Review Reports

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

Thank you for asking me to review this amended paper. It is pleasing to see that most of my suggestions have been considered and acted upon. Some issues still need to be addressed before publication:

1. Line 159: Do you mean that high-fat diets are associated with obesity (rather than cause)?
2. Please define what is meant by a high-fat diet in the context.
3. Please provide evidence to support the statement that vegetarian/vegan diets are associated with less obesity.
4. Section 3.6 should be written in the third person.

The discussion, conclusion, and limitations have been significantly improved.

Author Response

Dear Reviewer 1,

We would like to address each of your comments and suggestions.

“Line 159: Do you mean that high-fat diets are associated with obesity (rather than cause)?

Please define what is meant by a high-fat diet in the context.

Please provide evidence to support the statement that vegetarian/vegan diets are associated with less obesity.”

Answer: Thank you for these clarifications. Yes, our intent is association, not causation, when referring to high-fat diets and obesity in humans. We used “high-fat diet” as an umbrella term reflecting the operational definitions used in the included studies (predominantly preclinical paradigms) rather than imposing a single cut-off. Regarding vegetarian or vegan patterns, we refer to associations reported in the cited guidance rather than causal effects, and we have updated the manuscript by adding the most recent ESPGHAN position paper on vegan diets to provide the current context on nutritional adequacy and monitoring requirements.

 

“Section 3.6 should be written in the third person.”

The discussion, conclusion, and limitations have been significantly improved.

Answer: We rewrote it in the third person.

We thank you for your valuable comments and suggestions, and we hope our modifications meet your standards.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

Thank you for the opportunity to review the manuscript “The First 1000 Days: Maternal Nutrient Intake – A Window of Opportunity for Pulmonary Hypertension – A Review.” The manuscript addresses an important issue by linking the concept of nutritional programming with pulmonary vascular development and clinically significant forms of pulmonary hypertension in neonates. The authors have made a commendable effort to organize the evidence according to the degree of its direct association with pulmonary hypertension, which enhances the clarity and practical value of the work.

However, the manuscript requires some minor revisions:

• Errors in table numbering;

• In the Introduction section, there is a lack of justification for choosing pulmonary hypertension as the central focus (e.g., no information on the proportion of children diagnosed with pulmonary hypertension);

• Although this is a narrative review, it may be helpful to indicate how many studies involved human subjects versus animal models.

Author Response

Dear Reviewer 2,

We would like to address each of your comments and suggestions.

“In the Introduction section, there is a lack of justification for choosing pulmonary hypertension as the central focus (e.g., no information on the proportion of children diagnosed with pulmonary hypertension);”

Answer: We provided information on the proportion of children diagnosed with pulmonary hypertension and the mortality rate to justify choosing pulmonary hypertension as the central focus.

„Errors in table numbering;”

Answer: Thank you for pointing that out. We fixed the table numbering.

„Although this is a narrative review, it may be helpful to indicate how many studies involved human subjects versus animal models.”

Answer: We indicated how many studies involved human subjects versus animal models in Study selection and synthesis.

We thank you for your valuable comments and suggestions, and we hope our modifications meet your standards.

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Comments and Suggestions for Authors

Thank you for your submission, which explores the relationship between maternal nutrition during the first 1000 days and the risk of pulmonary hypertension (PH) in offspring. This is a highly relevant and emerging topic, and the review offers a valuable synthesis of currently scattered evidence. Below are my specific comments and suggestions for improving the manuscript:

1. Strength of Contribution

• The review is a useful starting point for understanding how early-life nutrition may influence pulmonary vascular development.

• The tiered evidence synthesis (direct vs. mechanistic vs. indirect) is a strong structural choice that aids clarity.

2. Evidence Base: Causality vs. Association

• Please revise language throughout the manuscript to clearly distinguish correlation, association, and causation. For instance:

  • Sentences such as "maternal high-fat diet leads to..." imply causation that is not supported by human data.

  • Consider using phrasing like "has been associated with", or "animal studies suggest..." unless human causal evidence exists.

3. Lack of Quality Assessment

• The manuscript does not include a formal risk-of-bias or quality appraisal of the included studies.

  • Even in a narrative review, it is strongly recommended to briefly evaluate the strength of evidence—particularly distinguishing between case reports, cohort studies, and animal models.

  • Consider adding a supplementary table or paragraph summarizing limitations or quality flags (e.g., sample size, lack of controls, species differences).

4. Overreliance on Preclinical Studies

• Many of the claims—especially for maternal high-fat diet, undernutrition, vitamin D, and high salt intake—are based predominantly on rodent models.

  • This is acceptable for mechanistic exploration, but should be clearly stated to avoid overgeneralization.

  • I suggest adding a visual table or diagram to separate findings by model type (human vs. animal) for transparency.

5. Clarify Figures and Tables

• Figure 2 (Polyphenol-containing foods) could unintentionally mislead readers into thinking these foods should be avoided during pregnancy.

  • Please add an explicit clarification that the concern is primarily about third-trimester excessive intake, and not routine consumption.

  • Consider rewording the caption to: “This figure illustrates common polyphenol-rich foods for awareness in the context of ductal constriction risk, not for avoidance unless clinically indicated.”

6. Confounding and Bias Not Addressed

• There is little discussion of potential confounding factors such as:

  • Maternal comorbidities (e.g., diabetes, infections)

  • Socioeconomic status and food access

  • Concurrent nutrient deficiencies or supplementation

• Please include a paragraph on how such confounding may influence interpretations in observational literature, and how future studies might address this.

7. Missing Review Protocol or Flowchart

• While this is a narrative review, I recommend adding:

  • A PRISMA-style flow diagram to show how the 28 included studies were selected from the search. A diagram appropriate for a narrative review

  • Alternatively, provide a brief flow of inclusion/exclusion to improve transparency.

8. Mechanistic Integration Could Be Stronger

• Mechanistic pathways are described well individually, but the manuscript lacks an integrated conceptual model that shows how maternal nutrition affects fetal lung development through epigenetics, inflammation, vascular remodeling, and other mechanisms.

  • Consider adding a unifying pathway diagram or summarizing these mechanisms visually.

9. Clinical Implications Section

• The discussion around thiamine deficiency and polyphenol intake offers high clinical value.

  • I recommend expanding these recommendations slightly to include:

    • Suggested screening questions for dietary intake

    • Specific clinical signs that might prompt thiamine supplementation or polyphenol limitation

10. Limitations Section – Good Start, Needs Expansion

• You appropriately mention study heterogeneity and publication bias.

  • However, please also discuss:

    • Limitations related to translating animal findings into clinical care

    • The impact of publication bias (e.g., small positive studies are more likely to be published)

    • The potential overinterpretation of isolated case series

      11. Language and Style

      • The writing is clear and well-structured overall.

        • However, a few sentences are overly complex or could benefit from further polishing for precision and flow.

        • For example: “This cluster of findings has immediate clinical implications for anamnesis importance…” — consider rephrasing to improve clarity (e.g., “This finding underscores the clinical importance of reviewing maternal dietary history…”)

Comments on the Quality of English Language

While the writing is clear and professionally presented, a few passages could be made more concise by summarizing numeric data rather than repeating detailed figures. However, this does not hinder comprehension and would be considered a stylistic refinement rather than a language issue.

Author Response

Dear Reviewer 3,

We would like to address each of your comments and suggestions.

2. Evidence Base: Causality vs. Association

„Please revise language throughout the manuscript to clearly distinguish correlation, association, and causation.”

Answer: We revised language throughout the manuscript to clearly distinguish correlation, association, and causation.

„3. Lack of Quality Assessment

The manuscript does not include a formal risk-of-bias or quality appraisal of the included studies.

Even in a narrative review, it is strongly recommended to briefly evaluate the strength of evidence—particularly distinguishing between case reports, cohort studies, and animal models.

Consider adding a supplementary table or paragraph summarizing limitations or quality flags (e.g., sample size, lack of controls, species differences).”

Answer: We summarized limitations in Section „5. Limitations of the study.”

„4. Overreliance on Preclinical Studies

Many of the claims—especially for maternal high-fat diet, undernutrition, vitamin D, and high salt intake—are based predominantly on rodent models.

This is acceptable for mechanistic exploration but should be clearly stated to avoid overgeneralization.

I suggest adding a visual table or diagram to separate findings by model type (human vs. animal) for transparency.”

Answer: In table 1, we mention which studies are conducted on human/animal models.

„5. Clarify Figures and Tables

Figure 2 (Polyphenol-containing foods) could unintentionally mislead readers into thinking these foods should be avoided during pregnancy.

Please add an explicit clarification that the concern is primarily about third-trimester excessive intake, and not routine consumption.”

Answer: As you suggested, we added a clear clarification to the Figure 2 caption stating that the foods shown should not be avoided throughout pregnancy.

Consider rewording the caption to: “This figure illustrates common polyphenol-rich foods for awareness in the context of ductal constriction risk, not for avoidance unless clinically indicated.”

“6. Confounding and Bias Not Addressed

There is little discussion of potential confounding factors such as:

Maternal comorbidities (e.g., diabetes, infections)

Socioeconomic status and food access

Concurrent nutrient deficiencies or supplementation

Please include a paragraph on how such confounding may influence interpretations in observational literature, and how future studies might address this.”

Answer: We included a paragraph in Section 4.4.

“7. Missing Review Protocol or Flowchart

While this is a narrative review, I recommend adding:

A PRISMA-style flow diagram to show how the 28 included studies were selected from the search. A diagram appropriate for a narrative review

Alternatively, provide a brief flow of inclusion/exclusion to improve transparency.”

Answer: To improve transparency, we describe the study selection process. Following the predefined eligibility criteria, records retrieved from PubMed and Embase were screened in two stages (title and abstract screening followed by full-text review). During the initial drafting phase, we did not prospectively record the number of records at each screening step (identified, de-duplicated, screened, and excluded by reason). However, we retained the final set of included studies (n = 28) that met inclusion criteria and formed the qualitative synthesis. We have therefore focused on clearly reporting the eligibility criteria and providing a qualitative appraisal of evidence strength to support appropriate interpretation.

“8. Mechanistic Integration Could Be Stronger

Mechanistic pathways are described well individually, but the manuscript lacks an integrated conceptual model that shows how maternal nutrition affects fetal lung development through epigenetics, inflammation, vascular remodeling, and other mechanisms.

Consider adding a unifying pathway diagram or summarizing these mechanisms visually.”

Answer: Thank you for the suggestion. We added to the Discussion an integrated description linking the mechanistic pathways previously described individually.

“9. Clinical Implications Section

The discussion around thiamine deficiency and polyphenol intake offers high clinical value.

I recommend expanding these recommendations slightly to include:

Suggested screening questions for dietary intake

Specific clinical signs that might prompt thiamine supplementation or polyphenol limitation”

Answer: We expanded the recommendations.

“10. Limitations Section – Good Start, Needs Expansion

You appropriately mention study heterogeneity and publication bias.

However, please also discuss:

Limitations related to translating animal findings into clinical care

The impact of publication bias (e.g., small positive studies are more likely to be published)

The potential overinterpretation of isolated case series”

Answer: We expanded the Limitations Section according to recommendations.

“11. Language and Style

The writing is clear and well-structured overall.

However, a few sentences are overly complex or could benefit from further polishing for precision and flow.

For example: “This cluster of findings has immediate clinical implications for anamnesis importance…” — consider rephrasing to improve clarity (e.g., “This finding underscores the clinical importance of reviewing maternal dietary history…”)”

Answer: We tried to polish the indicated sentences to make them more precise and less complex.

We thank you for your valuable comments and suggestions, and we hope our modifications meet your standards.

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors Dear Colleagues, I recently analyzed your paper, entitled ”The First 1000 Days: Maternal Nutrient Intake - A Window of Opportunity for Pulmonary Hypertension - A Review,” an interesting paper that correlates evidence linking various nutritional deficiencies or excesses to pulmonary hypertension during the first 1000 days of life. This is a courageous synthesis since pulmonary hypertension has various phenotypes during fetal, neonatal, and infant life. This is the main comment I have regarding your manuscript.  Here are my observations:

1. Consider adding ”narrative” to the title to reflect the content of the paper better.
2. The Abstract is concise, in line with the review's analysis.
3. The keywords are well-chosen.
4. In the Introduction section, please consider using the past tense for the entire paragraph between lines 60-68. Also, please consider adding more information on pulmonary hypertension phenotypes and etiology for a better understanding of the correlations found in the review. I suggest the following recent paper: Chojnacka K, Singh Y, Gahlaut S, Blaz W, Jerzak A, Szczapa T. Persistent Pulmonary Hypertension of the Newborn: A Pragmatic Review of Pathophysiology, Diagnosis, and Advances in Management. Biomedicines. 2025; 13(10):2332. https://doi.org/10.3390/biomedicines13102332
5. The Materials and Methods section presents the searching strategy and criteria to include and exclude studies. However, a flow chart would help readers to better understand your approach.
6. In the results section, please consider verying all the results of the reviews as we cannot link maternal nutrition during lactation with persistent pulmonary hypertension of the newborn, hypertension associated with fetal constriction of the persistent ductus arteriosus, or pulmonary hypertension related to prematurity during all infancy; this conditions occur perinatally and, except pulmonary hypertension related to prematurity, are solved before the neonatal periods ends.
7. Also, in the same section, please consider to discuss the last ESPGHAN comments on vegan and vegetarian diet in infants and children: Verduci E, Kӧglmeier J, Haiden N, Kivelä L, de Koning B, Hill S, Luque V, Moltu SJ, Norsa L, De Pipaon MS, Savino F, Bronsky J. Vegan diet and nutritional status in infants, children and adolescents: A position paper based on a systematic search by the ESPGHAN Nutrition Committee. J Pediatr Gastroenterol Nutr. 2025 Nov;81(5):1318-1345. doi: 10.1002/jpn3.70182. Epub 2025 Aug 17. PMID: 40819279; PMCID: PMC12580465.
8. Please consider reconstructing Figure 2 by adding the links between excessive polyphenols consumption and the possible adverse effects, not just graphically presenting the incriminated foods rich in polyphenols.
9. I would not consider salt as a food, as it does not bring calories. It can be regarded as a condiment or an additive source of minerals.
10. The Tables clearly present the information. However, the section 3.1. (of the Results section) merits a lot more discussion and not just an enumeration of the nutrient intake deficiencies and excesses presented in Table 2. The same applies to Table 3, corresponding to section 3.2 of the same section, namely, Estimated average nutrient requirements and recommendations for women during pregnancy and lactation. I suggest also the recent ASPEN paper on this subject, Talebi S, Kianifar HR, Mehdizadeh A. Nutritional requirements in pregnancy and lactation. Clin Nutr ESPEN. 2024 Dec;64:400-410. doi: 10.1016/j.clnesp.2024.10.155. Epub 2024 Nov 1. PMID: 39489298.
11. The Discussion and Conclusion sections are in line with the results of the review. However, the authors must refine the discussion based on the observations listed at 7 in this list of observations.
12. References are correctly cited.

Congratulations.  

Author Response

Dear Reviewer 4,

We would like to address each of your comments and suggestions.

 

Consider adding ”narrative” to the title to reflect the content of the paper better.

Answer: We added “narrative” to the title.

 

“In the Introduction section, please consider using the past tense for the entire paragraph between lines 60-68. Also, please consider adding more information on pulmonary hypertension phenotypes and etiology for a better understanding of the correlations found in the review. I suggest the following recent paper: Chojnacka K, Singh Y, Gahlaut S, Blaz W, Jerzak A, Szczapa T. Persistent Pulmonary Hypertension of the Newborn: A Pragmatic Review of Pathophysiology, Diagnosis, and Advances in Management. Biomedicines. 2025; 13(10):2332. https://doi.org/10.3390/biomedicines13102332”

Answer: Thank you for the valuable article provided. We added more information on pulmonary hypertension phenotypes and etiology from there. Also, we used the past tense for the entire paragraph between lines 60-68.

“The Materials and Methods section presents the searching strategy and criteria to include and exclude studies. However, a flow chart would help readers to better understand your approach.”

Answer: We did not prospectively record the number of records at each screening step (identified, de-duplicated, screened, and excluded by reason) to make a flow chart. However, we retained the final set of included studies (n = 28) that met inclusion criteria and formed the qualitative synthesis.

“In the results section, please consider verying all the results of the reviews as we cannot link maternal nutrition during lactation with persistent pulmonary hypertension of the newborn, hypertension associated with fetal constriction of the persistent ductus arteriosus, or pulmonary hypertension related to prematurity during all infancy; this conditions occur perinatally and, except pulmonary hypertension related to prematurity, are solved before the neonatal periods ends.”

Answer: Thank you for this important point regarding timing and clinical phenotypes. We revised the Results to avoid implying that maternal nutrition during lactation is linked to strictly perinatal entities such as fetal ductus arteriosus constriction or PPHN.

“Also, in the same section, please consider to discuss the last ESPGHAN comments on vegan and vegetarian diet in infants and children: Verduci E, Kӧglmeier J, Haiden N, Kivelä L, de Koning B, Hill S, Luque V, Moltu SJ, Norsa L, De Pipaon MS, Savino F, Bronsky J. Vegan diet and nutritional status in infants, children and adolescents: A position paper based on a systematic search by the ESPGHAN Nutrition Committee. J Pediatr Gastroenterol Nutr. 2025 Nov;81(5):1318-1345. doi: 10.1002/jpn3.70182. Epub 2025 Aug 17. PMID: 40819279; PMCID: PMC12580465.”

Answer: We revised the discussions presented in 3.3. Maternal high-fat diet to include the last ESPGHAN comments on vegan and vegetarian diets in infants and children.

“Please consider reconstructing Figure 2 by adding the links between excessive polyphenols consumption and the possible adverse effects, not just graphically presenting the incriminated foods rich in polyphenols.”

Answer: We reconstructed Figure 2 by adding the links between excessive polyphenol consumption and the possible adverse effects.

“I would not consider salt as a food, as it does not bring calories. It can be regarded as a condiment or an additive source of minerals.”

Answer: Thank you for this observation. We changed “food” with “condiment.”

“The Tables clearly present the information. However, the section 3.1. (of the Results section) merits a lot more discussion and not just an enumeration of the nutrient intake deficiencies and excesses presented in Table 2. The same applies to Table 3, corresponding to section 3.2 of the same section, namely, Estimated average nutrient requirements and recommendations for women during pregnancy and lactation. I suggest also the recent ASPEN paper on this subject, Talebi S, Kianifar HR, Mehdizadeh A. Nutritional requirements in pregnancy and lactation. Clin Nutr ESPEN. 2024 Dec;64:400-410. doi: 10.1016/j.clnesp.2024.10.155. Epub 2024 Nov 1. PMID: 39489298.”

Answer: Thank you for this comment. We expanded the Results narrative in sections 3.1 and 3.2 to provide descriptive synthesis rather than only enumerating values from Tables 2 and 3.

“The Discussion and Conclusion sections are in line with the results of the review. However, the authors must refine the discussion based on the observations listed at 7 in this list of observations.”

Answer: We refined the discussions based on the observations listed at 7 in your list of observations.

We thank you for your valuable comments and suggestions, and we hope our modifications meet your standards.

Round 2

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Thank you for revising most of the parts as indicated

Comments on the Quality of English Language

While the writing is clear and professionally presented, a few passages could be made more concise by summarizing numeric data rather than repeating detailed figures. However, this does not hinder comprehension and would be considered a stylistic refinement rather than a language issue.

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Colleagues, 

Congratulations on your work and thank you for considering my observations.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for asking me to review this potentially interesting paper. I have some suggestions for improvement:

Methods:

Further detail is needed regarding the search strategy used; for example, which type of papers were included or excluded? primary research, systematic reviews, other narrative reviews, grey literature, for example. This needs to be clarified. You need to indicate any Boolean search terms that were used, e.g. AND, OR etc., with the search terms.

You also need a 'Results' section that describes the papers found and included in your review. Sections 3-7 can then be subheadings of your results section. It reads rather disjointed at the moment, as 3-7 do not currently flow on from the methods section.

The statements in section 4 about maternal diet are not supported by referencing - are these findings from your literature review? If so, you need to indicate the papers where these statements are made. The statement about diet and lactation is controversial, as other studies show that only extremes of inadequacy in maternal diet adversely impact the quality of breastmilk.

Table 2 is not referred to in the text - this needs some commentary; it would also be helpful to know which country the reference values are from (as different countries have different reference values).

Section 5: The association between a high-fat diet and obesity is not clear here. Furthermore, it is not clear why vegetarian/vegan diets are mentioned in this section; is it because they are lower in fat? Is this why there is a reduced risk of obesity? Please clarify.

Figure 1 and 2 both need some commentary in the text.

If you have included animal studies in this review (mice/sheep etc.), this should be clearly stated in the inclusion criteria in the methods section. There should also be a rationale for including animal studies, as they have limited translation to human pregnancy.

Section 9: Please write in the third person, using an impersonal tone.

Discussion and conclusion: There is limited discussion of your findings in comparison with the wider literature here. The authors appear to be drawing conclusions about diet and the risk of infant pulmonary hypertension based on very limited evidence. Limitations are discussed but this does not justify some of the claims being made by this review.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors conduct a narrative review of how nutrient intake during pregnancy can modify the risk of offspring developing pulmonary hypertension, analyzing how both nutrient deficiencies and excesses can affect lung and cardiovascular development. Among the data they show is how malnutrition and thiamine deficiency are associated with pulmonary hypertension in children, while high fat and polyphenol intake is associated with adverse cardiovascular remodeling. Finally, they conclude that monitoring maternal nutrition during the first 1000 days of life could be an effective preventive measure to reduce pulmonary hypertension in children and its long-term consequences.

This seems to be an interesting review given that maternal nutrition has a significant impact on the concept or theory of early programming, and any information that helps to obtain clearer data on the influence of nutrients ingested by the mother on various fetal, neonatal or infant pathologies and their long-term consequences is of scientific, clinical and social interest.

Methods

The methodology described does not clearly show how the search was conducted. Specifically, what connectives were used? Why was the search only conducted in PubMed and not other databases? How many articles were found? What exclusion criteria were followed? What time period was used for the search (5 years, 10 years, 20 years, etc.)? This section needs much more detail to truly understand the validity of this review, even though it is a narrative review.

Although, as I mentioned earlier, these types of reviews, even narrative ones, are valuable if they provide new information—that is, if they serve to compare results or clarify doubts related to a process or pathology—in general, given the many aspects that would need to be modified, I believe this review offers nothing new to the well-known effect of maternal nutrition on placental and, consequently, fetal development. It is a poor review that, despite what the title suggests, does not focus on a specific pathology, as it conflates obesity, placental dysfunction, and other alterations associated with maternal nutrition with poor pulmonary and cardiovascular development, something already well-established.

Thus, studies on maternal nutritional needs should have been better defined, not based on a single study and only on a few micronutrients. They should have specified which of these nutrients have been most strongly associated with pulmonary pathology and studied them in more detail. If we consider the excesses or deficiencies shown in Table 1, these could have been explored further. Why focus on vitamins D and C, or thiamine (which doesn't appear to be either excessive or deficient in maternal nutrition), but not vitamin A, iron, or other nutrients linked to the cardiovascular system or pulmonary function? It does touch on many of them briefly, but nothing is explored in depth; perhaps more detail could be found regarding thiamine.

I don't believe this review adds anything new to what is already known.