Exogenous sex steroid hormones and asthma in females: protocol for a population-based retrospective cohort study using a UK primary care database.

INTRODUCTION: Female sex steroid hormones have been implicated in sex-related differences in the development and clinical outcomes of asthma. The role of exogenous sex steroids, however, remains unclear. Our recent systematic review highlighted the lack of high-quality population-based studies investigating this subject. We aim to investigate whether the use of hormonal contraception and hormone replacement therapy (HRT), subtypes and route of administration are associated with asthma onset and clinical outcomes in reproductive age and perimenopausal/postmenopausal females. METHODS AND ANALYSIS: Using the Optimum Patient Care Research Database (OPCRD), a national primary care database in the UK, we will construct a retrospective longitudinal cohort of reproductive age (16-45 years) and perimenopausal/postmenopausal (46-70 years) females. We will estimate the risk of new-onset asthma using Cox regression and multilevel modelling for repeated asthma outcomes, such as asthma attacks. We will adjust for confounding factors in all analyses. We will evaluate interactions between the use of exogenous sex hormones and body mass index and smoking by calculating the relative excess risk due to interaction and the attributable proportion due to interaction. With 90% power, we need 23 700 reproductive age females to detect a 20% reduction (risk ratio 0.8) in asthma attacks for use of any hormonal contraception and 6000 perimenopausal/postmenopausal females to detect a 40% (risk ratio 1.40) increased risk of asthma attacks for use of any HRT. ETHICS AND DISSEMINATION: We have obtained approval (ADEPT1317) from the Anonymised Data Ethics and Protocol Transparency Committee which grants project-specific ethics approvals for the use of OPCRD data. Optimum Patient Care has an existing NHS Health Research Authority ethics approval for the use of OPCRD data for research (15/EM/150). We will present our findings at national and international scientific meetings and publish the results in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS22967.

Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1): A Pilot Randomised Controlled Trial.

Chronic pelvic pain (CPP) affects 2.1-24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700 mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women's experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012-2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07-3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97-6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.

The financial costs to patients of diagnosing and excluding ectopic pregnancy.

OBJECTIVES: Health care costs are one of the greatest challenges in modern medicine. In gynaecology, diagnosing and excluding ectopic pregnancy (EP) has been shown to be a financial burden to health services because it commonly requires multiple investigations and hospital visits. However, the full economic costs are not captured by an analysis of health care costs alone. This study therefore aimed to assess the indirect costs to patients of diagnosing and excluding EP. METHODS: Patients presenting to a Pregnancy Support Centre in a large UK teaching hospital with abdominal pain and/or bleeding and a positive pregnancy test were recruited during the period June 2010-February 2011. Patients were provided with questionnaires to be completed at home and designed to record and quantify costs that they had incurred until a final diagnosis of their condition was made. A cost-description analysis was performed. RESULTS: 52/203 (26%) recruited patients returned completed questionnaires. The mean cost to patients of diagnosing or excluding EP was £135.13±£51.60 (median £20.70). The main cost drivers identified were hospital visits, holiday cancellations, income loss and household help. CONCLUSIONS: Quantification of the indirect costs of diagnosing and excluding EP is challenging because it relies on questionnaire feedback from patients at a time when they have suffered from the emotional impact of pregnancy loss. However, initial estimates suggest that such costs are significant due to diagnostic delays. This further highlights the importance of the development of potential biomarkers of EP to allow prompt diagnosis.

Has increased clinical experience with methotrexate reduced the direct costs of medical management of ectopic pregnancy compared to surgery?

BACKGROUND: There is a debate about the cost-efficiency of methotrexate for the management of ectopic pregnancy (EP), especially for patients presenting with serum human chorionic gonadotrophin levels of >1500 IU/L. We hypothesised that further experience with methotrexate, and increased use of guideline-based protocols, has reduced the direct costs of management with methotrexate. METHODS: We conducted a retrospective cost analysis on women treated for EP in a large UK teaching hospital to (1) investigate whether the cost of medical management is less expensive than surgical management for those patients eligible for both treatments and (2) to compare the cost of medical management for women with hCG concentrations 1500-3000 IU/L against those with similar hCG concentrations that elected for surgery. Three distinct treatment groups were identified: (1) those who had initial medical management with methotrexate, (2) those who were eligible for initial medical management but chose surgery ('elected' surgery) and (3) those who initially 'required' surgery and did not meet the eligibility criteria for methotrexate. We calculated the costs from the point of view of the National Health Service (NHS) in the UK. We summarised the cost per study group using the mean, standard deviation, median and range and, to account for the skewed nature of the data, we calculated 95% confidence intervals for differential costs using the nonparametric bootstrap method. RESULTS: Methotrexate was £1179 (CI 819-1550) per patient cheaper than surgery but there were no significant savings with methotrexate in women with hCG >1500 IU/L due to treatment failures. CONCLUSIONS: Our data support an ongoing unmet economic need for better medical treatments for EP with hCG >1500 IU/L.

Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium.

BACKGROUND: Determination of the mitotic index in sections of endometrium stained with haematoxylin and eosin (H&E) is difficult and time-consuming. We assessed the value of two mitotic markers as immunocytochemical reagents for measuring mitotic rates in endometrium. METHODS: Mitotic protein monoclonal antibody 2 (MPM-2) and anti-phosphorylated histone H3 (Phospho H3) were applied to paraffin sections of rhesus macaque and human endometrium. RESULTS: In estrogen-treated macaque endometrium the mean +/- SEM mitotic indices were: H&E 1.5 +/- 0.25%, Phospho H3 antibody 1.02 +/- 0.23% and MPM-2 antibody 0.69 +/- 0.17%; these were not statistically significantly different, but the Phospho H3 antibody gave a stronger and cleaner signal than the MPM-2 antibody. Comparisons were made between a computer-determined Phospho H3 index, the H&E-determined mitotic index and the Ki-67 index in samples of human endometrium across the cycle. All revealed that the highest proliferative rate occurred during the follicular phase, but the Phospho H3 and the mitotic indices were more highly correlated (R(2) = 0.89, P < 0.001) than the Ki-67 and mitotic indices (R(2) = 0.74, P < 0.05). CONCLUSIONS: The exceptionally high contrast staining and the excellent correlation between the Phospho H3 and mitotic indices validates the specificity of the Phospho H3 antibody as a new tool for the assessment of endometrial mitotic activity.