Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants

Abstract

Background: Women's reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank.

Methods and findings: A total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche <12 years and 1.19 (1.07, 1.34) (p = 0.024) for menarche >14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth <21 compared to 25 to 26 years; 0.82 (0.71, 0.94) (p = 0.006) for each abortion; 1.32 (1.15, 1.51) (p = 0.008) for natural menopause at <47 compared to 50 years; 1.12 (1.01, 1.25) (p = 0.039) for hysterectomy; 2.35 (1.06, 5.23) (p = 0.037) for hysterectomy with previous oophorectomy; and 0.80 (0.72, 0.88) (p < 0.001) for oral contraceptive pills use. The U-shaped associations between the number of children and the risk of dementia were similar for both sexes: Compared with those with 2 children, for those without children, the multiple adjusted HR ((95% CIs), p-value) was 1.18 (1.04, 1.33) (p = 0.027) for women and 1.10 (0.98, 1.23) (p = 0.164) for men, and the women-to-men ratio of HRs was 1.09 (0.92, 1.28) (p = 0.403); for those with 4 or more children, the HR was 1.14 (0.98, 1.33) (p = 0.132) for women and 1.26 (1.10, 1.45) (p = 0.003) for men, and the women-to-men ratio of HRs was 0.93 (0.76, 1.14) (p = 0.530). There was evidence that hysterectomy (HR, 1.31 (1.09, 1.59), p = 0.013) and oophorectomy (HR, 1.39 (1.08, 1.78), p = 0.002) were associated with a higher risk of dementia among women of relatively lower SES only. Limitations of the study include potential residual confounding and self-reported measures of reproductive factors, as well as the limited representativeness of the UK Biobank population.

Conclusions: In this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men.

Fig 1. Multiple adjusted restricted cubic splines (with kernel density plots) showing HRs for the risk of dementia associated with reproductive factors.

The blue line represents the hazard function, and the blue shaded area represents the 95% CIs. The shaded grey region represents the kernel density plot for the distribution of data. After excluding the values from the top and bottom 2.5% of the distribution, with the median value being the reference. Splines adjusted for age, Townsend deprivation index, ethnicity, smoking status, systolic blood pressure, BMI, diabetes, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. (A) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age at menarche. (B) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age at first birth. (C) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with reproductive years. (D) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age at natural menopause. (E) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age at hysterectomy. (F) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age at oophorectomy. (G) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age started contraceptive pills. (H) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with age started HRT. (I) Restricted cubic spline plot with multiple adjusted HRs (95% CI) for all-cause dementia associated with years using HRT. BMI, body mass index; CI, confidence interval; HR, hazard ratio; HRT, hormone replacement therapy.

Fig 2. Multiple adjusted HRs for the risk of dementia associated with number of children for women and men.

The HRs are plotted on a floating absolute scale. The squares represent the HRs, and the bars represent the 95% CIs. Analyses were adjusted for age, Townsend deprivation index, ethnicity, smoking status, systolic blood pressure, BMI, diabetes, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. BMI, body mass index; CI, confidence interval; HR, hazard ratio.