Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Summary : this is an interesting review on an important and debated public health topic. The manuscript raises relevant concerns about folic acid fortification and highlights some limitations in the current literature. However, several points would benefit from a more balanced discussion and from adding some key biological aspects of folate metabolism.

Major comments

1. Balance of the discussion : The manuscript mainly focuses on the potential limitations and risks of folic acid fortification. These points are important, but the discussion would benefit from being more balanced by also acknowledging evidence supporting population-level benefits. Some statements are quite strong and could be moderated.
2. Socioeconomic factors : The role of socioeconomic status is an important point. However, the interpretation is sometimes too direct. Comparisons between regions should be made with caution. In low-resource settings, including parts of sub-Saharan Africa, reported rates of neural tube defects may be underestimated due to limited surveillance systems, underreporting, and reduced access to diagnosis. This should be acknowledged when discussing global differences.
3. Folinic acid and different folate forms
   1. The section on folate metabolism is useful but incomplete. Folinic acid (5-formyltetrahydrofolate) should be mentioned, as it is a biologically active form that does not require reduction by DHFR and is used in clinical practice.
   2. More generally, the manuscript would benefit from discussing the differences between folic acid and reduced folate forms (such as 5-MTHF or folinic acid), especially in the context of individual variability (e.g., MTHFR variants).
   3. Folate transport : Folate status is not only determined by intake but also by transport mechanisms. It would be helpful to briefly mention key transporters: PCFT for intestinal absorption and FRα and RFC at the blood–brain barrier

These mechanisms are important for understanding variability between individuals and conditions such as cerebral folate deficiency.

4. Interpretation of evidence : Some conclusions, particularly regarding the lack of efficacy of fortification, would benefit from more cautious wording. It would be useful to clearly distinguish between well-established evidence and more speculative or emerging hypotheses.

Minor comments

• Keep a clear distinction between “folate” and “folic acid” throughout the text.

• Some sections could be slightly simplified for readability.

 

Conclusion : Overall, this is a valuable review. Improving balance, adding key biological elements (folinic acid, transport), and moderating some statements would strengthen the manuscript.

Author Response

please see attached file

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review aimed to addresses the difference between folate and folic acid and between supplementation and food fortification, critically evaluates the data in several recent publications supporting mandatory fortification of food products with folic acid, and presents the case for a more personalized medicine approach to the prevention of neural tube defects (NTDs). The reviewer believes this review clarifies the role of folic acid intake in NTD prevention and provides useful clinical information from the perspective of NTD prevention. Furthermore, the reviewer considers that this review thoroughly examines previous studies and summarizes it appropriately. However, the reviewer would like the authors to consider the following points.

 

Although this review aims to clarify the role of folic acid intake in NTD prevention, the reviewer considers that the title of this article does not reflect the authors’ research objectives. The authors’ research objectives are not conveyed just by looking at the title. The reviewer recommends revising the title to better reflect the authors’ research objectives.

 

In this study, the authors aim to clarify the role of folic acid intake in NTD prevention, but the circumstances that led the authors to conceive this study are unclear. In the “Introduction” section, the authors should explain the circumstances that led them to conceive of this study.

 

In this review, the authors discuss the current state and challenges of food fortification policy for folic acid in the United States. However, do these current situations and challenges apply to other regions as well? The authors should demonstrate that these current state and challenges are limited to the United States.

Author Response

please see attached file

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have adequately addressed most of the comments and the revised manuscript is clearly improved, particularly regarding the biological aspects of folate metabolism, the distinction between folate and folic acid, and the discussion of folate transport and reduced folate forms. The structure and readability of the manuscript have also improved.

However, some points would still benefit from minor revision before acceptance.

In particular:

• Some conclusions regarding the lack of efficacy of mandatory fortification remain stronger than warranted by the available evidence. The manuscript would benefit from slightly more cautious wording distinguishing “limitations of current evidence” from “evidence of no effect”.
• The discussion linking folic acid fortification with rising prevalence of autism, Alzheimer’s disease, and obesity remains speculative and should be substantially toned down or more clearly framed as hypothesis-generating rather than evidence-based.
• In a few sections, the critique of historical studies appears somewhat unbalanced, with speculative interpretations that go beyond the available data. A more neutral tone would strengthen the scientific rigor of the review.

Overall, this is a valuable and thought-provoking review on an important public health topic, and the revisions have significantly improved the manuscript. I would support publication after minor revision.

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I think all responses to reviewers' comments have been addressed satisfactorily.

I have no comments on the revised manuscript.

 

Author Response

Thank you.