Effectiveness and safety of menopause treatments: pitfalls of available evidence and future research need.

By 2050 more than 1.6 billion women worldwide will be of post-reproductive age, with >75% reporting severe menopausal symptoms. The last few years saw a gradual uplift in public awareness reaffirming the health needs of women with menopause. Still, effective translation of available evidence on menopause treatments is hindered by several methodological limitations and poor research conduct. We argue that a paradigm shift is required in menopause research to address the remaining knowledge gap and guide safe evidence-based care provision. A critical misconception across studies on menopause is the assumption that women represent a homogeneous group who respond similarly to a particular therapy irrespective of their exposure and individual risk factors. We highlight potential solutions to optimize the quality of future research in menopause including adopting robust trial methodology, standardize outcome reporting to capture quality-of-life measures, and improve lay patient and public involvement in future research.

Accuracy of imaging modalities for adnexal torsion: a systematic review and meta-analysis.

BACKGROUND: Adnexal torsion (AT), a serious gynaecological emergency, often presents with non-specific symptoms leading to delayed diagnosis. OBJECTIVE: To compare the test accuracy of ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) to diagnose AT. SEARCH STRATEGY: We searched EMBASE, MEDLINE and Cochrane CENTRAL until December 2019. SELECTION CRITERIA: Studies reporting on the accuracy of any imaging modality (Index Test) in female patients (paediatric and adult) suspected of AT compared with surgical diagnosis and/or standard clinical/radiological follow-up period until resolution of symptoms (Reference Standard). DATA COLLECTION AND ANALYSIS: We assessed study quality using QUADAS-2. We conducted test accuracy meta-analysis using a univariate model or a hierarchical model. MAIN RESULTS: We screened 3836 citations, included 18 studies (1654 women, 665 cases), and included 15 in the meta-analyses. Ultrasound pooled sensitivity (n = 12, 1187 women) was 0.79 (95% CI 0.63-0.92) and specificity was 0.76 (95% CI 0.54-0.93), with negative and positive likelihood ratios of 0.29 (95% CI 0.13-0.66) and 4.35 (95% CI 2.03-9.32), respectively. Using Doppler with ultrasound (n = 7, 845 women) yielded similar sensitivity (0.80, 95% CI 0.67-0.93) and specificity (0.88, 95% CI 0.72-1.00). For MRI (n = 3, 99 women), the pooled sensitivity was 0.81 (95% CI 0.63-0.91) and specificity was 0.91 (95% CI 0.80-0.96). A meta-analysis for CT was not possible with two case-control studies and one cohort study (n = 3, 232 women). Its sensitivity range was 0.74-0.95 and specificity was 0.80-0.90. CONCLUSIONS: Ultrasound has good performance as a first-line diagnostic test for suspected AT. Magnetic resonance imaging could offer improved specificity to investigate complex ovarian morphology, but more evidence is needed. TWEETABLE ABSTRACT: To investigate adnexal torsion, ultrasound is a good first-line diagnostic test with a pooled sensitivity of 0.79 and specificity of 0.76.

On-site test to detect syphilis in pregnancy: a systematic review of test accuracy studies.

BACKGROUND: Syphilis in pregnancy can lead to fetal and neonatal death or congenital anomalies. Accurate on-site tests are an essential part of effective prevention of mother-to-child transmission of the disease. OBJECTIVE: This systematic review assessed the accuracy of on-site tests to detect infection with Treponema pallidum in pregnant women. SEARCH STRATEGY: Major databases were searched from inception to January 2016 using terms: 'pregnancy', 'antenatal', 'syphilis', 'Treponema pallidum' with their variations, and the search limit for the relevant study design. SELECTION CRITERIA: We included studies that used dual reference standard (non-treponemal and treponemal tests) to detected syphilis in pregnancy. DATA COLLECTION AND ANALYSIS: Extracted accuracy data were tabulated and pooled using hierarchical, bivariate random effects model. MAIN RESULTS: Seven studies (combined sample 17 546) reporting the accuracy of four on-site tests met the eligibility criteria. On average, Determine™ and SD BioLine Syphilis 3.0 had the highest sensitivity of all the evaluated tests: 0.83 (95% CI 0.58, 0.98) and 0.86 (95% CI 0.82, 0.89), respectively, with a high specificity 0.96 (95% CI 0.89, 1.00) and 0.99 (95% CI 0.94, 1.00), respectively. The Qualitative Rapid Plasma Reagin card commonly used in clinical practice had a pooled sensitivity of 0.70 (95% CI 0.54, 0.88) and specificity of 0.97 (95% CI 0.96, 0.99). CONCLUSION: Immunochromatographic tests such as Determine™ and SD BioLine Syphilis 3.0 seem to be acceptable options in antenatal testing for syphilis, especially in resource-limited settings. Future research should seek more evidence to strengthen this claim. TWEETABLE ABSTRACT: On-site test to detect syphilis-options during antenatal care.

Development of composite outcomes for individual patient data (IPD) meta-analysis on the effects of diet and lifestyle in pregnancy: a Delphi survey.

OBJECTIVE: To develop maternal, fetal, and neonatal composite outcomes relevant to the evaluation of diet and lifestyle interventions in pregnancy by individual patient data (IPD) meta-analysis. DESIGN: Delphi survey. SETTING: The International Weight Management in Pregnancy (i-WIP) collaborative network. Sample Twenty-six researchers from the i-WIP collaborative network from 11 countries. METHODS: A two-generational Delphi survey involving members of the i-WIP collaborative network (26 members in 11 countries) was undertaken to prioritise the individual outcomes for their importance in clinical care. The final components of the composite outcomes were identified using pre-specified criteria. MAIN OUTCOME MEASURES: Composite outcomes considered to be important for the evaluation of the effect of diet and lifestyle in pregnancy. RESULTS: Of the 36 maternal outcomes, nine were prioritised and the following were included in the final composite: pre-eclampsia or pregnancy-induced hypertension, gestational diabetes mellitus (GDM), elective or emergency caesarean section, and preterm delivery. Of the 27 fetal and neonatal outcomes, nine were further evaluated, with the final composite consisting of intrauterine death, small for gestational age, large for gestational age, and admission to a neonatal intensive care unit (NICU). CONCLUSIONS: Our work has identified the components of maternal, fetal, and neonatal composite outcomes required for the assessment of diet and lifestyle interventions in pregnancy by IPD meta-analysis.

Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer. METHODS: Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4. RESULTS: Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92-98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85-95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL. CONCLUSIONS: Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.

Association between weight gain during pregnancy and pregnancy outcomes after dietary and lifestyle interventions: a meta-analysis.

OBJECTIVES: Lifestyle interventions in obese pregnant women reduce adverse maternal outcomes of pregnancy. However, the association between weight change due to interventions and the actual reduction in complications is unknown. The objective of this study was to determine the association between gestational weight gain (GWG) and the rate of pregnancy complications. STUDY DESIGN: The authors included randomized controlled trials (RCTs) assessing the effect of lifestyle interventions during pregnancy on GWG and adverse maternal and fetal outcomes. For each outcome they assessed the association between GWG and the risk of adverse pregnancy outcomes. RESULTS: They analyzed data of 23 RCTs (4,990 women). Increased GWG was associated with a nonsignificant increase in the incidence of preeclampsia (PE) (0.2% per gained kg, 95% confidence interval [CI] 0.5 to 0.9%, p > 0.05), gestational diabetes (GDM) (0.3% per gained kg, 95% CI -0.5 to 1.0%, p > 0.05), and induction of labor (IOL) (1.5% per gained kg, 95% CI -0.9 to 3.9%, p > 0.05). CONCLUSIONS: Reduction in GWG due to lifestyle interventions in pregnancy had statistically nonsignificant effects on lowering the incidence of PE, GDM, and IOL. Possibly, the beneficial effect of lifestyle interventions on pregnancy outcomes is due to an effect independent of the reduction of GWG.

Variation in outcomes in trials reporting effects of diet and lifestyle based intervention on pregnancy outcomes: a systematic review.

Obesity is a growing threat to women of childbearing age. Increased maternal weight or excessive weight gain in pregnancy is associated with adverse pregnancy outcomes. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on a number of clinical outcomes. There is no consensus amongst the trialists on the core outcomes that need to be reported to inform the clinical care of pregnant women. The aim of this systematic review is to evaluate variation in the type and quality of outcomes reported in systematic reviews and randomised controlled trials on diet and lifestyle interventions on maternal and fetal outcomes. We will assess the correlation between the type of outcome, the quality of the studies and journal impact factor. We searched the major databases from the inception to October 2013 without language restrictions. We used current recommendations for quality of outcome reporting using a 6-point scale. The quality assessment of systematic reviews and RCTs was performed using the AMSTAR and Jadad scoring systems. Additionally we obtained journals' impact factor in the year of publication. We calculated Spearman rank coefficient to assess the correlation between the type of outcome, and study quality. An overview of outcome reporting will show the current attitude of the researchers towards outcomes of importance when conducting trials on diet and lifestyle management in pregnancy. If our abstract is accepted, we will provide the details of the results.

Development of maternal and neonatal composite outcomes for trials evaluating management of late-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia is associated with significant maternal and neonatal complications, and delivery is often expedited to minimise complications. For randomised trials evaluating interventions in women with late-onset (>34 weeks) mild to moderate pre-eclampsia, no single outcome has been identified to be the most clinically important. Existing composite outcomes with more than one clinically relevant endpoint to evaluate interventions in pre-eclampsia provide limited justification for selection of the components. Our objective was to develop robust, valid composite maternal and neonatal outcome measures for clinical trials evaluating interventions in women with late-onset mild and moderate pre-eclampsia. STUDY DESIGN: A two-generational Delphi method was used to identify these clinically important maternal and neonatal outcomes. Composite outcomes were developed based on biological plausibility, independence from each other, frequency of occurrence and level of importance. RESULTS: The final maternal composite outcome included maternal death, eclampsia, stroke or reversible ischaemic neurological deficit, pulmonary oedema, major obstetric haemorrhage, need for positive inotropic support, haemolysis, elevated liver enzymes and low platelets syndrome and placental abruption; and the neonatal composite outcome included neonatal death, respiratory distress syndrome needing ventilator support and neurological outcomes as cystic periventricular leukomalacia and grade III/IV intraventricular haemorrhage. CONCLUSION: The composite outcomes developed will enable clinical trials to provide robust estimates on the effectiveness of the interventions in women with mild to moderate late onset pre-eclampsia to inform clinical practice. Caution is needed in the interpretation of composite outcomes due to variation in the importance of individual components.

Sentinel lymph node status in vulval cancer: systematic reviews of test accuracy and decision-analytic model-based economic evaluation.

BACKGROUND: Vulval cancer causes 3-5% of all gynaecological malignancies and requires surgical removal and inguinofemoral lymphadenectomy (IFL). Complications affect > 50% of patients, including groin wound infection, lymphoedema and cellulitis. A sentinel lymph node (SLN) is the first groin node with the highest probability of malignancy. SLN biopsy would be useful if it could accurately identify patients in whom cancer has spread to the groin, without removing all groin nodes. SLNs can be identified by isosulfan blue dye and/or technetium-99 ((99m)Tc) radioactive tracer during lymphoscintigraphy. The blue dye/(99m)Tc procedure only detects SLN, not metastases - this requires histological examination, which can include ultrastaging and staining with conventional haematoxylin and eosin (H&E) or immunohistochemistry. OBJECTIVES: To determine the test accuracy and cost-effectiveness of the SLN biopsy with (99m)Tc and/or blue dye compared with IFL or clinical follow-up for test negatives in vulval cancer, through systematic reviews and economic evaluation. DATA SOURCES: Standard medical databases, including MEDLINE, EMBASE, Science Citation Index and The Cochrane Library, medical search gateways, reference lists of review articles and included studies were searched to January 2011. METHODS: For accuracy and effectiveness, standard methods were used and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were to January 2011, with no language restrictions. Meta-analyses were carried out with Meta-Disc version 1.4 (Javier Zamora, Madrid, Spain) for accuracy; none was appropriate for effectiveness. The economic evaluation from a NHS perspective used a decision-tree model in DATA TreeAge Pro Healthcare 2001 (TreeAge Software, Inc., Williamstown, MA, USA). Six options (blue dye with H&E, blue dye with ultrastaging, (99m)Tc with H&E, (99m)Tc with ultrastaging, blue dye/(99m)Tc with H&E, blue dye/(99m)Tc with ultrastaging) were compared with IFL. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: For accuracy, of the 26 included studies, most evaluated (99m)Tc/blue dye combined. Four studies had clinical follow-up only for test negatives and five had clinical follow-up for all and IFL for test negatives. Numbers with no SLN found were difficult to distinguish from those with negative SLN biopsies. The largest group of 11 studies using (99m)Tc/blue dye, ultrastaging and immunohistochemistry had a pooled sensitivity of 95.6% [95% confidence interval (CI) 91.5% to 98.1%] and a specificity of 100% (95% CI 99.0% to 100%). Mean SLN detection rates were 94.6% for (99m)Tc, 68.7% for blue dye and 97.7% for both. One study measured global health status quality of life (QoL) and found no difference between SLN biopsy and IFL. One patient preference evaluation showed that 66% preferred IFL rather than a 5% false-negative rate from SLN biopsy. For effectiveness, of 14,038 references, one randomised controlled trial, three case-control studies and 13 case series were found. Approximately 50% died from vulval cancer and 50% from other causes during follow-ups. Recurrences were in the ratio of approximately 4 : 2 : 1 vulval, groin and distant, with more recurrences in node-positive patients. No studies reported QoL. For cost per death averted, IFL was less costly and more effective than strategies using SLN biopsy. For morbidity-free survival and long-term morbidity-free survival, (99m)Tc with ultrastaging was most cost-effective. Strategies with blue dye only and H&E only were never cost-effective. The incremental cost-effectiveness ratio for (99m)Tc with ultrastaging compared with IFL was £4300 per case of morbidity-free survival and £7100 per long-term morbidity-free survival. LIMITATIONS: The main limitations of this study include the lack of good-quality evidence on accuracy, effectiveness and QoL. A large project such as this takes time to publish, so the most recent studies are not included. CONCLUSIONS: A sensitive and specific combined metastatic SLN detection test and information on generic QoL in vulval cancer is urgently required. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Interventions to reduce or prevent obesity in pregnant women: a systematic review.

BACKGROUND: Around 50% of women of childbearing age are either overweight [body mass index (BMI) 25-29.9 kg/m(2)] or obese (BMI ≥ 30 kg/m(2)). The antenatal period provides an opportunity to manage weight in pregnancy. This has the potential to reduce maternal and fetal complications associated with excess weight gain and obesity. OBJECTIVES: To evaluate the effectiveness of dietary and lifestyle interventions in reducing or preventing obesity in pregnancy and to assess the beneficial and adverse effects of the interventions on obstetric, fetal and neonatal outcomes. DATA SOURCES: Major electronic databases including MEDLINE, EMBASE, BIOSIS and Science Citation Index were searched (1950 until March 2011) to identify relevant citations. Language restrictions were not applied. REVIEW METHODS: Systematic reviews of the effectiveness and harm of the interventions were carried out using a methodology in line with current recommendations. Studies that evaluated any dietary, physical activity or mixed approach intervention with the potential to influence weight change in pregnancy were included. The quality of the studies was assessed using accepted contemporary standards. Results were summarised as pooled relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous data. Continuous data were summarised as mean difference (MD) with standard deviation. The quality of the overall evidence synthesised for each outcome was summarised using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology and reported graphically as a two-dimensional chart. RESULTS: A total of 88 studies (40 randomised and 48 non-randomised and observational studies, involving 182,139 women) evaluated the effect of weight management interventions in pregnancy on maternal and fetal outcomes. Twenty-six studies involving 468,858 women reported the adverse effect of the interventions. Meta-analysis of 30 RCTs (4503 women) showed a reduction in weight gain in the intervention group of 0.97 kg compared with the control group (95% CI -1.60 kg to -0.34 kg; p = 0.003). Weight management interventions overall in pregnancy resulted in a significant reduction in the incidence of pre-eclampsia (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008) and shoulder dystocia (RR 0.39, 95% CI 0.22 to 0.70; p = 0.02). Dietary interventions in pregnancy resulted in a significant decrease in the risk of pre-eclampsia (RR 0.67, 95% CI 0.53 to 0.85; p = 0.0009), gestational hypertension (RR 0.30, 95% CI 0.10 to 0.88; p = 0.03) and preterm birth (RR 0.68, 95% CI 0.48 to 0.96; p = 0.03) and showed a trend in reducing the incidence of gestational diabetes (RR 0.52, 95% CI 0.27 to 1.03). There were no differences in the incidence of small-for-gestational-age infants between the groups (RR 0.99, 95% CI 0.76 to 1.29). There were no significant maternal or fetal adverse effects observed for the interventions in the included trials. The overall strength of evidence for weight gain in pregnancy and birthweight was moderate for all interventions considered together. There was high-quality evidence for small-for-gestational-age infants as an outcome. The quality of evidence for all interventions on pregnancy outcomes was very low to moderate. The quality of evidence for all adverse outcomes was very low. LIMITATIONS: The included studies varied in the reporting of population, intensity, type and frequency of intervention and patient complience, limiting the interpretation of the findings. There was significant heterogeneity for the beneficial effect of diet on gestational weight gain. CONCLUSIONS: Interventions in pregnancy to manage weight result in a significant reduction in weight gain in pregnancy (evidence quality was moderate). Dietary interventions are the most effective type of intervention in pregnancy in reducing gestational weight gain and the risks of pre-eclampsia, gestational hypertension and shoulder dystocia. There is no evidence of harm as a result of the dietary and physical activity-based interventions in pregnancy. Individual patient data meta-analysis is needed to provide robust evidence on the differential effect of intervention in various groups based on BMI, age, parity, socioeconomic status and medical conditions in pregnancy.

Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence.

OBJECTIVE: To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Major databases from inception to January 2012 without language restrictions. STUDY SELECTION: Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy. DATA SYNTHESIS: Results summarised as relative risks for dichotomous data and mean differences for continuous data. RESULTS: We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery. CONCLUSIONS: Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes.