44 results found
Pikovsky M, Tan MY, Ahmed A, et al., 2021, Euglycaemic ketoacidosis in pregnant women with COVID-19: two case reports, BMC Pregnancy and Childbirth, Vol: 21, ISSN: 1471-2393
Background: Euglycaemic ketoacidosis (EKA) is an infrequent but serious condition which usually follows a period of starvation, severe vomiting or illness in individuals with or without diabetes. Ketoacidosis is associated with materno-fetal morbidity and mortality necessitating prompt diagnosis and management. Physiological increases in insulin resistance render pregnancy a diabetogenic state with increased susceptibility to ketosis. COVID-19 is associated with worse clinical outcomes in patients with diabetes and is an independent risk factor for ketoacidosis in normoglycaemic individuals. Case presentations: We describe two cases of SARS-CoV-2 positive pregnant women presenting with normoglycaemic metabolic ketoacidosis. Both cases were associated with maternal and fetal compromise, requiring aggressive fluid and insulin resuscitation and early delivery.Conclusion: We discuss possible physiology and propose a management strategy for euglycaemic ketoacidosis in pregnancy.
Bonnardel F, Haslam SM, Dell A, et al., 2021, Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome, npj Biofilms and Microbiomes, Vol: 7, Pages: 1-10, ISSN: 2055-5008
Bacteria use carbohydrate-binding proteins (CBPs), such as lectins and carbohydrate-binding modules (CBMs), to anchor to specific sugars on host surfaces. CBPs in the gut microbiome are well studied, but their roles in the vagina microbiome and involvement in sexually transmitted infections, cervical cancer and preterm birth are largely unknown. We established a classification system for lectins and designed Hidden Markov Model (HMM) profiles for data mining of bacterial genomes, resulting in identification of >100,000 predicted bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species shows that those associated with infection and inflammation produce a larger CBPs repertoire, thus enabling them to potentially bind a wider array of glycans in the vagina. Both the number of predicted bacterial CBPs and their specificities correlated with pathogenicity. This study provides new insights into potential mechanisms of colonisation by commensals and potential pathogens of the reproductive tract that underpin health and disease states.
Zarasvand S, Bayar E, Adan M, et al., 2020, Rapid quality improvement in a preterm birth clinic care pathway during the COVID-19 pandemic, BMJ Open Quality, Vol: 9, Pages: 1-9, ISSN: 2399-6641
Background Preterm birth (PTB) occurs in 8% of births in the UK. At Imperial College Healthcare NHS Trust, our PTB prevention clinic manages the care of approximately 1000 women/year. Women referred to the clinic are seen from 12 weeks of pregnancy with subsequent appointments every 2–4 weeks to measure cervical length (CL) using transvaginal ultrasound (TVUS). Women with a history of cervical weakness or short cervix on TVUS are offered a cervical cerclage.Local problem During the COVID-19 outbreak, pregnant women were strongly advised to avoid social mixing and public transport. The National Health Service had to rapidly adopt remote consultation and redesign clinical pathways in order to reduce transmission, exposure and spread among women at high risk of PTB.Methods We focused on Specific, Measurable, Achievable, Realistic and Timebound aims and used a driver diagram to visualise our changes. We used a series of Plan Do Study Act cycles to evaluate and adapt change ideas through the UK’s national lockdown during the COVID-19 pandemic between 23 March and 29 May 2020.Results We reduced the number of face-to-face appointments by 54%. This was achieved by increasing remote telephone consultations from 0% to 64%, and by reducing the intensity of surveillance. The rate of regional anaesthetic was increased from 53% to 95% for cerclage placement in order to minimise the number of aerosol-generating procedures. Patient and staff satisfaction responses to these changes were used to tailor practices. No women tested positive for COVID-19 during the study period.Conclusions By using quality improvement methodology, we were able to safely and rapidly implement a new care pathway for women at high risk of PTB which was acceptable to patients and staff, and effective in reducing exposure of COVID-19.
Kim SH, MacIntyre D, Binkhamis R, et al., 2020, Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births, EBioMedicine, Vol: 62, ISSN: 2352-3964
BackgroundSmall-for-gestational-age fetuses (SGA) (birthweight <10th centile) are at high risk for stillbirth or long-term adverse outcomes. Here, we investigate the ability of circulating maternal plasma miRNAs to determine the risk of SGA births.MethodsMaternal plasma samples from 29 women of whom 16 subsequently delivered normally grown babies and 13 delivered SGA (birthweight <5th centile) were selected from a total of 511 women recruited to form a discovery cohort in which expression data for a total of 800 miRNAs was determined using the Nanostring nCounter miRNA assay. Validation by RT-qPCR was performed in an independent cohort.FindingsPartial least-squares discriminant analysis (PLS-DA) of the Nanostring nCounter miRNA assay initially identified seven miRNAs at 12–14+6 weeks gestation, which discriminated between SGA cases and controls. Four of these were technically validated by RT-qPCR. Differential expression of two miRNA markers; hsa-miR-374a-5p (p = 0•0176) and hsa-let-7d-5p (p = 0•0036), were validated in an independent population of 95 women (SGA n = 12, Control n = 83). In the validation cohort, which was enriched for SGA cases, the ROC AUCs were 0•71 for hsa-miR-374a-5p, and 0•74 for hsa-let-7d-5p, and 0•77 for the two combined.InterpretationWhilst larger population-wide studies are required to validate their performance, these findings highlight the potential of circulating miRNAs to act as biomarkers for early prediction of SGA births.
Preterm birth is a global health concern and continues to contribute to substantial neonatal morbidity and mortality despite advances in obstetric and neonatal care. The underlying aetiology is multi-factorial and remains incompletely understood. In this review, the complex interplay between the vaginal microbiome in pregnancy and its association with preterm birth is discussed in depth. Advances in the study of bacteriology and an improved understanding of the human microbiome have seen an improved awareness of the vaginal microbiota in both health and in disease.
Rasheed ZBM, Lee YS, Kim SH, et al., 2020, Differential response of gestational tissues to TLR3 viral priming prior to exposure to bacterial TLR2 and TLR2/6 agonists, Frontiers in Immunology, Vol: 11, Pages: 1-27, ISSN: 1664-3224
Background: Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in human in vitro models of ascending and haematogenous infection.Methods: Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-κB, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations.Results: TLR3 (“viral”) priming prior to TLR2/6 agonist (“bacterial”) exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased m
Ridout AE, Ibeto L, Ross G, et al., 2019, Cervical length and quantitative fetal fibronectin in the prediction of spontaneous preterm birth in asymptomatic women with congenital uterine anomaly, American Journal of Obstetrics and Gynecology, Vol: 221, Pages: 341.e1-341.e9, ISSN: 0002-9378
BACKGROUND: Congenital uterine anomalies (CUA) are associated with late miscarriage and spontaneous preterm birth (sPTB). OBJECTIVES: Our aim was to 1) determine the rate of sPTB in each type of CUA and 2) assess the performance of quantitative fetal fibronectin (qfFN) and transvaginal cervical length (CL) measurement by ultrasound in asymptomatic women with CUA for the prediction of sPTB at <34 and <37 weeks of gestation. STUDY DESIGN: This was a retrospective cohort of women with CUA asymptomatic for sPTB, from four UK tertiary referral centres (2001-2016). CUAs were categorised into fusion (unicornuate, didelphic and bicornuate uteri) or resorption defects (septate, with or without resection and arcuate uteri), based on pre-pregnancy diagnosis. All women underwent serial transvaginal ultrasound CL assessment in the second trimester (16 to 24 weeks' gestation); a subgroup underwent qfFN testing from 18 weeks' gestation. We investigated the relationship between CUA and predictive test performance for sPTB before 34 and 37 weeks' gestation. RESULTS: Three hundred and nineteen women were identified as having CUA within our high-risk population. 7% (23/319) delivered spontaneously <34 weeks, and 18% (56/319) <37 weeks' gestation. Rates of sPTB by type were: 26% (7/27) for unicornuate, 21% (7/34) for didelphic, 16% (31/189) for bicornuate, 13% (7/56) for septate and 31% (4/13) for arcuate. 80% (45/56) of women who had sPTB <37 weeks did not develop a short CL (<25 mm) during the surveillance period (16-24 weeks). The diagnostic accuracy of short CL had low sensitivity (20.3) for predicting sPTB <34 weeks. Cervical Length had ROC AUC of 0.56 (95% CI 0.48 to 0.64) and 0.59 (95% CI 0.55 to 0.64) for prediction of sPTB <34 and 37 weeks' respectively. The AUC for CL to predict sPTB <34 weeks was 0.48 for fusion defects (95% CI 0.39 to 0.57) but 0.78 (95% CI 0.66 to 0.91) for women with resorption defects. Overall quantitative fetal fibronectin had
Rasheed ZBM, Martin CRS, Sullivan MHF, et al., 2019, The placenta exhibits selective immune response in an in vitro model of haematogenous multi-pathogen-induced preterm labour, Publisher: WILEY, Pages: 158-158, ISSN: 1470-0328
Cook J, Bennett P, Kim SH, et al., 2019, First trimester circulating MicroRNA biomarkers predictive of subsequentpreterm delivery and cervical shortening, Scientific Reports, Vol: 9, ISSN: 2045-2322
Preterm birth (PTB) is the leading cause of infant death and disability worldwide. The onset of preterm uterine contractions is preceded by asymptomatic cervical remodelling and ripening, which can be seen on trans-vaginal ultrasound as cervical shortening. This study aimed to identify plasma miRNA biomarkers that predict preterm birth and/or cervical shortening. We collected serial plasma samples from pregnant women prospectively from 12 to 22 weeks gestation. The nCounter miRNA assay was used to identify differentially expressed miRNAs associated with spontaneous PTB and/or cervical shortening (n = 16 term no short, n = 13 preterm, n = 24 short). Predictive values of the miRNA biomarkers were confirmed in an independent validation cohort consisting of 96 women who delivered at term, 14 preterm and 21 early cervical shortening at <20 weeks gestation. Nine miRNAs (hsa-let-7a-5p, hsa-miR-374a-5p, hsa-miR-15b-5p, hsa-miR-19b-3p, hsa-miR-23a-3p, hsa-miR-93-5p, hsa-miR-150-5p, hsa-miR-185-5p and hsa-miR-191-5p) were differentially expressed (P < 0.001) in women subsequently experiencing PTB or cervical shortening. Hsa-miR-150-5p had the strongest ability to predict PTB (AUC = 0.8725) and cervical shortening (AUC = 0.8514). Plasma miRNAs in the first trimester can predict PTB and cervical shortening in women at risk of preterm delivery. This is a key period in pregnancy when early identification of PTB risk allows time to deliver outcome-modifying interventions.
Alqurashi M, Thurairajah S, Adan M, et al., 2019, Characterisation of Normal and Low Density Granulocytes in Pregnancy, Term Labour, and Women at High Risk of Preterm Labour., 66th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 122A-123A, ISSN: 1933-7191
Thurairajah S, Alqurashi M, Chan D, et al., 2019, Characterisation of Peripheral Blood Neutrophil Phenotype and Effector Functions during Pregnancy, Labour and in Women at High Risk of Preterm Labour., 66th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 123A-123A, ISSN: 1933-7191
Chan D, Lee YS, Ahmed S, et al., 2019, The Local and Systemic Immune Response in Preterm and Term Pregnancies and Their Association with the Vaginal Microbiota., 66th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 75A-75A, ISSN: 1933-7191
Sykes L, Bennett P, 2018, Efficacy of progesterone for prevention of preterm birth, Best Practice and Research: Clinical Obstetrics and Gynaecology, Vol: 52, Pages: 126-136, ISSN: 1521-6934
Preterm birth (PTB) occurs in 5–18% of pregnancies and is the leading cause of neonatal morbidity, mortality and infant death. Up to 30% of PTBs are due to iatrogenic reasons, but the remainder are due to the spontaneous onset of labour or pre-labour premature rupture of membranes (P-PROM). During pregnancy, the uterus remains quiescent and the cervix remains long and closed. Although the exact mechanisms that lead to spontaneous PTB (sPTB) are not fully understood, it is likely that the terminal pathways that are common to term labour are activated prematurely. Despite continued research efforts to develop preventative strategies, there have been no major advances resulting in the reduction of sPTB rates. Progesterone is the most researched prophylactic agent, yet, there is lack of consistency in the reported beneficial effects for the prevention of PTB and improvement in neonatal outcome. This is likely to stem from the multifactorial aetiology of sPTB, the varied patient cohorts recruited and the use of different preparations and routes of administration for progesterone. This review summarises the scientific rationale supporting the efficacy of progesterone and the results of major randomised controlled trials and finally emphasizes how targeted studies with more detailed patient stratification are essential to understand which population would benefit.
Chan DCY, Lee YS, Bura S, et al., 2018, The vaginal microbiota and the adaptive immune system in pregnant and nonpregnant women, Publisher: WILEY, Pages: E32-E32, ISSN: 1470-0328
Chan DCY, Lee YS, Bura S, et al., 2018, Recognition of vaginal microbiota by the adaptive maternal immune system, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 116A-116A, ISSN: 1933-7191
Rasheed ZBM, Rai RK, Lee YS, et al., 2018, The effect of TLR3 priming on TLR2, 4 and 6 induced activation of NF-kappa band AP-1 in human myometrium, amnion and vaginal epithelial cells, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 188A-188A, ISSN: 1933-7191
Kim SH, MacIntyre DA, Sykes L, et al., 2018, Comparing the Levels of miRNA Expression in Plasma from Blood Collected Using EDTA and Heparin Tubes, and Heparinase-Treated Plasma., 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 315A-315A, ISSN: 1933-7191
Kim SH, Binkhamis R, Cook JR, et al., 2018, A pilot study of circulating miRNAs as potential biomarkers for small-for-gestational-age births, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 282A-282A, ISSN: 1933-7191
Rasheed ZBM, Rai RK, Anucha E, et al., 2018, TLR3 priming increases TLR4-and TLR6-mediated pro-inflammatory cytokine production in amniocytes, myocytes and vaginal epithelial cells, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 258A-258A, ISSN: 1933-7191
MacIntyre DA, Sykes L, Bennett P, 2017, The human female urogenital microbiome: complexity in normality, Emerging Topics in Life Sciences, Vol: 1, Pages: 363-372, ISSN: 2397-8554
Microbial communities of the urogenital tract have long been recognised to play an important role in disease states. A revolution in methodological approaches is permitting the assessment of complex urogenital tract microbiota–host interactions and the metabolic and protein milieu of the mucosal interface. There is now great potential for significant advances in biomarker discovery and disease risk stratification, and for the elucidation of mechanisms underpinning the microbial community dynamics involved in urogenital tract pathology. Microbiota–host interactions in the female genital tract have a particular significance, because unlike in the male, there is direct communication between the external genitalia, the uterus and the peritoneal cavity. This review examines the microbial community composition at differing sites of the female urogenital tract and its relationship with health and disease. Key factors involved in the modulation of vaginal microbiome stability and structure, such as endocrine, immune and inflammatory pathways, are considered in the context of a woman's life cycle and disease pathogenesis.
Cook JR, Chatfield S, Chandiramani M, et al., 2017, Cerclage position, cervical length and preterm delivery in women undergoing ultrasound indicated cervical cerclage: A retrospective cohort study, PLOS One, Vol: 12, ISSN: 1932-6203
ObjectiveThe objectives were to assess whether anatomical location of ultrasound (USS) indicated cervical cerclage and/or the degree of cervical shortening (cervical length; CL) prior to and following cerclage affects the risk of preterm birth (PTB).MethodA retrospective cohort study of 179 women receiving cerclage for short cervix (≤25mm) was performed. Demographic data, CL before and after cerclage insertion, height of cerclage (distance from external os) and gestation at delivery were collected. Relative risk (RR) and odds ratio (OR) of preterm delivery were calculated according to the anatomical location of the cerclage within the cervix and the CL before and after cerclage as categorical and continuous variables. Partition tree analysis was used to identify the threshold cerclage height that best predicts PTB.Results25% (n = 45) delivered <34 weeks and 36% (n = 65) delivered <37 weeks. Risk of PTB was greater with cerclage in the distal 10mm (RR2.37, 95% CI 1.45–3.87) or the distal half of a closed cervix (RR2.16, 95% CI 1.45–3.87). Increasing absolute cerclage height was associated with a reduction in PTB (OR 0.87, 95% CI 0.82–0.94). A cerclage height <14.5 mm best predicts PTB (70.8%). Increasing CL following cerclage was associated with a reduction in PTB (OR0.87, 95% CI 0.82–0.94). Conversely, the risk of PTB was increased where CL remained static or shortened further following cerclage (RR2.34, 95% CI 1.04–5.25).ConclusionThe higher a cerclage was placed within a shortened cervix, the lower the subsequent odds of PTB. Women whose cerclage is placed in the distal 10mm of closed cervix or whose cervix fails to elongate subsequently, should remain under close surveillance as they have the highest risk of PTB.
Begam Mohammed Rasheed Z, Lee Y, MacIntyre D, et al., 2016, Activation of the TLR 3 receptor: A possible mechanism for virally induced preterm labour, Society for Reproductive Investigation
Sykes L, Anucha E, Begam Z, et al., 2016, The effect of TLR3 receptor priming on TLR 2, 4 and 6 agonist induced inflammation in placental implants, Society for Reproductive Investigation
Chan D, Lee Y, Teoh TG, et al., 2016, A comparison of TLR 1-9 induced cytokine responses in whole blood collected in the first trimester and at term and matched cord blood, Society for Reproductive Investigation
Sykes L, Thomson KR, Boyce EJ, et al., 2015, Sulfasalazine augments a pro-inflammatory response in IL-1β-stimulated amniocytes and myocytes., Immunology, Vol: 146, Pages: 630-644, ISSN: 0019-2805
Preterm birth occurs in 10% of pregnancies and is a major cause of neonatal morbidity and mortality. The majority of cases of early preterm labour (PTL) are associated with infection/inflammation, which places the fetal central nervous system at risk. Targeting immune activation is therefore an appealing therapeutic strategy for the prevention of PTL and neonatal brain injury. The expression of many labour-associated and inflammatory-response genes are controlled by the transcription factors NF-κB and Activator Protein-1 (AP-1), which makes them therapeutic targets of interest. Sulfasalazine (SASP) has been shown to inhibit NF-κB and reduce LPS-induced cytokine concentrations in fetal membrane explants and reduce the rate of E.coli-induced PTL in mice. Its effects upon AP-1 in the context of pregnancy are unknown. In this study the effect of SASP on IL-1β-induced NF-κB and AP-1 activity, cytokine production and COX-2 expression was examined in amniocytes and myocytes. A supra-therapeutic concentration (5 mM) was required to inhibit IL-1β-induced NF-κB (p<0.0001) in amniocytes and IL-1β-induced NF-κB (p<0.01), AP-1 (p<0.01) and COX-2 (p<0.05) in myocytes. Despite inhibiting IL-1β-induced cytokines, a basal increase in IL-6 (p<0.01), IL-8 (p<0.0001) and TNF-α (p<0.001) was seen with SASP 5 mM in amniocytes, and significant cytotoxic effects were seen in myocytes. The therapeutic concentration of 0.015 mM had no inhibitory effects on pro-inflammatory mediators, but led to an augmented response to IL-1β-induced IL-6 (p<0.01), IL-8 (p<0.05) and TNF-α (p<0.05) in amniocytes and IL-8 (p<0.05) in myocytes. SASP is therefore an unlikely therapeutic candidate for the prevention of inflammation-induced preterm labour. This article is protected by copyright. All rights reserved.
Migale R, Herbert BR, Lee YS, et al., 2015, Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor., American Journal of Pathology, Vol: 185, Pages: 2390-2401, ISSN: 1525-2191
Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at day 16 of gestation. Although control (phosphate-buffered saline)-treated animals were delivered at term approximately 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 were delivered 7 ± 2 hours p.i., O55:B5 were delivered 10 ± 3 hours p.i., O127:B8 were delivered 16 ± 10 hours p.i., and O128:B12 were delivered 17 ± 2 hours p.i. (data are given as means ± SD). A correlation between the onset of preterm birth and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in both myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. This may account for some reported differences in models of infection/inflammation-induced preterm labor. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models.
Sykes L, MacIntyre DA, Teoh TG, et al., 2014, Anti-inflammatory prostaglandins for the prevention of preterm labour., Reproduction
Preterm birth occurs in 10-12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. Tocolytics may therefore cause more harm by keeping the fetus in a hostile environment. Since inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has shifted towards exploring the potential for anti-inflammatory strategies. NF-κB is a transcription factor that controls the expression of many labour associated genes including COX-2, prostaglandins and the oxytocin receptor as well as key inflammatory genes. Targeting the inhibition of NF-κB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. Whilst prostaglandins are considered to be pro-labour and pro-inflammatory, the cyclopentenone prostaglandin 15-deoxy-Δ12,14PGJ2 (15dPGJ2) exhibits anti-inflammatory properties via the inhibition of NF-κB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15dPGJ2 also delays inflammation induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory prostaglandins may hold promise for the prevention of preterm labour and improved neonatal outcome.
Cook JR, Chatfield S, Chandiramani M, et al., 2014, Cerclage Position Predicts Risk of Preterm Delivery in Women Undergoing Ultrasound-Indicated Cervical Cerclage., REPRODUCTIVE SCIENCES, Vol: 21, Pages: 138A-138A, ISSN: 1933-7191
Kandola MK, Sykes L, Lee YS, et al., 2013, EP2 Receptor Activates Dual G Protein Signaling Pathways that Mediate Contrasting Proinflammatory and Relaxatory Responses in Term Pregnant Human Myometrium, Endocrinology, Vol: Epub ahead of print
Prostaglandin (PG) E2 (PGE2) plays a central role in the regulation of smooth muscle contractions. Classically, PGE2 stimulates contractions via EP1 and EP3 receptors, whereas EP2 and EP4 maintain quiescence. Labor involves a change from myometrial quiescence to contractions with a shift from anti- to proinflammatory pathways. EP2, a Gαs-coupled receptor, is known to mediate its actions via cAMP signaling. However, we have recently shown that EP2 also activates the proinflammatory PG G/H synthase-2 (PGHS-2). Here, we identify the mechanism underlying the ability of EP2 to maintain uterine quiescence and activate a proinflammatory/prolabor response in term-pregnant human myometrium. Human myometrial biopsies for in vivo and in vitro studies were taken at cesarean section at term, before or after the onset of labor. Activation of EP2 increased intracellular levels of cAMP and reduced contractility. Contrastingly, EP2 stimulation increased levels of PGHS-2, PG synthase mPGES-1, and PGE2. This was entirely dependent on EP2-mediated activation of calcium signaling. Both calcium signaling and up-regulation of PGHS-2 were insensitive to the Gαi inhibitor pertussis toxin but inhibited by siRNA knockdown of Gαq/11. There were no differences in EP2 mRNA or protein levels between upper or lower segment myometrium or between pre- and postlabor myometrium. However, in myocytes taken after the onset of labor, cAMP signaling was markedly attenuated, whereas activation of calcium and PGHS-2 was preserved. Overall, the dual coupling of EP2 to Gαs-cAMP and Gαq/11-calcium pathways underlies its ability to mediate contrasting functions in term pregnancy and the “switching” to a prolabor receptor.
Girling J, Sykes L, 2013, Thyroid disorders and other endocrinological disorders in pregnancy, Obstetrics, Gynaecology & Reproductive Medicine, Vol: 23, Pages: 171-179, ISSN: 1751-7214
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