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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., (© 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2024 American Institute of Ultrasound in Medicine.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

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., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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 < 2.5 th centile or an estimated fetal weight < 10 th centile and umbilical artery pulsatility index > 97.5 th 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., (© 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

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.

Objectives: To determine which echocardiographic features of hypoplastic left heart complex (HLHC) in the fetal period are predictive of biventricular (BV) circulation and to evaluate the long-term outcome of patients with HLHC, including rates of mortality, reintervention and development of further cardiac disease., Methods: Echocardiograms of fetuses with HLHC obtained at 18-26 weeks and 27-36 weeks' gestation between 2004 and 2017 were included in the analysis. The primary outcome was successful BV circulation (Group 1). Group 2 included patients with single-ventricle palliation, death or transplant. Univariate analysis was performed on data obtained at 18-26 and 27-36 weeks and multivariate logistic regression was performed on data obtained at 27-36 weeks only., Results: Of the 51 included cases, 44 achieved successful BV circulation (Group 1) and seven did not (Group 2). Right-to-left/bidirectional foramen ovale (FO) flow and a higher mitral valve (MV) annulus Z-score were associated with successful BV circulation on both univariate and multivariate analysis. Bidirectional or left-to-right FO flow, left ventricular length (LVL) Z-score of < -2.4 and a MV Z-score of < -4.5 correctly predicted 80% of Group 2 cases. Late follow-up was available for 41 patients. There were two late deaths in Group 2. Thirteen patients in Group 1 required reintervention, 12 developed mitral stenosis and five developed isolated subaortic stenosis., Conclusions: BV circulation is common in fetuses with HLHC. Higher MV annulus and LVL Z-scores and right to left direction of FO flow are important predictors of BV circulation. Long-term sequelae in those with BV circulation may include mitral and subaortic stenosis. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

[Figure: see text].

Objectives: Fetal cardiac function can be evaluated using a variety of parameters. Among these, cardiac cycle time-related parameters, such as filling time fraction (FTF) and ejection time fraction (ETF), are promising but rarely studied. We aimed to report the feasibility and reproducibility of fetal FTF and ETF measurements using pulsed-wave Doppler, to provide reference ranges for fetal FTF and ETF, after evaluating their relationship with heart rate (HR), gestational age (GA) and estimated fetal weight (EFW), and to evaluate their potential clinical utility in selected fetal conditions., Methods: This study included a low-risk prospective cohort of singleton pregnancies and a high-risk population of fetuses with severe twin-twin transfusion syndrome (TTTS), aortic stenosis (AoS) or aortic coarctation (CoA), from 18 to 41 weeks' gestation. Left ventricular (LV) and right ventricular inflow and outflow pulsed-wave Doppler signals were analyzed, using valve clicks as landmarks. FTF was calculated as: (filling time/cycle time) × 100. ETF was calculated as: (ejection time/cycle time) × 100. Intraclass correlation coefficients (ICC) were used to evaluate the intra- and interobserver reproducibility of FTF and ETF measurements in low-risk fetuses. The relationships of FTF and ETF with HR, GA and EFW were evaluated using multivariate regression analysis. Reference ranges for FTF and ETF were then constructed using the low-risk population. Z-scores of FTF and ETF in the high-risk fetuses were calculated and analyzed., Results: In total, 602 low-risk singleton pregnancies and 54 high-risk fetuses (nine pairs of monochorionic twins with severe TTTS, 16 fetuses with AoS and 20 fetuses with CoA) were included. Adequate Doppler traces for FTF and ETF could be obtained in 95% of low-risk cases. Intraobserver reproducibility was good to excellent (ICC, 0.831-0.905) and interobserver reproducibility was good (ICC, 0.801-0.837) for measurements of all timing parameters analyzed. Multivariate analysis of FTF and ETF in relation to HR, GA and EFW in low-risk fetuses identified HR as the only variable predictive of FTF, while ETF was dependent on both HR and GA. FTF increased with decreasing HR in low-risk fetuses, while ETF showed the opposite behavior, decreasing with decreasing HR. Most recipient twins with severe TTTS showed reduced FTF and preserved ETF. AoS was associated with decreased FTF and increased ETF in the LV, with seemingly different patterns associated with univentricular vs biventricular postnatal outcome. The majority of fetuses with CoA had FTF and ETF within the normal range in both ventricles., Conclusions: Measurement of FTF and ETF using pulsed-wave Doppler is feasible and reproducible in the fetus. The presented reference ranges account for associations of FTF with HR and of ETF with HR and GA. These time fractions are potentially useful for clinical monitoring of cardiac function in severe TTTS, AoS and other fetal conditions overloading the heart. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To investigate the impact of abnormal perinatal loading conditions on cardiac geometry and function in term fetuses and neonates with transposition of the great arteries with intact interventricular septum (simple TGA), and to explore the predictive value of fetal cardiac parameters for an urgent balloon atrial septostomy (BAS) after birth., Methods: This was a prospective longitudinal follow-up study of women delivering at term, including both uncomplicated pregnancies with normal outcome and pregnancies affected by fetal simple TGA. Conventional, spectral-tissue Doppler and speckle-tracking echocardiographic parameters were obtained within 1 week before delivery and within the first few hours after delivery. Neonates with simple TGA that required urgent BAS were assessed after the procedure and before corrective arterial switch surgery. Cardiac parameters were normalized by cardiac cycle length, ventricular end-diastolic length or end-diastolic dimension, as appropriate. Fetal and neonatal cardiac parameters were compared between simple-TGA cases and controls, and perinatal changes in the simple-TGA group were assessed. Receiver-operating-characteristics (ROC)-curve analysis was used to assess the predictive value of fetal cardiac parameters for urgent BAS after birth in the simple-TGA group., Results: A total of 67 pregnant women delivering at term were included in the study (54 normal pregnancies and 13 with a diagnosis of fetal simple TGA). Compared with normal term fetuses, term fetuses with simple TGA exhibited more globular hypertrophied ventricles, increased biventricular systolic function and diastolic dysfunction (right ventricular (RV) sphericity index (SI), 0.58 vs 0.54; left ventricular (LV)-SI, 0.55 vs 0.49; combined cardiac output (CCO), 483 vs 406 mL/min/kg; LV torsion, 4.3 vs 3.0 deg/cm; RV isovolumetric relaxation time (IVRT'), 127 vs 102 ms; P < 0.01 for all). Compared with normal neonates, neonates with simple TGA demonstrated biventricular hypertrophy, a more spherical right ventricle and altered systolic and diastolic functional parameters (RV-SI, 0.61 vs 0.43; RV myocardial performance index, 0.47 vs 0.34; CCO, 697 vs 486 mL/min/kg; LV-IVRT', 100 vs 79 ms; RV-IVRT', 106 vs 71 ms; P < 0.001 for all). Paired comparison of neonatal and fetal cardiac indices in the simple-TGA group showed persistence of the fetal phenotype, increased biventricular systolic myocardial contractility and CCO, and diastolic dysfunction (RV systolic myocardial velocity (S'), 0.31 vs 0.24 cm/s; LV-S', 0.23 vs 0.18 cm/s; CCO, 697 vs 483 mL/min/kg; LV torsion, 1.1 vs 4.3 deg/cm; P < 0.001 for all). Several fetal cardiac parameters in term fetuses with simple TGA demonstrated high predictive value for an urgent BAS procedure after birth. Our proposed novel fetal cardiac index, LV rotation-to-shortening ratio, as a potential marker of subendocardial dysfunction, for a cut-off value of ≥ 0.23, had an area under the ROC curve (AUC) of 0.94, sensitivity of 100% and specificity of 83%. For RV/LV end-diastolic area ratio ≥ 1.33, pulmonary-valve-to-aortic-valve-dimension ratio ≤ 0.89, RV/LV cardiac output ratio ≥ 1.38 and foramen-ovale-dimension-to-total-interatrial-septal-length ratio ≤ 0.27, AUC was 0.93-0.98, sensitivity was 86% and specificity was 83-100% for all., Conclusions: Simple-TGA fetuses exhibited cardiac remodeling at term with more profound alterations in these cardiac parameters after birth, suggestive of adaptation to abnormal loading conditions and possible adaptive responses to hypoxemia. Perinatal adaptation in simple TGA might reflect persistence of the abnormal parallel arrangement of cardiovascular circulation and the presence of widely patent fetal shunts imposing volume load on the neonatal heart. The fetal cardiac parameters that showed high predictive value for urgent BAS after birth might reflect the impact of late-gestation pathophysiology and progressive hypoxemia on fetal cardiac geometry and function in simple TGA. If these findings are validated in larger prospective studies, detailed cardiac assessment of fetuses with simple TGA near term could facilitate improvements in perinatal management and refinement of the timing of postnatal intervention strategies to prevent adverse pregnancy outcomes. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To assess differences in cardiac morphology and function in fetuses of mothers with gestational diabetes mellitus (GDM) compared to controls, and to assess whether, in women with GDM, fetal cardiac changes are accentuated with advancing gestational age., Methods: We studied 112 women with GDM and 224 women with uncomplicated pregnancy at 24-40 weeks' gestation. In all fetuses, a standard four-chamber oblique view was obtained and offline speckle-tracking analysis was performed to measure right and left endocardial global longitudinal strain (GLS) and tricuspid and mitral annular plane systolic excursion. Global sphericity index was also calculated. Echocardiographic parameters were compared between GDM fetuses and controls at two gestational time periods of 24 + 0 to 32 + 0 weeks and 32 + 1 to 40 + 1 weeks., Results: At 24 + 0 to 32 + 0 weeks, we phenotyped 43 fetuses from mothers with GDM and 71 from uncomplicated pregnancies, and, at 32 + 1 to 40 + 1 weeks, we phenotyped 69 fetuses from mothers with GDM and 153 from women with uncomplicated pregnancy. In fetuses of mothers with GDM, compared to controls, right ventricular functional indices were consistently lower both at 24 + 0 to 32 + 0 weeks and at 32 + 1 to 40 + 1 weeks. Right ventricular GLS was reduced in the GDM group at 24 + 0 to 32 + 0 weeks (adjusted mean difference, 0.7%; 95% CI, 0.3-1.1%) and at 32 + 1 to 40 + 1 weeks (adjusted mean difference, 0.9%; 95% CI, 0.6-1.1%). Fetal left ventricular global longitudinal function was similar in GDM pregnancies compared with controls, with the exception of the contractility of the left ventricular basal segment, which was reduced. Global sphericity index was reduced in GDM pregnancies only at 32 + 1 to 40 + 1 weeks (adjusted mean difference, -0.4; 95% CI, -0.7 to 0.1)., Conclusions: The offspring of women with GDM are at high risk for development of cardiovascular disease in childhood and early adulthood. Our study demonstrates that GDM is associated with a reduction mainly in fetal right ventricular function, compared to controls, and this response is not exaggerated with increasing gestational age. Further studies are needed to determine whether fetuses with the observed alterations in cardiac function are those at highest risk for subsequent development of cardiovascular disease. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

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% PO 2 ) 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.

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., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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-β1, 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.

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., (© 2020 John Wiley & Sons Ltd.)

The aim of the study was to investigate foetal cardiac function using the modified myocardial performance index (Mod-MPI) in poorly controlled gestational diabetics and its link with intrauterine markers for hypoxia and to an adverse outcome. In a prospective, cross sectional study, 44 consecutive women with severe or poorly controlled gestational diabetic pregnancies in their third trimester on insulin therapy were recruited and matched with 44 women with normal pregnancies which served as the control group. Using Doppler echocardiography the foetal Mod-MPI was calculated. The foetal Mod-MPI was significantly higher in the diabetic group compared to the controls indicating significant myocardial dysfunction. The Mod-MPI served as an excellent marker of adverse outcomes. Foetal myocardial function was significantly impaired in poorly controlled gestational diabetics and there was a significant link of Mod-MPI to intrauterine markers of hypoxia, as well as to an adverse outcome. Mod-MPI has the potential to improve foetal surveillance in gestational diabetes.IMPACT STATEMENT What is already known on this subject? Abnormal foetal cardiac function, as reflected in the modified myocardial performance index, has been reported to be significantly increased in foetuses of poorly controlled diabetics managed on insulin. What do the results of this study add? There is a significant link between abnormal foetal cardiac function to intrauterine markers of hypoxia, as well as to an adverse outcome; and that development of myocardial dysfunction could be one of the main mechanisms, inducing foetal compromise in poorly controlled gestational diabetes. What are the implications of these findings for clinical practice and/or further research? This study explores an interesting concept of foetal pathophysiology in gestational diabetes, namely the concept of "pseudo-hypoxia" in a foetus of a gestational diabetic mother, and this intrauterine "hypoxic stress" in turn leading to myocardial dysfunction. The Mod-MPI, a clinical marker for cardiac dysfunction, can therefore be used in the clinical setting to track a deteriorating metabolic state.

Objectives: Prenatal diagnosis of coarctation of the aorta (CoA) is associated with reduced mortality and morbidity, however, accurate prenatal prediction remains challenging. To date, studies have used retrospective measurements of the outflow tracts to evaluate their potential to predict CoA. Our primary objective was to evaluate prospectively acquired measurements of the outflow tracts in fetuses with prenatally suspected CoA. A secondary aim was to report the postnatal prevalence of bicuspid aortic valve in this cohort., Methods: Pregnancies with suspicion of isolated CoA and with a minimum of 6 months' postnatal follow-up available were identified from the cardiac database of a tertiary fetal cardiology center in the UK, between January 2002 and December 2017. Measurement of the aortic valve, pulmonary valve, distal transverse aortic arch (DTAA) and arterial duct (AD) diameters were undertaken routinely in fetuses with suspected CoA during the study period. Z-scores were computed using published reference ranges based on > 7000 fetuses from our own unit., Results: Of 149 pregnancies with prenatally suspected CoA included in the study, CoA was confirmed within 6 months after birth in 77/149 (51.7%) cases. DTAA diameter Z-score and the Z-score of second-trimester DTAA/AD diameter ratio were smaller in fetuses with postnatally confirmed CoA than those in false-positive cases (-2.8 vs -1.9; P = 0.039 and -3.13 vs -2.61; P = 0.005, respectively). Multiple regression analysis demonstrated that the Z-scores of DTAA and AD diameters were the only significant predictors of postnatal CoA (P = 0.001). Bicuspid aortic valve was identified in 30% of the false-positive cases., Conclusions: Measurement of DTAA and AD diameter Z-scores can be used to ascertain risk for postnatal CoA in a selected cohort. The high incidence of bicuspid aortic valve in false-positive cases merits further study with respect to both etiology and longer-term significance. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To assess the relationship between presence of a redundant foramen ovale flap (RFOF), in the absence of a clearly restrictive foramen ovale, and ventricular disproportion, in three groups of fetuses: (1) those with a final diagnosis of aortic coarctation (CoA); (2) those referred for suspicion of ventricular disproportion and/or CoA which did not develop CoA postnatally; and (3) normal fetuses., Methods: This was a retrospective study including 73 fetuses: 12 with a final diagnosis of isolated CoA; 30 referred for suspicion of ventricular disproportion and/or CoA, which did not develop CoA postnatally; and 31 normal fetuses. Four-dimensional volume datasets and clips were assessed offline. Maximum diameters of the FOF (FOFD), left atrium (LAD), right atrium, left and right ventricles and, when available, aortic isthmus, were measured, as were areas of the FOF (FOFA), left atrium (LAA) and right atrium. The left/right ratios for all segments of the heart, as well as the FOFD/LAD ratio and FOFA/LAA ratio, were calculated. Regression analysis was performed to assess the relationship between RFOF and ventricular disproportion and means were compared by ANOVA., Results: Repeatability was fair, with all variables having an intraclass correlation coefficient ≥ 83%. In the pooled group of fetuses with no CoA found at birth (normal fetuses plus those with ventricular disproportion (n = 61)), there was a significant linear correlation between redundancy of the FOF and degree of ventricular disproportion (P < 0.01 and P < 0.05 for diameter and area ratios, respectively). Categorizing the FOF redundancy, FOFD/LAD ratio ≥ 0.65 was significantly associated with ventricular disproportion (P = 0.006). Based on the degree of FOF prominence, we described four categories of redundancy, ranging from no redundancy/ventricular disproportion (Stage 0) to severe redundancy/ventricular disproportion with transient obstruction of the foramen ovale or mitral orifice (Stage III). Comparing cases without neonatal evidence of coarctation but FOFD/LAD ratio ≥ 0.65 vs those with neonatal evidence of coarctation, there was no statistically significant difference in the degree of ventricular disproportion or in the Z-score of the aortic isthmus maximum diameter., Conclusions: This study demonstrates that: (1) there is an association between RFOF and ventricular disproportion, independent of the association with a restrictive foramen ovale, and (2) the presence of a RFOF may mimic CoA. In fact, it causes both ventricular disproportion and a significant reduction in the diameter of the aortic isthmus, associated in some cases also with reversed isthmic flow. Future prospective studies are needed to evaluate whether focusing the sonologist's attention on the appearance of the foramen ovale may reduce the rate of false-positive diagnosis of CoA. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: Our primary aim was to confirm whether intertwin discordance in ventricular strain and ductus venosus (DV) time intervals predicts twin-twin transfusion syndrome (TTTS). Secondary aims were to create gestational-age ranges for ventricular strain in uncomplicated monochorionic diamniotic (MCDA) twin pregnancies without selective intrauterine growth restriction (sIUGR) and to characterize the relationship of ventricular strain with gestational age in MCDA twin pregnancies with sIUGR that did not develop TTTS., Methods: In the period 2015-2018, we enrolled 150 MCDA twin pregnancies consecutively into this prospective, blinded study of global longitudinal left and right ventricular strain. With the observer blinded to twin pairing and pregnancy outcome, videoclips of the four-chamber view, which had been recorded during ultrasound surveillance in the usual window for development of TTTS (16-26 completed gestational weeks), underwent offline measurement of strain. Uncomplicated MCDA twin pregnancies, without sIUGR, were used to test the association between strain, gestational age and estimated fetal weight using mixed-effects multilevel regression. Inter-rater reliability was tested in 208 strain measurements in 31 fetuses from pregnancies which did not develop TTTS and within-fetus variation was assessed in 16 such fetuses, in which multiple four-chamber views were taken on the same day. The effect of sIUGR on strain in otherwise uncomplicated MCDA twin pregnancy was analyzed. MCDA twin pregnancies were defined as 'pre-TTTS' when, having been referred for TTTS evaluation, they did not satisfy Quintero staging criteria, but subsequently developed TTTS requiring laser treatment. MCDA pregnancies which did not develop TTTS comprised the 'non-TTTS' group. Cardiovascular parameters measured in these cases included tissue Doppler parameters and DV early filling time as a percentage of the cardiac cycle (DVeT%). Intertwin strain and DVeT% discordance was compared between non-TTTS and pre-TTTS cases, matched for gestational age., Results: Paired strain data were available for intertwin comparison in 127/150 MCDA twin pregnancies, comprising 14 pre-TTTS and 113 non-TTTS pregnancies, after exclusions. Scans were collected at a median frame rate of 97 (range, 28-220) Hz. Laser therapy was performed at a median gestational age of 20.6 (range, 17.2-26.6) weeks. There were no group differences in right (RV) or left (LV) ventricular strain discordance between 68/113 non-TTTS and 13/14 pre-TTTS MCDA twin pregnancies < 20 completed gestational weeks (RV, P = 0.338; LV, P = 0.932). DVeT% discordance > 3.6% was found in eight of 13 pre-TTTS pregnancies. In non-TTTS pregnancies, the estimated variability in ventricular strain within each twin during the day was high (RV, 19.7; LV, 12.9). However, within each pair (intertwin variation), variability was low (RV, 5.5; LV, 2.9). Interclass correlation reflecting the proportion of total variability represented by the variability between twin pairs was low (RV, 0.22; LV, 0.18). Both RV (P < 0.001) and LV (P = 0.025) strain showed a negative association with gestational age. Among non-TTTS MCDA twin pregnancies, LV strain was, on average, higher by 1.83 in sIUGR compared with normally grown fetuses (P = 0.023), with no statistically significant difference in RV strain (P = 0.271)., Conclusions: Although ventricular strain has been reported previously as a possible predictor of developing TTTS, in this blinded, prospective study, we found no significant intergroup differences in ventricular strain in pre-TTTS compared with age-matched non-TTTS MCDA twin pregnancies. We recommend using DVeT% discordance as a more practical screening tool in MCDA twin pregnancies. This study also provides new information on the changes with gestational age, and the biological and technical variation, of global longitudinal ventricular strain in uncomplicated MCDA twin pregnancies and those with isolated sIUGR. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To perform a cost-effectiveness analysis of different follow-up strategies for non-obese and obese women who had incomplete fetal cardiac screening for major congenital heart disease (CHD)., Methods: Three decision-analytic models, one each for non-obese, obese and Class-III-obese women, were developed to compare five follow-up strategies for initial suboptimal fetal cardiac screening. The five strategies were: (1) no follow-up ultrasound (US) examination but direct referral to fetal echocardiography (FE); (2) one follow-up US, then FE if fetal cardiac views were still suboptimal; (3) up to two follow-up US, then FE if fetal cardiac views were still suboptimal; (4) one follow-up US and no FE; and (5) up to two follow-up US and no FE. The models were designed to identify fetuses with major CHD in a theoretical cohort of 4 000 000 births in the USA. Outcomes related to neonatal mortality and neurodevelopmental disability were evaluated. A cost-effectiveness willingness-to-pay threshold was set at US$100 000 per quality-adjusted life year (QALY). Base-case and sensitivity analysis and Monte-Carlo simulation were performed., Results: In our base-case models for all body mass index (BMI) groups, no follow-up US, but direct referral to FE led to the best outcomes, detecting 7%, 25% and 82% more fetuses with CHD in non-obese, obese and Class-III-obese women, respectively, compared with the baseline strategy of one follow-up US and no FE. However, no follow-up US, but direct referral to FE was above the US$100 000/QALY threshold and therefore not cost-effective. The cost-effective strategy for all BMI groups was one follow-up US and no FE. Both up to two follow-up US with no FE and up to two follow-up US with FE were dominated (being more costly and less effective), while one follow-up US with FE was over the cost-effectiveness threshold. One follow-up US and no FE was the optimal strategy in 97%, 93% and 86% of trials in Monte-Carlo simulation for non-obese, obese and Class-III-obese models, respectively., Conclusion: For both non-obese and obese women with incomplete fetal cardiac screening, the optimal CHD follow-up screening strategy is no further US and immediate referral to FE; however, this strategy is not cost-effective. Considering costs, one follow-up US and no FE is the preferred strategy. For both obese and non-obese women, Monte-Carlo simulations showed clearly that one follow-up US and no FE was the optimal strategy. Both non-obese and obese women with initial incomplete cardiac screening examination should therefore be offered one follow-up US. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To explore the contribution of single-gene defects to the genetic cause of cardiac left-sided lesions (LSLs), and to evaluate the incremental diagnostic yield of whole-exome sequencing (WES) for single-gene defects in fetuses with LSLs without aneuploidy or a pathogenic copy-number variant (pCNV)., Methods: Between 10 April 2015 and 30 October 2018, we recruited 80 pregnant women diagnosed with a LSL who had termination of pregnancy and genetic testing. Eligible LSLs were aortic valve atresia or stenosis, coarctation of the aorta, mitral atresia or stenosis and hypoplastic left heart syndrome (HLHS). CNV sequencing (CNV-seq) and WES were performed sequentially on specimens from these fetuses and their parents. CNV-seq was used to identify aneuploidies and pCNVs, while WES was used to identify diagnostic genetic variants in cases without aneuploidy or pCNV., Results: Of 80 pregnancies included in the study, 27 (33.8%) had a genetic diagnosis. CNV-seq analysis identified six (7.5%) fetuses with aneuploidy and eight (10.0%) with pCNVs. WES analysis of the remaining 66 cases revealed diagnostic genetic variants in 13 (19.7%) cases, indicating that the diagnostic yield of WES for the entire cohort was 16.3% (13/80). KMT2D was the most frequently mutated gene (7/66 (10.6%)) in fetuses with LSL without aneuploidy or pCNVs, followed by NOTCH1 (4/66 (6.1%)). HLHS was the most prevalent cardiac phenotype (4/7) in cases with a KMT2D mutation in this cohort. An additional six (9.1%) cases were found to have potentially deleterious variants in candidate genes., Conclusions: Single-gene defects contribute substantially to the genetic etiology of fetal LSLs. KMT2D mutations accounted for approximately 10% of LSLs in our fetal cohort. WES has the potential to provide genetic diagnoses in fetuses with LSLs without aneuploidy or pCNVs. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: Congenital heart defects (CHD) are still missed frequently in prenatal screening programs, which can result in severe morbidity or even death. The aim of this study was to evaluate the quality of fetal heart images, obtained during the second-trimester standard anomaly scan (SAS) in cases of CHD, to explore factors associated with a missed prenatal diagnosis., Methods: In this case-control study, all cases of a fetus born with isolated severe CHD in the Northwestern region of The Netherlands, between 2015 and 2016, were extracted from the PRECOR registry. Severe CHD was defined as need for surgical repair in the first year postpartum. Each cardiac view (four-chamber view (4CV), three-vessel (3V) view and left and right ventricular outflow tract (LVOT, RVOT) views) obtained during the SAS was scored for technical correctness on a scale of 0 to 5 by two fetal echocardiography experts, blinded to the diagnosis of CHD and whether it was detected prenatally. Quality parameters of the cardiac examination were compared between cases in which CHD was detected and those in which it was missed on the SAS. Regression analysis was used to assess the association of sonographer experience and of screening-center experience with the cardiac examination quality score., Results: A total of 114 cases of isolated severe CHD at birth were analyzed, of which 58 (50.9%) were missed and 56 (49.1%) were detected on the SAS. The defects comprised transposition of the great arteries (17%), aortic coarctation (16%), tetralogy of Fallot (10%), atrioventricular septal defect (6%), aortic valve stenosis (5%), ventricular septal defect (18%) and other defects (28%). No differences were found in fetal position, obstetric history, maternal age or body mass index (BMI) or gestational age at examination between missed and detected cases. Ninety-two cases had available cardiac images from the SAS. Compared with the detected group, the missed group had significantly lower cardiac examination quality scores (adequate score (≥ 12) in 32% vs 64%; P = 0.002), rate of proper use of magnification (58% vs 84%; P = 0.01) and quality scores for each individual cardiac plane (4CV (2.7 vs 3.9; P < 0.001), 3V view (3.0 vs 3.8; P = 0.02), LVOT view (1.9 vs 3.3; P < 0.001) and RVOT view (1.9 vs 3.3; P < 0.001)). In 49% of missed cases, the lack of detection was due to poor adaptational skills resulting in inadequate images in which the CHD was not clearly visible; in 31%, the images showed an abnormality (mainly septal defects and aortic arch anomalies) which had not been recognized at the time of the scan; and, in 20%, the cardiac planes had been obtained properly but showed normal anatomy. Multivariate regression analysis showed that the volume of SAS performed per year by each sonographer was associated significantly with quality score of the cardiac examination., Conclusions: A lack of adaptational skills when performing the SAS, as opposed to circumstantial factors such as BMI or fetal position, appears to play an important role in failure to detect CHD prenatally. The quality of the cardiac views was inadequate significantly more often in undetected compared with detected cases. Despite adequate quality of the images, CHD was not recognized in 31% of cases. A high volume of SAS performed by each sonographer in a large ultrasound center contributes significantly to prenatal detection. In 20% of undetected cases, CHD was not visible even though the quality of the images was good. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: The aim of this study is to review our institution's experience with fetal cardiac rhabdomyoma, and to document the prenatal genetic testing for tuberous sclerosis complex (TSC) and clinical outcome of the affected pregnancies., Study Design: During a four-year period, patients with fetal cardiac rhabdomyoma were detected by echocardiography in the second trimester of pregnancy. Molecular genetic analysis was conducted on fetuses to screen for variants of TSC1/TSC2 genes. We reviewed medical records of these affected pregnancies, including maternal demographics, sonographic findings, genotyping results and pregnancy outcomes., Results: Eleven cases with fetal cardiac rhabdomyoma were studied during the study period. A pathogenic variant of TSC1/TSC2 genes was detected in all cases, including two with an inherited variant and nine with a de novo variant. Out of these eleven cases diagnosed prenatally, eight pregnancies were terminated and three continued till term., Conclusions: Cardiac rhabdomyoma is the prenatal sign of TSC. A molecular investigation of TSC1/TSC2 genes should be recommended for fetuses with a rhabdomyoma and the parents, and the prognostic counselling should include TSC and its consequences., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To compare the recommended three-view fetal heart screening method to detect major congenital heart disease (CHD) with more elaborate screening strategies to determine the cost-effective strategy in unselected (low-risk) pregnancies., Methods: A decision-analytic model was designed to compare four screening strategies to identify fetuses with major CHD in a theoretical cohort of 4 000 000 births in the USA. The four strategies were: (1) three views: four-chamber view (4CV) and views of the left (LVOT) and right (RVOT) ventricular outflow tracts; (2) five views: 4CV, LVOT, RVOT and longitudinal views of the ductal arch and aortic arch; (3) five axial views: 4CV, LVOT, RVOT, three-vessel (3V) view and three-vessels-and-trachea view; and (4) six views: 4CV, LVOT, RVOT and 3V views and longitudinal views of the ductal arch and aortic arch. Outcomes related to neonatal mortality and neurodevelopmental disability were evaluated. The analysis was performed from a healthcare-system perspective, with a cost-effectiveness willingness-to-pay threshold set at $100 000 per quality-adjusted life year (QALY). Baseline analysis, one-way sensitivity analysis and Monte-Carlo simulation were performed., Results: In our baseline model, screening with five axial views was the optimal strategy, detecting 3520 more CHDs, and resulting in 259 fewer children with neurodevelopmental disability, 40 fewer neonatal deaths and only slightly higher costs, compared with screening with the currently recommended three views. Screening with six views was more effective, but also cost considerably more, compared with screening with five axial views, and had an incremental cost of $490 023/QALY, which was over the willingness-to-pay threshold. The five-view strategy was dominated by the other three strategies, i.e. it was more costly and less effective in comparison. The data were robust when tested with Monte-Carlo and one-way sensitivity analysis., Conclusion: Although current guidelines recommend a minimum of three views for detecting CHD during the mid-trimester anatomy scan, screening with five axial views is a cost-effective strategy that may lead to improved outcome compared with three-view screening. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To examine the association between fetal major heart defects and increased nuchal translucency thickness (NT), tricuspid regurgitation and abnormal flow in the ductus venosus in a large population of singleton pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation., Methods: This was a retrospective study of prospectively collected data from singleton pregnancies attending for a routine ultrasound scan at 11-13 weeks' gestation, which included examination of fetal anatomy, measurement of NT and assessment of blood flow across the tricuspid valve and in the ductus venosus, according to a standardized protocol. The incidence of fetal NT ≥ 95 th and ≥ 99 th percentiles, tricuspid regurgitation and reversed a-wave in the ductus venosus in fetuses with and those without a major heart defect was determined and the performance of each marker and their combination in the detection of major heart defects was calculated., Results: The study population of 93 209 pregnancies with no apparent chromosomal abnormality included 211 (0.23%) with a fetal major heart defect and 92 998 morphologically normal neonates. In 113 (53.6%) cases with a major heart defect, the diagnosis was made at the 11-13-week scan, in 82 (38.9%) at the 18-24-week scan, in 10 (4.7%) at the third-trimester scan and in six (2.8%) postnatally. At the 11-13-week scan, we diagnosed all cases of tricuspid or pulmonary atresia and polyvalvular dysplasia, > 90% of cases of hypoplastic left heart syndrome or atrioventricular septal defect, about 60% of complex heart defects and cases of left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), 30-40% of cases of tetralogy of Fallot and arch abnormalities, 25% of tricuspid valve abnormalities and about 15% of cases of transposition of the great arteries, but none of aortic or pulmonary stenosis or common arterial trunk. Fetal NT ≥ 95 th or ≥ 99 th percentile, tricuspid regurgitation or abnormal ductus venosus flow was observed in 77 (36.5%), 45 (21.3%), 61 (28.9%) and 58 (27.5%) fetuses with a major heart defect, respectively, and in 5678 (6.1%), 857 (0.9%), 1136 (1.2%) and 1644 (1.8%) of those without a heart defect. Any one of NT ≥ 95 th percentile, tricuspid regurgitation or abnormal flow in the ductus venosus was found in 117 (55.5%; 95% CI, 48.5-62.3%) fetuses with a heart defect and in 8166 (8.8%; 95% CI, 8.6-9.0%) of those without a heart defect. Any one of NT ≥ 99 th percentile or the other two markers was found in 99 (46.9%; 95% CI, 40.0-53.9%) fetuses with a heart defect and in 3517 (3.8%; 95% CI, 3.7-3.9%) of those without a heart defect., Conclusion: At 11-13 weeks' gestation, measurement of fetal NT and assessment of flow across the tricuspid valve and in the ductus venosus can lead to early diagnosis of major heart defect. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ release channels located on the ER membrane, which in mammals consist of 3 different subtypes (IP3R1, IP3R2, and IP3R3) encoded by 3 genes, Itpr1, Itpr2, and Itpr3, respectively. Studies utilizing genetic knockout mouse models have demonstrated that IP3Rs are essential for embryonic survival in a redundant manner. Deletion of both IP3R1 and IP3R2 has been shown to cause cardiovascular defects and embryonic lethality. However, it remains unknown which cell types account for the cardiovascular defects in IP3R1 and IP3R2 double knockout (DKO) mice. In this study, we generated conditional IP3R1 and IP3R2 knockout mouse models with both genes deleted in specific cardiovascular cell lineages. Our results revealed that deletion of IP3R1 and IP3R2 in cardiomyocytes by TnT-Cre, in endothelial / hematopoietic cells by Tie2-Cre and Flk1-Cre, or in early precursors of the cardiovascular lineages by Mesp1-Cre, resulted in no phenotypes. This demonstrated that deletion of both IP3R genes in cardiovascular cell lineages cannot account for the cardiovascular defects and embryonic lethality observed in DKO mice. We then revisited and performed more detailed phenotypic analysis in DKO embryos, and found that DKO embryos developed cardiovascular defects including reduced size of aortas, enlarged cardiac chambers, as well as growth retardation at embryonic day (E) 9.5, but in varied degrees of severity. Interestingly, we also observed allantoic-placental defects including reduced sizes of umbilical vessels and reduced depth of placental labyrinth in DKO embryos, which could occur independently from other phenotypes in DKO embryos even without obvious growth retardation. Furthermore, deletion of both IP3R1 and IP3R2 by the epiblast-specific Meox2-Cre, which targets all the fetal tissues and extraembryonic mesoderm but not extraembryonic trophoblast cells, also resulted in embryonic lethality and similar allantoic-placental defects. Taken together, our results demonstrated that IP3R1 and IP3R2 play an essential and redundant role in maintaining the integrity of fetal-maternal connection and embryonic viability., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate the performance of fetal intelligent navigation echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volumes in generating 3 specific abnormal cardiac views (left ventricular outflow tract, right ventricular outflow tract, and 3-vessel and trachea) used to screen for d-transposition of the great arteries (d-TGA)., Methods: In this prospective study, 1 or more STIC volumes were obtained from the 4-chamber view in 34 second- and third-trimester fetuses with d-TGA. Each appropriate STIC volume was evaluated by STICLoop (Samsung Medison, Seoul, Korea) before applying the FINE method. One optimal volume per fetus was selected by observers. The visualization rates of the 3 specific abnormal cardiac views of d-TGA and their diagnostic elements were calculated, and the reliability between 2 observers was verified by the intraclass correlation coefficient., Results: Fetal intelligent navigation echocardiography applied to STIC volume data sets of fetuses with d-TGA successfully generated the 3 specific abnormal cardiac views in the following manner for 2 observers: 75.0% (n = 21) for the left ventricular outflow tract, 89.2% (n = 25) for the right ventricular outflow tract, and 85.7% (n = 24) for the 3-vessel and trachea view. Twenty-four (85.7%) of the STIC volume data sets showed 2 or 3 of the abnormal cardiac views. The interobserver intraclass correlation coefficients between the 2 observers ranged from 0.842 to 1.000 (95% confidence interval), indicating almost perfect reliability for the 2 observers., Conclusions: In cases of d-TGA, the FINE method has a high success rate in generating 3 specific abnormal cardiac views and therefore can be performed to screen for this congenital defect., (© 2019 by the American Institute of Ultrasound in Medicine.)

Objective: EXTrauterine Environment for Neonatal Development (EXTEND) is a system to support ongoing fetal growth and organ development in an extrauterine environment, utilizing a pumpless low-resistance oxygenator circuit. The aim of this study was to evaluate hemodynamics and cardiac function in fetal sheep sustained on the EXTEND system., Methods: This was a prospective study of fetal sheep supported for a minimum of 3 weeks on EXTEND. Hemodynamic parameters were assessed weekly and included heart rate, mean arterial pressure (MAP), Doppler-echocardiography-derived cardiac output (CO), pulsatility indices (PIs) of the fetal middle cerebral artery (MCA), umbilical artery (UA) and ductus venosus and cardiac function, as assessed by speckle-tracking-derived global longitudinal strain and strain rate in the right (RV) and left (LV) ventricles. Parameters were compared at 0 days and 1, 2 and 3 weeks following placement on EXTEND., Results: Of 10 fetal sheep enrolled, seven survived for 3 weeks and were included in the analysis. Median gestational age at cannulation was 107 (range, 95-109) days. Heart rate decreased and MAP increased significantly, but within acceptable ranges, during the study period. The quantities and relative ratios of right and left CO remained stable within the anticipated physiological range throughout the study period. Vascular tracings and PIs appeared to be similar to those seen normally in the natural in-utero state, with MCA-PI being higher than UA-PI. UA tracings demonstrated maintained abundant diastolic flow despite the absence of placental circulation. In both the RV and LV, strain decreased significantly at 1 and 2 weeks relative to baseline but returned to baseline values by week 3., Conclusions: The EXTEND mechanical support system replicates natural physiology and creates a stable and sustainable cardiovascular construct that supports growth over a 3-week period. However, there is a period of depressed contractility within the first week with subsequent improvement by week 3. This may reflect a period of physiological accommodation that warrants further investigation. This study lays the foundation for further exploration as the EXTEND system moves towards human application. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To develop the Z score reference ranges of fetal cardiac output (CO) in healthy fetuses from 12 to 40 weeks of pregnancy., Methods: A cross-sectional descriptive study was undertaken among low-risk singleton pregnancies with healthy fetuses between 12 and 40 weeks. The right ventricular cardiac output (RCO), left ventricular cardiac output (LCO), and combined cardiac output (CCO) were measured by 2-dimensional ultrasound with the Doppler velocity of the aorta and pulmonary arteries. The pregnancies were followed until delivery RESULTS: The RCO, LCO, and CCO were determined in 700 fetuses. The predictive models of the CO as a function of gestational age (GA) and biparietal diameter were identified, and the Z score reference ranges were constructed. The means and standard deviations of CO on both sides were increased with GA and biparietal diameter as power models. Nomograms for the LCO, RCO, and CCO were established (ie, RCO = 0.000148 × GA 4.283034 ; SD = 0.000131 × GA 4.026209 ; LCO = 0.000514 × GA 3.790944 ; SD = 0.000169 × GA 3.815546 ). The RCO was much more increased than the LCO with advancing GA., Conclusions: The Z score reference ranges and percentile charts of fetal CO were constructed throughout gestation with a large sample size. This may be helpful in detection of cardiac disorders, especially cardiomyopathy, cardiac anomalies, fetal anemia, and fetal growth restriction., (© 2019 by the American Institute of Ultrasound in Medicine.)

Objectives: To investigate fetal hemodynamic alterations using transabdominal ultrasound in fetuses with isolated mild-to-moderate ventriculomegaly (VM)., Methods: Fetuses diagnosed with isolated mild-to-moderate VM by transabdominal ultrasound were evaluated for hemodynamic changes, including changes in fetal cardiac function, the umbilical artery, the ductus venosus, and the middle cerebral artery. The fetuses with isolated mild-to-moderate VM were divided into 2 groups, namely, before 32 weeks' gestation (20 weeks-31 weeks 6 days) and after 32 weeks' gestation (32-38 weeks), and matched to corresponding healthy control fetuses., Results: The 53 fetuses with VM before 32 weeks had a longer mean isovolumetric relaxation time (IRT; mean ± SD, 42.9 ± 6.8 versus 40.4 ± 5.0 milliseconds; P < .05) and an apparently higher modified myocardial performance index 0.46 ± 0.06 versus 0.43 ± 0.05; P < .01) than the healthy control fetuses. The 43 fetuses with VM after 32 weeks had a significantly longer mean IRT (45.5 ± 6.7 versus 40.9 ± 7.2 milliseconds; P < .01) and a lower UA pulsatility index (0.81 ± 0.13 versus 0.89 ± 0.11; P < .01). The optimal cutoff levels for the IRT in the prediction of adverse perinatal outcomes were 40 and 43 milliseconds before and after 32 weeks, respectively (sensitivity, 100% versus 100%; specificity, 40.4% versus 50.0%; area under the curve, 0.601 versus 0.748; 95% confidence interval, 0.457-0.733 versus 0.590-0.869; P = .291 versus .005)., Conclusions: Some fetuses with isolated mild-to-moderate VM may have impaired cardiac function, characterized by a higher modified myocardial performance index or longer IRT. This finding might be useful for improving fetal surveillance., (© 2019 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals, Inc. on behalf of the American Institute of Ultrasound in Medicine.)

Objectives: Early fetal echocardiography is becoming increasing common during the nuchal translucency scan period. The aim of this meta-analysis was to assess the accuracy of first-trimester fetal echocardiography in diagnosing congenital heart defects (CHDs)., Methods: The databases of PubMed, Embase, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature were systematically searched for the candidate articles, and the references of included studies were also examined. We recorded the characteristics of the included studies and assessed the quality of each study by the Quality Assessment of Diagnostic Accuracy Studies tool. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated with Meta-Disc version 1.4 software (Ramón y Cajal Hospital, Madrid, Spain). We also evaluated the publication bias by using Stata version 12.0 software (StataCorp, College Station, TX)., Results: This meta-analysis included 18 studies with 26,201 fetal hearts. The overall pooled sensitivity, specificity, PLR, and NLR were 0.750, 0.999, 392.95, and 0.277, respectively. The DOR and AUC were 1736.0 and 0.9331. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for major CHDs were 0.838, 1.000, 725.69, 0.203, 5084.8, and 0.9617., Conclusions: First-trimester fetal echocardiography had high value in diagnosing CHDs, especially major CHDs., (© 2019 by the American Institute of Ultrasound in Medicine.)

Formation of the human heart involves complex biological signals, interactions, specification of myocardial progenitor cells, and heart tube looping. To facilitate survival in the hypoxemic intrauterine environment, the fetus possesses structural, physiological, and functional cardiovascular adaptations that are fundamentally different from the neonate. At birth, upon separation from the placental circulation, the neonatal cardiovascular system takes over responsibility of vital processes for survival. The transition from the fetal to neonatal circulation is considered to be a period of intricate physiological, anatomical, and biochemical changes in the cardiovascular system. With a successful cardiopulmonary transition to the extrauterine environment, the fetal shunts are functionally modified or eliminated, enabling independent life. Investigations using medical imaging tools such as ultrasound and magnetic resonance imaging have helped to define normal and abnormal patterns of cardiac remodeling both in utero and ex utero. This has not only allowed for a better understanding of how congenital cardiac malformations alter the hemodynamic transition to the extrauterine environment but also how other more common complications during pregnancy including intrauterine growth restriction, preeclampsia, and preterm delivery adversely affect offspring cardiac remodeling during this early transitional period. This review article describes key cardiac progenitors involved in embryonic heart development; the cellular, physiological, and anatomical changes during the transition from fetal to neonatal circulation; as well as the unique impact that different pregnancy complications have on cardiac remodeling., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

The circulatory physiology of fetuses differs from that of neonates. The concept of biventricular combined cardiac output is necessary to understand and assess the fetal cardiac function. Fetal cardiac function has been estimated using echocardiographic methods such as M-mode, B-mode and pulsed wave Doppler. In addition, recent studies have reported the utility of tissue Doppler imaging in fetal echocardiography. However, parameters for fetal cardiac function remain to be established. Recently, we developed two novel techniques for assessing fetal cardiac function: an automatic fractional shortening method and E/e' determination using the dual-gate Doppler method. These two techniques are expected to be reliable and useful for assessing the fetal status in various pathological conditions., (© 2019 Japan Society of Obstetrics and Gynecology.)

Aim: To evaluate the level of agreement between M-mode and pulsed-wave tissue Doppler imaging (PW-TDI) techniques in assessing fetal mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE) and septal annular plane systolic excursion (SAPSE) in a low-risk population., Methods: This prospective longitudinal study included healthy fetuses assessed from 18 to 40 weeks of gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE were measured using anatomical M-mode and PW-TDI. The agreement between the two diagnostic tests was assessed using Bland-Altman analysis., Results: Fifty fetuses were included in the final analysis. Mean values of TASPE were higher than that of MAPSE. There was a progressive increase of TAPSE, MAPSE and SAPSE values with advancing gestation. For each parameter assessed, there was an overall good agreement between the measurements obtained with M-mode and PW-TDI techniques. However, the measurements made with M-mode were slightly higher than those obtained with PW-TDI (mean differences: 0.03, 0.05 and 0.03 cm for TAPSE, MAPSE and SAPSE, respectively). When stratifying the analyses by gestational age, the mean values of TAPSE, MAPSE and SAPSE measured with M-Mode were higher compared to those obtained with PW-TDI, although the mean differences between the two techniques tended to narrow with increasing gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE measurements were all significantly, positively associated with gestational age (all P < 0.001)., Conclusion: Fetal atrioventricular annular plane displacement can be assessed with M-mode technique, or with PW-TDI as the velocity-time integral of the myocardial systolic waveform. Atrioventricular annular plane displacement values obtained with M-mode technique are slightly higher than those obtained with PW-TDI., (© 2019 Japan Society of Obstetrics and Gynecology.)

Magnetic resonance imaging (MRI) is an appealing technology for fetal cardiovascular assessment. It can be used to visualize fetal cardiac and vascular anatomy, to quantify fetal blood flow, and to quantify fetal blood oxygen saturation and hematocrit. However, there are practical limitations to the use of conventional MRI for fetal cardiovascular assessment, including the small size and high heart rate of the human fetus, the lack of conventional cardiac gating methods to synchronize data acquisition, and the potential corruption of MRI data due to maternal respiration and unpredictable fetal movements. In this review, we discuss recent technical advances in accelerated imaging, image reconstruction, cardiac gating, and motion compensation that have enabled dynamic MRI of the fetal heart.

Embryogenesis of the heart involves the complex cellular differentiation of slow-conducting primary myocardium into the rapidly conducting chamber myocardium of the adult. However, small areas of relatively undifferentiated cells remain to form components of the adult cardiac conduction system (CCS) and nodal tissues. Further investigation has revealed additional areas of nodal-like tissues outside of the established CCS. The embryologic origins of these areas are similar to those of the adult CCS. Under pathologic conditions, these areas can give rise to important clinical arrhythmias. Here, we review the embryologic basis for these proarrhythmic structures within the heart., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To determine whether ultrasound (US) imaging of obese pregnant women in early gestation improves fetal cardiac visualization., Methods: We report a prospective longitudinal trial comparing late first- and early second-trimester US to traditional second-trimester US for fetal cardiac screening in maternal obesity. All study participants received US for fetal cardiac screening at a gestational age of 13 weeks to 15 weeks 6 days using a transvaginal or transabdominal approach (UST1). All patients also underwent a traditional transabdominal examination at 20 to 22 weeks (UST2). If UST2 failed to complete the cardiac visualization, a follow up examination (second UST2) was performed 2 to 4 weeks later. Imaging was considered complete if the visceral situs, 4 chambers, outflow tracts, and 3 vessels were visualized. The completion rates between UST1 and UST2 were the primary outcomes. A power analysis (85%) and sample size calculation (n = 145) were performed., Results: A total of 152 pregnancies met study criteria. Completion rates of cardiac screening were 77% for UST1 and 70% for UST2 (P = .143). This comparison reached statistical significance in patients with a body mass index of greater than 40 kg/m 2 (UST1 [69%] versus UST2 [38%]; P = .001). Sixty-two percent of patients with a body mass index of greater than 40 kg/m 2 required second UST2. The highest fetal cardiac screening completion rate was achieved when UST1 was combined with UST2 (96.1%). In 1 fetus, congenital heart disease was detected at UST1 and later confirmed., Conclusions: This study represents the largest prospective trial assessing early-gestation US for fetal cardiac screening in the setting of maternal obesity. In obese pregnancies, the addition of early-gestation US to the 20- to 22-week US substantially improves the visualization of fetal cardiac anatomy., (© 2018 by the American Institute of Ultrasound in Medicine.)

Objective: This study aims to evaluate the value of the ultrasound-related scoring system on pregnant patients receiving assisted reproductive technology (IVF/ICSI) and early pregnancy outcome., Materials and Methods: This prospective study included 208 pregnant women receiving assisted reproductive technology (IVF/ICSI). The following ultrasound parameters were measured: gestational sac size, the proportion of the embryo and gestational sac (embryo/gestational sac), yolk sac size, and fetal cardiac activity. The above data were assigned according to the ongoing pregnancy rate (up to 14 weeks), and the score increased parallel to the pregnancy rate. All patients were grouped according to their scores., Results: Patients with a score of 4-5 had a low ongoing pregnancy rate of 14.29%, while patients with a score of 6-7 had an ongoing pregnancy rate of 55.56%. Surprisingly, patients with a score of 8-9 had an ongoing pregnancy rate of 97.22%. In addition, it was found that the ongoing pregnancy rate was 100% (36/36) in patients with a score of 9. Conversely, there was no ongoing pregnancy in patients with a score of 4., Conclusion: First, this scoring system is strongly associated with an ongoing pregnancy of over 14 weeks. Second, some reassurance can be given to patients with favorable ultrasound parameters, regardless of maternal age or previous pregnancy loss. Third, it would be meaningless to continue the pregnancy in patients with a score of 4, according to the scoring system. Fourth, patients without cardiac activity and embryos at days 33-35 after embryo transfer should discontinue the pregnancy, while patients with embryos should proceed with the pregnancy., (Copyright © 2019. Published by Elsevier B.V.)