Search

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.)

Truncus arteriosus (TA) is a very rare congenital anomaly with complex cardiovascular anatomy and high lethality also due to severe associated anatomical variants and pathologies. As TA has a massive impact on the survival of a newborn and usually has to be surgically treated. Thus, it is of high importance to understand this congenital cardiovascular disease and associated complications, to improve life expectancy and outcome of these patients. We recently came across a newborn female patient with a rare complex case of persistent TA type 2 associated with further complex cardiovascular anomalies, who received a contrast enhanced CT scan on the 3 rd day post-partum, showing complex cardiovascular abnormalities that were ultimately incompatible with life.

Background: Postmortem analysis of fetal heart is crucial but challenging. Alternative techniques to autopsy have been studied. We investigate micro-CT diagnostic accuracy in the analysis of fetal heart coming from early and late termination of pregnancy. Methods: Micro-CT and autopsy analyzed human fetal heart using twenty-six indices of cardiac anatomy derived from segmental approach. Sub-analysis of smaller specimens was performed. Primary outcome is the agreement between techniques. Secondary outcomes are sensitivity, specificity, positive and negative predictive value. Indices are defined “visible” or “non-visible” (primary end point) and “normal”, “abnormal” or “non-diagnostic” (secondary end point). Results: Fifty-five cases were included. Agreement was 74.5% and 65.2% for primary end point and 93.3% and 91.8% for secondary end point in general population and in the group of smaller specimens, respectively. Sensitivity, specificity, positive and negative predictive value were 92.8%, 51.8%, 67.1%, 87.2% in the general population and 92.8%, 47.8%, 54.3%, 90.9% in the subgroup of smaller specimens for primary end point. They were 97.3%, 68.3%, 95.1%, 80.0% in the general population and 95.7%, 75.6%, 94.2%, 81.0% in the subgroup of smaller specimens for secondary end point. 86.1% and 91.5% of indices defined as “non-diagnostic” at autopsy would be visible by micro-CT in the two studied populations. Conclusion: Micro-CT represents a valid alternative to autopsy for postmortem evaluation of human fetal heart. We proposed to use micro-CT for initial analysis of fetal heart and to perform autopsy only in unsolved cases or if histological analysis is needed.

Abstract Background Fetal cardiovascular magnetic resonance (CMR) imaging may provide a valuable adjunct to fetal echocardiography in the evaluation of congenital cardiovascular pathologies. However, dynamic fetal CMR is difficult due to the lack of direct in-utero cardiac gating. The aim of this study was to investigate the effectiveness of a newly developed Doppler ultrasound (DUS) device in humans for fetal CMR gating. Methods Fifteen fetuses (gestational age 30–39 weeks) were examined using 1.5 T CMR scanners at three different imaging sites. A newly developed CMR-compatible DUS device was used to generate gating signals from fetal cardiac motion. Gated dynamic balanced steady-state free precession images were acquired in 4-chamber and short-axis cardiac views. Gating signals during data acquisition were analyzed with respect to trigger variability and sensitivity. Image quality was assessed by measuring endocardial blurring (EB) and by image evaluation using a 4-point scale. Left ventricular (LV) volumetry was performed using the single-plane ellipsoid model. Results Gating signals from the fetal heart were detected with a variability of 26 ± 22 ms and a sensitivity of trigger detection of 96 ± 4%. EB was 2.9 ± 0.6 pixels (4-chamber) and 2.5 ± 0.1 pixels (short axis). Image quality scores were 3.6 ± 0.6 (overall), 3.4 ± 0.7 (mitral valve), 3.4 ± 0.7 (foramen ovale), 3.6 ± 0.7 (atrial septum), 3.7 ± 0.5 (papillary muscles), 3.8 ± 0.4 (differentiation myocardium/lumen), 3.7 ± 0.5 (differentiation myocardium/lung), and 3.9 ± 0.4 (systolic myocardial thickening). Inter-observer agreement for the scores was moderate to very good (kappa 0.57–0.84) for all structures. LV volumetry revealed mean values of 2.8 ± 1.2 ml (end-diastolic volume), 0.9 ± 0.4 ml (end systolic volume), 1.9 ± 0.8 ml (stroke volume), and 69.1 ± 8.4% (ejection fraction). Conclusion High-quality dynamic fetal CMR was successfully performed using a newly developed DUS device for direct fetal cardiac gating. This technique has the potential to improve the utility of fetal CMR in the evaluation of congenital pathologies.

In prenatal ultrasound screening, rapid and accurate recognition of the fetal heart ultrasound standard planes(FHUSPs) can more objectively predict fetal heart growth. However, the small size and movement of the fetal heart make this process more difficult. Therefore, we design a deep learning-based FHUSP recognition network (FHUSP-NET), which can automatically recognize the five FHUSPs and detect tiny key anatomical structures at the same time. 3360 ultrasound images of five FHUSPs from 1300 mid-pregnancy pregnant women are included in this study. 10 fetal heart key anatomical structures are manually annotated by experts. We apply spatial pyramid pooling with a fully connected spatial pyramid convolution module to capture information about targets and scenes of different sizes as well as improve the perceptual ability and feature representation of the model. Additionally, we adopt the squeeze-and-excitation networks to improve the sensitivity of the model to the channel features. We also introduce a new loss function, the efficient IOU loss, which makes the model effective for optimizing similarity. The results demonstrate the superiority of FHUSP-NET in detecting fetal heart key anatomical structures and recognizing FHUSPs. In the detection task, the value of mAP@0.5, precision, and recall are 0.955, 0.958, and 0.931, respectively, while the accuracy reaches 0.964 in the recognition task. Furthermore, it takes only 13.6 ms to detect and recognize one FHUSP image. This method helps to improve ultrasonographers' quality control of the fetal heart ultrasound standard plane and aids in the identification of fetal heart structures in a less experienced group of physicians., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As presently conceptualised, the artificial placenta (AP) is an experimental life support platform for extremely preterm infants (i.e. 400-600 g; 21-23 +6 weeks of gestation) born at the border of viability. It is based around the oxygenation of the periviable fetus using gas-exchangers connected to the fetal vasculature. In this system, the lung remains fluid-filled and the fetus remains in a quiescent state. The AP has been in development for some sixty years. Over this time, animal experimental models have evolved iteratively from employing external pump-driven systems used to support comparatively mature fetuses (generally goats or sheep) to platforms driven by the fetal heart and used successfully to maintain extremely premature fetuses weighing around 600 g. Simultaneously, sizable advances in neonatal and obstetric care mean that the nature of a potential candidate patient for this therapy, and thus the threshold success level for justifying its adoption, have both changed markedly since this approach was first conceived. Five landmark breakthroughs have occurred over the developmental history of the AP: i) the first human studies reported in the 1950's; ii) foundation animal studies reported in the 1960's; iii) the first extended use of AP technology combined with fetal pulmonary resuscitation reported in the 1990s; iv) the development of AP systems powered by the fetal heart reported in the 2000's; and v) the adaption of this technology to maintain extremely preterm fetuses (i.e. 500-600 g body weight) reported in the 2010's. Using this framework, the present paper will provide a review of the developmental history of this long-running experimental system and up-to-date assessment of the published field today. With the apparent acceleration of AP technology towards clinical application, there has been an increase in the attention paid to the field, along with some inaccurate commentary regarding its potential application and merits. Additionally, this paper will address several misrepresentations regarding the potential application of AP technology that serve to distract from the significant potential of this approach to greatly improve outcomes for extremely preterm infants born at or close to the present border of viability., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Congenital heart defects (CHD) remain the most common class of birth defect worldwide, affecting 1 in every 110 live births. A host of clinical and morphological indicators of placental dysfunction are observed in pregnancies complicated by fetal CHD and, with the recent emergence of single-cell sequencing capabilities, the molecular and physiological associations between the embryonic heart and developing placenta are increasingly evident. In CHD pregnancies, a hostile intrauterine environment may negatively influence and alter fetal development. Placental maldevelopment and dysfunction creates this hostile in-utero environment and may manifest in the development of various subtypes of CHD, with downstream perfusion and flow-related alterations leading to yet further disruption in placental structure and function. The adverse in-utero environment of CHD-complicated pregnancies is well studied, however the specific etiological role that the placenta plays in CHD development remains unclear. Many mouse and rat models have been used to characterize the relationship between CHD and placental dysfunction, but these paradigms present substantial limitations in the assessment of both the heart and placenta. Improvements in non-invasive placental assessment can mitigate these limitations and drive human-specific investigation in relation to fetal and placental development. Here, we review the clinical, structural, and molecular relationships between CHD and placental dysfunction, the CHD subtype-dependence of these changes, and the future of Placenta-Heart axis modeling and investigation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Congenital heart disease is associated with an increased risk of smaller brain volumes and structural brain damage, and impaired growth of supratentorial brain structures in utero has been linked to poor neurodevelopmental outcomes. However, little is known on brainstem and cerebellar volumes in fetuses with congenital heart disease. Moreover, it is not clear whether impaired infratentorial growth, if present, is associated with only certain types of fetal cardiac defects or with supratentorial brain growth, and whether altered biometry is already present before the third trimester., Objective: This study aimed to investigate brainstem and cerebellar volumes in fetuses with congenital heart disease and to compare them to infratentorial brain volumes in fetuses with normal hearts. Secondarily, the study aimed to identify associations between infratentorial brain biometry and the type of cardiac defects, supratentorial brain volumes, and gestational age., Study Design: In this retrospective case-control study, 141 magnetic resonance imaging studies of 135 fetuses with congenital heart disease and 141 magnetic resonance imaging studies of 125 controls with normal hearts at 20 to 37 gestational weeks (median, 25 weeks) were evaluated. All cases and controls had normal birthweight and no evidence of structural brain disease or genetic syndrome. Six types of congenital heart disease were included: tetralogy of Fallot (n=32); double-outlet right ventricle (n=22); transposition of the great arteries (n=27); aortic obstruction (n=24); hypoplastic left heart syndrome (n=22); and hypoplastic right heart syndrome (n=14). First, brainstem and cerebellar volumes of each fetus were segmented and compared between cases and controls. In addition, transverse cerebellar diameters, vermian areas, and supratentorial brain and cerebrospinal fluid volumes were quantified and differences assessed between cases and controls. Volumetric differences were further analyzed according to types of cardiac defects and supratentorial brain volumes. Finally, volume ratios were created for each brain structure ([volume in fetus with congenital heart disease/respective volume in control fetus] × 100) and correlated to gestational age., Results: Brainstem (cases, 2.1 cm 3 vs controls, 2.4 cm 3 ; P<.001) and cerebellar (cases, 3.2 cm 3 vs controls, 3.4 cm 3 ; P<.001) volumes were smaller in fetuses with congenital heart disease than in controls, whereas transverse cerebellar diameters (P=.681) and vermian areas (P=.947) did not differ between groups. Brainstem and cerebellar volumes differed between types of cardiac defects. Overall, the volume ratio of cases to controls was 80.8% for the brainstem, 90.5% for the cerebellum, and 90.1% for the supratentorial brain. Fetuses with tetralogy of Fallot and transposition of the great arteries were most severely affected by total brain volume reduction. Gestational age had no effect on volume ratios., Conclusion: The volume of the infratentorial brain, which contains structures considered crucial to brain function, is significantly smaller in fetuses with congenital heart disease than in controls from midgestation onward. These findings suggest that impaired growth of both supra- and infratentorial brain structures in fetuses with congenital heart disease occurs in the second trimester. Further research is needed to elucidate associations between fetal brain volumes and neurodevelopmental outcomes in congenital heart disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Slice-to-volume registration (SVR) methods allow reconstruction of high-resolution 3D images from multiple motion-corrupted stacks. SVR-based pipelines have been increasingly used for motion correction for T2-weighted structural fetal MRI since they allow more informed and detailed diagnosis of brain and body anomalies including congenital heart defects (Lloyd et al., 2019). Recently, fully automated rigid SVR reconstruction of the fetal brain in the atlas space was achieved in Salehi et al. (2019) that used convolutional neural networks (CNNs) for segmentation and pose estimation. However, these CNN-based methods have not yet been applied to the fetal trunk region. Meanwhile, the existing rigid and deformable SVR (DSVR) solutions (Uus et al., 2020) for the fetal trunk region are limited by the requirement of manual input as well the narrow capture range of the classical gradient descent based registration methods that cannot resolve severe fetal motion frequently occurring at the early gestational age (GA). Furthermore, in our experience, the conventional 2D slice-wise CNN-based brain masking solutions are reportedly prone to errors that require manual corrections when applied on a wide range of acquisition protocols or abnormal cases in clinical setting. In this work, we propose a fully automated pipeline for reconstruction of the fetal thorax region for 21-36 weeks GA range T2-weighted MRI datasets. It includes 3D CNN-based intra-uterine localisation of the fetal trunk and landmark-guided pose estimation steps that allow automated DSVR reconstruction in the standard radiological space irrespective of the fetal trunk position or the regional stack coverage. The additional step for generation of the common template space and rejection of outliers provides the means for automated exclusion of stacks affected by low image quality or extreme motion. The pipeline was quantitatively evaluated on a series of experiments including fetal MRI datasets and simulated rotation motion. Furthermore, we performed a qualitative assessment of the image reconstruction quality in terms of the definition of vascular structures on 100 early (median 23.14 weeks) and late (median 31.79 weeks) GA group MRI datasets covering 21 to 36 weeks GA range., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In the current era, most single-ventricle heart disease (SVHD) is diagnosed prenatally by means of fetal echocardiography. Disparities exist, however, by socioeconomic status and remote location, which require further attention. Prenatal diagnosis affords the opportunity to counsel expectant parents regarding the life-long course of children with SVHD, including the stages of single-ventricle palliation and challenges of the Fontan circulation; to discuss pregnancy management options; and to optimise delivery planning and perinatal care. Prognosis may be refined by specific features on the fetal echocardiogram, such as ventricular morphology, total anomalous pulmonary venous return, and atrioventricular valve regurgitation. Expectant mothers should be referred for evaluation of extracardiac anomalies and/or a genetic syndrome, which also significantly affect outcome. Fetuses with SVHD should be cared for by a multidisciplinary team and ideally delivered at term at or near a cardiac surgical center. Serial echocardiograms refine the anticipated postnatal physiology to optimise transitional care, including the need for prostaglandin or urgent atrial septal intervention in fetuses with hypoplastic left heart syndrome. In selected patients, there may be a role for fetal cardiac intervention to improve mortality or achieve a biventricular circulation after birth. Together, these strategies enhance the preoperative status of the neonate. Recent advances in fetal cardiovascular magnetic resonance imaging have focused on studying the relationships between cardiovascular physiology and fetal growth and development. These novel techniques allow for the exploration of the physiologic effects of SVHD on the brain and open avenues for the investigation of neuroprotective therapies., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Wireless continuous electronic fetal monitoring (CEFM) using telemetry offers potential for increased mobility during labour. United Kingdom national recommendations are that telemetry should be offered to all women having CEFM during labour. There is limited contemporary evidence on experiences of telemetry use or impacts it may have., Aim: To gather in-depth knowledge about the experiences of women and midwives using telemetry, and to assess any impact that its use may have on clinical outcomes, mobility in labour, control or satisfaction., Methods: A convergent parallel mixed-methods study was employed. Grounded theory was adopted for interviews and analysis of 13 midwives, 10 women and 2 partners. Satisfaction, positions during labour and clinical outcome data was analysed from a cohort comparing telemetry (n = 64) with wired CEFM (n = 64). Qualitative and quantitative data were synthesised to give deeper understanding., Findings: Women using telemetry were more mobile and adopted more upright positions during labour. The core category A Sense of Normality encompassed themes of 'Being Free, Being in Control', 'Enabling and Facilitating' and 'Maternity Unit Culture'. Greater mobility resulted in increased feelings of internal and external control and increased perceptions of autonomy, normality and dignity. There was no difference in control or satisfaction between cohort groups., Conclusions: When CEFM is used during labour, telemetry provides an opportunity to improve experience and support physiological capability. The use of telemetry during labour contributes to humanising birth for women who have CEFM and its use places them at the centre and in control of their birth experience., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Background: The diagnostic value of ST analysis of the fetal electrocardiogram (fECG) during labor is uncertain. False alarms (ST events) may be explained by physiological variation of the fetal electrical heart axis. Adjusted ST events, based on a relative rather than an absolute rise from baseline, correct for this variation and may improve the diagnostic accuracy of ST analysis., Aims: Determine the optimal cut-off for relative ST events in fECG to detect fetal metabolic acidosis., Study Design: Post-hoc analysis on fECG tracings from the Dutch STAN trial (STAN+CTG branch)., Subjects: 1328 term singleton fetuses with scalp ECG tracing during labor, including 10 cases of metabolic acidosis., Outcome Measures: Cut-off value for relative ST events at the point closest to (0,1) in the receiver operating characteristic (ROC) curve with corresponding sensitivity and specificity., Results: Relative baseline ST events had an optimal cut-off at an increment of 85% from baseline. Relative ST events had a sensitivity of 90% and specificity of 80%., Conclusions: Adjusting the current definition of ST events may improve ST analysis, making it independent of CTG interpretation., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Postmortem confirmation of prenatally diagnosed congenital heart disease after termination of pregnancy and evaluation of potential cardiac defects after spontaneous fetal or neonatal death are essential. Conventional autopsy rates are decreasing, and 1.5Tesla magnetic resonance imaging has demonstrated limited diagnostic accuracy for postmortem cardiovascular assessment., Objective: This study aimed to evaluate the feasibility and image quality of cardiac 3Tesla postmortem magnetic resonance imaging and to assess its diagnostic accuracy in detecting fetal heart defects compared with conventional autopsy. Secondarily, the study aimed to explore whether clinical factors affect the quality of 3Tesla postmortem magnetic resonance imaging., Study Design: A total of 222 consecutive fetuses between 12 and 41 weeks' gestation, who underwent 3Tesla postmortem magnetic resonance imaging and conventional autopsy after spontaneous death or termination of pregnancy for fetal malformations, were included. First, 3Tesla postmortem magnetic resonance imaging of each fetus was rated as diagnostic or nondiagnostic for fetal cardiac assessment by 2 independent raters. The image quality of individual cardiac structures was then further evaluated by visual grading analysis. Finally, the presence or absence of a congenital heart defect was assessed by 2 radiologists and compared with autopsy results., Results: Overall, 87.8% of 3Tesla postmortem magnetic resonance imaging examinations were rated as diagnostic for the fetal heart. Diagnostic imaging rates of individual cardiac structures at 3Tesla postmortem magnetic resonance imaging ranged from 85.1% (atrioventricular valves) to 94.6% (pericardium), with an interrater agreement of 0.82 (0.78-0.86). Diagnostic imaging of the fetal aortic arch and the systemic veins at 3Tesla postmortem magnetic resonance imaging was possible from 12+5 weeks' gestation onward in 90.1% and 92.3% of cases, respectively. A total of 55 fetuses (24.8%) had at least 1 cardiac anomaly according to autopsy, 164 (73.9%) had a normal heart, and in 3 fetuses (1.4%), autopsy was nondiagnostic for the heart. Considering all examinations rated as diagnostic, 3Tesla postmortem magnetic resonance imaging provided high diagnostic accuracy for the detection of fetal congenital heart defects with a sensitivity of 87.8%, a specificity of 97.9%, and concordance with autopsy of 95.3%. 3Tesla postmortem magnetic resonance imaging was less accurate in young fetuses (<20 weeks compared with ≥20 weeks; P<.001), in fetuses with low birthweight (≤100 g compared with >100 g; P<.001), in cases after spontaneous fetal death (compared with other modes of death; P=.012), in cases with increasing latency between death and 3Tesla postmortem magnetic resonance imaging (P<.001), and in cases in which there was a high degree of maceration (maceration score of 3 compared with a score from 0 to 2; P=.004)., Conclusion: Diagnostic 3Tesla postmortem magnetic resonance imaging assessment of the fetal heart is feasible in most fetuses from 12 weeks' gestation onward. In diagnostic images, sensitivity and, particularly, specificity in the detection of congenital heart disease are high compared with conventional autopsy. Owing to its high diagnostic accuracy, we suggest that 3Tesla postmortem magnetic resonance imaging may serve as a suitable imaging modality with which to direct a targeted conventional autopsy when pathology resources are limited or to provide a virtual autopsy when full autopsy is declined by the parents., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The heart is the first organ to form during embryogenesis and its development is a complex process. In this study, we identified 120 ligand-receptor pairs including 65 ligands and 58 receptors specifically expressed in one of the nine cell types. The correlation analysis of the cell proportions revealed that the cell-to-cell contact exhibited spatial patterns in human fetal heart. Specifically, the cardiomyocytes (CMs) proportion might have negative correlation with proportion of endothelial cell in left atrium and ventricle during the heart development. In contrast, fibroblast-like cells and macrophages were jointly increased with the gestation. Furthermore, the ligand in CM, NPPA (Natriuretic Peptide A), and receptor in endothelial cell (EC), NPR3 (Natriuretic Peptide Receptor 3), were specifically expressed in atrial CM and endocardial cells, respectively, indicating that the atrial CM might communicate with endocardial cells via NPPA-NRP3 interaction. Moreover, the interplay between fibroblast-like cell and macrophage was observed in both left and right atriums via the ligand-receptor interactions of COL1A1/COL1A2 (Collagen Type I Alpha 1/2 Chain)-CD36 and CTGF (connective tissue growth factor)-ITGB2 (Integrin Subunit Beta 2). Functional enrichment analysis revealed that the ligand-receptor interactions might be associated with the intracellular activation of cGMP-PKG signaling pathway in ECs, PDGF-beta signaling pathway in fibroblast-like cell, and Toll-like receptor signaling in macrophage, respectively. Collectively, the present study unveiled the potential cell-cell communication and underlying mechanism involved in cardiac development, which broadened our insights into developmental biology of heart., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: To determine whether abnormal global, transverse, and longitudinal ventricular contractility of the heart in fetuses with an estimated fetal weight <10th centile is present, irrespective of Doppler studies of the umbilical artery and cerebroplacental ratio., Study Design: This was a retrospective study of 50 fetuses with an estimated fetal weight <10th centile that were classified based on Doppler results from the pulsatility indices of the umbilical artery and middle cerebral artery, and the calculated cerebroplacental ratio (pulsatility indices of the umbilical artery/middle cerebral artery). Right and left ventricular measurements were categorized into 3 groups: (1) global ventricular contractility (fractional area change), (2) transverse ventricular contractility (24-segment transverse fractional shortening), and (3) basal-apical longitudinal contractility (longitudinal strain, longitudinal displacement fractional shortening, and basal lateral and septal wall annular plane systolic excursion). Z scores for the above measurements were computed for fetuses with an estimated fetal weight <10th centile using the mean and standard deviation derived from normal controls. Ventricular contractility measurements were considered abnormal if their Z score values were <5th centile (z score <-1.65) or >95th centile (Z score >1.65), depending on the specific ventricular measurement., Results: The average gestational age at the time of the examination was 32 weeks 4 days (standard deviation 3 weeks 4 days). None of the 50 study fetuses demonstrated absent or reverse flow of the umbilical artery Doppler waveform. Eighty-eight percent (44/50) of fetuses had one or more abnormal measurements of cardiac contractility of 1 or both ventricles. Analysis of right ventricular contractility demonstrated 78% (39/50) to have 1 or more abnormal measurements, which were grouped as follows: global contractility 38% (19/50), transverse contractility 66% (33/50); and longitudinal contractility 48% (24/50). Analysis of left ventricular contractility demonstrated 1 or more abnormal measurements in 58% (29/50) that were grouped as follows: global contractility 38% (19/50); transverse contractility 40% (20/50); and longitudinal contractility 40% (20/50). Of the 50 study fetuses, 25 had normal pulsatility index of the umbilical artery and cerebroplacental ratios, 80% of whom had 1 or more abnormalities of right ventricular contractility and 56% of whom had 1 or more abnormalities of left ventricular contractility. Abnormal ventricular contractility for these fetuses was present in all 3 groups of measurements; global, transverse, and longitudinal. Those with an isolated abnormal pulsatility index of the umbilical artery (n=11) had abnormalities of transverse contractility of the right ventricular and global contractility in the left ventricle. When an isolated cerebroplacental ratio abnormality was present, the right ventricle demonstrated abnormal global, transverse, and longitudinal contractility, with the left ventricle only demonstrating abnormalities in transverse contractility. When both the pulsatility index of the umbilical artery and cerebroplacental ratio were abnormal (3/50), transverse and longitudinal contractility measurements were abnormal for both ventricles, as well as abnormal global contractility of the left ventricle., Conclusions: High rates of abnormal ventricular contractility were present in fetuses with an estimated fetal weight <10th centile, irrespective of the Doppler findings of the pulsatility index of the umbilical artery, and/or cerebroplacental ratio. Abnormalities of ventricular contractility were more prevalent in transverse measurements than global or longitudinal measurements. Abnormal transverse contractility was more common in the right than the left ventricle. Fetuses with estimated fetal weight less than the 10th centile may be considered to undergo assessment of ventricular contractility, even when Doppler measurements of the pulsatility index of the umbilical artery, and cerebroplacental ratio are normal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: High altitude hypoxia (HAH) exposure affects fetal development. However, the fetal cardiovascular responses to the HAH are not well understood. We have tested the hypothesis that long-term HAH exposure alters the hypoxia/ischemia-sensitive gene expressions, leading to an increase in fetal heart susceptibility to ischemia/reperfusion (I/R) injury and cardiac dysfunction., Methods: Time-dated pregnant sheep were exposed to high-altitude (3820 m) or were maintained at sea level (~300 m) for 110 days. Fetal hearts were isolated from the near-term ewes and subjected to I/R in a Langendorff preparation., Results: HAH decreased the fetal body and heart weights in the female but not male fetuses. HAH had no effect on the left ventricle (LV) function at baseline, but increased the LV infarct size and attenuated the post-ischemic recovery of LV function in both male and female fetuses, as compared with the normoxic groups. HAH increased the protein levels of hypoxia-inducible factor (HIF)-1α and DNA methyltransferases type 3b (DNMT3b), but attenuated protein kinase C epsilon (PKCε) levels in the fetal hearts. AHA induced a 4.3 fold increase of miR-210 in the males and a 2.9 fold increase in female hearts. In addition, HAH had no effect on mTOR protein and phosphorylation levels but increased the autophagy biomarker, LC3B-II protein levels and LC3B-II/LC3B-I ratio in the fetal hearts., Conclusion: The results suggest that gestational HAH exposure induces in utero programming of the hypoxia/ischemia-sensitive gene expression pattern in the developing heart and increases cardiac susceptibility to I/R injury., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Intrapartum fetal heart rate monitoring was introduced with the goal to reduce fetal hypoxia and deaths. However, continuous fetal heart rate monitoring has been shown to have a high sensitivity but also a high false-positive rate. To improve specificity, adjunctive technologies have been developed to identify fetuses at risk for intrapartum asphyxia. Intensive research on the value of ST-segment analysis of the fetal electrocardiogram as an adjunct to standard electronic fetal monitoring in lowering the rates of fetal metabolic acidosis and operative deliveries has been ongoing. The conflicting results in randomized and observational studies may partly be due to differences in study design., Objective: This study aims to determine the significance of the learning process for the introduction of ST analysis into clinical practice and its impact on initial and subsequent obstetric outcomes., Study Design: This was a prospective observational study with the primary objective to evaluate the importance of the learning period on the rates of metabolic acidosis and operative deliveries after the implementation of ST analysis. The study was conducted at the Turku University Hospital, Turku, Finland, with 3400-4200 annual deliveries. The whole study population consisted of all 42,146 deliveries during the study period 2001 through 2011. The ST analysis usage rate was 18%. The data were collected prospectively from labors monitored with ST analysis as an adjunct to conventional intrapartum fetal heart rate monitoring. Primary endpoints were the rates of metabolic acidosis (cord artery pH <7.05 and an extracellular fluid compartment base deficit >12.0 mmol/L), fetal scalp blood sampling, and operative deliveries. Comparisons of these outcomes were made between the initiation period (the first 2 years) and the subsequent usage period (the next 9 years)., Results: In the whole study population the prevalence of cord pH <7.05 decreased from 1.5-0.81% (relative risk, 0.54; 95% confidence interval, 0.43-0.67), the rate of cesarean deliveries from 17.2-14.1% (relative risk, 0.82; 95% confidence interval, 0.89-0.97), and the rate of fetal scalp blood sampling from 1.75-0.82% (relative risk, 0.47; 95% confidence interval, 0.38-0.58) when the 2 study periods were compared. In the ST analysis group, the frequency of cord metabolic acidosis rate was reduced from 1.0-0.25% (relative risk, 0.33; 95% confidence interval, 0.15-0.72)., Conclusion: We provide evidence that the results improve over time and there is a learning curve in the introduction of the ST analysis method. This was demonstrated by the lower rates of metabolic acidosis and operative deliveries after the initial implementation period., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study examined the effect on uterine contraction frequency (UCF), blood pressure (BP), heart rate (HR), fetal heart rate (FHR) patterns and psychophysical symptoms (physical discomfort, anxiety, and depression) of structured bed exercise (SBE) in hospitalized high-risk pregnant women prescribed bed rest., Methods: Forty-five hospitalized high risk pregnant women at >24 weeks of pregnancy prescribed bed rest were randomly assigned to the experimental or control group. From January to May 2014, data were collected using electronic fetal monitoring and patient monitoring of UCF, BP, HR and FHR patterns, and psychophysical symptoms were measured using the antenatal physical discomfort scale, state-trait anxiety scale, and Edinburgh postnatal depression scale., Results: UCF, BP, HR, and FHR patterns (rate, variability, acceleration, and deceleration) did not differ significantly between the experimental and control groups. The experimental group showed a significant increase in baseline FHR after SBE within the normal range, and after SBE, it reduced to the FHR before SBE. The variability, acceleration and deceleration of FHR before and after SBE did not differ significantly between two groups. Moreover, there was no statistically significant difference before and after SBE in the experimental group. Also, the experimental group showed statistically significant decreases in physical discomfort score. However, there were no significant differences in depression and anxiety score between two groups., Conclusions: SBE in hospitalized high-risk pregnant women under bed rest did not increase the risk to the fetus, and relieved physical discomfort and anxiety. Therefore, SBE should be considered as a nursing intervention in hospitalized high-risk pregnant women., (Copyright © 2018. Published by Elsevier B.V.)

Since the 1970s, researchers have studied the influence of exercise during pregnancy on offspring heart development. With the knowledge and current evidence of fetal programming effects, research has demonstrated that exercise is safe and beneficial for mother, fetus, and neonate. Predominantly, research has focused on maternal and fetal cardiac adaptations related to aerobic exercise during pregnancy; less is known regarding the effects of resistance or combination (aerobic and resistance) training during pregnancy. Ongoing research is focusing on fetal responses to different intensity, duration and modes of maternal exercise throughout pregnancy. This article will summarize our current state of knowledge regarding the influence of exercise intensity, duration, and modes during pregnancy on maternal and fetal cardiac responses., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Evidence supporting the efficacy of in utero hematopoietic cell transplantation (IUHCT) in a valid large animal model is needed prior to clinical application. The objective of this study was to establish clinically relevant levels of hematopoietic chimerism in a canine model of maternal-to-fetal IUHCT. We first assessed immune and hematopoietic ontogeny relevant to IUHCT in the canine model and identified 40 days' gestation (term 63 days) as a time point at the initiation of thymic selection, and prior to bone marrow hematopoiesis, that might be optimal for IUHCT. We next determined that intravascular administration of donor cells via intracardiac injection was far more efficient and resulted in much higher levels of donor cell engraftment than intraperitoneal injection. By applying these findings, we achieved stable long-term multilineage engraftment in 21 of 24 surviving recipients with an average level of initial chimerism of 11.7% (range 3% to 39%) without conditioning or evidence of graft-versus-host disease. Donor cell chimerism remained stable for up to 2 years and was associated with donor-specific tolerance for renal transplantation. The levels of donor cell chimerism achieved in this study would be therapeutic for many hematopoietic disorders and are supportive of a clinical trial of IUHCT., (© 2014 by The American Society of Hematology.)

Significant congenital heart disease (sCHD) affects 3.6 per 1000 births, and is often associated with extracardiac and chromosomal anomalies. Although early mortality has been substantially reduced and the rate of long-term survival has improved, sCHD is, after preterm birth, the second most frequent cause of neonatal infant death. The prenatal detection of cardiac and vascular abnormalities enables optimal parental counselling and perinatal management. Echocardiography (ECG) is the first-line examination and gold standard by which cardiac malformations are defined. However, adequate examination by an experienced healthcare provider with modern technical imaging equipment is required. In addition, maternal factors and the gestational age may lower the image quality. Fetal magnetic resonance imaging (MRI) has been implemented over the last several years and is already used in the clinical routine as a second-line approach to assess fetal abnormalities. MRI of the fetal heart is still not routinely performed. Nevertheless, fetal cardiac MRI has the potential to complement ultrasound in detecting cardiovascular malformations and extracardiac lesions. The present work reviews the potential of MRI to delineate the anatomy and pathologies of the fetal heart. This work also deals with the limitations and continuing developments designed to overcome the current problems in cardiac imaging, including fast fetal heart rates, the lack of ECG-gating, and the presence of fetal movements., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Following fetal diagnosis of a profound heart defect, transplantation (HTx) is an alternative to pregnancy termination or neonatal surgical palliation. Retrospective review of the cardiac and transplant databases of fetal listings for HTx between 1990 and July 2006 was undertaken to describe outcomes after listing. We identified 26 fetal listings (of 269 total listings). Diagnoses included congenital heart disease (n = 24) and cardiomyopathy (n = 2). Seven patients were delisted after birth: in five cases parents opted for surgical palliation, two clinically improved. One patient died wait-listed (stillborn). Time wait-listed as a fetus ranged from 1-41 days (median 19 days). Eighteen patients underwent HTx (median weight 2.8 kg, range 2.1-10.9 kg); median days wait-listed after birth was 22 (4 h-123 days). Two fetuses were surgically delivered at 36 weeks gestation when a donor organ became available; 11 were transplanted as neonates (<30 days). The median age at HTx was 1 month (4 h-2.6 months). Fetal listing for HTx increases the potential window of opportunity for a donor organ to become available; patients had low wait-list mortality and a fair intermediate-term outcome. Well-defined criteria for eligibility for fetal listing and priority allocation to infants over fetuses seem rational approaches for centers that offer fetal listing.

Background: The presence of an intact or highly restrictive atrial septum (I/HRAS) has long been recognized as a predictor of poor outcome among patients with hypoplastic left heart syndrome (HLHS), although the rarity of this condition has precluded conclusive study. The purpose of this review is to summarize recent surgical outcomes for these patients at our center and to identify predictors., Methods: We retrospectively identified all neonates with a diagnosis of HLHS and I/HRAS who underwent stage I palliation at Children's Hospital Boston between January 2001 and December 2006. Chart review enabled analysis of patient and procedural variables., Results: All 32 patients underwent left atrial decompression in utero or postnatally before surgery. Fourteen patients (44%) underwent fetal intervention, either atrial septoplasty (n = 9) or aortic valvuloplasty (n = 5). Twenty-nine of the 32 patients had postnatal left atrial hypertension and underwent transcatheter atrial septoplasty as neonates before surgery; 3 did not require postnatal atrial septoplasty after successful fetal atrial septoplasty. After stage I, hospital survival was 69% (22 of 32). Need for shunt revision (p = 0.02) and for extracorporeal membrane oxygenation use (p < 0.001) were associated with hospital mortality. Survival at 6 months was 69% for patients who had fetal intervention, and 38% for those who were treated only postnatally (p = 0.2)., Conclusions: Surgical outcome for patients with HLHS and I/HRAS continues to improve. Prenatal decompression of the left atrium may be associated with greater hospital survival. Proposed effects of fetal intervention on lung pathology and longer-term survival are subjects for future study in this unique group of patients.

Three different clinical patterns of acute fetal distress may be observed during labor: an ante-partum hypoxia with a persistent nonreactive and "fixed" fetal heart rate (FHR) on admission to the hospital, a progressive intra-partum asphyxia manifested, as the labor continues, by a substantial rise in baseline heart rate, a loss of variability and repetitive severe variable or late decelerations, and finally, as a result of a catastrophic event, a sudden prolonged FHR deceleration to approximately 60 beats per minute lasting until delivery. However the majority of fetuses with nonreassuring tracings of FHR are neurologically intact, as evidenced by the high false-positive rate of electronic fetal monitoring (EFM). Therefore the diagnosis of fetal distress must be corroborated by complementary methods, such as continuous recording of the fetal electrocardiogram or computed-assisted EFM, fetal pulse oximetry or fetal scalp sampling with immediate determination of blood gases or lactates. Defavorable outcome of an acute fetal distress leading to neonatal encephalopathy or death is best predicted by a persisting low Apgar score (<3) for more than 5 minutes and by a severe metabolic acidosis (umbilical artery pH<7,00 and base-excess>-12mmol/l).

Objective: The physiology of changes in the ST waveform of the fetal electrocardiogram has been elucidated in extensive animal and human observational studies. A combination of heart rate and ST waveform analysis might improve the predictive value of intrapartum monitoring. Our purpose was to compare operative intervention and neonatal outcome in labors monitored by the conventional cardiotocogram with those monitored by ST waveform plus the cardiotocogram., Study Design: A prospective, randomized clinical trial was performed on 2434 high-risk labors in a district general hospital in Plymouth, England. Statistical analysis was performed by Student t test and chi 2 analysis., Results: There was a 46% reduction (p < 0.001, odds ratio 1.85 [1.35-2.66]) in operative deliveries for "fetal distress" and a trend to less metabolic acidosis (p = 0.09, odds ratio 0.38 [0.13-1.07]) and fewer low 5-minute Apgar scores (p = 0.12, odds ratio 0.62 [0.35-1.08]) in the ST waveform plus cardiotocogram arm., Conclusions: ST waveform analysis discriminates cardiotocogram changes in labor, and the protocol for interpretation is safe. Further randomized studies are warranted.

Objective: We investigated the influences of gestational age and behavioral state on fetal baroreceptor activity., Study Design: Two protocols were used to analyze low-voltage fast activity and high-voltage slow activity in eight chronically instrumented ovine fetuses at days 127 to 142. In protocol 1 correction of fetal heart rate to mean arterial blood pressure was assessed under physiologic conditions, and the linear regression slope of fetal heart rate on mean arterial pressure was calculated. In protocol 2 an injection of 7.5 micrograms of norepinephrine was given during consecutive behavioral cycles. The ratio of fetal heart rate decrease to mean arterial pressure increase was determined as representing baroreceptor activity., Results: Under protocol 1 the slope was steeper in high-voltage slow activity (2.33 +/- 1.03) than in low-voltage fast activity (0.89 +/- 0.37) (n = 21, p less than 0.001), indicating that fetal heart rate changes are sensitive to blood pressure changes during high-voltage slow activity. Under protocol 2 inverse relationships were found between the ratio of fetal heart rate decrease to mean arterial pressure increase and gestational age in low-voltage fast activity and high-voltage slow activity., Conclusion: Fetal baroreceptor activity increased during high-voltage slow activity and decreased with gestational age.

Objectives: This study was undertaken to determine the influences of increased maternal prepregnancy weight and increased gestational weight gain on pregnancy outcome., Study Design: This was a longitudinal retrospective study of 7407 term pregnancies delivered from 1987 through 1989. After excluding cases with multiple fetuses, stillbirths, fetal anomalies, no prenatal care, selected medical and surgical complications, and those with incomplete medical records, 3191 cases remained for analyses by determination of odds ratios for obstetric outcomes, by chi 2 tests for significant differences and by adjustment for risk factors with stepwise logistic regression., Results: Both increased maternal prepregnancy weight (body mass index) and increased maternal gestational weight gain were associated with increased risks of fetal macrosomia (p less than 0.0001), labor abnormalities (p less than 0.0001), postdatism (p = 0.002), meconium staining (p less than 0.001), and unscheduled cesarean sections (p less than 0.0001). They were also associated with decreased frequencies of low birth weight (p less than 0.001). The magnitude of the last was less than that of the other outcomes., Conclusions: Increased maternal weight gain in pregnancy results in higher frequencies of fetal macrosomia, which in turn lead to increased rates of cesarean section and other major maternal and fetal complications. Because these costs of increased maternal weight gain appear to outweigh benefits, weight gain recommendations for pregnancy warrant careful review.