Early-onset Preeclampsia Research Articles

Circulating cardiovascular biomarkers during and after preeclampsia: Crosstalk with placental function?

Cardiovascular disease (CVD) is the leading cause of death in women, yet sex-specific risk factors remain understudied. Preeclampsia and other adverse pregnancy outcomes imply an increased maternal cardiovascular risk. We hypothesized that cardiac troponin T (cTnT), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) are increased in such pregnancies and correlate with markers of placental dysfunction. We also investigated these cardiovascular biomarkers 1 or 3years postpartum. Prior to delivery, we included serum from 417 pregnant women: 55 early-onset preeclampsia (EO-PE), 63 late-onset preeclampsia (LO-PE), 30 gestational hypertension (GH) and 269 healthy controls. Postpartum, we included 341 women 1 or 3years after delivery: 26 EO-PE, 107 LO-PE, 61 GH, and 147 healthy pregnancies. Prior to delivery, median cTnT and NT-proBNP concentrations were higher in women with EO-PE, LO-PE, or GH than in controls. Median GDF-15 was higher in EO-PE and LO-PE compared to controls. Postpartum, GDF-15 was elevated in women with previous EO-PE. Markers of placental dysfunction correlated with CVD biomarkers in pregnancy, but not postpartum. Our findings underscore the cardiovascular burden of hypertensive disorders of pregnancy and the crosstalk with placental function. The upregulation of circulating GDF-15 following early-onset preeclampsia is in line with the epidemiological excessive risk of premature CVD in this group of women. GDF-15 may be explored for targeting postpartum women with most to gain from intensified preventive follow-up for CVD.

The association between maternal tea consumption and the risk of pregnancy induced hypertension: A retrospective cohort study in Lanzhou, China.

Existing evidence on the relationship between maternal tea consumption and pregnancy induced hypertension (PIH) is inconclusive. This study aimed to evaluate the association between maternal tea consumption and the risk of PIH. This study analysed the data of women without chronic hypertension who participated in a retrospective birth cohort study conducted from 2010 to 2012 at the Gansu Provincial Maternity and Child Care Hospital in Lanzhou, China. Multivariable logistic regression models were used to estimate the association between tea consumption and the risk of PIH and its clinical subtypes by different tea exposure time windows. Among the 10,452 women included in this study, tea consumption during pregnancy was significantly associated with an increased risk of PIH (odds ratio [OR]=1.44, 95% confidence interval [CI]: 1.01, 2.05), gestational hypertension (OR=1.86, 95% CI: 1.07, 3.21), and early-onset preeclampsia (OR=2.93, 95% CI: 1.21, 7.09). This was especially the case with black tea (OR=3.57, 95% CI: 1.67, 7.62). Tea consumption during pregnancy might be associated with an increased risk of PIH, gestational hypertension, and early-onset preeclampsia. These findings have important implications for public health in reducing the PIH.

Intensive care patients with preeclampsia - Clinical risk factors and biomarkers for oxidative stress and angiogenic imbalance as discriminators for severe disease.

Approximately 180 mothers are treated in Swedish Intensive Care Units (ICU) due to preeclampsia each year. Although several clinical risk factors are known, prediction of critical disease is challenging. Two scavenger proteins, hemopexin (Hpx) and alpha-1-microglobulin (A1M) have been suggested to be associated with the oxidative stress seen in preeclampsia. The ratio of two other biomarkers, soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PIGF), is predictive of adverse pregnancy outcomes. In total 121 women were included in this study where we compared risk factors for preeclampsia, plasma levels of Hpx and A1M in ICU-patients with preeclampsia (n = 41) compared to uncomplicated preeclampsia cases (n = 40) and normotensive pregnancies (n = 40), with the objective to identify clinical risk patterns for severe disease. The sFlt-1/PIGF ratio was investigated in early and late onset preeclampsia ICU-patients. Blood samples were collected at admission to ICU and within 27 h postpartum for all groups. Hemopexin and A1M levels were significantly lower in the preeclampsia ICU-cohort compared to uncomplicated preeclampsia patients. The sFlt-1/PIGF-ratio was elevated in the ICU-patients but there was no difference between early and late onset preeclampsia. The ICU-patients had more clinical risk factors, refractory hypertension, and an increased rate of emergency Caesarean section. Intensive care patients have more clinical risk factors and a Hpx and A1M profile suggestive of depletion and thereby a reduced capacity to respond to oxidative stress. The ratios of sFlt-1/PIGF were high in the ICU-cohort and in accordance with pre-delivery levels predictive of adverse pregnancy outcomes.

Роль кластерина в прогнозировании развития ранней и поздней преэклампсии в первом триместре беременности

Preeclampsia (PE) occurs in 2–8% of pregnancies. It is one of the leading causes of maternal and perinatal morbidity and mortality. Today, there are no tests adopted by the practitioners that enable accurate prediction of early (weeks 20 through 34) or late (after week 34) onset of PE when the pregnancy is in its 11th to 14th week. This study aimed to evaluate the feasibility of using secretory clusterin quantification to predict early or late PE during the first trimester of pregnancy. The choice of this protein is determined, on the one hand, by the specificity of its expression for cytotrophoblast, syncytiotrophoblast, and extracellular trophoblast cells, and, on the other hand, by the proven negative effect of clusterin on the invasive properties of trophoblastic cells and gestational transformations of uterine vessels, which play a key role in the pathogenesis of PE. The study included 40 pregnant women aged 27–40 years who underwent a comprehensive screening examination in the first trimester of pregnancy. Western blotting revealed a significant increase in the level of secretory clusterin (40 kDa) in the blood serum of pregnant women in the case of PE compared to physiological pregnancy: in early-onset PE, a twofold increase in the level of clusterin in the vesicular and extravesicular fractions of blood serum (p = 0.03 and p = 0.004, respectively), with late-onset PE — a threefold increase only in the extravesicular fraction of blood serum (p = 0.002). According to logistic regression models, the level of secretory clusterin in the extravesicular fraction of blood serum of pregnant women in the first trimester has prognostic significance in assessing the likelihood of developing early-onset PE (AUC = 0.97, Se = 1, Sp = 0.875, cutoff = 0.3877) and late-onset PE ( AUC = 1, Se = 1, Sp = 1, cutoff = 0.5).

Maternal anxiety forecasts shorter prolongation of pregnancies complicated by early-onset preeclampsia

PurposeIn early-onset preeclampsia, each additional day of pregnancy prolongation reduces offspring infant mortality about 9%. We evaluated if maternal stress at admission to hospital for early-onset preeclampsia predicted admission-to-delivery intervals in days.MethodsThis prospective, longitudinal cohort-study involved 15 singleton pregnancies with a diagnosis of preeclampsia before 34 weeks gestation with intended expectant management. Upon hospital admission, maternal psychological stress was assessed with questionnaires and physiological stress with hair cortisol. Hair samples were analyzed in three hair segments representing the preconception period, and the first and second trimester of pregnancy.ResultsMean pregnancy prolongation was 16.2 days. Higher maternal anxiety at hospital admission significantly correlated with shorter admission-to-delivery intervals (r = − 0.54, p = 0.04). Chronically increased hair cortisol concentrations (i.e. from preconception through the second trimester) of pregnancy tended to be related to shorter admission-to-delivery intervals (p <. 10).ConclusionHigher reported anxiety is, and chronically high hair cortisol tended to be, related with fewer days of prolongation from admission to delivery in women with early-onset preeclampsia. These findings suggest that maternal stress might be a potential determinant of disease progression. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease.

WTAP dysregulation-mediated HMGN3-m6A modification inhibited trophoblast invasion in early-onset preeclampsia.

Early-onset preeclampsia (ePE) originates from abnormal implantation and placentation that involves trophoblast invasion, but its pathophysiology is not entirely understood. N6-methyladenosine (m6A) regulators mediate the progression of various cancers. The invasiveness of trophoblast cells is similar to that of tumor cells. However, little is known regarding the potential role of m6A modification in ePE and the underlying mechanism. This study aimed to explore the m6A level in placental tissue samples collected from ePE patients and to investigate whether m6A modification was an essential part of PE pathogenesis. The m6A level in placental tissue samples of 80 PE participants was examined. MeRIP-microarray, RNA-Seq, luciferase reporter assay, and RNA immunoprecipitation chip (RIP) assay were performed. The m6A level in the ePE group was significantly reduced compared with the control group. Wilms' tumor 1-associating protein (WTAP) regulated trophoblast cell migration and invasion. Mechanistically, the high mobility group nucleosomal binding domain 3 (HMGN3) gene was a target gene of WTAP in trophoblast (p < .05). WTAP enhanced the stability of HMGN3 mRNA through binding with its 3'-UTR m6A site(+485A, +522A). HMGN3 was recognized by m6A recognition protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which was inhibited when knocking down WTAP. Both m6A and WTAP levels were downregulated in ePE. The m6A modification mediated by WTAP/IGF2BP1/HMGN3 axis might contribute to abnormal trophoblast invasion. Our work provided a foundation for further exploration of RNA epigenetic regulatory patterns in ePE, and indicated a new treatment strategy for ePE.

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre-eclampsia.

To assess and compare circulating tissue inhibitor of metalloproteinase 3 (TIMP-3) concentrations between women with pre-eclampsia and healthy pregnant women. We also aimed to determine the relationships between circulating TIMP-3 and matrix metalloproteinase 2 (MMP-2), MMP-9, TIMP-1, and TIMP-2 concentrations in pre-eclampsia. A primary case-control study included patients with pre-eclampsia (n= 219) and gestational hypertension (n= 118), healthy pregnant women (n= 214), and non-pregnant women (n= 66), and a replication case-control study included patients with pre-eclampsia (n= 177) and healthy pregnant women (n= 124), all from southeastern Brazil. Plasma TIMP-3, MMP-2, MMP-9, TIMP-1, and TIMP-2 concentrations were assessed using commercially available enzyme-linked immunosorbent assay kits, and the relationships between them were analyzed using Spearman's correlation. In our primary study, patients with pre-eclampsia and gestational hypertension exhibited increased TIMP-3 concentrations compared with healthy pregnant women (both P< 0.0001) and non-pregnant women (both P< 0.001). These findings were confirmed in the replication study, showing elevated TIMP-3 concentrations in women with pre-eclampsia versus healthy pregnant women (P< 0.001). We found no difference in TIMP-3 concentrations between early-onset and late-onset pre-eclampsia. Moreover, TIMP-3 concentrations were significantly correlated with plasma concentrations of TIMP-1 (r= 0.2333; P= 0.0086) and MMP-2 (r= 0.2159; P= 0.0156) in pre-eclampsia. Circulating TIMP-3 concentration is increased in women with pre-eclampsia compared with healthy pregnant women, and it is positively correlated with plasma MMP-2 and TIMP-1 concentrations in pre-eclampsia.

Intertwin growth discordance throughout gestation and hypertensive disorders of pregnancy

Previous studies have established the association between intertwin birthweight discordance and hypertensive disorders of pregnancy. However, longitudinal fetal size discordance concerning gestational hypertension or preeclampsia remains unclear. This study aimed to compare the patterns of estimated fetal weight discordance throughout gestation among normotensive women, women with gestational hypertension, and women with preeclampsia and to evaluate the association between crown-rump length discordance at 11 to 14 weeks of gestation and hypertensive disorders of pregnancy. This was a retrospective cohort study of women with twin pregnancies who had antenatal care visits and delivered at a tertiary hospital between January 2013 and June 2021. The crown-rump length was measured at 11 to 14 weeks of gestation. Estimated fetal weight was calculated based on ultrasound examinations of fetal biometrics at 16 to 18, 20 to 24, 28 to 32, and ≥34 weeks of gestation, respectively. Crown-rump length and estimated fetal weight discordances were calculated: (larger crown-rump length- smaller crown-rump length)/larger crown-rump length× 100% and (larger estimated fetal weight- smaller estimated fetal weight)/larger estimated fetal weight× 100%, respectively. Multiple imputation was used to handle missing data, and all models accounted for the imputation. Multilevel model analysis was used to compare the differences in estimated fetal weight discordances throughout gestation among normotensive women, women with gestational hypertension, and women with preeclampsia. Generalized linear models were used to evaluate the association between crown-rump length discordance and hypertensive disorders of pregnancy, assuming a Poisson distribution. The possible nonlinear relationship between continuous crown-rump length discordance and hypertensive disorders of pregnancy was examined by generalized additive models. All analyses were stratified by chorionicity. Of the 3280 women with twin pregnancies who met the inclusion criteria, 187 (5.7%) developed gestational hypertension, and 436 (13.3%) developed preeclampsia, including 125 (3.8%) early-onset preeclampsia and 311 (9.5%) late-onset preeclampsia. In women with dichorionic twin pregnancies, compared with normotensive women, a substantial progression of estimated fetal weight discordance throughout pregnancy was identified in women who developed preeclampsia, and a large progression of estimated fetal weight discordance in late pregnancy was identified in women who developed gestational hypertension. In women with monochorionic twin pregnancies, estimated fetal weight discordances were more progressive from 20 to 24 weeks of gestation onward in women who developed preeclampsia than in normotensive women. Crown-rump length discordance at 11 to 14 weeks of gestation was associated with an increased risk of preeclampsia (relative risk, 1.03; 95% confidence interval, 1.00-1.05), particularly early-onset preeclampsia (relative risk, 1.09; 95% confidence interval, 1.04-1.13). A crown-rump length discordance of ≥10% had 1.2 times the increased risk of developing early-onset preeclampsia (relative risk, 2.27; 95% confidence interval, 1.28-4.03). This association was identified in dichorionic twins, but not in monochorionic twins. Our study demonstrated distinct growth discordant patterns among normotensive women, women with gestational hypertension, and women with preeclampsia in twin pregnancies. Intertwin crown-rump length discordance at 11 to 14 weeks of gestation was associated with an increased risk of preeclampsia, especially early-onset preeclampsia in dichorionic twin pregnancies, with a dose-response pattern.

Risk factors and foetal growth restriction associated with expectant treatment of early-onset preeclampsia

Objective To identify the factors affecting expectant management of early-onset preeclampsia, and evaluate the correlation between expectant treatment and foetal growth restriction. Materials and Methods The retrospective study included 72 women who were admitted for early-onset preeclampsia between February 2018 to April 2021. Data included maternal clinical parameters, demographic and maternal and neonatal outcomes, which were analysed for correlation. Results Multiple logistic regression analysis demonstrated that the time interval from the onset of 24-h proteinuria to termination of pregnancy showed a strong correlation with the expectant treatment; Univariate logistic analysis confirmed that there was no correlation between expectant treatment and foetal growth restriction. Conclusion There was a negative correlation between the duration of 24-h proteinuria and the expectant treatment of patients with early-onset preeclampsia; Expectant treatment could not improve the development of foetal growth restriction in patients with early-onset preeclampsia. KEY MESSAGES The duration of 24-h proteinuria affects the effectiveness of expectant management of early-onset preeclampsia. Expectant management can reduce adverse neonatal outcomes due to iatrogenic preterm delivery, but it cannot improve the occurrence of foetal growth restriction.

Contribution of Second Trimester Sonographic Placental Morphology to Uterine Artery Doppler in the Prediction of Placenta-Mediated Pregnancy Complications.

Second-trimester uterine artery Doppler is a well-established tool for the prediction of preeclampsia and fetal growth restriction. At delivery, placentas from affected pregnancies may have gross pathologic findings. Some of these features are detectable by ultrasound, but the relative importance of placental morphologic assessment and uterine artery Doppler in mid-pregnancy is presently unclear. To characterize the association of second-trimester sonographic placental morphology markers with placenta-mediated complications and determine whether these markers are predictive of placental dysfunction independent of uterine artery Doppler. This was a retrospective cohort study of patients with a singleton pregnancy at high risk of placental complications who underwent a sonographic placental study at mid-gestation (160/7-246/7 weeks' gestation) in a single tertiary referral center between 2016-2019. The sonographic placental study included assessment of placental dimensions (length, width, and thickness), placental texture appearance, umbilical cord anatomy, and uterine artery Doppler (mean pulsatility index and early diastolic notching). Placental area and volume were calculated based on placental length, width, and thickness. Continuous placental markers were converted to multiples on medians (MoM). The primary outcome was a composite of early-onset preeclampsia and birthweight &lt; 3rd centile. A total of 429 eligible patients were identified during the study period, of whom 45 (10.5%) experienced the primary outcome. The rate of the primary outcome increased progressively with decreasing placental length, width, and area, and increased progressively with increasing mean uterine artery pulsatility index (PI). By contrast, placental thickness followed a U-shaped relationship with the primary outcome. Placental length, width, and area, mean uterine artery PI and bilateral uterine artery notching were all associated with the primary outcome. However, in the adjusted analysis, the association persisted only for placenta area (adjusted odds ratio [aOR] 0.21, 95%-confidence interval [CI] 0.06-0.73) and mean uterine artery PI (aOR 11.71, 95%-CI 3.84-35.72). The area under the ROC curve was highest for mean uterine artery PI (0.80, 95%-CI 0.71-0.89) and was significantly higher than that of placental area (0.67, 95%-CI 0.57-0.76, p = 0.44). A model that included both mean uterine artery PI and placental area did not significantly increase the area under the curve (0.82, 95%-CI 0.74-0.90, p = 0.255), and was associated with a relatively minor increase in specificity for the primary outcome compared with mean uterine artery PI alone (63% [95%-CI 58-68%] vs. 52% [95%-CI 47-57%]). Placental area is independently associated with the risk of placenta-mediated complications yet, when combined with uterine artery Doppler, did not further improve the prediction of such complications compared with uterine artery Doppler alone.

Sickle Cell Disease-Specific Blood Pressure Thresholds for Hypertensive Disorders of Pregnancy: A Multinational Study

INTRODUCTION Although pregnant people with sickle cell disease (SCD) are at increased risk of hypertensive disorders of pregnancy (HDP), no evidence informs what blood pressure thresholds to apply to diagnose HDP in people with SCD. HDP are typically defined by blood pressure 140/90 mmHg and laboratory abnormalities indicative of end-organ damage. However, people with SCD have lower baseline blood pressure compared to the general population. Thus, the existing HDP definitions potentially under-diagnose HDP in pregnant people with SCD, increasing the risk of significant HDP-related morbidity. Early-onset preeclampsia develops prior to 34 weeks' gestation versus late-onset between 34 weeks and delivery. Early- and late-onset preeclampsia are believed to have distinct etiologic and prognostic significance and may be differently associated with blood pressure. The objectives of our study were (1) to evaluate the sensitivity of various blood pressure thresholds in classifying preeclampsia in pregnant people with SCD, and (2) to determine whether the accuracy with which blood pressure thresholds classify pregnant people with preeclampsia differs between those with early- versus late-onset preeclampsia. METHODS We reviewed all SCD pregnancies of at least 20 weeks' gestation that delivered at Mount Sinai Hospital, Toronto (1990-2017) or Johns Hopkins Hospital (2000-2021). We collected data on laboratory values, SCD complications, medication exposures, transfusion, delivery information, and fetal outcomes. We collected the highest systolic and diastolic blood pressure (SBP and DBP) in seven time periods: before pregnancy, at intake visit, 20-28 weeks' gestation, 28-34 weeks' gestation, last outpatient visit, at admission for birth, and six weeks postpartum. New or worsening proteinuria (NWP) was defined as 0.3g/g on urine protein:creatinine ratio or 300mg on 24-hour collection; or, if a patient had baseline proteinuria, as doubling from baseline. We compared the characteristics of pregnant people with NWP to those without. We then constructed receiver operating characteristic (ROC) curves to determine what SBPs and DBPs at the last outpatient visit most accurately classifies those with new or worsening proteinuria in SCD pregnancy. Finally, we divided patients with NWP into early- and late-onset and generated ROC curves for each group. RESULTS We included 198 patients with 292 singleton pregnancies (Table). Fifty-four pregnancies had NWP. Of these, 24 (44%) were diagnosed with an HDP. NWP was associated with older age at delivery, higher rates of disease-modifying therapy at conception, higher rates of HDP in a previous pregnancy, and higher rates of preterm deliveries that were mostly attributable to induction of delivery. There was no difference in birth weight centile between the groups. ROC curves indicate that blood pressure was modestly accurate at classifying those who developed NWP at any time after 20 weeks' gestation (Figure). For the cohort, the area under the curve (AUC) for SBP was 0.68 and for DBP was 0.63. Among those with HbSS/HbSβ0 the AUC for SBP was 0.70 and for DBP was 0.70. Among those with HbSC/HbSβ+ the AUC for SBP was 0.66 and for DBP was 0.53. Change in blood pressure from baseline was a poor predictor of NWP in both genotypes, with AUC<0.60 for SBP and DBP. Using NWP as a traditionally-accepted standard for diagnosis of preeclampsia, the established threshold for HDP of 140/90 was 18% sensitive and 94% specific with a positive predictive value (PPV) of 44% and a negative predictive value (NPV) of 82%. In our sample, the optimal blood pressure cut-off was 120/70, which was 64% sensitive and 63% specific with a PPV of 31% and an NPV of 87%. By timing of NWP onset, most (61%, n=33) had late-onset NWP. Blood pressure between 28 and 34 weeks' gestation did a poor job of classifying those who had early-onset NWP (AUC 0.44), while blood pressure between 34 weeks and delivery very accurately classified those who had late-onset NWP (AUC 0.82). CONCLUSIONS Existing blood pressure thresholds used to diagnose HDPs are not sensitive in the SCD population. There is a need to consider lowering the BP threshold for HDP diagnosis among pregnant people with SCD. We propose a new threshold of 120/70, the adoption of which would improve identification of patients with SCD who need increased observation, consideration of early delivery, eclampsia prophylaxis, or possibly chronic transfusion therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Low Vitamin D Level Status and Risk of Pre-Eclampsia and Preterm Birth in Women Using Low-Dose Aspirin

Objective: To determine the association between low Vitamin-D status and risk of pre-eclampsia and preterm birth in women using low-dose Aspirin in the tertiary care setting.&#x0D; Study Design: Prospective comparative study.&#x0D; Place and Duration of Study: Gynecology and Obstetrics Department, Pak Emirates Military Hospital, Rawalpindi Pakistan from Sep 2018 to Sep 2019.&#x0D; Methodology: A total of 383 pregnant women were divided into three Groups. Pregnant women were included based on the criteria; if one of the five high-risk factors or more than one moderate risk factors were met. High-risk factors were; 1) Type-1 or 2 diabetes mellitus, 2) chronic hypertension, 3) hypertensive disease in previous pregnancy, 4) autoimmune disease such as systemic lupus erythematous or antiphospholipid syndrome, 5) chronic kidney disease.&#x0D; Results: There were 127 pregnant women in Group-1 with Vitamin-D deficiency. In Group-2, there were pregnant women with Vitamin-D insufficiency; in Group-3, there were 18 pregnant women with Vitamin-D sufficiency. The mean Vitamin-D level in Group-1 was 22.40±1.50 nmol/L, the mean Vitamin-D level in Group-2 was 32.82±9.80nmol/L and in Group-3 mean Vitamin-D level was 76.63±8.00 nmol/L. Early onset pre-eclampsia, chronic hypertension with superimposed pre-eclampsia,gestational diabetes, spontaneous-vaginal delivery and delivery at term were found to statistically significant among the Groups (p&lt;0.05).&#x0D; Conclusion: We aimed to determine whether vitamin D status was linked with high-risk pregnancies, which could overshadow the impact of vitamin D under existing conditions. Our findings help relate the status and pre-eclampsia of maternal vitamin D to preterm birth.

Pregnancy outcomes and risk factors for preeclampsia in dichorionic twin pregnancies after in vitro fertilization: a five-year retrospective study

BackgroundBoth in vitro fertilization (IVF) and preeclampsia (PE) were associated with placental dysfunction. Although IVF can increase the incidence of PE, the pregnancy outcomes and risk factors for preeclampsia in dichorionic twin pregnancies conceived via IVF remain unclear. This study aimed to investigate the pregnancy outcomes and the risk factors for preeclampsia in dichorionic twin pregnancies conceived through IVF compared to those conceived after natural conception (NC).MethodsThis retrospective observational study enrolled 181 dichorionic twin pregnancy women with preeclampsia from 2016 to 2020. According to the mode of conception, they were allocated into IVF (n = 117) and NC groups (n = 64). The clinical characteristics of preeclampsia and pregnancy outcomes between the two groups were compared by using Student’s t test, chi-square test, and Fisher’s exact test, and logistic regression models were used to obtain adjusted odds ratios (aOR) with 95% confidence intervals (CI) for risk factors of early-onset preeclampsia.ResultsThe incidence of early-onset PE and growth discordance in dichorionic twin pregnancies with PE is significantly higher in IVF-PE group than in NC group (78.60% vs 43.80%, P < 0.001, 11.10% vs 25.00%, P = 0.015). We found that IVF (aOR = 4.635, 95% CI: 2.130–10.084, P < 0.001) and growth discordance (aOR = 3.288; 95% CI: 1.090–9.749, P < 0.05) increased the incidence of early-onset PE.ConclusionsIn preeclamptic dichorionic twin pregnancies, IVF and growth discordance were associated with the increased incidence of early-onset PE. The underlying mechanism for the relationship between IVF and early-onset PE or growth discordance may be placental dysfunction.

STOX1 promotor region -922 T > C polymorphism is associated with Early-Onset preeclampsia

Preeclampsia (PE), affecting 5–8% of pregnancies, is a common pregnancy disease that has harmful effects on mother and foetus. It has been found that the STOX1 (Storkhead Box 1), which is a transcription factor, carries variants associated with PE. Previous studies showed that, there was a strong relationship between PE and STOX1 variants. Therefore, we hypothesised that variants in the promoter region of the gene may be related to the onset of PE. The aim of this study is to investigate the contribution of STOX1 gene promoter region variants to PE. The blood samples taken from 118 PE patients and 96 healthy pregnant women were analysed by Sanger sequencing method. Sequence analysis results showed that, there is a-922 T > C polymorphism (rs884181) in the promoter region of the STOX1 gene. This polymorphism was found to be statistically significant in individuals with early onset PE (p = 0.02) and in PE (p = 0.014) compared to the control group. IMPACT STATEMENT What is already known on this subject? As a result of whole-exon studies on the STOX1 gene, polymorphisms were found to disrupt the structure/expression/function of the gene and strengthen its relationship with PE and HELLP syndrome. A previous study by our team found an association between Y153H, the most common polymorphism of STOX1, and early onset PE. What do the results of this study add? In our study, it was aimed to investigate the effect of genetic modifications in STOX1 gene promoter region on PE through the maternal genotype. Because any change in the promoter region affects the expression level of the gene. Also, for the first time, sequence analysis of the promoter region of STOX1 is investigated in PE. The variations in STOX1 appear to be important in PE especially in Early Onset PE. What are the implications of these findings for clinical practice and/or further research? Although PE is a disease that occurs with pregnancy and shows its effects most during this period, women and children with a history of PE are more prone to various disorders, especially cardiovascular diseases in the following years. Therefore, understanding the pathogenesis of the disease is important for both prevention and treatment process. Variations on STOX1 appear to be important in terms of disease risk.

Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction

Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

Maternal plasma proteome profiling of biomarkers and pathogenic mechanisms of early-onset and late-onset preeclampsia

Preeclampsia is still the leading cause of morbidity and mortality in pregnancy without a cure. There are two phenotypes of preeclampsia, early-onset (EOPE) and late-onset (LOPE) with poorly defined pathogenic differences. This study aimed to facilitate better understanding of the mechanisms of pathophysiology of EOPE and LOPE, and identify specific biomarkers or therapeutic targets. In this study, we conducted an untargeted, label-free quantitative proteomic analyses of plasma samples from pregnant women with EOPE (n = 17) and LOPE (n = 11), and age, BMI-matched normotensive controls (n = 18). Targeted proteomics approach was also employed to validate a subset of proteins (n = 17). In total, there were 26 and 20 differentially abundant proteins between EOPE or LOPE, and normotensive controls, respectively. A series of angiogenic and inflammatory proteins, including insulin-like growth factor-binding protein 4 (IGFBP4; EOPE: FDR = 0.0030 and LOPE: FDR = 0.00396) and inter-alpha-trypsin inhibitor heavy chain H2-4 (ITIH2-4), were significantly altered in abundance in both phenotypes. Through validation we confirmed that ITIH2 was perturbed only in LOPE (p = 0.005) whereas ITIH3 and ITIH4 were perturbed in both phenotypes (p < 0.05). Overall, lipid metabolism/transport proteins associated with atherosclerosis were highly abundant in LOPE, however, ECM proteins had a more pronounced role in EOPE. The complement cascade and binding and uptake of ligands by scavenger receptors, pathways, were associated with both EOPE and LOPE.

Characterization of Vascular Patterns Associated with Endothelial Glycocalyx Damage in Early- and Late-Onset Preeclampsia.

This paper provides an assessment of molecular and functional changes in blood vessels, and a description of vascular patterns during preeclampsia (PE). Patients with normal pregnancy, and pregnancy complicated by PE at earlier (20-34 weeks) and later terms (≥34 weeks) underwent a 24 h monitoring of blood pressure, central hemodynamics, arterial stiffness, and myocardial function. The blood levels of the structural components of endothelial glycocalyx (eGC): syndecan-1 (SDC 1), heparan sulfate proteoglycan 2 (HSPG2), and hyaluronic acid (HA) were determined. In early-onset PE, the vascular pattern comprised changes in all structural components of eGCs, including transmembrane proteoglycans levels, and severe disorders of central hemodynamics, arterial stiffness, and myocardial changes, probably leading to more severe course of PE and the formation of morphological grounds for cardiovascular disorders. The vascular pattern in late-onset PE, including changes in HA levels, central hemodynamics, and myocardial function, may be a signal of potential cardiovascular disorder. PE may change adaptive hemodynamic responses to a pathological reaction affecting both arterial elasticity and the left ventricular myocardium, with its subsequent hypertrophy and decompensation, leading to a delayed development of cardiovascular disorders after PE. Further clinical studies of these indicators will possibly identify predictors of PE and long-term consequences of the disease.

Regulation of the Placental Growth Factor Mediated by Sumoylation and Expression of miR-652-3p in Pregnant Women with Early-Onset Preeclampsia.

We studied regulation of the expression of placental growth factor (PlGF) that plays an important role in the trophoblast cells functions and reduced production of which by the placenta is associated with gestational complications. PlGF expression is regulated by transcription factors whose activity is controlled by sumoylation, which is also necessary for the formation of an adequate cellular response to hypoxia. Increased sumoylation and reduced expression of some miRNA targeted to transcription factors VEGF, GCM-1, and UBC9 conjugating SUMO with targets protein were detected in the placenta. Correlations were revealed between changes in the expression of miR-423-3p and miR-652-3p, the level of SUMO 1-4 and UBC9 in the placenta, reduced concentration of PlGF, and increased sFlt-1/PlGF ratio in the blood of pregnant women with early-onset preeclampsia, which attests to the presence of a regulatory mechanism along the axis of miR-652-3p/SUMO-2/3/4/UBC9/GCM-1/PlGF.

Clinical Comparative Analysis of Early-Onset Preeclampsia Combined with HELLP Syndrome

To explore the clinical characteristics of early-onset preeclampsia (PE) combined with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and to improve the capacity for early diagnosis and treatment. Pregnant women who received treatment at Women's Hospital, School of Medicine, Zhejiang University between March 2014 and October 2021 were retrospectively enrolled. There were two patient groups, the HELLP group consisting of 70 cases of early-onset PE combined with HELLP syndrome and the control group consisting of 140 cases of early-onset PE without HELLP syndrome. Patients in the two groups were matched by age. The general clinical data, characteristics of pathogenesis, and laboratory findings of the patients were collected and the perinatal outcomes of the two groups were compared and analyzed. 1) There was no significant difference in gravidity, pre-delivery body mass index, years from the last delivery, and family history of diabetes mellitus and hypertension between the two groups. 2) The highest systolic blood pressure, highest diastolic blood pressure during the pregnancy, and the postpartum hospital length-of-stay ( P<0.001) in the HELLP group were higher than those in the control group. The gestational age at the time of the diagnosis of PE ( P=0.001) and the gestational age at delivery ( P<0.001) in the HELLP group were significantly earlier than those in the control group. The difference between the gestational age at the time of blood pressure elevation and that at the time of delivery ( P<0.001), and the gestational age difference between the diagnosis of early-onset PE and delivery ( P=0.027) were lower than those in the control group. The incidences of eclampsia in the HELLP group, pleural effusion, and ascites were higher than those of the control group. 3) Neonates in the HELLP group had a higher probability of being admitted to NICU and developing cyanotic/pale asphyxia ( P<0.001). 4) Before the termination of pregnancy, the HELLP group had higher levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, urea, random glucose, lactate dehydrogenase, activated partial thromboplastin time, and the last 24-hour urine protein quantification than those of the control group (all P<0.05), while the platelet (PLT) counts were significantly lower than those of the control group ( P<0.001). 5) There was a significant correlation between PLT counts in the second trimester and the onset of HELLP syndrome ( P=0.006), with the area under the ROC curve reaching 0.746 (95% CI: 0.596-0.897). In comparison with early-onset PE patients without HELLP syndrome, patients with early-onset PE combined with HELLP syndrome are diagnosed for PE at an earlier gestational age, have higher blood pressure, are more prone to serious pregnancy complications, and have longer postpartum hospital length-of-stay and worse neonatal outcomes. Close monitoring of PLT counts of early-onset PE patients in the second trimester may help predict subsequent HELLP syndrome.

Fetal APOL1 Risk Variants Association With Adverse Maternal Outcomes of Early Onset Preeclampsia

Fetal APOL1 Risk Variants Association With Adverse Maternal Outcomes of Early Onset Preeclampsia