Women’s reproductive life patterns and risk of chronic conditions and multimorbidities: Insights from UK Biobank and FinnGen studies
-
GRAPHICAL ABSTRACT
DownLoad:
Full size image
-
PUBLIC SUMMARY
-
Women’s reproductive life patterns are associated with multiple chronic conditions and multimorbidity.
Genetically proxied reproductive factors were associated with specific multimorbidities.
Women with high-risk reproductive patterns should be prioritized in clinical practice and policy making.
-
-
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. -
-
REFERENCES
[1] World Health Organization. (2025). Monitoring health for the SDGs. https://www.who.int/data/gho/data/themes/world-health-statistics. [2] Carcel C., Haupt S., Arnott C., et al. (2024). A life-course approach to tackling noncommunicable diseases in women. Nat. Med. 30:61−75. DOI:10.1038/s41591-023-02738-1 [3] Peters S. A. and Woodward M. (2018). Women's reproductive factors and incident cardiovascular disease in the UK Biobank. Heart (British Cardiac Society) 104:1069−1075. DOI:10.1136/heartjnl-2017-312289 [4] Gong J., Harris K., Peters S. A. E., et al. (2022). Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants. Plos Med. 19:e1003955. DOI:10.1371/journal.pmed.1003955 [5] Han W. W., Miao M. Y., Lyu J. Q., et al. (2024). Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease. J. Clin. Endocr. Metab. 110:e970−e979. DOI:10.1210/clinem/dgae374 [6] Liang H. Y., Li D. W., Zhu Y. Q., et al. (2023). Associations between reproductive factors and the risk of adult-onset asthma: A prospective cohort study of European ancestry. J. Gen. Intern. Med. 38:2354−2363. DOI:10.1007/s11606-023-08173-9 [7] Prince C., Sharp G. C., Howe L. D., et al. (2022). The relationships between women's reproductive factors: A Mendelian randomisation analysis. BMC Med. 20:103. DOI:10.1186/s12916-022-02293-5 [8] Mishra G. D., Cooper R. and Kuh D. (2010). A life course approach to reproductive health: Theory and methods. Maturitas 65:92−97. DOI:10.1016/j.maturitas.2009.12.009 [9] Zuber V., Lewin A., Levin M. G., et al. (2023). Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes. Am. J. Hum. Genet. 110:1177−1199. DOI:10.1016/j.ajhg.2023.06.005 [10] Sudlow C., Gallacher J., Allen N., et al. (2015). UK biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age. Plos Med. 12:e1001779. DOI:10.1371/journal.pmed.1001779 [11] Pacca L., Dang K. V., Koenig L., et al. (2025). Using sequence and cluster analysis to characterize variables that unfold over time: Implementation and practical considerations for epidemiologists. Am. J. Epidemiol. 10:kwaf065. DOI:10.1093/aje/kwaf065 [12] Doran T., Kontopantelis E., Reeves D., et al. (2014). Setting performance targets in pay for performance programmes: What can we learn from QOF. BMJ 348:g1595. DOI:10.1136/bmj.g1595 [13] Barnett K., Mercer S. W., Norbury M., et al. (2012). Epidemiology of multimorbidity and implications for health care, research, and medical education: A cross-sectional study. Lancet 380:37−43. DOI:10.1016/S0140-6736(12)60240-2 [14] Ho I. S. S., Azcoaga-Lorenzo A., Akbari A., et al. (2022). Measuring multimorbidity in research: Delphi consensus study. BMJ Med. 1:e000247. DOI:10.1136/bmjmed-2022-000247 [15] Ronaldson A., de la Torre J. A., Prina M., et al. (2021). Associations between physical multimorbidity patterns and common mental health disorders in middle-aged adults: A prospective analysis using data from the UK Biobank. Lancet Reg Health Eur. 8:100149. DOI:10.1016/j.lanepe.2021.100149 [16] Chudasama Y. V., Khunti K., Gillies C. L., et al. (2020). Healthy lifestyle and life expectancy in people with multimorbidity in the UK Biobank: A longitudinal cohort study. Plos Med. 17:e1003332. DOI:10.1371/journal.pmed.1003332 [17] Gregson J., Sharples L., Stone G. W., et al. (2019). Nonproportional hazards for time-to-event outcomes in clinical trials. J. Am. Coll. Cardiol. 74:2102−2112. DOI:10.1016/j.jacc.2019.08.1034 [18] Müller P., Parmigiani G. and Rice K. (2007). FDR and Bayesian Multiple Comparisons Rules. Bernardo J. M., Bayarri M. J., Berger J. O., et al. (eds). Proceedings of the Eighth Valencia International Meeting June 2–6, 2006 (Oxford University Press), pp:0. DOI:10.1093/oso/9780199214655.003.0014 [19] Xu X. L., Jones M. and Mishra G. D. (2020). Age at natural menopause and development of chronic conditions and multimorbidity: Results from an Australian prospective cohort. Hum. Reprod. 35:203−211. DOI:10.1093/humrep/dez259 [20] Jiao J., Feng X., Gong A., et al. (2024). Association between reproductive lifespan and multimorbidity among Chinese postmenopausal women. Menopause 31:945-951. DOI:10.1097/gme.0000000000002419 [21] SadrAzar A., Sanaie S., Tutunchi H., et al. (2023). Is early age at menarche associated with multimorbidity. Findings from the Azar Cohort study. Eur. J. Obstet. Gyn. R. B. 287:46−51. DOI:10.1016/j.ejogrb.2023.05.029 [22] Rocca W. A., Gazzuola-Rocca L., Smith C. Y., et al. (2016). Accelerated accumulation of multimorbidity after bilateral oophorectomy: A population-based cohort study. Mayo Clin. Proc. 91:1577−1589. DOI:10.1016/j.mayocp.2016.08.002 [23] Farquhar C. M., Sadler L., Harvey S. A., et al. (2005). The association of hysterectomy and menopause: A prospective cohort study. BJOG 112:956−962. DOI:10.1111/j.1471-0528.2005.00696.x [24] Clarkson T. B., Meléndez G. C. and Appt S. E. (2013). Timing hypothesis for postmenopausal hormone therapy: Its origin, current status, and future. Menopause 20:342−353. DOI:10.1097/gme.0b013e3182843aad [25] Faramarzi E., Somi M. H., Tutunchi H., et al. (2023). The association of parity number with multimorbidity and polypharmacy among Iranian women in the Azarcohort: A cross-sectional study. BMC Womens Health 23:295. DOI:10.1186/s12905-023-02434-9 [26] Chen M. J., Guo J. H., Lin Y. W., et al. (2023). Life-course fertility and multimorbidity among middle-aged and elderly women in China: Evidence from China health and retirement longitudinal study. Front. Public Health 11:1090549. DOI:10.3389/fpubh.2023.1090549 [27] Fu C., Hao W., Ma Y., et al. (2023). Number of live births, age at the time of having a child, span of births and risk of dementia: A population-based cohort study of 253,611 U. K. women. J. Womens Health (Larchmt) 32:680−692. DOI:10.1089/jwh.2022.0396 [28] Aitken Z., Hewitt B., Keogh L., et al. (2016). Young maternal age at first birth and mental health later in life: Does the association vary by birth cohort. Soc. Sci. Med. 157:9−17. DOI:10.1016/j.socscimed.2016.03.037 [29] Guo W. S., Guo Y. Y., Song S. K., et al. (2024). Causal effect of the age at first birth with depression: A mendelian randomization study. BMC Med. Genomics 17:192. DOI:10.1186/s12920-024-01966-9 [30] Jin C., Tooth L. R., Xu X., et al. (2023). Do mothers or females without children have better health-related quality of life across their reproductive years. Qual. Life Res. 32:1481−1491. DOI:10.1007/s11136-022-03338-1 [31] Datta J., Palmer M. J., Tanton C., et al. (2016). Prevalence of infertility and help seeking among 15000 women and men. Hum. Reprod. 31:2108−2118. DOI:10.1093/humrep/dew123 [32] Liang C., Chung H. F., Dobson A. J., et al. (2022). Infertility, miscarriage, stillbirth, and the risk of stroke among women: A systematic review and meta-analysis. Stroke 53:328−337. DOI:10.1161/Strokeaha.121.036271 [33] Germain A. M., Romanik M. C., Guerra I., et al. (2007). Endothelial dysfunction: A link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events. Hypertension 49:90−95. DOI:10.1161/01.HYP.0000251522.18094.d4 [34] Matthiesen L., Kalkunte S. and Sharma S. (2012). Multiple pregnancy failures: An immunological paradigm. Am. J. Reprod. Immunol. 67:334−340. DOI:10.1111/j.1600-0897.2012.01121.x [35] Hadizadeh F., Johansson T., Johansson A., et al. (2023). Effects of oral contraceptives and menopausal hormone therapy on the risk of rheumatoid arthritis: A prospective cohort study. Rheumatology 63:2101−2108. DOI:10.1093/rheumatology/kead513 [36] Egan K. R. and Gleason C. E. (2012). Longer duration of hormonal contraceptive use predicts better cognitive outcomes later in life. J. Womens Health 21:1259−1266. DOI:10.1089/jwh.2012.3522 [37] Ortizo R., Lee S. Y., Nguyen E. T., et al. (2017). Exposure to oral contraceptives increases the risk for development of inflammatory bowel disease: A meta-analysis of case-controlled and cohort studies. Eur. J. Gastroen. Hepat. 29:1064−1070. DOI:10.1097/Meg.0000000000000915 [38] Johansson T., Fowler P., Ek W. E., et al. (2022). Oral contraceptives, hormone replacement therapy, and stroke risk. Stroke 53:3107−3115. DOI:10.1161/Strokeaha.121.038659 [39] Gartlehner G., Patel S., Reddy S., et al. (2023). Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 329:943. DOI:10.1001/jama.2023.0263 [40] Boardman H. M. P., Hartley L., Eisinga A., et al. (2015). Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Db. Syst. Rev. 2015:CD002229. DOI:10.1002/14651858.CD002229.pub4 [41] Hansen E. S. H., Aasbjerg K., Moeller A. L., et al. (2021). Hormone replacement therapy and development of new asthma. Chest 160:45−52. DOI:10.1016/j.chest.2021.01.054 -
ABOUT THIS ARTICLE
Cite this article:
Zhang Y., Kivimäki M., Tan Q., et al. (2026). Women’s reproductive life patterns and risk of chronic conditions and multimorbidities: Insights from UK Biobank and FinnGen studies. The Innovation Medicine 4:100210. https://doi.org/10.59717/j.xinn-med.2026.100210
Welcome!
To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.
Export File
Citation
Zhang Y., Kivimäki M., Tan Q., et al. (2026). Women’s reproductive life patterns and risk of chronic conditions and multimorbidities: Insights from UK Biobank and FinnGen studies. The Innovation Medicine 4:100210. https://doi.org/10.59717/j.xinn-med.2026.100210
Format
Content
-
Figure 1.
Illustration of the cumulative reproductive factors across the lifecourse on health
-
Figure 2.
Study design and population selection.
-
Figure 3.
Clusters of reproductive life patterns among UK female population
-
Figure 4.
Association of reproductive life patterns with the prevalence, incidence, new onset number, accumulative rate of multimorbidity and multimorbidity patterns
-
Figure 5.
Multi-response Mendelian randomization on genetically proxied reproductive factors with the risk of multimorbidity patterns
