestrictive defect is one with a velocity-time integral ratio greater than 5, while a severely restrictive defect is one with a ratio of less than 3. A severely restrictive defect signals the need for an emergency septostomy, whereas a ratio between 3 and 5 shows moderate restriction[32]. Limiting left-to-right shunting causes persistent pulmonary venous hypertension in utero, which causes clear lung alterations and disease along with arterialization of the pulmonary veins and lymphatic congestion[27,33]. For example, in some cases of HLHS, there are mitral valve abnormalities such as parachutes or arcade leaflets. Similarly, the aortic valve may be bicuspid or unicuspid[34]. As a result, the left ventricle appears poorly contractile, smaller than the right ventricle (RV), and hence, hypoplastic (Figures 3 and 4)[35,36]. The deviated development of the left ventricle is also associated with myocardial pathologies, such as endocardial fibroelastosis, along with changes in valvular anatomy.
Figure 3 Echocardiographic 4-chamber view of the heart in hypoplastic left heart syndrome[35].
Adapted under authorization from Patnana et al[35]. Citation: Patana SR, Turner DR. Pediatric Hypoplastic Left Heart Syndrome. Dec 15, 2020. [cited 26 November 2024]. Available from: https://emedicine.medscape.com/article/890196-overview#a4. This echocardiographic still frame shows a 4-chamber view of the heart in a patient with hypoplastic left heart syndrome. A large right ventricle and hypoplastic left ventricle (star) are seen. RA: Right atrium; RV: Right ventricle; LA: Left atrium.
The following ECHO characteristics can be used to diagnose HLHS: (1) A left ventricular end-diastolic dimension of less than 9 mm; (2) An aortic root diameter of less than 6 mm; (3) A ratio of left ventricular end-diastolic to right ventricular end-diastolic dimension of less than 0.6; and (4) An absence or significantly distorted and small-amplitude mitral valve echo[25]. In addition to fECHO, which has been the gold standard for the past two decades, fetal cardiac magnetic resonance imaging (MRI) has emerged as a promising tool that is being actively explored and developed. Recent research has highlighted the growing interest in this modality, particularly in addressing the known limitations of fECHO. With ongoing advancements, fetal cardiac MRI has the potential to become indispensable for achieving accurate and comprehensive diagnoses, enhancing the understanding of CHD anatomy and pathophysiology, providing precise prenatal counseling on outcomes, and facilitating tailored postnatal - and even prenatal - surgical planning[29]. During 2007-2008, cardiac MRI was performed on 32 fetuses that were diagnosed with CHD by prenatal ultrasound. All ultrasound findings were confirmed by MRI[30]. This shows that fetal cardiac MRI can produce reliable results consistent with initial investigations.
The development of 3D/4D ultrasonography has given researchers the chance to more easily and closely correlate the arteries and components of the fetal heart. After the advent of 3D-ultrasound in the 1990s, software called Spatio-Temporal Image Correlation was developed in the middle-2000s which made it possible to acquire volumetric data, its storage, and construction of a rendered 3D image, allowing for easier and more straightforward identification of developmental abnormalities[31]. By measuring the ventricular volume in conjunction with the virtual organ computer-aided analysis software and using the movement mode, Spatio-Temporal Image Correlation also makes it feasible to assess heart function.
Prenatal management
HLHS patients may benefit from prenatal management, as it can diminish the severity and progression of the disease, improving the survival of such fetuses and enhancing the likelihood of survival until definitive staged palliation can be undertaken. This is based on the prenatal diagnosis and assessment of disease severity. The strategies mainly include fetal aortic valvuloplasty (FAV), fetal atrial septoplasty (FAS), and maternal hyperoxygenation (MH). For moderate cases, FAV may be performed[37]. When to perform this procedure remains a topic of debate to date, as no specific criterion has yet been adopted to select the fetuses who might benefit from the approach. It may be considered in a fetus having a dilated left ventricle with poor contractility, patent foramen ovale, and retrograde aortic arch flow. Study groups from Boston, United States, and Linz Institution, Austria have tried to develop criteria for performing FAV[34-36]. In 2018, a decision tree was published by the group in Boston to predict neonatal biventricular outcome based on the pressure in the left ventricle, left ventricular diastolic diameter, mitral valve inflow pattern, and diameter of ascending aorta[38]. The Linz Institution group suggested using a combination of right-to-left ventricular ratio and left ventricular pressure estimates, predicting circulation type at the age of 1 year[39]. FAV has been shown to improve fetal hemodynamics, mitigate disease progression, and increase the likelihood of biventricular circulation achieved, as demonstrated by a study analyzed by the International Fetal Cardiac Intervention Registry comprising data from 18 centers[40]. Balloon dilation of a stenotic aortic valve under ultrasound guidance may hamper the development of HLHS. The effects of FAV on fetal cardiac function were studied by Ishii et al[41], reporting that the left ventricle strain rate was higher in fetuses who had a biventricular outcome as compared to those with a univentricular outcome. Apart from its benefits, the procedure poses an increased risk of fetal demise, premature delivery, and aortic regurgitation[37,39]. A schematic diagram illustrates the ideal fetal left ventricle approach for balloon dilation of severe aortic stenosis to prevent progression to HLHS (Figure 5)[42].
In cases where the inter-atrial septum is intact or the foramen ovale is restricted (a scenario observed in 6%-11% of HLHS fetuses), diminished left ventricle filling is coupled to elevated back pressures in the pulmonary circulation[31]. This, in turn, leads to pathological remodeling of the pulmonary vasculature. Fetuses born with such physiology may require urgent postnatal emergency care or sometimes ex-utero intrapartum treatment. Despite postnatal care, the mortality rate for this subset of patients approaches 100%. FAS may be done to decrease the back pressures and decompress the atrium[37]. The outcome of 21 fetuses with inter-atrial septum was described by Marshall et al[43]. A total of 19 out of 21 patients had successful interatrial communication, and communication of more than 3 mm was associated with higher postnatal oxygen saturation and decreased likelihood of undergoing an emergency atrial septoplasty. For continued shunting across the interatrial septum and improving the outcomes of the procedure, modifications were proposed, including atrial balloon septostomy, radiofrequency laser atrial septum perforation, and atrial septal stenting[44]. To date, there are limited reports on laser-guided atrial septostomy but atrial septal stenting is gaining more popularity and promises significant improvements in patients with HLHS[39]. Both these invasive procedures (FAV and FAS) are conducted under sterile ultrasound guidance, and hence pose little to no harm to the mother other than the complications of anesthesia itself. Fetal risks may range from local conditions like hemopericardium and bradycardia to fetal demise.
The survival of the fetus depends not only on the severity of the disease itself but also on other contributing factors, e.g. genetic or chromosomal abnormalities, prematurity, or other cardiac abnormalities. These abnormalities along with a diseased fetal heart increase the risk of fetal death. As far as prematurity is concerned, lung immaturity is a significant contributor to worse outcomes in HLHS patients[27,45]. The creation of a VSD has been proposed as a potential in-utero management technique for HLHS that may be used in any case of HLHS as opposed to currently used techniques[44].
Other than the invasive approaches, magnetic hyperthermia therapy can improve prenatal as well as postnatal hemodynamics of the fetus. The positive effects of chronic intermittent magnetic hyperthermia therapy were first described by Kohl et al[46] in 2010. The mother is supplemented with 100% oxygen during the later part of pregnancy. This serves to increase the fetal pulmonary blood flow and the preload to the left heart, therefore enhancing the growth of the hypoplastic left heart structures. This effect is increased with gestational age[47]. The outcomes, efficacy, and intra-uterine complications of MH were analyzed by Co-Vu et al[48] in a systematic review[48]. However, the effectiveness of this therapy has remained questionable to date and poses an increased theoretical risk of cerebral underdevelopment, though this has not been demonstrated clinically. There are concerns that this may lead to growth restriction, constriction of arterial ducts, and retinopathy. In the very severe form of HLHS, where the left-sided valves are atretic, the ascending aorta is stenotic (< 2 mm), and severe tricuspid regurgitation or RV failure is present, parents should be counseled for termination of pregnancy as the final option[32].
Predictive value of prenatal finding
HLHS is a sinister congenital deformity, which had high mortality in the past. It is more prevalent in males. However, due to modern advancements in imaging technology, this condition can be better tackled[49]. Especially with the introduction of prenatal diagnostic techniques like fECHO, the severity of the condition can be measured as early as 16 weeks of gestation. With an ECHO, the obvious signs of HLHS can be observed as mentioned in the previous section. These signs include a small left ventricle, stenosis or atresia of the mitral valve, and increased size of the RV and right atrium. The effect of these malformations is that the left half of the heart is not developed and it cannot pump blood effectively to the whole body, causing systemic poor blood circulation. These malformations can be detected using prenatal ultrasonography in the second trimester of gestation using a chamber view of the heart. Even if it is detected early in the gestational period, its prognosis is not good.
When diagnosed prenatally, the parents are given the option to terminate the pregnancy, as not every patient can go through extensive surgeries. Some parents choose not to go through these management options but instead follow the supportive care method[50]. One of the main reasons is that the surgical procedure causes much emotional stress on the parents. Some patients cannot go through the surgical route due to various medical reasons[51]. These reasons can include unfavorable cardiac anatomy, trisomy 18, and neurological impairment. Preterm babies, small for their gestational age babies, or babies with other major issues are also not ideal for the surgical route[52]. In patients with aortic atresia, it is also recommended to avoid this pathway due to the added complexity[53]. If a patient is accepted for the surgical method, they are first given prostaglandin E1 right after birth to prevent the closure of the ductus arteriosus. Then, a Norwood procedure is performed within the first 2 weeks of neonatal life[54]. The Glenn procedure can be performed at 4 months to 8 months of age, while the Fontan procedure can be performed between 1.5 years to 5 years of age[54].
The long-term prognosis is difficult to predict for patients with HLHS. This is because the major management methods for HLHS are surgical methods and cardiac transplants[55]. Both of these methods have drastically decreased the mortality rate of this condition. However, along with this decrease in mortality, both methods also offer various complications. In patients undergoing cardiac transplants, there is a need for continuous immunosuppression throughout the patient’s life. It can be altered by using low doses of immunosuppressants that are required to prevent transplant rejection but avoid the use of steroids in these children over the long term. Another long-term effect of surgical management is the effect on the central nervous system. According to Bove and Lloyd[56], 6% of patients suffering from this condition developed thromboembolic stroke and showed signs of developmental delay. In summary, while surgical interventions and cardiac transplants have significantly improved survival rates for HLHS patients, the associated long-term complications necessitate ongoing medical management and monitoring to optimize patient outcomes and quality of life.
Multidisciplinary approach to prenatal care
A multidisciplinary approach refers to a team approach involving all the concerned specialties. This approach allows early diagnosis, coordinated and more comprehensive treatment, and therefore a better prognosis for various syndromes and malignancies. Because HLHS represents a diagnostic and therapeutic challenge, it requires the expertise of specialists in obstetrics, neonatology, pediatric cardiology, and cardiac surgery, emphasizing the need for a multidisciplinary approach and coordination of these specialties with pathology[57]. In the past, the diagnosis of HLHS was only possible after birth, but with the evolution of ultrasound equipment, proper training, and appropriate referral to specialists, it can be diagnosed prenatally[58]. Most pregnant women today have a general obstetric ultrasound that includes the evaluation of all four cardiac chambers[59]. However, not all women have access to this test in many countries, thus limiting the screening range to 12%-75%. The exact percentage depends on the structure of the healthcare system of a particular country and the facilities available there[60].
Prenatal diagnosis of HLHS helps in the fetal management, family and genetic counseling, and optimization of postnatal management, allowing multidisciplinary coordination so that these fetuses are born in centers where all the required specialists are available and they can systematically coordinate to formulate a plan for the best possible management of the patient[4,61]. Patients with HLHS diagnosed prenatally, have reduced morbidity and mortality, a lower incidence of complications including heart failure, lesser need for antimicrobials, intermittent mandatory ventilation, or vasoactive support as compared to those diagnosed postnatally. The incidence of emergency surgery is also reduced. 20% of the cases of congenital cardiac defects are associated with chromosomal abnormalities[62]. Thus, prenatal diagnosis and a multidisciplinary approach are an absolute necessity for better determination of the prognosis and possibility of postnatal surgery.
Prenatal counselling and parent education
In 2000, Fruitman[63] stated that before the 1980s, the mortality rate of HLHS was 95%. While not the death sentence that it was in the 1980s, this defect still holds a high mortality rate[64]. It also forces the parents and doctors to make tough ethical and moral decisions regarding the management of this condition. The parents must know the management options and long-term effects of the surgical treatment. The severity of the condition can vary due to anatomical differences in patients[65]. Surgical treatment and cardiac transplantation are the two major methods for the management of HLHS postnatally. The parents must know that the perioperative rate of survival for the Norwood operation ranges from 47% to 85%[56]. Rogers et al[66] stated that at the average age of 38 months, 45% of the patients were underweight, while 73% of them had microcephaly following the surgical treatment[66]. In a study conducted by Jacobs et al[67], it is stated that for patients with aortic atresia who went on the surgical pathway, the survival rate was 50% at the end of the first year and 47% at the end of 3 years.
The second management option is cardiac transplantation. For this method, prenatal diagnosis is very important, as it gives time to find the donor. The patients that go through the surgical options may still require transplant after 1-2 years of their lives. The main difficulty with this pathway is the donor availability and transplant rejection. The long waiting period is also a major hurdle in this pathway. Patients on long waiting periods can develop systemic heart failure or multi-organ dysfunction. Throughout the waiting period, the patients are given prostaglandin E1 to maintain the patency of ducts. Mechanical ventilation can also be provided to the patients, which can then be weaned slowly. Another hurdle after cardiac transplant is the lifelong need for immunosuppression. These immunosuppressants can cause multiple issues like hypertension, renal dysfunction, and lymphoproliferative diseases[68]. Therefore, it is necessary to increase the donor pool and work on long-term management options and transplant rejection to increase the survival rate of patients suffering from this condition. Thanks to advancements in prenatal diagnostic methods, parents can now be informed if their child is likely to be affected by such conditions. This knowledge can represent an emotionally challenging time for families. It becomes the physician’s responsibility to provide compassionate counseling, outlining the available options. These may include planned termination of the pregnancy, enrolling the child on a transplant list, or pursuing surgical treatment[69].
Ethical considerations
The prognosis of HLHS is uncertain even after early diagnosis, optimum care conditions, and adoption of appropriate treatment modalities[70]. The post-operative neurological complications, along with prolonged stays at hospitals and the added emotional distress, demand various ethical considerations in this regard[70]. While treating complex diseases like HLHS, the clinicians and parents both have to face the circumstances where they make complex decisions that are in the best interest of the child[70,71]. In certain situations, parents with limited education and low socioeconomic status may defer the responsibility of decision-making to the clinicians involved. In such cases, it becomes the clinician’s duty to make a well-informed and balanced decision that prioritizes the best interests of the affected child[70]. In such circumstances, a methodical approach to deliberation should be adopted. Deliberation is a well-suited decision-making process that carefully considers clinical facts, ethical principles, and professional responsibilities, guiding the clinician to act in the best interest of the patient[72]. The bioethical principles that involve autonomy, beneficence, non-maleficence, and justice must always be kept in mind in decision-making[73]. When the parents can assess the outcomes of the relevant intervention and seek information from various resources, then their autonomy must be respected[70].
HLHS is the most common intrauterine disease whose diagnosis can be done from the 12th-14th gestational week[73]. Ethical issues in neonatal and fetal cardiology have been increasing day by day because even with the advancement of technologies used for intervention, they still put mother and fetus at risk[73]. Thus, for this reason, the outcomes of these interventions should be carefully weighed, and the maternal complications must also be kept in mind[69]. While dealing with fetal interventions, appropriate patient selection criteria must be adopted, however, fetuses having severe pulmonary stenosis, atresia, hypoplastic RV, or severe aortic stenosis are poor candidates for such interventions[73]. In every case, bioethical principles must be followed, i.e. autonomy, beneficence, non-maleficence, and justice. Whether palliative care should be given is a present-day ethical issue among expert clinicians[74]. Some propose that surgery is the best option for the child, while others are in favor of palliative care[75,76]. After prenatal diagnosis, one of the options available is termination of the pregnancy, which is a stressful event for parents[74,77]. Some of the parents make a quick decision in this regard, while others take time to gather information and weigh the risks and benefits of their decision[77]. This decision is significantly influenced by social, cultural, and religious values. Following a prenatal diagnosis of HLHS, five potential options are available: pregnancy termination and in-utero intervention as prenatal choices, heart transplantation, palliative repair, and palliative care as postnatal options[74]. The prenatal diagnosis of this syndrome forces the parents to seek immense knowledge regarding the disease under pressure from various sources like social media, education websites, and relevant literature from different professional databases[77,78]. The clinician should offer a clear and thorough explanation of the situation, enabling the parents to make an informed and thoughtful decision, which is highly valued by the respondents[78]. Counseling involves disclosing the information regarding diagnosis, prognosis, and treatment choices available[74,78]. This should be done so that they are well-prepared to face long-term follow-ups for medical care, multiple surgeries involved, probable resultant disabilities, and even death[78].
Follow-up and transition to postnatal care
The in-utero fetal interventions can improve the overall survival of HLHS patients. However, studies have also reported that most neonates will still require immediate postnatal interventions to relieve hypoxemia and septal obstruction[79]. The development of biventricular circulation after birth is highly dependent on in-utero fetal interventions. In particular, FAV for aortic stenosis or HLHS can increase the chances of postnatal biventricular circulation. However, the procedure carries significant risks, including the potential for fetal demise. Additionally, the procedure has a high likelihood of technical failure. Even if technically successful, HLHS may still progress to postnatal single ventricle circulation[80].
The Boston group has reported that fetuses who received prenatal interventions demonstrated improved early survival compared to patients who only received postnatal treatment[81]. Fetal position, timely diagnosis, and the ability to make a successful interatrial communication make fetal intervention a limiting process. Because of this, most patients with HLHS are not candidates for this strategy, which can be potentially beneficial to them. Patients who do not receive any prenatal intervention require immediate postnatal interventions to improve oxygenation and remove septal obstruction[82,83].
In-utero valvuloplasty has been reported to enhance hemodynamic stability, including promoting antegrade aortic arch perfusion by discharge time, which improves antegrade aortic valve flow. Additionally, a change in the mitral valve Doppler inflow pattern results in improved left ventricular filling. In some cases, the flow at the atrial level may reverse, becoming bidirectional[77]. These hemodynamic changes become predictive of biventricular shunt development when seen in later stages of gestation[84]. Some HLHS patients treated with in-utero aortic valvuloplasty develop severe aortic regurgitation, which is well-tolerated by most fetuses over the remaining pregnancy[85]. Absence of aortic regurgitation development after in-utero intervention may serve as an indicator of unsuccessful treatment. Left ventricular strain rates after in-utero aortic valvuloplasty in HLHS fetuses have also been studied. Pre- and post-procedure tissue deformation rates were analyzed along with the development of biventricular circulation of the heart after birth. It was reported that out of 57 treated fetuses, 34 had univentricular circulation while 23 had biventricular circulation. Fetuses with biventricular circulation showed higher left ventricle strain than univentricular circulation[41].
Preliminary outcomes of aortic valvuloplasty were reported by the International Fetal Cardiac Intervention Registry, which included a cohort of 86 fetuses from 18 institutions worldwide. According to this report, the technical success rate of aortic valvuloplasty in fetuses was 81%, while the demise rate was reported to be 17%[40]. Several common complications that can arise include ventricular dysfunction, bradycardia and haemopericardium. Epinephrine can be administered through an intracardiac injection immediately after intervention to treat bradycardia. In addition, hemopericardium can be drained if it is significant enough to affect hemodynamics[86].
Novel postnatal therapies for HLHS patients who fail to develop biventricular circulation after prenatal interventions include three-staged palliative surgical procedures ending with Fontan circulation (Figure 6)[87]. Stage one consists of the Norwood procedure, stage two is the bidirectional Glenn shunt operation, and stage three consists of the Fontan procedure. Norwood’s procedure aims at using the RV to pump blood into systemic circulation. Norwood operation includes creating a pulmonary homograft to connect the RV and aorta, RV-to-pulmonary artery (PA) (RV-PA) shunt or modified Blalock Taussing shunt and an atrial septectomy to ensure good atrial communication.
Hybrid procedures have also been introduced as a less intensive approach to the Norwood procedure. The hybrid approach maintains systemic perfusion with ductal arteriosis shunt, establishes pulmonary venous return with either balloon atrial septostomy or surgical atrial septectomy, and accomplishes controlled pulmonary blood flow with PA bands on the right and the left PA. After the hybrid procedure, the patient enters the inter-stage period, which refers to the time between the second-stage surgery and hospital discharge following the Norwood operation. During this period, the patient is continuously monitored, and cardiologic examinations are performed. The second-stage operation, which combines the Norwood procedure with the hemi-Fontan procedure, is more complex and involves a longer surgical process. In some institutions, this stage also serves as a preparatory step for the third stage of invasive cardiac defect treatment[88].
The third stage Fontan operation is performed between 24-48 months of age. This operation develops a connection between the inferior vena cava and the right PA to build a cava-pulmonary connection to passively achieve pulmonary blood flow. A Fontan operation restores circulation and saturation levels to near-normal levels. Several studies have been carried out to investigate the potential outcomes of the Fontan procedure[89,90]. The poor outcomes predicted from these studies include heterotaxy, longer hospital stays, cross-clamp times, and anomaly of atrioventricular valve. In live-born newborns, a high mortality rate is mainly due to the delayed diagnosis made in the postnatal period. However, prenatal diagnosis positively impacts the mortality and morbidity rates of HLHS fetuses, as they can be delivered in specialized pediatric cardiologic centers providing improved planning[91-93].
Future directions
The level of evidence in perinatal and pediatric cardiology could be significantly enhanced through prospectively controlled studies in both invasive and non-invasive fetal therapies. While diagnostic imaging tools like ultrasonography continue to be widely used, they are still hindered by technical limitations. However, three-dimensional and four-dimensional ultrasound are being actively researched and explored. Recent advancements in imaging technology have made cardiovascular magnetic resonance feasible for fetal heart and circulation studies. Despite its potential, cardiovascular magnetic resonance is not commonly available at centers that handle prenatal diagnoses of chronic heart diseases. With the rise of minimally invasive treatment options in fetal cardiology, there is an increasing need for direct intracardiac imaging. Some researchers have introduced miniaturized scopes for direct intracardiac visualization[94]. Apart from imaging technologies, challenges remain in fetal selection and positioning refinements, which can aid in avoiding maternal morbidity.
There is also a need for advanced treatment options in fetal cardiology, such as bioengineering therapies, stem cell therapy, and heart transplantation with bioengineered hearts. Although a clear signaling pathway that contributes to the development of fetal heart malformations is yet to be established, the genetic basis of HLHS remains an area of research in fetal cardiology. Comprehensive knowledge of the genetic basis of HLHS could set forth a new area of investigation for the development of novel therapeutic strategies. The current models used for the study of the development of HLHS need to be expanded to gain a cohesive understanding of altered gene expression linked to HLHS. Recent developments in bioengineering approaches related to patch engineering and human-induced pluripotent stem cell-derived cardiomyocytes might prove to be valuable in these studies.
Stem cell therapy remains another area of investigation to further advance the available treatment options for HLHS patients. So far, very few studies on a very small population have been carried out in this field of fetal cardiology. These studies used a consistent time of delivery (second stage palliation), varied sources and number of cells, while the mode of delivery was either intramyocardial or intracoronary. All of these approaches need to be optimized and the mode of action should be elaborated. In addition, combinational therapy of stem cells and growth factors may prove to be beneficial, as it may increase the right ventricular contractility[95]. Bioengineering therapies or models may also be used to support the hypoplastic left heart. For example, the bioengineered heart muscle can be added to the right ventricular musculature to support increased blood volume resulting from Norwood procedure. Another example includes the use of biological contractile pumps in the Fontan circuit to provide pumping support for blood[96]. Moreover, heart transplantation remains to be another effective therapeutic approach. In a study by Jacquemyn et al[14], the pooled mortality was 25% after hybrid and stage 2 palliation, which decreased to 16% post-stage 2 and 6% post-Fontan. High-risk patients faced greater challenges, with 43% mortality and 10% of patients requiring heart transplantation[14]. The initial interstage period posed the highest risk, highlighting the need for close monitoring. Prospective studies are essential to refine patient selection, indications, and hybrid strategies to improve HLHS outcomes. However, this option is limited due to the scarce availability of donor hearts and cannot be used as a routine management strategy. This limitation can also be bypassed with the availability of bioengineered hearts in the future. Bioengineered hearts can be expanded as potential treatment options for high-risk HLHS patients if not for all.
CONCLUSION
Advancements in the prenatal diagnosis and management of HLHS have ushered in a new era of possibilities in pediatric cardiology and maternal-fetal medicine. Prenatal detection and screening techniques, such as fUSG and fECHO, have revolutionized the early diagnosis of HLHS, providing healthcare providers with vital insights for optimizing family counseling and decision-making. These diagnostic methods enable early detection and offer valuable information on disease variations, allowing healthcare policymakers and specialists to make data-driven decisions. fUSG and ECHO provide a clear view of critical cardiac anomalies associated with HLHS, such as underdeveloped left ventricle, mitral valve issues, and right heart enlargement. Prenatal management strategies, including FAV, FAS, and MH therapy, show promise in improving outcomes for HLHS patients.
This narrative review provides in-depth insight covering many important points regarding the prenatal diagnosis and treatment of HLHS, unlike systematic reviews and meta-analysis that cover specific points or issues. For example, Sprong et al[12] highlight the impact of congenital cardiac defects on motor development, emphasizing how these conditions contribute to delays in achieving developmental milestones. However, this analysis is limited to addressing motor development and does not encompass broader aspects of the prenatal diagnosis, management strategies, or long-term outcomes associated with HLHS. Similarly, a systematic study by Iskander et al[13] provided a detailed comparison of the hybrid palliation and Norwood procedures, analyzing how these approaches impact outcomes for patients with HLHS. While this analysis offers valuable insights into the advantages and challenges associated with each method, it narrowly focuses on these two surgical strategies. It does not encompass the broader spectrum of treatment modalities available for HLHS, such as emerging bioengineering therapies, stem cell applications, or advancements in imaging and diagnostic techniques[12,13].
However, they come with inherent challenges and require careful patient selection, considering factors like fetal anatomy, gestational age, and maternal health. Prenatal diagnosis empowers parents to make informed decisions about their child's treatment, ranging from surgical interventions to supportive care. Ethical considerations and parental decision-making play a crucial role, necessitating healthcare providers to offer guidance that aligns with the child’s best interests. A multidisciplinary approach to prenatal care, involving obstetricians, neonatologists, pediatric cardiologists, and cardiac surgeons, is essential for delivering comprehensive and coordinated care. Prenatal counseling and education are pivotal in helping parents understand the complexity of the condition, the available management options, and the potential long-term effects of treatment. Long-term follow-up and a smooth transition to postnatal care are key for monitoring HLHS patients’ progress and adapting treatment strategies. Although advances in surgical techniques and staged palliation have improved survival rates, challenges remain, including hemodynamic issues, neurological complications, and the need for lifelong immunosuppression in transplant cases. Future directions in fetal cardiology include continued research into the genetic basis of HLHS, exploration of stem cell therapies, and bioengineering solutions, and expanding the availability of heart transplantation. These innovations hold great promise for improved outcomes, ultimately enhancing the quality of life and survival rates for HLHS patients.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed
Peer-review model: Single blind
Specialty type: Cardiac and cardiovascular systems
Country of origin: Afghanistan
Peer-review report’s classification
Scientific Quality: Grade A, Grade C, Grade D
Novelty: Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade B, Grade C
Scientific Significance: Grade B, Grade B, Grade C
P-Reviewer: Haurylenka D; Heathcock J; Zhang HJ S-Editor: Bai Y L-Editor: Filipodia P-Editor: Zhang L
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