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Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is often associated with intrauterine growth restriction (IUGR). Hallmarks of PE are placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using pregnant IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage. In this study, pregnant rats are divided into two groups: normal pregnant (NP) and hypertensive placental ischemic dams (RUPP). Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg) and pregnant control (CON Preg) rats. BP and other markers of PE were evaluated during late gestation. Pregnant IUGR rats had elevated BP and systemic OS. The maternal body weight of pregnant IUGR rats and their pups' weights were decreased, while the brains were enlarged with elevated OS. In summary, pregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Furthermore, this study shows that pregnant IUGR rats exhibit a preeclamptic-like phenotype, suggesting a new epigenetic model of PE., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Whether cardiovascular dysfunction is associated with preeclampsia in women without fetal growth restriction (FGR) is unclear. Our objective was to investigate associations between third-trimester cardiac output (CO) and systemic vascular resistance and risk of hypertensive disorders of pregnancy in women with and without FGR., Methods and Results: A case-cohort study in 906 pregnant women in Denmark with repeated third-trimester cardiac function assessments was performed using the Ultrasound Cardiac Output Monitor 1A. Using Cox regression, we compared rates of hypertensive disorders of pregnancy in women with low, normal, and high CO and normal and high systemic vascular resistance, by FGR status and gestational age, and evaluated associations between a third-trimester drop in CO or increase in systemic vascular resistance and preeclampsia risk in women without FGR. The analysis included 249 women with preeclampsia (42 with FGR) and 119 women with gestational hypertension. Low CO was strongly associated with preeclampsia at <37 weeks (women with FGR: hazard ratio [HR], 5.25 [95% CI, 1.26-21.9]; women without FGR: HR, 2.19 [95% CI, 1.07-4.48]). Our results also suggested an association between low CO and preeclampsia at ≥37 weeks among women without FGR (HR, 1.31 [95% CI, 0.84-2.03]), and between a third-trimester drop in CO >75th percentile and preeclampsia in women without FGR (odds ratio, 1.91 [95% CI, 0.84-4.36]). High systemic vascular resistance was strongly associated with increased rates of all forms of hypertensive disorders of pregnancy., Conclusions: Low CO is associated with preeclampsia risk in women with and without FGR, particularly before 37 weeks. Repeated measurements of third-trimester cardiovascular function might identify women without FGR for monitoring for preeclampsia, but this result needs to be confirmed in other studies.

One of the initiating events in preeclampsia (PE) is placental ischemia. Rodent models of placental ischemia do not present with vascular endothelial dysfunction, a hallmark of PE. We previously demonstrated a role for leptin in endothelial dysfunction in pregnancy in the absence of placental ischemia. We hypothesized that placental ischemia requires hyperleptinemia and endothelial mineralocorticoid receptor (ECMR) expression to induce PE-associated endothelial dysfunction in pregnant mice. We induced placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure in pregnant ECMR-intact ( ECMR +/+ ) and ECMR deletion ( ECMR -/- ) mice at gestational day (GD) 13 . ECMR +/+ RUPP pregnant mice also received concurrent leptin infusion via miniosmotic pump (0.9 mg/kg/day). RUPP increased blood pressure via radiotelemetry and decreased fetal growth in ECMR +/+ pregnant mice. Both increases in blood pressure and reduced fetal growth were abolished in RUPP ECMR -/- mice. Placental ischemia did not decrease endothelial-dependent relaxation to acetylcholine (ACh) but increased phenylephrine (Phe) contraction in mesenteric arteries of pregnant mice, which was ablated by ECMR deletion. Addition of leptin to RUPP mice significantly reduced ACh relaxation in ECMR +/+ pregnant mice, accompanied by an increase in soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio. In conclusion, our data indicate that high leptin levels drive endothelial dysfunction in PE and that ECMR is required for clinical characteristics of hypertension and fetal growth restriction in placental ischemia PE. Collectively, we show that both ECMR and leptin play a role to mediate PE. NEW & NOTEWORTHY Leptin is a key feature of preeclampsia that initiates vascular endothelial dysfunction in preeclampsia characterized by placental ischemia. Endothelial mineralocorticoid receptor (ECMR) deletion in placental ischemia protects pregnant mice from elevations in blood pressure and fetal growth restriction in pregnancy. Increases in leptin production mediate the key pathological feature of endothelial dysfunction in preeclampsia in rodents. ECMR activation contributes to the increase in blood pressure and fetal growth restriction in preeclampsia.

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in pregnancy are associated with the development of preeclampsia and fetal growth restriction (FGR). Recently, preeclampsia was linked to impaired maternal hemodynamic function. This retrospective study evaluated singleton pregnancies with COVID-19 during pregnancy and healthy pregnant controls matched for gestational age from November 2020 to March 2022. Non-invasive assessment of maternal hemodynamics by continuous wave Doppler ultrasound measurements (USCOM-1A ® Monitor) and oscillometric arterial stiffness (Arteriograph) was performed. Overall, 69 pregnant women were included-23 women after COVID-19 during pregnancy and 46 healthy controls. While two women (8.7%) were admitted to the hospital due to COVID-19-related symptoms, none required intensive care unit admission or non-invasive/invasive ventilation. There were no statistically significant differences in the majority of hemodynamic parameters between the two cohorts. The prevalence of FGR was significantly higher in the COVID-19 during pregnancy group (9.5% vs. healthy controls: 0.0%; p = 0.036), especially in nulliparous women. No difference in angiogenic markers and neonatal outcomes were observed between pregnant women after COVID-19 and healthy controls. In conclusion, no significant differences in hemodynamic parameters or neonatal outcome were observed in women with COVID-19 during pregnancy. However, an increased prevalence of FGR could be described.

Chronic hypoxia is a common cause of pulmonary hypertension, preeclampsia, and intrauterine growth restriction (IUGR). The molecular mechanisms underlying these diseases are not completely understood. Chronic hypoxia may induce the generation of reactive oxygen species (ROS) in mitochondria, promote endoplasmic reticulum (ER) stress, and result in the integrated stress response (ISR) in the pulmonary artery and uteroplacental tissues. Numerous studies have implicated hypoxia-inducible factors (HIFs), oxidative stress, and ER stress/unfolded protein response (UPR) in the development of pulmonary hypertension, preeclampsia and IUGR. This review highlights the roles of HIFs, mitochondria-derived ROS and UPR, as well as their interplay, in the pathogenesis of pulmonary hypertension and preeclampsia, and their implications in drug development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, and increased cytolytic natural killer cells (cNKs), which secrete interferon γ (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On gestation day ( GD ) 14 , the RUPP procedure was performed and on GDs 15 and 18 , a subset of normal pregnant rats (NP) and RUPP rats were injected with 10 μg/kg of an anti-rat IFNγ monoclonal antibody. On GD 18 , uterine artery resistance index (UARI) was measured via Doppler ultrasound and on GD 19 , mean arterial pressure (MAP) was measured, animals were euthanized, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared with NP and was reduced in RUPP + anti-IFNγ. Placental ROS was also increased in RUPP rats compared with NP rats and was normalized in RUPP + anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared with NP rats and was reduced in RUPP + anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.

Background: Uteroplacental vascular dysfunction, characterized by diminished uterine artery (UtA) blood flow in the second trimester is a clinically useful predictor of the further development of preeclampsia, fetal growth restriction and stillbirth. Efforts to develop effective treatments to protect pregnancies with abnormal UtA Dopplers would be of significant clinical benefit for mothers and their fetuses., Objective: The aim of this pilot non randomized control study was to use pravastatin +L-arginine to improve uteroplacental haemodynamics and prevent adverse maternal and neonatal outcomes in women with abnormal Dopplers and high risk for developing adverse pregnancy outcomes., Study Design: This study was performed between 2015 and 2018. All women received primary care at OB/GYN Polyclinic Jurisic and Narodni Front University Hospital, University of Belgrade Medical School, Serbia. Approval for investigational drug use was obtained and all women gave informed consent. 10 pregnant women with a poor obstetric history that developed uteroplacental dysfunction (UtA pulsatility index (PI) above the 95th percentile and notching) at 20.5 weeks IQR [17.7-22] gave consent to be treated daily with pravastatin (40 mg) and L-arginine (1.5 g) to improve placental blood flow and pregnancy outcomes. 5 women remained untreated after diagnosis at 21 weeks [20-22] (control group). Due to presence of risk factors for pregnancy complications, close maternal and fetal monitoring was undertaken in all patients. Doppler examinations were performed to monitor changes in placental vascular resistance and fetal well-being and growth., Results: PRAV+L-arginine improved uteroplacental haemodynamics, increased fetal growth and prevented early onset preeclampsia leading to delivery close to term (delivery date: median 38 weeks, IQR[36.5-39]) and appropriate weight for gestational age compared to controls, in which placental blood flow did not improve and 2 women developed severe early onset preeclampsia. Neonates from the control group were born preterm (25 weeks IQR[23.5-25]), growth restricted and spent several months at NICU. Two neonates died due to prematurity-associated complications. PRAV+L-arginine treatment prolonged pregnancies for 4.1 months, compared to 26 days in the untreated group, preventing neonatal complications associated with prematurity. The infants are now 1-3 years old and show normal growth and development., Conclusion: This study describes the successful management with pravastatin+L-arginine of 10 pregnant patients with uteroplacental vascular dysfunction and high risk of adverse maternal and fetal outcomes. A larger study is being organized to confirm these observations., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction., Objective: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes., Results: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations., Conclusion: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Preeclampsia is a major cause of maternal and neonatal morbidity and mortality in sub-Saharan Africa. Evidence indicates that endothelial dysfunction is central to the pathogenesis of preeclampsia. This study assessed the level of the components of the arginine-nitric oxide pathway to evaluate endothelial dysfunction in normotensive pregnancies and pregnancies complicated with preeclampsia., Methods: This case-control study was conducted among pregnant women who visited Comboni Hospital from January 2017 to May 2018. A total of 180 pregnant women comprising 88 preeclamptic women (PE) and 92 healthy normotensive pregnant women (NP) were recruited. Sociodemographic, clinical, and obstetric data were obtained using validated questionnaires. Blood pressure and anthropometrics were measured, and blood samples were collected for the estimation of nitric oxide (NO ∙ ), L-arginine, asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine using an enzyme-linked immunosorbent assay technique., Results: The mean NO ∙ ( p = 0.010) and L-arginine/ADMA ratio ( p < 0.0001) was significantly lower in PE compared to NP while mean L-arginine ( p = 0.034), ADMA ( p < 0.0001), and 3-nitrotyrosine ( p < 0.0001) were significantly higher in PE than NP. ADMA showed a significant positive association with systolic blood pressure ( β = 0.454, p = 0.036) in severe PE. Women with PE had significant intrauterine growth restriction ( p < 0.0001) and low birth weight infants ( p < 0.0001) when compared to NP., Conclusion: Preeclampsia is associated with reduced NO ∙ bioavailability, L-arginine/ADMA ratio, and elevated levels of ADMA and 3-nitrotyrosine. Measurements of the levels of these parameters can help in the early prediction of endothelial dysfunction in preeclampsia. Exogenous therapeutic supplementation with L-arginine during pregnancy to increase the L-arginine/ADMA ratio should be considered to improve endothelial function in preeclampsia and pregnant women at risk of developing preeclampsia., Competing Interests: The authors declare no competing interests., (Copyright © 2020 Worlanyo Tashie et al.)

Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Normal pregnancy is a complex and dynamic process that requires significant adaptation from the maternal system. Failure of this adaptive process in pregnancy contributes to many pregnancy related disorders, including the hypertensive disorders of pregnancy. This article discusses placental development and how abnormalities in the process of vascular remodeling contribute to the multisystem maternal and fetal disease that is preeclampsia and fetal growth restriction. We review some of the consequences of this condition on the mother and fetus, aspects of the clinical management of preeclampsia and how it can influence both mother and infant in the postnatal period and beyond., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective : To evaluate obstetric and kidney outcomes in pregnancies with kidney transplantation. Methods : We retrospectively reviewed 32 singleton pregnancies in kidney transplant recipients. Obstetric outcomes were explored according to the estimated glomerular filtration rates (eGFR) of patients. Results : The incidences of fetal growth restriction, preeclampsia were 18.8% and 34.4%, respectively. There was a significant negative correlation between first-trimester eGFR and perinatal mortality (r = -0.546, p = .0.001) and composite adverse obstetric outcome (r = -0.415, p = .0.018). Conclusion : The degree of transplanted kidney function impairment at the beginning of pregnancy is the major determinant of pregnancy outcome.

Objective : To investigate whether Euterpe oleracea Mart. (açaí) seed extract (ASE) prevents maternal cardiovascular changes and intrauterine growth restriction (IUGR) in experimental preeclampsia (PE). Methods : ASE administration (200 mg/kg/day) during mid to late pregnancy in a rat model of L-NAME-induced PE. Results : ASE impaired the maternal hypertension and microalbuminuria as well as the lower fetal and placental weight in experimental PE. ASE also prevented the maternal vascular dysfunction and lipoperoxidation in this model. Conclusion : ASE protected against maternal cardiovascular changes and IUGR in the L-NAME-induced PE. The protective effect of ASE may be partly explained by its antioxidant property.

Background There is little knowledge about the significance of extremely high values (>655) for the ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor). We aim to describe the time-to-delivery interval and maternal and perinatal outcomes when such values are demonstrated while assessing suspected or confirmed placental dysfunction based on clinical or sonographic criteria. Methods and Results A multicenter retrospective cohort study was performed on 237 singleton gestations between 20+0 and 37+0 weeks included at the time of first demonstrating a sFlt-1/PlGF ratio >655. Clinicians were aware of this result, but standard protocols were followed for delivery indication. Main outcomes were compared for women with and without preeclampsia at inclusion. In those with preeclampsia (n=185, of whom 77.3% had fetal growth restriction), severe preeclampsia features and fetal growth restriction in stages III or IV were present in 49.2% and 13.5% cases, respectively, at inclusion and in 77.3% and 28.6% cases, respectively, at delivery. In the group without preeclampsia (n=52, 82.7% had fetal growth restriction), these figures were 0% and 30.8%, respectively, at inclusion and 21.2% and 50%, respectively, at delivery. Interestingly, 28% of women without initial preeclampsia developed it later. The median time to delivery was 4 days (interquartile range: 1-6 days) and 7 days (interquartile range: 3-12 days), respectively ( P <0.01). Overall, perinatal mortality was 62.1% before 24 weeks; severe morbidity surpassed 50% before 29 weeks but became absent from 34 weeks. Maternal serious morbidity was high at any gestational age. Conclusions An sFlt-1/PlGF ratio >655 is almost invariably associated with preeclampsia or fetal growth restriction that progresses rapidly. In our tertiary care settings, we observed that maternal adverse outcomes were high throughout gestation, whereas perinatal adverse outcomes diminished as pregnancy advanced.

The dynamic field of perinatology entails ever-increasing search for molecular mechanisms of neonatal diseases, especially in the domain of fetal growth and neurodevelopmental outcome. There is an urgent need for new molecular biomarkers, to early identify newborn at high risk for developing diseases and to provide new treatment targets. The interest in biomarkers of oxidative stress in perinatal period have begun to grow in the last century, when it was evidenced the importance of the free radicals generation underlying the various disease conditions. To date, interesting researches have been carried out, representing milestones for implementation of oxidative stress biomarkers in perinatal medicine. Use of a panel of "oxidative stress biomarkers", particularly non protein bound iron, advanced oxidative protein products and isoprostanes, may provide valuable information regarding functional pathways underlying free radical mediated diseases of newborns and their early identification and prevention. Here, we will review recent advances and the current knowledge on the application of biomarkers of oxidative stress in neonatal/perinatal medicine including novel biomarker discovery, defining yet unrecognized biologic therapeutic targets, and linking of oxidative stress biomarkers to relevant standard indices and long-term outcomes., (Copyright © 2019. Published by Elsevier Inc.)

The scientific background of perinatal pathology, regarding both mother and offspring, from the lipidomic perspective, has highlighted the possibility of identifying new, promising clinical markers of oxidative stress and inflammation, closely related to the normal development of unborn and newborn children, together with their application. In this regard, in recent years, significant advances have been achieved, assisted by both newly developed analytical tools and basic knowledge on the biological implications of oxylipins. Hence, in the light of this recent progress, this review aims to provide an update on the relevance of human oxylipins during pregnancy and in the unborn and newborn child, covering two fundamental aspects. Firstly, the evidence from human clinical studies and dietary intervention trials will be used to shed light on the extent to which dietary supplementation can modulate the lipidomic markers of oxidative stress and inflammation in the perinatal state, emphasizing the role of the placenta and metabolic disturbances in the mother and fetus. The second part of this article comprises a review of existing data on specific pathophysiological aspects of human reproduction, in relation to lipidomic markers in pregnant women, unborn children, and newborn children. The information reviewed here evidences the current opportunity to correct reproductive disturbances, in the framework of lipidomics, by fine-tuning dietary interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oxidative stress is responsible for microvascular complications (hypertension, nephropathy, retinopathy, peripheral neuropathy) of diabetes, which during pregnancy increase both maternal and fetal complications. Chronic hypoxia and hyperglycemia result in increased oxidative stress and decreased antioxidant enzyme activity. However, oxidative stress induces also anti-oxidative reactions both in pregnant diabetes patients and in their fetuses. Not all type 1 diabetes patients with long-lasting disease develop microvascular complications, which suggests that some of these patients have protective mechanisms against these complications. Fetal erythropoietin (EPO) is the main regulator of red cell production in the mother and in the fetus, but it has also protective effects in various maternal and fetal tissues. This dual effect of EPO is based on EPO receptor (EPO-R) isoforms, which differ structurally and functionally from the hematopoietic EPO-R isoform. The tissue protective effects of EPO are based on its anti-apoptotic, anti-oxidative, anti-inflammatory, cell proliferative and angiogenic properties. Recent experimental and clinical studies have shown that EPO has also positive metabolic effects on hyperglycemia and diabetes, although these have not yet been fully delineated. Whether the tissue protective and metabolic effects of EPO could have clinical benefits, are important topics for future research in diabetic pregnancies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Preeclampsia is a prevalent pregnancy complication characterized by new-onset maternal hypertension and inflammation, with placental ischemia as the initiating event. Studies of others have provided evidence for the importance of lymphocytes in placental ischemia-induced hypertension; however, the contributions of B1 versus B2 lymphocytes are unknown. We hypothesized that peritoneal B1 lymphocytes are important for placental ischemia-induced hypertension. As an initial test of this hypothesis, the effect of anti-CD20 depletion on both B-cell populations was determined in a reduced utero-placental perfusion pressure (RUPP) model of preeclampsia. Anti-murine CD20 monoclonal antibody (5 mg/kg, Clone 5D2) or corresponding mu IgG2a isotype control was administered intraperitoneally to timed pregnant Sprague-Dawley rats on gestation day (GD)10 and 13. RUPP or sham control surgeries were performed on GD14, and mean arterial pressure (MAP) was measured on GD19 from a carotid catheter. As anticipated, RUPP surgery increased MAP and heart rate and decreased mean fetal and placental weight. However, anti-CD20 treatment did not affect these responses. On GD19, B-cell populations were enumerated in the blood, peritoneal cavity, spleen, and placenta with flow cytometry. B1 and B2 cells were not significantly increased following RUPP. Anti-CD20 depleted B1 and B2 cells in peritoneum and circulation but depleted only B2 lymphocytes in spleen and placenta, with no effect on circulating or peritoneal IgM. Overall, these data do not exclude a role for antibodies produced by B cells before depletion but indicate the presence of B lymphocytes in the last trimester of pregnancy is not critical for placental ischemia-induced hypertension. NEW & NOTEWORTHY The adaptive and innate immune systems are implicated in hypertension, including the pregnancy-specific hypertensive condition preeclampsia. However, the mechanism of immune system dysfunction leading to pregnancy-induced hypertension is unresolved. In contrast to previous reports, this study reveals that the presence of classic B2 lymphocytes and peritoneal and circulating B1 lymphocytes is not required for development of hypertension following third trimester placental ischemia in a rat model of pregnancy-induced hypertension.

Objective: To compare maternal hemodynamics and perinatal outcome, in pregnancies that do not develop pre-eclampsia (PE) or deliver a small-for-gestational-age (SGA) neonate, between those identified at 11-13 weeks' gestation as being screen positive or negative for preterm PE, by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, serum placental growth factor and pregnancy associated plasma protein-A., Methods: This was a prospective longitudinal cohort study of maternal cardiovascular function, assessed using a bioreactance method, in women undergoing first-trimester screening for PE. Maternal hemodynamics and perinatal outcome were compared between screen-positive and screen-negative women who did not have a medical comorbidity, did not develop PE or pregnancy-induced hypertension and delivered at term a live neonate with birth weight between the 5 th and 95 th percentiles. A multilevel linear mixed-effects model was used to compare the repeated measures of cardiac variables, controlling for maternal characteristics., Results: The screen-negative group (n = 926) had normal cardiac function changes across gestation, whereas the screen-positive group (n = 170) demonstrated static or reduced cardiac output and stroke volume and higher mean arterial pressure and peripheral vascular resistance with advancing gestation. In the screen-positive group, compared with screen-negative women, birth-weight Z-score was shifted toward lower values, with prevalence of delivery of a neonate below the 35 th , 30 th or 25 th percentile being about 70% higher, and the rate of operative delivery for fetal distress in labor also being higher., Conclusion: Women who were screen positive for impaired placentation, even though they did not develop PE or deliver a SGA neonate, had pathological cardiac adaptation in pregnancy and increased risk of adverse perinatal outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Background: A normally developed placenta is integral to a successful pregnancy. Preeclampsia (PE) and intrauterine growth restriction (IUGR) are two common pregnancy related complications that maybe a result of abnormal placental development. Placental microRNAs (miRNAs) have been investigated as potential biomarkers for these complications, as they may play a role in placental development and pathophysiology by influencing gene expression. The purpose of this study is to utilize next-generation sequencing to determine miRNA and gene expression in human placental (chorionic villous) samples from three distinct patient groups with early-onset (EO) PE, IUGR, or PE + IUGR., Methods: Placental tissues were collected from four patient groups (control [N = 21], EO-PE [N = 20], EO-IUGR [N = 18], and EO-PE + IUGR [N = 20]), and total RNA was used for miRNA and RNA sequencing on the Illumina Hiseq2000 platform. For stringent differential expression analysis multiple analysis programs were used to analyze both expression datasets in each patient group compared to gestational age-matched controls., Results: Analysis revealed miRNAs and genes that are disease-specific, as well as others that were common between disease groups, which suggests common underlying placental pathologies in EO-PE and EO-IUGR. More specifically, 6 miRNAs and 22 genes were identified to be differentially expressed in all three patient groups. In addition, integrative analysis between the miRNA and gene expression datasets revealed candidate gene targets for miRNAs of interest., Conclusions: Integration of miRNA and RNA profiling in the same three subgroups of pregnancy complications, provides an alternate level of molecular information, in addition it can be used to better understand both unique and common molecular mechanisms involved in the pathophysiology of these diseases.

Introduction : The last decade has seen massive efforts towards the identification and the potential use of predictive biomarkers for the pregnancy pathology preeclampsia. The angiogenic factors sFlt-1 and placental growth factor (PGF) have been in focus and have been massively supported. Areas covered : This review describes preeclampsia and intra-uterine growth restriction (IUGR), focusing on sFlt-1 and PGF, their sources during and outside pregnancy and the application of these markers in diseases outside pregnancy. Finally, the specificity of the angiogenic markers for preeclampsia is discussed. Expert commentary : The admixture of the two independent syndromes preeclampsia and IUGR has not helped in identifying the etiologies of either. Rather, it has made the search for new markers and pathways much more complicated as has the constriction on the angiogenic markers. The current markers sFlt-1 and PGF have a clear value once an adverse outcome is diagnosed but are not specific for preeclampsia. Also, they are mostly derived from the maternal vascular system rather than the placenta and are already in use as markers outside pregnancy. A new holistic approach using disease maps and interoperable workflows based on topic-related big data will help in broadening our understanding of the etiology of preeclampsia and hence, develop new markers and therapies.

Preeclampsia: New Classifications Abstract. Preeclampsia is a multisystem disease leading to systemic impairment of the maternal endothelial function. A dysbalance of pro- and antiangiogenic factors appears to be significantly involved. The vascular disease leads to the manifestation of symptoms such as arterial hypertension and involvement of end organs such as kidney, liver and brain. The classical diagnostic criterion for arterial hypertension, 'proteinuria' has been downgraded and is no longer obligatory for diagnosis, if other criteria, as maternal organ dysfunction or intrauterine growth retardation, are present. In addition, white-coat hypertension has been included in the classification of hypertension in pregnancy. To classify preeclampsia as 'mild' is being discouraged in the clinical setting to account for the possibility of rapid worsening with significant danger for mother and foetus.

Objectives: To evaluate body water volumes and cardiac output in each trimester of pregnancies complicated with hypertension and/or poor fetal growth, relative to uncomplicated pregnancy., Methods: In this semi-longitudinal cohort study, a standardised non-invasive maternal hemodynamics assessment in first, second or third trimester was performed in 1068 women with uncomplicated pregnancy (UP), 75 with early onset (EPE) and 117 with late onset preeclampsia (LPE), 139 with gestational hypertension (GH), 129 with small for gestational age (SGA) neonates and 43 with essential hypertension (EH). Women with hypertension or SGA were included prior to onset of symptoms or at diagnosis of disease; 46% of women (758/1631) were assessed in ≥ 2 trimesters. Impedance cardiography and spectrum analysis were used to measure cardiac output, total body water (TBW), extracellular (ECW) and intracellular water (ICW). A linear mixed model was used for inter-trimestrial comparison of parity-, age- and BMI-corrected values within and between groups., Results: For all pregnancies, TBW is higher in each consecutive trimester, mainly due to increasing fraction of ECW (ECW%). Compared to first trimester UP, ECW and ECW% are higher in EPE whereas TBW, ECW and ICW are lower in SGA. Compared to inter-trimestrial differences in UP, abnormal changes for body water volumes are observed in GH, EPE and LPE and for CO in EPE and LPE. Changes in EH are not different from UP., Conclusions: This study is the first to show that concomitant gestational changes of ECW and CO are different from UP already in preclinical stages of pregnancies complicated with hypertension and/or poor fetal growth, except EH. This finding highlights the relevance of early gestational assessment of maternal body fluid status in pregnancies at risk for hypertension or poor fetal growth., Competing Interests: The authors have declared that no competing interests exist.

Objective: The current study aims to assess the efficacy of fetal middle cerebral artery/umbilical artery pulsatility index ratio (cerebroplacental ratio CPR) in predicting the occurrence of adverse perinatal outcomes in pregnancies complicated with severe pre-eclampsia., Materials and Methods: This cohort study included 100 pregnant women between 34 and 40 weeks of gestation attended the labor ward and diagnosed with severe pre-eclampsia. Doppler evaluation was carried out to measure the CPR. Apgar score and fetal umbilical artery pH were assessed within 5 min of delivery. The rate of neonatal intensive care unit (NICU) admission was obtained., Results: Apgar score at 5 min >7 was in 82 cases (82%) and 12 cases (12%) scored < 7. Fetal blood PH was >7.2 in 67% of cases while 33% of cases had PH <7.2. As regard the NICU admission; 66% of neonates did not need admission while 34% of neonates were admitted to the NICU. There was a significant association between CPR and low Apgar score at 5 min (P < 0.001). The sensitivity of CPR in detection of Apgar score <7 was 50%, and specificity 88.1%. CPR had a poor predictive value of the low umbilical artery PH <7.2 (P = 0.318) with 43.75% sensitivity and 69.05% specificity. There was a significant association between CPR and NICU admission (P = 0.009)., Conclusions: Adding CPR ratio to routine antepartum fetal surveillance from 34 weeks gestation may help with patient counseling regarding adverse neonatal outcomes for women with severe pre-eclampsia as there is a strong correlation between it and adverse neonatal outcomes., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Purpose: Epidemiologic data suggest that in vitro fertilization (IVF) is associated with an increased risk of disorders of placentation including preeclampsia and fetal growth restriction. Specifically, studies have demonstrated that singleton pregnancies conceived following a fresh embryo transfer are at an increased risk of delivering an infant with low birth weight compared to those conceived following a frozen embryo transfer. The mechanism responsible for this association remains unclear. Procedures utilized in IVF have also been linked with epigenetic changes and gene expression changes in both fetal and maternal tissues. Data suggest that modifications in the maternal endometrium can lead to disordered trophoblast invasion and placentation. This study examines the effect of ovarian stimulation on endometrial gene expression and DNA methylation during the window of implantation to examine potential pathways playing a role in the adverse outcomes associated with IVF., Methods: Endometrial biopsies were obtained from oocyte donors and age-matched naturally cycling women 11 days following oocyte retrieval in donors or 12 days following luteinizing hormone (LH) surge in naturally cycling women. Global gene expression was analyzed via Affymetrix Human Gene 1.1 ST array and confirmed with RT-qPCR. DNA methylation was assessed with the Infinium DNA methylation 450 K BeadChip., Results: Analysis of endometrial gene expression from 23 women (11 oocyte donors and 12 controls) demonstrated 165 genes with a greater than twofold change in expression between donors and controls. While there were 785 genes with significant differential methylation in the endometrium of donors when compared with control subjects, none of the genes with altered expression showed significant changes in DNA methylation. Analysis of the differentially expressed genes showed enrichment for genes involved in endometrial remodeling including PLAT, HSPE2, MMP2, and TIMP1. Validation studies using RT-qPCR found a 73% reduction in expression of heparanase 2 (HSPE2) an enzyme associated with both angiogenesis and cell invasion, a greater than twofold increase in tissue-type plasminogen activator (PLAT), a serine protease participating in matrix degradation, and a 70% increase in MMP2, a gelatinase involved in collagen and fibronectin breakdown., Conclusions: Superovulation alters expression of genes critical to endometrial remodeling during early implantation. Such changes could lead to altered trophoblast migration and impaired endovascular invasion. These findings offer a potential mechanism for the adverse perinatal outcomes observed following embryo transfer during fresh IVF cycles.

Aim: To determine whether a single elevated myocardial performance index (MPI) value in the third trimester of pregnancy is a marker for later adverse obstetric outcomes in stable placental-mediated disease, defined as well-controlled pre-eclampsia (PE) on a single agent and/or uncompensated intra-uterine growth restriction (IUGR)., Methods: Fifty-five foetuses whose mothers had stable placental-mediated disease, either mild pre-eclampsia controlled on a single agent, and/or uncompensated IUGR in the third trimester, attending the Foetal Unit at Inkosi Albert Luthuli Hospital, Durban, South Africa were prospectively recruited with 55 matched controls. Recorded data for the subjects included demographic data of maternal age and parity, sonographic data of estimated foetal weight (EFW) and amniotic fluid index (AFI), myocardial performance index (MPI), and foetal Doppler data of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV)., Results: The mean gestational age in the controls, the IUGR and any PE cases was 31.4, 31.8 and 31.0 weeks, respectively. The distribution of MPI values was significantly lower in the controls compared to all other groups. The highest standardised MPI values were observed in the PE-IUGR group, where a median of 5.62 was observed. The only significant differences observed between the PE and IUGR groups was the UA resistance index ( p = 0.01), where the IUGR cases tended to have higher UA values compared to the combined PE group. Borderline statistical significance was observed for the MCA resistance index values ( p = 0.05) between these groups. The overall adverse event rate in the cases was 49%. The highest rate was observed in the PE + IUGR group, where eight out of 12 (67%) experienced adverse events. MPI z -scores served as a good marker of adverse events, as evidenced by the total area under the curve (AUC) of 0.90 on the ROC curve. A cut-off value of 4.5 on the MPI z-score conferred a sensitivity of 89% and specificity of 68% for an adverse event later in pregnancy. In univariate logistic regression, MPI z -score, AFI, EFW, UA Doppler, CPR category, DV Doppler and MCA Doppler were assessed separately as potential predictors of adverse outcome. The only significant predictor of adverse outcome was MPI z -score., Conclusions: A single elevated value of the MPI ( z -score > 4.5) in the third trimester in stable placental-mediated disease was a strong indicator of adverse obstetric outcomes later in pregnancy. This has the potential to be incorporated in conjunction with standard monitoring models in stable placental-mediated disease to predict an adverse event later in pregnancy and thus to reduce perinatal morbidity and mortality.

Objectives: To determine if, in a high-risk group of women in the first half of pregnancy, those who develop pre-eclampsia (PE) with fetal growth restriction (FGR) demonstrate distinct hemodynamics compared with those with PE in the absence of FGR (PE only)., Methods: Cardiac output (CO), peripheral vascular resistance (PVR) and mean arterial pressure (MAP) were measured at the first hospital visit at 9-24 weeks' gestation in 69 women who had chronic hypertension and 67 who had had a hypertensive disorder in a previous pregnancy. These women were divided into five groups according to pregnancy outcome. In total, 19 subsequently developed PE only, 22 developed PE with FGR, 17 developed pregnancy-induced hypertension, 39 had chronic hypertension without PE or FGR and 39 had had a hypertensive disorder in a previous pregnancy without PE, pregnancy-induced hypertension or FGR in the index pregnancy. The hemodynamic values in each of these groups were compared with those in a cohort of 300 low-risk women with normal pregnancy., Results: In all the high-risk groups, PVR and MAP were higher than in women with a normal pregnancy, but CO was lower in the group of women with PE and FGR, whereas in the other high-risk groups, it was not significantly different from normal., Conclusions: In women who develop PE, there is evidence of high PVR and MAP from the first half of pregnancy, whilst PE and FGR are associated with failure in physiological expansion of CO. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Preeclampsia and fetal growth restriction during pregnancy are associated with increased risk of maternal cardiovascular disease later in life. It is unclear whether this association is causal or driven by similar antecedent risk factors. Clarification requires recruitment before conception which is methodologically difficult with high attrition rates and loss of outcome numbers to nonconception/miscarriage. Few prospective studies have, therefore, been adequately powered to address these questions. We recruited 530 healthy women (mean age: 35.0 years) intending to conceive and assessed cardiac output, cardiac index, stroke volume, total peripheral resistance, mean arterial pressure, and heart rate before pregnancy. Participants were followed to completion of subsequent pregnancy with repeat longitudinal assessments. Of 356 spontaneously conceived pregnancies, 15 (4.2%) were affected by preeclampsia and fetal growth restriction. Women who subsequently developed preeclampsia/fetal growth restriction had lower preconception cardiac output (4.9 versus 5.8 L/min; P =0.002) and cardiac index (2.9 versus 3.3 L/min per meter 2 ; P =0.031) while mean arterial pressure (87.1 versus 82.3 mm Hg; P =0.05) and total peripheral resistance (1396.4 versus 1156.1 dynes sec cm - 5 ; P <0.001) were higher. Longitudinal trajectories for cardiac output and total peripheral resistance were similar between affected and healthy pregnancies, but the former group showed a more exaggerated fall in mean arterial pressure in the first trimester, followed by a steeper rise and a steeper fall to postpartum values. Significant relationships were observed between cardiac output, total peripheral resistance, and mean arterial pressure and gestational epoch. We conclude that in healthy women, an altered prepregnancy hemodynamic phenotype is associated with the subsequent development of preeclampsia/fetal growth restriction., (© 2018 The Authors.)

The objective of this study was to investigate soluble epidermal growth factor receptor (sEGFR), soluble vascular endothelial growth factor receptor 1 (sFlt-1), soluble endoglin (sEndoglin) and placenta growth factor (PLGF) concentrations in normotensive, preterm and term preeclamptic pregnancies' serum and thus to specify the clinical utility of these biochemical markers in monitoring severity and intrauterine growth retardation of preterm preeclampsia. 172 pregnant women were divided into the following groups: preterm preeclampsia, preterm control, term preeclampsia and term control. Preterm preeclampsia patients were stratified with severe feature (n = 50) and without severe feature (n = 22). sEGFR, sEndoglin and PLGF were assessed using Luminex multiplex immunoassay, whilesFlt-1 was assessed using ELISA. sEGFR was significantly lower in preterm preeclampsia than matched control (p < 0.001) and mildly lower in term preeclampsia than matched control (p < 0.01). On contrary, sFlt-1 was significantly higher in preterm preeclampsia than matched control (p < 0.001) and mildly higher in term preeclampsia than matched control (p < 0.01). sFlt-1, sFlt-1/sEGFR and sFlt-1/PLGF were positively correlated with the severity of preterm preeclampsia (P < 0.001, R value ≥ 0.6), especially sFlt-1/sEGFR had the highest R value (R value = 0.711) among them. Furthermore, sEndoglin and the ratio of sEndoglin/sEGFR were associated with neonatal birth weight small for gestational age (SGA, n = 25) in preterm preeclampsia group., Conclusions: The ratio of sFlt-1/sEGFR could be used as a novel candidate biochemical marker in monitoring the severity of preterm preeclampsia. sEndoglin and sEGFR may be involved in the pathogenesis of SGA in preterm preelampsia., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the usefulness of a clinical protocol for early detection of preeclampsia and/or fetal growth restriction (PE/FGR) using, in previously selected pregnancies, the measurement of the sFlt-1/PlGF ratio at 24-28 weeks of gestation., Study Design: Prospective observational cohort study carried out in a single tertiary hospital in Spain. 5601 consecutive singleton pregnancies with complete follow-up were included. High-risk women for PE/FGR were selected by combining data from maternal history and second trimester uterine artery Doppler. Subsequently these patients underwent intensive monitoring, including the measurement of the sFlt-1/PlGF ratio at 24-28 weeks to predict PE/FGR., Main Outcome Measures: Early, intermediate and late PE/FGR (delivery <32 + 0, 32 + 0 - <36 + 0 and ≥36 + 0 weeks, respectively)., Results: Overall incidence of early, intermediate and late PE/FGR was 0.3%, 0.7% and 3.2%, respectively, being higher in the 4.3% of women selected for intensive monitoring: 5.8%, 8.7% and 15.4%, respectively (all p < 0.001). The area under the curve (AUC) with 95%CI of the sFlt-1/PlGF ratio for detecting early PE/FGR was 0.98 (0.97-1.00), and the sFlt-1/PlGF ratio >95th centile showed a sensitivity (%) of 100 (95%CI, 78.5-100) and specificity (%) of 80.6 (95%CI, 75.0-85.2). The AUC of the sFlt-1/PlGF ratio for detecting intermediate and late PE/FGR was of 0.87 (95%CI, 0.77-0.97) and 0.68 (95%CI, 0.58-0.79), respectively., Conclusion: A contingent strategy of measuring the sFlt-1/PlGF ratio at 24-28 weeks in women previously selected by clinical factors and uterine artery Doppler enables an accurate prediction of PE/FGR. This performance is optimal to predict PE/FGR requiring delivery before 32 weeks., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of this study was the analysis of B-Cell Activating Factor (BAFF) levels in pregnancies affected by PE, and in pregnancies affected by fetal growth restriction without Hypertensive disorders and its possible correlation with pulse wave velocity and cardiac output., Study Design: Prospective study of 69 women at 24-40 weeks gestation. Haemodynamic function was assessed in those with Pre-eclampsia (PE, n = 19), fetal growth restriction (FGR, n = 10) and healthy pregnancies (n = 40). Maternal venous BAFF levels at recruitment were measured using ELISA. We analysed the relationship between BAFF and cardiac output (CO), and BAFF and PWV (pulse wave velocity); the gold standard for assessing arterial stiffness. PWV was measured with an oscillometric device and CO using inert gas rebreathing technique. PWV and CO were converted to gestation adjusted indices (z scores)., Main Outcome Measures: The association between BAFF levels in PE and FGR, and the relationship of BAFF with PWV and CO., Results: BAFF was higher in PE (p = 0.03) but not in FGR (p = 0.83) when compared to healthy pregnancies. There was a positive correlation between BAFF levels and z score PWV (r = 0.25, p = 0.04), but not CO (r = -0.01, p = 0.91). BAFF levels did not change with gestational age. (r = 0.012, p = 0.925)., Conclusions: These findings provide evidence of a possible contribution of BAFF to both maternal inflammation and arterial dysfunction associated with PE. Though no relationship was found with another disorder of placentation: normotensive FGR, this condition is not thought to be associated with maternal inflammation., (Copyright © 2018. Published by Elsevier B.V.)

Background: Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction., Objective: We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction., Study Design: We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24-40 weeks., Results: Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 ± 1.35; P = .0001) and lower peripheral vascular resistance Z scores (-0.76 ± 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 ± 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores (-0.80 ± 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 ± 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03)., Conclusion: Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.

Objectives: The aim of this study was to investigate, whether maternal serum levels of sFlt-1, PlGF and PAPP-A at third trimester of pregnancy are associated with late-onset PE and intrauterine growth retardation (IUGR) after 34 weeks of pregnancy., Methods: This was a prospective study measuring the maternal serum levels of soluble tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 32-37 weeks of pregnancy: 730 patients were enrolled and 676 had neither intrauterine growth restriction (IUGR) nor preeclampsia (PE) or pregnancy induced hypertension (PIH) throughout the pregnancy. 22 patients developed IUGR, 32 PE and 24 PIH., Results: Linear regression analyses after adjusting for maternal age, gestational age at the blood sampling and maternal BMI showed associations between PE and serum sFlt-1 levels (Exp(ß) = 3.29; 95% CI: 2.69-4.04), serum PlGF levels (Exp(ß) = 0.18; 95% CI: 0.13-0.24), sFlt-1/PlGF ratio (Exp(ß) = 15.59; 95% CI: 10.64-22.84) and serum PAPP-A (Exp(ß) = 1.48; 95% CI 1.15-1.89). sFlt-1, PlGF and sFlt-1/PlGF-Ratio showed comparable area under the curve (AUC) estimates with a predictive ability to discriminate pregnancies developing PE and IUGR from controls. The predictive ability of PAPP-A for PE was only slightly better than chance., Conclusions: This study supported the ability of a single measurement of sFlt-1/PlGF ratio at third trimester to predict PE and IUGR occurring after 34 weeks of pregnancy. However, larger multicentre studies are needed to replicate our results., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: To investigate the risks of delivering small-for-gestational-age (SGA) and large-for-gestational-age (LGA) infants in women with early- (delivered before 34weeks of gestation) and late-onset (delivered at or after 34weeks of gestation) preeclampsia., Study Design: We conducted a retrospective cohort study of 29,494 singleton deliveries after 24weeks' gestation, excluding pregnancies complicated by fetal anomalies, stillbirths, and prepregnancy diabetes mellitus. Univariate and multivariate logistic analyses adjusted for potential confounding factors, including prepregnancy body mass index (BMI), gestational weight gain (GWG), and gestational diabetes mellitus (GDM), were performed., Results: Among women who delivered before 34weeks, significantly more women with preeclampsia delivered SGA infants than women without preeclampsia (50.6% vs. 7.0%; adjusted odds ratio [OR] 16.3; 95% confidence interval [CI] 8.1-32.9). Among women who delivered at or after 34weeks, women with preeclampsia had higher rates of delivering SGA (25.5% vs. 7.0%) and LGA (13.7% vs. 9.9%) infants than women without preeclampsia. After adjustment for confounding factors, preeclampsia remained a significant risk factor for delivering SGA infants (adjusted OR 5.7; 95% CI 4.6-7.1), but the association between preeclampsia and the delivery of LGA infants was diminished (adjusted OR 0.8; 95% CI 0.6-1.1)., Conclusions: Our results confirm that preeclampsia is associated with SGA and that the association is stronger with early-onset disease. Although women with late-onset preeclampsia had a higher rate of delivering LGA infants, the association between late-onset preeclampsia and LGA is due to confounding factors, such as high prepregnancy BMI, excessive GWG, and GDM, related to maternal metabolic abnormalities., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To examine maternal and neonatal outcomes of gestational proteinuria, and to identify maternal characteristics for progression to pre-eclampsia., Study Design: Retrospective cohort. Included all pregnant women who delivered between Jan 2014-Feb 2017 with new onset proteinuria in a single obstetric unit. Demographic, maternal and neonatal outcomes were compared., Results: Eighteen (25%) out of 73 women with new onset gestational proteinuria developed pre-eclampsia. The incidence of gestational proteinuria was 0.54%. Compared with women that remained normotensive, those that developed hypertension had delivery at earlier gestation (p = .02), increased risk of fetal growth restriction (p = .01) and lower newborn birthweight (p = .002). Maximal proteinuria and fetal growth restriction were independent factors associated with development of pre-eclampsia. In particular, high proteinuria level ≥ 2 g/d constitute a major predictor for progression (p = .03)., Conclusion: Increased vigilance for antenatal surveillance is important in women with gestational proteinuria as a substantial portion progress to pre-eclampsia. Serial growth scan and proteinuria assay are suggested to predict possible pre-eclampsia development., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the test performance of 47 biomarkers and ultrasound parameters for the prediction of delivery of a small-for-gestational-age (SGA) infant and adverse perinatal outcome in women presenting with suspected pre-eclampsia., Methods: This was a prospective, multicenter observational study in which 47 biomarkers and ultrasound parameters were measured in 397 women with a singleton pregnancy presenting with suspected preterm pre-eclampsia between 20 + 0 and 36 + 6 weeks' gestation, with the objective of evaluating them as predictors of subsequent delivery of a SGA infant and adverse perinatal outcome. Women with confirmed pre-eclampsia at enrollment were excluded. Factor analysis and stepwise logistic regression were performed in two prespecified groups stratified according to gestational age at enrollment. The primary outcome was delivery of a SGA infant with a birth weight < 3 rd customized centile (SGA-3), and secondary outcomes were a SGA infant with a birth weight < 10 th customized centile and adverse perinatal outcome., Results: In 274 women presenting at 20 + 0 to 34 + 6 weeks' gestation, 96 (35%) delivered a SGA-3 infant. For prediction of SGA-3, low maternal placental growth factor (PlGF) concentration had a sensitivity of 93% (95% CI, 84-98%) and negative predictive value (NPV) of 90% (95% CI, 76-97%) compared with a sensitivity of 71% (95% CI, 58-82%) and a NPV of 79% (95% CI, 68-87%) for ultrasound parameters (estimated fetal weight or abdominal circumference < 10 th centile). No individual biomarker evaluated had a better performance than did PlGF, and marker combinations made only small improvements to the test performance. Similar results were found in 123 women presenting between 35 + 0 and 36 + 6 weeks' gestation., Conclusion: In women presenting with suspected preterm pre-eclampsia, measurement of PlGF offers a useful adjunct for identifying those at high risk of delivering a SGA infant, allowing appropriate surveillance and timely intervention. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: Women with a history of placenta-related pregnancy complications, such as preeclampsia, intrauterine growth restriction or preterm delivery, have an increased risk for recurrence of such complications. This recurrence is likely the result of underlying endothelial dysfunction that leads to abnormal placentation, especially in complications with an early onset. This study provides an overview of biomarkers of placental development and function in pregnancies from women with a history of placenta-related complications., Material and Methods: A systematic literature search was conducted limited to human studies and including keywords related to a history of placenta-related complications and markers of placental development and function. Two independent reviewers assessed eligibility and quality of 1553 retrieved unique articles., Results: Five articles reporting on placental development and function in women with an obstetric history of preeclampsia (n = 3), intrauterine growth restriction (n = 1) and preterm delivery (n = 2) were eligible for quality assessment. We identified associations between a history of preeclampsia and abnormal placental histological findings at term in the current pregnancy, but found contradictory results regarding presence of uterine artery notching. In women with a history of very preterm delivery (<32 weeks), one study showed associations with abnormal placental histology., Conclusion: Literature on the association between a history of placenta-related complications and placental development and function in subsequent pregnancies is scarce and studies are heterogeneous. However, literature shows that placenta-related pregnancy complications are associated with subsequent placental histology., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

To investigate the systemic and placental oxidant status as well as vascular function in experimental preeclampsia (PE) induced by nitro-L-arginine methyl ester (L-NAME). Fetal parameters and maternal blood pressure, proteinuria, mesenteric arterial bed (MAB) reactivity, and systemic and placental oxidative stress were compared between four groups: pregnant rats receiving L-NAME (60 mg/kg/day, orally) (P + L-NAME) or vehicle (P) from days 13 to 20 of pregnancy and nonpregnant rats receiving L-NAME (NP + L-NAME) or vehicle (NP) during 7 days. L-NAME administration during pregnancy induced some hallmarks of PE, such as hypertension and proteinuria. The P + L-NAME group presented lower weight gain and placental mass as well as reduced number and weight of live fetuses than P group. The vasodilator effect induced by acetylcholine (ACh) and angiotensin II (Ang II) was lower in the perfused MAB from NP + L-NAME and P + L-NAME than in control groups. Otherwise, the nitroglycerine-induced vasodilation and the phenylephrine- and Ang II-induced vasoconstriction were higher in MAB from NP + L-NAME and P + L-NAME groups than in the respective controls. Systemic and placental oxidative damage, assessed by malondialdehyde and carbonyl levels, was increased and activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced in P + L-NAME and NP + L-NAME groups compared to controls. The present data suggest that the oxidative stress and reduced bioavailability of nitric oxide may contribute to attenuation of vasodilator responses to ACh and Ang II, and hyperreactivity to Ang II in the mesentery of preeclamptic rat, which may contribute to the increased peripheral vascular resistance and BP, as well as intrauterine growth restriction in L-NAME-induced PE.

Abnormalities in the development of placental vasculature in early pregnancy and the failure of transformation of the spiral arteries are associated with the pathogenesis of preeclampsia. Sex hormones influence neovascularisation during pregnancy. However the profiling of estrogen and progesterone in preeclampsia is controversial. In this study we investigated the serum levels of estrogen and progesterone in women with preeclampsia. Blood samples were collected from 86 preeclamptic and 97 gestation-matched normotensive pregnancies. The levels of 17β-estradiol (E2), progesterone and 2-methoxyestradiol (2-ME) in serum were measured. In addition, the levels of E2 and progesterone in conditioned media from preeclamptic or normotensive term placental explant cultures or placental explants that had been treated with hydrogen peroxide (H 2 O 2 ) were measured. The expression of estrogen receptors (ER) and progesterone receptors (PR) in preeclamptic and control placentae were measured by immunohistochemistry. The serum levels of E2, progesterone and 2-ME were significantly reduced in women with preeclampsia compared to controls. There was no difference in the serum levels of E2 and progesterone between severe and mild or between early-onset and late-onset preeclampsia as well as between preeclampsia with and without fetal growth restriction (FGR). The levels of E2 and progesterone in preeclamptic placental explants cultures were significantly lower than in normotensive term placental explant cultures. Treatment with H 2 O 2 was found to be associated with a reduction in E2 production by the placenta. We demonstrated lower levels of estrogen in preeclampsia and speculate that this reduction may be due to the impairment of placental function in preeclampsia., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the usefulness of the uterine artery mean pulsatility index (mPI-UtA) and the sFlt-1/PlGF ratio in women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) for the prediction of placental dysfunction-related adverse outcomes (AO), namely pre-eclampsia (PE) and intrauterine growth restriction (IUGR), and for differential diagnosis between PE and SLE flares., Study Design: Observational prospective cohort study of 57 pregnant women with SLE or APS., Main Outcome Measures: mPI-UtA and sFlt-1/PlGF ratio in maternal serum were obtained at four gestational age periods (11-14, 19-22, 24-29 and 32-34 weeks). Comparisons among pregnancies with normal outcome, SLE flare and AO were performed., Results: Overall, we had 44 ongoing pregnancies (36 with SLE and 8 with APS) of which most (n = 35, 80%) were uncomplicated. The overall rate of AO was 9% (n = 4), that was diagnosed at a mean (SD) gestational age of 34.1 (7.5) weeks. Five SLE patients (14%) suffered a SLE flare. No differences for these markers were found between normal pregnancies and those affected by SLE flare. mUtA-PI values were significantly higher in the AO group when compared with normal and SLE flare groups, at 19-22 weeks (1.52, 0.95 and 0.76) and 32-34 weeks (1.13, 0.68 and 0.65), respectively. The sFlt-1/PlGF ratio was significantly higher in the AO group at 24-29 weeks (191.1, 3.1 and 9.2), respectively., Conclusion: Our preliminary results indicate that mPI-UtA and sFlt1/PlGF ratio may be useful to predict AO in women with SLE, and to make the differential diagnosis with a lupus flare., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: The pregnancy pathology preeclampsia is still among the leading causes of maternal and perinatal morbidity and mortality. At the same time, its etiology is far from being identified and remains obscure in a number of facets. A number of hypotheses have been developed to explain the altered interplay between placenta and mother leading to the clinical symptoms of preeclampsia. However, none of them offers the opportunity to explain the variability of cases with late-onset versus early-onset, mild versus severe and with or without additional fetal growth restriction., Conclusion: This paper identifies the weaknesses of the most important current hypothesis and at the same time offers a set of new elucidations including maternal susceptibility, and villous/extravillous trophoblast differentiation to explain the development of preeclampsia. Such elucidations allow following new scientific routes and pathways to untangle the etiology of preeclampsia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Examine the frequency with which the most accepted indicators for delivery in pre-eclampsia are used in a population with predominantly late-onset (birth > 32 weeks) pre-eclampsia (PE)., Methods: Retrospective cohort study using the St George Public Hospital (SGH) Hypertension in Pregnancy database. Demographic, pregnancy, and outcome details were extracted and verified by comparison with data collection sheets., Results: From 2001 to 2013, 908 women (970 babies) with PE were included, of which a subgroup of 303 women (33%) had clearly delineated delivery triggers available. This subgroup of women had similar demographic and outcome characteristics to the total PE population. In this group, the most common maternal trigger for delivery apart from gestational age 37+ weeks was difficult to control/severe hypertension (114 cases, 38%) and the most common fetal trigger intrauterine growth restriction (IUGR: 14 cases, 4%). 78 (35%) of term women had no specific delivery trigger other than gestation. A primary maternal trigger and/or associated complication was slightly more common in those delivering <37 weeks vs 37+ weeks (52 vs 38%, p = .03), while a fetal or combined maternal/fetal complication was over four times more common in preterm women (25 vs 6%, p < .001)., Conclusion: In our population of predominantly late-onset PE, maternal triggers for delivery (predominantly severe hypertension) far outweigh fetal triggers (predominantly IUGR). Fetal and mixed indicators for delivery were relatively more common in women delivering preterm, possibly reflecting the severity of placental dysfunction in this subgroup., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Serum gamma glutamyl transferase (GGT), produced and released mostly from the liver and bile duct, is an enzyme involved in response to oxidative stress, and has been used as a maker for prediction of cardiovascular events. Umbilical artery blood flow resistance index, e.g., the systolic/diastolic ratio (S/D ratio) as determined by ultrasound, has been used to assess the fetal intrauterine conditions. While changes of GGT and S/D ratio in preeclampsia are found to be associated with the risk for adverse perinatal outcome, the potential value of combined use of the two measurements for the prediction of adverse perinatal outcome has not been determined., Materials and Methods: This study included severe preeclampsia patients in late pregnancy and determined their serum GGT levels and ultrasonic flow resistance index of umbilical artery within a week before delivery. Demographic data and perinatal outcomes including perinatal death, five-minute Apgar score, admission to neonatal intensive care unit, respiratory distress syndrome, and intrauterine growth restriction, are documented and analyzed., Results: It was found that serum GGT combined with umbilical artery S/D ratio predicted perinatal adverse outcomes in severe preeclampsia patients with a sensitivity of 94.30% and a specificity of 80.00%. Moreover, absent or reversed UA diastolic blood flow was found to be an independent risk factor for intrauterine growth restriction., Conclusion: GGT in combination with umbilical artery S/D ratio is a potentially useful marker for the prediction of adverse outcome in severe preeclampsia patients. Future studies in a larger cohort of patients should be performed to verify the efficacy of the strategy. Early and accurate prediction of adverse perinatal events can facilitate the efforts to improve the perinatal outcomes of neonates associated with preeclamptic pregnancies., (Copyright © 2017. Published by Elsevier B.V.)

Introduction: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are separate disease entities that have frequently been reported as sharing the same pathogenesis. In both of them, angiogenesis disorders and generalized endothelial damage with an accompanying inflammation are the dominant symptoms. In this study, we attempted to prove that both these processes demonstrate the same profile in early PE, late PE and IUGR patients, while the only difference is in the degree of exacerbation of the lesions., Patients, Materials and Methods: In 167 patients divided into four groups, three of those with early PE, late PE and IUGR and one control group, fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), high sensitive c-reactive protein (hsCRP) and fibronectin were determined. The behavior of these parameters in each of the groups was studied, and correlations between them were sought for., Results: Higher concentrations of sFlt-1, hsCRP and fibronectin and a lower concentration of PlGF were found in the study groups compared to the control group. Significant correlations were observed between the factors concerned., Conclusions: The higher values of disordered angiogenesis markers, endothelial damage markers and inflammatory markers both in the PE and the intrauterine growth restriction (IUGR) groups suggest the existence of shared disorders in the development of these pathologies. The correlations between disordered angiogenesis markers and endothelial damage markers argue in favor of a mutual relationship between these two processes in the development of pathologies evolving as secondary to placental ischemia. The results obtained confirm that the lesion profiles are the same in both PE and IUGR patients, which can be utilized in developing common diagnostic criteria.

Purpose of Review: Preeclampsia affects 3-4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed., Recent Findings: Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities and/or the maternal symptoms which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction, and angiogenic imbalance, thus informing future human studies. Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved, and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.