Association of reproductive factors with dementia: A systematic review and dose-response meta-analyses of observational studies

Chunying Fu; Wenting Hao; Nipun Shrestha; Salim S Virani; Shiva Raj Mishra; Dongshan Zhu

doi:10.1016/j.eclinm.2021.101236

Association of reproductive factors with dementia: A systematic review and dose-response meta-analyses of observational studies

EClinicalMedicine. 2021 Dec 14:43:101236. doi: 10.1016/j.eclinm.2021.101236. eCollection 2022 Jan.

Authors

Chunying Fu^{1

2}, Wenting Hao^{1

2}, Nipun Shrestha³, Salim S Virani⁴, Shiva Raj Mishra^{5

6}, Dongshan Zhu^{1

2}

Affiliations

¹ Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
² NHC Key Lab of Health Economics and Policy Research (Shandong University), Jinan, 250012, China.
³ Department of Primary care and mental health, University of Liverpool.
⁴ Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, United States of America.
⁵ Academy for Data Sciences and Global Health, Kathmandu, Nepal.
⁶ Salim Yusuf Emerging Leaders Program, World Heart Federation, Geneva, Switzerland.

Abstract

Background: Associations between endogenous estrogen exposure indicators and risk of subtypes of dementia have been unclear.

Methods: Databases (PubMed, EMBASE and Web of Science) were searched electronically on 1st July and updated regularly until 12nd November 2021. Observational studies of English language were selected if reported an effect estimate [e.g., odds ratio (OR), rate ratio (RR) or hazard ratio (HR)] and 95% CI for the association between any exposure (age of menarche, age at menopause, reproductive period, estradiol level) and any endpoint variable [all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), cognitive impairment (CI)]. Random-effects models and dose-response meta-analyses were used to calculate estimates and to show the linear/nonlinear relationship. PROSPERO CRD42021274827.

Findings: We included 22 studies (475 9764 women) in this analysis. We found no clear relationship between late menarche (≥14 vs <14 years) and dementia, CI in categorical meta-analysis compared to a J-shape relationship in dose-response meta-analyses. Later menopause (≥45 vs <45 years) was consistently associated with a lower risk of all-cause dementia (pooled RR: 0.87, 95%CI: 0.78-0.97, I²=56.0%), AD (0.67, 0.44-0.99, I²=78.3%), VD (0.87, 0.80-0.94) and CI (0.82, 0.71-0.94, I²=19.3%) in categorical meta-analysis, showing similar results in dose-response meta-analyses. An inverse relationship between longer reproductive duration (≥35 vs <35 years) and dementia was observed in dose-response meta-analysis. In addition, estradiol levels after menopause were inversely correlated with the risk of AD and CI.

Interpretation: In this study, later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. There was an inverse relationship between higher postmenopausal estrogen levels and risk of AD and CI. Longitudinal study are needed to further explore the association between life-time estrogen exposure and risk of subtypes of dementia.

Funding: Start-up Foundation for Scientific Research in Shandong University.

Keywords: Cognitive impairment; Dementia; Estrogen level; Menarche; Reproductive period; menopause.