Early Diagnosis of Tuberous Sclerosis Complex: Prenatal Diagnosis.

BACKGROUND AND PURPOSE: Strong emphasis has been placed recently on early (4 postnatal months) detection of tuberous sclerosis complex and the introduction of antiepileptic treatment before seizure onset. This objective can be achieved prenatally: Cardiac rhabdomyomas and the major diagnostic tuberous sclerosis complex sign are detected during fetal ultrasound, and prenatal MR imaging allows detection of cerebral major manifestations: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. MATERIALS AND METHODS: We retrospectively reviewed 50 fetuses with ultrasound-detected cardiac tumors at 19-36 gestational weeks (median, 31 weeks). MR imaging with the use of 1.5T scanners was performed at 24-37 gestational weeks (median, 34 weeks). RESULTS: In 11 fetuses (22%), cardiac tumors remained the only criterion. In remaining 39 fetuses (78%), MR imaging revealed a prenatal diagnosis of tuberous sclerosis complex, having shown an additional 1-3 major criteria: subependymal nodules in all cases (39/39 = 100.0%), subependymal giant cell astrocytomas in 6 (6/39 = 15.4%), and cortical tubers in 24 (24/39 = 61.5%). Radial migration lines and cerebellar tuber, not published so far, were shown in 1 case each. CONCLUSIONS: A schedule of proper care of children with tuberous sclerosis complex can be established during the perinatal period due to education of women to report for mandatory ultrasound examinations during pregnancy, the good quality of ultrasound, and referral to MR imaging if a cardiac tumor is depicted on ultrasound. Gynecologists and pediatric cardiologists performing fetal ultrasound and radiologists performing prenatal MR imaging are a key to early diagnosis of tuberous sclerosis complex in many cases.

Cerebroplacental hemodynamics in fetuses with transposition of the great arteries and usefulness in predicting neonatal condition.

OBJECTIVES: Literature on cerebroplacental hemodynamics in fetuses with transposition of the great arteries (TGA) is scarce and provides conflicting results regarding the presence of a brain-sparing effect. The aims of this study were to examine Doppler parameters in the middle cerebral artery (MCA) and umbilical artery (UA) in a large cohort of fetuses with TGA, and to assess their possible utility in predicting the need for urgent balloon atrial septostomy (BAS) in the neonate. METHODS: This was a retrospective observational study of fetuses diagnosed with TGA between 2008 and 2022 and an age-matched cohort of normal fetuses, conducted in a single tertiary fetal cardiology center. Medical records and echocardiographic examinations were reviewed to collect demographic, sonographic and follow-up data. Selected Doppler parameters were compared between fetuses with TGA and normal fetuses, as well as between TGA fetuses with and those without an associated ventricular septal defect (VSD), to assess the impact of this congenital heart defect on cerebroplacental circulation. Additionally, Doppler indices in patients with a restrictive foramen ovale (FO) were analyzed to identify potential predictors of the need for urgent BAS. RESULTS: A total of 541 examinations of 159 fetuses with TGA performed between 19 and 40 weeks' gestation and 1300 examinations of 1215 age-matched normal fetuses were included in the study. MCA pulsatility index (PI) and UA-PI followed expected trends throughout pregnancy, with slightly higher values observed in TGA fetuses, albeit within the limits for the normal population. Cerebroplacental ratio (CPR) values were similar in normal and TGA fetuses. The presence of a small VSD did not have a clinically significant impact on Doppler parameters. Peak systolic velocity (PSV) in the MCA increased gradually after 35 weeks' gestation, especially in fetuses that did not develop restriction of the FO after birth. MCA-PSV values below 1.16 multiples of the median measured at 38 weeks or later predicted the need for urgent BAS with 81.4% sensitivity and 52.4% specificity. CONCLUSIONS: MCA-PI, UA-PI and CPR values in fetuses with TGA usually fall within normal limits throughout pregnancy. The presence of a small VSD does not affect the Doppler parameters significantly. MCA-PSV increases in TGA fetuses after 35 weeks, and its value measured at the last prenatal examination (ideally after 37 weeks) may serve as an additional predictive factor for the need for urgent BAS. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

4D imaging of fetal right ventricle-feasibility study and a review of the literature.

Functional analysis of the fetal cardiovascular system is crucial for the assessment of fetal condition. Evaluation of the right ventricle with standard 2D echocardiography is challenging due to its complex geometry and irregular muscle fibers arrangement. Software package TOMTEC 4D RV-Function is an analysis tool which allows assessment of right ventricular function based on volumetric measurements and myocardial deformation. The aim of this study was to determine the feasibility of this method in fetal echocardiography. The retrospective study was conducted in the high-flow Referral Center for Fetal Cardiology. We recorded 4D echocardiographic sequences of 46 fetuses with normal hearts. Following parameters were calculated: end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF), right ventricle longitudinal free-wall (RVLS free-wall) and septal strain (RVLS septum). Tei index was calculated as a standard measure or RV function for comparison. 4D assessment was feasible in 38 out of 46 fetuses (83%). RV volumetric parameters-EDV, ESV and SV-increased exponentially with gestational age. Functional parameters-RV Tei index, EF and strains-were independent of gestational age. Mean EF was 45.2% (± 6%), RV free-wall strain was - 21.2% and RV septal strain was - 21.5%. There was a statistically significant correlation between septal and free-wall strains (r = 0.51, p = 0.001) as well as between EF and RV free-wall strain (r = - 0.41, p = 0.011). 4D RV assessment is feasible in most fetuses. Its clinical application should be further investigated in larger prospective studies.

Fetal hemodynamic response to aortic valvuloplasty and postnatal outcome: a European multicenter study.

OBJECTIVE: Fetal aortic stenosis may progress to hypoplastic left heart syndrome. Fetal valvuloplasty (FV) has been proposed to improve left heart hemodynamics 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 ≤ 0.01). CONCLUSIONS: We report improvements in fetal hemodynamics and preservation of left heart growth following successful FV compared with NH. While the proportion of those achieving a BV circulation outcome was similar in both cohorts, FV survivors showed improved survival independent of final circulation to 10 years' follow-up. However, FV is associated with a 10% procedure-related loss and increased prematurity compared with the NH cohort, and therefore the risk-to-benefit ratio remains uncertain. We recommend a carefully designed trial incorporating appropriate and integrated fetal and postnatal management strategies to account for center-specific practices, so that the benefits achieved by fetal therapy vs surgical strategy can be demonstrated clearly. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Natural history of 107 cases of fetal aortic stenosis from a European multicenter retrospective study.

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. Of newborns with intention-to-treat, 69/85 (81%) survived ≥ 30 days. Survival at median 6 years was superior in cases with BV circulation (P = 0.041). Those with a postnatal UV circulation showed a trend towards smaller aortic valve diameters at first scan than did the BV cohort (P = 0.076), but aortic valve growth velocities were similar in both cohorts to term. In contrast, the mitral valve diameter was significantly smaller at first scan in those with postnatal UV outcomes (P = 0.004) and its growth velocity (P = 0.008), in common with the left ventricular inlet length (P = 0.004) and width (P = 0.002), were reduced significantly by term in fetuses with UV compared with BV outcome. Fetal data, recorded before 30 completed gestational weeks, from 70 treated neonates were evaluated to identify emerging HLHS. Forty-four had moderate or severe left ventricular depression and 38 of these had retrograde flow in the aortic arch and two had left-to-right flow at atrial level and reversed a-waves in the pulmonary veins. Thus 40 neonates met the criteria for emerging HLHS and BV circulation was documented in 13 (33%). Of these 40 cases, 12 (30%) had a threshold score of 4 or 5, of which five (42%) had BV circulation without fetal intervention. CONCLUSIONS: The natural history in our cohort of fetuses with aortic stenosis and known outcomes shows that a substantial proportion of fetuses meeting the criteria for emerging HLHS, with or without favorable selection criteria for FV, had a sustained BV circulation without fetal intervention. This indicates that further work is needed to refine the selection criteria to offer appropriate therapy to fetuses with aortic stenosis. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fetal aortic valvuloplasty: investigating institutional bias in surgical decision-making.

OBJECTIVES: Fetal aortic valvuloplasty may prevent the progression of aortic stenosis to hypoplastic left heart syndrome and allow biventricular rather than univentricular postnatal treatment. This study aimed to investigate whether blinded simulation of a multidisciplinary team approach aids interpretation of multicenter data to uncover institutional bias in postnatal decision-making following fetal cardiac intervention for aortic stenosis. METHODS: The study included 109 cases of prenatally diagnosed aortic stenosis from 13 European countries, of which 32 had undergone fetal cardiac intervention. The multidisciplinary team, blinded to fetal cardiac intervention, institutional location and postnatal treatment, retrospectively assigned a surgical pathway (biventricular or univentricular) based on a review of recorded postnatal imaging and clinical characteristics. The team's decisions were the numerical consensus of silent voting, with case review when a decision was split. Funnel plots showing concordance between the multidisciplinary team and the local team's surgical choice (first pathway) and with outcome (final pathway) were created. RESULTS: In 105 cases the multidisciplinary team reached a consensus decision regarding the surgical pathway, with no decision in four cases because the available imaging records were inadequate. Blinded multidisciplinary team consensus for the first pathway matched the decision of the surgical center in 93/105 (89%) cases, with no difference in agreement between those that had undergone successful fetal cardiac intervention (n = 32) and no (n = 74) or unsuccessful (n = 3) valvuloplasty (no fetal cardiac intervention) (κ = 0.73 (95% CI, 0.38-1.00) vs 0.74 (95% CI, 0.51-0.96)). However, funnel plots comparing multidisciplinary team individual decisions with those of the local teams displayed more discordance (meaning biventricular-univentricular conversion) for the final surgical pathway following fetal cardiac intervention than they did for cases without such intervention (36/74 vs 34/130; P = 0.002), and identified one outlying center. CONCLUSIONS: The use of a blinded multidisciplinary team to simulate decision-making and presentation of data in funnel plots may assist in the interpretation of data submitted to multicenter studies and permit the identification of outliers for further investigation. In the case of aortic stenosis, a high level of agreement was observed between the multidisciplinary team and the surgical centers, but one outlying center was identified.

Brain MRI in fetuses with cardiac tumours.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder which affects the skin, brain, heart and other organs. It is caused by mutations of two genes: TSC1 (on chromosome 9q34) or TSC2 (on 16p13.3). 70% of cases are sporadic with new mutations. This study aimed to highlight the utility of prenatal MRI as an adjunct imaging modality in the diagnosis and prognosis of tuberous sclerosis complex. Prenatal ultrasound and magnetic resonance imaging were performed in seven fetuses at a gestational age of 30, 32, 34 and 35 weeks using a 1.5 T MRI scanner. SSFSE,T2- and FGRE/T1-weighted images were obtained in axial, coronal and sagittal planes. Postnatal MRI was performed in two cases. Intracardiac tumors (rhabdomyomas) were revealed on ultrasound in all fetuses. On sonographic examination the brain tissue appeared normal in all cases. Brain MRI revealed focal low-signal-intensity lesions, localized along the walls of the lateral ventricles of five fetuses. Another hypointense lesion was seen at the grey/white matter junction in one case. Brain MRI of two fetuses was normal. The diagnosis of TSC was established in five cases. Postnatal MRI in two cases confirmed prenatal findings. MRI allows more complete evaluation of the fetus and helps to determine the diagnosis and prognosis in cases of TSC. The use of prenatal MR imaging in addition to prenatal sonography has the potential to improve genetic counseling and prenatal diagnosis of patients with tuberous sclerosis.

Successful surgical treatment of a neonate with prenatal diagnosis of severe Ebstein's anomaly.

We present a case of a patient with a severe form of Ebstein's anomaly diagnosed in a 36th week of gestation through prenatal echocardiographic evaluation. The emergency surgery consisted of closure of the tricuspid valve and creation of a residual atriventricular communication, enlargement of interatrial communication, closure of the pulmonary artery, and construction of an aortopulmonary shunt. Subsequently, the patient underwent the hemiFontan and Fontan operation. We conclude that prenatal echocardiographic diagnosis is crucial for the survival of children with a severe form of Ebstein's anomaly, which is a neonatal emergency and requires prompt decision mating to initiate surgical management.

Adenosine triphosphate for cardioversion of supraventricular tachycardia in two hydropic fetuses.

OBJECTIVE: We performed a retrospective study to check the effectiveness of adenosine triphosphate (Striadyne) for cardioversion of fetal supraventricular tachycardia (SVT) and to evaluate neonatal outcome after prenatal treatment of severe SVT with fetal hydrops. METHODS: Two hydropic fetuses with SVT were treated with Striadyne injection into the umbilical vein, as an additional treatment to the digoxin given intravenously to the mother. Both fetuses were in severe condition, with ultrasound, Doppler and laboratory signs of fetal distress and congestive heart failure. RESULTS: Sinus rhythm was obtained in both cases for different periods of time, without side effects of Striadyne. The children survived. There were severe cardiac and neurologic problems after delivery. CONCLUSIONS: Striadyne was an effective drug in converting SVT to the sinus rhythm in hydropic fetuses. Digoxin was useless in these fetuses in spite of the therapeutic level which was obtained in both mothers. We suppose that fetal SVT causing fetal hydrops could be the reason of brain damage, and intensive antiarrhythmic treatment seemed to be necessary.

Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders--clinical and echocardiographic findings in 64 patients.

Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. CONCLUSIONS; Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive.

The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds.

An increased incidence of colorectal cancer has been observed in breast and breast-ovarian cancer syndrome families, including those of Ashkenazi origin. Recently, a germ-line missense mutation in the APC gene, I1307K, was identified that may indirectly cause colorectal cancer in Ashkenazi Jews. To determine whether the excess of colon cancer in some breast-ovarian cancer families is related to the I1307K mutation, we evaluated 264 Ashkenazi Jews from 158 families. Most of these individuals had either a personal or a family history of breast and/or ovarian cancer, and 19.3% (51 of 264) carried one of the recurrent BRCA1 (185delAG or 5382 insC) or BRCA2 (6174delT) mutations. We detected the APC I1307K mutation in 7% (11 of 158) of the Ashkenazi Jewish families and in 4.5% (12 of 264) of the individuals participating in these studies. Of the families studied, 26.6% (42 of 158) had at least one case of colorectal cancer in a first-, second-, or third-degree relative of the proband. Significantly, of the 12 individuals who possessed the I1307K mutation, none was diagnosed with colorectal cancer and none had a known first-, second-, or third-degree relative diagnosed with colon cancer. The results suggest that factors other than the I1307K mutation contribute to the increased incidence of colon cancer in Ashkenazi breast-ovarian cancer families. Our results emphasize that only a subset of Ashkenazi Jewish individuals with a family history of colorectal cancer should be viewed as candidates for genetic susceptibility testing for the I1307K APC mutation.