Title: Associations between birthweight and preterm birth and the ages at menarche and
menopause
Version: 1 Date: 15 Feb 2024
Reviewer's report:
This paper examines associations between birthweight and premature birth with ages of
menarche and menopause based on retrospective data collected in the Women’s Health Initative,
when women were aged 50 to 79. Although a paper of interest as it examines the impact of
important birth outcomes to menarche and menopause, several issues need to be addressed.
ABSTRACT: Please include a sentence about the design (retrospective), age of women, and fact
that data is based on recall of reproductive timing and events. Please also translate the beta values
into months (meaningful for menopause = 4 months; trivial and much smaller than measurement
precision for menarche = ~ 2 weeks.)
METHODS
Measurement of birthweight. Troy reference is for younger women age 27-44, and the cohort
to state record Spearmen is 0.74. Notably mothers recall had a much higher correlation than
participants in the Nurses Health study.  Is there any data on recall for older women born when
hospital births were much less common?
Please provide the question used to assess preterm birth.
Please provide more detail on measurement of reproductive indicators.
a) Please provide exact questions for age at menarche and menopause and what response
categories were provided. Were these measured in one-year increments or monthly increments.
Level of precision of measurement is critical because it will impact validity of your measures
of difference.
b) What is meant by first “regular” period and last “regular” period and last vaginal bleeding.
Please provide exact questions and explain what you are trying to measure with these variables?
Please clarify your outcome inclusion and exclusion criteria. Second paragraph under “Outcome
definitions and measurement”  is confusing and contradictory. You first state  “we restricted
our menopause analyses … to women who experienced natural menopause”  but then state
that you define natural menopause using the primary menopause definition that “defines a
woman’s age at menopause as the age she first experienced any of the following: last had any
menstrual bleeding, had a bilateral oophorectomy, or began using hormone replacement therapy”
and then indicate that you exclude oophorectomy, but not those using hormone therapy (for
whom a natural menopause is not observed) or women who had a hysterectomy (for whom a
natural menopause is not observed), although you do conduct a sensitivity analysis excluding
women who had a hysterectomy before their age at menopause.   Please clarify your text or
conduct an analysis of observed natural menopause.  (Notably if you conducted a survival
analysis, you could include women with hysterectomy, oophorectomy and HT used at time
of the event respectively). Excluding women with these outcomes may well bias your age at
menopause estimates differentially in birthweight/premature categories given associations of
these categories with an unobserved natural menopause).
RESULTS
Please provide in text information on key characteristics eg % of women falling in each
birthweight category and % preterm. Median or mean age at menopause and menarche for the
entire sample.
Please provide information on distributions of age at menopause. What is the range of ages
reported? Did you observe digit preference as might be expected for a recalled age at event?
Does the Age at “Natural Menopause” include hysterectomies? Please provide mean age for
women with an observed final menses/natural menopause, and for women with hysterectomy/
oophorectomy.  Age reported in Table 1 (48.6-49.1) is younger than expectation for a natural
final menstrual period.
In the text, please translate the beta estimates from the linear regressions into months to provide
the reader with insight into the magnitude (and meaningfulness of the difference).  EG: Age at
menopause beta for menopause (-0.361) is four months earlier for birthweight <6lbs. This is a
meaningful difference. For menarche (-0.046) it is just two weeks which is not a meaningful
difference and is also much smaller than what appears to be precision of your measurement (to
the nearest year).
Given your focus on age at menarche and menopause, inclusion of additional variables such as
age at first regular period, age at last regular period and age at last vaginal bleed in Table 2 and
Table 5 is not helpful and confusing. Please delete from Table 2 and 5. (In fact it is not clear
why they are included in the manuscript at all). Information on oophorectomy and hysterectomy
should be presented with the menopause data in Table 2 and 5 sand in corresponding results
paragraph.
What is the purpose of table 3 and 6? How do regularity of menses and hot flashes relate to
your research question and hypotheses for this paper. They are not justified in the background,
described in method or discussed in the discussion. Suggest delete.
Text does not discuss results for preterm birth and menarche.
In the paragraph discussing Table 5, when you restricted analyses to preterm births <6 lbs, were
other preterm births (n=??) excluded from the analysis?
Stratfied files in the supplementary tables are not discussed. Suggest delete.
DISCUSSION
Please discuss limitation of recall of birth outcomes for fully. Many women would not have
been born in hospital (in 1930 ~ 30% of women gave birth in hospital) and may not have been
weighed. Please provide more discussion of the limitations of birthweight recall for women of
this age. The citation you provide (Troy et al.) was in women age 27-44, thus born after 1950
when hospital births (and weighing) were more common.
Please discuss bias in estimation of age at menopause and its association with outcomes when
excluding women with hysterectomy, hotflash, and oophorectomy.  There is literature on this
issue.
Discussion should address meaningfulness of the difference in age at menarche/menopause by
birthweight/preterm.  Magnitude of difference for menopause is meaningful, but for menarche
it likely is not. This should be done both for your findings and for the related literature. This
should also be placed in context of other covariates that have meaningful influences  on these
to ages. Eg for menopause – smoking, PFAs exposure, birth control use have large impacts on
age at menopause.
Table 1: please indicate mean (sd) for continuous variables