Title: Associations between birthweight and preterm birth and the ages at menarche and
menopause
Version: 1 Date: 07 Feb 2024
Reviewer's report:
The paper proposes to examine how a woman’s birth size or prematurity relate to timing of
menarche and menopause. This is an interesting set of questions. The methods are generally
appropriate. The writing is clear for the most part. However, the study seems underdeveloped
and the presentation of the results far more extensive than needed to support the points of the
manuscript (too many outcomes, too many tables).
Major points
1. The manuscript was very difficult to follow as a result of the very large number of similar
outcomes studied and the measures were mixed in tables in a seemingly random order. The 2
measures of menarche were in the first and 4th row: age at regular periods; age at menarche.
The four measures of menopause were in the second, third, fifth, and sixth rows: age at last
regular period; age at last vaginal bleeding; age at natural menopause; age at natural menopause
(conservative). Furthermore, there are 6 tables. The level of detail within and across the tables
does not illuminate the findings.
2. The authors do not provide the units for age. I assumed it was collected in years. The effect
size units are also unstated. The units are critical in the interpretation of the results and putting
the findings in context. Assuming the units are years, being born small was associated with a
reduction in age at menarche of about 2.3 weeks and a reduction in age at menopause of about
6 months. A decrease, even across the population, of 2.3 weeks hardly seems meaningful. It is
statistically significant because of the enormous sample size of the study.
3. For menarche, the small effect size (~2.3 weeks) is dwarfed by the trends over the past
5 decades in age at menarche  with a 2.3 month change seen over just one decade (https://
www.jpeds.com/article/S0022-3476(05)00682-7/fulltext).
4. The study focuses on postmenopausal women aged 50-79 years who were enrolled in a
clinical trial from 1993-1998. While the authors considered many outcomes, they failed to
delve into the heterogeneity of their sample which was of more than sufficient size to consider
stratum specific effects.  First, the age range includes women born in birth cohorts from
1910s through the 1940s. The authors note that their study results might not generalize to later
birth cohorts when survival of small or premature infants improved. However, they failed to
consider that variability within their own cohort. Infants born in the 1910s were much less
likely to survive than those born in the 1940s.  Furthermore, there are other changes with birth
cohort that support the need to stratify the results. There is strong evidence of a declining
age at menarche (see: https://www.jpeds.com/article/S0022-3476(05)00682-7/fulltext; https://
academic.oup.com/humrep/article/35/2/464/5716625).
5. While the authors consider the potential need to control for race/ethnicity, they do not
consider the possibility that the associations between birth size or prematurity and menarche (or
menopause) may vary by race/ethnicity. Again, this is one of the largest samples in which the
hypothesis can be tested. Few studies have sufficiently explored issues around menarche and
menopause for non-white women.
6. The study focuses on two outcomes that are separately predicted. While there is value in doing
so, it would have been far more innovative to consider the duration of women’s reproductive
periods. This is a unique study in that there was data on both menarche and menopause. Most
studies in the literature included only one endpoint.  Studies on the adverse effects of early
menopause point to reduced exposure to estrogen as the possible pathway to negative impacts.
Yet early menarched combined with early menopause might produce the same duration of
exposure to estrogen as late menarche coupled with late menopause.
Minor points
1. The abstract first sentence does not relate to the second sentence. Examining timing of
menarche and menopause related to birth size and prematurity does not follow as a natural next
step from the background.
2. The “region” variable is not defined.
3. The difference between socioeconomic status and education.