Reproductive factors and their association with physical and comprehensive frailty in middle-aged and older women: a large-scale population-based study.

Study question: Are women's reproductive factors associated with physical frailty and comprehensive frailty in middle-age and later life?

Summary answer: Early menarche at <13 years, age at menopause <45 years, surgical menopause, experiencing miscarriage and a shorter reproductive period of <35 years were associated with increased odds of frailty, while having two or three children was related to decreased likelihood of frailty.

What is known already: Evidence has shown that women are frailer than men in all age groups and across different populations, although women have longer lifespans. Female-specific reproductive factors may be related to risk of frailty in women.

Study design size duration: A population-based cross-sectional study involved 189 898 women from the UK Biobank.

Participants/materials setting methods: Frailty phenotype and frailty index were used to assess physical frailty and comprehensive frailty (assessed using 38 health indicators for physical and mental wellbeing), respectively. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CI between reproductive factors and likelihood of physical frailty and comprehensive frailty. Restricted cubic spline models were used to test the non-linear associations between them. In addition, we examined the combined effect of categorized age at menopause and menopause hormone therapy (MHT) on frailty.

Main results and the role of chance: There was a J-shape relationship between age at menarche, reproductive period, and frailty; age at menarche <13 years and >16 years, and reproductive period <35 years or >40 years were all associated with increased odds of frailty. There was a negative linear relationship between menopausal age (either natural or surgical) and odds of frailty. Surgical menopause was associated with 30% higher odds of physical frailty (1.34, 1.27-1.43) and 30% higher odds of comprehensive frailty (1.30, 1.25-1.35). Having two or three children was linked to the lowest likelihood of physical frailty (0.48, 0.38-0.59) and comprehensive frailty (0.72, 0.64-0.81). Experiencing a miscarriage increased the odds of frailty. MHT use was linked to increased odds of physical frailty in women with normal age at natural menopause (after 45 years), while no elevated likelihood was observed in women with early natural menopause taking MHT.

Limitations reasons for caution: The reproductive factors were self-reported and the data might be subject to recall bias. We lacked information on the types and initiation time of MHT, could not identify infertile women who later became pregnant, and the number of infertile women may be underestimated. Individuals participating in the UK Biobank are not representative of the general UK population, limiting the generalization of our findings.

Wider implication of the findings: The reproductive factors experienced by women throughout their life course can potentially predict frailty in middle and old age. Identifying these reproductive factors as potential predictors of frailty can inform healthcare providers and policymakers about the importance of considering a woman's reproductive history when assessing their risk for frailty.

Study funding/competing interests: This work was supported by the National Key Research and Development Program of China (2022YFC2703800), National Natural Science Foundation of China (82273702), Science Fund Program for Excellent Young Scholars of Shandong Province (Overseas) (2022HWYQ-030), Taishan Scholars Project Special Fund (No. tsqnz20221103), and the Qilu Young Scholar (Tier-1) Program (202099000066). All authors have no conflicts of interest to declare.

Trial registration number: N/A.