Oxidative stress and endothelial function in normal pregnancy versus pre-eclampsia, a combined longitudinal and case control study.

BACKGROUND: Pre-eclampsia (PE) is related to an impaired endothelial function. Endothelial dysfunction accounts for altered vascular reactivity, activation of the coagulation cascade and loss of vascular integrity. Impaired endothelial function originates from production of inflammatory and cytotoxic factors by the ischemic placenta and results in systemic oxidative stress (OS) and an altered bioavailability of nitric oxide (•NO). The free radical •NO, is an endogenous endothelium-derived relaxing factor influencing endothelial function. In placental circulation, endothelial release of •NO dilates the fetal placental vascular bed, ensuring feto-maternal exchange. The Endopreg study was designed to evaluate in vivo endothelial function and to quantify in vitro OS in normal and pre-eclamptic pregnancies. METHODS/DESIGN: The study is divided into two arms, a prospective longitudinal study and a matched case control study. In the longitudinal study, pregnant patients ≥18 years old with a singleton pregnancy will be followed throughout pregnancy and until 6 months post-partum. In the case control study, cases with PE will be compared to matched normotensive pregnant women. Maternal blood concentration of superoxide (O2•) and placental concentration of •NO will be determined using EPR (electron paramagnetic resonance). Endothelial function and arterial stiffness will be evaluated using respectively Peripheral Arterial Tonometry (PAT), Flow-Mediated Dilatation (FMD) and applanation tonometry. Placental expression of eNOS (endothelial NOS) will be determined using immune-histochemical staining. Target recruitment will be 110 patients for the longitudinal study and 90 patients in the case-control study. DISCUSSION: The results of Endopreg will provide longitudinal information on in vivo endothelial function and in vitro OS during normal pregnancy and PE. Adoption of these vascular tests in clinical practice potentially predicts patients at risk to develop cardiovascular events later in life after PE pregnancies. •NO, O2•- and eNOS measurements provide further inside in the pathophysiology of PE. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02603913 . Registered October 2015.

Flow-mediated dilation and peripheral arterial tonometry are disturbed in preeclampsia and reflect different aspects of endothelial function.

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy (P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy (P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy (P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy (P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy.

MicroRNAs targeting VEGF are related to vascular dysfunction in preeclampsia.

In preeclampsia (PE), pre-existent maternal endothelial dysfunction leads to impaired placentation and vascular maladaptation. The vascular endothelial growth factor (VEGF) pathway is essential in the placentation process and VEGF expression is regulated through post-transcriptional modification by microRNAs (miRNAs). We investigated the expression of VEGF-related circulating miR-16, miR-29b, miR-126, miR-155 and miR-200c in PE vs healthy pregnancies (HPs), and their relation with vascular function, oxidative stress (OS) and systemic inflammation. In this case-control study, 24 women with early PE (<34 weeks) were compared with 30 women with HP. Circulating microRNA levels (RT-qPCR), OS and systemic inflammation were assessed in plasma samples (PE 29.5 vs HP 25.8 weeks) and related to extensive in vivo vascular function (flow-mediated dilatation (FMD), modified FMD (mFMD), carotid-femoral pulse wave velocity (CF-PWV), heart rate corrected augmentation index (AIx75) and reactive hyperemia index (RHI)). FMD, CF-PWV, AIx75 and RHI were all significantly impaired in PE (P<0.05). PE patients had reduced levels of miR-16 (5.53 ± 0.36 vs 5.84 ± 0.61) and increased levels of miR-200c (1.34 ± 0.57 vs 0.97 ± 0.68) (P<0.05). Independent of age and parity, miR-16 was related to impaired FMD (ß 2.771, 95% C.I.: 0.023-5.519, P=0.048) and mFMD (ß 3.401, 95% C.I.: 0.201-6.602, P=0.038). Likewise, miR-200c was independently associated with CF-PWV (ß 0.513, 95% C.I.: 0.034-0.992, P=0.036). In conclusion, circulating levels of miR-16 were lower in PE, which correlated with impaired endothelial function. Circulating miR-200c was increased in PE and correlated with higher arterial stiffness. These findings suggest a post-transcriptional dysregulation of the VEGF pathway in PE and identify miR-16 and miR-200c as possible diagnostic biomarkers for PE.

The Effect of Exercise Training During Pregnancy to Improve Maternal Vascular Health: Focus on Gestational Hypertensive Disorders.

Hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, occur in up to 10% of pregnancies and are associated with increased life-long cardiovascular risk. Physical activity improves cardiovascular health in pregnancy and may lower the risk of developing hypertensive disorders of pregnancy. However, a minority of pregnant women comply with the recommended level of physical activity. Adequate knowledge on the physiological effects of exercise in healthy pregnancy could help to overcome potential barriers as pregnancy is a unique window of opportunity to improve health outcomes for both mother and child. In this mini review, we discuss structural and functional vascular adaptations during healthy and hypertensive pregnancies, we elaborate on the effects of exercise on the vasculature and review the safety and existing evidence of exercise training as preventive therapy for gestational hypertensive disorders.

Are neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and/or mean platelet volume (MPV) clinically useful as predictive parameters for preeclampsia?

OBJECTIVE: Preeclampsia (PE) is a severe pregnancy complication with significant maternal and neonatal morbi-mortality resulting in high health care costs. Prevention, mainly based on the administration of acetylsalicylic acid, is only possible if timely identification of high-risk patients can be realized in an easy, nonexpensive, and widely available method. This paper explores the clinical usability of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and/or mean platelet volume (MPV) in discriminating between women that will and those that will not develop PE. STUDY DESIGN: Demographic data and laboratory results were retrospectively collected and compared in 2050 pregnant women (164 PE and 1886 controls) between 1 January 2014 and 31 January 2016. RESULTS: In the PE group, gravidity, parity, gestational age, and birth weight were significantly lower compared to the control group. Before the 20th pregnancy week, MPV was significantly elevated in the PE group compared to the controls (p = .006), hence analysis revealed an optimal cut-off point of 8.15 (sensitivity 66.7%, specificity 56.3%) for predicting PE. At the end of pregnancy, NLR and MPV appeared to be higher and PLR lower in the PE group compared to the controls, which strengthens the current knowledge on the pathogenesis of PE. CONCLUSIONS: MPV is significantly elevated in the first half of pregnancy in women who later develop PE and might therefore be implemented in combination with other parameters in a PE prediction model.

Low-flow mediated constriction as a marker of endothelial function in healthy pregnancy and preeclampsia: A pilot study.

OBJECTIVES: Overwhelming clinical evidence exists on disturbed vascular and endothelial function in the pathophysiology of preeclampsia (PE). In a non-pregnant (NP) population, L-FMC (low-flow mediated constriction) provides insight in the 'resting' endothelial capacity in contrast to the gold standard of flow mediated dilatation (FMD), reflecting endothelial nitric oxide bioavailability. STUDY DESIGN: Longitudinal follow-up of 100 healthy pregnant (HP) women, 33 PE women and 16 NP controls with non-invasive vascular assessments. HP women were evaluated at 12 and 35 weeks of gestation and at 6 months postpartum. PE patients were assessed at diagnosis (mean 30 weeks) and 6 months postpartum. MAIN OUTCOME MEASURES: Endothelial function (L-FMC, FMD, peripheral arterial tonometry (PAT)) and arterial stiffness (pulse wave velocity (PWV) and analysis (PWA)) were measured at the different visits and compared between groups. RESULTS: Overall endothelial dysfunction is present in PE (FMD HP 9.09 ±â€¯4.20 vs PE 5.21 ±â€¯4.47, p = 0.0004; L-FMC HP -1.90 ±â€¯2.66 vs PE -0.40 ±â€¯2.09, p = 0.03). L-FMC gradually elevates during the course of a HP (1st trim -0.31 ±â€¯1.75 vs 3rd trim -1.97 ±â€¯3.02, p < 0.0001) and is present in 85% of women in the third trimester. In NP, only 27% of women has L-FMC. In PE, L-FMC is present in 50% of cases. Arterial stiffness is increased in PE (all p < 0.0001). There is no correlation between L-FMC and other markers of vascular function (p > 0.05). CONCLUSION: PE is characterized by dysfunction of both resting and recruitable endothelial capacity. This study offers new insights in different aspects of endothelial function in pregnancy, since L-FMC reflects an adaptation in HP that is absent in PE.

Oxidative stress in healthy pregnancy and preeclampsia is linked to chronic inflammation, iron status and vascular function.

BACKGROUND: During normal pregnancy, placental oxidative stress (OS) is present during all three trimesters and is necessary to obtain normal cell function. However, if OS reaches a certain level, pregnancy complications might arise. In preeclampsia (PE), a dangerous pregnancy specific hypertensive disorder, OS induced in the ischemic placenta causes a systemic inflammatory response and activates maternal endothelial cells. In this study, we aimed to quantify superoxide concentrations (as a measure of systemic OS) using electron paramagnetic resonance (EPR) and correlate them to markers of systemic inflammation, iron status and vascular function. METHODS: Fifty-nine women with a healthy pregnancy (HP), 10 non-pregnant controls (NP) and 28 PE patients (32±3.3weeks) were included. During HP, blood samples for superoxide, neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV) and iron status were taken at 10, 25 and 39 weeks. Vascular measurements for arterial stiffness (carotid-femoral pulse wave velocity (CF-PWV), augmentation index (AIx), augmentation Pressure (AP)) and microvascular endothelial function (reactive hyperemia index (RHI)) were performed at 35 weeks. In PE, all measurements were performed at diagnosis. CMH (1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine) was used as spin probe for EPR, since the formed CM radical corresponds to the amount of superoxide. RESULTS: Superoxide concentration remains stable during pregnancy (p = 0.92), but is significantly higher compared to the NP controls (p<0.0001). At 25 weeks, there is a significant positive correlation between superoxide and ferritin concentration. (p = 0.04) In PE, superoxide, systemic inflammation and iron status are much higher compared to HP (all p<0.001). During HP, superoxide concentrations correlate significantly with arterial stiffness (all p<0.04), while in PE superoxide is significantly correlated to microvascular endothelial function (p = 0.03). CONCLUSIONS: During HP there is an increased but stable oxidative environment, which is correlated to ferritin concentration. If superoxide levels increase, there is an augmentation in arterial stiffness. In PE pregnancies, systemic inflammation and superoxide concentrations are higher and result in a deterioration of endothelial function. Together, these findings support the hypothesis that vascular function is directly linked to the amount of OS and that measurement of OS in combination with vascular function tests might be used in the prediction of PE.

Use of ticagrelor in human pregnancy, the first experience.

Ticagrelor was daily administered throughout pregnancy to a 37-year-old pregnant woman until 36 weeks of gestation. The patient, with Behçet disease, suffered from a non-ST elevation myocardial infarction 4 months before conception, possibly related to hypertension and tobacco abuse. Pregnancy and postpartum periods were uneventful. She delivered a healthy but small-for-gestational-age term neonate.

Relapsing fetal bilateral hydrothorax, an isolated expression of a vein of Galen aneurysmal malformation.

We report a case of bilateral fetal hydrothorax presenting at 20 weeks of pregnancy, spontaneously resolving at 22 weeks and severely relapsing at 28 weeks in a fetus with normal karyotype. The cause was a high-output heart failure caused by vein of Galen malformation.

A rare cause of primary amenorrhoea, the XY female with gonadal dysgenesis.

Disorders of sexual development are conditions where sexual phenotype and genotype are discordant. Genetic sex is determined at conception as the ovum is fertilised by a spermatozoon that contains either an X or Y chromosome. A complex pathway determined by genes and hormones leads to gonadal differentiation into testis or ovary and promotes the development of internal and external genitalia. We present a case of an 18-year-old woman who presented with primary amenorrhoea. She was a virgin, and apart from hirsutism and overweight, had no complaints. Her family history was insignificant. The patient was tall and had underdeveloped breasts. Her blood results showed hypergonadotropic hypogonadism. A 46, XY genotype was detected with karyotype analysis. Ultrasound and MRI demonstrated the presence of a uterus, but no overt gonads. Laparoscopy was performed, with bilateral removal of streak ovaries.