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Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis

BMJ 2008; 336 doi: (Published 29 May 2008) Cite this as: BMJ 2008;336:1227
  1. Marianne Canonico, postdoctoral research fellow12,
  2. Geneviève Plu-Bureau, gynaecologist13,
  3. Gordon D O Lowe, professor of vascular medicine4,
  4. Pierre-Yves Scarabin, director of research (Inserm)12
  1. 1Inserm Unit 780, Cardiovascular Epidemiology Section, Villejuif Cedex, France
  2. 2IFR69, Université Paris-Sud Villejuif Cedex, France
  3. 3Université René Descartes Paris V, Paris, France
  4. 4University of Glasgow, Division of Cardiovascular and Medical Sciences, Royal Infirmary, Glasgow
  1. Correspondence to: M Canonico canonico{at}
  • Accepted 26 March 2008


Objective To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background.

Design Systematic review and meta-analysis.

Data sources Medline.

Studies reviewed Eight observational studies and nine randomised controlled trials.

Inclusion criteria Studies on hormone replacement therapy that reported venous thromboembolism.

Review measures Homogeneity between studies was analysed using χ2 and I2 statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.

Results Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.

Conclusion Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.


  • Contributors: MC and PYS reviewed the studies and collected the data. MC, GPB, and PYS did the statistical analysis. MC, GPB, GDL, and PYS drafted the manuscript. MC, GBP, GDL, and PYS revised the paper. PYS is guarantor.

  • Funding: MC and PYS are funded by Inserm (Institut National de la Santé et de la Recherche Biomédicale), GPB is funded by Assistance Publique des Hôpitaux de Paris, and GDL is funded by the University of Glasgow.

  • Competing interests: None declared.

  • Ethical approval: Not required.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Accepted 26 March 2008
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