Serum Placental Growth Factor Research Articles

Urinary sFlt-1 and PlGF as preeclampsia predictors: sFlt-1/creatinine ratio improves the prediction value

ObjectivesTo evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction. Study DesignThis case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios. ResultsUrine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863). ConclusionsUrinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable.

Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

Stability of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1)

Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) are biomarkers used for diagnosis and risk estimation of preeclampsia. Stability in room temperature (RT) may affect the usefulness of these analyses, as shipping at ambient temperature is the most practical and suitable way to ship samples. To date, scientific studies of such stability are lacking. We aimed to assess the stability of PlGF and sFlt-1 at RT in serum from pregnant women. In addition, a smaller study of stability at 4 °C was performed. Serum was collected from 69 pregnant women and stored at RT or at 4 °C for up to 192 h. Analytes were considered stable if the mean percent change ± 90 confidence interval of the mean was within the baseline concentration ± allowable bias. Allowable bias was calculated from data on biological variation. In addition, an instability equation was calculated to assess loss of stability, in line with recent European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recommendations. The mean percent change was <3.5% for PlGF, <1% for sFlt-1 and <4.5% for sFlt-1/PlGF ratio up to 192 h. PlGF was considered stable for 168 h, and sFlt-1 and sFlt-1/PlGF ratios were considered stable for 192 h at RT. At 4 °C, PlGF was considered stable for 120 h, sFlt-1 for 168 h and sFlt-1/PlGF ratio for 120 h. Both PlGF and sFlt-1 as well as sFlt-1/PlGF ratio show sufficient stability (minimum 168 h) for samples to be shipped at RT.

Prediction of preeclampsia using maternal circulating mRNAs in early pregnancy.

Preeclampsia (PE) is one of the most common and serious complications of pregnancy, and novel methods for the early prediction of PE are needed for clinical application. In this study, a circulating cell-free RNA (cfRNA) panel of target genes for PE prediction was designed and validated in a case-control cohort and a nested case-control cohort. The QPCR was applied to quantify the copy number of cfRNA, and the data were normalized as multiples of the median. Ratios of serum placental growth factor (PIGF) and soluble fms-like tyrosine kinase1 (sFLT-1) were also measured, and transabdominal ultrasonography was conducted for subjects in the prospective cohort. Binary logistic regression models for PE prediction were constructed and tested. Our results revealed that the women with PE showed significant alterations in serum cfRNA profiles from early pregnancy onward and before the onset of PE symptoms. Compared with PIGF/sFLT-1 measurement and ultrasonographic imaging, cfRNA test can detect PE at a very early stage of pregnancy. The predictive model exhibited the best performance at gestation week 32, with a detection rate of 100%. At 12weeks of gestation, the model still manifested an area under curve (AUC) of 0.9144, and sensitivity of 1.0000. If combined with clinical parameters and ultrasonographic indicators, the model can achieve the highest AUC for PE prediction at early gestation. Measurement of cfRNA can be used to effectively predict PE with high performance, providing an additional method for monitoring PE throughout the course of pregnancy.

First Trimester Preeclampsia Screening and Prevention: Perspective in Chinese Mainland

Abstract Preeclampsia (PE), a multisystem disorder in pregnancy, is one of the leading causes of perinatal morbidity and mortality that poses financial and physical burdens worldwide. Preterm PE with delivery at &lt;37 weeks of gestation is associated with a higher risk of adverse maternal and perinatal outcomes than term PE with delivery at ≥37 weeks of gestation. A myriad of first trimester screening models have been developed to identifying women at risk of preterm PE. In fact, the Fetal Medicine Foundation (FMF) first trimester prediction model has undergone successful internal and external validation. The FMF triple test enables the estimation of patient-specific risks, using Bayes theorem to combine maternal characteristics and medical history together with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor. Establishing a quality control process for regular monitoring and to ensure data standardization, reliability, and accuracy is key to maintaining optimal screening performance. The rate of preterm PE can be reduced by 62% by using the FMF prediction model, followed by the administration of low-dose aspirin. Recent evidence has also demonstrated that metformin has the potential for preventing PE in patients at high-risk of the disorder. In this article, we will summarize the existing literature on the different screening methods, different components of risk assessment, therapeutic interventions, and clinical implementation of the first trimester screening and prevention program for PE with specific considerations for Chinese mainland.

Performance of machine-learning approach for prediction ofpre-eclampsia in a middle-income country.

Pre-eclampsia (PE) is a serious complication of pregnancy associated with maternal and fetal morbidity and mortality. As current prediction models have limitations and may not be applicable in resource-limited settings, we aimed to develop a machine-learning (ML) algorithm that offers a potential solution for developing accurate and efficient first-trimester prediction of PE. We conducted a prospective cohort study in Mexico City, Mexico to develop a first-trimester prediction model for preterm PE (pPE) using ML. Maternal characteristics and locally derived multiples of the median (MoM) values for mean arterial pressure, uterine artery pulsatility index and serum placental growth factor were used for variable selection. The dataset was split into training, validation and test sets. An elastic-net method was employed for predictor selection, and model performance was evaluated using area under the receiver-operating-characteristics curve (AUC) and detection rates (DR) at 10% false-positive rates (FPR). The final analysis included 3050 pregnant women, of whom 124 (4.07%) developed PE. The ML model showed good performance, with AUCs of 0.897, 0.963 and 0.778 for pPE, early-onset PE (ePE) and any type of PE (all-PE), respectively. The DRs at 10% FPR were 76.5%, 88.2% and 50.1% for pPE, ePE and all-PE, respectively. Our ML model demonstrated high accuracy in predicting pPE and ePE using first-trimester maternal characteristics and locally derived MoM. The model may provide an efficient and accessible tool for early prediction of PE, facilitating timely intervention and improved maternal and fetal outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of different methods of screening for preterm pre-eclampsia: cohort study.

To compare the predictive performance for pre-eclampsia (PE) of three different first-trimester mathematical models of screening, which combine maternal risk factors with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF), and two risk scoring systems, based on NICE and ACOG recommendations. This was a prospective cohort study performed in eight fetal-medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with singleton pregnancies and non-malformed live fetuses attending their routine ultrasound examination at 11+0 to 13+6 weeks' gestation were invited to participate in the study. Maternal characteristics and medical history were recorded and measurements of MAP, UtA-PI, serum PlGF and pregnancy associated plasma protein-A (PAPP-A) were converted into multiples of the median (MoM). Risks for term, preterm-PE (< 37 weeks' gestation) and early-PE (< 34 weeks' gestation) were calculated according to the FMF competing risks model, the Crovetto et al., logistic regression model, and Serra et al., Gaussian model. Patient classification based on NICE and ACOG guidelines was also performed. We estimated detection rates (DR) with their 95% confidence intervals (CIs) at a fixed 10% screen positive rate (SPR), as well as the area under the receiver operating characteristic curve (AUROC) for preterm-PE, early-PE, and all PE for the three mathematical models. For the scoring systems, we calculated DR and SPR. Risk calibration was also assessed. The study population comprised of 10,110 singleton pregnancies, including 32 (0.3%) that developed early-PE, 72 (0.7%) that developed preterm-PE and 230 (2.3%) of any PE. At fixed 10% SPR, the FMF, Crovetto et al., and Serra et al., detected 82.7% (95% CI, 69.6 to 95.8%), 73.8% (95% CI, 58.7 to 88.9%), and 79.8% (95% CI, 66.1 to 93.5%) of early-PE; 72.7% (95% CI, 62.9 to 82.6%), 69.2% (95% CI, 58.8 to 79.6%), and 74.1% (95% CI, 64.2 to 83.9%) of preterm-PE and 55.1% (95% CI, 48.8 to 61.4%), 47.1% (95% CI, 40.6 to 53.5%), and 53.9% (95% CI, 47.4 to 60.4%) of all PE, respectively. The best correlation between predicted and observed cases was achieved by the FMF model, with an AUROC of 0.911 (95% CI, 0.879 to 0.943), a slope of 0.983 (95% CI, 0.846-1.120) and an intercept of 0.154 (95% CI, -0.091 to 0.397). The NICE criteria identified 46.7% (95% CI, 35.3 to 58.0%) of preterm-PE at 11% SPR and ACOG criteria identified 65.9% (95% CI, 55.4 to 76.4%) of preterm-PE at 33.8% SPR. The best performance of screening for preterm-PE is achieved by mathematical models that combine maternal factors with MAP, UtA-PI and PlGF, as compared to risk-scoring systems like NICE or ACOG criteria. While all three algorithms show similar results in terms of overall prediction, the FMF model showed the best performance at the individual level. This article is protected by copyright. All rights reserved.

Maternal cardiovascular function at mid-gestation is related to placental angiogenesis.

To investigate whether placental function, reflected in the levels of angiogenic factors, is associated with maternal cardiac function and hemodynamic responses at 19 to 24 weeks' gestation after adjustment for maternal risk factors and pregnancy complications. Prospective study on women with singleton pregnancies attending Kings' College Hospital, London, UK for a routine hospital visit at 19-24 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, maternal heart rate, serum placental growth factor and soluble fms-like tyrosine kinase 1 (sFLT-1).We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. Our cohort included 4006 women.Lower placental growth factor (PlGF) values were significantly associated with higher mean arterial pressure (MAP) (p<0.001), lower maternal heart rate (p<0.001), lower mitral valve s' velocity (p= 0.027) and higher left atrial volume (p=0.022) after adjustment for maternal characteristics and pregnancy complications. sFLT-1 was positively related to relative wall thickness (p= 0.012), whereas sFLT-1/ PlGF ratio was negatively associated with mitral valve A (p= 0.006) and positively associated with left atrial volume (p= 0.015) and MAP (p= 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors from their obstetric and medical history. A continuous link of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present at mid-gestation, independently of preexisting maternal risk factors and pregnancy complications. Impaired placental function appears to be related to a mild systolic and diastolic dysfunction and cardiac remodeling. This article is protected by copyright. All rights reserved.

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

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

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

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

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). Prospective, observational cohort study. Tertiary maternity hospital in Australia. There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0  weeks) and 109 (30.0%) late FGR (≥32+0  weeks). Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

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

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

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

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

Automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation predicts preterm preeclampsia: a retrospective cohort study.

Our aims were to obtain the gestational-age-specific median of common logarithmic placental growth factor (PlGF) values in the first trimester in women with a singleton pregnancy in order to generate the gestational-age-specific multiple of the median (MoM) of log10PlGF at 9-13 weeks of gestation, to evaluate screening parameters of MoM of log10PlGF at 9-13 weeks of gestation to predict preterm preeclampsia (PE), and to construct an appropriate prediction model for preterm PE using minimum risk factors in multivariable logistic regression analyses in a retrospective sub-cohort study. Preterm PE occurred in 2.9% (20/700), and PE in 5.1% (36/700). Serum PlGF levels were measured using Elecsys PlGF®. MoMs of log10PlGF at 9-13 weeks of gestation in Japanese women with a singleton pregnancy followed a normal distribution. We determined the appropriate cut-off value of MoM of log10PlGF to predict preterm PE at around a10% false-positive rate (0.854). The MoM of log10PlGF < 0.854 yielded sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (95% confidence interval [CI]), and negative likelihood ratio (95% CI) of 55.0%, 91.9%, 17.5%, 98.5%, 6.79 (4.22-10.91), and 0.49 (0.30-0.80), respectively. The combination of MoM of log10PlGF and presence of either chronic hypertension or history of PE/gestational hypertension (GH) yielded sensitivity and specificity of 80.0 and 85.7%, respectively, to predict preterm PE. In conclusion, the automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation may be useful to predict preterm PE.

Serum placental growth factor, total cholesterol, and triglycerides for prediction of intrahepatic cholestasis of pregnancy.

This study aims to investigate the predictive values of serum placental growth factor (PIGF), total cholesterol (TC), and triglycerides (TG) in the context of intrahepatic cholestasis of pregnancy (ICP). This retrospective case control study recruited pregnant women from January 2021 to December 2021 at the Maternal and Child Health Hospital of Hunan Province, encompassing pregnant women diagnosed with ICP and those with unremarkable prenatal examinations. A total of 433 pregnant women were included, among whom 167 were diagnosed with ICP after 24 weeks of pregnancy. Patients with ICP exhibited an average age of 31.30 ± 4.54 years and an average pregnancy week at delivery of 37.63 ± 1.45 weeks. Multivariable regression analysis showed that the pregnancy week at delivery (OR = 0.823, 95% CI: 0.769-0.879, P < .001), PIGF (OR = 0.994, 95% CI: 0.992-0.996, P < .001), TC (OR = 1.955, 95% CI: 1.586-2.409, P < .001), and TG (OR = 3.786, 95% CI: 2.655-5.399, P < .001) were independent risk factors for ICP. The area under the curve values for PIGF, TC, and TG in predicting ICP were 0.858 (95% CI: 0.822-0.893), 0.721 (95% CI: 0.670-0.772), and 0.830 (95% CI: 0.788-0.871), respectively. However, their combination yielded an area under the curve value of 0.922 (95% CI: 0.898-0.946). The composite assessment of PIGF, TC, and TG demonstrates potential efficacy in predicting ICP among pregnant women.

Reference range of placental growth factors at 11–14 weeks’ gestation in Indonesia

ObjectivesTo develop a reference chart for placental growth factor (PLGF) value during 11–14 weeks’ gestation in Indonesian population. MethodsThis was an observational study observing women in their first trimester. Maternal characteristics, biophysical tests, and serum PLGF levels were collected during the visit. PLGF Multiple of Median (MoM) was adjusted for maternal characteristics including age, parity, smoking habits, diabetes mellitus, weight, height, body mass index, gestational age, and crown-rump length (CRL) utilizing the linear regression analysis. Plot distributions of PLGF level and PLGF MoM adjusted to CRL were developed using logistic regression technique. ResultsOut of 2.062 consecutive women undergoing 11–14 weeks’ gestation ultrasound screening, the median of PLGF level and PLGF MoM were 50.38 pg/ml (1.09–265.20 pg/ml) and 1.00 (0.02–4.80), respectively. In the multivariate analysis, PLGF MoM was not significantly influenced by maternal factors such as age, parity, smoking habit, diabetes mellitus, height, weight, and BMI. The adjusted PLGF MoM reference chart according to the CRL was developed using quadratic linear regression. ConclusionPLGF levels at 11–14 weeks’ gestation were notably influenced by CRL but not by maternal characteristics. The usefulness of this parameter in combining with other established markers as a screening tool for the Indonesian population basis requires further investigation.

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

First, to evaluate the predictive performance for preterm growth-related neonatal morbidity of high soluble fms-like tyrosine kinase-1 (sFLT-1) / placental growth factor (PlGF) ratio or low PlGF at mid-gestation, and second, to compare the performance of the high sFLT-1/PlGF ratio or low PlGF with that of the competing risks model for small for gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI). This was a prospective observational study in women attending for a routine hospital visit at 19 to 24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFLT-1. The primary outcome was delivery <32 and <37 weeks' gestation of SGA neonate with birth weight <10th or <3rd percentile for gestational age, combined with neonatal unit (NNU) admission for ≥48 hours or a composite of major neonatal morbidity. The detection rates in screening by either PlGF <10th percentile, sFLT-1/PlGF ratio >90th percentile and the competing risks model for SGA were estimated and they were compared using McNemar's test. In the study population of 40241 women prediction of preterm growth-related neonatal morbidity provided by the competing risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio. For example, at screen positive rate (SPR) of 10.0%, as defined by the sFLT-1/ PlGF ratio >90th percentile, the competing risks model predicted 70.1% (95% CI 61.0 - 79.2) of SGA <10th percentile and 76.9% (67.6-86.3) of SGA <3rd percentile with NNU admission for ≥48 hours delivered <32 weeks gestation and these were significantly higher than the respective values of 35.0% (25.6-44.6) and 35.9% (25.3 - 46.5), achieved by the application of the sFLT-1/ PlGF ratio >90th percentile (p<0.0001 for both). The respective values for SGA with major neonatal morbidity were 73.8% (64.4-83.2), 77.9% (68.0-87.8), 38.1% (27.7-48.5) and 39.7% (28.1-51.3) (Both p<0.0001). At mid-gestation, the prediction of growth-related neonatal morbidity by the competing risks model for SGA is superior to that of high sFlt-1/PlGF ratio or low PlGF. This article is protected by copyright. All rights reserved.

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

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

Effects of sirtuin 1 deficiency on trophoblasts and its implications in the pathogenesis of pre-eclampsia

Background Sirtuin 1 (SIRT1) is mainly localised in syncytiotrophoblasts and cytotrophoblasts, and is involved in pregnancy regulation. However, data on the association between SIRT1 and pre-eclampsia (PE) remains limited. This study aimed to investigate the role of SIRT1 in PE pathophysiology. Methods Placental SIRT1 expression, as well as serum SIRT1, placental growth factor (PlGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) levels, were measured using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assays in 40 healthy pregnant women (NP group) and 40 women with severe PE (PE group). Additionally, the effects of SIRT1 on the migration, invasion, PlGF, and sFlt-1 secretion of HTR-8/SVneo cells were analysed. Results SIRT1 expression was significantly reduced in the placenta of patients with severe PE compared with that in healthy pregnant women. Compared with the NP group, serum SIRT1 and PlGF expression was significantly lower in the PE group; however, the expression of serum sFlt-1 was significantly higher in the PE group. Correlation analysis showed that in the PE group, placental SIRT1 protein levels positively correlated with serum PlGF levels (r = 0.468, P = .002) and negatively correlated with serum sFlt-1 levels (r = −0.542, P < .001). Cells with downregulated SIRT1 had a significantly shorter migration distance and a prominently reduced number of invasive cells compared with the corresponding negative control group, suggesting that SIRT1 deficiency may inhibit the migration and invasive ability of HTR-8/SVneo cells. The opposite results were observed after transfection with lentivirus overexpressing SIRT1. Compared with the corresponding controls, cells with downregulated SIRT1 had significantly reduced PlGF levels and significantly increased sFlt-1 levels in the cell culture supernatants, whereas SIRT1 overexpression produced the opposite results. Conclusions SIRT1 deficiency may contribute to the pathogenesis of pre-eclampsia by reducing trophoblastic migration, invasion, and PlGF secretion and increasing sFlt-1 secretion.

Placental growth factor and fetoplacental Doppler indices in combination predict preterm birth reliably in pregnancies complicated by fetal growth restriction.

To assess the association between placental biomarkers (placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio) and fetoplacental Doppler indices (umbilical artery (UA) pulsatility index (PI) and uterine artery (UtA) PI) in various combinations for predicting preterm birth (PTB) in pregnancies complicated by fetal growth restriction (FGR). This was a prospective observational cohort study, performed at Mater Mother's Hospital in Brisbane, Queensland, Australia, from May 2022 to June 2023, of pregnancies complicated by FGR and appropriate-for-gestational-age (AGA) pregnancies. Maternal serum PlGF levels, sFlt-1/PlGF ratio, UA-PI and UtA-PI were measured at 2-4-weekly intervals from recruitment until delivery. Harrell's concordance statistic (Harrell's C) was used to evaluate multivariable Cox proportional hazards regression models featuring various combinations of placental biomarkers and fetoplacental Doppler indices to ascertain the best combination to predict PTB (< 37 weeks). Multivariable Cox regression models were used with biomarkers as time-varying covariates. The study cohort included 320 singleton pregnancies, comprising 179 (55.9%) affected by FGR, defined according to a Delphi consensus, and 141 (44.1%) with an AGA fetus. In the FGR cohort, both low PlGF levels and elevated sFlt-1/PlGF ratio were associated with significantly shorter time to PTB. Low PlGF was a better predictor of PTB than was either sFlt-1/PlGF ratio or a combination of PlGF and sFlt-1/PlGF ratio (Harrell's C, 0.81, 0.78 and 0.79, respectively). Although both Doppler indices were significantly associated with time to PTB, in combination they were better predictors of PTB than was either UA-PI > 95th centile or UtA-PI > 95th centile alone (Harrell's C, 0.82, 0.75 and 0.76, respectively). Predictive utility for PTB was best when PlGF < 100 ng/L, UA-PI > 95th centile and UtA-PI > 95th centile were combined (Harrell's C, 0.88) (hazard ratio, 32.99; 95% CI, 10.74-101.32). Low maternal serum PlGF level (< 100 ng/L) and abnormal fetoplacental Doppler indices (UA-PI > 95th centile and UtA-PI > 95th centile) in combination have the greatest predictive utility for PTB in pregnancies complicated by FGR. Their assessment may help guide clinical management of these complex pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.