Introduction: Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV. Methods: A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806. Results: In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response [LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN)] proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive. Conclusion: Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.

Heart development is a complex process requiring dynamic transcriptional regulation. Disturbance of this process will lead to severe developmental defects such as congenital heart disease/defect (CHD). CHD is a group of complex disorder with high genetic heterogeneity, common pathways associated with CHD remains largely unknown. In the manuscript, we focused on the tissue specific genes in human fetal heart samples to explore such pathways. We used the RNA microarray dataset of human fetal tissues from ENCODE project to identify genes with heart tissue specific expression. A transcriptional network was constructed for these genes based on the Pearson correlation coefficients of their expression levels. Function, selective constraints and disease associations of these genes were then examined. Our analysis identified a network consisted of 316 genes with human fetal heart specific expression. The network was highly co-regulated and showed evolutionary conserved tissue expression pattern in tetrapod. Genes in this network are enriched in CHD specific genes and disease mutations. Using the transcriptomic data, we discovered a highly concerted gene network that might reflect a common pathway associated with the etiology of CHD. Such analysis should be helpful for disease associated gene identification in clinical studies.

Our research goal is to improve the intrapartum identification of tracings associated with severe acidosis at birth and subsequent hypoxic-ischemic encephalopathy so that timely interventions could avoid such complications without causing excessive unnecessary interventions in births with normal outcomes. The present study examines the evolution of fetal heart rate (FHR) features over the course of labor. We analyzed FHR signals collected in the last 6 hours before delivery in 21,853 births with normal neonatal outcomes and in 163 that developed hypoxic-ischemic encephalopathy (HIE) from 15 hospitals of Kaiser Permanente Northern California. We divided these six hours into 18 nonoverlapping 20-minute epochs. The power spectral density of each epoch was divided into three bands: low frequency (LF, 30-150 mHz), movement frequency (MF, 150-500 mHz), and high frequency (HF, 500-1000 mHz). We also estimated the LF/(MF+HF) ratio, the mean and standard deviation of the FHR signal, the approximate entropy (ApEn), and the deceleration capacity (DC). In our results, ApEn, the standard deviation, and DC showed a promising ability to detect risk of HIE as early as 120 minutes before birth, which gives enough leading time for timely interventions.

Fetal heart rate monitoring is an essential obstetric procedure, however, false-positive results cause unnecessary obstetric interventions and healthcare cost. In this study, we propose a low cost and non-invasive fetal phonocardiography based signal system to measure the fetal heart sounds and fetal heart rate. Phonocardiogram (PCG) signals contain acoustic information reflecting the contraction and relaxation of the heart. We have developed a four-channel recording device with four separated piezoelectric sensors harnessed by a cloth sheet to record abdominal phonogram signals. A multi-lag covariance matrix based eigenvalue decomposition technique was used to extract fetal and maternal heart sounds as well as maternal breathing movement. In order to validate the fetal heart sounds extracted by PCG signal processing, 10 minutes' simultaneous recordings of fetal Electrocardiogram (fECG) and abdominal phonogram from 15 pregnant women (27 ± 5-year-old) with fetal gestation ages between 33 and 40 weeks were obtained and processed. Highly significant (p < 0.01) correlation (r = 0.96; N = 270) was found between beat to beat fetal heart rate (FHRECG) from fECG and the same (FHRPCG) from fetal PCG signals. Bland-Altman plot of FHRECG and FHRPCG shows good agreement (<5% difference). We conclude that the proposed beat to beat fetal heart rate measurement system would be useful for monitoring fetal neurological wellbeing as a better alternative to traditional cardiotocogram based antenatal fetal heart rate monitoring.

Conditions during fetal development influence health and disease in adulthood, especially during critical windows of organogenesis. Fetal exposure to the endocrine disrupting chemical, bisphenol A (BPA) affects the development of multiple organ systems in rodents and monkeys. However, effects of BPA exposure on cardiac development have not been assessed. With evidence that maternal BPA is transplacentally delivered to the developing fetus, it becomes imperative to examine the physiological consequences of gestational exposure during primate development. Herein, we evaluate the effects of daily, oral BPA exposure of pregnant rhesus monkeys (Macaca mulatta) on the fetal heart transcriptome. Pregnant monkeys were given daily oral doses (400 µg/kg body weight) of BPA during early (50-100 ± 2 days post conception, dpc) or late (100 ± 2 dpc--term), gestation. At the end of treatment, fetal heart tissues were collected and chamber specific transcriptome expression was assessed using genome-wide microarray. Quantitative real-time PCR was conducted on select genes and ventricular tissue glycogen content was quantified. Our results show that BPA exposure alters transcription of genes that are recognized for their role in cardiac pathophysiologies. Importantly, myosin heavy chain, cardiac isoform alpha (Myh6) was down-regulated in the left ventricle, and 'A Disintegrin and Metalloprotease 12', long isoform (Adam12-l) was up-regulated in both ventricles, and the right atrium of the heart in BPA exposed fetuses. BPA induced alteration of these genes supports the hypothesis that exposure to BPA during fetal development may impact cardiovascular fitness. Our results intensify concerns about the role of BPA in the genesis of human metabolic and cardiovascular diseases.

Fetal heart rate (FHR) monitoring is a screening tool used by obstetricians to evaluate the fetal state. Because of the complexity and non-linearity, a visual interpretation of FHR signals using common guidelines usually results in significant subjective inter-observer and intra-observer variability.

Introduction Very preterm babies can be difficult to monitor using standard external Doppler fetal heart tracings (eFHR). External fetal electrocardiogram (fECG) is a potential alternative. Methods This was a prospective observational pilot study of hospitalized patients at 24 to 28 weeks' gestation. A total of 30 women were traced for up to 2 hours using eFHR followed by up to 2 hours using fECG. The percentage of time the fetal heart rate was traced during the 2-hour window for each modality was calculated. Differences of ≥ 60, ≥ 80, and ≥ 90% total time traced were compared between modalities using McNemar's test. Differences were also assessed for each method between nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) women using chi-square and Fisher's exact tests. Results Superior performance was found with eFHR at ≥ 60% (93.3 vs. 46.7%, p < 0.001), ≥ 80% (80.0 vs. 30.0%, p < 0.001), and ≥ 90% (60.0 vs. 23.3%, p < 0.01) total time traced. There was a statistically significant finding favoring nonobese women at ≥ 80% total time traced using fECG (7.1 vs. 50.0%, p = 0.017). Conclusion With current technology fECG performance in very preterm gestation was worse than conventional eFHR, although fECG may have a role in nonobese patients.

Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.

Prenatal detection of congenital heart disease facilitates the opportunity for potentially life-saving care immediately after the baby is born. Echocardiography is routinely used for screening of morphological malformations, but functional measurements of blood flow are scarcely used in fetal echocardiography due to technical assumptions and issues of reliability. Magnetic resonance imaging (MRI) is readily used for quantification of abnormal blood flow in adult hearts, however, existing in utero approaches are compromised by spontaneous fetal motion. Here, we present and validate a novel method of MRI velocity-encoding combined with a motion-robust reconstruction framework for four-dimensional visualization and quantification of blood flow in the human fetal heart and major vessels. We demonstrate simultaneous 4D visualization of the anatomy and circulation, which we use to quantify flow rates through various major vessels. The framework introduced here could enable new clinical opportunities for assessment of the fetal cardiovascular system in both health and disease.

Besides neuronal transmission, serotonin (5-HT) also acts as a trophic signal during the development of the central nervous and neural crest systems. In this study, we report that in addition to trophic effect, 5-HT increases the proliferation of fetal heart cells. We showed for the first time that the cultured heart cells, express serotonin transporter (5-HTT), which confirmed the previously observed accumulation of 5-HT in developing heart. The influence of 5-HT on developing heart cells is studied throughout the dosage. We found that 5-HT concentration at physiological level, 4 microM, permits an optimal proliferation of heart cells as indicated by the number of 5-bromo-deoxyuridine immunoreactive (BrdU-im) cells and myosin heavy chain immunoreactive cells (MF20-im); fluctuation towards either concentrations reduce the proliferation. We hypothesized that 5-HTT plays a role in the heart development. Our study indicated that the blockade of 5-HT uptake by paroxetine decreased the number of BrdU-im cells and MF20-im cells. These data indicate a role of 5-HT and 5-HTT on heart development. Abnormal 5-HT level or misuse of 5-HT uptake blocker may alter the heart development.

It is fundamental to diagnose fetal acidemia as early as possible, allowing adequate obstetrical interventions to prevent brain damage or perinatal death. The visual analysis of cardiotocography traces has been complemented by computerized methods in order to overcome some of its limitations in the screening of fetal hypoxia/acidemia. Spectral analysis has been proposed by several studies exploring fetal heart rate recordings while referring to a great variety of frequency bands for integrating the power spectrum. In this paper, the main goal was to systematically review the spectral bands reported in intrapartum fetal heart rate studies and to evaluate their performance in detecting fetal acidemia/hypoxia. A total of 176 articles were reviewed, from MEDLINE, and 26 were included for the extraction of frequency bands and other relevant methodological information. An open-access fetal heart rate database was used, with recordings of the last half an hour of labor of 246 fetuses. Four different umbilical artery pH cutoffs were considered for fetuses' classification into acidemic or non-acidemic: 7.05, 7.10, 7.15, and 7.20. The area under the receiver operating characteristic curve (AUROC) was used to quantify the frequency bands' ability to distinguish acidemic fetuses. Bands referring to low frequencies, mainly associated with neural sympathetic activity, were the best at detecting acidemic fetuses, with the more severe definition (pH ≤ 7.05) attaining the highest values for the AUROC. This study shows that the power spectrum analysis of the fetal heart rate is a simple and powerful tool that may become an adjunctive method to CTG, helping healthcare professionals to accurately identify fetuses at risk of intrapartum hypoxia and to implement timely obstetrical interventions to reduce the incidence of related adverse perinatal outcomes.

The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.

Fetal nerve maturation is a dynamic process, which is reflected in fetal movement and fetal heart rate (FHR) patterns. Classical FHR variability (fHRV) indices cannot fully reflect their complex interrelationship. This study aims to provide an alternative insight for fetal neural development by using the coupling analysis of uterine electromyography (UEMG) and FHR acceleration. We investigated 39 normal pregnancies with appropriate for gestational age (AGA) and 19 high-risk pregnancies with small for gestational age (SGA) at 28-39 weeks. The UEMG and FHR were recorded simultaneously by a trans-abdominal device during the night (10 p.m.-8 a.m.). Cross-wavelet analysis was used to characterize the dynamic relationship between FHR and UEMG. Subsequently, a UEMG-FHR coupling index (UFCI) was extracted from the multiscale coupling power spectrum. We examined the gestational-age dependency of UFCI by linear/quadratic regression models, and the ability to screen for SGA using binary logistic regression. Also, the performances of classical fHRV indices, including short-term variation (STV), averaged acceleration capacity (AAC), and averaged deceleration capacity (ADC), time- and frequency- domain indices, and multiscale entropy (MSE), were compared as references on the same recordings. The results showed that UFCI provided a stronger age predicting value with R2 = 0.480, in contrast to the best value among other fHRV indices with R2 = 0.335, by univariate regression models. Also, UFCI achieved superior performance for predicting SGA with the area under the curve (AUC) of 0.88, compared with 0.79 for best performance of other fHRV indices. The present results indicate that UFCI provides new information for early detection and comprehensive interpretation of intrauterine growth restriction in prenatal diagnosis, and helps improve the screening of SGA.

Previous studies using ultrasound technology showed that fetal heart rate (HR) may be responsive to maternal aerobic exercise. Although it is recognized that cardiac autonomic control may be influenced by the intrauterine environment, little is known about how maternal exercise affects fetal heart development.

Fetal congenital heart anomalies are the most common congenital anomalies in live births. Fetal echocardiography (FECG) is the only prenatal diagnostic approach used to detect fetal congenital heart disease (CHD). FECG is not widely used, and the antenatal diagnosis rate of CHD varies considerably. Thus, mastering the anatomical characteristics of different kinds of CHD is critical for ultrasound physicians to improve FECG technology. The aim of this study is to investigate the applications of a fetal CHD anatomic database in FECG teaching and training program.

Adequate maternal nutrient supply is critical for normal fetal organogenesis. We previously demonstrated that a global 50% nutrient restriction during the first half of gestation causes compensatory growth of both the left and right ventricles of the fetal heart by day 78 of gestation. Thus, it was hypothesized that maternal nutrient restriction significantly altered gene expression in the fetal cardiac left ventricle (LV). Pregnant ewes were randomly grouped into control (100% national research council (NRC) requirements) or nutrient-restricted groups (50% NRC requirements) from day 28 to day 78 of gestation, at which time fetal LV were collected. Fetal LV mRNA was used to construct a suppression subtraction cDNA library from which 11 cDNA clones were found by differential dot blot hybridization and virtual Northern analysis to be up-regulated by maternal nutrient restriction: caveolin, stathmin, G-1 cyclin, alpha-actin, titin, cardiac ankyrin repeat protein (CARP), cardiac-specific RNA-helicase activated by MEF2C (CHAMP), endothelial and smooth muscle derived neuropilin (ESDN), prostatic binding protein, NADH dehydrogenase subunit 2, and an unknown protein. Six of these clones (cardiac alpha-actin, cyclin G1, stathmin, NADH dehydrogenase subunit 2, titin and prostatic binding protein) have been linked to cardiac hypertrophy in other species including humans. Of the remaining clones, caveolin, CARP and CHAMP have been shown to inhibit remodelling of hypertrophic tissue. Compensatory growth of fetal LV in response to maternal undernutrition is concluded to be associated with increased transcription of genes related to cardiac hypertrophy, compensatory growth or remodelling. Counter-regulatory gene transcription may be increased, in part, as a response to moderating the degree of cardiac remodelling. The short- and long-term consequences of these changes in fetal heart gene expression and induction of specific homeostatic mechanisms in response to maternal undernutrition remain to be determined.

Micro-computed tomography (CT) is a non-invasive alternative to conventional macroscopic dissection for the evaluation of human fetal cardiac anatomy. This paper aims to systematically review the literature regarding the use of micro-CT to examine human fetal hearts, to illustrate its educational and research implications and to explain its possible directions for the future. A systematic literature review was conducted following the PRISMA statement to identify publications concerning micro-CT applications for the isolated human fetal heart. The search strategy identified nine eligible studies. Micro-CT is technically feasible for postmortem examination of the human fetal heart coming from early and late termination of pregnancy. It reaches high diagnostic accuracy, and it seems to perform better than autopsy in small samples or in the case of early termination of pregnancy. Applications derived from micro-CT allow multiple off-time evaluations and interdisciplinary comparisons for educational purposes and research perspectives in biological and bioengineering domains.

Non-invasive fetal electrocardiography (ECG) is based on the acquisition of signals from abdominal surface electrodes. The composite abdominal signal consists of the maternal electrocardiogram along with the fetal electrocardiogram and other electrical interferences. These recordings allow for the acquisition of valuable and reliable information that helps ensure fetal well-being during pregnancy. This paper introduces a procedure for fetal heart rate extraction from a single-channel abdominal ECG signal. The procedure is composed of three main stages: a method based on wavelet for signal denoising, a new clustering-based methodology for detecting fetal QRS complexes, and a final stage to correct false positives and false negatives. The novelty of the procedure thus relies on using clustering techniques to classify singularities from the abdominal ECG into three types: maternal QRS complexes, fetal QRS complexes, and noise. The amplitude and time distance of all the local maxima followed by a local minimum were selected as features for the clustering classification. A wide set of real abdominal ECG recordings from two different databases, providing a large range of different characteristics, was used to illustrate the efficiency of the proposed method. The accuracy achieved shows that the proposed technique exhibits a competitve performance when compared to other recent works in the literature and a better performance over threshold-based techniques.

Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%-16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.

Congenital heart disease (CHD) is one of the most important and common group of congenital malformations in humans. Concurrent development and close functional links between the fetal heart and placenta emphasise the importance of understanding placental function and its influence in pregnancy outcomes. The aim of this study was to evaluate placental oxygenation by relaxometry (T2*) to assess differences in placental phenotype and function in CHD.