Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways.

Maternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) or High (5 × 107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal-placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho-eIF2α. There were no differences in fetal-placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium-coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV-infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV-induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.

Twisting the theory on the origin of human umbilical cord coiling featuring monozygotic twins.

The human umbilical cord (hUC) is the lifeline that connects the fetus to the mother. Hypercoiling of the hUC is associated with pre- and perinatal morbidity and mortality. We investigated the origin of hUC hypercoiling using state-of-the-art imaging and omics approaches. Macroscopic inspection of the hUC revealed the helices to originate from the arteries rather than other components of the hUC. Digital reconstruction of the hUC arteries showed the dynamic alignment of two layers of muscle fibers in the tunica media aligning in opposing directions. We observed that genetically identical twins can be discordant for hUC coiling, excluding genetic, many environmental, and parental origins of hUC coiling. Comparing the transcriptomic and DNA methylation profile of the hUC arteries of four twin pairs with discordant cord coiling, we detected 28 differentially expressed genes, but no differentially methylated CpGs. These genes play a role in vascular development, cell-cell interaction, and axis formation and may account for the increased number of hUC helices. When combined, our results provide a novel framework to understand the origin of hUC helices in fetal development.

The key to understanding core knowledge resides in the fetus.

What Babies Know outlines a compelling case for why infancy research is fundamental for conceptualizing what it is to be human. There is another period in human development that is relatively inaccessible, yet is more important. In order to truly understand the nature of core knowledge, perception, and cognition, we must start not with the infant, but with the fetus.

An embodied approach to fetal and newborn perceptual and sensorimotor development.

The embodied approach argues that interaction with the environment plays a crucial role in brain development and that the presence of sensory effects generated by movements is fundamental. The movement of the fetus is initially random. Then, the repeated execution of the movement creates a link between it and its sensory effects, allowing the selection of movements that produce expected sensations. During fetal life, the brain develops from a transitory fetal circuit to the permanent cortical circuit, which completes development after birth. Accordingly, this process must concern the interaction of the fetus with the intrauterine environment and of the newborn with the new aerial environment, which provides a new sensory stimulation, light. The goal of the present review is to provide suggestions for neuroscientific research capable of shedding light on brain development process by describing from a functional point of view the relationship between the motor and sensory abilities of fetuses and newborns and the increasing complexity of their interaction with objects in the womb and outside of it.

Functional connectivity development in the prenatal and neonatal stages measured by functional magnetic resonance imaging: A systematic review.

The prenatal and neonatal periods are two of the most important developmental stages of the human brain. It is therefore crucial to understand normal brain development and how early connections are established during these periods, in order to advance the state of knowledge on altered brain development and eventually identify early brain markers of neurodevelopmental disorders and diseases. In this systematic review (Prospero ID: CRD42024511365), we compiled resting state functional magnetic resonance imaging (fMRI) studies in healthy fetuses and neonates, in order to outline the main characteristics of typical development of the functional brain connectivity during the prenatal and neonatal periods. A systematic search of five databases identified a total of 12 573 articles. Of those, 28 articles met pre-established selection criteria based determined by the authors after surveying and compiling the major limitations reported within the literature. Inclusion criteria were: (1) resting state studies; (2) presentation of original results; (3) use of fMRI with minimum one Tesla; (4) a population ranging from 20 weeks of GA to term birth (around 37-42 weeks of PMA); (5) singleton pregnancy with normal development (absence of any complications known to alter brain development). Exclusion criteria were: (1) preterm studies; (2) post-mortem studies; (3) clinical or pathological studies; (4) twin studies; (5) papers with a sole focus on methodology (i.e. focused on tool and analysis development); (6) volumetric studies; (7) activation map studies; (8) cortical analysis studies; (9) conference papers. A risk of bias assessment was also done to evaluate each article's methodological rigor. 1877 participants were included across all the reviewed articles. Results consistently revealed a developmental gradient of increasing functional brain connectivity from posterior to anterior regions and from proximal-to-distal regions. A decrease in local small-world organization shortly after birth was also observed; small-world characteristics were present in fetuses and newborns, but appeared weaker in the latter group. Also, the posterior-to-anterior gradient could be associated with earlier development of the sensorimotor networks in the posterior regions while more complex higher-order networks (e.g. attention-related) mature later in the anterior regions. The main limitations of this systematic review stem from the inherent limitations of functional imaging in fetuses, mainly: unevenly distributed populations and limited sample sizes; fetal movements in the womb and other imaging obstacles; and a large voxel resolution when imaging a small brain. Another limitation specific to this review is the relatively small number of included articles compared to very a large search result, which may have led to relevant articles having been overlooked.

Quantitative study of the ossification centers of the body of sphenoid bone in the human fetus.

The aim of the present study was to examine the growth dynamics of the two ossification centers of the body of sphenoid bone in the human fetus, based on their linear, planar and volumetric parameters. The examinations were carried out on 37 human fetuses of both sexes aged 18-30 weeks of gestation, which had been preserved in 10% neutral formalin solution. Using CT, digital image analysis software, 3D reconstruction and statistical methods, we evaluated the size of the presphenoid and postsphenoid ossification centers. The presphenoid ossification center grew proportionately in sagittal diameter, projection surface area and volume, and logarithmically in transverse diameter. The postsphenoid ossification center increased logarithmically in sagittal diameter, transverse diameter and projection surface area, while its volumetric growth followed proportionately. The numerical findings of the presphenoid and postsphenoid ossification centers may be considered age-specific reference values of potential relevance in monitoring the normal fetal growth and screening for congenital disorders in the fetus. The obtained results may contribute to a better understanding of the growing fetal skeleton, bringing new numerical information regarding its diagnosis and development.

The curse of the firstborn: Effects of dam primiparity on developmental programming in ruminant offspring.

The first parity, or first pregnancy, of ruminant females has negative effects on offspring during fetal, perinatal, and pre-weaning periods which ultimately lead to diminished pre-weaning productivity. Offspring born to primiparous ruminant females can have decreased fetal and pre-weaning growth, resulting in lower body weights at birth and weaning in cattle, sheep, and goats. Moreover, mortality is greater during both neonatal and pre-weaning periods. Insults during these critical developmental windows likely also have long-term consequences on first-parity offspring through developmental programming, but less research has been done to investigate effects in the post-weaning period. Many potential physiological, metabolic, and behavioral mechanisms exist for the outcomes of dam primiparity. Although competition for nutrient partitioning between maternal and fetal growth or lactation is often cited as a major contributor, we hypothesize that the most important mechanism causing most first-parity outcomes is the relative physiological inexperience of reproductive tissues such as the uterus and mammary gland during the first pregnancy and lactation, or a "first use theory" of tissues. More research is necessary to explore these areas, as well as if primiparous dams respond differently to stressors than multiparous dams, and if stress during the first parity affects subsequent parities.

Foetal programming in sheep: Reproductive and productive implications.

The aim of this study was to evaluate the effects of pregnant ewe nutrition on the performance of offspring in terms of meat, wool production, and reproduction. Foetal programming in sheep has focused on several aspects related to foetal growth, postnatal production, behaviour, and immunological performance. Currently, significant efforts are being made to understand the endocrine, metabolic, and epigenetic mechanisms involved in offspring development. Current studies have not only evaluated the foetal period, despite the pre-conception parental nutrition has demonstrated an effect on the foetal, embryonic, and pre-implantation periods and can generate permanent effects in the foetal and postnatal phases. The performance of offspring is the result of interactions between the genome, epigenome, and environmental interventions during conception. Several factors influence the expression of phenotypic characteristics in progenies; however, this study focused on presenting data on the effect of pregnant ewe nutrition alone on foetal growth and the productive aspects of their offspring.

First-trimester fetal size, accelerated growth in utero, and child neurodevelopment in a cohort study.

BACKGROUND: Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children's neurodevelopment remains to be assessed. This study aimed to explore the association between first-trimester fetal size and children's neurodevelopment and to examine whether intrauterine accelerated growth could compensate for the detrimental effects of first-trimester restricted growth on childhood neurodevelopment. METHODS: The participants were from a birth cohort enrolled from March 2014 to March 2019 in Wuhan, China. A total of 2058 fetuses with crown to rump length (CRL) (a proxy of first-trimester fetal size) measurements in the first trimester and neurodevelopmental assessment at age 2 years were included. We measured the first-trimester CRL and defined three fetal growth patterns based on the growth rate of estimated fetal weight from mid to late pregnancy. The neurodevelopment was assessed using the Bayley Scales of Infant Development of China Revision at 2 years. RESULTS: Each unit (a Z score) increase of first-trimester CRL was associated with increased scores in mental developmental index (MDI) (adjusted beta estimate = 1.19, (95% CI: 0.42, 1.95), P = 0.03) and psychomotor developmental index (PDI) (adjusted beta estimate = 1.36, (95% CI: 0.46, 2.26), P < 0.01) at age 2 years, respectively. No significant association was observed between fetal growth rate and PDI. For children with restricted first-trimester fetal size (the lowest tertile of first-trimester CRL), those with "intrauterine accelerated growth" pattern (higher growth rates) had significantly higher MDI (adjusted beta estimate = 6.14, (95% CI: 3.80, 8.49), P < 0.001) but indistinguishable PDI compared to those with "intrauterine faltering growth" pattern (lower growth rates). Main limitations of this study included potential misclassification of gestational age due to recall bias of the last menstrual period and residual confounding. CONCLUSIONS: The current study suggests that restricted first-trimester fetal size is associated with mental and psychomotor developmental delay in childhood. However, in children with restricted first-trimester fetal size, intrauterine accelerated growth was associated with improved mental development but had little effect on psychomotor development. Additional studies are needed to validate the results in diverse populations.

Developmental Windows for Effects of Choline and Folate on Excitatory and Inhibitory Neurotransmission During Human Gestation.

Choline and folate are critical nutrients for fetal brain development, but the timing of their influence during gestation has not been previously characterized. At different periods during gestation, choline stimulation of α7-nicotinic receptors facilitates conversion of γ-aminobutyric acid (GABA) receptors from excitatory to inhibitory and recruitment of GluR1-R2 receptors for faster excitatory responses to glutamate. The outcome of the fetal development of inhibition and excitation was assessed in 159 newborns by P50 cerebral auditory-evoked responses. Paired stimuli, S1, S2, were presented 500 msec apart. Higher P50 amplitude in response to S1 (P50S1microV) assesses excitation, and lower P50S2microV assesses inhibition in this paired-stimulus paradigm. Development of inhibition was related solely to maternal choline plasma concentration and folate supplementation at 16 weeks' gestation. Development of excitation was related only to maternal choline at 28 weeks. Higher maternal choline concentrations later in gestation did not compensate for earlier lower concentrations. At 4 years of age, increased behavior problems on the Child Behavior Checklist 1½-5yrs were related to both newborn inhibition and excitation. Incomplete development of inhibition and excitation associated with lower choline and folate during relatively brief periods of gestation thus has enduring effects on child development.

Autophagy and Exocytosis of Lipofuscin Into the Basolateral Extracellular Space of Human Retinal Pigment Epithelium From Fetal Development to Adolescence.

Purpose: To undertake the first ultrastructural characterization of human retinal pigment epithelial (RPE) differentiation from fetal development to adolescence. Methods: Ten fetal eyes and three eyes aged six, nine, and 17 years were examined in the temporal retina adjacent to the optic nerve head by transmission electron microscopy. The area, number, and distribution of RPE organelles were quantified and interpreted within the context of adjacent photoreceptors, Bruch's membrane, and choriocapillaris maturation. Results: Between eight to 12 weeks' gestation (WG), pseudostratified columnar epithelia with apical tight junctions differentiate to a simple cuboidal epithelium with random distribution of melanosomes and mitochondria. Between 12 to 26 WG, cells enlarge and show long apical microvilli and apicolateral junctional complexes. Coinciding with eye opening at 26 WG, melanosomes migrate apically whereas mitochondria distribute to perinuclear regions, with the first appearance of phagosomes, complex granules, and basolateral extracellular space (BES) formation. Significantly, autophagy and heterophagy, as evidenced by organelle recycling, and the gold standard of ultrastructural evidence for autophagy of double-membrane autophagosomes and mitophagosomes were evident from 32 WG, followed by basal infoldings of RPE cell membrane at 36 WG. Lipofuscin formation and deposition into the BES evident at six years increased at 17 years. Conclusions: We provide compelling ultrastructural evidence that heterophagy and autophagy begins in the third trimester of human fetal development and that deposition of cellular byproducts into the extracellular space of RPE takes place via exocytosis. Transplanted RPE cells must also demonstrate the capacity to subserve autophagic and heterophagic functions for effective disease mitigation.

Maternal nutrition and fetal imprinting of the male progeny.

The global population as well as the demand for human food is rapidly growing worldwide, which necessitates improvement of efficiency in livestock operations. In this context, environmental factors during fetal and/or neonatal life have been observed to influence normal physical and physiological function of an individual during adulthood, and this phenomenon is called fetal or developmental programming. While numerous studies have reported the impact of maternal factors on development of the female progeny, limited information is available on the potential effects of fetal programming on reproductive function of the male offspring. Therefore, the objective for this review article was to focus on available literature regarding the impact of maternal factors, particularly maternal nutrition, on reproductive system of the male offspring. To this end, we highlighted developmental programming of the male offspring in domestic species (i.e., pig, cow and sheep) as well as laboratory species (i.e., mice and rat) during pregnancy and lactation. In this sense, we pointed out the effects of maternal nutrition on various functions of the male offspring including hypothalamic-pituitary axis, hormonal levels, testicular tissue and semen parameters.

Fetal brain MRI atlases and datasets: A review.

Fetal brain development is a complex process involving different stages of growth and organization which are crucial for the development of brain circuits and neural connections. Fetal atlases and labeled datasets are promising tools to investigate prenatal brain development. They support the identification of atypical brain patterns, providing insights into potential early signs of clinical conditions. In a nutshell, prenatal brain imaging and post-processing via modern tools are a cutting-edge field that will significantly contribute to the advancement of our understanding of fetal development. In this work, we first provide terminological clarification for specific terms (i.e., "brain template" and "brain atlas"), highlighting potentially misleading interpretations related to inconsistent use of terms in the literature. We discuss the major structures and neurodevelopmental milestones characterizing fetal brain ontogenesis. Our main contribution is the systematic review of 18 prenatal brain atlases and 3 datasets. We also tangentially focus on clinical, research, and ethical implications of prenatal neuroimaging.

Comparative analysis of foetal and neonatal growth curves.

INTRODUCTION: Our aim was to determine which foetal or neonatal growth curves discriminate the probability of dying of newborns with low birth weight for their gestational age (small for gestational age, SGA) and sex (weight < 10th percentile) and to establish the curves that are presumably most useful for monitoring growth through age 10 years. MATERIAL AND METHODS: The analysis included every neonate (15 122) managed in our hospital (2013-2022) and all neonates born preterm before 32 weeks (6913) registered in the SEN1500 database (2019-2022). We considered most useful those curves with the highest likelihood ratio (LR) for dying with or without a history of SGA in each subgroup of gestational ages. Theoretically, the optimal curves for monitoring growth would be those with a higher R2 in the quantile regression formulas for the 50th percentile. RESULTS: The growth curves exhibiting the strongest association between SGA and hospital mortality are the Intergrowth fetal curves and the Fenton neonatal curves in infants born preterm before 32 weeks. However, the optimal curves for premature babies and neonates overall were those of Olsen and Intergrowth. The most useful curves to monitor anthropometric values alone until age 10 years of age are the longitudinal Intergrowth curves followed by the WHO standards, but if a single reference is desired from birth through age 10 years, the best option is the Fenton curves followed by the WHO standards. CONCLUSIONS: The Intergrowth reference provides the most discriminating foetal growth curves. In neonatal clinical practice, the optimal references are the Fenton followed by the WHO charts.

Neuroembryonic and fetal brain development: Relevance to fetal/neonatal neurological training.

Insight into neuroembryology, developmental neuroanatomy and neurophysiology distinguish the diagnostic approaches of paediatric from adult neurologists and general paediatricians. These fundamental disciplines of basic neuroscience could be more effectively taught during paediatric neurology and most residency programmes, that will strengthen career-long learning. Interdisciplinary training of fetal-neonatal neurology within these programs requires working knowledge of neuroembryology applied to maternal reproductive health influencing the maternal-placental-fetal triad, neonate, and young child. Systematic didactic teaching of development in terms of basic neuroscience with neuropathological context would better address needed clinical skill sets to be incorporated into paediatric neurology and neonatology residencies to address brain health and diseases across childhood. Trainees need to recognize the continuity of development, established by maternal reproductive health before conception with gene -environment influences over the first 1000 days. Considerations of neuroembryology that explain earlier brain development during the first half of pregnancy enhances an understanding of effects throughout gestation through parturition and into neonatal life. Neonatal EEG training enhances these clinical descriptions by applying serial EEG-state analyses of premature neonates through early childhood to recognize evolving patterns associated with neuronal maturation and synaptogenesis. Neuroimaging studies offer comparisons of normal structural images with malformations and destructive lesions to correlate with clinical and neurophysiological findings. This analysis better assesses aberrant developmental processes in the context of neuroembryology. Time-specific developmental events and semantic precision are important for accurate phenotypic descriptions for a better understanding of etiopathogenesis with maturation. Certification of paediatric neurology training programme curricula should apply practical knowledge of basic neuroscience in the context of nervous system development and maturation from conception through postnatal time periods. Interdisciplinary fetal-neonatal neurology training constitutes an important educational component for career-long learning.

Interdependence of placenta and fetal cardiac development.

The placenta and fetal heart undergo development concurrently during early pregnancy, and, while human studies have reported associations between placental abnormalities and congenital heart disease (CHD), the nature of this relationship remains incompletely understood. Evidence from animal studies suggests a plausible cause and effect connection between placental abnormalities and fetal CHD. Biomechanical models demonstrate the influence of mechanical forces on cardiac development, whereas genetic models highlight the role of confined placental mutations that can cause some forms of CHD. Similar definitive studies in humans are lacking; however, placental pathologies such as maternal and fetal vascular malperfusion and chronic deciduitis are frequently observed in pregnancies complicated by CHD. Moreover, maternal conditions such as diabetes and pre-eclampsia, which affect placental function, are associated with increased risk of CHD in offspring. Bridging the gap between animal models and human studies is crucial to understanding how placental abnormalities may contribute to human fetal CHD. The next steps will require new methodologies and multidisciplinary approaches combining innovative imaging modalities, comprehensive genomic testing, and histopathology. These studies may eventually lead to preventative strategies for some forms of CHD by targeting placental influences on fetal heart development.

Development and growth of bovine calves demi-embryos.

The aim of this study was to investigate the growth and development of animals produced from demi-embryos and compare them with whole embryos from fetus to adult life. To achieve this, calves produced from fresh demi-embryos and whole embryos were individually transferred and monitored from 60 days of pregnancy until slaughter at 550 days. Ultrasound scans were conducted on fetuses at 60 and 90 days to evaluate the biparietal, abdominal, umbilical cord, orbital, and aorta diameters. Subsequently, morphological traits of newborn calves were measured at 0, 7, and 21 days (N = 18). Live weight was recorded at birth, weaning, and every 30 days thereafter until slaughter at 550 days. The growth curve of each group was modeled using logistic regression, and the factors of the respective functions were compared. As early as 60 days of pregnancy, ultrasound evaluations revealed no morphometric differences between fetuses produced from demi-embryos and those from whole embryos. This lack of differentiation persisted in the morphometric evaluations of newborns up to 21 days of age, as well as in live weight and the growth curve from birth to slaughter. Moreover, there were no significant differences between the groups in terms of rib eye area and fat thickness evolution. Consequently, individuals from demi-embryos exhibited no discernible disparities to those whole embryos in growth and development from 60 days of gestation, through birth, and into adulthood.

Placental inflammation, oxidative stress, and fetal outcomes in maternal obesity.

The obesity epidemic has led to a growing body of research investigating the consequences of maternal obesity on pregnancy and offspring health. The placenta, traditionally viewed as a passive intermediary between mother and fetus, is known to play a critical role in modulating the intrauterine environment and fetal development, and we now know that maternal obesity leads to increased inflammation, oxidative stress, and altered placental function. Here, we review recent research exploring the involvement of inflammation and oxidative stress as mechanisms impacting the placenta and fetus during obese pregnancy. Understanding them is crucial for informing strategies that can mitigate the adverse health effects of maternal obesity on offspring development and disease risk.