Standardising outcome reporting for clinical trials of interventions for heavy menstrual bleeding: Development of a core outcome set.

OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.

Accuracy of fetal fibronectin for assessing preterm birth risk in asymptomatic pregnant women: a systematic review and meta-analysis.

INTRODUCTION: Fetal fibronectin (fFN) is a validated test for assessing risk of preterm birth for women presenting with symptoms. Our aim was to evaluate the accuracy of fFN to detect the risk of preterm birth in asymptomatic women. MATERIAL AND METHODS: Searches were conducted to identify studies where fFN was performed in asymptomatic women beyond 22 weeks' gestation. EMBASE, MEDLINE, CINHAL, AMED and BNI were searched between 2005 and 2017. Studies before 2005 were identified from a published systematic review. Women were grouped as singleton pregnancies, with and without risk factors for preterm birth, and multiple pregnancy. Quality assessment was performed using QUADAS-2. When possible, data were pooled using a hierarchical, bivariate random effects model. RESULTS: Fifteen studies met the inclusion criteria: six studies of singleton pregnancies in women without risk factors (1236 women), four in women with risk factors for preterm birth (2628 women) and five studies were of multiple pregnancy (1427 women). The pooled sensitivity and specificity of fFN in "no risk factors singletons" were 0.48 (95% CI 0.20-0.77), and 0.96 (95% CI 0.86-0.99), respectively. The likelihood ratio of a positive test result was 12 (95% CI 4.70-30.68). The pooled sensitivity and specificity of fFN in "risk factors singletons" were 0.34 (95% CI 0.24-0.43), and 0.91 (95% CI 0.88-0.93). The accuracy of fFN in multiple pregnancies was inconclusive. CONCLUSION: Our findings suggest in asymptomatic singleton pregnancies without risk factors, a positive fFN result indicates a large shift from pre- to post-test probability, possibly identifying women at increased risk of preterm birth.

Systematic review of randomized trials of the effect of iron supplementation on iron stores and oxygen carrying capacity in pregnancy.

INTRODUCTION: Anemia in pregnancy affects 25% of all pregnancies in Europe with iron deficiency affecting even more. Despite supplementation, iron deficiency persists. This review will assess the effect on serum ferritin (iron stores) and hemoglobin (oxygen-carrying capacity) following iron supplementation in pregnant women with anemic and non-anemic iron deficiency. MATERIAL AND METHODS: A systemic search of electronic databases and trial registers was conducted from inception to January 2014. Randomized controlled trials of iron supplementation that measured serum ferritin and hemoglobin levels before and after supplementation were selected. Two independent reviewers selected studies, extracted data and assessed quality. Descriptive analyses were carried out. RESULTS: The review included 23 randomized controlled trials (3525 women). In iron deficiency anemia, more studies described statistically significant increases in serum ferritin levels than in hemoglobin levels following intravenous iron supplementation. In non-anemic iron deficiency there were more statistically significant increases in serum ferritin levels than in hemoglobin levels following oral supplementation. There were no studies reporting maternal quality of life outcomes. CONCLUSIONS: Serum ferritin appears to change more than hemoglobin following iron supplementation. The clinical effects of this need further investigation.

Evidence quality in clinical guidelines: a comparison of two methods.

INTRODUCTION: Guidelines report the quality of the evidence used when formulating recommendations to ensure transparency and allow end-users to assess the estimates of effect that underlie the recommendation. The aim of this study was to investigate the differences in grading of evidence quality between the Scottish Intercollegiate Guideline Network (SIGN) model and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. MATERIALS AND METHODS: The GRADE system was used to create evidence profiles for recommendations from a guideline that used the SIGN method to assess the quality of evidence. Scores were allocated to the quality assessment in its GRADE and SIGN forms, so that the difference between the two methods could be quantified. RESULTS: The SIGN grading system led to quality ratings of the evidence of high and moderate but using the GRADE system, the majority of ratings were graded as low or very low. All of the recommendations were graded as higher quality by SIGN than by GRADE. The points' difference ranged from one to three points (maximum difference possible was four points). The most common reasons for downgrading evidence were "study limitations", "imprecision"' and "publication bias". "Indirectness" and "inconsistency" were rarely selected as reasons to downgrade the evidence. CONCLUSIONS: The GRADE and SIGN methods produce varying estimates of the quality of evidence.

A review of the literature regarding nutritional supplements and their effect on vaginal flora and preterm birth.

PURPOSE OF REVIEW: The aim of this review was to evaluate recently published review articles which examine the use of nutritional supplements to prevent preterm birth (PTB) by modifying vaginal bacteria. RECENT FINDINGS: Probiotics, vitamin D and vitamin C were all identified as nutritional supplements that have the potential to alter bacterial flora and consequently reduce PTB and treat or prevent genital infections. Evidence shows that probiotics may reduce the incidence of PTB as well as being effective at treating bacterial vaginosis, a known cause for PTB. Low vitamin D levels may be associated with bacterial vaginosis, although no evidence was identified which demonstrated that vitamin D supplementation reduced the risk of having bacterial vaginosis or PTB.There is little evidence regarding vitamin C supplementation, although it does suggest a possible benefit with regard to preterm rupture of membranes; however, this did not appear to reduce rates of PTB. SUMMARY: Although there is evidence that taking probiotics in pregnancy may reduce the incidence of PTB, it is mainly derived from small, poor quality studies. Vitamin D and vitamin C may have potential benefits, but these remain to be proven. Large randomized controlled trials are needed to more accurately evaluate the potential benefits of these low-cost interventions for reducing PTB and its consequences.

Methods used to assess outcome consistency in clinical studies: A literature-based evaluation.

Evaluation studies of outcomes used in clinical research and their consistency are appearing more frequently in the literature, as a key part of the core outcome set (COS) development. Current guidance suggests such evaluation studies should use systematic review methodology as their default. We aimed to examine the methods used. We searched the Core Outcome Measures in Effectiveness Trials (COMET) database (up to May 2019) supplementing it with additional resources. We included evaluation studies of outcome consistency in clinical studies across health subjects and used a subset of A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 (items 1-9) to assess their methods. Of 93 included evaluation studies of outcome consistency (90 full reports, three summaries), 91% (85/93) reported performing literature searches in at least one bibliographic database, and 79% (73/93) was labelled as a "systematic review". The evaluations varied in terms of satisfying AMSTAR 2 criteria, such that 81/93 (87%) had implemented PICO in the research question, whereas only 5/93 (6%) had included the exclusions list. None of the evaluation studies explained how inconsistency of outcomes was detected, however, 80/90 (88%) concluded inconsistency in individual outcomes (66%, 55/90) or outcome domains (20%, 18/90). Methods used in evaluation studies of outcome consistency in clinical studies differed considerably. Despite frequent being labelled as a "systematic review", adoption of systematic review methodology is selective. While the impact on COS development is unknown, authors of these studies should refrain from labelling them as "systematic review" and focus on ensuring that the methods used to generate the different outcomes and outcome domains are reported transparently.

Designing a lifestyle intervention to reduce risk of type 2 diabetes in postpartum mothers following gestational diabetes: An online survey with mothers and health professionals.

OBJECTIVE: The aim of this study was to identify what components of a postpartum lifestyle intervention would engage postpartum mothers who had a diagnosis of gestational diabetes. STUDY DESIGN: Two online surveys were conducted, one involving postnatal mothers with GDM (n=83), and a second for health professionals (n=46). RESULTS: Seventy-eight percent of mothers were aware that healthy eating, exercise and weight management were all important to reduce risk of subsequent type 2 diabetes. However, 80% of women in this survey were not ready to engage in a postpartum lifestyle intervention within the first 6 months of giving birth; in contrast 52% of health professionals recommended they should be engaged in the first six weeks. Group sessions were the most commonly chosen format to deliver an intervention (30%). A community setting was preferred to a medical one. Mothers wanted recipe ideas (95%) in preference to general dietary advice (76%) or cooking skills courses (39%). Walking was the main form of exercise for 79% of mothers in this sample. Women highlighted difficulty in focusing on their own health goals because of competing demands of looking after a baby (41% agreed, Median 3, IQR 2), tiredness (65% agreed, Md 4, IQR 1) and the need for childcare (64% agreed, Md 4, IQR 2). CONCLUSION: A walking programme, recipe ideas and weight monitoring may be useful components when designing a postpartum lifestyle intervention. Barriers to engagement are evident and the intervention should allow women to engage at a time that is appropriate for them.

A patient-preference cohort study of office versus inpatient uterine polyp treatment for abnormal uterine bleeding.

Uterine polyps can cause abnormal bleeding in women. Conventional practise is to remove them under general anaesthesia but advances in technology have made it possible to perform polypectomy in the office setting. We conducted a patient-preference study to explore women's preferences for treatment setting and to evaluate the effectiveness and treatment experience of women undergoing uterine polypectomy. Three hundred ninety-nine women with abnormal uterine bleeding who were found to have uterine polyps at diagnostic hysteroscopy were recruited. Office polypectomies were performed in office hysteroscopy clinics, and inpatient procedures were undertaken in operating theatres. Three hundred twenty-four of 399 (81 %) expressed a preference for office treatment. There was no difference found between office treatment and inpatient treatment in terms of alleviating abnormal uterine bleeding as assessed by patients and in improving disease-specific quality of life. Acceptability was lower and patient pain scores were significantly higher in the office group. When offered a choice of treatment setting for uterine polypectomy, patients have a preference for office over inpatient treatment. Ambulatory gynaecology services should be available within healthcare systems to meet patient demand.

Ambulatory hysteroscopy and its role in the management of abnormal uterine bleeding.

Hysteroscopy is now an ambulatory procedure, having moved from a conventional day-case operating theatre environment to the outpatient clinic setting. Outpatient hysteroscopy can be used as a diagnostic test and as a therapeutic modality for women presenting with abnormal uterine bleeding. In many cases women can be diagnosed and treated efficiently during a single hospital appointment. This article reviews the development of ambulatory hysteroscopy and how it should optimally be performed and implemented. The contemporary role of this technology for investigating and treating women with abnormal uterine bleeding is then discussed.

Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study.

OBJECTIVE: To compare the effectiveness and acceptability of outpatient polypectomy with inpatient polypectomy. DESIGN: Pragmatic multicentre randomised controlled non-inferiority study. SETTING: Outpatient hysteroscopy clinics in 31 UK National Health Service hospitals. PARTICIPANTS: 507 women who attended as outpatients for diagnostic hysteroscopy because of abnormal uterine bleeding and were found to have uterine polyps. INTERVENTIONS: Participants were randomly assigned to either outpatient uterine polypectomy under local anaesthetic or inpatient uterine polypectomy under general anaesthesia. Data were collected on women's self reported bleeding symptoms at baseline and at 6, 12, and 24 months. Data were also collected on pain and acceptability of the procedure at the time of polypectomy. MAIN OUTCOME MEASURES: The primary outcome was successful treatment, determined by the women's assessment of bleeding at six months, with a prespecified non-inferiority margin of 25%. Secondary outcomes included generic (EQ-5D) and disease specific (menorrhagia multi-attribute scale) quality of life, and feasibility and acceptability of the procedure. RESULTS: 73% (166/228) of women in the outpatient group and 80% (168/211) in the inpatient group reported successful treatment at six months (intention to treat relative risk 0.91, 95% confidence interval 0.82 to 1.02; per protocol relative risk 0.92, 0.82 to 1.02). Failure to remove polyps was higher (19% v 7%; relative risk 2.5, 1.5 to 4.1) and acceptability of the procedure was lower (83% v 92%; 0.90, 0.84 to 0.97) in the outpatient group Quality of life did not differ significantly between the groups. Four uterine perforations, one of which necessitated bowel resection, all occurred in the inpatient group. CONCLUSIONS: Outpatient polypectomy was non-inferior to inpatient polypectomy. Failure to remove a uterine polyp was, however, more likely with outpatient polypectomy and acceptability of the procedure was slightly lower. TRIAL REGISTRATION: International Clinical Trials Registry 65868569.

Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) and post-menopausal bleeding (PMB) together constitute the commonest gynaecological presentation in secondary care and impose substantial demands on health service resources. Accurate diagnosis is of key importance to realising effective treatment, reducing morbidity and, in the case of PMB, reducing mortality. There are many tests available, including transvaginal scan (TVS), endometrial biopsy (EBx), saline infusion sonography and outpatient hysteroscopy (OPH); however, optimal diagnostic work-up is unclear. OBJECTIVES: To determine the most cost-effective diagnostic testing strategy for the diagnosis and treatment of (i) HMB and (ii) PMB. DATA SOURCES: Parameter inputs were derived from systematic quantitative reviews, individual patient data (IPD) from existing data sets and focused searches for specific data. In the absence of data estimates, the consensus view of an expert clinical panel was obtained. METHODS: Two clinically informed decision-analytic models were constructed to reflect current service provision for the diagnostic work-up of women presenting with HMB and PMB. The model-based economic evaluation took the form of a cost-effectiveness analysis from the perspective of the NHS in a contemporary, 'one-stop' secondary care clinical setting, where all indicated testing modalities would be available during a single visit. RESULTS: Two potentially cost-effective testing strategies for the initial investigation of women with HMB were identified: OPH alone or in combination with EBx. Although a combination testing strategy of OPH + EBx was marginally more effective, the incremental cost-effectiveness ratio (ICER) was approximately £21,000 to gain one more satisfied patient, whereas for OPH it was just £360 when compared with treatment with the levonorgestrel intrauterine system (LNG-IUS) without investigation. Initial testing with OPH was the most cost-effective testing approach for women wishing to preserve fertility and for women with symptoms refractory to empirical treatment with a LNG-IUS. For the investigation of PMB, selective use of TVS based on historical risk prediction for the diagnostic work-up of women presenting with PMB generated an ICER compared with our reference strategy of 'no initial work-up' of £129,000 per extra woman surviving 5 years. The ICERs for the two other non-dominated testing strategies, combining history and TVS or combining OPH and TVS, were over £2M each. LIMITATIONS: In the absence of IPD, estimates of accuracy for test combinations presented some uncertainty where test results were modelled as being discordant. CONCLUSIONS: For initial investigation of women presenting to secondary care with HMB who do not require preservation of their fertility, our research suggests a choice between OPH alone or a combination of OPH and EBx. From our investigation, OPH appears to be the optimal first-line diagnostic test used for the investigation of women presenting to secondary care with HMB wishing to preserve their fertility or refractory to previous medical treatment with the LNG-IUS. We would suggest that the current recommendation of basing the initial investigation of women with PMB on the universal TVS measurement of endometrial thickness at a 5-mm threshold may need to be replaced by a strategy of restricting TVS to women with risk factors (e.g. increasing age-raised body mass index, diabetes or nulliparity), obtained from the preceding clinical assessment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The role of ambulatory hysteroscopy in reproduction.

Hysteroscopy is a mainstay of modern gynaecologic practice. However, the role of ambulatory hysteroscopy and associated procedures has increased dramatically in recent years. The outpatient setting has associated benefits, both for the patient and economically. The advent of less invasive vaginoscopic techniques means that diagnostic hysteroscopy is achievable safely, comfortably and efficiently in almost all women and avoids the risk of a general anaesthetic. This review aims to summarise first the role for ambulatory hysteroscopy in diagnosis of conditions contributing to reproductive failure. The second section of the review concentrates on the therapeutic interventions that can be performed hysteroscopically in the ambulatory setting such as tubal catheterisation, tubal occlusion and uteroplasty. Lastly, we discuss the role outpatient hysteroscopy plays in established contraceptive techniques such as intrauterine device placement, and the more recent advent of hysteroscopic sterilisation.

A systematic review of the effect of the distension medium on pain during outpatient hysteroscopy.

OBJECTIVE: To assess the effect of distension medium on pain during outpatient hysteroscopy. DESIGN: Systematic review and meta-analysis. SETTING: Outpatient hysteroscopy clinics. PATIENT(S): Women undergoing outpatient hysteroscopic examination. INTERVENTION(S): Use of normal saline versus carbon dioxide as distension medium for outpatient hysteroscopy. MAIN OUTCOME MEASURE(S): Pain scores. RESULT(S): There was no statistically significant difference in pain scores when carbon dioxide or normal saline were used as the distension medium for outpatient hysteroscopy (standardized mean differences=-0.05; 95% CI, -0.17 to 0.07; I2=92%). CONCLUSION(S): Carbon dioxide and normal saline are both suitable distending media for outpatient hysteroscopy as the procedural pain is comparable and the views obtained are satisfactory. However, normal saline does confer advantages that may make it more suitable for clinical use.

Local anaesthesia for pain control during outpatient hysteroscopy: systematic review and meta-analysis.

OBJECTIVE: To compare the effects of different types of local anaesthetic for pain control during outpatient hysteroscopy. DESIGN: Systematic review and meta-analysis of randomised controlled trials. SETTING: Outpatient hysteroscopy clinics. PARTICIPANTS: Women undergoing diagnostic or operative hysteroscopy as outpatients-that is, without general anaesthesia. Study selection criteria Medline, Embase, CINAHL, the Cochrane library, and reference lists of relevant studies. Two reviewers independently selected trials. Data were abstracted on quality, characteristics, and results. RESULTS: There were 20 trials (2851 participants). Data from 15 of these were meta-analysed in subgroups defined by type of intervention and study quality. Intracervical (standardised mean difference -0.36, 95% confidence interval -0.61 to -0.10, I(2)=0%) and paracervical (-1.28, -2.22 to -0.35, I(2)=97%) injections of local anaesthetic significantly reduced the pain in women undergoing hysteroscopy as outpatients, whereas transcervical (-0.11, -0.31 to 0.10, I(2)=27%) and topical application (-0.32, -0.97 to 0.33, I(2)= 90%) did not. Meta-regression showed that paracervical injection was superior to the other anaesthetic methods (P=0.04), a finding that was supported by the high quality subgroup of studies. Use of local anaesthetic did not have a significant effect on the incidence of vasovagal episodes (P=0.09). CONCLUSIONS: Paracervical local anaesthetic injection is the best method of pain control for women undergoing hysteroscopy as outpatients.