Abstract
Reproductive factors across lifetime, such as age at puberty and menopause, may affect women’s health, but their associations with multimorbidity remain unknown. We combined epidemiological analyses of an observational study with Mendelian Randomization analyses to examine associations of female-specific reproductive factors and their patterns with chronic conditions and multimorbidities. In observational study, we used data of 265,346 women from the UK Biobank and constructed reproductive life patterns using sequence and cluster analysis to assess associations of reproductive patterns with the prevalence, progression, cumulative rate, and patterns of multimorbidity. Five reproductive life patterns were observed: standard sequence (46.0%), early childbearing and oophorectomy menopause (6.5%), short reproductive span with natural menopause (17.8%), early childbearing and hysterectomy menopause (11.5%), and high parity with long birth span (18.1%). Compared to women with standard sequence, those with other four patterns had higher risks of presence, progression, and rapid accumulation of multimorbidity. Multi-response Mendelian Randomization was conducted to evaluate causality between reproductive factors and multimorbidity using genetic data from UK Biobank and FinnGen study. We observed that genetically proxied age at starting oral contraceptive pills or first live birth was associated with specific multimorbidities related to cardiovascular diseases, digestive diseases, and mental disorders. Weaker or less consistent epidemiological and Mendelian randomization associations were observed with other patterns of women’s lifecourse reproductive factors. In summary, convergent evidence from epidemiological studies and Mendelian Randomization analyses supports both independent and cumulative associations between reproductive life patterns and specific multimorbidities in later life. These findings have important implications for targeted prevention strategies aimed at improving women’s health.