Placental Growth Factor Levels Research Articles

Evaluation of the angiogenic factors sFlt-1, PlGF, and the sFlt-1/PlGF ratio in preeclampsia and associated features.

Soluble Fms-like tyrosine kinase-1 (sFLT-1) and placental growth factor (PlGF) were previously reported to play a key role in the pathogenesis of preeclampsia (PE). We tested the link between altered PlGF and sFLT-1 levels, and their ratio (sFlt-1/PlGF) with PE and PE-associated featured in Tunisian PE cases and age- and BMI-matched normotensive women. Peripheral blood specimens from 88 women with PE, and 60 control women were tested for PlGF and sFLT by commercially available ELISA. Significant increases in sFlt-1 levels and in the sFlt-1/PlGF ratio, more than changes in PlGF levels were noted in PE subjects when compared to control women. Elevation in sFlt-1 and sFlt-1/PlGF ratio was observed at different percentile values in PE cases. The receiver operating characteristic (ROC) area under the curve (AUC) for sFlt-1, PlGF, and sFlt-1/PlGF ratio were 0.869±0.031, 0.463±0.048, and 0.759±0.039, respectively. A systematic shift in sFlt-1, but not in PlGF, distributions for higher values occurred in PE subjects. A progressive increase in the adjusted OR paralleled increased sFlt-1 and the sFlt-1/PlGF ratio percentile values; no similar trend was noted for the PlGF percentiles. Increased sFlt-1 levels and sFlt-1/PlGF ratio were significantly correlated with dysmenorrhea, hypertension, baby weight, and C-section. In contrast, no correlation was found between PlGF and the PE-associated features tested. Increased sFlt-1 levels and corresponding sFlt-1/PlGF ratio, but not circulating PlGF levels, constitute an independent risk factor for PE.

Extended combined screening for preeclampsia prediction in women with diabetes mellitus

BACKGROUND:Early screening for preeclampsia has shown high efficiency for low-risk groups, however, the presence of systemic vascular disease in patients with diabetes mellitus complicates their use and requires the development of additional approaches to predicting preeclampsia in this group of patients.
 AIM:The aim of this study was to evaluate the effectiveness of early prediction of preeclampsia with extended combined screening in patients with pregestational types of diabetes mellitus.
 MATERIALS AND METHODS:This study included 75 pregnant women: 40 patients with type 1 diabetes mellitus, and 35 patients with type 2 diabetes mellitus. To determine the risk of further preeclampsia development, we evaluated biochemical, biophysical and anamnestic factors, along with the serum levels of placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin at 11+0to 13+6gestational weeks. The main outcome assessed was the development of preeclampsia.
 RESULTS:In patients with further development of preeclampsia (35% in type 1 and 40 % in type 2 diabetic women), we observed higher soluble fms-like tyrosine kinase 1 / placental growth factor ratios, as well as elevated serum soluble endoglin (type 1 diabetes mellitus) and soluble fms-like tyrosine kinase 1 (type 2 diabetes mellitus) levels. Isolated determination of placental growth factor showed no significant differences in the levels of this angiogenic factor in preeclampsia. A multivariate predictive model for preeclampsia demonstrated high prognostic parameters: for patients with type 1 diabetes mellitus, area under the curve was 0.96 (95% confidence interval 0.931.00), with positive predictive value 76.7% and negative predictive value 90.1%; for patients with type 2 diabetes mellitus, area under the curve was 0.94 (95% confidence interval 0.861.00), with positive predictive value 88.5% and negative predictive value 97.1%.
 CONCLUSIONS:Specific biochemical and biophysical markers of preeclampsia combined with maternal risk factors and assessment of carbohydrate metabolism can increase the predictive value of early screening studies for preeclampsia in women with pregestational diabetes mellitus.

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.
 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.
 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).
 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.
 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.

Predictive Value of Sflt-1/Plgf Ratio for Occurrence of Preeclampsia in Singleton Pregnancies: A Retrospective Study

Introduction: Preeclampsia is multisystem disorder of pregnancy, characterized by endothelial and placental dysfunction. It is classified as an early onset (which occurs &lt; 34 weeks) and late onset (which occurs ≥ 34 weeks). There is an increase of level of antiangiogenic factor of soluble form similar to tyrosine kinase 1 (sFlt-1) and decrease of level of proangiogenic placental growth factor (PlGF) at preeclampsia. High ratio sFlt-1/PlGF is connected to occurrence of preeclampsia. Materials and Methods: There was a retrospective study of the Clinic for Gynecology and Obstetrics of the University Clinical Center of Republic of Srpska (KGA UKC RS), which was implemented in period January 1st, 2020 – December 31st, 2021 and which included 224 patients hospitalized at the Department of Perinatology for suspected preeclampsia development, from 26+0 weeks of gestation until birth. One of the key criteria for the inclusion of patients in the study is the use of the sFlt-1/PlGF ratio as a marker for the onset of preeclampsia, and the determination of protein values in 24-hour urine (biuret). The antenatal state of the fetus was also monitored by ultrasound measurement of the flow resistance ratio (Ri) through the middle cerebral artery and the umbilical artery (C/U), as well as the values of the newborn’s Apgar score in the first and fifth minute of life (AS 1 and 5). The patients included in the study were divided into two groups according to gestational age: group 1 (&lt;33+6 NG) and group 2 (≥34NG). For the purposes of the research, data from patient protocol books for the specified period, as well as corresponding data from the Clinical Information System (KIS), were used. Results: Calculated values for cut off 38 for group 1 are: NPV= 76.9%, PPV=72.0%, sensitivity=85.7%, specificity=58.8%, and for group 2 are: NPV= 89 ,1%, PPV=40.8%, sensitivity=72.1%, specificity=68.5%. For cut off 85, the calculated values for group 1 are: NPV= 82.4%, PPV=85.7%, sensitivity=85.7%, specificity=82.4%, and for group 2 they are: NPV= 84.9 %, PPV=70.4%, sensitivity=44.2%, specificity=94.4%. For cutt off 110, the calculated values for group 1 are: NPV= 77.8%, PPV=85%, sensitivity=81%, specificity=82.4%, and for group 2 they are: NPV= 83.5 %, PPV=72.7%, sensitivity=37.2%, specificity=95.8%. The measured value of protein in 24h urine (biuret) in comparison with the measured values of the sFlt-1/PlGF ratio have statistical significance for predicting the onset of preeclampsia. Statistical data processing obtained by examining the measured values of the sFlt-1/PlGF ratio and the antenatal and natal condition of the fetus (C/U and AS 1 and 5) showed statistical significance, except for C/U for group 2, where p=0.32. Conclusion: Determination of the sFlt-1/PlGF ratio as well as biuret and monitoring of the antenatal and postnatal state of the fetus significantly contributes to the timely diagnostic of preeclampsia, which impacts reducing the incidence of undesirable outcomes for the mother and the fetus.

Circulatory and Placental Expression of Soluble Fms-like Tyrosine Kinase- 1 and Placental Growth Factor in HIV-infected Preeclampsia.

An imbalance between angiogenic and anti-angiogenic factors plays a fundamental role in the pathogenesis of preeclampsia (PE). Studies have shown a dysregulation of sFlt-1 and placental growth factor (PlGF) in PE. However, there are differing reports on the levels of these pro-/antiangiogenic factors in HIV-infected preeclamptic and normotensive pregnancies, possibly due to highly active antiretroviral therapy (HAART) and its immune reconstitution effect. The study aimed to investigate the effect of hypertension and ARVs on circulating and placental pro- and antiangiogenic factors in HIV-infected PE. The level of sFlt-1 expression is elevated in PE compared to normal pregnancies. PlGF was altered by placental dysfunction. Antiretroviral therapy does not impact the angiogenic shift in PE development. The angiogenic imbalance evident in the circulatory system by higher sFlt-1 compared to PlGF levels is replicated in the placenta by reduced expression of PlGF receptors in comparison to sFlt-1 receptors. However, there is a lack of data that explore the relationship between HAART and anti-angiogenic factors in the placenta and the circulation of PE comorbid with HIV infection.

Decreased serum placental growth factor levels in adult atopic dermatitis: a preliminary study.

Decreased serum placental growth factor levels in adult atopic dermatitis: a preliminary study.

Impairment of the balance of angiogenic and neurogenic polypeptides of the oral fluid in fractures of the maxilla

Introduction. Fractures of the maxilla are characterized by such features as the close location of vital anatomical structures, the visual organ, as well as the aesthetic importance of this area of the face and the presence of risk of serious complications. The aim of the work was to estimate the level of angiogenic factors in the oral fluid: vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor D (VEGF-D), placental growth factor (PIGF), platelet-derived growth factor BB (PDGF-BB) (VEGF-A, VEGF-D, PIGF, PDGF-BB) and neurotrophins: nerve growth factor (NGFb) and basic brain-derived neurotrophic factor (BDNF) in orbital maxilla fractures. Materials and methods. A single-center, open-label, prospective case-control study was conducted in which 10 patients an upper jaw fracture of the maxilla (study group) and 10 practically healthy volunteers (comparison group) were examined. Along with clinical-instrumental and laboratory examination, patients were also examined for the content of VEGF-A, VEGF-D, PIGF, PDGF-BB, NGFb and BDNF in oral fluid by multiparametric fluorescent analysis with magnetic microspheres (xMAP technology, Luminex 200, USA). Results. The content of VEGF-A, VEGF-D, NGFb did not differ significantly between trauma patients and healthy practically volunteers. The content of PIGF-1 and PDGF-BB was markedly elevated in maxillary fracture, with the latter concentration being 12-fold higher than in the comparison group. Discussion. The results suggest that such injuries are accompanies by an imbalance of angiogenic and neurogenic polypeptides, manifested by increased levels of placental growth factor, platelet-derived growth factor and basic brain-derived neurotrophic factor. Conclusions. The study of the vascular remodeling and neuroprotection is important not only for extensive skeletal and craniocerebral trauma, but also for relatively local trauma – skull bone fracture in the orbit.

EFFECT OF BLOOD GLUCOSE CONTROL TOWARDS PLASMA AND VITREOUS LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND PLACENTAL GROWTH FACTOR IN DIABETIC RATS

Purpose: To compare plasma and vitreous level of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in diabetic rats with poor blood glucose (BG) control, reconstitution of good BG control, and nondiabetic rats, and to investigate the effect of reconstitution of good BG control to VEGF and PlGF plasma and vitreous level. Methods: This is an experimental study using eighteen Sprague Dawley rats which were divided into intervention group (n=14) and control group (n=4). Intervention group were given Streptozotocin (STZ) injection to induce diabetes. After 4 weeks, intervention group was randomly divided into group I for termination and group II for reconstitution of good BG control with insulin for the following 4 weeks, and so was the control group. Plasma and vitreous samples were taken. VEGF and PlGF levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Results: Seventeen of 18 rats survived in intervention group. BG level of intervention group II decreased dramatically to normoglycemia. ELISA at month 1 showed that VEGF vitreous level tend to be higher in intervention group I compared to control I, 196.36 ± 65.24 pg/dL and 123.64 ± 44.99, respectively (p=0.20). ELISA at month 2 showed that PlGF vitreous level of intervention group I were significantly higher compared to control I, 59.04 ± 2.48 and 51.93 ± 3.15, respectively (p=0.01). Vitreous and plasma VEGF of intervention group I and II were not different, while vitreous and plasma PlGF were significantly higher in group II. Conclusions: Vitreous levels of VEGF and PlGF were increased in diabetic rats compared to nondiabetic, and reconstitution of good BG control for 1 month were unable to reduce VEGF and PlGF levels.

A phase I dose-escalation study of SYHA1813, a VEGFR and CSF1R inhibitor, in patients with recurrent High-Grade Gliomas or Advanced Solid Tumors

SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx; identifier ChiCTR2100045380).

Changes in concentrations of melatonin, PlGF, and cytokines in women with preeclampsia.

Preeclampsia (PE) is a pregnancy-related disorder that significantly increases the risk of maternal and fetal morbidity and mortality. Melatonin, a potent antioxidant, has been suggested to mitigate oxidative stress and associated damage in various pathological conditions. Placental growth factor (PlGF) plays a vital role in placental development by promoting angiogenesis. This study aimed to investigate whether the levels of melatonin, cytokines, and PlGF were higher in the venous blood of women with preeclampsia during the third trimester of pregnancy compared to those with uncomplicated pregnancies. The study involved 32 women with preeclampsia and 33 healthy pregnant women as a control group. The concentrations of melatonin and PlGF were significantly lower in women with preeclampsia compared to healthy pregnant women. Specifically, the mean level of melatonin in the preeclampsia group was 30.98 pg/ml and 55.20 pg/ml in the control group (p=0.029). Similarly, the mean level of PlGF in the preeclampsia group was 40.03 pg/ml and 213.31 pg/ml in the control group (p<0.0001). This suggests that alterations in the placental production of melatonin and PlGF may contribute to the development of preeclampsia. In contrast, we observed higher levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) in the preeclampsia group than in the control group. The mean concentration of IL-6 in the PE group was 270.79 pg/ml, whereas the control group had 224.30 pg/ml (p=0.022). Similarly, the mean concentration of IL-10 in the PE group was 41.90 pg/ml and 30.73 pg/ml in the control group (p=0.018). In women with uncomplicated pregnancies, the interaction between pro-inflammatory interleukine-6 and melatonin can be described by equality of statistical regression.

Reference ranges of anti-Müllerian hormone and interaction with placental biomarkers in early pregnancy: the Generation R Study, a population-based prospective cohort study.

The primary objective of this study is to establish maternal reference values of anti-Müllerian hormone (AMH) in a fertile multi-ethnic urban pregnant population and to evaluate the effect of gestational age. The secondary objective of this study is to explore the association between AMH and placental biomarkers. This study was embedded in the Generation R Study, an ongoing population-based prospective cohort study from early pregnancy onwards. City of Rotterdam, the Netherlands, out of hospital setting. In 5806 women, serum AMH levels were determined in early pregnancy (median 13.5 weeks; 95% range 10.5-17.2). None. Maternal AMH levels in early pregnancy and its association with placental biomarkers, including human chorionic gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFLT), and placental growth factor (PLGF). A nomogram of AMH in early pregnancy was developed. Serum AMH levels showed a decline with advancing gestational age. Higher AMH levels were associated with a higher level of the placental biomarkers hCG and sFLT in early pregnancy. This last association was predominantly mediated by hCG. AMH levels were negatively associated with PLGF levels. In this large study, we show that AMH levels in early pregnancy decrease with advancing gestational age. The association between AMH and the placental biomarkers hCG, sFLT, and PLGF suggests a better placental development with lower vascular resistance in mothers with higher AMH levels. Hence, AMH might be useful in predicting adverse pregnancy outcomes due to impaired placental development.

Preeclampsia is associated with reduced renin, aldosterone, and PlGF levels, and increased sFlt-1/PlGF ratio, and specific angiotensin-converting enzyme Ins-Del gene variants

We investigated the association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism with preeclampsia (PE) in Tunisian women. ACE I/D genotyping was done by PCR in 342 pregnant women with PE and 289 healthy pregnant women. The association between ACE I/D and PE and associated features were also evaluated. Decreased active renin concentration, plasma aldosterone concentration, and placental growth factor (PlGF) were observed in PE cases, while soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio was significantly higher in the PE group. Distribution of ACE I/D alleles and genotypes were comparable between women with PE and control women. A significant difference in the frequency of the I/I genotype was seen between PE cases and control women according to the recessive model, with a trend towards association in the codominant model. Carriers of the I/I genotype had significantly higher infant birth weights compared to the I/D and the D/D genotype carriers. A dose-dependent relationship was also seen in VEGF and PlGF plasma levels and specific ACE I/D genotypes, with the lowest VEGF levels seen in the I/I genotype carriers compared to the D/D genotype carriers. Similarly, the I/I genotype carriers had the lowest PlGF levels compared to I/D and D/D genotype carriers. Furthermore, when studying the linkage between PE features, we found a positive correlation between PAC and PIGF. Our study suggests a role for ACE I/D polymorphism in the pathogenesis of PE, possibly through modulating VEGF and PlGF levels and infant birth weight, and highlights the relationship between PAC and PlGF.

Placental Growth Factor and Pregnancy-Associated Plasma Protein-A as Potential Early Predictors of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and one of the main causes of adverse pregnancy outcomes. An early diagnosis of GDM is of fundamental importance in clinical practice. However, the major professional organizations recommend universal screening for GDM, using a 75 g oral glucose tolerance test at 24-28 weeks of gestation. A selective screening at an early stage of pregnancy is recommended only if there are maternal risk factors for diabetes. As a result, the GDM diagnosis is often delayed and established after the appearance of complications. The manifestation of GDM is directly related to insulin resistance, which is closely associated with endothelial dysfunction. The placenta, the placental peptides and hormones play a pivotal role in the manifestation and progression of insulin resistance during pregnancy. Recently, the placental growth factor (PlGF) and plasma-associated protein-A (PAPP-A), have been shown to significantly affect both insulin sensitivity and endothelial function. The principal function of PAPP-A appears to be the cleavage of circulating insulin-like growth factor binding protein-4 while PlGF has been shown to play a central role in the development and maturation of the placental vascular system and circulation. On one hand, these factors are widely used as early predictors (11-13 weeks of gestation) of complications during pregnancy, such as preeclampsia and fetal aneuploidies, in most countries. On the other hand, there is increasing evidence for their predictive role in the development of carbohydrate disorders, but some studies are rather controversial. Therefore, this review aims to summarize the available literature about the potential of serum levels of PlGF and PAPP-A as early predictors in the diagnosis of GDM.

Comparison of circulating maternal placenta growth factor levels and sonographic evaluation of patients with abnormal first trimester screening analytes.

To evaluate the role of mid-trimester placental growth factor (PlGF) in patients with abnormal circulating levels of first-trimester biomarkers. Retrospective cohort study including singleton pregnancies complicated by abnormal first-trimester biomarkers (2017-2020). Pregnancies complicated with chromosomal/structural anomalies were excluded. All patients had ultrasound imaging including uterine artery Doppler combined with measurement of maternal circulating PlGF. Sonographic findings, maternal and perinatal outcomes, and placental histopathology were compared between pregnancies with normal and low (<10th percentile for gestational age) PlGF levels. The diagnostic accuracy of PlGF for the prediction of specific placental-mediated complications was compared with the uterine artery Doppler assessment and additional sonographic findings. Seventy-one pregnancies were assessed, of which 35 (49.3%) had low PlGF levels. Maternal sociodemographic characteristics, nulliparity, and aspirin consumption were comparable. In comparison with patients with normal PlGF levels, individuals with low PlGF levels had a higher rate of fetal growth restriction (EFW <3rd centile; 42.9% vs. 8.3%, p=0.001), preterm-preeclampsia (22.9% vs. 0%, p=0.002), preterm delivery <34weeks (54.3% vs. 8.3%, p<0.001) and maternal vascular malperfusion placental pathology (72.7% vs. 21.7%, p<0.001) following delivery. Adjusting for uterine artery Doppler and fetal biometry status, mid-trimester low PlGF remained significantly associated with these placental-mediated complications. The predictive capacity of PlGF outperformed ultrasound imaging with only minimal diagnostic improvement when ultrasound information was combined with PlGF status. In pregnancies with unexplained abnormal first-trimester biomarkers, mid-trimester PlGF outperformed a comprehensive ultrasound assessment in the identification of a subset of patients destined to develop placental dysfunction. This blood test may be an alternative initial approach in this context, especially where access to specialist care is more geographically challenging.

Maternal serum levels of soluble fms-like tyrosine kinase-1 and placental growth factor at 20 and 28 weeks of gestational age and the risk of spontaneous preterm birth

Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear. This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks' gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth. The biomarkers were measured in maternal serum at 20- and 28-weeks' gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks' gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification. Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks' gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61-0.92]; P=.006 and 0.71 [0.59-0.87]; P=.0009, respectively). At 28 weeks' gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks' gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13-1.63]; P=.001) and the soluble fms-like tyrosine kinase-1:placental growth factor ratio (1.50 [1.30-1.73]; P<.0001), and a strong negative association with the rate of increase in placental growth factor (0.71 [0.61-0.82]; P<.0001). Women who were in the highest decile of increase in the soluble fms-like tyrosine kinase-1:placental growth factor ratio and the lowest decile of femur length growth between 20 and 28 weeks' gestation had approximately 9-fold risk of spontaneous preterm birth (9.27 [4.21-20.37]; P<.0001). Competing-risks regression yielded similar results. Changing levels of soluble fms-like tyrosine kinase-1 and placental growth factor are indicative of placental dysfunction and are strongly associated with the risk of spontaneous preterm birth, especially when combined with slower fetal femur length growth.

Correlation of sFlt/PlGF ratio with severity of preeclampsia in an Indian population

Preeclampsia affects 2% to 8% of pregnant women and significantly increases the risk for maternal and perinatal morbidity, especially in low- and middle-income countries. There is increasing evidence to support the use of biochemical markers such as placental growth factor and soluble fms-like tyrosine kinase-1 in predicting the severity of preeclampsia and to rule out severe disease in clinical conditions masquerading as severe preeclampsia. This study aimed to assess the role of the sFlt-1/PlGF ratio in predicting adverse perinatal and maternal outcomes in women with preeclampsia in a South Asian population with a higher rate of the disease and its associated complications. This was a prospective cohort study of women diagnosed with preeclampsia or suspected to have preeclampsia who underwent biophysical and biochemical investigations to measure the severity, including determining maternal hemodynamic indices, mean arterial pressure, fetal biometric and Doppler parameters, and soluble fms-like tyrosine kinase-1 and placental growth factor levels. The performance of these markers, individually or in combination, in predicting adverse perinatal and maternal outcomes was then assessed using receiver operating characteristic curve analysis. An adverse maternal outcome was defined as 1 or more of severe hypertension; admission to the intensive care unit; eclampsia; placental abruption; hemolysis, elevated liver enzymes, low-platelet count syndrome; disseminated intravascular coagulation; platelets <100×109/L; creatinine >1.1 mg/dL; and alanine aminotransferase >100 U/L. An adverse perinatal outcome was defined as 1 or more of preterm birth ≤34+0 weeks' gestation, neonatal intensive care unit admission for >48 hours, respiratory distress syndrome, intraventricular hemorrhage, hypoxic ischemic encephalopathy, necrotizing enterocolitis, retinopathy of prematurity, and confirmed fetal infection. We recruited 91 women with preeclampsia with a mean gestational age of 30.63±2.86 weeks. Women who had adverse maternal events had higher median maternal concentrations of soluble fms-like tyrosine kinase (11,500.0 pg/mL vs 3051.0 pg/mL; P<.001), lower concentrations of placental growth factor (44.88 pg/mL vs 148.50 pg/mL; P<.001), and a higher sFlt-1/PlGF ratio (306.22 vs 30.63; P<.001) than women who did not. Pregnancies with an adverse perinatal outcome also had a higher soluble fms-like tyrosine kinase concentration (12,100.0 pg/mL vs 3051.0 pg/mL; P<.001), lower placental growth factor concentration (27.2 pg/mL vs 148.50 pg/mL; P<.001), and higher sFlt-1/PlGF ratio (378.45.4 vs 30.63; P<.001). The area under the receiver operating characteristic curve showed that soluble fms-like tyrosine kinase and placental growth factor were the best biomarkers when compared with other biochemical markers to predict adverse maternal (area under the curve, 0.81; 95% confidence interval, 0.72-0.90) and fetal (area under the curve, 0.88; 95% confidence interval, 0.80-0.96) outcomes in preeclampsia. The sFlt-1/PlGF ratio correlates better with adverse maternal and perinatal outcomes than any other biochemical marker in an Indian population. The incorporation of the sFlt-1/PlGF ratio in women with preeclampsia can help in predicting the severity of the condition and the timings of the delivery.

Designing and Developing Enzyme-Linked Immunosorbent Assay Sandwich Kit for Measuring Placental Growth Factor Concentration.

Placental growth factor (PlGF) is an angiogenic factor belonging to vascular endothelial growth factor family. This factor is mainly expressed in the placenta and have important role in blood supply to embryonic tissues and fetal. According to accumulated data after 10th week of gestational age the expression of PlGF is increased. The peak of this factor is seen in the 30th week of pregnancy. The abnormal expression of PlGF have been seen in some diseases such as preeclampsia, eclampsia, cancer, and atherosclerotic lesions. Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys. As noted the level of PlGF decreased in preeclampsia is, therefore, timely and accurate measurement of this factor could help in diagnosing preeclampsia. In this study, we worked on development of sandwich enzyme-linked immunosorbent assay (ELISA) kit for measurement of PlGF, to this end, bivalent single-domain monoclonal antibody with high affinity binding was used as detection antibody and rabbit polyclonal antibody with strong signal to PlGF was used as capture antibody. Both types of antibodies were produced in the laboratory. Therefore, this study showed that the designed kit can measure PlGF up to 7.5 pg/mL. Intra-assay accuracy was <10% and interassay accuracy was <15%. The ELISA sandwich kit had the appropriate sensitivity and accuracy in measuring human PlGF.

Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of pre-eclampsia and fetal growth restriction.

Pre-eclampsia (PE) is characterized by placental and maternal endothelial dysfunction, and associated with fetal growth restriction (FGR), placental abruption, preterm delivery and stillbirth. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by placenta-related disorders. In this Review, we summarize the existing knowledge, examining the performance of maternal PlGF, sFlt-1 and the sFlt-1/PlGF ratio for screening PE, predicting development of PE in the short term, diagnosing PE, monitoring established PE and predicting other placenta-related disorders in singleton pregnancy. We also discuss the performance of PlGF and the sFlt-1/PlGF ratio for predicting PE in twin pregnancy. For first-trimester screening in singleton pregnancy, a more accurate way of identifying high-risk women than current practice is to combine maternal PlGF levels with clinical risk factors and ultrasound markers. Later in pregnancy, the sFlt-1/PlGF ratio has advantages over PlGF because it has a higher pooled sensitivity and specificity for diagnosing and monitoring PE. It has clinical value because it can rule out the development of PE in the 1-4-week period after the test. Once a diagnosis of PE is established, repeat measurement of sFlt-1 and PlGF can help monitor progression of the condition and may inform clinical decision-making regarding the optimal time for delivery. The sFlt-1/PlGF ratio is useful for predicting FGR and preterm delivery, but the association between stillbirth and the angiogenic factors is unclear. The sFlt-1/PlGF ratio can be used to predict PE in twin pregnancy, although different sFlt-1/PlGF ratio cut-offs from those for singleton pregnancy should be applied for optimal performance. In summary, PlGF, sFlt-1 and the sFlt-1/PlGF ratio are useful for screening, diagnosing, predicting and monitoring placenta-related disorders in singleton and twin pregnancy. We propose that tests for these angiogenic factors are integrated more fully into clinical practice.© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A prospective and comparative investigation of blood sFlt-1, P1GF, and niacin concentrations in women with premature ovarian insufficiency.

Endothelial dysfunction is an important component of preeclampsia like premature ovarian insufficiency (POI), and it is reported that placental growth factor (P1GF) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1) levels are important in preeclampsia. Extra-placental sources for P1GF and sFlt-1 have also been identified, including various cell types. In animal models of POI, niacin treatment inhibited follicular apoptosis under hazardous conditions while significantly reducing cumulus cell apoptosis. The number of developing follicles also increased after niacin was given. This study was designed to determine blood sFlt-1, P1GF, and niacin concentrations in women with idiopathic POI (iPOI) compared with those of healthy women. The study comprised 45 women with iPOI and 45 healthy women. Blood was obtained and analyzed at the early follicular phase of the menstrual cycle and sFlt-1, P1GF, and niacin levels were measured using a commercially available enzyme-linked immunosorbent assay kit. No significant differences were observed in the two groups according to the gravidity numbers, parity, abortion, live births, and menarche ages (p ≥ 0.05). In the iPOI group, the mean anti-mullerian hormone value was 0.03 ± 0.04 (min-max, 0.00-0.21)ng/ml. sFlt-1, P1GF, niacin levels, and also the sFlt-1/P1GF ratio were lower in the iPOI group (p < 0.01). A significant discriminative role of sFlt-1, P1GF, niacin levels, and the sFlt-1/P1GF ratio for the presence of iPOI, with cut-off values of 5.13, 10.28, 37.17, and 0.61 ng/ml, respectively, were reported in the receiver operating characteristics curve analysis. Lower levels of P1GF, sFlt-1, niacin, and sFlt-1/P1GF ratios may be associated with the development of POI/iPOI. Further studies are required to better understand the etiopathogenesis of POI/iPOI. NCT04641624 (clinicaltrials.gov).