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. 2020 Dec 1;5(12):1410-1418.
doi: 10.1001/jamacardio.2020.4105.

Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease: A Pooled Analysis of Individual Patient Data From 12 Studies

Shiva R Mishra  1 , Hsin-Fang Chung  1 , Michael Waller  1 , Annette J Dobson  1 , Darren C Greenwood  2 , Janet E Cade  2 , Graham G Giles  3   4   5 , Fiona Bruinsma  3 , Mette Kildevæld Simonsen  6 , Rebecca Hardy  7 , Diana Kuh  8 , Ellen B Gold  9 , Sybil L Crawford  10 , Carol A Derby  11   12 , Karen A Matthews  13 , Panayotes Demakakos  14 , Jung Su Lee  15 , Hideki Mizunuma  16 , Kunihiko Hayashi  17 , Lynnette L Sievert  18 , Daniel E Brown  19 , Sven Sandin  20   21 , Elisabete Weiderpass  22 , Gita D Mishra  1
Affiliations

Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease: A Pooled Analysis of Individual Patient Data From 12 Studies

Shiva R Mishra et al. JAMA Cardiol. .

Abstract

Importance: Early menarche and early menopause are associated with increased risk of cardiovascular disease (CVD) in midlife, but little is known about the association between reproductive life span and the risk of CVD.

Objective: To investigate the association between the length of reproductive life span and risk of incident CVD events, while also considering the timing of menarche and menopause.

Design, setting, and participants: Individual-level data were pooled from 12 studies participating in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events consortium. Women provided complete information on the timing of menarche and menopause, nonfatal CVD events, and covariates. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs, adjusted for covariates. The association between reproductive life span and CVD was adjusted for age at menarche and age at menopause separately. Analysis began March 2018 and ended December 2019.

Exposures: Reproductive life span was calculated by subtracting age at menarche from age at menopause and categorized as younger than 30, 30 to 32, 33 to 35, 36 to 38 (reference group), 39 to 41, 42 to 44, and 45 years or older.

Main outcomes and measures: First nonfatal CVD event, including coronary heart disease and stroke events.

Results: A total of 307 855 women were included. Overall, the mean (SD) ages at menarche, menopause, and reproductive life span were 13.0 (1.5) years, 50.2 (4.4) years, and 37.2 (4.6) years, respectively. Pooled analyses showed that women with a very short reproductive life span (<30 years) were at 1.71 (95% CI, 1.58-1.84) times higher risk of incident CVD events than women with a reproductive life span of 36 to 38 years after adjustment for covariates. This association remained unchanged when adjusted for age at menarche but was attenuated to 1.26 (95% CI, 1.09-1.46) when adjusted for age at menopause. There was a significant interaction between reproductive life span and age at menarche associated with CVD risk (P < .001). Women who had both short reproductive life span (<33 years) and early menarche (age ≤11 years) had the highest risk of CVD (hazard ratio, 2.06; 95% CI, 1.76-2.41) compared with those with a reproductive life span of 36 to 38 years and menarche at age 13 years.

Conclusions and relevance: Short reproductive life span was associated with an increased risk of nonfatal CVD events in midlife, and the risk was significantly higher for women with early age at menarche.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cade reports being director of Spin-Out Company Dietary Assessment Ltd. Dr Giles reports grants from National Health and Medical Research Council during the conduct of the study. Dr Hardy reports grants from UK Medical Research Council and UK Economic and Social Research Council during the conduct of the study. Dr Kuh reports grants from UK Medical Research Council during the conduct of the study. Dr Gold reports grants from National Institute on Aging during the conduct of the study. Dr Crawford reports grants from National Institutes of Health during the conduct of the study. Dr Derby reports grants from National Institutes of Health during the conduct of the study. Dr Hayashi reports grants from Japan Society for the Promotion of Science and Japan Agency for Medical Research and Development outside the submitted work. Dr Sievert reports grants from National Institutes of Health during the conduct of the study. Dr Brown reports grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Hazard Ratio (HR) and 95% CI of Incident Cardiovascular Disease by Age at Menarche
The estimates used in the figure are shown in Table 2. The HRs were fully adjusted for women’s year at birth, race/ethnicity, education, smoking status at baseline, body mass index at baseline, number of children, age at first birth, and menopausal hormone therapy use. The reference category was menarche at age 13 years. The area of the square was inversely proportional to the variance of log HR.
Figure 2.
Figure 2.. Heat Map for the Association Between Reproductive Life Span and Age at Menarche
The association (hazard ratios and 95% CI) between the combination of reproductive life span (<33, 33-35, 36-38, 39-41, ≥42 years) and age at menarche (≤11, 12, 13, 14, ≥15 years) with nonfatal cardiovascular disease events is displayed. The hazard ratios were fully adjusted for women’s year at birth, race/ethnicity, education, smoking status at baseline, body mass index at baseline, number of children, age at first birth, and menopausal hormone therapy use. The number above each hazard ratio shows the mean age at menopause for that combination. A darker color (in a gradient from green to red) shows increasing risk of nonfatal cardiovascular disease. The estimates are shown in eTable 4 in the Supplement.
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