Abstract
Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38–1·73; p<0·0001), early menopause (age 40–44 years; 1·30, 1·22–1·39; p<0·0001), and relatively early menopause (age 45–49 years; 1·12, 1·07–1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62–2·20; p<0·0001) and early menopause (1·40, 1·27–1·54; p<0·0001), but were attenuated at age 60–69 years, with no significant association observed at age 70 years and older. Interpretation: Compared with women who had menopause at age 50–51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women. Funding: Australian National Health and Medical Research Council.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e553-e564 |
| Journal | The Lancet Public Health |
| Volume | 4 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2019 |
ASJC Scopus subject areas
- Public Health, Environmental and Occupational Health
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Age at natural menopause and risk of incident cardiovascular disease : a pooled analysis of individual patient data. / Zhu, Dongshan; Chung, Hsin Fang; Dobson, Annette J. et al.
In: The Lancet Public Health, Vol. 4, No. 11, 11.2019, p. e553-e564.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Age at natural menopause and risk of incident cardiovascular disease
T2 - a pooled analysis of individual patient data
AU - Zhu, Dongshan
AU - Chung, Hsin Fang
AU - Dobson, Annette J.
AU - Pandeya, Nirmala
AU - Giles, Graham G.
AU - Bruinsma, Fiona
AU - Brunner, Eric J.
AU - Kuh, Diana
AU - Hardy, Rebecca
AU - Avis, Nancy E.
AU - Gold, Ellen B.
AU - Derby, Carol A.
AU - Matthews, Karen A.
AU - Cade, Janet E.
AU - Greenwood, Darren C.
AU - Demakakos, Panayotes
AU - Brown, Daniel E.
AU - Sievert, Lynnette L.
AU - Anderson, Debra
AU - Hayashi, Kunihiko
AU - Lee, Jung Su
AU - Mizunuma, Hideki
AU - Tillin, Therese
AU - Simonsen, Mette Kildevæld
AU - Adami, Hans Olov
AU - Weiderpass, Elisabete
AU - Mishra, Gita D.
N1 - Funding Information: The risk of non-fatal cardiovascular disease events was more than 1·5 times higher among women with premature menopause (<40 years) and 1·3 times higher among women with early menopause (40–44 years) than women who had natural menopause at 50–51 years. Additionally, the risk of experiencing a cardiovascular disease before the age of 60 years was around two times higher among women with premature menopause and 1·4 times higher among women with early menopause than women in the reference group. Although short reproductive duration 29 and surgical menopause have been shown to increase the risk of coronary heart disease, 30 data on the association between earlier natural menopause and incident cardiovascular disease have been inconsistent. 31 In one study, early menopause was associated with an approximately two times higher risk of a coronary heart disease event, but after adjusting for family history of coronary heart disease, the association was not statistically significant (HR 1·80, 95% CI 0·99–3·29); this study included both women with early natural and surgical menopause. 32 In the Nurses' Health Study, 33 the relative risk of 1·04 (95% CI 1·01–1·07) of coronary heart disease for each year of decrease in age at natural menopause was only observed for current smokers. Also, in the DNC study, 34 a significant association was found between premature menopause and risk of coronary heart disease (HR 2·2, 1·0–4·9), but the association was not statistically significant when women were stratified by menopausal hormone therapy use. We found that both premature and early menopause were associated with a higher risk of first coronary heart disease event when menopause at 50–51 years was used as the reference group, which is consistent with the results from two previous studies. 29,35 An approximately linear relationship was observed, with a 3% increased risk of incident coronary heart disease per 1 year decrease in age at menopause, which is consistent with the results of a previous study. 36 The association remained unchanged when family history of cardiovascular disease was included in the statistical model and was not materially affected by smoking or menopausal hormone therapy status. In the Women's Health Initiative study, women who began menopausal hormone therapy before age 60 years had a lower risk of coronary heart disease than those who began therapy after age 60 years, while no association was observed for stroke. 37 However, the Women's Health Initiative studies included older women (mean age 63·2 years) and the results might be generalisable to women with premature or early menopause. 37 Existing literature on the association between age at natural menopause and risk of stroke is inconclusive. 8,38 In three cohort studies, premature and early menopause were not significantly associated with risk of ischaemic or haemorrhagic stroke. 33,39,40 However, two studies 33,40 only included women who never used menopausal hormone therapy, and one 40 had only a small number of stroke events. In the Framingham cohort study, women with natural menopause before age 42 years had twice the risk of ischaemic stroke compared with women with natural menopause later than 42 years; this association persisted in never smokers and non-menopausal hormone therapy users. 41 Consistent with two recent studies, 29,35 we found premature and early menopause were similarly associated with both ischaemic and haemorrhagic stroke. We also found that menopausal hormone therapy users had a higher risk of incident stroke than non-users. A recent Cochrane review also found a 24% increased risk of stroke following use of menopausal hormone therapy prescribed for primary or secondary prevention of cardiovascular disease. 42 One of our main findings was that the excess risk of cardiovascular disease following premature or early menopause was largely confined to events occurring at ages younger than 70 years and was highest before the age of 60 years. Few studies have examined in detail the association between age at menopause and timing of onset of cardiovascular disease events. In one study, women with earlier menopause had higher risk of cardiovascular mortality at age 65 years than those with later menopause. 43 However, this study did not include non-fatal cardiovascular disease. Our findings might help to identify women at high risk of cardiovascular disease at an early age. Additionally, the J-shaped curve observed for risk of stroke after age 70 years might arise because more than 50% of women in this age group were overweight or obese, and a J-shaped curve has been found between overweight BMI and age at natural menopause. 14 Several mechanisms have been proposed to explain the association between earlier menopause and increased risk of postmenopausal cardiovascular disease. Endogenous oestrogens have protective effects on the cardiovascular system. 44 Oestrogen increases vasodilatation 45 and inhibits the response of blood vessels to injury and the development of atherosclerosis. 44 Early loss of oestrogen might impair vascular function and increase the expression of inflammatory cytokines at younger ages, which might further damage the vascular function. 46 Circulating androgen and sex hormone-binding globulin concentrations are also associated with risk of cardiovascular disease. 47 High concentrations of androgen and low concentrations of sex hormone-binding globulin are associated with both risk of postmenopausal cardiovascular disease events 48 and adverse cardiovascular disease risk factor profiles. Additionally, genetic or environmental factors need to be considered. An adverse cardiovascular disease risk factor profile in premenopausal women might be associated with both earlier menopause and occurrence of cardiovascular disease. 49 Also, the changes in cardiovascular disease risk factors (eg, lipid concentrations), which coincide with the oestrogen reduction during the menopausal transition, might contribute to risk of cardiovascular disease, although no consistent conclusions have been reported in the literature. 50,51 The main strength of our study was the large sample of pooled individual-level data, which was obtained from 15 studies across different geographical regions and populations, representing many different ethnic groups. The participant-level data in InterLACE enabled us to harmonise variables using common definitions, coding, and cutoff points, which is not usually possible with meta-analyses of published results. Our study also has several limitations. First, about 40% of postmenopausal cardiovascular disease events were self-reported but consistent findings were observed in analyses confined to cardiovascular disease events ascertained through medical records. Second, smoking is a well-known shared risk factor for early menopause and cardiovascular disease 13 and BMI is another modifiable variable associated with both age at menopause and cardiovascular disease. 14 Additionally, postmenopausal menopausal hormone therapy status might mediate the association between age at menopause and cardiovascular disease. 42 We used variables reported at middle age (41–53 years) and postmenopausal menopausal hormone therapy status at a specific timepoint as covariates rather than treating them as time-varying covariates, which could have caused some bias. However, of the studies included in InterLACE that included women who reported smoking status and BMI levels both before and after menopause (ie, UK Biobank, 12 NSHD, 23 NCDS, 24 SWAN, 21 and SABRE 28 ), the concordance rate was approximately 85%. Additionally, around 80% of women used menopausal hormone therapy for more than 6 years. 52 Thus, we assume the bias caused by not using time-varying covariates is small. Third, information about post-menopausal lipid concentrations was not available, which might mediate the association between age at natural menopause and cardiovascular disease events. However, no evidence of changes in lipid concentrations between premenopause and perimenopause was found in the NSHD study. 51 Fourth, little information was available about types and doses of menopausal hormone therapy. Nevertheless, one study has found the association among different types of menopausal hormone therapy (oestrogen alone or oestrogen with progestin) and incident coronary heart disease or stroke was similar. 53 Fifth, menopause status was based on self-report, which might induce recall bias. However, previous studies have shown that the validity and reproducibility of self-reported age at menopause was good. 54 Also, validated questionnaires and standard questions were used in each study; thus we assume the heterogeneity of menopause status among studies is limited. Sixth, as the outcome of this study was non-fatal cardiovascular disease events, the exclusion on fatal cardiovascular disease events might bias our results. However, since only 7·2% of first cardiovascular disease events are fatal, 55 and earlier menopause has been associated with higher cardiovascular disease mortality, 8 the inclusion of fatal events in the analyses would only strengthen the association between earlier age at menopause and incident cardiovascular disease. Finally, more than 80% of the women included in our study were white, which could limit the generalisability of the findings to other ethnicities. Compared with women with average age at menopause, women with premature and early menopause had higher risk of a non-fatal cardiovascular disease event with an almost linear dose-response relationship for each year of decrease in age at menopause. This excess risk was highest before the age of 60 years, but was greatly diminished by the age of 70 years. A systematic review showed that the prevalence of premature (3·7%) and early menopause (12·2%) in women is considerable. 56 WHO estimates that 1·2 billion women worldwide will be perimenopausal or postmenopausal by the year 2030, with 47 million women becoming menopausal each year. 57 Studies have shown that in the past 30 years, cardiovascular disease mortality rates have decreased sharply whereas the decrease in incidence has been less steep. 58,59 Our findings could have important clinical and public health implications. First, strategies to reduce the risk of early menopause, such as the avoidance of cigarette smoking and maintaining a normal BMI, provide primary prevention measures for cardiovascular disease. Second, identification of women with early menopause offers a window of opportunity to implement active management of other cardiovascular disease risk factors in these women to improve overall cardiovascular health in postmenopausal years. These women might also need close monitoring in clinical practice. Third, early or premature menopause might also be considered as an important factor in risk stratification of cardiovascular disease. Further research is needed to assess the added value of including the timing of menopause as a predictor in existing cardiovascular disease models for women and to provide physicians with a more accurate prediction model for women. Contributors DZ did the literature review, statistical analyses, and drafted the manuscript. H-FC and NP harmonised the data and contributed to the interpretation of the results. AJD contributed to the statistical analyses and interpretation of the results. GGG, FB, EJB, DK, RH, NEA, EBG, CAD, KAM, JEC, DCG, PD, DEB, LLS, DA, KH, JSL, HM, TT, MKS, H-OA, and EW provided study data. GDM conceived the study design and contributed to interpretation of the results. All authors critically revised the manuscript. Declaration of interests We declare no competing interests. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this Article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. Acknowledgments The InterLACE consortium is funded by the Australian National Health and Medical Research Council project ( grant APP1027196 ). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship ( APP1121844 ). The data on which this research is based were drawn from 15 observational studies included in the InterLACE consortium. The findings and views reported in this Article are not necessarily those of the original studies or their respective funding agencies. All studies would like to thank the participants for volunteering their time to be involved in the respective studies. Publisher Copyright: © 2019 World Health Organization
PY - 2019/11
Y1 - 2019/11
N2 - Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38–1·73; p<0·0001), early menopause (age 40–44 years; 1·30, 1·22–1·39; p<0·0001), and relatively early menopause (age 45–49 years; 1·12, 1·07–1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62–2·20; p<0·0001) and early menopause (1·40, 1·27–1·54; p<0·0001), but were attenuated at age 60–69 years, with no significant association observed at age 70 years and older. Interpretation: Compared with women who had menopause at age 50–51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women. Funding: Australian National Health and Medical Research Council.
AB - Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40–44 years (early menopause), 45–49 years (relatively early), 50–51 years (reference category), 52–54 years (relatively late), and 55 years or older (late menopause). Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50–51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38–1·73; p<0·0001), early menopause (age 40–44 years; 1·30, 1·22–1·39; p<0·0001), and relatively early menopause (age 45–49 years; 1·12, 1·07–1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62–2·20; p<0·0001) and early menopause (1·40, 1·27–1·54; p<0·0001), but were attenuated at age 60–69 years, with no significant association observed at age 70 years and older. Interpretation: Compared with women who had menopause at age 50–51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women. Funding: Australian National Health and Medical Research Council.
UR - http://www.scopus.com/inward/record.url?scp=85074039669&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074039669&partnerID=8YFLogxK
U2 - 10.1016/S2468-2667(19)30155-0
DO - 10.1016/S2468-2667(19)30155-0
M3 - Article
C2 - 31588031
AN - SCOPUS:85074039669
SN - 2468-2667
VL - 4
SP - e553-e564
JO - The Lancet Public Health
JF - The Lancet Public Health
IS - 11
ER -