JAMA Cardiol. Published online September 14, 2016. doi:10.1001/jamacardio.2016.2415

Author
Taulant Muka, MD, PhD¹; Clare Oliver-Williams, PhD²; Setor Kunutsor, MD, PhD²; Joop S. E. Laven, MD, PhD³; Bart C. J. M. Fauser, MD, PhD⁴; Rajiv Chowdhury, MD, PhD²; Maryam Kavousi, MD, PhD¹; Oscar H. Franco, MD, PhD¹

Author information
¹Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands 
²Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England 
³Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, The Netherlands 
⁴Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands

ABSTRACT

Importance  
As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women.

Objective  
To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality.

Data Sources  
Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015.

Study Selection  
Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women.

Data Extraction and Synthesis  
Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity.

Main Outcomes and Measures  
Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points.

Results  
Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results.

Conclusions and Relevance  
The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause