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PLoS Med. 2018 Nov 27;15(11):e1002704. doi: 10.1371/journal.pmed.1002704. eCollection 2018 Nov.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

Author information

The University of Queensland, School of Public Health, Brisbane, Queensland, Australia.
Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nutritional Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom.
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Department of Public Health Sciences, University of California, Davis School of Medicine, California, United States of America.
Family and Child Nursing, School of Nursing, University of Washington, Seattle, Washington, United States of America.
Biobehavioral Nursing and Health Systems, School of Nursing, University of Washington, Seattle, Washington, United States of America.
Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
Department of Anthropology, University of Hawaii, Hilo, Hawaii, United States of America.
Department of Anthropology, UMass Amherst, Amherst, Massachusetts, United States of America.
Department of Epidemiology and Public Health, University College London, London, United Kingdom.
Medical Research Council Unit for Lifelong Health and Ageing at UCL, London, United Kingdom.
School of Health Sciences, Gunma University, Maebashi City, Gunma, Japan.
Department of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Fukushima Medical Center for Children and Women, Fukushima Medical University, Fukushima, Japan.
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Institute of Cardiovascular Science, University College London, London, United Kingdom.
UcDiakonissen and Parker Institute, Frederiksberg, Denmark.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway.
Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
Paris-Saclay University, Paris-South University, UVSQ, Center for Research in Epidemiology and Population Health, INSERM, France.
INSERM, University Montpellier, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France.



Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause.


A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias.


The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: JEC is a director of Dietary Assessment Ltd, a University of Leeds spin out company to support measurement of dietary intake. All other authors have declared that no competing interests exist.

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