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Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin −10−/− mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10−/− mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10−/− mice injected with sPE sera (IL-10−/−sPE). Vasomotor function of isolated aortas was assessed. The IL-10−/−sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10−/−sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10−/−sPE murine model of preeclampsia, and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

Background Studies have recently examined the role of epigenetic mechanisms in preeclampsia pathophysiology. One commonly examined epigenetic process is DNA methylation. This heritable epigenetic marker is involved in many important cellular functions. The aim of this study was to establish the association between DNA methylation and preeclampsia and to critically appraise the roles of major study characteristics that can significantly impact the association between DNA methylation and preeclampsia. Main body A systematic review was performed by searching PubMed, Web of Science, and EMBASE for original research articles published over time, until May 31, 2019 in English. Eligible studies compared DNA methylation levels in pregnant women with vs. without preeclampsia. Ninety articles were included. Epigenome-wide studies identified hundreds of differentially methylated places/regions in preeclamptic patients. Hypomethylation was the predominant finding in studies analyzing placental tissue (14/19), while hypermethylation was detected in three studies that analyzed maternal white blood cells (3/3). In candidate gene studies, methylation alterations for a number of genes were found to be associated with preeclampsia. A greater number of differentially methylated genes was found when analyzing more severe preeclampsia (70/82), compared to studies analyzing less severe preeclampsia vs. controls (13/27). A high degree of heterogeneity existed among the studies in terms of methodological study characteristics including design (study design, definition of preeclampsia, control group, sample size, confounders), implementation (biological sample, DNA methylation method, purification of DNA extraction, and validation of methylation), analysis (analytical method, batch effect, genotyping, and gene expression), and data presentation (methylation quantification measure, measure of variability, reporting). Based on the results of this review, we provide recommendations for study design and analytical approach for further studies. Conclusions The findings from this review support the role of DNA methylation in the pathophysiology of preeclampsia. Establishing field-wide methodological and analytical standards may increase value and reduce waste, allowing researchers to gain additional insights into the role of DNA methylation in the pathophysiology of preeclampsia.

Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin+ EVs-to-nephrin+ EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin+ EVs-to-nephrin+ EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin+ EVs-to-nephrin+ EVs ratio and may be mediated by prolonged exposure to cellfree HbF.

Objectives Pre-eclampsia (PE) is a pregnancy-specific hypertensive disorder that has been associated with cardiovascular risk factors and vascular changes, such as acute atherosis in placental blood vessels, similar to early-stage atherosclerosis. The objective of this study was to determine whether women with PE have increased atherosclerotic burden, as determined by the carotid intima–media thickness (CIMT), compared with women without PE. Methods We conducted a systematic review and meta-analysis of studies that reported CIMT, a non-invasive, ultrasound-based measure of subclinical atherosclerosis, in women who did vs those who did not have PE. Studies were eligible if they had been conducted during pregnancy or during the first decade postpartum, and if CIMT was measured in the common carotid artery. Studies published before 7 March 2016 were identified through PubMed, EMBASE and Web of Science. Two reviewers used predefined forms and protocols to evaluate independently the eligibility of studies based on titles and abstracts and to perform full-text screening, data abstraction and quality assessment. Heterogeneity was assessed using the I2 statistic. Standardized mean difference (SMD) was used as a measure of effect size. Results Fourteen studies were included in the meta-analysis. Seven studies were carried out during pregnancy complicated by PE, 10 were carried out up to 10 years postpartum and three included measurements obtained at both time periods. Women who had PE had significantly higher CIMT than did those who did not have PE, both at the time of diagnosis (SMD, 1.10 (95% CI, 0.73–1.48); P < 0.001) and in the first decade postpartum (SMD, 0.58 (95% CI, 0.36–0.79); P < 0.001). Conclusions Atherosclerotic load is present at the time of PE and may be a mechanism associated with the disease. Measurement of CIMT may offer an opportunity for the early identification of premenopausal women with atherosclerotic burden after a PE pregnancy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. RESUMEN Objetivos La preeclampsia (PE) es un trastorno hipertensivo especifico del embarazo que ha sido asociada con factores de riesgo cardiovascular y cambios vasculares, tales como aterosis aguda en los vasos sanguineos de la placenta, similares a las primeras etapas de la aterosclerosis. El objetivo de este estudio fue determinar si las mujeres con PE han aumentado la carga aterosclerotica, segun lo determinado por el espesor del complejo intima-media de la arteria carotida (CIMT, por sus siglas en ingles), en comparacion con las mujeres sin PE. Metodos Se realizo una revision sistematica y un metaanalisis de estudios que reportaron el CIMT, una medida no invasiva de la aterosclerosis subclinica obtenida mediante ecografia, comparando mujeres con PE y mujeres sin ella. Solo se incluyeron estudios llevados a cabo durante el embarazo o durante la primera decada despues del parto, y en los que se midio el CIMT en la arteria carotida comun. Se usaron las bases de datos de PubMed, EMBASE y Web of Science para identificar estudios publicados antes del 7 marzo de 2016. Dos revisores utilizaron formularios y protocolos preestablecidos para evaluar de forma independiente la elegibilidad de los estudios, a partir de los titulos y los resumenes, y para realizar un cribado del texto completo, un resumen de los datos y una evaluacion de calidad. La heterogeneidad se evaluo mediante el test estadistico I2. Se uso la diferencia de medias estandarizada (SMD, por sus siglas en ingles) como una medida de la magnitud del efecto. Resultados En el metaanalisis se incluyeron catorce estudios. Siete de los estudios se llevaron a cabo durante embarazos complicados por PE, 10 se realizaron hasta 10 anos despues del parto y tres incluyeron mediciones tomadas en ambos periodos. Las mujeres con PE tuvieron un CIMT significativamente mayor que aquellas que no la tenian, tanto en el momento del diagnostico (SMD 1,10 (I 95%, 0,73-1,48), P

Background Hypertensive disorders of pregnancy (HDP) are associated with increased risks for cardiovascular disease later in life. The HDP incidence is commonly assessed using diagnostic codes, which are not reliable; and typically are expressed per-pregnancy, which may underestimate the number of women with an HDP history after their reproductive years. Objectives This study sought to determine the incidence of HDP expressed as both per-pregnancy and per-woman, and to establish their associations with future chronic conditions and multimorbidity, a measure of accelerated aging, in a population-based cohort study. Methods Using the Rochester Epidemiology Project medical record-linkage system, the authors identified residents of Olmsted County, Minnesota, who delivered between 1976 and 1982. The authors classified pregnancies into normotensive, gestational hypertension, pre-eclampsia, eclampsia, pre-eclampsia superimposed on chronic hypertension, and chronic hypertension using a validated electronic algorithm, and calculated the incidence of HDP both per-pregnancy and per-woman. The risk of chronic conditions between women with versus those without a history of HDP (age and parity 1:2 matched) was quantified using the hazard ratio and corresponding 95% confidence interval estimated from a Cox model. Results Among 9,862 pregnancies, we identified 719 (7.3%) with HDP and 324 (3.3%) with pre-eclampsia. The incidence of HDP and pre-eclampsia doubled when assessed on a per-woman basis: 15.3% (281 of 1,839) and 7.5% (138 of 1,839), respectively. Women with a history of HDP were at increased risk for subsequent diagnoses of stroke (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.37 to 3.76), coronary artery disease (HR: 1.89; 95% CI: 1.26 to 2.82), cardiac arrhythmias (HR: 1.62; 95% CI: 1.28 to 2.05), chronic kidney disease (HR: 2.41; 95% CI: 1.54 to 3.78), and multimorbidity (HR: 1.25; 95% CI: 1.15 to 1.35). Conclusions The HDP population-based incidence expressed per-pregnancy underestimates the number of women affected by this condition during their reproductive years. A history of HDP confers significant increase in risks for future chronic conditions and multimorbidity.

Background Preeclampsia is a pregnancy-specific hypertensive disorder characterized by impaired angiogenesis. We postulate that senescence of mesenchymal stem cells (MSC), multipotent cells with pro-angiogenic activities, is one of the mechanisms by which systemic inflammation exerts inhibitory effects on angiogenesis in preeclampsia. Methods MSC were isolated from abdominal fat tissue explants removed during medically indicated C-sections from women with preeclampsia (PE-MSC, n = 10) and those with normotensive pregnancies (NP-MSC, n = 12). Sections of the frozen subcutaneous adipose tissue were assessed for inflammation by staining for tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1. Viability, proliferation, and migration were compared between PE-MSC vs. NP-MSC. Apoptosis and angiogenesis were assayed before and after treatment with a senolytic agent (1 μM dasatinib) using the IncuCyte S3 Live-Cell Analysis System. Similarly, staining for senescence-associated beta galactosidase (SABG) and qPCR for gene expression of senescence markers, p16 and p21, as well as senescence-associated secretory phenotype (SASP) components, IL-6, IL-8, MCP-1, and PAI-1, were studied before and after treatment with dasatinib and compared between PE and NP. Results After in vitro exposure to TNF-alpha, MSC demonstrated upregulation of SASP components, including interleukins-6 and -8 and MCP-1. Staining of the subcutaneous adipose tissue sections revealed a greater inflammatory response in preeclampsia, based on the higher levels of both TNF-alpha and MCP-1 compared to normotensive pregnancies (p p = 0.012), lower proliferation (p = 0.005), and higher migration (p = 0.023). At baseline, PE-MSC demonstrated a senescent phenotype, reflected by more abundant staining for SABG (p p p Conclusions Our data suggest that MSC senescence exerts inhibitory effects on angiogenesis in preeclampsia. Senolytic agents may offer the opportunity for mechanism-based therapies.

Background The endothelial glycocalyx is a vasoprotective barrier between the blood and endothelium. We hypothesized that glycocalyx degradation is present in preeclampsia, a pregnancy‐specific hypertensive disorder characterized by endothelial dysfunction and activation. Methods and Results We examined the sublingual glycocalyx noninvasively using sidestream dark field imaging in the third trimester among women with normotensive pregnancies (n=73), early (n=14) or late (n=29) onset preeclampsia, or gestational diabetes mellitus (n=21). We calculated the width of the glycocalyx that was permeable to red blood cells (called the perfused boundary region , a measure of glycocalyx degradation) and the percentage of vessels that were filled with red blood cells ≥50% of the time (a measure of microvascular perfusion). In addition, we measured circulating levels of glycocalyx components, including heparan sulfate proteoglycans, hyaluronic acid, and SDC1 (syndecan 1), in a subset of participants by ELISA . Repeated‐measures ANOVA was performed to adjust for vessel diameter and caffeine intake. Women with early onset preeclampsia showed higher glycocalyx degradation, indicated by a larger perfused boundary region (mean: 2.14 [95% CI, 2.05–2.20]), than the remaining groups (mean: normotensive: 1.99 [95% CI, 1.95–2.02], P =0.002; late‐onset preeclampsia: 2.01 [95% CI, 1.96–2.07], P =0.024; gestational diabetes mellitus: 1.97 [95% CI, 1.91–2.04], P =0.004). The percentage of vessels that were filled with red blood cells was significantly lower in early onset preeclampsia. These structural glycocalyx changes were accompanied by elevated plasma concentrations of the glycocalyx components, heparan sulfate proteoglycans and hyaluronic acid, in early onset preeclampsia compared with normotensive pregnancy. Conclusions Glycocalyx degradation and reduced microvascular perfusion are associated with endothelial dysfunction and activation and vascular injury in early onset preeclampsia.

Endothelial dysfunction is believed to play a critical role in preeclampsia; however, it is unclear whether this dysfunction precedes the pregnancy or is caused by pathophysiological events in early pregnancy. It is also unclear for how long vascular dysfunction may persist postpartum and whether it represents a mechanism linking preeclampsia with future cardiovascular disease. Our objective was to determine whether women with preeclampsia had worse vascular function compared with women who did not have preeclampsia by performing a systematic review and meta-analysis of studies that examined endothelial dysfunction using flow-mediated dilation. We included studies published before May 29, 2015, that examined flow-mediated dilation before, during, or after preeclampsia. Differences in flow-mediated dilation between study groups were evaluated by standardized mean differences. Out of 610 abstracts identified through PubMED, EMBASE, and Web of Science, 37 studies were eligible for the meta-analysis. When compared with women who did not have preeclampsia, women who had preeclampsia had lower flow-mediated dilation before the development of preeclampsia (≈20–29 weeks gestation), at the time of preeclampsia, and for 3 years postpartum, with the estimated magnitude of the effect ranging between 0.5 and 3 standard deviations. Similar effects were observed when the analysis was limited to studies that excluded women with chronic hypertension, smokers, or both. Vascular dysfunction predates preeclampsia and may contribute to its pathogenesis. Future studies should address whether vascular changes that persist after preeclamptic pregnancies may represent a mechanistic link with increased risk for future cardiovascular disease.

Background Atrial fibrillation/flutter ( AF ) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders ( HPD s) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without. Methods and Results A nested case–control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57±8 (mean± SD ) years, (controls 56±8 years), 32±8 years (controls 31±8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPD s, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21–6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92–5.23). Conclusions Women with AF are more likely to have had a HPD , a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF , studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed.

To determine whether women who had a hypertensive pregnancy disorder (HPD) have elevated uric acid concentrations decades after pregnancy as compared with women who had normotensive pregnancies.The Genetic Epidemiology Network of Arteriopathy study measured uric acid concentrations in Hispanic (30%), non-Hispanic white (28%), and non-Hispanic black (42%) women (mean age, 60 ± 10 years). This cross-sectional study was conducted between July 1, 2000, and December 31, 2004. Hispanic participants were recruited from families with high rates of diabetes, whereas non-Hispanic participants were recruited from families with high rates of hypertension. This analysis compared uric acid concentrations in women with a history of normotensive (n = 1846) or hypertensive (n = 408) pregnancies by logistic regression.Women who had an HPD had higher uric acid concentrations (median, 5.7 mg/dL vs 5.3 mg/dL; P.001) and were more likely to have uric acid concentrations above 5.5 mg/dL (54.4% vs 42.4%; P = .001) than were women who had normotensive pregnancies. These differences persisted after adjusting for traditional cardiovascular risk factors, comorbidities, and other factors that affect uric acid concentrations. A family-based subgroup analysis comparing uric acid concentrations in women who had an HPD (n = 308) and their parous sisters who had normotensive pregnancies (n = 250) gave similar results (median uric acid concentrations, 5.7 mg/dL vs 5.2 mg/dL, P = 0.02; proportion of women with uric acid concentrations5.5 mg/dL, 54.0% vs 40.3%, P.001).Decades after pregnancy, women who had an HPD have higher uric acid concentrations. This effect does not appear to be explained by a familial predisposition to elevated uric acid concentrations.

Objectives To develop and validate criteria for the retrospective diagnoses of hypertensive disorders of pregnancy that would be amenable to the development of an electronic algorithm, and to compare the accuracy of diagnoses based on both the algorithm and diagnostic codes with the gold standard, of physician-made diagnoses based on a detailed review of medical records using accepted clinical criteria. Patients and Methods An algorithm for hypertensive disorders of pregnancy was developed by first defining a set of criteria for retrospective diagnoses, which included relevant clinical variables and diagnosis of hypertension that required blood pressure elevations in greater than 50% of readings ("the 50% rule"). The algorithm was validated using the Rochester Epidemiology Project (Rochester, Minnesota). A stratified random sample of pregnancies and deliveries between January 1, 1976, and December 31, 1982, with the algorithm-based diagnoses was generated for review and physician-made diagnoses (normotensive, gestational hypertension, and preeclampsia), which served as the gold standard; the targeted cohort size for analysis was 25 per diagnosis category according to the gold standard. Agreements between (1) algorithm-based diagnoses and (2) diagnostic codes and the gold standard were analyzed. Results Sensitivities of the algorithm for 25 normotensive pregnancies, 25 with gestational hypertension, and 25 with preeclampsia were 100%, 88%, and 100%, respectively, and specificities were 94%, 100%, and 100%, respectively. Diagnostic code sensitivities were 96% for normotensive pregnancies, 32% for gestational hypertension, and 96% for preeclampsia, and specificities were 78%, 96%, and 88%, respectively. Conclusion The electronic diagnostic algorithm was highly sensitive and specific in identifying and classifying hypertensive disorders of pregnancy and was superior to diagnostic codes.

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.

Free vascular endothelial growth factor (VEGF) is undetectable in plasma during human pregnancy. However, studies examining pregnant rats have reported both low (8–29 pg/ml) and high (527–1,030 pg/ml) free VEGF. These discrepancies cast uncertainty over the use of rat models to study angiogenic factors in pregnancy and preeclampsia. This study investigates methodological factors that may explain these discrepancies. Plasma VEGF in nonpregnant, day 7 pregnant, and day 19 pregnant rats was measured using rat and mouse ELISAs (R&D Systems). The rat ELISA detected VEGF in plasma from nonpregnant rats but not in plasma from day 19 pregnant rats. The mouse ELISA detected higher VEGF concentrations than the rat ELISA in every sample tested. This discrepancy was greater in day 19 pregnant rats (median: 2,273 vs. 0 pg/ml) than in nonpregnant (97 vs. 20 pg/ml) and day 7 pregnant (66 vs. 2 pg/ml) rats. Recovery of recombinant rat VEGF (rrVEGF) spiked into plasma from nonpregnant and day 7 pregnant rats was high for the rat ELISA (82–105%) but low for the mouse ELISA (17–22%). The rat ELISA did not recover rrVEGF in plasma from day 19 pregnant rats, suggesting that this ELISA measures free VEGF. The use of the rat versus mouse ELISA likely explains the differences in reported VEGF concentrations in pregnant rats. While the rat ELISA appears to measure free VEGF, plasma concentrations in nonpregnant and pregnant rats are below the assay sensitivity limit. As most previous studies of pregnant rats used the mouse VEGF ELISA, these data should be interpreted cautiously.

The anti-oxidant and proangiogenic protein haptoglobin (Hp) is believed to be important for implantation and pregnancy, although its specific role is not known. The three phenotypes (1-1, 2-1 and 2-2) differ in structure and function. Hp 2-2 is associated with increased vascular stiffness in other populations. We examined whether Hp phenotype is associated with abnormal uterine artery Doppler (UAD) in pregnancy.We conducted a secondary analysis of a preeclampsia prediction cohort nested within a larger placebo-controlled randomized clinical trial of antioxidants for prevention of preeclampsia. We determined Hp phenotype in 2184 women who completed UAD assessments at 17 weeks gestation. Women with notching were re-evaluated for persistent notching at 24 weeks' gestation. Logistic regression was used to assess differences in UAD indices between phenotype groups.Hp phenotype did not significantly influence the odds of having any notch (p = 0.32), bilateral notches (p = 0.72), or a resistance index (p = 0.28) or pulsatility index (p = 0.67) above the 90th percentile at 17 weeks' gestation. Hp phenotype also did not influence the odds of persistent notching at 24 weeks (p = 0.25).Hp phenotype is not associated with abnormal UAD at 17 weeks' gestation or with persistent notching at 24 weeks.

Objective To measure carotid artery intima-media thickness (CIMT), a marker of subclinical atherosclerosis, in postmenopausal women with and without histories of preeclampsia and to synthesize these results with those from prior studies of CIMT performed 10 or more years after preeclamptic pregnancies. Patients and Methods Forty women (median age, 59 years) with histories of preeclampsia and 40 with histories of normotensive pregnancy (confirmed by medical record review) were selected from women who resided and gave birth in Olmsted County, Minnesota, between January 1, 1976, and December 31, 1982. The participants were identified and recruited in 2014-2015, and CIMT was measured by B-mode ultrasonography. Meta-analysis included CIMT studies that were performed 10 or more years after preeclamptic pregnancies and which were identified through PubMed, EMBASE, and Web of Science. Heterogeneity was assessed using the I 2 statistic. Standardized mean difference was used as a measure of effect size. Results Carotid artery intima-media thickness, expressed as a median (interquartile range), was greater in the preeclamptic than in the normotensive group (0.80 mm [0.75-0.85 mm] vs 0.73 mm [0.70-0.78]; P =.004); the odds of having CIMT higher than threshold (0.77 mm) was statistically significant after adjusting for confounding factors (odds ratio, 3.17; 95% CI, 1.10-9.14). A meta-analysis of 10 studies conducted 10 or more years post partum included 813 women with and 2874 without histories of preeclampsia. Carotid artery intima-media thickness was greater among women with histories of preeclampsia, with a standardized mean difference of 0.18 and 95% CI of 0.05 to 0.30 mm ( P =.004). Conclusion Among women with histories of preeclampsia, CIMT may identify those with subclinical atherosclerosis, thus offering an opportunity for early intervention.

Data presentation for scientific publications in small sample size studies has not changed substantially in decades. It relies on static figures and tables that may not provide sufficient information for critical evaluation, particularly of the results from small sample size studies. Interactive graphics have the potential to transform scientific publications from static reports of experiments into interactive datasets. We designed an interactive line graph that demonstrates how dynamic alternatives to static graphics for small sample size studies allow for additional exploration of empirical datasets. This simple, free, web-based tool (http://statistika.mfub.bg.ac.rs/interactive-graph/) demonstrates the overall concept and may promote widespread use of interactive graphics., This article examines the potential for interactive graphics to transform scientific papers from static publications into interactive datasets and provides a web-based tool for creating interactive line graphs.

Several registry-based studies, using diagnostic codes, have suggested that preeclampsia is a risk factor for end-stage renal disease (ESRD). However, because the 2 diseases share risk factors, the true nature of their association remains uncertain. Our goals were to conduct a population-based study to determine the magnitude of the association between preeclampsia and ESRD and evaluate the role of shared risk factors.Population-based nested case-control study.The US Renal Data System was used to identify women with ESRD from a cohort of 34,581 women who gave birth in 1976 to 2010 in Olmsted County, MN. 44 cases of ESRD were identified and each one was matched to 2 controls based on year of birth (±1 year), age at first pregnancy (±2 years), and parity (±1 or ≥4).Preeclamptic pregnancy, confirmed by medical record review.ESRD.Prepregnancy serum creatinine and urine protein measurements were recorded. Comorbid conditions existing prior to pregnancy were abstracted from medical records and included kidney disease, obesity, diabetes, and hypertension.There was evidence of kidney disease prior to the first pregnancy in 9 of 44 (21%) cases and 1 of 88 (1%) controls. Per chart review, 8 of 44 (18%) cases versus 4 of 88 (5%) controls had preeclamptic pregnancies (unadjusted OR, 4.0; 95% CI, 1.21-13.28). Results were similar after independent adjustment for race, education, diabetes, and hypertension prior to pregnancy. However, the association was attenuated and no longer significant after adjustment for obesity (OR, 3.25; 95% CI, 0.93-11.37).The limited number of ESRD cases and missing data for prepregnancy kidney function.Our findings confirm that there is a sizable association between preeclampsia and ESRD; however, obesity is a previously unexplored confounder. Pre-existing kidney disease was common, but not consistently coded or diagnosed.

Background— Hypertensive pregnancy disorders have been associated with subjective cognitive complaints or brain white-matter lesions 5 to 10 years after the hypertensive pregnancy. The long-term effects of hypertensive pregnancies on brain structure and cognitive function remain unknown. Methods and Results— This study included 1279 women who participated in the Family Blood Pressure Project Genetic Epidemiology Network of Arteriopathy (GENOA) study. As part of the ancillary Genetics of Microangiopathic Brain Injury (GMBI) study, a neurocognitive battery was administered; 1075 also had a brain magnetic resonance imaging. A history of a hypertensive pregnancy disorder was obtained by a self-report using a validated questionnaire. Linear models fit with generalized estimating equations were used to assess the association between hypertensive pregnancy disorders and cognition, adjusting for age, race, education, body mass index, smoking, current hypertension, hypertension duration, and family history of hypertension. Regression models for the brain magnetic resonance imaging outcomes also were adjusted for total intracranial volume. Women with histories of hypertensive pregnancy disorders performed worse on all measures of processing speed (Digital Symbol Substitution Test [mean score, 41.2 versus 43.4; P =0.005], Trail Making Test Part A [mean seconds, 45.1 versus 42.2; P =0.035], and Stroop [mean score, 173.9 versus 181.0; P =0.002]) and had smaller brain volumes compared with women with histories of normotensive pregnancies (286 versus 297; P =0.023). Conclusions— Hypertensive pregnancy disorders are associated with worse performance on tests of processing speed and smaller brain volumes decades later. Population-based studies are needed to provide critical insight as to the contribution of hypertensive pregnancies to risk of cognitive decline and dementia.

Whether brachial artery FMD (flow-mediated dilation) is altered in pregnancy by 28–35 weeks compared with non-pregnant women remains controversial. The controversy may be due to limitations of previous studies that include failing to: (i) test non-pregnant controls in the mid-late luteal phase, (ii) account for effects of pregnancy on the dilatory shear stimulus, (iii) account for physical activity or (iv) control for inter-individual variation in the time to peak FMD. In the present study, brachial artery FMD was measured in 17 active and eight sedentary pregnant women (34.1±1.6 weeks of gestation), and in 19 active and 11 sedentary non-pregnant women (mid-late luteal phase). Decreased vascular tone secondary to increased shear stress contributes minimally to pregnancy-induced increases in baseline brachial artery diameter, as shear stress removal during distal cuff inflation in pregnant women did not reduce diameter to baseline levels observed in non-pregnant controls. Neither the shear stimulus nor the percentage FMD was affected by pregnancy or regular exercise. Continuous diameter measurements are required to control for delayed peak dilation during pregnancy (57±15 compared with 46±15 s; P=0.012), as post-release diameter measured at 60 or 55–65 s post-release underestimated FMD to a greater extent in non-pregnant than in pregnant women.

Radial artery diameter decreases when a wrist cuff is inflated to stop blood flow to distal tissue. This phenomenon, referred to as low flow-mediated vasoconstriction (L-FMC), was proposed as a vascular function test. Recommendations that L-FMC be measured concurrently with flow-mediated dilation (FMD) were based on radial artery data. However, cardiovascular disease prediction studies traditionally measure brachial artery FMD. Therefore, studies should determine whether L-FMC occurs in the brachial artery. The hypothesis that reduced shear causes L-FMC has not been tested. Brachial and radial artery L-FMC and FMD were assessed in active nonpregnant ( n = 17), inactive nonpregnant ( n = 10), active pregnant ( n = 15, 34.1 ± 1.2 wk gestation), and inactive pregnant ( n = 8, 34.2 ± 2.2 wk gestation) women. Radial artery diameter decreased significantly during occlusion in all groups (nonpregnant, −4.4 ± 4.2%; pregnant, −6.4 ± 3.2%). Brachial artery diameter did not change in active and inactive nonpregnant, and inactive pregnant women; however, the small decrease in active pregnant women was significant. Occlusion decreased shear rate in both arteries, yet L-FMC only occurred in the radial artery. Radial artery L-FMC was not correlated with the reduction in shear rate. L-FMC occurs in the radial but not the brachial artery and is not related to changes in shear rate. Positive correlations between L-FMC (negative values) and FMD (positive values) suggest that radial artery FMD may be reduced among women who experience greater L-FMC. Studies should clarify the underlying stimulus and mechanisms regulating L-FMC, and test the hypothesis that endothelial dysfunction is manifested as enhanced brachial artery L-FMC, but attenuated radial artery L-FMC.

Hypertension in pregnancy is a risk factor for future hypertension and cardiovascular disease. This may reflect an underlying familial predisposition or persistent damage caused by the hypertensive pregnancy. We sought to isolate the effect of hypertension in pregnancy by comparing the risk of hypertension and cardiovascular disease in women who had hypertension in pregnancy and their sisters who did not using the dataset from the Genetic Epidemiology Network of Arteriopathy study, which examined the genetics of hypertension in white, black, and Hispanic siblings. This analysis included all sibships with at least one parous woman and at least one other sibling. After gathering demographic and pregnancy data, BP and serum analytes were measured. Disease-free survival was examined using Kaplan-Meier curves and Cox proportional hazards regression. Compared with their sisters who did not have hypertension in pregnancy, women who had hypertension in pregnancy were more likely to develop new onset hypertension later in life, after adjusting for body mass index and diabetes (hazard ratio 1.75, 95% confidence interval 1.27-2.42). A sibling history of hypertension in pregnancy was also associated with an increased risk of hypertension in brothers and unaffected sisters, whereas an increased risk of cardiovascular events was observed in brothers only. These results suggest familial factors contribute to the increased risk of future hypertension in women who had hypertension in pregnancy. Further studies are needed to clarify the potential role of nonfamilial factors. Furthermore, a sibling history of hypertension in pregnancy may be a novel familial risk factor for future hypertension.

Objective Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies. Methods In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies. Results Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups. Conclusions A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy. Clinical trial registrations GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268.

Preeclampsia is diagnosed in women presenting with new onset hypertension accompanied by proteinuria or other signs of severe organ dysfunction in the second half of pregnancy. Preeclampsia risk is increased 2- to 4-fold among women with type 1 or type 2 diabetes. The limited number of pregnant women with preexisting diabetes and the difficulties associated with diagnosing preeclampsia in women with proteinuria prior to pregnancy are significant barriers to research in this high-risk population. Gestational diabetes mellitus (GDM) also increases preeclampsia risk, although it is unclear whether these two conditions share a common pathophysiological pathway. Nondiabetic women who have had preeclampsia are more likely to develop type 2 diabetes later in life. Among women with type 1 diabetes, a history of preeclampsia is associated with an increased risk of retinopathy and nephropathy. More research examining the pathophysiology, treatment, and the long-term health implications of preeclampsia among women with preexisting and gestational diabetes is needed.

Evidence-based guidelines indicate that regular prenatal exercise is an important component of a healthy pregnancy. In addition to maintaining physical fitness, exercise may be beneficial in preventing or treating maternal–fetal diseases. Women who are the most physically active have the lowest prevalence of gestational diabetes (GDM), and prevention of GDM may decrease the incidence of obesity and type 2 diabetes in both mother and offspring. However, few studies have investigated the effectiveness of exercise in delaying or preventing GDM in at-risk women, and exercise prescriptions that optimize outcomes for women with GDM are lacking. Physically active women are also less likely to develop pre-eclampsia, and we have proposed the following 4 mechanisms that may explain this protective effect: enhanced placental growth and vascularity, reduced oxidative stress, reduced inflammation, and correction of disease-related endothelial dysfunction. Exercise may also prevent reproductive complications associated with maternal obesity. Obesity increases the risk of infertility and miscarriage, and weight loss programs that incorporate diet and exercise are a cost-effective fertility treatment that may also reduce the probability of obesity-related complications during pregnancy. Regular exercise following conception may prevent excessive gestational weight gain and reduce post-partum weight retention.

Endothelial dysfunction is a key feature of preeclampsia, and may contribute to increased cardiovascular disease risk years after pregnancy. Flow-mediated dilation (FMD) is a non-invasive endothelial function test that predicts cardiovascular event risk. New protocols allow researchers to measure three components of the FMD response: FMD, low flow-mediated constriction and the shear stimulus. This review encourages researchers to think beyond “low FMD” by examining how these three components may provide additional insights into the mechanisms and location of vascular dysfunction. The review then examines what FMD studies reveal about vascular dysfunction in preeclampsia, while highlighting opportunities to gain greater mechanistic insight from new protocols. Studies using traditional protocols show that FMD is low in mid-pregnancy prior to preeclampsia, at diagnosis, and for three years post-partum. However, FMD returns to normal by ten years post-partum. Studies using new protocols are needed to gain more mechanistic insight.

Context: Research examining the source of excess soluble fms-like tyrosine kinase 1 (sFLT1) in preeclampsia has focused on the placenta. The potential contribution of the releasable store of sFLT1 in the systemic vasculature is unknown. Objective: We asked whether the nonplacental releasable store of sFLT1 is larger in women with previous preeclampsia than in women with a previous uncomplicated pregnancy. Design: We administered heparin to nulligravid women and to women with previous preeclampsia or a previous uncomplicated pregnancy. We compared post-heparin sFLT1 concentrations with those observed in uncomplicated pregnancy and preeclampsia. Setting: The study was performed at Magee-Womens Hospital. Patients: Participants included nulligravidas (n = 8), women 6–24 months postpartum (previous uncomplicated pregnancy, n = 16; previous preeclampsia, n = 15), and pregnant women (uncomplicated pregnancy, n = 30; preeclampsia, n = 25). Intervention: Nonpregnant women received an unfractionated heparin bolus. Main Outcome Measures: Pre- and post-heparin plasma sFLT1, placental growth factor, and vascular endothelial growth factor were measured. Results: In nonpregnant women, heparin increased plasma sFLT1 by 250-fold (P < .01), increased placental growth factor by 7-fold (P < .01), and decreased free vascular endothelial growth factor (P < .01). These changes did not differ between nulligravidas, women with previous preeclampsia, and women with a previous uncomplicated pregnancy. Post-heparin sFLT1 in nonpregnant women was higher than sFLT1 in uncomplicated pregnancy, but lower than sFLT1 in preeclampsia. Baseline and post-heparin sFLT1 were positively correlated (r2 = 0.19; P < .01). Heparin increased the concentration of the 100-kDa sFLT1 isoform. Adding heparin to whole blood or plasma did not increase sFLT1. Conclusions: Nonpregnant women have a significant vascular store of releasable sFLT1. The size of this store does not differ between women with previous preeclampsia vs women with previous uncomplicated pregnancy.

An ankle-brachial index (ABI) (the ratio of ankle to brachial artery systolic blood pressure) value ≤0.9 identifies patients with peripheral arterial disease (PAD) and elevated cardiovascular event risk. This study examined whether women with a history of hypertension in pregnancy are more likely to have an ABI ≤0.9 decades after pregnancy.ABI was measured in nulliparous women (n = 144), and women with a history of normotensive (n = 1272) or hypertensive (n = 281) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study [non-Hispanic white (39%) and black (61%) women, 60 (mean) ± 10 (SD) years of age]. Relationships between PAD and pregnancy history were examined by logistic regression. Compared to women with a history of normotensive pregnancy, women with a history of hypertensive pregnancy had greater odds of PAD (1.61 (odds ratio); 1.04-2.49 (95% confidence interval), p = 0.03, adjusted for age, race, height and heart rate). Additional adjustment for ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education did not attenuate this relationship (1.63; 1.02-2.62, p = 0.04). PAD risk did not differ between women with a history of normotensive pregnancy and nulliparous women (1.06; 0.52-2.14, p = 0.87).Hypertension in pregnancy is an independent risk factor for PAD decades after pregnancy after adjusting for race, age, height, heart rate, ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education.

OBJECTIVE: We sought to determine whether haptoglobin (Hp) phenotype is related to preeclampsia risk, or to plasma concentrations of soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF). STUDY DESIGN: Hp phenotype was retrospectively determined in primiparous women with uncomplicated pregnancies (n 309), gestationalhypertension(n215),andpreeclampsia(n249).Phenotype was assessed by peroxidase staining following native polyacrylamide gel electrophoresis of hemoglobin-supplemented serum. RESULTS: ComparedwithHp1-1,Hp2-1wasassociatedwithasignificantly increased risk of preeclampsia (odds ratio, 2.11; 95% confidence interval, 1.07‐4.18) and term preeclampsia (odds ratio, 2.45; 95% confidence interval, 1.07‐5.83) in Caucasian women. Hp phenotype was not associated with preeclampsia risk in African Americans. Preeclamptic women had higher plasma sEng and sFlt-1, and lower PlGF,thancontrolsubjects.sEng,sFlt-1,andPlGFdidnotdifferamong women of different Hp phenotypes. CONCLUSION: Hp 2-1 is associated with higher preeclampsia risk in primiparous Caucasian women.

After conception, the corpus luteum, placenta, and developing embryo release hormones, growth factors, and other substances into the maternal circulation. These substances trigger a cascade of events that transform the functioning of the maternal cardiovascular, respiratory, and renal systems, which in turn alter the physicochemical determinants of [H+]. Following implantation, maternal adaptations fulfill 4 important functions that support fetal growth. Increased availability of substrates and precursors for fetal-placental metabolism and hormone production is mediated by increases in dietary intake, as well as endocrine changes that increase the availability of glucose and low-density lipoprotein (LDL) cholesterol. Transport capacity is enhanced by increases in cardiac output, facilitating the transport of substrates and precursors to the placenta, and fetal waste products to maternal organs for disposal. Maternal-fetal exchange is regulated by the placenta after 10-12 weeks gestation, but it may occur through histiotrophic mechanisms before this time. Disposal of additional waste products (heat, carbon dioxide, and metabolic byproducts) occurs through peripheral vasodilation and increases in skin blood flow, ventilation, and renal filtration. The maternal physiological adaptations described above must meet the combined demands of maternal exercise and fetal growth. More research is needed to formulate evidence-based guidelines for healthy physical activity in early pregnancy.Key words: maternal adaptation, first trimester, exercise, fetal growth and development, hormones.

This study determined the time course of changes in resting and exercising respiratory responses during the first half of human pregnancy, and examined the potential roles of plasma osmolality and the strong ion difference ([SID]) as mediators of pregnancy-induced increases in ventilation. Healthy active women (n = 11) were studied serially from 7 to 22 weeks gestation. Responses were compared with preconception data from 14 subjects (six of whom were tested in early pregnancy), and with late-gestation resting data from 10 additional women. Resting and exercising measurements included ventilation, PaCO2, progesterone, osmolality and [SID]. Results were analyzed using mixed-model linear regression. By 7 weeks gestation, increased ventilation resulted in a very large decrease in PaCO2 at rest and during moderate-intensity exercise. Large correlations (r > 0.5) between resting progesterone and PaCO2 support the traditional theory that circulating progesterone stimulates ventilation during pregnancy. The similar time course of changes and large correlations between raw and delta values of PaCO2 and each of plasma osmolality and [SID] also suggest that both variables may influence respiratory control at rest and during exercise in the first half of pregnancy. Future experiments should continue to explore the hypothesis that osmolality and [SID] contribute to pregnancy-induced respiratory changes.

Objectives: To review the existing literature on the physiology of exercise in pregnancy as a basis for clinical practice guidelines for prenatal exercise prescription. Methods: MEDLINE search for English language abstracts and articles published between 1966 and 2003 related to physiological adaptations to pregnancy, effects of pregnancy on responses to acute exercise and aerobic conditioning, effects of acute maternal exercise on indexes of fetal well-being, impact of physical conditioning on birth weight and other pregnancy outcomes, and use of exercise to prevent or treat gestational diabetes mellitus and preeclampsia. Results: Maximal aerobic power (VO 2 max, L/min) is well-preserved in pregnant women who remain physically active, but anaerobic working capacity may be reduced in late gestation. The increase in resting heart rate, reduction in maximal heart rate, and resulting smaller heart rate reserve render heart rate a less precise way of estimating exercise intensity. As rating of perceived exertion (RPE) is not altered by pregnancy, the use of revised pulse rate target zones along with Borg's RPE scale is recommended to prescribe exercise intensity during pregnancy. Responses to prolonged submaximal exercise (>30 min) in late gestation include a moderate reduction in maternal blood glucose concentration, which may transiently reduce fetal glucose availability. The normal response to sustained submaximal exercise is an increase in fetal heart rate (FHR) baseline. Transient reductions in FHR reactivity, fetal breathing movements, and FHR variability may also occur in association with more strenuous exercise. Controlled prospective studies have demonstrated that moderate prenatal exercise during the second and third trimesters is useful to improve aerobic fitness and maternal-fetal physiological reserve without affecting fetal growth. Conclusions: The Physical Activity Readiness Medical Examination for Pregnancy is recommended for use by physicians and mid-wives to provide medical clearance for prenatal exercise. Evidence-based prenatal exercise guidelines are needed to counsel healthy and fit pregnant women on the safety of involvement in more strenuous physical conditioning. Future study is also recommended to determine the usefulness of prenatal exercise in the prevention and treatment of gestational diabetes mellitus and preeclampsia.

Addendum to: Kidney International (2014) 86, 275–285; doi:10.1038/ki.2014.17; published online 26 February 2014

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p

Preeclampsia is a hypertensive pregnancy disorder characterized by development of hypertension and proteinuria after 20 weeks of gestation that remains a leading cause of maternal and neonatal morbidity and mortality. While preeclampsia is believed to result from complex interactions between maternal and placental factors, the proximate pathophysiology of this syndrome remains elusive. Cell-to-cell communication is a critical signaling mechanism for feto-placental development in normal pregnancies. One mechanism of cellular communication relates to activated cell-derived sealed membrane vesicles called extracellular vesicles (EVs). The concentrations and contents of EVs in biological fluids depend upon their cells of origin and the stimuli which trigger their production. Research on EVs in preeclampsia has focused on EVs derived from the maternal vasculature (endothelium, vascular smooth muscle) and blood (erythrocytes, leukocytes, and platelets), as well as placental syncytiotrophoblasts. Changes in the concentrations and contents of these EVs may contribute to the pathophysiology of preeclampsia by accentuating the pro-inflammatory and pro-coagulatory states of pregnancy. This review focuses on possible interactions among placental- and maternal-derived EVs and their contents in the initiation and progression of the pathogenesis of preeclampsia. Understanding the contributions of EVs in the pathogenesis of preeclampsia may facilitate their use as diagnostic and prognostic biomarkers.