Early Preeclampsia Research Articles

First-trimester maternal tryptophan metabolites, utero-placental (vascular)development and hypertensive disorders of pregnancy: The Rotterdam periconceptional cohort

BackgroundHypertensive disorders of pregnancy (HDP) are a significant cause of maternal and perinatal mortality and morbidity. Knowledge on the placenta-related pathophysiology of HDP is increasing. Since maternal tryptophan metabolites are involved in placentation, we investigated associations between first-trimester tryptophan metabolites and utero-placental (vascular) development, and the occurrence of HDP. Methods911 women were included from a prospective tertiary hospital cohort. Serum tryptophan metabolites were determined at 8.1 ± 1.4 weeks gestation. Placental volume (PV) and utero-placental vascular volume (uPVV) were determined at 7, 9 and 11 weeks gestation. HDP, including hypertension in early pregnancy, gestational hypertension, and preeclampsia, were retrieved from medical records. Associations with PV- and uPVV-trajectories were assessed using mixed models, and HDP risks were estimated by logistic regression models, adjusted for confounders. A mediation analysis was performed to evaluate whether blood pressure was a mediator in the associations with utero-placental (vascular) development. ResultsA negative association between kynurenine and PV-trajectories was found (β = −0.129, 95%CI = −0.220 to –0.039), which was not mediated by blood pressure. No significant associations between other tryptophan metabolites and PV- and uPVV-trajectories were observed. Higher 5-hydroxytryptophan was associated with hypertension in early pregnancy (OR = 1.405, 95%CI = 1.210–1.681), and with an increased risk of preeclampsia in these women. No associations between tryptophan metabolites and other HDP were found. ConclusionsHigher first-trimester kynurenine concentrations were associated with impaired utero-placental (vascular) development. Higher first-trimester 5-hydroxytryptophan concentrations were associated with early pregnancy hypertension, and an increased risk of preeclampsia, indicating its clinical potential as biomarker for future prediction, prevention and treatment of HDP.

Features of preeclampsia in patients with chronic kidney disease

Aims: to study the characteristics of preeclampsia (PE) in women with chronic kidney disease (CKD) compared to PE in the general population.Method: a prospective observational study analyzed the course of PE in 24 women with a previously established diagnosis of CKD (Group 1) and 39 women in the general population (Group 2) without a complicating somatic history. In patients with CKD with a known pregestational creatinine level, the physiological response of the kidneys to pregnancy was assessed, defined as a decrease in serum creatinine by more than 10% in the first trimester. The angiogenic ratio (sFlt-1/PLGF) was studied in 13 patients with CKD.Results: the two groups did not differ in age or parity. In the first group, 16 patients had CKD stage 1-2, 5 had CKD 3A, and one patient each had CKD 3B, 4 and 5 (the later receiving hemodialysis). Nineteen (79%) of women with CKD had hypertension, proteinuria (PU), renal impairment or a combination of these factors before conception. Only 3 out of 16 patients had a physiological renal response. Early PE developed in 58.3% of patients with CKD compared to 35.3% in second group (p = 0.082). The duration of PE inversely correlated with the stage of CKD (r = -0.630; p = 0.001). As pregnancy progressed in patients with CKD, PU increased, reaching nephrotic level in 54% of women by the time of PE. HELLP syndrome or isolated hematological signs of TMA were noted in 8 patients in the general population group, and in 1 in the CKD group. The average sFlt-1/PLGF value in patients with early stages of CKD (n = 9) was 81.0±24.0, with late stages (n = 4) it was 14±8.Conclusion: the study identified the features of PE in CKD: early onset, increased PU reaching nephrotic level in half of the cases by the time PE is diagnosed, and the absence of a histological renal response to pregnancy in the 1st trimester. The lack of changes in the angiogenic coefficient in women with PE and late-stage CKD requires further study in a larger group of patients.

Oxidative Stress and Anti-Carbonic Anhydrase Antibody Levels in Early Preeclampsia: A Clinical Investigation

Objective: Preeclampsia (PE) is a dangerous condition that affects 3–5% of pregnancies and has a substantial risk of death and morbidity for both mothers and newborns. The processes behind the etiology of PE are not entirely known, despite the fact that it is the primary cause of illness and death among mothers globally. In order to further understand the correlations between these parameters, this study will look at the levels and presence of anti-carbonicianhydrase (CA) I and II antibodies, total oxidanticapacity (TOC), total antioxidanticapacity (T-AOC), and malondialdehyde (MDA) in early PE. Methods: The research analyzed 30 pregnant women with early PE and 30 normal pregnant women as the control group. Serumxlevels of anti-CAiI (pg/mL), anti-CAxII (ng/mL), MDA (nmol/mL), TOS (U/mL), T-AOC (U/mL) were measured and compared between the two groups. Results: Significant variations were noted in the amount of anti-CA I, anti-CA II, MDA, TOS, and T-AOC (both p

Predictors of Vaginal Delivery among Patients Admitted with Severe Preeclampsia.

This study aimed to assess the rates of vaginal delivery (VD) and the predictors of VD in a cohort of patients with early (<34 weeks) preeclampsia with severe features (Early Severe PreEClampsia [ESPEC]). We conducted a retrospective cohort study of patients with ESPEC admitted to a single center from 2013 to 2019. Exclusion criteria included patients with contraindications to labor, multifetal gestation, or presenting in spontaneous labor. Patient characteristics were abstracted. The primary outcome was rate of VD. Secondary outcome was factors associated with VD. Secondary analysis performed including only primiparous patients. Bivariate statistics and logistic regression were used to analyze data. Of 229 patients with ESPEC, 184 (80%) were candidates for labor. Of those, 74 (40%) underwent prelabor cesarean delivery (CD). Among the 110 remaining patients who attempted VD, 47 (43%) were successful. No significant differences in characteristics between VD and CD patients were found on bivariate analysis. In regression models, BMI ≥ 40 was associated with increased odds of CD (adjusted odds ratio [aOR]: 2.83, 95% confidence interval [CI]: 1.01, 7.95), whereas private insurance was associated with reduced odds of CD (aOR: 0.37, 95% CI: 0.16, 0.86). In planned secondary analysis of primiparous patients, 101/123 (82%) were candidates for labor. Of those, 29 underwent prelabor CD. The VD rate among primiparous patients attempting labor was 40% (29/72). In this subgroup, private insurance was associated with VD (71 vs. 46%, p = 0.03). In regression models, only private insurance remained associated with CD (aOR: 0.30, 95% CI: 0.10, 0.92). Patients with ESPEC who attempted VD were successful less than half of the time, with similar rates among the subset of primiparous patients. BMI ≥ 40 was associated with increased odds of CD, whereas private insurance was associated with reduced odds of CD. These data may aid providers in counseling patients with ESPEC on the likelihood of successful VD. · Only 43% of ESPEC patients who attempted VD were successful.. · Subset of primiparous patients w/ESPEC had similar VD rate.. · BMI ≥40 kg/m2 in ESPEC patients was associated with increased odds of CD..

Routine ante-natal screening using maternal risk factors and biomarkers for preeclampsia in 11-13+6 weeks of gestation.

Prediction of preeclampsia in first trimester can lead to early initiation of preventative measures, as well as timely therapeutic intervention, that will prevent the maternal and perinatal morbidity and mortality. This study, prediction of preeclampsia at 11-13+6 weeks of gestation, was conducted by using serum placental growth factor (PlGF), serum pregnancy associated plasma protein - A (PAPP-A), uterine artery Doppler indices, and mean arterial pressure (MAP), in low-risk pregnant women. It is an observational longitudinal prospective study. Pregnant women with singleton pregnancies of gestational age 11-13+6 weeks were recruited. MAP, bilateral uterine artery Doppler indices, serum PAPP-A, and PlGF were measured. The follow-up of the patients was regularly done till termination of pregnancy and incidence of preeclampsia were noted. Qualitative variables were compared using Chi-square/Fisher exact test, and sensitivity and specificity of each test were analyzed. Among 139 women, 27 (19%) developed preeclampsia, out of which 10 had early preeclampsia and 17 developed late preeclampsia. By combining all the parameters, the sensitivity in detecting early preeclampsia was found to be 70% and for late preeclampsia cases, 64.7%. The sensitivity of all the parameters in predicting cases of preeclampsia in general is 66.7%, specificity is 74.1%, PPV is 38.3%, and NPV is 72%. The maternal biomarkers serum PAPP-A, serum PlGF, uterine artery PI, MAP have sensitivity of 70% in detecting early preeclampsia cases and for late preeclampsia cases, 64.71%, in first trimester and it will help in early initiation of preventative measures as well as timely therapeutic intervention.

Profitability of the angiogenic ratio in the follow-up of pregnant women at high risk of early preeclampsia treated with acetylsalicylic acid

Profitability of the angiogenic ratio in the follow-up of pregnant women at high risk of early preeclampsia treated with acetylsalicylic acid

Preeclampsia and timing of delivery: Disease severity, maternal and perinatal outcomes

ObjectivesThis study aimed to elucidate clinical characteristics, disease severity, and obstetric outcomes in women with pregnancy complicated with preeclampsia stratified by gestational age at delivery. Study designThis retrospective study was conducted at a tertiary care facility from January 2011 to December 2020. Main outcome measuresMaternal characteristics, risk factors, clinical signs and symptoms, laboratory test results, and maternal and perinatal outcomes were compared between early (<34 weeks) versus late (≥34 weeks) and preterm (<37 weeks) versus term (≥37 weeks) preeclampsia. ResultsMore than half of the women (56 %, 612/1094) had preterm preeclampsia. Overall, 30 % (329/1094) delivered before 34 weeks of gestation. Pregnancies with early preeclampsia had the worst maternal signs and symptoms, the highest median blood pressure level, and more abnormal laboratory abnormalities compared to those with late preeclampsia. Additionally, women with co-morbid diseases (chronic hypertension, chronic kidney disease, and systemic lupus erythematosus) were more likely to develop early than late preeclampsia. Of note, although adverse maternal and perinatal events occurred more commonly in early rather than late preeclampsia, 18 % (7/39) of eclampsia and 16 % (8/50) of hemolysis, elevated liver enzymes, and low platelet count syndrome cases occurred after 37 weeks of gestation. ConclusionsEarly preeclampsia posed the highest risk to the mother and infant(s); however, adverse maternal and perinatal events were still present even in cases of preeclampsia at term. Therefore, it is crucial for healthcare practitioners to remain vigilant and manage all cases with great care to prevent adverse outcomes.

Umbilical Artery Doppler and Adverse Outcomes in Severe Preeclampsia Without Fetal Growth Restriction: A Retrospective Cohort Study.

Background and objective Severe preeclampsia may be managed expectantly before 34 weeks gestation with close surveillance.Utilized in fetal growth restriction (FGR), evidence supports umbilical artery (UA) Dopplerpreventing neonatal morbidity from hypertensive disease and predicting adverse outcomes in preeclampsia. We evaluated the association of abnormal UA Doppler waveforms with early delivery (before 34 weeks gestation) and adverse maternal-fetal outcomes in patients with early severe preeclampsia without FGR. Methodology This is a retrospective cohort study of singleton pregnancies with International Classification of Diseases (ICD) Ninth or Tenth Revision, defined severe preeclampsia diagnosed before 34 weeks gestation without FGR from January 1, 2018, through January 27, 2023, at a large tertiary care center where S/D ratios were calculated from UA Doppler interrogation of a free loop of cord at least once weekly. This study was approved by the IRB (ID:00002216) and granted a full Health Insurance Portability and Accountability Act (HIPAA) waiver of consent. Exclusion criteria were major congenital anomalies, congenital infection, aneuploidy, leaving against medical advice >24 hours, and patient instability on admission defined as condition(s) precluding expectant management by the American College of Obstetrics and Gynecology. The primary outcome was delivery before 34 weeks gestation. Secondary outcomes were the mode of delivery and maternal/fetal complications. Patient characteristics and outcomes for normal versus abnormal UA Doppler groups were compared with chi-square, t-tests, and Fisher's exact test. Odds ratios and relative risks were calculated to compare outcomes. Results Of 194 patients with severe preeclampsia, 107 met inclusion criteria. Thirty-four patients had abnormal UA Doppler studies. There were no differences in demographic and clinical data between patients with normal and abnormal UA Doppler studies. Patients with abnormal UA Doppler studies were more likely to deliver before 34 weeks (OR=3.91; 95%CI 1.24-12.33) for worsening severe features (OR=3.85; 95% CI 1.42-10.41), and were less likely to deliver vaginally (OR=0.12; 95% CI 0.03-0.54). Abnormal UA Doppler studies were associatedwith an increased risk of neonatal complications (OR=6.46; 95% CI 1.42-29.42) and respiratory distress syndrome (RDS) (OR=4.75; 95%CI 1.32-17.16). Abnormal UA Doppler subgroups were divided into patients with elevated S/D >95% Acharya (N=22) and absent end-diastolic flow (EDF) (N=10). The elevated S/D group tended to deliver before 34 weeks gestation for worsening severe features (OR=3.71, 95% CI 1.144-12.050) and had a higher risk of neonatal complications (RR 1.404; 95% CI 1.213-1.624). The absent EDF subgroup was more likely to deliver before 34 weeks (RR=1.52; 95%CI 1.29-1.79) for abnormal fetal testing (OR=6.92; 95%CI 1.71-28.08) and undergo primary cesarean delivery (OR=7.23; 95%CI 1.43-36.61). Conclusion Pregnancies with severe preeclampsia without FGR displayed a high incidence of abnormal UA Doppler waveforms associated with loss of clinical stability and adverse fetal outcomes. The groups with more impedance to umbilical artery flow tended to deliver earlier, and as the Doppler shifted from elevated S/D to absent end-diastolic flow, the mode of delivery shifted to cesarean delivery with increased risk of abnormal fetal testing. These results support the utility of UA Doppler surveillance in severe preeclampsia.

Pathogenetic role of a number of factors in the development and progression of preeclampsia with varying severity in pregnant women.

Context Preeclampsia is a common pregnancy complication, posing significant risks to both the mother and fetus. Predicting and determining the risks of this disease is crucial. Aims This research aims to understand the pathogenetic role of several factors in the development and progression of preeclampsia, particularly in relation to its severity in pregnant patients. Methods The study included 60 pregnant women diagnosed with either mild or severe preeclampsia and 40 healthy pregnant women for comparison. Blood plasma was analysed using biochemical methods, and blood microcirculation parameters were determined to identify homeostatic abnormalities in early preeclampsia. Key results A molecular genetic study revealed the frequency of the endothelial nitric oxide gene eNOSC774T . Homeostatic abnormalities were statistically correlated with polymorphic genotypes of the eNOSC774T gene. Conclusions The research found a correlation between the T774T eNOS genotype mutation and the severity of preeclampsia, alongside significant homeostasis abnormalities in patients. Implications The T774T mutant genotype of the eNOS gene and higher levels of lipid peroxidation products are strongly linked to the severity and progression of preeclampsia. This highlights a significant connection between genetic predisposition and biochemical abnormalities in the disease's development.

Preliminary study on the role of human defensins and interleukins in early and late preeclampsia

Preliminary study on the role of human defensins and interleukins in early and late preeclampsia

The prognostic value of extremely high sFlt-1/PLGF in the progression of early onset severe preeclampsia

The prognostic value of extremely high sFlt-1/PLGF in the progression of early onset severe preeclampsia

Peculiarities of morpho-functional characteristics of platelets in women with early and late preeclampsia

Introduction. In preeclampsia (PE), the hemostasis system, including the platelet component, changes significantly. The purpose of the work was to identify the peculiarities of the morpho-functional characteristics of platelets in women with early and late PE. Material and methods. The main group consisted of 26 women with early PE and 46 women with late PE. The control group consisted of women with normal pregnancies without hypertensive disorders, of whom 17 were at a gestational age of 260–336 weeks and 42 were at a gestational age of 340–394 weeks. The ADVIA 2120i hematology analyzer was used to evaluate platelet concentration (PLT), platelet distribution width (PDW), mean platelet volume (MPV), concentration of large platelets (Large PLT), percentage of large platelets from the total number of platelets (%LP), mean platelet component concentration (MPC), mean dry platelet mass (MPM). Results. Women with early PE have increased PDW, MPV, LargePlt, %LP and MPM indices compared to women with normal pregnancies up to 34 weeks. Female patients with late PE had lower PLT and higher PDW, %LP, MPC, MPM compared to women with normal pregnancies after 34 weeks. In late PE, PLT is reduced and PDW, %LP and MPM are increased compared to early PE. Conclusion. The detected changes in platelet indices in women with PE, regardless of the period of its onset, indirectly indicate increased thrombopoiesis and high functional activity of young platelets. However, the mechanisms that increase platelet activation in early and late preeclampsia differ.

Bowtie Nanoantenna LSPR Biosensor for Early Prediction of Preeclampsia.

The concentration of the placental circulating factor in early pregnancy is often extremely low, and the traditional prediction method cannot meet the clinical demand for early detection preeclampsia in high-risk gravida. It is of prime importance to seek an ultra-sensitive early prediction method. In this study, finite-different time-domain (FDTD) and Discrete Dipole Approximation (DDA) simulation, and electron beam lithography (EBL) methods were used to develop a bowtie nanoantenna (BNA) with the best field enhancement and maximum coupling efficiency. Bio-modification of the placental circulating factor (sFlt-1, PLGF) to the noble nanoparticles based on the amino coupling method were explored. A BNA LSPR biosensor which can specifically identify the placental circulating factor in preeclampsia was constructed. The BNA LSPR biosensor can detect serum placental circulating factors without toxic labeling. Serum sFlt-1 extinction signal (Δλmax) in the preeclampsia group was higher than that in the normal pregnancy group (14.37 ± 2.56 nm vs. 4.21 ± 1.36 nm), p = 0.008, while the serum PLGF extinction signal in the preeclampsia group was lower than that in the normal pregnancy group (5.36 ± 3.15 nm vs. 11.47 ± 4.92 nm), p = 0.013. The LSPR biosensor detection results were linearly consistent with the ELISA kit. LSPR biosensor based on BNA can identify the serum placental circulating factor of preeclampsia with high sensitivity, without toxic labeling and with simple operation, and it is expected to be an early detection method for preeclampsia.

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

To compare the predictive performance of three different mathematical models for first-trimester screening of pre-eclampsia (PE), 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. 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 pregnancy and a non-malformed live fetus 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 PE, 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 the Serra et al. Gaussian model. PE classification was also performed based on the recommendations of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG). We estimated detection rates (DR) with their 95% CIs at a fixed 10% screen-positive rate (SPR), as well as the area under the receiver-operating-characteristics curve (AUC) 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 10 110 singleton pregnancies, including 32 (0.3%) that developed early PE, 72 (0.7%) that developed preterm PE and 230 (2.3%) with any PE. At a fixed 10% SPR, the FMF, Crovetto et al. and Serra et al. models detected 82.7% (95% CI, 69.6-95.8%), 73.8% (95% CI, 58.7-88.9%) and 79.8% (95% CI, 66.1-93.5%) of early PE; 72.7% (95% CI, 62.9-82.6%), 69.2% (95% CI, 58.8-79.6%) and 74.1% (95% CI, 64.2-83.9%) of preterm PE; and 55.1% (95% CI, 48.8-61.4%), 47.1% (95% CI, 40.6-53.5%) and 53.9% (95% CI, 47.4-60.4%) of all PE, respectively. The best correlation between predicted and observed cases was achieved by the FMF model, with an AUC of 0.911 (95% CI, 0.879-0.943), 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, 35.3-58.0%) of preterm PE at 11% SPR and ACOG criteria identified 65.9% (95% CI, 55.4-76.4%) 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 such as those of NICE and ACOG. While all three algorithms show similar results in terms of overall prediction, the FMF model showed the best performance at an individual level. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Impact of Inherited Thrombophilia in Women with Obstetric Antiphospholipid Syndrome: A Single-Center Study and Literature Review.

Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal-maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11-79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal-fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

First-trimester serum biomarkers in twin pregnancies and adverse obstetric outcomes–a single center cohort study

PurposeThis study aimed to determine the association of first-trimester maternal serum biomarkers with preterm birth (PTB), fetal growth restriction (FGR) and hypertensive disorders of pregnancy (HDP) in twin pregnancies.MethodsThis is a retrospective cohort study of twin pregnancies followed at Maternidade Dr. Alfredo da Costa, Lisbon, Portugal, between January 2010 and December 2022. We included women who completed first-trimester screening in our unit and had ongoing pregnancies with two live fetuses, and delivered after 24 weeks. Maternal characteristics, pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG) levels were analyzed for different outcomes: small for gestational age (SGA), gestational hypertension (GH), early and late-onset pre-eclampsia (PE), as well as the composite outcome of PTB associated with FGR and/or HDP. Univariable, multivariable logistic regression analyses and receiver-operating characteristic curve were used.Results466 twin pregnancies met the inclusion criteria. Overall, 185 (39.7%) pregnancies were affected by SGA < 5th percentile and/or HDP. PAPP-A demonstrated a linear association with gestational age at birth and mean birth weight. PAPP-A proved to be an independent risk factor for SGA and PTB (< 34 and < 36 weeks) related to FGR and/or HDP. None of the women with PAPP-A MoM > 90th percentile developed early-onset PE or PTB < 34 weeks.ConclusionA high serum PAPP-A (> 90th percentile) ruled out early-onset PE and PTB < 34 weeks. Unless other major risk factors for hypertensive disorders are present, these women should not be considered candidates for aspirin prophylaxis. Nevertheless, close monitoring of all TwP for adverse obstetric outcomes is still recommended.

Exposure to synthesized tribromobisphenol A and critical effects: Metabolic pathways, disease signature, and benchmark dose derivation

2,2′,6-Tribromobisphenol A (Tri-BBPA), the main debrominated congener of tetrabromobisphenol A (TBBPA), is ubiquitous in the environment and human body but with unknown toxicity. Tri-BBPA was synthesized and applied to investigate its sub-chronic exposure effects on 28 organ coefficients and clinical health indicators related to liver function, kidney function, and cardiovascular system function in female mice. Results showed that the liver was the targeted organ of Tri-BBPA exposure. Compared to the control group, the changes in liver coefficient, cholinesterase, total protein, albumin, γ-glutamyl transpeptidase, lactate dehydrogenase, and creatine kinase levels ranged from −61.2 % to 35.5 % in the high-exposed group. Creatine kinase was identified as a critical effect indicator of Tri-BBPA exposure. Using the Bayesian benchmark dose derivation method, a lower reference dose than TBBPA was established for Tri-BBPA (10.6 μg/kg-day). Serum metabolomics revealed that Tri-BBPA exposure may primarily damage the liver by disrupting tryptophan metabolism related to L-alanine, tryptamine, 5-hydroxyindoleacetic acid, and 5-methoxyindoleacetate in liver cells and leading to liver dysfunction. Notably, epilepsy, schizophrenia, early preeclampsia, and late-onset preeclampsia were the top six enriched diseases, suggesting that the nervous system may be particularly affected by Tri-BBPA exposure. Our findings hinted a non-negligible health risk of exposure to debrominated products of TBBPA.

Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion Toward the Uterine Spiral Artery.

Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling. Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG's potential as an early preeclampsia predictor using clinical plasma samples. TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors. These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia.

Association of preeclampsia, placental pathology, and maternal-fetal features with gestational hypertension before and after 34 weeks of pregnancy

Objective: Evaluating the preeclampsia, placental pathology, maternal and fetal features in women with gestational hypertension (GH) at varying gestational ages. Methods: A series of maternal, fetal, placental pathological, and neonatal variables were prospectively evaluated and compared between two 30-tuple groups of eligible pregnant women with early GH before 34 weeks' gestation and those with late GH after 34 weeks' gestation. Results: Proteinuria and preeclampsia were more prevalent in the early GH group compared with the late GH group (80% vs 20%, P:0.001). The maternal high blood pressure and proteinuria were significantly associated with the early GH and preeclampsia (p&lt;0.05). The percentage of syncytial knots significantly increased as preeclampsia progressed (P&lt;0.05). A significant positive correlation existed between the early GH and the percentage of newborns admitted to NICU, the length of hospitalization, and the levels of the doppler indexes of umbilical and uterine arteries (p&lt;0.05); the newborn Apgar scores were also lower in the early GH group (p&lt;0.05). The mortality rate of newborns born to early hypertensive mothers (13.30%) was insignificantly higher than those delivered by the late hypertensive mothers (3.30%, p:0.16). Conclusion: Maternal high blood pressure and proteinuria may be predicting risk factors for the early GH and/or preeclampsia. The placentas of women with early GH were partially different from those with GH after 34 weeks' gestation. Higher rates of maternal and fetal pregnancy-related complications in the early GH group may be indicative of the different effects of GH and preeclampsia on pregnancy outcomes depending on the gestational age.

USING A MULTI-OMICS LANDSCAPE OF THE MATERNAL-FETAL INTERFACE TO MODEL THE LONGITUDINAL PATHOGENESIS OF EARLY-ONSET PRE-ECLAMPSIA

Objective: Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications. We currently lack efficient screening tools and early therapies to address PE. Design and method: To identify candidate biomarkers and operative pathways in early onset PE (eoPE, severe PE with onset before week 34), we performed spatio-temporal multi-omics profiling of human eoPE placentae and healthy controls, and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-sequencing combined with spatial proteo- and transcriptomics and mechanistic in vitro signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. Results: We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts in eoPE. We found a significant increase in the senescence markers in preeclamptic maternal serum in early gestation and late gestation, before the development of clinical symptoms, indicating that the placental syndrome drives systemic maternal syndrome, even before clinical manifestation of eoPE. Conclusions: Our work describes a new disease progression model, starting with dysregulated transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.