Predictive potential of various plasma inflammation-, angiogenesis-, and extracellular matrix remodeling-associated mediators for intra-amniotic inflammation and/or microbial invasion of the amniotic cavity in preterm labor.

PURPOSE: To determine whether various inflammatory-, angiogenic/anti-angiogenic-, and extracellular matrix remodeling-associated proteins in plasma, alone or in combination with conventional blood-based markers, can predict intra-amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with spontaneous preterm labor (PTL). METHODS: A total of 193 singleton pregnant women with PTL (23-33 weeks) were included in this retrospective cohort study. Plasma samples were obtained at the time of amniocentesis. Amniotic fluid (AF) was cultured for microorganism detection and consequent MIAC diagnosis. IL-6 levels were determined in AF and used to identify IAI (AF IL-6 ≥ 2.6 ng/mL). Endostatin, haptoglobin, IGFBP-2/3, LBP, M-CSF, MMP-2/8, pentraxin 3, PlGF, S100A8/A9, and VEGFR-1 levels were assayed in plasma samples by ELISA. CRP levels and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Plasma LBP, MMP-8, and S100A8/A9 levels, CRP levels, and NLR were significantly higher, and plasma IGFBP-2 and MMP-2 levels were significantly lower in women with IAI/MIAC than in those without this condition, whereas no baseline variables differed significantly between the two groups. Using a stepwise regression analysis, a noninvasive prediction model for IAI/MIAC was developed, which included plasma LBP, MMP-2, and MMP-8 levels (area under the curve [AUC], 0.785). The AUC for this prediction model was significantly or borderline greater than that of any single factor included in the model. CONCLUSIONS: IGFBP-2, LBP, MMP-2, MMP-8, and S100A8/A9 may represent valuable plasma biomarkers for predicting IAI/MIAC in women with PTL. Combination of LBP, MMP-2, and MMP-8 expression data can significantly improve the predictive potential for IAI/MIAC.

A prospective cohort study of postpartum glucose metabolic disorders in early versus standard diagnosed gestational diabetes mellitus.

Early gestational diabetes mellitus (eGDM) is diagnosed when fasting plasma glucose before 24 weeks of gestation (WG) is ≥ 5.1 mmol/L, whilst standard GDM is diagnosed between 24 and 28 WG by oral glucose tolerance test (OGTT). eGDM seems to have worse obstetric outcomes than standard GDM. We compared the rates of postpartum glucose metabolism disorders between women with early versus standard GDM in this prospective study on women with GDM from three university hospitals between 2014 and 2016. Patients were included if they were < 24 WG with at least one risk factor for GDM and excluded if they had type 2 diabetes. Patients were assigned to Group 1 (G1) for eGDM according to IADPSG: fasting blood glucose < 24 WG between 5.1 and 7 mmol/L. Group 2 (G2) consisted of patients presenting a standard GDM at 24-28 WG on OGTT results according to IADPSG: T0 ≥ 5.1 mmol/L or T60 ≥ 10.0 mmol g/L or T120 ≥ 8.5 mmol/L. The primary outcome was postpartum OGTT result. Five hundred patients were analysed, with 273 patients undergoing OGTT at 4-18 weeks postpartum: 192 patients in G1 (early) and 81 in G2 (standard). Patients in G1 experienced more insulin therapy during pregnancy than G2 (52.2% versus 32.5%, p < 0.001), but no patients were taking insulin postpartum in either group. G1 patients experienced less preterm labour (2.6% versus 9.1%, p = 0.043), more induced deliveries (38% versus 25%, p = 0.049) and reduced foetal complications (29.2% versus 42.0%, p = 0.048). There was no significant difference in the rate of postpartum glucose metabolism disorders (type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia) between groups: 48/192 (25%) in G1 and 17/81 (21%) in G2, p = 0.58. Thus the frequency of early postpartum glucose metabolism disorders is high, without difference between eGDM and standard GDM. This supports measurement of fasting plasma glucose before 24 WG and the threshold of 5.1 mmol/L seems appropriate until verification in future studies.Trial registration: NCT01839448, ClinicalTrials.gov on 22/04/2013.

Effects of Relaxation-Focused Nursing Care in Women in Preterm Labor.

BACKGROUND: Threatened preterm labor is a common problem that causes women to be hospitalized. During this period, physical problems such as a decrease in muscle functions, edema and pain, and psychological problems such as anxiety and stress may develop. OBJECTIVE: This study aimed to investigate the effect of relaxation-focused nursing care state anxiety, cortisol, contraction severity, nursing care satisfaction, knowledge, and birth weeks on threatened preterm labor. METHOD: This study was a pre-post single-blind randomized controlled trial. The study was conducted with 66 women in the threatened preterm labor process, 33 in the intervention group and 33 in the control group. The intervention group received relaxation-focused nursing care, which comprises a 2-day program in four stages. The data were collected before and after the relaxation-focused nursing care, and after the birth. RESULTS: In the intervention group, state anxiety, cortisol level, and contraction severity were lower than those in the control group (p < .05). The knowledge level about threatened preterm labor, satisfaction from nursing care, and birth weeks were higher in the intervention group (p < .05). CONCLUSION: Relaxation-focused nursing care was found to reduce the state anxiety in women, improve the knowledge level about threatened preterm labor and birth weeks, and decrease the level of cortisol. Therefore, it is recommended to use relaxation-focused nursing care in threatened preterm labor.

Alpha-2-macroglobulin from circulating exosome-like vesicles is increased in women with preterm pregnancies.

Preterm labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) impose substantial morbimortality on mothers and newborns. Exosomes act in intercellular communication carrying molecules involved in physiopathological processes. Little is known about exosomal proteins in prematurity. Our aim was to evaluate the protein expression of hemopexin, C1 inhibitor (C1INH) and alpha-2-macroglobulin (A2M) from circulating exosomes of women with PTL and PPROM. Plasma was obtained from PTL, PPROM, Term in labor and Term out of labor (T) patients, exosomes were isolated by ultracentrifugation, then lysed and the proteins quantified. Western Blot (WB) and Nanoparticle Tracking Analysis (NTA) were performed. Data were compared by Kruskal-Wallis, unpaired T-test and one-way ANOVA. WB and NTA confirmed exosome isolation (concentration: 4.3 × 1010 particles/ml ± 1.9 × 1010). There was no difference regarding hemopexin or C1INH expression between the groups. For A2M, the fold change was significantly higher on preterm groups when compared to term groups (1.07 ± 0.30 vs. 0.42 ± 0.17, p < 0.0001). Higher levels of A2M in circulating exosomes are linked to preterm pregnancies. sEV are strong candidates to intermediate maternal-fetal communication, carrying preterm labor-related immunomodulatory proteins.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

Is maternal serum inhibin A a good predictor in preterm labor? - Experience from a community hospital in Taiwan.

BACKGROUND: We aimed to determine whether inhibin A could be a reliable and accurate predictor of preterm birth, and discuss the possible pathogenic processes of inhibin A leading to preterm birth. METHODS: A retrospective cohort study was conducted on consecutive singleton pregnant women who underwent the second-trimester quad screen test at a gestational age of 15-20 weeks at Keelung Chang-Gung Memorial Hospital from March 2011 to May 2015. Data including maternal characteristics and pregnancy outcomes were collected from an electric medical record database. Data regarding pregnancy terminations before a gestational age of 24 weeks and regarding pregnancies that involved chromosomal or congenital anomalies were excluded from this analysis. One-way analysis of variance was used to compare second-trimester α-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A in women with preterm deliveries versus those with term deliveries. RESULTS: Although a total of 935 women with singleton pregnancies were enrolled, pregnancy outcome and complete maternal data were obtained from only 770 (82.3%)of them. In total, 687 (89.2%) women delivered at or after 37 weeks of gestation and 83 (10.8%) women delivered before 37 weeks of gestation. The results showed that the inhibin A level was significantly increased in the preterm labor group (p = 0.009). A cutoff inhibin A value above 2.25 was identified statistical significantly in the preterm labor group. CONCLUSIONS: From our results, an inhibin A level above 2.25 multiples of the median in the quad screen test may be associated with preterm labor afterward. Closely monitoring for uterine contractions or cervical length measurement in the second trimester may be indicated in patients with unexplained elevated inhibin A levels.

Comparison of term and preterm labor procalcitonin and leukocyte cell volume, conductivity and light scatter (VCS) parameters in order to demonstrate the impact of inflammation on the triggering mechanisms of preterm uterin contractions.

AIM: Comparison of mean channels of cell volume, conductivity and light scatter (VCS) parameters of neutrophil, monocyte and lymphocyte, procalcitonin (PCT) and white blood cell count (WBC) during term and preterm labor to evaluate the impact of inflammation on the triggering mechanisms of uterine contractions. METHODS: This study is consisted of 16 preterm and 60 term pregnancies at the beginning of the first stages of the labor. Leukocyte VCS parameters, PCT plasma levels and WBC count were evaluated. RESULTS: We could not demonstrate statistically significant difference in between leukocyte VCS parameters in preterm and term deliveries (P ˃ 0.050 for all). WBC counts were 10.6 and 11.8 × 103 /µL in the preterm and term groups respectively (P = 0.270). PCT levels were 0.04 and 0.03 ng/mL for preterm and term pregnancies (P = 0.062). CONCLUSION: Inflammation related markers such as leukocyte VCS parameters, PCT values and WBC count does not differentiate at the first stage of labor in preterm and term deliveries. These variables do not seem to have a prominent role at the biological events behind preterm contractions.

Cell-Free Fetal DNA Increases Prior to Labor at Term and in a Subset of Preterm Births.

Cell-free fetal DNA in the maternal circulation has been associated with the onset of labor at term. Moreover, clinical studies have suggested that cell-free fetal DNA has value to predict pregnancy complications such as spontaneous preterm labor leading to preterm birth. However, a mechanistic link between cell-free fetal DNA and preterm labor and birth has not been established. Herein, using an allogeneic mouse model in which a paternal green fluorescent protein (GFP) can be tracked in the fetuses, we established that cell-free fetal DNA (Egfp) concentrations were higher in late gestation compared to mid-pregnancy and were maintained at increased levels during the onset of labor at term, followed by a rapid decrease after birth. A positive correlation between cell-free fetal DNA concentrations and the number of GFP-positive pups was also observed. The increase in cell-free fetal DNA concentrations prior to labor at term was not linked to a surge in any specific cytokine/chemokine; yet, specific chemokines (i.e., CCL2, CCL7, and CXCL2) increased as gestation progressed and maintained elevated levels in the postpartum period. In addition, cell-free fetal DNA concentrations increased prior to systemic inflammation-induced preterm birth, which was associated with a strong cytokine response in the maternal circulation. However, cell-free fetal DNA concentrations were not increased prior to intra-amniotic inflammation-induced preterm birth, but in this model, a mild inflammatory response was observed in the maternal circulation. Collectively, these findings suggest that an elevation in cell-free fetal DNA concentrations in the maternal circulation precedes the physiological process of labor at term and the pathological process of preterm labor linked with systemic inflammation, but not that associated with intra-amniotic inflammation.

A Protein Microarray Analysis of Plasma Proteins for the Prediction of Spontaneous Preterm Delivery in Women with Preterm Labor.

We aimed to identify novel biomarkers in maternal plasma that predict spontaneous preterm delivery (SPTD) in women with preterm labor (PTL) using an antibody microarray and to develop the best prediction model for SPTD based on these biomarkers in combination with clinical and ultrasound factors. This retrospective cohort study included 215 women with singleton pregnancies and PTL (23-33 weeks) who gave plasma samples. In a nested case-control study design, plasma proteomes from SPTD (case subjects, n = 15) and term delivery (control subjects, n = 15) groups were differentially profiled using a membrane-based antibody microarray. Six candidate biomarkers of interest were validated by enzyme-linked immunosorbent assay (ELISA) in the total cohort (n = 215). Cervical lengths were also measured. The primary outcome measure was SPTD within 48 h after sampling. Twenty of the molecules studied displayed significant intergroup differences. Validation by ELISA confirmed significantly higher levels of plasma endostatin and lipopolysaccharide binding protein (LBP) in women who had SPTD within 48 h than in those delivering after 48 h. However, plasma macrophage inflammatory protein (MIP)-1α levels were significantly lower in women who delivered within 48 h. A combined model was developed to predict SPTD within 48 h using a stepwise regression procedure, which included plasma endostatin and LBP levels, nulliparity, and cervical length (area under the curve = 0.920). Plasma LBP, endostatin, and MIP-1α are potential new biomarkers for predicting imminent SPTD and a combined noninvasive model based on these biomarkers and clinical and ultrasound factors can accurately predict imminent SPTD in women with PTL.

The diagnostic value of fetal fibronectin testing in clinical practice.

AIM: To evaluate the clinical management to withhold treatment for preterm labor in symptomatic women with an intermediate cervical length and negative fetal fibronectin (fFN) testing. METHODS: A retrospective cohort study was performed in a tertiary care teaching hospital in the Netherlands. Pregnant women with a gestational age between 23+5 to 34+0 weeks, with the presence of regular uterine contractions accompanied by a cervical length between 15 and 30 mm and intact membranes, who underwent fFN testing were included to obtain the diagnostic value of fFN testing for preterm delivery within 7 days. RESULTS: Fetal fibronectin testing has an extremely high negative predictive value (100%) and sensitivity (100%) for delivery within 7 days, in singleton and multiple pregnancies. However, specificity (64%) and positive predictive value (10%) of fFN testing in singleton pregnancies are low. Blood present on the fFN sample does not affect the reliability of the fFN test; the negative predictive value remains 100%. CONCLUSION: Women with symptoms of early preterm labor, intact membranes, a cervical length between 15 and 30 mm and negative fFN testing do not deliver within 7 days. Administration of corticosteroids and tocolytics can safely be withhold. Furthermore, blood on the fFN sample does not change the reliability of the fFN test.

Hypoxia-inducible factor-1α, hepcidin and interleukin-6 levels in pregnancies with preterm labour.

The aim of the study was to investigate whether serum hypoxia-inducible factor-1alpha (HIF-1α), hepcidin and interleukin-6 (IL-6) concentrations differed between threatened preterm labour (TPL) and uncomplicated pregnancies. This study was conducted on 54 women with TDL pregnancies and 26 healthy pregnant women. The TPL group was further divided into two subgroups according to the gestational age at delivery. Patients who gave birth within 48-72 h after the hospitalisation were referred to as preterm delivery (PD) and who gave birth at ≥37 weeks were referred to as term delivery (TD). Maternal levels of serum HIF-1α, hepcidin and IL-6 were measured with the use of enzyme-linked immunosorbent assay kits. The mean maternal serum HIF-1α, hepcidin and IL-6 levels of PD were significantly higher than TD (p < .001*) and control group (p < .001*). The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group (p=.058, p = .064). The mean maternal serum IL-6 level of TD was significantly higher than the control group (p < .001*). A negative correlation was found between serum concentration of HIF1α, hepcidin, IL-6 with the gestational week of delivery (r = -0.421, p < .01* for HIF-1α; r = -0.578, p < .01* for hepcidin and r = -0.435, p < .01* for IL-6). High levels of HIF-1α, hepcidin and IL-6 may have potential to be used as biomarkers for the differentiation of PD and TD.Impact statementWhat is already known on this subject? It is known that hypoxia-inducible factor-1alpha (HIF-1α) is a hypoxia marker and hepcidin and interleukin-6 (IL-6) increase in inflammation. Our study is the comparison of maternal serum HIF-1α, hepcidin and IL-6 levels between the TPL group (TD and PD) and healthy control group.What the results of this study add? The present study demonstrates that serum HIF-1α, hepcidin and IL-6 levels were significantly higher in TPD group than uncomplicated group. The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group.What the implications are of these findings for clinical practice and/or further research? High levels of HIF-1α, hepcidin and IL-6 may be biomarkers in the determination of true preterm labour within the TPL group.

Prediction of preterm labour from a single blood test: The role of the endocannabinoid system in predicting preterm birth in high-risk women.

OBJECTIVE: To determine if plasma concentrations of the N-acylethanolamines (NAEs) N-arachidonoylethanolamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) increase in women at high risk for preterm birth (PTB) and whether these could be used to predict preterm delivery and if so, how they compare with current methods. DESIGN: Prospective cohort study. SETTING: A large UK teaching hospital. POPULATION: 217 pregnant women were recruited between 24 and 34 gestational weeks at 'high-risk' for PTB, recruited from a prematurity prevention clinic or antenatal wards. METHODS: Plasma AEA, OEA, and PEA concentrations were measured using ultra-high performance liquid chromatography-tandem mass spectrometry whilst FAAH enzyme activity was measured by fluorometric radiometric assay and CL by ultrasound scan. The clinical usefulness of these measurements were determined by ROC and multivariate analyses. RESULTS: AEA and PEA concentrations were significantly higher in women who delivered prematurely. An AEA concentration >1.095 nM predicted PTB, the gestational age at delivery and the recruitment to delivery interval (RTDI). A PEA concentration >17.50 nM only predicted PTB; FAAH enzyme activity was not related to these changes. Multivariate analysis (all variables) generated an equation to accurately predict the RTDI. CONCLUSIONS: A single plasma AEA or PEA measurement can predict PTB. A single AEA measurement predicts the gestational age of delivery and the remaining period of pregnancy with reasonable accuracy and better than existing conventional tests thus offering a better window for primary prevention of PTB.

Exploring Inflammatory Mediators in Fetal and Maternal Compartments During Human Parturition.

OBJECTIVE: To examine inflammatory mediators in three fetomaternal biological compartments to inform theory related to 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 one of four 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 membranes (PROM; n=8). We measured two damage-associated molecular pattern markers (high-mobility group box-1 [HMGB1] and uric acid) and two 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 four conditions (term not in labor, term labor, preterm birth, and preterm PROM) were calculated. To explore whether there were distributional differences in each analyte across each of the four 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. CONCLUSION: 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.

MicroRNA-transcriptome networks in whole blood and monocytes of women undergoing preterm labour.

Preterm birth is attributed to neonatal morbidity as well as cognitive and physiological challenges. We have previously identified significant differences in mRNA expression in whole blood and monocytes, as well as differences in miRNA concentration in blood plasma, extracellular vesicles (EV) and EV-depleted plasma in women undergoing spontaneous preterm labour (sPTL). The goal of this analysis was to identify differences in miRNA expression within whole blood (WB) and peripheral monocytes (PM) from the same population of women undergoing sPTL compared with non-labouring controls matched by gestational age. We performed single-end small RNA sequencing in whole blood and peripheral monocytes from women undergoing sPTL with active contractions (24-34 weeks of gestation, N = 15) matched for gestational age to healthy pregnant non-labouring controls (>37 weeks gestation, N = 30) who later delivered at term as a part of the Ontario Birth Study (Toronto, Ontario CA). We identified significant differences in expression of 16 miRNAs in PMs and nine miRNAs in WB in women undergoing sPTL. In PMs, these miRNAs were predicted targets of 541 genes, including 28 previously associated with sPTL. In WB, miRNAs were predicted to target 303 genes, including nine previously associated with sPTL. These genes were involved in a variety of immune pathways, including interleukin-2 signalling. This study is the first to identify changes in miRNA expression in WB and PMs of women undergoing sPTL. Our results shed light on potential mechanisms by which miRNAs may play a role in mediating systemic inflammatory response in pregnant women that deliver prematurely.

Evaluation of the effectiveness of foetal fibronectin as a predictor of preterm birth in symptomatic preterm labour women.

BACKGROUND: The prediction of preterm birth (PTB) is important in the management of symptomatic preterm labour women. We evaluated the effectiveness of the foetal fibronectin (fFN) test for predicting PTB in symptomatic preterm labour women with consideration of physiologic changes in cervical length (CL) during pregnancy. METHODS: This prospective study included 85 women with symptomatic preterm labour of a singleton pregnancy. Positive fFN was defined as a fFN level of > 50 ng/mL in cervicovaginal secretion, while a short CL was defined as that below 25th percentile at the corresponding gestational age. We evaluated effectiveness of the fFN test, CL, and the combination of these two tests, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), positive likelihood ratio (LR+), negative likelihood ratio (LR-) to predict the PTB within 7 and 14 days of testing and PTB at < 34 and 37 weeks of gestation. We also present the odds ratios (ORs) of the test results, defining the women with both negative results as the reference group. RESULTS: Of the 85 women, 31 (36.5%) showed a positive fFN and 44 (51.8%) had a short CL. PTB occurred within 7 and 14 days of testing and before 34 and 37 weeks of gestation in 17.6, 20.0, 23.5 and 49.4% of the women, respectively. The fFN and CL results showed low predictive effectiveness for the studied outcomes with LR+ (fFN, 1.5-1.9; CL, 1.0-1.5) and LR- (fFN, 0.7; CL, 0.7-0.9). The combined use of fFN and CL could not improve these results (LR+, 1.4-2.3; LR-, 0.7-0.9). However, the risk of PTB before 37 weeks was increased in women with positive fFN but not CL shortening compared to the reference group (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.1-1.3). The risk of PTB before 34 weeks was increased in both positive fFN and CL compared to the reference group (OR, 8.1; 95% CI, 1.9-34.5). CONCLUSION: Although, our approach could not improve the ability to predict PTB, it could identify women at risk for delivery before 34 or 37 weeks of gestation. Therefore, it could be used to manage women with symptomatic preterm labour.

Cathelicidins and the Onset of Labour.

Preterm birth, defined as delivery before 37 weeks of gestation, is the leading cause of neonatal mortality and morbidity. Infection and inflammation are frequent antecedents of spontaneous preterm birth. Cathelicidin, an antimicrobial host defence peptide, is induced by infection and inflammation and although expressed in the reproductive tract and fetal tissues, its role in the pathogenesis of spontaneous preterm birth is unknown. Here we demonstrate that cathelicidin expression is increased at RNA and protein level in the mouse uterus in a model of inflammation-induced labour, where ultrasound guided intrauterine injection of lipopolysaccharide (LPS) at E17 stimulates preterm delivery within 24 hours. Cathelicidin-deficient (Camp-/-) mice are less susceptible to preterm delivery than wild type mice following intrauterine injection of 1 µg of LPS, and this is accompanied by a decrease in circulating IL-6, an inflammatory mediator implicated in the onset of labour. We also show that the proportion of cathelicidin expressing cells in the myometrium is higher in samples obtained from women in labour at term than pre-labour. Together, these data suggest that cathelicidin has roles in mediating pro-inflammatory responses in a murine model of inflammation-induced labour, and in human term labour.

Immune biomarkers in maternal plasma to identify histologic chorioamnionitis in women with preterm labor.

PURPOSE: To determine whether various selected immune-related proteins in maternal plasma, alone or in combination, can predict histologic chorioamnionitis (HCA) in women with preterm labor, and to compare the predictive abilities of these biomarkers with that of serum C-reactive protein (CRP). METHODS: This retrospective cohort study included 74 consecutive women with preterm labor (23-34 gestational weeks) who delivered within 96 h of blood sampling. Their serum CRP levels were also measured. The stored maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, angiopoietin-2, S100 A8/A9, CXCL14, APRIL, and insulin-like growth factor-binding protein-2 (IGFBP-2), using ELISA kits. The primary outcome measure was HCA. RESULTS: HCA was detected in 59.4% (44/74) of women. Women with HCA had a significantly lower median gestational age at sampling and plasma IGFBP-2 level, and higher median plasma IL-6 and S100 A8/A9 levels than those without HCA. In multivariable analysis, high plasma IL-6 and low plasma IGFBP-2 levels were independently associated with the occurrence of HCA. However, the sensitivities, specificities, and areas under the curve of plasma IL-6, S100 A8/A9, and IGFBP-2, alone or in combination, were similar to or lower than those of serum CRP, for detecting HCA. CONCLUSIONS: Our data suggest that plasma IL-6, S100 A8/A9, and IGFBP-2 could be potential novel biomarkers for predicting HCA in women with PTL; however, elevated plasma levels of these biomarkers, alone or in combination, do not predict HCA better than serum CRP.

EQUIPTT: The Evaluation of the QUiPP app for Triage and Transfer protocol for a cluster randomised trial to evaluate the impact of the QUiPP app on inappropriate management for threatened preterm labour.

BACKGROUND: Accurate diagnosis of preterm labour is needed to ensure correct management of those most at risk of preterm birth and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the large majority of women, who do not deliver within a week of presentation. Intervention "just-in-case" results in many avoidable admissions, women being transferred out of their local hospital unnecessarily and most women receiving unwarranted drugs, such as steroids and tocolytics. It also precludes appropriate transfers for others as neonatal cots are blocked pre-emptively, resulting in more dangerous ex-utero transfers. We have developed the QUiPP App which is a clinical decision-making aid based on previous outcomes of women, quantitative fetal fibronectin (qfFN) values and cervical length. It is hypothesised that using the QUiPP app will reduce inappropriate admissions and transfers. METHODS: A multi-site cluster randomised trial will evaluate whether the QUiPP app reduces inappropriate management for threatened preterm labour. The 13 participating centres will be randomly allocated to receive either intervention or control. If the QUiPP app calculates risk of delivery within 7 days to be is less than 5%, clinicians are advised that interventions may be withheld. Women's experience of threatened preterm labour assessment will be explored using self-completed questionnaires, with a subset of participants being invited to semi-structured interview. A health economics analysis is also planned. DISCUSSION: We hypothesise that the QUiPP app will improve identification of the most appropriate women for admission and transfer and ensure that therapies known to reduce risk of preterm neonatal morbidities are offered to those who need them. We will determine which women do not require these therapies, thereby reducing over-medicalisation and the associated maternal and fetal risks for these women. The findings will inform future national guidelines on threatened preterm labour. Beyond obstetrics, evaluating the impact of an app in an emergency setting, and our emphasis on balancing harms of over-treatment as well as under-treatment, make EQUIPTT a valuable contribution to translational medicine. TRIAL REGISTRATION: The EQUIPTT trial was prospectively registered on 16th January 2018 with the ISRCTN registry (no. 17846337 ).