Title: Stillbirth increase long-term health risks of diabetes, CVD, CVD mortality, and all-cause
mortality
Version: 1 Date: 12 Mar 2025
Reviewer's report:
This manuscript presents valuable insights into the relationship between stillbirth and long-
term health risks. While the manuscript is well-structured, there remain important aspects that
need clarification to strengthen its scientific rigor and enhance clarity. Below are the detailed
comments aimed at further improving the manuscript. Please consider the following suggestions
to enhance the manuscript:
#Major comments#
1. Clarification of Methodology
• Explicitly discuss potential selection bias resulting from exclusion criteria. Please clarify why
"participants with diabetes and CVD onset before stillbirth were excluded (n = 9)" and how this
limited number may impact results. Number of patients diagnosed before questionnaires is too
small, compared to the number of diabetes patients diagnosed during the first two years. Please
explain the definition and how long these outcomes are assessed before the questionnaires.
• Define explicitly how gestational diabetes was evaluated and whether it was included in the
exclusion criteria.
• Provide a detailed definition of "poor physical health," clearly indicating the objective
measures or specific questionnaire items used to assess this factor, as noted by: “Physical health
is determined by the question, 'In general, how would you rate your overall health?'” Please
consider adding the result in the baseline tables and in the adjusted model.
• Clearly address medical compliance issues, such as access to medical services during
pregnancy and frequency of medical visits, and how these could act as confounding factors.
2. Validation and Transparency of Results
• Provide detailed descriptions for the timing of baseline disease evaluations, including the exact
start and end points of observation, median, and interquartile range (IQR).
• Clarify explicitly that BMI values were measured at the time of questionnaire administration,
not at the time of stillbirth, and discuss potential limitations.
3. Strengthening Discussion
• Further elaborate on the role of Nerve Growth Factor (NGF) at a molecular level, particularly
its involvement via the PI3K/AKT signaling pathway, as suggested by the statement: "...the
reduction of NGF levels is closely associated with the apoptosis of pancreatic #-cells, a process
that results in impaired insulin secretion through the inhibition of the PI3K and AKT signaling
pathways..."
• Discuss medical compliance (access to healthcare, medical visits during pregnancy) as
potential confounding factors influencing long-term health risks.
• Emphasize the limitation regarding the predominance of white participants ("95.0% were
White") and explicitly recommend further studies involving diverse ethnic groups.
4. Conclusions
• "Women who experienced stillbirth faced a significantly elevated risk of a variety of long-
term health outcomes, including diabetes, CVD, IHD, Stroke, HF, MI, all-cause mortality, and
cardiovascular mortality." Although the association between stillbirth and these health outcomes
has been clearly demonstrated by this observational study, the wording should explicitly avoid
implying a causal relationship. A more appropriate phrasing would emphasize the association
rather than suggesting causality. Therefore, I recommend revising the sentence as follows:
"Women who experienced stillbirth were found to have a significantly elevated risk of various
long-term health outcomes, including diabetes, cardiovascular disease (CVD), ischemic heart
disease (IHD), stroke, heart failure (HF), myocardial infarction (MI), all-cause mortality,
and cardiovascular mortality; however, given the observational nature of this study, these
associations should not be interpreted as evidence of causal relationships." This change will help
accurately reflect the methodological limitations discussed in the manuscript.
#Minor comments#
1. Result Table Clarifications
• Clearly distinguish between percentage (%) and standard deviation (SD) notations in Table 1
to enhance readability.
2. Conclusion Enhancement
• Re-emphasize clearly the modifying effects of income ("...no significant association with
all-cause mortality among participants with annual household income #31,000 pounds...") and
hypertension on health risks, and specify the need for future research addressing underlying
biological mechanisms and ethnic variations.