Maternal IL-6 Research Articles

Erythroferrone Is Associated with Maternal Erythropoietic Drive During Pregnancy

Abstract Objectives Iron (Fe) homeostasis must be tightly regulated during pregnancy to meet both maternal and fetal Fe demands. Several hormones are known to impact Fe homeostasis including hepcidin, erythropoietin and erythroferrone (ERFE). Few data are available on determinants of ERFE in pregnant women or in their newborns at birth. The objective of this study was to characterize concentrations of ERFE across gestation and evaluate this hormone in relation to other Fe status biomarkers and regulatory hormones in mothers across pregnancy. Methods ERFE was measured in serum from pregnant adolescents (n = 166, age 14–19) or women carrying multiple fetuses (n = 61, age 20–46). ERFE concentrations across gestation (wks 8 – 42.1) were compared to Fe status and nutritional indicators (hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), total body Fe (TBI), TR-F index (sTfR/log(SF)), folate and vitamin B-12), as well as regulatory hormones (erythropoietin (EPO), hepcidin) and inflammatory markers (IL-6, C-reactive protein (CRP)). Results ERFE concentrations increased significantly across pregnancy in women carrying multiple fetuses (P < 0.01), but did not change across pregnancy in the adolescents (P = 0.3). In both populations, 16% (n = 30) of women were anemic at midgestation (MG) and 24% (n = 75) at delivery. ERFE concentrations were significantly increased in anemic women at both MG (P = 0.02) and at delivery (P = 0.02). At MG (median 26 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P = 0.002). Maternal TfR, IL-6 and serum Fe were the strongest determinants of maternal MG ERFE, and explained 29% of variance in ERFE. At delivery (median 38 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P < 0.001), which together explained 18% of variance in ERFE at delivery. ERFE was not significantly associated with hepcidin at either MG (P = 0.87) or delivery (P = 0.52). Conclusions ERFE was significantly higher in anemic women across pregnancy and, as expected, was positively associated with indicators of erythropoietic drive. ERFE however, was not significantly associated with hepcidin, possibly because hepcidin is regulated by multiple competing signals. More research is needed to understand the relationship between maternal ERFE and neonatal Fe status at birth. Funding Sources Funded by the NIH (NIDDK/NICHD).

Circulating metal concentrations, inflammatory cytokines and gestational weight gain: Shanghai MCPC cohort.

Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. The GWG during pregnancy was 13.76±1.40kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100kg (95% CI 0.005, 0.195) and 0.120kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing.

Maternal chronic stress correlates with serum levels of cortisol, glucose and C-peptide in the fetus, and maternal non chronic stress with fetal growth

IntroductionDuring pregnancy, maternal stressors cause changes in both maternal and fetal HPA axes. We therefore investigated the impact of maternal non chronic and chronic stress on fetal glucose metabolism and growth, and serum levels of cortisol in the fetus. Materials and methodsNormal weight pregnant women (n = 192; mean ± SD 27.9 ± 4.2 years old, and; 26.9 ± 2.4 kg/m²) were assessed during the 2nd and 3rd trimester with anthropometry, fetal ultrasound, blood samples for serum CRH, cortisol and IL6, and STAI trait and state stress questionnaires. We measured serum cortisol, insulin and c-peptide, and plasma glucose from cord blood. Neonates underwent anthropometry at the 3rd post-delivery day. ResultsIn both 2nd and 3rd trimesters, women with STAI trait scores ≥40 had significantly greater levels of fasting serum CRH and cortisol than those with STAI trait scores<40.2nd trimester: STAI trait scores correlated positively with cord blood glucose and c-peptide. Maternal serum CRH correlated negatively with U/S fetal biparietal head diameter, while serum cortisol correlated positively with abdominal circumference. Maternal serum IL6, CRH and cortisol all correlated positively with birth waist circumference.3rd trimester: Women with STAI state scores ≥40 had fetuses with larger U/S abdominal and smaller head circumferences compared to those of women with STAI scores <40. Women with STAI trait scores ≥40 had greater levels of cord blood cortisol, glucose, and c-peptide compared to women with STAI scores <40. STAI state scores ≥40 correlated positively with maternal CRH and U/S fetal abdominal circumference, and negatively with fetal head circumference and biparietal diameter. STAI trait scores correlated positively with cord blood c-peptide, glucose, insulin and cortisol. Maternal serum levels of CRH correlated positively with U/S fetal abdominal circumference and cord blood cortisol, and negatively with fetal head circumference and biparietal head diameter. Maternal serum levels of both CRH and cortisol correlated positively with cord blood c-peptide, glucose, and insulin. STAI trait was the best positive predictor of cord blood cortisol, glucose and c-peptide, whilst STAI state was the best positive and negative predictor, respectively of fetal abdominal circumference and fetal head circumference or biparietal diameter. ConclusionsIncreased maternal chronic stress (reflected by the STAI trait score) associates with increased fetal cortisol, glucose, c-peptide secretion and thus, insulin resistance. Maternal non chronic stress (STAI state) in the 3rd trimester associates with changes in fetal growth pattern, including increased and decreased measurements of fetal abdominal and head growth respectively.

The Identification of Immune-Related Plasma Proteins Associated with Spontaneous Preterm Delivery and Intra-Amniotic Infection in Women with Premature Cervical Dilation or an Asymptomatic Short Cervix

BackgroundWe aimed to investigate whether various immune-related plasma proteins, alone or in combination with conventional clinical risk factors, can predict spontaneous preterm delivery (SPTD) and intra-amniotic infection in women with premature cervical dilation or a short cervix (≤ 25 mm).MethodsThis retrospective study included 80 asymptomatic women with premature cervical dilation (n = 50) or a short cervix (n = 30), who underwent amniocentesis at 17–29 weeks. Amniotic fluid (AF) was cultured, and maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and complements C3a and C5a, using enzyme-linked immunosorbent assay (ELISA) kits. The primary outcome measures were SPTD at < 32 weeks and positive AF cultures.ResultsThe plasma levels of IL-6, C3a, and C5a, but not of MMP-9 and TIMP-1, were significantly higher in women with SPTD at < 32 weeks than in those who delivered at ≥ 32 weeks. The women who delivered at < 32 weeks had more advanced cervical dilatation, and higher rates of antibiotic and tocolytic administration and were less likely to be given vaginal progesterone than those who delivered at ≥ 32 weeks. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma IL-6 and C3a levels, and cervical dilatation (area under the curve [AUC], 0.901). The AUC for this model was significantly greater than that for any single variable included in the predictive model. In the univariate analysis, plasma IL-6 level was the only significant predictor of intra-amniotic infection.ConclusionIn women with premature cervical dilation or a short cervix, maternal plasma IL-6, C3a, and C5a levels could be useful non-invasive predictors of SPTD at < 32 weeks. A combination of these biomarkers and conventional clinical factors may clearly improve the predictability for SPTD, as compared with the biomarkers alone. An increased plasma level of IL-6 predicted intra-amniotic infection.

PERBEDAAN RERATA KADAR IL-6 SERUM MATERNAL BERDASARKAN KEBERHASILAN PEMBERIAN TOKOLITIK PADA PARTUS PREMATURUS IMMINENS

Preterm labor needs to be prevented, one of the prevention methods is by tocolytic administration which could prevent labor thus providing a chance for lung maturation. Preterm Pregnancy is associated with increased concentrations of cytokines such as Interleukin (IL). The increasing concentration of maternal serum IL-6 can be used to predict preterm labor. This research uses the design Cross-Sectional Comparative to determine differences in means of maternal serum levels of IL-6 based on the success of the administration of a tocolytic agent on preterm labor. This study was performed on pregnant women who come to the obstetric emergency room of DR. MA. Hanafiah Batusangkar Hospital within August-November 2015. The total number which was included in statistical analysis was 34 pregnant women which were divided into 2 groups, 17 people in the group of patients who failed in tocolytic agent administration, and 17 people in the group who success in managed with a tocolytic agent. Statistical analysis was performed to analyze the validity using the T-test. There are significant differences in the average rate of maternal serum IL-6 in patients who failed to treat with a tocolytic agent and successful to treat with a tocolytic agent. Seen from the p-value 0.000. Levels of maternal serum IL-6 in patients who failed to treat with a tocolytic agent were higher than successful to treat with a tocolytic agent.Keywords: IL-6, Tocolytic, Preterm labor

Increased levels of serum IL-33 is associated with adverse maternal outcomes in placenta previa accreta

Purpose IL-33 is associated with invasion, proliferation, and metastasis of various cancers. The trophoblastic cells of placenta previa accreta (PPA) invade into the myometrium in a similar way to the invasion of cancers. We studied the role of IL-33 in PPA and also aimed to investigate its relation with adverse maternal outcome in this placental disorder. Methods A total of 87 pregnant patients were enrolled in this prospective case-control study [27 with PPA, 30 with placenta previa totalis (PPT; nonadherent placenta previa), and 30 controls]. IL-33 and IL-6 levels were studied in maternal serum at late preterm gestation weeks. Multiple logistic regression analyses analyzed the risk factors which are associated with PPA and adverse maternal outcomes. Adjusted odds ratios and 95% confidence intervals were also calculated. Enzyme-linked immunosorbent assay (ELISA) method was used to determine maternal serum IL-33 and IL-6 levels. Results Serum IL-33 levels were significantly higher in PPA patients when compared with both nonadherent PPT and the control groups (p = .011, p = .010). Serum IL-6 and neutrophil/lymphocyte ratio levels were significantly higher than the control group’s (p = .045, p = .028). IL-33 levels and history of previous cesarean section were found to be significantly associated with PPA (OR: 1.039, 95% CI: 1.004–1.075; p = .030 and OR: 0.067, 95% CI: 0.014–0.309, p = .001, respectively). Serum IL-33 levels were positively correlated with previous cesarean section history in PPA. Increased maternal serum IL-33 levels were found to be independently associated with a cesarean hysterectomy and massive transfusion in PPA patients (OR: 1.098, 95% CI: 0.998–1.207; p = .049 and OR: 1.162 95% CI: 1.010–1.337; p = .036). Conclusion Increased levels of maternal serum IL-33 and history of previous cesarean section were found to be significantly associated with PPA, and also increased maternal serum IL-33 levels were related to cesarean hysterectomy and massive blood transfusion in PPA. We suggest that IL-33 may have a role in abnormal placental invasion.

Poly(I:C) source, molecular weight and endotoxin contamination affect dam and prenatal outcomes, implications for models of maternal immune activation

The viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) is increasingly used to induce maternal immune activation (mIA) to model neurodevelopmental disorders (NDDs). Robust and reproducible phenotypes across studies are essential for the generation of models that will enhance our understanding of NDDs and enable the development of improved therapeutic strategies. However, differences in mIA-induced phenotypes using poly(I:C) have been widely observed, and this has prompted the reporting of useful and much needed methodological guidelines. Here, we perform a detailed investigation of molecular weight and endotoxin variations in poly(I:C) procured from two of the most commonly used suppliers, Sigma and InvivoGen. We demonstrate that endotoxin contamination and molecular weight differences in poly(I:C) composition lead to considerable variability in maternal IL-6 response in rats treated on gestational day (GD)15 and impact on fetal outcomes. Specifically, both endotoxin contamination and molecular weight predicted reductions in litter size on GD21. Further, molecular weight predicted a reduction in placental weight at GD21. While fetal body weight at GD21 was not affected by poly(I:C) treatment, male fetal brain weight was significantly reduced by poly(I:C), dependent on supplier. Our data are in agreement with recent reports of the importance of poly(I:C) molecular weight, and extend this work to demonstrate a key role of endotoxin on relevant phenotypic outcomes. We recommend that the source and batch numbers of poly(I:C) used should always be stated and that molecular weight variability and endotoxin contamination should be minimised for more robust mIA modelling.

How are maternal dietary patterns and maternal/fetal cytokines associated with birth weight? A path analysis.

The aim of the study was to investigate how maternal dietary patterns and maternal/fetal cytokines are associated with birth weight and whether cytokines mediate the association. A total of 469 pregnant women and their children were recruited for this prospective study. Dietary patterns in pregnancy were identified using factor analysis of data from three consecutive 24 h dietary recalls. Maternal and umbilical blood serum cytokines (adiponectin (APN), IL-6 and interferon-γ) were measured via ELISA. Path analysis was used to explore the relationships between maternal diet, cytokines and birth weight. Four dietary patterns were identified: a mainly fruit, dairy products and poultry diet (FDP); a mainly vegetables, beans and pork diet (VBP); a mainly fish, shrimp and soup diet (FS) and a mainly tuber and egg diet (TE). Path analysis showed the order of effects of dietary patterns on birth weight was FS&gt;FDP&gt;TE&gt;VBP (β=0·130, 0·109, -0·094 and 0·046, respectively). Only the TE pattern's effect was negative. Maternal and fetal APN were positively associated with birth weight (β=0·045 and 0·226, respectively), and they mediated the association between the TE pattern and birth weight (indirect effect was 5·3 %). Maternal IL-6 was negatively associated with birth weight (β=-0·067) and mediated the association between maternal FDP and VBP patterns and birth weight (indirect effects were 10·1 and 100·0 %, respectively). All variables in the path explained 33·6 % of variation. These results suggested that maternal dietary patterns in pregnancy are associated with birth weight and mediated directly and indirectly through some maternal/fetal serum cytokines.

Regulation of inflammation during gestation and birth outcomes: Inflammatory cytokine balance predicts birth weight and length.

The maternal environment during gestation influences offspring health at birth and throughout the life course. Recent research has demonstrated that endogenous immune processes such as dysregulated inflammation adversely impact birth outcomes, increasing the risk for preterm birth and restricted fetal growth. Prior analyses examining this association suggest a relationship between maternal C-reactive protein (CRP), a summary measure of inflammation, and offspring anthropometric outcomes. This study investigates pro- and anti-inflammatory cytokines, and their ratio, to gain deeper insight into the regulation of inflammation during pregnancy. IL6, IL10, TNFɑ, and CRP were quantified in dried blood spots collected in the early third trimester (mean = 29.9 weeks) of 407 pregnancies in Metropolitan Cebu, Philippines. Relationships between these immune markers and offspring anthropometrics (birth weight, length, head circumference, and sum of skinfold thicknesses) were evaluated using multivariate regression analyses. Ratios of pro- to anti-inflammatory cytokines were generated. Higher maternal IL6 relative to IL10 was associated with reduced offspring weight and length at birth. Individual cytokines did not predict birth outcomes. Consistent with the idea that the relative balance of cytokines with pro- and anti-inflammatory effects is a key regulator of inflammation in pregnancy, the IL6:IL10 ratio, but neither cytokine on its own, predicted offspring birth outcomes. Our findings suggest that prior reports of association between CRP and fetal growth may reflect, in part, the balance between pro- and anti-inflammatory cytokines, and that the gestational environment is significantly shaped by cytokine imbalance.

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats.

Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings (Lins et al., 2018). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.

Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines

BackgroundInvestigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production.MethodsThis study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12–20 weeks gestation) and after supplementation (34–36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis.ResultsWe enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations.ConclusionsPrenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations.Trial registrationClinical Trial Registration: registration number NCT00711971 7/7/2008.

The Influence of Lipid and Proinflammatory Status on Maternal Uterine Blood Flow in Women With Late Onset Gestational Diabetes.

Gestational diabetes mellitus (GDM) is associated with increased proinflammatory cytokines and is also associated with adverse cardiovascular disease (CVD) outcomes later in life. We aim to evaluate the relationships between uterine arteries vascularization and endothelial dysfunction markers, proinflammatory cytokines, and glycemic and lipid profile in women with GDM. Fifty pregnant women were recruited at the third trimester of pregnancy for a prospective cohort study. They were classified into 2 groups: control and GDM. Comparisons of maternal plasma concentrations of endothelial dysfunction markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and plasminogen activator inhibitor 1), proinflammatory cytokines and mediators (interleukin 6 [IL-6], tumor necrosis factor α, vascular endothelial growth factor, placental growth factor, leptin, leukocyte count, and C-reactive protein), lipid profile, glucose, and glycosylated hemoglobin levels were performed. Mean uterine arteries Doppler pulsatility index (PI) was calculated and the relationships between the variables and PI were also analyzed. Women with GDM showed higher proinflammatory cytokines, however, endothelial dysfunction markers were similar in both groups. In the diabetic group, significant correlations were found between the mean uterine arteries PI and maternal IL-6 ( r = .56, P = .01), triglycerides ( r = .49; P = .03), total cholesterol/high-density lipoprotein cholesterol (HDL-c) ratio ( r = .61; P = .006), glucose (r = .62, P = .005), and glycosylated hemoglobin ( r = .48; P = .03). A negative significant correlation between mean uterine arteries PI and HDLc ( r = -.58; P = .02) was also found. The proinflammatory status, hyperlipidemia, and metabolic control correlate with uterine blood flow velocity waveforms in women with gestational diabetes.

Creating a diversion.

Elevated maternal IL-6 in the maternal circulation can enter the fetus via the maternal—placental—fetal route and alter neurodevelopmental processes, with potentially wide-ranging effects on brain function later in life.

Maternal Serum Interleukin-6: A Non-Invasive Predictor of Histological Chorioamnionitis in Women with Preterm-Prelabor Rupture of Membranes

Objective: To assess the added value of maternal serum levels of IL-6 in women with preterm-prelabor rupture of membranes (PPROM) as a non-invasive test for the prediction of histological chorioamnionitis (HCA). Methods: This was a prospective cohort study of pregnant women between 20 + 0 and 36 + 6 weeks of gestation with a confirmed diagnosis of PPROM. Logistic regression models were created for the prediction of HCA and compared by assessing the improvement in their Naegelkerke R² as a measure of goodness of fit. Predictive performance of all models was assessed by receiver operating characteristics curve (ROC) analysis and compared by the DeLong method. Results: From 47 women with PPROM, 31 (66%) developed HCA. Maternal serum IL-6 ≥19.5 pg/dL was the best cut-off point for the prediction of HCA (OR = 15; 95% CI: 3.6–61; p < 0.01). A model comprising maternal characteristics and IL-6 ≥19.5 pg/dL showed an area under the curve of 0.85 (95% CI: 0.74–0.95), significantly improving the previous models of IL-6 ≥19.5 pg/dL (R²: 23.3 vs. 34.1%; p = 0.01) or maternal characteristics (R²: 8.4 vs. 34.1%; p < 0.01). Conclusions: A model comprising maternal serum levels of IL-6 plus maternal characteristics proves to be a good non-invasive predictor of HCA.

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.

Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a β-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1-stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94-104] and 64 [57-68], respectively, P = .002; lateral septum, 102 [96-111] and 68 [65-69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20-26] and 17 [15-18], respectively, P = .005; dorsal hippocampus, 27 [22-32] and 16 [14-19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of β-actin intensity versus IL-6, 41.5% ± 24%, P < .001). Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.

Cytokine distribution in mothers and breastfed children after omega-3 LCPUFAs supplementation during the last trimester of pregnancy and the lactation period: A randomized, controlled trial

ObjectiveTo determine whether maternal diet supplementation with omega-3 long chain polyunsaturated fatty acids (omega-3 LC-PUFAs) during the last trimester of pregnancy and the breastfeeding period influences the levels of inflammatory cytokines in mother and infants. Material and methodThis registered, double-blind randomized study included 46 pregnant women, who were randomly allocated to either an experimental group receiving 400mL/day of a fish oil-enriched dairy drink [320mg docosahexaenoic acid (DHA) + 72mg eicoapentaenoic acid] (FO group, n = 24) or to a control group receiving 400mL/day of a non-supplemented dairy drink (CT group, n = 22), from week 28 of pregnancy until the fourth month of lactation. During the study, maternal dietary patterns were monitored by a nutritionist, who encouraged compliance with current recommendations of fatty acids intake. DHA concentrations and cytokine levels (GM-CSF, IL-2, IL-4, IL-6, IL-10, INF-γ and TNF-α) were measured in maternal plasma at the moment of recruitment and in maternal (n = 46) and infant (n = 46) plasma at birth and 2.5 months after birth. ResultsMaternal plasmatic IL-4 levels were higher in FO than in CT subjects (p = 0.009). Additionally, a tendency was observed to higher IL-10 and IL-2 in the FO group. Plasmatic IL-6 however, was higher in CT mothers (p = 0.001). TNF-α was higher in CT infants at birth and 2.5 months after birth (p = 0.005). An analysis of possible relationships between DHA and the concentrations of different cytokines revealed negative correlation between maternal plasmatic IL-6 and DHA (higher plasmatic DHA corresponded to lower IL-6). ConclusionsMaternal dietary omega-3 LC-PUFAs supplementation during critical periods like pregnancy, lactation and early newborn development may influence the levels of certain inflammatory cytokines, reducing pro-inflammatory cytokines and promoting an anti-inflammatory “environment”.

Levels of multiple proteins in gingival crevicular fluid and intra-amniotic complications in women with preterm prelabor rupture of membranes

Objective: The primary aim of this study was to identify the association between the local inflammatory response in gingival crevicular fluid measured by the levels of multiple proteins and maternal and intra-amniotic inflammatory responses measured by maternal serum C-reactive protein (CRP) and amniotic fluid interleukin (IL)-6 concentrations, respectively, in women with preterm prelabor rupture of membranes (PPROM).Methods: A prospective study was performed in which 78 women with singleton pregnancies complicated by PPROM between 24 + 0 and 36 + 6 weeks of gestation were included. Transabdominal amniocenteses were performed at the time of admission. A bedside assessment of amniotic fluid IL-6 was performed. Maternal serum CRP concentration was also measured at the time of admission. Gingival crevicular fluid was collected from the pocket of the selected tooth (the tooth with the deepest pocket) using standard sterile paper strips within 72 h after admission. Twenty-six proteins in the gingival crevicular fluid were assessed by multiplex the Meso-Scale technology.Results: No correlations between the levels of proteins in the gingival crevicular fluid and maternal serum CRP and amniotic fluid IL-6 concentrations were found, except for a weak positive correlation between granulocyte macrophage colony-stimulating factor and CRP.Conclusions: The local inflammatory response in the gingival crevicular fluid is not related to the maternal and intra-amniotic inflammatory responses in women with PPROM.

The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.

This study was conducted to evaluate the influence of back-fat thickness (BF), at mating of sows, on the maternal and newborn circulating lipids, expression of placental fatty acids (FA) transporters and lipid accumulation in placenta. Full-term placentas were obtained by vaginal delivery from BFI (9-14mm; n=37), BFII (15-19mm; n=43) and BFIII (20-27mm; n=38) sows according to BF at mating, and frozen placental sections were analysed for fat accumulation. Blood samples were collected from the sows of day 105 pregnancy and from cord blood at delivery. mRNA and protein expression levels were evaluated with real-time RT-PCR and Western blotting. Our results demonstrated that BFII females had significantly increased litter weight and placental efficiency, decreased maternal triglyceride (TG) and non-esterified fatty acids (NEFA) levels, decreased maternal IL-6, TNFα and leptin levels compared to BFIII females (p<.05). BFIII sows were associated with significantly decreased newborn TG levels, increased newborn glucose, IL-6 and TNFα levels compared to BFI or BFII sows (p<.05). BFI and BFII females had significantly decreased placental TG, NEFA and cholesterol (CHOL) contents compared to BFIII females (p<.05). Moreover, decreased CD36, FATP1, FABP4, and FABP1 mRNA and protein and FATP4 protein expression, and increased LPL activity were also observed in BFIII group compared with BFII group (p<.05). PPARγ mRNA and protein and lipogenic genes such as SREBP-1c, ACSL1, ACCα, FAS and SCD mRNA expression were downregulated or upregulated, respectively, in the placentas of BFIII sows compared to BFI or BFII sows (p<.05). Overall, this study demonstrated that there is no advantage, in terms of litter live size, litter weight and placental FA transport and metabolism, in performing the mating of sows with BF>19mm.

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

Background/Aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain. Methods: Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [³H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, ‘fetal-units’ (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected. Results: PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [³H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed. Conclusion: Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.