Introduction
CHD, the most common congenital malformation, had a prevalence rate of 17.32 per 1,000 among perinatal infants (from 28 weeks of gestation to 7 days after birth) in 2020. Reference Zhang, Wang and Zhao1 Among them, the incidence of aortic stenosis (AS) accounted for 8.1% of all CHD cases, and hypoplastic left heart syndrome (HLHS) accounted for 1.11%. Reference Zhao, Liu, Wu, Ma, Niu and Huang2 Pulmonary stenosis (PS) and pulmonary atresia with intact ventricular septum (PA/IVS) ranked fourth in the subtypes of CHD, and their incidence in China was relatively higher than that in Europe and America, accounting for 11.80% of all CHD cases. Reference Zhao, Liu, Wu, Ma, Niu and Huang2,Reference van der Linde, Konings and Slager3 The conditions of these fetuses may worsen as the gestational age increases, affecting ventricular function and development. Some of these children may only be eligible for single ventricle corrective surgery after birth. Therefore, if these diseases are not intervened during the fetal period, it can lead to irreversible damage to the cardiovascular system and even cause fetal oedema, heart failure, or intrauterine death. According to a survey by the Maternal and Child Health Department of the National Health Commission, the incidence of CHD still ranks first among all birth defect diseases at present, and it is the leading cause of infant mortality, imposing an increasingly significant burden on families and society. With the rapid economic development of the country and the continuous improvement of the health needs of the people, there is an urgent need for an ideal method to improve the effective diagnosis and treatment rate of complex CHDs with poor therapeutic effects and poor long-term prognosis. Therefore, under the leadership of the National Health Commission, China is gradually establishing and improving a three-level prevention and control system of “integration of prenatal and postnatal care,” to increase the screening rate and timely treatment rate of CHD, including in fetuses.
Currently, fetal cardiac intervention (FCI) mainly includes fetal aortic valvuloplasty (FAV), fetal pulmonary valvuloplasty (FPV), and fetal atrial septal intervention (FASI). The approach is mainly to puncture through the pregnant woman’s abdominal wall and uterus under ultrasound guidance, reach the fetal precordial chest wall, puncture the fetal ventricle, and deliver the instrument to the target site for treatment. The aim is to rescue the fetus before irreversible changes occur in the cardiovascular system, relieve cardiac obstruction, promote the development of ventricles and major cardiac vessels, and strive for the opportunity for biventricular correction after birth, while avoiding possible neurological development problems. Fetal aortic valvuloplasty involves expanding the aortic valve and the mitral valve to increase left ventricular blood flow, reduce left ventricular pressure load, optimise the growth trajectory and haemodynamics of the left heart during pregnancy, prevent the occurrence of HLHS, and facilitate biventricular circulation (BVC). Reference McElhinney, Tworetzky and Lock4,Reference Bradford, Tworetzky and Callahan5 Fetal pulmonary valvuloplasty expands the pulmonary valve and the tricuspid valve to improve the disease process, relieve right ventricular outflow tract obstruction, promote the growth of the right ventricle and the tricuspid valve, reduce myocardial damage, promote BVC, and reduce the incidence and mortality. Reference Tulzer, Arzt, Franklin, Loughna, Mair and Gardiner6 At present, there is a lack of comprehensive reviews on prenatal interventional treatment for CHDs in fetuses. This article will focus on this field, particularly on FAV and FPV, and will discuss the latest research progress in this area. The aim of this article is to introduce the current development status and preliminary achievements in intrauterine interventional treatment of complex CHDs in fetuses both domestically and internationally and to summarise the surgical techniques, indications, risk assessment strategies, and clinical treatment outcomes. At the same time, this article will also explore the current problems and shortcomings in fetal CHD interventional treatment, analyse the development opportunities and challenges of fetal cardiac interventional treatment, and put forward constructive suggestions for future research directions and improvement measures, with the aim of providing reference for the further development of this field.
Clinical exploration and development of fetal aortic valvuloplasty
Pathophysiological mechanisms of FAV
The spectrum of fetal AS is extensive. In mild cases, it is difficult to detect through fetal echocardiography during the fetal period. In severe cases, it can develop into HLHS during the fetal stage. Left ventricular outflow tract obstruction leads to mitral valve insufficiency, and mitral valve regurgitation causes an increase in left atrial pressure, further increasing the burden on the left ventricle. Due to mitral valve regurgitation and increased left ventricular filling pressure, the left atrium gradually expands, resulting in obstruction of pulmonary venous return and subsequently causing an increase in pulmonary circulation pressure. During the fetal period, the foramen ovale and ductus arteriosus are open, allowing blood to flow from the right atrium to the left atrium, partially relieving the pressure in the left atrium. This compensatory mechanism can maintain a relatively stable haemodynamic state during the fetal period, but after birth, the foramen ovale and ductus arteriosus close, the compensatory mechanism disappears, and ultimately, the left ventricle is unable to maintain sufficient systemic cardiac output, causing severe haemodynamic disorders. FAV alleviates left ventricular systolic obstruction, prevents the persistent presence of abnormal blood flow from further damaging the myocardium, increases left ventricular blood flow, promotes left ventricular development, reverses, prevents or delays the progression of malformations and the occurrence of delayed development of the systemic vascular bed, prolongs the pregnancy period to allow the left ventricle to continue developing, meets the requirements for the postnatal systemic circulation burden, and can improve the abnormal haemodynamic state and the intrauterine abnormal hypoxia state on the perfusion of important fetal organs and the development of the nervous system, thereby improving fetal growth and development, and increasing the survival rate of the fetus and newborns. Reference Donofrio, Duplessis and Limperopoulos7 The schematic diagram of FAV surgery is shown in Figure 1.
The schematic diagram of FAV surgery. The ideal fetal position is a prerequisite for the smooth progress of the surgery. During the FAV procedure, the fetal heart should be facing forward and adhering to the pregnant woman’s abdominal wall. Under ultrasound guidance, the puncture needle path should be on the same plane as the left ventricular outflow tract and the aortic valve. Under ultrasound guidance, select a 18 G or 19 G puncture needle and perform a layer-by-layer puncture into the left ventricular outflow tract. Pass a 0.014-inch coronary artery guidewire through the aortic valve and into the ascending aorta. Insert a 2.5- to 3.5-mm coronary artery balloon along the guidewire, with its central part crossing the aortic valve annulus. Apply 200 to 300 kPa pressure to expand the balloon. Immediately after the procedure, withdraw the puncture needle along with the deflated balloon out of the heart cavity. Postoperative colour Doppler imaging indicates that a significant increase in the aortic valve-crossing jet is a sign of successful surgery.
Surgical indications and risk assessment strategies for FAV
In 1991, Maxwell et al. Reference Maxwell, Allan and Tynan8 first attempted to perform FAV. In the two cases they reported, one case achieved technical success, but both fetuses failed to achieve long-term survival outcomes. With the continuous innovation of intrauterine interventional techniques and the in-depth exploration of the evolution mechanism of AS disease, FAV surgery has undergone 30 years of development and has achieved many technical success cases. According to the International Fetal Congenital Heart Disease Intervention Registry, FAV accounts for 75.9% of all fetal interventional surgeries. This surgery can improve left heart haemodynamics, promote fetal mitral valve development and left ventricular function recovery, and the postoperative BVC repair rate is 45 to 80%. Reference Friedman, Sleeper and Freud9–Reference Zhao, Wang and Xia14 The first case of FAV in China was carried out in 2018 by the expert team of Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. They performed the first FAV on a fetus with critical AS, achieving a breakthrough in domestic technology. Reference Zhao, Wang and Xia14 The incidence rate in China is low, and there is still a lack of experience in performing this surgery. The surgical indications are also highly controversial. Considering the possibility that cerebral blood supply is insufficient in the late pregnancy of critical AS fetuses, leading to neurological damage, the “window period” for FAV intervention is generally recommended to be between the 20th and 26th weeks of pregnancy. Reference Marshall, Tworetzky and Bergersen15 The main researchers in the field of FAV are the research team from Boston Children’s Hospital in the United States. The team summarised the inclusion criteria for fetuses undergoing intrauterine balloon aortic valvuloplasty Reference McElhinney, Marshall and Wilkins-Haug16–Reference Makikallio, McElhinney and Levine18 : ① Aortic valve stenosis is the main malformation causing haemodynamic changes; ② The left ventricle must have salvage value (the left ventricular length at diagnosis cannot be lower than 2 standard deviations or Z-score ≥ 2 for the corresponding gestational age group); ③ The diagnosis was made before 30 weeks of gestation; ④ The fetus had not undergone interventional treatment before; ⑤ There were no other severe non-cardiac malformations. Exclusion criteria: ① Multiple pregnancies; ② Other severe malformations besides cardiac malformations; ③ Incomplete cervical closure; ④ The mother had contraindications to general anaesthesia or uterine contraction inhibitors. Furthermore, as the research progressed, the research team from Boston Children’s Hospital in the United States Reference McElhinney, Tworetzky and Lock4,Reference McElhinney, Marshall and Wilkins-Haug16 utilised multivariate analysis to establish a multivariate threshold scoring system for predicting the possibility of BVC in fetuses with severe AS accompanied by progressive HLHS during the mid-pregnancy stage, as well as for screening fetuses for FAV. This standard includes: ① Left ventricular long-axis Z-score>0, ② Left ventricular short-axis Z-score>0, ③ Aortic valve annulus Z-score > −3.5, ④ Mitral valve annulus Z-score > −2, ⑤ Mitral valve or aortic valve pressure difference ≥ 20 mm Hg. Each of the above 5 items is scored 1 point, and a score of >4 indicates a sensitivity of 100% for establishing biventricular circulation after birth, a specificity of 53%, a positive predicted value of 38%, and a negative predicted value of 100%. In 2018, Friedman et al. Reference Friedman, Sleeper and Freud9 added two new items to the original standard: left ventricular pressure >47 mm Hg and ascending aorta z-value > 0.57. They also pointed out that left ventricular pressure, ascending aorta size z-value, mitral valve inflow time z-value, left ventricular long-axis size z-value, etc. were independent predictors significantly related to the BVC results. At the same time, they emphasised the key significance of aortic valve size z-value in evaluating fetal heart conditions and predicting the postoperative outcome of FAV. In 2022, Tulzer et al. Reference Tulzer, Arzt and Gitter13 proposed using the ratio of right ventricular to left ventricular length to predict BVC results. This method avoids complex z-value calculations and, combined with the maximum velocity of mitral valve regurgitation, can improve the prediction accuracy.
Clinical outcomes of FAV
FAV aims to restore the blood flow of the aortic valve, optimise the cardiac haemodynamics, promote the growth and development of the left ventricular myocardium, and improve the natural course of fetal AS evolving into HLHS during the second trimester of pregnancy, with the goal of achieving BVC after the birth of the fetus. A study showed Reference Friedman, Sleeper and Freud9 that in the intervention group, the z-value of the aortic valve annulus increased from −2.9 ± 1.0 before the operation to −2.5 ± 0.9, the z-value of the mitral valve annulus increased from −2.2 ± 1.3 to −1.2 ± 1.2, the z-value of the ascending aorta increased from −0.6 ± 1.5 to −0.4 ± 2.0, and the z-value of the left ventricular long axis increased from 0.9 ± 1.8 to 1.4 ± 1.5, all of which were better than those in the untreated group, indicating that the development of the ventricles and valves has been improved to a certain extent. The success rate of single-centre FAP reported by Boston Children’s Hospital increased from 70% in 2004 to 94%, the rate of fetal miscarriage decreased from 9.8 to 6%, and 59% of the live-born infants could complete biventricular repair. Reference Friedman and Tworetzky19 In 2014, the team of Boston Children’s Hospital Reference Freud, McElhinney and Marshall20 conducted a retrospective analysis of the first 100 cases of FAV fetuses they had performed, indicating that 77 cases achieved technical success, and 38 fetuses received biventricular circulation correction after birth. The overall survival rate of these children at 1 year after surgery was (80 ± 4)%, and the 5-year overall survival rate was (75 ± 5)%. During an average follow-up period of 5.4 years, 96% of the children who underwent biventricular circulation correction did not experience cardiac death within 5 years, and at 10 years, it was (84 ± 12)%, which was better than that of children with single ventricular circulation (log-rank P = 0.04). In the most recent echocardiography examination, 80% of the children had normal ejection fraction. A multicentre retrospective study in Europe Reference Kovacevic, Ohman and Tulzer21 found that, compared with the natural course cohort of CAS, the proportion of fetal biventricular repair after FAV surgery was similar (36% vs. 38%), but the 10-year survival rate of the postoperative survivors significantly increased. At the same time, 10% of the FAV fetuses had surgical complications, increasing the probability of premature birth. Laraja et al. Reference Laraja, Sadhwani and Tworetzky22 conducted long-term follow-up on 52 live-born infants who underwent successful FAV surgery. They evaluated the neurological development of these infants using multiple neurological scoring systems. The results showed that compared with children who did not receive FAV intervention, the children who achieved BVC after FAV surgery had delayed neurological development and no significant improvement. Therefore, the benefits of FAV surgery for fetuses remain controversial, and further verification is needed through large-sample prospective randomised controlled trials.
Clinical exploration and development of fetal pulmonary valvuloplasty
Pathophysiological mechanisms of FPV
The condition of critical PS fetuses can progress with the increase of gestational age, eventually developing into complete closure of the pulmonary valve, resulting in PA. In patients with PA/IVS or critical PS/IVS, the right ventricle morphology during the fetal stage is unstable, and abnormal right ventricle-coronary artery shunting may occur, but there is almost no association with endocardial fibroelastosis. Scholars attribute the underdevelopment of the right ventricle to the extreme thickening of the right ventricular wall, which leads to obstruction of the outflow tract of the right ventricle. When the right heart morphology is observed to be smaller in mid-pregnancy or late pregnancy by ultrasound, the right heart system will show a continuous shrinking trend in the following gestational weeks, ultimately resulting in underdevelopment of the right heart. Most of these children’s tricuspid valves are relatively small or even dysplastic, and they can also have varying degrees of tricuspid regurgitation, which to some extent will affect the prognosis of the disease. FPV, as an intrauterine interventional surgery for treating severe PS or PA/IVS in fetuses, aims to optimise the right ventricular haemodynamics during the fetal stage, promote the development of the right ventricle and tricuspid valve, and increase the possibility of BVC after birth. Its clinical significance lies in changing the natural course of fetal right heart dysplasia syndrome (HRHS), reducing myocardial damage, improving the fetal haemodynamic status, thereby increasing the survival rate and quality of life of the fetus after birth, reducing the need for single ventricle repair surgery, and improving the success rate of BVC. Reference Mendel, Kohar and Yumnanisha23
Surgical indications and risk assessment strategies for FPV
In 2002, the Linz Children’s Hospital in Austria was the first to perform two cases of FPV. Although both fetuses developed valve restenosis 12 weeks after the surgery and were delivered prematurely for another operation, Doppler echocardiography showed that FPV significantly improved right ventricular function and prolonged the gestational period. Eventually, both fetuses achieved BVC, highlighting the potential of FPV while also revealing many challenges that need to be overcome. Reference Tulzer, Arzt, Franklin, Loughna, Mair and Gardiner6 The first case of FPV in China was completed in 2016 at the Heart Center of Guangdong Provincial People’s Hospital. The medical team of this centre collaborated with Professor Tulzer from the Linz Children’s Hospital in Austria to perform FPV on a fetus with PA/IVS, marking the first step in the exploration of FCI treatment in China. Reference Pang, Zhou and Zhang24 The following year, the team successfully performed in utero FPV treatment on another fetus with critical PS/IVS. In June 2018, an expert team from three hospitals in Shanghai successfully performed FPV on a fetus with critical PS/IVS and HRHS. This marked that domestic medical teams could independently complete such surgeries. In July 2018, a single-centre team from Qingdao Women and Children’s Hospital independently performed FPV treatment on a fetus with PA/IVS and HRHS at 26 weeks of gestation, achieving a breakthrough in the minimum gestational age for FCI treatment in China, and the technique was close to the international level. Reference Xing, Sun, Luo, Zhang, Chen and Pan25 The main focus of FPV intervention is on HRHS in the early pregnancy. The ultrasound diagnosis criteria for PA/IVS with HRHS in China are already mature and consistent, and they can be clearly diagnosed in mid-pregnancy (18–26 weeks). The gestational age for FPV treatment intervention is 26–29 weeks, which is basically consistent with the reports from abroad. In terms of the exploration of FPV, due to the different evaluation indicators adopted by different centres for such diseases, there is no unified standard for the indications of FPV. Each centre selects cases based on its experience, the level of experts, the cooperation ability, the suitability of the equipment, and other factors. In 2007, Roman et al. Reference Roman, Fouron, Nii, Smallhorn, Chaturvedi and Jaeggi26 attempted to predict the outcome of single ventricle using indicators such as the ratio of tricuspid annulus diameter to mitral annulus diameter was <0.7, the ratio of right ventricular length to left ventricular length was <0.6, and the ratio of tricuspid inflow time to cardiac cycle was <0.3. In 2012, Professor Galindo from the Fetal Cardiology Research Group in Spain reported on the exploration of the inclusion criteria for fetuses with right ventricular outflow tract obstruction. Reference Gomez, Herraiz, Mendoza and Galindo27 The study summarised the following four indicators: ①the ratio of tricuspid annulus diameter to mitral annulus diameter ≤ 0.83; ②the ratio of right ventricular length to left ventricular length ≤ 0.64; ③the ratio of pulmonary annulus diameter to aortic annulus diameter ≤ 0.75; ④the ratio of tricuspid inflow time to cardiac cycle ≤ 0.37. If three of the above indicators were present in the fetus before 32 weeks of gestation, the sensitivity and specificity for predicting the need for a single ventricle circulation after birth were 100 and 92%, respectively; if all four indicators were present, the sensitivity and specificity for predicting the need for a single ventricle circulation after birth were both 100%. Therefore, it is recommended to jointly evaluate these four indicators as the inclusion criteria for FPV. The Boston Centre criteria Reference Jaeggi, Renaud, Ryan and Chaturvedi28 state that when the z value of the tricuspid annulus diameter is < −3, the possibility of biventricular repair is extremely low. Therefore, the FCI criteria cover a small but clear right ventricle and a z value of the tricuspid annulus diameter < −2. The contraindications for FPV are: (1) the pregnant mother has contraindications for anaesthesia; (2) the fetus has other severe cardiac malformations and severe extracardiac malformations, and genetic screening confirms the presence of a genetic syndrome; (3) the FPV fetus is one of the twins or multiple fetuses in a pregnancy; (4) the fetus has muscular closure of the right ventricular outflow tract and/or right ventricular-dependent coronary circulation; (5) right ventricular hypertrophy with low-speed shunt of the oval foramen and low-speed tricuspid valve reflux (< 2.0 m/s). Reference Gottschalk, Strizek and Menzel29
Clinical outcomes of FPV
Currently, international reports indicate that the rate of biventricular repair in fetuses after FPV surgery ranges from 40 to 89%. Reference Gomez, Herraiz, Mendoza and Galindo27,Reference Gottschalk, Strizek and Menzel29–Reference Tulzer, Arzt and Gitter31 The morphology of the right ventricle and the size of the tricuspid valve annulus are important indicators for evaluating right ventricular development and are also the main determinants of the biventricular outcome. Austrian Tulzer et al. Reference Tulzer, Arzt and Gitter31 reviewed the immediate postoperative effects and outcomes of FPV surgery. They performed FPV on 23 fetuses, with 25 procedures in total, including 15 cases of PA/IVS and 8 cases of CPS. In the 17 cases with successful techniques, all indicators showed significant improvement immediately after the surgery. Two cases died in the neonatal period due to haemodynamic instability after cardiac surgery and severe necrotising enterocolitis. In the remaining 21 cases, 15 underwent biventricular correction, 3 underwent one-half ventricular correction, and 3 were undetermined. During a follow-up period ranging from 0.1 to 16.36 years (with an average follow-up time of 1.63 years), the survival rate of the children at 1 year after birth was 90.2%. In a 2020 study of PA/IVS intrauterine treatment at Boston Children’s Hospital, 41 out of 58 fetuses (70.7%) achieved technical success, and 35 (60.3%) resulted in live births. Among the 31 surviving children at discharge, 87% achieved biventricular circulation, and 10% underwent one-half ventricular correction. Reference McElhinney, Marshall and Wilkins-Haug16 The Guangdong Provincial People’s Hospital team in China has completed 7 such surgeries. A total of 4 cases received a percutaneous balloon pulmonary valve dilation procedure in the neonatal period and ultimately achieved BVC, 1 case underwent surgical correction of biventricles, 1 case achieved one-half ventricular correction through surgery, and the result of 1 case was not reported. Reference Zhi-weia and Jin-jin32 The team at Xinhua Hospital in Shanghai achieved BVC in the postnatal period of FPV-treated fetuses through percutaneous balloon pulmonary valve dilation. Reference Zhao, Wang and Xia14 Overall, FPV can improve fetal haemodynamics, promote right ventricular growth and functional recovery, and significantly improve the size and function of the tricuspid and pulmonary valves. However, most of the existing studies are short-term follow-ups, and there is a lack of long-term prognosis data, especially information on postoperative ventricular function, quality of life, and long-term survival rate, which urgently needs to be supplemented.
Clinical exploration and development of atrial septal intervention
Pathophysiological mechanisms of FASI
In the normal fetal circulation, the oxygen-rich blood from the umbilical cord flows through the foramen ovale into the left heart system, thereby supplying the entire body. When the atrial septum is intact or restricted, the passage for blood to flow from the right atrium to the left atrium is blocked or completely blocked, resulting in the absence of communication between the left and right atria, which impedes the supply of oxygen-rich blood from the placenta through the left heart to the ascending aorta and systemic circulation. This is the most fatal disease during the fetal period, which can cause changes in the direction of blood flow in the left atrium and remodelling of the left heart chamber and eventually progresses to HLHS. In addition, a complete or restricted atrial septum during the fetal period can also lead to fetal non-immune oedema and intrauterine distress, and secondary pulmonary abnormalities manifest as congenital pulmonary cystic lymphatic dilation and pulmonary vein myxosis. This condition cannot be reversed after birth and affects the survival rate after birth. Fetal atrial septal intervention (FASI) is applicable for HLHS with intact or restricted atrial septum (I/RAS). It promotes blood flow into the left heart system by artificially creating atrial-level communication, facilitating the development of the dual ventricle system. Currently, the methods of artificially creating atrial-level communication during the fetal period include balloon dilation, stent implantation, and radiofrequency perforation. Radiofrequency perforation can only create a very small channel on the atrial septum, which will close quickly after the operation. Therefore, balloon atrial septal intervention or stent implantation are currently recommended, as these two surgeries can keep the atrial-level communication open until birth.
Surgical indications and risk assessment strategies for FASI
At present, there are still no objective indicators for the indications of FASI treatment. The ultrasound echocardiographic features of fetuses with left heart dysplasia are obvious, and the prenatal screening rate can reach 90%. The observation of left atrium and pulmonary vein dilation through echocardiography, and the bidirectional and significant retrograde flow of pulmonary vein blood flow during systole are the reference indicators for this surgery. The threshold scoring method for left heart dysplasia Reference McElhinney, Tworetzky and Lock4 : Z value of left ventricular long-axis diameter > 0, Z value of left ventricular short-axis diameter > 0, Z value of aortic annulus > −3.5, Z value of tricuspid annulus > −2, and the pressure difference across the tricuspid or aortic valve ≥ 20 mmHg (1 mmHg = 0.133 kPa) can be used as the reference. Any one of the above conditions can be used for surgical intervention. For fetuses with HLHS accompanied by I/RAS, the fetal pulmonary capillary malformation can be confirmed by the 23rd gestational week. Therefore, FASI should be performed as soon as possible. For fetuses with HLHS who have a diameter of the atrial level communication <1 mm and haemodynamic and anatomical changes suggesting the need for emergency left atrial decompression after birth, FASI can be considered.
Clinical outcomes of FASI
In 2008, Boston Center reported the largest single-centre case of FASI. Reference Marshall, Levine and Morash17 Among 21 cases attempting balloon dilation, 19 were technically successful, but the postoperative survival rate was only 58%. In 2011, a related report from the Linz Children’s Hospital also showed a relatively low survival rate for fetuses. Reference Arzt, Wertaschnigg, Veit, Klement, Gitter and Tulzer33 In 2018, the Qingdao Women and Children’s Hospital successfully carried out the first FASI case in China. Reference Luo, Zhang and Chen34 In 2024, a study Reference Mustafa, Aghajani, Jawwad, Shah, Abuhamad and Khalil35 compared the results of FASI treatment and expectant management for HLHS with I/RAS fetuses. Among 123 FASI patients, 107 cases were technically successful. Compared with 623 cases in the expectant management group, there were no differences in average gestational age at delivery or neonatal outcomes at birth. In some cases with thick atrial septa and muscular tissue, simply performing balloon atrial septal ostium surgery could not maintain the atrial septal communication for a long time, so stents needed to be placed. However, stent implantation was significantly more difficult than balloon ostium creation, and the risk of complications was also increased, especially the risk of embolism and/or thrombosis. In 8 cases of stent implantation completed at the Toronto Center, in 7 cases of successful technical outcomes, 1 case had stent embolism, and 1 case had thrombosis. Reference Chaturvedi, Ryan, Seed, van Arsdell and Jaeggi36 At the Boston Center, 4 cases were technically successful, and 3 cases had thrombosis. Reference Kalish, Tworetzky and Benson37 Therefore, both at home and abroad, carefully designed clinical trial studies are needed to clearly prove that FASI surgery truly benefits HLHS fetuses with I/RAS in the long term.
Challenges and prospects of fetal cardiac intervention
Exploration of the FCI entry path
Some scholars have pointed out that the current mainstream clinical approach—puncturing the fetal ventricle—often leads to complications such as pericardial haemorrhage, arrhythmia, and injury to the heart during the puncture. Therefore, attempts have been made to use the umbilical vein or hepatic vein of the fetus as the puncture route in an attempt to reduce these injuries. Jouannic et al. Reference Jouannic, Boudjemline, Benifla and Bonnet38 made an incision in the abdominal wall of pregnant sheep, placed the uterus outside the body, and then used ultrasound to locate the right hepatic vein of the fetal sheep. After that, the catheter was sent into the pulmonary artery, and the fetal sheep’s pulmonary valve repair surgery was successfully performed. The Edwards research team Reference Edwards, Menahem and Veldman39 conducted fetal cardiovascular angiography under ultrasound guidance by percutaneously puncturing the umbilical vein, but the operation was unsuccessful. Then, they switched to the hepatic vein approach and successfully performed 8 cases of fetal cardiovascular angiography. The amount of bleeding in the fetuses during the procedure was 4 to 20 mL. One fetus died during the cardiac catheterisation, and the other 7 survived until the end of the surgery. Five cases resulted in full-term delivery. Autopsies did not reveal any damage to the heart or valves. In 2013, Nugent et al. Reference Nugent, Kowal, Juraszek, Ikemba and Magee40 conducted an FCI in vitro experiment. On the in vitro fetal heart and major blood vessel model, using MRI-guided guide wires and expansion balloons to reach the aortic valve ring level of the model through the umbilical vein or hepatic vein path, they performed dozens of repeated and multi-angle attempts, all achieving the expected results, and the time taken gradually shortened. The success of these animal experiments is expected to be applied in clinical practice in the future, which will help reduce the incidence of complications after FCI.
Strengthen the training of multidisciplinary team members
At present, in China, once fetal CHD is diagnosed prenatally, regardless of the complexity of the deformity and the treatment outcome, approximately 90% of the fetuses will face the outcome of induced labour. This is due to the lack of correct prenatal consultation and guidance. FCI involves multiple disciplines such as fetal medicine, obstetrics, cardiology, anaesthesiology, ultrasound, and neonatology. Medical staff have varying levels of understanding of the disease spectrum, surgical indications, technical operations, complications, and prognosis of fetal CHD interventional treatment. In some cases, there is even a complete lack of understanding. Therefore, it is crucial to strengthen the collaborative training of the multidisciplinary team. FCI requires experts from different professional fields such as obstetricians, paediatric cardiologists, and ultrasound physicians to work together. Not only should cardiologists specialising in fetal CHD diagnosis and treatment undergo strict training to familiarise themselves with the indications for interventional treatment of fetal CHD, as well as the technical operation methods, drug resuscitation treatment measures, but it is even more important to enhance communication and training among multiple disciplines to improve the understanding of medical staff in perinatal disciplines such as obstetrics and fetal medicine, so that they can acquire the necessary professional background knowledge and gradually expand the social impact of FCI treatment, avoiding excessive induced labour for fetuses with PA/IVS, especially.
Development and selection of FCI surgical devices
Device development is another key factor to improve the effectiveness of FCI. Most of the currently used devices are based on the design of adult cardiac interventional therapy, which may not be suitable for the anatomical characteristics of the fetus. Therefore, the development of interventional devices specifically designed for the fetus, such as smaller balloon catheters and more accurate positioning systems, is of great importance to improve surgical outcomes and reduce complications.
Conclusions
In conclusion, with the advancement of diagnostic and therapeutic technologies and the establishment of multidisciplinary teams, the safety and efficacy of FCI have been increasingly recognised by fetal medicine and fetal cardiologists worldwide. It has been implemented in multiple paediatric cardiac centres around the world. More and more evidence shows that FCI can optimise ventricular haemodynamics, prevent ventricular dysplasia, promote the establishment of BVC, help alleviate or change the course of the disease, and can be used as a treatment method to rescue the development of ventricles and large cardiac vessels. However, there are many controversies and uncertainties in case selection, and there is a lack of some animal experiments and multicentre large-sample prospective clinical cohort studies to conduct a comprehensive assessment of the surgical timing, surgical indications, and long-term prognosis and to improve the inclusion criteria for indications.
Data availability statement
All data are incorporated into the article, and the data underlying this article are available in the article.
Acknowledgements
We acknowledge the roles of our colleagues, perfusionists, nurses, and others involved in the care of the study participants.
Author contributions
Zhangwei Wang: Conceptualisation; Data curation; Formal analysis; Investigation; Methodology; Software; Validation; Visualisation; Writing – original draft. Honghao Fu: Writing – review & editing. Shoujun Li: Writing – review & editing.
Financial support
No funding was received for this work.
Competing interests
None declared.
