The effect of combination tocolysis on the inhibition of human myometrial contractions and inflammation in preterm labour

Introduction: Preterm birth is a major cause of neonatal morbidity and mortality worldwide. Current management of preterm labour (PTL) focuses on the reduction of myometrial contractions and has limited efficacy. We hypothesise that combining tocolytics that act via different pathways can lead to additive or synergistic inhibitory effects. Oxytocin (OT) receptor antagonist, atosiban, is the only licensed tocolytic in Europe. A novel prostaglandin F2α (PGF2α) receptor antagonist, OBE002, has been developed for management of PTL. In this study, we aimed to investigate the effects of these tocolytics on myometrial contractility and inflammation. Methods: Human myometrial biopsies from term, non-labouring patients were used for the study of contractility and pro-inflammatory signalling in response to OT and PGF2α stimulation in presence of tocolytics. Results: We have demonstrated that OT- and PGF2α-induced myometrial contractility was suppressed by both atosiban and OBE002 via inhibition of an increase in intracellular calcium levels in response to OT or PGF2α stimulation. The combination of atosiban and OBE002 had an enhanced inhibitory effect on OT-induced, but not PGF2α-induced contractions. Both OT and PGF2α activated pro-inflammatory signalling in human myometrial cells. No significant additive effect was observed for the combination of atosiban and OBE002 on OT- or PGF2α-mediated inflammation but their combination showed a trend of an enhanced inhibitory effect on OT-mediated COX-2 expression. Using proximity ligation assay, we detected interaction between OT and PGF2α receptors, potentially indicating a crosstalk between OT and PGF2α signalling through the formation of heteromers. Conclusion: We have shown that combining atosiban and OBE002 has an additive inhibitory effect on myometrial contractility. Additionally, they both suppress pro-inflammatory effects of OT and PGF2α. This may be through direct receptor interaction leading to functional crosstalk. In conclusion, this study highlights the potential use of combining OT and PGF2α receptor antagonists for the development of future tocolytic strategies.Open Acces

Women's views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: a multi-methods study in the UK.

BACKGROUND: COVID-19 vaccines are advised for pregnant women in the United Kingdom (UK) however COVID-19 vaccine uptake among pregnant women is inadequate. METHODS: An online survey and semi-structured interviews were used to investigate pregnant women's views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. One thousand one hundred eighty-one women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rd August-11th October 2020. Ten women were interviewed. RESULTS: The majority of women surveyed (81.2%) reported that they would 'definitely' or were 'leaning towards' accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p < 0.005) and for their babies (69.9%, p < 0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p < 0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines. CONCLUSION: Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine decisions. Targeted interventions to promote COVID-19 vaccine uptake among ethnic minority and lower-income women may be needed

Women’s views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: A multi-methods study in the UK.

BACKGROUND: COVID-19 vaccines are the cornerstone of the pandemic response and now advised for pregnant women in the United Kingdom(UK) however COVID-19 vaccine acceptance among pregnant women is unknown. METHODS: An online survey and semi-structured interviews were used to investigate pregnant women’s views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. 1,181 women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rd August–11th October 2020. Ten women were interviewed. RESULTS: The majority of women surveyed (81.2%) reported that they would ‘definitely’ or were ‘leaning towards’ accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p<0.005) and for their babies (69.9%, p<0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p<0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines. CONCLUSION: Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine decisions. Targeted interventions to promote COVID-19 vaccine uptake among ethnic minority and lower-income women may be needed

Prostaglandin F2α requires activation of calcium-dependent signalling to trigger inflammation in human myometrium

IntroductionPreterm birth is one of the major causes of neonatal morbidity and mortality across the world. Both term and preterm labour are preceded by inflammatory activation in uterine tissues. This includes increased leukocyte infiltration, and subsequent increase in chemokine and cytokine levels, activation of pro-inflammatory transcription factors as NF-κB and increased prostaglandin synthesis. Prostaglandin F2α (PGF2α) is one of the myometrial activators and stimulators.MethodsHere we investigated the role of PGF2α in pro-inflammatory signalling pathways in human myometrial cells isolated from term non-labouring uterine tissue. Primary myometrial cells were treated with G protein inhibitors, calcium chelators and/or PGF2α. Nuclear extracts were analysed by TranSignal cAMP/Calcium Protein/DNA Array. Whole cell protein lysates were analysed by Western blotting. mRNA levels of target genes were analysed by RT-PCR.ResultsThe results show that PGF2α increases inflammation in myometrial cells through increased activation of NF-κB and MAP kinases and increased expression of COX-2. PGF2α was found to activate several calcium/cAMP-dependent transcription factors, such as CREB and C/EBP-β. mRNA levels of NF-κB-regulated cytokines and chemokines were also elevated with PGF2α stimulation. We have shown that the increase in PGF2α-mediated COX-2 expression in myometrial cells requires coupling of the FP receptor to both Gαq and Gαi proteins. Additionally, PGF2α-induced calcium response was also mediated through Gαq and Gαi coupling.DiscussionIn summary, our findings suggest that PGF2α-induced inflammation in myometrial cells involves activation of several transcription factors – NF-κB, MAP kinases, CREB and C/EBP-β. Our results indicate that the FP receptor signals via Gαq and Gαi coupling in myometrium. This work provides insight into PGF2α pro-inflammatory signalling in term myometrium prior to the onset of labour and suggests that PGF2α signalling pathways could be a potential target for management of preterm labour