Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis

Veerle Dam^{1

2}, Yvonne T van der Schouw¹, N Charlotte Onland-Moret¹, Rolf H H Groenwold¹, Sanne A E Peters³, Stephen Burgess^{4

5}, Angela M Wood⁵, Maria-Dolores Chirlaque^{6

7}, Karel G M Moons¹, Clare Oliver-Williams^{8

9}, Ewoud Schuit¹, Kaja Tikk^{10

11}, Elisabete Weiderpass^{12

13

14

15}, Marianne Holm¹⁶, Anne Tjønneland¹⁶, Tilman Kühn¹⁷, Renée T Fortner¹⁷, Antonia Trichopoulou^{18

19}, Anna Karakatsani^{18

20}, Carlo La Vecchia^{18

21}, Pietro Ferrari²², Marc Gunter²², Giovanna Masala²³, Sabina Sieri²⁴, Rosario Tumino²⁵, Salvatore Panico²⁶, Jolanda M A Boer²⁷, W M Monique Verschuren^{1

27}, Elena Salamanca-Fernández^{7

28}, Larraitz Arriola^{7

29}, Conchi Moreno-Iribas^{30

31}, Gunnar Engström³², Olle Melander³², Maria Nordendahl³³, Patrik Wennberg³³, Timothy J Key³⁴, Sandra Colorado-Yohar^{35

36}, Giuseppe Matullo^{37

38}, Kim Overvad³⁹, Francoise Clavel-Chapelon⁴⁰, Heiner Boeing⁴¹, J Ramon Quiros⁴², Emanuele di Angelantonio⁴, Claudia Langenberg⁴³, Michael J Sweeting⁴, Elio Riboli⁴⁴, Nicholas J Wareham⁴³, John Danesh⁴³, Adam Butterworth^{5

45}

Affiliations

¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
² Netherlands Heart Institute, Utrecht, The Netherlands.
³ The George Institute for Global Health, University of Oxford, Oxford, UK.
⁴ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Department of Epidemiology, Regional Health Authority, IMIB-Arraxaca, Murcia University, Murcia, Spain.
⁷ Department of Epidemiology, CIBER de Epidemiología y Salud Pública (CIBERESP),Madrid, Spain.
⁸ Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge, UK.
⁹ Homerton College, Cambridge, UK.
¹⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
¹³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
¹⁵ Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
¹⁶ Department of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ 2nd Pulmonary Medicine Department, Hellenic Health Foundation, Athens, Greece.
¹⁹ Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
²⁰ 2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, 'ATTIKON' University Hospital, Haidari, Greece.
²¹ Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
²² International Agency for Research on Cancer, Lyon, France.
²³ Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute, ISPO, Florence, Italy.
²⁴ Epidemiology and Prevention Unit, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.
²⁵ Cancer Registry and Histopathology Department, 'Civic-M.P.Arezzo' Hospital, ASP Ragusa, Ragusa, Italy.
²⁶ Dipartimento di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
²⁷ Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
²⁸ Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, Granada, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
²⁹ Public Health Division of Gipuzkoa, Instituto BIO-Donostia, Basque Government, Donostia, Spain.
³⁰ Instituto de Salud Pública de Navarra, IdiSNA, Navarre Institute for Health Research, Pamplona, Spain.
³¹ Red de Servicios de Salud Orientados a Enfermedades Crónicas, REDISSEC, Pamplona, Spain.
³² Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
³³ Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
³⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁵ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³⁶ Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
³⁷ Department of Medical Sciences, University of Torino, Turin, Italy.
³⁸ Department Medical Sciences, Italian Institute for Genomic Medicine -IIGM/HuGeF, Turin, Italy.
³⁹ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
⁴⁰ INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones, and Women's Health Team, Institut Gustave Roussy, Villejuif, France.
⁴¹ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
⁴² Public Health Directorate, Asturias, Spain.
⁴³ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁴⁴ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁴⁵ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

PMID: 30796459
PMCID: PMC6693816
DOI: 10.1093/ije/dyz016

Multicenter Study

Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis

Veerle Dam et al. Int J Epidemiol. 2019.

. 2019 Aug 1;48(4):1275-1285.

doi: 10.1093/ije/dyz016.

Authors

Affiliations

¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
² Netherlands Heart Institute, Utrecht, The Netherlands.
³ The George Institute for Global Health, University of Oxford, Oxford, UK.
⁴ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Department of Epidemiology, Regional Health Authority, IMIB-Arraxaca, Murcia University, Murcia, Spain.
⁷ Department of Epidemiology, CIBER de Epidemiología y Salud Pública (CIBERESP),Madrid, Spain.
⁸ Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge, UK.
⁹ Homerton College, Cambridge, UK.
¹⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
¹³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
¹⁵ Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
¹⁶ Department of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ 2nd Pulmonary Medicine Department, Hellenic Health Foundation, Athens, Greece.
¹⁹ Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
²⁰ 2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, 'ATTIKON' University Hospital, Haidari, Greece.
²¹ Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
²² International Agency for Research on Cancer, Lyon, France.
²³ Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute, ISPO, Florence, Italy.
²⁴ Epidemiology and Prevention Unit, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.
²⁵ Cancer Registry and Histopathology Department, 'Civic-M.P.Arezzo' Hospital, ASP Ragusa, Ragusa, Italy.
²⁶ Dipartimento di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
²⁷ Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
²⁸ Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, Granada, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
²⁹ Public Health Division of Gipuzkoa, Instituto BIO-Donostia, Basque Government, Donostia, Spain.
³⁰ Instituto de Salud Pública de Navarra, IdiSNA, Navarre Institute for Health Research, Pamplona, Spain.
³¹ Red de Servicios de Salud Orientados a Enfermedades Crónicas, REDISSEC, Pamplona, Spain.
³² Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
³³ Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
³⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁵ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³⁶ Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
³⁷ Department of Medical Sciences, University of Torino, Turin, Italy.
³⁸ Department Medical Sciences, Italian Institute for Genomic Medicine -IIGM/HuGeF, Turin, Italy.
³⁹ Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
⁴⁰ INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones, and Women's Health Team, Institut Gustave Roussy, Villejuif, France.
⁴¹ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
⁴² Public Health Directorate, Asturias, Spain.
⁴³ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁴⁴ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁴⁵ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

PMID: 30796459
PMCID: PMC6693816
DOI: 10.1093/ije/dyz016

Abstract

Background: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors.

Methods: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders.

Results: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors.

Conclusions: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.

Keywords: Epidemiology; Menopause; ageing; coronary disease; risk factors; women.

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Figures

**Figure 1.**
Graphical display of the linear relationship between age at menopause and CHD using floating absolute risks to display the hazard ratios (HRs) for age at menopause categories [<40, 40–44, 45–49, 50–54, ≥55 years (reference), with 364, 551, 1284, 1563, 312 CHD events, respectively]. HRs were plotted against the mean age at menopause of each category, which are 34, 42, 47, 51 and 57 accordingly.

See this image and copyright information in PMC

References

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Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis

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Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis

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