The majority of low placentation identified on first-trimester transabdominal ultrasound resolves; however, whether this resolution is associated with adverse outcome remains poorly understood. This investigation aimed to determine whether patients with resolved first-trimester low placentation had different delivery outcomes compared to patients who never had low placentation. This is a retrospective cohort study of singleton pregnancies with low placentation, defined as low-lying placenta or placenta covering the internal os, on first-trimester transabdominal ultrasound between 12+0 weeks and 13+6 weeks, delivering at a single tertiary care center from January to December 2022. We compared outcomes stratified by first-trimester low placentation that resolved by the second trimester, or those without low placentation at any point. The primary outcome was quantitative blood loss at delivery by volumetric measurement. Secondary outcomes included postpartum hemorrhage (PPH) defined as blood loss ≥1000 cc, unplanned cesarean delivery, preterm birth, 5-min Apgar < 7, and composite maternal adverse outcomes including the use of atony device, retained products of conception, blood transfusion, peripartum hysterectomy, intensive care unit admission, or death. This cohort included 437 low placentation patients and 491 patients without low placentation. Resolved first-trimester low placentation was associated with a significant increase in quantitative blood loss at delivery (405 ± 369 cc vs. 331 ± 253 cc, p < 0.01) but no difference in incidence of PPH (6.4% vs. 4.7%, p = 0.25). Resolved first-trimester low placentation was also associated with increased tranexamic acid (TXA) administration (11.9% vs. 7.7%, p = 0.03), blood transfusion (1.8% vs. 0.4%, p = 0.04), and unplanned cesarean delivery (15.3% vs. 9.2%, p < 0.01) without differences in the indications for unplanned cesarean delivery. In our multivariable regression, resolved first-trimester low placentation remained associated with TXA administration (adjusted odds ratio [OR], 1.70; 95% confidence interval [CI], 1.07-2.70) and unplanned cesarean delivery (adjusted OR 1.73; 95% CI, 1.12-2.68). There were no associations with adverse neonatal outcomes or composite maternal outcome. Resolved first-trimester low placentation is not associated with clinically significant adverse outcomes. However, given changes in unplanned cesarean delivery rate, resolved low placentation may indicate altered uterine physiology. Future research would be valuable to better understand the relationship between resolved low placentation and unplanned cesarean deliveries.
Placental pathology has been linked to neonatal encephalopathy (NE). Despite the high prevalence of NE in low- and middle- income countries (LMICs), there are limited published studies exploring this association from LMICs. To describe and analyse the histopathology of placentas from neonates diagnosed with encephalopathy shortly after birth. A retrospective analytical study was conducted on neonates diagnosed with encephalopathy at Klerksdorp/Tshepong hospital complex, South Africa. Placentas from term and near-term neonates (birthweight ≥2 000 g) diagnosed with encephalopathy within the first 24 hours of life were sent for histopathological examination. Neonates were grouped into those with encephalopathy with or without intrapartum hypoxia (IH) (base deficit ≥12 mmol/L). The severity of NE was assessed as mild, moderate or severe, according to Sarnat staging. The types and extent of placental lesions were compared between those with mild and moderate-to-severe NE, and between cases with or without IH. Of 16 336 live births, 271 neonates were diagnosed with NE, and of these, 193 (71.2%) had NE with IH. Placental histopathology results were available for 239 neonates (88.2%). The median placental weight was 428 g, with 46.6% of placentas weighing below the 10th percentile. Cord abnormalities were observed in 27.2% of placentas. Nearly all placentas (98.2%) exhibited at least one histopathological lesion. The most common microscopic placental lesions identified were maternal vascular malperfusion (MVM) (55.6%), fetal vascular malperfusion (55.1%), acute chorioamnionitis (41.2%) and villitis of unknown aetiology (28.9%). There was a significant association between NE with IH and the presence of MVM, with an adjusted odds ratio of 3.24 (95% confidence interval 1.19 - 8.79). No significant association was found between the presence or number of different placental lesions and the severity of NE. Factors associated with severity of any NE (with and without IH) included an Apgar score <7 at 10 minutes (p<0.001) and pH <7.00 (p<0.001). A high proportion of neonates with encephalopathy showed evidence of IH. Approximately half of the placentas were below the 10th percentile in weight, and about a quarter had macroscopic cord abnormalities. Almost all neonates with encephalopathy displayed ≥1 microscopic placental lesion. A strong association was found between the presence of MVM and NE with IH.
We hypothesized that arboviruses impair the placental expression of key functional markers implicated in fetal brain development. Singleton placentae (n = 54) affected by chikungunya (CHIKV, n = 12), dengue (DENV, n = 8), zika (ZIKV, n = 15), or healthy controls (HC, n = 15) were analysed. Immunohistochemical quantification of key transporter systems, cell turnover markers, and signalling pathways related to extracellular matrix remodelling, vascular maintenance, and nutrient sensing was undertaken. Maternal age and BMI were lower in CHIKV/ZIKV, whereas birth weight was reduced in DENV pregnancies compared with HC. CHIKV/ZIKV exhibited reduced syncytiotrophoblast area, CHIKV/DENV showed reduced syncytial knot area, whereas DENV showed increased fetal blood vessel and reduced connective tissue areas. Histopathology detected predominantly mild vascular and stromal lesions across groups, with DENV placentae exhibiting moderate congestion in 100% of cases. Decreased expression of P-gp, BCRP, ABCA1 and SNAT2 were detected in all groups. CHIKV/ZIKV also exhibited decreased GLUT1, while ZIKV showed reduced SNAT1 expression. MCT8 expression was significantly elevated in CHIKV. Placental Ki-67 was increased in CHIKV/ZIKV, indicating altered trophoblast turnover. VEGFB expression was reduced and p-mTOR signalling was increased across all arbovirus-exposed placentae, while MMP9 expression was unchanged. Principal components analysis (PCA) distinguished infected from uninfected groups based on placental functional markers related to fetal brain development, but not on histomorphometry. Arboviral-infected placentae showed distinct structural remodelling and altered transporter expression, potentially increasing fetal brain vulnerability and long-term neurodevelopmental risks, even in the absence of neonatal symptoms. KEY POINTS: Virus-specific placental histomorphometric changes were detected, including altered syncytiotrophoblast/syncytial knot, connective tissue and fetal blood vessel areas. Arboviruses reduced the placental efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and disrupted the expression of ABCA1, SNAT2, GLUT1 and SNAT4 nutrient transporters, while ZIKV additionally reduced SNAT1 expression. Placental functional adaptation to arboviral infection comprised changes in the expression of placental markers of proliferation (Ki-67), angiogenesis (VEGFB), and nutrient sensing (p-mTOR). Arbovirus-exposed placentae exhibited greater functional alterations rather than overt structural pathology, suggesting potential subclinical effects on fetal neurodevelopment, even in the absence of major neonatal abnormalities.
Placental abruption is a serious complication in pregnant women with preeclampsia. This study investigated the risk factors for placental abruption and developed a predictive model using the Synthetic Minority Over-sampling Technique (SMOTE). A total of 280 pregnant women with preeclampsia treated between September 2020 and September 2025 were enrolled and classified into placental abruption and non-placental abruption groups. Logistic regression showed that parity ≥3, severe preeclampsia, anemia, polyhydramnios, and short umbilical cord were independent risk factors for placental abruption. ROC analysis demonstrated that the SMOTE-based model had better predictive performance than the original model, with a higher AUC (0.863, 95% CI: 0.817-0.901 vs 0.792, 95% CI: 0.739-0.838; z=2.163, P=0.031). The SMOTE-based model also showed higher F-score and positive predictive value, although its true positive rate was lower than that of the original model. These findings indicate that a SMOTE-based predictive model may provide useful support for early risk assessment and prevention of placental abruption in women with preeclampsia. L'hématome rétro-placentaire (ou décollement prématuré du placenta) est une complication grave chez les femmes enceintes atteintes de prééclampsie. Cette étude a examiné les facteurs de risque de cette complication et a élaboré un modèle prédictif utilisant la technique SMOTE (*Synthetic Minority Over-sampling Technique*). Au total, 280 femmes enceintes atteintes de prééclampsie, prises en charge entre septembre 2020 et septembre 2025, ont été incluses et réparties en deux groupes : celles ayant présenté un hématome rétro-placentaire et celles n'en ayant pas présenté. La régression logistique a révélé qu'une parité ≥ 3, la prééclampsie sévère, l'anémie, le hydramnios et un cordon ombilical court constituaient des facteurs de risque indépendants d'hématome rétro-placentaire. L'analyse des courbes ROC a démontré que le modèle basé sur la technique SMOTE offrait de meilleures performances prédictives que le modèle initial, avec une aire sous la courbe (AUC) plus élevée (0,863 ; IC à 95 % : 0,817–0,901 contre 0,792 ; IC à 95 % : 0,739–0,838 ; z = 2,163 ; P = 0,031). Le modèle basé sur SMOTE présentait également un score F (*F-score*) et une valeur prédictive positive plus élevés, bien que son taux de vrais positifs fût inférieur à celui du modèle initial. Ces résultats indiquent qu'un modèle prédictif basé sur la technique SMOTE pourrait constituer un outil utile pour l'évaluation précoce des risques et la prévention de l'hématome rétro-placentaire chez les femmes atteintes de prééclampsie.
Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of embryonic day (E) 13.5 placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of Hand1 and Tfap2c, transcription factors involved in trophoblast differentiation and placental development, while increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased Tnf expression and sustained suppression of Hand1 in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.
The placenta is a highly dynamic organ that supports the growth and development of the fetus during gestation. Malfunction of the placenta causes disorders of the pregnancy, including preeclampsia and pre-term birth. The study of the pathophysiology of the placenta throughout pregnancy has been hindered by limited access to the human placenta and lack of predictive cellular and animal models. Here, we describe 3D bioprinted human placenta barrier (hPB) tissue models using primary human trophoblasts and stroma cells that recapitulate the physiology of the human placenta at early and late stages of gestation. These bioprinted vascularized hPB tissue models mimic the architecture and function early and late-stages human placenta, including barrier function, nutrient uptake, transporters activity and hormones secretion. Assembled in a 96-well transwell plate format, this deeply characterized platform provides a robust high-fidelity system for predictive screening of therapeutics and potentially hazardous agents for placenta diseases and safety, and a better understanding of placental pathophysiology.
Microplastic (MP) contamination has emerged as a global environmental concern, with increasing evidence of its presence in human placental tissue. However, no previous human studies have directly evaluated the association between placental microplastic exposure and fetal cardiac physiology during labor. Our study aimed to investigate the relationship between placental MP accumulation and the occurrence of intrapartum non-reassuring fetal heart rate (NRFHR). A prospective cohort study was conducted among 2738 pregnant women recruited from China between 2023 and 2024. Placental MPs were quantified using laser direct infrared (LD-IR) chemical imaging, focusing on polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), and polybutylene succinate (PBS). Multivariable logistic regression models were used to examine associations between placental MP concentrations and NRFHR, adjusting for maternal, socioeconomic, and pregnancy-related covariates. Stratified analyses, mixture models using quantile g-computation (g-comp) and generalized weighted quantile sum (gWQS), and sensitivity analyses were also performed. The median total placental MP concentration was 22 particles/10 g tissue (IQR: 11), with PVC showing the highest concentrations. Higher placental concentrations of PVC, PBS, PET, and total MPs were significantly associated with higher odds of NRFHR. In adjusted models, each IQR increase in PVC, PBS, PET, and total MPs was associated with 33% (OR: 1.33, 95% CI: 1.08-1.64), 80% (OR: 1.80, 95% CI: 1.44-2.25), 40% (OR: 1.40, 95% CI: 1.14-1.73), and 47% (OR: 1.47, 95% CI: 1.25-1.74) higher odds of NRFHR, respectively. Mixture analyses confirmed a significant positive joint effect of placental MPs on NRFHR, with PBS and PET contributing most strongly. Associations were more pronounced among pregnancies with environmental tobacco exposure. Placental microplastic exposure was associated with a higher risk of NRFHR, suggesting that prenatal MP accumulation may adversely affect fetal cardiac regulation during labor.
Early-onset preeclampsia (EOPE) is a severe maternal hypertensive disorder of pregnancy, where placental dysfunction is a component of the pathophysiology. Previously, we developed the eoPRED tool, which is a DNA methylation (DNAme)-based method that estimates the likelihood that a placenta came from a pregnancy complicated by EOPE. We hypothesize that this score may reflect maternal vascular malperfusion (MVM), which is the most common placental pathology observed in early-onset preeclampsia (EOPE), but is also associated with preterm birth and fetal growth restriction. To test this we evaluated whether eoPRED score is associated with the severity of MVM pathology in placentas from both preeclamptic and non-preeclamptic pregnancies. We utilized 493 placentas with both Infinium EPICv1.0 DNA methylation data and histopathologic characterization by a placental pathologist. We evaluated associations between eoPRED score and four major classes of placental pathology: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), chronic inflammation (CI), and acute inflammation (AI). eoPRED score was higher in placentas from pregnancies with EOPE (n = 7) than controls without preeclampsia (n = 402, p < 0.001). Independent of EOPE, eoPRED correlated with the grade of MVM (R = 0.34, p < 0.01), but was not associated with any other pathology class. eoPRED score can not only be used to identify cases of likely EOPE but is also associated with placental maternal vascular dysfunction in the absence of preeclampsia. This score may thus be useful in placental DNAme datasets lacking pathology information to identify associations between exposures/and or birth outcomes with placental dysfunction.
Placenta Accreta Spectrum is a leading cause of maternal morbidity and mortality and is increasing in incidence, yet only 30-50% of cases are diagnosed antenatally in some cases. While ultrasonographic findings may inform risk of Placenta Accreta Spectrum, multiple factors may lead to inconclusive or misdiagnosis. We hypothesized that a novel artificial intelligence model could be used as a screening tool to accurately predict Placenta Accreta Spectrum by image classification of 2D placental ultrasounds. This single-center retrospective study included 756 placental ultrasound DICOM files from which 38,907 grayscale PNG frames were extracted from 113 patients at risk for PAS from 2018 to 2025. Mean gestational age at ultrasound was 30.89 ± 3.67 weeks. Patients were stratified to produce 79/17/17 train/validation/test groups. Images were classified by final pathologic grades. We used an ImageNet pretrained EfficientNetB0 backbone, followed by global average pooling and a regularized fully connected layer with sigmoid activation for binary classification. Frame level probabilities from the convolutional neural network output were averaged to patient level consensus scores. These scores, together with number of prior Cesarean sections and previa status were input as variables into training a logistic regression, random forest, and gradient boosting classifier which were ensembled for final prediction of PAS incorporating patient identifiable risk factors. The convolutional neural network ensembled model predicted the presence or absence of Placenta Accreta Spectrum accurately in 88% (95% CI 63.6%-98.5%) of cases with a sensitivity of 100% (95% CI 66.4%-100.0%) and specificity of 75% (95% CI 34.9%-96.8%). The positive predictive value was 81.8% (95% CI 48.2%-97.7%) and the negative predictive value was 100% (95% CI 54.1%-100.0%). There were no false negatives in the testing cohort. The AUC-ROC was 0.972 (95% CI 0.875-1.000). Model variable importance scores concentrated at the placental interface, highlighting biological plausibility. This novel artificial intelligence model achieved accurate, sensitive Placenta Accreta Spectrum prediction before delivery. The results of the model support its potential use as a screening tool for earlier diagnosis of Placenta Accreta Spectrum screening, warranting future prospective trials.
Maternal obesity and viral infection induce placental inflammation, but how their co-exposure influence fetoplacental development remains unclear. We hypothesised that maternal high fat (HF) diet and viral infection would independently induce placental inflammation and lipid peroxidation, reduce antioxidant defence, and cellular turnover. Further, HF diet would compromise placental capacity to adapt to infection. Female C57BL/6J mice were fed a control (CON) or 62% HF diet six weeks before and throughout pregnancy and injected with poly(I:C) (viral mimic) or vehicle (VEH) 24 h before sacrifice at gestational days (GD) 12.5, 15.5, and 18.5 (n = 5-8/group/GD). Placental inflammasome (NLRP3), oxidative stress (4-HNE), antioxidant defence (GPx-4), and cellular proliferation-to-death ratio (Ki-67, Caspase-3) were assessed by immunohistochemistry, and mRNA expression of Tlr3, Irf3, Tlr4, Tirap, and Il-1β were measured by qPCR. Data were analysed by linear mixed models (p ≤ 0.05). At GD12.5, infection was associated with increased Tlr3 mRNA and immunoreactive (ir)-4-HNE, and reduced ir-GPx-4 expression in the placental labyrinth zone (LZ). By GD15.5, HF diet was associated with increased ir-NLRP3 in both LZ and junctional zones (JZ). Exposure to infection alone and co-exposure to HF diet and infection further increased LZ ir-NLRP3. At GD18.5, HF diet was associated with increased Tirap and Il-1β mRNA expression, ir-4-HNE in the JZ and ir-Caspase-3 in the LZ. Maternal HF diet and infection exert distinct effects on the placenta across gestation, suggesting that maternal overnutrition might reduce the placenta's capacity to handle adverse exposures, which may increase susceptibility to poor fetal outcomes.
Maternal obesity compromises placental development and fetal growth, yet the mechanisms remain unknown. Here, we investigated the impact of high-fat diet (HFD) on placental energy homeostasis in mice. Female C57BL/6 mice were fed a control diet or an HFD, with a subset receiving FerroTerminator-1 (FOT1) to modulate metabolic dysfunction. At embryonic day 18.5, maternal metabolic status, fetal growth, placental morphology, energy metabolism, and oxidative stress were assessed. HFD-fed dams developed dyslipidemia and insulin resistance, and exhibited placental lipid accumulation and impaired labyrinth zone development, resulting in reduced fetal weight and altered fetal liver lipid and glycogen contents. The placenta showed mitochondrial damage, accompanied by reduced ATP content, mitochondrial membrane potential, mitochondrial DNA copy number, and suppressed respiratory chain complex activities. Placental metabolomic profiling showed that HFD was associated with altered levels of metabolites in glycolysis and oxidative phosphorylation pathways. These alterations coincided with placental iron-associated oxidative stress, evidenced by elevated non-heme iron, lipid peroxidation products, upregulation of transferrin receptor (TFRC) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), downregulation of ferritin heavy chain 1 (FTH1) and solute carrier family 40 member 1 (SLC40A1), a reduced glutathione to oxidized glutathione ratio, and impaired glutathione peroxidase 4 (GPX4) expression and activity. Meanwhile, FOT1 administration attenuated placental oxidative stress, partially restored ATP production and mitochondrial function, and improved fetal growth in HFD-fed mice. Collectively, maternal obesity was associated with placental iron-associated oxidative stress and bioenergetic impairment, which may contribute to reduced placental efficiency and FGR.
Over the first trimester, vasculogenesis (the de novo formation of blood vessels) and angiogenesis (creation of new vessels from existing vessels) together create the backbone of the placental vascular network, which becomes increasingly complex as gestation progresses to term. Many different ex vivo imaging modalities, including computed tomography, synchrotron X-ray tomography, confocal and electron microscopy, and traditional histology and stereology, have been used to study the vascularity of the human placenta in detail. However, many of these techniques often come with trade-offs between resolution, maximum sample size and cost. Light sheet fluorescence microscopy is an attractive method capable of imaging placental 3D morphology at the micro-scale, whilst also enabling imaging of comparatively larger placental explants than other microscopy techniques, allowing capture of more generations of villous and vascular trees. Advances in tissue clearing for optical imaging have led to a multitude of different published light sheet fluorescence microscopy protocols across tissue types. However, optimising placenta-specific protocols is imperative for high-quality imaging and downstream three-dimensional analysis of this unique tissue. Finally, the placental vascular architecture is notoriously disorganised, heterogenous and convoluted, making it more challenging to segment and obtain meaningful data than from vasculature in other organ systems. Here, we present a comprehensive pipeline for placental tissue preparation, light sheet fluorescence imaging and image segmentation of first trimester and term human placental villous explants, enabling physiologically relevant quantitative analysis of vascularity at different stages of gestation.
Gestational diabetes mellitus (GDM) affects maternal metabolism and may be associated with altered placental bacterial DNA community profiles and early neonatal gut microbiota. This prospective cohort study assesses GDM's impact on the placental-neonatal gut microbial axis and links key bacterial taxa to short-term perinatal outcomes and clinical significance. Pregnant women with GDM and healthy controls were enrolled. Placental tissue and first-pass neonatal meconium samples were collected. Bacterial community composition, diversity, and differential genera were analyzed using 5-region 16S rRNA sequencing. FEAST was used to model potential maternal-neonatal microbial sources. Associations among gestational weight gain (GWG), microbial features, and the risk of neonatal hospitalization were also assessed. The GDM and control groups showed significant differences in placental and early neonatal meconium microbial community structures, with increased α-diversity and distinct community separation in both sample types. In placental samples, Brevundimonas was decreased, whereas Lactobacillus and Sphingomonas were enriched. In neonatal meconium, potentially inflammation-related genera, including Staphylococcus, Streptococcus, and Clostridium, were enriched. GWG had limited effects on overall community structure but exerted refined regulation on specific genera. Source tracking showed a reduced placenta-attributed similarity contribution to neonatal meconium microbiota in the GDM group. The abundances of specific placental genera, including Escherichia, Curvibacter, and Pelomonas, were significantly associated with neonatal hospitalization. GDM is associated with altered placental bacterial DNA community profiles and early neonatal meconium microbiota, potentially affecting maternal-neonatal microbial continuity. Specific bacterial genera are associated with early neonatal hospitalization. The study provides a microbial perspective for understanding GDM-related perinatal risk.
Congenital syphilis, a severe maternal-fetal disease caused by vertical transmission of Treponema pallidum (T. pallidum) via the placenta, affects over one million pregnancies annually and remains a leading cause of preventable adverse fetal outcomes. While the clinical consequences are well recognized, the molecular mechanisms underlying placental penetration are incompletely understood. This review synthesizes current evidence into a unified conceptual framework known as the adhesion-degradation-immune evasion cascade. Established findings, supported by direct placental studies, indicate that T. pallidum adhesins, including Tp0751 and Tp0136, bind trophoblast extracellular matrix receptors, while secreted enzymes such as hyaluronidase and the metalloproteinase Tp0751 degrade basement membrane components. Critically, several proposed mechanisms, including trophoblast cytoskeletal reprogramming and endocytosis, exploitation of maternal-fetal immune tolerance checkpoints (PD-L1/IDO), and modulation of Hofbauer cell polarization, await placental validation and are currently extrapolated from endothelial models, non-placental tissues, or related pathogens. This conceptual model provides a rigorous theoretical foundation for developing targeted interventions, including adhesion-blocking strategies and immune-modulatory approaches, to reduce the global burden of congenital syphilis.
Rho related BTB domain containing 1 (RhoBTB1) is highly expressed in placenta and functions to deliver protein targets to the Cullin-3 (CUL3) E3 ubiquitin ligase where they are targeted for ubiquitination and degradation. The targets of RhoBTB1 in placenta have not been identified. Using RNAscope, we show that RhoBTB1 is mainly expressed in syncytiotrophoblasts (SCT) in the human and mouse placenta. We employed ascorbate peroxidase 2-mediated targeted proteomics to identify RhoBTB1 binding proteins in immortalized human extravillous trophoblast (HTR8/SVneo) cells. We selected 9 RhoBTB1-interacting proteins to examine functionally. Two of these, S-Phase Kinase Associated Protein 2 (SKP2) and Rho GTPase-Activating Protein 29 (ArhGAP29), increased in abundance when Cullin activity was blocked by the neddylation inhibitor MLN4924 and co-immunoprecipitated with RhoBTB1. SKP2 increased in abundance in CRISPR-Cas9 HEK293 cells that lack CUL3, and in HTR8/SVneo cells after siRNA-mediated inhibition of RhoBTB1. SKP2 was ubiquitinated by a RhoBTB1- and CUL3-dependent mechanism providing evidence that its stability is regulated by RhoBTB1/CUL3. Like RhoBTB1, SKP2 is highly expressed in the placenta. Reanalysis of single cell RNA sequencing data sets revealed that SKP2 exhibits co-expression with RhoBTB1 in SCT precursor cells, SCTs, and cytotrophoblasts. These findings identify SKP2 as a RhoBTB1/CUL3 target in the placenta.
Mammalian placentas vary dramatically in invasiveness, parallel aggressive cancers, and are dysregulated in pregnancy disorders, yet whether they share regulatory architecture remains unclear. We investigated single-cell transcriptomes of the maternal-fetal interface across nine mammals spanning all major placental morphotypes and integrated it with thirteen cancers and five pregnancy complications. A conserved cellular framework is deployed through three discrete regulatory programs: a cancer-like program in hemochorials, endothelial-cooperation program in endotheliochorials, and collagen-rich invasion-suppressing program in epitheliochorials. Aggressive cancers selectively converge on hemochorial program, and we functionally validated share invasion regulators including the VGLL3-TEAD1 interaction and APOE . Pregnancy disorders are partially, mismatched deployments of these programs; placental APOE knockdown in mice phenocopies preeclampsia with concurrent collapse of both M1/M2 macrophage programs. These findings unify placental diversity, cancer convergence, and obstetric disorders under a regulatory-mismatch principle, whereby evolved placental invasion programs becomes pathological when deployed outside their evolutionary context.
Diabetes mellitus (DM) is one of the most common medical complications of pregnancy and is associated with increased maternal and fetal morbidity and mortality. The placenta has a unique role as a transient organ that can profoundly influence the lifelong health of both mother and child. In pregnancies complicated by diabetes, the placenta plays a central role in bridging maternal vascular and metabolic effects on fetal neurodevelopment. The objective of this study is to review the current literature on in vivo placental and fetal neurodevelopment in pregnant women with DM. We present a narrative literature review detailing human studies of placental and fetal neurodevelopment in pregnant persons with DM, along with promising new avenues of in vivo placental assessments. Advances in imaging, particularly sonography and magnetic resonance imaging, provides novel insights on placental structure and function, as well as fetal brain development in pregnant women with DM. Improving our understanding of the in vivo consequences of maternal DM may provide new opportunities to intervene and mitigate adverse pregnancy outcomes in future.
The objective was to analyze the mRNA expression of leptin, leptin receptor (ObRb), adiponectin, adiponectin receptor (AdipoR1), and resistin in the placental tissue of cows with and without hyperketonemia, relating it to their metabolic profile. Samples were collected from 135 cows during birth, divided into two groups: G1: without hyperketonemia (n = 120) and G2: with hyperketonemia (n = 15). Biochemical and hormonal indicators and insulin sensitivity were evaluated. Placental fragments were analyzed by qPCR. The variables were tested for normality and Pearson's correlation coefficient was applied. The significance level was 5%. Cows with hyperketonemia showed increased concentrations of NEFA (p = 0.0002), urea (p = 0.0302), higher expressions of leptin (p = 0.0174) and ObRb (p < 0.0001), while healthy cows showed higher expression of AdipoR1 (p < 0.0001) and resistin (p = 0.0435). Glucose concentrations were lower in G2 (p = 0.0132), as were the percentages of RQUICKIβHB (p < 0.0001). Among the varying degrees of correlations between the variables, the following stand out: positive correlation of leptin expression with β-Hydroxybutyrate and ObRb expression; positive correlation of ObRb expression with β-hydroxybutyrate, NEFA, GGT and AST, and negative correlation with glucose; positive correlation of AdipoR1 expression with glucose, RQUICK and RQUICKβHB, and negative correlation with β-Hydroxybutyrate, NEFA and GGT. Gene expression analysis of adipokines in the placenta is a promising tool to understand their role in metabolic regulation in cows, especially in the dynamics of hyperketonemia. It is concluded that the placental production of these hormones has an important contribution to metabolic conditions in the transition period, bringing implications for the physiology, health and productivity of females.
The escalating environmental prevalence of micro- and nanoplastics (NPs) poses a growing threat to maternal-fetal health, with the placenta being a particularly vulnerable interface. However, the precise metabolic mechanisms by which NPs compromise placental function and contribute to adverse pregnancy outcomes remain poorly understood. This study, employing untargeted metabolomics, reveals that gestational exposure to polystyrene nanoplastics (PS-NPs) severely disrupts placental nicotinamide (NAM) metabolism and impairs mitochondrial energetics. A key mechanistic discovery is the central role of NMNAT3, a mitochondrial NAD+ synthase. PS-NPs exposure downregulated NMNAT3, leading to NAD+ depletion, mitochondrial dysfunction, oxidative stress, and lipid peroxidation in trophoblasts, which collectively triggered ferritinophagy-mediated ferroptosis. Notably, NMNAT3 overexpression rescued these defects by suppressing ferritinophagy, limiting cytotoxic iron release, and inhibiting ferroptosis. Importantly, NAM, as a metabolic modulator, can inhibit ferroptosis and improve pregnancy outcomes by restoring NAD+ homeostasis. Collectively, our findings delineate a novel pathogenic axis wherein PS-NPs impair placental health via NMNAT3-dependent disruption of NAM metabolism and iron homeostasis, highlighting NAM supplementation as potential strategies to counteract nanoplastic-induced reproductive toxicity.
Maternal immune adaptation during pregnancy is orchestrated by dynamic signals from the uterine microenvironment, including placental extracellular vesicles (pEVs) released into maternal circulation. EVs have emerged as key mediators of this crosstalk; however, their role in sex-specific immune modulation remains incompletely defined. Here, we investigated whether pEVs derived from term placentas induce sex-dependent changes in the phenotype, metabolism, and function of human monocytes. pEVs were isolated from 13 term uncomplicated placentas (six male-derived, M-pEVs, and seven female-derived, F-pEVs) and characterized by complementary approaches, revealing similar size distributions and concentrations, with differences in physicochemical properties and molecular cargo. Circulating monocytes from 17 non-pregnant female donors were exposed to M-pEVs or F-pEVs and analyzed for phenotypic, metabolic, and functional responses. pEVs induced distinct activation profiles depending on fetal sex. F-pEVs reduced CD11b and CD11c expression while increasing CD14, CD39 and IL-10 production. On the other hand, M-pEVs increased CD14 expression and enhanced IL-1β secretion. Both nanovesicles populations increased IL-10 and CXCL8 release and promoted a shift toward classical monocytes (CD14+CD16-) with a reduction in the intermediate subsets. Metabolic analyses revealed divergent immunometabolic programs: M-pEVs promoted lactate and reactive oxygen species production, whereas F-pEVs enhanced lactate production, fatty acid uptake, lipid droplet accumulation, and mitochondrial activity without increasing ROS. Functionally, both pEV populations increased efferocytosis, with a distinct sensitivity to metabolic inhibitors. These findings demonstrate that pEVs differentially modulate circulating monocytes according to fetal sex and support a role for fetal sex in shaping maternal immunometabolic responses.