TGFß signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy.

BACKGROUND: The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFß) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFß signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFß signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFß signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFß is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE: This comprehensive review aims to explore and elucidate the roles of the major members of the TGFß superfamily, including TGFßs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS: A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfß', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfß signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfß signalling', 'placental macrophages tgfß', 'endothelial cells tgfß', 'endothelium tgfß signalling', 'trophoblast invasion tgfß signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfß', 'tgfß preeclampsia', 'tgfß placental development', 'TGFß placental function', 'endothelial dysfunction preeclampsia tgfß signalling', 'vascular remodelling placenta TGFß', 'inflammation pregnancy tgfß', 'immune response pregnancy tgfß', 'immune tolerance pregnancy tgfß', 'TGFß pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfß pregnancy tregs', 'TGFß placenta NK cells', 'TGFß placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES: A comprehensive understanding of TGFß signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFß ligands contribute to the proper functioning of a healthy maternal-foetal interface. However, dysregulation of TGFß signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFß signalling. WIDER IMPLICATIONS: The dysregulation of TGFß signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFß signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE.

l-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia.

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new-onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcomes. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal l-citrulline supplementation on pregnancy-specific vascular dysfunction in the male C57BL/6J × female C57BL/6J C1q-/- preeclampsia-like mouse model. l-Citrulline is a nonessential amino acid that is converted to l-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO)-mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams was supplemented with l-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 mo of age. Main findings show that l-citrulline reduced blood pressure, increased vascular glycocalyx volume, and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of l-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 mo of age. l-Citrulline-mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, l-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health, which may have translational implications for improved maternal cardiovascular health.

Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy.

[Figure: see text].

Role of Heat Shock Protein 70 (HSP-70) after Giving Nanoherbal Haramonting (Rhodomyrtus tomentosa) in Preeclamptic Rats.

BACKGROUND AND OBJECTIVE: Haramonting (Rhodomyrtus tomentosa) is an alternative herb to improve health because it has many biological activities and antioxidant. HSP-70 levels as biomarkers of preeclampsia affected the anti-apoptosis of damaged cells in the placenta. This study aimed to evaluate the role of HSP-70 expressions by investigating whether effect haramonting leaves in PE rats. MATERIALS AND METHODS: The study design was control (C): pregnant rats without treatment, PE: Preeclamptic rats, PE+E: PE rats were given 1 mL EVOO kg-1 b.wt./day orally (pregnancy 13-19), PE+H: PE rats were given nano herbal haramonting 100 mg kg-1 b.wt. (pregnancy 13-19 days). PE+E+H: PE rats were given EVOO 0.5 mL kg-1 b.wt. and nano herbal haramonting 50 mg kg-1 b.wt. (pregnancy 13-19 day). Surgery was performed by taking blood from the heart for the SGOT/SGPT parameters, creatinine and HSP70. RESULTS: A significant difference was observed in all groups with the value p<0.0001 and HSP-70 Expressions affect in preeclamptic rats after given this herbal. The value of SGOT, SGPT and creatinine can affect preeclamptic rats and can be as a biomarker of preeclampsia. A significant difference also in fetus weight (p<0.01) but an insignificant difference in placental weight (p>0.05). CONCLUSION: These findings indicate that Nano herbal haramonting and EVOO possess antioxidative effects and a promising drug for the future in the treatment of preeclampsia.

Association of Maternal Hyperuricemia with Post-Spinal Hypotension in Pre-Eclamptic Parturients Undergoing Emergency Cesarean Delivery: a Prospective Observational Study.

Pre-eclampsia is commonly associated with higher serum uric acid levels, which is known to increase vascular tone. A previous retrospective study established a positive correlation between raised serum uric acid levels and reduced incidence of post-spinal hypotension. However, until date, this correlation has not been prospectively evaluated in exclusively pre-eclamptic women. Pre-eclamptic parturients undergoing emergency cesarean delivery under subarachnoid block were included. Sample for measuring serum uric acid level was obtained prior to shifting patients for cesarean delivery. Following spinal anesthesia, we recorded episodes of hypotension (fall of mean arterial pressure more than 20% from baseline values), use of vasopressors, and intraoperative blood loss. Our primary objective was to study the association between maternal hyperuricemia and incidence of post-spinal hypotension. Our secondary objectives included amount of vasopressors administered to maintain targeted mean arterial pressure before delivery of the baby, intraoperative blood loss, and immediate neonatal outcome. A total of 95% parturients had hyperuricemia, with mean serum uric acid level being 6.94 ± 0.9 mg/dl. Incidence of post-spinal hypotension was significantly lower in women who had hyperuricemia as compared with those with normal serum uric acid levels (21% vs 75%; p = 0.015). Mean serum uric acid levels were significantly high (p = 0.001) in patients not requiring any vasopressors (7.2 ± 1.2 mg/dl) than in those requiring moderate (5.70 ± 0.79 mg/dl) to high dose (5.75 ± 0.77 mg/dl) of vasopressors. There is a high incidence of hyperuricemia in pre-eclamptic parturients. In these patients, elevated serum uric acid levels is associated with lower incidence of post-spinal hypotension and reduced need of vasopressors to maintain maternal blood pressure within a normal range.

Implicações da deficiência materna de vitamina D: uma revisão sistemática / Implication of maternal vitamin D deficiency: a systematic review

O estudo objetiva avaliar a relação dos níveis de vitamina D em gestantes com as principais complicações gestacionais. A pesquisa foi realizada nas bases de dados PubMed, LILACS e BIREME, sendo selecionados artigos relevantes publicados de 2013 a 2018, usando os descritores: "vitamin D" AND "maternity" OR "pregnancy". Foram revisados 14 estudos observacionais incluindo casos-controles e coortes que investigaram a relação dos níveis de vitamina D maternos com pré-eclâmpsia, diabetes mellitus gestacional e prematuridade, sendo excluídos os estudos que utilizaram suplementação de vitamina D. Os dados foram extraídos por meio de uma tabulação com as seguintes informações: autor, ano da publicação, país do estudo, score obtido no downs and black, ano da coleta da amostra, tipo do estudo, número de participantes, método de obtenção da amostra de 25(OH)D, tempo da gestação na obtenção da amostra, complicação obstétrica, fatores de confusão ajustados e os principais desfechos. Foi obtido um total de 32.505 pacientes após a soma das amostras de todos os artigos analisados. O principal resultado encontrado, abrangendo as três comorbidades analisadas, relaciona níveis menores que 30 nmol/L de vitamina D como potencial fator de risco para pré-eclâmpsia, diabetes mellitus gestacional e prematuridade.(AU)

The study aims to assess the relationship between vitamin D levels in pregnant women and the main gestational complications. The research was carried out in the PubMed, LILACS and BIREME databases, with the selection of relevant articles published from 2013 to 2018, using the descriptors: "vitamin D" AND "maternity" OR "pregnancy". 14 observational studies were reviewed including control cases and cohorts that investigated the relationship between maternal vitamin D levels and pre-eclampsia, gestational diabetes mellitus and prematurity, and studies that used vitamin D supplementation were excluded. Data were extracted using a tabulation with the following information: author, year of publication, country of study, score obtained in downs and black, year of sample collection, type of study, number of participants, method of obtaining the sample of 25(OH)D, time of pregnancy in obtaining the sample, obstetric complication, adjusted confounding factors and the main outcomes. A total of 32,505 patients were obtained after adding the samples of all analyzed articles. The main result found, covering the three comorbidities analyzed, lists levels below 30 nmol/L of vitamin D as a potential risk factor for pre-eclampsia, gestational diabetes mellitus and prematurity.(AU)

Altered Bioavailability of Nitric Oxide and L-Arginine Is a Key Determinant of Endothelial Dysfunction in Preeclampsia.

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 (ß = 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.

Nephrotic syndrome due to preeclampsia before 20 weeks of gestation: a case report.

BACKGROUND: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period. CASE PRESENTATION: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely. CONCLUSIONS: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Açaí (Euterpe oleracea Mart) seed extract protects against maternal vascular dysfunction, hypertension, and fetal growth restriction in experimental preeclampsia.

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.

Identification of factors associated with delayed treatment of obstetric hypertensive emergencies.

BACKGROUND: Obstetric hypertensive emergency is defined as having systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg, confirmed 15 minutes apart. The American College of Obstetricians and Gynecologists recommends that acute-onset, severe hypertension be treated with first line-therapy (intravenous labetalol, intravenous hydralazine or oral nifedipine) within 60 minutes to reduce risk of maternal morbidity and death. OBJECTIVE: Our objective was to identify barriers that lead to delayed treatment of obstetric hypertensive emergency. STUDY DESIGN: A retrospective cohort study was performed that compared women who were treated appropriately within 60 minutes vs those with delay in first-line therapy. We identified 604 patients with discharge diagnoses of chronic hypertension, gestational hypertension, or preeclampsia using International Classification of Diseases-10 codes and obstetric antihypertensive usage in a pharmacy database at 1 academic institution from January 2017 through June 2018. Of these, 267 women (44.2%) experienced obstetric hypertensive emergency in the intrapartum period or within 2 days of delivery; the results from 213 women were used for analysis. We evaluated maternal characteristics, presenting symptoms and circumstances, timing of hypertensive emergency, gestational age at presentation, and administered medications. Chi square, Fisher's exact, Wilcoxon rank-sum, and sample t-tests were used to compare the 2 groups. Univariable logistic regression was applied to determine predictors of delayed treatment. Multivariable regression model was also performed; C-statistic and Hosmer and Lemeshow goodness-of-fit test were used to assess the model fit. A result was considered statistically significant at P<.05. RESULTS: Of the 213 women, 110 (51.6%) had delayed treatment vs 103 (48.4%) who were treated within 60 minutes. Patients who had delayed treatment were 3.2 times more likely to have an initial blood pressure in the nonsevere range vs those who had timely treatment (odds ratio, 3.24; 95% confidence interval, 1.85-5.68). Timeliness of treatment was associated with presence or absence of preeclampsia symptoms; patients without preeclampsia symptoms were 2.7 times more likely to have delayed treatment (odds ratio, 2.68; 95% confidence interval, 1.50-4.80). Patients with hypertensive emergencies that occurred overnight between 10 pm and 6 am were 2.7 times more likely to have delayed treatment vs those emergencies that occurred between 6 am and 10 pm (odds ratio, 2.72; 95% confidence interval, 1.27-5.83). Delayed treatment also had an association with race, with white patients being 1.8 times more likely to have delayed treatment (odds ratio, 1.79; 95% confidence interval, 1.04-3.08). Patients who were treated at <60 minutes had a lower gestational age at presentation vs those with delayed treatment (34.6±5 vs 36.6±4 weeks, respectively; P<.001). For every 1-week increase in gestational age at presentation, there was a 9% increase in the likelihood of delayed treatment (odds ratio, 1.11; 95% confidence interval, 1.04-1.19). Another factor that was associated with delay of treatment was having a complaint of labor symptoms, which made patients 2.2 times as likely to experience treatment delay (odds ratio, 2.17; 95% confidence interval, 1.07-4.41). CONCLUSION: Initial blood pressure in the nonsevere range, absence of preeclampsia symptoms, presentation overnight, white race, having complaint of labor symptoms, and increasing gestational age at presentation are barriers that lead to a delay in the treatment of obstetric hypertensive emergency. Quality improvement initiatives that target these barriers should be instituted to improve timely treatment.

L-(+)-Ergothioneine Significantly Improves the Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model.

Preeclampsia is a multifactorial hypertensive disorder of pregnancy founded on abnormal placentation, and the resultant placental ischemic microenvironment is thought to play a crucial role in its pathophysiology. Placental ischemia because of fluctuations in the delivery of oxygen results in oxidative stress, and recent evidence suggests that mitochondrial dysfunction may be a prime mediator. However, large clinical trials of therapeutic antioxidants such as vitamins C and E for the treatment of preeclampsia have been disappointing. L-(+)-ergothioneine (ERG)-an unusual amino acid betaine derived from histidine-has important cytoprotective and antioxidant properties under conditions of high oxidative stress. In this study, we investigated the potential therapeutic effects of administration of ERG in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. ERG (25 mg/kg per day) was administered to rats on gestational day 11. On gestational day 14, RUPP surgery was performed, and on gestational day 19, blood pressure (mean arterial pressure) and fetal growth were measured. Production of mitochondria-specific H2O2 was analyzed in vivo in kidney samples. ERG ameliorated the hypertension (129±3 versus 115±4 mm Hg; P=0.01; n=8) and significantly increased pup weight in RUPP rats. ERG also significantly decreased circulating levels of antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) in RUPP rats (1367±245 pg/mL; P=0.04). Mitochondria-specific H2O2 (0.022±0.003 versus 0.029±0.001; MitoP/B ratio, n=3; P=0.05) was also significantly decreased in kidney tissue in RUPP rats treated with ERG. These data support the potential use of ERG for the treatment of preeclampsia.

Comparing levels of vitamin D, calcium and phosphorus in normotensive pregnant women and pregnant women with preeclampsia.

Vitamin D and calcium deficiency have been reported as one of the causes of preeclampsia. In this study, levels of vitamin D, calcium and phosphorus were evaluated in 51 normotensive pregnant women and 52 women with preeclampsia at the gestational age between 28 and 36 weeks in Tabriz. Logistic regression and general linear models were used for comparing levels and means of vitamin D, calcium and phosphorus between the two groups adjusting for education and Body Mass Index (BMI). The results showed that mean serum vitamin D (p = .73), calcium (p = .12) and phosphorus (p = .60) levels were not significantly different between the groups after adjusting for education and BMI. Based on this study, no relationship was observed between vitamin D deficiency and preeclampsia; however, it was seen that the hypocalcaemia could increase the risk of preeclampsia up to 8.5 times. Based on our results and the literature, it seems that further studies need to be done to provide more insights into this area.Impact statementWhat is already known on this subject? Preeclampsia is one of the three leading causes of maternal morbidity and mortality worldwide. Despite the importance of preeclampsia, the causes and methods of prevention of this disease are still unknown. Deficiency of vitamin D affects the calcium balance of mothers and fetuses and has also been reported as one of the causes of preeclampsia disease. Reducing serum calcium can lead to increased blood pressure in preeclamptic women. Changes in calcium metabolism during pregnancy could be one of the potential causes of preeclampsia. Although the association of vitamin D, calcium and phosphorus with preeclampsia have been discussed previously, the results are not consistent.What do the results of this study add? The results showed that mean serum vitamin D, calcium and phosphorus levels were not significantly different between the groups.What are the implications of these findings for clinical practice and/or future research? Based on this study, no relationship was observed between vitamin D deficiency and preeclampsia; however, it was seen that the hypocalcaemia could increase the risk of preeclampsia by up to 8.5 times. Based on our results and the literature, it seems that further studies need to be done to provide more insights into this area.

Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Ameliorative effects of pre-eclampsia by quercetin supplement to aspirin in a rat model induced by L-NAME.

As an inflammatory disease, pre-eclampsia is correlated with elevation of pro-inflammatory cytokines and maternal endothelial dysfunction. Aspirin plays an important role in the prevention and therapy of pre-eclampsia. Quercetin is a bioflavonoid which has anti-oxidant and reno-protective abilities. We aimed to figure out the effects of quercetin supplement to aspirin on the therapy against pre-eclampsia. Female pregnant Sprague-Dawley rats were divided into five groups according to the drug treatment. Aspirin [1.5 mg/kg body weight (BW)] or quercetin (2 mg/kg BW) treatment was administered from gestational day (GD) 4 to GD19. Rat model of pre-eclampsia was induced by NG-nitro-Larginine-methyl-ester (L-NAME). In pre-eclampsia rats induced by L-NAME, systolic blood pressures (SBP), proteinuria, malonyldialdehyde (MDA), and inflammatory cytokines levels were decreased by the treatment of quercetin supplement to aspirin. In the uterus, quercetin supplement to aspirin prevented the expression of VEGF and sFlt-1 mRNA. The treatment of quercetin supplement to aspirin rescued the declined survival rate and weight of pups caused by L-NAME-induced pre-eclampsia. Based on our study, compared with the treatment of aspirin alone, quercetin supplement to aspirin enhanced the therapeutic effects of aspirin on pre-eclampsia rats induced by L-NAME.

Update on oxidative stress and inflammation in pregnant women, unborn children (nasciturus), and newborns - Nutritional and dietary effects.

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.

Radicals, Oxidative/Nitrosative Stress and Preeclampsia.

Preeclampsia (PE) has a profound effect in increasing both maternal and fetal morbidity and mortality especially in third World. Disturbances of extravillous trophoblast migration toward uterine spiral arteries is characteristic feature of PE, which, in turn, leads to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Underlying pathogenesis appeared to be an altered bioavailability of nitric oxide (NO•) and tissue damage caused by increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The increase in ROS and RNS production or the decrease in antioxidant mechanisms generates a condition called oxidative and nitrosative stress, respectively, defined as the imbalance between pro- and antioxidants in favor of the oxidants. Additionally, ROS might trigger platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. As a consequence of these disorders could result in deficiencies in oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the one hand, enzymatic and nonenzymatic antioxidants scavenge ROS and protect tissues against oxidative damage. More specifically, placental antioxidant enzymes including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) protect the vasculature from ROS, maintaining the vascular function. On the other hand, ischemia in placenta in PE reduces the antioxidant activity. Collectively, the extent of oxidative stress would increase and therefore leads to the development of the pathological findings of PE including hypertension and proteinuria. Our goal in this article is to review current literature about researches demonstrating the interplay between oxidative, nitrosative stresses and PE, about their roles in the pathophysiology of PE and also about the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.

Parturient on Magnesium Infusion and Its Effectiveness as an Adjuvant Analgesic after Cesarean Delivery: A Retrospective Analysis.

BACKGROUND: Perioperative use of intravenous magnesium as part of multimodal analgesia has been increasing in recent years in an effort to decrease the use of opioids. The aim of this study was to evaluate the effectiveness of magnesium sulfate infusion in lowering analgesic requirement and decreasing the intensity of pain score after cesarean delivery. METHODS: Sixty-four patients who underwent cesarean delivery under spinal anesthesia were included in this medical record review: 32 patients received magnesium infusion after cesarean delivery for treatment of mild preeclampsia (Mg group); 32 patients received routine post-cesarean delivery care (control group). Primary outcome was total analgesic consumption and secondary was visual analogue scores (VAS) of pain in each group during the first 24 hours following delivery. These measures were compared using Student's t-tests and Mann-Whitney U-tests. RESULTS: Our study found that patients in the Mg group had significantly less requirement for analgesia than the control group. In the 24 h after cesarean delivery, the Mg group received significantly less intravenous ketorolac (the standard initial rescue analgesic agent) when compared to the control group (79 ± 23 mg vs. 90 ± 0 mg; P = 0.008). The Mg group also received significantly less intravenous morphine equivalents than the control group (median 5.0 (IRQ: 0.0 - 10.0) vs. 9.3 (IRQ: 6.0 - 21.1); P = 0.001) during the first 24 h after cesarean delivery. The Mg group also had significantly lower VAS pain scores than the control group (median 1.75 (IRQ: 0.4 - 2.6) vs. median 3.2 (IRQ: 2.3 - 4.5); P < 0.001). CONCLUSIONS: Our results suggest that magnesium sulfate infusion decreases total analgesic requirements and lowers VAS pain scores during the first 24 h after cesarean delivery.

Flow mediated dilatation of Taiwanese women with normal singleton pregnancies.

OBJECTIVE: To determine the normal values of flow mediated dilatation (FMD) in Taiwanese women with normal singleton pregnancies for the early detection of preeclampsia. MATERIALS AND METHODS: Data of women with normal singleton pregnancies seen at the Tri-Service General Hospital and Taiji Clinic between January 2014 and December 2015 were collected and analyzed. FMD was measured using high-resolution ultrasonography of the brachial artery for the assessment of endothelial function at the first and second trimester. The relationship between the FMD values and maternal gestational age was analyzed. RESULTS: A total of 122 pregnant women were included in the study. Systole FMD values first and second trimester were 9.05 ± 3.72 and 10.93 ± 3.74, respectively; and the diastole were 9.24 ± 3.64 and 11.18 ± 3.93, respectively. FMD and gestational age were positively correlated (systole, p = 0.0175; diastole, p = 0.0149). CONCLUSION: The normal values of FMD in Taiwanese women with normal singleton pregnancies were established, and data suggests that both systolic and diastolic FMD increase with gestational age. Because of the high failure rate, measurement of FMD may not be suitable as a routine clinical examination.

Oral antioxidant therapy for prevention and treatment of preeclampsia: Meta-analysis of randomized controlled trials.

AIMS: To determine whether oral antioxidant therapies, of various types and doses, are able to prevent or treat women with preeclampsia. DATA SYNTHESIS: The following databases were searched: MEDLINE, CENTRAL, LILACS, and Web of Science. Inclusion criteria were: a) randomized clinical trials; b) oral antioxidant supplementation; c) study in pregnant women; d) control group, treated or not with placebo. Papers were excluded if they evaluated antioxidant nutrient supplementation associated with other non-antioxidant therapies. Data were extracted and the risk of bias of each study was assessed. Heterogeneity was analyzed using the Cochran Q test, and I2 statistics and pre-specified sensitivity analyses were performed. Meta-analyses were conducted on prevention and treatment studies, separately. The primary outcome was the incidence of preeclampsia in prevention trials, and of perinatal death in treatment trials. Twenty-nine studies were included in the analysis, 19 for prevention and 10 for treatment. The antioxidants used in these studies were vitamins C and E, selenium, l-arginine, allicin, lycopene and coenzyme Q10, none of which showed beneficial effects on the prevention of preeclampsia (RR: 0.89, CI 95%: [0.79-1.02], P = 0.09; I2 = 39%, P = 0.04) and other outcomes. The antioxidants used in the treatment studies were vitamins C and E, N-acetylcysteine, l-arginine, and resveratrol. A beneficial effect was found in intrauterine growth restriction. CONCLUSIONS: Antioxidant therapy had no effects in the prevention of preeclampsia but did show beneficial effects in intrauterine growth restriction, when used in the treatment of this condition.