Placental Growth Factor Concentrations Research Articles

Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system

ObjectiveThis study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Materials and MethodsBased on their 24-hour sodium excretion pregnant women (37–40 weeks’ gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N=12), high salt (HS, 5.75–10.25 g/day, N=36), and very high salt (VHS, >10.25 g/day, N=17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. ResultsPI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. ConclusionsHS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake.

Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort.

Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature. In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing-or vessel points and total vascular length. At 11weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories. Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development. Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.

Is the sFlt-1/PlGF ratio efficient in predicting adverse neonatal outcomes in small-for-gestational-age newborns? A prospective observational multicenter cohort study.

Fetuses with growth abnormalities are at an increased risk of adverse neonatal outcomes. The aim of this study was to investigate if placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), or the sFlt-1/PlGF ratio were efficient predictive factors of adverse neonatal outcomes in small-for-gestational-age (SGA) newborns. A prospective observational multicenter cohort study was performed between 2020 and 2023. At the time of the SGA fetus diagnosis, serum angiogenic biomarker measurements were performed. The primary outcome was an adverse neonatal outcome, diagnosed in the case of any of the following: <34 weeks of gestation: mechanical ventilation, sepsis, necrotizing enterocolitis, intraventricular hemorrhage grade III or IV, and neonatal death before discharge; ≥34 weeks of gestation: Neonatal Intensive Care Unit hospitalization, mechanical ventilation, continuous positive airway pressure, sepsis, necrotizing enterocolitis, intraventricular hemorrhage grade III or IV, and neonatal death before discharge. In total, 192 women who delivered SGA newborns were included in the study. The serum concentrations of PlGF were lower, leading to a higher sFlt-1/PlGF ratio in the adverse outcome group. No significant differences in sFlt-1 levels were observed between the groups. Both PlGF and sFlt-1 had a moderate correlation with adverse neonatal outcomes (PlGF: R - 0.5, p < 0.001; sFlt-1: 0.5, p < 0.001). The sFlt-1/PlGF ratio showed a correlation of 0.6 (p < 0.001) with adverse outcomes. The uterine artery pulsatility index (PI) and the sFlt-1/PlGF ratio were identified as the only independent risk factors for adverse outcomes. An sFlt-1/PlGF ratio of 19.1 exhibited high sensitivity (85.1%) but low specificity (35.9%) in predicting adverse outcomes and had the strongest correlation with them. This ratio allowed the risk of adverse outcomes to be assessed as low with approximately 80% certainty. The sFlt-1/PlGF ratio seems to be an efficient predictive tool in adverse outcome risk assessment. More studies on large cohorts of SGA-complicated pregnancies with and without preeclampsia are needed to develop an optimal and detailed formula for the risk assessment of adverse outcomes in SGA newborns.

Serum concentration of placental growth factor in pregnancy screening for placental dysfunction and low molecular weight heparin treatment

Serum concentration of placental growth factor in pregnancy screening for placental dysfunction and low molecular weight heparin treatment

Comparison of competing-risks model with angiogenic factors in midgestation screening for preterm growth-related neonatal morbidity.

First, to evaluate the predictive performance for preterm growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF at midgestation and, second, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for small-for-gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight and uterine artery pulsatility index. This was a prospective observational study in women attending for a routine hospital visit at 19-24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFlt-1. The primary outcome was delivery < 32 and < 37 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile and the competing-risks model for SGA were estimated and then compared using McNemar's test. In the study population of 40 241 women, prediction of preterm growth-related neonatal morbidity provided by the competing-risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF ratio. For example, at a screen-positive rate of 10.0%, as defined by the sFlt-1/PlGF ratio > 90th percentile, the competing-risks model predicted 70.1% (95%CI, 61.0-79.2%) of SGA < 10th percentile and 76.9% (95%CI, 67.6-86.3%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered < 32 weeks' gestation. The respective values for SGA with major neonatal morbidity were 73.8% (95%CI, 64.4-83.2%) and 77.9% (95%CI, 68.0-87.8%). These were significantly higher than the respective values of 35.1% (95%CI, 25.6-44.6%), 35.9% (95%CI, 25.3-46.5%), 38.1% (95%CI, 27.7-48.5%) and 39.7% (95%CI, 28.1-51.3%) achieved by the application of the sFlt-1/PlGF ratio > 90th percentile (all P < 0.0001). At midgestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ghrelin alleviates placental dysfunction by down-regulating NF-κB phosphorylation in LPS-induced rat model of preeclampsia

In our previous study, we uncovered that ghrelin promotes angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro by activating the Jagged1/Notch2/VEGF pathway in preeclampsia (PE). However, the regulatory effects of ghrelin on placental dysfunction in PE are unclear. Therefore, we applied Normal pregnant Sprague-Dawley (SD) rats, treated with lipopolysaccharide (LPS), to establish a PE-like rat model. The hematoxylin-eosin (HE) staining method and immunohistochemistry (IHC) technology were used to detect morphological features of the placenta. IHC and Western blot were applied to examine Bax and Bcl-2 expression levels. The concentrations of serum soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PIGF) were assessed by enzyme-linked immunosorbent assay (ELISA) kit. In addition, the apoptosis rates of JEG-3 and HTR-8/SVneo trophoblast cells were determined by Annexin V-FITC/PI apoptosis detection kit. Cell migratory capacities were assessed by scratch-wound assay, and RNA-sequencing assay was used to determine the mechanism of ghrelin in regulating trophoblast apoptosis. It has been found that ghrelin significantly reduced blood pressure, urinary protein, and urine creatinine in rats with PE, at the meanwhile, ameliorated placental and fetal injuries. Second, ghrelin clearly inhibited placental Bax expression and circulating sFlt-1 as well as elevated placental Bcl-2 expression and circulating PIGF, restored apoptosis and invasion deficiency of trophoblast cells caused by LPS in vitro. Finally, transcriptomics indicated that nuclear factor kappa B (NF-κB) was the potential downstream pathway of ghrelin. Our findings illustrated that ghrelin supplementation significantly improved LPS-induced PE-like symptoms and adverse pregnancy outcomes in rats by alleviating placental apoptosis and promoting trophoblast migration.

Angiogenic imbalance in pregnancies with preterm prelabor rupture of membranes between 34 and 37 weeks of gestation.

This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

Impact of physical activity on preeclampsia and angiogenic markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort

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.

Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial

BackgroundCirculating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. Method2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. ResultsAt baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, p-value = 0.002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], p-value< 0.001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], p-value= 0.07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95%CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], p-value=0.30). ConclusionsPeople with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. Clinical TrialCREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791

Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer's Disease.

Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility.

Ophthalmic artery Doppler at 36 weeks' gestation in prediction of pre-eclampsia: validation and update of previous model.

To validate and extend a model incorporating maternal ophthalmic artery Doppler at 35-37 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE). This was a prospective validation study of screening for PE (defined according to the 2019 American College of Obstetricians and Gynecologists criteria) by maternal ophthalmic artery peak systolic velocity (PSV) ratio in 6746 singleton pregnancies undergoing routine care at 35 + 0 to 36 + 6 weeks' gestation (validation dataset). Additionally, the data from the validation dataset were combined with those of 2287 pregnancies that were previously used for development of the model (training dataset), and the combined data were used to update the original model parameters. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at any time and within 3 weeks from assessment by a combination of maternal demographic characteristics and medical history with PSV ratio alone and in combination with the established PE biomarkers of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). We evaluated the predictive performance of the model by examining, first, the ability to discriminate between the PE and non-PE groups using the area under the receiver-operating-characteristics curve and the detection rate (DR) at fixed screen-positive (SPR) and false-positive rates of 10% and, second, calibration by measuring the calibration slope and calibration-in-the-large. McNemar's test was used to compare the performance of screening by a biophysical test (maternal factors, MAP, UtA-PI and PSV ratio) vs a biochemical test (maternal factors, PlGF and sFlt-1), low PlGF concentration (< 10th percentile) or high sFlt-1/PlGF concentration ratio (> 90th percentile). In the validation dataset, the performance of screening by maternal factors and PSV ratio for delivery with PE within 3 weeks and at any time after assessment was consistent with that in the training dataset, and there was good agreement between the predicted and observed incidence of PE. In the combined data from the training and validation datasets, good prediction for PE was achieved in screening by a combination of maternal factors, MAP, UtA-PI, PlGF, sFlt-1 and PSV ratio, with a DR, at a 10% SPR, of 85.0% (95% CI, 76.5-91.4%) for delivery with PE within 3 weeks and 65.7% (95% CI, 59.2-71.7%) for delivery with PE at any time after assessment. The performance of a biophysical test was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio but not significantly different from the performance of a biochemical test combining maternal factors with PlGF and sFlt-1 for both PE within 3 weeks and PE at any time after assessment. Maternal ophthalmic artery PSV ratio at 35-37 weeks' gestation in combination with other biomarkers provides effective prediction of subsequent development of PE. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Predictive value of maternal serum placental growth factor levels for discordantfetal growthin twins: a retrospective cohort study.

Accurate prenatal recognition of discordantfetal growth in twins is critical for deciding suitable management strategies. We explored the predictive value of the level of maternal second-trimester placental growth factor (PLGF) as a novel indicator of discordantfetal growth. A total of 860 women pregnant with twins were enrolled, including 168 women with monochorionic twins (31 cases of discordant fetal growth and 137 without) and 692 with dichorionic twins (79 cases of discordant fetal growth and 613 without). Maternal second-trimester PLGF concentrations were measured via immunofluorescence. Maternal second-trimester PLGF levels were significantly lower in women pregnant with twins who subsequently developed discordant fetal growth than in those who did not (monochorionic twin pregnancy: P < 0.001; dichorionic twin pregnancy: P < 0.001). A 3-4 fold difference in median PLGF concentrations was detected between the two groups with both monochorionic and dichorionic twin pregnancies. Maternal second-trimester PLGF levels were significantly correlated with birth weight differences (monochorionic twin pregnancy: r = - 0.331, P < 0.001; dichorionic twin pregnancy: r = - 0.234, P < 0.001). A receiver operating characteristic curve was used to evaluate the predictive efficiency. In monochorionic twin pregnancies, the area under the curve (AUC) was 0.751 (95% confidence interval [CI]: 0.649-0.852), and the cutoff value was 187.5pg/mL with a sensitivity of 77.4% and specificity of 71.0%. In dichorionic twin pregnancies, the AUC was 0.716 (95% CI; 0.655-0.777), and the cutoff value was 252.5pg/mL with a sensitivity of 65.1% and specificity of 69.6%. Based on the above cutoff values, univariate and multivariate logistic regression analyses were performed to calculate the odds ratios (OR) for the PLGF levels. After adjustment for potential confounding factors, low PLGF concentrations still significantly increased the risk of discordant fetal growth (monochorionic twin pregnancy: adjusted OR: 7.039, 95% CI: 2.798-17.710, P < 0.001; dichorionic twin pregnancy: adjusted OR: 4.279, 95% CI: 2.572-7.120, P < 0.001). A low maternal second-trimester PLGF level is considered a remarkable risk factor and potential predictor of discordant fetal growth. This finding provides a complementary screening strategy for the prediction of discordant fetal growth and offers a unique perspective for the subsequent research in this field.

Screening for pre-eclampsia by maternal serum glycosylated fibronectin and angiogenic markers at 36 weeks' gestation.

First, to examine the predictive performance of maternal serum glycosylated fibronectin (GlyFn) at 35 + 0 to 36 + 6 weeks' gestation in screening for delivery with pre-eclampsia (PE) and delivery with gestational hypertension (GH) at ≥ 37 weeks' gestation, both within 3 weeks and at any time after the examination. Second, to compare the predictive performance for delivery with PE and delivery with GH of various combinations of biomarkers, including GlyFn, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Third, to compare the predictive performance for delivery with PE and delivery with GH by serum PlGF concentration, sFlt-1/PlGF concentration ratio and the competing-risks model with different combinations of biomarkers as above. Fourth, to compare the predictive performance of screening at 11 + 0 to 13 + 6 weeks vs 35 + 0 to 36 + 6 weeks for delivery with PE and delivery with GH at ≥ 37 weeks' gestation. This was a case-control study in which maternal serum GlyFn was measured in stored samples from a non-intervention screening study in singleton pregnancies at 35 + 0 to 36 + 6 weeks' gestation using a point-of-care device. We used samples from women who delivered at ≥ 37 weeks' gestation, including 100 who developed PE, 100 who developed GH and 600 controls who did not develop PE or GH. In all cases, MAP, UtA-PI, PlGF and sFlt-1 were measured during the routine visit at 35 + 0 to 36 + 6 weeks. We used samples from patients that had been examined previously at 11 + 0 to 13 + 6 weeks' gestation. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements from the medical history. Similarly, the measured values of MAP, UtA-PI, PlGF and sFlt-1 were converted to MoM. The competing-risks model was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal risk factors, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE. The performance of screening of different strategies was estimated by examining the detection rate (DR) at a 10% fixed false-positive rate (FPR) and McNemar's test was used to compare the DRs between the different methods of screening. The DR, at 10% FPR, of screening by the triple test (maternal risk factors plus MAP, PlGF and sFlt-1) was 83.7% (95% CI, 70.3-92.7%) for delivery with PE within 3 weeks of screening and 80.0% (95% CI, 70.8-87.3%) for delivery with PE at any time after screening, and this performance was not improved by the addition of GlyFn. The performance of screening by a combination of maternal risk factors, MAP, PlGF and GlyFn was similar to that of the triple test, both for delivery with PE within 3 weeks and at any time after screening. The performance of screening by a combination of maternal risk factors, MAP, UtA-PI and GlyFn was similar to that of the triple test, and they were both superior to screening by low PlGF concentration (PE within 3 weeks: DR, 65.3% (95% CI, 50.4-78.3%); PE at any time: DR, 56.0% (95% CI, 45.7-65.9%)) or high sFlt-1/PlGF concentration ratio (PE within 3 weeks: DR, 73.5% (95% CI, 58.9-85.1%); PE at any time: DR, 63.0% (95% CI, 52.8-72.4%)). The predictive performance of screening at 35 + 0 to 36 + 6 weeks' gestation for delivery with PE and delivery with GH at ≥ 37 weeks' gestation was by far superior to screening at 11 + 0 to 13 + 6 weeks. GlyFn is a potentially useful biomarker in third-trimester screening for term PE and term GH, but the findings of this case-control study need to be validated by prospective screening studies. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction using serum glycosylated fibronectin and angiogenic factors of superimposed pre-eclampsia in women with chronic hypertension.

To compare the predictive performance for delivery with pre-eclampsia (PE) within 2 weeks of assessment in women with chronic hypertension at 24-41 weeks' gestation between serum glycosylated fibronectin (GlyFn) concentration, serum placental growth factor (PlGF) concentration and soluble fms-like tyrosine kinase-1 (sFlt-1) to PlGF concentration ratio. This was a prospective study of 104 women with a singleton pregnancy and chronic hypertension presenting at 24-41 weeks' gestation. Twenty-six (25.0%) cases developed superimposed PE within 2 weeks of sampling. We compared the predictive performance for superimposed PE between GlyFn, PlGF and the sFlt-1/PlGF ratio at a fixed screen-positive rate of approximately 10%. The median gestational age at sampling was 34.1 (interquartile range, 31.5-35.6)weeks and 84.6% (88/104) of cases were sampled at < 36 weeks. The predictive performance for superimposed PE of the three methods of screening was similar, with detection rates of about 23-27%, at a screen-positive rate of 11% and a false-positive rate of about 5%. Measurement of GlyFn is a simple point-of-care test that can be carried out without need for a laboratory and provide results within 10 min of testing. In this respect, it could potentially replace the angiogenic markers that are used currently in the prediction of imminent PE in high-risk women. However, neither GlyFn nor angiogenic factors are likely to improve the management of women with chronic hypertension because their predictive performance for superimposed PE is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Association of GDF15, NTpoBNP and PLGF with subclinical cardiac dysfunction in type 2 diabetes: effects of novel antidiabetic treatment

Abstract Background In type 2 diabetics, we investigated the effects of insulin, GLP-1Ra, SGLT-2i and their combination on blood biomarkers of cardiac function and their association with left ventricular and atrial function. Patients and methods A total of 200 diabetics (60.3±10.3-year-old) treated with metformin were randomized to insulin (n= 50), liraglutide (n=50), empagliflozin (n=50) or their combination (GLP-1RA+SGLT-2i) (n= 50) . We measured at baseline and 6 months post-treatment: (a) perfused boundary region of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness), (b) pulse wave velocity (PWV), (c) Left Ventricular (LV) Global Longitudinal Strain (GLS) and Torsion, (d) LV Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE), (e) Left atrial reservoir strain (LASr) and (f) Growth/Differentiation Factor-15 (GDF-15), NTproBNP, Placental Growth Factor (PLGF) as markers of cardiac dysfunction. Results Increasing GGDF-15 levels at baseline were related with increasing PWV (r=0.357, p&amp;lt;0.001). Moreover, increasing GDF-15 was related with reduced absolute GLS values (r=-0.425, p=0.005), increased LV Torsion (r=0.309, p=0.035), Twisting Velocity (r=0.345, p=0.018) and E/E’ (r=0.307, p=0.041) as well as reduced Untwisting velocity (r=-0.383, p=0.008) and LASr (r=-0,388, p=0.005). Increasing NTproBNP concentration at baseline was related with increasing PWV (r=0.445, p=0.001 and PBR5-25 (r=0.222, p=0.04) . Also, increasing NTroBNP was related with reduced absolute GLS (r=-0.454, p=0.002), LV GL strain rate (r=-0.360, p=0.008) , increased LV Torsion (r=0.329, p=0.029) and E/E’ (r=0.365, p=0.021). Increasing NTproBNP was also related with decreasing GWI (r=-0.471, p&amp;lt;0.001), GWE (r=-0.555, p&amp;lt;0.001), Untwisting velocity (r=-0.383, p=0.008) and LASr (r=-0,424, p=0.002). PLGF concentration at baseline was related with reduced absolute GLS (r=-0.341, p=0.012), LV GL strain rate (r=-0.302, p=0.008) and LASr (r=-0.321, p=0.036). At 6 months, the reduction of GDF-15 and NTproBNP levels was related with the respective reduction of PWV (p=0.022 and p=0.34) Furthermore, the reduction of NTproBNP at 6 months was related with an increase of GWI and GWE (r=0.455, p=0.006/ r=0.631, p=0.001,respectively). In patients treated with GLP-1RA, SGLT-2i and their combination, there was greater improvement of GLS, Torsion, Myocardial Work, LASr, NTproBNP, GDF-15 PLGF compared to patients treated with insulin (p&amp;lt;0.05) post-treatment. In patients treated with insulin, NTproBNP, GDF-15 and PLGF changes post-treatment were not related with the respective changes of the examined cardiac and vascular markers. Conclusion Elevated levels of GDF15, PLGF and NTproBNP are associated with cardiac and vascular dysfunction in patients with type 2 diabetics and their improvement after 6 months of treatment with GLP-1RA and /or SGLT2i is associated with improved cardiovascular function.

The role of periodic measurement of sFlt-1 and PlGF in predicting the remaining pregnancy duration in hypertensive disorders of pregnancy

ObjectivesThis study aimed to explore whether one-time or periodic measurement of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) could contribute to the prediction of the remaining pregnancy duration in hypertensive disorders of pregnancy. Study designIn this retrospective study, we enrolled pregnant women with singleton pregnancies who were admitted to our hospital due to a new rise in blood pressure at or after 20 weeks of gestation or because of worsening chronic hypertension (CH). Main outcome measuresThe concentrations of sFlt-1 and PlGF, as well as the sFlt-1/PlGF ratio, were measured only on admission or on admission and every week until delivery. The effect of these concentrations was correlated with the remaining pregnancy duration. ResultsIn this study, we enrolled 32 pregnant women: 13 were diagnosed with preeclampsia (PE), 9 with gestational hypertension (GH), and 10 with CH on admission. In the PE group, the concentration of sFlt-1 on admission had a significant negative correlation with the remaining pregnancy duration (R = -0.61, P = 0.03). In three women with PE, the concentrations were measured periodically, with increasing sFlt-1 concentrations. Among the pregnant women with CH on admission, two developed superimposed PE and their measured concentrations of sFlt-1 periodically increased. ConclusionsOnly the concentration of sFlt-1 on admission in the PE group was associated with the remaining pregnancy duration. The concentrations of sFlt-1 in PE cases periodically measured increased towards delivery. Pregnant women with CH could develop sPE if the sFlt-1 value measured periodically increase.

Maternal vascular indices at 36 weeks’ gestation in the prediction of preeclampsia

Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they wereboth superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Prognostic value of anti- and proangiogenic factors in severe preeclampsia

BACKGROUND:Over the years, preeclampsia has remained a common pathology of pregnancy. Its severe form poses a significant threat to the health of the woman and the fetus. To assess the risk of developing preeclampsia, biochemical screening for placental growth factor and soluble tyrosine kinase-1 is carried out. The soluble glycoprotein endoglin, which regulates angiogenesis by influencing cell activation, adhesion, and migration, can supplement the idea of the imbalance of vascular factors in severe preeclampsia. A holistic study of anti- and proangiogenic factors can significantly complement the diagnosis of preeclampsia at the preclinical stage and a look at the course and treatment of this pregnancy complication.&#x0D; AIM:The aim of this work was to evaluate the concentrations of anti- and proangiogenic factors (soluble glycoprotein endoglin, soluble tyrosine kinase-1, placental growth factor) and compare the obtained data with the clinical manifestations of severe preeclampsia.&#x0D; MATERIALS AND METHODS:This case-control study included 81 pregnant women. The main group consisted of patients with severe preeclampsia (n= 41), while the control group comprised individuals with normal pregnancy (n= 40). To determine soluble glycoprotein endoglin levels in biological fluids, we used a new ELISA kit developed in the Laboratory of Hybridoma Technology, Academician A.M. Granov Russian Research Center for Radiology and Surgical Technologies (Saint Petersburg, Russia). placental growth factor and soluble tyrosine kinase-1 concentrations were assessed by electrochemiluminescence immunoassay using commercial Roche Diagnostics kits. Statistical analysis was performed using the StatTech v.3.0.6 program (Stattech Ltd., Russia).&#x0D; RESULTS:When analyzing the concentrations of anti- and proangiogenic factors (soluble glycoprotein endoglin in the blood serum and urine, soluble tyrosine kinase-1, placental growth factor and the ratio of these factors), depending on the study group, statistically significant results were obtained (p 0.05). The diagnostic significance of serum and urine soluble glycoprotein endoglin levels in predicting the probability of severe preeclampsia was assessed by the method of ROC curve analysis. Statistically significant differences (p 0.05) were found in the analysis of the concentrations of anti- and pro-angiogenic factors depending on the clinical manifestations such as systolic blood pressure 160 mm Hg (except for placental growth factor level), a multiple increase in urine soluble glycoprotein endoglin level with massive proteinuria, an increase in soluble glycoprotein endoglin levels in biological fluids with an increase in edematous syndrome. Correlation analysis revealed a significant relationship between anti- and proangiogenic factors and the term of delivery, as well as urine soluble glycoprotein endoglin level and the duration of the treatment.&#x0D; CONCLUSIONS:The data obtained complement the concept of severe preeclampsia. Knowing the concentrations of soluble glycoprotein endoglin in the blood serum and urine allows for predicting the timing of delivery and the possible duration of treatment, which is critical in the management of patients with severe preeclampsia.

Impact of Angiogenic and Cardiovascular Biomarkers for Prediction of Placental Dysfunction in the First Trimester of Pregnancy.

Algorithms for first-trimester prediction of pre-eclampsia usually include maternal risk factors, blood pressure, placental growth factor (PlGF), and uterine artery Doppler pulsatility index. However, these models lack sensitivity for the prediction of late-onset pre-eclampsia and other placental complications of pregnancy, such as small for gestational age infants or preterm birth. The aim of this study was to assess the screening performance of PlGF, soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), uric acid, and high-sensitivity cardiac troponin T (hs-TnT) in the prediction of adverse obstetric outcomes related to placental insufficiency. This retrospective case-control study was based on a cohort of 1390 pregnant women, among which 210 presented pre-eclampsia, small for gestational age infants, or preterm birth. Two hundred and eight women with healthy pregnancies were selected as controls. Serum samples were collected between weeks 9 and 13 of gestation, and maternal serum concentrations of PlGF, sFlt-1, NT-proBNP, uric acid, and hs-TnT were measured. Multivariate regression analysis was used to generate predictive models combining maternal factors with the above-mentioned biomarkers. Women with placental dysfunction had lower median concentrations of PlGF (25.77 vs. 32.00 pg/mL; p < 0.001), sFlt-1 (1212.0 vs. 1363.5 pg/mL; p = 0.001), and NT-proBNP (51.22 vs. 68.71 ng/L; p < 0.001) and higher levels of uric acid (193.66 µmol/L vs. 177.40 µmol/L; p = 0.001). There was no significant difference between groups regarding the sFlt-1/PlGF ratio. Hs-TnT was not detected in 70% of the maternal serums analyzed. Altered biomarker concentrations increased the risk of the analyzed complications both in univariate and multivariate analyses. The addition of PlGF, sFlt-1, and NT-proBNP to maternal variables improved the prediction of pre-eclampsia, small for gestational age infants, and preterm birth (area under the curve: 0.710, 0.697, 0.727, and 0.697 vs. 0.668, respectively). Reclassification improvement was greater in maternal factors plus the PlGF model and maternal factors plus the NT-p roBNP model (net reclassification index, NRI: 42.2% and 53.5%, respectively). PlGF, sFlt-1, NT-proBNP, and uric acid measurements in the first trimester of pregnancy, combined with maternal factors, can improve the prediction of adverse perinatal outcomes related to placental dysfunction. In addition to PlGF, uric acid and NT-proBNP are two promising predictive biomarkers for placental dysfunction in the first trimester of pregnancy.