Preeclampsia Status Research Articles

Red blood cell in preeclampsia: attenuated nitric oxide generation and enhanced reactive oxygen species formation and eryptosis

Preeclampsia (PE) pathogenesis is strongly related to diminished nitric oxide (NO) bioavailability and enhanced oxidative stress. Emerging evidence suggests that red blood cells (RBCs) eNOS enzyme contributes to systemic NO bioavailability by its ability of both NO and ROS generation. We aimed to investigate RBC eNOS enzyme activity, NO and ROS generation capacity, eryptosis index and aggregation levels in preeclamptic and uncomplicated pregnant women. Fifty-eight PE patients and 36 healthy pregnant women were included to the investigation. RBC eNOS enzyme activity, intracellular NO, calcium and ROS concentrations and eryptosis levels were determined via flow cytometric methods. RBC deformability and aggregation were measured via LORRCA. Intracellular NO and phosphorylated RBC eNOS levels decreased in PE group compared to healthy pregnant group (p < 0.05, p < 0.001 respectively). Intracellular ROS and calcium levels, eryptosis values and aggregation indexes in the PE group were significantly higher than healthy pregnant group (p < 0.05, p < 0.01, p < 0.05, p < 0.05 respectively). Our results demonstrate for the first time that RBC produce lower NO and higher ROS under PE conditions. Further, RBC of PE patients were more prone to eryptosis and aggregation compared to control group. Our results suggest that, in addition to endothelial cells, RBC also contribute to decreased plasma NO bioavailability via producing less NO and high ROS in PE. Considering increased tendency to eryptosis and aggregation, RBC seem to play role in haemodynamic changes of PE pathogenesis.

Preeclampsia, Fetal Growth Restriction, and 24-Month Neurodevelopment in Very Preterm Infants

Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized. To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants. In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care units (NICUs). Eligible infants were born before 30 weeks' gestation. Infants were excluded for any major congenital anomalies and for maternal age younger than 18 years or cognitive impairment impacting the ability to provide informed consent. Data analysis was performed from November 2023 to January 2024. Maternal preeclampsia and FGR in very preterm infants. The Bayley-III cognition, motor, and language scores less than 85 (-1 SD) indicated developmental delay. Child Behavior Checklist/Preschool 1.5-5 T-scores greater than or equal to 64 for internalizing, externalizing, or total problems indicated clinical importance. Of 704 infants enrolled, 529 (mean [SD] gestational age, 27.0 [1.9] weeks; 287 male [54.3%]) were studied at 24-month follow-up. A total of 94 infants' mothers had preeclampsia (23.2%), and 46 infants (8.7%) had FGR. In adjusted models, preeclampsia was not associated with Bayley-III (cognitive, B = 3.43 [95% CI, -0.19 to 6.66]; language, B = 3.92 [95% CI, 0.44 to 7.39]; motor, B = 1.86 [95% CI, -1.74 to 5.47]) or Child Behavior Checklist/Preschool 1.5-5 (internalizing, B = -0.08 [95% CI, -2.58 to 2.73]; externalizing, B = 0.69 [95% CI, -1.76 to 3.15]; total, B = 0.21 [95% CI, -2.48 to 2.91]) outcomes. FGR was associated with significantly lower Bayley-III scores (cognitive, B = -8.61 [95% CI, -13.33 to -3.89]; language, B = -8.29 [95% CI, -12.95 to -3.63]; motor, B = -7.60 [95% CI, -12.40 to -2.66]), regardless of preeclampsia status. In this cohort study of preterm infants, preeclampsia was not associated with developmental and/or behavioral outcomes, but infants with FGR may be prone to developmental delays. These findings suggest future areas of research for understanding the roles of preeclampsia and FGR separately and together in early child development for preterm infants.

DNA methylation-mediated 11βHSD2 downregulation drives the increases in angiotensin-converting enzyme and angiotensin II within preeclamptic placentas.

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11β-hydroxysteroid dehydrogenases (11βHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11βHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11βHSD2 gene promoter and its expression, meanwhile, 11βHSD2 expression was negatively correlated with cortisol and ACE levels. Invitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11βHSD2 knockdown could enhance this activating effect. An invivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11βHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE.

Abstract HUP1: Health Inequities in Preeclampsia and Maternal Ischemic Stroke: A Cross-Sectional Analysis of the National Inpatient Sample

Introduction: Maternal stroke affects 30 per 100,000 pregnancies, a 3-fold higher risk as compared to stroke rate in young adults. One study reported that preeclampsia (PE) or eclampsia was seen in 36% of pregnant patients with ischemic stroke. The objective of this study is to evaluate the odds of PE and maternal ischemic stroke (MIS) in a national sample. Methods: We utilized the National Inpatient Sample from Q4 2015 to 2020 to examine the rates of PE and MIS in women aged 20-44. To be included in the analysis, the primary Major Diagnostic Category (MDC) code on the record was for Pregnancy, Childbirth, and Puerperium (n=3,921,672) or Newborn and Other Neonates, Perinatal Period (n=178). Univariate analysis provided crude odds of relevant variables. Multivariate logistic regression models were fitted to determine the odds of PE based on known PE risk factors; a second model was fitted to determine the odds of maternal stroke in women who had PE. Covariates in both models were age, primary payer, gestational diabetes, and obesity. Results: Consistent with previous knowledge, univariate analysis showed that Black women had 69% higher odds of PE compared to white women (cOR=1.69, 95%CI=1.66-1.71), while Latinas had 8% higher odds of PE compared to white women (cOR=1.08, 95%Ci=1.06-1.11). Compared to white women, Black women had 42% increased odds of MIS (cOR=1.42, 95%CI=1.14-1.78), while Latinas had 24% decreased odds of MIS (cOR=0.76, 95%CI=0.59-0.99). In multivariate analysis, PE was associated with increased odds of MIS, aOR=1.74 (95% CI=1.31-2.31). When stratified by race, this result was only found among white women (aOR=1.85, 95% CI=1.26-2.75). Having PE was not associated with odds of MIS in Black women when compared to Black women without PE (aOR=1.52, 95% CI=0.90-2.56). Conclusion: This study found that preeclampsia increases the odds of MIS overall. These odds are higher if patients also have other risk factors such as gestational diabetes, history of hypertension, and history of stroke. Our results also found no significant difference in MIS among Black women or Latinas based on PE status. Future directions could address other potential contributing factors, including structural factors that contribute to health inequities.

Assessment of Nailfold Capillaroscopy Findings in Pregnant Women having Preeclampsia: A Research Protocol

Introduction: Pregnancy causes significant vascular and cutaneous changes in a woman’s body. Preeclampsia is one of the life-threatening conditions associated with high blood pressure and proteinuria after the 20th week of pregnancy. It can cause placental hypoperfusion and placental insufficiency, leading to foetal defects or, in severe cases, foetal loss, which can be prevented by early diagnosis and treatment. There are many ways to observe and study the microcirculation non invasively the safest and most accessible method is nailfold capillaroscopy. Nail-fold Video Capillaroscopy (NVC) is a handheld digital microscope used to observe the microcirculation at the nailfold of the hands. Thus, comparing the capillary status with healthy subjects will help establish an early diagnosis and manage cases to prevent further complications in the mother and newborn. Need of the Study: The pathophysiology states that preeclampsia is related to systemic endothelial dysfunction, causing the release of Tumour Necrosis Factor (TNF) alpha, a proinflammatory mediator, leading to hypoxia of the placenta and the loss of endothelial cell-lined capillaries. Thus, there is a need to find if there is an established correlation in association of decreased Capillary Density (CD) in individuals with preeclampsia. Although evidence supporting a link between decreased CD and preeclampsia is limited, timely assessment and prevention are crucial. Nailfold capillaroscopy, an accessible and non invasive imaging method, holds promising calibre for understanding microvascular changes in preeclampsia. This could facilitate post-conception monitoring and early interventions to identify and address circulatory issues in affected women with preeclampsia. Aim: To study and compare the nailfold capillary changes in women diagnosed with preeclampsia and women having normal and uneventful pregnancies. Materials and Methods: A comparative cross-sectional study will be done in the Outpatient Department (OPD) and Inpatient Department (IPD) of Obstetrics and Gynaecology and the Outpatient Department of Dermatology at AVBRH Sawangi Meghe, Wardha, Maharashtra, India, from March 2023 to March 2025. A total of 150 pregnant women will be considered in the study, with 75 women being normal pregnant women (controls) and 75 pregnant women diagnosed with preeclampsia (cases). In order to confirm the gestational age of the patients, fundal height and abdominal circumference measurements will be taken. Demographic data, Basal Metabolic Index (BMI), weight gain during pregnancy, laboratory reports including Complete Blood Count (CBC), coagulation profile (Prothrombin Time, International Normalised Ratio, Activated Partial Thromboplastin Time), liver function tests, kidney function tests, urine examinations, and serial ultrasonography reports available for the patients will be noted. Pre-examination blood pressure will be recorded and compared with the baseline to confirm the status of preeclampsia after obtaining written consent from the patients. Nailfold capillaroscopy will be performed using a (Dinolite -AF4115ZT) dermoscope equipped with a 200X magnification, high-resolution lens in a non polarised light setting with oil immersion as a fluid coupling. The observations will be used to interpret the results of the study. Results will be calculated for finding differences between the two comparative groups of cases and controls at a p-value of ≤0.05.

Application of Mamdani’s Fuzzy Inference System in the Diagnosis of Pre-eclampsia

Pre-eclampsia is the second of the top three causes of death in pregnant women after bleeding and followed by infection. By knowing the risk factors, early detection of pre-eclampsia in pregnant womenneeds to be done so that later it can be treated more quickly to prevent further complications. This studyaims to design a practical application of a decision-making system for the diagnosis of pre-eclampsia inpregnant women using the Fuzzy Inference System (FIS) method so it can be used efficiently and effectively for the early diagnosis of pre-eclampsia. The method used in data analysis is the FIS Mamdanimethod with defuzzification using the centroid method. The designed system considers blood pressureand proteinuria as input variables and pre-eclampsia status as output variables. The research resultsshow that the system has 7.27% of Mean Absolute Percentage Error (MAPE) value and when comparing the final diagnosis of the system and expert diagnoses (doctors) from 20 patients at two hospitals, itwas found that the system diagnosis was 100% in accordance with the expert diagnoses.

Inhibiting HNF4A suppresses inflammation whilst promoting trophoblast invasion and migration: A promising target for the treatment of preeclampsia

Preeclampsia (PE) is a complex disease of pregnancy, and an important cause of this disease is insufficient trophoblast invasion and migration. However, the underlying mechanism of PE remains largely unknown. Here, transcriptome sequencing analysis found the high expression of hepatocyte nuclear factor 4 alpha (HNF4A) in PE placentas. Meanwhile, we found that HNF4A expression was up-regulated in the placentas of PE patients. Thus, we assumed that HNF4A might be involved in PE progression. To validate our hypothesis, l-arginine methyl ester (l-NAME) or lipopolysaccharide (LPS)-treated rats were used to mimic the pathological status of PE in vivo. Consistently, HTR8/SVneo cells were treated with hypoxia/reoxygenation (H/R) or LPS to simulate PE progression in vitro. The results observed an increase in elevated urine protein levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which indicated that the PE-like rat model was successfully established. Meanwhile, the expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-1β was increased in PE placentas. HTR8/SVneo cells were used to further explore the underlying mechanism of PE in vitro. H/R conditions up-regulated the acetylation level of HNF4A. Further analysis showed that HNF4A overexpression inhibited trophoblast invasion and migration, while HNF4A knockdown promoted the progression. Additionally, inhibiting HNF4A was found to reduce the levels of IL-6 and IL-1β secretion in HTR8/SVneo cells following H/R or LPS exposure. Conclusively, these findings suggest that inhibiting HNF4A suppresses inflammation whilst promoting trophoblast invasion and migration in PE, providing a promising target for the treatment of PE.

Bayesian Accelerated Failure Time Model for Risk Pregnancy Detection

Preeclampsia (PE) also known as a hypertension during third trisemester of pregnancy. PE, is one of the most feared complications of pregnancy because it can potentially become serious complications in the future, including mother and fetus’s death. The goal of this study is other than to have a bettter undestanding about risk factor in pregnancy by modelling the relationship between several factors and the time until deliveries under the PE condition. Data on 924 patients at obstetric and gynecology department in Jakarta were used in the analysis. Accelerated Failure Time (AFT) model was proposed to indentify some risk factors that influenced the condition. Model parameters were estimated using Bayesian method. Due to imbalance data, undersampling method will be used as a pre-procesing stage. Ratio between PE and non-PE data will be 60:40. Flat prior and posterior sample will be used using MCMC simulation with 12,000 iterations (including 2,000 iterations as a burnin stage) to get a convergen result. The iteration was repeated for 100 times so that the chosen data from undersampling was not error and biased. A consistent result for credible interval of the mean result was considered as the factors that affect PE condition consistently. From this study, there are two factors that have consistent Credible Interval result, Body Mass Index (BMI) and Mean Arterial Pressure (MAP).

Screening for pre-eclampsia by maternal serum glycosylated fibronectin at 11-13 weeks' gestation.

To examine the performance of screening for preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of maternal serum glycosylated fibronectin (GlyFn), mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). This was a case-control study in which maternal serum GlyFn was measured using a point-of-care device in stored samples from a non-intervention screening study of singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation. In the same samples, PlGF was measured by time-resolved fluorometry. We used samples from women who delivered with PE at < 37 weeks' gestation (n = 100), PE at ≥ 37 weeks (n = 100), gestational hypertension (GH) at < 37 weeks (n = 100), GH at ≥ 37 weeks (n = 100) and 1000 normotensive controls with no pregnancy complications. In all cases, MAP and UtA-PI had been measured during the routine 11-13-week visit. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements of medical history. Similarly, the measured values of MAP, UtA-PI and PlGF were converted to MoMs. The competing-risks model was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE or GH at < 37 and ≥ 37 weeks' gestation. Screening performance was estimated by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at 10% fixed false-positive rate (FPR). The maternal characteristics and elements of medical history with a significant effect on the measurement of GlyFn were maternal age, weight, height, race, smoking status and history of PE. In pregnancies that developed PE, GlyFn MoM was increased and the deviation from normal decreased with increasing gestational age at delivery. The DR and AUC of screening for delivery with PE at < 37 weeks' gestation by maternal factors alone were 50% and 0.834, respectively, and these increased to 80% and 0.949, respectively, when maternal risk factors were combined with MAP, UtA-PI and PlGF (triple test). The performance of the triple test was similar to that of screening by a combination of maternal factors, MAP, UtA-PI and GlyFn (DR, 79%; AUC, 0.946) and that of screening by a combination of maternal factors, MAP, PlGF and GlyFn (DR, 81%; AUC, 0.932). The performance of screening for delivery with PE at ≥ 37 weeks' gestation was poor; the DR for screening by maternal factors alone was 35% and increased to only 39% with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. The DR of screening for GH with delivery at < 37 and ≥ 37 weeks' gestation by maternal factors alone was 34% and 25%, respectively, and increased to 54% and 31%, respectively, with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. GlyFn is a potentially useful biomarker in first-trimester screening for preterm PE, but the findings of this case-control study need to be validated by prospective screening studies. The performance of screening for term PE or GH at 11 + 0 to 13 + 6 weeks' gestation by any combination of biomarkers is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Rates ofPreeclampsia andPost-preeclamptic Cardiovascular Disease Among US Military Servicewomen: A Retrospective Case-cohort Study.

Preeclampsia (PE), a hypertensive-inflammatory disorder of pregnancy, poses acute risks of seizures, stroke, and heart attack during pregnancy and up to 6 weeks post-delivery. Recent data suggest that residual increased risks for cardiovascular disease (CVD) linger for much longer, possibly decades, after PE pregnancies. In civilian studies, PE and the major vascular events resulting from it disproportionately affect women from minority groups, especially African American women. The Military Health System (MHS) provides equal access to care for all active-duty servicewomen (ADSW), thus theoretically mitigating disparities. Racial/ethnic breakdown for PE and post PE CVD has not been studied in the MHS. We identified healthy pregnancies in the MHS electronic health records of ADSW in the years 2009/2010 and those with a PE diagnosis. Patients with preexisting conditions of PE or CVD based on a look-back period of two calendar years were excluded. Cases were matched to controls based on age at pregnancy within 5 years and race/ethnicity. Cohort was assessed for diagnosed CVDs, race, age, and service during 2011-2017. Time to first CVD event was assessed with Cox proportional hazards model, results reported as relative risks (95% CI). All variables were summarized using mean (SD) for normally distributed continuous variables; non-normal continuous variables were characterized by median [IQR] and categorical variables were summarized by counts and frequencies. All statistical testings were two-sided with a significance level of 5% and were completed using SAS-EG version 9.2 or R version 3.5.2. From an analysis of 106,808 inpatient ADSW records, PE incidence by race is 11.8% for White, 12% for African American, 11.4% for Asian/Pacific Islander, 11.2% for Native American, 9.5% for Other, and 7.6% for unknown (not documented) race. Thus, in the US Military, African American women have comparable (0.2% higher) PE rate than White women in contrast with civilian studies that often report much higher incidence in the African American population. Using Asians as referent group, PE increases the risk of CVD. White women have a hazard ratio (HR) of 1.47 95%CI (1.15-1.88), African Americans a HR of 1.51 95% CI (1.18-1.93), and Other a HR of 1.39 95% CI (1.01-1.91). In this study, we report overall higher incidence of PE in military women than what is published for civilian women in all races and across all services. Importantly, we do not find significantly higher numbers of PE and post-PE CVD for African American, compared to White women in the military. Our study is not designed to address differences between military and civilian PE epidemiology, but these results deserve further exploration. This study shines light on a health risk unique to women, which we found to be more prevalent in the US Military than published civilian population. Further study to determine the details of long-term morbidity, disability, and death attributable to PE (CVD, stroke, and kidney diseases) are needed to design optimal medical management protocols, ensure readiness for duty, and protect our Women Warfighters.

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas.

Hydroxychloroquine (HCQ), an anti-malarial drug, is suggested as a promising candidate for the treatment of pregnancy-related disorders associated with endothelial activation, among which there is preeclampsia (PE). Arterial feto-placental endothelial cells (fpECAs) were isolated from control (CTR) and early-onset preeclamptic (EO-PE) placentas. The aim of this study was to test potential protective effects of HCQ in an in vitro model of endothelial activation as well as in cells isolated from EO-PE placentas. To mimic PE conditions, CTR fpECAs were exposed to a pro-inflammatory environment consisting of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β (furtherly referred as MIX) with or without varying concentrations of HCQ (1 µg/mL and 10 µg/mL). Their effect on wound healing and endothelial barrier integrity was analyzed. Variations in the expression of IL-8 and leukocyte adhesion molecules (LAM) on both mRNA and protein levels were determined between CTR and PE fpECAs in the presence or absence of HCQ. MIX decreased wound healing and stability of the endothelial barrier, but HCQ did not affect it. Significant differences between CTR and EO-PE fpECAs were observed in IL-8 mRNA, protein secretion, and vascular cell adhesion protein 1 (VCAM-1) mRNA expression levels. After challenging CTR fpECAs with MIX, upregulation of both mRNA and protein levels was observed in all molecules. Combined treatment of HCQ and MIX slightly lowered VCAM-1 total protein amount. In CTR fpECAs, treatment with low concentrations of HCQ alone (1 µg/mL) reduced basal levels of IL-8 and VCAM-1 mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of IL-8. Conclusion: These results provide additional support for the safety of HCQ, as it did not adversely affect endothelial functionality in control fpECAs at the tested concentration. Furthermore, the observed limited effects on IL-8 secretion in EO-PE fpECAs warrant further investigation, highlighting the need for clinical trials to assess the potential therapeutic effects of HCQ in preeclampsia. Conducting clinical trials would offer a more comprehensive understanding of HCQ's efficacy and safety, allowing us to explore its potential benefits and limitations in a real-world clinical setting.

Evaluating the characteristics of myocardial work by two-dimensional echocardiography during pre-eclampsia pregnancy.

This study aimed to analyze the changes in myocardial work (MyW) properties and the correlation of MyW with cardiovascular and clinical indices during the pre-eclampsia (PE) pregnancy. Standard two-dimensional and speckle-tracking echocardiography were sequentially performed on 77 women with PE and 89 with normal pregnancy. Four components of MyW: global myocardial work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were measured. The significant increased GWI, GCW and GWW were observed, while GWW elevated more than GCW with consequently resulting the decline in GWE among PE cases. Although there was a diverse relationship between MyW components and LV morphological as well as functional indices, MyW parameters were significantly correlated with the grades of arterial hypertension and the incidence of adverse outcome of PE. With the hypertension stages, GWI, GCW and GWW gradually increased but GWE decreased. Meanwhile, the higher GWI and GCW and the lower GWE, the more adverse events occurred in PE group. In conclusion, during the PE pregnancy, GWI, GCW and GWW increase, while GWW elevates more than GCW, which leads to the decrease in GWE. Moreover, the changes in MyW are associated with the hypertension grades and the poor prognosis in PE. The non-invasive manner for MyW assessment provides a new perspective on the myocardial biomechanics, cardio-metabolic conditions and pathophysiological changes in the condition of PE.

SERUM COPEPTIN AS A PROGNOSTIC MARKER IN PRE-ECLAMPSIA

Objective: Pre-eclampsia (PE) is as a risk factor for subsequent cardiovascular and kidney disease. Serum copeptin correlates with adverse kidney outcomes in the general population and is increased during PE as compared to healthy pregnancy. We describe the association between copeptin and subsequent kidney outcomes in pregnant women. Design and method: We enrolled 372 patients with PE and 82 with healthy pregnancy in this prospective cohort study. Serum copeptin was measured at 6 weeks post-partum (PP). Office blood pressure (BP), eGFR and albuminuria were measured at 6 weeks as well as at 1 year PP in a sub-group of 110 patients. Interaction effect was tested using likelihood ratio test (LRT). Results: As compared to healthy controls, patients with PE were less frequently Caucasian, more likely smokers and had higher body mass index (p &lt; 0.05). At 6 weeks PP, copeptin levels were similar between groups. At one year PP, systolic BP (SBP), diastolic BP (DBP) and albuminuria were higher in PE as compared to control patients (p &lt; 0.05) while eGFR was similar between groups. A significant interaction existed between copeptin and PE status regarding DBP at 1 year PP (p = 0.045 for LRT). A similar but borderline interaction existed between copeptin and PE status for albuminuria at 1 year PP (p = 0.126 for LRT). Conclusions: At 6 weeks PP, women who suffered from PE do not have increased copeptin levels as compared to healthy controls. However, in case of PE only, copeptin levels are associated with subsequent adverse kidney outcome. Whether this association is causal and would represent a potential therapeutic target remains to be tested.

Preeclampsia after Kidney Transplantation: Rates and Association with Graft Survival and Function.

Transplanted women have high rates of preeclampsia. However, determinants of preeclampsia and association with graft survival and function remain uncertain. We aimed to determine rates of preeclampsia and its association with kidney transplant survival and function. This was a retrospective cohort study analyzing postkidney transplantation pregnancies (≥20 weeks gestation) from the Australia and New Zealand Dialysis and Transplant Registry (2000-2021). Graft survival was assessed in three models accounting for repeated pregnancies and episodes of preeclampsia. Preeclampsia status was captured in 357 of 390 pregnancies and occurred in 133 pregnancies (37%). The percentage of pregnancies reported to have preeclampsia rose from 27% in 2000-2004 to 48% from 2018 to 2021. Reported prior exposure to calcineurin inhibitors was high overall and higher in women who had preeclampsia (97% versus 88%, P = 0.005). Seventy-two (27%) graft failures were identified after a pregnancy, with a median follow-up of 8.08 years. Although women with preeclampsia had higher median preconception serum creatinine concentration (1.24 [interquartile range, 1.00-1.50] versus 1.13 [0.99-1.36] mg/dl; P = 0.02), in all survival models, preeclampsia was not associated with higher death-censored graft failure. In multivariable analysis of maternal factors (age, body mass index, primary kidney disease and transplant-pregnancy interval, preconception serum creatinine concentration, era of birth event, and tacrolimus or cyclosporin exposure), only era and preconception serum creatinine concentration ≥1.24 mg/dl (odds ratio, 2.48; 95% confidence interval [CI], 1.19 to 5.18) were associated with higher preeclampsia risk. Both preconception eGFR <45 ml/min per 1.73 m 2 (adjusted hazard ratio [HR], 5.55; 95% CI, 3.27 to 9.44, P < 0.001) and preconception serum creatinine concentration ≥1.24 mg/dl (adjusted HR, 3.06; 95% CI, 1.77 to 5.27, P < 0.001) were associated with a higher risk of graft failure even after adjusting for maternal characteristics. In this large and contemporaneous registry cohort, preeclampsia was not associated with worse graft survival or function. Preconception kidney function was the main determinant of graft survival.

HTRA1 in Placental Cell Models: A Possible Role in Preeclampsia

The HtrA serine peptidase 1 (HTRA1) is a multidomain secretory protein with serine-protease activity involved in the regulation of many cellular processes in both physiological and pathological conditions. HTRA1 is normally expressed in the human placenta, and its expression is higher in the first trimester compared to the third trimester, suggesting an important role of this serine protease in the early phases of human placenta development. The aim of this study was to evaluate the functional role of HTRA1 in in vitro models of human placenta in order to define the role of this serine protease in preeclampsia (PE). BeWo and HTR8/SVneo cells expressing HTRA1 were used as syncytiotrophoblast and cytotrophoblast models, respectively. Oxidative stress was induced by treating BeWo and HTR8/SVneo cells with H2O2 to mimic PE conditions in order to evaluate its effect on HTRA1 expression. In addition, HTRA1 overexpression and silencing experiments were performed to evaluate the effects on syncytialization, cell mobility, and invasion processes. Our main data showed that oxidative stress significantly increased HTRA1 expression in both BeWo and HTR8/SVneo cells. In addition, we demonstrated that HTRA1 has a pivotal role in cell motility and invasion processes. In particular, HTRA1 overexpression increased while HTRA1 silencing decreased cell motility and invasion in HTR8/SVneo cell model. In conclusion, our results suggest an important role of HTRA1 in regulating extravillous cytotrophoblast invasion and motility during the early stage of placentation in the first trimester of gestation, suggesting a key role of this serine protease in PE onset.

Lipidomics Reveals Elevated Plasmalogens in Women with Obesity Who Develop Preeclampsia.

Objective: Preeclampsia (PE) is a prevalent pregnancy disorder worldwide with limited preventative treatments available. Obesity triples the risk for PE, yet only 10% of women with obesity develop PE. The factors that distinguish PE from uncomplicated pregnancies in the context of obesity have not been fully established. Methods: We studied a cohort of women with obesity throughout pregnancy to identify lipid mediators and/or biomarkers of PE. Blood samples were collected at each trimester and analyzed by both targeted lipidomics and standard lipid panels. Individual lipid species were compared by PE status at each trimester, as well as by self-identified race (Black vs. White) and fetal sex. Results: Standard lipid panels and clinical measurements revealed few differences between PE and uncomplicated pregnancies. Targeted lipidomics, however, identified plasmalogen, phosphatidylethanolamine, and free fatty acid species that were elevated in the third trimester of women with PE. Furthermore, race and trimester of pregnancy were considerable sources of plasma lipidomic variation in women with obesity. Conclusions: First and second trimester individual plasma lipid species do not predict the development of PE in obese women. In the third trimester, PE patients have elevated levels of plasmalogens-a class of lipoprotein-associated phospholipids that have been implicated in the response to oxidative stress.

Regulatory mechanism and research progress of ferroptosis in obstetrical and gynecological diseases.

Ferroptosis is a novel type of regulated cell death driven by iron-dependent lipid peroxidation, which is distinguished from traditional types of programmed cell death, such as apoptosis, proptosis and necrosis et al. Impaired iron homeostasis, lipid peroxidation and antioxidants depletion are three hallmarks of ferroptosis. Over the past years, emerging studies support the notion that ferroptosis might be involved in the pathology of obstetrical and gynecological diseases, including preeclampsia (PE), endometriosis (EMs) and polycystic ovarian syndrome (PCOS). In the PE condition, the high sensitivity of trophoblasts towards ferroptosis has been found to potentially link to inflammation, suboptimal vascular remodeling and aberrant hemodynamics, which are three prominent pathophysiological features of PE. As for EMs, compromised ferroptosis of endometrial cells was associated with the formation ectopic lesions, whereas in the nearby lesions, the presence of ferroptosis was suggested to promote the progression of EMs, contributing to the relative clinical manifestations. Ferroptosis has been implicated a crucial role in the initiation of ovarian follicular atresia, which might help to manage ovulation in PCOS patients. Taken together, this review explored the basis of ferroptosis mechanisms and comprehensively summarized the latest discovery of roles of ferroptosis on PE, EMs and PCOS, gaining a deeper insight into the pathogenesis of these obstetrical and gynecological diseases and investigation of novel therapeutic interventions.

Altered Cytokine Production in Human Intervillous Blood T Cells in Preeclampsia.

Conventional and regulatory T cells (Treg) are dynamic mediators of maternal immune tolerance to the developing feto-placental unit. Functional evaluation of T cells at the maternal-fetal interface is crucial to elucidate the immunologic basis of obstetric complications. Our objective was to define the T cell phenotype and function of uterine intervillous blood (IVB) in pregnancy with and without preeclampsia. We hypothesize that preeclampsia is associated with impaired immune tolerance and a pro-inflammatory uterine T cell microenvironment. In this cross-sectional study, maternal peripheral blood (PB) and uterine IVB (obtained from the surgical sponge used to clean the placental bed during cesarean delivery) were collected from participants with and without preeclampsia. Proportion, activation, and cytokine production of T cell subsets were quantified by flow cytometry. T cell parameters were compared by tissue source and by preeclampsia status. Sixty participants, 26 with preeclampsia, were included. Induced Treg made up a greater proportion of IVB T cells compared to PB and had greater cytokine-producing capacity. Preeclampsia was associated with increased ratio of pro-inflammatory IL-17α to suppressive IL-10 cytokine production by CD4 T cell subsets in IVB, but not in PB. Human uterine IVB is composed of activated, cytokine-producing T cell subsets distinct from maternal PB. Preeclampsia is associated with a pro-inflammatory IVB profile, with increased IL-17α /IL-10 ratio in all CD4 T cell subsets. IVB sampling is a useful tool for investigating human T cell biology at the maternal-fetal interface that may inform immunotherapeutic strategies for preeclampsia.

A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy

BackgroundWhile preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls).ResultsIn the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample.ConclusionsThe discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.

Obesity Is Associated With Higher Risk of Adverse Maternal and Neonatal Outcomes Than Supervised Gestational Diabetes.

Unlike gestational diabetic mellitus (GDM), which is strictly managed by most patients and physicians, obesity does not have proper management guidelines, and the importance of its management during pregnancy is often ignored. The aim of this study was to compare maternal and neonatal outcomes according to obesity and GDM, alone or in combination. This was a retrospective cohort study of 3,078 consecutive pregnant women who experienced prenatal care and delivery of a live singleton neonate between January 2016 and December 2020 at our institution. Study participants were categorized into 4 mutually exclusive groups, as follows: group 1, no GDM without obesity; group 2, GDM without obesity; group 3, no GDM with obesity; and group 4, GDM with obesity. Compared to group 2, group 3 had higher rates of pre-eclampsia, cesarean section including emergent cesarean section rate. Also, neonates in group 3 were heavier and had lower glucose levels compared to those in group 2. Of note, there was no significant difference in maternal or neonatal outcomes except the rate of large-for-gestational-age (LGA) between group 1 and group 2. Among the GDM groups, group 4 had higher risks for pre-eclampsia, cesarean section, and LGA infant status than group 2. Our data showed that obese women without GDM face higher risk of adverse pregnancy outcomes than women with supervised GDM and non-obese women. We also confirmed that adverse pregnancy outcomes associated with GDM were mainly attributable to obesity among women receiving GDM education.