Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy

IntroductionThe prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR].MethodsWe obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays.ResultsMultivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level.DiscussionMaternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP.     

Pentoxifylline inhibits lipopolysaccharide-induced inflammatory mediators in human second trimester placenta explants

BackgroundIntrauterine infection and inflammation during pregnancy, which leads to up-regulation of inflammatory cytokines and prostaglandin synthesis, has been implicated in the pathogenesis of preterm delivery and other pregnancy complications. Effective preventive and therapeutic strategies to reduce these outcomes are lacking to date. Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate and decreases production of pro-inflammatory mediators while enhancing anti-inflammatory cytokines. We hypothesized that pentoxifylline will decrease lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production in human placental explants.MethodsPlacental explants derived from normal second trimester human placentas were treated with PTX, stimulated with LPS and cultured at 37 °C in 5% CO₂. Conditioned media were assayed for pro- and anti-inflammatory mediators with multiplex immunoassays or ELISA, and explant tissues for mRNA with real time PCR. Means of PTX-treated and untreated samples were compared using paired t tests and Wilcoxon-signed rank tests.ResultsPTX preferentially inhibited placental expression and production of LPS-induced pro-inflammatory cytokines including TNF-α (25461 vs. 1908 pg/ml, p < 0.001), IL-1β (2921 vs. 1067 pg/ml, p < 0.001) and IFN-γ (2190 vs 427 pg/ml, p < 0.001) with relative preservation of anti-inflammatory mediators. The suppressive effects on LPS-induced placental inflammation were independent of the timing of PTX administration in relation to LPS-induced stimulation.ConclusionOur study suggests that PTX attenuates the LPS-induced pro-inflammatory milieu in human placental explants. We speculate that PTX may have utility as a candidate anti-inflammatory agent for prophylaxis and/or treatment of human placental inflammation.     

Increased placental trophoblast inclusions in placenta accreta

IntroductionTrophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non-accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics.MethodsForty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta.ResultsForty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%).DiscussionPlacenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients.ConclusionThis study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs.     

Lipidomic analysis reveals the significant increase in diacylglycerophosphocholines in umbilical cord blood from pregnant women with gestational hypercholesterolemia

Gestational hypercholesterolemia has been recognized as a risk factor of some pregnancy complications. We supposed that maternal hypercholesterolemia modified the lipid profile of the fetus. Thirty pregnant women with hypercholesterolemia and matched controls were recruited and cord blood was sampled. Lipidomic analysis was used to evaluate the lipid profile change between the two groups. The results showed that the content of diacylglycerophosphocholines (PC) was significantly high in cord blood from hypercholesterolemic pregnant women. PC (16:0/20:4) and PC (18:0/20:4) were selected as the most important lipid species in cord plasma and their contents were positively related to the total cholesterol and high-density lipoprotein cholesterol levels in cord blood. The contents of these two PCs were significantly higher in the hypercholesterolemic group than in the control group. These results suggested that gestational hypercholesterolemia might program the phospholipid metabolism in offspring.     

Docosahexaenoic acid (DHA) accretion in the placenta but not the fetus is matched by plasma unesterified DHA uptake rates in pregnant Long Evans rats

Maternal delivery of docosahexaenoic acid (DHA, 22:6n-3) to the developing fetus via the placenta is required for fetal neurodevelopment, and is the only mechanism by which DHA can be accreted in the fetus. The aim of the current study was to utilize a balance model of DHA accretion combined with kinetic measures of serum unesterified DHA uptake to better understand the mechanism by which maternal DHA is delivered to the fetus via the placenta. Female rats maintained on a 2% α-linolenic acid diet free of DHA for 56 days were mated, and for balance analysis, sacrificed at 18 days of pregnancy, and fetus, placenta and maternal carcass fatty acid concentration were determined. For tissue DHA uptake, pregnant dams (14–18 days) were infused for 5 min with radiolabeled ¹⁴C-DHA and kinetic modeling was used to determine fetal and placental serum unesterified DHA uptake rates. DHA accretion rates in the fetus were determined to be 38 ± 2 nmol/d/g, 859 ± 100 nmol/d/litter and 74 ± 3 nmol/d/pup, which are all higher (P < 0.05) than the fetal serum unesterified DHA uptake rates of 16 ± 6 nmol/d/g, 239 ± 145 nmol/d/litter and 14 ± 8 nmol/d/pup. No differences (p > 0.05) in placental DHA accretion rates versus serum unesterified DHA uptake rates were observed as values varied only 6–35% between studies. No differences in placental accretion and uptake rates suggests that serum unesterified DHA is a significant pool for the maternal-placental transfer of DHA, and lower fetal DHA uptake compared to accretion supports remodeling of placental DHA for delivery to the fetus.     

Abnormal labyrinthine zone in the Hectd1-null placenta

IntroductionThe labyrinthine zone of the placenta is where exchange of nutrients and waste occurs between maternal and fetal circulations. Proper development of the placental labyrinth is essential for successful growth of the developing fetus and abnormalities in placental development are associated with intrauterine growth restriction (IUGR), preeclampsia and fetal demise. Our previous studies demonstrate that Hectd1 is essential for development of the junctional and labyrinthine zones of the placenta. Here we further characterize labyrinthine zone defects in the Hectd1 mutant placenta.MethodsThe structure of the mutant placenta was compared to wildtype littermates using histological methods. The expression of cell type specific markers was examined by immunohistochemistry and in situ hybridization.ResultsHectd1 is expressed in the labyrinthine zone throughout development and the protein is enriched in syncytiotrophoblast layer type I cells (SynT-I) and Sinusoidal Trophoblast Giant cells (S-TGCs) in the mature placenta. Mutation of Hectd1 results in pale placentas with frequent hemorrhages along with gross abnormalities in the structure of the labyrinthine zone including a smaller overall volume and a poorly elaborated fetal vasculature that contain fewer fetal blood cells. Examination of molecular markers of labyrinthine trophoblast cell types reveals increased Dlx3 positive cells and Syna positive SynT-I cells, along with decreased Hand1 and Ctsq positive sinusoidal trophoblast giant cells (S-TGCs).DiscussionTogether these defects indicate that Hectd1 is required for development of the labyrinthine zonethe mouse placenta.     

Association of first-trimester angiogenic factors with placental histological findings in late-onset preeclampsia

ObjectiveTo explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP).MethodsA nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (>34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP).ResultsIn 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p < 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p < 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p < 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis.DiscussionIn late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8–10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases.ConclusionIn late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.     

Changes in d-dimer levels in pregnant women according to gestational week

We performed a retrospective review of medical charts regarding blood d-dimer levels determined cross-sectionally by the latex agglutination assay in 1952 samples from 1185 women to determine changes in d-dimer levels according to the stage of pregnancy. Three of 17 women in whom further investigations were performed were found to have clinical venous thromboembolism (VTE). The median and 95th percentile values of d-dimer (μg/mL) in the 1182 women without clinical VTE, 0.54 and 2.41 at gestational week (GW) 4–13, increased gradually to 1.22 and 5.03 at GW 14–27, 1.81 and 6.18 at GW 28–35, and 2.13 and 5.85 at GW 36–42, respectively. A total of nine women (0.76%), including three women with clinical VTE, exhibited a d-dimer level >14.0 μg/mL, which was well above the 99th percentile for any stage of pregnancy. Thus, 3 (33%) of the nine with a d-dimer level >14 μg/mL developed clinical VTE, while none of the remaining 1176 women with a d-dimer level ?14 μg/mL developed clinical VTE. Although further prospective studies are required, our results suggested that there is a certain cut-off d-dimer value that would allow us to differentiate between pregnant women with and without clinical VTE.     

The effect of yoga training on enhancement of Adrenocorticotropic hormone (ACTH) and cortisol levels in female patients with multiple sclerosis

The effect of 8 weeks yoga training on cortisol and Adrenocorticotropic hormone (ACTH) levels in female patients with Multiple Sclerosis (MS) is examined. Twenty four MS female patients with Expanded Disability Status Scale (EDSS) 1 to 5.5 participated in this study as the subject. The participants were divided into control (n = 10) or training group (n = 14) randomly. Training group performed 90 min yoga training per session, 3 days a week for 8 weeks. Assessments include body composition measurement and blood sampling 48 h before first session and 48 h after the intervention. The results demonstrated that ACTH increased and cortisol decreased compared to the control group (P < 0.05); In conclusion, it seems that yoga training modulates ACTH level in concomitant with reduction in cortisol level in female patients with MS.     

Obstetrical outcome in women with endometriosis including spontaneous hemoperitoneum and bowel perforation: a systematic review

Increasing evidence suggests that pregnant women with endometriosis have a higher risk of adverse obstetrical complications. The aim of this study was to systematically review the existing literature on this aspect. A PubMed/MEDLINE search was performed from its inception until September 2017 for studies on adverse obstetrical complications in pregnant women with endometriosis, including: preeclampsia, preterm birth, small for gestational age (SGA), antepartum hemorrhage, spontaneous hemoperitoneum, spontaneous bowel perforation, preterm birth, cesarean delivery, stillbirth and postpartum hemorrhage. Overall, the results showed an increased risk of preterm delivery, antepartum hemorrhage, delivery by cesarian section, and the rare complications of spontaneous hemorrhage in pregnancy and spontaneous bowel perforation. There is no firm evidence for any increased risk of preeclampsia, having a child born small for gestational age, stillbirth, or postpartum hemorrhage. In conclusion, pregnant patients with endometriosis should be offered special clinical attention.     

Role of hysteroscopy in the evaluation of tubal patency in infertile women

Study objectiveTo evaluate the effectiveness of hysteroscopy as a method for the diagnosis of tubal patency using saline distention media.DesignProspective cohort study.SettingInfertility clinic of the Ain-shams University maternity hospital.Materials & methodsSixty-four infertile women underwent hysteroscopy (HSC) and hysterosalpingography (HSG) on two consecutive days. Transvaginal ultrasonography (TVS) was carried out before and after hysteroscopy in order to measure the fluid in the cul-de-sac. The difference between the two methods in the diagnosis of tubal patency was compared using laparoscopy/chromotubation as a gold standard.Main outcome measuresFluid volume measurements were used to determine a cut off value for tubal patency. Pain was recorded at the end of the process.ResultsAccording to the laparoscopy, the sensitivity and specificity of HSC and HSG in detecting tubal patency were 94.6% and 100% vs. 92.8% and 50%, respectively. The best cut off point of the fluid volume in the cul-de-sac at which both tubes are patent is 6 ml. All of the patients reported significantly less pain during hysteroscopy in response to HSG.ConclusionsOffice hysteroscopy combined with TVS may be used as an alternative to HSG, as an effective, easy, safe and minimal invasive office procedure that can be offered as a first line method for the evaluation of the uterine cavity along with the tubes in infertile women.     

The effect of exercise and metformin treatment on circulating free DNA in pregnancy

IntroductionSome pregnancy complications are characterized by increased levels of cell-free fetal (cffDNA) and maternal DNA (cfmDNA), the latter may also be elevated during physical strain. This study aims at assessing the impact of exercise and metformin intervention in pregnancy, and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis.MethodsConsecutive women from two previous randomized controlled trials in pregnancy were included. Women came from a trial with organized exercise vs. standard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women. Levels of cffDNA, cfmDNA and cell-free total DNA (cftDNA) were measured by qPCR.ResultsTraining in pregnancy did not affect the levels of cffDNA, cfmDNA or cftDNA.PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 (mean ± SD: 301 ± 162 versus 570 ± 337, p = 0.012, 345 ± 173 versus 635 ± 370, p = 0.019); otherwise the levels were comparable to PCOS-controls. Metformin-treated PCOS-women had higher cffDNA at inclusion, in the 1st trimester; later on in pregnancy the levels in the metformin and placebo groups were equal.A comparison of pregnant women in the exercise study (TRIP) to placebo-treated pregnant PCOS-women, showed the levels of cffDNA, cfmDNA or cftDNA during mid-pregnancy (weeks 18–36) to be equal.DiscussionTraining during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA, but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women.     

Placental concentrations of bisphenol A and birth weight from births in the Southeastern U.S.

IntroductionBisphenol A (BPA) is a weakly estrogenic compound that has been detected in a wide variety of food products and biological matrices (saliva, blood, urine, etc). Despite the potential risk of human exposure to BPA, little information exists concerning maternal and fetal exposure to BPA during pregnancy. The aim of this study is to evaluate the correlation between placental BPA concentration, infant birth weight and calculated birth weight centile, and several other maternal and infant parameters.MethodsPlacental sample were collected from 200 subjects. BPA levels were measured by isotope dilution GC–MS. Additional maternal and infant data were gathered from medical charts and were potential correlates with placental BPA levels.ResultsPlacental BPA concentrations ranged from 4.4 ng/g to 273.9 ng/g in oven-dried tissue (average 103.4 ± 61.8 ng/g). There was a significant negative correlation between calculated birth weight centile and levels of placental BPA (p < 0.05). Low birth weight and small for gestational age infants also had significantly greater placental BPA concentrations as compared to normal weight infants and average/large for gestational age infants. Infants born to African American mothers also had greater placental BPA concentrations as compared to infants born to Hispanic mothers.DiscussionPlacental BPA concentrations are correlated with the growth potential of the fetus and may play a role in reduced fetal growth.     

Increased placental phospholipase A2 gene expression and free F2-isoprostane levels in response to oxidative stress in preeclampsia

Vasoactive eicosanoids such as thromboxane (TX) A₂ and F₂-isoprostanes (F₂-isoPs) were shown to be increased in the preeclamptic placenta. Only one of the 64 possible isomers of F₂-isoPs derived from the oxidation of arachidonic acid was investigated in the placenta so far. F₂-isoPs are released from membrane phospholipids by phospholipases A₂ (PLA₂) and were shown to act on the TXA₂ receptor (TBXA2R). However, the PLA₂ deregulated in preeclampsia (PE) remains to be determined. In this study, we analyzed the concentrations of six isomers of F₂-isoPs; 8-iso-PGF_2α, 8-iso-15(R)-PGF_2α, 15(R)-PGF_2α, iPF_2α-IV, iPF_2α-VI, 5-iPF_2α-VI and the concentrations of the stable metabolites of TXA₂, TXB_2, by high performance liquid chromatography coupled with tandem mass spectrometry in placentas of PE (n = 17) and normotensive (n = 15) pregnancies according to the biopsy site: peri-insertion or periphery. In the same biopsies, relative mRNA expression of PLA2G2A, PLA2G4A, PLA2G5, PLA2G7, the PLA2 receptor (PLA2R1), the TXA₂ synthase and TBXAR2 were measured by quantitative RT-PCR. We observed similar concentrations of total F₂-isoP isomers between groups whereas higher concentrations (>40%) of free F₂-isoP were observed for all isomers (p ≤ 0.033) in PE than normotensive controls. As expected, we also observed higher placental concentrations of TXB₂ in PE (p = 0.005). Interestingly, we concomitantly found higher mRNA expression of secretory PLA2G2A (p = 0.010), PLA2G5 (p = 0.038) and TBXA2R (p = 0.023) in PE than normotensive placentas. In sum, deregulated PLA₂ could potentially be implicated in freeing F₂-isoP which could participate in local hypertension observed in the PE placenta through the TX pathway.     

Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation

IntroductionVisfatin/nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in energy metabolism and sirtuins, SIRT1 and SIRT3, which are NAD-dependent deacetylases, are critical for cellular function. All three either regulate or are regulated by intracellular NAD+ levels and therefore available cellular energy, important for placental cell survival and successful pregnancy. This study investigates whether these protective proteins are involved in the placental pathophysiology of pre-eclampsia (PE) and if they are associated with 8-oxo-deoxyguanosine (8OHdG), a marker of oxidative damage or with placental telomere length.MethodsMaternal blood and placental samples were collected from 31 patients with PE and 30 controls between 31 and 40 weeks gestation. Quantitative immunohistochemistry was performed on placental specimens for visfatin/Nampt, SIRT1, SIRT3, and nuclear 8OHdG. Plasma visfatin was measured by ELISA and telomere length by Southern blot analysis of telomere restriction fragments.ResultsVisfatin/Nampt and SIRT1 in syncytiotrophoblast decreased in PE compared to controls (p < 0.0001, p = 0.004 respectively). SIRT3 decreased in PE most significantly at preterm (p = 0.002). 8OHdG was only significantly lower in preterm controls compared to term controls (p = 0.01) and correlated with SIRT1 in all samples (r = 0.27). Telomere length was not different in PE and controls.DiscussionDecreased visfatin/Nampt, SIRT1 and SIRT3 in syncytiotrophoblast in PE suggests a lack of placental reserve in metabolic energy efficiency, increased inflammation, and lower resistance to environmental stressors. However, there was little effect on nuclear function, or evidence of genomic DNA damage, which would lead to cellular senescence and death.