The contribution of Kv7 channels to pregnant mouse and human myometrial contractility.

Premature birth accounts for approximately 75% of neonatal mortality and morbidity in the developed world. Despite this, methods for identifying and treating women at risk of preterm labour are limited and many women still present in preterm labour requiring tocolytic therapy to suppress uterine contractility. The aim of this study was to assess the utility of Kv7 channel activators as potential uterine smooth muscle (myometrium) relaxants in tissues from pregnant mice and women. Myometrium was obtained from early and late pregnant mice and from lipopolysaccharide (LPS)-injected mice (day 15 of gestation; model of infection in pregnancy). Human myometrium was obtained at the time of Caesarean section from women at term (38-41 weeks). RT-PCR/qRT-PCR detected KCNQ and KCNE expression in mouse and human myometrium. In mice, there was a global suppression of all KCNQ isoforms, except KCNQ3, in early pregnancy (n= 6, P < 0.001 versus late pregnant); expression subsequently increased in late pregnancy (n= 6). KCNE isoforms were also gestationally regulated (P < 0.05). KCNQ and KCNE isoform expression was slightly down-regulated in myometrium from LPS-treated-mice versus controls (P < 0.05, n= 3-4). XE991 (10 μM, Kv7 inhibitor) significantly increased spontaneous myometrial contractions in vitro in both human and mouse myometrial tissues (P < 0.05) and retigabine/flupirtine (20 μM, Kv7 channel activators) caused profound myometrial relaxation (P < 0.05). In summary, Kv7 activators suppressed myometrial contraction and KCNQ gene expression was sustained throughout gestation, particularly at term. Consequently, activation of the encoded channels represents a novel mechanism for treatment of preterm labour

Mobile phone apps for clinical decision support in pregnancy: a scoping review

BACKGROUND: The use of digital technology in healthcare has been found to be useful for data collection, provision of health information and communications. Despite increasing use of medical mobile phone applications (apps), by both clinicians and patients, there appears to be a paucity of peer-reviewed publications evaluating their use, particularly in pregnancy. This scoping review explored the use of mobile phone apps for clinical decision support in pregnancy. Specific objectives were to: 1. determine the current landscape of mobile phone app use for clinical decision support in pregnancy; 2. identify perceived benefits and potential hazards of use and 3. identify facilitators and barriers to implementation of these apps into clinical practice. METHODS: Papers eligible for inclusion were primary research or reports on the development and evaluation of apps for use by clinicians for decision support in pregnancy, published in peer-reviewed journals. Research databases included Medline, Embase, PsychoInfo, the Cochrane Database of Systematic Reviews and the online digital health journals JMIR mHealth and uHealth. Charting and thematic analysis was undertaken using NVivo qualitative data management software and the Framework approach. RESULTS: After screening for eligibility, 13 papers were identified, mainly reporting early stage development of the mobile app, and feasibility or acceptability studies designed to inform further development. Thematic analysis revealed four main themes across the included papers: 1. acceptability and satisfaction; 2. ease of use and portability; 3. multi-functionality and 4. the importance of user involvement in development and evaluation. CONCLUSIONS: This review highlights the benefits of mobile apps for clinical decision support in pregnancy and potential barriers to implementation, but reveals a lack of rigorous reporting of evaluation of their use and data security. This situation may change, however, following the issue of FDA and MHRA guidelines and implementation of UK government and other international strategies. Overall, the findings suggest that ease of use, portability and multi-functionality make mobile apps for clinical decision support in pregnancy useful and acceptable tools for clinicians

Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor‐related proteins in pregnant human myometrial tissues

Progesterone (P4) and cyclic adenosine monophosphate (cAMP) are regarded as pro-quiescent factors that suppress uterine contractions during pregnancy. We previously used human primary cells in vitro and mice in vivo to demonstrate that simultaneously enhancing myometrial P4 and cAMP levels may reduce inflammation-associated preterm labor. Here, we assessed whether aminophylline (Ami; phosphodiesterase inhibitor) and P4 can reduce myometrial contractility and contraction-associated proteins (CAPs) better together than individually; both agents are clinically used drugs. Myometrial tissues from pregnant non-laboring women were treated ex vivo with Ami acutely (while spontaneous contracting) or throughout 24-h tissue culture (±P4); isometric tension measurements, PKA assays, and Western blotting were used to assess tissue contractility, cAMP action, and inflammation. Acute (1 h) treatment with 250 and 750 μM Ami reduced contractions by 50% and 84%, respectively, which was not associated with a directly proportional increase in whole tissue PKA activity. Sustained myometrial relaxation was observed during 24-h tissue culture with 750 μM Ami, which did not require P4 nor reduce CAPs. COX-2 protein can be reduced by 300 nM P4 but this did not equate to myometrial relaxation. Ami (250 μM) and P4 (100 and 300 nM) co-treatment did not prevent oxytocin-augmented contractions nor reduce CAPs during interleukin-1β stimulation. Overall, Ami and P4 co-treatment did not suppress myometrial contractions more than either agent alone, which may be attributed to low specificity and efficacy of Ami; cAMP and P4 action at in utero neighboring reproductive tissues during pregnancy should also be considered

Ten women's decision-making experiences in threatened preterm labour: Qualitative findings from the EQUIPTT trial.

BACKGROUND: Clinical triage of women in threatened preterm labour (TPTL) could be improved through utilising the QUiPP App, as symptoms alone are poor predictors of early delivery. As most women in TPTL ultimately deliver at term, they must weigh this likelihood with their own personal considerations, and responsibilities. The importance of personal considerations was highlighted by the 2015 Montgomery ruling, and the significance of shared decision-making. AIMS: Through qualitative interviews, the primary aim was to explore women's decision-making experiences in TPTL through onset of symptoms, triage, clinical assessment, and discharge. METHODS: Qualitative interviews were undertaken as part of the EQUIPTT study (REC: 17/LO/1802) using a semi-structured interview schedule. Descriptive labels of the coding scheme were applied to the raw transcript data. This coding scheme was then increasingly refined into key themes and allowed parallels to be made within and between cases. RESULTS: Ten ethnically diverse women who presented at six different London hospitals sites in TPTL were interviewed. Three final themes emerged from the data incorporating 10 sub-themes, 'Seeking help', 'Being "assessed" vs making clinical decisions together', and 'End result.' CONCLUSION: Women described their busy lives and the need to juggle their commitments. Participants drew comparisons between their TPTL symptoms and 'period pain,' contrasting to typical medical terminology. Shared decision-making and the clinician-patient relationship could be improved through clinicians utilizing terminology women understand and relate to. Women used language that highlighted the clinician-patient power balance. While not fully involved in shared decision-making, women were overall satisfied with their care

Clinicians' experiences of using and implementing a medical mobile phone app (QUiPP V2) designed to predict the risk of preterm birth and aid clinical decision making.

BACKGROUND: As the vast majority of women who present in threatened preterm labour (TPTL) will not deliver early, clinicians need to balance the risks of over-medicalising the majority of women, against the potential risk of preterm delivery for those discharged home. The QUiPP app is a free, validated app which can support clinical decision-making as it produces individualised risks of delivery within relevant timeframes. Recent evidence has highlighted that clinicians would welcome a decision-support tool that accurately predicts preterm birth. METHODS: Qualitative interviews were undertaken as part of the EQUIPTT study (The Evaluation of the QUiPP app for Triage and Transfer) (REC: 17/LO/1802) which aimed to evaluate the impact of the QUiPP app on management of TPTL. Individual semi-structured telephone interviews were used to explore clinicians' (obstetricians' and midwives') experiences of using the QUiPP app and how it was implemented at their hospital sites. Thematic analysis was chosen to explore the meaning of the data, through a framework approach. RESULTS: Nineteen participants from 10 hospital sites in England took part. Data analysis revealed three overarching themes which were: 'experience of using the app', 'how QUiPP risk changes practice' and 'successfully adopting QUiPP: context is everything'. With these final themes we appeared to have achieved our aim of exploring the clinicians' experiences of using and implementing the QUiPP app. CONCLUSION: This study explored different clinician's experiences of implementing the app. The organizational and cultural context at different sites appeared to have a large impact on how well the QUiPP app was implemented. Future work needs to be undertaken to understand how best to embed the intervention within different settings. This will inform scale up of QUiPP app use across the UK and ensure that clinicians have access to this free, easy-to-use tool which can positively aid clinical decision making when caring for women in TPTL. CLINICAL TRIAL REGISTRY AND REGISTRATION NUMBER: ISRCTN 17846337, registered 08th January 2018, https://doi.org/10.1186/ISRCTN17846337

A translational approach to studying preterm labour

Preterm labour continues to be a major contributor to neonatal and infant morbidity. Recent data from the USA indicate that the number of preterm deliveries (including those associated with preterm labour) has risen in the last 20 years by 30%. This increase is despite considerable efforts to introduce new therapies for the prevention and treatment of preterm labour and highlights the need to assess research in this area from a fresh perspective. In this paper we discuss i) the limitations of our knowledge concerning prediction, prevention and treatment of preterm labour and ii) future multidisciplinary strategies for improving our approach

The interaction between protein kinase A and progesterone on basal and inflammation-induced myometrial oxytocin receptor expression

Our previous work has shown myometrial PKA activity declines in term and twin-preterm labour in association with an increase in the expression of the oxytocin receptor (OTR). Here we investigate the action of cAMP/PKA in basal conditions, with the addition of progesterone (P4) and/or IL-1β to understand how cAMP/PKA acts to maintain pregnancy and whether the combination of cAMP and P4 would be a viable therapeutic combination for the prevention of preterm labour (PTL). Further, given that we have previously found that cAMP enhances P4 action we wanted to test the hypothesis that changes in the cAMP effector system are responsible for the functional withdrawal of myometrial P4 action. Myometrial cells were grown from biopsies obtained from women at the time of elective Caesarean section before the onset of labour. The addition of forskolin, an adenylyl cyclase activator, repressed basal OTR mRNA levels at all doses and P4 only enhanced this effect at its highest dose. Forskolin repressed the IL-1β-induced increase in OTR mRNA and protein levels in a PKA-dependent fashion and repressed IL-1β-activation and nuclear transfer of NFκB and AP-1. P4 had similar effects and the combination P4 and forskolin had greater effects on OTR and NFκB than forskolin alone. While PKA knockdown had no effect on the ability of P4 to repress IL-1β-induced OTR expression it reversed the repressive effect of the combination of P4 and forskolin and resulted in a greater increase than observed with IL-1β alone. These studies suggest that cAMP acts via PKA to repress inflammation-driven OTR expression, but that when PKA activity is reduced, the combination of cAMP and P4 actually enhances the OTR response to inflammation, promoting the onset of labour and suggesting that changes in the cAMP effector system can induce a functional P4 withdrawal

Inflammatory pathways in the mechanism of parturition

Increasing evidence suggests that parturition is an inflammatory process. In this brief overview, inflammatory events occurring in association with parturition, and the mechanism by which they may contribute to labour and delivery will be discussed. Mention will be made of how this information may be of use in regulating the timing and the onset of parturition

The PROMISES study: A mixed methods approach to explore the acceptability of salivary progesterone testing for preterm birth risk among pregnant women and trained frontline healthcare workers in rural India

Introduction India has an overall neonatal mortality rate of 28/1000 live births, with higher rates in rural India. Approximately 3.5 million pregnancies in India are affected by preterm birth (PTB) annually and contribute to approximately a quarter of PTBs globally. Embedded within the PROMISES study (which aims to validate a low-cost salivary progesterone test for early detection of PTB risk), we present a mixed methods explanatory sequential feasibility substudy of the salivary progesterone test. Methods A pretraining and post-training questionnaire to assess Accredited Social Health Activists (ASHAs) (n=201) knowledge and experience of PTB and salivary progesterone sampling was analysed using the McNemar test. Descriptive statistics for a cross-sectional survey of pregnant women (n=400) are presented in which the acceptability of this test for pregnant women is assessed. Structured interviews were undertaken with ASHAs (n=10) and pregnant women (n=9), and were analysed using thematic framework analysis to explore the barriers and facilitators influencing the use of this test in rural India. Results Before training, ASHAs' knowledge of PTB (including risk factors, causes, postnatal support and testing) was very limited. After the training programme, there was a significant improvement in the ASHAs' knowledge of PTB. All 400 women reported the salivary test was acceptable with the majority finding it easy but not quick or better than drawing blood. For the qualitative aspects of the study, analysis of interview data with ASHAs and women, our thematic framework comprised of three main areas: implementation of intervention; networks of influence and access to healthcare. Qualitative data were stratified and presented as barriers and facilitators. Conclusion This study suggests support for ongoing investigations validating PTB testing using salivary progesterone in rural settings

PRECISE pregnancy cohort: challenges and strategies in setting up a biorepository in sub-Saharan Africa.

BACKGROUND AND OBJECTIVE: PRECISE is a population-based, prospective pregnancy cohort study designed for deep phenotyping of pregnancies in women with placenta-related disorders, and in healthy controls. The PRECISE Network is recruiting ~ 10,000 pregnant women in three countries (The Gambia, Kenya, and Mozambique) representing sub-Saharan Africa. The principal aim is to improve our understanding of pre-eclampsia, fetal growth restriction and stillbirth. This involves the creation of a highly curated biorepository for state of the art discovery science and a rich database of antenatal variables and maternal and neonatal outcomes. Our overarching aim is to provide large sample numbers with adequate power to address key scientific questions. Here we describe our experience of establishing a biorepository in the PRECISE Network and review the issues and challenges surrounding set-up, management and scientific use. METHODS: The feasibility of collecting and processing each sample type was assessed in each setting and plans made for establishing the necessary infrastructure. Quality control (QC) protocols were established to ensure that biological samples are 'fit-for-purpose'. The management structures required for standardised sample collection and processing were developed. This included the need for transport of samples between participating countries and to external academic/commercial institutions. RESULTS: Numerous practical challenges were encountered in setting up the infrastructure including facilities, staffing, training, cultural barriers, procurement, shipping and sample storage. Whilst delaying the project, these were overcome by establishing good communication with the sites, training workshops and constant engagement with the necessary commercial suppliers. A Project Executive Committee and Biology Working Group together defined the biospecimens required to answer the research questions paying particular attention to harmonisation of protocols with other cohorts so as to enable cross-biorepository collaboration. Governance structures implemented include a Data and Sample Committee to ensure biospecimens and data will be used according to consent, and prioritisation by scientific excellence. A coordinated sample and data transfer agreement will prevent delay in sample sharing. DISCUSSION: With adequate training and infrastructure, it is possible to establish high quality sample collections to facilitate research programmes such as the PRECISE Network in sub-Saharan Africa. These preparations are pre-requisites for effective execution of a biomarker-based approach to better understand the complexities of placental disease in these settings, and others