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Age at menopause, reproductive history, and venous thromboembolism risk among postmenopausal women: the Women’s Health Initiative hormone therapy clinical trials

Canonico, Marianne PhD1, 2; Plu-Bureau, Geneviève MD, PhD1,2,3; O’Sullivan, Mary Jo MD4; Stefanick, Marcia L. PhD5; Cochrane, Barbara PhD6; Scarabin, Pierre-Yves MD1,2; Manson, JoAnn E. MD, DrPH7

doi: 10.1097/GME.0b013e31829752e0
Original Articles

Objective This study aims to investigate venous thromboembolism (VTE) risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause, as well as any interaction with randomized hormone therapy (HT) assignment, among postmenopausal women.

Methods Using pooled data from the Women’s Health Initiative HT clinical trials including 27,035 postmenopausal women aged 50 to 79 years who had no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause by Cox proportional hazards models. Linear trends, quadratic relationships, and interactions of reproductive life characteristics with HT on VTE risk were systematically tested.

Results During follow-up, 426 women reported a first VTE, including 294 non–procedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected, and there was not a significant association between VTE and age at menarche, age at menopause, parity, oophorectomy, or time since menopause. However, analyses restricted to non–procedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (P < 0.01). Compared with women aged 40 to 49 years at menopause, those who had early menopause (age <40 y) or late menopause (age >55 y) had a significantly increased VTE risk (hazard ratio [95% CI]: 1.8 [1.2-2.7] and 1.5 [1.0-2.4], respectively).

Conclusions Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for non–procedure-related VTE.

From the 1Hormones and Cardiovascular Disease, Center for Research in Epidemiology and Population Health, Villejuif, France; 2Université Paris Sud, UMRS 1018, Villejuif, France; 3Paris Descartes University and Cochin-Port Royal Hospital, Paris, France; 4Department of Obstetrics and Gynecology, Miller School of Medicine, University of Miami, Miami, FL; 5Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA; 6University of Washington School of Nursing, Seattle, WA; and 7Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Received February 5, 2013; revised and accepted April 9, 2013.

Study sponsors had no role in the design of the study; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Funding/support: The research reported in this article was supported by contracts from the National Heart, Lung, and Blood Institute. The Women’s Health Initiative program was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The complete list of Women’s Health Initiative centers and investigators can be found online at

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Marianne Canonico, PhD, 16 av. Paul Vaillant Couturier, Villejuif Cedex 94807, France. E-mail:

© 2014 by The North American Menopause Society.