Search

Importance Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline’s core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

Importance: The quality of reporting of randomized clinical trials is suboptimal. In an era in which the need for greater research transparency is paramount, inadequate reporting hinders assessment of the reliability and validity of trial findings. The Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement was developed to improve the reporting of randomized clinical trials, but the primary focus was on parallel-group trials with 2 groups. Multi-arm trials that use a parallel-group design (comparing treatments by concurrently randomizing participants to one of the treatment groups, usually with equal probability) but have 3 or more groups are relatively common. The quality of reporting of multi-arm trials varies substantially, making judgments and interpretation difficult. While the majority of the elements of the CONSORT 2010 Statement apply equally to multi-arm trials, some elements need adaptation, and, in some cases, additional issues need to be clarified. Objective: To present an extension to the CONSORT 2010 Statement for reporting multi-arm trials to facilitate the reporting of such trials. Design: A guideline writing group, which included all authors, formed following the CONSORT group meeting in 2014. The authors met in person and by teleconference bimonthly between 2014 and 2018 to develop and revise the checklist and the accompanying text, with additional discussions by email. A draft manuscript was circulated to the wider CONSORT group of 36 individuals, plus 5 other selected individuals known for their specialist knowledge in clinical trials, for review. Extensive feedback was received from 14 individuals and, after detailed consideration of their comments, a final revised version of the extension was prepared. Findings: This CONSORT extension for multi-arm trials expands on 10 items of the CONSORT 2010 checklist and provides examples of good reporting and a rationale for the importance of each extension item. Key recommendations are that multi-arm trials should be identified as such and require clear objectives and hypotheses referring to all of the treatment groups. Primary treatment comparisons should be identified and authors should report the planned and unplanned comparisons resulting from multiple groups completely and transparently. If statistical adjustments for multiplicity are applied, the rationale and method used should be described. Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides specific guidance for the reporting of multi-arm parallel-group randomized clinical trials and should help provide greater transparency and accuracy in the reporting of such trials.

The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration (2001) (Part II).

The Consortium has produced these medical and service delivery guidelines about oral emergency contraceptive pills to assist family planning programs and providers in assuring that the women they serve can use these regimens effectively and safely. This document reflects the latest available evidence and has been reviewed by internationally recognized reproductive health experts. Local programs are welcome to adapt these guidelines as needed to comply with national or other requirements. These guidelines do not discuss the use of the copper-bearing intrauterine device for emergency contraception. This device is the most effective emergency contraceptive option and should be offered to women when appropriate. Some of the new research and data updated include: New details on the hormone UPA and new studies on the influence of BMI on effectiveness are briefly discussed as well as how ECP regimens work their efficacy and safety guidelines on repeat use and considerations for starting or resuming regular contraceptives following ECP regimens. This update includes a Clinical Summary document (https://www.cecinfo.org/wp-content/uploads/2018/12/18-209_ICEC-Clinical-Summary_121918.pdf) which highlights essential takeaways.

Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

Background The Consolidated Standards of Reporting Trials (CONSORT) Statement is intended to facilitate better reporting of randomised clinical trials (RCTs). A systematic review recently published in the Cochrane Library assesses whether journal endorsement of CONSORT impacts the completeness of reporting of RCTs; those findings are summarised here. Methods Evaluations assessing the completeness of reporting of RCTs based on any of 27 outcomes formulated based on the 1996 or 2001 CONSORT checklists were included; two primary comparisons were evaluated. The 27 outcomes were: the 22 items of the 2001 CONSORT checklist, four sub-items describing blinding and a ‘total summary score’ of aggregate items, as reported. Relative risks (RR) and 99% confidence intervals were calculated to determine effect estimates for each outcome across evaluations. Results Fifty-three reports describing 50 evaluations of 16,604 RCTs were assessed for adherence to at least one of 27 outcomes. Sixty-nine of 81 meta-analyses show relative benefit from CONSORT endorsement on completeness of reporting. Between endorsing and non-endorsing journals, 25 outcomes are improved with CONSORT endorsement, five of these significantly (α = 0.01). The number of evaluations per meta-analysis was often low with substantial heterogeneity; validity was assessed as low or unclear for many evaluations. Conclusions The results of this review suggest that journal endorsement of CONSORT may benefit the completeness of reporting of RCTs they publish. No evidence suggests that endorsement hinders the completeness of RCT reporting. However, despite relative improvements when CONSORT is endorsed by journals, the completeness of reporting of trials remains sub-optimal. Journals are not sending a clear message about endorsement to authors submitting manuscripts for publication. As such, fidelity of endorsement as an ‘intervention’ has been weak to date. Journals need to take further action regarding their endorsement and implementation of CONSORT to facilitate accurate, transparent and complete reporting of trials.

Background An overwhelming body of evidence stating that the completeness of reporting of randomised controlled trials (RCTs) is not optimal has accrued over time. In the mid-1990s, in response to these concerns, an international group of clinical trialists, statisticians, epidemiologists, and biomedical journal editors developed the CONsolidated Standards Of Reporting Trials (CONSORT) Statement. The CONSORT Statement, most recently updated in March 2010, is an evidence-based minimum set of recommendations including a checklist and flow diagram for reporting RCTs and is intended to facilitate the complete and transparent reporting of trials and aid their critical appraisal and interpretation. In 2006, a systematic review of eight studies evaluating the "effectiveness of CONSORT in improving reporting quality in journals" was published. Objectives To update the earlier systematic review assessing whether journal endorsement of the 1996 and 2001 CONSORT checklists influences the completeness of reporting of RCTs published in medical journals. Search methods We conducted electronic searches, known item searching, and reference list scans to identify reports of evaluations assessing the completeness of reporting of RCTs. The electronic search strategy was developed in MEDLINE and tailored to EMBASE. We searched the Cochrane Methodology Register and the Cochrane Database of Systematic Reviews using the Wiley interface. We searched the Science Citation Index, Social Science Citation Index, and Arts and Humanities Citation Index through the ISI Web of Knowledge interface. We conducted all searches to identify reports published between January 2005 and March 2010, inclusive. Selection criteria In addition to studies identified in the original systematic review on this topic, comparative studies evaluating the completeness of reporting of RCTs in any of the following comparison groups were eligible for inclusion in this review: 1) Completeness of reporting of RCTs published in journals that have and have not endorsed the CONSORT Statement; 2) Completeness of reporting of RCTs published in CONSORT-endorsing journals before and after endorsement; or 3) Completeness of reporting of RCTs before and after the publication of the CONSORT Statement (1996 or 2001). We used a broad definition of CONSORT endorsement that includes any of the following: (a) requirement or recommendation in journal's 'Instructions to Authors' to follow CONSORT guidelines; (b) journal editorial statement endorsing the CONSORT Statement; or (c) editorial requirement for authors to submit a CONSORT checklist and/or flow diagram with their manuscript. We contacted authors of evaluations reporting data that could be included in any comparison group(s), but not presented as such in the published report and asked them to provide additional data in order to determine eligibility of their evaluation. Evaluations were not excluded due to language of publication or validity assessment. Data collection and analysis We completed screening and data extraction using standardised electronic forms, where conflicts, reasons for exclusion, and level of agreement were all automatically and centrally managed in web-based management software, DistillerSR®. One of two authors extracted general characteristics of included evaluations and all data were verified by a second author. Data describing completeness of reporting were extracted by one author using a pre-specified form; a 10% random sample of evaluations was verified by a second author. Any discrepancies were discussed by both authors; we made no modifications to the extracted data. Validity assessments of included evaluations were conducted by one author and independently verified by one of three authors. We resolved all conflicts by consensus. For each comparison we collected data on 27 outcomes: 22 items of the CONSORT 2001 checklist, plus four items relating to the reporting of blinding, and one item of aggregate CONSORT scores. Where reported, we extracted and qualitatively synthesised data on the methodological quality of RCTs, by scale or score. Main results Fifty-three publications reporting 50 evaluations were included. The total number of RCTs assessed within evaluations was 16,604 (median per evaluation 123 (interquartile range (IQR) 77 to 226) published in a median of six (IQR 3 to 26) journals. Characteristics of the included RCT populations were variable, resulting in heterogeneity between included evaluations. Validity assessments of included studies resulted in largely unclear judgements. The included evaluations are not RCTs and less than 8% (4/53) of the evaluations reported adjusting for potential confounding factors. Twenty-five of 27 outcomes assessing completeness of reporting in RCTs appeared to favour CONSORT-endorsing journals over non-endorsers, of which five were statistically significant. 'Allocation concealment' resulted in the largest effect, with risk ratio (RR) 1.81 (99% confidence interval (CI) 1.25 to 2.61), suggesting that 81% more RCTs published in CONSORT-endorsing journals adequately describe allocation concealment compared to those published in non-endorsing journals. Allocation concealment was reported adequately in 45% (393/876) of RCTs in CONSORT-endorsing journals and in 22% (329/1520) of RCTs in non-endorsing journals. Other outcomes with results that were significant include: scientific rationale and background in the 'Introduction' (RR 1.07, 99% CI 1.01 to 1.14); 'sample size' (RR 1.61, 99% CI 1.13 to 2.29); method used for 'sequence generation' (RR 1.59, 99% CI 1.38 to 1.84); and an aggregate score over reported CONSORT items, 'total sum score' (standardised mean difference (SMD) 0.68 (99% CI 0.38 to 0.98)). Authors' conclusions Evidence has accumulated to suggest that the reporting of RCTs remains sub-optimal. This review updates a previous systematic review of eight evaluations. The findings of this review are similar to those from the original review and demonstrate that, despite the general inadequacies of reporting of RCTs, journal endorsement of the CONSORT Statement may beneficially influence the completeness of reporting of trials published in medical journals. Future prospective studies are needed to explore the influence of the CONSORT Statement dependent on the extent of editorial policies to ensure adherence to CONSORT guidance.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Background The CONsolidated Standards Of Reporting Trials (CONSORT) Statement provides a minimum standard set of items to be reported in published clinical trials; it has received widespread recognition within the biomedical publishing community. This research aims to provide an update on the endorsement of CONSORT by high impact medical journals. Methods We performed a cross-sectional examination of the online “Instructions to Authors” of 168 high impact factor (2012) biomedical journals between July and December 2014. We assessed whether the text of the “Instructions to Authors” mentioned the CONSORT Statement and any CONSORT extensions, and we quantified the extent and nature of the journals’ endorsements of these. These data were described by frequencies. We also determined whether journals mentioned trial registration and the International Committee of Medical Journal Editors (ICMJE; other than in regards to trial registration) and whether either of these was associated with CONSORT endorsement (relative risk and 95 % confidence interval). We compared our findings to the two previous iterations of this survey (in 2003 and 2007). We also identified the publishers of the included journals. Results Sixty-three percent (106/168) of the included journals mentioned CONSORT in their “Instructions to Authors.” Forty-four endorsers (42 %) explicitly stated that authors “must” use CONSORT to prepare their trial manuscript, 38 % required an accompanying completed CONSORT checklist as a condition of submission, and 39 % explicitly requested the inclusion of a flow diagram with the submission. CONSORT extensions were endorsed by very few journals. One hundred and thirty journals (77 %) mentioned ICMJE, and 106 (63 %) mentioned trial registration. Conclusions The endorsement of CONSORT by high impact journals has increased over time; however, specific instructions on how CONSORT should be used by authors are inconsistent across journals and publishers. Publishers and journals should encourage authors to use CONSORT and set clear expectations for authors about compliance with CONSORT.

Supplementary Material Supplementary appendix Download Summary This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

Objective: To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. Design: Combined analysis of data from three metaepidemiological studies based on collections of metaanalyses. Data sources 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. Main outcome measures Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios

Die reiche Geschichte der Verblindung erstreckt sich uber zwei Jahrhunderte. Weltweit wissen die meisten Wissenschaftler, was mit Verblindung gemeint ist, doch hinter einem nur allgemeinen Verstandnis lauert oftmals Verwirrung. Begriffe wie einfachblind, doppelblind und dreifachblind haben fur verschiedene Personen unterschiedliche Bedeutung. Auserdem verwechseln viele medizinische Forscher die Verblindung mit der Geheimhaltung der Randomisierungsliste. Solche Verwechslungen zeigen, dass beide Begriffe missverstanden werden. Verblindung bedeutet, das Studienteilnehmer, Studienarzte (meist diejenigen, die die Behandlung verabreichen) oder Bewerter (diejenigen, die die Outcome-Daten erheben) die zugeteilte Intervention nicht kennen, sodass sie durch dieses Wissen nicht beeinflusst werden. Im Allgemeinen fuhrt die Verblindung zu einem Ruckgang der unterschiedlichen Bewertung von Behandlungsergebnissen (Informationsbias). Sie kann bei den Studienteilnehmern aber auch die Compliance und die Bereitschaft zum Verbleib in der Studie verbessern, wahrend sie die Anwendung zusatzlicher Pflege- oder Therapiemasnahmen (manchmal als Ko-Intervention bezeichnet) reduziert. Studienarzte und Leser gehen vielfach gutglaubig davon aus, dass eine randomisierte Studie einfach dann als hochwertig anzusehen ist, wenn sie doppelt verblindet wurde, als ob es sich bei der doppelten Verblindung um die Conditio sine qua non einer randomisierten, kontrollierten Studie handelte. Auch wenn die Doppelverblindung (Verblindung von Studienarzten, Studienteilnehmern und Bewertern der Behandlungsergebnisse) auf eine solide Studienplanung schliesen lasst, durfen Studien ohne Doppelverblindung nicht automatisch als minderwertig eingestuft werden. Anstatt sich ausschlieslich auf Begriffe wie Doppelverblindung zu verlassen, sollten Wissenschaftler explizit angeben, wer wie verblindet wurde. Wir empfehlen, den Ergebnissen mehr Glauben zu schenken, wenn zumindest die Bewertung der Studienergebnisse verblindet erfolgte, mit Ausnahme von objektiven Endpunkten wie etwa der Mortalitat, die kaum Raum fur systematische Fehler (Bias) lassen. Wenn Studienarzte ihre Verblindungsmasnahmen korrekt angeben, kann der Leser sie beurteilen. Leider lasst die Berichterstattung in vielen Artikeln zu wunschen ubrig. Wenn in einem Beitrag behauptet wird, es habe eine Verblindung stattgefunden, ohne dies weiter zu erklaren, sollte der Leser hinsichtlich ihrer Bias reduzierenden Wirkung skeptisch bleiben.

Surrogate end points in clinical research pose real danger. A surrogate end point is an outcome measure, commonly a laboratory test, that substitutes for a clinical event of true importance. Resistance to activated protein C, for example, has been used as a surrogate for venous thrombosis in women using oral contraceptives. Other examples of inappropriate surrogate end points in contraception include the postcoital test instead of pregnancy to evaluate new spermicides, breakage and slippage instead of pregnancy to evaluate condoms, and bone mineral density instead of fracture to assess the safety of depo-medroxyprogesterone acetate. None of these markers captures the effect of the treatment on the true outcome. A valid surrogate end point must both correlate with and accurately predict the outcome of interest. Although many surrogate markers correlate with an outcome, few have been shown to capture the effect of a treatment (for example, oral contraceptives) on the outcome (venous thrombosis). As a result, thousands of useless and misleading reports on surrogate end points litter the medical literature. New drugs have been shown to benefit a surrogate marker, but, paradoxically, triple the risk of death. Thousands of patients have died needlessly because of reliance on invalid surrogate markers. Researchers should avoid surrogate end points unless they have been validated; that requires at least one well done trial using both the surrogate and true outcome. The clinical maxim that "a difference to be a difference must make a difference" applies to research as well. Clinical research should focus on outcomes that matter.

Likelihood ratios can refine clinical diagnosis on the basis of signs and symptoms; however, they are underused for patients' care. A likelihood ratio is the percentage of ill people with a given test result divided by the percentage of well individuals with the same result. Ideally, abnormal test results should be much more typical in ill individuals than in those who are well (high likelihood ratio) and normal test results should be most frequent in well people than in sick people (low likelihood ratio). Likelihood ratios near unity have little effect on decision-making; by contrast, high or low ratios can greatly shift the clinician's estimate of the probability of disease. Likelihood ratios can be calculated not only for dichotomous (positive or negative) tests but also for tests with multiple levels of results, such as creatine kinase or ventilation-perfusion scans. When combined with an accurate clinical diagnosis, likelihood ratios from ancillary tests improve diagnostic accuracy in a synergistic manner.

Summary Investigators should properly calculate sample sizes before the start of their randomised trials and adequately describe the details in their published report. In these a-priori calculations, determining the effect size to detect—eg, event rates in treatment and control groups—reflects inherently subjective clinical judgments. Furthermore, these judgments greatly affect sample size calculations. We question the branding of trials as unethical on the basis of an imprecise sample size calculation process. So-called underpowered trials might be acceptable if investigators use methodological rigor to eliminate bias, properly report to avoid misinterpretation, and always publish results to avert publication bias. Some shift of emphasis from a fixation on sample size to a focus on methodological quality would yield more trials with less bias. Unbiased trials with imprecise results trump no results at all. Clinicians and patients deserve guidance now.

Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). This review of randomized controlled trials tested the hypothesis that COCs containingor=20 microg ethinyl estradiol (EE) perform similarly to those containing20 microg in terms of contraceptive effectiveness, bleeding patterns, discontinuation and side effects. Data from the 18 eligible trials conducted to date are inadequate for detecting possible differences in contraceptive effectiveness. Several COCs containing 20 microg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea/infrequent bleeding and irregular, prolonged, frequent bleeding or breakthrough bleeding or spotting) than their higher-estrogen comparison pills. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. While health care providers and women might select COCs containing 20 microg EE based on theoretical improvements in safety profile from the reduced dose of estrogen, no evidence is available to support this choice.

To comprehend the result of a randomized controlled trial (RCT), readers must understand its design, conduct, analysis and interpretation. That goal can be achieved only through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this article incorporates new evidence and addresses some criticism of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Comment. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage or participants through an RCT. The revised flow diagram depicts information from 4 stages of a trial (enrollment, intervention allocation, follow-up and analysis). The diagram explicitly includes the number of participants, according to each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting or an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.

Objective Many women and clinicians believe that combination estrogen-progestin contraceptive use can lead to weight gain. This concern can deter women from starting hormonal contraception or lead to premature quitting. This review evaluated the association between combination contraceptive use and change in body weight. Data sources The computerized databases CENTRAL, MEDLINE, EMBASE, Popline, and LILACS (from their inception to 2002) were used to conduct this review. Known investigators and manufacturers were contacted for information about other trials not discovered in the database search. Methods of study selection All English-language, randomized controlled trials measuring weight change that were at least 3 treatment cycles in duration and that compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length were eligible for inclusion. Of the 570 reports of randomized controlled trials of eligible interventions that were identified, 42 trials were included in the systematic review. Tabulation, integration, and results Two reviewers independently abstracted data from the eligible trials using a standard form. Depending on the data available, the weighted mean difference using a fixed effect model with 95% confidence intervals was calculated for the mean change in weight between baseline and posttreatment measurements or the Peto odds ratio with 95% confidence intervals was calculated by using the proportion of women who gained or lost more than a specified amount of weight. The 3 placebo-controlled, randomized trials did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight gain. Most comparisons from the 40 trials that compared 2 or more combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight gain did not differ between groups when this factor was studied. Conclusion Available evidence is insufficient to determine the effect of combination contraceptives on weight, but no large effect is evident.

Contraception choices may be limited for lactating women due to concerns about hormonal effects on quality and quantity of milk, passage of hormones to the infant and infant growth. We conducted a systematic review of randomized controlled trials to determine the effect of hormonal contraception on lactation. We sought all randomized controlled trials, reported in any language, that included any form of hormonal contraception compared with another form of hormonal contraception, nonhormonal contraception or placebo during lactation. Seven reports from five randomized controlled trials met the inclusion criteria. Most of the five trials did not specify their method used to generate a random sequence, method of allocation concealment, blinding of treatments or use of an intention-to-treat analysis. Additionally, high loss-to-follow-up rates invalidated at least two trials. The findings from two trials comparing oral contraceptives to placebo during lactation were conflicting. Another trial found no inhibitory effects on lactation from progestin-only contraceptives. Finally, the World Health Organization trial found a statistically significant decline in breast milk volume in women using combined oral contraceptives compared to women using progestin-only pills. However, infant growth for the two groups did not differ. The limited evidence from randomized controlled trials on the effect of hormonal contraceptives during lactation is of poor quality and insufficient to establish an effect of hormonal contraception, if any, on milk quality and quantity. At least one properly conducted randomized controlled trial of adequate size is urgently needed to make recommendations regarding hormonal contraceptive use for lactating women.

The contraceptive vaginal sponge was developed as an alternative to the contraceptive diaphragm. Unlike the diaphragm, the sponge can be used for more than one coital act within 24 h without the insertion of additional spermicide, and it does not require fitting or a prescription from a physician. We conducted a systematic review of randomized controlled trials that compared the vaginal contraceptive sponge with the diaphragm used with a spermicide in order to evaluate the efficacy and continuation rates of the two devices. The sponge was statistically significantly less effective in preventing overall pregnancy than was the diaphragm in the two trials that met our inclusion criteria. The 12-month cumulative life table termination rates per 100 women for overall pregnancy were 17.4 for the sponge versus 12.8 for the diaphragm in the larger US trial, and 24.5 for the sponge and 10.9 for the diaphragm in the UK trial. Similarly, discontinuation rates at 12 months were higher with the sponge than with the diaphragm [odds ratio 1.3; 95% confidence interval (CI) 1.1-1.6]. Allergic-type reactions were more common with the sponge in both trials, although the frequency of discontinuation for discomfort differed in the two trials. Other randomized controlled trials will be needed to resolve the role of spermicides in preventing sexually transmitted infections or in causing adverse effects.

In the early 1800s, Karl Baedeker, a German publisher, launched a series of travel guidebooks. By the twentieth century, the guidebooks had achieved such international fame that his name became synonymous with the genre. As clinicians wade into the flood of clinical research being published, a guidebook can be a handy navigational aid. In this article, we offer a Baedeker for reading the literature, an approach distilled from our three decades of clinical practice and research experience. Interested readers can find more detail in our recent series on research methods in The Lancet (1–11). Reading research is mandatory if a clinician is to keep up. With greater age and experience, clinical practice should improve. Paradoxically, however, greater age and clinical experience often translate into rusty practice. As has been shown for treatment of hypertension, one of the strongest determinants of appropriate practice is number of years since medical school graduation; stated alternatively, practice quality deteriorates over time (12, 13). Keeping current is difficult after leaving formal training, and that difficulty may be greater for those who practice in smaller communities (14). If one cannot (or chooses not to) read, then one’s practice is condemned to becoming obsolete. This indirectly hurts patients. A second benefit of critical reading of clinical research is appropriate adoption (or rejection) of new technologies. Obstetrics and gynecology has a long, blemished record of adoption and dissemination of new tests and procedures without evidence of benefit (15). Episiotomy, one of the most common operations performed on adults in the last century, swept into practice based on DeLee’s analogy that childbirth is tantamount to impalement on a pitchfork (16). Urinary estriol measurement to monitor a fetus thought to be in jeopardy has been replaced by an even more expensive and cumbersome test (nonstress testing) for which no evidence of benefit exists either (17). Electronic fetal monitoring took U.S. obstetrics by storm in the absence of demonstrable benefit; a quarter century of study has failed to show any lasting benefit to babies (18), and the poor predictive value of worrisome tracings has needlessly driven up the cesarean delivery rate. Liquid-based cervical cytology screening has not been shown to reduce cervical cancer incidence or mortality, and the cost per case of cancer detected is higher with this approach than with conventional cytology (19). Ironically, poor women at highest risk of this cancer may not be able to afford the screening (20). Reports of new laparoscopy operations have recently been retracted by an editor, because the reported information could not be corroborated (21, 22). This hurt patients as well. While reading clinical research is clearly important, the task is daunting. First, the volume being published is overwhelming, with an estimated 25,000 biomedical journals in print. One challenge is picking and choosing what to read. In general, most readers should limit themselves to articles that are both relevant to their practices and likely to be of high scientific value. These two criteria will immediately narrow the field. Once an article is selected, another problem emerges: many clinicians in obstetrics and gynecology report that they cannot critically read the literature (23). Our graduates leave their training full of the Correspondence to: Family Health International, P.O. Box 13950, Research Triangle Park, NC 27709. Email: dgrimes@fhi.org

Summary Proper randomisation means little if investigators cannot include all randomised participants in the primary analysis. Participants might ignore follow-up, leave town, or take aspartame when instructed to take aspirin. Exclusions before randomisation do not bias the treatment comparison, but they can hurt generalisability. Eligibility criteria for a trial should be clear, specific, and applied before randomisation. Readers should assess whether any of the criteria make the trial sample atypical or unrepresentative of the people in which they are interested. In principle, assessment of exclusions after randomisation is simple: none are allowed. For the primary analysis, all participants enrolled should be included and analysed as part of the original group assigned (an intent-to-treat analysis). In reality, however, losses frequently occur. Investigators should, therefore, commit adequate resources to develop and implement procedures to maximise retention of participants. Moreover, researchers should provide clear, explicit information on the progress of all randomised participants through the trial by use of, for instance, a trial profile. Investigators can also do secondary analyses on, for instance, per-protocol or as-treated participants. Such analyses should be described as secondary and non-randomised comparisons. Mishandling of exclusions causes serious methodological difficulties. Unfortunately, some explanations for mishandling exclusions intuitively appeal to readers, disguising the seriousness of the issues. Creative mismanagement of exclusions can undermine trial validity.

Summary Epidemiologists benefit greatly from having case-control study designs in their research armamentarium. Case-control studies can yield important scientific findings with relatively little time, money, and effort compared with other study designs. This seemingly quick road to research results entices many newly trained epidemiologists. Indeed, investigators implement case-control studies more frequently than any other analytical epidemiological study. Unfortunately, case-control designs also tend to be more susceptible to biases than other comparative studies. Although easier to do, they are also easier to do wrong. Five main notions guide investigators who do, or readers who assess, case-control studies. First, investigators must explicitly define the criteria for diagnosis of a case and any eligibility criteria used for selection. Second, controls should come from the same population as the cases, and their selection should be independent of the exposures of interest. Third, investigators should blind the data gatherers to the case or control status of participants or, if impossible, at least blind them to the main hypothesis of the study. Fourth, data gatherers need to be thoroughly trained to elicit exposure in a similar manner from cases and controls; they should use memory aids to facilitate and balance recall between cases and controls. Finally, investigators should address confounding in case-control studies, either in the design stage or with analytical techniques. Devotion of meticulous attention to these points enhances the validity of the results and bolsters the reader's confidence in the findings.

The outcomes reported for trials often differ from those specified in the protocol. Douglas Altman , David Moher , and Kenneth Schulz call for journals to do more to ensure that authors follow guidelines

Background The use of an effective contraceptive may be necessary after an abortion. Insertion of an intrauterine device (IUD) may be done the same day or later. Immediate IUD insertion is an option since the woman is not pregnant, pain of insertion is less because the cervical os is open, and her motivation to use contraception may be high. However, insertion of an IUD immediately after a pregnancy ends carries risks, such as spontaneous expulsion. Objectives To assess the safety and efficacy of IUD insertion immediately after spontaneous or induced abortion. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP in January 27, 2014. We also contacted investigators to identify other trials. Selection criteria We sought all randomised controlled trials (RCTs) with at least one treatment arm that involved IUD insertion immediately after an induced abortion or after curettage for spontaneous abortion. Data collection and analysis We evaluated the methodological quality of each report and abstracted the data. We focused on discontinuation rates for accidental pregnancy, perforation, expulsion, and pelvic inflammatory disease. We computed the weighted average of the rate ratios. We computed risk ratios (RRs) with 95% Confidence Intervals (CIs). We performed an intention-to-treat (ITT) analysis by including all randomised participants in the analysis according to the Cochrane Handbook for Systematic Reviews of Interventions. Main results We identified 12 trials most of which are of moderate risk of bias involving 7,119 participants which described random assignment. Five trials randomised to either immediate or delayed insertion of IUD. One of them randomised to immediate versus delayed insertion of Copper 7 showed immediate insertion of the Copper 7 was associated with a higher risk of expulsion than was delayed insertion (RR 11.98, 95% CI 1.61 to 89.35,1 study, 259 participants); the quality of evidence was moderate. Moderate quality of evidence also suggests that use and expulsion of levonorgestrel-releasing intrauterine system or CuT380A was more likely for immediate compared to delayed insertion risk ratio (RR) 1.40 (95% CI 1.24 to 1.58; 3 studies; 878 participants) and RR 2.64 ( 95% CI 1.16 to 6.00; 3 studies; 878 participants) respectively. Another trial randomised to the levonorgestrel IUD or Nova T showed discontinuation rates due to pregnancy were likely to be higher for women in the Nova T group. (MD 8.70, 95% CI 3.92 to 13.48;1 study; 438 participants); moderate quality evidence. Seven trials examined immediate insertion of IUD only. From meta-analysis of two multicentre trials, pregnancy was less likely for the TCu 220C versus the Lippes Loop (RR 0.43, 95% CI 0.24 to 0.75; 2 studies; 2257 participants ) as was expulsion (RR 0.61, 95% CI 0.46 to 0.81; 2 studies; 2257 participants). Estimates for the TCu 220 versus the Copper 7 were RR 0.42 ( 95% CI 0.23 to 0.77; 2 studies, 2,274 participants) and RR 0.68, (95% CI 0.51 to 0.91); 2 studies, 2,274 participants), respectively. In other work, adding copper sleeves to the Lippes Loop improved efficacy (RR 3.40, 95% CI 1.28 to 9.04, 1 study, 400 participants) and reduced expulsion (RR 3.00, 95% CI 1.51 to 5.97; 1 study, 400 participants). Authors' conclusions Moderate quality evidence shows that insertion of an IUD immediately after abortion is safe and practical. IUD expulsion rates appear higher immediately after abortions compared to delayed insertions. However, at six months postabortion, IUD use is higher following immediate insertion compared to delayed insertion.

Background Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally. Objectives Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women. Search methods Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials. Selection criteria Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group. Data collection and analysis We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality. Main results We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons. The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg. Authors' conclusions Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.

Background Weight gain is often considered a side effect of combination hormonal contraceptives, and many women and clinicians believe that an association exists. Concern about weight gain can limit the use of this highly effective method of contraception by deterring the initiation of its use and causing early discontinuation among users. However, a causal relationship between combination contraceptives and weight gain has not been established. Objectives The aim of the review was to evaluate the potential association between combination contraceptive use and changes in weight. Search methods In November 2013, we searched the computerized databases CENTRAL (The Cochrane Library), MEDLINE, POPLINE, EMBASE, and LILACS for studies of combination contraceptives, as well as ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP). For the initial review, we also wrote to known investigators and manufacturers to request information about other published or unpublished trials not discovered in our search. Selection criteria All English-language, randomized controlled trials were eligible if they had at least three treatment cycles and compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length. Data collection and analysis All titles and abstracts located in the literature searches were assessed. Data were entered and analyzed with RevMan. A second author verified the data entered. For continuous data, we calculated the mean difference and 95% confidence interval (CI) for the mean change in weight between baseline and post-treatment measurements using a fixed-effect model. For categorical data, such as the proportion of women who gained or lost more than a specified amount of weight, the Peto odds ratio with 95% CI was calculated. Main results We found 49 trials that met our inclusion criteria. The trials included 85 weight change comparisons for 52 distinct contraceptive pairs (or placebos). The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. Authors' conclusions Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Trials to evaluate the link between combination contraceptives and weight change require a placebo or non-hormonal group to control for other factors, including changes in weight over time.

Immediate postabortal insertion of an intrauterine contraceptive device (IUCD) has many benefits, including the imminent return of ovulation, immediate protection, and avoiding the discomfort and bleeding of a separate procedure. Some clinicians, however, are concerned that IUCD perforation and expulsion may be more frequent in the postabortal uterus and that immediate insertion may increase the risk of upper genital tract infection. In addition, the contraceptive efficacy of the IUCD in this setting is not clear. Consequently, the authors reviewed eight randomized trials with at least one treatment arm entailing IUCD insertion immediately after induced or spontaneous miscarriage. Women of any age and gravidity were eligible for inclusion. The trials, in general, were of fair methodological quality. After 2 years of follow-up in a trial of IUCD insertion immediately after induced abortion, there were three perforations, representing 1 per 1000 insertions, and 157 expulsions (7%). The 70 intrauterine or ectopic pregnancies represented 2 per 100 woman-years. Twelve cases of pelvic inflammatory disease translated into 0.4 per 100 woman-years. In this trial and one of IUCD insertion after miscarriage, continuation rates at 12 months ranged from 54% to 64%. The Copper T 220C proved better than the Lippes Loop D and Copper 7 models in World Health Organization trials. Pregnancy rates after 1 year ranged from 0.6% to 2.1%. There were no significant differences in the one trial that directly compared immediate with delayed postabortal insertion. The risk of expulsion increased with advancing gestational age. The investigators believe that postabortal IUCD insertion is an effective and safe practice. Rates of pelvic inflammatory disease are low. A higher risk of IUCD expulsion with increasing gestational age may be outweighed by the opportunity for immediate, highly effective contraception in a single procedure.

Postpartum haemorrhage is a leading cause of maternal morbidity and mortality. Active management of the third stage of labour, including use of a uterotonic agent, has been shown to reduce blood loss. Misoprostol (a prostaglandin E1 analogue) has been suggested for this purpose because it has strong uterotonic effects, can be given orally, is inexpensive, and does not need refrigeration for storage. We did a multicentre, double-blind, randomised controlled trial to determine whether oral misoprostol is as effective as oxytocin during the third stage of labour.In hospitals in Argentina, China, Egypt, Ireland, Nigeria, South Africa, Switzerland, Thailand, and Vietnam, we randomly assigned women about to deliver vaginally to receive 600 microg misoprostol orally or 10 IU oxytocin intravenously or intramuscularly, according to routine practice, plus corresponding identical placebos. The medications were administered immediately after delivery as part of the active management of the third stage of labour. The primary outcomes were measured postpartum blood loss of 1000 mL or more, and the use of additional uterotonics without an unacceptable level of side-effects. We chose an upper limit of a 35% increase in the risk of blood loss of 1000 mL or more as the margin of clinical equivalence, which was assessed by the confidence interval of the relative risk. Analysis was by intention to treat.9264 women were assigned misoprostol and 9266 oxytocin. 37 women in the misoprostol group and 34 in the oxytocin group had emergency caesarean sections and were excluded. 366 (4%) of women on misoprostol had a measured blood loss of 1000 mL or more, compared with 263 (3%) of those on oxytocin (relative risk 1.39 [95% CI 1.19-1.63], p0.0001). 1398 (15%) women in the misoprostol group and 1002 (11%) in the oxytocin group required additional uterotonics (1.40 [1.29-1.51], p0.0001). Misoprostol use was also associated with a significantly higher incidence of shivering (3.48 [3.15-3.84]) and raised body temperature (7.17 [5.67-9.07]) in the first hour after delivery.10 IU oxytocin (intravenous or intramuscular) is preferable to 600 microg oral misoprostol in the active management of the third stage of labour in hospital settings where active management is the norm.

Sponsored by the nonprofit Berlex Foundation, this 6-day Faculty Development Course introduces small groups of new faculty to research design, critical appraisal of the literature, scientific writing, and evidence-based medicine. The course includes didactic presentations, small group discussions, and individual protocol development. Its influence on academic careers is impossible to determine, because defining an appropriate comparison group is not feasible. However, the cumulative effect should be to increase the research expertise of some young faculty in academic departments nationwide. In addition, many participants have introduced the principles of evidence-based medicine in their own teaching programs.

In the late 1960s, states began to liberalize their abortion laws, and a new era in women's health began. Under the leadership of Jack Smith, the Centers for Disease Control and Prevention (CDC) established a voluntary abortion surveillance system that provided the first nationwide information on the numbers and characteristics of women having abortions. Studies of abortion morbidity done by the CDC revealed that suction curettage was safer than sharp curettage, local anesthesia was safer than general anesthesia, free-standing clinics were safer than hospitals, and dilation and evacuation (D&E) was safer than the alternative of labor induction for early second-trimester abortions. This evidence, which contradicted traditional medical tenets, rapidly changed the practice of abortion in the United States. CDC also established a surveillance system for abortion deaths. This demonstrated a rapid improvement in the safety of abortion in the early 1970s. Lessons learned from mortality investigations helped to change practice as well.Today, more is known about the epidemiology of abortion than any other operation in the history of medicine. In the midst of strident debate over the abortion issue, CDC abortion surveillance data have helped to guide judicial rulings, legislative actions, and Surgeon General's reports, which have supported safer choices for women of reproductive age. When medical historians of the future look back on this century, the increasing availability of safe, legal abortion will stand out as a public health triumph.

Including only a portion of all available evidence may introduce systematic errors into the meta-analytic process and threaten its validity. We set out to examine whether language restricted meta-analyses, compared to language inclusive meta-analyses, provide different estimates of the effectiveness of interventions evaluated in randomized trials. We identified and retrieved all 79 meta-analyses from several disease areas in which explicit eligibility criteria regarding trial selection were reported. General characteristics and quality of reporting of the meta-analyses were assessed using a validated instrument. We explored the effects of language of publication of the randomized trials on the quantitative results using logistic regression analyses. Language restricted meta-analyses, compared to language inclusive meta-analyses, did not differ with respect to the estimate of benefit of the effectiveness of an intervention (ROR = 0.98; 95% CI: 0.81-1.17). These results were also robust after a series of sensitivity analyses. This study provides no evidence that language restricted meta-analyses lead to biased estimates of intervention effectiveness. We encourage others to replicate this study using different sampling frames, clinical topics and interventions.

No investigator has attempted to measure prospectively the true efficacy of a contraceptive method, compared with a control group using no method, because contraceptive trials focus on women trying to avoid pregnancy and ethical concerns do not permit the withholding of contraception. We tested the feasibility of an approach that recruited women who desired pregnancy but were willing to postpone conception by 1 month. In this protocol, we restricted frequency and timing of intercourse to one coital act on the most fertile day of the menstrual cycle, as measured by a luteinizing hormone (LH) detection kit. Participants were randomized to use either a male latex condom, spermicidal film, or no method. In this feasibility study we recruited 58 women at three sites, with one site recruiting 25 women in 5 months. Among 54 women who completed the study, we found a 12% pregnancy rate for the group using no method (2/17; 95% confidence interval [CI], 1-36%) and an 11% pregnancy rate for the group using spermicidal film (2/18; 95% CI, 1-35%). No pregnancies occurred among the 19 women using condoms (0/19; 95% CI, 0-18%). The wide confidence intervals illustrate the small sample size of this pilot study and no conclusions can be drawn about the relative efficacy of the methods. Having demonstrated the feasibility of this study design, we now urge the initiation of a large-scale study to evaluate the efficacy of barrier methods using our randomized approach, with a control arm using no method of contraception.

BACKGROUND: Concern about estrogen‐related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns. OBJECTIVES: To test the hypothesis that COCs containing ≤ 20 μg ethinyl estradiol (EE) perform similarly as those containing > 20 μg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects. SEARCH METHODS: In July 2013, we searched CENTRAL, MEDLINE, and POPLINE, and examined references of potentially eligible trials. We also searched for recent clinical trials using ClinicalTrials.gov and ICTRP. No new trials met the inclusion criteria. Previous searches included EMBASE. For the initial review, we wrote to oral contraceptive manufacturers to identify trials. SELECTION CRITERIA: English‐language reports of randomized controlled trials were eligible that compare a COC containing ≤ 20 μg EE with a COC containing > 20 μg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non‐contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding‐related reasons or other side effects, or side effects to be included in the review. DATA COLLECTION AND ANALYSIS: One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan. MAIN RESULTS: No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher‐estrogen pills, several COCs containing 20 μg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). AUTHORS' CONCLUSIONS: While COCs containing 20 μg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low‐dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow‐up rates are essential for meaningful interpretation of results.

BACKGROUND: The contraceptive vaginal sponge was developed as an alternative to the contraceptive diaphragm. The sponge, made of polyurethane impregnated with nonoxynol‐9 (1g), releases 125 mg of the spermicide over 24 hours of use. Unlike the diaphragm, the sponge can be used for more than one coital act within 24 hours without the insertion of additional spermicide, and the sponge does not require fitting or a prescription from a physician. How the sponge compares with the diaphragm in terms of efficacy and continuation is not clear. OBJECTIVES: To compare the efficacy and continuation rates of the sponge with the diaphragm (used with nonoxynol‐9). Our a priori hypothesis was that the sponge would have higher rates for failure and discontinuation than the diaphragm. SEARCH METHODS: In April 2013, we searched the computerized databases MEDLINE, POPLINE, LILACS, CENTRAL, ClinicalTrials.gov and ICTRP. Earlier searches also included EMBASE. For the initial review, we searched the reference lists of relevant articles and book chapters. We also contacted investigators involved with the identified trials for other published or unpublished trials. SELECTION CRITERIA: We included randomized controlled trials comparing the vaginal contraceptive sponge (Today; Collatex) with any diaphragm used with nonoxynol‐9 to prevent pregnancy. DATA COLLECTION AND ANALYSIS: We examined the studies identified through the literature searches for possible inclusion and evaluated their methodological quality using the Cochrane guidelines. We entered data into RevMan and calculated Peto odds ratios for overall pregnancy and 12‐month discontinuation using numbers of women as the denominator. We also abstracted 12‐month cumulative life‐table ratios for these same outcomes but were unable to aggregate these data. MAIN RESULTS: Two trials met the inclusion criteria. The sponge was significantly less effective in both trials in preventing overall pregnancy than was the diaphragm. In the larger USA trial, the 12‐month cumulative life‐table termination rates per 100 women for overall pregnancy were 17.4 for the sponge and 12.8 for the diaphragm. The rates were 24.5 for the sponge and 10.9 for the diaphragm in the UK trial. Similarly, discontinuation rates at 12 months were higher with the sponge than with the diaphragm (Odds ratio 1.31; 95% CI 1.07 to 1.59). Allergic‐type reactions were more common with the sponge, although discontinuation for discomfort differed in the two trials. No new trials have been identified since the initial review. AUTHORS' CONCLUSIONS: The sponge was less effective than the diaphragm in preventing pregnancy. Discontinuation rates were higher at 12 months as well. Other randomized controlled trials will be needed to resolve the potential role of spermicides in preventing sexually transmitted infections or in causing adverse effects.

Background Combination injectable contraceptives (CICs) provide a highly effective, reversible method of preventing pregnancy, and they do not require daily administration or use at the time of coitus. Although they are used in many countries, their acceptability could be limited by method characteristics, such as the need to obtain a monthly injection or bleeding pattern changes. Objectives To assess the contraceptive efficacy, bleeding patterns, discontinuation, user preferences, and side effects of CICs. Search methods In January and February 2013, we searched for randomized controlled trials (RCTs) of combination injectable contraceptives. Databases include MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS. We searched for current trials in ClinicalTrials.gov and ICTRP. Earlier searches also included AIM and IMEMR. For the initial review, we also assessed the references listed in review articles and in the eligible trial reports. Selection criteria RCTs were eligible if they compared a combination injectable contraceptive with any other contraceptive method (e.g., a second CIC, a progestin-only injectable contraceptive, another hormonal contraceptive or a barrier method) or a placebo. We limited the review to marketed CICs. Data collection and analysis Two authors independently extracted data on contraceptive efficacy, bleeding patterns, continuation, and side effects. We calculated the Peto odds ratio or mean difference with 95% confidence interval for dichotomous or continuous outcome, respectively. Survival analysis estimates for method discontinuation were presented where available. Main results Twelve trials met the inclusion criteria. Combination injectable contraceptives include depot medroxyprogesterone acetate (DMPA) 25 mg plus estradiol cypionate (E2C) 5 mg, as well as norethisterone enanthate (NET-EN) 50 mg plus estradiol valerate (E2V) 5 mg. These contraceptives resulted in lower rates of early study discontinuation due to amenorrhea or other bleeding problems than progestin-only contraceptives. However, rates were higher for overall discontinuation and discontinuation due to other medical reasons. Acceptability results favored the CIC in one study and the progestin-only in another. Studies comparing two CICs found that NET-EN 50 mg plus E2V 5 mg resulted in less overall discontinuation and less discontinuation due to amenorrhea or prolonged bleeding than DMPA 25 mg plus E2C 5 mg. However, these differences were not detected in all trials. The NET-EN plus E2V group also had more regular bleeding and fewer prolonged bleeding reference periods than the DMPA plus E2C group. The groups did not differ in their amenorrhea rates. Authors' conclusions While discontinuation rates can be viewed as a measure of method acceptability, the findings should be interpreted with caution since discontinuation depends on many factors. Future research should be directed toward improving the acceptability of combination injectable contraceptives, such as providing injections in settings more convenient than clinics, methods for women to administer their own injections, and counseling about possible bleeding pattern changes.