Reproductive History and Age at Menarche in Relation to Reproductive Lifespan and Natural Menopause: A population-based analysis from NHANES 1999–March 2020
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
To evaluate the associations of reproductive history(gravidity, parity, pregnancy loss) and age at menarche (AAM) with age at natural menopause (ANM) and reproductive lifespan (RL = ANM − AAM), and to assess effect modification and nonlinearity using a design-based, multiple-imputation framework.
Methods
We analyzed data from in NHANES 1999–March 2020 using stratified, clustered, survey-weighted methods with five imputations pooled by Rubin’s rules. We included women aged ≥60 years with self-reported AAM, ANM, gravidity and parity, excluding surgical or induced menopause. Primary outcomes were RL and ANM. Main analyses used linear models under two strategies: independent effects and mutual adjustment. Nonlinearity was assessed with restricted cubic splines (RCS) via joint Wald tests and AIC; pregnancy loss (approximately 65% zeros) was additionally evaluated using two-part models. Prespecified effect modifiers were income, race/ethnicity, and smoking; exploratory modifiers underwent BH-FDR control.
Results
The analytic sample included 3,167 participants. AAM showed a robust linear inverse association with RL (fully adjusted β = −0.871 years per later menarche year; 95% CI −1.011 to − 0.731; FDR p<0.001) and a borderline positive association with ANM (β = 0.129; 95% CI −0.011 to 0.269; p=0.07). Overall, parity and pregnancy loss were not significantly associated with RL or ANM across adjustment tiers. Two-part models indicated no transition effect and no dose–response among pregnancy-loss >0. Smoking modified the parity→ RL association (prespecified joint Wald p=0.026). Income displayed a nonlinear association with RL, with larger gains from low to middle income.
Discussion
In nationally representative data using rigorous design-based and multiple-imputation analyses, AAM was a stable determinant of RL with an approximately linear inverse association. In contrast, independent effects of gravidity, parity, and pregnancy loss on ANM/RL were limited. Lifestyle factors(smoking) and socioeconomic context modified specific associations. Confirmation in longitudinal cohorts with biomarker endpoints is needed to establish causality.
