Pub Date : 2025-12-24DOI: 10.1016/j.placenta.2025.12.013
Li Gao , Xiaoyu Li , Xiang Ying , Jiawen Yang , Shujing Liu , Lanlan Zhang , Yan Bi , Yanlin Wang
In dichorionic twins, male-male pairs exhibited the highest maternal peripheral blood cell-free fetal DNA and seemingly the greatest risk of preterm birth and premature rupture of membranes. The preterm birth rate in other twin pregnancies was significantly lower than that in male-male pairs. Within opposite sex twins, male fetal placentas exhibited higher apoptosis, while female placentas showed a propensity for greater proliferation. Thus, the protective effect might come from the lower placental apoptosis index observed in female fetuses, although the exact molecular pathways underlying this sex specific modulation remained to be elucidated and represented an important direction for future research.
{"title":"Fetal sex-related preterm birth and placental cell turnover in dichorionic twins","authors":"Li Gao , Xiaoyu Li , Xiang Ying , Jiawen Yang , Shujing Liu , Lanlan Zhang , Yan Bi , Yanlin Wang","doi":"10.1016/j.placenta.2025.12.013","DOIUrl":"10.1016/j.placenta.2025.12.013","url":null,"abstract":"<div><div>In dichorionic twins, male-male pairs exhibited the highest maternal peripheral blood cell-free fetal DNA and seemingly the greatest risk of preterm birth and premature rupture of membranes. The preterm birth rate in other twin pregnancies was significantly lower than that in male-male pairs. Within opposite sex twins, male fetal placentas exhibited higher apoptosis, while female placentas showed a propensity for greater proliferation. Thus, the protective effect might come from the lower placental apoptosis index observed in female fetuses, although the exact molecular pathways underlying this sex specific modulation remained to be elucidated and represented an important direction for future research.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 138-141"},"PeriodicalIF":2.5,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.placenta.2025.12.012
Ankit Balhara , Xin Chen , Aditya R. Kumar , Morgan E. Wasickanin , Joshua W. Monson , Jennifer R. Damicis , Hillary J. Kinsman , Nicholas Ieronimakis , Jashvant D. Unadkat
We previously showed that THC is effluxed in the perfused human placenta cotyledons, but surprisingly this efflux was not inhibited by valspodar, a P-gp and BCRP inhibitor. P-gp and BCRP have multiple binding sites, and therefore THC may be binding to a transport site not blocked by valspodar. To test this hypothesis, we perfused human placenta cotyledons with THC in the absence and presence of a cocktail of P-gp and BCRP inhibitors. The inhibitor cocktail significantly increased the unbound maternal-to-fetal THC clearance index, indicating that P-gp and/or BCRP are likely involved in determining fetal THC exposure.
{"title":"Elucidating the role of ABC transporters in the placental efflux of (−)- Δ9-tetrahydrocannabinol (THC) using a cocktail of ABC transport inhibitors","authors":"Ankit Balhara , Xin Chen , Aditya R. Kumar , Morgan E. Wasickanin , Joshua W. Monson , Jennifer R. Damicis , Hillary J. Kinsman , Nicholas Ieronimakis , Jashvant D. Unadkat","doi":"10.1016/j.placenta.2025.12.012","DOIUrl":"10.1016/j.placenta.2025.12.012","url":null,"abstract":"<div><div>We previously showed that THC is effluxed in the perfused human placenta cotyledons, but surprisingly this efflux was not inhibited by valspodar, a P-gp and BCRP inhibitor. P-gp and BCRP have multiple binding sites, and therefore THC may be binding to a transport site not blocked by valspodar. To test this hypothesis, we perfused human placenta cotyledons with THC in the absence and presence of a cocktail of P-gp and BCRP inhibitors. The inhibitor cocktail significantly increased the unbound maternal-to-fetal THC clearance index, indicating that P-gp and/or BCRP are likely involved in determining fetal THC exposure.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 174-177"},"PeriodicalIF":2.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.placenta.2025.12.011
Yike Yang , Huifeng Shi , Haoyu Zuo , Yan Wang , Yangyu Zhao
Introduction
Preeclampsia (PE), particularly when associated with small-for-gestational-age (SGA) infants, is a major cause of maternal and neonatal morbidity. While dysregulated iron metabolism is linked to PE, its role in placental dysfunction and fetal growth restriction remains unclear.
Methods
In a retrospective case-control study nested within a cohort of 47,289 singleton pregnancies, we compared 1576 PE cases (1275 PE alone; 301 PE + SGA) with 25,634 controls. Propensity score matching (PSM, with ratio of 1:5) was applied to balance baseline covariates. Longitudinal hematologic parameters were assessed across gestation. Placental iron deposition was evaluated by Perls' Prussian blue staining, and iron transporter expression (FTH1, TFR, DMT1, FPN) was measured via RT-qPCR in PE + SGA and matched controls.
Results
PE + SGA pregnancies were linked to poorer outcomes, including earlier delivery and lower birthweight. Maternal blood tests revealed elevated ferritin, hemoglobin, and RBC counts—most pronounced in PE + SGA. The PE-SGA group showed persistently higher WBC counts and dynamic platelet changes. Trends across groups mirrored those in the PSM cohort. Placental analysis in PE + SGA cases revealed significant iron accumulation in syncytiotrophoblasts, along with increased expression of iron importers (FTH1, TFR, DMT1) and reduced ferroportin (FPN).
Discussion
Preeclampsia is associated with disrupted iron balance, characterized by maternal iron overload and relative fetal iron insufficiency due to placental dysregulation. The findings support the sub - classification of preeclampsia into placental (PE + SGA) and maternal (PE - SGA) subtypes. This cautions against universal iron supplementation and highlights the need for personalized management.
{"title":"Dysregulation of iron metabolism in preeclamptic women with small-for-gestational-age offspring: A retrospective cohort analysis with nested case-control assessment","authors":"Yike Yang , Huifeng Shi , Haoyu Zuo , Yan Wang , Yangyu Zhao","doi":"10.1016/j.placenta.2025.12.011","DOIUrl":"10.1016/j.placenta.2025.12.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE), particularly when associated with small-for-gestational-age (SGA) infants, is a major cause of maternal and neonatal morbidity. While dysregulated iron metabolism is linked to PE, its role in placental dysfunction and fetal growth restriction remains unclear.</div></div><div><h3>Methods</h3><div>In a retrospective case-control study nested within a cohort of 47,289 singleton pregnancies, we compared 1576 PE cases (1275 PE alone; 301 PE + SGA) with 25,634 controls. Propensity score matching (PSM, with ratio of 1:5) was applied to balance baseline covariates. Longitudinal hematologic parameters were assessed across gestation. Placental iron deposition was evaluated by Perls' Prussian blue staining, and iron transporter expression (FTH1, TFR, DMT1, FPN) was measured via RT-qPCR in PE + SGA and matched controls.</div></div><div><h3>Results</h3><div>PE + SGA pregnancies were linked to poorer outcomes, including earlier delivery and lower birthweight. Maternal blood tests revealed elevated ferritin, hemoglobin, and RBC counts—most pronounced in PE + SGA. The PE-SGA group showed persistently higher WBC counts and dynamic platelet changes. Trends across groups mirrored those in the PSM cohort. Placental analysis in PE + SGA cases revealed significant iron accumulation in syncytiotrophoblasts, along with increased expression of iron importers (FTH1, TFR, DMT1) and reduced ferroportin (FPN).</div></div><div><h3>Discussion</h3><div>Preeclampsia is associated with disrupted iron balance, characterized by maternal iron overload and relative fetal iron insufficiency due to placental dysregulation. The findings support the sub - classification of preeclampsia into placental (PE + SGA) and maternal (PE - SGA) subtypes. This cautions against universal iron supplementation and highlights the need for personalized management.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 142-152"},"PeriodicalIF":2.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Imbalanced levels of Vascular Endothelial Growth Factor (VEGF) may contribute to adverse perinatal outcomes, such as preeclampsia (PE), due to placental ischemia and endothelial damage. Objective: To analyze the ratio between placental and umbilical cord VEGF levels and its association with maternal characteristics and fetal outcomes in pregnancies complicated by PE.
Methods
A cross-sectional study approved by the Research Ethics Committee (35743614.1.0000.5013) was conducted in 2017 at a university hospital in Maceió, Brazil, involving 100 pregnant women with PE and 50 without (controls). VEGF concentrations in placental and umbilical cord tissue extracts were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using SPSS v.20.0 (α = 5%).
Results
No significant differences were observed in placental or umbilical cord VEGF levels between groups (p > 0.05). However, placental VEGF levels were significantly associated with Black race (382.4 pg/mL in PE vs 788.2 pg/mL in controls; interaction p = 0.02) and low 5-min Apgar scores (1806.5 pg/mL vs 57.3 pg/mL; interaction p = 0.01). The placental:umbilical cord VEGF ratio was significantly associated with birth weight (interaction p = 0.04).
Conclusion
The placental:umbilical cord VEGF ratio was associated with birth weight in pregnancies complicated by preeclampsia. Although preliminary, this finding suggests that VEGF distribution between gestational tissues may play a role in fetal adaptation and warrants further investigation in larger samples.
{"title":"Ratio of placental and umbilical cord Vascular Endothelial Growth Factor (VEGF) levels in pregnancies with preeclampsia and its association with maternal variables and fetal outcome","authors":"Maria Gracyella Ferreira da Silva , Marilene Brandão Tenório Fragoso , Thiago Marques Wanderley , Tauane Alves Dutra , Nassib Bezerra Bueno , Alexandre Urban Borbely , Alane Cabral Menezes de Oliveira","doi":"10.1016/j.placenta.2025.12.008","DOIUrl":"10.1016/j.placenta.2025.12.008","url":null,"abstract":"<div><h3>Background</h3><div>Imbalanced levels of Vascular Endothelial Growth Factor (VEGF) may contribute to adverse perinatal outcomes, such as preeclampsia (PE), due to placental ischemia and endothelial damage. Objective: To analyze the ratio between placental and umbilical cord VEGF levels and its association with maternal characteristics and fetal outcomes in pregnancies complicated by PE.</div></div><div><h3>Methods</h3><div>A cross-sectional study approved by the Research Ethics Committee (35743614.1.0000.5013) was conducted in 2017 at a university hospital in Maceió, Brazil, involving 100 pregnant women with PE and 50 without (controls). VEGF concentrations in placental and umbilical cord tissue extracts were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using SPSS v.20.0 (α = 5%).</div></div><div><h3>Results</h3><div>No significant differences were observed in placental or umbilical cord VEGF levels between groups (p > 0.05). However, placental VEGF levels were significantly associated with Black race (382.4 pg/mL in PE vs 788.2 pg/mL in controls; interaction p = 0.02) and low 5-min Apgar scores (1806.5 pg/mL vs 57.3 pg/mL; interaction p = 0.01). The placental:umbilical cord VEGF ratio was significantly associated with birth weight (interaction p = 0.04).</div></div><div><h3>Conclusion</h3><div>The placental:umbilical cord VEGF ratio was associated with birth weight in pregnancies complicated by preeclampsia. Although preliminary, this finding suggests that VEGF distribution between gestational tissues may play a role in fetal adaptation and warrants further investigation in larger samples.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 166-173"},"PeriodicalIF":2.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145865018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.placenta.2025.12.009
Qianghua Wang , Nana Yang , Huijuan Chen , Biao Ding , Chengli Dou , Xuegu Wang , Xingchen Pan , Xiaojing Wang , Xiang Li
Background
Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.
Methods
Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.
Results
EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.
Conclusion
Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.
{"title":"HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia","authors":"Qianghua Wang , Nana Yang , Huijuan Chen , Biao Ding , Chengli Dou , Xuegu Wang , Xingchen Pan , Xiaojing Wang , Xiang Li","doi":"10.1016/j.placenta.2025.12.009","DOIUrl":"10.1016/j.placenta.2025.12.009","url":null,"abstract":"<div><h3>Background</h3><div>Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.</div></div><div><h3>Methods</h3><div>Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.</div></div><div><h3>Results</h3><div>EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.</div></div><div><h3>Conclusion</h3><div>Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 126-137"},"PeriodicalIF":2.5,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-14DOI: 10.1016/j.placenta.2025.12.007
Ana María Arboleda-Borrero , Eliécer Jiménez-Charris , Laura Andrea Gómez , Wilmar Saldarriaga , Javier Fonseca , Mildrey Mosquera Escudero
Background
The NLRP3 inflammasome is a key regulator of innate immunity. Its overactivation contributes to cytokine release and tissue inflammation during SARS-CoV-2 infection. However, its role in placental inflammation and pregnancy outcomes remains unclear.
Objective
To evaluate whether SARS-CoV-2 infection during pregnancy induces NLRP3 inflammasome activation in placental tissue and to assess its association with maternal and neonatal outcomes.
Methods
A prospective cohort study included 25 pregnant women with RT-PCR–confirmed COVID-19 and 25 healthy controls. Placental NLRP3, Caspase-1, IL-1β, and IL-18 expression were analyzed by qRT-PCR and Western blotting. Maternal and cord plasma cytokines were quantified by ELISA and cytometric bead array. Viral RNA, antibody transfer, and nutrient transporter gene expression were also evaluated.
Results
Placentas from infected women showed higher NLRP3 (p = 0.015) and Caspase-1 (p = 0.029) mRNA levels compared with controls. Western blotting detected procaspase-1 (∼50 kDa) and cleaved caspase-1 (∼35 kDa), indicating inflammasome activation. Maternal IL-18 concentrations were elevated (p = 0.013), while IL-1β remained unchanged. SARS-CoV-2 RNA was identified in 8 % of placentas (variants 21H and 20A). IgG antibodies were found in 28 % of maternal and 24 % of cord samples (p = 0.017). Infected pregnancies showed lower gestational age at delivery (p = 0.023), higher cesarean rate (p = 0.004), and lower neonatal Apgar scores (p = 0.006, p = 0.015). Nutrient transporter expression was preserved.
Conclusion
SARS-CoV-2 infection during pregnancy induces activation of the NLRP3 inflammasome in placental tissue and systemic elevation of IL-18, indicating both local and systemic inflammation.
{"title":"NLRP3 inflammasome activation in the placenta during SARS-CoV-2 infection","authors":"Ana María Arboleda-Borrero , Eliécer Jiménez-Charris , Laura Andrea Gómez , Wilmar Saldarriaga , Javier Fonseca , Mildrey Mosquera Escudero","doi":"10.1016/j.placenta.2025.12.007","DOIUrl":"10.1016/j.placenta.2025.12.007","url":null,"abstract":"<div><h3>Background</h3><div>The NLRP3 inflammasome is a key regulator of innate immunity. Its overactivation contributes to cytokine release and tissue inflammation during SARS-CoV-2 infection. However, its role in placental inflammation and pregnancy outcomes remains unclear.</div></div><div><h3>Objective</h3><div>To evaluate whether SARS-CoV-2 infection during pregnancy induces NLRP3 inflammasome activation in placental tissue and to assess its association with maternal and neonatal outcomes.</div></div><div><h3>Methods</h3><div>A prospective cohort study included 25 pregnant women with RT-PCR–confirmed COVID-19 and 25 healthy controls. Placental <em>NLRP3</em>, <em>Caspase-1</em>, <em>IL-1β</em>, and <em>IL-18</em> expression were analyzed by qRT-PCR and Western blotting. Maternal and cord plasma cytokines were quantified by ELISA and cytometric bead array. Viral RNA, antibody transfer, and nutrient transporter gene expression were also evaluated.</div></div><div><h3>Results</h3><div>Placentas from infected women showed higher <em>NLRP3</em> (p = 0.015) and <em>Caspase-1</em> (p = 0.029) mRNA levels compared with controls. Western blotting detected procaspase-1 (∼50 kDa) and cleaved caspase-1 (∼35 kDa), indicating inflammasome activation. Maternal IL-18 concentrations were elevated (p = 0.013), while IL-1β remained unchanged. SARS-CoV-2 RNA was identified in 8 % of placentas (variants 21H and 20A). IgG antibodies were found in 28 % of maternal and 24 % of cord samples (p = 0.017). Infected pregnancies showed lower gestational age at delivery (p = 0.023), higher cesarean rate (p = 0.004), and lower neonatal Apgar scores (p = 0.006, p = 0.015). Nutrient transporter expression was preserved.</div></div><div><h3>Conclusion</h3><div>SARS-CoV-2 infection during pregnancy induces activation of the NLRP3 inflammasome in placental tissue and systemic elevation of IL-18, indicating both local and systemic inflammation.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 117-125"},"PeriodicalIF":2.5,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.placenta.2025.12.005
Mingqun Li , Xiaoqiang Han , Yao Peng , Yang He , Qiangqiang You , Jiaqi Zhang
Introduction
This study aimed to characterize placental vascular morphological alterations across different severities of preeclampsia (PE) using advanced three-dimensional (3D) imaging and histological techniques, exploring correlations between placental microvascular changes and disease severity.
Methods
A prospective observational study included 122 singleton pregnancies, categorized as normal (n = 45), mild PE (n = 51), or severe PE (n = 26). Placental vascular casts were created through modified resin casting, followed by 3D computed tomography (CT) reconstruction, scanning electron microscopy (SEM), and histopathological analysis. Vascular morphometry, volume, density, and microstructural features were quantitatively assessed.
Results
Significant intergroup differences in placental vascular characteristics were identified. Compared with normal placentas, mild PE exhibited compensatory increases in total vascular volume, primarily due to venous expansion, while severe PE demonstrated significantly reduced vascular volumes and grades (P < 0.01). Morphometric analysis indicated progressive narrowing of distal venous (V3–V5: 24.9–32.5 %) and arterial branches (A3–A4: 19.7–23.2 %) correlating with PE severity. Vascular density analysis showed a marked stepwise reduction from normal to severe PE groups, with venous networks being most affected (31.1 % decrease, P < 0.001). SEM and histopathological examinations confirmed severe vascular rarefaction, abnormal vessel morphology, and hallmark pathological changes in severe PE. Further correlation analysis demonstrated that total placental vascular density was positively associated with neonatal birth weight (ρ = 0.523, P < 0.001), MCA peak systolic velocity (ρ = 0.218, P = 0.042), and 1-min Apgar score (ρ = 0.344, P = 0.005), while showing significant negative correlations with umbilical artery PI (ρ = −0.387, P = 0.003), NICU admission (ρ = −0.297, P = 0.011), maternal serum creatinine (ρ = −0.262, P = 0.027), and maternal ALT levels (ρ = −0.233, P = 0.038).
Discussion
Placental microvascular alterations correlate significantly with preeclampsia severity. Our findings highlight distinct vascular remodeling patterns in PE and provide essential morphological evidence supporting microcirculatory dysfunction as a key pathological mechanism in preeclampsia progression.
{"title":"Placental vascular remodeling in preeclampsia: A three-dimensional analysis of microvascular alterations across disease severity","authors":"Mingqun Li , Xiaoqiang Han , Yao Peng , Yang He , Qiangqiang You , Jiaqi Zhang","doi":"10.1016/j.placenta.2025.12.005","DOIUrl":"10.1016/j.placenta.2025.12.005","url":null,"abstract":"<div><h3>Introduction</h3><div>This study aimed to characterize placental vascular morphological alterations across different severities of preeclampsia (PE) using advanced three-dimensional (3D) imaging and histological techniques, exploring correlations between placental microvascular changes and disease severity.</div></div><div><h3>Methods</h3><div>A prospective observational study included 122 singleton pregnancies, categorized as normal (n = 45), mild PE (n = 51), or severe PE (n = 26). Placental vascular casts were created through modified resin casting, followed by 3D computed tomography (CT) reconstruction, scanning electron microscopy (SEM), and histopathological analysis. Vascular morphometry, volume, density, and microstructural features were quantitatively assessed.</div></div><div><h3>Results</h3><div>Significant intergroup differences in placental vascular characteristics were identified. Compared with normal placentas, mild PE exhibited compensatory increases in total vascular volume, primarily due to venous expansion, while severe PE demonstrated significantly reduced vascular volumes and grades (<em>P</em> < 0.01). Morphometric analysis indicated progressive narrowing of distal venous (V3–V5: 24.9–32.5 %) and arterial branches (A3–A4: 19.7–23.2 %) correlating with PE severity. Vascular density analysis showed a marked stepwise reduction from normal to severe PE groups, with venous networks being most affected (31.1 % decrease, <em>P</em> < 0.001). SEM and histopathological examinations confirmed severe vascular rarefaction, abnormal vessel morphology, and hallmark pathological changes in severe PE. Further correlation analysis demonstrated that total placental vascular density was positively associated with neonatal birth weight (ρ = 0.523, <em>P</em> < 0.001), MCA peak systolic velocity (ρ = 0.218, <em>P</em> = 0.042), and 1-min Apgar score (ρ = 0.344, <em>P</em> = 0.005), while showing significant negative correlations with umbilical artery PI (ρ = −0.387, P = 0.003), NICU admission (ρ = −0.297, <em>P</em> = 0.011), maternal serum creatinine (ρ = −0.262, <em>P</em> = 0.027), and maternal ALT levels (ρ = −0.233, <em>P</em> = 0.038).</div></div><div><h3>Discussion</h3><div>Placental microvascular alterations correlate significantly with preeclampsia severity. Our findings highlight distinct vascular remodeling patterns in PE and provide essential morphological evidence supporting microcirculatory dysfunction as a key pathological mechanism in preeclampsia progression.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 96-108"},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.placenta.2025.12.006
M.M. van Vliet , R.G. Boers , R.J.H. Galjaard , J.B. Boers , R.P.M. Steegers-Theunissen , J. Gribnau , S. Schoenmakers
Introduction
Distinct DNA methylation profiles have been identified in maternal plasma cell-free DNA (cfDNA) in early-onset preeclampsia (EOPE). However, findings across studies often lack concordance and the biological mechanisms driving methylation differences are largely unknown. We aimed to identify EOPE-associated differentially methylated regions (DMRs), investigate changes in tissue-specific cfDNA contributions and validate previously reported EOPE-associated regions.
Methods
First-trimester cfDNA (n = 35) and cfDNA after diagnosis (n = 21) were collected from EOPE pregnancies and matched-controls. Placental tissues were collected from EOPE (n = 5) and control (n = 7) pregnancies. MeD-seq assays were performed to identify DMRs. Placental-contribution to cfDNA, cfDNA concentration, EOPE-specific placental markers, and methylation levels at previously identified EOPE-associated regions were compared between cases and controls. Additionally, liver-, kidney-, and endothelium-specific hypermethylated regions were identified using publicly available datasets and compared in cfDNA.
Results
We identified one DMR in the first trimester and 249 DMRs in our after diagnosis cohort. Total cfDNA concentration was 20-fold higher after EOPE diagnosis compared to controls (p < 0.001). We identified 606 DMRs in EOPE placentas, which unexpectedly were almost not present in cfDNA after EOPE diagnosis. Also, the placental-, liver-, and kidney-specific contributions were relatively decreased, while endothelium-specific methylation was increased. Only 2.7–8.4 % of previously identified regions showed significant differential methylation in our cohort.
Discussion
Differential tissue contributions to cfDNA likely account for DMRs identified after EOPE diagnosis. Further research is required to clarify the (tissue) origins of identified cfDNA DMRs in more detail. Lack of concordance across studies remains a significant limitation, potentially explained by methodological heterogeneity.
{"title":"Cell-free DNA methylation profiling in early-onset preeclampsia using methylated DNA sequencing","authors":"M.M. van Vliet , R.G. Boers , R.J.H. Galjaard , J.B. Boers , R.P.M. Steegers-Theunissen , J. Gribnau , S. Schoenmakers","doi":"10.1016/j.placenta.2025.12.006","DOIUrl":"10.1016/j.placenta.2025.12.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Distinct DNA methylation profiles have been identified in maternal plasma cell-free DNA (cfDNA) in early-onset preeclampsia (EOPE). However, findings across studies often lack concordance and the biological mechanisms driving methylation differences are largely unknown. We aimed to identify EOPE-associated differentially methylated regions (DMRs), investigate changes in tissue-specific cfDNA contributions and validate previously reported EOPE-associated regions.</div></div><div><h3>Methods</h3><div>First-trimester cfDNA (n = 35) and cfDNA after diagnosis (n = 21) were collected from EOPE pregnancies and matched-controls. Placental tissues were collected from EOPE (n = 5) and control (n = 7) pregnancies. MeD-seq assays were performed to identify DMRs. Placental-contribution to cfDNA, cfDNA concentration, EOPE-specific placental markers, and methylation levels at previously identified EOPE-associated regions were compared between cases and controls. Additionally, liver-, kidney-, and endothelium-specific hypermethylated regions were identified using publicly available datasets and compared in cfDNA.</div></div><div><h3>Results</h3><div>We identified one DMR in the first trimester and 249 DMRs in our after diagnosis cohort. Total cfDNA concentration was 20-fold higher after EOPE diagnosis compared to controls (p < 0.001). We identified 606 DMRs in EOPE placentas, which unexpectedly were almost not present in cfDNA after EOPE diagnosis. Also, the placental-, liver-, and kidney-specific contributions were relatively decreased, while endothelium-specific methylation was increased. Only 2.7–8.4 % of previously identified regions showed significant differential methylation in our cohort.</div></div><div><h3>Discussion</h3><div>Differential tissue contributions to cfDNA likely account for DMRs identified after EOPE diagnosis. Further research is required to clarify the (tissue) origins of identified cfDNA DMRs in more detail. Lack of concordance across studies remains a significant limitation, potentially explained by methodological heterogeneity.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 186-195"},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-05DOI: 10.1016/j.placenta.2025.11.014
Zoe Warland , Angela Xue , Samantha Thomas , Frank Wu , Tracie Barber , Josh Brandt , Claire Taylor , Trixie Kong , Alec William Welsh
Objectives
Many critical obstetric pathologies are associated with deficiencies in placental perfusion. However, there are limited diagnostic tools available to evaluate this and there is marked variability. We previously used the validated tool, Three-Dimensional Fractional Moving Blood Volume (3D-FMBV), combined with infra-red camera tracking technology to quantify perfusion in the entire third-trimester placenta. This pilot study aimed to describe and evaluate the heterogeneity of placental perfusion, visualise this as a ‘perfusion map,’ and assess changes over gestation.
Methods
This single-centre, prospective, cross-sectional study included 27 uncomplicated, third-trimester singleton pregnancies with anterior placentas. Multiple 3D Power Doppler Ultrasound (3D-PD-US) volumes were acquired with infra-red camera tracking coordinates, stitched and manually segmented to calculate the entire placental 3D-FMBV and volume. Heterogeneity was described using the coefficient of variation (CoV) of 3D-FMBV between defined cubic regions.
Results
In third-trimester placentas, mean CoV was 34.1 % (±5.0), declining as global perfusion increased (p = 0.02). With advancing gestation, perfusion non-significantly increased (p = 0.11) and became more homogenous (p = 0.27), while overall placental volume significantly increased (p = 0.02). Two-way mixed measure ICCs were 0.78, 0.63 and 0.95 for global 3D-FMBV, CoV and placental volume respectively.
Conclusion
This study successfully reconstructed entire third-trimester placentas using infra-red camera tracking technology, quantified perfusion using 3D-FMBV and demonstrated its heterogeneity. As gestation advances, perfusion appears to increase and become more uniform, potentially reflecting greater involvement of the placental bed to maximise fetoplacental exchange. Future work will explore automating our method, evaluating a larger cohort, and assessing differences in complicated pregnancies at-risk of stillbirth.
{"title":"Determining a method for description and evaluation of heterogeneity of perfusion in the third-trimester placenta","authors":"Zoe Warland , Angela Xue , Samantha Thomas , Frank Wu , Tracie Barber , Josh Brandt , Claire Taylor , Trixie Kong , Alec William Welsh","doi":"10.1016/j.placenta.2025.11.014","DOIUrl":"10.1016/j.placenta.2025.11.014","url":null,"abstract":"<div><h3>Objectives</h3><div>Many critical obstetric pathologies are associated with deficiencies in placental perfusion. However, there are limited diagnostic tools available to evaluate this and there is marked variability. We previously used the validated tool, Three-Dimensional Fractional Moving Blood Volume (3D-FMBV), combined with infra-red camera tracking technology to quantify perfusion in the entire third-trimester placenta. This pilot study aimed to describe and evaluate the heterogeneity of placental perfusion, visualise this as a ‘perfusion map,’ and assess changes over gestation.</div></div><div><h3>Methods</h3><div>This single-centre, prospective, cross-sectional study included 27 uncomplicated, third-trimester singleton pregnancies with anterior placentas. Multiple 3D Power Doppler Ultrasound (3D-PD-US) volumes were acquired with infra-red camera tracking coordinates, stitched and manually segmented to calculate the entire placental 3D-FMBV and volume. Heterogeneity was described using the coefficient of variation (CoV) of 3D-FMBV between defined cubic regions.</div></div><div><h3>Results</h3><div>In third-trimester placentas, mean CoV was 34.1 % (±5.0), declining as global perfusion increased (p = 0.02). With advancing gestation, perfusion non-significantly increased (p = 0.11) and became more homogenous (p = 0.27), while overall placental volume significantly increased (p = 0.02). Two-way mixed measure ICCs were 0.78, 0.63 and 0.95 for global 3D-FMBV, CoV and placental volume respectively.</div></div><div><h3>Conclusion</h3><div>This study successfully reconstructed entire third-trimester placentas using infra-red camera tracking technology, quantified perfusion using 3D-FMBV and demonstrated its heterogeneity. As gestation advances, perfusion appears to increase and become more uniform, potentially reflecting greater involvement of the placental bed to maximise fetoplacental exchange. Future work will explore automating our method, evaluating a larger cohort, and assessing differences in complicated pregnancies at-risk of stillbirth.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 109-116"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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