Title: Pregnancy-related Factors May Signal Additional Protection or Risk of Future
Cardiovascular Disease
Version: 0 Date: 21 Oct 2022
Reviewer's report:
Review of manuscript «Pregnancy-related Factors May Signal Additional Protection or Risk of
Future Cardiovascular Disease»
Authors: Shivani M. Reddy, Tamy H. M. Tsujimoto, Bajhat F. Qaqish, Jason P. Fine, Wanda
K. Nicholson
The authors are assessing the contribution of a history of low birthweight (LBW) infant and
breastfeeding to cardiovascular disease (CVD) risk in addition to traditional risk factors by using
data from NHANES 1999-2006. The authors state that there is a consistent reduction in CVD
outcomes among women with a history of breastfeeding. No association was found for LBW.
The manuscript is well-written and easy to follow. The methods and statistics seem appropriate
to answer the research question. The statements are appropriately discussed in the context of
previous literature and limitations. However, there are some key drawbacks.
1. The authors describe the use of risk calculators to estimate 10-year risk of CVD. In the method
section they write that they were planning to add the pregnancy-related factors to the PCE
and re-estimate the risk equations, but this could not be done due to few events. The reviewer
recommends using less space in the manuscript on mention on the risk model/calculator as this
is not part of the current study. This is confusing for the reader. Focus on what has been done.
2. Since NHANES do not include data on incident non-fatal myocardial infarction or stroke the
authors created a proxy variable termed CVD deaths + surrogate CVD. Surrogate CVD was
defined as non-CVD deaths with diabetes or hypertension as a contributing cause of death. The
authors assume that participants whom diabetes or hypertension was a contributing cause of
death may have been more likely to have experienced a non-fatal MI or stroke. This assumption
is weak and highly uncertain, and the risk of misclassification is high.  Do inclusion of this
endpoint ad much to the results in the current paper?
The results are presented for CVD death and for CVD death+ CVD surrogate. Why are not the
results on only surrogate CVD presented? The HR for the association of breastfeeding with the
two outcomes is more or less similar.
3. Even though the authors find an association between breastfeeding and CVD the results are
statistically non-significant and this should be clearer stated, i.e. in the abstract. What were the
unadjusted results? Did the HR change after adjustment? I appreciate having both unadjusted
and adjusted results presented in the manuscript.
4. The observed associations on breastfeeding are likely due to reverse causation, or maybe
sociodemographic status. What were the quality of the variables measuring sociodemographic
status? It would be interesting to have measurements of pre-pregnancy risk factors as the authors
mention in the discussion. The women with “no breastfeeding” seem to have more CVD risk
factors than those who breastfeed (table 1). Was there no available information after pregnancy?
May weight loss after pregnancy be relevant?
5. Breastfeeding was defined as breastfeeding of an infant for 1 month or more. The quality of
the study would be much better with more information on duration of breastfeeding. Is longer
duration of breastfeeding associated with CVD risk? As stated by the authors, women who have
given birth to more children tend to have longer lifetime durations of breastfeeding.
6. The authors to not take into account in which pregnancy the mother was breastfeeding. Does
it matter if the women ended her reproductive career breastfeeding versus breastfeeding e.g.
in her first pregnancy and not the second? One may see in table 1 that more women with “no
breastfeeding” had only one live birth. What can be the explanation of that?
7. It would be interesting to know more about the reasons for not breastfeeding. The decision to
initiate breastfeeding is affected by a variety of factors including work situation, smoking, being
overweight, feeling depressed and general physical health. A relatively low number (depending
on country) of women did breastfeed more than 1 month in this study.
Do you have any information on exclusive breastfeeding vs. breastfeeding supplemented by
complementary food?
8. The mean age of women was around 55 years old. Have you tested if the benefits from
breastfeeding dimmish with increasing age (other than adjusting for age)? How about before/
after menopause?
9. How have the authors considered other pregnancy-complications such as gestational
hypertension, preeclampsia and diabetes? Did women giving birth to infants with low
birthweight and women who did not breastfeed have more of these complications?
10. Reverse causation, recall bias and residual confounding are important limitations in this
study. The authors have a precise discussion of this in the manuscript.