Title: Age at menarche, age at menopause, reproductive years and risk of fatal stroke occurrence
among Chinese women: The Guangzhou Biobank Cohort Study
Version: 1 Date: 14 Sep 2021
Reviewer's report:
Re: Age at menarche, age at menopause, reproductive years, and risk of fatal stroke occurrence
among Chinese women.
Thank you for the opportunity to review this study, aiming to examine the association between
women’s reproductive characteristics and risk of fatal stroke among Chinese women and further
investigate whether the associations differ by birth cohorts and stroke subtypes. The authors
found that late menarche, early menopause, and short reproductive years were associated with
an increased risk of stroke, and these associations were only observed among women born
before 1940 but not among those born after 1940. I have several major concerns, especially
the statistical analysis and interpretation of results. The analyses stratified by birth cohort and
subtypes were based on very small stroke events (many cells less than 5), making the models
very unstable and showing opposite risk directions between age categories (e.g. <=12, 13, 14
years). Authors reported the results based on statistically significance of p<0.05 rather than the
effect size. Specific comments are:
1. Introduction (lines 55-57) mentioned that the association between menarche and stroke
differed between different birth cohorts, whether this was reported in Chinese women other
ethnic groups. More background is needed about the trend in ages of menarche and menopause in
Chinese women and the effect of Great Chinese Famine (1959-61) if authors want to investigate
the birth cohort effect.
2. Lack of details on the two birth cohorts (born before and after 1940) and why choose 1940
as cut-point? What were the mean/median age (IQR), follow-up duration, and the number of
events for the two birth cohorts? Whether the younger cohort was old enough or followed long
enough to develop stroke events.
3. Exposure indicators: please clarify the definition of age at menopause – whether all based on
natural menopause or included those with induced menopause. If it included natural menopause
only, why the sensitivity analysis was needed to exclude women with the removal of uterus and
ovaries – those with surgery (mostly before natural menopause) should be excluded from this
study. If it included both natural and induced menopause, what was the definition of induced
menopause, what was the proportion, and most of them would have an earlier age at menopause
compared with natural menopause. So the effect of early menopause may be due to induced
menopause.
4. Please revise exposure indicators in line 83 to outcome indicators.
5. Statistical analysis (lines 114-117): authors mentioned that further analysis was conducted
by birth cohort; by smoking status; and by stroke mortality. There were no results presented by
smoking status, and for stroke mortality, do you mean by stroke subtypes?
6. How many women were excluded in the sensitivity analysis?
7. Figure 1: what is WBCs? Please spell out or explain in the footnote.
8. Why authors chose menopause at 51-52 years as a reference when the average at menopause
was 49 and the majority of women in the menopause 48-50 years category? Please explain why
the analysis for age at menopause was not conducted for the younger cohort and not by subtypes.
9. Results: line 143, do you mean higher or lower proportion of women with number of children
born >3? Line 148: should it be lower family income and higher proportion of women with
number of children >3?
10. The stratified analyses by birth cohort and stroke subtype had low statistical power to provide
conclusive findings, especially the results for the younger cohort and subtypes. The number
of events in certain categories were very small (less than 5 events), and the effect estimates
were showing opposite risk direction between age at menarche #12 years (HR: 6.16, 95% CI
1.69-22.40), 13 years (HR: 0.84, 0.15-4.61), and 14 years (HR 3.28, 1.00-10.75). Authors only
reported statistically significant HRs in the results (lines 164-168).
11. The association between age at menarche and stroke seemed to be U-shaped. The effect
estimate for menarche #12 years was larger (though p=0.07) than that for menarche #18 years
after adjustment (Table 2) in both the whole cohort and older cohort, but authors only reported
the results with p<0.05, suggesting that late menarche was associated with stroke. Please remove
all the p-values in the results, effect size and 95% CIs are more important than statistically
significance of p<0.05.
12. Discussion lines 200-205: a Japanese cohort showed late menarche #17 was associated with
lower risk of stroke mortality, and a Korean cohort show an association between risk of mortality
from stroke and thrombotic stroke. And authors stated that our findings were similar in that late
menarche was associated with an increased risk of fatal stroke. These sentences were conflicting,
and whether late menarche was associated with an increased or decreased risk in Korean women?
13. Discussion lines 209-211: authors stated that the different associations between menarche
and stroke and subtypes need to be further explored in different ethnic populations. As the results
for subtypes and birth cohort were not conclusive due to very small number of events, the results
need to be interpreted with caution and large prospective studies are needed to replicate the
findings.
14. Discussion lines 212-215 suggested reproductive hormonal effect is not involved. This
should be revised as the timing of menarche and menopause and reproductive lifespan are all
influenced by reproductive hormones.
15. Discussion line 217: authors suggested that smoking is not an important factor. This
should be revised as well. Even the association remains after adjustment; it doesn’t mean
the confounders are not important factors. Smoking is an important risk factor for both early
menopause and stroke.