Maternal vitamin D status and risk of gestational diabetes mellitus in twin pregnancies: a longitudinal twin pregnancies birth cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, with significant short-term and long-term implications for both mothers and their offspring. Previous studies have indicated the potential benefits of vitamin D in reducing the risk of GDM, yet little is known about this association in twin pregnancies. This study aimed to investigate maternal vitamin D status in the second trimester and examine its association with the risk of GDM in twin pregnancies. METHODS: We conducted a prospective cohort study based on data from the Chongqing Longitudinal Twin Study (LoTiS). Peripheral blood serum was collected from the mothers in the second trimester to measure 25(OH)D concentrations. GDM was diagnosed at 23-26 weeks of gestation using a 75-g 2-h oral glucose tolerance test. We used multivariable logistic regression analyses to examine the correlations between vitamin D status and the risk of GDM. RESULTS: Of the total participants, 93 (29.9%) women were diagnosed with GDM. The mean serum 25(OH)D concentration in the second trimester was 31.1 ± 11.2 ng/mL, and the rate of vitamin D insufficiency and deficiency were 23.5% and 18.7%, respectively. Compared to women with a 25(OH)D concentration < 30 ng/mL, those with a 25(OH)D concentration ≥ 30 ng/mL had a significantly lower risk of GDM (RR 0.61; 95% CI: 0.43, 0.86), especially those who were overweight before pregnancy (RR 0.32; 95% CI: 0.16, 0.64). The restricted cubic splines model showed an inverted J-shaped relationship between vitamin D concentrations and GDM risk. CONCLUSIONS: The risk of GDM was significantly reduced in twin pregnant women with vitamin D concentrations ≥ 30 ng/mL in the second trimester. TRIAL REGISTRATION: ChiCTR-OOC-16,008,203. Retrospectively registered on 1 April 2016.

The effects of gestational diabetes mellitus with maternal age between 35 and 40 years on the metabolite profiles of plasma and urine.

BACKGROUND: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35-40 years at early and late gestation. METHODS: Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS). RESULTS: One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester. CONCLUSION: This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35-40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age.

[Glucose Metabolism-Derived Nicotinamide Adenine Dinucleotide Phosphate in Late-Onset Preeclampsia Placenta Tissue and Its Correlation with Oxidative Stress].

Objective: To study the changes in the expression of nicotinamide adenine dinucleotide phosphate (NADPH), a glucose metabolism-derived antioxidant, in late-onset preeclampsia (LOPE) placenta tissue and the correlation with oxidative stress. Methods: A total of 13 normal pregnant women and 13 pregnant women with LOPE who were hospitalized in the Obstetrics Department, the First Affiliated Hospital of Chongqing Medical University and who underwent elective cesarean section between November 2020 and October 2021 were included in the study. Placenta tissues were collected from the subjects. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was done to determine the ROS levels in the placenta tissues of the LOPE group and the normal control group. Spectrophotometric analysis was conducted to determine the levels of NADPH, glutathione (GSH), and glucose, and the expressions and activities of glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD), key rate-limiting enzymes of the pentose phosphate pathway (PPP), in the placenta tissues of the LOPE group and the normal control group. Western blot was done to determine changes in the protein expressions of phosphofructokinase 1 (PFK1), a key rate-limiting enzyme of the glycolytic pathway, G6PD, and PGD in the placenta tissues from the two groups. Results: ROS levels in the placenta tissue of the LOPE group were significantly higher than those of the control group ( P<0.05). The levels of NADPH and GSH, two antioxidants, and glucose in the LOPE placenta were significantly higher than those of the control group ( P<0.05). The expression of PFK1 was significantly elevated in the LOPE group ( P<0.05). However, there were no significant differences in the activities and protein expression of G6PD and PGD between the two groups. Conclusion: Glucose metabolism reprogramming takes place in LOPE placenta tissue, which may be one of the causes of the abnormal elevation of NADPH and GSH.

LRP6 regulates Rab7-mediated autophagy through the Wnt/ß-catenin pathway to modulate trophoblast cell migration and invasion.

Pre-eclampsia is a common complication during pregnancy; however, the underlying mechanisms of the crosstalk between low-density lipoprotein receptor-related protein 6 (LRP6) and autophagy in trophoblast cells are still not fully explored. Messenger RNA (mRNA) and protein levels of LRP6, beclin 1, Unc-51-like autophagy activating kinase 1 (ULK1), p62, vimentin, matrix metallopeptidase-9 (MMP-9), ß-catenin, c-Myc, and Rab7, as well as the ratio of LC3-II/LC3-I, were analysed by quantitative real-time polymerase chain reaction or Western blot analysis, respectively. An MTT assay was used to measure cell growth, and transwell and wound healing assays were carried out to evaluate the invasion and migration abilities of the trophoblasts used. An immunofluorescence assay was used to measure LC3. The mRFP-GFP-LC3 tandem fluorescence assay was applied to detect autophagic flow. LRP6 overexpression was achieved by constructing pcDNA3.1-LRP6 vectors. LRP6 was expressed at low levels in HTR-8/SVneo cells under hypoxia/reoxygenation (H/R) conditions. H/R inhibited the activation of autophagy. LRP6 overexpression promoted cell proliferation and activated autophagy, which led to the upregulation of beclin 1 and ULK1, as well as the ratio of LC3-II/LC3-I and the downregulation of p62. Furthermore, LRP6 overexpression elevated the migration and invasion abilities of the indicated cells and increased vimentin and MMP-9 expression levels. Furthermore, LRP6 upregulated Rab7 and activated autophagy through the Wnt/ß-catenin pathway. The late autophagy inhibitor bafilomycin A1 (Baf-A1) and the Wnt/ß-catenin pathway inhibitor PKF115-584 reversed the effects of LRP6 on trophoblast autophagy, migration and invasion. LRP6 promotes Rab7-mediated autophagy by activating the Wnt/ß-catenin pathway, which leads to increasing migration and invasion of trophoblast cells. Our study paves a new avenue for clinical treatment, and LRP6 may serve as an essential target in pre-eclampsia.

Preterm Birth in China Between 2015 and 2016.

Objectives. To describe the incidence, risk factors, and potential causes of preterm birth (PTB) in China between 2015 and 2016.Methods. The China Labor and Delivery Survey was a population-based multicenter study conducted from 2015 to 2016. We assigned each birth a weight based on the sampling frame. We calculated the incidence of PTB and the multivariable logistic regression, and we used 2-step cluster analysis to examine the relationships between PTB and maternal, fetal, and placental conditions.Results. The weighted nationwide incidence of PTB was 7.3% of all births and 6.7% of live births at 24 or more weeks of gestation. Of the PTBs, 70.5% were born after 34 weeks and 42.7% were iatrogenic. Nearly two thirds of all preterm births were attributable to maternal, fetal, or placental conditions, and one third had unknown etiology.Conclusions. This study provided information on the incidence of PTB in China and identified several factors associated with PTB. The high frequency of iatrogenic PTB calls for a careful assessment and prudent management of such pregnancies, as PTB has short- and long-term health consequences.

Down-Regulation of Laminin (LN)- α5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway.

BACKGROUND/AIMS: Preeclampsia (PE) is a gestational disorder defined as hypertension and proteinuria, which is deemed a major cause of maternal and neonatal mortality and morbidity worldwide. The aim of this study was to investigate the expression patterns of placental laminin (LN)-α5 expression in normal and PE pregnancies, as well as evaluating the effects of LN-α5 on trophoblast proliferation, apoptosis, and invasion. METHODS: LN-α5 expression levels were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), and further confirmed by western blotting and immunofluorescence staining. Cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry. Cell invasion was assessed by matrigel-based transwell assay. LN-α5 DNA methylation in placentas was determined by bisulfite sequencing PCR (BSP). RESULTS: LN-α5 expression levels in PE placentas were significantly lower than that of normal pregnancies. Deficiency in LN-α5 expression resulted in decreased trophoblast proliferation and invasion but increased cell apoptosis, meanwhile, PI3K/AKT/mTOR signaling pathway was impaired by LN-α5 silencing. LN-α5 promoter methylation didn't show significant difference between PE and normal placentas. CONCLUSION: LN-α5 downregulation is associated with PE placenta and impairs trophoblast viability and invasiveness, which could be a causative factor of PE pathogenesis.

MiR-200a is involved in proliferation and apoptosis in the human endometrial adenocarcinoma cell line HEC-1B by targeting the tumor suppressor PTEN.

Abnormal cell proliferation is a main driver of tumor formation and development, which involves the deletion, mutation, and downregulation of tumor suppressor genes. One study recently demonstrated that miR-200a plays an oncogenic role by inhibiting phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression. In the human endometrial adenocarcinoma cell line HEC-1B, suppression of miR-200a expression inhibited cell proliferation and promoted apoptosis, whereas its over-expression had no effect on proliferation and apoptosis. Furthermore, inhibition or over-expression of miR-200a increased or reduced the expression of PTEN, respectively, with no change in PTEN mRNA levels. These effects were achieved by directly targeting miR-200a to the 3' untranslated region of the PTEN mRNA to inhibit its translation. Taken together, we propose that in HEC-1B cells, miR-200a functions as an oncogene, affecting proliferation and apoptosis by regulating the expression of the tumor suppressor PTEN at the translational level.

Comparative study of placental α-microglobulin-1, insulin-like growth factor binding protein-1 and nitrazine test to diagnose premature rupture of membranes: a randomized controlled trial.

AIM: The aim of this study was to compare the accuracy of placental α-microglobulin-1 (PAMG-1), insulin-like growth factor binding protein-1 (IGFBP-1) and nitrazine test to diagnose premature rupture of membranes. MATERIAL AND METHODS: A total of 120 pregnant women between 11 and 42 weeks with signs/symptoms of membrane rupture were eligible for our study. These women were evaluated with the PAMG-1, IGFBP-1, and nitrazine tests. RESULTS: In the 120 women, the sensitivity, specificity, positive predictive value, and negative predictive value of PAMG-1, IGFBP-1 and nitrazine test were 100%, 100%, 100%, and 100%, 93.33%, 98.89%, 96.55% and 97.80%, and 93.33%, 94.44%, 84.85%, and 97.7%, respectively. In a comparison of the PAMG-1 test and the nitrazine test, positive coincidence rate was 84.85%, negative coincidence rate was 97.70%, total coincidence rate was 94.17%, and kappa value was 0.85. In a comparison of the PAMG-1 test and the IGFBP-1 test, the positive coincidence rate, negative coincidence rate and total coincidence rate were 96.55%, 97.80%, and 97.50%, and kappa value was 0.93. CONCLUSION: PAMG-1 assay was the most accurate method to diagnose premature rupture of membranes with the highest sensitivity, specificity, positive predictive value and negative predictive value.

Endothelial progenitor cells control remodeling of uterine spiral arteries for the establishment of utero-placental circulation.

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.

[Analysis of clinical characteristics and perinatal outcome of early-onset intrahepatic cholestasis of pregnancy].

OBJECTIVE: To analyze the clinical characteristics and perinatal outcome of early-onset intrahepatic cholestasis of pregnancy (ICP). METHODS: A total of 305 ICP cases were collected in the First Affiliated Hospital of Chongqing Medical University between June 2006 and May 2012. According to the onset time of ICP, patients were divided into early-onset ICP group (onset time < 28 gestational weeks) and late-onset ICP group (onset time ≥ 28 gestational weeks). The late-onset ICP group was further divided into 28 - 31(+6) gestational weeks and ≥ 32 gestational weeks according to the onset time. The biochemical indices and perinatal outcome of each group were assessed. RESULTS: (1) When the diagnosis was made for the first time, the maternal serum concentrations of total bile acid (TBA) and total bilirubin (TBIL) in early-onset ICP group were (41 ± 9) and (32 ± 9) µmol/L, respectively; while TBA and TBIL in late-onset ICP group were (32 ± 6) and (22 ± 9) µmol/L, and the difference between the two groups was statistically significant (P < 0.05). (2) There was no significant difference in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) between early-onset ICP group and late-onset ICP group (P > 0.05). The ALT of early-onset ICP group and late-onset ICP group were (159 ± 50) and (145 ± 52) U/L, respectively; and AST were (151 ± 49) and (138 ± 44) U/L, respectively. (3) The early-onset ICP group had significant higher (P < 0.05) incidence of meconium staining (18.8% vs. 7.4%), fetal distress (22.9% vs. 8.9%), newborn asphyxia (14.6% vs. 5.4%), premature delivery (33.3% vs. 15.6%), developing into severe ICP (41.7% vs. 25.3%) and cesarean section (91.7% vs. 78.6%) when compared to the late-onset ICP group. No significant difference in the incidence of premature delivery, developing into severe ICP and cesarean section was found between the two types of late-onset ICP. (4) There was significant differences in average birth weight and gestational weeks at delivery between the two groups [early-onset ICP group: (3113 ± 443) g and (36.3 ± 2.6) weeks]; late-onset ICP group: [(3513 ± 450) g and (37.7 ± 1.6) weeks]. CONCLUSION: The early-onset ICP patients presented worse clinical manifestations than late-onset ICP patients, and early-onset ICP is more likely to lead to premature delivery and fetal distress.

[Expression of KLF-8 and MMP-9 in placentas and their relationship with the pathogenesis of preeclampsia].

OBJECTIVE: To evaluate the expression of Krüppel-like factor 8 (KLF-8) and matrix metalloproteinase 9 (MMP-9) in placentas and their relationship with the pathogenesis of preeclampsia (PE). METHODS: Twenty-two women with PE(mild PE:4 cases; severe PE:18 cases) who received cesarean sections in the First Affiliated Hospital of Chongqing Medical University from September 2011 to March 2012 were recruited as the PE group (n = 22). And twenty women who received elective term cesarean section without perinatal complications were chosen as the control group (n = 20). Placentas were collected and immunohistochemical SP method were employed to detect the localization of KLF-8 protein.KLF-8 mRNA level was determined by quantitative real-time PCR technique and western blot analysis was used to quantify KLF-8 and MMP-9 protein levels. RESULTS: (1) There was no difference of KLF-8 protein distribution in placentas of the PE group and the control group.It was mainly located in the nuclear and cytoplasm of syncytiotrophoblasts.KLF-8 immunostaining was apparently decreased in the placentas of preeclamptic women when compared with the control group.(2)The KLF-8 mRNA levels were significantly decreased in placentas of the PE group (0.69 ± 0.08) compared to those of the control group (1.14 ± 0.09, P < 0.01). (3) KLF-8 and MMP-9 protein levels significantly decreased in the PE placentas (0.68 ± 0.05 and 0.21 ± 0.03) when compared to the control group (0.94 ± 0.06 and 0.34 ± 0.03, respectively, P < 0.01).(4) There was a positive correlation between the expression of KLF-8 and MMP-9 protein in the placentas from PE and normal pregnancies (r = 0.64, P < 0.01). CONCLUSIONS: KLF-8 mRNA and protein levels were decreased in placentas of PE patients compared to those of normotensive women.KLF-8 protein was primarily located in the invasion-related trophoblast cells and its expression had a positive correlation with MMP-9 levels.KLF-8 might have an important role in the pathogenesis of PE by regulation of trophoblast invasion.

The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis.

UNLABELLED: can improve the rates of clinical pregnancy and live birth, but the optimal duration of treatment remains controversial. The objective of this meta-analysis was to investigate the effects of early progesterone cessation on pregnancy outcomes in women undergoing IVF/ICSI. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese biomedicine (CBM) literature database, and the Wanfang database. The final search was performed in July 2012. All available randomised trials that compared the effects of early progesterone cessation with progesterone continuation during early pregnancy after IVF/ICSI were included. The main outcome measures were live birth rate, miscarriage rate and ongoing pregnancy rate. Fixed or random-effects models were chosen to calculate the risk ratio (RR). RESULTS: Six eligible studies with a total of 1,201 randomised participants were included in the final analysis. No statistically significant differences were detected between patients who underwent early progesterone cessation and those who received progesterone continuation for luteal phase support in terms of live birth rate (RR: 0.95, 95% CI: 0.86-1.05), miscarriage rate (RR: 1.01, 95% CI: 0.74-1.38) or ongoing pregnancy rate (RR: 0.97, 95% CI: 0.90-1.05). These results did not change after a sensitivity analysis. CONCLUSIONS: The currently available evidence suggests that progesterone supplementation beyond the first positive hCG test after IVF/ICSI might generally be unnecessary, although large-scale randomised controlled trials are needed to strengthen this conclusion.

The expression of pentraxin 3 and tumor necrosis factor-alpha is increased in preeclamptic placental tissue and maternal serum.

OBJECTIVE: To evaluate the expression of pentraxin 3 (PTX3) and tumor necrosis factor-alpha (TNF-α) in preeclampsia. METHODS: Twenty-two preeclamptic patients, six preeclamptic patients with intrauterine growth restriction (IUGR) and 30 women with uncomplicated pregnancies were included in this study. The expression of PTX3 and TNF-α in placental tissue was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western immunoblotting. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of PTX3 and TNF-α in maternal sera. The localization and immunoreaction of PTX3 and TNF-α in placenta were determined via immunohistochemistry (IHC). RESULTS: Expression of PTX3 and TNF-α in placental tissues and maternal sera was significantly increased in preeclamptic patients, as well as in those with IUGR. PTX3 was mainly expressed in villous stroma, decidual cells and terminal villi, and TNF-α was mostly localized in trophoblast, vascular endothelial cells, decidual cells and in the stroma of the stem villi. Moreover, PTX3 expression was correlated with TNF-α expression in maternal sera of preeclamptic women. CONCLUSIONS: PTX3 and TNF-α are increased in preeclampsia and are likely involved in the pathogenesis of preeclampsia.

[Expression of pentraxin-3 in placentas and its relationship with severe preeclampsia].

OBJECTIVE: To explore the expression of pentraxin-3 (PTX3) in placentas from patients with severe preeclampsia and the relationship between PTX3 and the pathogenesis of severe preeclampsia. METHODS: Fifty-three pregnant women who delivered from October 2010 to March 2011 in the First Affiliated Hospital of Chongqing Medical University were included in the study. Twenty-three women with severe preeclampsia were chosen as the preeclampsia group, and thirty healthy pregnant women were identified as the control group. All the women received cesarean section. The location of PTX3 protein in placentas was studied by immunohistochemical SP method. Quantitative real-time PCR technique and western blot analysis were employed to assay the levels of PTX3 mRNA and protein in placentas, respectively. RESULTS: (1) The location of PTX3 protein in placentas: PTX3 protein was expressed in placentas from both groups, and there was no difference of PTX3 distribution between normal and preeclamptic placentas. PTX3 was mainly located in perivascular stroma, decidual cells and terminal villi. Neutrophilic infiltration was observed in the preeclamptic placentas. (2) The expression of PTX3 mRNA and protein in placentas:the level of PTX3 mRNA in placentas from the preeclampsia group was higher than that in the control group (1.98 ± 0.54 vs. 0.87 ± 0.27, P < 0.05). Compared with the control group, the level of PTX3 protein was significantly elevated in the preeclampsia group (1.42 ± 0.29 vs. 0.56 ± 0.25, P < 0.01). CONCLUSION: The high expression of PTX3 in placentas from the preeclamptic patients suggests that PTX3 may be involved in the pathologic process of preeclampsia.

An Investigation of the Relationship Between Dietary Patterns in Early Pregnancy and Maternal/Infant Health Outcomes in a Chinese Cohort.

Background: Studies assessing links between maternal diet and pregnancy outcomes have focused predominantly on individual nutrients or foods. However, nutrients are typically consumed in combinations of foods or beverages (i.e., dietary patterns). Taking into account the diet as a whole appreciates that nutrient absorption and metabolism are influenced by other nutrients and the food matrix. Objective: The aim of this study was to investigate the relationship between dietary pattern consumption in early pregnancy and pregnancy/infant outcomes, including gestational diabetes mellitus, gestational weight gain, preeclampsia, placental weight, gestational age at delivery, small-for-gestational-age, large-for-gestational-age, macrosomia, measures of infant body composition, and scores on two main indices of the Bayley Scales of Infant Development [Mental Development Index (MDI) and the Psychomotor Development Index (PDI)] at 12 months. Design: Our study included 1,437 participants from a mother-infant cohort in Chongqing, China. Maternal diet was assessed using a 96-item food frequency questionnaire at 11-14 weeks gestation. Dietary patterns were constructed using principal component analysis. Multivariate regressions were performed to assess associations between maternal dietary pattern scores and pregnancy and infant outcomes, adjusting for confounders. Results: Two dietary patterns were derived: a pattern high in pasta, sweetened beverages, and oils and condiments (PSO-based dietary pattern) and a pattern high in fish, poultry, and vegetables (FPV-based dietary pattern). Higher scores on the PSO-based dietary pattern were associated with lower infant standardized scores on the PDI of the Bayley Scales of Infant Development, ß (95% confidence interval) = -1.276 (-2.392, -0.160); lower placental weight, ß (95% CI) = -6.413 (-12.352g, -0.473); and higher infant's tricep skinfold thickness at 6 weeks of age. ß (95% CI) = 0.279 (0.033, 0.526). Higher scores on the FPV-based dietary pattern were associated with higher gestational weight gain between visit 1 (11-14 week's gestation) and 3 (32-34 week's gestation). ß (95% CI) = 25.612 (13.255, 37.969). No significant associations were observed between dietary pattern scores and the remaining pregnancy/infant outcomes investigated or MDI scores on the Bayley Scales of Infant Development. This was the first study to investigate the association between dietary patterns in early pregnancy and infant neurocognition in a Chinese cohort.

Measuring maternal body composition by biomedical impedance can predict risk for gestational diabetes mellitus: a retrospective study among 22,223 women.

OBJECTIVES: This study aimed to identify which element of body composition measurements taken before 17th week gestation was the strongest risk factor for gestational diabetes mellitus (GDM) in Chinese pregnant women. DESIGN AND SETTING: A retrospective study was performed using data retrieved from the Electronic Medical Record database of Chongqing Health Center for Women and Children (China) from January 2014 to December 2015. PARTICIPANTS: A total of 22,223 women were included with singleton pregnancies and no preexisting diabetes who underwent bioelectrical impedance analysis (BIA) before 17 gestational weeks and 75-g OGTT at 24-28 gestational weeks. RESULTS: The prevalence of GDM from 2014 to 2015 was 27.13% (IADPSG). All indicators of BIA (total body water, fat mass, fat-free mass, percent body fat, muscle mass, visceral fat levels, proteins, bone minerals, basal metabolic rate, lean trunk mass), age, weight and body mass index (BMI) were risk factors that significantly increased the occurrence of GDM (p < .001 for all). Women older than 30 years or with a BMI more than 23, had a significantly higher GDM prevalence (34.89% and 34.77%). After adjusted covariates, visceral fat levels at the third quartile, the ORs of GDM were 1.142 (95% CI 1.032-1.263) in model I and 1.419 (95% CI 1.274-1.581) in model II used the first quartile as reference (p < .05 for both); bone minerals at the third quartile, the ORs of GDM were 1.124 (95% CI 1.020-1.238) in model I and 1.311 (95% CI 1.192-1.442) in model II (p < .05 for both). After adjusted for age, visceral fat levels and bone minerals, OR of GDM for percent body fat more than 28.77% at the third quartile was 1.334 (95% CI 1.201-1.482) in model II (p < .05 for both). CONCLUSIONS: Visceral fat levels, bone minerals and percent body fat were significantly associated with an increased risk of GDM, providing the reference ranges of visceral fat levels, bone minerals and percent body fat as predictive factors for Chinese women to estimate the risk of GDM by BIA during pregnancy.

Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia.

Preeclampsia (PE) is known to be associated with increased circulating levels of anti-angiogenic factors, such as soluble fms-related tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). However, the way that placental oxidative stress results in the elevation of these two factors remains enigmatic. We have observed the overexpression of growth arrest and DNA damage-inducible 45 alpha (Gadd45α) and excessive activation of p38 mitogen-activated protein kinase (MAPK) in preeclamptic placentas compared with normotensive controls, together with increased levels of sFlt-1 and sEng in maternal sera in patients with PE. Moreover, Gadd45α knockdown or p38 inhibition provides protective effects in hypoxia/reoxygenation (H/R)-exposed human umbilical vein endothelial cells (HUVECs) by suppressing oxidative stress, inhibiting apoptosis, and promoting their potential for in vitro angiogenesis. A regulatory signaling pathway in which H/R intervention causes the induction of Gadd45α leading to p38 activation and ultimately an increase in sFlt-1 and sEng secretion in HUVECs has concurrently been established. Our study opens up a promising new avenue of investigation for increasing the understanding of the origin of sFlt-1 and sEng in PE and provides novel therapeutic targets for pregnancy complications arising from placental endothelial dysfunction.

[Study on p38 mitogen activated protein kinase in vascular endothelial cells dysfunction in preeclampsia].

OBJECTIVE: To study expression and activation of p38 mitogen activated protein kinase (MAPK) in vascular endothelial cells dysfunction in preeclampsia. METHODS: From Sept. 2009 to Mar. 2010, 54 pregnant women underwent deliveries in the First Affiliated Hospital of Chongqing Medical University were enrolled in this study, including 20 patients in mild preeclampsia group, 16 patients in severe preeclampsia group and 18 women with term cesarean section without perinatal complications as control group. Placental endothelial cells were labeled by CD34 to assay microvessel density (MVD) of each group. Immunohistochemical SP and western blot were used to detect localization and expression of p-p38 MAPK protein, respectively. The levels of sera soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured by ELISA. RESULTS: (1) The MVD of placenta were 103 ± 3 in control group, 81 ± 5 in mild preeclampsia group and 63 ± 4 in severe group, respectively, which showed statistical difference among each group (P < 0.05). (2) The expression of p38 MAPK protein were 0.84 ± 0.05 in control group, 0.90 ± 0.14 in mild group and 0.86 ± 0.18 in severe group, which did not reach remarkable difference among each group (P > 0.05). The expression of p-p38 MAPK protein were 0.13 ± 0.05 in control group, 0.59 ± 0.12 in mild group and 1.16 ± 0.18 in severe group, which show statistical difference among each group (P < 0.05). (3) The localization of p-p38 was in trophoblast, endothelial cells and a few stromal cells in placenta. (4) The level of sFlt-1 and sEng: (1) The concentration of sFlt-1 and sEng were (5.2 ± 0.3) and (10.9 ± 0.4) µg/L in control group, (12.5 ± 1.2) and (20.4 ± 5.3) µg/L in mild group and (19.3 ± 3.0) and (29.5 ± 3.7) µg/L in severe group. When drawing paired comparison in those groups, the differences showed statistical difference (P < 0.05). (2) There were positive correlations between p-p38 MAPK protein levels and the concentrations of serum sFlt-1, sEng in preeclampsia groups (r = 0.68, P < 0.05; r = 0.87, P < 0.05). CONCLUSIONS: The remarkable activation of the p38 MAPK in the placenta of patients with preeclampsia induced the increased levels of sFlt-l and sEng in maternal serum, which confer the injury of vascular endothelial cells that caused the significant decline of MVD in placentas. p38 MAPK signaling might be one of the key pathways in vascular endothelial cell dysfunction in preeclampsia.

The role of umbilical artery velocities in the clinical assessment of twin-twin transfusion syndrome at stage.

OBJECTIVE: To analyze the discordances of the umbilical artery velocities between pregnancies with twin-twin transfusion syndrome (TTTS) at stage I and those with normal monochorionic-diamniotic (MCDA) twins, and investigate the value of their discordances in predicting TTTS at stage I. METHODS: We recruited 58 twin pregnancies with TTTS at stage I and 60 normal MCDA twin pregnancies in a tertiary referral center retrospectively. The umbilical artery velocities and their discordances were compared between the normal and TTTS twins. RESULTS: The discordances of umbilical artery mean diastolic velocity (UA-MDV), umbilical artery time-averaged maximum velocity (UA-TAmax), umbilical artery peak systolic velocity (UA-PSV), and umbilical artery end-diastolic velocity (UA-EDV) were higher in the TTTS group than in the normal group. In TTTS co-twins, the UA-MDV, UA-TAmax, UA-PSV, and UA-EDV in recipients were higher than those in donors. The discordances of UA-TAmax and UA-PSV were found to be independent predicting factors for TTTS at stage I. CONCLUSION: Co-twin umbilical artery velocity discordances were significantly associated with stage I TTTS. The results suggest that UA-TAmax and UA-PSV might be new parameters for predicting TTTS at stage I.

Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis.

Impaired invasion of extravillous trophoblasts and severe oxidative stress manifest the poor placentation in preeclampsia, which is life-threatening and more than a hypertensive disease of pregnancy. Previous studies have reported that G protein-coupled receptor kinases (GRKs) play a key role in initiating hypertension and hypertensive renal damage, yet little evidence so far suggests a link between GRKs and preeclampsia-related hypertension. Here, we demonstrate GRK2 expression is significantly downregulated (P < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis in vivo. These further induced preeclampsia-like phenotype in mice: hypertension, proteinuria, and elevated pro-angiogenic cytokines. By human extra-villous invasive trophoblast cell line (HTR8/SVneo cells), we revealed the knockdown or inhibition of GRK2 triggered excessive death with typical necroptotic characteristics: nuclear envelope rupture and the activation of RIPK1, RIPK3, and MLKL. Necrostatin-1, an inhibitor of RIPK1, is able to restore the survival of trophoblasts. Together, our findings demonstrated that insufficient GRK2 activity compromises spiral artery remodeling and initiates necrotic events in placentae, thereby leading to preeclampsia. These findings advance our understanding of GRK2 in the pathogenesis of preeclampsia and could shed light on a potential treatment for preeclampsia.