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Original Investigation
November 18, 2019

Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease

Author Affiliations
  • 1Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Program in Medical and Population Genetics, Broad Institute of Harvard, Cambridge, Massachusetts
  • 4Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston
  • 5Yale University School of Medicine, New Haven, Connecticut
  • 6Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville
  • 7Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2019;322(24):2411-2421. doi:10.1001/jama.2019.19191
Key Points

Question  Are natural and surgical premature menopause (occurring before age 40 years) associated with future development of cardiovascular diseases?

Findings  In a cohort study that included 144 260 postmenopausal women, premature menopause, compared with no premature menopause, was significantly associated with increased risk for a composite outcome that included coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. For natural premature menopause, the hazard ratio was 1.36; for surgical premature menopause, the hazard ratio was 1.87.

Meaning  Natural and surgical premature menopause may be associated with increased risk for a composite of cardiovascular diseases.

Abstract

Importance  Recent guidelines endorse using history of menopause before age 40 years to refine atherosclerotic cardiovascular disease risk assessments among middle-aged women. Robust data on cardiovascular disease risk in this population are lacking.

Objective  To examine the development of cardiovascular diseases and cardiovascular risk factors in women with natural and surgical menopause before age 40 years.

Design, Setting, and Participants  Cohort study (UK Biobank), with adult residents of the United Kingdom recruited between 2006 and 2010. Of women who were 40 to 69 years old and postmenopausal at study enrollment, 144 260 were eligible for inclusion. Follow-up occurred through August 2016.

Exposures  Natural premature menopause (menopause before age 40 without oophorectomy) and surgical premature menopause (bilateral oophorectomy before age 40). Postmenopausal women without premature menopause served as the reference group.

Main Outcomes and Measures  The primary outcome was a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Secondary outcomes included individual components of the primary outcome, incident hypertension, hyperlipidemia, and type 2 diabetes.

Results  Of 144 260 postmenopausal women included (mean [SD] age at enrollment, 59.9 [5.4] years), 4904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. Participants were followed up for a median of 7 years (interquartile range, 6.3-7.7). The primary outcome occurred in 5415 women (3.9%) with no premature menopause (incidence, 5.70/1000 woman-years), 292 women (6.0%) with natural premature menopause (incidence, 8.78/1000 woman-years) (difference vs no premature menopause, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P < .001), and 49 women (7.6%) with surgical premature menopause (incidence, 11.27/1000 woman-years) (difference vs no premature menopause, +5.57/1000 woman-years [95% CI, 2.41-8.73]; P < .001). For the primary outcome, natural and surgical premature menopause were associated with hazard ratios of 1.36 (95% CI, 1.19-1.56; P < .001) and 1.87 (95% CI, 1.36-2.58; P < .001), respectively, after adjustment for conventional cardiovascular disease risk factors and use of menopausal hormone therapy.

Conclusions and Relevance  Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations.

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