Placental Growth Factor Ratio Research Articles

Added value in low-risk pregnancies of longitudinal changes in uterine Doppler and circulating angiogenic factors during the third trimester in predicting term preeclampsia.

To assess the relationship between longitudinal changes in the uterine Doppler velocimetry and the maternal profile of angiogenic factors in the third trimester of pregnancy and to assess their ability to predict term preeclampsia. A cohort of low-risk pregnant women was constructed at second trimester routine scan and scheduled for a uterine Doppler evaluation and measurement of the circulating levels of angiogenic factors at ~30 and ~36 weeks. The performance of both parameters at both time-points and their change over time from the first to the second measurement in predicting term preeclampsia was evaluated by logistic regression and receiver operating characteristic curve (ROC) analyses. A total of 1172 women were analyzed, of which 28 (2.4%) women developed term preeclampsia. At ~30 weeks, a model including the ratio sFlt-1/PlGF (fms-like tyrosine kinase-1/placental growth factor) and the uterine Doppler explained 16.2% of the uncertainty of developing term preeclampsia, while at ~36 weeks the same variables explained 25.2% [p<0.001]. A model including the longitudinal changes of both predictors had an R2 of 26.8%, which was not significantly different from that of the ~36 weeks evaluation [p=0.45]. The area under the curve (AUC) of the ~36 weeks sFlt-1/PlGF ratio was significantly higher than at ~30 weeks (0.86 [0.77-0.94] vs. 0.81 [0.73-0.9]; p=0.043). The AUC of the 30-to-36 week change of the sFlt-1/PlGF ratio (0.85 [0.77-0.94]) did not significantly differ from that of at ~36 weeks (p=0.82). At ~36 weeks, for a 10% of false positives, the sFlt-1/PlGF ratio had a detection rate of 71.4%, with positive and negative likelihood ratios of 7.3 and 0.32, respectively. A cross-sectional measurement of the sFlt-1/PlGF ratio outperforms uterine Doppler in predicting term preeclampsia. The combination of both markers does not improve such prediction, nor the evaluation of the longitudinal changes between ~30 and ~36 weeks.

SFlt-1/PLGF ratio: A promising marker for early detection of preeclampsia in the second and third trimester

: Preeclampsia (PE), characterized by endothelial dysfunction, remains a significant concern in obstetrics due to its association with maternal and fetal morbidity and mortality. One significant contributor to the clinical manifestations of PE is the imbalance in the placental release of various angiogenesis regulatory factors into the maternal circulation. Low levels of the pro-angiogenic biomarker Placental Growth Factor (PLGF) and high levels of antiangiogenic biomarker sFlt-1 (soluble Fms like tyrosine kinase -1) levels are detectable several weeks before the clinical presentation of PE, making them a promising marker for early diagnosis.: This study investigates the utility of the sFlt-1/PLGF ratio in predicting and diagnosing preeclampsia during the second and third trimesters of pregnancy.: A prospective cohort study was conducted with 150 study participants comprising normotensive controls and preeclamptic cases, diagnosed based on blood pressure and proteinuria criteria. Serum samples collected in the second trimester (24-28 weeks) and third trimester (&amp;#62;28 weeks) were analyzed for PLGF and sFlt-1 levels using ELISA kit method. The sFlt-1/PLGF ratio was calculated and evaluated for its diagnostic accuracy through ROC curve analysis.: Significantly lower PLGF levels and higher sFlt-1 levels in preeclamptic pregnancies compared to normotensive pregnancies were seen in both trimesters (p &amp;#60; 0.001). The sFlt-1/PLGF ratio was markedly elevated in preeclampsia, showing strong predictive characteristics with an AUC of 0.929 (sensitivity 90%, specificity 90%) in the second trimester and an AUC of 0.986 (sensitivity 90%, specificity 96.7%) in the third trimester. These findings highlight the potential of the sFlt-1/PLGF ratio as a biomarker for early detection and risk stratification in pregnancies complicated by preeclampsia.

The Predictive Value of sFlt-1/PlGF Ratio for Postpartum Preeclampsia

Abstract Background Preeclampsia (PE) is a leading cause of maternal mortality, affecting 5% to 8% of pregnancies worldwide. Postpartum PE typically develops within the first 48 hours and can occur up to 6 weeks after childbirth and requires immediate clinical management. However, overdiagnosis may lead to unnecessary hospital admissions and overuse of medical resources. The ratio of soluble fms like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) has been evaluated as a tool to predict PE, but its utility in the postpartum setting is yet to be established. Methods In this study, we conducted a non-interventional, prospective study at NewYork-Presbysterian-Weill Cornell Hospital, measuring serum sFlt-1 and PlGF levels using Elecsys® and cobas e411 analyzer. The primary aim was to determine the predictive accuracy of the sFlt-1/PlGF ratio in postpartum PE, focusing on its sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) using a cutoff 38, as established in the PROGNOSIS study. Results Among 47 participants, 9 (19.1%) developed postpartum PE. The sFlt-1/PlGF ratio was significantly higher for the women who developed PE (55.9, IQR, 48.6-196.2) than for women without PE (19.9, IQR, 5.8-29.1). There was no significant difference in age, first-trimester body-mass index (BMI), gestational week of delivery, smoking status and nulliparous between PE and non-PE groups. Moreover, the sFlt-1/PlGF ratio at 38 cutoff point had a sensitivity of 77.8% (95% CI, 45.0-93.7) and a specificity of 81.6% (95% CI, 66.6-90.8), with a PPV of 50.0% (95% CI, 33.9-66.1). Notably, it demonstrated a high NPV of 93.9% (95% CI, 80.4-98.3). Conclusion Our findings suggest that the sFlt-1/PlGF ratio may be used as a predictor of postpartum PE, highlighting its significance in managing postpartum PE.

Understanding the role of soluble proteins and exosomes in non-invasive urine-based diagnosis of preeclampsia

Preeclampsia is a hypertensive disorder of pregnancy that can lead to stillbirth and preterm birth if not treated promptly. Currently, the diagnosis of preeclampsia relies on clinical symptoms such as hypertension and proteinuria, along with invasive blood tests. Here, we investigate the role of soluble proteins and exosomes in noninvasive diagnosing preeclampsia non-invasively using maternal urine and urine-derived exosomes. We quantified the levels of particles and the presence of TSG101 and CD63 in urine and urinary exosomes via the biologically intact exosome separation technology (BEST) platform. Then, we obtained higher levels of soluble proteins such as fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) from urine as it was than urinary exosomes. Compared to commercial blood tests, the sensitivity of the sFlt-1/PlGF ratio was found to be 4.0 times higher in urine tests and 1.5 times higher in tests utilizing urine-derived exosomes. Our findings offer promising possibilities for the early and non-invasive identification of high-risk individuals at risk of preeclampsia, allowing for comprehensive preventive management.

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-h 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.

A-311 Evaluating the Predictive Value of the sFlt-1/PlGF Ratio in Hypertensive Pregnancies for Preeclampsia

Abstract Background Preeclampsia (PE) is a hypertensive pregnancy disorder affecting around 5% of all pregnancies, and it continues to be a leading cause of maternal and neonatal morbidity and mortality in the United States. The incidence of hypertensive pregnancies is on the rise, attributed to the increasing prevalence of obesity and chronic hypertension. The development of a straightforward diagnostic test to accurately differentiate PE from gestational or chronic hypertension is crucial to avoid unnecessary hospitalizations. Despite the ongoing development of prediction models for PE, conventional clinical and laboratory measures have not been effective in predicting disease progression. Recent research has focused on the ratio of two serum biomarkers: soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), particularly in patients with a clinical suspicion of PE in acute settings. These studies have shown promise, with many indicating that the sFlt-1/PlGF ratio can effectively predict the presence or absence of PE. This study was conducted to assess the predictive value of the sFlt-1/PlGF ratio in pregnancies complicated by hypertension, aiming to contribute to the early detection and management of PE. Methods Pregnant individuals with hypertensive disorders at or above the age of 18 receiving prenatal care at NewYork-Presbysterian-Weill Cornell Hospital were enrolled in this study. We measured the levels of sFlt-1 and PlGF using fully automated Elecsys immunoassays (Roche Diagnostics). Subsequently, a prospective analysis of the serum sFlt-1/PlGF ratio was performed. A receiver operating characteristic (ROC) curve was used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the ratio in predicting PE. To assess the prognostic accuracy of the sFlt-1/PlGF ratio, patients were randomly assigned to a development and a validation cohort at a ratio of 30:70. Results We collected a total of 137 serum samples of hypertensive pregnancies, with all ≥20 weeks of gestational age (GA). Of these, 47 (34.3%) developed PE within 2 weeks. The samples were divided into two cohorts: 98 were included in the development cohort, and 39 in the validation cohort. Within these groups, 34 (34.7%) of the development cohort and 13 (33.3%) of the validation cohort developed PE within 2 weeks, respectively. In the development cohort, the median sFlt-1/PlGF ratio was 85 (Interquartile range, [IQR], 44-164) among pregnant women who developed PE within 2 weeks. This was significantly higher compared to a median ratio of 8 (IQR, 3-35) observed in those who did not develop PE (p&amp;lt;0.001). The area under the ROC curve was 0.87, indicating good discriminative ability. An optimized cutoff ratio of 38 was determined, based on the max of combined sensitivity and specificity. When applied into the validation cohort, this cutoff yields a 90% (95% confidence interval [CI], 70-97) NPV and 58% (95%CI, 37-76) PPV with an 85% sensitivity (95%CI, 58-96) and a 69% specificity (95%CI, 50-83). Conclusions In women with a hypertensive disorder of pregnancy presenting GA≥20 weeks of gestation, the measurement of serum sFlt-1/PlGF ratio demonstrated clinical value in predicting the development of PE.

A-313 Use of the Preeclampsia Ratio in the Prognosis of Preterm Delivery and Adverse Outcomes

Abstract Background Preeclampsia (PE) is a hypertensive disorder of pregnancy that is characterized by high blood pressure and end-organ dysfunction with or without proteinuria after 20 weeks gestation. PE occurs in 6-8% of pregnancies and contributes to significant fetal, neonatal, and maternal morbidity and mortality. The ratio of two angiogenic placental proteins, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), are used in the management of PE. The purpose of this study was to evaluate use of the sFlt-1/PlGF ratio (PE ratio) generated using the ADVIA Centaur® and Atellica® IM sFlt-1 assay and the ADVIA Centaur and Atellica IM PlGF assays in the prognosis of preterm delivery and adverse outcomes in women presenting with signs and symptoms of PE. Methods A total of 654 females with singleton pregnancies between gestational weeks 20+0 days and 35+6 days and who had signs and symptoms of PE, but without severe features of PE were enrolled at 24 collection sites and followed prospectively for two weeks. Serum samples were collected at enrollment and adverse outcomes that included preterm delivery were prospectively collected within the two weeks after enrollment. Serum samples from approximately half of the population (n=316) were tested in singlicate using the sFlt-1 and PlGF assays on the ADVIA Centaur system in a derivation study that determined the optimal cutoff of the PE ratio in relation to adverse outcome. The remaining serum samples (n=338) were subsequently tested on the ADVIA Centaur system in a cut-off validation study that evaluated the clinical performance (sensitivity [SE], specificity [SP], positive predictive value [PPV], negative predictive value [NPV]) of the PE ratio at the derived cutoff in relation to adverse outcome. Method comparison studies were performed between the ADVIA Centaur versus the Roche Elecsys sFlt-1 and PlGF assays (n=255) and the ADVIA Centaur versus the Atellica IM sFlt-1 and PlGF assays (n=316). Results The rate of maternal adverse outcomes within two weeks was similar in the derivation study (32.3%) and validation study (28.1%). Using a receiver operating characteristic (ROC) curve analysis with the derivation cohort, a derived cutoff of 38 showed optimal clinical performance of the PE ratio in relation to adverse outcome (SE=72.5%, SP=94.7%, PPV=84.6%, NPV=89.5%). Similar clinical performance results of the PE ratio at the cutoff of 38 in relation to adverse outcome were found with the verification cohort (SE=88.42%, SP=87.65%, PPV=73.68%, NPV=95.09%). Weighted Deming regression analysis demonstrated equivalency between the Centaur, Roche, and Atellica PE ratios with correlation coefficients (r) of 0.9242 (Centaur vs Roche) and 0.995 (Centaur vs Atellica). Conclusions Measurement of sFlt-1 and PlGF to determine PE ratio can be performed on either the ADVIA Centaur or Atellica Analyzer and can be used to identify women presenting with PE or signs and symptoms of PE who are at high risk of experiencing an adverse event in the subsequent two weeks. Not available for sale in the U.S.A. The products/features mentioned herein are not commercially available in all countries. Their future availability cannot be guaranteed.

A-308 Placental Growth Factor Kryptor Immunoassay Reveals Quality Control Imprecision and Drift

Abstract Background The utility and value of determining the soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio for predicting the likelihood of progression to pre-eclampsia in pregnant women admitted with hypertension are increasingly becoming widely recognized. A key finding of the multi-center PRAECIS trial (NEJM Evid 2022;1(12)) is the observation that sFlt-1/PlGF ratios ≥ 40 correlate with higher risk for adverse maternal outcomes. The sFlt-1 and PlGF immunoassays performed on the ThermoFisher Scientific B·R·A·H·M·S Kryptor autoanalyzer became the first FDA-approved tests in 2023 for determining sFlt-1/PlGF ratio. In this study, an evaluation of the analytical performance of the sFlt-1 and PlGF KRYPTOR immunoassays was performed, which included analyte measuring range (AMR), accuracy, precision, and stability studies. Methods Calibration and QC materials (consisting of lyophilized recombinant human proteins), test reagents and solutions, and consumables were purchased and provided by ThermoFisher Scientific. Analytical runs were performed according to vendor’s instructions by trained medical laboratory scientists. Between-day precision of our two instruments for both immunoassays was assessed by assaying all three levels of sFlt-1 and PlGF QC materials, as well as patient serum pools with low PlGF concentration, once to twice daily for multiple consecutive days. Results While the analytical performance of the sFlt-1 immunoassay was robust and performed according to expectation (within-day CV &amp;lt;1% and between-day CV &amp;lt;3%), the PlGF immunoassay was surprisingly less reliable. Imprecision and inaccuracy of the PlGF immunoassay at the low end of its analytical measurement range was reflected by both sporadically out-of-control between-day measurements of all three QC levels (with target ranges of 24 - 36 pg/mL, 80 - 120 pg/mL, and 320 - 480 pg/mL), as well as slow downward drifts of particularly the low level QC material. In one instance, a downtrend was observed from 28 pg/mL to 14 pg/mL over 6 days, even with fresh reagents, solutions, and calibration. Such shortened stability of the PlGF assay does not meet the vendor’s claims of calibration stability of 15 days and onboard kit stability of 29 days. Using vendor’s provided material, the AMR of both sFlt-1 and PlGF were adequately verified and showed excellent linearity (r2&amp;gt; 0.99). Conclusions Despite low level QC imprecision and drift, the sFlt-1/PlGF ratios determined using the B·R·A·H·M·S Kryptor analyzers are acceptable for clinical use but with the caveat that we will perform batch testing with bracketing QCs and conduct stringent QC monitoring, frequent calibrations, and reduce the onboard kit stability as defined by ThermoFisher Scientific. Our findings serve as a reminder that FDA approval does not preclude thorough verification studies of any assay prior to implementation for clinical use.

Discussion on the evaluation of the therapeutic efficacy of uterine artery blood flow parameters and serum PLGF and sFlt-1 in patients with recurrent spontaneous abortion

ObjectiveTo investigate the effects of different drug treatments on uterine artery blood flow parameters, serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and sFlt-1/PLGF in patients with recurrent spontaneous abortion and to explore the predictive value of uterine artery blood flow parameters, serum PLGF, sFlt-1, and sFlt-1/PLGF for pregnancy outcomes.MethodsThis retrospective cohort study included 173 patients who experienced recurrent spontaneous abortion and 100 control patients. Patients with recurrent spontaneous abortion were divided into an aspirin group (75 patients), aspirin combined with low molecular weight heparin (LMWH) group (68 patients), and non-drug group (30 patients) based on different drug treatments. Uterine artery blood flow parameters at gestational weeks 30-31+6 were monitored for the four groups, and serum samples were collected at gestational weeks 30-31+6 to measure the levels of serum PLGF and sFlt-1 and calculate the sFlt-1/PLGF ratio.Results1. Uterine artery blood flow parameters at gestational weeks 30-31+6 were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 2. Serum PLGF levels and the sFlt-1/PLGF ratio at gestational weeks 30-31+6 were significantly lower in the non-drug group than in the aspirin group, combined drug group, and control group, while serum sFlt-1 levels were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 3. Serum PLGF, sFlt-1, and sFlt-1/PLGF had lower diagnostic efficiency for predicting hypertensive disorders during pregnancy than the combined diagnostic efficiency of serum PLGF, sFlt-1, and sFlt-1/PLGF with uterine artery blood flow parameters at gestational weeks 30-31+6.ConclusionAspirin and aspirin combined with LMWH can upregulate serum PLGF and decrease serum sFlt-1 levels in patients with recurrent spontaneous abortion, reduce the miscarriage rate, and significantly improve pregnancy outcomes. The combination of serum PLGF, sFlt-1, sFlt-1/PLGF, and uterine artery blood flow parameters can effectively predict hypertensive disorders during pregnancy.

Prediction of adverse maternal and perinatal outcomes associated with pre-eclampsia and hypertensive disorders of pregnancy: a systematic review and meta-analysis

Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality. If women at high risk for developing complications could be identified early, level of care could be triaged, limited resources could be correctly allocated and targeted interventions to prevent complications could be implemented. We updated a systematic review and meta-analysis and added single outcomes. Women with hypertensive disorders of pregnancy were included. Exposures were tests predicting adverse maternal and/or perinatal outcomes. We searched Medline, Embase, CINAHL, and Cochrane library from January 2016-February 2024. We included studies identified from the previous review. We calculated effect measures. For similar predictive tests and outcomes, area under the receiver-operating-characteristic curve (AUROC) were pooled. This study was registered by PROSPERO: CRD42022336368. Of the 2898 studies identified, 80 were included. Thirty were added from the previous review resulting in 110 included studies with 506,178 women. Despite more than 1500 tests being performed, most outcomes could not be pooled due to heterogeneity in populations, tests, and outcome definitions. For maternal outcomes, only studies reporting on the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) model could be pooled. For the composite outcome within 48-h the AUROC was 0.78 (95% CI 0.71-0.86, N=8). There was significant heterogeneity (I 2 =95.7%). For perinatal outcomes, data were pooled for pulsatility index in the umbilical artery and soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio. Biomarkers like the sFlt-1/PlGF ratio showed promising predictive performance for some outcomes but were not externally validated. Despite including over 100 studies with more than 1500 predictors, we were unable to pool any single maternal outcomes and only a few individual perinatal outcomes. The fullPIERS model was externally validated, showing moderate accuracy which varied across studies and should be validated in each new population. Angiogenic biomarkers showed promise but need validation. Future studies should use standardized outcome measures and validate promising tests. VB is supported by the Swedish Research Council, Grant number 2020-01481. University of Gothenburg.

Expression and significance of CEMIP and CYP11B2 in serum in women with foetal growth restriction

Background Foetal growth restriction (FGR) occurs when a foetus fails to reach its growth potential. This observational study assessed the expression and significance of cell migration-including protein (CEMIP) and aldosterone synthase (CYP11B2) in the serum of pregnant women with FGR. Methods 40 singleton FGR-suffered pregnant women, as well as 40 normal singleton pregnant women, were enrolled. The expression of CEMIP and CYP11B2 in serum was detected in early pregnancy. The correlations between parameters were evaluated. The predictive variables for FGR were determined. The diagnostic value of CEMIP and CYP11B2 for FGR was analysed. Results CEMIP and CYP11B2 mRNA expression in the serum of pregnant women with FGR decreased (both P < 0.001). CEMIP (95%CI: 0.802–0.921, P < 0.001) and CYP11B2 (95%CI: 0.795–0.907, P < 0.001) mRNA expression in serum and soluble fms like tyrosine kinase-1 (sFLT1)/placental growth factor (PlGF) ratio (95%CI: 0.866–0.974, P < 0.001) were independent predictors of FGR, and CEMIP (r = −0.578, P = 0.001) and CYP11B2 (r = −0.602, P < 0.001) mRNA expression in serum were negatively correlated with sFLT1/PlGF ratio. CEMIP (AUC = 0.741) and CYP11B2 (AUC = 0.764) mRNA expression in serum had good diagnostic value for FGR. Conclusion The expression of CEMIP and CYP11B2 is reduced in the serum of pregnant women with FGR and may become new diagnostic markers for FGR.

Placental growth factor at 24-28 weeks for aspirin discontinuation in pregnancies at high risk for preterm preeclampsia: Post hoc analysis of StopPRE trial.

This study aims to evaluate the safety of discontinuing aspirin treatment at 24-28 weeks in women at high risk after first-trimester combined screening for preeclampsia (PE) and normal placental growth factor (PlGF) levels at 24-28 weeks of gestation. This is a post hoc analysis of the StopPRE trial, conducted at nine Spanish maternity hospitals from September 2019 to September 2021. In the StopPRE trial, all high-risk single pregnancies identified during first-trimester screening for PE were treated with 150 mg of daily aspirin. Out of 1604 eligible women with a soluble fms-like tyrosine kinase-1 to PlGF ratio (sFlt-1/PlGF) ≤38 at 24-28 weeks, 968 were randomly assigned in a 1:1 ratio to either continue aspirin until 36 weeks (control group) or discontinue it (intervention group). In this secondary analysis, only women with PlGF ≥100 pg/mL at 24-28 weeks were included. As in the StopPRE trial, the non-inferiority margin was set at a 1.9% difference in preterm PE incidence between the groups. Among the 13 983 screened pregnant women, 1984 (14.2%) were deemed high-risk for preterm PE, of which 397 (20.0%) were ineligible, 636 declined participation, and 32 were excluded. Ultimately, 919 women with PlGF >100 pg/mL were randomized and included in this analysis. Preterm PE occurred in 0.9% of the intervention group (4 out of 465) and 1.5% of the control group (7 out of 454), indicating non-inferiority of aspirin discontinuation. There were no significant differences between the groups in adverse pregnancy outcomes before 37 weeks, at <34 weeks, or ≥37 weeks. Minor antepartum hemorrhage incidence was significantly lower in the intervention group (absolute difference, -5.96; 95% CI, -10.10 to -1.82). Discontinuation of aspirin treatment at 24-28 weeks in women with PlGF levels ≥100 pg/mL was non-inferior to continuing until 36 weeks for preventing preterm PE. However, these findings should be interpreted with caution, as they originate from a subanalysis of the StopPRE trial.

Predictive and Diagnostic Value of the Angiogenic Proteins in Patients With Chronic Kidney Disease.

Our objective was to investigate the predictive and diagnostic accuracy of the angiogenic proteins sFlt-1 (soluble fms-like tyrosine kinase-1) and PlGF (placental growth factor) for preterm preeclampsia and explore the relationship between renal function and these proteins. We completed a blinded, prospective, longitudinal, observational study of patients with chronic kidney disease followed at a tertiary center (2018-2023). Serum samples were obtained at 3 time points along gestation (planned sampling): 12-16, 18-22, and 28-32 weeks. In addition, samples were obtained whenever preeclampsia was suspected (indicated sampling). sFlt-1 and PlGF levels remained concealed until the study ended. The primary outcome was preterm preeclampsia. The planned and indicated samples were used to estimate the predictive and diagnostic accuracy of the angiogenic proteins, respectively. Of the 97 participants, 21 (21.6%) experienced preterm preeclampsia. In asymptomatic patients with chronic kidney disease, the angiogenic proteins were predictive of preterm preeclampsia only when sampled in the third trimester, in which case the sFlt-1/PlGF ratio (false positive rate of 37% for a detection rate of 80%) was more predictive than either sFlt-1 or PlGF in isolation. In patients with suspected preeclampsia, the diagnostic accuracy of the sFlt-1/PlGF ratio (false positive rate of 26% for a detection rate of 80%) was higher than that of sFlt-1 and PlGF in isolation. Diminished renal function was associated with increased levels of PlGF. sFlt-1 and PlGF can effectively predict and improve the diagnostic accuracy for preterm preeclampsia among patients with chronic kidney disease. The optimal sFlt-1/PlGF ratio cutoff to rule out preeclampsia may need to be lower in patients with impaired renal function.

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.

Midwifery experiences in rural Southern Aotearoa New Zealand: insights into pre-eclampsia management

aim: This study investigated the experiences of rural midwives in the Southern region of Aotearoa New Zealand, focussing on practices and challenges in caring for pregnant individuals displaying signs of pre-eclampsia (PE). method: Conducted as part of the University of Otago’s Trainee Intern Healthcare Evaluation Project, investigating the efficacy of the soluble FMS-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio test, this exploratory study employed qualitative research methods. Twenty-three midwives from nine locations across the Southern region were interviewed by trainee intern doctors (TIs) using a semi-structured interview protocol. Thematic analysis was applied to the data. results: The study highlighted the challenging context of rural midwifery, emphasising diverse working conditions, geographic complexities and the impact of the midwifery shortage. Midwives’ decision making about PE depended on location, experience, scientific evidence, holistic model of care and the constant concern about PE. A model illustrating midwifery decision making in PE management was developed. conclusion: Rural midwives in Aotearoa New Zealand’s Southern region managing PE cases face complex challenges. The model derived from this study illustrates the delicate balance that rural midwives navigate, emphasising the need for strategies to support their practice and preserve Aotearoa New Zealand’s distinctive maternity care model.

Soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks’ gestation: association with spontaneous onset of labor and intrapartum fetal compromise in low-risk pregnancies

Previous evidence showed that placental dysfunction triggers spontaneous preterm or term births and intrapartum fetal compromise and often requires urgent delivery, thereby exposing both the fetus and the mother to significant risks. Predicting spontaneous labor onset and intrapartum fetal compromise could improve obstetrical management and outcomes, but this is currently difficult, particularly in low-risk populations. The objective of this study was to examine whether placental dysfunction, as assessed at 36 weeks' gestation by the soluble fms-like tyrosine kinase-1 to placental growth factor ratio, is associated with the interval to spontaneous onset of labor and intrapartum fetal compromise that requires cesarean delivery in a routinely examined population. This was a retrospective analysis of prospectively collected data of women with singleton pregnancies who underwent routine assessment at 35+0 to 36+6 weeks' gestation at the King's College Hospital (London, England). Using a general linear model, the study examined the outcomes related to the soluble fms-like tyrosine kinase-1/placental growth factor ratio, including the time interval from testing to spontaneous onset of labor and the subsequent rate of fetal compromise that required a cesarean delivery. Patients who underwent induction of labor or prelabor cesarean deliveries were excluded from the study. Competing risks regression and Cox regression models were used to estimate the cumulative incidence and the risk of the outcomes of interest. In the screened population of 45,375 patients, 23,831 (52.5%) had spontaneous onset of labor and were included in the analysis. Cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 delivered about 1 week earlier than those with a ratio of ≤50 (39.2 vs 40.0 weeks' gestation; P<.001). The general linear model showed that a larger soluble fms-like tyrosine kinase-1/placental growth factor ratio was associated with earlier spontaneous onset of labor (P<.001), particularly among multiparous women. The soluble fms-like tyrosine kinase-1/placental growth factor ratio was significantly associated, as expected, with cases of preeclampsia and advanced maternal age. The cumulative incidence of spontaneous onset of labor was significantly higher in cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 than in those with a ratio 50 (P<.001). Cox regression showed that the risk for spontaneous onset of labor increased with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 (hazard ratio, 1.424; 95% confidence interval, 1.253-1.618; P<.001) and, as expected, the risk was mitigated over time from when the soluble fms-like tyrosine kinase-1/placental growth factor ratio was measured to spontaneous labor onset (P<.001). Cases with intrapartum fetal compromise had a higher mean soluble fms-like tyrosine kinase-1/placental growth factor ratio than those without intrapartum fetal compromise (21.79 vs 17.67; P<.001). Qualitative addition of fetal compromise to the general linear model showed a higher soluble fms-like tyrosine kinase-1/placental growth factor ratio in cases with fetal compromise than in those without fetal compromise (P=.014). Competing risks regression showed a positive dose-response effect for fetal compromise with increasing soluble fms-like tyrosine kinase-1/placental growth factor ratios (P<.001). Above and below the optimal cutoff of 50, the quoted cumulative incidences were 6.7% and 4.7%, respectively (P<.001). The effect of the soluble fms-like tyrosine kinase-1/placental growth factor ratio remained significant even after adjusting for preeclampsia, which is a well-known major risk factor for fetal compromise. Finally, the proportion of cases with intrapartum fetal compromise who had an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 decreased from 35% to 0% with advancing gestation. This study showed that an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks' gestation is associated with an earlier gestational age at spontaneous onset of labor and higher rates of intrapartum fetal compromise. There are 2 major implications, namely an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 indicates imminent labor onset with about a 40% mean risk increase and immediate clinical translation for term pregnancy monitoring. In addition, an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio increases the risk for intrapartum fetal compromise, although outcome variability indicates reassessment within multimarker models.

Biomarkers of placental dysfunction. Clinical experience

The objective: to determine the diagnostic value of biomarkers of placental dysfunction at different stages of gestation.Materials and methods. The research was carried out in 2015–2022 on the basis of the municipal non-commercial enterprise “Maternity House No.5” of the Odesa City Council.We analyzed the course and clinical outcomes of pregnancies in 118 women (the main group) who developed and established placental dysfunction (PD) during pregnancy at different stages of gestation. The control group included 78 healthy women whose pregnancies occurred without PD.In women of both groups the frequency of detection of risk factors for PD was assessed by analyzing the content of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) biomarkers in blood serum, Pregnancy-Associated Plasma Protein A (PAPP-A) and β-subunit of chorionic gonadotropin (hCG).Fetal growth retardation was determined by deviations of fetal metric indicators (abdominal circumference, head circumference, biparietal size, thigh length, estimated fetal weight) below the 10th percentile.Statistical processing of the obtained results was carried out using Statistica 14.0 software (TIBCO, USA).Results. Among the examined women of both groups, cases where the pregnancy occurred at the age of 30 years or more and was the first pregnancy that did not end in abortion prevailed. The average age of women in the main group was 33.4±2.3 years, the control group – 29.3±1.4 years.The main group had more women with a history of multiple abortions (odds ratio (OR)=5.6, 95% confidence interval (CI): 1.9–18.8). Disorders of the menstrual cycle in history were found in 39 (33.1%) women of the main group and in 18 (23%) women of the control group (OR=1.6, 95% CI: 0.9–3.2). Concomitant gynecological diseases were represented by uterine fibroids – in 16 (13.6%) pregnant women of the main group and in 8 (10.2%) women of the control group (OR=1.4, 95% CI: 0.6–3.4), benign ovarian tumors – in 13 (11.0%); OR=20.1, 95% CI: 1.2–343.1), mastopathy – in 19 (16.1%; OR=30.8, 95% CI: 1.8–517.6) women of the main group.A significant number of women in the main group had a hypertrophic nutritional status – the body mass index (BMI) at the time of pregnancy was on average 26.7±0.9 kg/m2, women in the control group were represented by the normotrophic type (BMI – 22.2±0.3 kg/m2), in 4 women the indicator was more 30 kg/m2.In the vast majority of pregnant women (68 persons – 57.6%) of the main group the signs of placental malperfusion were registered up to 34 weeks. In 12 (10.2%) cases a primary PD was established.The content of PIGF in women of the main group at the 20th week of pregnancy decreased to 83±4 pg/ml, which is significantly less than the reference values (≥100 pg/ml). On the other hand, in the control group the PIGF concentration was 147±8 pg/ml (p&lt;0.05). The sFlt-1 amount in the main group corresponded to the level of 3395±62 pg/ml. Therefore, the ratio of sFlt-1/PlGF was equal to 40.8±0.4, which is prognostically unfavorable.The PAPP-A indicator, according to monitoring data at the 20th week of pregnancy, was 0.77±0.08 mU/l. In pregnant women with lower values in the future PD occurred earlier. As for the indicators of the β-subunit of hCG, the levels of this hormone in most cases corresponded to the normative values, amounting to an average of 4.7±0.1 IU/l in a pregnancy with a male fetus and 8133±21 IU/l in a pregnancy with a female fetus.Signs of preeclampsia were determined in 22 (18.6%) pregnant women of the main group. The value of the sFlt-1/PlGF ratio in these pregnant women exceeded 50.0.Conclusions. In the vast majority of pregnant women of the main group (68 – 57.6%) the signs of placental malperfusion were found up to 34 weeks. In 22 (18.6%) pregnant women with placental dysfunction (PD) the signs of preeclampsia were detected, the development of which increases when the sFlt-1/PlGF ratio exceeds 50, starting from the II trimester of pregnancy, which is an early biomarker of PD.

Clinical Analysis of Serum Soluble Tyrosine Kinase Receptor-1 and Placental Growth Factor in Pre-eclampsia

Objective: To study the clinical application effect of using serum soluble tyrosine kinase receptor-1 (sFlt-1) and placental growth factor (PlGF) in pre-eclampsia. Methods: From September 2021 to September 2023, 58 cases of pre-eclampsia patients who underwent physical examination during pregnancy and eventually gave birth in Xinghua People’s Hospital were the observation group of this study and 795 cases of healthy pregnant women who underwent pregnancy examination in this hospital during the same period of time were the control group of this study; 38 cases of mild pre-eclampsia in the observation group were treated as the mild group and 20 cases of severe pre-eclampsia patients were treated as the severe group and the serum sFlt-1 and PlGF were used to compare the results of the observation group and the control group. Compare the serum sFlt-1 and PlGF levels between the observation and control groups; compare the serum sFlt-1 and PlGF levels between the mild and severe groups. Results: The serum PlGF level of the observation group was lower than that of the control group, and the sFlt-1 level was higher than that of the control group, P &lt; 0.05; the serum PlGF level of the mild group was higher than that of the severe group, and the sFlt-1 level was lower than that of the control group, P &lt; 0.05; the results showed that the serum and urine sFlt-1 and PlGF levels of pregnant women of all the three groups were elevated with the aggravation of the condition of pre-eclampsia, and the sFlt-1/PlGF ratio also increased. The differences of sFlt-1/PlGF in serum and urine of the three groups were compared, with P &lt; 0.05; the above ratios of the patients in the mild group were higher than those of the control group and those of the severe group were higher than those of the mild group, with P &lt; 0.05. Conclusion: Serum sFlt-1 level was high in preeclamptic patients, while serum PlGF was low in preeclamptic patients.

Maternal cardiovascular function in midgestation is related to placental angiogenesis.

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

SFlt-1/PlGF ratio predicts serious outcomes in confirmed early-onset preeclampsia

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