Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.
Level 3 - non-randomized controlled study
Pooled individual participant data analysis of 17 observational (cohort and cross-sectional) studies.
PubMed 30481189 · doi:10.1371/journal.pmed.1002704
What was done
Researchers pooled individual-level data from 17 observational studies across seven countries (Australia, Denmark, France, Japan, Sweden, UK, US) within the InterLACE consortium, comprising 207,231 postmenopausal women in cross-sectional analyses and 27,580 in prospective analyses. They evaluated smoking status, intensity (cigarettes/day), duration, pack-years, age at initiation, and time since cessation. Multinomial logistic regression models estimated relative risk ratios (RRRs) and 95% confidence intervals for premature (<40 years), early (40–44 years), and intermediate (45–49 years) menopause compared to reference menopause age (50–51 years).
What was found
Premature and early menopause occurred in 1.9% and 7.3% of women, respectively. Compared to never smokers, current smokers had elevated risks of premature menopause (RRR 2.05; 95% CI 1.73–2.44; p < 0.001) and early menopause (RRR 1.80; 95% CI 1.66–1.95; p < 0.001). For former smokers, risks were attenuated (premature menopause RRR 1.13, 95% CI 1.04–1.23; early menopause RRR 1.15, 95% CI 1.05–1.27). Clear dose-response relationships were observed: current smokers with 15–20 years of smoking duration had an RRR of 15.58 (95% CI 11.29–19.86) for premature menopause and 6.55 (95% CI 5.04–8.52) for early menopause. Those with 11–15 pack-years had an RRR of 4.35 (95% CI 2.78–5.92) for premature menopause. Former smokers who quit for more than 10 years had risk levels comparable to never smokers (RRR 1.04; 95% CI 0.98–1.10; p = 0.176).
Why it matters
This large pooled study confirms that smoking duration and cumulative dose substantially accelerate natural ovarian aging, while providing actionable evidence that quitting smoking for over a decade neutralizes this excess risk.
Limits
The study relies on self-reported smoking history and age at menopause, making it susceptible to recall bias and measurement error. The observational design cannot fully exclude residual confounding across diverse international cohorts, and non-fatal retrospective reporting may introduce survivor or selection biases.
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