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Fetal aortic valvuloplasty (FAV) has become a treatment option for critical fetal aortic stenosis (AS) with the goal of preserving biventricular circulation (BVC); however, to date, it is unclear how many patients undergoing FAV achieve BVC. The aim of this systematic review and meta-analysis was to investigate the type of postnatal circulation achieved following FAV.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. MEDLINE, EMBASE, Web of Science and the Cochrane Library were searched systematically for studies investigating postnatal circulation in patients with AS following FAV. Eligible for inclusion were original papers in the English language, published from 2000 to 2020, with at least 12 months of follow-up after birth. Review papers, abstracts, expert opinions, books, editorials and case reports were excluded. The titles and abstracts of all retrieved literature were screened, duplicates were excluded and the full texts of potentially eligible articles were obtained and assessed. The primary endpoint was type of postnatal circulation. Additional assessed outcomes included fetal death, live birth, neonatal death (NND), termination of pregnancy (TOP) and technical success of the FAV procedure. The quality of articles was assessed using the Critical Appraisal Skills Programme (CASP) tool. To estimate the overall proportion of each endpoint, meta-analysis of proportions was employed using a random-effects model.The electronic search identified 579 studies, of which seven were considered eligible for inclusion in the systematic review and meta-analysis. A total of 266 fetuses underwent FAV with median follow-up per study from 12 months to 13.2 years. There were no maternal deaths and only one case of FAV-related maternal complication was reported. Hydrops was present in 29 (11%) patients. The pooled prevalence of BVC and univentricular circulation (UVC) among liveborn patients was 45.8% (95% CI, 39.2-52.4%) and 43.6% (95% CI, 33.9-53.8%), respectively. The pooled prevalence of technically successful FAV procedure was 82.1% (95% CI, 74.3-87.9%), of fetal death it was 16.0% (95% CI, 11.2-22.4%), of TOP 5.7% (95% CI, 2.0-15.5%), of live birth 78.8% (95% CI, 66.5-87.4%), of NND 8.7% (95% CI, 4.7-15.5%), of palliative care 4.0% (95% CI, 1.9-8.4%) and of infant death 10.3% (95% CI, 3.6-26.1%). The pooled prevalence of BVC and UVC among liveborn patients who had technically successful FAV was 51.9% (95% CI, 44.7-59.1%) and 39.8% (95% CI, 29.7-50.9%), respectively.This study showed a BVC rate of 46% among liveborn patients with AS undergoing FAV, which improved to 52% when subjects underwent technically successful FAV. Given the lack of randomized clinical trials, results should be interpreted with caution. Currently, data do not suggest a true benefit of FAV for achieving BVC. © 2022 The Authors. Ultrasound in ObstetricsGynecology published by John WileySons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses. Electronic supplementary material The online version of this article (10.1007/s10439-020-02683-x) contains supplementary material, which is available to authorized users.

Congenital aortic stenosis (AS) occurs in around 0.2–0.5% of newborns, and its clinical severity is quite variable. Some of the newborns with AS require urgent medical care: prostaglandin infusion, balloon aortic valvuloplasty, or surgical intervention. Despite having a severe clinical evolution in neonates, the prenatal diagnosis of congenital AS is quite low. We present the case of a fetus with critical AS, who had been prenatally diagnosed at 35 weeks of gestation, via fetal cardiac ultra-sound. The echocardiographic parameters revealed a severely depressed left ventricular systolic function, with dilated chambers, and a severe aortic stenosis. Offline speckle-tracking analysis was performed in order to aid in deciding the optimal methods and timing of delivery. Left ventricular analysis revealed a severely impaired global longitudinal strain of 2.1%, left ventricular ejection fraction 18.4%, increased LV volumes, while the right ventricular function was only mildly depressed. Therefore, the decision was to delay the premature delivery, and the fetus was born at a gestational age of 38 weeks, in a hospital with a neonatal cardiovascular surgery department. The patient had undergone surgical repair of the cardiac anomaly at 3 days after birth.

Fetal cardiac intervention was first proposed in the early 1990s to impact cardiac development and survival of fetuses with fetal aortic stenosis and evolving hypoplastic left heart syndrome (HLHS). Although initial attempts of fetal aortic valvuloplasty were unsuccessful and carried a high rate of morbidity and mortality, our collaborative group at the Brigham and Women's Hospital and Boston Children's Hospital have reinvigorated the procedure using improvements in imaging, anesthesia, balloon catheters, and surgical techniques. Two decades of experience have now allowed us to document the safety of in utero intervention and to achieve a better understanding of the impact of midgestation intervention on developing HLHS. Research into underlying genetics, predictive biomarkers, and ways to incorporate stem cell technology will hopefully allow us to further refine the procedure to most benefit children with this historically lethal disease.

In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity and associate myocardial deformation on fetal ultrasound with postmortem histopathological characteristics. During routine fetal echocardiography, speckle tracking recordings of the cardiac four-chamber view were performed to assess myocardial strain as parameter for myocardial deformation. After pregnancy termination, postmortem cardiac specimens were examined using immunohistochemical labeling (IHC) of key markers for myocardial organization, differentiation and fibrosis and compared to normal fetal hearts. Two cases with critical AS presented extremely decreased left ventricular (LV) strain on fetal ultrasound. IHC showed overt endocardial fibro-elastosis, which correlated with pathological fibrosis patterns in the myocardium and extremely disturbed cardiomyocyte organization. The LV in severe AS showed mildly reduced myocardial strain and less severe disorganization of the cardiomyocytes. In conclusion, the degree of reduction in myocardial deformation corresponded with high extent to the amount of pathological fibrosis patterns and cardiomyocyte disorganization. Myocardial deformation on fetal ultrasound seems to hold promise as a potential biomarker for left ventricular structural damage in AS.

Fetal therapy is a rapidly changing sub speciality, carried out in only a few specialist tertiary centres requiring multi disciplinary teamwork. It is being used to treat an increasing number of lethal and non-lethal fetal conditions. There are ongoing trials which require us to be up to date with literature and evolving techniques. Advances in diagnosis using ultrasound and magnetic resonance imaging (MRI) have led to a more accurate diagnosis and earlier detection of fetal abnormalities. In this chapter we will be discussing Twin-twin Transfusion syndrome, critical fetal aortic stenosis, congenital diaphragmatic hernia, lower urinary tract obstruction, congenital lung malformations and Ex utero intrapartum treatment procedure. We will also be looking at reasons to consider the need for both maternal and fetal analgesia, and the need for tocolysis in preventing pre term labour.

Background Fetal aortic stenosis may progress to hypoplastic left heart syndrome (HLHS), which carries a poor prognosis. We report two infants with fetal aortic stenosis successfully treated with fetal aortic valvuloplasty (FAV) using balloon dilatation. Case presentation Of five fetuses with aortic stenosis fulfilling the FAV criteria of severe aortic stenosis with a left ventricular length Z-score of ≥ − 2, retrograde flow in the transverse aortic arch, left-to-right flow across the foramen ovale, monophasic mitral inflow, and significant left ventricular dysfunction, we obtained permission for FAV in two fetuses. FAV was performed successfully under echocardiographic guidance using balloon dilatation. Both fetuses survived to birth. During FAV, mild pericardial effusion developed when introducing the stylet needle in the second fetus, and this resolved within 48 h. No intraprocedural complications occurred in the first patient, and no maternal complications occurred. The first infant underwent the Ross procedure after birth and is currently 7 years old and doing well. The second patient underwent aortic and mitral valve repair with endocardial fibroelastosis resection approximately 2 weeks after birth, which temporarily addressed the mitral valve stenosis; high doses of inotropes were subsequently required. The infant died of sepsis at 2 months of age. Conclusion FAV using balloon dilatation to treat fetal aortic stenosis was successful in our two patients, with subsequent neonatal biventricular repair resulting in long-term survival in one patient and death secondary to sepsis in the second patient.

Objective Fetal aortic stenosis may progress to hypoplastic left heart syndrome. Fetal valvuloplasty (FV) has been proposed to improve left heart hemo-dynamics and maintain biventricular (BV) circulation. The aim of this study was to assess FV efficacy by comparing survival and postnatal circulation between fetuses that underwent FV and those that did not. Methods This was a retrospective multicenter study of fetuses with aortic stenosis that underwent FV between 2005 and 2012, compared with contemporaneously enrolled natural history (NH) cases sharing similar characteristics at presentation but not undergoing FV. Main outcome measures were overall survival, BV-circulation survival and survival after birth. Secondary outcomes were hemodynamic change and left heart growth. A propensity score model was created including 54/67 FV and 60/147 NH fetuses. Analyses were performed using logistic, Cox or linear regression models with inverse probability of treatment weighting (IPTW) restricted to fetuses with a propensity score of 0.14-0.9, to create a final cohort for analysis of 42 FV and 29 NH cases. Results FV was technically successful in 59/67 fetuses at a median age of 26 (21-34) weeks. There were 7/72 10%) procedure-related losses, and 22/53 (42%) FV babies were delivered at < 37 weeks. IPTW demonstrated improved survival of liveborn infants following FV (hazard ratio, 0.38; 95% CI, 0.23-0.64; P = 0.0001), after adjusting for circulation and postnatal surgical center. Similar proportions had BV circulation (36% for the FV cohort and 38% for the NH cohort) and survival was similar between final circulations. Successful FV cases showed improved hemodynamic response and less deterioration of left heart growth compared with NH cases (P

Background Fetal aortic stenosis (AoS) may progress to hypoplastic left heart syndrome (HLHS) in utero. There are currently no data, prenatal or postnatal, describing survival of fetuses or neonates with AoS or HLHS in a country with suboptimal postnatal management. Study design Prospective cohort study performed in Mexico, including cases diagnosed with AoS and HLHS within a 6-year period. AoS patients fulfilling previously published criteria for evolving HLHS (eHLHS) were offered fetal aortic valvuloplasty. Outcome variables were perinatal mortality, postnatal management, type of postnatal circulation, and overall survival. Results Fifty-four patients were included: 16 AoS and 38 HLHS. Eighteen patients had associated anomalies and/or an abnormal karyotype. Seventy-four percent of HLHS received comfort measures, with only three cases reporting an attempt at surgical palliation, and one survivor of the first stage. Fetal aortic valvuloplasty was performed successfully in nine cases of eHLHS. Overall postnatal survival was 44% in AoS with fetal aortic valvuloplasty, and one case (ongoing) in the HLHS group. Conclusions HLHS in Mexico carries more than a 95% risk of postnatal death, with little or no experience at surgical palliation in most centers. Fetal aortic valvuloplasty in AoS may prevent progression to HLHS and in this small cohort was associated with ≈50% survival.

Fetal cardiac intervention (FCI) is a novel and evolving technique that allows for in utero treatment of a subset of congenital heart disease. This review describes the rationale, selection criteria, technical features, and current outcomes for the three most commonly performed FCI: fetal aortic stenosis with evolving hypoplastic left heart syndrome (HLHS); HLHS with intact or restrictive atrial septum; and pulmonary atresia with intact ventricular septum, with concern for worsening right ventricular (RV) hypoplasia.

Objectives: Fetal aortic valvuloplasty (FV) aims to prevent fetal aortic valve stenosis progressing into hypoplastic left heart syndrome (HLHS), which results in postnatal univentricular (UV) circulation. Despite increasing numbers of FVs performed worldwide, the natural history of the disease in fetal life remains poorly defined. The primary aim of this study was to describe the natural history of fetal aortic stenosis, and a secondary aim was to test previously published criteria designed to identify cases of emerging HLHS with the potential for a biventricular (BV) outcome after FV. Methods: From a European multicenter retrospective study of 214 fetuses with aortic stenosis (2005-2012), 107 fetuses in ongoing pregnancies that did not undergo FV were included in this study and their natural history was reported. We examined longitudinal changes in Z-scores of aortic and mitral valve and left ventricular dimensions and documented direction of flow across the foramen ovale and aortic arch, and mitral valve inflow pattern and any gestational changes. Data were used to identify fetuses satisfying the Boston criteria for emerging HLHS and estimate the proportion of these that would have been ideal FV candidates. We applied the threshold score whereby a score of 1 was assigned to fetuses for each Z-score meeting the following criteria: left ventricular length and width > 0; mitral valve diameter -2; aortic valve diameter > -3.5; and pressure gradient across either the mitral or aortic valve > 20 mmHg. We compared the predicted circulation with known survival and final postnatal circulation (BV, UV or conversion from BV to UV). Results: Among the 107 ongoing pregnancies there were eight spontaneous fetal deaths and 99 livebirths. Five were lost to follow-up, five had comfort care and four had mild aortic stenosis not requiring intervention. There was intention-to-treat in these 85 newborns but five died prior to surgery, before circulation could be determined, and thus 80 underwent postnatal procedures with 44 BV, 29 UV and seven BV-to-UV circulatory outcomes.

OBJECTIVE: To describe the early hemodynamic changes after fetal aortic valvuloplasty (FAV) for evolving hypoplastic left heart syndrome due to mid-gestational aortic stenosis and to assess whether these early changes predict biventricular (BiV) circulation at neonatal discharge. METHOD: We retrospectively reviewed all technically successful FAV cases resulting in live birth between 2000 and 2015 (n = 93,45% BiV circulation at neonatal discharge). Paired testing methods were used to compare pre-intervention and post-intervention measures of left ventricular hemodynamics. Logistic regression was used to determine whether these changes were predictive of post-natal outcome. RESULTS: Measures of left heart physiology were markedly abnormal pre-FAV and improved significantly post-FAV. No subjects had systolic antegrade transverse aortic arch flow pre-FAV and 65% of subjects had antegrade flow post-FAV. The number of subjects with abnormal left-to-right patent foramen ovale flow decreased, and the number with biphasic mitral valve inflow increased. The median left ventricular ejection fraction improved after intervention. Amongst the pre-post changes, gaining partially or exclusively antegrade systolic arch flow was the most significant independent predictor of BiV circulation (OR 9.80 and 19.83, respectively, both P < 0.001). CONCLUSION: Technically successful FAV is associated with immediate improvements in left heart physiology that are predictive of BiV circulation at neonatal discharge.

At our institution a multidisciplinary team has performed fetal aortic valvuloplasty (FAV) for severe aortic stenosis with evolving hypoplastic left heart syndrome with high technical success rates. Measurement of postnatal success has been biventricular circulation (BC). Postnatal survival for patients after FAV who achieved a BC appears encouraging. However, there are limited late clinical and hemodynamic outcomes in this cohort and there is concern for diastolic dysfunction. We reviewed all patients with FAV at our institution who initially underwent single ventricle palliation and subsequently BC, as this is likely the subset at high-risk for poor outcomes. Clinical, imaging, and surgical data were collected. Two of 7 patients (29%) died within 16 months of BC, and 1 patient has been listed for transplant. Diastolic dysfunction was common and progressive with median left ventricular end diastolic pressure of 12 mm Hg before BC, and increasing to 22 mm Hg for survivors at last follow-up. Left ventricular size was adequate with all patients reaching a left ventricular end diastolic volume (LVEDV) z score in the normal or elevated range. Presence and severity of residual valve lesions decreased over time secondary to a median of 6 interventions (range 3 to 10), either surgical or cath-based, performed for these 7 patients during the study period. In conclusion, clinical outcomes are concerning for this high-risk group. Diastolic dysfunction is persistent and progressive despite anatomic interventions and adequate left ventricular growth. The main contributing factor to poor outcomes may be intrinsic myocardial dysfunction and primordial pathology. Achievement of a BC after FAV may not be an appropriate measure of success.

Objectives To better understand the natural history and spectrum of fetal aortic stenosis (AS), we aimed to (1) determine the prenatal diagnosis rate of neonates with critical AS and a biventricular (BV) outcome, and (2) describe the findings at fetal echocardiography in patients diagnosed prenatally. Methods A multicenter, retrospective study was performed on neonates who presented with critical AS and who were discharged with a BV outcome from 2000 to 2013. The prenatal diagnosis rate was compared with that reported for hypoplastic left heart syndrome (HLHS). We reviewed fetal echocardiographic findings in patients who were diagnosed prenatally. Results In only 10 (8.5%) of 117 neonates with critical AS and a BV outcome was the diagnosis made prenatally, a rate significantly lower than that for HLHS in the contemporary era (82%; P

Fetal aortic stenosis (AS) imposes pressure load on the developing left ventricle (LV) and leads to derangements in myocardial structure and function via mechanisms that are not well characterized.We compared amniotic fluid NT-BNP and troponin levels in fetuses with AS prior to fetal valvuloplasty and controls. We estimated correlations between NT-BNP and fetal echo parameters and identify NT-BNP cutoff associated with biventricular outcome RESULTS: Median NT-BNP level was higher in fetal AS than controls (3858 vs 1737 pg/mL, P 0.012). By contrast, troponin levels were lower in fetal AS, with troponindetectable in 0/25 (0%) AS cases compared with 22/85 (26%) controls (P = 0.03). Of 25 fetal AS cases, 12 (48%) had biventricular outcome. Fetuses with NT-BNP 910 pg/mL were more likely to have biventricular (OR =10) compared with those ≥910 pg/mL (P = 0.045). Higher NT-BNP correlated with earlier gestational age and measures of larger left heart size.NT-BNP is elevated in fetal AS, suggesting that LV pressure load and increased wall stress lead to maladaptive stretch-related myocardial remodeling. Troponin is normal in mid-gestation fetal AS, suggesting that ischemia is not the primary factor in fetal response to LV pressure load.

The mortality and morbidity of fetal aortic stenosis (AS) depend on the degree of the hemodynamic effects of the stenosis, and left ventricular (LV) adaptation, development and function during fetal life. In the case of critical AS, the development of hydrops and death in utero are well recognized entities. A 23-week gestation fetus was diagnosed with critical severe AS, cardiomegaly, a dilated LV with very poor contractility, and mitral regurgitation. There was a reversal of flow in the aortic arch through the ductus arteriosis and a reversed a-wave in the ductus venosus on Doppler examination. The fetus had hydrops with ascites, and massive scalp, face and skin edema. Fetal amniocentesis was normal. Aortic valvuloplasty was performed under general anesthesia and echocardiographic guidance. Pericardial effusion was not observed after the procedure. However, LV function could not be ameliorated and continued to diminish. There was no cardiac activity in the fetus two hours after the intervention. Aortic valvuloplasty in utero for AS is technically feasible. Mortality is mainly associated with technical errors, LV function, and the degree of endofibroelastosis in the effected fetuses.

Aortic stenosis encompasses a spectrum of abnormality ranging from mild to critical forms. Antenatal diagnosis of aortic stenosis can be made in the full range of the spectrum, but it is the more severe cases that are dominant in the fetal series, as these are more easily detected during obstetric screening scans. The progressive nature of obstructive lesions detected in the fetus has been well described, and this type of progression was first described in a case of fetal aortic stenosis [1]. In this chapter, we discuss the echocardiographic features, natural history, and progression of fetal aortic stenosis in relation to the degree and timing of aortic obstruction.

Intrauterine dilation of critical fetal aortic stenosis (AS) and pulmonary stenosis or atresia has the potential to change the natural course of these congenital heart defects preventing progression to a single ventricle circulation. This article reviews the world experience in fetal cardiac interventions. In carefully selected cases, fetal cardiac surgery can reverse end-stage heart failure and can provide biventricular outcome postnatally in about two thirds of the cases with successful interventions.

Background— Aortic stenosis in the midgestation fetus with a normal-sized or dilated left ventricle predictably progresses to hypoplastic left heart syndrome when associated with certain physiological findings. Prenatal balloon aortic valvuloplasty may improve left heart growth and function, possibly preventing evolution to hypoplastic left heart syndrome. Methods and Results— Between March 2000 and October 2008, 70 fetuses underwent attempted aortic valvuloplasty for critical aortic stenosis with evolving hypoplastic left heart syndrome. We analyzed this experience to determine factors associated with procedural and postnatal outcome. The median gestational age at intervention was 23 weeks. The procedure was technically successful in 52 fetuses (74%). Relative to 21 untreated comparison fetuses, subsequent prenatal growth of the aortic and mitral valves, but not the left ventricle, was improved after intervention. Nine pregnancies (13%) did not reach a viable term or preterm birth. Seventeen patients had a biventricular circulation postnatally, 15 from birth. Larger left heart structures and higher left ventricular pressure at the time of intervention were associated with biventricular outcome. A multivariable threshold scoring system was able to discriminate fetuses with a biventricular outcome with 100% sensitivity and modest positive predictive value. Conclusions— Technically successful aortic valvuloplasty alters left heart valvar growth in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome and, in a subset of cases, appeared to contribute to a biventricular outcome after birth. Fetal aortic valvuloplasty carries a risk of fetal demise. Fetuses undergoing in utero aortic valvuloplasty with an unfavorable multivariable threshold score at the time of intervention are very unlikely to achieve a biventricular circulation postnatally.

Objective Severe aortic stenosis in the mid-gestation fetus can progress to hypoplastic left heart syndrome (HLHS). @ In-utero aortic valvuloplasty is an innovative therapy to promote left ventricular growth and function and potentially to prevent HLHS. This study evaluated the effects of mid-gestation fetal balloon aortic valvuloplasty on subsequent fetal left ventricular function and left heart Doppler characteristics. Methods We reviewed fetuses with aortic stenosis that underwent attempted in-utero aortic valvuloplasty between 2000 and 2006. Pre-intervention and the latest post-intervention fetal echocardiograms were analyzed to characterize changes in left heart function and Doppler characteristics in utero. Results Forty-two fetuses underwent attempted aortic valvuloplasty during the study period, 12 of which were excluded from analysis secondary to inadequate follow-up data, termination or fetal demise. Study fetuses (n = 30) underwent pre-intervention echocardiography at a median gestational age of 23 weeks, and were followed for a median of 66 ± 23 days post-intervention. In 26 fetuses, aortic valvuloplasty was technically successful. Among these 26, left heart physiology was abnormal pre-intervention and improved or normalized after intervention in most cases: biphasic mitral inflow was present in 5/25 (20%) cases pre-intervention and in 21/23 (91%) post-intervention (P < 0.001); moderate or severe mitral regurgitation was present in 14/26 (54%) cases pre-intervention and in 5/23 (22%) post-intervention (P = 0.02); bidirectional flow across the patent foramen ovale was present in 0/26 cases pre-intervention and in 6/25 (24%) post-intervention (P = 0.01); antegrade flow in the transverse arch was present in 0/25 cases pre-intervention and in 17/26 (65%) post-intervention (P < 0.001). The left ventricular ejection fraction increased from 19 ± 10% pre-intervention to 39 ± 14% post-intervention (P < 0.001). These changes were not observed in control fetuses (n = 18). Conclusion Fetal aortic valvuloplasty, when technically successful, improves left ventricular systolic function and left heart Doppler characteristics. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.

Background— Fetal aortic valvuloplasty may prevent progression of aortic stenosis (AS) to hypoplastic left heart syndrome (HLHS). Predicting which fetuses with AS will develop HLHS is essential to optimize patient selection for fetal intervention. The aim of this study was to define echocardiographic features associated with progression of midgestation fetal AS to HLHS. Methods and Results— Fetal echocardiograms were reviewed from 43 fetuses diagnosed with AS and normal left ventricular (LV) length at ≤30 weeks’ gestation. Of 23 live-born patients with available follow-up data, 17 had HLHS and 6 had a biventricular circulation. At the time of diagnosis, LV length, mitral valve, aortic valve, and ascending aortic diameter Z-scores did not differ between fetuses that ultimately developed HLHS and those that maintained a biventricular circulation postnatally. However, all of the fetuses that progressed to HLHS had retrograde flow in the transverse aortic arch (TAA), 88% had left-to-right flow across the foramen ovale, 91% had monophasic mitral inflow, and 94% had significant LV dysfunction. In contrast, all 6 fetuses with a biventricular circulation postnatally had antegrade flow in the TAA, biphasic mitral inflow, and normal LV function. With advancing gestation, growth arrest of left heart structures became evident in fetuses developing HLHS. Conclusions— In midgestation fetuses with AS and normal LV length, reversed flow in the TAA and foramen ovale, monophasic mitral inflow, and LV dysfunction are predictive of progression to HLHS. These physiological features may help refine patient selection for fetal intervention to prevent the progression of AS to HLHS.

Fetal hydrops of various etiologies can be associated with maternal mirror syndrome. The exact pathophysiology of this rare disorder remains unclear, yet it can result in significant maternal and fetal morbidity. The recent advances in prenatal diagnosis and therapeutic interventions have focused on altering the course of pathologies associated with an expected poor prognosis. Severe fetal aortic valve stenosis with its potential for hypoplastic left heart fit this category. We report a case of maternal mirror syndrome in a parturient following intrauterine therapy for severe fetal aortic stenosis and hydrops. Despite a technically successful intervention, the mother required emergency cesarean section. We review the few reports of mirror syndrome as well as the current approaches to fetal aortic stenosis. This case reinforces the need for in depth risk analysis prior to fetal interventions. It also emphasizes the advantage of earlier detection and therapy with fetal aortic stenosis since fetal hydrops carries a somber prognosis.

BACKGROUND: Fetal aortic valvuloplasty (FAV) has shown promise in averting the progression of fetal aortic stenosis to hypoplastic left heart syndrome. Altered loading conditions due to valvar disease, intrinsic endomyocardial abnormalities, and procedures that alter endomyocardial mechanics may place patients with biventricular circulation (BiV) after FAV at risk for abnormal LV remodeling and function. METHODS: Using the most recent echo data on BiV patients after technically successful FAV (n=34) we evaluated LV remodeling pattern, risk factors for pathologic LV remodeling, and the association between LV remodeling pattern and LV function. RESULTS: Median age at follow up was 4.7 years (range 1.0–12.5). Cardiac interventions were common. At latest follow-up, no patient had hypoplastic LV. Nineteen patients (55%) had dilated LV and 5 (16%) patients had severely dilated LV. LV remodeling patterns were: 12 (35%) normal ventricle, 11 (32%) mixed hypertrophy, 8 (24%) eccentric hypertrophy or remodeling, and 3 (9%) concentric hypertrophy. Univariate factors associated with pathologic LV remodeling were long-standing AR, ≥ 2 cardiac interventions, EFE resection, and aortic or mitral regurgitation ≥ moderate at most recent follow-up. In multivariate analysis only long-standing AR fraction remained associated with pathologic remodeling. Pathologic LV remodeling was associated with depressed ejection fraction, lower septal E,’ and higher E/E’. CONCLUSION: Pathologic LV remodeling, primarily eccentric or mixed hypertrophy, is common in BiV patients after FAV and is related to LV loading conditions imposed by valvar disease. Pathologic remodeling is associated with both systolic and diastolic dysfunction in this population.

Background: In fetuses with severe mid-gestational aortic stenosis, fetal aortic valvuloplasty (FAV) can promote left ventricular growth and function, and may prevent progression to hypoplastic left heart syndrome. Previous small studies suggest that post-intervention LVEF and the presence of

Background— Fetal aortic valvuloplasty can be performed for severe midgestation aortic stenosis in an attempt to prevent progression to hypoplastic left heart syndrome (HLHS). A subset of patients has achieved a biventricular (BV) circulation after fetal aortic valvuloplasty. The postnatal outcomes and survival of the BV patients, in comparison with those managed as HLHS, have not been reported. Methods and Results— We included 100 patients who underwent fetal aortic valvuloplasty for severe midgestation aortic stenosis with evolving HLHS from March 2000 to January 2013. Patients were categorized based on postnatal management as BV or HLHS. Clinical records were reviewed. Eighty-eight fetuses were live-born, and 38 had a BV circulation (31 from birth, 7 converted after initial univentricular palliation). Left-sided structures, namely aortic and mitral valve sizes and left ventricular volume, were significantly larger in the BV group at the time of birth ( P P =0.04). There was no cardiac mortality in patients with a BV circulation from birth. All but 1 of the BV patients required postnatal intervention; 42% underwent aortic or mitral valve replacement. On the most recent echocardiogram, the median left ventricular end-diastolic volume z score was +1.7 (range, −1.3 to +8.2), and 80% had normal ejection fraction. Conclusions— Short- and intermediate-term survival among patients who underwent fetal aortic valvuloplasty and achieved a BV circulation postnatally is encouraging. However, morbidity still exists, and ongoing assessment is warranted.

Fetal aortic balloon valvuloplasty (FAV) has shown promise in averting progression of midgestation aortic stenosis (AS) to hypoplastic left heart syndrome in a subset of patients. Patients who achieve biventricular circulation after FAV frequently have left ventricular (LV) diastolic dysfunction (DD). This study evaluates DD in fetuses with AS by comparing echocardiographic indices of LV diastolic function in fetuses underwent FAV (n = 20) with controls (n = 40) and evaluates for LV factors associated with DD in patients with FAV. We also compared pre-FAV and post-FAV DD variables (n = 16). Median gestational age (24 weeks, range 18 to 29 weeks) and fetal heart rate were similar between FAV and controls. Compared with controls, patients with FAV had universally abnormal LV diastolic parameters including fused mitral inflow E and A waves (p = 0.008), higher E velocity (p 0.001), shorter mitral inflow time (p = 0.001), lower LV lateral annulus E' (p0.001), septal E' (p = 0.003), and higher E/E' (p0.001) than controls. Patients with FAV had abnormal right ventricular mechanics with higher tricuspid inflow E velocity (p0.001) and shorter tricuspid inflow time (p = 0.03). Worse LV diastolic function (lower LV E') was associated with higher endocardial fibroelastosis grade (r = 0.74, p0.001), large LV volume (r = 0.55, p = 0.013), and sphericity (r = 0.58, p = 0.009) and with lower LV pressure by mitral regurgitation jet (r = -0.68, p0.001). Post-FAV, fewer patients had fused mitral inflow E and A than pre-FAV (p = 0.05) and septal E' was higher (=0.04). In conclusion, fetuses with midgestation AS have evidence of marked DD. Worse DD is associated with larger, more spherical LV, with more extensive endocardial fibroelastosis and lower LV pressure.

Prenatal alleviation of severe fetal aortic valve obstructions by percutaneous ultrasound-guided balloon valvuloplasty has been performed to improve the fate of affected fetuses. The purpose of this study was to analyze the current world experience of these procedures in human fetuses. Data from 12 human fetuses were available for analysis. The mean gestational age at intervention was 29.2 weeks (range 27 to 33). The mean time period between initial presentation and intervention was 3.3 weeks (range 3 days to 9 weeks). Technically successful balloon valvuloplasties were achieved in 7 fetuses, none of whom had an atretic valve. Only 1 of these fetuses remains alive today. Of the 5 remaining technical failures, 1 patient with severe aortic stenosis underwent successful postnatal intervention and remains alive. Six patients who survived prenatal intervention died from cardiac dysfunction or at surgery in the first days or weeks after delivery. Four fetuses died early within 24 hours after the procedure, 1 from a bleeding complication, 2 from persistent bradycardias, and 1 at valvotomy after emergency delivery. Thus, the early clinical experience of percutaneous ultrasound-guided fetal balloon valvuloplasty in human fetuses with severe aortic valve obstruction has been poor due to selection of severe cases, technical problems during the procedure, and high postnatal operative mortality in fetuses who survived gestation. Improved patient selection and technical modifications in interventional methods may hold promise to improve outcome in future cases.

Systematic evaluation of left ventricular (LV) endocardial fibroelastosis (EFE) in the fetus has not been reported. The role of EFE in the pre- and postnatal evolution of hypoplastic left heart disease, and the implications of EFE for outcomes after prenatal intervention for fetal aortic stenosis with evolving hypoplastic left heart syndrome have also not been determined. A 4-point grading system (0-3) was devised for the assessment of fetal LV echogenicity, which was presumed to be due to EFE. Two reviewers independently graded EFE on the preintervention echocardiograms of fetuses treated with in utero aortic valvuloplasty for evolving hypoplastic left heart syndrome from 2000 to 2008. Intra- and interobserver reproducibility was determined for the EFE grade and characterization of related echocardiographic features. The relations among EFE severity, other left heart anatomic and physiologic variables, and postintervention outcomes were analyzed. The assessment and grading of EFE was possible for both observers in all 74 fetuses studied. By consensus, the EFE severity was grade 1 in 31 patients, grade 2 in 32, and grade 3 in 11. Fetuses with mild (grade 1) EFE had significantly greater maximum instantaneous aortic stenosis gradients (e.g., higher LV pressures) and less globular LV geometry than patients with grade 2 or 3 EFE on preintervention echocardiogram. The severity of EFE was not associated with the size of the aortic valve or LV. From preintervention to late gestation, the time-indexed change in LV end-diastolic volume was significantly greater in fetuses with grade 1 EFE than those with more severe EFE. Incorporation of EFE severity into our previously published threshold score improved the sensitivity and positive predictive value for the postnatal biventricular outcomes. In conclusion, echocardiographic grading of EFE is possible, with reasonable intra- and interobserver reliability in midgestation fetuses with evolving hypoplastic left heart syndrome. EFE severity corresponded to some indexes of left heart size, geometry, and function and with the probability of a biventricular outcome postnatally. Additional experience and external validation of the EFE grading scoring system are necessary.

Children with hypoplastic left heart syndrome (HLHS) are at risk for neurodevelopmental dysfunction; prenatal factors may play a role in this predilection. Cerebral blood flow profiles are abnormal in fetuses with HLHS, raising the possibility that cerebral hemodynamics in utero may be related to neurodevelopmental abnormalities. Prenatal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is technically feasible and improves left heart hemodynamics. This study aimed to assess the effects of prenatal intervention on cerebral blood flow profiles and head circumference in fetuses with evolving HLHS. Seventy fetuses underwent prenatal aortic valvuloplasty for evolving HLHS (median 23 weeks gestation). Among 46 fetuses that had successful valvuloplasty and available data, middle cerebral artery (MCA) pulsatility (PI) and resistive (RI) indices were abnormal (Z-scores -1.7+/-1.1 and -2.2+/-1.4, p

Objective Natriuretic peptides, especially brain natriuretic peptide (BNP), have demonstrated great usefulness in pediatric and adult cardiology. We studied their usefulness, based on amniotic fluid concentrations, in an ovine model of fetal aortic stenosis and in response to fetal cardiac intervention. Study Design After their natural history was established with gestation (n = 18 fetuses), natriuretic peptide levels were measured in a fetal model of aortic stenosis (50-60 days; term, 148 days; n=9) and were correlated to the severity of fetal heart disease. Response to fetal cardiac intervention in 3 hydropic fetuses was also assessed. Significance was established with 2-sided paired t -tests at a probability value of Results Amniotic fluid BNP (but not atrial natriuretic peptide) concentrations were elevated significantly with aortic stenosis (181.9 ± 109.9 pg/mL vs 50.0 ± 40.5 pg/mL in control fetuses), especially if complicated with hydrops (283 ± 74.4 pg/mL), and were correlated positively with the severity of stenosis and left ventricle hypertrophy. In the 1 animal surviving fetal intervention, BNP levels normalized. Conclusion Amniotic fluid BNP concentrations correlate with the severity of fetal aortic stenosis.

Imaging of the fetal heart to diagnose congenital heart disease has become commonplace during the past 30 years, to the point that institutions such as the American College of Obstetrics and Gynecology, the American College of Radiology, and the American Institute of Ultrasound in Medicine have established, as a standard of care, routine screening for congenital heart disease in the scanning protocol of fetuses undergoing ultrasound study for any reason during the second or third trimester of pregnancy. Article p 1401 Until recently, the parents of fetuses diagnosed with congenital heart disease have had to face the limited but difficult decisions of continuation or termination of the pregnancy for these offspring and, when the pregnancy was continued, the decision of where, when, and how to deliver and whether to seek aggressive medical and surgical therapy during the neonatal period. More recently, however, the option of catheter intervention to alter the natural history of fetal aortic stenosis or pulmonary atresia has been offered at several medical centers.1–5 Although attempting to prevent the progression of aortic stenosis into hypoplastic left heart syndrome (HLHS) on its surface might appear to be an obvious choice, it should be noted that by engaging in fetal therapy, the pediatric cardiology community as a group is entering a field with complex and unique legal and ethical underpinnings that have been formulated during a period of more than 35 years. Unless the pediatric cardiology community takes note of the experiences of our colleagues in maternal-fetal medicine and pediatric surgery in the field of fetal intervention, it is likely that we and our patients will be doomed to revisit the errors of judgment that were made in well-intentioned efforts to treat fetal conditions such as diaphragmatic hernia,6–8 obstructive uropathy,9,10 and hydrocephaly.11–13 In those situations, frustration …

Objectives To describe technical aspects of successful fetal aortic valvuloplasty, with particular attention to balloon size. Study design We retrospectively reviewed all procedural records and echocardiograms pertaining to 26 attempts at fetal aortic valve dilation performed at a single center over a period of 4 years. We assessed the effect of valvuloplasty as determined by echocardiographic appearance at the time of intervention and in follow-up. Results In 20 of 26 fetuses who had technically successful aortic valve dilation (median balloon:annulus ratio=1.1), all had improved antegrade flow and 12 had at least mild regurgitation after dilation. Use of an oversized balloon was associated with the onset of moderate or severe aortic regurgitation, seen in 5 fetuses. This aortic regurgitation was well tolerated and improved through the remainder of gestation. Conclusions These data imply that fetal aortic valves can be dilated safely with larger balloons than are commonly used for postnatal dilation. The observation of spontaneous improvement in postdilation aortic regurgitation further suggests that fetal valve tissue behaves uniquely.

Background— Preventing the progression of fetal aortic stenosis (AS) to hypoplastic left heart syndrome (HLHS) requires identification of fetuses with salvageable left hearts who would progress to HLHS if left untreated, a successful in utero valvotomy, and demonstration that a successful valvotomy promotes left heart growth in utero. Fetuses meeting the first criterion are undefined, and previous reports of fetal AS dilation have not evaluated the impact of intervention on in utero growth of left heart structures. Methods and Results— We offered fetal AS dilation to 24 mothers whose fetuses had AS. At least 3 echocardiographers assigned a high probability that all 24 fetuses would progress to HLHS if left untreated. Twenty (21 to 29 weeks’ gestation) underwent attempted AS dilation, with technical success in 14. Ideal fetal positioning for cannula puncture site and course of the needle (with or without laparotomy) proved to be necessary for procedural success. Serial fetal echocardiograms after intervention demonstrated growth arrest of the left heart structures in unsuccessful cases and in those who declined the procedure, while ongoing left heart growth was seen in successful cases. Resumed left heart growth led to a 2-ventricle circulation at birth in 3 babies. Conclusions— Fetal echocardiography can identify midgestation fetuses with AS who are at high risk for developing HLHS. Timely and successful aortic valve dilation requires ideal fetal and cannula positioning, prevents left heart growth arrest, and may result in normal ventricular anatomy and function at birth.

Objective Valvuloplasty of the fetal aortic valve has the potential to prevent progression of critical aortic stenosis (AS) to hypoplastic left heart syndrome (HLHS). The aim of the study was to assess 24 aortic valvuloplasties regarding indications, success rate, procedure-related risks and outcome. Methods Between January 2001 and December 2009 we performed 24 aortic valvuloplasties in 23 fetuses with critical AS at a median gestational age of 26 + 4( range, 21 + 3t o 32+ 5) weeks by a transabdominal ultrasoundguided approach. Four fetuses had hydrops as a late sign of heart failure. Results In 16/24 procedures (66.7%) corresponding to 16/23 fetuses (69.6%) the procedures were technically successful, with one intrauterine death in this group. After an initial learning curve, success rate improved to 78.6% (11 of the last 14 interventions were successful). In 10 out of the 15 (66.7%) successfully-treated and liveborn fetuses a biventricular circulation could be achieved postnatally. All four fetuses with hydrops had successful interventions, hydrops disappearing within 5 weeks. In 8/24 interventions (33.3%) the aortic valve could not be treated successfully, with intrauterine fetal death in two of these cases. In one fetus a repeat procedure was successful. All surviving fetuses with unsuccessful (n = 5) or no (n = 5) procedure performed developed HLHS until delivery. Conclusions Fetal aortic valvuloplasty could be performed successfully in selected fetuses with critical AS and evolving HLHS, with a biventricular outcome in two thirds of the patients. Safety and success rate were dependent on patient selection and the level of experience of the whole interventional team. In fetuses with AS and hydrops, aortic valvuloplasty could reverse end-stage heart failure and hydrops and ensure fetal survival. Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.

OBJECTIVE: To document the growth of the left heart structures and outcome of fetuses with aortic stenosis. DESIGN: Retrospective echocardiographic and clinical study. SETTING: Tertiary centre for fetal cardiology. PATIENTS: 27 consecutive fetuses with aortic stenosis. MAIN OUTCOME MEASURES: Survival of affected fetuses. Measurement of left ventricular end diastolic volume (LVEDV), aortic root diameter, and ejection fraction. RESULTS: Before 25 weeks' gestation, the LVEDV was normal or increased in all cases. In six of eight fetuses studied sequentially, the LVEDV fell across normal centiles. Initial ejection fraction was reduced in 23 fetuses (88%). Before 28 weeks' gestation, the aortic root was normal in all but one case, but after 29 weeks, 11 of 13 fetuses had values below the 50th centile. In two fetuses prenatal aortic valvoplasty was attempted, 10 babies had postnatal interventions, and there were six survivors. Biventricular repair was attempted in eight cases, of whom five survived. A first stage Norwood operation was performed in three babies, of whom one survived. The four fetuses with the highest aortic root z scores had successful biventricular repair. The two fetuses with initially normal ejection fractions survived. Successful biventricular repair was achieved even where the LVEDV was below the 5th centile. CONCLUSIONS: In aortic stenosis diagnosed prenatally, failure of growth of the left ventricle and aortic root often occurs. The outcome of affected fetuses is better than previously reported. Prenatal echocardiography may assist selection of suitable candidates for biventricular versus Norwood repair.

Because they had irreversible damage to the left ventricular myocardium none of 12 patients with critical aortic stenosis diagnosed prenatally survived after postnatal treatment. This experience prompted three attempts at intrauterine balloon dilatation of the aortic valve in two fetuses with this condition. On each attempt the balloon catheter was successfully delivered to the left ventricle. In the first fetus the aortic valve was not crossed and the fetus died the next day. In the second fetus the balloon was correctly positioned across the aortic valve and inflated in the valve ring. After delivery, a further balloon angioplasty was performed; this relieved the stenosis but the patient died five weeks later from persisting left ventricular dysfunction related to endocardial fibroelastosis. Balloon angioplasty is feasible in fetal life but the prognosis depends on the ability of the relief of stenosis to limit, prevent, or allow regression of left ventricular damage before delivery.

Hydrops fetalis is the final common hemodynamic pathway for a variety of pathological states in the fetus, including high output states associated with fetal anemia or arterio-venous fistulas and abnormalities of both cardiac structure and rhythm. Hydrops fetalis secondary to cardiovascular decompensation is usually accompanied by elevations in fetal systemic venous pressure as evidenced by alterations in venous Doppler waveforms. We present two cases of severe fetal aortic stenosis with left ventricular fibroelastosis and mitral regurgitation and in utero closure or stenosis of the foramen ovale, with severe hydrops fetalis, despite normal systemic venous Doppler flow profiles. Both cases demonstrated markedly abnormal fetal pulmonary venous Doppler waveforms and after birth, both infants were hypoalbuminemic. The presence of normal systemic venous Doppler waveforms in fetuses with severe hydrops fetalis and structural cardiac disease challenges our understanding of the etiology of this pathological state. These cases have led us to reconsider the presumed etiology of cardiogenic hydrops fetalis in fetuses with severely impaired left ventricular pump function and secondary mitral regurgitation. We hypothesize that elevated pulmonary venous pressure, with only mildly increased central venous pressure, may negatively impact pulmonary lymphatic flow, decrease serum oncotic pressure due to loss of protein-rich fluid in the pulmonary interstitium, increase venous hydrostatic pressure, and lead to hydrops fetalis.