Maternal Plasma Levels Research Articles

Over-Expression of MicroRNA-210 and MicroRNA-185-5p in Normotensive Late-Fetal Growth Restriction: Preliminary Cohort Study

OBJECTIVE: Late Fetal Growth Restriction (LFGR), a condition associated with perinatal and long-term neurodevelopmental problems, is caused by inadequate placental transfer of oxygen and nutrients to the fetus. This preliminary study evaluates the expression profiles and clinical significance of hypoxia-sensitive microRNA-210 (miR-210) and microRNA-185-5p (miR-185-5p) in placental and maternal circulation. The potential clinical implications of this research could significantly enhance the management of LFGR. STUDY DESIGN: In this prospective cohort study conducted at the Gynecology and Obstetrics Clinic of Trakya University Faculty of Medicine Hospital, miR-210 and miR-185-5p expression was evaluated in the placenta of healthy (n=30) and LFGR (n=30) cases. In healthy (n=15) and LFGR (n=15) cases, miRNA levels in maternal plasma were studied. We determined these two miRNAs using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and statistically analyzed them with clinical data to determine robustness. We provided a comprehensive evaluation. RESULTS: Both the placenta and maternal plasma samples exhibited significant correlations with miR-210 and miR-185-5p expression (r=0.615; r=0.771, p<0.01). The expression levels in both placenta and plasma were significantly higher in the LFGR group. Placental miR-210 demonstrated an AUC (0.908), sensitivity (93.3%), and specificity (96.7%), while plasma miR-210 showed AUC (0.738), sensitivity (86.7%), and specificity (66.7%). In contrast, placental miRNA 185-5p displayed a diagnostic performance with AUC (0.926), sensitivity (76.1%), and specificity (63.8%); plasma miRNA 185-5p exhibited an AUC (0.778), sensitivity (86.7%), and specificity (86.7%). However, placental miR-210 and miR-185-5p did not fully correlate with birth weight, placental weight, and fetal cerebroplacental Doppler ratio. CONCLUSION: Placental miRNA-210 showed superior diagnostic performance over placental miRNA 185-5p in LFGR pregnancies. However, it is crucial to emphasize that further studies are needed to validate these findings and correlate them with clinical data, underscoring the ongoing importance of research in this field.

Effect of Dietary Protein Intake from Different Sources on Maternal and Umbilical Cord Plasma Amino Acid Levels.

To assess the associations of dietary protein intake from different sources during pregnancy with maternal and umbilical cord plasma amino acid levels. The study includes 216 pregnant women and 39 newborns from the Tongji Birth Cohort in Wuhan, China. The study examines the levels of 21 amino acids in maternal and cord plasma samples using ultra-performance liquid chromatography with tandem mass spectrometry. A significant positive relationship is observed between dietary protein intake from refined grains and maternal plasma cysteine levels. Dietary protein intake from dairy products is positively associated with maternal plasma levels of sulfur amino acid (mainly cystine), but negatively associated with maternal plasma levels of glutamic acid. In addition, the study observes that pre-pregnancy body mass index and parity may be potential determinants of maternal plasma amino acid levels, whereas a history of passive smoking during pregnancy is an important factor influencing cord plasma amino acid levels. These findings suggest that dietary protein intakes from specific sources during pregnancy may affect maternal plasma levels of amino acids.

Impact of in-utero exposure to HIV and latent TB on infant humoral responses.

Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination.

Transcriptomics and metabolomics reveal the regulation of reproductive performance and egg quality of blotched snakehead Channa maculata broodstock induced by a high protein diet

To evaluate the effects of dietary protein on reproductive performance, egg quality and larval health of the blotched snakehead Channa maculata, three groups were designed: a high protein group (HP) with 48% protein content, a low protein group (LP) with 44% protein content, and a control group (C) fed with commercial feed containing 40% protein. The results demonstrated that the HP diet significantly enhanced maternal absolute fecundity, egg size and offspring health; however, it had no impact on fertilization rate and hatching rate. The maternal plasma levels of 11-ketotestosterone, 17β-estradiol, and vitellogenin in the HP group were found to be significantly higher compared to those in the C group. Plasma SOD activity and T-AOC capacity in the HP group were significantly higher than those in the C group, while MDA content showed an opposite trend. The trend of T-AOC in 7 days post-hatching larvae exhibited a consistent pattern with that observed in the maternal. Metabolomics and transcriptomics results indirectly indicated that the differences in reproductive and egg quality of the broodstock were associated with the regulation of arachidonic acid metabolism, steroid hormone biosynthesis, cholesterol metabolism, glycerophospholipid metabolism, and glycerolipid metabolism. The expression levels of star, zp3, foxo3, tgf-β, ghr, igf, cyp17a1, and cyp19a1 genes associated with reproduction and were significantly upregulated in the HP group. By depleting the abundance of metabolites in key pathway such as the pentose phosphate pathway, glycolysis/gluconeogenesis, nicotinate and nicotinamide metabolism, vitamin B6 metabolism within the ovary, there is an elevation in arachidonic acid metabolite abundance, thereby facilitating ovarian maturation and regulating egg quality. In conclusion, the high protein diet may affect the reproductive process and egg quality by inducing an upregulation of TGF-beta signaling pathway and ovarian steroidogenesis and arachidonic acid metabolism, leading to increased plasma cholesterol levels and enhanced steroid hormone synthesis.

Lactational transfer of sulforaphane-N-acetylcysteine in vivo and in human breast milk

Sulforaphane (SFN) is a bioactive phytonutrient found in cruciferous vegetables. There is a lack of detailed information on the lactational transfer of SFN and SFN metabolites, and potential pharmacological effects on breastfeeding infants. We carried out two maternal supplementation studies in a mouse model, wherein lactating dams received either vehicle, 300 or 600 ppm SFN from postnatal day (PND) 1 to 5, or in a second experiment, vehicle or 600 ppm SFN from PND 1 to 14. The parent compound was only detectable in milk and plasma from dams receiving 600 ppm SFN for five days. The predominant metabolite SFN-N-acetylcysteine (SFN-NAC) was readily detected in milk from dams receiving 300 and 600 ppm SFN for five days or 600 ppm for 14 days. Maternal SFN-NAC plasma levels were elevated in both 600 ppm groups. Maternal hepatic and pulmonary expression of NRF2-related genes, Nqo1, Gsta2, Gstm1, and Gstp1, were significantly increased, generally following a dose-response; however, offspring induction varied. PND5 neonates in the 600-ppm group exhibited significantly elevated expression of Nqo1, Gsta2, and Gstp1 in liver, and Gstm1 and Gstp1 in lung. Findings support maternal dietary supplementation with SFN induces NRF2-related gene expression in neonates via lactational transfer of SFN-NAC. However, NQO1 enzyme activity was not significantly elevated, highlighting the need to optimize dosing strategy. Additionally, in a pilot investigation of lactating women consuming a typical diet, without any purified SFN supplementation, 7 out of 8 breast milk samples showed SFN-NAC above the limit of quantification (LOQ). Notably, the one sample below the LOQ was collected from the only participant who reported no consumption of cruciferous vegetables in the past 24 h. The parent compound was not detected in any of the human breast milk samples. Overall, these data indicate lactational transfer of SFN-NAC at dietary relevant levels. Future studies are needed to evaluate pharmacokinetics and pharmacodynamics of lactational transfer for potential preventive or therapeutic effects in breastfeeding children.

Effects of Otarian Gymnastics on Malondialdehyde (GoM) Levels in Postpartum Women

If a woman is in a physiological postpartum condition, her body will increase the production of free radicals. This situation will be worse if the woman is undergoing pathological postpartum, the production of free radicals in her body will be even greater. This condition is known as oxidative stress. This situation can be prevented by postpartum mothers doing Otaria exercises. The design used in this research was Post Test Only Control Group Design or Post-test with an experimental group of 20 respondents and 20 respondents in a control group of 20 respondents. The research was conducted in the PKM Karang Intan 2 working area, Banjar Regency, South Kalimantan Province, which includes 13 villages. The research instrument or measuring tool used to see the effect of exercise on MDA levels in postpartum mothers is the GoM Assay Kit (TBA method) from Assay Genie with product catalog: MAES0037. In the treatment group with a low average GoM, it can be seen that the average GoM shows an increase in the control group. This shows that Otaria exercise is able to reduce GoM levels significantly. Oxidative stress can be prevented with antioxidants as a mechanism for the body's defense system against free radicals. Oxidative stress in mothers during the post-partum period can be prevented by doing Otaria exercises which have been proven to be able to reduce GoM levels in post-partum maternal plasma

Omega-3 Polyunsaturated Fatty Acid Levels in Maternal and Cord Plasma Are Associated with Maternal Socioeconomic Status.

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) play a crucial role in fetal growth and neurodevelopment, while omega-6 (n-6) PUFAs have been associated with adverse pregnancy outcomes. Previous studies have demonstrated that socioeconomic status (SES) influences dietary intake of n-3 and n-6 PUFAs, but few studies have evaluated the association between maternal and cord plasma biomarkers of PUFAs and socioeconomic markers. An IRB-approved study enrolled mother-infant pairs (n = 55) at the time of delivery. Maternal and cord plasma PUFA concentrations were analyzed using gas chromatography. Markers of SES were obtained from validated surveys and maternal medical records. Mann-Whitney U tests and linear regression models were utilized for statistical analysis. Maternal eicosapentaenoic acid (EPA) (p = 0.02), cord EPA (p = 0.04), and total cord n-3 PUFA concentrations (p = 0.04) were significantly higher in college-educated mothers vs. mothers with less than a college education after adjustment for relevant confounders. Insurance type and household income were not significantly associated with n-3 or n-6 PUFA plasma concentrations after adjustment. Our findings suggest that mothers with lower educational status may be at risk of lower plasma concentrations of n-3 PUFAs at delivery, which could confer increased susceptibility to adverse pregnancy and birth outcomes.

CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12–16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: − 1.82 95% CI (− 5.86, 2.22) vs placebo: − 5.00 95% CI (− 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20)Graphical In pregnant women with chronic hypertension, L-citrulline is an acceptable intervention which increased plasma L-citrulline bioavailability but did not affect BP, potentially due to altered pharmacokinetics of pregnancy.

Evaluation of second trimester plasma lipoxin A4, VEGFR-1, IL-6, and TNF-α levels in pregnant women with gestational diabetes mellitus

Abstract In this study, our objective was to explore the association between gestational diabetes mellitus (GDM) and second trimester maternal plasma levels of lipoxin A4 (LXA4), along with proinflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α), and the anti-angiogenic factor vascular endothelial growth factor receptor 1 (VEGFR-1) in pregnant women. The study included a cohort of 30 pregnant women with GDM and a control group of 30 normoglycaemic pregnant women matched for age, body mass index, and gestational age. Plasma samples were collected and analysed by enzyme-linked immunosorbent assay to assess specific biomarkers. The GDM group had significantly lower levels of LXA4 and higher levels of TNF-α and VEGFR-1 compared to the control group (p = 0.038, p = 0.025, and p = 0.002, respectively). A statistically significant decrease in the LXA4/TNF-α ratio was observed in the GDM group (p = 0.004). The results suggest that each unit decrease in the LXA4/TNF-α ratio is associated with a 1.280-fold increase in the risk of GDM. These findings suggest a potential diagnostic role for the LXA4/TNFα ratio as a marker for women with GDM. This work provides new insights into the pathogenesis of GDM and highlights the important interplay between inflammation and metabolic dysregulation.

Profile Tumor Necrosis Factor Alpha and Procalcitonin in Preeclampsia and Preeclampsia with Sepsis

BACKGROUND: Preeclampsia is hypertension in pregnancy which are characterized by high blood pressure, proteinuria that occur after 20 weeks of GA. Preeclampsia remains a massive cause of maternal morbidity and mortality that 50.000 death annually. The cause of preeclampsia is still unclear but there is a possibility caused by immunological processes in micro placenta environment during the early age of pregnancy. It is suggested that cytokines such as tumor necrosis factor (TNF-α) has an important role in the pathogenesis of preeclampsia. Preeclampsia is an extreme feature of the systemic inflammatory response during pregnancy. Systemic inflammation in preeclampsia can cause organ damage and induce sepsis. The pathophysiology is initiated by a high level of pro-inflammatory cytokine that released by peripheral blood mononuclear cell (PBMC). Beside pro-inflammatory cytokine, the marker of sepsis can be shown by procalcitonin (PCT) that produced by PBMC which is activated by TNF-α. AIM: The objective of the study is to evaluate profile maternal plasma levels of TNF-α and PCT and analyze their correlation in normotensive pregnant woman, preeclamptic and preeclampsia with sepsis. METHODS: An observational cross-sectional study. The sample were normotensive, preeclamptic, and preeclamptic with sepsis (n = 18) in Bangil Hospital, Pasuruan. The level of TNF-α and PCT was measured by ELISA. The statistical analysis with SPSS 18.0 with p &lt; 0.05. RESULTS: This study showed level of TNF-α and PCT in preeclamptic with sepsis was significantly higher than control (p &lt; 0.05) and not a significant difference in preeclampsia (p &gt; 0.05). The level of TNF-α and PCT in preeclampsia compared with control was not a significant difference (p &gt; 0.05). This study showed there was no correlation between TNF-α and PCT in patients with preeclampsia with sepsis. CONCLUSION: The plasma level of TNF-α and PCT was statistically different between the control group, preeclampsia and preeclampsia with sepsis. There was no significant difference of TNF-α and PCT plasma level in preeclampsia with sepsis than preeclampsia group. There was no significant correlation between preeclampsia in woman and preeclampsia with sepsis in maternal plasma TNF-α and PCT levels.

Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system

BackgroundThe reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding.AimTo systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems.MethodsSystematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables.ResultsInfusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2–3 times physiological levels.Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher.Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus.ConclusionsSynthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2–3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.

Persistent Organic Pollutant Levels in Maternal and Cord Blood Plasma and Breast Milk: Results from the Rio Birth Cohort Pilot Study of Environmental Exposure and Childhood Development (PIPA Study).

Levels of polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) were evaluated in the breast milk and maternal and umbilical cord blood of pregnant women and their newborns in Rio de Janeiro, Brazil. The concentration of 11 PCB and 17 OCP were measured in 135 samples of maternal, and 116 samples of cord blood plasma, as well as 40, 47, and 45 samples of breast milk at 1st, 3rd, and 6th months after birth, respectively, using gas chromatography-mass spectrometry (GC-MS-MS). Women were asked to answer an enrollment questionnaire with reproductive, lifestyle, residential and sociodemographic questions. The most commonly detected OCPs and PCBs in the maternal and cord blood were 4,4'-DDE; β-HCH; ɣ-HCH; and PCB 28. 4,4'-DDE was also the most commonly detected OCP in breast milk samples. Although not statistically significant, ∑DDT levels were higher among women with pregestational BMI ≥ 30, and who were non-white and older (age > 40). Newborns with an Apgar score ≤ 8 at minute 5 of life showed significantly higher levels of ∑DDT in the cord blood. Persistent OCPs and PCBs were still detected in maternal and umbilical cord blood and breast milk, even after decades of their banishment in Brazil. They may pose a risk to maternal, fetal and children's health.

Supplementation of L-Ornithine Could Increase Sleep-like Behavior in the Mouse Pups.

Along the maternal-fetal-neonatal axis, one of the problems relating to the maternal-neonatal axis is infant sleep problems including nighttime crying. One possible solution could be to provide the newborn with sleep-promoting ingredients through breast milk or formula. So far, it has been reported that L-ornithine has a sleep-related effect. Therefore, we investigated the effect of dietary L-ornithine on maternal mouse plasma and milk L-ornithine levels in Experiment 1. In Experiment 2, a single dose of L-ornithine was applied to know the time-course changes in plasma, mammary gland and milk L-ornithine levels. Experiment 3 was conducted to confirm sleep behavior as well as changes in polyamine levels in milk. L-Ornithine levels in maternal plasma significantly increased by both dietary regimen and single oral administration in Experiments 1 and 2. Both L-ornithine treatments also increased its levels in milk, although not to a concentration as high as in plasma. In Experiment 3, the level of polyamines, which are metabolized from L-ornithine, did not significantly differ after L-ornithine administration. In sleep-like behavior observations, the average concentration of L-ornithine in milk did not increase the sleep-like behavior of mouse pups. However, more concentrated L-ornithine solutions can significantly increase sleep-like behavior. These results revealed that even if mothers ingested L-ornithine to increase L-ornithine levels in breast milk, it is difficult to promote sleep in newborns. Because it is difficult to raise L-ornithine in breast milk to sleep-inducing levels, L-ornithine added formula may partially improve infant sleep and has the potential for preventing infant sleep problems such as nighttime crying.

Upregulation of miR-181a-5p and miR-125b-2-3p in the Maternal Circulation of Fetuses with Rh-Negative Hemolytic Disease of the Fetus and Newborn Could Be Related to Dysfunction of Placental Function.

The transplacental transfer of maternal antibodies to the fetus is a critical mechanism for infant protection and perinatal disease. Hemolytic disease of the fetus and newborn (HDFN) is a representative fetal disease caused by transplacental transfer of maternal IgG antibodies. However, it is unclear whether placental-related miRNAs are expressed in Rh-HDFN. Through the investigation of the miR-181a-5p and miR-125b-2-3p levels in maternal plasma using qPCR, we found that both miR-181a-5p and miR-125b-2-3p were highly expressed in maternal plasma of newborns with Rh-HDFN compared with healthy controls, indicating the potential roles of these two miRNAs in Rh-HDFN. To demonstrate whether dysregulation of miR-125b-2-3p and miR-181a-5p contributes to Rh-HDFN development, we analyze the placental miRNA-/mRNA sequencing data (GSE73714) using weighted gene coexpression network analysis (WGCNA), miRNA target predictive databases, and DAVID (Database for Annotation, Visualization, and Integrated Discovery). The results showed that miR-125b-2-3p and miR-181a-5p could regulate several biological processes including cytoplasmic microtubule organization and angiogenesis. Moreover, core promoter sequence-specific DNA binding and protein binding were highly enriched molecular functions, indicating the potential roles of transcriptional regulation. Further pathway enrichment showed that miR-181a-5p and miR-125b-2-3p could regulate several biological pathways that were closely related to placental function, including the FoxO signaling pathway, focal adhesion, mTOR signaling pathway, and central carbon metabolism in cancer. In conclusion, the present results first revealed miRNA expression in the maternal circulation of newborns with Rh-HDFN, which could be caused by dysfunction of the placenta.

Maternal obesity reduces apelin level in cord blood without altering the placental apelin/elabela-APJ system

The APJ receptor and its two endogenous ligands, apelin and elabela, exert key roles in fetoplacental development. In adult, this system is altered by obesity but no data are available during pregnancy. We measured apelin and elabela levels in maternal plasma and cord blood and quantified placental gene expression of apelin, elabela and APJ in obese and non-obese mothers. We found that obesity reduced apelin level in cord blood without affecting maternal and cord blood elabela levels as well as placental gene expression of this system. Our data suggest that obesity alters fetal apelinemia in humans.

Inhibition of the AT1R agonistic autoantibody in a rat model of preeclampsia improves fetal growth in late gestation.

Placenta ischemia, the initiating event in preeclampsia (PE), is associated with fetal growth restriction. Inhibition of the agonistic autoantibody against the angiotensin type 1 receptor AT1-AA, using an epitope-binding inhibitory peptide ('n7AAc') attenuates increased blood pressure at gestational day (G)19 in the clinically relevant reduced uterine perfusion pressure (RUPP) model of PE. Thus we tested the hypothesis that maternal administration of 'n7AAc' does not transfer to the fetus, improves uterine blood flow and fetal growth, and attenuates elevated placental expression of miRNAs implicated in PE and FGR. Sham or RUPP surgery was performed at G14 with vehicle or 'n7AAc' (144 µg/day) administered via an osmotic pump from G14 to G20. Maternal plasma levels of the peptide on G20 were 16.28 ± 4.4 nM, and fetal plasma levels were significantly lower at 1.15 ± 1.7 nM (P = 0.0007). The uterine artery resistance index was significantly elevated in RUPP (P < 0.0001) but was not increased in 'n7AAc'-RUPP or 'n7AAc'-Sham versus Sham. A significant reduction in fetal weight at G20 in RUPP (P = 0.003) was not observed in 'n7AAc'-RUPP. Yet, percent survival was reduced in RUPP (P = 0.0007) and 'n7AAc'-RUPP (P < 0.0002). Correlation analysis indicated the reduction in percent survival during gestation was specific to the RUPP (r = 0.5342, P = 0.043) and independent of 'n7AAc'. Placental miR-155 (P = 0.0091) and miR-181a (P = 0.0384) expression was upregulated in RUPP at G20 but was not elevated in 'n7AAc'-RUPP. Collectively, our results suggest that maternal administration of 'n7AAc' does not alter fetal growth in the RUPP implicating its potential as a therapeutic for the treatment of PE.NEW & NOTEWORTHY The seven amino acid inhibitory peptide to the AT1-AA ('n7AAc') has limited transfer to the fetus at gestational day 20, improves uterine blood flow and fetal growth in the reduced uterine perfusion pressure model of preeclampsia (PE), and does not impair fetal survival during gestation in sham-operated or placental ischemic rats. Collectively, these findings suggest that maternal administration of 'n7AAc' as an effective strategy for the treatment of PE is associated with improved outcomes in the fetus.

Abnormal Expression of the LAG-3/FGL-1 Signaling Pathway in Patients with Early-Onset Preeclampsia.

BackgroundPreeclampsia (PE) is a serious pregnancy disorder associated with immune tolerance imbalance. The etiology of preeclampsia has not been fully elucidated. The aim of this study was to clarify the possible role of the lymphocyte activation gene 3 (LAG-3)/fibrinogen-like protein 1 (FGL-1) signaling pathway in the immune imbalance of early-onset PE.Material/MethodsWe enrolled 34 women with early-onset PE and 34 age-matched normal pregnancies (NPs). Flow cytometry was performed to determine the expression of LAG-3 on peripheral T cell subsets (CD3+, CD4+, and CD8+ T cells). We measured LAG-3 expression on decidual T cells to determine whether there was a difference in the expression of LAG-3 between decidual and peripheral T cells. Maternal plasma levels of FGL-1 were measured by ELISA.ResultsThere was no significant difference in LAG-3 expression on peripheral CD3+ T cells between NP and early-onset PE. Compared to NP, the significant decrease expression of LAG-3 by peripheral CD4+ and CD8+T cells was found in early-onset PE. The LAG-3 expression was higher on decidual T cells than peripheral counterparts in all pregnancies. The plasma level of FGL-1 was significantly elevated in early-onset PE compared with NP.ConclusionsAbnormal expression of LAG-3/FGL-1 signaling pathway may be associated with immune activation of effector T cells and impaired immune tolerance in early-onset PE.

Association between Preterm Premature Rupture of Membranes and Vitamin D Levels in Maternal Plasma and Umbilical Cord Blood of Newborns: A Prospective Study

Background: Preterm premature rupture of membranes (PPROM) is a major cause of preterm birth. There are few reports on vitamin D deficiency associated with PPROM. We aimed to investigate the association between PPROM and vitamin D levels in maternal plasma and the umbilical cord blood of newborns. Methods: This prospective study included 355 pregnant women who delivered live infants between March 2017 and December 2018 at a medical center. Vitamin D levels were measured in the maternal plasma at the first, second, third trimesters of pregnancy and just before delivery, and in the umbilical cord blood of newborns at birth. In addition, we evaluated the pregnancy and neonatal outcomes according to vitamin D status. Results: The rate of PPROM in the vitamin D deficiency group (25(OH)D &lt;20 ng/mL) was higher than in the non-deficiency group (25(OH)D ≥20 ng/mL) (p = 0.003). Vitamin D levels were significantly lower in the PPROM group than non-PPROM group in maternal plasma [at the first (p = 0.020) and second trimesters (p = 0.029), just before delivery (p = 0.015)], and in the cord blood of newborns (p = 0.006). Multiple logistic regression analysis showed that the odds ratio of PPROM by the increase of 1ng/mL of vitamin D levels in the cord blood of newborns was 0.907 (95% confidence interval 0.836–0.983) after adjustment for other confounders (age, gravidity, parity, and body mass index). Conclusions: Vitamin D deficiency has a significant association with PPROM. Our study would aid in understanding the mechanism of prevention of PPROM associated with vitamin D deficiency as well as reduction in preterm births.

Variation of Complement Protein Levels in Maternal Plasma and Umbilical Cord Blood during Normal Pregnancy: An Observational Study.

The complement system constitutes a crucial part of the innate immunity, mediating opsonization, lysis, inflammation, and elimination of potential pathogens. In general, there is an increased activity of the complement system during pregnancy, which is essential for maintaining the host’s defense and fetal survival. Unbalanced or excessive activation of the complement system in the placenta is associated with pregnancy complications, such as miscarriage, preeclampsia, and premature birth. Nonetheless, the actual clinical value of monitoring the activation of the complement system during pregnancy remains to be investigated. Unfortunately, normal reference values specifically for pregnant women are missing, and for umbilical cord blood (UCB), data on complement protein levels are scarce. Herein, complement protein analyses (C1q, C3, C4, C3d levels, and C3d/C3 ratio) were performed in plasma samples from 100 healthy, non-medicated and non-smoking pregnant women, collected during different trimesters and at the time of delivery. In addition, UCB was collected at all deliveries. Maternal plasma C1q and C3d/C3 ratio showed the highest mean values during the first trimester, whereas C3, C4, and C3d had rising values until delivery. We observed low levels of C1q and C4 as well as increased C3d and C3d/C3 ratio, particularly during the first trimester, as a sign of complement activation in some women. However, the reference limits of complement analyses applied for the general population appeared appropriate for the majority of the samples. As expected, the mean complement concentrations in UCB were much lower than in maternal plasma, due to the immature complement system in neonates.

Mid-pregnancy poly(I:C) viral mimic disrupts placental ABC transporter expression and leads to long-term offspring motor and cognitive dysfunction

Limited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We hypothesized that maternal exposure to polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA viral mimic, would impair placental cell turnover, the expression of selected ABC transporters and adult offspring behavior. C57BL/6 mice were administered poly(I:C) (10 mg/Kg;ip) or vehicle at gestational day (GD) 13.5 (mid-pregnancy). Dams were euthanized for blood collection 4 h after injection, fetal and placental collection at GD18.5 or allowed to deliver spontaneously at term. At GD 13.5, poly(I:C) induced an acute pro-inflammatory response characterized by an increase in maternal plasma levels of IL-6, CXCL-1 and CCL-2/MCP-1. At GD 18.5, poly(I:C) decreased cell proliferation/death in the labyrinthine and increased cell death in the junctional zones, characterizing a disruption of placental cell turnover. Abca1 and Abcg1 immunolabelling was decreased in the labyrinthine zone, whereas Abca1, Abcg1 and breast cancer resistance transporter (Bcrp) expression increased in the junctional zone. Moreover, adult offspring showed motor and cognitive impairments in the Rotarod and T-water maze tests. These results indicate that viral infection during mid-pregnancy may disrupt relevant placental efflux transporters, as well as placental cell turnover and offspring behavior in adult life.