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Vitamin D modulates the transcription factors of T cell subsets to anti-inflammatory and regulatory profiles in preeclampsia.
Ribeiro, VR, Romao-Veiga, M, Nunes, PR, Matias, ML, Peracoli, JC, Peracoli, MTS
International immunopharmacology. 2021;(Pt B):108366
Abstract
Vitamin D (VD) is a multifunctional prohormone and low VD status in pregnancy may contribute to the risk of adverse perinatal outcomes, such as preeclampsia (PE). This molecule may modulate the polarization of T cell subsets during gestation. This study evaluated the in vitro immunomodulatory effect of VD [1,25(OH)2D3] on the gene expression of transcription factors and on cytokine production by T cell subsets. Twenty pregnant women with PE and twenty normotensive (NT) pregnant women were studied. Plasma concentration of VD, [25(OH)D3], was evaluated by chemiluminescence. PBMCs from preeclamptic and NT pregnant women were cultured in the absence or presence of VD to determine gene expression of T-bet (Th1), GATA-3 (Th2), RORγt, and RUNX1 (Th17), FoxP3 (regulatory T cell- Treg), and the receptors of VD (VDR) and IL-23 (IL-23R) by quantitative PCR. The concentration of cytokines in the PBMC supernatant culture was determined by cytometric bead array and ELISA immunoassay. The results showed that plasmatic levels of VD were significantly lower in the PE group. The treatment of PBMCs from PE pregnant women with VD induced downregulation of genes related to inflammatory profiles (Th1 and Th17), as well as an increase of the Th2 and Treg profiles. Thus, VD treatment decreased the release of IFN-γ, TNF-α, IL-17, IL-6, and IL-23 while it increased the levels of IL-10 in the PE group. VD induces an immunomodulatory effect in T cell subsets from pregnant women with PE, polarizing these cells to an anti-inflammatory and regulatory profile.
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The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.
Manders, V, Visser, A, Keijser, R, Min, N, Poutsma, A, Mulders, J, van den Berkmortel, T, Hortensius, M, Jongejan, A, Pajkrt, E, et al
Scientific reports. 2020;(1):21857
Abstract
Using genome-wide transcriptome analysis by RNA sequencing of first trimester plasma RNA, we tested whether the identification of pregnancies at risk of developing pre-eclampsia with or without preterm birth or growth restriction is possible between weeks 9-14, prior to the appearance of clinical symptoms. We implemented a metaheuristic approach in the self-learning SVM algorithm for differential gene expression analysis of normal pregnancies (n = 108), affected pregnancies (n = 34) and non-pregnant controls (n = 19). Presymptomatic candidate markers for affected pregnancies were validated by RT-qPCR in first trimester samples (n = 34) from an independent cohort. PRKG1 was significantly downregulated in a subset of pregnancies with birth weights below the 10thpercentile as shared symptom. The NRIP1/ZEB2 ratio was found to be upregulated in pregnancies with pre-eclampsia or trisomy 21. Complementary quantitative analysis of both the linear and circular forms of NRIP1 permitted discrimination between pre-eclampsia and trisomy 21. Pre-eclamptic pregnancies showed an increase in linear NRIP1 compared to circular NRIP1, while trisomy 21 pregnancies did not.
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Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.
Wen, SW, White, RR, Rybak, N, Gaudet, LM, Robson, S, Hague, W, Simms-Stewart, D, Carroli, G, Smith, G, Fraser, WD, et al
BMJ (Clinical research ed.). 2018;:k3478
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Abstract
OBJECTIVE To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN Randomised, phase III, double blinded international, multicentre clinical trial. SETTING 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.
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Preeclampsia and gestational weight gain in the Norwegian Fit for Delivery trial.
Hillesund, ER, Seland, S, Bere, E, Sagedal, LR, Torstveit, MK, Lohne-Seiler, H, Vistad, I, Øverby, NC
BMC research notes. 2018;(1):282
Abstract
OBJECTIVE Excessive gestational weight gain is linked to risk of preeclampsia, but it is not clear whether the association is causal. The purpose of this paper was to examine gestational weight gain in the Norwegian Fit for Delivery study among women who developed preeclampsia compared to those who did not, and to further explore associations between weight gain and preeclampsia by including data on body composition (bioimpedance) assessed in the last trimester of pregnancy. RESULTS A total of 550 women were eligible for the study. Women who developed preeclampsia gained more weight than women who did not (difference 3.7 kg, p = 0.004), with a 3.5 kg difference in total body water observed in week 36 (p = 0.040). Adjusted for age, education, pre-pregnancy body mass index (BMI), randomization, and fat mass, a one kg increase in GWG was associated with 1.3 times higher odds of preeclampsia (OR: 1.31, 95% CI 1.15-1.49, p < 0.001). An independent inverse association between fat mass in week 36 and odds of preeclampsia was observed (OR: 0.79, 95% CI 0.68-0.92, p = 0.002). Given the observed difference in total body water, these findings point to excess fluid as the component driving the association between gestational weight gain and preeclampsia in the present study. Trial registration The NFFD trial has the Clinical Trials registration: clinicaltrial.gov NCT0100168.
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The presence of B-cell activating factor (BAFF) in umbilical cord blood in both healthy and pre-eclamptic pregnancies and in human breast milk.
Bienertova-Vasku, J, Zlamal, F, Tomandl, J, Hodicka, Z, Novak, J, Splichal, Z, Ventruba, P, Thon, V, Vasku, A
Journal of reproductive immunology. 2015;:89-93
Abstract
B-cell activating factor (BAFF) is an important immune regulator that was recently reported to be secreted by placenta. The aim of the study was to investigate the presence of BAFF in umbilical cord blood, maternal serum, and breast milk in normal and in pre-eclamptic pregnancies. Pairs of maternal serum/umbilical cord blood were obtained from 12 pre-eclamptic and 34 physiological pregnancies. Another cohort of 10 healthy lactating women was established that was followed up for 6 months following delivery to investigate BAFF levels in breast milk. BAFF levels in maternal peripheral blood were significantly higher in physiological pregnancies than in pre-eclamptic pregnancies (p < 0.03). Furthermore, we observed a consistent presence of BAFF in breast milk during the 6-month post-partum period of breastfeeding. In this study, we demonstrate that BAFF levels are significantly lower in maternal peripheral blood in pre-eclamptic pregnancies. We also report the consistent presence of BAFF in breast milk in healthy women. More research into the role of BAFF in pregnancy, and during breastfeeding, is imperative.
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Strong ion and weak acid analysis in severe preeclampsia: potential clinical significance.
Ortner, CM, Combrinck, B, Allie, S, Story, D, Landau, R, Cain, K, Dyer, RA
British journal of anaesthesia. 2015;(2):275-84
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Abstract
BACKGROUND The influence of common disturbances seen in preeclampsia, such as changes in strong ions and weak acids (particularly albumin) on acid-base status, has not been fully elucidated. The aims of this study were to provide a comprehensive acid-base analysis in severe preeclampsia and to identify potential new biological predictors of disease severity. METHODS Fifty women with severe preeclampsia, 25 healthy non-pregnant- and 46 healthy pregnant controls (26-40 weeks' gestation), were enrolled in this prospective case-control study. Acid-base analysis was performed by applying the physicochemical approach of Stewart and Gilfix. RESULTS Mean [sd] base excess was similar in preeclamptic- and healthy pregnant women (-3.3 [2.3], and -2.8 [1.5] mEq/L respectively). In preeclampsia, there were greater offsetting contributions to the base excess, in the form of hyperchloraemia (BE(Cl) -2 [2.3] vs -0.4 [2.3] mEq/L, P<0.001) and hypoalbuminaemia (BE(Alb) 3.6 [1] vs 2.1 [0.8] mEq/L, P<0.001). In preeclampsia, hypoalbuminaemic metabolic alkalosis was associated with a non-reassuring/abnormal fetal heart tracing (P<0.001). Quantitative analysis in healthy pregnancy revealed respiratory and hypoalbuminaemic alkalosis that was metabolically offset by acidosis, secondary to unmeasured anions and dilution. CONCLUSIONS While the overall base excess in severe preeclampsia is similar to that in healthy pregnancy, preeclampsia is associated with a greater imbalance offsetting hypoalbuminaemic alkalosis and hyperchloraemic acidosis. Rather than the absolute value of base excess, the magnitude of these opposing contributors may be a better indicator of the severity of this disease. Hypoalbuminaemic alkalosis may also be a predictor of fetal compromise. CLINICAL TRIAL REGISTRATION clinicaltrials.gov: NCT 02164370.
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Effects of nutritional management intervention on gestational weight gain and perinatal outcome.
Luo, XD, Dong, X, Zhou, J
Saudi medical journal. 2014;(10):1267-70
Abstract
OBJECTIVES To evaluate whether nutritional management intervention can prevent excessive weight gain during pregnancy and improve perinatal outcomes. METHODS This cross-sectional study included 276 pregnant women undergoing prenatal care between June 2010 and December 2011 at the Obstetrics and Gynecology Department of the Second Affiliate Hospital of the ChongQing University of Medical Sciences, Chongqing, China. Of them, 131 women received individualized nutritional management in addition to routine prenatal care (intervention group), and 145 women received only routine prenatal care (control group). The primary study outcome was gestational weight gain (GWG). Secondary outcomes included birth weight, Apgar score, and incidence of pregnancy complications. RESULTS Baseline demographic characteristics of the 2 groups were the same. The average GWG was higher in the control group (12.57+/-4.62 kg) compared with the intervention group (7.58+/-1.59 kg; p=0.000). The incidence rate of preeclampsia was 3.1% and gestational diabetes was 3.8% for the intervention group, compared with 11% for preeclampsia and 14.5% gestational diabetes for the control group (p<0.05). The incidence rates of premature rupture of membranes, preterm labor, birth weight, birth of a newborn, and major congenital anomalies did not significantly differ between the 2 groups. CONCLUSION Nutritional management intervention prevented excessive GWG and improved perinatal outcomes. These results support the hypothesis that nutritional management intervention can decrease the rate of complications experienced by expecting mothers.
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Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study.
Kahn, SR, Platt, R, McNamara, H, Rozen, R, Chen, MF, Genest, J, Goulet, L, Lydon, J, Seguin, L, Dassa, C, et al
American journal of obstetrics and gynecology. 2009;(2):151.e1-9; discussion e1-5
Abstract
OBJECTIVE We sought to evaluate the association between inherited thrombophilia and preeclampsia. STUDY DESIGN From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia and selected 443 control subjects who did not have preeclampsia or nonproteinuric gestational hypertension. Blood samples were tested for DNA polymorphisms affecting thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T polymorphism), homocysteine, and folate levels, and placentae underwent pathological evaluation. RESULTS Thrombophilia was present in 14% of patients and 21% of control subjects (adjusted logistic regression odds ratio, 0.6; 95% confidence interval, 0.3-1.3). Placental underperfusion was present in 63% of patients vs 46% of control subjects (P < .001) and was more frequent in women with folate levels in the lowest quartile (P = .04), but was not associated with thrombophilia. CONCLUSION We did not find evidence to support an association between inherited thrombophilia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophilia.
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Vitamin C and E supplementation in women at high risk for preeclampsia: a double-blind, placebo-controlled trial.
Beazley, D, Ahokas, R, Livingston, J, Griggs, M, Sibai, BM
American journal of obstetrics and gynecology. 2005;(2):520-1
Abstract
OBJECTIVE We sought to determine the effect of supplemental antioxidant vitamins C and E on the rate of preeclampsia in high-risk pregnant women. STUDY DESIGN Women at risk for preeclampsia (previous preeclampsia, chronic hypertension, pregestational diabetes, or multifetal gestation) were recruited at 14 to 20 weeks' gestation and randomly assigned to receive either 1000 mg of vitamin C and 400 IU of vitamin E or placebo daily in addition to their regular prenatal vitamins. The primary outcome was the occurrence of preeclampsia. An estimated sample size of 220 women in each arm was determined to be necessary to demonstrate a 50% reduction in the rate of preeclampsia. RESULTS Funding was terminated after 109 women had been recruited; 9 were lost to follow-up or withdrew. We analyzed data from the remaining 100 women to look for differences in outcome and to estimate the required sample size for future studies. The rate of preeclampsia was not different: 17.3% in women who received supplemental vitamins C and E, versus 18.8% in the placebo group. Assuming a baseline rate of preeclampsia in the placebo group between 15% and 20%, we can estimate that 500 to 950 women in each arm will be required to show a clinically important reduction in the rate of preeclampsia. CONCLUSION The potential benefit of vitamin C and E supplementation to prevent preeclampsia in women with clinical risk factors is smaller than we estimated. Future studies of antioxidant vitamin supplementation in this population will require more than 500 women in each arm.
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Plasma carotenoids, retinol, tocopherols, and lipoproteins in preeclamptic and normotensive pregnant Zimbabwean women.
Williams, MA, Woelk, GB, King, IB, Jenkins, L, Mahomed, K
American journal of hypertension. 2003;(8):665-72
Abstract
BACKGROUND We examined the relationship between maternal plasma lipoprotein and antioxidant status with risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe. METHODS One hundred seventy-three pregnant women with preeclampsia and 186 controls were included in a case-control study. Maternal plasma total cholesterol, high-density lipoprotein (HDL), and total triglycerides were measured using enzymatic methods. Plasma carotenoids (alpha-carotene, beta-carotene, lycopene, lutein, beta-cryptoxanthin, zeaxanthin), retinol, and tocopherols (alpha-tocopherol and gamma-tocopherol) were determined using high performance liquid chromatography. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Preeclampsia risk increased with successively higher quartiles of plasma triglyceride (OR: 1.00, 1.70, 2.00, 5.26, with the lowest quartile as referent; P for trend <.001). We noted an inverse association between preeclampsia risk and HDL cholesterol concentrations (OR: 1.00, 0.87, 0.66, 0.68, with the first quartile as the referent group; P for trend =.169), although the trend was not statistically significant. After adjusting for confounders, we noted decreases in preeclampsia risk with increasing concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin, respectively. Women with beta-carotene concentrations in the highest quartile, as compared with those in the lowest quartile experienced a 50% decreased risk of preeclampsia (OR = 0.50, 95% CI 0.25-1.00). There was no clear pattern of preeclampsia risk with lycopene concentrations or with concentrations of gamma- and alpha-tocopherol. CONCLUSIONS Our results are consistent with some, although not all, previous reports. Prospective studies are needed to determine the temporal relationship between observed alterations in lipid and antioxidant concentrations in preeclamptic pregnancies.