Search Results (48)

Background/Objectives: Gestational diabetes mellitus (GDM) is one of the most common metabolic complications of pregnancy and is associated with adverse maternal and neonatal outcomes. Current screening strategies are generally performed during the end of the second trimester, limiting opportunities for early intervention. Increasing evidence suggests that placental and fetal ultrasound markers detectable in early pregnancy may reflect the pathophysiological changes preceding the clinical diagnosis of GDM. This narrative review aims to summarize the current evidence regarding first- and second-trimester placental and fetal ultrasound markers associated with the subsequent development of GDM. Methods: A narrative review of the literature was conducted focusing on studies evaluating ultrasound markers of placental morphology, placental vascularization and function, uterine artery Doppler indices, placental volume, placental thickness, and fetal biometric and functional parameters in relation to later GDM diagnosis. Twenty-two studies were identified and analyzed to assess their clinical utility and predictive value. Results: Increasing evidence suggests that placental and fetal ultrasound markers detectable in early pregnancy may reflect pathophysiological changes preceding the clinical diagnosis of GDM. Three-dimensional power Doppler, particularly the vascularization–flow index, has demonstrated reduced placental vascularization in pregnancies subsequently complicated by GDM. Placental elastography and artificial intelligence-based radiomic analysis also show promising predictive potential. Uterine artery Doppler has demonstrated limited and inconsistent value. Fetal findings suggest that conventional biometry has limited predictive utility, whereas fetal growth velocity and markers of adiposity, including anterior abdominal wall thickness and abdominal overgrowth, more consistently identify early adaptations associated with later GDM. However, substantial methodological heterogeneity limits interpretation. Conclusions: Early placental and fetal ultrasound markers represent promising non-invasive tools for the early identification of pregnancies at risk for GDM. Further large-scale prospective studies are required to validate their predictive performance and establish standardized assessment protocols. Integrating maternal clinical characteristics and biochemical parameters may enhance future screening strategies for GDM. Full article

The first trimester (FT) of pregnancy is characterized by rapid placental growth and differentiation, rendering this period sensitive to maternal metabolic influences. Maternal obesity is associated with chronic low-grade inflammation and altered redox homeostasis with implications in later cardiometabolic risk in offspring, yet its impact on early placental oxidative stress remains unclear. Here, we investigated whether maternal overweight and obesity are associated with oxidative lipid and protein damage and altered expression of antioxidant enzymes and stress signaling pathways. Placental tissue from lean (BMI < 25 kg/m²), overweight (BMI ≥ 25 kg/m²) and obese (BMI ≥ 30 kg/m²) non-smoking women (5–12 weeks’ gestation) was analyzed. Oxidative damage was assessed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine, and antioxidant and stress-related transcripts were quantified using targeted mRNA arrays. Explants were exposed to increased oxygen tension or TNF-α to evaluate transcriptional responsiveness. No differences in oxidative lipid or protein modifications were detected between groups. In contrast, overweight and obesity were associated with reduced expression of selected antioxidant enzymes and transcriptional remodeling of MAPK-related genes. These changes correlated with IL6 expression but not with oxidative damage markers. Collectively, maternal overweight and obesity are linked to inflammation-associated transcriptional adaptation in FT placenta without detectable oxidative injury. Full article

The Barker hypothesis links intrauterine conditions, mainly low birth weight, subject to poor nutrition with paradoxically improved standards of living and nutrition after World War II in Western countries, to adult disease, mainly coronary heart disease. The limitations of his hypothesis include the fact that it is based only on human epidemiological data and animal studies, and also that it is difficult to isolate the effect of the intrauterine environment from postnatal conditions, familial and genetic background. In the last 20 years, the introduction of ultrasound and Doppler techniques in the assessment of fetal and maternal vascularity added a major contribution to the evaluation of the intrauterine environment. Studies based on ultrasound and Doppler assist in differentiating between prematurity and fetal growth restriction (FGR), mainly in those with placental insufficiency, and postnatal morbidity and even mortality. In addition, the Pedersen hypothesis regarding fetuses with overgrowth, mainly with diabetic mothers, states that they are also prone to postnatal morbidity. However, most of the studies on the issue do not emphasize the effects of the intrauterine environment on fetal organs, such as the brain, heart, liver, kidneys and pancreas in FGR and fetal overgrowth, that may impose a different prognosis in later life. This narrative review aims to summarize current evidence from animal and human studies regarding the impact of intrauterine undernutrition and overnutrition on fetal organ development, and to evaluate how ultrasound and Doppler findings may contribute to understanding the link between the intrauterine environment and postnatal morbidity. Full article

Over recent decades, a substantial body of research has expanded our understanding of how early-life conditions influence long-term health. These observations led to the formulation of the Barker Hypothesis, which postulates that adverse nutritional exposures during fetal life can induce persistent physiological and metabolic adaptations, thereby increasing susceptibility to chronic diseases later in life. This narrative review aims to provide a comprehensive overview of current recommendations for adequate maternal nutrition during pregnancy, with particular emphasis on key nutrients and specific dietary patterns. In addition, the effects of maternal diet on placental function and fetal growth are examined. A literature search was conducted in the following electronic databases: MEDLINE (via PubMed), Scopus, Web of Science, Embase, and the Cochrane Library. Manuscripts published between 2005 and 2025 were considered. The impact of prenatal nutritional exposures on immune development, neurodevelopment, metabolic regulation, and gut microbiota is also discussed, highlighting how these mechanisms may contribute to an increased long-term risk of non-communicable diseases, including obesity, metabolic syndrome, and neuropsychiatric disorders. Maternal nutrition during pregnancy plays a crucial role in shaping infants’ and children’s health, particularly regarding the development of non-communicable diseases. Therefore, ensuring adequate nutritional intake during this critical period—both quantitatively and qualitatively—is essential to optimize health outcomes for the newborn and to promote long-term well-being throughout childhood and beyond. Full article

Physiological hypoxia is a defining feature of early pregnancy, coordinating menstrual repair, implantation, decidualization, placental development, and fetoplacental adaptation. Hypoxia-inducible factors, HIF-1α and HIF-2α, act as master regulators of these processes by sensing oxygen tension and orchestrating cellular responses in metabolism, angiogenesis, immune regulation, and tissue remodeling. Although structurally related, HIF-1α and HIF-2α exhibit distinct spatial and temporal functions across reproductive stages. Embryonic HIF-1α is primarily involved in early embryonic development, whereas embryonic HIF-2α is required for later developmental stages. Furthermore, maternal HIF-1α acts early in pregnancy, coordinating metabolic adaptation, endometrial regeneration, decidualization, angiogenic expansion, placental organization, and maternal immune tolerance. In contrast, maternal HIF-2α regulates epithelial breakdown, trophoblast invasion, implantation mechanics, and vesicle-mediated trafficking. Mouse genetics demonstrate that disruption of either isoform leads to non-redundant defects in reproductive success, from failed implantation to placental insufficiency and fetal lethality. Pathological hypoxia or aberrant HIF signaling drives pregnancy disorders including preeclampsia, fetal growth restriction, recurrent pregnancy loss, and heavy menstrual bleeding. Defining the distinct roles of HIF-1α and HIF-2α supports the development of therapies targeting hypoxia-responsive pathways in infertility and obstetric disease. Full article

Background/Objectives: Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring. Methods: Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6. Results: MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6. Conclusions: Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring. Full article

Preeclampsia is a common pregnancy complication that may threaten the health of pregnant women and their fetuses. Intrauterine growth restriction is the most serious complication in fetal development observed in preeclampsia. In their later years, women with preeclampsia are at risk of cardiovascular disease. The use of multiple biomarkers can usually improve diagnostic performance. Currently, S100A8 and S100A9 are gaining increased attention as inflammatory markers of preeclampsia. Our review aims to present an integrated view of the potential role of S100A8/A9 in the physiopathology of preeclampsia. We also explored the potential role as biomarker or in targeted treatment. At the moment, there is no efficient treatment for PE other than birth. Understanding the pathological mechanisms and the importance of calprotectin can shape a new strategy for large-scale approaches to change diagnostic and therapeutic management. The value of the calcium binding proteins S100A8/A9 as a potential prognostic biomarker in placental disfunctions based on malperfusion has not yet been investigated. Encouraging results have been obtained in experimental and clinical interventional studies with S100A8/A9 blockers as a form of therapeutic management for autoimmune disease and cancer. It may also be limited because of safety issues for the fetus. However, future investigations can emerge. Full article

First-trimester placental development comprises many critical yet understudied cellular events that determine pregnancy outcomes. Improper placentation leads to a host of health issues that not only impact the fetal period but also influence later-life offspring health. Thus, an experimental paradigm for studying early placental development is necessary and has spurred the development of new in vitro models. Organoid model systems are three-dimensional structures comprising multiple differentiated cell types that originate from a progenitor population. Trophoblasts are the progenitor cells that serve as the proliferative base for the differentiation and maintenance of the placenta. Due to research constraints, experimental studies on the causal mechanisms underlying pathological pregnancies cannot readily be performed in human subjects. The nonhuman primate (NHP) offers a solution to this problem as it circumvents the limitations of human pregnancy sampling. Importantly, NHPs share many developmental features of human pregnancy, including placenta type and a similar fetal growth trajectory, making longitudinal pregnancy studies feasible and relevant. Since perturbations made in vivo can be validated in vitro, an NHP model of early pregnancy would facilitate mechanistic studies of pregnancy disorders. Herein, we describe the methodology for the establishment of a first-trimester NHP placenta trophoblast organoid model system. Full article

Background/Objective: Preeclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality. Early prediction is crucial for timely intervention and management. The ophthalmic artery (OA) Doppler assessment in the first trimester has emerged as a potential tool for predicting PE, particularly early PE, with delivery <37 weeks of gestation. This study aimed to evaluate and compare the relationship of ophthalmic artery Doppler parameters at 11–13 weeks of gestation with the subsequent development of early and late PE. Methods: A prospective observational analysis was conducted on 4054 pregnant women, including 114 who developed PE. OA Doppler assessment of the pulsatility index (PI) and peak systolic velocity (PSV) ratio, mean arterial pressure (MAP), uterine artery PI (UtA-PI), and serum placental growth factor (PlGF) were compared between women who later developed early PE and late PE with those who did not develop PE. Results: In the PE groups, particularly those with early PE, compared to the no PE group, the OA PSV ratio and UtA-PI were higher and PlGF was lower. Conclusion: A first-trimester OA Doppler assessment shows promise as a non-invasive method for the prediction of PE. Further prospective, multicenter studies are needed to validate these findings. Full article

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor RUNX1, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated. Full article

(1) Background: The follicular fluid (FF) comprises a large portion of ovarian follicles, and serves as both a communication and growth medium for oocytes, and thus should be representative of the metabolomic status of the follicle. This review aims to explore FF biomarkers as well as their effects on fertilization, oocyte, and embryo development, and later on implantation and maintenance of pregnancy. (2) Methods: This review was registered in the PROSPERO database with the ID: CRD42025633101. We parsed PubMed, Scopus, and Google Scholar for research on the effects of different FF biomarkers on IVF/ICSI outcomes in normo-ovulatory women. Included studies were assessed for risk of bias using the NOS scale. Data were extracted and tabulated by two independent researchers. (3) Results: 22 included articles, with a sample size range of 31 to 414 and a median of 60 participants, contained 61 biomarkers, including proteins, growth factors, steroid and polypeptide hormones, inflammation and oxidative stress markers, amino acids, vitamins, lipids of different types, and miRNAs. Most of the biomarkers studied had significant effects on IVF/ICSI outcomes, and seem to have roles in various cellular pathways responsible for oocyte and embryo growth, implantation, placental formation, and maintenance of pregnancy. The FF metabolome also seems to be interconnected, with its various components influencing the levels and activities of each other through feedback loops. (4) Conclusions: FF biomarkers can be utilized for diagnostic and therapeutic purposes in IVF; however, further studies are required for choosing the most promising ones due to heterogeneity of results. Widespread adoption of LC-MS and miRNA microarrays can help quantify a representative FF metabolome, and we see great potential for in vitro supplementation (IVS) of some FF biomarkers in improving IVF/ICSI outcomes. Full article

Introduction: Early-life neurological and inflammatory disorders significantly affect long-term cognitive, social, and emotional development. The ‘Developmental Origins of Health and Disease’ hypothesis states that an adverse intrauterine environment may predispose offspring to chronic health conditions due to altered growth and development. Factors measured in umbilical cord blood can provide information about the status of the in utero environment during development. Evidence indicates that umbilical cord blood adipokines, namely leptin and adiponectin, may influence fetal programming and could be useful in predicting offspring health outcomes. Leptin and adiponectin are crucial in energy homeostasis, immune response, and placental function, and some studies suggest that altered concentrations may increase the risk of developing inflammatory and neurological disorders in later life. Further, limited studies have demonstrated sex-specific differences in adipokine concentrations and disease risk. Conclusions: Understanding the role of umbilical cord blood adipokines in fetal programming could offer new insights into early risk prediction and intervention strategies, promoting better health outcomes for children at risk of neurological and inflammatory diseases due to an adverse maternal environment during pregnancy. Full article

Maternal hormonal and metabolic disorders, such as diabetes and obesity, can adversely affect the intrauterine environment, resulting in suboptimal fetal growth and an elevated risk of cardiovascular and metabolic diseases in the later life of the offspring. In this review, we examine the long-term impact of elevated maternal androgen levels during pregnancy on offspring. Maternal hyperandrogenemia is linked to various neurodevelopmental disorders, including attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety-like behaviors, mediated by alterations in key brain regions responsible for emotion and cognition. Furthermore, children born to mothers with hyperandrogenemia exhibit heightened risk of metabolic and cardiovascular dysfunctions, such as obesity, insulin resistance, and hypertension, which can manifest early in life. Prenatal exposure to androgens has also been linked to reduced birth weights and altered fetal growth, potentially due to impaired placental function. Additionally, maternal testosterone levels influence offspring sex ratios, often favoring male births, though exceptions occur in certain conditions, such as congenital adrenal hyperplasia. The findings of this review underscore the need for healthcare professionals to monitor maternal serum androgen profiles during pregnancy. Further research is needed to determine underlying mechanisms and potential interventions to mitigate these risks. Full article

Placentation disorders, including severe preeclampsia and fetal growth restriction, have their origins in early pregnancy, whereas symptoms typically present later on. To investigate the pathogenesis of these diseases, there is a need for a reliable in vitro model system of early placenta development with known pregnancy outcomes. Therefore, we optimized the generation of human induced trophoblast stem cells (iTSCs) from term umbilical cord, enabling non-invasive collection of patient-derived material immediately after birth. Using a direct reprogramming approach previously described for dermal fibroblasts, we investigated the effects of three supplements (A-485, BMP4, and EPZ-6438) to assess their potential to enhance iTSC induction. The generated iTSCs fulfilled the criteria for bona fide first-trimester trophoblasts and exhibited key functional capacities, including long-term self-renewal, differentiation into hormone-producing syncytiotrophoblasts and invasive extravillous trophoblasts, and the formation of organoids. Furthermore, transcriptomic analysis revealed high similarity between the generated iTSCs and trophoblast stem cells derived from first-trimester placental tissue. The supplements did not improve the generation of iTSCs. In conclusion, we successfully generated bona fide iTSCs from term umbilical cord using a direct reprogramming approach, providing a robust and clinically relevant model to study early placentation mechanisms in patient-derived trophoblasts. Full article

Pregnancy is a vulnerable period of time during which pregnant people are prone to infections like COVID-19, which can increase risks for both the mother and fetus. These infections may lead to complications such as preterm birth, developmental delays, and congenital abnormalities. While COVID-19 poses additional risks like placental dysfunction and neonatal infections, studies on long-term effects remain limited. Ongoing research and monitoring are essential to understand and mitigate potential cognitive and developmental challenges in children born to mothers infected with COVID-19. This review aims to guide clinicians in managing these risks throughout childhood. Maternal COVID-19 infection during pregnancy can have significant implications for fetal development, even if the newborn is not infected at birth. The release of inflammatory cytokines may cross the placental barrier, potentially disrupting fetal brain development and increasing the risk of long-term cognitive and behavioral issues, such as ADHD or autism. Placental dysfunction, caused by inflammation or thrombosis, can lead to intrauterine growth restriction (IUGR), preterm birth, or hypoxia, affecting both neurological and respiratory health in newborns. Furthermore, a compromised fetal immune system can increase susceptibility to autoimmune conditions and infections. The early diagnosis and management of infections during pregnancy are crucial in mitigating risks to both the mother and fetus. Swift intervention can prevent complications like preterm birth and long-term developmental challenges, ensuring better health outcomes for both the mother and child. Long-term monitoring of children born to mothers infected with COVID-19 is necessary to understand the full extent of the virus’s impact. This review evaluates the long-term systemic effects of maternal COVID-19 infection during pregnancy on fetuses, newborns, and children, focusing beyond vertical transmission. It highlights the broader impacts on fetal development, offering insights to help clinicians manage potential issues that may arise later in life. Full article