Association between placental DNA methylation and fetal congenital heart disease.

Congenital heart disease (CHD) is a worldwide problem with high morbidity and mortality. Early diagnosis of congenital heart disease is still a challenge in clinical work. In recent years, few studies indicated that placental methylation may be predictors of CHD. More studies are needed to confirm the association between placental methylation and CHD. The aim of this study was to investigate the association between prenatal placental DNA methylation and CHD. Placental tissues were obtained from four fetuses during the second trimester with isolated, non-syndromic congenital heart disease, including three cases with double outlet right ventricle (DORV) and one case with tetralogy of Fallot (TOF), and four unaffected fetuses as controls. The Illumina Infinium Human Methylation 850K BeadChip assay was employed to identify differential methylation sites (DMSs) and differential methylation regions (DMRs). Differential methylation was evaluated by comparing the ß-values for individual CpG loci in cases vs. controls. In addition, the function of genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis and KEGG pathway analysis. Compared with the control group, we identified 9625 differential methylation genes on 26,202 DMSs (p < 0.05), of which 6997 were hyper-methylation and 2628 were hypo-methylation. The top 30 terms of GO biological process and KEGG enrichment analysis of DMSs were connected with multiple important pathways of heart development and disease. Ten differentially methylated regions and the genes related to DMRs, such as TLL1, CRABP1, FDFT1, and PCK2, were identified. The deformity caused by the loss of function of these genes is remarkably consistent with the clinical phenotype of our cases. The DNA methylation level of placental tissue is closely associated with fetal congenital heart disease.

[Clinical and genetic characteristics of 12 cases of Loeys-Dietz syndrome].

OBJECTIVE: To summarize the clinical features and spectrum of genetic variants in 12 patients with Loeys-Dietz syndrome (LDS), and to explore the correlation between the type of genetic variants and clinical phenotypes. METHODS: Twelve patients suspected for LDS at Beijing Anzhen Hospital Affiliated to Capital Medical University from January 2015 to January 2022 were selected as the study subjects. Clinical data of the patients were collected. Genomic DNA was extracted from peripheral blood samples and subjected to genetic testing. Pathogenicity of candidate variants was analyzed. RESULTS: The clinical phenotypes of the 12 patients have mainly included cardiovascular, musculoskeletal, craniofacial, skin, ocular and other systemic signs. Four patients (patients 5-1, 5-2, 6, 7) have carried heterozygous missense variants of the TGFBR1 gene, 5 patients (patients 1-1, 1-2, 2, 3, 4) have carried heterozygous variants of the TGFBR2 gene, and 2 patients (patients 8-1, 8-2) had carried heterozygous frameshift variants of the TGFB3 gene. One patient (patient 9) had carried a heterozygous missense variant of the SMAD3 gene. Among these, TGFBR1 c.603T>G (p.1201M) and TGFB3 c.536delA (p.H179FS35) had not been reported previously. CONCLUSION: Variants of the TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2 genes are mainly associated with LDS. The severity of the disease phenotype caused by the same variant may vary, whilst the clinical phenotype caused by different variant sites may be specific.

Diagnosis of fetal total anomalous pulmonary venous connection based on the post-left atrium space ratio using artificial intelligence.

OBJECTIVE: To explore whether the post-left atrium space (PLAS) ratio would be useful for prenatal diagnosis of total anomalous pulmonary venous connection (TAPVC) using echocardiography and artificial intelligence. METHODS: We retrospectively included 642 frames of four-chamber views from 319 fetuses (32 with TAPVC and 287 without TAPVC) in end-systolic and end-diastolic periods with multiple apex directions. The average gestational age was 25.6 ± 2.7 weeks. No other cardiac or extracardiac malformations were observed. The dataset was divided into a training set (n = 540; 48 with TAPVC and 492 without TAPVC) and test set (n = 102; 20 with TAPVC and 82 without TAPVC). The PLAS ratio was defined as the ratio of the epicardium-descending aortic distance to the center of the heart-descending aortic distance. Supervised learning was used in DeepLabv3+, FastFCN, PSPNet, and DenseASPP segmentation models. The area under the curve (AUC) was used on the test set. RESULTS: Expert annotations showed that this ratio was not related to the period or apex direction. It was higher in the TAPVC group than in the control group detected by the expert and the four models. The AUC of expert annotations, DeepLabv3+, FastFCN, PSPNet, and DenseASPP were 0.977, 0.941, 0.925, 0.856, and 0.887, respectively. CONCLUSION: Segmentation models achieve good diagnostic accuracy for TAPVC based on the PLAS ratio.

Retrograde flow in aortic isthmus in normal and fetal heart disease by principal component analysis and computational fluid dynamics.

OBJECTIVES: Reverse flow Retrograde flow (RF) of blood in the aortic isthmus can be observed in different types of fetal heart disease (FHD), including abnormalities in heart structure and function. This study sought to investigate the relationship between RF and blood flow parameters, and develop a computational fluid dynamics (CFD) model to understand the mechanisms underlying this observation. MATERIAL AND METHODS: A total of 281 fetuses (gestational age [GA] 26.6±.3 weeks) with FHD and 2803 normal fetuses (GA: 26.1±.1 weeks) by fetal echocardiography collected from May 2016 to December 2018. Principal component analysis (PCA) was performed to find the relationship and the CFD model reconstructed from 3D/4D spatio-temporal image correlation (STIC) images to simulate hemodynamics. RESULTS: There was a significant difference in the percentages of RF between the study (80/201 (39%)) and control (29/2803 (1%)) groups (p < 0.05). The RF occur when the aorta flow rate (left heart) is reduced to 60% by CFD stimulation. Pearson correlation analysis showed significant correlations between flow rate and wall shear stress(WSS) (r = .883, p = 0.047) variables at the AI. CONCLUSION: Volumetric flow rate of AO or left heart was the main component of the cause of RF. The hemodynamics of the cardiovascular system have highly complex behavior hinge on the turbulent nature of circulating blood flow.

Prenatal diagnosis of isolation of aortic brachiocephalic artery.

BACKGROUND: Isolated aortic brachiocephalic artery (IABA) is a rare congenital aortic arch anomaly. It is difficult to diagnose IABA prenatally and the prevalence in the prenatal population is unknown. PURPOSE: To evaluate the echocardiographic characteristics and associations in fetuses with IABA. MATERIAL AND METHODS: We retrospectively analyzed all cases of prenatal diagnosis of IABA from January 2012 to November 2020 and reviewed the follow-up results. Copy Number Variation Sequencing (CNV-Seq) was performed using the biological specimens of the of the fetuses and family members. RESULTS: Ten cases (10/45652, 0.022%) of IABA were identified in our center. The prevalence of the cases with isolated left subclavian artery (ILSCA) in the right aortic arch (RAA) population was 0.98% (6/613). The ILSCA was the most common isolated arch branch. All the isolated branches were on the opposite side of aortic arch in all the cases. The "ice stick" sign in the coronal section could be seen in most cases of IABA. Of the 10 cases, 8 (8/10, 80%) were associated with tetralogy of Fallot (TOF). Two cases of IABA were combined with 22q11.2 deletion syndrome. CONCLUSION: IABA is a rare aortic anomaly. ILSCA was the most common isolated arch branch and TOF was the most common associated intra-cardiac anomaly. The "ice stick" sign in the coronal section could indicate a diagnosis of the IABA.

Fetal atrial appendage aneurysm: Prenatal diagnosis by echocardiography and prognosis.

BACKGROUND: Congenital atrial appendage aneurysm (AAA) is a rare malformation which can coexist with potentially lethal complications. We aimed to summary echocardiographic characteristics and prognosis of fetal AAA. METHODS: We retrospectively analyzed the echocardiographic data of 17 fetuses with AAA，and their outcomes or pathological reports were also collected. RESULTS: Eight fetuses with left AAA (LAAA) and 9 fetuses with right AAA (RAAA) were identified. Five fetuses were diagnosed with other cardiac defects. Two fetuses with RAAA presented with arrhythmias, including atrial premature beats (n = 1) and bradyarrhythmia (n = 1). LAAA could be detected by four-chamber view (50.0%) and short-axis view (100.0%). RAAA could be detected by four-chamber view (100.0%), and view of right ventricular inflow tract (33.3%). There were three cases with mild pericardial effusion. Three cases with complex cardiac defects were selectively terminated, with confirmation of LAAA by autopsy in one case. Fourteen fetuses were born. After following 2 (range, 1-5) years, the AAA disappeared in one case with LAAA and two cases with RAAA. While, 11 cases were still diagnosed with AAA. Atrial premature beats with RAAA, which appeared in prenatal period, still persisted after birth. CONCLUSION: Congenital AAA is a rare abnormality in utero. The short-axis view and the four-chamber view were the most useful views to detect fetal AAA. Fetal AAA may disappear in childhood. Atrial tachyarrhythmias in utero may exist persistently after birth. Patients with AAA should be followed up closely and appropriate intervention should be taken when complications appeared.

The Differential Diagnosis of Double Aortic Arch and Right Aortic Arch with Mirror-Image Branches in the Fetus: A Potential Novel Method.

The objective of this study was to explore a new method for the differential diagnosis between fetal double aortic arch (DAA) and right aortic arch with mirror-image branches (RAA-MB). Clinical data and prenatal echocardiographic features of the DAA (n = 22) and RAA-MB (n = 65) confirmed by postnatal or autopsy findings were analyzed retrospectively. The angles between the two aortic arches in the DAA group and between the right aortic arch and the mirror branch were measured. The differences between the two groups and differential diagnosis value of the angles were compared and analyzed based on the receiver operating characteristic curve. The proportion of left-sided ductal arteriosus (100%) was higher in the DAA group than that (32.3%) in the RAA-MB group, (P < 0.05). The proportion of conotruncal anomalies is higher in the RAA-MB group (64.6%) than in the DAA group (18.2%) (P < 0.05). There was a significant difference in the angles between the groups (DAA: 50.3° ± 8.3° vs. RAA-MB: 82.9° ± 13.8°) (P < 0.01). When the cutoff value was 62.8°, the sensitivity and specificity of the differential diagnosis were 95.5% and 96.9%, respectively. Distinguishing the angle measurement between DAA and RAA-MB is helpful in prenatal prognosis. We recommend a cutoff value of 62.8°.

Fetal Ultrasonic Evaluation of Bronchial Morphology in Fetuses with Isomerism.

OBJECTIVE: The aim of the study was to evaluate whether fetal ultrasound could determine bronchial isomerism and distinguish left isomerism from right isomerism. METHODS: We identified 110 healthy fetuses and 28 fetuses with isomerism. The outer angle between the tracheal midline and the inner margin of the bronchus is measured. The bronchial angles and the ratio of left/right bronchial angle were used to differentiate bronchial morphology and confirm the presence of bronchial isomerism in pathological cases. RESULTS: The normal angles of the left and right bronchi were 146.98° (95% CI, 145.15-147.81°) and 167.37° (95% CI, 166.30-168.44°), separately. The cutoff bronchial angle of 156.5° was used to distinguish left bronchus from right bronchus. The bronchial isomerism could be identified in all pathological cases by autopsy and bronchial-atrial concordance occurred in 27 pathological cases (96.4%). In 21 pathological cases, the bilateral bronchial angle was <156.5 versus >156.5 differentiated left from right isomerism, respectively. The ratio of the left/right bronchial angle of >0.935 identified 92.9% (26/28) of all pathological cases, with a sensitivity of 89.7%. CONCLUSIONS: Fetal ultrasound can detect the bronchial morphology and the presence of bronchial isomerism in fetuses with isomerism according to bronchial angles and the ratio of left/right bronchial angle.

Prenatal diagnosis of left-sided aortic arch, right descending aorta and right-sided ductus arteriosus associated with anomalous origin of left pulmonary artery from ascending aorta.

Left-sided aortic arch (LAA), right descending aorta (rDAo), and right-sided ductus arteriosus (RDA) constitute a rare aortic arch anomaly. Moreover, anomalous origin of the pulmonary artery from the ascending aorta, especially that of the left pulmonary artery, is also a rare anomaly of the pulmonary artery branches. Because of the presence of the ductus arteriosus, prenatal ultrasound is an optimal diagnostic tool for the LAA with rDAo. Four-dimensional color Doppler can clearly demonstrate the spatial relationship between the LAA, rDAo, and RDA and the anomalous origin of the left pulmonary artery from the ascending aorta.

Diagnosis of double-chambered left ventricle by echocardiogram and cardiac magnetic resonance imaging: A rare case in an adult.

Double-chambered left ventricle (DCLV) is a very rare malformation which is congenital. In most cases, the left ventricle (LV) is divided into two parallel chambers by a septum or aberrant muscular structure, with fewer superior-inferior arrangement. Here, we present the case of an asymptomatic 25-year-old man who was diagnosed with superior-inferior arrangement DCLV on transthoracic echocardiography and cardiac magnetic resonance (CMR). DCLV generally does not cause serious outcomes. Owing to absence of any symptoms, no treatment was provided, and the patient was regularly followed up.

Differential diagnosis of fetal large ventricular septal defect and tetralogy of Fallot based on big data analysis.

BACKGROUND AND OBJECTIVES: To analyze echocardiographic parameters of fetal large ventricular septal defect (VSD) and tetralogy of Fallot (TOF) in the context of multicenter data and big data analysis because these two diseases are often misdiagnosed in fetuses, and to find the key parameters for the differential diagnosis of these two diseases. METHODS: A total of 305 cases of large VSD and 192 cases of TOF diagnosed by fetal echocardiography from August 2010 to July 2016 from the database of Beijing Key Laboratory of Fetal Heart Defects were analyzed. Quantile regression of the 48 echocardiographic parameters of the 6272 normal fetuses from seven Chinese medical institutions was performed to determine the Q-score. The forward selection method and the naive Bayesian classification method were used to analyze the core differential diagnostic variables of fetal TOF and VSD. RESULTS: The Q-score of the internal diameter of the aorta (AO Q-score), the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO), and the Q-score of the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO Q-score) were key parameters for the differential diagnosis of fetal large VSD and TOF. PA/AO was the primary parameter, with an area under the receiver operating characteristic curve of 0.951. CONCLUSIONS: These findings provide a new method for the prenatal diagnosis of large VSD and TOF and a theoretical basis for the intelligent diagnosis of large VSD and TOF.

Prenatal Diagnosis of the Fetal Retroesophageal Left Brachiocephalic Vein: Case Series and Review of the Literature.

A retroesophageal left brachiocephalic vein (LBCV) is a highly rare anomaly. We retrospectively analyzed 7 cases of a retroesophageal LBCV that were prenatally diagnosed from a database of fetal echocardiogram of 31,356 cases. The 3-vessel view and the long-axis view are the main views for confirming a fetal retroesophageal LBCV. An isolated retroesophageal LBCV is rare, and it is typically associated with congenital heart defects, especially conotruncal defects and a right aortic arch. An isolated fetal retroesophageal LBCV has a good prognosis and does not need surgical treatment.

Post-Left Atrium Space Index in Fetuses With Total Anomalous Pulmonary Venous Connection and Other Congenital Heart Diseases.

OBJECTIVES: We aimed to explore the value of the post-left atrium space (PLAS) index in the diagnosis of total anomalous pulmonary venous connection (TAPVC) and the effect of other congenital heart diseases on the PLAS index in the fetus. METHODS: The PLAS index of 69 fetuses with TAPVC was analyzed retrospectively. Approximately 252 healthy fetuses were randomly selected as controls, and 110 cases of intracardiac malformations were randomly selected for comparison. The PLAS index was defined as the ratio of the left atrium-descending aorta distance divided by the descending aorta diameter from the 4-chamber view in the end-systolic phase. RESULTS: There were no significant differences in the PLAS index among the 3 groups of isolated TAPVC subtypes (P > .05), or among the isolated TAPVC group and the simple and complex cardiac anomaly groups (P > .05). Compared with the control group, the PLAS index of the TAPVC group was significantly increased (P < .001). The PLAS index was significantly higher in the TAPVC group than in hypoplastic left heart syndrome, endocardial cushion defect, conotruncal defect, and ventricular septal defect groups (P < .05). The PLAS indices of the hypoplastic left heart syndrome, endocardial cushion defect, and conotruncal defect groups were all higher than that of the control group (P < .05). There was no significant difference in the PLAS index between the ventricular septal defect and control groups (P > .05). CONCLUSIONS: The PLAS index is a sensitive parameter for the diagnosis of fetal TAPVC. There were no significant differences in the PLAS index among different TAPVC types. Complex intracardiac anomalies have an influence on the PLAS index.

Technical feasibility of umbilical cannulation in midgestation lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND).

EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system for supporting extremely premature infants that replicates in utero conditions by maintaining a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit connected to the umbilical vessels. Target gestational age (GA) for EXTEND support in human infants is 23-27 weeks, when immature lungs are most susceptible to injury in the setting of air ventilation. We previously demonstrated physiologic support of premature lambs cannulated at 105-117 days GA (lungs developmentally analogous to the 23-27 week GA human infant) for up to 28 days on EXTEND. In the present study, we sought to determine the technical feasibility of umbilical vessel cannulation in 85-96 days GA lambs delivered to EXTEND at weights equivalent to the 23-27 week GA human infant (500-850 g). Five preterm lambs were cannulated at 85-96 days GA (term 145 days) and supported on EXTEND for 4-7 days. All lambs underwent umbilical artery and umbilical vein cannulation. Circuit flows and pressures were monitored continuously, and blood gases were obtained at regular intervals for assessment of oxygen parameters. Systemic pH and lactate were measured at least once daily. Mean body weight at cannulation was 641 ± 71 g (range 480-850 g). All lambs were cannulated successfully (cannula size varied from 8 to 12 Fr), and mean survival on EXTEND was 140 ± 7 hours. Mean circuit flow was 213 ± 15 mL/kg*min, mean pH was 7.37 ± 0.01, and mean lactate was 1.6 ± 0.2 mmol/L. During the initial 120 hours after EXTEND cannulation, there were no significant differences between 85-96 days GA lambs and 105-117 days GA lambs in weight-adjusted circuit flows, oxygen delivery, pH, or lactate levels. This study demonstrates successful umbilical cord cannulation and adequate circuit flows and oxygen delivery in midgestation lambs size-matched to the 23-27 week GA human fetus, which represents an important step in the translation of EXTEND to clinical practice.

Prenatal diagnosis of tetralogy of Fallot associated with pulmonary artery sling: Two case reports.

Tetralogy of Fallot (TOF) is a common condition accounting for 10%-20% of all fetal cyanotic congenital heart disease cases. Pulmonary artery sling (PAS), or aberrant left pulmonary artery, is a rare congenital cardiovascular malformation. Approximately 58%-83% of PAS is associated with other cardiovascular malformations, TOF being rarest. The diagnosis of PAS is generally incidental or made at autopsy. Cases of prenatal diagnoses of TOF associated with PAS have not yet been reported. Here, we report two cases of TOF associated with PAS diagnosed prenatally in our hospital.

Double-chambered left ventricle diagnosis by 2D and 3D echocardiography: From fetus to birth.

Double-chambered left ventricle (DCLV) is a rare cardiac anomaly and is characterized by the division of the left ventricle by abnormal muscle and/or fiber bundles into two chambers. We hereby report a fetus which was diagnosed with DCLV in utero by 2D and 3D Fetal echocardiography and the findings were confirmed after birth.

Echocardiographic features of interventricular septal dissection in patients with Behçet's disease.

Involvement of the heart in Behçet's disease (BD) is rare. We retrospectively analyzed these three patients with interventricular septal (IVS) dissection in BD and discussed the echocardiographic manifestations of IVS dissections. In our patients, the echocardiographic characteristics of IVS dissection were echo-free space in the IVS basal segment or basal to middle segment, dilatation in the diastole and contraction in systole, and abnormal turbulent blood flow in the heart.

Comparison of prenatal ultrasound and postmortem findings in fetuses with common pulmonary vein atresia.

BACKGROUND: The previous literature on common pulmonary vein atresia (CPVA) mainly consists of neonatal case reports. There is a lack of research on the prenatal diagnosis of CPVA. METHODS: We conducted a retrospective study of all fetuses with CPVA confirmed by autopsy between August 2010 and May 2018. Prenatal echocardiographic features, autopsy findings, and genetic test results were analyzed. We compared fetal CPVA with total anomalous pulmonary venous return (TAPVR) and neonatal CPVA. RESULTS: During the study period, fetal echocardiography was performed on 31 617 fetuses. Six cases of CPVA were identified by autopsies, including 1 case performed with a cardiovascular cast. All 6 cases (100%) had asplenia syndrome (AS) and bilateral superior vena cava (BSVC). In 1 case (16.7%), the prenatal ultrasound results were in complete agreement with the postmortem findings. Four cases (66.7%) were misdiagnosed as TAPVR by prenatal echocardiography. For the remaining case (16.7%), no pulmonary venous anomalies were detected on prenatal echocardiography. No aneuploidy was identified in any of the cases. There were no statistically significant differences among the proportions of associated complex anomalies and AS between the fetal CPVA and TAPVR groups. The proportion of associated complex anomalies and AS in the fetal CPVA group was higher than that in the neonatal group (P < 0.05). CONCLUSIONS: Prenatal diagnosis of fetal CPVA is difficult and challenging even for experts. Our study showed that fetal CPVA is often combined with AS, complex cardiac malformations, and BSVC. These findings may help in the diagnosis of fetal CPVA.

Umbilical cannulation optimizes circuit flows in premature lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND).

KEY POINTS: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel 'artificial womb' system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology. ABSTRACT: EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105-117 days (term 145-150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight-adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger-bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post-membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow.

Isolated premature restriction or closure of foramen ovale in fetuses: Echocardiographic characteristics and outcome.

BACKGROUND: Premature restriction or closure of foramen ovale (FO) in otherwise structurally normal hearts may be associated with right ventricular dilation, tricuspid regurgitation, pericardial effusion, heart failure, even poor perinatal outcomes. Data about these rare conditions are lacking. METHODS: We retrospectively reviewed the echocardiographic records of 9704 fetuses seen from 2010 to 2014 in Beijing Anzhen Hospital, a regional and national referral center, to ascertain the presence of restriction or closure of FO. We collected the fetal echocardiography and perinatal outcome data for this group of fetuses with restriction or closure of FO. RESULTS: In this large, single-institution cohort (n = 9704), 6707 fetuses seen between 23 and 37 weeks of gestation had normal heart structures; of these, 60 (0.89%) had restrictive FO (rFO) and 5 (0.07%) had closure of FO (cFO). Fetal echocardiographic images showed right atrial dilation in 48 (73.84%), right ventricular dilation in 38 (58.46%), tricuspid regurgitation in 19 (29.23%), and pericardial effusion in 10 (15.38%). Also in this group, 50 (83.3%) with rFO and 4 (80.0%) with cFO had follow-up data. No prenatal deaths occurred in either the rFO or the cFO group, but the neonatal mortality included 1 in the rFO group and 2 in the cFO group. CONCLUSION: Premature rFO/cFO are rare in fetuses with otherwise structurally normal hearts. The fetal echocardiographic characteristics include right atrial and ventricular dilated, tricuspid regurgitation, and pericardial effusion. Most fetuses had a good outcome, although there was an association between rFO, especially cFO, with neonatal morality and complications (prematurity, maternal preeclampsia and placental abruption, hydrops fetalis, and necrotizing enterocolitis with perforation).