Placental Growth Factor Levels Research Articles

The link between diabetic retinal and renal microvasculopathy is associated with dyslipidemia and upregulated circulating level of cytokines.

To investigate the mechanisms underlying the correlations between diabetic retinopathy (DR) and diabetic nephropathy (DKD) and examine whether circulating cytokines and dyslipidemia contribute to both DR and DKD in patients with 2 diabetes mellitus (T2DM). A total of 122 patients with T2DM were enrolled and categorized into the DM group (without no DR and DKD), DR group [non-proliferative DR (NPDR), and proliferative DR (PDR)] with no DKD), DR complicated with DKD groups (DR+DKD group). The biochemical profile, including fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and lipid profile were estimated, and plasma inflammatory and angiogenic cytokines [monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF)-A, C, D, and placental growth factor (PlGF)] were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein-cholesterol (HDL-C); atherogenic index (AI) was calculated as [(total cholesterol (TC) -HDL-C)/HDL-C], and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C). By multivariable disordered regression analysis, after controlling for duration of DM and hypertension, LDL-C (p = 0.019) and VEGF-D (p = 0.029) resulted as independent risk factors for DR. Albumin-to-creatinine ratio (uACR) (p = 0.003) was an independent risk factor for DR with DKD. In DR, NPDR, and PDR groups, grades of A1, A2, and A3 of albuminuria increased with the severity of DR. In A1, A2, and A3 grade groups, the severity of DR (DM, NPDR, and PDR) increased with higher albuminuria grades. Kendall's tau-b correlation coefficient analysis revealed that FBG (p = 0.019), circulating level of PlGF (p = 0.002), and VEGF-D (p = 0.008) were significantly positively correlated with the grades of uACR (p < 0.001), and uACR grades were significantly correlated with DR severity (p < 0.001). The occurrence and severity of DR are closely correlated with kidney dysfunction. Among the three kidney functional parameters, uACR resulted as the better indicator of DR severity and progression than glomerular filtration (eGFR) and serum creatinine (Scr). Impaired FBG was associated with microalbuminuria, emphasizing that well-controlled FBG is important for both DR and DKD. The link between diabetic retinal and renal microvasculopathy was associated with dyslipidemia and upregulated circulating level of angiogenic cytokines.

Combination of Maternal Serum ESM-1 and PLGF with Uterine Artery Doppler PI for Predicting Preeclampsia.

This study aimed to determine whether the combination of pregnancy-associated endothelial cell-specific molecule 1 (ESM-1), the placental growth factor (PLGF) in the first- and second-trimester maternal serum, and the uterine artery Doppler pulsatility index (PI) in the second trimester can predict preeclampsia (PE). The serum levels of ESM-1 and PLGF in 33 severe preeclampsia (SPE) patients, 18 mild preeclampsia patients (MPE), and 60 age-matched normal controls (CON) were measured. The Doppler ultrasonography was performed, and the artery pulsatility index (PI) was calculated for the same subjects. The 2nd PLGF level was significantly lower and the 2nd PI was higher than those in the MPE group. Combining the 2nd PLGF with the 2nd PI yielded an AUC of 0.819 (83.33% sensitivity and 70.00% specificity). In the SPE group, the 1st ESM-1 level and the 2nd PLGF level were significantly lower, and the 2nd ESM-1 level and the 2nd PI were significantly higher in the SPE group. The combination of the 1st ESM-1, the 2nd PLGF, and the 2nd PI yielded an AUC of 0.912 (72.73% sensitivity and 95.00% specificity). The 1st ESM-1 and the 2nd PLGF levels and the 2nd PI were associated with PE. The combination of serum biomarkers and the PI improved the screening efficiency of the PE prediction, especially for SPE.

PlGF (Placental Growth Factor) testing in clinical practice – identifying the optimal threshold

Accurate diagnosis of preterm preeclampsia (PE) may improve the management of affected pregnancies. Previous studies have demonstrated that reduced levels of Placental growth factor (PlGF) levels (< 100 pg/mL) provide superior diagnostic performance to evaluate pregnant individuals with suspected hypertension. A single cut-off may not provide optimal test interpretation, since PlGF levels vary considerably across gestational age (GA) range. Our group recently generated centile curves for PlGF levels by combining data from Toronto and Cambridge, UK. We compared the diagnostic accuracy of GA-specific percentile values of PlGF, vs. a single cutoff of 100 pg/mL, in the setting of diagnostic testing for suspected preeclampsia in a single high-risk pregnancy center. Secondary analysis of published data in 979 high-risk pregnant women with singleton pregnancies evaluated between 2017-2019 at Mount Sinai Hospital, Toronto, Canada. PlGF testing was performed between 20+0 and 35+6 weeks of gestation. We compared the diagnostic accuracy of PlGF< 100 pg\mL vs. PlGF< 2.5% for GA. Primary outcomes were prediction of early-onset PE and preterm birth (PTB)< 32 weeks’ gestation. Overall, 374 (38.2%) had a normotensive pregnancy, 244 (24.9%) developed gestational hypertension19.3%, 189 () developed late-onset PE, and 172 (17.6%) developed early-onset PE. PlGF< 2.5% for GA provided better sensitivity with comparable specificity for diagnosis of early-onset PE and PTB< 32 weeks, when compared to a single threshold of 100 pg\mL, thereby improving the area under the ROC curve (Figure 1). Table 1 compares adjusted odds ratios (aOR) for maternal and fetal outcomes, between PlGF interpretation methods. Compared to PlGF< 100 pg\mL., PlGF < 2.5% for GA increased aOR for early-onset PE and PTB< 32 weeks (58.2 vs to 95.1 and 15.7 vs. 20.6 respectively). Low PlGF levels in high-risk pregnant women are strongly associated with adverse pregnancy outcomes. Adopting a PlGF < 2.5% for GA interpretation approach provides better diagnostic accuracy for the diagnosis of early-onset PE and PTB< 32 weeks.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Angiogenic Biomarker Placental Growth Factor (PLGF) in the Prediction and Diagnosis of Placental Dysfunction in Pre-eclampsia: A Cohort Study

Introduction: Pre-eclampsia (PE), a pregnancy induced hypertensive disorder affects approximately 8-10% of all pregnancies in developing countries. A highly sensitive and specific marker for diagnosis of PE is the need of the hour as diagnostic criteria are still based on non-specific clinical symptoms, ultrasound, and laboratory findings. Imbalance in the placental release of various angiogenesis regulatory factors to the maternal circulation is one of the significant contributors to its clinical manifestations. Low levels of pro-angiogenic biomarker Placental Growth Factor (PLGF) are detectable several weeks before clinical presentation of PE. Aim: To determine the association of serum levels of PLGF with PE in second and third trimester of pregnancy. Materials and Methods: A prospective cohort study was performed in a tertiary care hospital from December 2018 to November 2021, on 130 patients by dividing study participants into two groups: Pre-eclamptic cases, Normotensive controls. At enrollment in second trimester (24-28 weeks) and during third trimester (beyond 28 weeks) serum PLGF concentration was measured by using the Enzyme-linked Immunosorbent Assay (ELISA) kit method. Data was statistically analysed. Student’s t-test was used for comparing differences between study groups. The chi-square test was used to compare qualitative categorical data. Evaluation of the Area Under the Curve (AUC), diagnostic accuracy, sensitivity and specificity was done by Receiver Operating Characteristics (ROC) curve analysis done using software defined cut-off values. Results: Total of 115 patients were analysed in the present study with 55 patients in group 1(mean age: 25.83±3.27 years) and 60 patients in group 2 (mean age: 30.52±5.63 years) When compared with normotensive group PLGF levels were significantly lower in pre-eclamptic group with median 16.27 ng/mL versus 12.20 ng/ mL (p &lt;0.001) in second and 14.05 ng/mL versus 10.50 ng/mL (p &lt;0.001) in third trimesters respectively. ROC curve analysis using cut-off point of 14.91 ng/mL showed sensitivity 80%, specificity 96.7%, AUC 0.896, 95%CI:(0.832-.959) in second trimester and in third trimester at cut-off point of 13 ng/mL sensitivity 73%, specificity 96.7%, AUC 0.882 95% CI:(0.816-.948) was found. Conclusion: PLGF may be used as a biomarker for early prediction, diagnosis, and management of PE. It might serve as ideal discriminating biochemical markers of PE. In the near future, the clinical utility of disease specific angiogenic biomarker in early detection of PE might improve health outcomes by preventing adverse maternal and neonatal outcomes and serious complications.

PS-C32-1: DEMOGRAPHIC, ANTHROPOMETRIC AND BIOCHEMICAL CORRELATES AS EARLY PREDICTIVE INDICES OF HYPERTENSIVE DISORDERS IN PREGNANT WOMEN FROM NIGERIA

Objective: this study was conducted to evaluate maternal demographic, anthropometric and biochemical indices to predict Hypertensive Disorders of Pregnancy (HDP) at early stage. Design and method: Non-hypertensive pregnant women (n = 521) of &lt; 20 weeks gestation, attending antenatal clinics of four different tertiary health facilities in Nigeria enrolled into this longitudinal study. From this, 471 participants were followed up to delivery. Demographic data were obtained through a semi-structured questionnaire while BMI and Percentage Body Fat (PBF) were determined using standard methods. Blood and urine samples were collected at baseline, second and third trimesters. Placental Growth Factor (PLGF), leptin and insulin were analysed in serum using ELISA. Triglycerides, total cholesterol, HDLc, uric acid, creatinine and Fasting Plasma Glucose (FPG) in plasma were analysed spectrophotometrically. Urinalysis was performed using dipstick while LDLc was calculated. Data were analysed using Chi-square, ANOVA and Cox proportional hazard model at &lt; 0.05. Results: Ten (2.1%) and 24 (5.1%) of the pregnant women developed HDP at second and third trimester. From the 34 that developed HDP, 19 (55.9%), 12 (35.3%), 2 (5.9%) and 1 (2.9%) developed Preeclampsia-Eclampsia, Gestational Hypertension, Chronic Hypertension and Preeclampsia Superimposed on Chronic Hypertension, respectively. Maternal age and marital age of HDP women (32.4 ± 5.0; 28.9 ± 4.3 years) were respectively higher than normotensive (30.5 ± 4.4; 27.2 ± 3.7 years). Risk of HDP was higher at marital age of 35–42 years compared with 13–25 years (HR = 8.44, 95% CI: 2.01–35.35). Body mass index (30.4 ± 1.6 vs. 26.6 ± 0.3Kg/m2) and PBF (40.6 ± 1.5 vs. 36.0 ± 0.5) were higher in HDP women than normotensive. Reduced PLGF level (HR = 0.77, 95% CI: 0.64–0.94) in second trimester increased risk of HDP. Leptin (6.9 ± 1.9 vs. 14.1 ± 1.5ng/mL) in first trimester and insulin (1.5 ± 0.5 vs. 10.5 ± 1.5 μIU/mL and 7.9 ± 3.2 vs. 17.5 ± 2.1 μIU/mL) in first and second trimesters were lower in HDP than normotensive women, respectively. Uric acid (2.8 ± 0.1 vs. 4.2 ± 0.8 mg/dL) and creatinine (0.8 ± 0.01 vs. 2.6 ± 1.7 mg/dL) were significantly decreased in normotensive compared with HDP women in first trimester. The FPG (78.1 ± 2.6: 73.0 ± 1.4: 71.4 ± 1.5 mg/dL) was significantly reduced from first, second to third trimesters in normotensive women. In HDP women FPG (76.1 ± 4.1; 74.5 ± 6.7 vs. 65.8 ± 5.5 mg/dL) was increased in second and third trimesters, respectively compared to first trimester. Increased LDLc (HR = 1.28, 95% CI: 1.04–1.58) was associated with increased risk of HDP in second trimester. Conclusions: Maternal age, obesity, decreased levels of placental growth factor, leptin, insulin, uric acid; increased levels of fasting plasma glucose and low density lipoprotein cholesterol are critical risk factors for early prediction of hypertensive disorders during pregnancy.

OBSTETRIC AND PERINATAL ASPECTS OF METABOLIC DISORDERS IN PREGNANT WOMEN.

The aim: To determine the feasibility of using Tivortin in metabolic disorders during pregnancy and its effect on the course of pregnancy, childbirth, fetal and neonatal status. Materials and methods: We examined 210 pregnant women with metabolic disorders using clinical and laboratory data, uterine artery Doppler, determi¬nation of lipid peroxidation and antioxidant system, leptin and placental growth factor content. The fetal condition was assessed by ultrasound examination with Doppler, determination of biophysical profile, and cardiotocography. Results: Metabolic disorders in pregnant women increase the risk of obstetric and perinatal complications by activating lipid peroxidation and inhibiting the antioxidant system, reducing the content of placental growth factor and increasing the level of leptin in the blood plasma. After treatment, there was a significant decrease in leptin levels and an increase in placental growth factor levels, normalization of lipid peroxidation and antioxidant system, uterine artery pulsatility index and umbilical cord peak systolic velocity index, systolic-diastolic ratio, fetal biophysical profile and cardiotocography. The incidence of complications in childbirth decreased by 3 times, surgical interventions - by 2 times, postpartum infectious complications - by 1.7 times, and the birth of infants in a state of asphyxia - by 1.8 times. Conclusions: Metabolic disorders in pregnant women are a significant factor in the development of obstetric and perinatal complications due to the intensity of lipid peroxidation and depression of the antioxidant system, and a decrease in the content of placental growth factor. The use of Tivortin in the treatment of pregnant women with metabolic disorders has proven its safety and efficacy.

Redefining maternal vascular malperfusion (MVM) placental disease by circulating placental growth factor (PlGF) level

Maternal Vascular Malperfusion (MVM) is the most common placental diagnosis associated with preeclampsia, fetal growth restriction (FGR) and stillbirth. However, 50% of placentas meeting diagnostic criteria for MVM result in healthy term pregnancies. Our objective was to determine which features currently used to establish a pathologic diagnosis (MVM) are most strongly correlated with low circulating placental growth factor (PlGF) as a marker of clinically meaningful placental dysfunction, as well as investigate patterns of association between pathologic features. We conducted a single-centre, retrospective cohort study in women with singleton pregnancies where decreased PlGF (< 100pg/mL) was measured between 20 and 36 weeks gestation, with placental evaluation following delivery. Placental characteristics were systematically analyzed according to the Amsterdam Consensus for MVM. Findings were compared between MVM and non-MVM groups using a Chi-Square test. Cluster analysis was then performed using K-Modes unsupervised clustering algorithm. Between March 2017 and December 2019, 337 pregnancies met inclusion criteria, of which 242 (71.8%) met current diagnostic criteria of MVM disease. Features significantly associated with MVM diagnosis were placental weight < 10%ile, eccentric cord insertion, placental infarction, distal villous hypoplasia, accelerated villous maturation, and decidual vasculopathy (p< 0.01) (table 1). The features most specific to MVM pathology were distal villous hypoplasia (specificity 99%, PPV 99%,), and decidual vasculopathy (specificity 95%, PPV 96%). Cluster analysis identified four phenotypic clusters (figure 1). These findings highlight the features which define maternal vascular malperfusion in the context of low circulating PlGF, as well as the heterogeneity of MVM placental disease under the current diagnostic criteria. This knowledge may be used to establish a hierarchy of specific gross and histologic observations to define MVM disease with greater diagnostic precision for meaningful adverse clinical outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

First trimester screening and prediction of preeclampsia by Application of Fetal Medicine Foundation Algorithm at Tanta University

Background: Preeclampsia (PE) is a complex illness linked to conception that affects a variety of bodily functions and is usually connected with perinatal morbidity and deaths. Early PE anticipation will reduce this linked morbidity and death by allowing for routine maternal and foetal monitoring and the use of preventative measures. Aim of the work: the goal of this study is to investigate whether the measurement of maternal serum placental growth factor (PlGF) combined with uterine artery Doppler ultrasound, are useful in early predicting PE and to examine the diagnostic accuracy of the Fetal Medicine Foundation (FMF) Algorithm for the early screening and anticipation of the high- risk PE at 11-13 weeks conception in a group of pregnant women. Patients and Methods: one hundred and twenty primigravida women with living, singleton fetus at 11-13 weeks conception without risk factors other than being primigravida attending antenatal care clinic at the Department of Obstetrics and Gynecology at Tanta University Hospitals. All cases were subjected to ; A signed informed written consent, proper history taking, full clinical examination, estimation of body mass index (BMI), blood pressures and determination of mean arterial blood pressure (MAP), ultrasound, Uterine artery doppler ultrasound examination with the determination of the mean Pulsatility index (PI) of the uterine arteries. Maternal serum levels of PlGF were also measured by specific immunoassay (ELISA). The measured values of MAP, mean uterine artery pulsatility index (PI) and PlGF were converted into multiples of the median (MoM). Then the FMF model was used for the determination of patient-specific risk of PE at 11-13 weeks conception in each case. Results: The main results of the present study revealed that; Only 11 of 120 normal pregnant women were categorized as a high PE risk with a percentage of 9.2% and the rest 109 cases were low PE risk with a percentage of 90.8% by application of FMF algorithm. There was a significant difference between the high and low risks regarding the mean uterian UtA-Pi and PIGF levels at 11–13 weeks. Receiver operating characteristic curve (ROC) demonstrate to what extent it can be depended on PlGF, mean UtA-PI and MAP as a predictor for PE denoting the significant diagnostic performance for PIGF and mean uterine artery pulsatility index (PI). The optimal cutoff value of PlGF value using the ROC curve was ≤40 leading to a sensitivity of 90.91%, a specificity of 96.33%, a PPV of 71.4, a NPV of 99.1% and an accuracy of 95.83%. While the optimal cutoff measure of mean uterine artery PI value using the ROC curve was >1.91 leading to a sensitivity of 90.91%, a specificity of 96.33%, PPV of 71.4, NPV of 99.1% and an accuracy of 95.83%. Conclusion: On the basis of these results, it could be concluded that the combined measurement of maternal serum PlGF concentrations and mean PI of the uterine arteries at 11–13 weeks of conception may help to predict the high-risk PE in primigravida when other parameters of PE anticipation are normal. And The FMF screening algorithm for the high-risk PE group performing satisfactorily. PE estimated by the competing risk model incorporated in the FMF algorithm may be applicable locally, and the earlier screening in conception would allow women at a higher risk to be monitored accordingly, participate in early intervention trials, and commence prophylactic therapy.

A trial of positive airway pressure for the treatment of sleep apnea in pregnancy

The pathophysiology of obstructive sleep apnea in pregnancy remains poorly understood and studies examining the effect of treatment with positive airway pressure on pregnancy have been limited. This study aimed to perform a randomized controlled trial of positive airway pressure treatment for obstructive sleep apnea in pregnancy. Participants with a body mass index ≥30 kg/m2 underwent polysomnography at 14 to 20 weeks' gestation (visit 1) and those with obstructive sleep apnea (apnea-hypopnea index ≥5 but <50) were enrolled. In phase 1, participants were randomized to autotitrating positive airway pressure vs sham positive airway pressure; in phase 2, the sham arm was replaced with a sleep hygiene control. Participants returned at 28 to 31 weeks' gestation (visit 2). The mean arterial blood pressure, uterine artery Doppler pulsatility index, endoglin, soluble FMS-like tyrosine kinase 1 levels, and placental growth factor levels were measured, as well as fasting glucose and insulin to calculate insulin resistance (homeostatic model assessment for insulin resistance). The primary outcome was a composite of the uterine artery Doppler pulsatility index, soluble FMS-like tyrosine kinase 1 to placental growth factor ratio, and the homeostatic model assessment for insulin resistance. For secondary analyses, each outcome variable was analyzed independently. Adherence to treatment was examined. A total of 241 participants completed visit 1, and 89 (37%) had an apnea-hypopnea index between 5 and 50. Of the those, 51 participants were randomized in phase 1 and 38 in phase 2. There was no significant difference in our primary outcome by treatment group. In secondary analyses, the uterine artery Doppler pulsatility index was lower in participants on autotitrating positive airway pressure when compared with sleep hygiene controls. Otherwise, there were no differences in the mean arterial blood pressure, angiogenic markers, or metabolic markers in phase 1, phase 2, or across the entire study. The overall adherence to autotitrating positive airway pressure therapy was low, but the mean use was greater in phase 2 (0.3±0.6 hours/night vs 1.3±2.3 hours/night; P=.10). For those on active therapy, fasting glucose values decreased as adherence increased. This randomized controlled trial of autotitrating positive airway pressure in pregnancy did not find any differences in a composite primary cardiometabolic risk profile between the treatment groups. Higher autotitrating positive airway pressure adherence was associated with lower fasting glucose levels. The use of a sham positive airway pressure control arm in phase1 may have negatively impacted adherence to active treatment.

Clinical value of flow-mediated dilatation of brachial artery in hypertensive disorders complicating pregnancy.

Hypertensive disorders complicating pregnancy (HDCP) are common pregnancy-related disorders. In this study, we aimed to study the clinical value of flow-mediated dilation (FMD) in HDCP and its association with endothelial dysfunction and HDCP-related factors. 160 HDCP patients and 120 healthy pregnancies were enrolled in the study. The expressions of endothelial function markers and FMD were determined. In addition, their correlations in HDCP patients were also analyzed using Pearson's correlation analysis. FMD value decreased gradually from normal pregnancy to severe PE. The levels of plasma nitric oxidase (NO) were significantly lower in the HDCP group than those in the control group, while the levels of plasma endothelin-1 (ET-1) were increased dramatically in the HDCP group. Moreover, the levels of placental growth factor (PLGF) in HDCP women were significantly lower, while the soluble FMS-like tyrosine kinase 1 (sFLt-1) levels were markedly higher than those in control. In addition, the FMD value was correlated with the levels of plasma NO, ET-1, PLGF and sFlt1. It was also found that lower levels of FMD correspond to endothelial dysfunction and abnormal concentrations of PLGF and sFlt-1. The FMD value was associated with endothelial function indicators and could be a strong and non-invasive measure to predict HDCP. The association between the FMD values and endothelial function indicators in HDCP could be helpful for the prediction of pregnant hypertension more accurately.

Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns

BackgroundIncreasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low “proangiogenic” placental growth factor concentrations and increased “antiangiogenic” soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome. ObjectiveThis study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low “proangiogenic” placental growth factor levels, increased “antiangiogenic” soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1–placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome. Study DesignThis was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37+0), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups—the “complicated” group (n=32) and the “uncomplicated” group (n=924)—according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results. ResultsMean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P=.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start (rs=−0.068; 95% confidence interval, −0.131 to −0.004; P=.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end (rs=−0.068; 95% confidence interval, −0.131 to −0.005; P=.036), and high soluble fms-like tyrosine kinase-1–placental growth factor ratio and low short-term variation end (rs=−0.071; 95% confidence interval, −0.134 to −0.008; P=.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the “complicated” compared with the “uncomplicated” group (0% to 17% vs 4% to 8%). ConclusionMore automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile (lower placental growth factor) increased the rates of alerts more rapidly in pregnancies with adverse neonatal outcome compared with those without. We suggest that future studies developing and testing prediction tools for intrapartum fetal compromise include predelivery maternal placental growth factor measurements.

Ulinastatin ameliorates preeclampsia induced by N(gamma)-nitro-l-arginine methyl ester in a rat model via inhibition of the systemic and placental inflammatory response.

The pathogenesis of preeclampsia (PE) is associated with inflammation and endothelial damage. Ulinastatin (UTI) mainly inhibits proteolytic activity and significantly reduces the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) from macrophages. It also ameliorates vascular endothelial damage in pathological conditions. Hence, we investigated the effects of UTI in a rat model of PE induced using N(gamma)-nitro-l-arginine methyl ester (L-NAME). Although inducing PE in a rat model, 5000 U/kg of UTI were injected daily. Systolic blood pressure (SBP) and protein levels in the urine were measured. Renal function, and serum concentrations of TNF-α, IL-6, placental growth factor (PLGF), and von Willebrand factor (vWF) were evaluated. The number and weight of live fetuses as well as the weight of placentas were measured. Placentas were collected for western blot and pathological analysis. UTI slightly ameliorated proteinuria and the increases in SBP, blood urea nitrogen (BUN), and serum creatinine. Furthermore, UTI improved serum and placental protein expression levels of TNF-α, IL-6, vWF, and PLGF. Pathological analysis revealed that vascular density and blood flow perfusion was enhanced, vessel wall thickening and neutrophil infiltration were diminished, and the weight and number of live fetuses as well as the weight of the placentas were improved with UTI. Preventive use of UTI in the PE rat model induced by L-NAME partially alleviated hypertension, proteinuria, and impaired renal function; improved fetal growth restriction; diminished vascular endothelial injury; and ameliorated placental vasculogenesis abnormality and malperfusion by inhibiting the systemic and placental inflammatory response, suggesting that UTI is a potential drug for PE prevention or treatment.

Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction

Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

Biomarkers for anti-vascular endothelial growth factor drugs.

Angiogenesis is regulated by interactions between vascular endothelial growth factors (VEGFs) and VEGF receptors. VEGF-A, VEGF-D, placental growth factor (PlGF) and plasminogen activator inhibitor-1 (PAI-1) have tumor angiogenic activity. VEGF-A and PAI-1 levels in the blood may impact the activity of bevacizumab, and VEGF-D levels may similarly diminish the efficacy of ramucirumab. However, the dynamics of these angiogenic biomarkers for anti-VEGF therapy have not been well established; therefore, they were evaluated in this retrospective study, which included two cohorts. Cohort 1 included patients who were treated with cytotoxic agents and bevacizumab as first-line chemotherapy, and Cohort 2 comprised patients who were treated with cytotoxic agents and anti-VEGF drugs (bevacizumab, ramucirumab or aflibercept) as second-line chemotherapy. VEGF-A, VEGF-D, PlGF and PAI-1 levels were measured before starting chemotherapy and were re-assessed every 1-2 months until disease progression. Bevacizumab had reduced benefit as a first-line chemotherapeutant in patients with very low or very high levels of VEGF-A. Bevacizumab increased VEGF-A and PlGF levels, but not VEGF-D or PAI-1. Anti-VEGF drugs offered the greatest benefit to patients with high PAI-1 before first- and second-line chemotherapy. PAI-1 levels were not affected by anti-VEGF drugs. Since ramucirumab increased VEGF-D, it offered less benefit to patients with high VEGF-D in second-line chemotherapy. Conversely, aflibercept offered greater benefits to patients with high VEGF-D, without increasing VEGF-D. These biomarkers may be useful for the prediction of drug efficacy and may predict resistance to anti-VEGF drugs.

Mother-Fetus Immune Cross-Talk Coordinates "Extrinsic"/"Intrinsic" Embryo Gene Expression Noise and Growth Stability.

Developmental instability (DI) is thought to be inversely related to a capacity of an organism to buffer its development against random genetic and environmental perturbations. DI is represented by a trait’s inter- and intra-individual variabilities. The inter-individual variability (inversely referred to as canalization) indicates the capability of organisms to reproduce a trait from individual to individual. The intra-individual variability reflects an organism’s capability to stabilize a trait internally under the same conditions, and, for symmetric traits, it is expressed as fluctuating asymmetry (FA). When representing a trait as a random variable conditioned on environmental fluctuations, it is clear that, in statistical terms, the DI partitions into “extrinsic” (canalization) and “intrinsic” (FA) components of a trait’s variance/noise. We established a simple statistical framework to dissect both parts of a symmetric trait variance/noise using a PCA (principal component analysis) projection of the left/right measurements on eigenvectors followed by GAMLSS (generalized additive models for location scale and shape) modeling of eigenvalues. The first eigenvalue represents “extrinsic” and the second—“intrinsic” DI components. We applied this framework to investigate the impact of mother–fetus major histocompatibility complex (MHC)-mediated immune cross-talk on gene expression noise and developmental stability. We showed that “intrinsic” gene noise for the entire transcriptional landscape could be estimated from a small subset of randomly selected genes. Using a diagnostic set of genes, we found that allogeneic MHC combinations tended to decrease “extrinsic” and “intrinsic” gene noise in C57BL/6J embryos developing in the surrogate NOD-SCID and BALB/c mothers. The “intrinsic” gene noise was negatively correlated with growth (embryonic mass) and the levels of placental growth factor (PLGF), but not vascular endothelial growth factor (VEGF). However, it was positively associated with phenotypic growth instability and noise in PLGF. In mammals, the mother–fetus MHC interaction plays a significant role in development, contributing to the fitness of the offspring. Our results demonstrate that a positive impact of distant MHC combinations on embryonic growth could be mediated by the reduction of “intrinsic” gene noise followed by the developmental stabilization of growth.

INDICATORS OF ANGIOGENESIS IN PREGNANT WOMEN WITH ARTERIAL HYPERTENSION

The role of the factors of angiogenesis and hormones of pregnancy in pregnant women with hypertension has been studied inadequately and their interaction in such patients is not fully elucidated at present time. Aim. To detect peculiarities of angiogenesis factors and placental hormones in pregnant women with arterial hypertension I and II grades in comparison with results of healthy pregnant women. Materials and methods. Conducting a prospective study of 88 pregnant women, which included: analysis of clinical and anamnestic characteristics and study of the peculiarities of pregnancy in women with chronic hypertension in the first trimester of pregnancy (11-12 weeks). The open prospective controlled study involved 61 pregnant women with chronic arterial hypertension (CAH) 1-2 degree, who were included in the first - the main group. The second control group included 27 healthy pregnant women with physiological pregnancies. Among the angiogenesis indices, the placental growth factor (PlGF), as a pro-angiogenic factor and placental soluble fms-like tyrosine kinase (sFlt-1) was determined as an anti-angiogenic factor, sFlt-1/PlGF ratio was also estimated. Statistical analysis was done by using «STATISTICA® for Windows 6.0» (Stat Soft Inc., № AXXR712D833214FAN5). Results. In the first trimester of pregnancy (11-12 weeks of gestation) in women with CAH is determined by a shift in the balance between pro- and antiangiogenic factors, manifested by statistically significant (p˂0.05) increase in sFlt-1 levels (1700, 9 pg / ml) and a decrease in PlGF levels in3.7 times (9.1 pg / ml) and, accordingly, an increase in the levels of the coefficient K in 5.3 times (sFlt-1 / PlGF) (184.5). The mean values of estradiol, progesterone and chorionic gonadotropin levels in pregnant women with CAH did not differ statistically significantly from those of the control group (p˃0.05). These changes indicate the presence of angiogenesis disorders in pregnant women with chronic hypertension, starting from the first trimester of gestation. Conclusions. Pregnant women with CAH in І trimester have disturbances in balance between pro-angiogenic and anti-angiogenic factors with prevalence of sFlt-1 and reducing of PlGF in serum plasma. Due to such disbalance in pregnant women with CAH of 1 and 2 grade changed cooperation between angiogenesis factors and hormones from direct to inverse. It may lead to development of placental insufficiency in future. That’s why treatment/prophylaxis of it should be administered to pregnant women with CAH in 1 trimester.

Imbalanced Angiogenesis in Pregnancies Complicated by SARS-CoV-2 Infection.

COVID-19 and preeclampsia (preE) share the ANG-II mediated endothelial dysfunction, resulting from a significant dysregulation of RAS and an imbalanced proportion of anti-angiogenic and pro-angiogenic soluble plasmatic factors. Of note, an increased incidence of preE has been reported among COVID-19-infected mothers compared to the general pregnant population. The two most promising angiogenic markers are the soluble fms-like tyrosine kinase receptor-1 (sFlt-1), the major antiangiogenic factor, and the placental growth factor (PlGF), a powerful angiogenic factor. Since these markers have proven useful in the prediction, diagnosis, and severity of preE, this study aimed to evaluate their maternal serum levels in pregnancies complicated by SARS-CoV-2 infection and to assess their potential use to guide the management of these women. A retrospective analysis of SARS-CoV-2-positive pregnant women was performed. The serum levels of sFlt-1 and PlGF were collected at the diagnosis of SARS-CoV-2 infection at the hospital, before the beginning of steroid/hydroxychloroquine and/or antithrombotic therapy. The sFlt-1/PlGF ratio was stratified using cut-off values clinically utilized in the diagnosis and prediction of preE (low < 38, intermediate 38–85/110* and high >85/110*, * if before or after the 34th week of gestation). A total of 57 women were included, of whom 20 (35%) had signs and symptoms of COVID-19 at hospital presentation and 37 (65%) were asymptomatic. None were vaccinated. The mean gestational age at diagnosis of SARS-CoV-2 infection was 32 weeks in symptomatic patients and 37 weeks and 5 days in asymptomatic ones (p = 0.089). sFlt-1 serum levels were higher in SARS-CoV-2 positive asymptomatic patients compared to women with COVID-19 related symptoms (4899 ± 4357 pg/mL vs. 3187 ± 2426 pg/mL, p = 0.005). sFlt-1/PlGF at admission was <38 in 18 of the 20 symptomatic women (90%) compared to 22 (59%) of the asymptomatic patients (p = 0.018). Of note, two of the three women admitted to the intensive care unit had a very low ratio (<2). In turn, rates of patients with sFlt-1/PlGF at admission > 85/110 were not significantly different between the two groups: 11% in asymptomatic patients (4/37) vs. none of the symptomatic patients (p = 0.286), and all of them presented a placental dysfunction, like preE (n = 1) and FGR (n = 3). Of note, there were no stillbirths or maternal or neonatal deaths among symptomatic patients; also, no cases of preE, FGR, or small for gestational age neonates were diagnosed. In conclusion, our data suggest that SARS-CoV-2 infection during pregnancy could influence the angiogenic balance. A significant pathological alteration of the sFlt-1/PlGF ratio cannot be identified during the symptomatic phase; however, if left untreated, SARS-CoV-2 infection could potentially trigger placental dysfunction.

Predictive Value Analysis of Serum sFlt-1 and PLGF Levels/Ratio in Preeclampsia

Background: This study is to explore the clinical significance of serum sFlt-1, and placental growth factor (PLGF) contents, as well as sFlt-1/PLGF ratio in predicting and diagnosing preeclampsia. Methods: Peripheral venous blood was collected from all pregnant women at 11–33+6 weeks for biomarker detection. Totally 105 patients with preeclampsia and 57 patients with severe preeclampsia were included. Serum sFlt-1 and PLGF levels were determined, and sFlt-1/PLGF ratio was calculated. Correlation between sFlt-1, PLGF, sFlt-1/PLGF ratio and serum total cholesterol, triglyceride, lactate dehydrogenase and calcium content levels were analyzed. receiver operating characteristic (ROC) analysis was used to evaluate values of sFlt-1, PLGF and sFlt-1/PLGF ratios in disease diagnosis and prediction. Results: Serum sFlt-1 content and sFlt-1/PLGF ratio in Preeclampsia (PE) patients were significantly higher than control. Serum sFlt-1 content and sFlt-1/PLGF ratio of the severe PE group were significantly higher than the PE group. Serum PLGF contents of the PE and severe PE group were significantly lower than control, and the difference in PLGF content between the severe and PE groups was not significant. There was a moderate correlation between the sFlt-1 content and the lactate dehydrogenase level. There was a low-level correlation between the sFlt-1/PLGF ratio and the lactate dehydrogenase level. The receiver ROC curve analysis showed that sFlt/PLGF had greater predictive value for preeclampsia, with a sensitivity of 98.1% and a specificity of 78.2%. Conclusions: Serum sFlt-1 level and sFlt-1/PlGF ratio have better predictive and diagnostic values, as well as better auxiliary efficiency for preeclampsia. The diagnostic efficiency of sFlt-1/PlGF ratio is better than sFlt-1 content alone.

Associations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia.

BackgroundThe angiogenic factors soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) are postulated to be pathogenic disease drivers of preeclampsia. If true, then circulating levels should become more deranged with increasing disease severity.Methods and ResultsWe investigated the association between circulating sFlt‐1 and PlGF levels and severe adverse maternal outcomes among 348 women with preeclampsia. Compared with 125 women with preeclampsia without severe features, 25 women with preeclampsia and any of hemolysis, elevated liver enzymes, low platelet count syndrome, disseminated intravascular coagulation, or severe renal involvement had sFlt‐1 levels that were 2.63‐fold higher (95% CI, 1.81–3.82), sFlt‐1/PlGF levels that were 10.07‐fold higher (95% CI, 5.36–18.91) and PlGF levels that were 74% lower (adjusted fold change, 0.26 [95% CI, 0.18–0.39]). Compared with 125 women with preeclampsia without severe features, 37 with eclampsia had sFlt‐1 levels that were 2‐fold higher (2.02 [95% CI, 1.32–3.09]), sFlt‐1/PIGF levels that were 4.71‐fold higher (95% CI, 2.30–9.66) and PIGF levels that were 63% lower (0.43‐fold change [95% CI, 0.27–0.68]). Compared with those without severe features, preeclampsia with severe hypertension (n=146) was also associated with altered angiogenic levels (sFlt‐1, 1.71‐fold change [95% CI, 1.39–2.11]; sFlt/PlGF, 2.91 [95% CI, 2.04–4.15]; PlGF, 0.59 [95%CI 0.47–0.74]). We also found that sFlt‐1 and PlGF levels were altered by the number of maternal complications experienced.ConclusionsFurther angiogenic imbalance among women with preeclampsia is likely a pathogenic disease driver responsible for the life‐threatening maternal complications.

Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states.

With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient's medical records. Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP were evaluated. A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0% vs 50.2%, p=0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (pg/ml) (3168 [IQR: 2160-4945] vs 2678 [IQR: 1752-4271]; p=0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs 12 [IQR: 5-30]; p=0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a covariate when studying angiogenic factors in normotensive pregnant patients.