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Meta-analysis of gene expression profiles in preeclampsia.
Vennou, KE, Kontou, PI, Braliou, GG, Bagos, PG
Pregnancy hypertension. 2020;:52-60
Abstract
OBJECTIVE Preeclampsia (PE) is a serious complication of pregnancy. It is considered a complex condition influenced by maternal genes, environmental factors and a deregulated immune response of the mother, but the etiology is largely unknown. The aim of this study is to identify differentially expressed genes (DEGs) in PE, to help elucidate the identification of the disease etiological mechanisms. STUDY DESIGN The databases Pubmed and GEO were searched according to PRISMA guidelines for the existence of gene expression data on placental samples from case-control studies. After meta-analysis the identified DEGs were further analyzed with STRING and PANTHER to retrieve interaction networks and overrepresented biochemical pathways. RESULTS Only 10 gene expression datasets and articles fulfilled inclusion criteria, containing data on 195 patients and 231 controls, and were analyzed. Meta-analysis identified 629 DEGs to be associated with PE at a False Discovery Rate p-value of 0.01. Network analysis showed few highly interconnected genes involved in innate immunity and signal transduction pathways indicative of a multifaceted disease with etiological heterogeneity. over representation analysis revealed that these genes participate mainly in carbohydrates, amino acids and pyrimidine metabolism, circadian clock system and signal transduction pathways. CONCLUSIONS This work, combining rigorous methods of meta-analysis and the use of modern bioinformatics tools, proposes the existence of novel, overlooked so far, biochemical pathways and mechanisms to contribute to PE development such as carbohydrate, aminoacids and pyrimidine metabolism. Our findings pave the way for further investigation of the above pathways in experimental efforts to decipher the orchestrating mechanisms for PE development.
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2.
Lipid profiling in maternal and fetal circulations in preeclampsia and fetal growth restriction-a prospective case control observational study.
Alahakoon, TI, Medbury, HJ, Williams, H, Lee, VW
BMC pregnancy and childbirth. 2020;(1):61
Abstract
BACKGROUND While many risk factors for preeclampsia, such as increased body mass index, advanced maternal age, chronic hypertension, diabetes, are now established in clinical practice, maternal lipid profile has not been included in the risk assessment for preeclampsia. We aim to characterize the serum levels of Total Cholesterol (TC), High density lipoprotein (HDL), Low density lipoprotein (LDL), Triglycerides (TG), Apolipoprotein A1, Apolipoprotein B and their ratios TC/HDL and ApoB/ApoA1 in the maternal and fetal circulations of normal pregnancy, preeclampsia (PE), fetal growth restriction (FGR) and PE + FGR. METHODS A prospective cross-sectional case control study was conducted measuring maternal and fetal lipid levels by enzymatic analysis and immune-turbidimetric enzymatic assays. FGR was defined by elevated umbilical artery Doppler resistance in association with estimated fetal weight < 10%. Kruskal Wallis non-parametric analysis of variance was used to test for homogeneity across the clinical groups for each of the variables, Mann-Whitney tests for pairwise comparisons and Spearman rank correlation were used to quantify gestational age-related changes. RESULTS (1) TG levels were elevated in maternal PE and cord blood PE + FGR groups compared to normal pregnancies. (2) A statistically significant elevation of fetal ApoB levels was observed in PE, FGR and PE + FGR compared to normal pregnancies. Apolipoprotein levels A1 and B were not different between maternal groups. (3) TC, HDL, LDL and TC/HDL levels did not show any significant gestational variation or between clinical groups in the maternal or fetal circulation. CONCLUSIONS Elevation in maternal TG levels may have a role in the pathogenesis of PE. The implications of elevated maternal and fetal TG levels and elevated fetal Apolipoprotein B levels deserves further exploration of their role in long term cardiovascular risk in the mother as well as the offspring.
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3.
Effect of preeclampsia on human milk cytokine levels.
Freitas, NA, Santiago, LTC, Kurokawa, CS, Meira Junior, JD, Corrente, JE, Rugolo, LMSS
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(13):2209-2213
Abstract
INTRODUCTION Preeclampsia (PE) is a systemic inflammatory disease, and its effect on human milk immune components is poorly understood. OBJECTIVE To investigate whether PE affects human milk cytokine levels. METHODS This was a prospective observational study involving mothers diagnosed with PE and with singleton pregnancy with no fetal malformation. The following cases were excluded: diabetes, chorioamnionitis, use of illicit drugs and alcohol, mastitis and congenital infection. In total, 228 mothers were studied and divided into two groups matched by gestational age: PE (n = 114) and normotensive (control, n = 114). Colostrum was collected from 24-72 hours postpartum, and mature milk was collected at the end of the first month. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, and TNF-α) were measured using flow cytometry. A generalized linear model with a gamma distribution was used to analyze the differences between groups versus time interaction. RESULTS The mean gestational age was 36 weeks. Increased IL-1 and IL-6 levels and reduced IL-12 levels in the colostrum were detected in PE, while in the mature milk, the IL-6 and IL-8 levels were lower than those of the control group. CONCLUSIONS PE is associated with increased levels of inflammatory cytokines in colostrum and decreased levels in mature milk.
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4.
Association of vitamin D level and vitamin D deficiency with risk of preeclampsia: A systematic review and updated meta-analysis.
Akbari, S, Khodadadi, B, Ahmadi, SAY, Abbaszadeh, S, Shahsavar, F
Taiwanese journal of obstetrics & gynecology. 2018;(2):241-247
Abstract
OBJECTIVES Because of the immune modulatory effects of vitamin D3 in preeclampsia, we intend to have a systematic review and meta-analysis on association of both 25-hydroxy vitamin D (25-OHD) level (parametric approach) and 25-OHD deficiency (non-parametric approach) with preeclampsia. As well, for the parametric part, we used receiver operating characteristic (ROC) curve model. MATERIALS AND METHODS We used Web of Science, PubMed and Science Direct data bases through searching in titles. Google Scholar search engine was used in order to find missing papers. Finally 23 studies were imported. Both random and fixed models were reported. RESULTS Based on the forest plot, lower levels of 25-OHD were significantly associated with risk of preeclampsia (fixed and random P < 0.001). Based on the forest plot, vitamin D deficiency (25-OHD < 20 ng/ml) was significantly associated with risk of preeclampsia (fixed P < 0.0001; random P = 0.0029; fixed OR = 1.33; random OR = 1.54). Based on ROC curve results, we found 2 cutoffs of 10.60 and 20.05 ng/ml. CONCLUSION Women with vitamin D deficiency at cutoff 20 ng/ml are more at risk of preeclampsia. This association can be specific up to 90% at 10.60 ng/ml cutoff. Treatment of vitamin D deficiency is necessary before pregnancy.
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5.
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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6.
Novel ideas about salt, blood pressure, and pregnancy.
Rakova, N, Muller, DN, Staff, AC, Luft, FC, Dechend, R
Journal of reproductive immunology. 2014;:135-139
Abstract
The molecular mechanisms leading to preeclampsia are poorly understood. It has been related to certain immune mechanisms, as well as the pathological regulation of the renin-angiotensin system together with perturbed salt and plasma volume regulation. Finally, a non-specific, vascular, inflammatory response is generated, which leads to the clinical syndrome. Here, we present novel findings in salt (NaCl) metabolism implying that salt is not only important in blood pressure control and volume homeostasis, but also in immune regulation. Sodium and chloride can be stored without accumulation of water in the interstitium at hypertonic concentrations through interactions with proteoglycans. Macrophages in the interstitium act as osmosensors for salt, producing increased amounts of vascular endothelial factor C, which increases the density of the lymph-capillary network and the production of nitric oxide in vessels. An increased interstitial salt concentration activates the innate immune system, especially Th17 cells, and may be an important trigger for autoimmune diseases. The novel findings with the idea of sodium storage and local mechanisms of volume and immune regulation are appealing for preeclampsia and may unify the "immune" and "vascular" hypotheses of preeclampsia.
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7.
Is vitamin E a safe prophylaxis for preeclampsia?
Banerjee, S, Chambers, AE, Campbell, S
American journal of obstetrics and gynecology. 2006;(5):1228-33
Abstract
The prophylactic use of vitamins E and C for the prevention of preeclampsia is currently being evaluated in multiple clinical trials in Canada, Mexico, the United Kingdom, the United States, and other developing countries. In addition to its antioxidant capacity, exogenous vitamin E may prevent an immunologic switch (Th1 to Th2) that is vital for early-to late transition in normal pregnancies. Moreover, vitamin E could be a potential interferon-gamma (IFN-gamma) mimic facilitating persistent proinflammatory reactions at the fetal-maternal interface. These untoward effects of dietary intake of vitamin E may be more pronounced in those treated cases that fail to develop preeclampsia. A critical test of this hypothesis would be to establish whether, under variable O2 tension, vitamin E is capable of affecting cytokine signaling in placental trophoblasts and maternal immune effector cells, both in early and late human pregnancies.
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8.
Vitamin D for the prevention of preeclampsia? A hypothesis.
Hyppönen, E
Nutrition reviews. 2005;(7):225-32
Abstract
Preeclampsia has been suggested to result from a partial breakdown of tolerance to the developing fetus after maternal immune maladaptation. Several of the proposed immunomodulatory properties of the hormonal vitamin D system could potentially have beneficial effects for successful maintenance of pregnancy. Preeclampsia is characterized by marked changes in vitamin D metabolism. This paper reviews the evidence suggesting that the immunomodulatory properties of 1,25(OH)2D may play a key role in maintaining immunological tolerance in pregnancy, and proposes that ensuring adequate vitamin D status/intake may help in the prevention and management of preeclampsia.