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During gestation, the decidua is an essential layer of the maternal-fetal interface, providing immune support and maintaining inflammatory homeostasis. Although Chlamydia (C.) trachomatis is associated with adverse pregnancy outcomes the pathogenic effects on maternal decidua contributing to adverse events are not understood. This study examined how C. trachomatis antigen affects cell signaling, cell death, and inflammation in the decidua.Primary decidua cells (pDECs) from term, not-in-labor, fetal membrane-decidua were cultured using the following conditions: (1) control - standard cell culture conditions, (2) 100 ng/ml or (3) 200 ng/ml of C. trachomatis antigen to model decidual cell infection in vitro. Differential expression of Toll-like receptor (TLR) 4 (receptor for C. trachomatis antigen), signaling pathway markers phosphorylated TGF-Beta Activated Kinase 1 (PTAB1), TAB1, phosphorylated p38 mitogen-activated protein kinases (Pp38 MAPK), and p38 MAPK (western blot), decidual cell apoptosis and necrosis (flow cytometry), and inflammation (ELISA for cytokines) were determined in cells exposed to C. trachomatis antigen. T-test was used to assess statistical significance (p 0.05).C. trachomatis antigen significantly induced expression of TLR4 (p = 0.03) and activation of TAB1 (p = 0.02) compared to controls. However, it did not induce p38 MAPK activation. In addition, pDECs maintained their stromal cell morphology when exposed to C. trachomatis antigen showing no signs of apoptosis and/or necrosis but did induce pro-inflammatory cytokine interleukin (IL)-6 (100 ng/ml: p = 0.02 and 200 ng/ml: p = 0.03), in pDECs compared to controls.Prenatal C. trachomatis infection can produce antigens that induce TLR4-TAB1 signaling and IL-6 inflammation independent of Pp38 MAPK and apoptosis and necrosis. This suggests that C. trachomatis can imbalance decidual inflammatory homeostasis, potentially contributing to adverse events during pregnancy. This article is protected by copyright. All rights reserved.

Fetal neuroinflammation has been linked to preterm birth-related intraamniotic infection and inflammation; However, the contribution of fetal sex and maternal race/ethnicity is unknown. To determine if fetal sex and maternal race/ethnicity influence neuroinflammation, an organ-on-chip (OOC) model were established under normal or pathologic conditions utilizing amniotic fluid.OOC is composed of two-cell culture chambers connected by Type IV collagen-coated microchannels. Human fetal astroglia (SVGp12) and microglia (HMC3) were co-cultured at an 80:20 ratio in the inner chamber. The outer chamber contained amniotic fluid (AF) from male and female fetuses of White Hispanic (WH) and African-American (AA) pregnant women with or without lipopolysaccharide (LPS-100 ng/ml) and incubated for 48 h. Glial migration (brightfield microscopy), activation (Immunocytochemistry), and cytokine production (Luminex assays) were quantified and compared (N = 4 for each category of sex and race/ethnicity).In a pooled analysis, AF+LPS did not induce glial activation or inflammatory changes compared to AF alone. When stratified by sex, male AF+LPS promoted significant glial activation (high CD11b:p 0.05; low Iba1:p 0.01) compared to male AF without LPS; however, this was not associated with changes in pro-inflammatory cytokines. When stratified by race/ethnicity, AF+LPS induced glial activation in both groups, but a differential increase in pro-inflammatory cytokines was seen between WH and AA AF (WH-interleukin-1β: p 0.05; AA-interleukin-8: p 0.01).This OOC model of fetal neuroinflammation has determined that race/ethnicity differences do exist for perinatal brain injury. The fetal sex of neonates was not a determining factor of susceptibility to intraamniotic inflammation leading to neuroinflammation.

We evaluated relationships between preconception adiposity and human offspring sex and sex ratio. Using data from a prospective preconception cohort nested within a randomized controlled trial based at 4 US clinical sites (2006–2012), we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for male:female sex ratio, and log-identity regression to estimate risk differences (RDs) and 95% CIs for male and female livebirth according to preconception adiposity measures. Inverse-probability weights accounted for potential selection bias. Among 603 women attempting pregnancy, there were meaningful reductions in sex ratio for the highest category of each adiposity measure. The lowest sex ratios were observed for obesity (body mass index of ≥30, calculated as weight (kg)/height (m)2, OR = 0.48, 95% CI: 0.26, 0.88) relative to normal body mass index, and the top tertiles (tertile 3) of serum leptin (OR = 0.50, 95% CI: 0.32, 0.80) and skinfold measurements (OR = 0.50, 95% CI: 0.32, 0.79) relative to the lowest tertiles. Reductions were driven by 11–15 fewer male livebirths per 100 women (for obesity, RD = −15, 95% CI: −23, −6.7; for leptin tertile 3, RD = −11, 95% CI: −20, −3.2; and for skinfolds tertile 3, RD = −11, 95% CI: −19, −3.3). We found that relationships between preconception adiposity measures and reduced sex ratio were driven by a reduction in male births.

Background Mycoplasma genitalium is associated with adverse reproductive problems. However, prevalence estimates from studies that screen women not seeking care are rare. Studies have reported co-occurrence of M. genitalium with bacterial vaginosis (BV), but no prior study of specific BV-associated bacteria has been conducted in African Americans whose reproductive tract infection burden is high. Methods Using quantitative polymerase chain reaction, we screened vaginal swabs for M. genitalium, 9 BV-associated bacteria, and 4 Lactobacillus species from 200 participants drawn from a cohort of African Americans 23 to 35 years old. Sexual history, herpes serostatus, and Nugent score had been assessed. Prevalence of M. genitalium was computed. The associations of other vaginal bacteria with M. genitalium were examined with binomial regression. Results M. genitalium prevalence was 18%. Detection and quantity of 2 BV-associated bacteria were significantly associated with a higher prevalence of M. genitalium (Leptotrichia/Sneathia: detection prevalence ratio (PR) of 2.9 [95% confidence interval {CI}, 1.1-7.7] and quantity PR of 1.2 [95% CI, 1.0-1.3]; Megasphaera phylotype 1: detection PR of 2.2 [95% CI, 1.2-4.2] and quantity PR of 1.1 [95% CI, 1.0-1.2]). Increased quantity of L. iners was also positively associated with M. genitalium (PR, 1.3 [95% CI, 1.0-1.8]). Nugent ≥7, herpes serostatus, and lifetime number of sex partners were not associated with M. genitalium. Conclusions Specific BV-associated microbes and L. iners were associated with M. genitalium, but Nugent ≥7 was not. Studies are needed to confirm a high prevalence of M. genitalium in African Americans and to understand its interactions with other vaginal bacteria.

BACKGROUND: Studies on Chlamydia trachomatis associated pregnancy outcomes are largely conflicting, ignoring the heterogeneous natures of pregnancy complications and potential effect modification by maternal age. This study determined if prenatal Chlamydia trachomatis infection is associated with preterm birth (PTB) and preeclampsia subtypes. METHODS: A retrospective cohort study was conducted using 22,772 singleton pregnancies with a prenatal C. trachomatis diagnostic test. Spontaneous and medically indicated preterm births, term and preterm preeclampsia were outcomes. Modified Poisson regression calculated relative risk (RR) and 95% confidence intervals (CI) with propensity score adjustments stratified by maternal age

Short-chain fatty acids (SCFAs) are by-products from microbial metabolism of fibers with anti-inflammatory effects. SCFAs may mitigate inflammatory conditions such as obesity through modulation of histone acetylation. Lipid metabolism and inflammation play critical roles during pregnancy. However, few studies have examined maternal SCFAs in relation to pregnancy outcomes. This pilot study examined plasma SCFAs in spontaneous preterm birth. This study used stored plasma from an existing cohort to measure seven (proponic acid, methanoic acid, butanoic acid, isovaleric acid, pentanoic acid, methylpropylbutanoic and methylbutanoic acids) SCFAs in 20 women with spontaneous preterm delivery (

To fully enable the development of diagnostic tools and progressive pharmaceutical drugs, it is imperative to understand the molecular changes occurring before and during disease onset and progression. Systems biology assessments utilizing multi-omic analyses (e.g. the combination of proteomics, lipidomics, genomics, etc.) have shown enormous value in determining molecules prevalent in diseases and their associated mechanisms. Herein, we utilized multi-omic evaluations, multi-dimensional analysis methods, and new cheminformatics-based visualization tools to provide an in depth understanding of the molecular changes taking place in preeclampsia (PRE) and gestational diabetes mellitus (GDM) patients. Since PRE and GDM are two prevalent pregnancy complications that result in adverse health effects for both the mother and fetus during pregnancy and later in life, a better understanding of each is essential. The multi-omic evaluations performed here provide new insight into the end-stage molecular profiles of each disease, thereby supplying information potentially crucial for earlier diagnosis and treatments.

This study examined association between foreign-born (FB) status and a sexually transmitted infection (STI) diagnosis of Chlamydia trachomatis, Neisseria gonorrhoeae, or syphilis among a cohort of expecting mothers, and stratified by race/ethnicity. As a secondary analysis, subsequent adverse birth outcomes following STIs were examined. We used data from a large perinatal database to conduct a retrospective cohort study of 37,211 singleton births. Logistic regression was used to determine the association between FB status and STIs. We adjusted for maternal demographics, prior complications, and chronic disease. As a secondary analysis, we examined the association between STIs, and adverse birth outcomes stratified by FB status. FB women had lower odds of STI diagnosis (ORadj 0.81, 95% CI 0.71–0.93); this was observed for each STI. Among Hispanic women, FB status did not reduce odds of STIs (ORadj 0.89, 95% CI 0.76–1.04). However, FB Black women had reduced odds of STIs (ORadj 0.53, 95% CI 0.36–0.79). Secondary analyses revealed that STIs increased odds of adverse birth outcomes among US-born Black women but not US-born Hispanic women. Among FB Black women, STIs increased odds of medically indicated preterm birth (ORadj 3.77, 95% CI 1.19–12.00) and preeclampsia (ORadj 2.35, 95% CI 1.02–5.42). This was not observed among FB Hispanic women. Previous studies suggest that FB women are less likely to have adverse birth outcomes; our study extends this observation to risk of prenatal STIs. However, FB status does not protect Black women against adverse birth outcomes following an STI.

OBJECTIVE: To examine inflammatory mediators in 3 feto-maternal biological compartments to inform the theory that the fetal and maternal inflammatory contributions to parturition at term and preterm. METHODS: We conducted a cross-sectional study of amniotic fluid, cord blood, and maternal plasma from women with singleton pregnancies. Women had 1 of 4 conditions: term labor (n = 11), term not in labor (n = 13), spontaneous preterm birth with intact membranes (preterm birth; n = 13), or preterm prelabor rupture of the membranes (PROM; n = 8). We measured 2 damage-associated molecular pattern markers (high-mobility group box 1 [HMGB1] and uric acid) and 2 acute phase response markers (interleukin [IL]-6 and C-reactive protein [CRP]) using enzyme-linked immunosorbent assay. The distribution of each analyte within amniotic fluid, cord blood, and maternal plasma across the 4 conditions (term not in labor, term labor, preterm birth, and preterm PROM) were calculated. To explore if there were distributional differences in each analyte across each of the 4 labor conditions, we used a nonparametric Kruskal Wallis test. For analytes that differed across groups, we further compared distributions by labor group (term labor vs term not in labor and preterm PROM vs preterm birth). RESULTS: Fetal compartments (amniotic fluid and cord blood) showed higher HMGB1 in term labor vs. term not in labor and preterm PROM vs. preterm birth. Amniotic fluid IL-6, cord blood CRP and cord blood uric acid were higher in term vs term not in labor). Cord blood uric acid was higher in preterm PROM vs preterm birth. Only maternal plasma IL-6 was higher in term labor vs. term not in labor. CONCLUSIONS: Accumulation of HMGB1 and an overall increase in inflammation observed on the fetal side, but not the maternal side, may be signals of parturition. Understanding fetal-derived proparturition inflammatory signals at term and preterm, especially in preterm PROM, might provide fetal-specific biomarkers and identify underlying mechanisms and targets for interventions to reduce the risk of preterm birth and preterm PROM.

Purpose Syndemic theory suggests that the convergence of social, environmental, and ecological factors can interact to exacerbate behavioral health problems and are often intensified by social conditions and disparities. This study used latent class analysis (LCA) to determine gender and racial/ethnic specific classes for sexually transmitted infection (STI) risk. Methods LCA included 18 measured socioeconomic, depression, substance use, and sexual behavioral variables from 1,664 young adults ages 18–25 in the NHANES. Models were stratified by gender and then by race/ethnicity. Logistic regression determined associations between latent class membership and testing positive for one or more STIs (Chlamydia trachomatis, HIV or herpes simplex virus-II). For each stratified analysis, classes with the lowest probability of reported risk factors in the LCA were the reference groups. Results Class 3 in females (highest probability of reporting both socioeconomic and behavioral factors) and class 3 in males (majority behavioral factors) had increased odds of STI (females: OR = 2.7, 95% CI 1.6–4.5; males: OR 2.5, 95% CI 1.3–4.6). By race for females, depression (highest in Hispanics), poverty, and less educated households (highest in blacks and Hispanics) were evident in classes associated with STI. Class 1 black males (majority behavioral factors) had a higher odds of STI compared with low risk white males (OR = 16.4 95% CI 3.7–72.0) However, no other associations were observed among males. Conclusions Risk patterns for STI differed by gender and race/ethnicity. Consistent with syndemic theory, effective STI interventions need to address socioeconomic factors and mental health rather than individual behaviors, particularly for minority women.

Extracellular vesicles play a crucial role in feto-maternal communication and provide an important paracrine signaling mechanism in pregnancy. We hypothesized that fetal cells-derived exosomes and microvesicles (MVs) under oxidative stress (OS) carry unique cargo and traffic through feto-maternal interface, which cause inflammation in uterine cells associated with parturition. Exosomes and MVs, from primary amnion epithelial cell (AEC) culture media under normal or OS-induced conditions, were isolated by optimized differential centrifugation method followed by characterization for size (nanoparticle tracking analyzer), shape (transmission electron microscopy), and protein markers (western blot and immunofluorescence). Cargo and canonical pathways were identified by mass spectroscopy and ingenuity pathway analysis. Myometrial, decidual, and cervical cells were treated with 1 × 107 control/OS-derived exosomes/MVs. Pro-inflammatory cytokines were measured using a Luminex assay. Statistical significance was determined by paired T-test (P < 0.05). AEC produced cup-shaped exosomes of 90–150 nm and circular MVs of 160–400 nm. CD9, heat shock protein 70, and Nanog were detected in exosomes, whereas OCT-4, human leukocyte antigen G, and calnexin were found in MVs. MVs, but not exosomes, were stained for phosphatidylserine. The protein profiles for control versus OS-derived exosomes and MVs were significantly different. Several inflammatory pathways related to OS were upregulated that were distinct between exosomes and MVs. Both OS-derived exosomes and MVs significantly increased pro-inflammatory cytokines (granulocyte-macrophage colony-stimulating factor, interleukin 6 (IL-6), and IL-8) in maternal cells compared with control (P < 0.05). Our findings suggest that fetal-derived exosomes and MVs under OS exhibited distinct characteristics and a synergistic inflammatory role in uterine cells associated with the initiation of parturition. Summary sentence Oxidative stress-induced fetal membrane cells produce exosomes and MVs with distinct properties and cargo and may function as paracrine signalers at the feto-maternal interface during pregnancy and parturition. Graphical Abstract

Low birth weight is an important risk factor for many co-morbidities both in early life as well as in adulthood. Numerous studies report associations between prenatal exposure to particulate matter (PM) air pollution and low birth weight. Previous systematic reviews and meta-analyses report varying effect sizes and significant heterogeneity between studies, but did not systematically evaluate the quality of individual studies or the overall body of evidence. We conducted a new systematic review to determine how prenatal exposure to PM(2.5), PM(10), and coarse PM (PM(2.5–10)) by trimester and across pregnancy affects infant birth weight. Using the Navigation Guide methodology, we developed and applied a systematic review protocol [CRD42017058805] that included a comprehensive search of the epidemiological literature, risk of bias (ROB) determination, meta-analysis, and evidence evaluation, all using pre-established criteria. In total, 53 studies met our inclusion criteria, which included evaluation of birth weight as a continuous variable. For PM(2.5) and PM(10), we restricted meta-analyses to studies determined overall as “low” or “probably low” ROB; none of the studies evaluating coarse PM were rated as “low” or “probably low” risk of bias, so all studies were used. For PM(2.5), we observed that for every 10 μg/m(3) increase in exposure to PM(2.5) in the 2(nd) or 3(rd) trimester, respectively, there was an associated 5.69g decrease (I(2): 68%, 95% CI: −10.58, −0.79) or 10.67g decrease in birth weight (I(2): 84%, 95% CI: −20.91, −0.43). Over the entire pregnancy, for every 10 μg/m(3) increase in PM(2.5) exposure, there was an associated 27.55g decrease in birth weight (I(2): 94%, 95% CI: −48.45, −6.65). However, the quality of evidence for PM(2.5) was rated as “low” due to imprecision and/or unexplained heterogeneity among different studies. For PM(10), we observed that for every 10 μg/m(3) increase in exposure in the 3(rd) trimester or the entire pregnancy, there was a 6.57g decrease (I(2): 0%, 95% CI: −10.66, −2.48) or 8.65g decrease in birth weight (I(2): 84%, 95% CI: −16.83, −0.48), respectively. The quality of evidence for PM(10) was rated as “moderate,” as heterogeneity was either absent or could be explained. The quality of evidence for coarse PM was rated as very low/low (for risk of bias and imprecision). Overall, while evidence for PM(2.5) and course PM was inadequate primarily due to heterogeneity and risk of bias, respectively, our results support the existence of an inverse association between prenatal PM(10) exposure and low birth weight.

OBJECTIVES: Provision of long-acting reversible contraception (LARC) after delivery and prior to discharge is safe and advantageous, yet few Texas hospitals offer this service. Our study describes experiences of Texas hospitals that implemented immediate postpartum LARC (IPLARC) programs, in order to inform the development of other IPLARC programs and guide future research on system-level barriers to broader adoption. METHODS: Eight Texas hospitals that had implemented an IPLARC program were identified, and six agreed to participate in the study. Interviews with 19 key hospital staff covered (1) factors that led the development of an IPLARC program; (2) billing, pharmacy, and administrative operations related to implementation; (3) patient demand and readiness; (4) the consent process; (5) staff training; and (6) hospital plans for monitoring and evaluation of IPLARC services. RESULTS: Most hospitals in this study primarily served Medicaid and un- or under-insured populations. Participants from all six hospitals perceived high levels of patient demand for IPLARC and provider interest in providing this service. The major challenges were related to financing IPLARC programs. Participants from half of the hospitals reported that leadership had concerns about financial viability of providing IPLARC. The hospitals with the longest-running IPLARC programs were safety net hospitals with family planning training programs. CONCLUSIONS FOR PRACTICE: We found that hospitals with IPLARC programs all had strong support from both providers and hospital leadership and had funding sources to offset costs that were not reimbursed. Strategies to reduce the financial risks related to IPLARC provision could provide the impetus for new programs to launch and support their sustainability.

OBJECTIVE: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers. METHODS: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (

ObjectiveAssess risk factors for incident and endometrial Mycoplasma genitalium infection and determine if M. genitalium is associated with histological endometritis, an indicator of pelvic inflammatory disease.MethodsThis study was a secondary data analysis within the T cell Response Against Chlamydia (TRAC) Study, a prospective evaluation of 246 women with or at risk for Chlamydia trachomatis from urban outpatient clinics, who were followed quarterly for 12 months. Risk factors for incident M. genitalium infection were determined by Cox regression. Relative risks were estimated by Poisson regression with robust error measurements for models examining the association between M. genitalium and endometritis (histological evidence of plasma cells in endometrial stroma and neutrophils in the endometrial epithelium) and for models examining risk factors for detection of endometrial M. genitalium infection.ResultsM. genitalium prevalence was 16.7%, incidence was 25.3 per 100 person-years and 23% had repeated positive tests. Black race (non-black HRadj 0.4, 95% CI 0.2 to 0.9), less education (HRadj 2.4, 95% CI 1.2 to 5.1) and a new sexual partner (HRadj 3.1, 95% CI 1.7 to 5.4) were associated with incident M. genitalium. M. genitalium was associated with endometritis (RRadj 2.0, 95% CI 1.1 to 3.7). Trichomonas vaginalis (RRadj 2.0, 95% CI 1.2 to 3.4) and endometrial C. trachomatis (RRadj 1.7, 95% CI 1.1 to 2.8) were associated with endometrial M. genitalium.ConclusionsM. genitalium is prevalent in women at high risk for C. trachomatis, persists over multiple follow-up visits and is associated with histological endometritis. Studies are needed to determine if screening for M. genitalium will improve reproductive outcomes.

VRE are associated with ∼1300 deaths per year in the USA. Recent literature suggests that daptomycin, a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity, is the preferred treatment option for VRE bacteraemia, yet the optimal dosing strategy for this indication has not been established. In vitro evidence suggests that higher-than-labelled doses of daptomycin are required to optimally treat VRE bacteraemia and to inhibit the development of resistance. However, concern of dose-dependent toxicities, notably increases in creatine phosphokinase and the development of rhabdomyolysis, are a barrier to initiating high-dose schemes in clinical practice. Thus, the effectiveness and safety of high-dose daptomycin regimens in clinical practice have remained unclear. While early studies failed to identify differences in mortality, newer, larger investigations suggest high-dose (≥9 mg/kg) daptomycin is associated with reduced mortality in patients with VRE bacteraemia compared with standard (6 mg/kg) dosing regimens. Additionally, the high-dose regimens appear to be safe and may be associated with improved microbiological outcomes. The purpose of this review is to examine the published evidence on the effectiveness and safety of high-dose daptomycin compared with standard dosing regimens for VRE bacteraemia.

Arsenic is a prevalent environmental contaminant, and its folate-dependent methylation is important for detoxification in the body. In this study, we investigated the association between serum folate levels and methylation using data from the US National Health and Nutrition Examination Survey (NHANES) (2003–2012) (N = 11,016). Multivariate linear regression and penalized spline regression models were used to examine the association and possible upper limit of folate level regarding its impact on methylation in children (≤18 years) and adults (>18 years), respectively. Serum folate levels, methylation metabolites including urinary monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), and demographic variables were extracted from NHANES. Results showed that urinary percentage of DMA(V) (%DMA(V)) was positively associated with log(serum folate levels) after adjustment in children (β = 1.93, p

BACKGROUND Ideal management of sexually transmitted infections (STI) may require risk markers for pathology or vaccine development. Previously, we identified common genetic variants associated with chlamydial pelvic inflammatory disease (PID) and reduced fecundity. As this explains only a proportion of the long-term morbidity risk, we used whole-exome sequencing to identify biological pathways that may be associated with STI-related infertility. METHODS We obtained stored DNA from 43 non-Hispanic black women with PID from the PID Evaluation and Clinical Health Study. Infertility was assessed at a mean of 84 months. Principal component analysis revealed no population stratification. Potential covariates did not significantly differ between groups. Sequencing kernel association test was used to examine associations between aggregates of variants on a single gene and infertility. The results from the sequencing kernel association test were used to choose "focus genes" (P < 0.01; n = 150) for subsequent Ingenuity Pathway Analysis to identify "gene sets" that are enriched in biologically relevant pathways. RESULTS Pathway analysis revealed that focus genes were enriched in canonical pathways including, IL-1 signaling, P2Y purinergic receptor signaling, and bone morphogenic protein signaling. CONCLUSIONS Focus genes were enriched in pathways that impact innate and adaptive immunity, protein kinase A activity, cellular growth, and DNA repair. These may alter host resistance or immunopathology after infection. Targeted sequencing of biological pathways identified in this study may provide insight into STI-related infertility.

Background Syndemics theory proposes that diseases may cluster and intensify based on multiple interacting factors. Few studies have compared methods to identify syndemics related to sexually transmitted infection (STI) risk. The purpose of this study is to compare the use of a composite scoring method and latent class analysis to identify syndemics of STI risk. Methods Youth were aged 18–25 who participated in the National Health and Nutrition Examination Survey, 2011–2014 (N=1,803). Syndemic composite scoring was tabulated by an accumulation of indicators by gender, and latent class analysis (LCA) was conducted to extract classes of risk based on indicators reported by gender. The outcome, STIs, was defined as a determinant result for Chlamydia trachomatis, Herpes Simplex Virus type-2, or HIV. The odds of STI were calculated using the patterns of risk by sex adjusted for demographic and poverty indicators. Results Composite score results suggest that males with an accumulation of 3 to 5 syndemic indicators (AOR: 2.10 CI 95% 1.0–4.2) and 6 or more indicators (AOR: 2.84 CI 95% 1.2–6.7) had an increased odds of STI. Similarly, females with 6 or more indicators (AOR: 3.20 CI 95% 1.7–6.0) had increased odds of STI. The LCA suggested that men with the highest probability of smoking and sexual risk behaviors were at increased odds of STI (AOR: 2.42 CI 95% 1.1–5.4), while women exhibit a syndemic of depression, smoking, drug use and sexual risk behaviors (AOR: 2.19 CI 95% 1.2–3.8). Conclusion The co-occurrence of mental health,substance use and smoking were important indicators of STI risk in women. LCA was able to determine indicators that co-occurred in men and women and sexual risk behaviors that differed by gender, while the syndemic scoring show an accumulation of indicators increased STI risk. Disclosure No significant relationships.

To examine the association between early menarche and gestational diabetes mellitus (GDM). Data from the National Health and Nutrition Examination Survey 2007–2012 were used to investigate the association between age at menarche and the risk of GDM at first birth among 5914 women. A growth mixture model was used to detect distinctive menarche onset patterns based on self-reported age at menarche. Logistic regression models were then used to examine the associations between menarche initiation patterns and GDM after adjusting for sociodemographic factors, family history of diabetes mellitus, lifetime greatest Body Mass Index, smoking status, and physical activity level. Among the 5914 first-time mothers, 3.4 % had self-reported GDM. We detected three groups with heterogeneous menarche onset patterns, the Early, Normal, and Late Menarche Groups. The regression model shows that compared to the Normal Menarche Group, the Early Menarche Group had 1.75 (95 % CI 1.10, 2.79) times the odds of having GDM. No statistically significant difference was observed between the Normal and the Late Menarche Group. This study suggests that early menarche may be a risk factor of GDM. Future studies are warranted to examine and confirm this finding.

Objectives To determine if mid-pregnancy circulating immune biomarkers are associated with preeclampsia. Study design Nested case-control study of 410 preeclamptic women and 297 normotensive controls with primiparous singleton pregnancies enrolled in the Danish National Birth Cohort. The mean gestational age in our cohort is 16weeks (range 9–26). Main outcome measures Preeclampsia was defined by blood pressure ⩾140/90mmHg and proteinuria ⩾3g/24h. Serum immune biomarkers included interleukin (IL)-6, IL-6 receptor, IL-4, IL-4 receptor, IL-5, IL-12, IL-2, TNF-α, TNF-β, TNF-receptor, IL-1β, IL-1α, IL-8, IL-10, IFN-γ, IL-18, macrophage migration inhibitory factor, macrophage inflammatory protein, transforming growth factor-beta (TGF-β), and RANTES. Associations with preeclampsia, term preeclampsia and preterm preeclampsia were determined using two logistic regression models; (1) biomarkers were dichotomized by the limit of detection (LOD); (2) on the continuous scale, non-detectable values were imputed by LOD/2 and transformed (base 2). All models were adjusted for body mass index and smoking. Results IL1β was significantly associated with a decrease in the log odds of preeclampsia ( p =0.0065), term preeclampsia ( p =0.0230) and preterm preeclampsia ( p =0.0068). Results were similar for IL4r and preeclampsia ( p =0.0383). In the dichotomized models, detectable TNF-β was significantly associated with preeclampsia (OR adj 1.6, 95% CI 1.1–2.3) and term preeclampsia (OR 1.7, 95% CI 1.1–2.5) but not preterm preeclampsia. Detectable IL6 was significantly with term preeclampsia only (OR 1.5, 95% CI 1.1–2.2). Conclusion Mid-pregnancy circulating IL1β, IL4r, IL6, and TNFβ were associated with preeclampsia. However, results were not consistent across statistical models. As the relationship is complex, future studies should explore cytokine clusters in preeclampsia risk.

Objectives As pelvic inflammatory disease (PID) aetiology is not completely understood, we examined the relationship between select novel bacteria, PID and long-term sequelae. Methods Fastidious bacterial vaginosis (BV)-associated bacteria ( Sneathia (Leptotrichia) sanguinegens , Sneathia amnionii , Atopobium vaginae and BV-associated bacteria 1 (BVAB1)), as well as Ureaplasma urealyticum and Ureaplasma parvum were identified in cervical and endometrial specimens using organism-specific PCR assays among 545 women enrolled in the PID Evaluation and Clinical Health study. Risk ratios and 95% CIs were constructed to determine associations between bacteria, histologically confirmed endometritis, recurrent PID and infertility, adjusting for age, race, gonorrhoea and chlamydia. Infertility models were additionally adjusted for baseline infertility. Results Persistent detection of BV-associated bacteria was common (range 58% for A. vaginae to 82% for BVAB1) and elevated the risk for persistent endometritis (RR adj 8.5, 95% CI 1.6 to 44.6) 30 days post-cefoxitin/doxycycline treatment, independent of gonorrhoea and chlamydia. In models adjusted for gonorrhoea and chlamydia, endometrial BV-associated bacteria were associated with recurrent PID (RR adj 4.7, 95% CI 1.7 to 12.8), and women who tested positive in the cervix and/or endometrium were more likely to develop infertility (RR adj 3.4, 95% CI 1.1 to 10.4). Associations between ureaplasmas and PID sequelae were modest. Conclusions To our knowledge, this is the first prospective study to demonstrate that S. sanguinegens , S. amnionii , BVAB1 and A. vaginae are associated with PID, failure of the Centers for Disease Control and Prevention-recommended treatment to eliminate short-term endometritis, recurrent PID and infertility. Optimal antibiotic regimens for PID may require coverage of novel BV-associated microbes.

PROBLEM Recently characterized interferon epsilon (IFNe) protects against sexually transmitted infections, including genital herpes simplex virus (HSV), in animal models. There are no reports of IFNe in genital tract secretions of pregnant women, and data on IFNe in non-pregnant women are limited. This pilot study is the first to measure concentrations of IFNe in vaginal and cervical secretions during pregnancy and compare values between healthy and genital HSV-infected women. METHOD OF STUDY Vaginal or cervical specimens from 30 pregnant women were obtained from the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) repository. Cervical samples were collected during the first trimester and vaginal samples across pregnancy. Enzyme-linked immunosorbent assay determined concentrations of IFNe (pg/mL). Data for IFNe were log-transformed and compared by maternal demographics, clinical variables, and HSV status using t tests and linear regression. Repeated measures analysis explored trends across pregnancy. RESULTS Among the entire cohort, first trimester concentrations of IFNe in vaginal or cervical secretions decreased as body mass index increased (β = -0.14, P = .0466). Concentrations of vaginal IFNe increased across pregnancy in HSV-infected and healthy women (P = .009). Average vaginal IFNe across pregnancy was lower in women with HSV compared to healthy women (P = .0009). CONCLUSION Interferon epsilon increased across pregnancy, but was less abundant in women with HSV. This pilot investigation cannot make any definitive conclusions. However, animal models suggest that IFNe may protect against STIs. Thus, larger studies are required to validate expression of IFNe in the reproductive tract of pregnant women with and without genital infections.

Assess risk factors for incident and endometrialThis study was a secondary data analysis within the T cell Response Against Chlamydia (TRAC) Study, a prospective evaluation of 246 women with or at risk for

Objective Bacterial vaginosis (BV) is a common condition associated with serious complications including pelvic inflammatory disease (PID). However, the pathogenesis of BV is poorly understood. Toll-like receptors (TLR) are responsible for microbial recognition and elimination through inflammatory responses. TLR variants have been implicated in infectious and inflammatory diseases and may be involved in BV pathogenesis. We conducted a cross-sectional study to determine if TLR variants are associated with BV. Methods Logistic regression was used to test associations between 14 variants assayed in 6 genes (TLR1, TLR2, TLR4, TLR6, TIRAP and MyD88) and BV/intermediate flora among 192 African–American women with clinical PID from the PID Evaluation and Clinical Health (PEACH) Study. Additionally, we examined associations between variants and endometrial BV-associated anaerobes. To account for multiple comparisons a permutated p Results African–American women with PID carrying the AA genotype for TLR2 SNP rs1898830 had a threefold increased rate of BV/intermediate flora (OR 2.9, 95% CI 1.2 to 7.3). This was not significant after accounting for multiple comparisons (p=0.0201). TLR2 variants rs1898830, rs11938228 and rs3804099 were associated with increased endometrial anaerobic gram-negative rods (p=0.0107, p=0.0076 p=0.0121), anaerobic non-pigmented Gram-negative rods (p=0.0231, p=0.0083, p=0.0044), and anaerobic Gram-positive cocci (p=0.0596, p=0.0640, p=0.1459). Conclusions Among African–American women with PID, we observed trends between TLR2 variants, BV/intermediate flora, and BV-associated microbes. This provides some insight into BV pathogenesis. As not all BV-associated microbes may lead to pathology, future studies should focus on associations between TLR variants and individual BV-associated microbes.

Pelvic inflammatory disease (PID), the infection and inflammation of the female upper genital tract, is a condition that can lead to infertility, chronic pelvic pain, and ectopic pregnancy [1]. Microbes such as Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and aerobes and anaerobes commonly associated with bacterial vaginosis (BV) have been implicated in the etiology of PID [2]. Race is a risk factor for PID, as well as chlamydia, gonorrhea, and BV [3–6]. Racial disparities exist in other inflammatory diseases including preterm birth, systemic lupus erythematosus, and cardiovascular disease [7–9]. The reasons for these racial differences are not completely understood. Socioeconomic, behavioral, and psychosocial factors only explain some of the racial disparities [10, 11]. Studies have found that African Americans are more likely to carry alleles that upregulate proinflammatory cytokines including interleukin 6, interleukin 1, and tumor necrosis factor (TNF) [12–14]. This may result in an imbalanced immune response, leading to excessive and harmful inflammation. As African Americans are at increased risk for inflammatory diseases, genetic variations that lead to increased inflammatory responses in the presence of infectious agents may also be more frequent in this group. The innate immune system relies on pattern recognition receptors (PRRs) for microbial recognition. Toll-like receptors (TLRs) are a family of PRRs that are essential for microbial elimination through the induction of inflammatory cytokine and chemokine genes [15]. The adaptor molecules Toll/interleukin-1 receptor domain–containing adaptor protein (TIRAP) and myeloid differentiation primary response protein 88 (MyD88) help to mediate TLR signaling. Examination of human tissues for expression of TLRs has revealed messenger RNA for TLRs 1–9 in uterine epithelium [16]. TLR2 is highly expressed in fallopian tubes and the cervix [17], whereas TLR4 is weakly expressed in fallopian tubes [17], and transcripts of TLR4 and its adaptor MD-2 are not detected in human cervical epithelial cells [18]. TLR2 forms homodimers with itself or heterodimers with TLR1 or TLR6 to bind pathogen ligands, whereas TLR4 requires the adaptor protein MD-2. TLR2 and TLR4 can recognize several bacteria associated with PID, including C. trachomatis, N. gonorrhoeae, and M. genitalium [18–20]. Although TLRs play a critical role in cytokine expression, few studies have examined racial differences in functional TLR polymorphisms. Barreiro et al suggests that variants in TLR genes may result in differential contributions to disease outcomes following infection in different populations [21]. For example, after examining the evolution of TLRs and their contribution to host defense, the authors found that Europeans had a diminished TLR2:TLR1-mediated immune response reducing inflammation. Thus, the authors concluded that those who carry certain alleles may avoid excessive inflammation, possibly inferring a selective advantage [21]. We have previously found that TLR1 variants are associated with C. trachomatis, upper genital tract infection, and reduced pregnancy rates among African American women with PID [22]. As racial disparities in reproductive and infectious diseases exist and TLR genes are involved in immunopathology, our objective was to determine the racial differences in the genotypic distribution of functional TLR variants among women with clinically suspected PID. We hypothesized that African American women would be more likely to carry TLR variants that are reported to increase inflammatory responses compared to white women. In addition, we examined the associations between race, TLR single-nucleotide polymorphisms (SNPs), and upper genital tract infection and inflammation.

Introduction Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls. Methods Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20 weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37 weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age. Results In first trimester samples, IL-12 was associated with preeclampsia (p = 0.0255). IFN-gamma (p = 0.0063), IL1-beta (p = 0.0006), IL5 (p = 0.0422) and TNFr (p = 0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p = 0.0180) and term preeclampsia (p = 0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p = 0.0288). Discussion Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction.

BACKGROUND Natural infection induces partial immunity to Chlamydia trachomatis Identification of chlamydial antigens that induce interferon γ (IFN-) secretion by T cells from immune women could advance vaccine development. METHODS IFN-γ production by CD4+ and CD8+ peripheral blood T cells from 58 high-risk women was measured after coculture with antigen-presenting cells preincubated with recombinant Escherichia coli expressing a panel of 275 chlamydial antigens. Quantile median regression analysis was used to compare frequencies of IFN-γ responses in women with only cervical infection to those in women with endometrial infection and frequencies in women who remained uninfected for over 1 year to those in women who developed incident infection. Statistical methods were then used to identify proteins associated with protection. RESULTS A higher median frequency of CD8+ T-cell responses was detected in women with lower genital tract chlamydial infection, compared with those with upper genital tract chlamydial infection (13.8% vs 9.5%; P =04), but the CD4+ T-cell response frequencies were not different. Women who remained uninfected displayed a greater frequency of positive CD4+ T-cell responses (29% vs 18%; P < .0001), compared with women who had incident infection, while the frequencies of CD8+ T-cell responses did not differ. A subset of proteins involved in central metabolism, type III secretion, and protein synthesis were associated with protection. CONCLUSIONS Investigations in naturally exposed women reveal protective responses and identify chlamydial vaccine candidate antigens.

Background. Chlamydia trachomatis genital tract infection is a major cause of female reproductive morbidity. Risk factors for ascending infection are unknown, and the role for antibody in protection is not well established. Methods. We recruited 225 women from urban outpatient clinics and followed them for a median of 12 months. We performed a cross-sectional analysis of serum anti-chlamydial immunoglobulin G (IgG), behavioral factors, and microbiological factors associated with endometrial infection at enrollment, and a longitudinal analysis of factors associated with incident infection. Results. Oral contraceptives (adjusted relative risk [RR], 2.02 [95% confidence interval {CI}, 1.38–2.97]) and gonorrhea (adjusted RR, 1.66 [95% CI, 1.07–2.60]) were associated with endometrial infection. Gonorrhea (adjusted hazard ratio [HR], 3.09 [95% CI, 1.41–6.78]), cervical infection at enrollment (adjusted HR, 2.33 [95% CI, 1.07–5.11]), and exposure to uncircumcised partners (adjusted HR, 2.65 [95% CI, 1.21–5.82]) or infected partners (adjusted HR, 4.99 [95% CI, 2.66–9.39]) significantly increased the risk of incident infection. Seropositivity was associated with a reduced cervical burden (P < .05) but no differences in rates of ascending infection (adjusted RR, 1.24 [95% CI, .71–2.19]) or incident infection (adjusted HR, 0.94 [95% CI, .52–1.69]). Conclusions. Serum anti-chlamydial IgG is not associated with a lowered rate of ascending or repeat infection. Identification of factors associated with ascending infection and increased risk of incident infection provide guidance for targeted screening of women at increased risk for sequelae.

Chlamydia trachomatis is the most common bacterial sexually transmitted infection in the United States [1] and can lead to serious complications such as pelvic inflammatory disease (PID) and its subsequent sequelae, including ectopic pregnancy, infertility, and chronic pelvic pain [2, 3]. However, some women may develop PID and reproductive sequelae following chlamydial infection, whereas others may not [1, 4–6]. As the mechanisms underlying the pathogenesis of C. trachomatis have yet to be completely elucidated, the reasons for this variability in outcome are unknown. It is known that Chlamydia spp. can infect epithelial cells, causing secretion of proinflammatory cytokines [7–9]. Researchers have suggested that this inflammatory response may be responsible for disease progression [9], especially among those with chronic infections. Thus, it is possible that variations in host innate immune receptor genes may contribute to the variability in outcomes following chlamydial genital tract infection. The innate immune system serves as the first line of defense after exposure to pathogens and depends on pattern recognition receptors (PRRs) for microbial recognition [10–12]. A conserved family of PRRs called the Toll-like receptor (TLR) family [11] is responsible for induction of inflammatory cytokine and chemokine genes and priming of the adaptive immune system that leads to microbial elimination. Ten different TLRs (TLRs 1–10) have been identified in humans, and the overlap between them allows identification of a diverse range of pathogens through ligand binding [10–12]. Adaptor molecules, including myeloid differentiation primary response protein 88 (MyD88) and Toll/interleukin 1 receptor domain–containing adaptor protein (TIRAP), help to mediate TLR signaling [10]. However, as important as TLRs and their adaptor molecules are for a healthy immune response, variations in these genes may lead to an overexuberant or inadequate response, possibly influencing disease progression. Because TLRs are expressed in the reproductive tract [12] and can stimulate proinflammatory genes after binding to a bacterial ligand, it is possible that they may play a role in chlamydial pathogenesis. Studies have examined TLR pathways in chlamydial infections and have suggested a role for TLR2 in cytokine production [13, 14]. O’Connell et al [14] found that TLR2 was required for interleukin 8 (IL-8) expression, whereas TLR4/MD-2 had minimal effects on cytokine production in vitro. Darville et al [13], using a murine model of genital tract infection, found that mice genetically deficient for TLR2 exhibited reduced oviduct pathology and production of select proinflammatory cytokines, whereas TLR4-deficient mice had outcomes similar to wild-type mice. However, very few studies have examined TLRs in C. trachomatis pathogenesis among human subjects. Studies among Dutch white populations have been unable to show any significant associations between functional polymorphisms in the TLR4 and TLR2 genes and C. trachomatis [15–17]. Our objective was to explore the role of TLR2, TLR4, TLR6, MyD88, and TIRAP gene polymorphisms in C. trachomatis infection among women with clinically suspected PID.

Mycoplasma genitaliumis a sexually transmitted pathogen that is increasingly identified among women with pelvic inflammatory disease (PID). AlthoughChlamydia trachomatisandNeisseria gonorrhoeaefrequently cause PID, up to 70% of cases have an unidentified etiology. This paper summarizes evidence linkingM. genitaliumto PID and its long-term reproductive sequelae. Several PCR studies have demonstrated thatM. genitaliumis associated with PID, independent of gonococcal and chlamydial infection. Most have been cross-sectional, although one prospective investigation suggested thatM. genitaliumwas associated with over a thirteenfold risk of endometritis. Further, a nested case-control posttermination study demonstrated a sixfold increased risk of PID amongM. genitaliumpositive patients. Whether or notM. genitaliumupper genital tract infection results in long-term reproductive morbidity is unclear, although tubal factor infertility patients have been found to have elevatedM. genitaliumantibodies. Several lines of evidence suggest thatM. genitaliumis likely resistant to many frequently used PID treatment regimens. Correspondingly,M. genitaliumhas been associated with treatment failure following cefoxitin and doxycycline treatment for clinically suspected PID. Collectively, strong evidence suggests thatM. genitaliumis associated with PID. Further study ofM. genitaliumupper genital tract infection diagnosis, treatment and long-term sequelae is warranted.

Brandie D Taylor, Catherine L HaggertyUniversity of Pittsburgh, Department of Epidemiology, Pittsburgh, PA, USAAbstract: Chlamydia trachomatis is a prevalent sexually transmitted infection that can lead to serious reproductive morbidity. Management and control of C. trachomatis is a challenge, largely due to its asymptomatic nature and our incomplete understanding of its natural history. Although chlamydia screening programs have been implemented worldwide, several countries have observed increasing rates of reported chlamydia cases. We reviewed the literature relating to the long-term complications of C. trachomatis, as well as screening strategies, treatment, and prevention strategies for reducing chlamydia in the population. Articles from 1950–2010 were identified through a Medline search using the keyword “Chlamydia trachomatis” combined with “screening”, “pelvic inflammatory disease”, “endometritis”, “salpingitis”, “infertility”, "ectopic pregnancy”, “urethritis”, “epididymitis”, “proctitis”, “prostatitis”, “reinfection”, “cost-effectiveness”, “treatment”, “vaccines”, or “prevention”. Progression of C. trachomatis varies, and recurrent infections are common. Currently, there is limited evidence on the effectiveness of chlamydia screening. Higher quality studies are needed to determine the efficacy of more frequent screening, on a broader range of sequelae, including infertility and ectopic pregnancy, in addition to pelvic inflammatory disease. Studies should focus on delineating the natural history of recurrent infections, paying particular attention to treatment failures. Furthermore, alternatives to screening, such as vaccines, should continue to be explored.Keywords: Chlamydia trachomatis, sexually transmitted disease, chlamydia screening, chlamydia treatment

Background Fetal endocrine signals are generally considered to contribute to the timing of birth and the initiation of labor. Fetal tissues under oxidative stress release inflammatory mediators that lead to sterile inflammation within the maternal-fetal interface. Importantly, these inflammatory mediators are packaged into exosomes, bioactive cell-derived extra cellular vesicles that function as vectors and transport them from the fetal side to the uterine tissues where they deposit their cargo into target cells enhancing uterine inflammatory load. This exosome-mediated signaling is a novel mechanism for fetal-maternal communication. Objective This report tested the hypothesis that oxidative stress can induce fetal amnion cells to produce exosomes, which function as a paracrine intermediary between the fetus and mother and biochemically signal readiness for parturition. Study Design Primary amnion epithelial cells were grown in normal cell culture (control) or exposed to oxidative stress conditions (induced by cigarette smoke extract). Exosomes were isolated from cell supernatant by sequential ultracentrifugation. Exosomes were quantified and characterized based on size, shape, and biochemical markers. Myometrial, decidual, and placental cells (BeWo) were treated with 2 × 105, 2 × 107, and 2 × 109 control or oxidative stress–derived amnion epithelial cell exosomes for 24 hours. Entry of amnion epithelial cell exosomes into cells was confirmed by confocal microscopy of fluorescent-labeled exosomes. The effect of amnion epithelial cell exosomes on target cell inflammatory status was determined by measuring production of interleukin-6, interleukin-8, interleukin-1β, tumor necrosis factor-α, and prostaglandin E2 by enzyme-linked immunosorbent assay and inflammatory gene transcription factor (nuclear factor-κβ) activation status by immunoblotting for phosphorylated RelA/p65. Localization of NANOG in term human myometrium and decidua obtained from women before labor and during labor was performed using immunohistochemistry. Data were analyzed by Wilcoxon-Mann-Whitney test to compare effects of exosomes from control and oxidative stress-treated amnion epithelial cells on inflammatory status of target cells. Results Amnion epithelial cells released ∼125 nm, cup-shaped exosomes with ∼899 and 1211 exosomes released per cell from control and oxidative stress–induced cells, respectively. Amnion epithelial cell exosomes were detected in each target cell type after treatment using confocal microscopy. Treatment with amnion epithelial cell exosomes increased secretion of interleukin-6, interleukin-8, and PGE2 and activation of NF-κβ (each P Conclusion In vitro, amnion epithelial cell exosomes lead to an increased inflammatory response in maternal uterine cells whereas placental cells showed refractoriness. Fetal cell exosomes may function to signal parturition by increasing maternal gestational cell inflammation.

Problem: A handful of studies report sexual dimorphism in the maternal angiogenic profile possibly influencing placental development and preeclampsia risk. This secondary analysis explored associations between fetal sex and soluble fms-like tyrosine kinase-1 (sFLT) and endoglin (9-35 weeks gestation) using data from a nested case-control study within the Danish National Birth Cohort. Method of study: A total of 448 preeclamptic women and 328 normotensive women had data on sFLT and endoglin. Preeclampsia was defined by blood pressure ≥140/90 mm Hg and proteinuria (≥0.3g or 300 mg/24 h.). Generalized linear models adjusting for gestational age of blood draw, body mass index, maternal age, and smoking determined associations between fetal sex and log-transformed biomarkers. Results: Male fetal sex is associated with 11% lower sFLT levels (β = −0.11, P = 0.03) in preeclamptic women. There were no differences observed in normotensive women. We found no statistically significant differences in endoglin by fetal sex among groups. Conclusion: Our results are similar with other studies suggesting that women with female fetuses have increased sFLT levels. However, significant difference was only among women with preeclampsia. This study was exploratory and longitudinal investigations across pregnancy are required to understand the relationship between fetal sex and systemic maternal angiogenic biomarkers.

Problem Oxidative stress (OS)-induced, p38 mitogen-activated protein kinase (p38MAPK)-mediated chorioamniotic senescence and inflammation (senescence-associated secretory phenotype [SASP]) are associated with parturition. In response to OS-inducing risk factors, premature senescence contributes to preterm premature rupture of the membranes (pPROM) and spontaneous preterm birth (PTB). We determined the effect of simvastatin, rosuvastatin, and progesterone in downregulating p38MAPK-mediated senescence and SASP. Method of study Normal term, not-in-labor fetal membranes (n = 8) were exposed to cigarette smoke extract (CSE: OS inducer) alone or combined with simvastatin (100 and 200 ng/mL), rosuvastatin (100 and 200 ng/mL), and progesterone (10-6 mol/L). p38MAPK expression changes were studied by Western blot, senescence was determined by senescence-associated β-Galactosidase (SA-β-Gal) staining, and multiplex analysis determined changes associated with 4 SASP markers (IL-8, IL-10, TNF-α, and GM-CSF). A pairwise comparison between groups was conducted by ANOVA. Results Compared to untreated controls, CSE induced p38MAPK-mediated senescence and SASP. CSE cotreatment with simvastatin and rosuvastatin significantly reduced p38MAPK activation, senescence (decrease in SA-β-Gal) and SASP markers, GM-CSF, and TNF, but not IL-8, while increasing anti-inflammatory IL-10 in a dose-dependent manner. Cotreatment of CSE and progesterone had no effect on reducing p38MAPK activation, senescence, or SASP. Conclusion Both simvastatin and rosuvastatin downregulated OS-induced p38MAPK activation, senescence, and SASP, while rosuvastatin showed a pronounced effect. Progesterone did not reduce OS-induced fetal membrane senescence and SASP. Simvastatin or rosuvastatin may reduce the incidences of OS-associated PTB and pPROM by preventing premature senescence and SASP.

Problem Toll-like (TLR) receptor genetic variants have been implicated in bacterial vaginosis (BV). We determined whether TLR variants are associated with fastidious BV-associated microbes that are linked with infertility following pelvic inflammatory disease (PID). Method of study Sneathia spp., Atopobium vaginae, BVAB1, and Ureaplasma urealyticum were measured in 250 women from the PID Evaluation and Clinical Health (PEACH) study. Relative risk (RR) and 95% confidence intervals (CI) were calculated adjusting for chlamydia and gonorrhea. Principal component analysis was used to adjust for population stratification. A false discovery rate q-value of 0.05 was significant. Results TLR2-1733C>A (P = .003) and TLR2-616A>G (P = .004) were associated with cervical A. vaginae. TLR2-1733C>A and TLR6-438C>T were associated with A. vaginae detection in the endometrium, but this was not significant after adjustment for multiple comparisons (FDR q-value = 0.06). Conclusion Host gene variants in TLR2 signaling pathways were modestly associated with cervical A. vaginae in women with clinical PID.

Background Since the landmark study conducted by Huggins and Hodges in 1941, a failure to distinguish between the role of testosterone in prostate cancer development and progression has led to the prevailing opinion that high levels of testosterone increase the risk of prostate cancer. To date, this claim remains unproven. Presentation of the hypothesis We present a novel dynamic mode of the relationship between testosterone and prostate cancer by hypothesizing that the magnitude of age-related declines in testosterone, rather than a static level of testosterone measured at a single point, may trigger and promote the development of prostate cancer. Testing the hypothesis Although not easily testable currently, prospective cohort studies with population-representative samples and repeated measurements of testosterone or retrospective cohorts with stored blood samples from different ages are warranted in future to test the hypothesis. Implications of the hypothesis Our dynamic model can satisfactorily explain the observed age patterns of prostate cancer incidence, the apparent conflicts in epidemiological findings on testosterone and risk of prostate cancer, racial disparities in prostate cancer incidence, risk factors associated with prostate cancer, and the role of testosterone in prostate cancer progression. Our dynamic model may also have implications for testosterone replacement therapy.

Made available in DSpace on 2015-12-07T15:31:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2015. Added 1 bitstream(s) on 2015-12-07T15:52:45Z : No. of bitstreams: 1 PMC4580414.pdf: 8286022 bytes, checksum: 53177f4f8c45fc0ba7b10a9f5c72cf41 (MD5) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Oxidative stress (OS)-induced senescence of the amniochorion has been associated with parturition at term. We investigated whether telomere fragments shed into the amniotic fluid (AF) correlated with labor status and tested if exogenous telomere fragments (T-oligos) could induce human and murine amnion cell senescence. In a cross-sectional clinical study, AF telomere fragment concentrations quantitated by a validated real-time PCR assay were higher in women in labor at term compared to those not in labor. In vitro treatment of primary human amnion epithelial cells with 40 μM T-oligos ([TTAGGG]2) that mimic telomere fragments, activated p38MAPK, produced senescence-associated (SA) β-gal staining and increased interleukin (IL)-6 and IL-8 production compared to cells treated with complementary DNA sequences (Cont-oligos, [AATCCC]2). T-oligos injected into the uteri of pregnant CD1 mice on day 14 of gestation, led to increased p38MAPK, SA-β-gal (SA β-gal) staining in murine amniotic sacs and higher AF IL-8 levels on day 18, compared to saline treated controls. In summary, term labor AF samples had higher telomere fragments than term not in labor AF. In vitro and in situ telomere fragments increased human and murine amnion p38MAPK, senescence and inflammatory cytokines. We propose that telomere fragments released from senescent fetal cells are indicative of fetal cell aging. Based on our data, these telomere fragments cause oxidative stress associated damages to the term amniotic sac and force them to release other DAMPS, which, in turn, provide a sterile immune response that may be one of the many inflammatory signals required to initiate parturition at term. Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America; Department of Pathology, Botucatu Medical School, UNESP-Univ. Estadual Paulista, Botucatu, Sao Paulo, Brazil. Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America. Department of Epidemiology & Biostatistics, Texas A&M University System Health Science Center, College Station, Texas, United States of America. Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, North Carolina, United States of America. Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America; Department of Pathology, Botucatu Medical School, UNESP-Univ. Estadual Paulista, Botucatu, Sao Paulo, Brazil.

Study hypothesis In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture. Study finding We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation. What is known already Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. Study design, samples/materials, methods Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups. Main results and the role of chance Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROM had higher numbers of cells with DNA damage, prosenescence stress kinase (p38 MAPK) activation and signs of senescence. Limitations, reasons for caution Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM. Wider implications of the findings Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome. Study funding and competing interests This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of Texas Medical Branch at Galveston and funds to Dr M. Kacerovský from the Ministry of Health Czech Republic (UHHK, 001799906). The authors report no conflict of interest.

Leptin, an adipocyte-derived hormone, plays an important role in reproduction and angiogenesis. Studies examining leptin in preeclampsia are inconsistent, possibly because of small sample sizes and variability in sampling and outcome. We conducted a nested case–control study to examine associations between serum leptin (measured: 9–26 weeks gestation) and preeclampsia among 430 primiparous preeclamptic women and 316 primiparous normotensive controls from the Danish National Birth Cohort. Median (interquartile range) leptin concentrations were calculated. Associations between leptin and preeclampsia (blood pressure ≥140/90 mm Hg), term preeclampsia (preeclampsia and delivery ≥37 weeks gestation), or preterm preeclampsia (preeclampsia and delivery P =0.0117) and term preeclampsia (30.4 [24.9]; P =0.0228) compared with controls (20.9 [28.3]). There was no significant difference between preterm preeclampsia (30.6 [23.4]; P =0.2210) and controls. Leptin is a possible mediator of the association between body mass index and preeclampsia ( P =0.0276). Leptin concentrations are higher in women with preeclampsia compared with normotensive controls and may mediate some of the relationship between body mass index and preeclampsia.

Bacterial vaginosis (BV) is a common condition associated with serious complications including pelvic inflammatory disease (PID). However, the pathogenesis of BV is poorly understood. Toll-like receptors (TLR) are responsible for microbial recognition and elimination through inflammatory responses. TLR variants have been implicated in infectious and inflammatory diseases and may be involved in BV pathogenesis. We conducted a cross-sectional study to determine if TLR variants are associated with BV.Logistic regression was used to test associations between 14 variants assayed in 6 genes (TLR1, TLR2, TLR4, TLR6, TIRAP and MyD88) and BV/intermediate flora among 192 African-American women with clinical PID from the PID Evaluation and Clinical Health (PEACH) Study. Additionally, we examined associations between variants and endometrial BV-associated anaerobes. To account for multiple comparisons a permutated p0.003 was used to determine statistical significance.African-American women with PID carrying the AA genotype for TLR2 SNP rs1898830 had a threefold increased rate of BV/intermediate flora (OR 2.9, 95% CI 1.2 to 7.3). This was not significant after accounting for multiple comparisons (p=0.0201). TLR2 variants rs1898830, rs11938228 and rs3804099 were associated with increased endometrial anaerobic gram-negative rods (p=0.0107, p=0.0076 p=0.0121), anaerobic non-pigmented Gram-negative rods (p=0.0231, p=0.0083, p=0.0044), and anaerobic Gram-positive cocci (p=0.0596, p=0.0640, p=0.1459).Among African-American women with PID, we observed trends between TLR2 variants, BV/intermediate flora, and BV-associated microbes. This provides some insight into BV pathogenesis. As not all BV-associated microbes may lead to pathology, future studies should focus on associations between TLR variants and individual BV-associated microbes.