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BACKGROUND: Gestational diabetes (GDM) impacts 8-18% of pregnancies and greatly increases both maternal and child risk of developing non-communicable diseases such as type 2 diabetes and obesity. Whilst lifestyle interventions in pregnancy and postpartum reduce this risk, a research translation gap remains around delivering implementable interventions with adequate population penetration and participation. Impact Diabetes Bump2Baby is an implementation project of an evidence-based system of care for the prevention of overweight and obesity. Bump2Baby and Me is the multicentre randomised controlled trial investigating the effectiveness of a mHealth coaching programme in pregnancy and postpartum for women at high risk of developing GDM. METHODS: Eight hundred women will be recruited in early pregnancy from 4 clinical sites within Ireland, the UK, Spain, and Australia. Women will be screened for eligibility using the validated Monash GDM screening tool. Participants will be enrolled from 12 to 24 weeks' gestation and randomised on a 1:1 basis into the intervention or control arm. Alongside usual care, the intervention involves mHealth coaching via a smartphone application, which uses a combination of synchronous and asynchronous video and text messaging, and allows for personalised support and goal setting with a trained health coach. The control arm receives usual care. All women and their children will be followed from early pregnancy until 12 months postpartum. The primary outcome will be a difference in maternal body mass index (BMI) of 0.8 kg/m2 at 12 months postpartum. Secondary maternal and infant outcomes include the development of GDM, gestational weight gain, pregnancy outcomes, improvements in diet, physical activity, sleep, and neonatal weight and infant growth patterns. The 5-year project is funded by the EU Commission Horizon 2020 and the Australian National Health and Medical Research Council. Ethical approval has been received. DISCUSSION: Previous inte

OBJECTIVE: The My Baby's Movements (MBM) trial aimed to evaluate the impact on stillbirth rates of a multifaceted awareness package (the MBM intervention). DESIGN: Stepped-wedge cluster-randomised controlled trial. SETTING: Twenty-seven maternity hospitals in Australia and New Zealand. POPULATION: Women with a singleton pregnancy without major fetal anomaly at ≥28 weeks of gestation from August 2016 to May 2019. METHODS: The MBM intervention was implemented at randomly assigned time points, with the sequential introduction of eight groups of between three and five hospitals at 4-monthly intervals. Using generalised linear mixed models, the stillbirth rate was compared in the control and the intervention periods, adjusting for calendar time, study population characteristics and hospital effects. MAIN OUTCOME MEASURES: Stillbirth at ≥28 weeks of gestation. RESULTS: There were 304 850 births with 290 105 births meeting the inclusion criteria: 150 053 in the control and 140 052 in the intervention periods. The stillbirth rate was lower (although not statistically significantly so) during the intervention compared with the control period (2.2/1000 versus 2.4/1000 births; aOR 1.18, 95% CI 0.93-1.50; P = 0.18). The decrease in stillbirth rate was greater across calendar time: 2.7/1000 in the first versus 2.0/1000 in the last 18 months. No increase in secondary outcomes, including obstetric intervention or adverse neonatal outcome, was evident. CONCLUSIONS: The MBM intervention did not reduce stillbirths beyond the downward trend over time. As a result of low uptake, the role of the intervention remains unclear, although the downward trend across time suggests some benefit in lowering the stillbirth rate. In this study setting, an awareness of the importance of fetal movements may have reached pregnant women and clinicians prior to the implementation of the intervention. TWEETABLE ABSTRACT: The My Baby's Movements intervention to raise awareness of decreased fetal movement

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions

BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. SETTING: A total of 48 hospitals in the UK. PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding. INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and thr

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

BACKGROUND: Stillbirth is a devastating pregnancy outcome that has a profound and lasting impact on women and families. Globally, there are over 2.6 million stillbirths annually and progress in reducing these deaths has been slow. Maternal perception of decreased fetal movements (DFM) is strongly associated with stillbirth. However, maternal awareness of DFM and clinical management of women reporting DFM is often suboptimal. The My Baby's Movements trial aims to evaluate an intervention package for maternity services including a mobile phone application for women and clinician education (MBM intervention) in reducing late gestation stillbirth rates. METHODS/DESIGN: This is a stepped wedge cluster randomised controlled trial with sequential introduction of the MBM intervention to 8 groups of 3-5 hospitals at four-monthly intervals over 3 years. The target population is women with a singleton pregnancy, without lethal fetal abnormality, attending for antenatal care and clinicians providing maternity care at 26 maternity services in Australia and New Zealand. The primary outcome is stillbirth from 28 weeks' gestation. Secondary outcomes address: a) neonatal morbidity and mortality; b) maternal psychosocial outcomes and health-seeking behaviour; c) health services utilisation; d) women's and clinicians' knowledge of fetal movements; and e) cost. 256,700 births (average of 3170 per hospital) will detect a 30% reduction in stillbirth rates from 3/1000 births to 2/1000 births, assuming a significance level of 5%. Analysis will utilise generalised linear mixed models. DISCUSSION: Maternal perception of DFM is a marker of an at-risk pregnancy and commonly precedes a stillbirth. MBM offers a simple, inexpensive resource to reduce the number of stillborn babies, and families suffering the distressing consequences of such a loss. This large pragmatic trial will provide evidence on benefits and potential harms of raising awareness of DFM using a mobile phone app. TRIAL REGISTRAT

INTRODUCTION: A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP). METHODS AND ANALYSIS: The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North-East Newcastle & North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISCRTN88609453; Pre-results.

BACKGROUND: Obtaining prospective written consent from women to participate in trials when they are experiencing an obstetric emergency is challenging. Alternative consent pathways, such as gaining verbal consent at enrolment followed, later, by obtaining written consent, have been advocated by some clinicians and bioethicists but have received little empirical attention. We explored women's and staff views about the consent procedures used during the internal pilot of a trial (GOT-IT), where the protocol permitted staff to gain verbal consent at recruitment. METHODS: Interviews with staff (n = 27) and participating women (n = 22). Data were analysed thematically and interviews were cross-compared to identify differences and similarities in participants' views about the consent procedures used. RESULTS: Women and some staff highlighted benefits to obtaining verbal consent at trial enrolment, including expediting recruitment and reducing the burden on those left exhausted by their births. However, most staff with direct responsibility for taking consent expressed extreme reluctance to proceed with enrolment until they had obtained written consent, despite being comfortable using verbal procedures in their clinical practice. To account for this resistance, staff drew a strong distinction between research and clinical care and suggested that a higher level of consent was needed when recruiting into trials. In doing so, staff emphasised the need to engage women in reflexive decision-making and highlighted the role that completing the consent form could play in enabling and evidencing this process. While most staff cited their ethical responsibilities to women, they also voiced concerns that the absence of a signed consent form at recruitment could expose them to greater risk of litigation were an individual to experience a complication during the trial. Inexperience of recruiting into peripartum trials and limited availability of staff trained to take consent also reinf

INTRODUCTION: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000-10 000 IU/L METHODS AND ANALYSIS: We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000-10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m(2)) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and publis

Background: Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.Methods/design: We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.Discussion: Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups. © 2012 Schuit et al; licensee BioMed Central Ltd.

BACKGROUND: Dinoflagellates comprise an ecologically significant and diverse eukaryotic phylum that is sister to the phylum containing apicomplexan endoparasites. The mitochondrial genome of apicomplexans is uniquely reduced in gene content and size, encoding only three proteins and two ribosomal RNAs (rRNAs) within a highly compacted 6 kb DNA. Dinoflagellate mitochondrial genomes have been comparatively poorly studied: limited available data suggest some similarities with apicomplexan mitochondrial genomes but an even more radical type of genomic organization. Here, we investigate structure, content and expression of dinoflagellate mitochondrial genomes. RESULTS: From two dinoflagellates, Crypthecodinium cohnii and Karlodinium micrum, we generated over 42 kb of mitochondrial genomic data that indicate a reduced gene content paralleling that of mitochondrial genomes in apicomplexans, i.e., only three protein-encoding genes and at least eight conserved components of the highly fragmented large and small subunit rRNAs. Unlike in apicomplexans, dinoflagellate mitochondrial genes occur in multiple copies, often as gene fragments, and in numerous genomic contexts. Analysis of cDNAs suggests several novel aspects of dinoflagellate mitochondrial gene expression. Polycistronic transcripts were found, standard start codons are absent, and oligoadenylation occurs upstream of stop codons, resulting in the absence of termination codons. Transcripts of at least one gene, cox3, are apparently trans-spliced to generate full-length mRNAs. RNA substitutional editing, a process previously identified for mRNAs in dinoflagellate mitochondria, is also implicated in rRNA expression. CONCLUSION: The dinoflagellate mitochondrial genome shares the same gene complement and fragmentation of rRNA genes with its apicomplexan counterpart. However, it also exhibits several unique characteristics. Most notable are the expansion of gene copy numbers and their arrangements within the genome, RNA edi