Abstract
OBJECTIVE: To test, among women with natural menopause, whether: infertility, miscarriage, stillbirth, and low parity are associated with a higher risk of osteoporosis; menopause age can partly explain their associations. DESIGN: Pooled analysis of five retrospective and prospective cohorts within the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events. SUBJECTS: A total of 141,222 naturally postmenopausal women with data on fertility factors (i.e., infertility, miscarriage, stillbirth, or parity), osteoporosis, and covariates (i.e., race, age at last follow-up, education level, smoking status, alcohol intake, body mass index, physical activity level, and age at menarche). EXPOSURE: The history of infertility, miscarriage, stillbirth, and parity was self-reported. MAIN OUTCOME MEASURES: Osteoporosis was identified through surveys, hospital, death registry, primary care, or pharmaceutical data. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between fertility factors and osteoporosis, taking into account clustering within each cohort. All models were first adjusted for fixed covariates, including race, education level, smoking status, alcohol intake, body mass index, physical activity level, and age at menarche, and then time-varying covariate of age at natural menopause. RESULTS: There was a modestly higher risk of osteoporosis for women with a history of infertility (HR = 1.16, 95% CI: 1.13-1.19), recurrent miscarriages (≥3; HR = 1.17, 95% CI: 1.05-1.30), stillbirth (HR = 1.14, 95% CI: 1.10-1.17), and low parity (no live births: HR = 1.20, 95% CI: 1.15-1.25; 1 live birth: HR = 1.15, 95% CI: 1.14-1.16). These associations were unchanged or only slightly attenuated after additional adjustment for age at natural menopause. CONCLUSION: These female-specific factors could be considered as part of the risk assessment and may inform prevention strategies for osteoporosis.