Is there a link between infertility, miscarriage, stillbirth, and premature or early menopause? Results from pooled analyses of nine cohort studies

Background

Some reproductive factors (such as age at menarche and parity) have been shown to be associated with age at natural menopause, but there has been little quantitative analysis of the association between infertility, miscarriage, stillbirth, and premature (<40 years of age) or early menopause (40-44 years). Additionally, it was unknown whether the association would be different between Asian and non-Asian women, even though the age at natural menopause was younger among Asian women.

Objective

This study aimed to investigate the association of infertility, miscarriage, and stillbirth with age at natural menopause, and whether the association differed by race (Asian and non-Asian).

Study design

This was a pooled individual participant data analysis from nine observational studies, contributing to the InterLACE consortium. Naturally postmenopausal women with data on at least one of the reproductive factors (i.e., infertility, miscarriage, and stillbirth), age at menopause, and confounders (i.e., race, education level, age at menarche, body-mass index, and smoking status) were included. Multinominal logistic regression model was used to estimate relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the association of infertility, miscarriage, and stillbirth with premature or early menopause, adjusting for confounders. Between study difference and within-study correlation were taken into account by including study as a fixed effect and indicating study as a cluster variable. We also examined the association with number of miscarriages (0, 1, 2, ≥3) and stillbirths (0, 1, ≥2) and tested whether the strength of association differed between Asian and non-Asian women.

Results

A total of 303,594 postmenopausal women were included. Their median age at natural menopause was 50.0 years (interquartile range: 47.0 – 52.0). The percentages of women with premature and early menopause were 2.1% and 8.4%, respectively. The RRRs (95%CIs) of premature and early menopause were 2.72 (1.77, 4.17) and 1.42 (1.15, 1.74) for women with infertility; 1.31 (1.08, 1.59) and 1.37 (1.14, 1.65) for women with recurrent miscarriages; and 1.54 (1.52, 1.56) and 1.39 (1.35, 1.43) for women with recurrent stillbirths. Asian women with infertility, recurrent miscarriages (≥3), or recurrent stillbirths (≥2) had higher risk of premature and early menopause compared to non-Asian women with the same reproductive history.

Conclusion

The histories of infertility, recurrent miscarriages and stillbirths were associated with higher risk of premature and early menopause, and the associations differed by race, with stronger associations for Asian women with such reproductive history.