Placental Growth Factor Concentrations Research Articles

Diagnostic accuracy of the Gaussian first-trimester combined screening for pre-eclampsia to predict small-for-gestational-age neonates.

Pre-eclampsia and delivery of small-for-gestational-age (SGA) neonates can be predicted from the first trimester. A Gaussian model for prediction of PE has recently been described, although its capacity to predict SGA is still unknown. This was a secondary analysis of a prospective cohort study conducted at Vall d'Hebron University Hospital (Barcelona) in 2483 single pregnancies from October 2015 to September 2017. Mean arterial blood pressure and mean uterine artery pulsatility index were recorded at the first-trimester scan. Serum concentrations of placental growth factor and pregnancy-associated plasma protein-A were assessed between 8+0 and 13+6 weeks. The predictive capacities of early (<32weeks) and preterm (<37weeks) SGA were tested. For SGA without pre-eclampsia, detection rates of 25.0% (95% confidence interval [CI] 0-75.0) for early SGA and 14.3% (95% CI 3.6-28.6) for preterm SGA were achieved. For SGA with pre-eclampsia, the algorithm showed detection rates of 100.0% (95% CI 25.0-100.0) for early SGA and 56.3% (95% CI 31.3-81.3) for preterm SGA. This algorithm identifies 62.5% of early SGA and 27.3% of preterm SGA. Combined screening for predicting both pre-eclampsia and SGA by using the Gaussian algorithm is feasible and would simplify clinical practice.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies

Objective: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. Methods: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. Results: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks’ gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks’ gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days’ gestation. Conclusions: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks’ gestation but appear higher in twin pregnancies thereafter.

Diagnostic and prognostic value of placental growth factor serum concentration in clear cell renal cell carcinoma.

Placental Growth Factor (PlGF) plays a crucial role in angiogenesis and was identified as a potential prognostic biomarker in various types of cancer. Therefore, we evaluated the diagnostic accuracy and prognostic value of PlGF serum concentration in patients with clear cell renal cell carcinoma (ccRCC). A total of 49 patients subjected to partial or radical nephrectomy for ccRCC [localized without relapse (lccRCC; n=31), localized with later relapse (rccRCC; n=8), primary metastatic cancer (mccRCC; n=10); median of follow-up 4.4 years] were enrolled in a prospective study to assess the significance of PlGF serum concentration. PlGF was measured prior to surgery and 3 months postoperatively. Our control group consisted of 38 healthy subjects. PlGF serum concentration was significantly higher in ccRCC compared to controls (P=0.002). The cut-off value of PlGF concentration for the risk of ccRCC was determined at 12.71 pg/mL (AUC=0.729; P=0.0001). Prior to surgery, among ccRCC subgroups, significantly higher PlGF concentration was detected in mccRCC compared to lccRCC (P=0.002). Postoperatively, we observed a tendency to higher PlGF serum concentration in rccRCC compared to lccRCC subgroup, however without significance (P=0.17). The cut-off value for the risk of relapse was 11.41 pg/mL (AUC=0.792; P=0.0003). In subjects with localized ccRCC with PlGF concentration below 11.41 pg/mL 3-years cancer specific survival was 93% compared to 61% in subject with concentration above the cut-off value (P=0.018). Based on our findings, PlGF serum concentration seems to be a useful biomarker in diagnostics and prediction of prognosis in ccRCC.

Individual exposure to urban air pollution and its correlation with placental angiogenic markers in the first trimester of pregnancy, in São Paulo, Brazil.

Pollution of the atmosphere is known that may lead to adverse obstetric outcomes, including fetal growth restriction, gestational hypertension, and preeclampsia. Such disorders are correlated with imbalances in angiogenic factors, which may also be involved in the pathological mechanism as the pollutants impact placental and maternal physiology. In the first trimester of gestation, this study assessed the outcomes of personal maternal short period exposure to air pollution on soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PLGF) of pregnant women blood concentrations. This was a cross-sectional study, held in the city of São Paulo, Brazil, and conducted with low-risk pregnant women, who carried personal passive nitrogen dioxide (NO2) and ozone (O3) monitors for about a few days preceding the ultrasound evaluation, and on this day, the venous blood sample was collected to measure the angiogenic factors sFlt1 and PLGF and their ratio (sFlt1/PLGF) by enzyme-linked immunosorbent assay (ELISA). By means of multiple regression models, the effect of the studied pollutants on the log-transformed concentrations of the angiogenic factors was evaluated. One hundred thirty-one patients were included. The log of the sFlt1/PLGF ratio increased with rising NO2 levels (p = 0.021 and beta = 0.206), and the log of the PLGF concentration showed a negative correlation with NO2 (p = 0.008 and beta = - 0.234). NO2, an indicator of the levels of primary air pollutants, presented significant positive correlation with an increased sFlt1/PLGF ratio and diminished PLGF levels, which may reflect an antiangiogenic state generated by air pollution exposure.

27 Metformin to treat Preterm Pre-eclampsia (PI-2): A randomised, double blind, placebo-controlled trial

Preterm preeclampsia has high rates of maternal and perinatal morbidity and mortality. No drugs have clearly shown a prolongation in gestation. Preclinical studies have identified metformin as a potential treatment. We performed a double-blind, randomised placebo-controlled trial at Tygerberg Hospital, South Africa. We randomly assigned women with preterm preeclampsia between 26+0 to 31+6 weeks gestation and undergoing expectant management to 3 grams of oral metformin XR (extended released) in divided doses, or placebo. The primary outcome was prolongation of pregnancy. Secondary outcomes included maternal and neonatal composite, and individual outcomes. Before the trial we performed metformin pharmacokinetic studies on 15 women with preterm preeclampsia. Between Feb 2018 and Mar 2020 we randomly allocated 180 participants to receive metformin (n=90) or placebo (n=90). Pharmacokinetic studies demonstrated oral metformin XR resulted in good circulating drug concentrations. The primary outcome analysis included 87 allocated to metformin and 84 assigned to placebo. The median time from randomization to delivery was 16.2 days (interquartile range (IQR), 5.2-28.8 days) in the metformin group and 9.5 days (IQR 3.4-22.7) days in the placebo group (difference of 6.7 days (95% Confidence Interval (CI) -0.17 to 13.64; P=0.056; Fig 1). In a pre-specified per protocol analysis that included only those who were compliant, the median prolongation was 16.2 (IQR 5.3-27.5; n=75) versus 7.4 (IQR 2.9-21.2; n=72) days, respectively (difference of 8.4 days, 95%CI 1.0-15.8; P=0.026). There were trends towards increased birthweight (1538g vs 1402g, difference of 136g, 95% CI-12 to 285;P=0.07) and a decreased length of stay (12 vs 18.0, difference of 6 days (95% CI-0.4 to 12.4;P=0.07) in the neonatal nursery among those in the metformin group (Table 1). There were no differences in composite maternal or neonatal outcomes or circulating concentrations of sFlt-1 or placental growth factor. In women with preterm preeclampsia, metformin prolongs gestation and may improve neonatal outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Macular Microvascular Changes and Their Correlation With Peripheral Nonperfusion in Branch Retinal Vein Occlusion

To investigate the correlation between macular microvascular alterations on optical coherence tomography angiography (OCTA) and retinal ischemia on ultra-widefield fluorescein angiography (UWF FA) in eyes with branch retinal vein occlusion (BRVO). Cross-sectional study. This prospective study was performed from September 2019 to June 2020 at Yeungnam University Medical Center. We included 60 patients with treatment-naïve BRVO. Two independent, masked graders analyzed OCTA parameters, including vessel density, skeletal density, and fractal dimension (FD), and UWF FA parameters, including retinal nonperfusion area (NPA) and ischemic index (ISI), from various concentric regions (perimacular region, 0.5-3mm radius; near-peripheral region, 3-10mm; midperipheral region, 10-15mm; far-peripheral region, >15mm). A repeated-measures analysis of variance test and a paired t test were performed for inter-visit and inter-regional comparisons, and Pearson correlation coefficient and multivariate regression analyses were performed to examine the correlation between UWF FA and OCTA parameters. The OCTA parameters from both the superficial and deep capillary plexuses (DCP) were significantly correlated with NPA and ISI in all concentric regions. Even after adjusting for several covariates, all OCTA parameters revealed a significant association with ISI on UWF FA. Moreover, OCTA parameters from DCP were significantly correlated with concentrations of placental growth factor and vascular endothelial growth factor. Although all OCTA parameters achieved excellent results of area under the curve (AUC) > 0.9 for detecting severe retinal ischemia, defined as ISI >10%, FD reduction in DCP was the most reliable parameter (AUC= 0.948, P < .001), and 5.39% was the best cut-off point for predicting ISI > 10%. OCTA is a useful noninvasive tool not only for evaluation of macular microvasculature but for supposition of peripheral nonperfusion in eyes with BRVO.

Increasing efficiency of preterm birth prediction

Abstract. The disturbed placentation in a certain way plays an important role in the pathogenesis of great obstetric syndromes. Therefore, the possibility of using biochemical indicators of the level of placental growth factor (PlGF) and fms-like tyrosine kinase (sFlt-1) for predicting preterm labor is of great interest. The aim of the study was developing criteria for predicting preterm labor based on the combined use of ultrasound cervicometry and the concentration of PlGF and sFlt-1. Materials and methods. A total of 227 pregnant women were examined, 190 of whom had preterm birth. Group I included 48 women whose pregnancy completed at 23 to 27 weeks. In group II, 142 women with prematurity in terms of 28 to 36 weeks were observed. Group III included 37 women with a healthy pregnancy, which completed at 38–41 weeks. All patients involved in the study underwent ultrasound cervicometry on a Voluson 730 (GE Healthcare, USA) at 16 weeks, and also the concentration of PlGF and sFlt-1 in blood serum by electrochemiluminescence immunoassay using a Cobas e411 analyzer was studied (Roche diagnostics, Switzerland). Results. The study revealed a significant (p &lt; 0.001) decrease in the average concentration of PlGF in the blood serum by 65 % associated with an increased level of sFlt-1 by 93% in women with early termination of pregnancy – 23–27 weeks (group I) in relation to women with a healthy pregnancy. In women with preterm birth at 28–36 weeks of gestation (group II), a similar trend of changes was observed: the PlGF level significantly (p = 0.014) decreased on average by 68 % in relation to women with a healthy pregnancy. In women of group I, the value of the sFlt-1 / PlGF ratio exceeded (p &lt; 0.001) the values of patients in group III by 14 times. But an even more pronounced imbalance of angiogenic factors was observed in women of group II – on average 16 times. Two main markers were used to predict premature birth: shortening of the cervix according to ultrasound cervicometry data of less than 30 mm, as well as the sFlt-1/PlGF ratio of more than 50 conv. units. The odds ratio (OR) of preterm birth in the case of using only the length of the cervix was 34,133 (95 % confidence interval – 12.308–94.660). OR in the case of combined use of cervicometry data and angiogenesis variables was 148.750 (95 % confidence interval – 33.243–665.593). Conclusion. Thus, the use of an additional biochemical marker significantly improved the accuracy of preterm labor prediction.

Study of the relationship between the parameters of complex prenatal screening of the first trimester of pregnancy with a risk of the most common aneuploidies

Complex prenatal screening of the first trimester remains the most accessible and effective way of stratifying the risks of fetal chromosomal abnormalities in the general population, which has satisfactory sensitivity and specificity. Over the last decade, due to including additional parameters (average pulsation index of blood flow in the uterine arteries, average blood pressure, placental growth factor concentration, obstetric and somatic anamnesis data), it has also become a tool for determining obstetric risks. The objective: to study the effect of these additional parameters on the accuracy of predicting the most common aneuploidies was made. Materials and methods. The cohort included 2164 pregnant women at 11+0 – 13+6 weeks of gestation, who underwent extended complex screening of the first trimester, which aimed to determine the risk of trisomy on the 21st, 13th and 18th chromosomes in the fetus and calculation risk of perinatal complications, namely: premature birth, preeclampsia and fetal growth retardation. Results. It was found that the history of miscarriage at 13–22 weeks of pregnancy (P=0,0006), increased resistance in the uterine arteries (P=0,0307), decreased concentration of placental growth factor (P=&lt;0,0001) and increased mean blood pressure (P=0,0125) correlate with a high risk of trisomy of chromosome 21. Type I diabetes mellitus in pregnant women (P=0,0477) correlates with an increased risk of trisomy on chromosome 18. The concentration of placental growth factor (P=&lt;0,0001) correlates with an increased risk of trisomy on chromosome 13. Conclusions. The data obtained require detailed analysis in the context of the possibility of optimizing mathematical models for predicting aneuploidy, as well as studying the relationship between markers of trophoblast invasion and chromosomal pathology of the fetus to better understand the mechanisms of first trimester fetal loss and placental dysfunction in the second half of pregnancy.

Plasma levels of melatonin, certain cytokines and placental growth factor at non-pharmacological correction of pineal function in pregnant women with intrauterine growth restriction

The pineal gland produces the important hormone melatonin, the level of which in the blood of pregnant women decreases in case of placental insufficiency. The effect of dysfunction of the pineal gland on the immune system of pregnant women and on the angiogenic activity of the placenta during pregnancy remains insufficiently studied. Objective: to establish the effect of our method of non-drug correction of function of pineal gland on the state of the cytokine part of the immune system and on the synthesis of placental growth factor (PlGF) in pregnant women with placental insufficiency manifesting as fetal intrauterine growth restriction (IUGR). Material and methods. 46 pregnant women with IUGR at 30-36 weeks of gestation were examined. The group was divided into two subgroups: with non-drug correction of the pineal gland function (n = 25) and without correction (n = 21). The method of correction included a set of measures of following of lighting regimen, activity and sleep for 14 days. The control group consisted of 20 women with uncomplicated pregnancy. Levels of melatonin, PlGF, TNF-α, IL-1β, IL-6, IL-4, IL-10 were determined in the venous blood by enzyme-linked immunosorbent assay. Results. It was established that the concentration of melatonin in the blood of pregnant women with IUGR was significantly reduced, as well as the concentration of PlGF (p &lt; 0.01). Significant changes were also found in pregnant women with placental insufficiency, namely, increased concentrations of proinflammatory cytokines, such as TNF-α (p &lt; 0.05), IL-1-β (p &lt; 0.001) and IL-6 (p &lt; 0.05), comparing to healthy pregnant women. Also, in the group of pregnant women with IUGR the levels of anti-inflammatory cytokines IL-4 (p &lt;0.001) and IL-10 (p &lt; 0.001) were elevated in comparison to the control group. After application of the developed complex of non-drug correction of pineal gland function, the concentration of melatonin in the blood of pregnant women in the subgroup of correction increased significantly, comparing to the subgroup without correction (p &lt; 0.001), as well as the level of PlGF (p &lt; 0.05). Also, significantly lower levels of proinflammatory cytokines TNF-α, IL-1-β and IL-6 were observed in pregnant women in the subgroup of correction (p &lt; 0.01). Regarding anti-inflammatory cytokines, under the influence of the developed complex of measures there was a decrease in the level of IL-4 and an increase in the level of IL-10 (p &lt; 0.01). Conclusions. When the measures, aimed at non-drug correction of function of pineal gland, are applied in pregnant women with placental insufficiency, manifested as IUGR, the following changes are observed: increased of plasma levels of melatonin and placental growth factor, decreased of levels of proinflammatory cytokines. We suggest that the pineal gland exerts its effect on the immune system through melatonin, which moderates the activity of pro- and anti-inflammatory cytokines, thereby reducing the influence of inflammation on placental tissue, what results in increasing of concentrations of placental growth factor in the blood of pregnant women.

Placental Growth Factor Predicts Time to Delivery in Women With Signs or Symptoms of Early Preterm Preeclampsia: A Prospective Multicenter Study

(Am J Obstet Gynecol. 2020;222:259.e1–259.e11) There is a clear need for quantitative testing methods to determine which patients with signs of preeclampsia may be at heightened risk for adverse pregnancy outcomes. The altered angiogenic factor concentrations including placental growth factor (PlGF) have been found to be associated with preeclampsia and precede the onset of preeclampsia by several weeks. While previous studies have found encouraging evidence that PlGF concentrations may predict adverse pregnancy outcomes, the association between angiogenic factors and time to delivery (TTD) is still unclear. This study aimed to examine the relationship between TTD and PlGF in pregnant women with gestational age &lt;35 weeks with signs of preeclampsia and to evaluate the performance of PlGF as a predictor for TTD.

Evaluation of Angiogenic Factors (PlGF and sFlt-1) in Pre-eclampsia Diagnosis.

Recent observations support the hypothesis that an imbalance between angiogenic factors has a fundamental role in the pathogenesis of pre-eclampsia and is responsible for the clinical manifestations of the disease. The goal of the present study was to evaluate the sensitivity, specificity, and the best accuracy level of Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in maternal serum and protein/creatinine ratio in urine sample to define the best cutoff point of these tests to discriminate between the patients with gestational hypertension and the patients with pre-eclampsia, to evaluate the possibility of using them as diagnostic methods. A prospective longitudinal study was performed, and blood samples were collected from 95 pregnant patients with hypertension to measure serum concentrations of biomarkers sFlt-1 and PlGF. Urine samples were collected for protein screening. Significance was set as p < 0.05. The sFlt-1/PlGF ratio demonstrated a sensitivity of 57.5% and a specificity of 60% using 50.4 as a cutoff point. The test that showed the best accuracy in the diagnosis of pre-eclampsia was protein/creatinine ratio, with a sensitivity of 78.9% and a specificity of 70% using 0.4 as a cutoff point and showing an area under the receiver operating characteristic curve of 0.80 (p < 0.001). No studied laboratory test proved to be fairly accurate for the diagnosis of pre-eclampsia, except for the protein/creatinine ratio. The evidence is insufficient to recommend biomarkers sFlt-1 and PlGF to be used for the diagnosis of pre-eclampsia.

FEATURES OF REPRODUCTIVE HEALTH OF WOMEN WITH LOW BIRTH WEIGHT AND OVERWEIGHT AT BIRTH

The aim of the study was to clarify obstetric and perinatal risk in women born with low or overweight. Materials and methods. 343 women with birth weight abnormalities were examined. From them 3 groups are made, according to criterion “weight of the woman at a birth”: I – 107 women with low weight at a birth, II – 126 with excess, III – 110 people with normal weight. The anamnesis, in particular, family and own perinatal, as well as nutritional support, anthropometric data, the structure of pregnancy complications, the rate of growth and development of the fetus, perinatal results were determined. Levels of eicosapentaenoic and docosahexaenoic acids were determined as markers of nutritional support of the organism, as indicators of angiogenesis were determined – concentration of vascular endothelial growth factor and placental growth factor in blood, morpho-functional studies of placenta were performed. Results. Women born underweight are more likely to have menstrual disorders (every 4), infertility (every 10), miscarriage (every 5) and gynecological diseases. The pathology of gestation in such women and their mothers is similar in spectrum, which is an example of intrauterine programming. The implementation of this program is facilitated by negative factors of nutritional provision: inadequate breastfeeding, economical type of nutrition in favor of restricting protein foods and deviations in the process of angiogenesis. Conclusions. The importance of perinatal history as a factor that determines the increased risk of menstrual disorders, the frequency of infertility, the pathological course of gestation during pregnancy, the predisposition to placental insufficiency and the birth of a child with low weight. Women born with low birth weight and overweight are a contingent of increased perinatal risk, which is associated with a complicated own perinatal history on the background of obstetric pathology in their mothers. This fact complements the concept of intrauterine programming.

Angiogenin, FGF-\u03b1, and IL-36\u03b2 have higher expression levels in aqueous humor of nAMD patients in comparison to cataract patients

BackgroundNumerous cytokines have been proven to participate in the pathogenesis of neovascular age-related macular degeneration (nAMD). The present study aimed to investigate the aqueous humor cytokine expression profile in nAMD patients before and after ranibizumab treatments in comparison to cataract patients.MethodsThis prospective study included 20 treatment-naïve nAMD eyes of 20 patients who received three consecutive monthly injections of ranibizumab. Aqueous humor samples were collected before the first (baseline), second (1 month later), and third (2 months later) injections. Controls were 20 age- and gender-matched cataract patients without any other ocular disease. The aqueous concentrations of 28 cytokines were measured using a multiplex bead assay. Central macular thickness (CMT) and maximum retinal thickness (MRT)-3 mm were measured by spectral domain optical coherence tomography (SD-OCT). The greatest linear diameter (GLD) was measured by fundus fluorescein angiography (FA).ResultsThree cytokines in aqueous humor, including angiogenin, interleukin-36β (IL-36β), and fibroblast growth factor-acidic (FGF-α) were significantly higher in nAMD patients in comparison to cataract patients, both before and after two consecutive monthly ranibizumab injections. Compared with the nAMD patients’ basal levels, two consecutive monthly ranibizumab injections effectively reduced the aqueous concentrations of VEGF-A and placental growth factor (PlGF), as well as the values of CMT, MRT-3 mm, and GLD.ConclusionsAngiogenin, IL-36β, and FGF-α have higher expression levels in nAMD patients in comparison to cataract patients, both before and after 2 months of ranibizumab therapy. These cytokines may have correlations with the pathogenesis of nAMD.

Effect of magnesium sulfate combined with labetalol on serum sFlt-1/PlGF ratio in patients with early-onset severe pre-eclampsia.

The aim of the present study was to investigate the therapeutic effect of magnesium sulfate combined with labetalol on the early-onset severe pre-eclampsia (ES-PE) and explore the role of soluble fms-like tyrosine kinase-1 (sFlT-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in the treatment. A total of 164 ES-PE patients admitted to the Maternity and Child Health Care Hospital of Hubei (Wuhan, China) were assigned to this observational study. Among them, 83 patients were enrolled in group A and treated with magnesium sulfate combined with labetalol hydrochloride, and 81 patients were enrolled in group B and treated with magnesium sulfate. The therapeutic effect, adverse reactions and pregnancy outcomes in the two groups were analyzed. Serum sFlt-1 and PlGF concentrations, before and after treatment, were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of pre-treatment serum sFlt-1/PlGF ratio for the clinical outcome. The effective rate was significantly higher in group A than that in group B. Group A presented superior pregnancy outcomes over group B. The serum sFlt-1 concentration and sFlt-1/PlGF ratio after treatment were significantly lower than those before treatment in groups A and B, whereas PlGF concentration was significantly higher after treatment in both groups. After treatment, group A had markedly lower serum sFlt-1 concentration and sFlt-1/PlGF ratio than group B, and markedly higher PlGF concentration than group B. The area under curve (AUC) of serum sFlt-1/PlGF ratio before treatment for the prediction of the clinical efficacy was 0.737. In conclusion, magnesium sulfate combined with labetalol could be effectively used for the treatment of ES-PE. The results of ELISA revealed that the balance of sFlT-1 and PlGF was improved after treatment and the sFlT-1/PlGF ratio was decreased. The assessment of sFlt-1/PlGF ratio before treatment was shown to have a certain predictive value for the efficacy of ES-PE treatment.

Preeclampsia and Increased Permeability Over the Blood–Brain Barrier: A Role of Vascular Endothelial Growth Receptor 2

Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood-brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia. The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert was exposed (12 hours) to plasma from women with preeclampsia (n = 28), normal pregnancy (n = 28), and nonpregnant (n = 16) controls. Transendothelial electrical resistance (TEER) and permeability to 70 kDa fluorescein isothiocyanate (FITC)-dextran were measured for the assessment of BBB integrity. We explored possible underlying mechanisms, with a focus on the expression of tight junction proteins and phosphorylation of 2 tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were also measured. hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70 kDa FITC-dextran. These cells upregulated the messenger ribonucleic acid (mRNA) levels of VEGFR2, and pY951-VEGFR2, but reduced pY1175-VEGFR2 (P < 0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between groups. There was no correlation between angiogenic biomarkers and BBB permeability. We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.

Functional response of systemic and intrafollicular placental growth factor in cycling mares.

The aim of the study was to assess the physiological reference values for systemic and intrafollicular placental growth factor (PlGF) concentrations in different categories of follicular sizes in cycling mares, according to progesterone (P4) and oestradiol (E2) patterns. Sixty ovaries were taken after slaughter from 30 clinically healthy mares. Regarding their size, the follicles were classified into three different categories, i.e. small (20-30 mm), medium-sized (31-40 mm) and large (≥41 mm), and follicular fluid (FF) was sampled from each single follicle. Intrafollicular PlGF concentrations were significantly increased in larger and medium-sized follicles compared to small follicles, and their values were 1.48 and 1.36 times higher than the systemic values, respectively. On the other hand, systemic PlGF concentrations were 1.3 times higher than those in the FF of follicles of small size. Intrafollicular P4 concentrations were significantly higher in larger follicles than in small ones, and their concentrations were 6.74 and 3.42 times higher than the systemic values, respectively. Intrafollicular E2 concentrations were significantly higher in large and medium-sized follicles than in follicles of small size, and their concentrations were 21.1, 15.4 and 8.35 times higher than the systemic values, respectively. Intrafollicular and systemic PlGF concentrations were strongly and positively correlated; nevertheless, no correlations between intrafollicular and systemic steroid hormones, PlGF and follicle diameters, PlGF and E2, or PlGF and P4 were observed. This represents the first study to characterise systemic and intrafollicular PlGF concentrations in cycling normal mares, providing evidence that the bioavailability of this factor in follicles of medium and large sizes was higher than in small follicles, independently of steroid hormone concentrations. Further studies are needed to assess the presumable implications of PlGF in follicular angiogenesis in mares, similar to those already observed in women and primates.

Cut-off values for Gaussian first-trimester screening for early-onset preeclampsia with maternal history, biochemical markers and uterine artery Doppler

IntroductionSeveral algorithms for first-trimester screening for preeclampsia are available; however, the Gaussian model algorithm is more likely to match the characteristics of different populations. It is recommended to validate a screening strategy before being implemented in clinical practice; unfortunately, the validation process might not be feasible in all settings. Thus, the aim of this study was to provide cut-off values for the Gaussian model for its use in clinical practice. Material and methodsThis prospective cohort study was conducted at Vall d’Hebron University Hospital (Barcelona) from October 2015 to September 2017. A total of 2641 women with singleton pregnancies were recruited. Recorded at the first-trimester scan were demographic characteristics, maternal obstetric history, maternal history, uterine artery Doppler and arterial blood pressure. Serum concentrations of pregnancy-associated plasma protein-A and placental growth factor were assessed from the first-trimester blood test. Detection rates and cut-off values for fixed 5%, 10 %, 15 %, 20 %, 25 % and 30 % false-positive rates were calculated for all combinations of markers. ResultsNinety (3.41 %) of the 2641 women developed preeclampsia, which was early-onset in 11 (0.42 %). The cut-off values and their respective detection rates, for the screening of early-onset PE by all possible combinations of markers involved in this model, are provided. DiscussionWhen external validation of first-trimester screening for preeclampsia before its clinical implementation is not feasible, the cut-off values from the Gaussian model algorithm provided in this study could be used and median values corrected prospectively if necessary.

Comparison of ELISA and chemiluminescence immunoassay methods for quantification of human Placental growth factor in serum

Placental growth factor (PlGF) is crucial during placental development in early pregnancy. Several studies in pregnancies with complications such as preeclampsia or small for gestational age neonates find that PlGF levels are significantly lower in the first trimester, which implies that the concentration of PlGF could be used as an early screening biomarker for these conditions. This study aimed to compare the performance of chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) for the quantification of human PlGF in serum. This is a comparative study on 88 pregnant women in the first trimester subjected to measurement of PlGF in serum using two commercially available kits: Human PlGF Quantikine HS ELISA (R&amp;amp;D Systems) and PlGF CLIA (Snibe). The overall coefficient of correlation between the tests was 0.93. When the cut-off value of 40 pg/mL was applied, it dropped significantly to 0.50 towards the lower values, while remaining an excellent 0.91 in the group with higher concentrations of PlGF. While R&amp;amp;D Systems’s ELISA seems to have better sensitivity, it is not very convenient to use for a small number of samples. Snibe’s CLIA automated method is user-friendly, fast and powerful. Both tests show excellent performance when indicating risk-free pregnancies.

Placental Growth Factor and Soluble, Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Case-Cohort (PEARL) Study.

Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. We conducted a case-cohort study including low-risk nulliparous women recruited at 11-13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35-37 weeks) and late-onset (>37 weeks) preeclampsia. The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25-38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P < 0.05). We observed a significant difference between cases and controls, with a median ratio 100 times higher in early preeclampsia (P < 0.001), 13 times higher in intermediate preeclampsia (P < 0.001), but no significant difference between groups in late-onset preeclampsia with matched controls. PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

T2* Placental Magnetic Resonance Imaging in Preterm Preeclampsia

Placental dysfunction underlies the cause of pregnancies complicated by preeclampsia. The use of placental magnetic resonance imaging to provide an insight into the pathophysiology of preeclampsia and thus assess its potential use to inform prognosis and clinical management was explored. In this prospective observational cohort study, 14 women with preterm preeclampsia and 48 gestation-matched controls using 3-Tesla magnetic resonance imaging at median of 31.6 weeks (interquartile range [IQR], 28.6-34.6) and 32.2 weeks (IQR, 28.6-33.8), respectively, were imaged. The acquired data included T2-weighted images and T2* maps of the placenta, the latter an indicative measure of placental oxygenation. Placentae in women with preeclampsia demonstrated advanced lobulation, varied lobule sizes, high granularity, and substantial areas of low-signal intensity on T2-weighted imaging, with reduced entire placental mean T2* values for gestational age (2 sample t test, t=7.49) correlating with a reduction in maternal PlGF (placental growth factor) concentrations (Spearman rank correlation coefficient 0.76) and increased lacunarity values (t=3.26). Median mean T2* reduced from 67 ms (IQR, 54-73) at 26.0 to 29.8 weeks' gestation to 38 ms (IQR, 28-40) at 34.0 to 37.9 weeks' gestation in the control group. In women with preeclampsia, median T2* was 23 ms (IQR, 20-23) at 26.0 to 29.8 weeks' gestation and remained low (22 ms [IQR, 20-26] at 34.0-37.8 weeks' gestation). Histological features of maternal vascular malperfusion were only found in placentae from women with preeclampsia. Placental volume did not differ between the control group and women with preeclampsia. Placental magnetic resonance imaging allows both objective quantification of placental function in vivo and elucidation of the complex mechanisms underlying preeclampsia development.