Placental extracellular vesicles promote cardiomyocyte maturation and fetal heart development.

Congenital heart defects are leading causes of neonatal mortality and are often associated with placental abnormalities, but mechanisms linking placenta and heart development are poorly understood. Herein, we investigated a potential signaling network connecting the placenta and nascent heart in mice. We found that fetal hearts exposed to media conditioned by placental tissue or differentiated wild-type trophoblast stem (TS) cells, but not undifferentiated TS cells, showed increased heart rate and epicardial cell outgrowth. This effect was not observed when hearts were exposed to media from TS cells lacking OVO-Like 2, a transcription factor required for trophoblast differentiation and placental development. Trophoblasts released abundant extracellular vesicles into media, and these vesicles were sufficient to mediate cardio-promoting effects. Our findings provide a potential mechanism whereby the placenta communicates with the fetal heart to promote cardiac morphogenesis, and offers insight into the link between poor placentation and a higher incidence of heart defects.

Single-cell RNA sequencing reveals the gene expression profile and cellular communication in human fetal heart development.

The heart is the central organ of the circulatory system, and its proper development is vital to maintain human life. As fetal heart development is complex and poorly understood, we use single-cell RNA sequencing to profile the gene expression landscapes of human fetal hearts from the four-time points: 8, 10, 11, 17 gestational weeks (GW8, GW10, GW11, GW17), and identified 11 major types of cells: erythroid cells, fibroblasts, heart endothelial cells, ventricular cardiomyocytes, atrial cardiomyocytes, macrophage, DCs, smooth muscle, pericytes, neural cells, schwann cells. In addition, we identified a series of differentially expressed genes and signaling pathways in each cell type between different gestational weeks. Notably, we found that ANNEXIN, MIF, PTN, GRN signalling pathways were simple and fewer intercellular connections in GW8, however, they were significantly more complex and had more intercellular communication in GW10, GW11, and GW17. Notably, the interaction strength of OSM signalling pathways was gradually decreased during this period of time (from GW8 to GW17). Together, in this study, we presented a comprehensive and clear description of the differentiation processes of all the main cell types in the human fetal hearts, which may provide information and reference data for heart regeneration and heart disease treatment.

Isolated non-immune-mediated second-degree atrioventricular block in the fetus: natural history and predictive factors for spontaneous recovery.

OBJECTIVES: To determine the clinical course of fetal isolated non-immune-mediated second-degree atrioventricular block (AVB) and the factors associated with spontaneous recovery in these cases. METHODS: Fetuses with isolated non-immune-mediated second-degree AVB were recruited prospectively between 2014 and 2022. These fetuses were divided into two groups: those which recovered spontaneously and those which did not. Maternal and fetal characteristics and intrauterine and postnatal outcomes were compared between the two groups. RESULTS: The study cohort included 20 fetuses with isolated non-immune-mediated second-degree AVB, diagnosed at a median gestational age of 22.0 (range, 17.0-35.0) weeks. In 12 fetuses, 1:1 atrioventricular conduction was restored spontaneously in utero and there was no recurrence during the postnatal follow-up period. In the remaining eight fetuses, second-degree AVB was maintained and, in six of these, the pregnancy was terminated on parental request. Of the two liveborn children who had persistent second-degree AVB prenatally, one had progressed to complete AVB at the latest follow-up, at the age of 34 months, but was asymptomatic, without heart enlargement or dysfunction. The other child progressed to complete AVB after delivery and was diagnosed with type-2 long QT syndrome. This infant died aged 2 months. Fetuses in the group that recovered spontaneously had earlier gestational age at diagnosis (median, 20.0 (range, 17.0-26.0) vs 24.5 (range, 18.0-35.0) weeks; P = 0.004) and higher atrial rate at diagnosis (median, 147 (range, 130-160) vs 138 (range, 125-149) bpm; P = 0.006) in comparison with the group that did not recover spontaneously. The best cut-off values for prediction of failure to recover spontaneously were 22.5 weeks' gestational age at diagnosis and 144 bpm atrial rate at diagnosis, with sensitivities of 87.5% and 75.0%, respectively, and specificities of 92.0% and 87.5%, respectively. CONCLUSIONS: The outcome of 60% of fetuses with isolated non-immune-mediated second-degree AVB was favorable. Earlier gestational age and higher atrial rate at diagnosis were associated with spontaneous reversion to normal sinus rhythm. Prenatal genetic testing should be performed in cases with persistent AVB, to exclude heritable disorders including long QT syndrome. These findings provide important information for clinical management and prenatal counseling in these cases. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of Left Ventricular Stroke Volume in 2nd- and 3rd-Trimester Fetuses Measured by the Product of VTI and Aortic Annular Area With That Assessed by Simpson's Single-Plane Rule Using the STE Technique.

OBJECTIVES: The aim of the study was to compare left ventricle stroke volume in healthy, eutrophic fetuses in the 2nd and 3rd trimesters evaluated using the velocity time integral and aortic annulus area with left ventricular stroke volume measured using Simpson's single-plane rule and to determine the discrepancy equation. METHODS: The study included 354 fetuses. In each fetus, during the same examination, simultaneous assessment of stroke volume was performed by pulsed-wave Doppler using the product of the velocity time integral and aortic annulus area and by the fetalHQ® software using Simpson's single-plane rule. The Mann-Whitney U test was used to compare the "product-derived" stroke volume and stroke volume using fetalHQ® software values in the 2nd and 3rd trimesters separately. The agreement between the two methods were verified using Bland-Altman analysis. A linear regression model was used to obtain the discrepancy equation. RESULTS: In the 2nd trimester, the mean percentage difference between both the techniques showed that the stroke volume values determined using pulsed-wave Doppler were, on average, 88% higher than the stroke volume values determined using fetalHQ®. The upper limit of agreement between the compared techniques was approximately 146% and the lower limit of agreement was equal to 29.6%. In the 3rd trimester, the results indicated that the stroke volume values determined using pulsed-wave Doppler were, on average, 76% higher than the stroke volume values determined using fetalHQ®. The upper limit of agreement between the compared techniques was approximately 129% and the lower limit of agreement was 23%. Based on the results of the linear regression models, discrepancy formulas of the stroke volume values were obtained. The equations to calculate the predicted mean and standard deviations were used to compute the reference intervals for the mean, 5th and 95th centiles. CONCLUSION: The calculation of left ventricular stroke volume using pulsed Doppler has higher result in relation to stroke volume determined using Simpson's rule significantly. The aortic annulus area showed a higher correlation regarding stroke volume than the velocity time integral in both the 2nd and 3rd trimesters. Stroke volume increased with the increase in aortic annulus area, whereas the velocity time integral remained relatively constant. The retrospective analysis of the collected material enabled the determination of the discrepancy equation.

Role of artificial-intelligence-assisted automated cardiac biometrics in prenatal screening for coarctation of aorta.

OBJECTIVE: Although remarkable strides have been made in fetal medicine and the prenatal diagnosis of congenital heart disease, around 60% of newborns with isolated coarctation of the aorta (CoA) are not identified prior to birth. The prenatal detection of CoA has been shown to have a notable impact on survival rates of affected infants. To this end, implementation of artificial intelligence (AI) in fetal ultrasound may represent a groundbreaking advance. We aimed to investigate whether the use of automated cardiac biometric measurements with AI during the 18-22-week anomaly scan would enhance the identification of fetuses that are at risk of developing CoA. METHODS: We developed an AI model capable of identifying standard cardiac planes and conducting automated cardiac biometric measurements. Our data consisted of pregnancy ultrasound image and outcome data spanning from 2008 to 2018 and collected from four distinct regions in Denmark. Cases with a postnatal diagnosis of CoA were paired with healthy controls in a ratio of 1:100 and matched for gestational age within 2 days. Cardiac biometrics obtained from the four-chamber and three-vessel views were included in a logistic regression-based prediction model. To assess its predictive capabilities, we assessed sensitivity and specificity on receiver-operating-characteristics (ROC) curves. RESULTS: At the 18-22-week scan, the right ventricle (RV) area and length, left ventricle (LV) diameter and the ratios of RV/LV areas and main pulmonary artery/ascending aorta diameters showed significant differences, with Z-scores above 0.7, when comparing subjects with a postnatal diagnosis of CoA (n = 73) and healthy controls (n = 7300). Using logistic regression and backward feature selection, our prediction model had an area under the ROC curve of 0.96 and a specificity of 88.9% at a sensitivity of 90.4%. CONCLUSIONS: The integration of AI technology with automated cardiac biometric measurements obtained during the 18-22-week anomaly scan has the potential to enhance substantially the performance of screening for fetal CoA and subsequently the detection rate of CoA. Future research should clarify how AI technology can be used to aid in the screening and detection of congenital heart anomalies to improve neonatal outcomes. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Anatomical and physiological diagnostic discrepancies in fetuses with single-ventricle congenital heart disease in a contemporary cohort.

OBJECTIVE: Image quality of fetal echocardiography (FE) has improved in the recent era, but few recent studies have reported the accuracy of FE, specifically in single ventricle (SV) congenital heart disease (CHD). This study aimed to assess the ability of FE to correctly predict SV-CHD postnatal anatomy and physiology in a contemporary cohort. METHODS: The contemporary clinical reports of patients with SV-CHD, in which FE was performed between July 2017 and July 2021, were compared with postnatal echocardiograms from a formal quality assurance program. SV fetuses were grouped by anatomical subtype. Diagnostic errors were designated as major if the error would have caused significant alteration in parental counseling or postnatal management. The remaining errors were classified as minor. Physiological discrepancies, including prostaglandin-E (PGE) dependency, atrioventricular valve regurgitation (AVVR), pulmonary venous obstruction and restrictive atrial septum (RAS), were assessed by chart review of the postnatal course. RESULTS: A total of 119 subjects were analyzed. SV subtypes in the cohort included hypoplastic left heart syndrome (HLHS) (n = 68), tricuspid atresia (n = 16), double-inlet left ventricle (n = 12), unbalanced atrioventricular canal (UAVC) (n = 11), heterotaxy (n = 9) and other (n = 3). The rate of major anatomical and physiological errors was low (n = 6 (5.0%)). A higher proportion of minor errors was noted in HLHS and tricuspid atresia, but the differences were not statistically significant. Physiological discrepancies were uncommon, with three major discrepancies, including underestimation of the degree of venous obstruction in one non-HLHS fetus with total anomalous pulmonary venous return, overestimation of RAS in one HLHS fetus and incorrect prediction of PGE dependency in one case false-negative for pulmonary blood flow. No discrepancy in degree of AVVR or RAS affected postnatal care. Minor physiological discrepancies included two false-positive predictions of PGE dependency with one false-positive for ductal-dependent systemic flow and one false-positive for pulmonary blood flow. CONCLUSIONS: In this contemporary review of FE at our center, there was high accuracy in describing anatomical and physiological findings in SV-CHD. Major physiological discrepancies were uncommon but included important cases of false-negative prediction of PGE dependency and underestimation of obstruction of total anomalous pulmonary venous return. These data can inform more accurate counseling of families with SV-CHD fetuses and guide diagnostic improvement efforts. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester ultrasound detection of fetal heart anomalies: systematic review and meta-analysis.

OBJECTIVES: To determine the diagnostic accuracy of ultrasound at 11-14 weeks' gestation in the detection of fetal cardiac abnormalities and to evaluate factors that impact the detection rate. METHODS: This was a systematic review of studies evaluating the diagnostic accuracy of ultrasound in the detection of fetal cardiac anomalies at 11-14 weeks' gestation, performed by two independent reviewers. An electronic search of four databases (MEDLINE, EMBASE, Web of Science Core Collection and The Cochrane Library) was conducted for studies published between January 1998 and July 2020. Prospective and retrospective studies evaluating pregnancies at any prior level of risk and in any healthcare setting were eligible for inclusion. The reference standard used was the detection of a cardiac abnormality on postnatal or postmortem examination. Data were extracted from the included studies to populate 2 × 2 tables. Meta-analysis was performed using a random-effects model in order to determine the performance of first-trimester ultrasound in the detection of major cardiac abnormalities overall and of individual types of cardiac abnormality. Data were analyzed separately for high-risk and non-high-risk populations. Preplanned secondary analyses were conducted in order to assess factors that may impact screening performance, including the imaging protocol used for cardiac assessment (including the use of color-flow Doppler), ultrasound modality, year of publication and the index of sonographer suspicion at the time of the scan. Risk of bias and quality assessment were undertaken for all included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTS: The electronic search yielded 4108 citations. Following review of titles and abstracts, 223 publications underwent full-text review, of which 63 studies, reporting on 328 262 fetuses, were selected for inclusion in the meta-analysis. In the non-high-risk population (45 studies, 306 872 fetuses), 1445 major cardiac anomalies were identified (prevalence, 0.41% (95% CI, 0.39-0.43%)). Of these, 767 were detected on first-trimester ultrasound examination of the heart and 678 were not detected. First-trimester ultrasound had a pooled sensitivity of 55.80% (95% CI, 45.87-65.50%), specificity of 99.98% (95% CI, 99.97-99.99%) and positive predictive value of 94.85% (95% CI, 91.63-97.32%) in the non-high-risk population. The cases diagnosed in the first trimester represented 63.67% (95% CI, 54.35-72.49%) of all antenatally diagnosed major cardiac abnormalities in the non-high-risk population. In the high-risk population (18 studies, 21 390 fetuses), 480 major cardiac anomalies were identified (prevalence, 1.36% (95% CI, 1.20-1.52%)). Of these, 338 were detected on first-trimester ultrasound examination and 142 were not detected. First-trimester ultrasound had a pooled sensitivity of 67.74% (95% CI, 55.25-79.06%), specificity of 99.75% (95% CI, 99.47-99.92%) and positive predictive value of 94.22% (95% CI, 90.22-97.22%) in the high-risk population. The cases diagnosed in the first trimester represented 79.86% (95% CI, 69.89-88.25%) of all antenatally diagnosed major cardiac abnormalities in the high-risk population. The imaging protocol used for examination was found to have an important impact on screening performance in both populations (P < 0.0001), with a significantly higher detection rate observed in studies using at least one outflow-tract view or color-flow Doppler imaging (both P < 0.0001). Different types of cardiac anomaly were not equally amenable to detection on first-trimester ultrasound. CONCLUSIONS: First-trimester ultrasound examination of the fetal heart allows identification of over half of fetuses affected by major cardiac pathology. Future first-trimester screening programs should follow structured anatomical assessment protocols and consider the introduction of outflow-tract views and color-flow Doppler imaging, as this would improve detection rates of fetal cardiac pathology. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Abnormal Extracardiac Development in Fetuses With Congenital Heart Disease.

BACKGROUND: Knowledge about extracardiac anomalies (ECA) in fetal congenital heart disease (CHD) can improve our understanding of the developmental origins of various outcomes in these infants. The prevalence and spectrum of ECA, including structural brain anomalies (SBA), on magnetic resonance imaging (MRI) in fetuses with different types of CHD and at different gestational ages, is unknown. OBJECTIVES: The purpose of this study was to evaluate ECA rates and types on MRI in fetuses with different types of CHD and across gestation. METHODS: A total of 429 consecutive fetuses with CHD and MRI between 17 and 38 gestational weeks were evaluated. ECA and SBA rates were assessed for each type of CHD and classified by gestational age (<25 or ≥25 weeks) at MRI. RESULTS: Of all 429 fetuses with CHD, 243 (56.6%) had ECA on MRI, and 109 (25.4%) had SBA. Among the 191 fetuses with normal genetic testing results, the ECA rate was 54.5% and the SBA rate 19.4%. Besides SBA, extrafetal (21.2%) and urogenital anomalies (10.7%) were the most prevalent ECA on MRI in all types of CHD. Predominant SBA were anomalies of hindbrain-midbrain (11.0% of all CHD), dorsal prosencephalon (10.0%) development, and abnormal cerebrospinal fluid spaces (10.5%). There was no difference in the prevalence or pattern of ECA between early (<25 weeks; 45.7%) and late (≥25 weeks; 54.3%) fetal MRI. CONCLUSIONS: ECA and SBA rates on fetal MRI are high across all types of CHD studied, and ECA as well as SBA are already present from midgestation onward.

The high platelet counts as predictor for early foetal demise.

Objectives: Early fetal demise (absence of cardiac activity in a visible fetus) is a very common event, but there are no reliable biomarkers to predict it. The purpose of the study was to assess the association of platelet parameters with early fetal demise.Methods: In this case-control study, we included women with normal deliveries or those ultrasound diagnosed as early fetal demise. For those who were identified with early fetal demise, the platelet parameters were analyzed before the ultrasound diagnosis, which is based on the absence of either an embryo within a gestational sac or cardiac activity in a visible embryo in the 5-10 weeks of gestation. The association between the risk of early fetal demise with the women's mean platelet volume (MPV) and platelet counts was calculated by logistic regression. Duplicate measurements of platelet aggregation were performed with VerifyNow. Results: In total, 99 women identified with early fetal demise and 170 women who had an uncomplicated pregnancy with normal delivery from January 2017 and August 2020 were included in the study. We found that platelet counts in the early fetal demise group were significantly higher than healthy pregnancies. In addition, platelet reactivity is higher in the normal delivery group than those in early fetal demise group (p < .05). High levels of platelet counts resulted in an adjusted odds ratio (OR) of 2.075 (95% confidence interval [95% CI], 1.215-3.544; p = .008) for early fetal demise. Conclusions: Increased platelet counts in the first trimester may be a predictor for the risk of early fetal demise.

Automated quantitative evaluation of fetal atrioventricular annular plane systolic excursion.

OBJECTIVES: The primary aim of this study was to evaluate the feasibility of automated measurement of fetal atrioventricular (AV) plane displacement (AVPD) over several cardiac cycles using myocardial velocity traces obtained by color tissue Doppler imaging (cTDI). The secondary objectives were to establish reference ranges for AVPD during the second half of normal pregnancy, to assess fetal AVPD in prolonged pregnancy in relation to adverse perinatal outcome and to evaluate AVPD in fetuses with a suspicion of intrauterine growth restriction (IUGR). METHODS: The population used to develop the reference ranges consisted of women with an uncomplicated singleton pregnancy at 18-42 weeks of gestation (n = 201). The prolonged-pregnancy group comprised women with an uncomplicated singleton pregnancy at ≥ 41 + 0 weeks of gestation (n = 107). The third study cohort comprised women with a singleton pregnancy and suspicion of IUGR, defined as an estimated fetal weight < 2.5th centile or an estimated fetal weight < 10th centile and umbilical artery pulsatility index > 97.5th centile (n = 35). Cineloops of the four-chamber view of the fetal heart were recorded using cTDI. Regions of interest were placed at the AV plane in the left and right ventricular walls and the interventricular septum, and myocardial velocity traces were integrated and analyzed using an automated algorithm developed in-house to obtain mitral (MAPSE), tricuspid (TAPSE) and septal (SAPSE) annular plane systolic excursion. Gestational-age specific reference ranges were constructed and normalized for cardiac size. The correlation between AVPD measurements obtained using cTDI and those obtained by anatomic M-mode were evaluated, and agreement between these two methods was assessed using Bland-Altman analysis. The mean Z-scores of fetal AVPD in the cohort of prolonged pregnancies were compared between cases with normal and those with adverse outcome using Mann-Whitney U-test. The mean Z-scores of fetal AVPD in IUGR fetuses were compared with those in the normal reference population using Mann-Whitney U-test. Inter- and intraobserver variability for acquisition of cTDI recordings and offline analysis was assessed by calculating coefficients of variation (CV) using the root mean square method. RESULTS: Fetal MAPSE, SAPSE and TAPSE increased with gestational age but did not change significantly when normalized for cardiac size. The fitted mean was highest for TAPSE throughout the second half of gestation, followed by SAPSE and MAPSE. There was a significant correlation between MAPSE (r = 0.64; P < 0.001), SAPSE (r = 0.72; P < 0.001) and TAPSE (r = 0.84; P < 0.001) measurements obtained by M-mode and those obtained by cTDI. The geometric means of ratios between AVPD measured by cTDI and by M-mode were 1.38 (95% limits of agreement (LoA), 0.84-2.25) for MAPSE, 1.00 (95% LoA, 0.72-1.40) for SAPSE and 1.20 (95% LoA, 0.92-1.57) for TAPSE. In the prolonged-pregnancy group, the mean ± SD Z-scores for MAPSE (0.14 ± 0.97), SAPSE (0.09 ± 1.02) and TAPSE (0.15 ± 0.90) did not show any significant difference compared to the reference ranges. Twenty-one of the 107 (19.6%) prolonged pregnancies had adverse perinatal outcome. The AVPD Z-scores were not significantly different between pregnancies with normal and those with adverse outcome in the prolonged-pregnancy cohort. The mean ± SD Z-scores for SAPSE (-0.62 ± 1.07; P = 0.006) and TAPSE (-0.60 ± 0.89; P = 0.002) were significantly lower in the IUGR group compared to those in the normal reference population, but the differences were not significant when the values were corrected for cardiac size. The interobserver CVs for the automated measurement of MAPSE, SAPSE and TAPSE were 28.1%, 17.7% and 15.3%, respectively, and the respective intraobserver CVs were 33.5%, 15.0% and 17.9%. CONCLUSIONS: This study showed that fetal AVPD can be measured automatically by integrating cTDI velocities over several cardiac cycles. Automated analysis of AVPD could potentially help gather larger datasets to facilitate use of machine-learning models to study fetal cardiac function. The gestational-age associated increase in AVPD is most likely a result of increasing cardiac size, as the AVPD normalized for cardiac size did not change significantly between 18 and 42 weeks. A decrease was seen in TAPSE and SAPSE in IUGR fetuses, but not after correction for cardiac size. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Unveiling Complexity and Multipotentiality of Early Heart Fields.

[Figure: see text].

Prenatal cardiac biometry and flow assessment in fetuses with bicuspid aortic valve at 20 weeks' gestation: multicenter cohort study.

OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Cardiac rhabdomyoma with hydrops fetalis: Prenatal management by abdominal drainage.

OBJECTIVE: We described a case of fetal cardiac rhabdomyoma complicated by hydrops. And we discussed our approach during pregnancy. CASE REPORT: A 23-year-old woman primigravida was referred at 29 weeks of gestation (WG) to prenatal unit for a large hyperechogenic intracardiac mass associated with fetal hydrops. An intrauterine peritoneo-amniotic shunt was placed. Complete regression of ascites and pericardial effusions were observed after 34 WG with drain in good position. CONCLUSION: Cardiac rhabdomyoma is the most common prenatal cardiac tumor. These tumors are benign, asymptomatic and spontaneously regress after birth. However, in some cases, these tumors may cause severe obstructions on the fetal heart and need specific treatment.

Gestational intermittent hyperoxia rescues murine genetic congenital heart disease in part.

Cardiac development is a dynamic process, temporally and spatially. When disturbed, it leads to congenital cardiac anomalies that affect approximately 1% of live births. Genetic variants in several loci lead to anomalies, with the transcription factor NKX2-5 being one of the largest. However, there are also non-genetic factors that influence cardiac malformations. We examined the hypothesis that hyperoxia may be beneficial and can rescue genetic cardiac anomalies induced by an Nkx2-5 mutation. Intermittent mild hyperoxia (40% PO2) was applied for 10 h per day to normal wild-type female mice mated with heterozygous Nkx2-5 mutant males from gestational day 8.5 to birth. Hyperoxia therapy reduced excessive trabeculation in Nkx2-5 mutant mice compared to normoxic conditions (ratio of trabecular layer relative to compact layer area, normoxia 1.84 ± 0.07 vs. hyperoxia 1.51 ± 0.04) and frequency of muscular ventricular septal defects per heart (1.53 ± 0.32 vs. 0.68 ± 0.15); however, the incidence of membranous ventricular septal defects in Nkx2-5 mutant hearts was not changed. Nkx2-5 mutant embryonic hearts showed defective coronary vessel organization, which was improved by intermittent mild hyperoxia. The results of our study showed that mild gestational hyperoxia therapy rescued genetic cardiac malformation induced by Nkx2-5 mutation in part.

Automatic quality assessment for 2D fetal sonographic standard plane based on multitask learning.

ABSTRACT: The quality control of fetal sonographic (FS) images is essential for the correct biometric measurements and fetal anomaly diagnosis. However, quality control requires professional sonographers to perform and is often labor-intensive. To solve this problem, we propose an automatic image quality assessment scheme based on multitask learning to assist in FS image quality control. An essential criterion for FS image quality control is that all the essential anatomical structures in the section should appear full and remarkable with a clear boundary. Therefore, our scheme aims to identify those essential anatomical structures to judge whether an FS image is the standard image, which is achieved by 3 convolutional neural networks. The Feature Extraction Network aims to extract deep level features of FS images. Based on the extracted features, the Class Prediction Network determines whether the structure meets the standard and Region Proposal Network identifies its position. The scheme has been applied to 3 types of fetal sections, which are the head, abdominal, and heart. The experimental results show that our method can make a quality assessment of an FS image within less a second. Also, our method achieves competitive performance in both the segmentation and diagnosis compared with state-of-the-art methods.

Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation.

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-ß1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.

Fetal cardiac function at 35-37 weeks' gestation in pregnancies that subsequently develop pre-eclampsia.

OBJECTIVE: To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. METHODS: This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. RESULTS: In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. CONCLUSION: Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal features, associated co-morbidities and clinical course of agenesis of the ductus venosus in the current era.

OBJECTIVES: Agenesis of the ductus venosus (ADV) has been associated with additional anomalies in up to 83% of cases. We sought to investigate characteristics, co-morbidities and outcomes of ADV in the current era. We hypothesized that rates of cardiac and non-cardiac diagnoses and survival would be higher, due to advances in genetic testing, prenatal diagnosis and surveillance. METHODS: A retrospective series of cases diagnosed at our institution from 2007 to 2018 were identified by searching our database. Cardiac and obstetric charts were reviewed for cardiac and extra-cardiac anomalies, genetic results and outcomes. RESULTS: Fourteen cases were diagnosed at a mean gestational age of 23.9 weeks (range 13-33). All had associated genetic, cardiac or extra-cardiac anomalies. Eight (57%) had cardiac anomalies and one other developed cardiomyopathy by 6 months. Extra-cardiac anomalies were present in 93% (13/14) and genetic diagnoses made in 75% (6/8) of those tested. Cardiac output Z-scores were >2 in 60% (6/10) prior to delivery. Two had hydrops, there was one intra-uterine death, 13 live-births and two neonatal deaths. CONCLUSION: Our cohort had more associated diagnoses and a lower mortality than previously reported. In our experience, high output occurs frequently, however with a relatively low risk of hydrops and intrauterine death.

Reference ranges for fetal cardiac, ventricular and atrial relative size, sphericity, ventricular dominance, wall asymmetry and relative wall thickness from 18 to 41 gestational weeks.

OBJECTIVE: To construct nomograms for fetal cardiac, ventricular and atrial relative size and geometry parameters from 18 to 41 weeks' gestation using a low-risk population of singleton pregnancies. METHODS: This was a prospective cohort study of 602 low-risk singleton pregnancies undergoing comprehensive fetal echocardiography, from 18 to 41 weeks of gestation, to assess fetal cardiac, atrial and ventricular relative size and sphericity, ventricular dominance, wall asymmetry and relative wall thickness. Intra- and interobserver measurement reproducibility was evaluated using intraclass correlation coefficients (ICC). In order to construct reference ranges across pregnancy, parametric regressions were tested to model each measurement against gestational age and estimated fetal weight. The measurements evaluated were: cardiothoracic ratio; atrial-to-heart area ratios; ventricular-to-heart area ratios; cardiac, ventricular and atrial sphericity indices; right-to-left basal and midventricular ratios; septal-to-free wall thickness ratios; and relative wall thickness. RESULTS: Fetal cardiac, ventricular and atrial morphometry for assessing relative size and geometry could be successfully performed in > 95% of the population, with moderate-to-excellent interobserver reproducibility (ICC, 0.623-0.907) and good-to-excellent intraobserver reproducibility (ICC, 0.787-0.938). Cardiothoracic ratio and ventricular right-to-left ratio showed a modest increase throughout gestation. Atrial-to-heart and ventricular-to-heart area ratios, atrial sphericity indices and septal-to-free wall thickness ratios were constant with gestational age. Left and right ventricular basal sphericity indices showed a tendency to decrease at the end of gestation, while left and right midventricular sphericity indices tended to decrease in the second trimester. The cardiac sphericity index and left and right relative wall thickness showed a modest decrease with gestational age. Nomograms across gestation were constructed for all echocardiographic parameters described. CONCLUSIONS: The assessment of cardiac, ventricular and atrial relative size and geometry is feasible and reproducible in the fetus. We provide standardized reference ranges for these parameters throughout gestation, enabling the accurate assessment of cardiac remodeling patterns during fetal life. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

3D/4D spatiotemporal image correlation (STIC) fetal echocardiography provides incremental benefit over 2D fetal echocardiography in predicting postnatal surgical approach in double-outlet right ventricle.

OBJECTIVE: To analyze the incremental benefit of 3D/4D spatiotemporal image correlation (STIC) fetal echocardiography over 2D fetal echocardiography with respect to the accuracy of identification of anatomic details crucial for surgical decision-making and in predicting surgical approach in fetuses with double-outlet right ventricle (DORV). METHODS: This was a retrospective study of fetuses with DORV which had undergone both 2D echocardiography and 3D/4D STIC echocardiography and which underwent surgery postnatally in a tertiary pediatric cardiac center in Kerala between October 2015 and March 2019. All such cases with normal atrial arrangement, concordant atrioventricular connections and balanced ventricles were included. 2D and 3D/4D STIC fetal echocardiographic data were analyzed by two experienced observers blinded to the other dataset. Anatomic variables crucial for surgical decision-making, i.e. location and routability of the ventricular septal defect, relationship of the great arteries and presence of outflow obstruction, were compared between the two modalities with respect to agreement with postnatal echocardiography. The accuracy of prenatal prediction of the surgical pathway was compared between 2D and 3D/4D modalities with respect to the procedure undertaken. RESULTS: Included in the study were 22 fetuses with DORV which had undergone both 2D and 3D/4D imaging as well as postnatal surgery. Accuracy of prenatal interpretation of all four anatomic variables was significantly higher using 3D/4D STIC than using 2D fetal echocardiography (19/22 (86.4%) vs 8/22 (36.4%), P < 0.001). Surgical procedures included single-stage repair in 14 (63.5%) patients and a multistage approach in eight (36.4%). Prenatal prediction of the surgical pathway was significantly more accurate on 3D/4D STIC than on 2D echocardiography (20/22 (90.9%) vs 12/22 (54.5%), P = 0.021). Prenatal predictive accuracy of single-stage biventricular repair was significantly better for 3D/4D STIC than for 2D echocardiography (14/14 (100%) vs 8/14 (57.1%), P = 0.04). CONCLUSION: Addition of 3D/4D STIC to conventional 2D fetal echocardiography confers incremental benefit on the accuracy of identification of anatomic details crucial for surgical decision-making and the prediction of postnatal surgical approach in fetuses with DORV, thereby potentially aiding prenatal counseling. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.