Early and late-onset preeclampsia: effects of DDAH2 polymorphisms on ADMA levels and association with DDAH2 haplotypes.

Objective: To examine whether the DDAH2 promoter polymorphisms -1415G/A (rs2272592), -1151A/C (rs805304) and -449G/C (rs805305), and their haplotypes, are associated with PE compared with normotensive pregnant women, and whether they affect ADMA levels in these groups. Methods: A total of 208 pregnant women were included in the study and classified as early-onset (N=57) or late-onset PE (N =49), and as normotensive pregnant women (N = 102). Results: Pregnant with early-onset PE carrying the GC and GG genotypes for the DDAH2 -449G/C polymorphism had increased ADMA levels (P=0.01). No association of DDAH2 polymorphisms with PE in single-locus analysis was found. However, the G-C-G haplotype was associated with the risk for late-onset PE. Conclusion: It is suggested that DDAH2 polymorphisms could affect ADMA levels in PE, and that DDAH2 haplotypes may affect the risk for PE.

Metabolomic prediction of severe maternal and newborn complications in preeclampsia.

INTRODUCTION: Preeclampsia (PreE) remains a major source of maternal and newborn complications. Prenatal prediction of these complications could significantly improve pregnancy management. OBJECTIVES: Using metabolomic analysis we investigated the prenatal prediction of maternal and newborn complications in early and late PreE and investigated the pathogenesis of such complications. METHODS: Serum samples from 76 cases of PreE (36 early-onset and 40 late-onset), and 40 unaffected controls were collected. Direct Injection Liquid Chromatography-Mass Spectrometry combined with Nuclear Magnetic Resonance (NMR) spectroscopy was performed. Logistic regression analysis was used to generate models for prediction of adverse maternal and neonatal outcomes in patients with PreE. Metabolite set enrichment analysis (MSEA) was used to identify the most dysregulated metabolites and pathways in PreE. RESULTS: Forty-three metabolites were significantly altered (p < 0.05) in PreE cases with maternal complications and 162 metabolites were altered in PreE cases with newborn adverse outcomes. The top metabolite prediction model achieved an area under the receiver operating characteristic curve (AUC) = 0.806 (0.660-0.952) for predicting adverse maternal outcomes in early-onset PreE, while the AUC for late-onset PreE was 0.843 (0.712-0.974). For the prediction of adverse newborn outcomes, regression models achieved an AUC = 0.828 (0.674-0.982) in early-onset PreE and 0.911 (0.828-0.994) in late-onset PreE. Profound alterations of lipid metabolism were associated with adverse outcomes. CONCLUSION: Prenatal metabolomic markers achieved robust prediction, superior to conventional markers for the prediction of adverse maternal and newborn outcomes in patients with PreE. We report for the first-time the prediction and metabolomic basis of adverse maternal and newborn outcomes in patients with PreE.

Prediction of severe preeclampsia and intrauterine growth restriction based on serum placental exosome miR-520a-5p levels during the first-trimester.

BACKGROUND: To assess the predictive capabilities of serum exosomal levels of micro-RNA-520a-5p (miR-520a-5p) concerning the occurrence of severe preeclampsia (sPE) and fetal growth restriction (FGR) during the first trimester of pregnancy. METHODS: During the period spanning from October 2020 to October 2021, serum samples were procured from the first trimester and subsequently preserved by freezing at -80 ℃. These samples were obtained from 105 pregnant women in a nested case-control study. This cohort consisted of individuals who later developed sPE (sPE group, n = 35) and FGR (FGR group, n = 35) during the third trimester. Additionally, 35 women with normal blood pressure were denoted as normal pregnancy group. Serum samples from the first trimester were retrieved from all groups for further analysis after thawing. Exosomes were extracted from the serum samples collected during the first trimester and examined using transmission electron microscopy, western blot, and nanoparticle tracking analysis. Additionally, the determination of their placental origin was also established during the course of the study. Exosome miR-520a-5p levels were measured using real-time quantitative polymerase chain reaction assays, primarily involving quantitative reverse transcription polymerase chain reactions. Fetal placental tissues from the 3 groups were collected shortly after birth, and miR-520a-5p expression was measured using real-time quantitative polymerase chain reaction. Serum placental exosomes and fetal placental tissues were compared for miR-520a-5p levels. Placental trophoblasts were identified as the source of serum exosomes in all 3 groups. RESULTS: It was found that serum placental exosomes exhibited lower levels of miR-520a-5p in both the sPE and FGR groups when compared to the normal pregnancy group. This finding was consistent with observations made in postpartum placental tissues. The predictive accuracy for sPE using miR-520a-5p levels in serum placental exosomes during the first trimester was notably higher (area under the receiver operating characteristic curve = 0.806, P <.05) compared to the prediction of FGR (area under the receiver operating characteristic curve = 0.628, P <.05). CONCLUSION: Placenta-derived exosomes can be extracted from maternal serum during the first trimester of pregnancy and miR-520a-5p detected from the exosomes. The downregulation of miR-520a-5p serves as a more predictive indicator for the subsequent development of sPE compared to predicting FGR.

Immunometric and functional measurement of endogenous vasoinhibin in human sera.

Introduction: Circulating levels of the antiangiogenic protein vasoinhibin, a fragment of prolactin, are of interest in vasoproliferative retinopathies, preeclampsia, and peripartum cardiomyopathy; however, it is difficult to determine the circulating levels of vasoinhibin due to the lack of quantitative assays. Methods: This study used human serum samples to assess the concentration and bioactivity of vasoinhibin using a novel enzyme-linked immunosorbent assay (ELISA) for human vasoinhibin, which employs an anti-vasoinhibin monoclonal antibody, a human umbilical vein endothelial cell (HUVEC) proliferation assay, and a chick chorioallantoic membrane (CAM) angiogenesis assay. Results: Serum samples from 17 pregnant women without (one group) and with preeclampsia and pregnancy induced hypertension (another group) demonstrated endogenous vasoinhibin concentrations in the range of 5-340 ng/ml. Immunoactive vasoinhibin levels were significantly higher in preeclampsia serum compared to healthy pregnancy serum (mean 63.09 ± 22.15 SD vs. 19.67 ± 13.34 ng/ml, p = 0.0003), as was the bioactive vasoinhibin level as determined by the HUVEC proliferation assay (56.12 ± 19.83 vs. 13.38 ± 4.88 ng/ml, p < 0.0001). There was a correlation between the concentration of vasoinhibin measured by ELISA and the HUVEC proliferation assay (Pearson r = 0.95, p < 0.0001). Healthy serum demonstrated a proangiogenic effect in the CAM assay (p < 0.05, compared to control), while serum from preeclamptic patients demonstrated an antiangiogenic effect (p < 0.05 vs. control), as did recombinant human vasoinhibin and a synthetic circular retro-inverse vasoinhibin analogue (CRIVi45-51). The antiangiogenic effects in the CAM assay and the inhibition of HUVEC proliferation were abolished by addition of the ELISA anti-vasoinhibin monoclonal antibody, but not by mouse IgG. Discussion: These results demonstrate the first quantitation of endogenous vasoinhibin in human sera and the elevation of it levels and antiangiogenic activity in sera from women with preeclampsia. The development and implementation of a quantitative assay for vasoinhibin overcomes a long-standing barrier and suggests the thorough clinical verification of vasoinhibin as a relevant biomarker.

Association of prothrombin time, thrombin time and activated partial thromboplastin time levels with preeclampsia: a systematic review and meta-analysis.

BACKGROUND: Preeclampsia (PE), an obstetric disorder, remains one of the leading causes of maternal and infant mortality worldwide. In individuals with PE, the coagulation-fibrinolytic system is believed to be among the most significantly impacted systems due to maternal inflammatory responses and immune dysfunction. Therefore, this systematic review and meta-analysis aimed to assess the association of prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) levels with preeclampsia. METHODS: This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines. Articles relevant to the study, published from July 26, 2013, to July 26, 2023, were systematically searched across various databases including PubMed, Scopus, Embase, and Hinari. The methodological quality of the articles was evaluated using the Joanna Briggs Institute critical appraisal checklist. Utilizing Stata version 14.0, a random-effects model was employed to estimate the pooled standardized mean difference (SMD) along with the respective 95% CIs. The I2 statistics and Cochrane Q test were utilized to assess heterogeneity, while subgroup analyses were performed to explore its sources. Furthermore, Egger's regression test and funnel plot were employed to assess publication bias among the included studies. RESULTS: A total of 30 articles, involving 5,964 individuals (2,883 with PE and 3,081 as normotensive pregnant mothers), were included in this study. The overall pooled SMD for PT, APTT, and TT between PE and normotensive pregnant mothers were 0.97 (95% CI: 0.65-1.29, p < 0.001), 1.05 (95% CI: 0.74-1.36, p < 0.001), and 0.30 (95% CI: -0.08-0.69, p = 0.11), respectively. The pooled SMD indicates a significant increase in PT and APTT levels among PE patients compared to normotensive pregnant mothers, while the increase in TT levels among PE patients was not statistically significant. CONCLUSIONS: The meta-analysis underscores the association between PE and prolonged PT and APTT. This suggests that evaluating coagulation parameters like PT, APTT, and TT in pregnant women could offer easily accessible and cost-effective clinical indicators for assessing PE. However, multicenter longitudinal studies are needed to evaluate their effectiveness across various gestational weeks of pregnancy.

Predictive biomarkers and initial analysis of maternal immune alterations in postpartum preeclampsia reveal an immune-driven pathology.

Introduction: Postpartum preeclampsia (PPPE) is an under-diagnosed condition, developing within 48 hours to 6 weeks following an uncomplicated pregnancy. The etiology of PPPE is still unknown, leaving patients vulnerable and making the identification and treatment of patients requiring postpartum care an unmet need. We aimed to understand the immune contribution to PPPE at the time of diagnosis, as well as uncover the predictive potential of perinatal biomarkers for the early postnatal identification of high-risk patients. Methods: Placentas were collected at delivery from uncomplicated pregnancies (CTL) and PPPE patients for immunohistochemistry analysis. In this initial study, blood samples in PPPE patients were collected at the time of PPPE diagnosis (48h-25 days postpartum; mean 7.4 days) and compared to CTL blood samples taken 24h after delivery. Single-cell transcriptomics, flow cytometry, intracellular cytokine staining, and the circulating levels of inflammatory mediators were evaluated in the blood. Results: Placental CD163+ cells and 1st trimester blood pressures can be valuable non-invasive and predictive biomarkers of PPPE with strong clinical application prospects. Furthermore, changes in immune cell populations, as well as cytokine production by CD14+, CD4+, and CD8+ cells, suggested a dampened response with an exhausted phenotype including decreased IL1ß, IL12, and IFNγ as well as elevated IL10. Discussion: Understanding maternal immune changes at the time of diagnosis and prenatally within the placenta in our sizable cohort will serve as groundwork for pre-clinical and clinical research, as well as guiding clinical practice for example in the development of immune-targeted therapies, and early postnatal identification of patients who would benefit from more thorough follow-ups and risk education in the weeks following an uncomplicated pregnancy.

Serum levels of sirtuins, leptin and adiponectin in women with pregnancy-induced hypertension.

INTRODUCTION: Pregnancy-induced hypertension (PIH) and preeclampsia (PE) are associated with disturbed maternal inflammatory response, oxidative stress and vascular endothelial cell dysfunction. Obesity is one of risk factors of PE. Leptin is elevated in obesity and its level correlates positively with the amount of adipose tissue. In contrast, adiponectin levels are decreased in obesity. Sirtuins are expressed in the placenta, however their role in pregnancy-related pathology in humans is not known. AIM OF THE STUDY: The aim of our study was to measure serum concentrations of selected sirtuins, adiponectin and leptin in healthy pregnancy and in women with PIH. MATERIALS AND METHODS: The study included 70 women: 38 healthy pregnant women and 32 women with PIH. Blood samples were obtained between the 20th and 40th week of gestation. Serum levels of sirtuins 1, 3, 6, leptin and adiponectin were measured with ELISA. RESULTS: Leptin levels were significantly higher in PIH group as compared to the controls and correlated positively with BMI. Highest leptin levels were observed in women who needed a cesarean section. Levels of sirtuins 1, 3 and 6 were similar in both groups and did not correlate with BMI. CONCLUSIONS: High leptin levels in PIH women during 3rd trimester might be helpful to predict the necessity for a caesarian section. Blood levels of sirtuins 1, 3 and 6 measured after the 20th week of gestation cannot be regarded as a single diagnostic test for PIH or preeclampsia. More studies to clarify significance of sirtuins in PIH and PE development and diagnosis are needed.

Polymeric optical fiber biosensor with PAMAM dendrimer-based surface modification and PlGF detection for pre-eclampsia diagnosis.

Pre-eclampsia (PE) is a life-threatening complication that occurs during pregnancy, affecting a large number of pregnant women and newborns worldwide. Rapid, on-site and affordable screening of PE at an early stage is necessary to ensure timely treatment and minimize both maternal and neonatal morbidity and mortality rates. Placental growth factor (PlGF) is an angiogenic blood biomarker used for PE diagnosis. Herein, we report the plasmonic fiber optic absorbance biosensor (P-FAB) strategy for detecting PlGF at femtomolar concentration using polymethyl methacrylate (PMMA) based U-bent polymeric optical fiber (POF) sensor probes. A novel poly(amidoamine) (PAMAM) dendrimer based PMMA surface modification is established to obtain a greater immobilization of the bioreceptors compared to a linear molecule like hexamethylenediamine (HMDA). Plasmonic sandwich immunoassay was realized by immobilizing the mouse anti-PlGF (3H1) on the U-bent POF sensor probe surface and gold nanoparticles (AuNP) labels conjugated with mouse anti-PlGF (6H9). The POF sensor probes could measure PlGF within 30 min using the P-FAB strategy. The limit-of-detection (LoD) was found to be 0.19 pg/mL and 0.57 pg/mL in phosphate-buffered saline and 10× diluted serum, respectively. The clinical sample testing, with eleven positive and eleven negative preeclamptic pregnancy samples, successfully confirmed the accuracy, reliability, specificity, and sensitivity of the P-FAB based POF sensor platform, thereby paving the way for cost-effective technology for PlGF detection and its potential for pre-eclampsia diagnosis.

Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction).

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare-through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence-the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with hypertensive disorders of pregnancy in the Atlanta African American Maternal-Child cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals that are slow to break down in the environment and widely detected in humans. Epidemiological evidence suggests that prenatal exposure to perfluorooctanoic acid (PFOA), a legacy PFAS, is linked to gestational hypertension and preeclampsia. However, the relationship between other PFAS, which are structurally similar, and these outcomes remains largely understudied, despite biologic plausibility. Here, we examined associations between serum PFAS mixtures in relation to hypertensive disorders of pregnancy within a birth cohort of African Americans. METHODS: Participants in the present study were enrolled in the Atlanta African American Maternal-Child cohort between 2014 and 2020 (n = 513). Serum samples collected between 8 and 14 weeks gestation were analyzed for four PFAS. Logistic regression was used to assess associations between individual natural log transformed PFAS and specific hypertensive disorders of pregnancy (preeclampsia, gestational hypertension), while quantile g-computation was used to estimate mixture effects. Preeclampsia and gestational hypertension were treated as separate outcomes in individual models. All models were adjusted for maternal education, maternal age, early pregnancy body mass index, parity, and any alcohol, tobacco, or marijuana use. RESULTS: The geometric mean of PFOS and PFHxS was slightly lower among those with preeclampsia relative to those without a hypertensive disorder (e.g., geometric mean for PFOS was 1.89 and 1.94, respectively). Serum concentrations of PFAS were not strongly associated with gestational hypertension or preeclampsia in single pollutant or mixture models. For example, using quantile g-computation, a simultaneous one quartile increase in all PFAS was not associated with odds of gestational hypertension (odds ratio = 0.86, 95% CI = 0.60, 1.23), relative to those without a hypertensive disorder of pregnancy. CONCLUSIONS: In this birth cohort of African Americans, there was no association between serum PFAS measured in early pregnancy and hypertensive disorders of pregnancy, which may be reflective of the fairly low PFAS levels in our study population.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

N-terminal prohormone of brain natriuretic peptide in gestational hypertension and preeclampsia - State of the art.

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is a non-active prohormone secreted by ventricular cardiomyocytes into the circulation in response to ventricle overload, mainly due to increased blood volume. The changes in NT-proBNP levels during pregnancy have been investigated in multiple studies. In the case of hypertensive disorders of pregnancy, increased vasoconstriction leads to increased blood pressure and afterload. Together with the volume overload of pregnancy, it leads to higher NT-proBNP secretion. As hypertensive disorders of pregnancy are among the leading causes of prematurity and perinatal mortality, early prediction and diagnosis of gestational hypertension, and preeclampsia are essential for improving maternal and infant prognosis. NT-proBNP has been regarded as a potential biomarker of hypertensive disorders of pregnancy. In this review, we have thoroughly summarized the current data on the prognostic and diagnostic utility of NT-proBNP in patients with gestational hypertension and preeclampsia. NT-proBNP values may help distinguish between non-preeclamptic and preeclamptic patients, even if there are no significant differences in blood pressure. Moreover, in pregnancies complicated by preeclampsia, the value of increased NT-proBNP level is related to the stage and the severity of the disease. Further improvement of our knowledge about NT-proBNP as a diagnostic biomarker and a putative predictor of adverse cardiac events in women with hypertensive disorders of pregnancy should lead to better management of these patients.

Alteration in maternal serum uric acid levels in pre-eclampsia and associated perinatal outcomes: a cross-sectional study in Ghana.

Introduction: pre-eclampsia (PE) is a multisystemic pregnancy-specific hypertensive disorder associated with significant adverse maternal and perinatal outcomes. Maternal serum uric acid level is hypothesized as a reliable marker for predicting the severity and adverse outcomes of pre-eclampsia and facilitating clinical decisions. This study explored the association between maternal serum uric acid and adverse pregnancy outcomes in pre-eclampsia. Methods: a cross-sectional study involving women diagnosed with pre-eclampsia was conducted at Korle-Bu Teaching Hospital (KBTH), a tertiary hospital in Ghana. Descriptive analyses were performed and multivariable logistic regression model was used to explore the association between maternal serum uric acid levels and pregnancy outcomes using R software. Results: we included 100 women with pre-eclampsia comprising 79% and 21% preterm and term pre-eclampsia respectively and with mean gestational age (GA) at diagnosis of 32.35±2.66 weeks and 35.96±1.94 weeks respectively. The mean maternal age of preterm and term pre-eclampsia groups was 29.81±5.29 years and 29.46±5.78 years respectively. Hyperuricemia (serum uric acid >375 µmol/L) occurred in 61% of the pre-eclamptic women. The mean gestational age (in weeks) at diagnosis was significantly lower in the pre-eclamptic women with hyperuricemia compared with those with normal levels of uric acid (33.51±3.03 versus 34.80±2.71). There was a significant negative association (moderate correlation) between maternal serum uric acid levels and birth weight (R= -0.34, p < 0.001) in pre-eclampsia; the statistical significance was limited to preterm only (Pearson R= -0.39, p-value <0.001) but not term pre-eclampsia. Hyperuricemia was significantly associated with low birth weight [aOR: 3.222 (95% CI: 1.098, 10.393)], caesarean section [aOR: 2.281 (95% CI: 1.084, 7.568)] and severe diastolic pressure at birth [aOR: 3.517 (95% CI: 1.123, 11.939)]. Conclusion: hyperuricemia in pre-eclampsia was significantly associated with both maternal (caesarean section and severe hypertension) and neonatal (low birth weight) adverse outcomes. Hyperuricemia seems clinically useful in predicting pregnancy outcomes, especially in preterm pre-eclampsia. Further longitudinal study is recommended in exploring the clinical significance of maternal uric acid levels and pregnancy outcomes in pre-eclampsia.

The causal role of circulating immunity-inflammation in preeclampsia: A Mendelian randomization.

Patients with systemic autoimmune diseases, such as systemic lupus erythematosus, were at a higher risk for preeclampsia. The causal relationship between immunological inflammation and preeclampsia (PE) remains uncertain. We aimed to investigate the causal relationship between circulating immune inflammation and PE. Genetically predicted blood immune cells and circulating inflammatory proteins were identified using two genome-wide association studies (GWAS). We used a two-sample Mendelian randomization (MR) method to determine whether circulating immunological inflammation causes PE. Our findings indicated that ten immunophenotypes were identified to be significantly associated with PE risk: CD62L- Dendritic Cell Absolute Count, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD62L- myeloid Dendritic Cell Absolute Count, CD86+ myeloid Dendritic Cell Absolute Count, CD62L- myeloid Dendritic Cell %Dendritic Cell, CD62L- CD86+ myeloid Dendritic Cell %Dendritic Cell, CD62L- CD86+ myeloid Dendritic Cell Absolute Count, CD16 on CD14+ CD16+ monocyte, HLA DR+ Natural Killer Absolute Count, and T cell Absolute Count. Ninety-one inflammation-related proteins had no statistically significant effect on PE following false discovery rate (FDR) correction. Certain proteins exhibited unadjusted low p-values that merited mention. These proteins include interleukin-10 (OR = 0.76, 95%CI = 0.63-0.93, p = .006), fibroblast growth factor 21 (OR = 1.23, 95%CI = 1.01-1.47, p = .035), and Caspase 8 (OR = 0.65, 95%CI = 0.50-0.85, p = .001). The ELISA analysis demonstrated elevated levels of FGF-21 and decreased levels of IL-10 and Caspase-8 in the plasma of patients with PE. These findings reveal that immunophenotypes and circulating inflammatory proteins may induce PE, confirming the importance of peripheral Immunity-Inflammation in PE. The discovery has the potential to lead to earlier detection and more effective treatment techniques.

Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Serum fatty acid binding protein 4 and Doppler of uterine artery ultrasound in the first trimester for the prediction of preeclampsia.

The objective of this study was to determine the predictive value of serum fatty acid binding protein 4 (FABP4) combined with Doppler of the uterine artery in singleton pregnancy at gestational age (GA) 11-13+6 weeks for prediction of preeclampsia. A prospective observational study included singleton pregnant women at GA 11-13+6 weeks and was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, between December 2020 and April 2022. Serum FABP4 levels and Doppler of the uterine artery were performed. Pregnancy outcomes were recorded. The predictive values of these combined tests at the optimal cut-off values were determined to predict preeclampsia. A total of 330 participants with 15 cases of preeclampsia (4.5%) and 6 cases of them had preterm preeclampsia (GA < 37 weeks) (1.8%) were analyzed. Women with preeclampsia had significantly higher serum FABP4 levels than normal pregnant women (12.9 ± 6.5 ng/ml vs 10.1 ± 4.8 ng/ml, p = 0.034) but no difference in the mean pulsatility index (PI) of the uterine artery and the presence of an early diastolic notch. When using serum FABP4 levels greater than 1.0 multiple of the median of GA as a cut-off value to predict preeclampsia, combined with abnormal Doppler PI of the uterine artery, the sensitivity, specificity, positive predictive value, and negative predictive value were 73.3%, 47.3%, 6.2%, and 97.4%, respectively. This study demonstrated that serum FABP4 levels combined with Doppler of the uterine artery at GA 11-13+6 weeks were effective in predicting preeclampsia.

Detection of serum major histocompatibility complex I (HLA-1) and ß2-microglobulin (ß2M) in pre-eclampsia using isobaric tags for relative and absolute quantitation (iTRAQ).

OBJECTIVE: The purpose of this preliminary investigation into the pathogenesis of pre-eclampsia was to screen the differential proteins in the serum of pregnant women with normal pregnancy and early-onset pre-eclampsia using isobaric tags for relative and absolute quantitation (iTRAQ), so as to identify serum biomarkers for the early diagnosis of pre-eclampsia. METHODS: We examined the peripheral serum of 58 normal pregnant women and 42 pregnant women with early-onset pre-eclampsia using iTRAQ; the differentially expressed proteins were screened for bioinformatics analysis; and the expression of candidate proteins human leukocyte antigen-1 (HLA-1) and ß2-microglobulin (ß2M) in placental tissues was detected using western blot. RESULTS: We identified a total of 63 differential proteins in the serum of patients from the normal control group and the pre-eclampsia group, and this included 24 up-regulated proteins and 39 down-regulated proteins. The western blot results of placental tissue showed reduced HLA-1 expression (1.12 ± 0.23) in the placenta in the pre-eclampsia group as compared with the normal control group (1.34 ± 0.22). Consistent with the results observed in the serum, ß2M in the placenta in the pre-eclampsia group was significantly elevated (1.05 ± 0.47) in comparison with the normal group (0.75 ± 0.33) (P < 0.05). CONCLUSION: In this study, we found that iTRAQ technology was useful for identifying differentially expressed proteins in the peripheral serum of pregnant women with pre-eclampsia, and that HLA-1 and ß2M, which may be involved in the occurrence of pre-eclampsia, show promise as predictive markers of pre-eclampsia.