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Background: Human cancers, including head and neck squamous cell carcinoma (HNSCC), are complex and heterogeneous diseases driven by uncontrolled cell growth and proliferation. Post-translational modifications (PTMs) of proteins play a crucial role in cancer progression, making them a promising target for pharmacological intervention. This study aims to identify key exercise-related genes with prognostic value in HNSCC through comprehensive bioinformatics analysis, with a particular focus on the therapeutic potential of placental growth factor (PIGF). Methods: Transcriptome data for HNSCC were obtained from The Cancer Genome Atlas (TCGA) database. Differently expressed genes (DEGs) were identified and analyzed for their prognostic significance. Exercise-related gene sets were retrieved from the Gene Set Enrichment Analysis (GSEA) database. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA, were conducted. The biological functions and clinical implications of key genes were further explored through single-gene expression analysis, immune infiltration analysis, and in vitro cellular experiments. Results: The study identified exercise-related genes associated with survival prognosis in HNSCC. GO and KEGG pathway analyses highlighted the biological functions of these genes, and Kaplan-Meier survival curves confirmed their prognostic value. PIGF expression analysis using TCGA data showed its diagnostic potential, with higher expression linked to advanced tumor stages. Single-cell sequencing revealed PIGF's role in the tumor microenvironment. In vitro experiments demonstrated that PIGF plays a pivotal role in enhancing cell proliferation and colony formation in HNSCC, with PIGF knockdown significantly impairing these functions, highlighting its importance in tumor growth regulation. Additionally, PIGF's predictive performance in drug sensitivity across cancer datasets suggests its potential as a pharmacological target, offering opportunities to modulate the immune microenvironment and improve therapeutic outcomes in cancer treatment. Conclusion: This study provides new insights into the molecular mechanisms underlying HNSCC and identifies exercise-related genes, particularly PIGF, as promising biomarkers for clinical treatment and personalized medicine. By focusing on PTMs and their role in cancer progression, our findings suggest that targeting PIGF may offer innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Participants Measurements Results Conclusions A link between maternal thyroid function and the placental biomarkers, soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), has been brought forward. This study aimed to describe their association in early pregnancy.Retrospective cohort study.Eight hundred and fifty‐eight pregnant women from the North Denmark Region, 2013, with blood samples drawn in early pregnancy.Thyroid‐stimulating hormone (TSH), free thyroxine (fT4), thyroid‐peroxidase antibodies (TPO‐Ab), thyroglobulin antibodies (Tg‐Ab) (ADVIA Centaur XPT, Siemens Healthineers), sFlt‐1 and PlGF (Kryptor Compact, ThermoFisher Scientific) were measured. The association between maternal TSH and fT4 and percentile (pc) levels of sFlt‐1 and PlGF (< 25th pc, 25–75th pc, > 75th pc) was evaluated using regression analysis and reported as adjusted beta coefficient (aβ). The frequency of maternal thyroid autoantibodies (TPO‐Ab > 60 U/mL or Tg‐Ab > 33 U/mL) by pc levels of sFlt‐1 and PlGF was compared using chi‐squared test.Higher levels (> 75th pc) of sFlt‐1 associated with lower TSH (aβ 0.62, 95% CI: 0.51–0.76) and higher fT4 (aβ 1.03, 95% CI: 1.01–1.05). Higher levels of PlGF associated with lower TSH (aβ 0.82, 95% CI: 0.69–0.98), but not with levels of fT4 (aβ 1.00, 95% CI: 0.97–1.02). No association with maternal thyroid autoantibodies was found (TPO‐Ab: sFlt‐1: p‐value 0.5 and PlGF: p‐value 0.1; Tg‐Ab: sFlt‐1: p‐value 0.7 and PlGF: p‐value 0.1).In a large cohort of Danish pregnant women, higher levels of sFlt‐1 and PlGF associated with maternal thyroid function in early pregnancy, while there was no association with maternal thyroid autoantibodies. [ABSTRACT FROM AUTHOR]

Placental Growth factor (PlGF) is one of the biomarkers useful for detecting pregnancy hypertension disorder, Pre‐eclampsia. Herein, we focus on developing a label‐free immunosensor using simple electrochemical methods to detect PlGF antigens for pre‐eclampsia diagnosis. The work includes the electrochemical deposition of Palladium nanoparticles (PdNPs) on the glassy carbon electrode (GCE) surface using amperometry followed by electropolymerization of diaminobenzoic acid (DABA) onto the PdNPs/GCE. Antibody (aPlGF) was covalently immobilized on the pDABA/PdNPs/GCE using EDC/NHS reaction. The interaction of the antibody with the antigen was measured using differential pulse voltammetric technique. The linear range obtained for the immunosensor is 1–25 ng mL−1 with a limit of detection of 53 pg mL−1. The stability and reproducibility of the sensor were obtained in the acceptable range. The developed sensor was used to detect PlGF antigen in artificial blood and urine samples by spike recovery analysis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Preeclampsia (PE) is a systemic disease that affects 4.6% of pregnancies. Despite the existence of a first-trimester screening for the prediction of preterm PE, no consensus exists regarding neither the right moment to end the pregnancy nor the appropriate variables to estimate the prognosis. The objective of this study was to obtain a prediction model for perinatal death in patients with preterm PE, useful for clinical practice. Methods: Singleton pregnant women with PE and preterm delivery were included in an observational retrospective study. Multiple maternal and fetal variables were collected, and several multivariable logistic regression analyses were applied to construct models to predict perinatal death, selecting the most accurate and reproducible according to the highest area under the curve (AUC) and the lowest Akaike Information Criteria (AIC). Results: A group of 148 pregnant women were included, and 18 perinatal deaths were registered. Univariable logistic regression selected as statistically significant variables the following: gestational age (GA) at admission, fetal sex, poor response to antihypertensive drugs, PlGF, umbilical artery (UA) pulsatility index (PI), cerebroplacental ratio (CPR), and absent/reversed ductus venosus (DV). The multivariable model, including all these parameters, presented an AUC of 0.95 and an AIC of 76.5. However, a model including only GA and fetal sex presented a similar accuracy with the highest simplicity (AUC 0.93, AIC 67.6). Finally, in fetuses with a similar GA, fetal death became dependent on PlGF and fetal sex, underlying the role of fetal sex in all circumstances. Conclusions: Female fetal sex and low PlGF are notorious predictors of perinatal death in preterm PE, only surpassed by early GA at birth. [ABSTRACT FROM AUTHOR]

Objective • To explore the relationship between the expression of placental growth factor (PLGF) and Zeste homolog enhancer 2 (EZH2) in placental tissues of women with gestational diabetes (GDM), placental function, and pregnancy outcome. Methods • Select 100 women with GDM diagnosed in our hospital from January 2019 to May 2020 as the GDM group and 100 women with normal pregnancy at the same time as the control group. Detection and analysis of the expression levels of PLGF and EZH2 proteins in placental tissue after delivery of the two components. Observation of the expression of different PLGF and EZH2 proteins using an electron microscope, and analyze the ultrastructural changes in placental tissue of women with GDM. Finally, assess the differences in pregnancy outcomes. Results • The expression intensity of PLGF protein in the GDM group was higher than that in the control group (P < .001), and the expression intensity of EZH2 protein in the GDM group was lower than that in the control group (P < .001); the positive rate of PLGF protein in the GDM group was 67.00% higher than that of the control group 35.00% (P < .001), the positive rate of EZH2 protein in the GDM group was 15.00% lower than 33.00% in the control group (P = .003); the placental ultrastructural change rate of PLGF-positive GDM women was 71.64% higher than that in the negative expression group 45.45 % (P = .011); the placental ultrastructural change rate of EZH2 protein- positive GDM mothers was 33.33% lower than that of negative expression of A mixed 68.24% (P = .01); the incidence of premature infants (26.87%) and fetal respiratory distress (13.43%) in the PLGF-positive GDM group, the rate was higher than that in the negative expression group (9.09%, 0%) (P = .027, .04); the incidence of preterm infants in the EZH2 protein-positive GDM group (0.00%) was lower than that in the negative expression group (24.71%) (P = .03). Conclusion • The expression of PLGF is up-regulated and the expression of EZH2 is down-regulated in the placental tissue of GDM women, which causes ultrastructural changes in the placental tissue and increases the incidence of preterm birth and fetal respiratory distress to a certain extent. [ABSTRACT FROM AUTHOR]

Objective: To identify which components of maternal vascular malperfusion (MVM) pathology are associated with adverse pregnancy outcomes and to investigate the morphological phenotypes of MVM placental pathology and their relationship with distinct clinical presentations of pre‐eclampsia and/or fetal growth restriction (FGR). Design: Retrospective cohort study. Setting: Tertiary care hospital in Toronto, Canada. Population: Pregnant individuals with low circulating maternal placental growth factor (PlGF) levels (<100 pg/mL) and placental pathology analysis between March 2017 and December 2019. Methods: Association between each pathological finding and the outcomes of interest were calculated using the chi‐square test. Cluster analysis and logistic regression was used to identify phenotypic clusters, and their association with adverse pregnancy outcomes. Cluster analysis was performed using the K‐modes unsupervised clustering algorithm. Main outcome measures: Preterm delivery <34+0 weeks of gestation, early onset pre‐eclampsia with delivery <34+0 weeks of gestation, birthweight <10th percentile (small for gestational age, SGA) and stillbirth. Results: The diagnostic features of MVM most strongly associated with delivery <34+0 weeks of gestation were: infarction, accelerated villous maturation, distal villous hypoplasia and decidual vasculopathy. Two dominant phenotypic clusters of MVM pathology were identified. The largest cluster (n = 104) was characterised by both reduced placental mass and hypoxic ischaemic injury (infarction and accelerated villous maturation), and was associated with combined pre‐eclampsia and SGA. The second dominant cluster (n = 59) was characterised by infarction and accelerated villous maturation alone, and was associated with pre‐eclampsia and average birthweight for gestational age. Conclusions: Patients with placental MVM disease are at high risk of pre‐eclampsia and FGR, and distinct pathological findings correlate with different clinical phenotypes, suggestive of distinct subtypes of MVM disease. [ABSTRACT FROM AUTHOR]

Preeclampsia is a pregnancy syndrome characterized by complex symptoms which cause maternal and fetal problems and deaths. The aim of this study is to achieve preeclampsia risk prediction and early risk prediction in Xinjiang, China, based on the placental growth factor measured using the SiMoA or Elecsys platform. A novel reliable calibration modeling method and missing data imputing method are proposed, in which different strategies are used to adapt to small samples, training data, test data, independent features, and dependent feature pairs. Multiple machine learning algorithms were applied to train models using various datasets, such as single-platform versus bi-platform data, early pregnancy versus early plus non-early pregnancy data, and real versus real plus augmented data. It was found that a combination of two types of mono-platform data could improve risk prediction performance, and non-early pregnancy data could enhance early risk prediction performance when limited early pregnancy data were available. Additionally, the inclusion of augmented data resulted in achieving a high but unstable performance. The models in this study significantly reduced the incidence of preeclampsia in the region from 7.2% to 2.0%, and the mortality rate was reduced to 0%. [ABSTRACT FROM AUTHOR]

Introduction: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro‐inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process. Methods: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis‐related proteins (NLRP3, pro‐caspase1, caspase1, IL‐1β, and Gasdermin D [GSDMD]) as well as autophagy‐related proteins (LC3‐II, Beclin1, and p62) were examined by Western blotting. The GFP‐mRFP‐LC3‐II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN‐induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR‐8/SVneo cells. Results: Our results show that hyperglycemia upregulates NLRP3, pro‐caspase1, caspase1, IL‐1β at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta‐gal‐positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis‐related protein levels of NLRP3, pro‐caspase1, caspase1, IL‐1β, and GSDMD, Gasdermin D N‐terminal domain (GSDMD‐N). HG‐induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy. Conclusion: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first‐trimester screening for pre‐eclampsia in a large Asian population. Methods: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11–13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first‐trimester prediction of preterm pre‐eclampsia (<37 weeks), term pre‐eclampsia (≥37 weeks), and any pre‐eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. Results: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre‐eclampsia (0.82, 95% confidence interval [CI] 0.77–0.87 vs. 0.86, 95% CI 0.811–0.91, P = 0.019), term pre‐eclampsia (0.75, 95% CI 0.71–0.80 vs. 0.79, 95% CI 0.75–0.83, P = 0.006), and any pre‐eclampsia (0.78, 95% CI 0.74–0.81 vs. 0.82, 95% CI 0.79–0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre‐eclampsia, term pre‐eclampsia, and any pre‐eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80–0.89), 0.77 (95% CI 0.73–0.81), and 0.80 (95% CI 0.76–0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre‐eclampsia (P = 0.135) and term pre‐eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre‐eclampsia (P = 0.024). Conclusion: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre‐eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population. Synopsis: Machine learning model achieved comparable predictive performance to that of the FMF competing risk model in predicting preterm and term pre‐eclampsia in an Asian population. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality. This was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified. There were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively). MVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity. • MVM is the commonest placental abnormality in pregnancies complicated by FGR. • Early-onset FGR is more likely to have MVM abnormalities than late-onset disease. • MVM changes are associated with abnormal placental biomarkers and fetoplacental Dopplers. • Higher rates of hypertension and pre-eclampsia were seen in MVM, FVM, and CHI. • MVM, FVM, and CHI are strongly associated with adverse perinatal and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effects of the Galectin‐3 (Gal‐3) inhibitor TD139 on inflammation and the extracellular signal‐regulated kinase (ERK)/c‐Jun N‐terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF‐α, assessing Gal‐3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post‐delivery placental tissues were analyzed. Data were analyzed using one‐way or two‐way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF‐α‐induced increases in Gal‐3, IL‐1β, IL‐6, MCP‐1, and ERK/JNK/p38 activation in placental tissues. In STZ‐induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF‐α, IL‐1β, IL‐6, and MCP‐1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF‐α stimulated placental tissues and STZ‐induced GDM mice, suggesting its therapeutic potential for managing GDM‐related placental inflammation and improving pregnancy outcomes. The study used TNF‐α to mimic GDM in placental tissues and an STZ‐induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions To compare the diagnostic performance of different manufacturers' immunoassays for the soluble fms‐like tyrosine kinase‐1 (sFlt‐1)‐to‐placental growth factor (PlGF) ratio with that of a point‐of‐care test for glycosylated fibronectin (GlyFn) in women with suspected pre‐eclampsia (PE).This was a prospective, single‐center, double‐blinded, non‐interventional study of East Asian women with a singleton pregnancy who presented with hypertension with or without clinical features of PE after 20 weeks' gestation between January 2020 and March 2022. Maternal serum samples were collected at the time of presentation, and subsequent management followed the departmental protocol, based on gestational age, severity of hypertension, fetal condition and presence of severe PE features. Women diagnosed with PE at presentation were excluded. PE was diagnosed according to the 2018 International Society for the Study of Hypertension in Pregnancy classification. Levels of sFlt‐1 and PlGF were measured using the Cobas e411 (Roche Diagnostics), BRAHMS KRYPTOR (ThermoFisher Scientific) and iMAGIN 1800 (Ningbo‐Aucheer) platforms. GlyFn levels were measured using the Lumella™ GlyFn PoC test (Diabetomics). The predictive performance of each test to rule out PE within 7 days and rule in PE within 28 days from the date of presentation was assessed. Based on the PROGNOSIS study, a sFlt‐1/PlGF ratio of ≤ 38 on the Roche platform was used to predict the absence of PE within 7 days. The sFlt‐1/PlGF ratio was classified as high or low using platform‐specific thresholds equivalent to a Roche sFlt‐1/PlGF ratio of 38, which were derived using Passing–Bablok regression. GlyFn was categorized as high or low using two reported clinical management thresholds (263 μg/mL and 510 μg/mL).Overall, 236 women with suspected PE were included, of whom 70 (29.7%) were diagnosed with PE; 36 (51.4%) and 70 (100%) developed PE within 7 days and 28 days, respectively. Eighty‐eight (37.3%) women had a sFlt‐1/PlGF ratio of > 38 on the Roche platform, 79 (33.5%) women had a sFlt‐1/PlGF ratio of > 55 on the KRYPTOR platform and 96 (40.7%) women had a sFlt‐1/PlGF ratio of > 40 on the iMAGIN 1800 platform. Furthermore, 62 (26.3%) and four (1.7%) women had a GlyFn level of > 263 μg/mL and > 510 μg/mL, respectively. The negative predictive value (NPV) of the sFlt‐1/PlGF ratio measured on the Roche, KRYPTOR and iMAGIN 1800 platforms to rule out PE within 7 days after presentation was 83.3%, 82.0% and 82.9%, respectively, while that for GlyFn > 263 μg/mL and > 510 μg/mL was 82.6% and 70.4%, respectively. The corresponding positive predictive values (PPV) to rule in PE within 28 days after presentation were 50.5%, 52.3% and 46.7%, respectively, for the sFlt‐1/PlGF ratio, and 35.4% and 50.0%, respectively, for GlyFn > 263 μg/mL and > 510 μg/mL.The predictive performance of different manufacturers' assays for the sFlt‐1/PlGF ratio to rule in and rule out PE were similar once standardized to a common threshold. Our findings suggest that the sFlt‐1/PlGF ratio and GlyFn using a cut‐off of 263 μg/mL can both be utilized to rule out PE within 7 days after assessment, with a moderate NPV. The PPV for ruling in PE within 28 days remains poor. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of different drug treatments on uterine artery blood flow parameters, serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and sFlt-1/PLGF in patients with recurrent spontaneous abortion and to explore the predictive value of uterine artery blood flow parameters, serum PLGF, sFlt-1, and sFlt-1/PLGF for pregnancy outcomes. Methods: This retrospective cohort study included 173 patients who experienced recurrent spontaneous abortion and 100 control patients. Patients with recurrent spontaneous abortion were divided into an aspirin group (75 patients), aspirin combined with low molecular weight heparin (LMWH) group (68 patients), and non-drug group (30 patients) based on different drug treatments. Uterine artery blood flow parameters at gestational weeks 30-31+6 were monitored for the four groups, and serum samples were collected at gestational weeks 30-31+6 to measure the levels of serum PLGF and sFlt-1 and calculate the sFlt-1/PLGF ratio. Results: 1. Uterine artery blood flow parameters at gestational weeks 30-31+6 were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 2. Serum PLGF levels and the sFlt-1/PLGF ratio at gestational weeks 30-31+6 were significantly lower in the non-drug group than in the aspirin group, combined drug group, and control group, while serum sFlt-1 levels were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 3. Serum PLGF, sFlt-1, and sFlt-1/PLGF had lower diagnostic efficiency for predicting hypertensive disorders during pregnancy than the combined diagnostic efficiency of serum PLGF, sFlt-1, and sFlt-1/PLGF with uterine artery blood flow parameters at gestational weeks 30-31+6. Conclusion: Aspirin and aspirin combined with LMWH can upregulate serum PLGF and decrease serum sFlt-1 levels in patients with recurrent spontaneous abortion, reduce the miscarriage rate, and significantly improve pregnancy outcomes. The combination of serum PLGF, sFlt-1, sFlt-1/PLGF, and uterine artery blood flow parameters can effectively predict hypertensive disorders during pregnancy. [ABSTRACT FROM AUTHOR]

Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H 2 O 2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling. • PlGF overexpression leads to fibroblasts and cardiomyocytes activation under Angiotensin II. • SB203580 blocks the PlGF and Angiotensin II-induced fibroblast proliferation. • PlGF elevates ROS, NF- k B activation, and cytokine production in fibroblasts. • High PlGF levels may regulate cardiac remodeling via p38 MAPK/NF- k B pathways. [ABSTRACT FROM AUTHOR]

Objectives: During human pregnancy, placental extravillous trophoblasts replace vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling them into distensible low‐resistance vessels to promote placental perfusion. The present study determined whether B‐flow/spatiotemporal image correlation (STIC) M‐mode ultrasonography provides an in‐vivo imaging method able to digitally quantify spiral artery luminal distensibility as a physiological index of spiral artery remodeling during the advancing stages of normal human pregnancy. Methods: A prospective, longitudinal, observational study was conducted to quantify spiral artery distensibility (i.e. vessel luminal diameter at systole minus diameter at diastole) by B‐flow/STIC M‐mode ultrasonography during the first, second and third trimesters in 290 women exhibiting a normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1), growth factors that modulate important events in spiral artery remodeling, were quantified in a subset of the women in the first, second and third trimesters of pregnancy. Results: Median (interquartile range (IQR)) spiral artery distensibility increased progressively between the first (0.17 (0.14–0.21) cm), second (0.23 (0.18–0.28) cm) and third (0.26 (0.21–0.35) cm) trimesters of pregnancy (P < 0.0001 for all). Median (IQR) spiral artery volume flow increased progressively between the first (2.49 (1.38–4.99) mL/cardiac cycle), second (3.86 (2.06–6.91) mL/cardiac cycle) and third (7.79 (3.83–14.98) mL/cardiac cycle) trimesters (P < 0.001 for all). In accordance with the elevation in spiral artery distensibility, the median (IQR) ratio of serum PlGF/sFlt‐1 × 103 levels increased between the first (7.2 (4.5–10.0)), second (22.7 (18.6–42.2)) and third (56.2 (41.9–92.5)) trimesters (P < 0.001 for all). Conclusions: The present study shows that B‐flow/STIC M‐mode ultrasonography provides an in‐vivo imaging technology to quantify digitally the structural and physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

• Angiogenic biomarkers are important tools for the early prediction and diagnosis of preeclampsia. • Data from intervention trials do not support using angiogenic biomarkers for monitoring progressing of preeclampsia or deciding the timing of delivery. • There is insufficient evidence to recommend angiogenic biomarkers as an alternative to Doppler for surveillance and timing of delivery in fetal growth restriction. • Angiogenic biomarkers may have help differentiate between hypertension in chronic kidney disease from superimposed preeclampsia in pregnant women. Monitoring and timing of delivery in preterm preeclampsia and fetal growth restriction is one of the biggest challenges in Obstetrics. Finding the optimal time of delivery of these fetuses usually involves a trade-off between the severity of the disease and prematurity. So far, most clinical guidelines recommend the use of a combination between clinical, laboratory and ultrasound markers to guide the time of delivery. Angiogenic biomarkers, especially placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), have gained significant attention in recent years for their potential role in the prediction and diagnosis of placenta-related disorders including preeclampsia and fetal growth restriction. Another potential clinical application of the angiogenic biomarkers is for the differential diagnosis of patients with chronic kidney disease, as this condition shares similar clinical features with preeclampsia. Consequently, angiogenic biomarkers have been advocated as tools for monitoring and deciding the optimal time of the delivery of fetuses affected by placental dysfunction. In this clinical opinion, we critically review the available literature on PlGF and sFlt-1 for the surveillance and time of the delivery in fetuses affected by preterm preeclampsia and fetal growth restriction. Moreover, we explore the use of angiogenic biomarkers for the differentiation between chronic kidney disease and superimposed preeclampsia. [ABSTRACT FROM AUTHOR]

• The relationship between the sFlt-1/PlGF ratio and outcomes in early preeclampsia was examined. • Serious adverse outcomes within 1 week were associated with a higher sFlt-1/PlGF ratio. • A cutoff of ratio 224.6 predicted serious adverse outcomes (sensitivity 81 %, specificity 71 %). • Delivery within 1 week following testing was more common with a ratio ≥224.6. We aimed to determine whether a high ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) would be associated with serious negative consequences and shorter pregnancy duration in cases of early-onset preeclampsia (PE). This retrospective cohort study included women (n = 65) diagnosed with PE at <34.0 weeks of gestation and recruited from a single primary and tertiary medical centre in Japan. The sFlt-1/PlGF ratio in the study participants was measured. To determine the optimal threshold for the sFlt-1/PlGF ratio, a receiver operating characteristic curve was employed, with the aim of predicting serious adverse outcomes within 1 week after serum angiogenic marker measurements. We performed Kaplan–Meier analysis and the log-rank test to assess delivery probability based on the sFlt-1/PlGF ratio. Thirty-seven women (56.9 %) delivered within 1 week of serum angiogenic marker measurements due to the aggravation of early-onset preeclampsia. Women who developed serious adverse outcomes within 1 week had a significantly higher sFlt-1/PlGF ratio than that of women who did not develop serious complications (408.5 vs. 166.6, P < 0.001). A cut-off value of 224.6 for the sFlt-1/PlGF ratio predicted serious adverse outcomes, with a sensitivity of 81.1 % and a specificity of 71.4 % (area under the curve: 0.77). Moreover, 78.9 % of women with an sFlt-1/PlGF ratio ≥ 224.6 compared to 25.9 % of those with an sFlt-1/PlGF ratio < 224.6 delivered within 1 week of presentation (P < 0.001). Women with confirmed early-onset preeclampsia and high sFlt-1/PlGF ratio are more likely to develop serious adverse outcomes within 1 week after serum angiogenic marker measurements. [ABSTRACT FROM AUTHOR]

Pre-eclampsia, which mostly occurs often after 20 weeks of gestation, severely affects maternal and fetal health and is a major cause of increased maternal and perinatal mortality worldwide. Therefore, it is important to explore biomarkers that can expedite the diagnosis of preeclampsia. Establishing a diagnostic model for preeclampsia in early and mid-pregnancy is a top priority for reducing maternal and infant mortality. In this article, we review the pathogenesis of pre-eclampsia and the clinical application of angiogenic markers such as placental growth factor, with the aim of improving the early diagnosis of pre-eclampsia and reducing the risk of maternal complications and perinatal morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women. Methods: We conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM. Results: Of the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68--0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929). Conclusion: Downregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM. [ABSTRACT FROM AUTHOR]

After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE. [ABSTRACT FROM AUTHOR]

Anti-Mullerian hormone (AMH) has been implicated in the pathogenesis of preeclampsia. The present study was primarily designed to determine the placental tissue AMH, Anti-Mullerian hormone Receptor II (AMHRII), vascular endothelial growth factor (VEGF) and microRNA (miRNA) 26a/126/155/210 expressions and serum miRNA 26a/126/155/210 levels in patients with preeclampsia to examine their potential role in the pathogenesis of preeclampsia. Placental tissue samples from patients with preeclampsia (n = 20) and control subjects (n = 20) were examined by immunohistochemical staining and quantitative polymerase chain reaction (qPCR) for AMH, AMHRII, VEGF mRNA expression levels and miRNA 26a/126/155/210 expressions. Serum levels of miRNA 26a/126/155/210 were measured by qPCR. Patients with preeclampsia had lower AMH/AMHRII immunostaining, particularly in syncytiotrophoblastic cells compared to control subjects (p < 0.05). The relative mRNA expressions of AMH/AMHRII were increased (1.535 ± 0.121 and 1.155 ± 0.049 fold, p < 0.0002 and p < 0.033, respectively) and the relative mRNA expression of VEGF was decreased (4.878 ± 0.331 fold, p < 0.0002) in patients with preeclampsia compared to control subjects. The miR-26a expression was increased and miR-126 expression was decreased in serum samples of patients with preeclampsia compared to control subjects (p < 0.0002). miR-155 and miR-210 expressions were increased in serum and placental tissue samples of patients with preeclampsia compared to control subjects (p < 0.0002). In conclusion, reduced placental tissue immunostaining of AMH/AMHRII along with increased AMH/AMHRII mRNA expressions may indicate posttranscriptional dysregulation. Robust increase in expressions of hypoxia/inflammation-related miRNAs particularly miR-155 and miR-210 might have a role in this mechanistic pathway. Increased serum levels of miR 26a, 155 and 210 are potential early diagnostic markers for preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: Analysis of serum three acyl glycerin (TAG), oxidized modified low density lipoprotein (OX-LDL) and placental growth factor (PLGF) with preeclampsia disease progression and the relationship between the risk of spontaneous abortion. Methods: A total of 120 pregnant women with preeclampsia (observation group) and 120 pregnant women with normal pregnancy test results (control group) admitted to our hospital from February 2022 to February 2023 were selected as research objects. The expression levels of serum TAG, OX-LDL and PLGF in all pregnant women were detected, and the progress of preeclampsia was recorded. More progress with stable condition group TAG,OX-LDL, serum PLGF expression level indicators and uterine artery blood flow mechanics. Using multiariable Logistic regression analysis of serum TAG, OX-LDL, PLGF and preeclampsia progression, the relationship between the receiver-operating characteristic curve (ROC) analysis of serum TAG, OX-LDL and PLGF to preeclampsia prediction to miscarry. Results: Observation group TAG, OX-LDL is higher than the control group, serum PLGF level lower than the control group, (P＜0.05). Progression group serum TAG, OX-LDL level group were higher than in a stable condition and PLGF level under stable condition group (P＜0.05). The multi-factor Logistic regression analysis, TAG, OX-LDL, serum PLGF were preeclampsia is an independent predictor of disease progression (P＜0.05). Progression group of uterine artery pulsation index (PI), resistance index (RI), systolic and diastolic blood flow velocity ratio (S/D) were greater than in a stable condition group (P＜0.05). The Pearson correlation analysis, preeclampsia pregnant uterine artery PI, RI and S/D and serum TAG, OX-LDL expression levels were positively correlated (P＜0.05), and negatively correlated to the level of PLGF (P＜0.05). According to ROC curve analysis, the AUC of serum TAG, OX-LDL combined with PLGF in predicting abortion of preeclampsia pregnant women was 0.908, which was greater than 0.648 of TAG, 0.660 of OX-LDL and 0.673 of PLGF (P＜0.05). Conclusion: Serum TAG, OX-LDL and PLGF are closely related to the progression of preeclampsia. The combined application has a certain predictive value for abortion and is worthy of clinical attention. [ABSTRACT FROM AUTHOR]

Background Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management. Methods Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15 ml/min/1.7 m2) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek® panels and 119   765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied. Results We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3), and a newly discovered miRNA—mRNA pair (MIR1205–DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease. Conclusions These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment. [ABSTRACT FROM AUTHOR]

Aims: Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt‐1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. Methods and results: ELISA assays for sFlt‐1, PlGF and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt‐1 or PlGF levels were genotyped. sFlt‐1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All‐cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt‐1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt‐1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt‐1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57–16.1; p < 0.001) in PEOPLE, independent of age, NT‐proBNP, ischaemic aetiology, diabetic status and beta‐blocker therapy. Conclusions: Plasma sFlt‐1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF. [ABSTRACT FROM AUTHOR]

• The diagnosis of fetal growth restriction (FGR) due to uteroplacental insufficiency improves perinatal outcome. • Using angiogenic markers to diagnose small for gestational age fetuses can enhance the current diagnostic FGR consensus. • Further studies are needed to integrate angiogenic markers into ultrasound parameters currently used for FGR diagnosis. The identification of fetal growth restriction (FGR) due to uteroplacental insufficiency is important to improve perinatal outcomes. To distinguish FGR from small for gestational age (SGA), FGR consensus definition is currently based on biometry and/or additional biophysical parameters. This study aims to verify if this definition might be modified by including circulating angiogenic factors. This historical cohort study included singleton pregnancies with SGA fetuses after 20 weeks. All patients underwent detailed ultrasound and measurements of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) at first assessment. ISUOG criteria for FGR were applied. Total PlGF was calculated using free PlGF, sFlt-1 and a receptor pharmacology model, and multiple of the median (MoM) values for sFlt-1, free PlGF, total PlGF and sFlt-1/PlGF ratio were calculated to adjust for gestational age. 72 pregnancies with SGA were first evaluated at median (IQR) of 28+5 (26+2 –31+3) weeks' gestation, and 51 fetuses (70.8 %) satisfied the FGR consensus definition. Pregnancies with FGR showed significantly lower levels of free and total PlGF MoM (0.12, 95 % IQR: 0.07–0.36 vs 0.32, 95 % IQR: 0.20–0.53, p = 0.008) and 0.26, 95 % CI: 0.16–0.55 vs 0.43, 95 % IQR: 0.23–0.53, p = 0.028) respectively; and higher sFlt-1 MoM (4.62, 95 % IQR: 1.80–7.30 vs 1.74, 95 % IQR:1.11–3.61, p = 0.014) than pregnancies not classified as FGR. Free and total PlGF MoM correlated significantly with gestational age at delivery (r = 0.776, p < 0.001 and r = 0.707, p < 0.001, respectively). sFlt-1 MoM and sFlt-1/PlGF ratio MoM also correlated with gestational age at delivery (r = -0.681, p < 0.001 and r = -0.823, p < 0.001). Six cases identified as FGR at first ultrasound were not confirmed at birth showing significantly higher levels of free PlGF MoM (0.77, 95 % IQR: 0.27–3.07 vs 0.17, 95 % IQR: 0.08–0.43, p = 0.022). These findings show that total as well as free PlGF levels are lower in pregnancies affected with placental growth restriction. Angiogenic biomarkers might improve the differentiation between placental growth restriction and constitutional smallness. Further studies are needed to determine how to integrate them into the current definitions of FGR. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether angiogenic markers of placental function are associated with maternal cardiac function and hemodynamic responses at 19–23 weeks' gestation, controlling for maternal risk factors and pregnancy complications. Methods: This was a prospective study of women with singleton pregnancy attending King's College Hospital, London, UK, for a routine hospital visit at 19–23 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure (MAP), maternal heart rate, serum placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1). We also performed maternal echocardiography to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. Results: Our cohort included 4006 women. Lower PlGF values were significantly associated with higher MAP (P < 0.0001), lower maternal heart rate (P < 0.0001), lower mitral valve s′ mean velocity (P = 0.027) and higher left atrial area (P = 0.022) after adjustment for maternal characteristics and pregnancy complications. sFlt‐1 was associated positively with relative wall thickness (P = 0.012), whereas sFlt‐1/PlGF ratio was associated negatively with mitral valve A (P = 0.006) and positively with left atrial area (P = 0.015) and MAP (P = 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors based on their obstetric and medical history. Conclusions: A continuous association of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present in midgestation, independently of pre‐existing maternal risk factors and pregnancy complications. Impaired placental function appears to be related to mild systolic and diastolic dysfunction and cardiac remodeling. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background and Aims: Preeclampsia poses a heightened risk for women, particularly in the development of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, leading to adverse outcomes for both mothers and newborns. The incidence of HELLP syndrome tends to be notably higher among women with preeclampsia compared with those with normotensive pregnancies. However, there is a dearth of research on the frequency of HELLP syndrome within the context of preeclampsia specifically in Ghana. Furthermore, the potential predictive value of serum erythrocyte adenylate kinase (EAK), a marker of hemolysis, in anticipating the onset of preeclampsia remains largely unexplored. Methods: Conducted between May 2020 and April 2022, this research employed a case‐control methodology at the War Memorial and Upper East Regional Hospitals. A total of 291 pregnant women participated, comprising 111 diagnosed with preeclampsia and 180 control subjects, aged between 18 and 43 years. Venous blood samples were collected and subjected to analysis for platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and EAK, utilizing automated analyzers, alongside the ELISA technique. Diagnosis of HELLP syndrome was established using the Mississippi triple‐class definition. Results: The median serum ALT level (with interquartile range) was significantly elevated in the preeclampsia group compared with controls [20.0 (13.7–27.0) vs. 13.0 (9.4–18.6); p < 0.001]. Moreover, the frequency of Mississippi class 3 HELLP syndrome was notably higher among preeclampsia cases (2/111; 1.8%) compared with controls (1/180; 0.6%). Serum ALT emerged as the superior predictor of preeclampsia, outperforming LDH (with an area under the curve of 0.73 compared with 0.58). The sensitivity and specificity of ALT were measured at 47.8% and 87.2%, respectively. Conclusion: Although the occurrence of HELLP syndrome in preeclampsia cases appears relatively low, it may escalate as the prevalence of preeclampsia is anticipated to rise in low and middle‐income nations. [ABSTRACT FROM AUTHOR]

Background: Prediction of preeclampsia in first trimester can lead to early initiation of preventative measures, as well as timely therapeutic intervention, that will prevent the maternal and perinatal morbidity and mortality. This study, prediction of preeclampsia at 11-13+6 weeks of gestation, was conducted by using serum placental growth factor (PlGF), serum pregnancy associated plasma protein – A (PAPP-A), uterine artery Doppler indices, and mean arterial pressure (MAP), in low-risk pregnant women. Methods: It is an observational longitudinal prospective study. Pregnant women with singleton pregnancies of gestational age 11-13+6 weeks were recruited. MAP, bilateral uterine artery Doppler indices, serum PAPP-A, and PlGF were measured. The follow-up of the patients was regularly done till termination of pregnancy and incidence of preeclampsia were noted. Qualitative variables were compared using Chi-square/Fisher exact test, and sensitivity and specificity of each test were analyzed. Result: Among 139 women, 27 (19%) developed preeclampsia, out of which 10 had early preeclampsia and 17 developed late preeclampsia. By combining all the parameters, the sensitivity in detecting early preeclampsia was found to be 70% and for late preeclampsia cases, 64.7%. The sensitivity of all the parameters in predicting cases of preeclampsia in general is 66.7%, specificity is 74.1%, PPV is 38.3%, and NPV is 72%. Conclusion: The maternal biomarkers serum PAPP-A, serum PlGF, uterine artery PI, MAP have sensitivity of 70% in detecting early preeclampsia cases and for late preeclampsia cases, 64.71%, in first trimester and it will help in early initiation of preventative measures as well as timely therapeutic intervention.

Background: Prediabetes (PD) is associated with intermediate hyperglycemia, dyslipidaemia, reduced nitric oxide (NO) bioavailability and moderate hypertension. All these factors are risk factor for preeclampsia (PE). However, the effects of the PD on placental function have not been shown. Accordingly, this study sought to investigate a possible link between maternal PD and the risk of developing PE. Methods: Pregnant female Sprague-Dawley rats (N = 18) were divided into normal, preeclamptic and prediabetic groups (n = 6 in each group) to study the effects of maternal PD on placenta function over the period of 19 days. Blood glucose and blood pressure were measured on gestational day (GND) 0, 9 and 18. Placental vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) mRNA expression were measured terminally. Data were analysed using ANOVA followed by the Tukey-Kramer post hoc test. Values of p < .05 were used to indicate statistical significance. Results: Maternal PD and PE significantly increased blood glucose, decrease NO concentration and increase in MAP by comparison to the normal pregnant control group. Maternal PD significantly decreased VEGF, PlGF mRNA expression with a slight increase in sFlt-1 mRNA expression comparison to the normal pregnant control group. Conclusions: Maternal PD is associated with placental dysfunction due to impaired glucose handling, endothelial dysfunction and an imbalance in angiogenic and antiangiogenic factors. Therefore, maternal PD is a risk factor of PE. [ABSTRACT FROM AUTHOR]

Introduction: Effect of physical activity in pregnancy on preeclampsia (PE) and angiogenic markers is not well understood. We studied the association of physical activity and PE in a case-control setting and assessed whether exercise in PE and non-PE women associate with maternal serum concentrations of soluble fms-like tyrosine kinase 1 (s-Flt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and sFlt-1/PlGF ratio in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort. Materials and methods: Participants completed a questionnaire on their background information and serum samples were collected from a subset. Questionnaire data on physical activity were available from 708 PE women and 724 non-PE women. Both first trimester serum samples and questionnaire data on physical activity were available from 160 PE women and 160 non-PE women, and second/third trimester serum samples and questionnaire data on physical activity were available from 139 PE women and 47 non-PE women. The PE and non-PE women were divided into categories of physically active (exercise 2-3 times/week or more) and physically inactive (exercise less than 2-3 times/week). Results: A total of 43.4% of the PE women and 42.4% of the non-PE women were categorized as physically active. There were no differences in physical activity and exercise habits between the groups. The physically active women were more often nulliparous and non-smokers and had a lower body mass index. There were no differences in the concentrations of angiogenic markers (sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio) between the groups who exercised more or less than 2-3 times/week. Conclusions: In the FINNPEC study cohort, there was no association between physical activity and PE and no associations of physical activity in pregnant women with and without PE with maternal serum concentrations of sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio. [ABSTRACT FROM AUTHOR]

• We have used a modified e-Delphi study to prioritise risk factors for stillbirth prediction in early pregnancy. • Prioritised maternal characteristics include age, smoking, drug misuse, heritable thrombophilia, hypertension, renal disease, and diabetes. • Prioritised maternal characteristics related to pregnancy history include previous stillbirth, and multiple pregnancy. • Prioritised ultrasound markers for stillbirth prediction are uterine artery Doppler pulsatility index and congenital fetal anomaly. • Placental growth factor is the only prioritised biochemical marker for stillbirth prediction. To identify and prioritise early pregnancy risk factors for stillbirth to inform prognostic factor and model research. We used a modified e-Delphi method and consultation meeting to achieve consensus. Risk factors for early, late and stillbirth at any gestation identified from an umbrella review of risk factors for stillbirth were entered into a two-stage online Delphi survey with an international group of stakeholders made up of healthcare professionals and researchers. The RAND/ University of California at Los Angeles appropriateness method was used to evaluate consensus. Responders voted on a scale of 1–9 for each risk factor in terms of importance for early, late, and stillbirth at any gestation. Consensus for inclusion was reached if the median score was in the top tertile and at least two thirds of panellists had scored the risk factor within the top tertile. Twenty-six risk factors were identified from an umbrella review and presented to stakeholders in round 1 of our e-Delphi survey. Round 1 was completed by 68 stakeholders, 79% (54/68) of whom went on to complete the second round. Seventeen risk factors were discussed at the consensus meeting. From the twenty-six risk factors identified, fifteen of these were prioritised for stillbirth at any gestation, eleven for early stillbirth, and sixteen for late stillbirth, across three domains of maternal characteristics, ultrasound markers and biochemical markers. The prioritised maternal characteristics common to early, late, and stillbirth at any gestation were: maternal age, smoking, drug misuse, history of heritable thrombophilia, hypertension, renal disease, diabetes, previous stillbirth and multiple pregnancy. Maternal BMI, access to healthcare, and socioeconomic status were prioritised for late stillbirth and stillbirth at any gestation. Previous pre-eclampsia and previous small for gestational age baby were prioritised for late stillbirth. Of the ultrasound markers, uterine artery Doppler pulsatility index and congenital fetal anomaly were prioritised for all. One biochemical marker, placental growth factor, was prioritised for stillbirth at any gestation. Our prioritised risk factors for stillbirth can inform formal factor-outcome evaluation of early pregnancy risk factors to influence public health strategies on prevention of such risk factors to prevent stillbirth. [ABSTRACT FROM AUTHOR]

Background Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. Methods We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per.1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. Results The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were −5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity,.70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were −20% for the upper limit of TSH and −15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. Conclusion We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits. [ABSTRACT FROM AUTHOR]

Abstract Background Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. Methods Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24–28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (

Background: Hypertensive disorders of pregnancy are becoming the leading cause of maternal morbidity and mortality worldwide and are responsible for 9–25% of deaths 1. They are believed to occur due to an imbalance between pro-angiogenic factors, like placental growth factor (PlGF) and anti-angiogenic factors, like soluble fms-like tyrosine kinase-1 (sFLT-1). Aims and Objectives: The aim of the study was to evaluate the role of the sFLT-1/PlGF ratio along with uterine artery Doppler for the prediction of pre-eclampsia (PE). Materials and Methods: The current study was a prospective case–control study conducted at Sri Ramachandra Medical College and Hospital, Chennai, from 2018 to 2020. Blood samples for sFLT-1 and PlGF and uterine artery Doppler were done in 100 pregnant mothers who are at 16–20-week gestation attending antenatal outpatient department in the Department of Obstetrics and Gynecology. Results: We found that the mean sFLT-1 in high-risk group was 826.17 ng/L (standard deviation [SD]±251.31) compared to 924.69 ng/L (SD±360.61) in low-risk groups. The mean PlGF in the high-risk group was 23.07 ng/L (SD±4.68) compared to 27.43 ng/L (SD±5.62) in low-risk group. The mean sFLT-1/PlGF ratio was increased in high-risk group of about 39.68 (SD±22.77) compared to 35 (SD±16.98) in low-risk group. Women with high resistance uterine artery Doppler have 8.5 odds of getting PE compared to those with normal uterine artery Doppler. Conclusion: According to our study, the sFLT-1/PlGF ratio carries more sensitivity (90%) and negative predictive value (74.19%) if we keep the value as 32.25 along with uterine Doppler rather than their individual values for the prediction of PE.

Context: Pre-eclampsia is a pregnancy-related condition characterized by hypertension, proteinuria, and edema occurring after 20 weeks of pregnancy or during the postpartum period. Several markers are often assessed to determine the suitable option for confirming pre-eclampsia diagnosis, one of which is the examination of placental growth factor (PlGF) as a placental ischemia indicator. Aims: To evaluate the impact of prenatal yoga on PlGF and mean arterial pressure (MAP) levels in pre-eclampsia within the Madura region. Methods: A randomized controlled trial was conducted on fifty subjects that were randomly allocated to the experimental group with pre-post control groups consisting of 50 participants, namely 25 pregnant women with pre-eclampsia and 25 healthy individuals. The selection was conducted based on the following inclusion criteria: belonging to Madura ethnicity spanning three generations, exhibiting pregnancy duration >20 weeks, maternal ages ranging from 20–35 years, pre-pregnancy body mass index (BMI) >25, a history of hypertension, diabetes mellitus (DM), kidney disorders, pre-eclampsia, chronic hypertension, or family history of chronic high blood pressure and pre-eclampsia among those at risk. PlGF levels were estimated using an ELISA kit, while blood pressure was measured with an Omron brand sphygmomanometer. Results: Statistical analysis performed with the Wilcoxon sign test and T-test indicated significant differences (p

Syncytins are endogenous retroviral envelope proteins which induce the fusion of membranes. A human representative of this group, endogenous retrovirus group W member 1 envelope (ERVW-1) or syncytin-1 is present in trophoblast-derived extracellular vesicles and supports the incorporation of these extracellular vesicles into recipient cells. During pregnancy, placenta-derived extracellular vesicles participate in feto-maternal communication. Bovine fetal binucleate trophoblast cells express the syncytin, bovine endogenous retroviral envelope protein K1 (BERV-K1). These cells release extracellular vesicles into the maternal stroma, but it is unclear whether BERV-K1 is included in these extracellular vesicles. Here, extracellular vesicles were isolated from bovine placental tissue using collagenase digestion, ultracentrifugation, and size exclusion chromatography. They were characterized with transmission electron microscopy, nanoparticle tracking analysis, immunoblotting and mass spectrometry. Immunohistochemistry and immunoelectron microscopy were used to localize BERV-K1 within the bovine placental tissue. The isolated extracellular vesicles range between 50 and 300 nm, carrying multiple extracellular vesicle biomarkers. Proteomic analysis and immunoelectron microscopy confirmed BERV-K1 presence on the isolated extracellular vesicles. Further, BERV-K1 was localized on intraluminal vesicles in secretory granules of binucleate trophoblast cells. The presence of BERV-K1 on bovine placental extracellular vesicles suggests their role in feto-maternal communication and potential involvement of BERV-K1 in uptake of extracellular vesicles by target cells. • Extracellular vesicles (EVs) were isolated from bovine caruncular tissue. • EVs from bovine caruncular tissue carry the fusogenic bovine endogenous retroviral envelope protein K1 (BERV-K1). • BERV-K1 is more expressed around stem villi than terminal villi at midgestation. • Before parturition, the distribution of BERV-K1 is more evenly distributed between stem villi and terminal placental villi. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusion To compare the temporal changes in mean arterial pressure (MAP), uterine artery pulsatility index (UtA‐PI), placental growth factor (PlGF), and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) across gestation between assisted reproductive technology (ART) pregnancies complicated with great obstetrical syndromes (GOS) or gestational diabetes (GDM) ± large‐for‐gestational‐age (LGA) fetus, and uncomplicated ART pregnancies.This was a prospective longitudinal study of 143 women with singleton pregnancies who conceived through ART at the Department of Obstetrics and Gynecology, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong SAR between December 2017 and January 2020. The participants were followed up at 6–6+3, 11–13+6, 20–24+6, 30–34+6, and 35–37+6 weeks for the measurement of MAP, UtA‐PI, PlGF, and sFlt‐1. A linear mixed‐effects analysis was performed to compare the biomarkers in the GOS, GDM ± LGA, and uncomplicated groups across gestation.Thirty‐three (23.1%) and fifty‐five (31.5%) women were diagnosed with GOS and GDM ± LGA, respectively. The GOS group had higher estimated marginal mean log10 MAP mulitples of the median (MoM) across gestation, compared with the uncomplicated group (0.00771 vs −0.02022; P < 0.001), when adjusting for clinical visits and days of embryo transfer. The absolute mean log10 MAP MoM in the GOS group was found to be significantly higher than that of the uncomplicated group at all clinical visits from 6 weeks onwards. Furthermore, the estimated marginal mean log10 PlGF MoM was significantly lower in the GOS group across gestation, compared with the uncomplicated group (−0.04226 vs 0.05566; P = 0.010). The significant difference in log10 PlGF MoM was observed from 11–13+6 to 30–34+6 week of gestation (P < 0.05). However, no significant differences in the estimated marginal means of log10 UtA‐PI MoM and log10 sFlt‐1 MoM between GOS and uncomplicated groups were observed. GDM ± LGA group had a lower estimated marginal mean log10 PlGF MoM throughout pregnancy compared with the uncomplicated group (−0.01536 vs 0.05572; P = 0.032). In the individual visit analysis, the significant difference was observed at the 20–24+6 and 35–37+6 weeks visits (P < 0.05). There were no significant differences in estimated marginal mean log10 MoM of MAP, UtA‐PI, and sFlt‐1 between GDM ± LGA and uncomplicated groups during pregnancy.Our study has revealed that among pregnancies conceived through ART, GOS is associated with higher MAP and lower PlGF from early gestation until late third trimester, while GDM ± LGA is associated with lower PlGF during the second half of pregnancy. The same degree of differences in MAP and PlGF persists from early until late gestation in the GOS group and these findings highlight the importance of early screening during the first trimester to identify women who are at risk for developing GOS following ART procedures. Lastly, the potential of PlGF in predicting the development of GDM from the second trimester of pregnancy requires further investigation. [ABSTRACT FROM AUTHOR]

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13's role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10−4 M) and guanylate cyclase (ODQ at 10−5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on the activation of the nitric oxide–cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a pregnancy disorder associated with short‐ and long‐term adverse outcomes in both mothers and infants. The current clinical test of blood glucose levels late in the second trimester is inadequate for early detection of GDM. Here we show the utility of Raman spectroscopy (RS) for rapid and highly sensitive maternal metabolome screening for GDM in the first trimester. Key metabolites, including phospholipids, carbohydrates, and major amino acids, were identified with RS and validated with mass spectrometry, enabling insights into associated metabolic pathway enrichment. Using classical machine learning (ML) approaches, we showed the performance of the RS metabolic model (cross‐validation AUC 0.97) surpassed that achieved with patients' clinical data alone (cross‐validation AUC 0.59) or prior studies with single biomarkers. Further, we analyzed novel proteins and identified fetuin‐A as a promising candidate for early GDM prediction. A correlation analysis showed a moderate to strong correlation between multiple metabolites and proteins, suggesting a combined protein‐metabolic analysis integrated with ML would enable a powerful screening platform for first trimester diagnosis. Our study underscores RS metabolic profiling as a cost‐effective tool that can be integrated into the current clinical workflow for accurate risk stratification of GDM and to improve both maternal and neonatal outcomes. [ABSTRACT FROM AUTHOR]

In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion To evaluate the accuracy of combined models of maternal biophysical factors, ultrasound, and biochemical markers for predicting stillbirths.A retrospective cohort study of pregnant women undergoing first‐trimester pre‐eclampsia screening at 11–13 gestational weeks was conducted. Maternal characteristics and history, mean arterial pressure (MAP) measurement, uterine artery pulsatility index (UtA‐PI) ultrasound, maternal ophthalmic peak ratio Doppler, and placental growth factor (PlGF) serum were collected during the visit. Stillbirth was classified as placental dysfunction‐related when it occurred with pre‐eclampsia or birth weight <10th percentile. Combined prediction models were developed from significant variables in stillbirths, placental dysfunction‐related, and controls. We used the area under the receiver‐operating‐characteristics curve (AUC), sensitivity, and specificity based on a specific cutoff to evaluate the model's predictive performance by measuring the capacity to distinguish between stillbirths and live births.There were 13 (0.79%) cases of stillbirth in 1643 women included in the analysis. The combination of maternal factors, MAP, UtA‐PI, and PlGF, significantly contributed to the prediction of stillbirth. This model was a good predictor for all (including controls) types of stillbirth (AUC 0.879, 95% CI: 0.799–0.959, sensitivity of 99.3%, specificity of 38.5%), and an excellent predictor for placental dysfunction‐related stillbirth (AUC 0.984, 95% CI: 0.960–1.000, sensitivity of 98.5, specificity of 85.7).Screening at 11–13 weeks' gestation by combining maternal factors, MAP, UtA‐PI, and PlGF, can predict a high proportion of stillbirths. Our model has good accuracy for predicting stillbirths, predominantly placental dysfunction‐related stillbirths. [ABSTRACT FROM AUTHOR]

Purpose: Preeclampsia (PE) is one of the most common and serious complications of pregnancy, and novel methods for the early prediction of PE are needed for clinical application. Methods: In this study, a circulating cell-free RNA (cfRNA) panel of target genes for PE prediction was designed and validated in a case–control cohort and a nested case–control cohort. The QPCR was applied to quantify the copy number of cfRNA, and the data were normalized as multiples of the median. Ratios of serum placental growth factor (PIGF) and soluble fms-like tyrosine kinase 1 (sFLT-1) were also measured, and transabdominal ultrasonography was conducted for subjects in the prospective cohort. Binary logistic regression models for PE prediction were constructed and tested. Results: Our results revealed that the women with PE showed significant alterations in serum cfRNA profiles from early pregnancy onward and before the onset of PE symptoms. Compared with PIGF/sFLT-1 measurement and ultrasonographic imaging, cfRNA test can detect PE at a very early stage of pregnancy. The predictive model exhibited the best performance at gestation week 32, with a detection rate of 100%. At 12 weeks of gestation, the model still manifested an area under curve (AUC) of 0.9144, and sensitivity of 1.0000. If combined with clinical parameters and ultrasonographic indicators, the model can achieve the highest AUC for PE prediction at early gestation. Conclusion: Measurement of cfRNA can be used to effectively predict PE with high performance, providing an additional method for monitoring PE throughout the course of pregnancy. [ABSTRACT FROM AUTHOR]

Objective: To assess the utility of placental growth factor (PlGF) levels and the soluble fms‐like tyrosine kinase‐1/placental growth factor (sFlt‐1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). Design: Prospective, observational cohort study. Setting: Tertiary maternity hospital in Australia. Population: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). Methods: Maternal serum PlGF and sFlt‐1/PlGF ratio were measured at 4‐weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt‐1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt‐1/PlGF ratio to the time of birth or censoring. Main outcome measures: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. Results: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt‐1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt‐1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt‐1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt‐1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48–175.46). Conclusions: Low maternal PlGF levels and elevated sFlt‐1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies. [ABSTRACT FROM AUTHOR]

BACKGROUND With increasing significance of developmental programming effects associated with placental dysfunction, more investigations are devoted to improving the characterization and understanding of placental signatures in health and disease. The placenta is a transitory but dynamic organ adapting to the shifting demands of fetal development and available resources of the maternal supply throughout pregnancy. Trophoblasts (cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts) are placental-specific cell types responsible for the main placental exchanges and adaptations. Transcriptomic studies with single-cell resolution have led to advances in understanding the placenta's role in health and disease. These studies, however, often show discrepancies in characterization of the different placental cell types. OBJECTIVE AND RATIONALE We aim to review the knowledge regarding placental structure and function gained from the use of single-cell RNA sequencing (scRNAseq), followed by comparing cell-type-specific genes, highlighting their similarities and differences. Moreover, we intend to identify consensus marker genes for the various trophoblast cell types across studies. Finally, we will discuss the contributions and potential applications of scRNAseq in studying pregnancy-related diseases. SEARCH METHODS We conducted a comprehensive systematic literature review to identify different cell types and their functions at the human maternal–fetal interface, focusing on all original scRNAseq studies on placentas published before March 2023 and published reviews (total of 28 studies identified) using PubMed search. Our approach involved curating cell types and subtypes that had previously been defined using scRNAseq and comparing the genes used as markers or identified as potential new markers. Next, we reanalyzed expression matrices from the six available scRNAseq raw datasets with cell annotations (four from first trimester and two at term), using Wilcoxon rank-sum tests to compare gene expression among studies and annotate trophoblast cell markers in both first trimester and term placentas. Furthermore, we integrated scRNAseq raw data available from 18 healthy first trimester and nine term placentas, and performed clustering and differential gene expression analysis. We further compared markers obtained with the analysis of annotated and raw datasets with the literature to obtain a common signature gene list for major placental cell types. OUTCOMES Variations in the sampling site, gestational age, fetal sex, and subsequent sequencing and analysis methods were observed between the studies. Although their proportions varied, the three trophoblast types were consistently identified across all scRNAseq studies, unlike other non-trophoblast cell types. Notably, no marker genes were shared by all studies for any of the investigated cell types. Moreover, most of the newly defined markers in one study were not observed in other studies. These discrepancies were confirmed by our analysis on trophoblast cell types, where hundreds of potential marker genes were identified in each study but with little overlap across studies. From 35 461 and 23 378 cells of high quality in the first trimester and term placentas, respectively, we obtained major placental cell types, including perivascular cells that previously had not been identified in the first trimester. Importantly, our meta-analysis provides marker genes for major placental cell types based on our extensive curation. WIDER IMPLICATIONS This review and meta-analysis emphasizes the need for establishing a consensus for annotating placental cell types from scRNAseq data. The marker genes identified here can be deployed for defining human placental cell types, thereby facilitating and improving the reproducibility of trophoblast cell annotation. [ABSTRACT FROM AUTHOR]

• Women with moderate-severe depressive symptoms in late pregnancy have lower placental QPRT and ACMSD expression. • Low expression of placental IDO and QPRT associates with increased IL-6 levels and QUIN/KYNA ratio in maternal plasma. • Interactions between placental enzyme expression and peripheral cytokine and metabolite patterns differ in depressed women. Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy. 68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes. Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation. Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a pregnancy-specific disorder associated with shallow invasion of the trophoblast cells and insufficient remodeling of the uterine spiral artery. Protein glycosylation plays an important role in trophoblast cell invasion. However, the glycobiological mechanism of PE has not been fully elucidated. In the current study, employing the Lectin array, we found that soybean agglutinin (SBA), which recognizes the terminal N-acetylgalactosamine α1,3-galactose (GalNAc α1,3 Gal) glycotype, was significantly increased in placental trophoblast cells from PE patients compared with third-trimester pregnant controls. Upregulating the expression of the key enzyme α1,3 N-acetylgalactosaminyl transferase (GTA) promoted the biosynthesis of terminal GalNAc α1,3 Gal and inhibited the migration/invasion of HTR8/SVneo trophoblast cells. Moreover, the methylation status of GTA promoter in placental tissues from PE patients was lower than that in the third trimester by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) analysis. Elevated GTA expression in combination with the DNA methylation inhibitor 5-azacytidine (5-AzaC) treatment increased the glycotype biosynthesis and impaired the invasion potential of trophoblast cells, leading to preeclampsia. This study suggests that elevated terminal GalNAc α1,3 Gal biosynthesis and GTA expression may be applied as the new markers for evaluating placental function and the auxiliary diagnosis of preeclampsia. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy. Herein, an EGFR antibody-conjugated LNP (aEGFR-LNP) platform was developed by engineering LNPs with increasing densities of antibody functionalization. aEGFR-LNPs were screened in vitro in immortalized placental trophoblasts and in vivo in non-pregnant and pregnant mice and compared to non-targeted formulations for extrahepatic, antibody-targeted mRNA LNP delivery to the placenta. Our top performing LNP with an intermediate density of antibody functionalization (1:5 aEGFR-LNP) mediated a ∼twofold increase in mRNA delivery in murine placentas and a ∼twofold increase in LNP uptake in EGFR-expressing trophoblasts compared to non-targeted counterparts. These results demonstrate the potential of antibody-conjugated LNPs for achieving extrahepatic tropism, and the ability of aEGFR-LNPs in promoting mRNA delivery to EGFR-expressing cell types in the placenta. [Display omitted] • Strain-promoted azide-DBCO cycloaddition produces stable antibody-conjugated LNPs • Pregnancy alters EGFR antibody-conjugated LNP biodistribution in vivo • Intermediate EGFR antibody density enhances mRNA LNP delivery to the placenta • EGFR antibody-conjugated LNPs enhance uptake in EGFR-expressing trophoblasts [ABSTRACT FROM AUTHOR]

• Urinary PlGF is a tight reference of serum PlGF. • Urinary PlGF is the best predictor of prenatal cerebral vasodilatation. • Reliability of urinary sFlt-1 values are relative to serum creatinine concentration. To evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction. This case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios. Urine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863). Urinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable. [ABSTRACT FROM AUTHOR]