Value of cervical electrical impedance spectroscopy to predict spontaneous preterm delivery in asymptomatic women: the ECCLIPPx prospective cohort study.

OBJECTIVES: Preterm birth (PTB) accounts for two-thirds of deaths of structurally normal babies and is associated with substantial lifetime healthcare costs. Prevention of PTB remains limited by the modest accuracy of prediction methods, namely transvaginal ultrasound (TVS) cervical length (CL) measurement and quantitative cervicovaginal fetal fibronectin (FFN) estimation. We report the first substantive study detailing the predictive performance of a cervical probe device based on electrical impedance spectroscopy (EIS) for PTB - the EleCtriCaL Impedance Prediction of Preterm birth by spectroscopy of the cervix (ECCLIPPx) study. We aimed to compare the accuracy of cervical EIS-based prediction of spontaneous PTB with that of prediction using TVS-CL and FFN in asymptomatic women in the mid-trimester. METHODS: We studied asymptomatic women with a singleton pregnancy at 20-22 weeks' and 26-28 weeks' gestation. EIS was performed using a Sheffield Mark 5.0 device that makes measurements in the frequency range 76 Hz to 625 kHz using a small probe housing tetrapolar electrodes. TVS-CL and FFN were also measured. The associations of cervical EIS, TVS-CL and FFN with spontaneous delivery before 37 weeks and before 32 weeks were determined by multivariate linear and non-linear logistic regression analysis. Areas under the receiver-operating-characteristics curves (AUC) plots of sensitivity against specificity were used to compare the predictive performance of all parameters, both in isolation and in combination. RESULTS: Of the 365 asymptomatic women studied at 20-22 weeks who were not receiving treatment, 29 had spontaneous PTB, 14 had indicated PTB and 322 had term birth. At the higher frequencies assessed, cervical EIS predicted spontaneous PTB before 37 weeks with an AUC of 0.76 (95% CI, 0.71-0.81), compared with AUCs of 0.72 (95% CI, 0.66-0.76) for TVS-CL and 0.62 (95% CI, 0.56-0.72) for FFN. Combining all three assessments improved the prediction of spontaneous PTB before 37 weeks (AUC, 0.79 (95% CI, 0.74-0.83)) compared with TVS-CL and FFN alone. Incorporating a history of spontaneous PTB (defined as previous mid-trimester miscarriage or spontaneous PTB (14 to < 37 weeks)) into the cervical EIS prediction model improved the accuracy of prediction of spontaneous PTB before 37 weeks (AUC, 0.83 (95% CI, 0.78-0.87)) and before 32 weeks (AUC, 0.86 (95% CI, 0.82-0.90)). CONCLUSIONS: Mid-trimester cervical EIS assessment predicts spontaneous PTB. Larger confirmatory studies investigating its potential clinical utility and to inform effective preventive interventions are required. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Inhibition of sialidase activity and cellular invasion by the bacterial vaginosis pathogen Gardnerella vaginalis.

Bacterial vaginosis is a genital tract infection, thought to be caused by transformation of a lactobacillus-rich flora to a dysbiotic microbiota enriched in mixed anaerobes. The most prominent of these is Gardnerella vaginalis (GV), an anaerobic pathogen that produces sialidase enzyme to cleave terminal sialic acid residues from human glycans. Notably, high sialidase activity is associated with preterm birth and low birthweight. We explored the potential of the sialidase inhibitor Zanamavir against GV whole cell sialidase activity using methyl-umbelliferyl neuraminic acid (MU-NANA) cleavage assays, with Zanamavir causing a 30% reduction in whole cell GV sialidase activity (p < 0.05). Furthermore, cellular invasion assays using HeLa cervical epithelial cells, infected with GV, demonstrated that Zanamivir elicited a 50% reduction in cell association and invasion (p < 0.05). Our data thus highlight that pharmacological sialidase inhibitors are able to modify BV-associated sialidase activity and influence host-pathogen interactions and may represent novel therapeutic adjuncts.

Techniques for detecting cervical remodeling as a predictor for spontaneous preterm birth: current evidence and future research avenues in patients with multiple pregnancies.

BACKGROUND: Spontaneous preterm birth occurs more frequently in multiple pregnancies. This syndrome has multiple triggers that result in a unified downstream pathway of cervical remodeling, uterine activity, and progressive cervical dilatation. Whilst the triggers for labor in multiple pregnancy may be different from singletons, the downstream changes will be the same. Identifying patients at risk of preterm birth is a priority as interventions to delay delivery and optimize the fetus can be initiated. Methods for screening for risk of preterm birth which focus on the detection of cervical remodeling may therefore have potential in this population. METHODS: This review explores the evidence for the predictive utility for preterm birth of several published techniques that assess the physical, biomechanical, and optical properties of the cervix, with a focus on those which have been studied in multiple pregnancies and highlighting targets for future research in this population. RESULTS: Fifteen techniques are discussed which assess the physical, biomechanical, and optical properties of the cervix in pregnancy. Of these, only three techniques that evaluated the predictive accuracy of a technique in patients with multiple pregnancies were identified: uterocervical angle, cervical consistency index, and cervical elastography. Of these, measurement of the uterocervical angle has the strongest evidence. Several techniques have shown predictive potential in singleton pregnancies, but have not yet been studied in multiple pregnancies, which would be a logical expansion of research. CONCLUSION: Research on techniques with predictive utility for PTB in patients with multiple pregnancies is limited but should be a research priority. Overall, the theory supports the investigation of cervical remodeling as a predictor of PTB, and there are numerous techniques in development that may have potential in this field.

OS006. Functional expression of endogenous ligands of Toll like receptor4 on monocytes and placentae from women during normal pregnancy andpre-eclampsia.

INTRODUCTION: Preeclampsia (PE) is characterized by an exaggerated systemic inflammatory response (ESIR). Several recent studies by our group and others have demonstrated up-regulation of Toll like receptor 4 (TLR4) in trophoblast, placenta and leukocytes in PE but the exact role of TLR4 in the pathogenesis of PE remains unclear. OBJECTIVES: We sought to determine the expression levels of endogenous ligands of TLR4 in plasma and placentas from women with PE vs normotensive pregnant women (NP), and to compare the inflammatory cytokine expression profiles of monocytes from women with PE to NP, in order to identify which of these endogenous ligands of TLR4 may play a functional role in the pathogenesis of PE for further study. METHODS: We recruited 16 PE (gestational age=33.6±3.0weeks), 10 normal pregnant (gestational age=31.6±3.8weeks) and 10 non-pregnant women. Plasma levels of endogenous TLR4 ligands-heparan sulfate, hyaluronan, fibronectin, fibrinogen and High mobility group box-1(HMGB1)-were measured by ELISA. Monocytes were isolated from peripheral blood, cultured and stimulated by lipopolysaccharide (LPS; TLR4 bacterial ligand) and endogenous TLR4 ligands, and inflammatory cytokines were measured in supernatant medium by cytometric array. Placental tissue from PE and NP were investigated for the different endogenous ligands by immunohistochemistry. RESULTS: Plasma levels of heparan sulfate and fibronectin did not differ between study groups, but HMGB1 was higher in PE (P<0.05) whilst fibrinogen was significantly lower in PE compared to NP (P<0.05). Stimulation of PE monocytes with LPS resulted in profound secretion of various cytokines: IL-6, IL-8, IL-1ß, TNFα and IL-10, in comparison with NP. Moreover, exposure to fibrinogen, but not to other endogenous TLR4 ligands, was also associated with significantly increased production of inflammatory cytokines in PE compared to NP. Also, we observed altered distribution levels of studied endogenous ligands in the placenta from PE vs NP. CONCLUSION: Our findings of increased inflammatory cytokine expression levels in PE in response to LPS are consistent with upregulation of TLR4 in PE. A similar response induced by fibrinogen suggests an important role for this endogenous ligand of TLR4 in the pathogenesis of PE. Whether our observation of decreased plasma levels of fibrinogen in PE is linked to this observation, or represents increased fibrinogenesis and fibrinolysis associated with the abnormal coagulopathy seen in this condition, is unclear.