Comparison of Pre-eclampsia Screening Algorithms in the First Trimester of Pregnancy Being Used in Thai Nguyen Province.

Objective To compare the rates of pregnancies in high-risk groups for preeclampsia recommended for aspirin prophylactic when screened using various common algorithms. Methods This cross-sectional study was conducted on 1726 pregnant women from 11 to 13 weeks six days of gestation receiving antenatal care at two hospitals: Thai Nguyen National Hospital and a hospital in Thai Nguyen Province from October 2022 to October 2023. All participants provided consent for the study. We collected maternal characteristics, obstetric history, mean arterial pressure (MAP), mean uterine artery-PI (UtA-PI), and placental growth factor serum (PLGF). Screening performance estimates were calculated using the Fetal Medicine Foundation (FMF) and National Institute for Health and Care Excellence (NICE) guidelines. All pregnant women in the study had their preeclampsia risk assessed using all three algorithms with two cut-off points. Our data was collected, entered and analyzed using SPSS software 20.0 (IBM Corp., Armonk, NY). Categorical data was reported as frequency and percentage. McNemar's test was used for analyzing differences in the sizes of individual groups. Results In our study, the most common high-risk factor identified was the history of preeclampsia, 132 cases (7.6%). According to the NICE guideline, BMI ≥ 35 (kg/m²) is considered a moderate risk factor for preeclampsia. Several risk factors, such as BMI ≥ 35 kg/m² and history of diabetes mellitus type 1, were not present in any participants. Only one pregnant woman had chronic kidney disease (0.06%). Out of the 1726 pregnant women surveyed, the rates of high-risk preeclampsia were as follows: 9.9% (171 cases) based on algorithm 1; 10.8% (187 cases) based on algorithm 2 with a cut-off point > 1/100, 11.8% (203 cases) with a cut-off point > 1/150; 10.3 % (178 cases) based on algorithm 3 with a cut-off point > 1/100, and 11.6% (201 cases) with a cut-off point > 1/150. Among these algorithms, pregnant women in the high-risk preeclampsia group were advised to consider taking low-dose aspirin. Conclusion Screening for pre-eclampsia based on NICE recommendations resulted in a lower number of high-risk pregnant women requiring prophylactic aspirin use compared to other algorithms. This means that some pregnant women at risk of developing preeclampsia are not recommended to use aspirin as a preventive measure. Adding PLGF to the screening strategy will help us get closer to pregnant women who are truly at risk of progressing to preterm preeclampsia.

Serum and Vitreous Levels of Placenta Growth Factor in Diabetic Retinopathy Patients: Correlation With Disease Severity and Optical Coherence Tomographic Parameters.

Purpose The primary objective of this study was to compare placenta growth factor (PlGF) levels in the serum and vitreous of diabetic retinopathy (DR) patients to non-diabetic controls. Additionally, the study aimed to establish associations between serum and vitreous PlGF concentrations and to examine the correlation between vitreous PlGF in DR patients and morphological parameters. Methods This study included serum and vitreous samples from 38 patients, including 21 patients with DR and 17 non-diabetic controls. The control group included non-diabetic patients with rhegmatogenous retinal detachment with retinal tears secondary to posterior vitreous detachment or trauma. PlGF levels were quantified in vitreous and serum samples using an enzyme-linked immunosorbent assay (ELISA). Optical coherence tomography (OCT) scans from DR patients were evaluated to measure the central retinal thickness (CRT) and macular volume (MV). Results DR patients had significantly higher mean vitreous PlGF levels compared to non-DR patients (70.0±39.2 vs. 46.47±9.7 pg/mL, p-value=0.004). However, no significant increase in mean serum PlGF levels was observed in DR patients (p-value=0.232). Within the DR group, proliferative DR (PDR) patients presented significantly higher vitreous PlGF levels than non-PDR (NPDR) patients (76.5±41.0 vs. 42.5±5.0 pg/mL, p-value=0.009). There was no association between serum and vitreous PlGF levels. The correlation between vitreous PlGF levels and morphological parameters was rsp=0.175, p-value=0.488 for CRT, and rsp=0.288, p-value=0.262 for MV. Conclusion This study emphasizes the important role of PlGF in neovascularization, specifically highlighting its overexpression exclusively in vitreous from PDR patients. The observed increase in PlGF levels may be indicative of disease severity. The lack of correlation between vitreous and serum PlGF levels suggests a potential dissociation between intravitreal and systemic PlGF synthesis. Consequently, targeting PlGF in therapeutic approaches may offer an additional strategy for ocular pathologies with a neovascular component.

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Unraveling the Predictive Power: Placenta Growth Factor and Pregnancy-Associated Plasma Protein A in Pre-eclampsia.

This review provides a comprehensive exploration of the roles of placenta growth factor (PlGF) and pregnancy-associated plasma protein A (PAPP-A) in the context of pre-eclampsia, a pregnancy-related hypertensive disorder with significant implications for maternal and fetal health. The background elucidates the clinical significance of pre-eclampsia, highlighting its prevalence and impact. The review delves into the biological importance of PlGF and PAPP-A, emphasizing their critical roles in normal placental development and their dysregulation in pre-eclampsia. Notably, altered levels of these biomarkers emerge as potential diagnostic indicators, offering insights into the pathophysiology of the disorder. The exploration of pathophysiological mechanisms, including angiogenic imbalance and placental dysfunction, provides a nuanced understanding of pre-eclampsia's molecular landscape. The therapeutic implications of targeting PlGF and PAPP-A open avenues for future research, aiming at effective intervention strategies. The conclusion summarizes key findings, outlines implications for future research, and underscores the crucial role of PlGF and PAPP-A in understanding and managing pre-eclampsia, with the ultimate goal of improving outcomes for both mothers and infants.

Guideline No. 442: Fetal Growth Restriction: Screening, Diagnosis, and Management in Singleton Pregnancies.

OBJECTIVE: Fetal growth restriction is a common obstetrical complication that affects up to 10% of pregnancies in the general population and is most commonly due to underlying placental diseases. The purpose of this guideline is to provide summary statements and recommendations to support a clinical framework for effective screening, diagnosis, and management of pregnancies that are either at risk of or affected by fetal growth restriction. TARGET POPULATION: All pregnant patients with a singleton pregnancy. BENEFITS, HARMS, AND COSTS: Implementation of the recommendations in this guideline should increase clinician competency to detect fetal growth restriction and provide appropriate interventions. EVIDENCE: Published literature in English was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library through to September 2022 using appropriate controlled vocabulary via MeSH terms (fetal growth retardation and small for gestational age) and key words (fetal growth, restriction, growth retardation, IUGR, FGR, low birth weight, small for gestational age, Doppler, placenta, pathology). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Grey literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Table A1 for definitions and Table A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Obstetricians, family physicians, nurses, midwives, maternal-fetal medicine specialists, radiologists, and other health care providers who care for pregnant patients. TWEETABLE ABSTRACT: Updated guidelines on screening, diagnosis, and management of pregnancies at risk of or affected by FGR. SUMMARY STATEMENTS: RECOMMENDATIONS: Prediction of FGR Prevention of FGR Detection of FGR Investigations in Pregnancies with Suspected Fetal Growth Restriction Management of Early-Onset Fetal Growth Restriction Management of Late-Onset FGR Postpartum management and preconception counselling.

The role of the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PIGF) - ratio in clinical practice in obstetrics: diagnostic and prognostic value.

OBJECTIVES: Analyze the diagnostic and prognostic value of the sFlt-1/PlGF ratio in pregnant women with at least one sign/symptom of suspected/diagnosed pre-eclampsia. METHODS: This retrospective observational study included 170 pregnant women with at least one sign/symptom of pre-eclampsia, who had sFlt-1/PlGF ratio values. The following information was evaluated: pregnant women's demographic data and clinical history; laboratory data (urine protein/creatinine ratio; sFlt-1/PlGF ratio); signs and symptoms presented; clinical outcome; fetal complications; data related to childbirth. Statistical analysis was performed by R Software Version 3.5.2. RESULTS: Among the 170 patients, 78 presented pre-eclampsia. The median sFlt-1/PlGF ratio was significantly higher [143.1 (2.2-2,927.1)] for women who presented pre-eclampsia than for women without pre-eclampsia [33.5 (0.8-400.2)]. The negative predictive value of sFlt-1/PlGF ratio <38 was 83.9 % (95 % CI, 71.7-92.4 %) and the positive predictive value of sFlt-1/PlGF ratio >85 or 110 (for late onset pre-eclampsia) was 76.4 % (95 % CI, 66.2-84.8 %). sFlt-1/PlGF >85 or 110 was associated with pre-eclampsia clinical development, fetal complications, shorter gestational age at birth, higher number of caesarean deliveries and lower birth weight. CONCLUSIONS: The sFlt-1/PlGF ratio, together with the standard diagnostic criteria, can be used to rule out pre-eclampsia, identify high-risk patients and predict the occurrence of adverse outcomes.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction.

BACKGROUND: Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR. METHODS: We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls. RESULTS: The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81). CONCLUSIONS: We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.

Risk ractors for the occurrence of preeclampsia and the predictive value of serum VEGFR-1 and PLGF for preeclampsia / 中国医师杂志

Objective:To explore the risk factors for the occurrence of preeclampsia (PE) and the predictive value of serum vascular endothelial growth factor receptor-1 (VEGFR-1) and placental growth factor (PLGF) for PE.Methods:A retrospective study was conducted to select 148 pregnant women who underwent prenatal examinations at the First People′s Hospital of Chenzhou from January 2020 to January 2022 and were ultimately diagnosed with PE as the PE group, and 148 healthy pregnant women who underwent prenatal examinations during the same period as the PE group were selected as the control group. The levels of VEGFR-1, PLGF, and VEGFR-1/PLGF were compared between two groups of pregnant women. Logistic regression analysis was performed on the risk factors for PE, and the correlation between VEGFR-1, PLGF, VEGFR-1/PLGF and risk factors was analyzed. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of VEGFR-1, PLGF, and VEGFR-1/PLGF for PE and obtain cutoff values. The survival curve of pregnant women with PE was plotted based on the cutoff values.Results:The levels of VEGFR-1 and VEGFR-1/PLGF in the PE group were higher than those in the control group (all P<0.05), while the levels of PLGF were lower than those in the control group ( P<0.05). Logistic regression analysis showed that age, body mass index (BMI), pregnancy induced hypertension, pregnancy induced diabetes, family history of hypertension, preeclampsia, VEGFR-1 and VEGFR-1/PLGF were risk factors for PE (all P<0.05), and PLGF was a protective factor for PE ( P<0.05). VEGFR-1, VEGFR-1/PLGF were positively correlated with age, BMI, pregnancy induced hypertension, pregnancy induced diabetes, hypertension family history, and PE (all P<0.001), while PLGF was negatively correlated with age, BMI, pregnancy induced hypertension, pregnancy induced diabetes, hypertension family history, and preeclampsia (all P<0.001). VEGFR-1, PLGF, and VEGFR-1/PLGF had higher predictive value for PE (AUC=0.773, 0.791, 0.825), with cutoff values of 9190.83 ng/L, 508.17 ng/L, and 21.64, respectively. According to the cutoff value, 296 pregnant women were divided into three groups: low, medium, and high risk. The survival analysis results showed that the probabilities of PE occurrence in the three groups were 1.36%, 18.97%, and 66.67%, respectively. Conclusions:VEGFR-1 and PLGF have high predictive value for PE, and clinical monitoring of VEGFR-1/PLGF levels combined with other examination methods can improve the accuracy of PE diagnosis and prediction, and improve pregnancy outcomes.

Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction.

BACKGROUND: Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined. OBJECTIVE: To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes. STUDY DESIGN: A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded. RESULTS: A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death. CONCLUSION: Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Preeclampsia risk prediction model for Chinese pregnant women (ChiPERM): research protocol for a randomized stepped-wedge cluster trial.

BACKGROUND: Despite international clinical guideline recommendations, implementation of Bayes-theorem based preeclampsia risk prediction model in first trimester among Chinese women is limited. The aim of this study is to examine the effectiveness of this risk predictive strategy in reducing the risk of preeclampsia. METHODS: The study will be a randomized, stepped-wedge controlled trial conducted in eighteen hospitals in China. Stepped implementation of Bayes-theorem based risk prediction model will be delivered to hospitals in a random order to support the introduction of this prediction model of preeclampsia. A staged process will be undertaken to develop the risk prediction strategies, which comprise of: combined risk evaluation by maternal risk factors, medium arterial pressure, uterine artery pulse index and placenta growth factor during 11-13+6 gestational weeks, monthly follow up (including blood pressure, newly onset complications, adherence to aspirin). Repeated cross-sectional outcome data will be gathered weekly across all hospitals for the study duration. The primary outcome measures are the incidence of preeclampsia within 42 days postpartum. Data on resources expended during intervention development and implementation will be collected. The incidence of pregnancy related complications will be measured as secondary outcomes. DISCUSSION: This will be the first randomized controlled trial to evaluate the effectiveness of the Bayes-theorem based preeclampsia risk prediction strategies in first trimester by competing risk model validation. If positive changes in clinical practice are found, this evidence will support health service adoption of this risk prediction model to reduce the risk of preeclampsia among Chinese pregnant women. TRIAL REGISTRATION: Chinese Clinical Trials Registry, No. ChiCTR2100043520 (date registered:21/2/2021).

Maternal preconception and pregnancy tobacco and cannabis use in relation to placental developmental markers: A population-based study.

Maternal tobacco and cannabis use during pregnancy are associated with adverse perinatal outcomes. We hypothesized that maternal tobacco and cannabis use are associated with placental adaptations, which subsequently lead to adverse perinatal outcomes. In a population-based prospective cohort study of 8008 pregnant women, we assessed maternal tobacco and cannabis use by questionnaires. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the first and second trimester and at delivery from blood samples. Placental weight and pregnancy complications were obtained from medical records. We observed that tobacco use before and during first-trimester only was not associated with any angiogenic factors. As compared to no tobacco use, continued use during pregnancy was associated with higher PlGF, lower sFlt-1 concentrations, and lower sFlt-1/PlGF ratio in second trimester (all p-values <0.05). Also, compared to no cannabis use, use before and during pregnancy was associated with higher PlGF concentrations and lower sFlt-1/PlGF ratio in first and second trimester (all p-values <0.05). First trimester only cannabis use was associated with higher sFlt-1 concentrations and higher sFlt-1/PlGF ratio at delivery (all p-values <0.05). Compared to non-use, tobacco use before pregnancy was associated with a higher placental weight, whereas continued tobacco use during pregnancy was associated with a lower placental weight. Continued tobacco or cannabis use was related to higher placental weight to birth weight ratio and higher risk of pregnancy complications (all p-values <0.05). These results suggest that maternal tobacco and cannabis use lead to placental vascular maladaptation predisposing to adverse pregnancy outcomes.

Phenotype-Directed Management of Hypertension in Pregnancy.

Hypertensive disorders of pregnancy are among the most serious conditions that pregnancy care providers face; however, little attention has been paid to the concept of tailoring clinical care to reduce associated adverse maternal and perinatal outcomes based on the underlying disease pathogenesis. This narrative review discusses the integration of phenotype-based clinical strategies in the management of high-risk pregnant patients that are currently not common clinical practice: real-time placental growth factor testing at Mount Sinai Hospital, Toronto and noninvasive hemodynamic monitoring to guide antihypertensive therapy at the University of Washington Medical Center, Seattle. Future work should focus on promoting more widespread integration of these novel strategies into obstetric care to improve outcomes of pregnancies at high risk of adverse maternal-fetal outcomes from these complications of pregnancy.

The neutrophil elastase-upregulated placenta growth factor promotes the pathogenesis and progression of periodontal disease.

BACKGROUND: Periodontal disease is a chronic inflammatory disease. Given its high prevalence, especially in aging population, the detailed mechanisms about pathogenesis of periodontal disease are important issues for study. Neutrophil firstly infiltrates to periodontal disease-associated pathogen loci and amplifies the inflammatory response for host defense. However, excessive neutrophil-secreted neutrophil elastase (NE) damages the affected gingival. In lung and esophageal epithelium, NE had been proved to upregulate several growth factors including placenta growth factor (PGF). PGF is an angiogenic factor with proinflammatory properties, which mediates the progression of inflammatory disease. Therefore, we hypothesize excessive NE upregulates PGF and participates in the pathogenesis and progression of periodontal disease. METHODS: In gingival epithelial cells (GEC), growth factors array demonstrated NE-increased growth factors and further be corroborated by Western blot assay and ELISA. The GEC inflammation was evaluated by ELISA. In mice, the immunohistochemistry results demonstrated ligature implantation-induced neutrophil infiltration and growth factor upregulation. By multiplex assay, the ligature-induced proinflammatory cytokines level in gingival crevicular fluid (GCF) were evaluated. Finally, alveolar bone absorption was analyzed by micro-CT images and H & E staining. RESULTS: NE upregulated PGF expression and secretion in GEC. PGF promoted GEC to secret IL-1ß, IL-6, and TNF-α in GCF In periodontal disease animal model, ligature implantation triggered NE infiltration and PGF expression. Blockade of PGF attenuated the ligature implantation-induced IL-1ß, IL-6, TNF-α and MIP-2 secretion and ameliorated the alveolar bone loss in mice. CONCLUSION: In conclusion, the NE-induced PGF triggers gingival epithelium inflammation and promotes the pathogenesis and progression of periodontal disease.

First trimester placental growth factor in maternal blood and placenta related disorders.

OBJECTIVE: To describe and compare the placental growth factor levels at first trimester in patients that developed preeclampsia, gestational hypertension, IUGR and in those patients without impaired placentation diseases. METHODS: Observational study based on a prospective cohort of 422 pregnant women. PlGF values were compared between the different groups (preeclampsia, intrauterine growth restriction (IUGR), gestational hypertension or normal group-patients without impaired placentation diseases). RESULTS: The 85.3% (n = 360, 95% CI = 81.9-88.7) had a normal pregnancy, 7.6% (n = 32, 95% CI = 5.1-10.1) had preeclampsia, 3.8% (n = 16, 95% CI = 2.0-5.6) had IUGR and 3.3% (n = 14, 95% CI = 1.6-5.0) had gestational hypertension. The median level of PlGF for preeclampsia (0.76) and IUGR (0.75) were lower than gestational hypertension (0.82) and normal group (1.02). The groups of preeclampsia >34 weeks (0.76), preeclampsia <37 weeks (0.73), and preeclampsia ≥37 weeks (0.77), were significantly lower than the normal group. The sensitivity and specificity of PlGF for impaired placentation diseases is 65% and 64.9%, respectively. CONCLUSION: It was found in this study that PlGF has significantly lower levels in gestational hypertension than normal pregnancies, in concordance with the other impaired placentation diseases. Additionally, a better comparison of the PlGF values was obtained when separating early onset of preeclampsia <37 weeks and late-onset of preeclampsia 37≥ weeks of gestations.

Predictive value of vascular endothelial growth factor and placenta growth factor for placenta accreta spectrum.

This study aimed to assess the maternal features, Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PLGF) in the Placenta Accreta Spectrum (PAS); then, to determine a predictive value of VEGF and PLGF in the PAS. This prospective case-control study was conducted on 90 pregnant women including 45 PAS, and 45 Normal Placenta (NP). Maternal age, gravidity, C/S, and serum levels of VEGF and PLGF were assessed between NP and PAS, and among NP and PAS sub-groups, including Placenta Accreta (PA), Placenta Increta (PI), and Placenta Percreta (PP). The Multi-gravidity, previous C/S, maternal age, and serum level of PLGF were significantly higher in the PAS group compared to the NP group OR = 42, 8.1, 1.17, and 1.002 (p-value <.05 for all); however, there was no difference regarding serum level of VEGF (p-value >.05). The same differences were seen among NP with PA, PI, and PP sub-groups (p-value <.05 for all, but p-value >.05 for VEGF). Placenta Previa was uniformly distributed across the PAS sub-groups (p-value >.05), also the VEGF and PLGF serum levels did not differ between PAS with Previa and PAS without Previa groups (p-value >.05). A valid cut-off point for PLGF was reported at 63.55. A predictive value of PLGF for the PAS patients is presented enjoying high accuracy and generalisability for the study population.Impact statementWhat is already known on this subject? The Placenta Accreta Spectrum (PAS), in which the placenta grows too deep in the uterine wall, is responsible for maternal-foetal morbidity and mortality worldwide; so, the antenatal diagnosis of PAS is an important key to improve maternal-foetal health. Normal placental implantation requires a fine balance among the levels of angiogenic and anti-angiogenic factors, such as the Placenta Growth Factor (PLGF), the Vascular Endothelial Growth Factor (VEGF), and soluble Fms-like tyrosine kinase-1. However, there is still controversy regarding The PLGF and VEGF level changes in PAS patients.What do the results of this study add? Despite traditional measuring the levels of PLGF and VEGF from the placenta at the time of delivery; in this study including 90 participants (28-34 weeks of gestation) the maternal serum levels of PLGF and VEGF were measured in advance (temporality causation), resulted in presenting a more valid cut-off point for PLGF in PAS group. In addition, the serum level of PLGF was significantly higher in the PAS and PAS sub-groups compared to the Normal Placenta group. Also, the Previa status of PAS patients did not affect the VEGF and PLGF serum levels.What are the implications of these findings for clinical practice and/or further research? PLGF cut-off point derived from the maternal serum level could predict PAS validly and, if used as a screening test in an earlier pregnancy, the maternal-foetal morbidity and mortality would decrease.

Preeclampsia-Like Syndrome in a Pregnant Patient With Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Hypertension, proteinuria, and hepatic dysfunction have been described as manifestations of coronavirus disease 2019 (COVID-19) and are generally accepted as poor prognostic factors. However, these same findings can also occur in pregnant women with preeclampsia, thus creating a diagnostic challenge. CASE: We report a case of COVID-19 infection in an otherwise healthy pregnant patient with secondary hypertension, proteinuria, and significant hepatic dysfunction. Maternal placental growth factor (PlGF) testing was used to rule out preeclampsia. The patient received supportive care and improved significantly. She went on to have a spontaneous vaginal term delivery of a healthy male baby. CONCLUSION: COVID-19 infection in pregnancy may present as preeclampsia-like syndrome. PlGF testing can be used to differentiate preeclampsia from COVID-19 and facilitate appropriate management.

The clinical value of platelet parameters combined with sFlt-1/PlGF in predicting preeclampsia.

BACKGROUND: The aim of this study is to evaluate the association between platelet parameters and soluble vascular endothelial growth factor receptor-1 (sFlt-1)/placenta growth factor (PlGF) in preeclampsia (PE) and establish a prediction model by analyzing commonly used biochemical markers. METHODS: A nested case-control study involving 270 pregnant women in their second trimester from the Beijing Jishuitan Hospital was conducted. They were divided into PE group and control group. The levels of PlGF, sFlt-1, sFlt-1/PlGF, and platelet parameters were recorded and compared at 20-24 gestational weeks. The correlation between platelet parameters and PlGF, sFlt-1, and sFlt-1/PLGF was then analyzed. A receiver operating characteristic (ROC) curve was used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various biomarkers in predicting PE. RESULTS: In PE group, the levels of mean platelet volume (MPV), platelet distribution width (PDW), sFlt-1, and sFlt-1/PLGF were higher than in the control group, while the levels of platelet count (PC), PC/MPV, and PLGF in PE group were lower. Spearman correlation analysis showed that PC and PC/MPV were negatively correlated with sFlt-1 and sFlt-1/PLGF, and positively correlated with PLGF, while further analysis found that PC/MPV had the largest area under the ROC curve with sensitivity of 83.7% and specificity of 86.2%. The area under curve (AUC) of sFlt-1, PLGF, and sFlt-1/PLGF for predicting PE were 0.731, 0.772, and 0.825, respectively. Their AUCs could be improved to 0.820, 0.838, and 0.873 when combined with PC/MPV. CONCLUSIONS: The accuracy of sFlt-1/PlGF in predicting the risk of PE in the second trimester is significantly improved when combined with PC/MPV, which is expected to be an ideal tool for PE prediction.

Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia.

BACKGROUND: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. RESULTS: A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. CONCLUSIONS: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

Can placental growth factors explain birthweight variation in offspring of women with type 1 diabetes?

AIMS/HYPOTHESIS: Maternal hyperglycaemia alone does not explain the incidence of large offspring amongst women with type 1 diabetes. The objective of the study was to determine if there is an association between placental function, as measured by angiogenic factors, and offspring birthweight z score in women with type 1 diabetes. METHODS: This cohort study included samples from 157 Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT) trial participants. Correlations were estimated between birthweight z score and placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) levels measured at baseline and at 24 and 34 weeks of gestation. Linear regression was used to assess the relationship between birthweight z score and placental health, as measured by PlGF and sFlt-1/PlGF ratio, stratified by glycaemic status (continuous glucose monitoring and HbA1c measures) and adjusted for potential confounders of maternal BMI, smoking and weight gain. Higher PlGF levels and lower sFlt-1/PlGF ratios represent healthy placentas, while lower PlGF levels and higher sFlt-1/PlGF ratios represent unhealthy placentas. RESULTS: Among CONCEPTT participants, the slopes relating PlGF levels to birthweight z scores differed according to maternal glycaemia at 34 weeks of gestation (p = 0.003). With optimal maternal glycaemia (HbA1c < 48 mmol/mol [6.5%]/ or continuous glucose monitoring time above range ≤ 30%), birthweight z scores were reduced towards zero (normal weight) with increasing PlGF values (representing a healthy placenta), and increased with decreasing PlGF values. With suboptimal glycaemic status (HbA1c ≥ 48 mmol/mol [6.5%] or time above range > 30%), increasing PlGF values were associated with heavier infants. Those with a healthy placenta (PlGF > 100) and suboptimal glycaemic control had a higher mean z score (2.45) than those with an unhealthy placenta (mean z score = 1.86). Similar relationships were seen when using sFlt-1/PlGF ratio as a marker for a healthy vs unhealthy placenta. CONCLUSIONS/INTERPRETATION: In women with type 1 diabetes, infant birthweight is influenced by both glycaemic status and placental function. In women with suboptimal glycaemia, infant birthweight was heavier when placentas were healthy. Suboptimal placental function should be considered in the setting of suboptimal glycaemia and apparently 'normal' birthweight.

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification. Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008). Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.