Metformin in the prevention of type 2 diabetes after gestational diabetes in postnatal women (OMAhA): a UK multicentre randomised, placebo-controlled, double-blind feasibility trial with nested qualitative study.

OBJECTIVE: To determine the feasibility of a definitive trial of metformin to prevent type 2 diabetes in the postnatal period in women with gestational diabetes. DESIGN: A multicentre, placebo-controlled, double-blind randomised feasibility trial with qualitative evaluation. SETTING: Three inner-city UK National Health Service hospitals in London. PARTICIPANTS: Pregnant women with gestational diabetes treated with medication. INTERVENTIONS: 2 g of metformin (intervention) or placebo (control) from delivery until 1 year postnatally. PRIMARY OUTCOME MEASURES: Rates of recruitment, randomisation, follow-up, attrition and adherence to the intervention. SECONDARY OUTCOME MEASURES: Preliminary estimates of glycaemic effects, qualitative exploration, acceptability of the intervention and costs. RESULTS: Out of 302 eligible women, 57.9% (175/302) were recruited. We randomised 82.3% (144/175) of those recruited, with 71 women in the metformin group and 73 women in the placebo group. Of the participants remaining in the study and providing any adherence information, 54.1% (59/109) took at least 75% of the target intervention dose; the overall mean adherence was 64% (SD 33.6). Study procedures were found to be acceptable to women and healthcare professionals. An increased perceived risk of developing type 2 diabetes, or a positive experience of taking metformin during pregnancy, encouraged participation and adherence to the intervention. Barriers to adherence included disruption to the medication schedule caused by the washout periods ahead of each study visit or having insufficient daily reminders. CONCLUSIONS: It is feasible to run a full-scale definitive trial on the effectiveness of metformin to prevent type 2 diabetes in women with gestational diabetes, during the early postnatal period. Adherence and engagement with the study could be improved with more regular reminders and potentially the addition of ongoing educational or peer support to reinforce messages around type 2 diabetes prevention. TRIAL REGISTRATION NUMBER: ISRCTN20930880.

Increasing Patient Age, Ambulatory Surgery Center Setting, and Surgeon Experience Are Associated With Shorter Operative Duration for Anterior Cruciate Ligament Reconstruction.

Purpose: To identify variables associated with operative duration and intraoperative or perioperative complications after primary anterior cruciate ligament reconstruction (ACLR). Methods: Surgeons who performed a minimum of 20 arthroscopic cases per month were recruited for participation through the Arthroscopy Association of North America from 2011 through 2013. All participants agreed to voluntarily submit data for 6 months of consecutive knee and shoulder arthroscopy cases. Only subjects coded for ACLR were analyzed, whereas revision cases were excluded. ACLRs were subdivided into isolated ACLR, ACLR with minor concomitant procedures, and ACLR with major concomitant procedures. Patient, surgeon, and surgical variables were analyzed for their effect on operative duration and complications. Results: One hundred thirty-five orthopaedic surgeons participated, providing 1,180 primary ACLRs (399 isolated ACLRs, 441 ACLRs plus minor procedures, and 340 ACLRs plus major procedures). Most surgeons were in private practice (72.8%). Most patients were male patients (58.8%), and the mean body mass index (BMI) was 26.2 ± 5.1. The overall mean operative duration was 95.9 ± 42.0 minutes (isolated ACLRs, 88.4 ± 36.8 minutes; ACLRs plus minor concomitant procedures, 90.1 ± 37.6 minutes; and ACLRs plus major concomitant procedures, 118.5 ± 112.4 minutes; P < .001). Patient age was inversely correlated with operative duration (ρ = -0.221, P < .001). Surgical procedures performed in an ambulatory surgery center had a shorter mean operative duration (91.5 ± 40.4 minutes) compared with those performed in a hospital setting (105.0 ± 43.8 minutes, P < .001). There were 22 intraoperative and 47 early postoperative complications, with the most common being deep vein thrombosis (n = 15). Surgical volume (knee arthroscopy cases per month) correlated inversely with operative time (ρ = -0.200, P = .001) and complication rate (ρ = -0.112, P < .001). Patient BMI was associated with increased odds of early postoperative complications on multivariate analysis (odds ratio, 1.060; P = .044; 95% confidence interval, 1.002-1.121). Conclusions: Increasing patient age, private practice, ambulatory surgery center setting, and surgeon experience are associated with a shorter operative duration for ACLR. Although an increasing number of arthroscopic knee procedures performed by surgeons correlated with fewer complications, only increasing patient BMI significantly predicted odds of complications. Level of Evidence: Level IV, prognostic case series.

Venous Thromboembolism Prophylaxis and Hormonal Contraceptive Management Practice Patterns in the Perioperative Period for Anterior Cruciate Ligament Reconstruction.

Purpose: To evaluate the venous thromboembolism (VTE) prophylaxis practices of surgeons performing anterior cruciate ligament reconstruction (ACLR) in female patients using hormonal contraceptives. Methods: Our research team designed an investigational survey using branching logic that was made available to the AANA membership. The survey was designed to identify clinical decision making regarding VTE prophylaxis after ACLR in patients without risk factors for VTE, the counseling of patients about VTE risk associated with hormonal contraceptives, and the use of VTE prophylaxis after ACLR in patients taking hormonal contraceptives. Results: Ninety-four respondents completed the survey. Eighty-nine respondents identified their gender (63% male and 37% female respondents). Respondents reported performing the following number of ACLRs annually: more than 50 (40%), 30 to 50 (29%), 15 to 30 (29%), and fewer than 15 (2%). Of the respondents, 62 (67%) reported that VTE developed after ACLR in their patients (male patients only, 32%; female patients only, 24%; and both male and female patients, 34%). Sixty-seven percent used chemoprophylaxis after ACLR. Surgeons who asked about hormonal contraceptive use were more likely to be women (P = .01; odds ratio [OR], 4.2). Surgeons who changed their VTE prophylaxis plan as a result of asking about hormonal contraceptive use were more likely to be women (P = .02; OR, 2.8). Surgeons who asked about hormonal contraceptive use were more likely to have female patients with VTE after ACLR (P = .03; OR, 2.9). Surgeons who changed their VTE prophylaxis plan as a result of asking about hormonal contraceptive use were more likely to have female patients with VTE after ACLR (P = .001; OR, 4.6). Conclusions: There is no standard of care for VTE prophylaxis after ACLR. A surgeon's own gender and prior clinical experience with VTE after ACLR may influence his or her likelihood to consider a patient's hormonal contraceptive use regarding VTE risk after ACLR. Clinical Relevance: The use of hormonal contraception is a risk factor for VTE in female patients undergoing ACLR. It is important to identify current practice patterns and the need for a standard of care.

Myo-inositol nutritional supplement for prevention of gestational diabetes (EMmY): a randomised, placebo-controlled, double-blind pilot trial with nested qualitative study.

OBJECTIVES: To determine the feasibility and acceptability of conducting a randomised trial on the effects of myo-inositol in preventing gestational diabetes in high-risk pregnant women. DESIGN: A multicentre, double-blind, placebo-controlled, pilot randomised trial with nested qualitative evaluation. SETTING: Five inner city UK National Health Service hospitals PARTICIPANTS: Multiethnic pregnant women at 12+0 and 15+6 weeks' gestation with risk factors for gestational diabetes. INTERVENTIONS: 2 g of myo-inositol or placebo, both included 200 µg folic acid, twice daily until delivery. PRIMARY OUTCOME MEASURES: Rates of recruitment, randomisation, adherence and follow-up. SECONDARY OUTCOME MEASURES: Glycaemic indices (including homoeostatic model assessment-insulin resistance HOMA-IR), gestational diabetes (diagnosed using oral glucose tolerance test at 28 weeks and by delivery), maternal, perinatal outcomes, acceptability of intervention and costs. RESULTS: Of the 1326 women screened, 58% (773/1326) were potentially eligible, and 27% (205/773) were recruited. We randomised 97% (198/205) of all recruited women (99 each in intervention and placebo arms) and ascertained outcomes in 90% of women (178/198) by delivery. The mean adherence was 52% (SD 44) at 28 weeks' and 34% (SD 41) at 36 weeks' gestation. HOMA-IR and serum insulin levels were lower in the myo-inositol vs placebo arm (mean difference -0.6, 95% CI -1.2 to 0.0 and -2.69, 95% CI -5.26 to -0.18, respectively). The study procedures were acceptable to women and healthcare professionals. Women who perceived themselves at high risk of gestational diabetes were more likely to participate and adhere to the intervention. The powder form of myo-inositol and placebo, along with nausea in pregnancy were key barriers to adherence. CONCLUSIONS: A future trial on myo-inositol versus placebo to prevent gestational diabetes is feasible. The intervention will need to be delivered in a non-powder form to improve adherence. There is a signal for efficacy in reducing insulin resistance in pregnancy with myo-inositol. TRIAL REGISTRATION NUMBER: ISRCTN48872100.

A rapid intrapartum test for group B Streptococcus to reduce antibiotic usage in mothers with risk factors: the GBS2 cluster RCT.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. OBJECTIVES: We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. DESIGN: An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. SETTING: UK maternity units were randomised to either a strategy of rapid test or usual care. PARTICIPANTS: Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. MAIN OUTCOME MEASURES: Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. CONCLUSIONS: The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. FUTURE WORK: The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN74746075. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Group B Streptococcus is a common bacterium found in the vagina and intestines of approximately one in four women. Group B Streptococcus may be passed to the baby around birth and cause severe infection. In the UK, women are offered antibiotics in labour to protect their baby from group B Streptococcus infection when specific risk factors are present. Most women with risk factors do not carry group B Streptococcus and their babies are unnecessarily exposed to antibiotics. Most women carrying group B Streptococcus do not have risk factors and so will not be offered antibiotics to protect their babies. WHAT DID WE PLAN TO DO?: We planned to find out if, for women with risk factors, a 'rapid test' in labour resulted in fewer women receiving antibiotics compared with 'usual care'. We also wanted to establish if the test correctly identified if mothers were carrying group B Streptococcus, helped reduce infections in babies and represented value for money. WHAT DID WE FIND?: We involved 1627 women (1700 babies) from 20 hospitals randomly allocated to rapid test or usual care. Using the 'rapid test' did not reduce antibiotics provided to mothers (41% in rapid test units and 36% in usual-care units). The test correctly identified 86% of women carrying group B Streptococcus, 89% of those who did not and failed to provide a result in 14% of women. A rapid test policy resulted in 13% fewer babies receiving antibiotics. The rapid test generated no cost savings when only the mothers' care was considered, but there was potential for reduced costs when including the newborns' hospital stay. WHAT DOES THIS MEAN?: The rapid test is accurate; however, using it for women with risk factors for their baby developing group B Streptococcus infection does not reduce antibiotic usage in mothers, although it does in babies. Value for money is uncertain and depends on what costs are included.

Development and Validation of Clinical Prediction Models for Surgical Success in Patients With Endometriosis: Protocol for a Mixed Methods Study.

BACKGROUND: Endometriosis is a chronic inflammatory condition affecting 6%-10% of women of reproductive age and is defined by the presence of endometrial-like tissue outside the uterus (lesions), commonly affecting the pelvis and ovaries. It is associated with debilitating pelvic pain, infertility, and fatigue and often has devastating effects on the quality of life (QoL). Although it is as common as back pain, it is poorly understood, and treatment and diagnosis are often delayed, leading to unnecessary suffering. Endometriosis has no cure. Surgery is one of several management options. Quantifying the probability of successful surgery is important for guiding clinical decisions and treatment strategies. Factors predicting success through pain reduction after endometriosis surgery have not yet been adequately identified. OBJECTIVE: This study aims to determine which women with confirmed endometriosis benefit from surgical improvement in pain and QoL and whether these women could be identified from clinical symptoms measured before laparoscopy. METHODS: First, we will carry out a systematic search and review and, if appropriate, meta-analysis of observational cohort and case-control studies reporting one or more risk factors for endometriosis and postsurgical treatment success. We will search PubMed, Embase, and Cochrane databases from inception without language restrictions and supplement the reference lists by manual searches. Second, we will develop separate clinical prediction models for women with confirmed and suspected diagnoses of endometriosis. A total of three suitable databases have been identified for development and external validation (the MEDAL [ISRCTN13028601] and LUNA [ISRCTN41196151] studies, and the BSGE database), and access has been guaranteed. The models will be developed using a linear regression approach that links candidate factors to outcomes. Third, we will hold 2 stakeholder co-design workshops involving eight clinicians and eight women with endometriosis separately and then bring all 16 participants together. Participants will discuss the implementation, delivery, usefulness, and sustainability of the prediction models. Clinicians will also focus on the ease of use and access to clinical prediction tools. RESULTS: This project was funded in March 2018 and approved by the Institutional Research Ethics Board in December 2019. At the time of writing, this study was in the data analysis phase, and the results are expected to be available in April 2021. CONCLUSIONS: This study is the first to aim to predict who will benefit most from laparoscopic surgery through the reduction of pain or increased QoL. The models will provide clinicians with robustly developed and externally validated support tools, improving decision making in the diagnosis and treatment of women. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/20986.

Systematic review of patient-specific pre-operative predictors of pain improvement to endometriosis surgery.

BACKGROUND: Up to 28% of endometriosis patients do not get pain relief from therapeutic laparoscopy but this subgroup is not defined. OBJECTIVES: To identify any prognostic patient-specific factors (such as but not limited to patients' type or location of endometriosis, sociodemographics and lifestyle) associated with a clinically meaningful reduction in post-surgical pain response to operative laparoscopic surgery for endometriosis. SEARCH STRATEGY: PubMed, Cochrane and Embase databases were searched from inception to 19 May 2020 without language restrictions. Backward and forward citation tracking was used. SELECTION CRITERIA DATA COLLECTION AND ANALYSIS: Cohort studies reporting prognostic factors, along with scores for domains of pain associated with endometriosis before and after surgery, were included. Studies that compared surgeries, or laboratory tests, or outcomes without stratification were excluded. Results were synthesised but variation in study designs and inconsistency of outcome reporting precluded us from doing a meta-analysis. MAIN RESULTS: Five studies were included. Quality assessment using the Newcastle-Ottawa scale graded three studies as high, one as moderate and one as having a low risk of bias. Four of five included studies separately reported that a relationship exists between more severe endometriosis and stronger pain relief from laparoscopic surgery. CONCLUSION: Currently, there are few studies of appropriate quality to answer the research question. We recommend future studies report core outcome sets to enable meta-analysis. LAY SUMMARY: Endometriosis is a painful condition caused by displaced cells from the lining of the womb, causing inflammation and scarring inside the body. It affects 6-10% of women and there is no permanent cure. Medical and laparoscopic surgical treatments are available, but about 28% of patients do not get the hoped-for pain relief after surgery. Currently, there is no way of predicting who gets better and who does not. We systematically searched the world literature to establish who may get better, in order to improve counselling when women choose treatment options. We identified five studies of variable quality showing: More complex disease (in specialist hands) responds better to surgery than less, but more studies needed.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

TILT: Time-Lapse Imaging Trial-a pragmatic, multi-centre, three-arm randomised controlled trial to assess the clinical effectiveness and safety of time-lapse imaging in in vitro fertilisation treatment.

BACKGROUND: Subfertility is a common problem for which in vitro fertilisation (IVF) treatment is commonly recommended. Success rates following IVF are suboptimal and have remained static over the last few years. This imposes a considerable financial burden on overstretched healthcare resources. Time-lapse imaging (TLI) of developing embryos in IVF treatment is hypothesised to improve the success rates of treatment. This may be either by providing undisturbed culture conditions or by improving the predictive accuracy for optimal embryo selection from a cohort of available embryos. However, the current best evidence for its effectiveness is inconclusive. METHODS: The time-lapse imaging trial is a pragmatic, multi-centre, three-arm parallel-group randomised controlled trial using re-randomisation. The primary objective of the trial is to determine if the use of TLI or undisturbed culture in IVF treatment results in a higher live birth rate when compared to current standard methods of embryo incubation and assessment. Secondary outcomes include measures of clinical efficacy and safety. The trial will randomise 1575 participants to detect an increase in live birth from 26.5 to 35.25%. DISCUSSION: In the absence of high-quality evidence, there is no current national guidance, recommendation or policy for the use of TLI. The use of TLI is not consistently incorporated into standard IVF care. A large, pragmatic, multi-centre, trial will provide much needed definitive evidence regarding the effectiveness of TLI. If proven to be effective, its incorporation into standard care would translate into significant clinical and economic benefits. If not, it would allow allocation of resources to more effective interventions. TRIAL REGISTRATION: ISRCTN registry ISRCTN17792989 . Prospectively registered on 18 April 2018.

Effect of early cryoprecipitate transfusion versus standard care in women who develop severe postpartum haemorrhage (ACROBAT) in the UK: a protocol for a pilot cluster randomised trial.

INTRODUCTION: The incidence of severe postpartum haemorrhage (PPH) that requires blood transfusion is on the increase. Fibrinogen levels have been shown to drop early and significantly during PPH, which is associated with worse outcomes. Early fibrinogen replacement could potentially improve outcomes. No studies have investigated the clinical impact of early cryoprecipitate transfusion in PPH. Prior to performing a full-scale trial, a pilot study is needed to determine feasibility of the intervention and recruitment. METHODS: ACROBAT is a cluster-randomised pilot study with a qualitative evaluation. Four large London maternity units are randomised to either the intervention or control group. The intervention group will adapt their major obstetric haemorrhage procedures to administer cryoprecipitate early for primary PPH. The control group will retain their standard of care.We include women at >24 weeks gestation who are actively bleeding within 24 hours of delivery and for whom transfusion of red blood cells (RBCs) has been started. We exclude women who decline blood transfusions in advance or have inherited Factor XIII or fibrinogen deficiency. Due to the emergency nature of the intervention, informed consent for administering the intervention is waived.The primary objective is to assess the feasibility of administering cryoprecipitate within 90 min of RBC request, as compared with standard treatment where cryoprecipitate is given later or not at all. Secondary objectives include the feasibility of recruitment and data collection, reasons for and barriers to consent, preliminary maternal clinical outcomes, identification of the optimal infrastructure pathways for study delivery, and acceptability of the intervention and outcomes. ETHICS AND DISSEMINATION: The trial has approvals from the London-Brighton & Sussex Research Ethics Committee (ref. 18/LO/2062), the Confidentiality Advisory Group (ref. 18/CAG/0199) and Health Research Authority (IRAS number 237959). Data analysis and publication of manuscripts will start in Q3 2020. TRIAL REGISTRATION NUMBER: ISRCTN12146519.

Effectiveness and acceptability of metformin in preventing the onset of type 2 diabetes after gestational diabetes in postnatal women: a protocol for a randomised, placebo-controlled, double-blind feasibility trial­Optimising health outcomes with Metformin to prevent diAbetes After pregnancy (OMAhA).

INTRODUCTION: Up to half of all women diagnosed with gestational diabetes mellitus develop type 2 diabetes within 5 years after delivery. Metformin is effective in preventing type 2 diabetes in high-risk non-pregnant individuals, but its effect when commenced in the postnatal period is not known. We plan to assess the feasibility of evaluating metformin versus placebo in minimising the risk of dysglycaemia including type 2 diabetes after delivery in postnatal women with a history of gestational diabetes through a randomised trial. METHODS AND ANALYSIS: Optimising health outcomes with Metformin to prevent diAbetes After pregnancy (OMAhA) is a multicentre placebo-controlled double-blind randomised feasibility trial, where we will randomly allocate 160 postnatal women with gestational diabetes treated with medication to either metformin (intervention) or placebo (control) tablets to be taken until 1 year after delivery. The primary outcomes are rates of recruitment, randomisation, adherence and attrition. The secondary outcomes are maternal dysglycaemia, cost and quality of life outcomes in both arms, and acceptability of the study and intervention, which will be evaluated through a nested qualitative study. Feasibility outcomes will be summarised using descriptive statistics, point estimates and 95% CIs. ETHICS AND DISSEMINATION: The OMAhA study received ethics approval from the London-Brent Research Ethics Committee (18/LO/0505). Trial findings will be published in a peer-reviewed journal, disseminated at conferences, through our Patient and Public Involvement advisory group (Katie's Team) and through social media platforms. TRIAL REGISTRATION NUMBER: ISRCTN20930880.

MEMPHIS: a smartphone app using psychological approaches for women with chronic pelvic pain presenting to gynaecology clinics: a randomised feasibility trial.

OBJECTIVES: To evaluate the feasibility of a randomised trial of a modified, pre-existing, mindfulness meditation smartphone app for women with chronic pelvic pain. DESIGN: Three arm randomised feasibility trial. SETTING: Women were recruited at two gynaecology clinics in the UK. Interventions were delivered via smartphone or computer at a location of participants choosing. PARTICIPANTS: Women were eligible for the study if they were over 18, had been experiencing organic or non-organic chronic pelvic pain for 6 months or more, and had access to a computer or smartphone. 90 women were randomised. INTERVENTIONS: Daily mindfulness meditation delivered by smartphone app, an active control app which delivered muscle relaxation techniques, and usual care without app. Interventions were delivered over 60 days. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes included length of recruitment, follow-up rates, adherence to the app interventions, and clinical outcomes measured at baseline, two, three and 6 months. RESULTS: The target sample size was recruited in 145 days. Adherence to the app interventions was extremely low (mean app use 1.8 days mindfulness meditation group, 7.0 days active control). Fifty-seven (63%) women completed 6-month follow-up, and 75 (83%) women completed at least one postrandomisation follow-up. The 95% CIs for clinical outcomes were consistent with no benefit from the mindfulness meditation app; for example, mean differences in pain acceptance scores at 60 days (higher scores are better) were -2.3 (mindfulness meditation vs usual care, 95% CI: -6.6 to 2.0) and -4.0 (mindfulness meditation vs active control, 95% CI: -8.1 to 0.1). CONCLUSIONS: Despite high recruitment and adequate follow-up rates, demonstrating feasibility, the extremely low adherence suggests a definitive randomised trial of the mindfulness meditation app used in this study is not warranted. Future research should focus on improving patient engagement. TRIAL REGISTRATION NUMBERS: NCT02721108; ISRCTN10925965; Results.

mHealth: providing a mindfulness app for women with chronic pelvic pain in gynaecology outpatient clinics: qualitative data analysis of user experience and lessons learnt.

OBJECTIVES: To determine whether a pre-existing smartphone app to teach mindfulness meditation is acceptable to women with chronic pelvic pain (CPP) and can be integrated into clinical practice within the National Health Service (NHS) CPP pathways, and to inform the design of a potential randomised clinical trial. DESIGN: A prestudy patient and public involvement (PPI) group to collect feedback on the acceptability of the existing app and study design was followed by a three-arm randomised feasibility trial. In addition, we undertook interviews and focus groups with patients and staff to explore app usability and acceptability. We also obtained participant comments on the research process, such as acceptability of the study questionnaires. SETTING: Two gynaecology clinics within Barts Health NHS, London, UK. PARTICIPANTS: Patients with CPP lasting ≥6 months with access to smartphone or personal computer and understanding of basic English. INTERVENTION: The intervention was mindfulness meditation content plus additional pain module delivered by a smartphone app. Active controls received muscle relaxation content from the same app. Passive (waiting list) controls received usual care. MAIN OUTCOME MEASURES: Themes on user feedback, app usability and integration, and reasons for using/not using the app. RESULTS: The use of the app was low in both active groups. Patients in the prestudy PPI group, all volunteers, were enthusiastic about the app (convenience, content, portability, flexibility, ease of use). Women contributing to the interview or focus group data (n=14), from a 'real world' clinic (some not regular app users), were less positive, citing as barriers lack of opportunities/motivation to use the app and lack of familiarity and capabilities with technology. Staff (n=7) were concerned about the potential need for extra support for them and for the patients, and considered the app needed organisational backing and peer acceptance. CONCLUSION: The opinions of prestudy PPI volunteers meeting in their private time may not represent those of patients recruited at a routine clinic appointment. It may be more successful to codesign/codevelop an app with typical users than to adapt existing apps for use in real-world clinical populations. TRIAL REGISTRATION NUMBER: ISRCTN10925965.

Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicentre randomised trial.

BACKGROUND: Pregnant women with metabolic risk factors are at high risk of complications. We aimed to assess whether a Mediterranean-style diet reduces adverse pregnancy outcomes in high-risk women. METHODS AND FINDINGS: We conducted a multicentre randomised trial in 5 maternity units (4 in London and 1 in Birmingham) between 12 September 2014 and 29 February 2016. We randomised inner-city pregnant women with metabolic risk factors (obesity, chronic hypertension, or hypertriglyceridaemia) to a Mediterranean-style diet with high intake of nuts, extra virgin olive oil, fruits, vegetables, nonrefined grains, and legumes; moderate to high consumption of fish; low to moderate intake of poultry and dairy products; low intake of red and processed meat; and avoidance of sugary drinks, fast food, and food rich in animal fat versus usual care. Participants received individualised dietary advice at 18, 20, and 28 weeks' gestation. The primary endpoints were composite maternal (gestational diabetes or preeclampsia) and composite offspring (stillbirth, small for gestational age, or admission to neonatal care unit) outcomes prioritised by a Delphi survey. We used an intention-to-treat (ITT) analysis with multivariable models and identified the stratification variables and prognostic factors a priori. We screened 7,950 and randomised 1,252 women. Baseline data were available for 593 women in the intervention (93.3% follow-up, 553/593) and 612 in the control (95.6% follow-up, 585/612) groups. Over a quarter of randomised women were primigravida (330/1,205; 27%), 60% (729/1,205) were of Black or Asian ethnicity, and 69% (836/1,205) were obese. Women in the intervention arm consumed more nuts (70.1% versus 22.9%; adjusted odds ratio [aOR] 6.8, 95% confidence interval [CI] 4.3-10.6, p ≤ 0.001) and extra virgin olive oil (93.2% versus 49.0%; aOR 32.2, 95% CI 16.0-64.6, p ≤ 0.001) than controls; increased their intake of fish (p < 0.001), white meat (p < 0.001), and pulses (p = 0.05); and reduced their intake of red meat (p < 0.001), butter, margarine, and cream (p < 0.001). There was no significant reduction in the composite maternal (22.8% versus 28.6%; aOR 0.76, 95% CI 0.56-1.03, p = 0.08) or composite offspring (17.3% versus 20.9%; aOR 0.79, 95% CI 0.58-1.08, p = 0.14) outcomes. There was an apparent reduction in the odds of gestational diabetes by 35% (aOR 0.65, 95% CI 0.47-0.91, p = 0.01) but not in other individual components of the composite outcomes. Mothers gained less gestational weight (mean 6.8 versus 8.3 kg; adjusted difference -1.2 Kg, 95% CI -2.2 to -0.2, p = 0.03) with intervention versus control. There was no difference in any of the other maternal and offspring complications between both groups. When we pooled findings from the Effect of Simple, Targeted Diet in Pregnant Women With Metabolic Risk Factors on Pregnancy Outcomes (ESTEEM) trial with similar trials using random effects meta-analysis, we observed a significant reduction in gestational diabetes (odds ratio [OR] 0.67, 95% CI 0.53-0.84, I2 = 0%), with no heterogeneity (2 trials, 2,397 women). The study's limitations include the use of participant reported tools for adherence to the intervention instead of objective biomarkers. CONCLUSIONS: A simple, individualised, Mediterranean-style diet in pregnancy did not reduce the overall risk of adverse maternal and offspring complications but has the potential to reduce gestational weight gain and the risk of gestational diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02218931.

Cost-effectiveness of cell salvage and donor blood transfusion during caesarean section: results from a randomised controlled trial.

OBJECTIVES: To evaluate the cost-effectiveness of routine use of cell salvage during caesarean section in mothers at risk of haemorrhage compared with current standard of care. DESIGN: Model-based cost-effectiveness evaluation alongside a multicentre randomised controlled trial. Three main analyses were carried out on the trial data: (1) based on the intention-to-treat principle; (2) based on the per-protocol principle; (3) only participants who underwent an emergency caesarean section. SETTING: 26 obstetric units in the UK. PARTICIPANTS: 3028 women at risk of haemorrhage recruited between June 2013 and April 2016. INTERVENTIONS: Cell salvage (intervention) versus routine care without salvage (control). PRIMARY OUTCOME MEASURES: Cost-effectiveness based on incremental cost per donor blood transfusion avoided. RESULTS: In the intention-to-treat analysis, the mean difference in total costs between cell salvage and standard care was £83. The estimated incremental cost-effectiveness ratio (ICER) was £8110 per donor blood transfusion avoided. For the per-protocol analysis, the mean difference in total costs was £92 and the ICER was £8252. In the emergency caesarean section analysis, the mean difference in total costs was £55 and the ICER was £13 713 per donor blood transfusion avoided. This ICER is driven by the increased probability that these patients would require a higher level of postoperative care and additional surgeries. The results of these analyses were shown to be robust for the majority of deterministic sensitivity analyses. CONCLUSIONS: The results of the economic evaluation suggest that while routine cell salvage is a marginally more effective strategy than standard care in avoiding a donor blood transfusion, there is uncertainty in relation to whether it is a less or more costly strategy. The lack of long-term data on the health and quality of life of patients in both arms of the trial means that further research is needed to fully understand the cost implications of both strategies. TRIAL REGISTRATION NUMBER: ISRCTN66118656.

Research prioritization of interventions for the primary prevention of preterm birth: An international survey.

OBJECTIVE: To identify research priorities of interventions for the primary prevention of preterm birth (PTB), by conducting an international stakeholder survey. STUDY DESIGN: A prospective cross-sectional online survey was conducted in November 2016. Fifteen interventions to prevent spontaneous PTB were identified and ranked by stakeholders (n = 159) in the field of maternal and perinatal health research, using nine equally weighted criteria. Medians and interquartile ranges (IQRs) were calculated and the interventions ranked accordingly. RESULTS: Respondents to the survey were from 46 different countries, mostly from low and middle-income countries (62%, 99/159) and were mainly clinicians (80%, 127/159). Of the fifteen interventions ranked, the following five were identified as research priorities in the primary prevention of PTB: dietary counselling and nutritional education, risk scoring, vitamin D supplementation, exercise and antioxidant supplementation. CONCLUSION: We have identified research priorities of interventions to prevent spontaneous PTB through a global stakeholder survey. The interventions prioritized in this exercise can be used by researchers, grant funding bodies and research-policy decision makers to inform calls on future clinical trials or individual patient data meta-analyses on the primary prevention of PTB.

Arthroscopic Treatment of Popliteal Cysts.

Popliteal cysts, often referred to as Baker's cysts, are a common occurrence in the adult knee. Although controversy exists as to the exact indications for treatment, these structures can cause extreme discomfort and morbidity, including pain from rupture and symptoms from neurovascular compromise. Prior to the development of the arthroscope, open treatment of popliteal cysts was not uncommon. Complications such as poor wound healing, cyst recurrence, and knee flexion contractures were reported after such treatment. Owing to the presence of a valve-type structure, also called the posterior transverse synovial infold, there is 1-way flow of synovial fluid into the cyst. Although seldom described, there is a reproducible and relatively straightforward arthroscopic treatment for this pathology. This technical report will describe the arthroscopic treatment of popliteal cysts and clarify the posterior knee anatomy that gives the surgeon the landmarks to perform safe and effective arthroscopic treatment of popliteal cysts.

Effectiveness and acceptability of myo-inositol nutritional supplement in the prevention of gestational diabetes (EMmY): a protocol for a randomised, placebo-controlled, double-blind pilot trial.

INTRODUCTION: Gestational diabetes increases maternal and offspring complications in pregnancy and cardiovascular complications in the long term. The nutritional supplement myo-inositol may prevent gestational diabetes; however, further evaluation is required, especially in multiethnic high-risk mothers. Our pilot trial on myo-inositol to prevent gestational diabetes will evaluate trial processes, assess acceptability to mothers and obtain preliminary estimates of effect and cost data prior to a large full-scale trial. METHODS AND ANALYSIS: EMmY is a multicentre, placebo-controlled, double-blind, pilot, randomised trial, with qualitative evaluation. We will recruit pregnant women at 12-15+6 weeks' gestation, with gestational diabetes risk factors, from five maternity units in England between 2018 and 2019. We will randomise 200 women to take either 2 g of myo-inositol powder (intervention) or placebo, twice daily until delivery. We will assess rates of recruitment, randomisation, adherence to intervention and follow-up. Gestational diabetes will be diagnosed at 24-28 weeks as per the National Institute for Health and Care Excellence (NICE) criteria (fasting plasma glucose: ≥5.6 mmol/L and 2-hour plasma glucose: ≥7.8 mmol/L). We will assess the effects of myo-inositol on glycaemic indices at 28 weeks and on other maternal, fetal and neonatal outcomes at postnatal discharge. Qualitative evaluation will explore the acceptability of the trial and the intervention among women and healthcare professionals. Cost data and health-related quality of life measures will be captured. We will summarise feasibility outcomes using standard methods for proportions and other descriptive statistics, and where appropriate, report point estimates of effect sizes (eg, mean differences and relative risks) and associated 95% CIs. ETHICS AND DISSEMINATION: Ethical approval was obtained through the London Queen Square Research Ethics Committee (17/LO/1741). Study findings will be submitted for publication in peer-reviewed journals. Newsletters will be made available to participants, healthcare professionals and members of Katie's Team (a patient and public advisory group) to disseminate. TRIAL REGISTRATION NUMBER: ISRCTN48872100. PROTOCOL VERSION AND DATE: Version 4.0, 15 January 2018.

AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.

BACKGROUND: Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. OBJECTIVE: To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. DESIGN: A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. SETTING: Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. PARTICIPANTS: Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. INTERVENTIONS: In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. MAIN OUTCOME MEASURES: Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. ANALYSIS: Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. RESULTS: A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. LIMITATIONS: Fewer women than the original target were recruited. CONCLUSION: There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. FUTURE WORK RECOMMENDATIONS: Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01253916. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

A randomised controlled trial and economic evaluation of intraoperative cell salvage during caesarean section in women at risk of haemorrhage: the SALVO (cell SALVage in Obstetrics) trial.

BACKGROUND: Caesarean section is associated with blood loss and maternal morbidity. Excessive blood loss requires transfusion of donor (allogeneic) blood, which is a finite resource. Cell salvage returns blood lost during surgery to the mother. It may avoid the need for donor blood transfusion, but reliable evidence of its effects is lacking. OBJECTIVES: To determine if routine use of cell salvage during caesarean section in mothers at risk of haemorrhage reduces the rates of blood transfusion and postpartum maternal morbidity, and is cost-effective, in comparison with standard practice without routine salvage use. DESIGN: Individually randomised controlled, multicentre trial with cost-effectiveness analysis. Treatment was not blinded. SETTING: A total of 26 UK obstetric units. PARTICIPANTS: Out of 3054 women recruited between June 2013 and April 2016, we randomly assigned 3028 women at risk of haemorrhage to cell salvage or routine care. Randomisation was stratified using random permuted blocks of variable sizes. Of these, 1672 had emergency and 1356 had elective caesareans. We excluded women for whom cell salvage or donor blood transfusion was contraindicated. INTERVENTIONS: Cell salvage (intervention) versus routine care without salvage (control). In the intervention group, salvage was set up in 95.6% of the women and, of these, 50.8% had salvaged blood returned. In the control group, 3.9% had salvage deployed. MAIN OUTCOME MEASURES: Primary - donor blood transfusion. Secondary - units of donor blood transfused, time to mobilisation, length of hospitalisation, mean fall in haemoglobin, fetomaternal haemorrhage (FMH) measured by Kleihauer-Betke test, and maternal fatigue. Analyses were adjusted for stratification factors and other factors that were believed to be prognostic a priori. Cost-effectiveness outcomes - costs of resources and service provision taking the UK NHS perspective. RESULTS: We analysed 1498 and 1492 participants in the intervention and control groups, respectively. Overall, the transfusion rate was 2.5% in the intervention group and 3.5% in the control group [adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42 to 1.01; p = 0.056]. In a planned subgroup analysis, the transfusion rate was 3.0% in the intervention group and 4.6% in the control group among emergency caesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 1.8% in the intervention group and 2.2% in the control group among elective caesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46, suggesting that the difference in effect between subgroups was not statistically significant). Secondary outcomes did not differ between groups, except for FMH, which was higher under salvage in rhesus D (RhD)-negative women with RhD-positive babies (25.6% vs. 10.5%, adjusted OR 5.63, 95% CI 1.43 to 22.14; p = 0.013). No case of amniotic fluid embolism was observed. The additional cost of routine cell salvage during caesarean was estimated, on average, at £8110 per donor blood transfusion avoided. CONCLUSIONS: The modest evidence for an effect of routine use of cell salvage during caesarean section on rates of donor blood transfusion was associated with increased FMH, which emphasises the need for adherence to guidance on anti-D prophylaxis. We are unable to comment on long-term antibody sensitisation effects. Based on the findings of this trial, cell salvage is unlikely to be considered cost-effective. FUTURE WORK: Research into risk of alloimmunisation among women exposed to cell salvage is needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66118656. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 2. See the NIHR Journals Library website for further project information.