Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study

Abstract

Objective: To evaluate whether irregular or long menstrual cycles throughout the life course are associated with all cause and cause specific premature mortality (age <70 years).

Design: Prospective cohort study.

Setting: Nurses' Health Study II (1993-2017).

Participants: 79 505 premenopausal women without a history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages 14-17 years, 18-22 years, and 29-46 years.

Main outcome measures: Hazard ratios and 95% confidence intervals for all cause and cause specific premature mortality (death before age 70 years) were estimated from multivariable Cox proportional hazards models.

Results: During 24 years of follow-up, 1975 premature deaths were documented, including 894 from cancer and 172 from cardiovascular disease. Women who reported always having irregular menstrual cycles experienced higher mortality rates during follow-up than women who reported very regular cycles in the same age ranges. The crude mortality rate per 1000 person years of follow-up for women reporting very regular cycles and women reporting always irregular cycles were 1.05 and 1.23 for cycle characteristics at ages 14-17 years, 1.00 and 1.37 for cycle characteristics at ages 18-22 years, and 1.00 and 1.68 for cycle characteristics at ages 29-46 years. The corresponding multivariable adjusted hazard ratios for premature death during follow-up were 1.18 (95% confidence interval 1.02 to 1.37), 1.37 (1.09 to 1.73), and 1.39 (1.14 to 1.70), respectively. Similarly, women who reported that their usual cycle length was 40 days or more at ages 18-22 years and 29-46 years were more likely to die prematurely than women who reported a usual cycle length of 26-31 days in the same age ranges (1.34, 1.06 to 1.69; and 1.40, 1.17 to 1.68, respectively). These relations were strongest for deaths related to cardiovascular disease. The higher mortality associated with long and irregular menstrual cycles was slightly stronger among current smokers.

Conclusions: Irregular and long menstrual cycles in adolescence and adulthood are associated with a greater risk of premature mortality (age <70 years). This relation is slightly stronger among women who smoke.

Fig 1

Adjusted hazard ratios and 95% confidence intervals for risk of premature mortality (<70 years) according to menstrual cycle regularity (at ages 14-17 years, 18-22 years, and 18-48 years) and length (ages 18-22 years and 29-46 years) among 79 505 women (Nurses’ Health Study II, 1993-2017). *Multivariable models were adjusted for age (continuous); menopausal status (premenopausal, never, past, or current menopausal hormone use); age at menarche (≤10, 11, 12, 13, or ≥14 years); race (white or other); family history of myocardial infarction, stroke, or diabetes (yes or no); baseline hypertension or high blood cholesterol level (yes or no); and updated parity (0, 1, or ≥2). †Multivariable models were further adjusted for updated alcohol consumption (0, 0.1-4.9, 5.0-9.9, 10.0-14.9, 15.0-29.9, or ≥30 g/day), body mass index (<23, 23-24.9, 25-29.9, 30-34.9, or ≥35), physical activity (0, 0.1-0.9, 1.0-3.4, 3.5-5.9, or ≥6 hours/week), smoking consumption (never smoker, former smoker, current smoker: 1-14, 15-24, or ≥25 cigarettes/day), and fifths of alternative healthy eating index 2010 score. P values for trend were calculated across the categories of menstrual cycle regularity or length, excluding women who used oral contraceptives