Menu
Search BMJ Group Search BMJ Group Journals Jobs Education Decision support Quality improvement Community BMJ Group
From trainee to consultant, BMJ Group offers doctors around the world tailored information, special events, learning resources and recruitment services at every step along their career path.
... by doctors, for doctors, for patients About BMJ Group Customer Service Subscriptions & Sales Working for BMJ Group BMJ Media Centre BMJ Group Awards Advertising & Sponsorship Rights & Licensing Affinity & Society Publishing Online learning BMJ Learning High-quality CME / CPD for doctors and other healthcare professionals. BMJ Learning features hundreds of accredited, peer-reviewed learning modules in text, video, and audio formats. Find out more Courses and Qualifications BMJ Masterclasses BMJ Masterclasses, led by experts, help clinicians to use the latest evidence and recent guidelines in practice and meet their CPD/CME requirements. Find out more Exam Preparation 
The leading provider of online exam preparation, helping over 167,000 healthcare professionals to pass their exams. Find out more BMJ Learning BMJ Portfolio BMJ Masterclasses Clinical Leadership Programme Diabetes Qualifications and Courses onExamination Decision support and clinical reference BMJ Evidence Centre The BMJ Evidence Centre builds evidence into practice, to support improvements in the consistency and quality of health care.
Best Practice Clinical Evidence Evidence Updates Best Health Action Sets
Informatica Systems Informatica Systems delivers performance management systems and innovative software solutions to primary care. Learn more Audit + Contract + Health Checks FrontDesk BMJ Quality 
The latest news, research, events, opinion and guidance related to quality and safety in health care.
The 2013 event will take place in London from 16th- 19th April 2013. Find out more BMJ Quality BMJ Quality and Safety International Forum on Quality and Safety in Healthcare BMJ The flagship general medical journal, published since 1840, updated daily online, weekly in print and on the iPad.
BMJBMJ Journals BMJ Journals division publishes over 40 journals across a broad range of specialties.
BMJ JournalsstudentBMJ An international medical journal written for students by students.
Student BMJ JobsBMJ Careers BMJ Careers makes it easy for you to find the right job with the latest healthcare vacancies, upcoming careers fairs, advice on choosing the right specialty, pay and working conditions.
19-20 October 2012 at the Business Design Centre in Islington, London. Register here BMJ Careers Jobs and vacancies at BMJ Group BMJ Careers Fair Community 
Join the discussions on our community site doc2doc or our social pages
... by doctors, for doctors, for patientsWe are open for entries! doc2doc Follow BMJ Group on Twitter BMJ Group on Facebook BMJ Group Awards Subscribe My account
Update my details
Manage my emails
BMA Members Sign in Username: * Password: * Forgot your sign in details?BMA membersAthens or your organisation BMJ Helping doctors make better decisions Search bmj.com: Advanced search Home Research Education News Comment Multimedia Specialties Archive Search all BMJ research articles: From18401841184218431844184518461847184818491850185118521853185418551856185718581859186018611862186318641865186618671868186918701871187218731874187518761877187818791880188118821883188418851886188718881889189018911892189318941895189618971898189919001901190219031904190519061907190819091910191119121913191419151916191719181919192019211922192319241925192619271928192919301931193219331934193519361937193819391940194119421943194419451946194719481949195019511952195319541955195619571958195919601961196219631964196519661967196819691970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009201020112012JanFebMarAprMayJunJulAugSepOctNovDec To18401841184218431844184518461847184818491850185118521853185418551856185718581859186018611862186318641865186618671868186918701871187218731874187518761877187818791880188118821883188418851886188718881889189018911892189318941895189618971898189919001901190219031904190519061907190819091910191119121913191419151916191719181919192019211922192319241925192619271928192919301931193219331934193519361937193819391940194119421943194419451946194719481949195019511952195319541955195619571958195919601961196219631964196519661967196819691970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009201020112012JanFebMarAprMayJunJulAugSepOctNovDec Limit by AllResearchMethods and reporting Our online table of contents is updated at least twice each day. Read all articles published in the last 7 days. You can use bmj.com to help you with your continuing medical education. Find out about CME/CPD credits for BMJ articles Keep up to date with cardiology: Access the latest cardiovascular medicine resources from across BMJ Group.OPEN ACCESS: All research articles are freely available online, with no word limit. Find out more about the BMJ's open access policy. Submit your paper. Find out how study types differ in our How to read a paper section. Countdown to London 2012: BMJ Group's Olympics portal highlights latest Olympics and sports medicine-themed research, comment and learning Research Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis BMJ 2012; 345 doi: 10.1136/bmj.e4944 (Published 7 August 2012) Cite this as: BMJ 2012;345:e4944 Reproductive medicine Contraception Drugs: obstetrics and gynaecology Sexual health More topics Clinical trials (epidemiology) Internet Fewer topics Article Related content Article metrics S Mantha, senior staff haematologist1, R Karp, clinical fellow in medicine2, V Raghavan, clinical fellow in medicine3, N Terrin, associate professor of medicine4, K A Bauer, professor of medicine25, J I Zwicker, assistant professor of medicine21Division of Hematology-Oncology, Lahey Clinic, Burlington, MA, USA2Beth Israel Deaconess Medical Center, Harvard Medical School, Divisions of Thrombosis and Hemostasis and Hematology-Oncology, 330 Brookline Ave, Boston, MA 02215, USA3Harvard Medical School, Mt Auburn Hospital, Cambridge, MA4Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA5Harvard Medical School, VA Boston Healthcare System, Boston, MACorrespondence to: J I Zwicker jzwicker{at}bidmc.harvard.eduAccepted 28 June 2012AbstractObjectives To evaluate the risk of venous thromboembolic events associated with the use of progestin-only contraception and whether that risk differs with the mode of drug delivery (oral, intrauterine, or depot injection).Design Systematic review and meta-analysis of randomised controlled trials and observational studies.Data sources Pubmed, Embase, Cochrane Library, and reference lists of relevant reviews.Study selection Randomised controlled trials and case-control, cohort, and cross sectional studies with venous thromboembolic outcome for progestin-only contraception reported relative to a non-hormone comparator group.Data extraction Data were extracted by two independent investigators, and consensus for inclusion was reached after assessment by additional investigators.Results Among the 2022 unique references identified by all searches, eight observational studies fulfilled inclusion criteria. A total of 147 women across all studies were diagnosed with a venous thromboembolic event while taking progestin-only contraception, and the summary measure for the adjusted relative risk of a venous thromboembolic episode for users versus non-users of a progestin-only contraceptive was, based on the random effects model, 1.03 (95% CI 0.76 to 1.39). Subgroup analysis confirmed there was no association between venous thromboembolic risk and progestin-only pills (relative risk 0.90 (0.57 to 1.45)) or a progestin intrauterine device (0.61 (0.24 to 1.53)). The relative risk of a venous thromboembolic event for users of an injectable progestin versus non-users was 2.67 (1.29 to 5.53).Conclusions Published data assessing the risk of venous thromboembolism in women prescribed progestin-only contraception are limited. In this meta-analysis of eight observational studies, the use of progestin-only contraception was not associated with an increased risk of venous thromboembolism compared with non-users of hormonal contraception. The potential association between injectable progestins and thrombosis requires further study.IntroductionSince their introduction in the 1960s, combined oestrogen-progestin oral contraceptives have been associated with an increased risk of venous thromboembolic events. This thrombotic risk was attributed to the oestrogen content, which prompted the development of oral contraceptives containing less oestrogen. Use of formulations containing lower dose oestrogen still confer about twofold to fourfold increased risk of venous thromboembolic events compared with non-use.1 2 3 4 5 Epidemiological data suggest that subsequent changes in the composition of combined oral contraceptives by altering the progestin content can exacerbate thrombotic risk. Accordingly, newer progestins such as desogestrel, gestodene, and norgestimate have been associated with a greater venous thromboembolic risk than the older progestins such as levonorgestrel, lynestrenol, and norethisterone.4 5 6 7 8 When combined with an oestrogen, the newer progestins increase activated protein C resistance more than older progestins, which may account for the observed increased incidence of venous thromboembolism.9 10 11 12 Despite evidence that progestins may influence the risk of venous thromboembolism, there are only limited data evaluating the association between progestin-only contraception and thrombosis. Progestin-only contraception is generally thought to pose little risk of thrombosis and is recommended for women at high risk—such as post partum or with hereditary thrombophilia or a history of venous thromboembolism.13 14 We performed a meta-analysis to evaluate the risk of venous thromboembolism associated with progestin-only contraception.MethodsWe performed a systematic review and meta-analysis of studies to evaluate the hypothesis that progestin-only contraceptives do not increase the risk of venous thromboembolic events. We conducted a literature search of journal articles published on or before 31 December 2011 using PubMed, Embase, and the Cochrane Database of Systematic Reviews. The index (MeSH or Emtree) fields were queried for the key words “progestin,” “progesterone,” “progestogen,” “progestagen,” “gestagen,” “contraceptive,” “thrombosis,” “thromboembolism,” and “thrombotic” (see appendix on bmj.com). Because of available resources, we considered only English language publications. We also performed a hand search of all the references included in a previous meta-analysis that analysed progesterone-only contraception and the risk of venous thromboembolic events15 and a review of contraception in thrombophilic adolescents.16Inclusion criteriaStudies were included if they met all of the following conditions: a randomised trial or case-control, cohort, or cross sectional study (prospective or retrospective); presence of a treatment arm featuring use of progestin-only contraceptives and a control arm with no hormone use; use of progestin for the purpose of contraception only (excluding postcoital contraception); independent analysis of premenopausal women; incidence of venous thromboembolic events (defined as deep venous thrombosis or pulmonary embolism) reported; study featured human data only; one or more of three possible administration routes (oral, injectable, or intrauterine) were considered.Data extractionThe initial search of the three databases was performed by SM; the references obtained were screened independently by two reviewers (RK and VR). Abstracts were assessed for relevance, and the full text of potentially suitable articles were retrieved. Each of those papers was assessed independently by the two reviewers (RK and VR) for inclusion in the meta-analysis; the reason for exclusion was noted for rejected articles. Two other reviewers (SM and JIZ) read the final subset of papers retained; mutual consensus was required for a study to be included in the analysis.Validity assessmentTwo reviewers (SM and JIZ) independently qualitatively evaluated the risk of confounding and the design quality of selected studies. Observational studies were assessed as suggested by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) Group.17 The characteristics of individuals in the case and control groups or exposed and unexposed patients were compared; the use of matching or stratification was noted, and covariates used for adjustment in multivariate analysis were recorded. For randomised trials, the plan was to use the Cochrane Collaboration’s tool for assessing risk of bias.18Statistical analysisWe estimated the risk ratio of venous thromboembolism for users of progestin-only oral contraceptives versus non-users. Venous thromboembolism was defined as including both deep venous thrombosis and pulmonary embolism. We assumed that venous thromboembolic events had a low incidence (<10% a year) in women aged <50 years taking oral contraceptives; this was based on previous reports estimating the yearly incidence of those events to about 0.06% per year.4 For infrequent events, the risk ratio, odds ratio, and rate ratio are considered equivalent measures of relative risk.19 With this in mind, we used the Comprehensive Meta-Analysis (CMA) version 2.2 software platform, entering each measure of relative risk in the same data table as if it were a risk ratio. The DerSimonian and Laird random effects model was used with the study as the unit of analysis. The primary analysis was performed with the adjusted measures of effect. As a secondary analysis, we estimated the adjusted risk ratio of venous thromboembolism for users versus non-users of a hormone in each subgroup according to route of administration (oral, injectable and intrauterine). Additionally, an unadjusted odds ratio of venous thromboembolic event for users versus non-users of progestin was calculated using the raw event data. Heterogeneity across studies was estimated by means of the I2 statistic, itself calculated from the Q statistic. Sensitivity analysis was performed by repeating the primary analysis while excluding selected subgroups in order to determine if they had an inordinate effect on the estimated measure of effect.ResultsA total of 2045 references were identified: 1827 from PubMed, 215 from Embase, and none from the Cochrane Database of Systematic Reviews (fig 1?). Two journal articles were identified from reading reviews of the subject matter,15 16 20 21 and one from personal knowledge of an author.22 After removal of duplicates, 2022 records remained and were screened for inclusion in the analysis. Of these, 1922 were excluded after review of the abstract for lack of pertinence, leaving 100 articles to be retrieved. The full text of these papers were evaluated: 92 were excluded, with eight remaining for analysis.20 22 23 24 25 26 27 28 The reasons for exclusion were not being a case-control or cohort study or randomised trial (n=41), results not reported separately for a progestin-only arm (n=39), absence of a no hormone arm (n=4), progestin not administered for contraception only (n=4), results for venous thromboembolism not reported (n=3), and old version of a study with a recent update (n=1).
View larger version:In a new windowDownload as PowerPoint SlideFig 1 Flow diagram of studies included in meta-analysisCharacteristics of included studiesThe methods used by the authors of the eight selected studies are summarised in table 1?. Our search found no randomised trial including a group of women taking a progestin-only contraceptive versus a group taking no hormone; three studies were retrospective cohort analyses, and five were case-control studies. All the case-control studies matched participants by age, and all but one study evaluated patients taking a progesterone-only pill with some also including individuals with a depot or intrauterine progestin-only contraceptive. Only two studies made use of stratification, but all of them performed multivariate analysis. The regression techniques varied widely: logistic regression was the most common approach,20 26 27 28 followed by Poisson regression23 24 and Cox modelling.22 23 Body mass index was the variable most commonly adjusted for, with five sets of authors using it in their model. Two of the three retrospective cohort studies adjusted results for age in multivariate analysis. After considering these details, our reviewers determined that all of the eight papers retrieved in the search were of sufficient quality to be included in the meta-analysis.View this table:View PopupView InlineTable 1 Characteristics of studies included in review of risk of venous thromboembolic events in women taking progestin-only contraceptivesA total of 147 women sustained a venous thromboembolic event, and table 2? shows the results of the articles retained for final analysis. The largest study was that of Lidegaard et al,24 with 1882 episodes of venous thromboembolism recorded in the combined group of individuals exposed to a progestin or to no hormone, followed by the WHO study,27 which featured 667 cases of venous thromboembolism for progestin-only users and non-users. The remaining six papers included a total of 777 events. The mean ages of case and control groups or exposed and unexposed groups were similar in the articles where the data were available. Since logistic regression was used in most papers, the odds ratio was the most common measure of effect.View this table:View PopupView InlineTable 2 Progestin exposure characteristics in studies of venous thromboembolic events in women taking progestin-only contraceptivesRisk of venous thromboembolismThe adjusted relative risk of a venous thromboembolic event for users of progestin-only contraception versus non-users varied from 0.68 to 1.93, as shown in table 3?. None of the studies reported a statistically significant difference in the risk of venous thromboembolic event for users versus non-users of progestin-only contraceptive, whether for subgroups of users or all users versus non-users. However, Lidegaard et al reported the results for three different progestin-only formulations separately.24 We combined these three risk ratio estimates, corresponding to the three progestins, using the random effect models and setting the study as the unit of analysis. We assumed the three estimates were independent because there was insufficient information to account for their dependence. Hence the confidence interval of the estimate (0.61 to 0.98) may be too narrow (table 2?).View this table:View PopupView InlineTable 3 Total number of venous thromboembolic events and adjusted relative risk in women taking progestin-only contraceptives or no hormone among included studiesThe summary measure for the adjusted relative risk of a venous thromboembolic event for users versus non-users of a progestin-only contraceptive was 1.03 (95% CI 0.76 to1.39) with the random effects model (fig 2?). This value was similar to the one obtained by combining the crude results (relative risk 1.21 (0.92 to 1.59)). However, the largest study (by Lidegaard et al24) could not be included in this latter estimate because the numbers of exposed and unexposed individuals were not provided (fig 3?).
View larger version:In a new windowDownload as PowerPoint SlideFig 2 Adjusted relative risk of venous thromboembolism for users versus non-users of a progestin-only contraceptive, all subgroups combined
View larger version:In a new windowDownload as PowerPoint SlideFig 3 Unadjusted relative risk of venous thromboembolism for users versus non-users of a progestin-only contraceptive, all subgroups combinedSubset analysis was performed on the adjusted results with the random effects model. A total of 54 women developed a venous thromboembolic event while taking a progestin-only pill (excluding the study by Vasilakis et al,25 which did not specify the route of administration), and they showed no significant increase in risk of venous thromboembolism compared with non-users (relative risk 0.90 (0.57 to 1.45)). On the other hand, the relative risk of an event for users of an injectable progestin formulation versus non-users was 2.67((1.29 to 5.53) (fig 4?). Only two studies could be used to compute this value because no other article reported the results separately for that subgroup. Those two papers featured a total of 31 venous thromboembolic events in users of injectable progestins, which represents 21% of all cases in progestin-only users among all of the eight studies. Similarly, only two papers reported the results for the risk of venous thromboembolism in users of a progestin-only intrauterine device, and the combined measure of effect was 0.61 (0.24 to 1.53). These two studies reported 58 thromboembolic events in users of a progestin-only intrauterine device, which corresponds to 39% of all such episodes in progestin-only users among all of the eight studies. Notably, most of the information on these thromboembolic events comes from Lidegaard et al,24 with 55 venous thromboembolic event episodes in comparison with only three episodes in the paper from van Hylckama Vlieg et al.26
View larger version:In a new windowDownload as PowerPoint SlideFig 4 Adjusted relative risk of venous thromboembolism for users versus non-users of a progestin-only contraceptive, injectable formulation onlyHeterogeneity was low, with an I2 of 24% and P=0.24 for the adjusted results (fig 2?). Sensitivity analysis was done by repeating the meta-analysis with one of the studies removed on an iterative basis: for all iterations, the 95% confidence intervals overlapped largely with those of the main analysis (data not shown).DiscussionThe primary objective of this meta-analysis is to assess the risk of venous thromboembolic events in women taking progestin-only contraception compared with non-users. A total of eight studies were included in this analysis, and the summary statistic did not identify a significant risk of venous thromboembolism associated with use of progestin-only contraception. There was a low degree of heterogeneity between studies, and we performed subgroup analysis to determine whether the apparent lack of association with venous thromboembolism was independent of route of administration of progestin (oral, depot injection, or intrauterine device).All studies except that of van Hylckama Vlieg et al26 included patients taking an oral progestin; pooling of the results for the five papers reporting results separately for that subgroup indicated no increase in risk of venous thromboembolism for users versus non-users. The oral formulations included in this meta-analysis consisted of numerous different compounds, so it is not possible to evaluate a relation between risk of venous thromboembolism and individual types of progestin. In the studies that included women using a progestin-only intrauterine device, no excess risk of venous thromboembolism was detected. However, our analysis suggests that depot administration more than doubles the risk of venous thromboembolism. Only two studies reported results separately for this subgroup, representing about a fifth of the total number of venous thromboembolic episodes in the progestin-only users for the eight studies.The relative safety of progestin-only contraception by oral and intrauterine delivery may in part be explained by dose, absorption, or metabolism. The amount of progestin included in a progestin-only “mini-pill” is considerably less than that commonly supplied in a combined oestrogen-progestin oral contraceptive. For instance, norethindrone is the only marketed progestin-only pill marketed in the United States, and when used alone the dose is 0.35 mg daily or about a third of the dose commonly found in combined oestrogen-progestin formulations.29 Similarly, the levonorgestrel-containing intrauterine device releases about 20 µg of levonorgestrel daily, most of which is concentrated in the endometrium with plasma concentrations ranging between 74 and 166 pg/mL.30 By comparison, after intramuscular injection of medroxyprogesterone 150 mg, the peak plasma concentration is 2500–7000 pg/mL and remains greater than 430 pg/mL at three months.31 32Different progestins are also known to influence the risk of thrombosis differently. Evidence suggests that third generation progestins such as desogestrel in combination with oestrogen are more prothrombotic than earlier formulations such as levonorgestrel or norethisterone.4 5 6 7 8 24 Progestins can modulate oestrogen induced activated protein C resistance12 and have been shown to influence the cellular expression of tissue factor33 34 as well as circulating tissue factor pathway inhibitor.10 35 In a mouse model of vascular injury administration of medroxyprogesterone significantly shortened the time to development of an occlusive thrombus.36 In the studies included in this meta-analysis, the vast majority of women used older progestins, potentially masking an association with venous thromboembolism. However, the study by Lidegaard et al analysed more than 29?000 women years for a third generation progestin-only pill and failed to show any increased risk associated with its use (adjusted venous thromboembolic event rate 0.64 (95% confidence interval 0.29 to 1.42)).24Strengths and limitations of the meta-analysisA potential limitation of this study remains the paucity of published literature on the topic, with a total of only eight studies available for analysis and no randomised trials. The inclusion of several recently published large epidemiological studies permits a more robust summary analysis with tighter confidence intervals than a previously published meta-analysis, which evaluated only four studies (without an analysis according to method of delivery).15 The consistency of the results for different oral formulations reassures the validity of the measure of effect for this group. The subgroup analysis for intrauterine devices and depot injections should be interpreted with caution because of the limited number of studies available for analysis.Control for confounding in the individual studies was usually limited. Also, selection bias cannot be excluded as the basis of the significant association between depot administration and venous thromboembolism. However, this is unlikely as the study that contributed most to the summary statistic for depot injection specifically excluded highest risk women (that is, those with a personal history of venous thromboembolism).26 We did not observe evidence of publication or reporting bias. However, the small number of studies limits our ability to formally assess these potential biases.37 Bias and lack of adjustment for confounders at the level of the individual studies cannot be corrected in the meta-analysis, so the validity of these results is dependent on quality of the primary observational data.Implications for patient careDeciding on the optimal contraceptive method is often difficult for women considered at increased risk of venous thromboembolism, such as those with a history of thrombophilia. The World Health Organization and US Centers for Disease Control and Prevention publish similarly titled guidelines on the topic, “Medical eligibility criteria for contraceptive use.” All modes of progestin-only contraception are advocated, even for higher risk women such as those with hereditary thrombophilia, history of oestrogen induced venous thromboembolism, or history of recurrent venous thromboembolism.13 14 This meta-analysis offers further reassurance that such guidance is appropriate. However, only two of the studies were specifically conducted in high risk populations, with a total of 360 women.22 23 Our analysis also suggests that the relative safety of progestin-only agents may be limited to oral and intrauterine formulations, whereas the thrombotic risk associated with injectable progestin seems to be of similar magnitude to oral contraceptives containing oestrogen.ConclusionCollectively, progestin-only contraceptives were not associated with an increased risk of venous thromboembolism compared with non-users in a limited number of observational studies. In the subset of women in this analysis prescribed injectable progestins, there was an approximate twofold increase in thrombotic risk. These results require confirmation as selection bias cannot be excluded. In the interim, we suggest consideration of non-injectable forms of progestin-only contraception for highest risk women.What is already known on this topicThe risk of venous thromboembolic events associated with use of hormone contraceptives is influenced by the dose of oestrogen and formulation of progestinProgestin-only contraception is the preferred hormone contraceptive in women considered higher risk for development of venous thromboembolismWhat this study addsThis meta-analysis of eight observational studies did not identify an association between oral progestin-only contraception and risk of venous thromboembolismSubgroup analysis suggests that injectable progestin contraception is associated with an approximate twofold increased risk of risk of venous thromboembolism relative to women not taking hormonal contraceptionNotesCite this as: BMJ 2012;345:e4944FootnotesContributors: RK and VR performed initial literature searches and data extraction. JIZ and SM performed data extraction, statistical analysis, and coauthored the manuscript. NT provided statistical analysis and editing. KAB performed manuscript review and editing.Funding: This study was funded by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (grant No UL1 RR025752). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from US National Institute of Health for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Data sharing: No additional data available.This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.References?Helmerhorst FM, Bloemenkamp KW, Rosendaal FR, Vandenbroucke JP. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost1997;78:327-33.OpenUrlMedlineWeb of Science?Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. BMJ1986;292:526.OpenUrlFREE Full Text?Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol1991;133:32-7.OpenUrlFREE Full Text?Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ2009;339:1-8.OpenUrl?Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ2009;339:b2921.OpenUrlFREE Full Text?Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet1995;346:1589-93.OpenUrlCrossRefMedlineWeb of Science?World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet1995;346:1575-82.OpenUrlMedlineWeb of Science?Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ2001;323:131-4.OpenUrlFREE Full Text?Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet1999;354:2036-40.OpenUrlCrossRefMedlineWeb of Science?Van Vliet HA, Bertina RM, Dahm AE, Rosendaal FR, Rosing J, Sandset PM, et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008;6:346-51.OpenUrlMedlineWeb of Science?Tchaikovski SN, van Vliet HA, Thomassen MC, Bertina RM, Rosendaal FR, Sandset PM, et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. J Thromb Haemost2007;98:1350-6.OpenUrl?Kemmeren JM, Algra A, Meijers JC, Tans G, Bouma BN, Curvers J, et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood2004;103:927-33.OpenUrlFREE Full Text?Centers for Disease Control and Prevention. US medical eligibility criteria for contraceptive use. MMWR Early Release2010;59:1-86.OpenUrl?Department of Reproductive Health WHO. Medical eligibility criteria for contraceptive use. 4th ed. WHO Press, 2009.?Bergendal A, Odlind V, Persson I, Kieler H. Limited knowledge on progestogen-only contraception and risk of venous thromboembolism. Acta Obstet Gynecol Scand2009;88:261-6.OpenUrlCrossRefMedline?Rott H. Hormonal contraception in thrombophilic adolescents. Risk of thrombosis and recommendations. Hamostaseologie2012;32:15-21.OpenUrlMedlineWeb of Science?Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al for the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA2000;283:2008-12.OpenUrlCrossRefMedlineWeb of Science?Higgins JPT, Green S, Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Wiley-Blackwell, 2008.?Pagano M, Gauvreau K. Principles of biostatistics. 2nd ed. Duxbury, 2000.?Heinemann LA, Assmann A, DoMinh T, Garbe E. Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Eur J Contraception Reprod Health 1999;4:67-73.OpenUrlCrossRef?Meirik O, Farley TM, Sivin I. Safety and efficacy of levonorgestrel implant, intrauterine device, and sterilization. Obstet Gynecol2001;97:539-47.OpenUrlCrossRefMedlineWeb of Science?Vaillant-Roussel H, Ouchchane L, Dauphin C, Philippe P, Ruivard M. Risk factors for recurrence of venous thromboembolism associated with the use of oral contraceptives. Contraception2011;84:e23-30.OpenUrlCrossRefMedline?Conard J, Plu-Bureau G, Bahi N, Horellou MH, Pelissier C, Thalabard JC. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception2004;70:437-41.OpenUrlCrossRefMedlineWeb of Science?Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ2011;343:d6423.OpenUrlFREE Full Text?Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet1999;354:1610-1.OpenUrlMedlineWeb of Science?Van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol2010;30:2297-300.OpenUrlFREE Full Text?World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. Contraception1998;57:315-24.OpenUrlCrossRefMedlineWeb of Science?Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res2010;126:373-8.OpenUrlCrossRefMedline?Stanczyk FZ, Mroszczak EJ, Ling T, Runkel R, Henzl M, Miyakawa I, et al. Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women. Contraception1983;28:241-51.OpenUrlCrossRefMedlineWeb of Science?Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril1986;45:805-7.OpenUrlMedlineWeb of Science?Nanda K, Amaral E, Hays M, Viscola MA, Mehta N, Bahamondes L. Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril2008;90:965-71.OpenUrlCrossRefMedline?Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med2003;9:458-62.OpenUrlCrossRefMedlineWeb of Science?Lockwood CJ, Murk W, Kayisli UA, Buchwalder LF, Huang ST, Funai EF, et al. Progestin and thrombin regulate tissue factor expression in human term decidual cells. J Clin Endocrinol Metab2009;94:2164-70.OpenUrlFREE Full Text?Kato S, Pinto M, Carvajal A, Espinoza N, Monso C, Sadarangani A, et al. Progesterone increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1. J Clin Endocrinol Metab2005;90:1181-8.OpenUrlFREE Full Text?Shirk RA, Zhang Z, Winneker RC. Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat. J Steroid Biochem Molecular Biol2005;94:361-8.OpenUrlCrossRef?Freudenberger T, Oppermann M, Marzoll A, Heim HK, Mayer P, Kojda G, et al. Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice. Br J Pharmacol2009;158:1951-60.OpenUrlCrossRefMedlineWeb of Science?Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ2011;343:d4002.OpenUrlFREE Full Text Open access PDFEasy ReadData supplementRespond to this article Tweet Services Email to friendDownload to citation managerAdd article to BMJ portfolioRequest permission Citations Find similar articles in PubMedArticles by S ManthaArticles by R KarpArticles by V RaghavanArticles by N TerrinArticles by K A BauerArticles by J I ZwickerCiting articles via Web of ScienceCiting articles via Scopus Social bookmarking 
CiteULike
Connotea
Del.icio.us
Digg
Facebook
Mendeley
Reddit
Twitter
Stumbleupon Latest jobsUK jobsInternational jobsUK jobs Eames Jones Judge Hawkings European Medical Affairs Director (30 Jul 2012)UNIVERSITY OF CAMBRIDGE UNIVERSITY LECTURER/HONORARY CONSULTANT IN PSYCHIATRY (19 Jul 2012)University of Cambridge The Professorship of Stroke Medicine (19 Jul 2012)University of Cambridge Clinical Lecturer in Anaesthesia (19 Jul 2012) show me all jobs >> International jobs DOCTORS - ENJOY THE GREAT LIFESTYLE in Australia and New Zealand. SHO/ Registrar/ Consultant and GP openings. (6 Jul 2012)LONDON INTERVIEWS Saudi Arabian Hospital Group September 2012 Consultant (7 Aug 2012)Two rare GP opportunities in Melbourne, VIC, Australia (6 Aug 2012)New Zealand - Emergency Specialists, Urgent care and GPs please. (6 Aug 2012) show me all jobs >> Rapid responses Latest ResponsesMost responsesLatest Responses Re: How a charity oversells mammography Published 8 August 2012 Re: Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies (Authors' reply) Published 8 August 2012 Re: Management of osteoarthritis of the knee Published 8 August 2012 Need to redefine the term and post term pregnancies Published 8 August 2012 The Marconi Sign: The Value of Clinical Examination Published 8 August 2012 more Most responses The truth about sports drinks (12 responses) Published 19 July 2012
In praise of young doctors (11 responses)Published 11 July 2012
Sanctity of life law has gone too far (6 responses)Published 12 July 2012
Vitamin D: some perspective please (5 responses)Published 19 July 2012
Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies (5 responses)Published 31 July 2012
more THIS WEEK'S POLLRead related article
See previous polls
Recent blogs and podcastsBlogsPodcastsBlogs Richard Lehman’s journal review – 6 August 2012 (6 Aug 2012)K M Venkat Narayan: Ten barriers to trans-disciplinary science (6 Aug 2012)John Davies: An Olympics day off with Leonardo da Vinci (6 Aug 2012)Richard Smith: An open blog to Prime Minister David Cameron (3 Aug 2012)Olympic volunteer John Davies: Working with athletes (3 Aug 2012) more >> Podcasts Renal patient records (3 Aug 2012)Shift workers' health and assessing risk of violence (27 Jul 2012)Insanity in the dock (20 Jul 2012)Telehealth: Running before walking? (13 Jul 2012)Obama's healthcare reforms on trial (6 Jul 2012) more >> BMJ most popular Most sharedMost searchedMost shared The truth about sports drinks (877 views)Management of osteoarthritis of the knee (807 views)Treating prostate cancer (651 views)Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies (571 views)How a charity oversells mammography (532 views) Most searched Kathleen Hilditchguyattirritable bowel syndromeclinical governance and the drivediabetes cardiovascular disease biomarker Follow BMJ Ontwitter.com/bmj_latestfacebook.com/bmjdotcomyoutube.com/user/BMJmedia Content Links Last 7 daysResearchEducationNewsCommentArchiveBlogsVideoPrint Issue My Account Email alertsActivate subscription Resources AuthorsReviewersBMA membersReadersSubscribersAdvertisers and sponsorsMedia Information Contact usFeedback BMJ About usEditorial staffAdvisersPoliciesComplaintsPartnershipsSubmit your paper Explore BMJ About BMJ GroupJunior Doctors: Agents for ChangeOlympics portalStudent BMJdoc2docPandemic FluBMJ Group BMJ Group Privacy and Cookie Policy Website T & Cs Revenue Sources HighWire Press Feedback Help © 2012 BMJ Publishing Group Ltd window.fbAsyncInit = function() {FB.init({appId: '154318714596620', status: true, cookie: true,xfbml: true});};(function() {var e = document.createElement('script'); e.async = true;e.src = document.location.protocol + '//connect.facebook.net/en_US/all.js';document.getElementById('fb-root').appendChild(e);}());View the original article here
This post was made using the Auto Blogging Software from WebMagnates.org This line will not appear when posts are made after activating the software to full version.
ليست هناك تعليقات:
إرسال تعليق