Healthy Human Fetuses Research Articles

Spatiotemporal Atlas of the Fetal Brain Depicts Cortical Developmental Gradient.

The fetal brains experience rapid and complex development in utero during the second and third trimesters. In utero MRI of the fetal brain in this period enables us to quantify normal fetal brain development in the spatiotemporal domain. In this study, we established a high-quality spatiotemporal atlas between 23 and 38 weeks gestational age (GA) from 90 healthy Chinese human fetuses of both sexes using a pairwise and groupwise registration pipeline. We quantified the fetal cortical morphology indices and characterized their spatiotemporal developmental pattern. The cortical thickness exhibited a biphasic pattern that first increased and then decreased; the curvature fitted well into the Gompertz growth model; sulcal depth increased linearly, while surface area expanded exponentially. The cortical thickness and curvature trajectories consistently pointed to a characteristic time point around GA of 31 weeks. The characteristic GA and growth rate obtained from individual cortical regions suggested a central-to-peripheral developmental gradient, with the earliest development in the parietal lobe, and we also observed a superior-to-inferior gradient within the temporal lobe. These findings may be linked to biophysical events, such as dendritic arborization and thalamocortical fibers ingrowth. The proposed atlas was also compared with an existing fetal atlas from a white/mixed population. Finally, we examined the structural asymmetry of the fetal brains and found extensive asymmetry that dynamically changed with development. The current study depicted a comprehensive profile of fetal cortical development, and the established atlas could be used as a normative reference for neurodevelopmental and diagnostic purposes, especially in the Chinese population.SIGNIFICANCE STATEMENT We generated a high-quality 4D spatiotemporal atlas of the normal fetal brain development from 23 to 38 gestational weeks in a Chinese population and characterized the spatiotemporal developmental pattern of cortical morphology. According to the cortical development trajectories, the fetal cerebral cortex development follows a central-to-peripheral developmental gradient that may be related to the underlying cellular events. The majority of cortical regions already exhibit significant asymmetry during the fetal period.

Lineage tracing of human development through somatic mutations.

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.

Prenatal neural origins of infant motor development: Associations between fetal brain and infant motor development.

Functional circuits of the human brain emerge and change dramatically over the second half of gestation. It is possible that variation in neural functional system connectivity in utero predicts individual differences in infant behavioral development, but this possibility has yet to be examined. The current study examines the association between fetal sensorimotor brain system functional connectivity and infant postnatal motor ability. Resting-state functional connectivity data was obtained in 96 healthy human fetuses during the second and third trimesters of pregnancy. Infant motor ability was measured 7 months after birth using the Bayley Scales of Infant Development. Increased connectivity between the emerging motor network and regions of the prefrontal cortex, temporal lobes, posterior cingulate, and supplementary motor regions was observed in infants that showed more mature motor functions. In addition, females demonstrated stronger fetal-brain to infant-behavior associations. These observations extend prior longitudinal research back into prenatal brain development and raise exciting new ideas about the advent of risk and the ontogeny of early sex differences.

Cerebrospinal Fluid and Parenchymal Brain Development and Growth in the Healthy Fetus

Objective: The objective of this study was to apply quantitative magnetic resonance imaging to characterize absolute cerebrospinal fluid (CSF) development, as well as its relative development to fetal brain parenchyma in the healthy human fetus. Design: We created three-dimensional high-resolution reconstructions of the developing brain for healthy fetuses between 18 and 40 weeks' gestation, segmented the parenchymal and CSF spaces, and calculated the volumes for the lateral, third, and fourth ventricles; extra-axial CSF space; and the cerebrum, cerebellum, and brainstem. From these data, we constructed normograms of the resulting volumes according to gestational age and described the relative development of CSF to fetal brain parenchyma. Results: Each CSF space demonstrated major increases in volumetric growth during the second half of gestation: third ventricle (23-fold), extra-axial CSF (11-fold), fourth ventricle (8-fold), and lateral ventricle (2-fold). Total CSF volume was related to total brain volume (p < 0.01), as was lateral ventricle to cerebral volume (p < 0.01); however, the fourth ventricle was not related to cerebellar or brainstem volume (p = 0.18-0.19). Relevance: Abnormalities of the CSF spaces are the most common anomalies of neurologic development detected on fetal screening using neurosonography. Normative values of absolute CSF volume, as well as relative growth in comparison to intracranial parenchyma, provide valuable insight into normal fetal neurodevelopment. These data may provide important biomarkers of early deviations from normal growth, better distinguish between benign variants and early disease, and serve as reference standards for postnatal growth and development in the premature infant.

Complex Trajectories of Brain Development in the Healthy Human Fetus.

This study characterizes global and hemispheric brain growth in healthy human fetuses during the second half of pregnancy using three-dimensional MRI techniques. We studied 166 healthy fetuses that underwent MRI between 18 and 39 completed weeks gestation. We created three-dimensional high-resolution reconstructions of the brain and calculated volumes for left and right cortical gray matter (CGM), fetal white matter (FWM), deep subcortical structures (DSS), and the cerebellum. We calculated the rate of growth for each tissue class according to gestational age and described patterns of hemispheric growth. Each brain region demonstrated major increases in volume during the second half of gestation, the most pronounced being the cerebellum (34-fold), followed by FWM (22-fold), CGM (21-fold), and DSS (10-fold). The left cerebellar hemisphere, CGM, and DSS had larger volumes early in gestation, but these equalized by term. It has been increasingly recognized that brain asymmetry evolves throughout the human life span. Advanced quantitative MRI provides noninvasive measurements of early structural asymmetry between the left and right fetal brain that may inform functional and behavioral laterality differences seen in children and young adulthood.

Metal-based particles in human amniotic fluids of fetuses with normal karyotype and congenital malformation--a pilot study.

This study explores the inorganic composition of amniotic fluid in healthy human fetuses and fetuses with congenital malformation with a special attention to presence of metal-based solid particles. Amniotic fluid originates from maternal blood and provides fetus mechanical protection and nutrients. In spite of this crucial role, the environmental impact on the composition of amniotic fluid remains poorly studied. The samples of human amniotic fluids were obtained by amniocentesis, including both healthy pregnancies and those with congenital malformations. The samples were analysed using several techniques, including Raman microspectroscopy, scanning electron microscopy with energy-dispersed spectrometry (SEM-EDS), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis. Several metal-based particles containing barium, titanium, iron, and other elements were detected by SEM-EDS and Raman microspectroscopy. XRD analysis detected only sodium chloride as the main component of all amniotic fluid samples. Infrared spectroscopy detected protein-like organic components. Majority of particles were in form of agglomerates up to tens of micrometres in size, consisting of mainly submicron particles. By statistical analysis (multiple correspondence analysis), it was observed that groups of healthy and diagnosed fetuses form two separate groups and therefore, qualitative differences in chemical composition may have distinct biological impact. Overall, our results suggest that metal-based nanosized pollutants penetrate into the amniotic fluid and may affect human fetuses.

Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus.

The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

Cardiac vectors in the healthy human fetus: developmental changes assessed by magnetocardiography and realistic approximations of the volume conductor

This study sought to characterize the developmental changes of three measures used to describe the morphology of the fetal cardiac vector: QRS peak-amplitude, QRS duration and QRS time-amplitude integral. To achieve this objective, we rely on a recently developed methodology for fetal cardiac vector estimation, using multichannel fetal magnetocardiographic (fMCG) recordings and realistic approximations of the volume conductors obtained from free-hand ultrasound imaging. fMCG recordings and 3D ultrasound images were obtained from 23 healthy, uncomplicated pregnancies for a total of 77 recordings performed at gestational ages between 22 and 37 weeks. We report the developmental changes of the cardiac vector parameters with respect to gestational age and estimated fetal weight, as well as their dependence on the estimated ventricular mass derived from cardiac dimensions measured with M-mode ultrasound. The normative values can be used along with the cardiac time intervals reported by previous fMCG studies to assist future clinical studies investigating conditions that affect fetal cardiac function.

Cross-hemispheric functional connectivity in the human fetal brain.

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

Watching the fetal brain at ‘rest’

Functional magnetic resonance imaging (fMRI) has allowed insights into the spatiotemporal distribution of human brain networks. According to the neurophysiological property of the fetal brain to generate spontaneous activity, we aimed to determine the feasibility of investigating the maturation of intrinsic networks, beginning at gestational week 20 in healthy human fetuses by combining resting-state fMRI and an analytical approach, independent component analysis (ICA). In this study, functional images of 16 fetuses with morphologically normal brain development, from 20 to 36 gestational weeks of age, were acquired on a 1.5 T unit (Philips Medical Systems, Best, The Netherlands) using single-shot, gradient-recalled echo-planar imaging. After preprocessing (motion correction, brain extraction), images were analyzed using single-subject ICA. We visualized a bilateral occipital network and medial and lateral prefrontal activity pattern that involved the future Brodmann areas 9–11. Furthermore, there was one either predominantly right (3/7 cases) or left (4/7 cases) hemispheric lateralized network that involved the superior temporal cortical regions (Brodmann areas 22 and 39). Frequency oscillations were in the range of 0.01–0.06 Hz for all networks. This study shows that resting-state networks (RSNs) are shaped and are detectable in utero. Further investigations of resting-state measurements in the fetus may therefore allow developmental brain activity monitoring and may provide insights into early brain function.

OP12.06: Full-volume three-dimensional echocardiographic assessment of left ventricular volume in healthy human fetuses

OP12.06: Full-volume three-dimensional echocardiographic assessment of left ventricular volume in healthy human fetuses

Full-volume three-dimensional echocardiographic assessment of left ventricular volume in healthy human fetuses

Objective To evaluate the feasibility and accuracy of full volume three-dimensional echocardiography(FV3DE) for quantifying the left ventricular volume in healthy fetuses. Methods Two hundred and twenty-two normal fetuses with gestational ages between 20 and 40 weeks were investigated. Full volume three-dimensional, two-dimensional (2D) and M-mode images were acquired by Philips iE33 system and data was processed offline using QLAB analysis software. Left ventricular end-systolic volume(ESV) and end-diastolic volume ( EDV) were measured using semiautomated border detection echocardiographic techniques, and compared with 2D biplane Simpson's method and M-mode Teichholz formula. Results Thirty-six fetuses with poor three-dimensional images and 5 twin pregnancies were excluded,the study subjects consisted of 181 singleton fetuses. The highest concordance correlation ( r =0.987 for EDV, r =0.988 for ESV) P <0. 001) was noted between 2D biplane Simpson's and FV3DE-derived values with a small bias (0. 332 ml for EDV,0. 135 ml for ESV). The Bland-Altman analysis showed that FV3DE had the best reproducibility than M-mode Teichholz formula and 2D biplane Simpson's method. Intra- and interobserver error of EDV were 2.85% and 4.22% for FV3DE,8.37% and 8.98% for 2D biplane Simpson's rule,30. 63% and 54. 70% for M-mode Teichholz formula. Intra- and interobserver error of ESV were 2.34% and 6. 14% for FV3DE,6. 26% and 11.7% for 2D biplane Simpson's rule,43.06% and 66.03% for M-mode Teichholz formula. Conclusions FV3DE is a novel technique that can be more accurate than conventional methods in quantification of fetal left ventricular volumes, it may provide new insight into evolving fetal cardiac structure and function. Key words: Ultrasonography,prenatal s Fetus; Cardiac volume,left

Fetal autonomic response to severe acidaemia during labour

Spectral analysis of heart-rate variability is used to monitor autonomic nervous system fluctuations. The low-frequency component is associated with sympathetic and parasympathetic modulation and the high-frequency component is associated with parasympathetic modulation. The objective was to study whether changes in low-frequency or high-frequency power of heart-rate variability occur in case of fetal distress. Case-control study. Obstetric unit of a tertiary-care teaching hospital. Twenty healthy human fetuses during labour at term of which ten had an umbilical artery pH < 7.05 (cases), and ten had an arterial pH > 7.20 (controls) after birth. Spectral information about fetal beat-to-beat heart rate, calculated from direct fetal electrocardiogram registrations, was obtained by using a short-time Fourier transform. Absolute power and normalised power in the low-frequency and high-frequency bands. No differences were found between fetuses with and without acidaemia in absolute low or high frequency power (P = 0.2 and P = 0.3, respectively). During the last 30 minutes of labour, acidaemic fetuses had significantly increased normalised low-frequency power (P = 0.01) and decreased normalised high-frequency power (P = 0.03) compared with non-acidaemic fetuses. These differences were not observed from 3 to 2 hours before birth (P = 0.7 and P = 0.9, respectively). The autonomic nervous system of human fetuses at term responds adequately to severe stress during labour. Normalised low and high frequency power of heart-rate variability might be able to discriminate between normal and abnormal fetal condition.

Reference ranges for fetal pulmonary venous blood flow parameters and changes in hypoplastic left heard syndroms (HLHS)

Objectives Our main objectiv was to analyse changes in fetal pulmonary venous blood flow pattern in infants with hypoplastic left heart syndrome (HLHS). Furthermore, we aimed to establish reference ranges of the pulmonary venous blood flow pattern for the second half of pregnancy in healthy human fetuses. We contrasted these ranges with present normative data and with pulmonary venous Doppler parameters of fetuses with HLHS.

Coronary arteries in fetal life: physiology, malformations and the “heart‐sparing effect”

The present knowledge of coronary arteries in prenatal diagnosis is reviewed with a focus on three aspects: the physiology and visualization of coronary flow, malformations involving the coronary arteries, and the "heart-sparing effect". Visualization of coronary arteries in a healthy human fetus is possible in real-time and colour Doppler during the last 10 wk of gestation when ultrasound conditions are excellent. Visualization at an earlier gestational age (up to 13 wk) is feasible mainly in association with malformations and impending hypoxia. The main coronary malformations that can be visualized in utero are the ventriculo-coronary communications in fetuses with pulmonary atresia. In the last few years, interest has been focused on the "heart-sparing effect", defined as the increased perfusion of the coronary arteries in fetuses with severe growth restriction and abnormal Doppler velocimetry in the peripheral vessels. Increased perfusion detectable with colour and pulsed Doppler is a late sign of fetal compromise in hypoxaemia. It confirms animal experiments that have demonstrated dilatory reserves of the fetal coronary arteries under chronic hypoxaemia. The outcome of 21 fetuses showing the "heart-sparing effect" before 32 wk gestation was poor: nine fetuses died in utero and two after birth, the median weight at birth was 630 g. In summary, our knowledge of the coronary arteries in the fetus is based on the diagnostic means used in prenatal diagnosis. New information in this field may also contribute to a better understanding of coronary heart disease later in life.

Assessment of fetal heart rate and fetal movements in detecting oxygen deprivation in-utero

This article reviews the physiological principles underlying the application of assessment of fetal movements and fetal heart rate (FHR) in detecting fetal hypoxia. Studies in both fetal sheep and healthy human fetuses are discussed including those which have demonstrated the importance of appreciating the existence of rest-activity cycles under normal physiological conditions. The role of adenosine in mediating the hypoxic inhibition of fetal breathing movements (FBMs) is reviewed as is the previously unrecognized importance of fetal gasping as a possible new measure of fetal hypoxia.

Eyelid movements in normal human fetuses.

We undertook this study to investigate the characteristics of blinking activity in healthy human fetuses. Blinking activity was studied sonographically in healthy fetuses between 33 and 42 weeks' menstrual age. Horizontal and coronal sonographic views of the eye were obtained and videotaped. Fetal blinking movements were analyzed by reviewing the videotape in slow motion. Fetal vibroacoustic stimulation was also used when clinically indicated. We examined a total of 18 healthy fetuses. Fetal blinking was detected in 89% of cases, with a mean frequency of 6.2 movements per 60-minute observation period. Vibroacoustic stimulation was associated with increased fetal blinking in the 6 fetuses in which it was applied (mean, 15.3 movements per 60-minute observation period). Blinking is a normal fetal activity. The increased frequency of blinking activity associated with vibroacoustic stimulation may be considered a part of the normal startle reflex.

Phenotypic and functional analysis of human T lymphocytes in early second- and third-trimester fetuses.

This study was undertaken to investigate the phenotypic and functional status of T lymphocytes of human fetuses from early second- to third-trimester. Cord blood samples were obtained from 19 healthy human fetuses (gestation weeks: 18-36), by cordocentesis, and 16 term newborns (gestation weeks 37-42). Maternal and unrelated male blood samples were also taken as controls. Percentage of lymphocytes in fetal white blood cells was 79.3%, reducing to 40% by term birth, much higher than that of adults. Cord blood mononuclear cells (CBMC), prepared by density gradient centrifugation followed by lysis of erythrocytes, were stained using PE- or FITC-labelled monoclonal Abs and analysed by flow cytometry. The frequencies of CD3+ T cells in fetal (40.1%) and neonatal (42.4%) CBMC were significantly lower than that of men (59.6%) and pregnant women (53.6%). Proportions of CD8+ T cells (9.5%), gammadelta-T cells (0.5%) and NK cells (4.8%) in fetal CBMC were also lower than that of neonates (except gammadelta-T cells) and adults. A negative linear correlation (r = -0.609) between the ratio of CD4+/CD8+ T cells in fetal blood and gestation age could also be established. Fetal CBMC showed vigorous spontaneous proliferation but failed to respond to mitogen (PHA) or allogeneic stimulation in vitro. The fetal mononuclear cells were unable to produce IL-2, IL-4 or IFN-gamma, but spontaneously secreted IL-10, IL-6 and TNF-alphain vitro. Stimulation with PHA up-regulated the production of IL-10, IL-6 and TNF-alpha substantially.

Three‐dimensional quantitative echocardiographic assessment of ventricular volume in healthy human fetuses with and in fetuses with congenital heart disease

We examined the feasibility and appearance of 3D fetal echo assessment of ventricular volumes in 29 normal fetuses and 22 fetuses with congenital heart disease (gestation 18–35 weeks). Gated 3D volume sets could be obtained in 51 of 57 cases. Normal right and left ventricular volume, stroke volume data, and RV/LV ratios were obtained, together with normal changes with gestation. In patients with congenital heart disease, those with a biventricular heart (index lesion teratology of Fallot) demonstrated normal combined ventricular volumes and right/left volume ratios for gestation age. Fetuses with single ventricular heart with intact septum (hypoplastic left or right heart) demonstrated a small but significant reduction in combined ventricular size and stroke volume for gestation age.

Three-dimensional quantitative echocardiographic assessment of ventricular volume in healthy human fetuses and in fetuses with congenital heart disease.

The purpose of this study was to evaluate the feasibility of three-dimensional freehand echocardiographic assessment of ventricular volumetry in healthy fetuses and in fetuses with congenital heart disease. The study was approved by the hospital institutional review board. After echocardiographic examination by conventional ultrasonographic equipment interfaced with a magnetic tracking system, three-dimensional cardiac data were collected prospectively in 57 fetuses. Ventricular volumes were determined from three-dimensional data sets, and 22 fetuses with congenital heart disease were compared with 29 healthy fetuses. A multiple regression analysis of covariance was performed to assess between-group differences. Gated three-dimensional volume data sets enabled assessment of ventricular volumes in 51 of the 57 fetuses. Both fetuses with and without congenital heart disease had exponential increases in cardiac volumes during gestation. In fetuses with congenital heart disease and a marked inequality of ventricular size but no heart failure, the combined end-diastolic and stroke volumes of both ventricles were found to be significantly reduced compared with controls with no disease and fetuses with other types of congenital heart disease. Three-dimensional imaging can provide estimates of ventricular volume changes in fetal hearts with abnormal ventricular morphology that cannot easily be performed by two-dimensional echocardiography, and it may provide insight into evolving congenital heart disease.