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The objective of this study was to investigate the immune mechanisms involved in preterm labor (PTL), preterm prelabor rupture of the membranes (PPROM), and normal pregnancies. The second objective was to explore immune profiles in PTL for association with early ( < 34 gestational weeks (gw)) or instant ( < 48 h) delivery. This prospective observational multi-center study included women with singleton pregnancies with PTL (n = 80) or PPROM (n = 40) before 34 gw, women with normal pregnancies scheduled for antenatal visits (n = 44), and women with normal pregnancies in active labor at term (n = 40). Plasma samples obtained at admission were analyzed for cytokine and chemokine quantification using a multiplex bead assay in order to compare the immune profiles between PTL, PPROM, and normal pregnancies. In PTL, CXCL1 and CCL17 were significantly higher compared to gestational age-matched women at antenatal visits, whereas for PPROM, CXCL1 and IL-6 were increased. Women in term labor had a more pronounced inflammatory pattern with higher levels of CXCL1, CXCL8, and IL-6 compared with PTL (p = 0.007, 0.003, and 0.013, respectively), as well as higher levels of CCL17, CXCL1 and IL-6 (all p < 0.001) compared with the women at antenatal visits. In PTL, CXCL8 was higher in women with delivery before 34 gw, whereas CXCL8, GM-CSF, and IL-6 were significantly higher in women with delivery within 48 h. To conclude, PTL and PPROM were associated with a complex pattern of inflammation, both involving Th17 (CXCL1) responses. Although further studies are needed, CXCL8, GM-CSF, and IL-6 may be potential candidates for predicting preterm birth in PTL., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the role of inflammatory markers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), c-reactive protein (CRP) to albumin ratio (CAR), fibrinogen to albumin ratio (FAR), and fibrinogen to CRP ratio (FCR) in predicting the latency period (≤72 vs. >72 hours) before preterm birth., Materials and Methods: In a retrospective study, we assessed 135 patients meeting the specified criteria with signs of preterm labor (<34 weeks). The patients were categorized into two groups: 71 patients giving birth within 72 h (latency ≤ 72 h) and 64 patients giving birth after 72 h (latency > 72 h). We examined the demographic and medical characteristics and perinatal outcomes of all participants. Categorical variables between groups were compared using the Chi-square test. The Student's t-test was utilized for normally distributed continuous variables, and the Mann-Whitney U test was applied for non-normally distributed data. Receiver operating characteristic (ROC) curve analysis was conducted to identify the optimal cut-off levels for inflammatory markers in predicting the latency period before birth., Results: Among the parameters examined, significant differences were observed between the groups only in terms of CAR and FCR. While CAR showed a significantly higher value in the group with latency period ≤72 h (0.537 ± 1.239 vs. 0.247 ± 0.325, p = 0.022), FCR showed a significantly lower value in the group with latency period ≤72 h (63.58 (2.99-1165) vs. 88.93 (9.35-1165), p = 0.013). The identified cut-off value for CAR was 0.190, providing a sensitivity of 57.7% and a specificity of 56.3% (p = 0.022). The cut-off value for FCR was 71.67, with a sensitivity of 42.3% and a specificity of 42.2% (p = 0.013)., Conclusions: The CAR and the FCR, serving as predictive markers for preterm labor, may offer a simple, cost-effective, and easily accessible approach, particularly in resource-limited settings., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to identify plasma proteins that could serve as potential biomarkers for microbial invasion of the amniotic cavity (MIAC) or intra-amniotic inflammation (IAI) in women with preterm labor (PTL). A retrospective cohort comprised singleton pregnant women with PTL (24-34 weeks) who underwent amniocentesis. Pooled plasma samples were analyzed by label-free liquid chromatography-tandem mass spectrometry for proteome profiling in a nested case-control study (concomitant MIAC/IAI cases vs. non-MIAC/IAI controls [n = 10 per group]). Eight target proteins associated with MIAC/IAI were further verified by immunoassays in a large cohort (n = 230). Shotgun proteomic analysis revealed 133 differentially expressed proteins (fold change > 1.5, P < 0.05) in the plasma of MIAC/IAI cases. Further quantification confirmed that the levels of AFP were higher and those of kallistatin and TGFBI were lower in the plasma of women with MIAC and that the levels of kallistatin and TGFBI were lower in the plasma of women with IAI than in those without these conditions. The area under the curves of plasma AFP, kallistatin, and TGFBI ranged within 0.67-0.81 with respect to each endpoint. In summary, plasma AFP, kallistatin, and TGFBI may represent valuable non-invasive biomarkers for predicting MIAC or IAI in women with PTL., (© 2024. The Author(s).)

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.

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.

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 × 10 10  particles/ml ± 1.9 × 10 10 ). 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.

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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 statement What is already know n 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 result s 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.

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 × 10 3 /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., (© 2020 Japan Society of Obstetrics and Gynecology.)

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.

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., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 Japan Society of Obstetrics and Gynecology.)

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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To evaluate the relationship between first and second trimester maternal serum-free β-hCG and the risk of spontaneous preterm delivery (PTD). Study design: This was a case-control study of women evaluated and delivered at our institution from 2011 to 2015. Spontaneous PTD was defined as delivery before 37 weeks due to spontaneous preterm labor or premature rupture of membranes. Patient with multifetal gestation and those with medically indicated term or PTD were excluded. Results: Of 877 women meeting the inclusion criteria, 173 delivered preterm and 704 delivered at term, and 8.1% had high free β-hCG in one or both trimesters. High maternal first and/or second trimester free β-hCG (≥95th percentile) was associated with lower rates of PTD. Thirty-two women with high free β-hCG in both first and second trimesters delivered at term. Gestational age at delivery and birth weights were lower in women who did not have high free β-hCG in any trimester. Low free β-hCG (≤5th percentile) in either trimester was not associated with an increased or decreased likelihood of PTD. Logistic regression demonstrated an independent association of high free β-hCG (≥95th percentile) with a reduced likelihood of PTD. Stratified analysis revealed a stronger impact of this association in women with no prior history of PTD. Conclusions: High free β-hCG, in the absence of risk factors for medically indicated PTD, is associated with a reduced likelihood of spontaneous PTD and may represent a marker indicating lower risk.

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., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

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.

Objective: To evaluate the value of maternal serum advanced glycation end products (AGEs) level at 11-13 weeks' gestation for the prediction of preterm labor and or preterm premature rupture of membranes (PPROM)., Materials and Methods: This prospective cross-sectional study is performed in a university-affiliated hospital between February and April 2016. The participants of this study are low-risk pregnant women. Blood samples for maternal AGEs level were collected in the first trimester of pregnancy and all women completed their antenatal follow-up and delivered in our center. During the follow-up 21 women developed preterm labor/PPROM. The first trimester maternal AGEs levels of preterm labor/PPROM cases were compared with uncomplicated cases (n = 25) matched for age-parity and BMI. The predictive value of AGEs levels for preterm labor/PPROM was also assessed., Results: First-trimester AGEs levels were significantly higher in cases complicated with preterm labor/PPROM (1832 (415-6682) versus 1276 (466-6445) ng/L, p = .001 and 1722 (804-6682) versus 1343 (466-6445) ng/L, p = .025). According to receiver-operating characteristic curve analysis, the calculated cut off value of AGEs was 1538 ng/L with the sensitivity 91.7%, specificity 73.8%; and the negative and positive predictive values were 91.6% and 29.5%, respectively., Conclusions: For the prediction of preterm labor/PPROM, the relatively high AGEs levels in the first trimester might be a useful marker.

Background: Preterm birth is associated with significant perinatal morbidity and mortality. The fetal fibronectin test (fFN) is used to manage women presenting with threatened preterm labour (TPTL)., Aim: To evaluate the use of fFN in women presenting with TPTL with regard to hospital admission, tertiary hospital transfer and use of tocolytics and steroids in our hospital, against recommended guidelines. The ability of fFN <10 ng/mL, 10-49 ng/mL, 50-199 ng/mL and >200 ng/mL to predict outcome was also examined., Material and Methods: This was a single-centre retrospective study from January 2015 to June 2017. All women who presented to Ipswich hospital, a level two facility for births at >32 weeks of gestation, between 23 and 34 6  weeks of gestation with TPTL and who had fFN tests were included in the study., Results: Fetal fibronectin <50 ng/mL had a negative predictive value of 93.5% (95% CI 86.5-97.1). Despite this assurance, one in four presentations resulted in hospital admission and nearly one in ten in steroids and tocolysis administration. Birth <34 weeks was 0% for fFN <10 and 2% for women with fFN levels <200 ng/mL compared to nearly 30% for levels >200 ng/mL., Conclusion: There is noncompliance with use of fFN to its full potential. This small study also provides support for the use of a 200 ng/mL cut-off fFN level for birth <34 weeks. This would avoid the need to transfer to a tertiary facility many women who present with TPTL., (© 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

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.

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.

The manufacturer of a popular qualitative fFN assay, changed to using a quantitative assay following results from EQUIPPE study. The objective of our study was to compare our hospital data collated from our qualitative fFN assay with EQUIPPE's data, with a view to establish its validity in our hospital. We undertook a retrospective study over a 22-month period to review the data of 432 preterm pregnant women at less than 34 weeks of gestation, who presented to the labour ward with symptoms of threatened preterm labour warranting a fFN test. None of the patient with results between 11 and 199 ng/mL delivered within 7 days. However, there was a rise in percentage of delivery at higher levels. For example, 73% of patients with levels greater or equal to 500 ng/mL delivered within 7 days. Our results are comparable with those of the EQUIPPE study. This has led to changes that could potentially save our hospital money. Impact statement What is already known on this subject? The fFN test is a well validated test used to diagnose a preterm delivery. Most units are changing from the qualitative assays that just show positive or negative results to quantitative assays that give specific numeric values. Manufacturers give a numeric range for positive and negative results. What do the results of this study add? Although our study is local to our population, our findings show that potentially more money could be saved and fewer women separated from their families, if the negative level of the fFN test is increased (following a review of their local practice). What are the implications of these findings for clinical practice and/or further research? More units should review or audit their fFN results and choose what levels to use as a cut off for the test locally. More importantly, a multicentre research is needed to validate if the negative level needs increasing from 49 ng/mL.

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.

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 ).

Chronic inflammation has been implicated as the underlying mechanism responsible for the pathophysiology of preterm labour. Mannose-binding lectin (MBL) plays a central role in the innate immune response and is thus an important component of the first line of defense. The aim of this study was to investigate whether serum concentrations of MBL correlated with the incidence of preterm birth and low birthweight in a cohort of women with signs of threatened preterm birth. A cohort of 60 patients who presented with regular contractions and/or short cervix (group A) between 24 and 32 weeks of gestation and 20 healthy controls (group B) who had no pregnancy complications and delivered at term were recruited into a prospective study. The following outcomes were recorded: presence of preterm labour and birthweight in all patients. MBL and high sensitivity C-reactive protein levels were measured in all serum samples. The serum concentrations of MBL were significantly reduced in patients with threatened preterm labour (Group A), compared to the control Group B. Furthermore, infants born to Group A mothers with MBL deficiency (n = 13, MBL ≤100 ng/mL) had significantly lower birthweights, compared to those born to Group A women with normal MBL serum concentrations (P < .0001). Our small cohort study demonstrated a strong association between MBL deficiency and preterm delivery, and associated low birthweight. MBL deficiency could thus be considered an important risk factor for preterm birth., (© 2018 The Foundation for the Scandinavian Journal of Immunology.)

Preterm birth (PTB) can lead to lifelong complications and challenges. Identifying and monitoring molecular signals in easily accessible biological samples that can diagnose or predict the risk of preterm labour (PTL) in pregnant women will reduce or prevent PTBs. A number of studies identified putative biomarkers for PTL including protein, miRNA and hormones from various body fluids. However, biomarkers identified from these studies usually lack consistency and reproducibility. Extracellular vesicles (EVs) in circulation have gained significant interest in recent years as these vesicles may be involved in cell-cell communication. We have used an improved small RNA library construction protocol and a newly developed size exclusion chromatography (SEC)-based EV purification method to gain a comprehensive view of circulating RNA in plasma and its distribution by analysing RNAs in whole plasma and EV-associated and EV-depleted plasma. We identified a number of miRNAs in EVs that can be used as biomarkers for PTL, and these miRNAs may reflect the pathological changes of the placenta during the development of PTL. To our knowledge, this is the first study to report a comprehensive picture of circulating RNA, including RNA in whole plasma, EV and EV-depleted plasma, in PTL and reveal the usefulness of EV-associated RNAs in disease diagnosis., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Preterm birth is the leading cause of newborn death worldwide, and is associated with significant cognitive and physiological challenges in later life. There is a pressing need to define the mechanisms that initiate spontaneous preterm labor, and for development of novel clinical biomarkers to identify high-risk pregnancies. Most preterm birth studies utilize fetal tissues, and there is limited understanding of the transcriptional changes that occur in mothers undergoing spontaneous preterm labor. Earlier work revealed that a specific population of maternal peripheral leukocytes (macrophages/monocytes) play an active role in the initiation of labor. Thus, we hypothesized that there are dynamic gene expression changes in maternal blood leukocytes during preterm labor., Objective: Using next-generation sequencing we aim to characterize the transcriptome in whole blood leukocytes and peripheral monocytes of women undergoing spontaneous preterm labor compared to healthy pregnant women who subsequently delivered at full term., Study Design: RNA sequencing was performed in both whole blood and peripheral monocytes from women who underwent preterm labor (24-34 weeks of gestation, N = 20) matched for gestational age to healthy pregnant controls (N = 30). All participants were a part of the Ontario Birth Study cohort (Toronto, Ontario, Canada)., Results: We identified significant differences in expression of 262 genes in peripheral monocytes and 184 genes in whole blood of women who were in active spontaneous preterm labor compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both whole blood and peripheral monocytes. ADAMTS2 expression was significantly increased in women actively undergoing spontaneous preterm labor, which we validated through digital droplet reverse transcriptase polymerase chain reaction. Intriguingly, we have also identified a number of gene sets including signaling by stem cell factor-KIT, nucleotide metabolism, and trans-Golgi network vesicle budding, which exhibited changes in relative gene expression that was predictive of preterm labor status in both maternal whole blood and peripheral monocytes., Conclusion: This study is the first to investigate changes in both whole blood leukocytes and peripheral monocytes of women actively undergoing spontaneous preterm labor through robust transcript measurements from RNA sequencing. Our unique study design overcame confounding based on gestational age by collecting blood samples from women matched by gestational age, allowing us to study transcriptomic changes directly related to the active preterm parturition. We performed RNA profiling using whole genome sequencing, which is highly sensitive and allowed us to identify subtle changes in specific genes. ADAMTS2 expression emerged as a marker of prematurity within peripheral blood leukocytes, an accessible tissue that plays a functional role in signaling during the onset of labor. We identified changes in relative gene expression in a number of gene sets related to signaling in monocytes and whole blood of women undergoing spontaneous preterm labor compared to controls. These genes and pathways may help identify potential targets for the development of novel drugs for preterm birth prevention., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To profile maternal plasma metabolome in spontaneous preterm birth., Method: In this retrospective case-control study, we have examined plasma of patient with preterm birth (between 22 and 36 weeks of pregnancy ( n = 57)), with threatened preterm labor (between 23 and 36 weeks of pregnancy ( n = 49)), and with term delivery ( n = 25). Plasma samples were analysed using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) in positive and negative polarity modes., Results: We found 168 differentially expressed metabolites that were significantly distinct between study groups. We determined 51 metabolites using publicly available databases that could be subdivided into one of the five groups: amino acids, fatty acids, lipids, hormones, and bile acids. PLS-DA models, verified by SVM classification accuracy, differentiated preterm birth and term delivery groups., Conclusions: Maternal plasma metabolites are different between term and preterm parturitions. Part of them may be related with preterm labor, while others may be affected by gestational age or the beginning of labor. Metabolite profile can classify preterm or term delivery groups raising the potential of metabolome as a biomarker to identify high-risk pregnancies. Metabolomic studies are also a tool to detect individual compounds that may be further tested in targeted researches.

The aim of this prospective study was to determine clinical factors associated with adverse pregnancy outcomes in women with systematic lupus erythematosus (SLE). Fifty-six pregnancies from 46 women with SLE were enrolled. Risk factors for pregnancy loss, premature delivery, hypertensive disorders of pregnancy (HDP), and light-for-date neonate (LFD), were evaluated. Univariate and multivariate logistic regression analyses revealed a history of two or more pregnancy losses before 10 gestational weeks (GW) (OR 11.5, 95%CI 1.72-76.8) as a risk factor for pregnancy loss; low levels of blood complements (OR 7.55, 95%CI 1.10-51.9) and antiphospholipid syndrome (OR 26.5, 95%CI 3.17-219) as risk factors for premature delivery before 37 GW; SLEDAI score at conception (OR 1.68, 95%CI 1.05-2.68) and positive tests for two or more antiphospholipid antibodies (OR 6.89, 95%CI 1.13-41.9) as risk factors for premature delivery before 34 GW; prednisolone therapy >14mg/day (OR 7.55, 95%CI 1.10-51.9) as a risk factor for HDP; and low dose aspirin therapy (OR 0.21, 95%CI 0.05-0.97) decreased the risk for LFD neonate. These results have important implications for clinicians managing SLE complicated pregnancy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the value of measurement of serum ferritin level in pregnant women to predict preterm labour. The study included 236 women whose haemoglobin (Hb) levels were ≥10.5 gm/dl and gestational age (GA) was less than 30 weeks. Serum ferritin levels were measured at 30 weeks of gestational age. At the end of the study, 23 women delivered with preterm premature rupture of membrane (PPROM) and 17 women delivered before 37 weeks but without PROM (study group). The rest of the pregnant women (196 women) delivered between 37 and 40 weeks (control group). We found a significant difference between the two groups with respect to serum ferritin level. The cut off value of serum ferritin between the two groups was 31 ng/ml with sensitivity 92.8%, specificity 99.4%, positive predictive value 97.5%, negative predictive value 98.4% and accuracy 98.3%. Impact statement What is already known on this subject: maternal serum ferritin has been found to be elevated in women who delivered preterm. What the results of this study add: In this study, we have shown that serum ferritin 31 ng/ml is the optimal cut-point between preterm and full-term women. What the implications are of these findings for clinical practice and/or further research: Serum ferritin 31 ng/ml could be proposed as a potential helpful marker to predict preterm labour.

Aim: Preterm premature rupture of membranes (PPROM) is not only the most common distinguishable cause of preterm delivery, but is also associated with adverse neonatal outcomes. We determined the platelet indices in PPROM cases and evaluated their relationship to adverse neonatal outcomes., Methods: Fifty patients with PPROM and 50 patients who experienced spontaneous preterm labor at < 37 gestational weeks were evaluated. Complete blood counts, birth weights, Apgar scores, presence of sepsis and respiratory distress syndrome (RDS) and neonatal intensive care unit admission were recorded., Results: Patients with PPROM had increased mean platelet volumes (9.40 vs 10; P = 0.01), plateletcrit (0.19 vs 0.21; P = 0.03) and a higher frequency of neonatal sepsis (18% vs 38%; P = 0.02). Platelet indices in the patient group were compared according to the development of RDS. Plateletcrit values were higher in the RDS positive group (0.23 ± 0.05 vs. 0.21 ± 0.04; P = 0.04). The cut-off value for plateletcrit was determined as > 0.22, and the probability of RDS increased 5.86 times when plateletcrit values exceeded 0.22 (odds ratio 5.86, 95% confidence interval 1.01-32.01; P = 0.04). A one-unit increase in platelet distribution width resulted in a 1.33-fold increase in the risk of RDS (odds ratio 1.33, 95% confidence interval 1.01-1.77; P = 0.04)., Conclusion: Mean platelet volumes and plateletcrit significantly increased and plateletcrit had a predictive value for RDS in PPROM cases. Monitoring plateletcrit may be promising for predicting the development of RDS, one of the most common and serious complications of PPROM rupture., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aim: To evaluate the clinical application of the new Hologic quantitative foetal fibronectin (qfFN) bedside test for the prediction of spontaneous preterm birth (sPTB) in patients with symptoms suggestive of spontaneous threatened preterm labour (sPTL)., Methods: A prospective observational study with 154 pregnant women presenting signs and symptoms of sPTL was conducted. These women were subjected to a qfFN test between 22 and 35 weeks of gestation For each cut-off threshold, the ability to predict sPTB at within 14 days of conducting the test and <37 weeks was assessed by calculating the positive predictive value (PPV), negative predictive value (NPV), likelihood ratios, odds ratios, sensitivity, and specificity., Results: For the outcome of delivery within 14 days of the test, qfFN <10 ng/mL had a 100% NPV and >200 ng/mL produced a 50.0% PPV; thus, qfFN added enhanced discrimination between high- and low-risk patients. The overall rate of sPTB (<37) was 13.3% (16/120), which increased progressively with increasing levels of fFN, with rates of 9.8% (8/81), 11.5% (3/26), 14.2% (1/7), 50% (3/6) within the 4 categories (fFN 0-9, 10-49, 50-200, 200+) respectively., Conclusions: The use of the qfFN testing in symptomatic patients allowed for more accurate identification of women at risk of sPTB and thus more directed management., (© 2017 S. Karger AG, Basel.)

Objective: We aimed to determine the potential value of maternal serum levels of acute phase reactants in the prediction of preterm delivery in women with threatened preterm labor (TPL)., Methods: Ninety-one pregnant women diagnosed with TPL and 83 healthy pregnant women as a control group were included in this prospective controlled study. All the pregnant women were followed until delivery and obstetric data and the serum levels of acute phase reactants were recorded for each participant. The study group was further divided into two groups according to the gestational age at delivery, which include women delivering prematurely and the ones who gave birth at term., Results: Serum albumin levels were significantly lower and mean serum ferritin levels were significantly higher in the study groups when compared the control group., Conclusion: Although an association between decreased serum albumin level and TPL, also between increased serum ferritin levels and preterm birth and low birth weight were demonstrated, more extensive studies are needed to clarify the potential use of the acute phase reactants in the prediction of preterm birth.

The onset of labour in rodents and in humans is associated with physiological inflammation which is manifested by infiltration of activated maternal peripheral leukocytes (mPLs) into uterine tissues. Here, we used flow cytometry to immunophenotype mPLs throughout gestation and labour, both term and preterm. Peripheral blood was collected from non-pregnant women and pregnant women in the 1st, 2nd and 3rd trimesters. Samples were also collected from women in active labour at term (TL) or preterm (PTL) and compared with women term not-in-labour (TNIL) and preterm not-in-labour (PTNIL). Different leukocyte populations were identified by surface markers such as CD45, CD14, CD15, CD3, CD4, CD8, CD19 and CD56. Their activation status was measured by the expression levels of CD11b, CD44, CD55, CD181 and CD192 proteins. Of all circulating CD45+ leukocytes, we detected significant increases in CD15+ granulocytes (i) in pregnant women versus non-pregnant; (ii) in TL women versus TNIL and versus pregnant women in the 1st/2nd/3rd trimester; (iii) in PTL women versus PTNIL. TL was characterized by (iv) increased expressions of CD11b, CD55 and CD192 on granulocytes; (v) increased mean fluorescent intensity (MFI) of CD55 and CD192 on monocytes; (vi) increased CD44 MFI on CD3+ lymphocytes as compared to late gestation. In summary, we have identified sub-populations of mPLs that are specifically activated in association with gestation (granulocytes) or with the onset of labour (granulocytes, monocytes and lymphocytes). Additionally, beta regression analysis created a set of reference values to rank this association between immune markers of pregnancy and to identify activation status with potential prognostic and diagnostic capability., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: To investigate serum inflammatory markers in singleton gestations complicated with threatened preterm labour (TPL)., Methods: Pregnant women complicated with TPL (n = 61) were recruited to measure maternal serum levels of a panel of cytokines and C-reactive protein and then compared to controls without TPL, matched for gestational age (n = 64) and term pregnancies in the prodromal phase of labour (PPL) (n = 31). In addition, baseline cytokine levels were compared among cases and controls according to the outcome., Results: Women with TPL displayed higher CRP and white blood counts levels together with lower granulocyte macrophage colony-stimulating factor (GMC-SF) compared to both controls without TPL and to term gestations in the PPL. Also, interleukin 10 (IL-10), IL-6, IL-7, IL-8 and tumour necrosis alpha (TNF-α) levels were found significantly higher in TPL cases as compared to controls without TPL and term women in the PLL. Baseline cytokine levels (except IL-10) were higher among TPL cases who later delivered preterm. TPL cases delivering preterm displayed lower GMC-SF levels as compared to those delivering at term. Multivariate analysis found that gestational age at birth positively correlated with cervical length and inversely with CRP, IL-6 and TNF-α levels (p < 0.0001)., Conclusions: TPL and preterm birth were related to inflammatory changes in the maternal side that correlate with cervical shortening and the initiation of uterine contractions.

Objective: Preterm labour is defined as the onset of labour between weeks 23 and before 37 of gestation. The purpose of this study was to compare the cytokine profile in the blood serum of patients experiencing threatened premature labour, along with the time of delivery and the foetus body mass at birth., Methods: The study included 89 women hospitalised at the Obstetrics and Gynaecology Clinical Hospital in the period 2011-2013. Group 1 comprised 31 patients diagnosed with threatened preterm labour, prior to tocolytic treatment. Group 2 comprised 32 patients with tocolytic treatment. Group 3 constituted the control group., Results: Groups 1, 2 and 3 differed considerably in terms of the week of delivery of pregnancy (p = 0.006). Analogous results were obtained by analysing the body mass at birth, where a statistically significant difference in body mass at birth was found between Groups 1, 2 and 3 (p  < 0.001). Our analysis focussed on the cytokine profile of the women included in the study, but no considerable changes in cytokine concentration were observed., Conclusions: No statistically significant differences were found in the cytokine profile among those patients in normally progressing pregnancy or in threatened preterm labour. No suitability of progesterone treatment in threatened preterm labour was observed.

Objective: To investigate the association between subclinical hypothyroidism and preterm contractions., Methods: Prospective observational study among women at 23 + 0/7 and 34 + 6/7 weeks of gestation, with no known thyroid function abnormality, and preterm uterine contractions (PTC). All patients underwent laboratory evaluation of Thyroid Stimulating Hormone (TSH) and Free Thyroxin (FT4). Patients with and without PTC were compared., Results: No association was found between PTC and subclinical hypothyroidism. Rate of spontaneous preterm delivery (PTD) was comparable between women with abnormal and normal thyroid function tests. Excluding indicated PTD, patients in the study group had a higher rate of spontaneous PTD (24.7% versus 9.6%, p = 0.03). Patients with past PTD and preterm contractions had higher rates of hypothyroxinemia compared with patients without past PTD (54.6% versus 19.0% and 31.2%, p = 0.001), and patients with past PTD (regardless of the presence or absence of PTC) had higher rate of subclinical hypothyroidism compared with patients with PTC and without PTD (59.1% and 66.7% versus 31.6%, p = 0.017)., Conclusions: No association was found between PTC and subclinical hypothyroidism in the entire cohort, except for patients with preterm contractions and a history of past PTD. This specific group of patients might benefit from thyroid function evaluation.

Objective: The objective of the study was to analyse placental hormone profiles in twin pregnancies to determine if they could be used to predict preterm birth., Study Design: Progesterone, estradiol, estriol and corticotropin-releasing hormone were measured using competitive immunoassay and radioimmunoassay in serum and saliva samples of 98 women with twin pregnancies,at 3 or more gestational timepoints. Hormone profiles throughout gestation were compared between very preterm (<34 weeks; n = 8), preterm (<37 weeks; n = 40) and term (37+ weeks; n = 50) deliveries., Results: No significant differences were found between preterm and term deliveries in either absolute hormone concentrations or ratios. Estimated hormone concentrations and ratios at 26 weeks did not appear to predict preterm delivery. Salivary and serum hormone concentrations were generally poorly correlated., Conclusion: Our results suggest that serial progesterone, estradiol, estriol and corticotropin-releasing hormone measurements in saliva and serum are not robust biomarkers for preterm birth in twin pregnancies.

Background and Objectives: Pregnancy complications hypothesized to be related to vitamin D include preeclampsia, gestational diabetes, low birth weight, preterm delivery, Cesarean section and infectious disease. There have been a few studies which have demonstrated maternal serum vitamin D to be associated with preterm labor. The objective was to evaluate the serum vitamin D concentrations in Thai pregnant women with and without preterm labor and to find the prevalence of vitamin D deficiency and insufficiency in both groups., Methods and Study Design: Blood samples were collected from pregnant women with and without preterm labor (matched for gestational age). Serum 25-hydroxyvitamin D (25-OHD) concentrations were measured by chemiluminescence method., Results: A total of 60 pregnant women were included into the study, 30 patients in the preterm labor group and another 30 patients in the control group. The serum 25-OHD concentration was 21.0±7.5 ng/mL and the prevalence of vitamin D deficiency was 48.3% in total group of pregnant women. The serum 25-OHD concentrations were not different between the preterm labor and the control groups (20.9±8.4 vs 21.2±6.7 ng/mL, p=0.91). The prevalence of vitamin D deficiency and insufficiency were not different between the preterm labor and the control groups (53.3% vs 43.3%, p=0.44 and 83.3% vs 90%, p=0.45, respectively)., Conclusion: The serum 25-hydroxyvitamin D concentrations and the prevalence of vitamin D deficiency and insufficiency were not different between the preterm labor and the control groups. The serum 25-OHD could not predict preterm labor in this Thai population.

Aim: To identify if there is a relationship between the deiodinase D2-Thr92Ala genetic variant, thyroid hormone levels and biochemical hypothyroidism in preeclampsia., Materials and Methods: We genotyped 125 women with preeclampsia and 131 normal pregnant women using PCR-RFLP. Serum thyroid hormone levels were determined using ELISA., Results: Our study showed higher TSH and FT4 levels and lower FT3 levels in women with preeclampsia compared to normal pregnant women, with statistical significance for women with mild and severe preeclampsia. The risk to develop pregnancy-induced hypertension (PIH), mild or severe preeclampsia was increased in carriers of at least one D2-Ala92 allele. TSH and FT4 levels were significantly higher and FT3 levels were significantly lower in preeclamptic women with severe preeclampsia if they carried the D2-Ala92 allele compared to non-carriers. Pregnant women with PIH and mild preeclampsia, carriers of at least one D2-Ala92 allele, delivered at lower gestational age neonates with a lower birth weight compared to non-carriers, but the results were statistically significant only in severe preeclampsia., Conclusion: The D2-Thr92Ala genetic variant is associated with the severity and the obstetric outcome of preeclampsia, and it also influences thyroid hormone levels. The study demonstrates non-thyroidal biochemical hypothyroidism - as a result of deiodination effects due to D2 genotypes.

Chorioamnionitis is associated with an increased risk of spontaneous preterm birth. The aim of this study was to investigate the serum levels of high mobility group box-1 (HMGB1) in pregnancies with histological chorioamnionitis (HCA)-associated preterm labor (PTL) with intact membranes or preterm premature rupture of membranes (PPROM), and to access the role of serum HMGB1 in HCA and HCA-associated PTL. A total of 190 pregnant women were enrolled in this study: PLT patients with (n = 28) or without HCA (n = 36), PPROM patients with (n = 26) or without HCA (n = 65), and non-HCA PTL controls (n = 35). Maternal serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay. Serum HMGB1 levels were significantly higher in PTL or PPROM patients than in control group (p < 0.01, respectively). The PPROM patients also exhibited higher serum HMGB1 levels compared to PTL patients (p = 0.015). HCA patients were characterized by significantly increased levels of serum HMGB1 when compared with non-HCA patients (p < 0.01). Therefore, maternal serum HMGB1 may become a potential biomarker of HCA and HCA-associated PTL.

Background: Parturition at term and preterm is characterized by sterile inflammatory processes occurring in the absence of infection whereby peripheral leukocytes infiltrate gestational tissues in response to chemotactic signals. In response to a homing signal, recruited leukocytes undergo diapedesis and extravasate through capillaries, migrating into stromal tissue. There they interact with resident immune and stromal cells to produce a mixture of matrix metalloproteinases, prostaglandins and cytokines including interleukin-1β (IL-1β) and IL-6 that in turn transform the uterus from pregnancy to parturition. Since migration is an early parturitional event our purpose was to study the migration of maternal peripheral blood leukocytes in response to a standard chemotactic signal during several different conditions of late pregnancy., Methods: We used a cross-sectional observational study design. Subjects were (sTL) spontaneous normal labour delivered vaginally at term, (TNL) elective caesarean section at term without labour, (PTL) preterm in labour, (PTNL) preterm not in labour, (TPTL) threatened preterm labour, and (pPROM) preterm with premature rupture of membranes. Leukocytes (100,000) obtained by venipuncture and chemotactic factor isolated from term labour fetal membranes were placed in the upper and lower halves, respectively, of a Boyden chamber separated by a filter with 3μm pores. Migrated leukocytes were assessed by flow cytometry. The number of leukocytes that migrated in 90 min was the primary outcome measure., Results: Increased numbers of leukocytes from peripheral blood of women in labour (TL or PTL) or soon to go into labour (PPROM) migrated towards a chemotactic signal than did leukocytes from women not in labour (TNL, PTNL, or TPTL) (p < 0.0001). All pPROM delivered within 7d; TPTL delivered >30d. Receiver operating characteristic curve parameters indicated the cut-off point for delivery within 7d to be 37,082 leukocytes with sensitivity 78.1%, specificity 88.9%, positive predictive value 91.4%, negative predictive value 72.7%, and area under the curve 0.83., Conclusion: Leukocyte migration to a fetal membrane signal varies in a predictable fashion during various clinical situations of late gestation. This principle has the potential to be improved to become a clinical test to predict delivery.

Ritodrine, a drug for the treatment of threatened premature labor, is a highly selective beta-2 agonist with the major metabolites of sulfate and glucuronide conjugates. This study investigated the continuous evaluation of the concentration of ritodrine conjugates in relation to the clinical course in twin pregnancy. The subjects were 9 twin-pregnancy mothers who delivered after receiving ritodrine treatment between April 2012 and December 2013. Serum ritodrine sulfate and glucuronide conjugates were deconjugated using their specific enzymes. Ritodrine concentration was measured by liquid chromatography-tandem mass spectrometry. The continuous infusion rate of ritodrine was 2.66±0.67 (0.8-3.54) µg/min/kg, and the average concentration of unchanged ritodrine was 118.8±33.2 (63.8-194.0) ng/mL. During the study period between week 32 and week 36 of gestation, the average ratio of unchanged ritodrine concentration and sulfate ritodrine conjugate concentration for weeks 32, 33, 34, 35, and 36 were 1.7, 1.9, 1.5, 1.7, and 1.7 not significant (N.S.), respectively. The average ratio of unchanged ritodrine concentration and glucuronide ritodrine conjugate concentration were 1.8, 2.2, 1.9, 1.8, and 2.1 (N.S.), respectively. No statistical difference was identified in the ratios of unchanged ritodrine concentration and sulfate or glucuronide ritodrine conjugate concentrations. Large individual differences were shown in the concentration of sulfate and glucuronide during the gestational period. No change in the ratio of the formation of ritodrine metabolites was identified as the gestational age progressed.

Objectives: The purpose of this study was to determined the predictive value of maternal serum alpha-fetoprotein (MSAFP) as a marker for adverse pregnancy outcomes., Material and Methods: This study was carried out at Dr. Zekai Tahir Burak Women's Health Education and Research Hospital between 2009 and 2010. This study included a total of 1,177 pregnant women, including 170 in the study group and 1,007 in the control group. Pregnancy outcomes and characteristics were analyzed with regard to the MSAFP value., Results: Gestational week, birth weight and APGAR scores were significantly lower in the elevated MSAFP group (p < 0.001). Adverse pregnancy outcomes, such as preterm delivery, preterm premature rupture of membranes (PPROM), oligohydramnios and intrauterine growth restriction (IUGR) rates were increased in the elevated MSAFP group., Conclusions: Although ultrasound outweighs as a screening method for neural tube defects and non-invasive prenatal testing outweighs for aneuploidy screening MSAFP level in the second trimester is still an important predictor for poor maternal/fetal outcomes.

Objective: To define the management of preterm labor (MAP)., Method: The literature search was conducted using computer databases Medline and the Cochrane Library for a period from 1969 to March 2016., Results: Leukocytosis screening may be useful in case of hospitalization for Preterm labor (PTL). Its use is not routine (professional consensus). Screening for urinary tract infection by urine culture should be systematic and antibiotic treatment should be performed in cases of bacterial colonization or urinary tract infection for a period of 7 days (grade A). The vaginal swab is useful to detect a strep B and was prescribed antibiotics during labor if positive (grade A). Routine antibiotic therapy is not recommended in case of PTL (grade A). Prolonged hospitalization does not reduce the risk of preterm delivery (NP3) and is not recommended (grade B). Bed rest does not reduce the risk of PTL (NP3), increases the risk of thromboembolism (NP3), and is not recommended (grade C). After hospitalization for PTL, a regular visit by a caregiver at home may be helpful when patients belong to a precarious environment or are psychologically vulnerable (Professional consensus). The benefit of monitoring home uterine activity repeated in the aftermath of hospitalization for PTL is not shown (NP3). It is not recommended to follow-up uterine activity systematically after hospitalization for PTL (grade C)., Conclusion: The management of PTL should be individualized, include searching and treatment of infection and avoid prolonged hospitalization or bed rest., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objective and Methods: To measure 25-hydroxyvitamin D [25(OH)D] and C-reactive protein (CRP) serum levels in singleton gestations complicated with threatened preterm labour (TPL, n = 59) and compare to normal controls matched for gestational age (n = 64). Cases were treated after blood sample according to institutional protocol. Also, analyte levels were compared among cases according to the outcome., Results: Mean serum 25(OH)D levels were similar between cases and controls, with median white blood cell count and CRP levels found significantly higher in TPL cases. Women with TPL delivering preterm displayed shorter mean cervical lengths along with higher CRP and lower 25(OH)D serum levels when compared to those delivering at term. Two multiple linear regression models were constructed to analyse factors related to gestational age at delivery (pooled analysis and only those with TPL). In both models, gestational age positively correlated to cervical length and inversely to CRP levels; whereas, in the TPL model, only 25(OH)D levels correlated positively., Conclusion: Women complicated with TPL showed similar serum 25(OH)D yet higher CRP levels as compared to controls. TPL cases delivering preterm displayed lower 25(OH)D and higher CRP correlated levels.

Magnesium deficiency is prevalent in women of childbearing age in both developing and developed countries. The need for magnesium increases during pregnancy, and the majority of pregnant women likely do not meet this increased need. Magnesium deficiency or insufficiency during pregnancy may pose a health risk for both the mother and the newborn, with implications that may extend into adulthood of the offspring. The measurement of serum magnesium is the most widely used method for determining magnesium levels, but it has significant limitations that have both hindered the assessment of deficiency and affected the reliability of studies in pregnant women. Thus far, limited studies have suggested links between magnesium inadequacy and certain conditions in pregnancy associated with high mortality and morbidity, such as gestational diabetes, preterm labor, preeclampsia, and small for gestational age or intrauterine growth restriction. This review provides recommendations for further study and improved testing using measurement of red cell magnesium. Pregnant women should be counseled to increase their intake of magnesium-rich foods such as nuts, seeds, beans, and leafy greens and/or to supplement with magnesium at a safe level., (© The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)