Choline—An Underappreciated Component of a Mother-to-Be’s Diet

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors The work is well done, however, it seems to me that the methodology used is not consistent with scientific work that attempts to substantiate the importance of Choline as an essential micronutrient for pregnant women. It would have been appropriate to use a systematic review or meta-analysis to base this review more rigorously.
Although an adequate bibliographical reference is observed, there is still the feeling that there is a lack of empirical evidence to justify in this context the dietary consumption of Choline above 930 mg/d. My difficulty in supporting the study lies in the methodology used and not its content.

Author Response

We made our best efforts to improve the manuscript and we hope we have met your expectations. Thank you for your constructive comments.

 

Response to Reviewer 1 comments

 

We express our appreciation to the reviewers and the editorial board for taking the time and effort to improve our work and provide such insightful comments.

 

We are pleased to have been allowed to revise our manuscript entitled:

Choline – An Underappreciated Component of a Mother-to-Be’s Diet

Reviewer comments

 

The work is well done, however, it seems to me that the methodology used is not consistent with scientific work that attempts to substantiate the importance of Choline as an essential micronutrient for pregnant women. It would have been appropriate to use a systematic review or meta-analysis to base this review more rigorously.

Although an adequate bibliographical reference is observed, there is still the feeling that there is a lack of empirical evidence to justify in this context the dietary consumption of Choline above 930 mg/d. My difficulty in supporting the study lies in the methodology used and not its content.

 

All responses to reviewer comments are in blue.

 

Thank you for your positive feedback on the content of our article and for your constructive comments on the methodology used. We really appreciate the time and effort you have taken to review our work.

 

Indeed, the methodology was not presented in detail, and we apologize for this oversight. Thank you very much; your comments prompted us to improve our work, and we hope we have met your expectations.

 

In response, we have taken several steps to enhance the rigor and transparency of our study. Firstly, we have provided a more detailed explanation of our methodology to make our approach clearer and more transparent. Additionally, we have enriched our manuscript with new sections:

• Discussing the relationship of choline with microbiota: we added references to studies such as Mjaaseth et al., 2021; Ye et al., 2018; Iliodromiti et al., 2023; Miko et al., 2022; Barrientos et al., 2024 which explore the impact of choline on gut microbiota and its implications for maternal and fetal health;
• Pregnancy complications: studies such as Wang et al., 2022; Jiang et al., 2013; Zhu et al., 2020 were included to discuss how choline supplementation may mitigate certain pregnancy complications;
• Epigenetic mechanisms: studies such as Wang et al., 2016; Paules et al., 2023 were referenced to illustrate how choline influences epigenetic regulations that affect fetal development;
• Various forms of choline supplements: we also included studies like Kanskar et al., 2023; Ernst et al., 2022; Cho et al., 2020 to highlight the efficacy and safety of different forms of choline supplements.

 

These sections are supported by numerous references to recent and relevant studies.

 

Regarding the choline intake above 930 mg/d, we acknowledge that while some studies have indicated a beneficial effect of this dose on fetal development, these studies have limitations. We emphasize in our manuscript that further randomized controlled trials (RCTs) are necessary to confirm these effects and ensure safety. Moreover, we highlight the issue that many pregnant women do not meet the recommended intake levels of choline, underscoring the need for greater education and awareness.

 

We have thoroughly revised our manuscript to incorporate your insightful comments and hope that these revisions enhance the quality and value of our work.

 

If there are any further areas you feel need improvement, we would greatly appreciate additional suggestions. We are committed to refining our manuscript and addressing any further comments you may have.

Reviewer 2 Report

Comments and Suggestions for Authors

This short narrative review article delves into the importance of dietary choline intake in pregnant women. While the manuscript provides a fundamental examination of the topic, it lacks a thorough analysis of specific key components.

Major points:

-Overlooking microbiota modulation: The review overlooks the potential impact of dietary choline intake on the modulation of microbiota during pregnancy, an increasingly significant area of interest in maternal-fetal health research.

-Limited references: With a mere 27 citations, many of which are dated beyond the past 3-5 years, the review fails to incorporate recent advancements in the field, thereby compromising the credibility and relevance of the article.

-Insufficient coverage: The manuscript does not provide a thorough analysis of the negative impacts of insufficient dietary choline intake on common pregnancy complications (ie. gestational diabetes).

 

Author Response

We made our best efforts to improve the manuscript and we hope we have met your expectations. Thank you for your constructive comments.

 

Response to Reviewer 2 comments

 

We express our appreciation to the reviewers and the editorial board for taking the time and effort to improve our work and provide such insightful comments.

 

We are pleased to have been allowed to revise our manuscript entitled:

Choline – An Underappreciated Component of a Mother-to-Be’s Diet

Reviewer comments

 

This short narrative review article delves into the importance of dietary choline intake in pregnant women. While the manuscript provides a fundamental examination of the topic, it lacks a thorough analysis of specific key components.

 

All responses to reviewer comments are in blue.

 

We are grateful to you for your perceptive observations and suggestions. We concur that a more comprehensive analysis of the key aspects of choline intake in pregnant women would be beneficial. In light of the valuable insights you have provided, we have made the necessary amendments to our manuscript in response. We are extremely thankful for both the time and effort you have invested in reviewing our work.

 

Below we explain how we revised the paper based on your comments and recommendations:

 

Overlooking microbiota modulation: The review overlooks the potential impact of dietary choline intake on the modulation of microbiota during pregnancy, an increasingly significant area of interest in maternal-fetal health research.

Response: We concur with this valid observation. We have added a new section to the paper, 'Maternal choline and gut microbiota', in which we explained the links between choline and gut microbiota in the context of maternal and fetal health.

Please see line 361-413.

 

Limited references: With a mere 27 citations, many of which are dated beyond the past 3-5 years, the review fails to incorporate recent advancements in the field, thereby compromising the credibility and relevance of the article.

Response: We agree that timeliness and the number of sources cited are crucial to ensure the credibility and relevance of the article. We have enriched the article with additional paragraphs (e.g., on the relationship of choline to microbiota, pregnancy complications, epigenetic mechanisms, and outlining different forms of choline supplements), and added numerous references to recent studies (total citations = 79), which we hope has improved the quality of our paper.

 

Insufficient coverage: The manuscript does not provide a thorough analysis of the negative impacts of insufficient dietary choline intake on common pregnancy complications (ie. gestational diabetes).

Response: Based on recently published research, we have added a new section entitled 'Maternal choline deficiency and adverse pregnancy outcomes', which describes the impact of inadequate maternal choline supply on the risk of preterm birth, small for gestational age, preeclampsia, and gestational diabetes.

Please see line 519-572.

 

We made our best efforts to improve the manuscript and we hope we have met your expectations. Thank you once again for your constructive comments.

 

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

In this review, the authors mentioned about nutritional significance of choline for developing baby with recent reports indicating the importance of adequate choline intake during the pregnancy, and lactation period. Choline is well-studied to play an important role not only in the biosynthesis of cell membrane but also in DNA and histone methylation. By addressing these suggestions, the authors can strengthen the quality and impact of their review.

 

I suggest to mention about the molecular mechanism about choline intake and epigenetic regulation in fetal and neonatal brains. Many animal studies have been conducted to elucidate importance of adequate choline intake during pregnancy and lactation period for epigenetic regulation. Please cite some papers on animal experiments and summarize the information.

 

Choline is widely contained in foods as some forms: glycerophosphocholine, free choline and phosphatidylcholine. In line 220-222, they speculated about the difference in dietary effect between the choline forms. Please discuss about the variations in the dietary effect among choline supplements

 

Line 268-270, It is not clear why pregnant women who consumed 480 mg of choline per day showed significantly lower concentrations of: DMG (down 38%), sarcosine (down 49%), and betaine (down 55%). What they compared with in this study? Why adequate choline intake (480 mg) decreased the choline concentrations?

Author Response

We made our best efforts to improve the manuscript and we hope we have met your expectations. Thank you for your constructive comments.

 

Response to Reviewer 3 comments

 

We express our appreciation to the reviewers and the editorial board for taking the time and effort to improve our work and provide such insightful comments.

 

We are pleased to have been allowed to revise our manuscript entitled:

Choline – An Underappreciated Component of a Mother-to-Be’s Diet

Reviewer comments

 

In this review, the authors mentioned about nutritional significance of choline for developing baby with recent reports indicating the importance of adequate choline intake during the pregnancy, and lactation period. Choline is well-studied to play an important role not only in the biosynthesis of cell membrane but also in DNA and histone methylation. By addressing these suggestions, the authors can strengthen the quality and impact of their review.

 

All responses to reviewer comments are in blue.

 

Thank you very much for your insightful comments. Your expertise and valuable suggestions have significantly contributed to the improvement of the paper. We are truly grateful for the time and effort you dedicated to reviewing our work.

 

Below we explain how we revised the paper based on your comments and recommendations:

 

I suggest to mention about the molecular mechanism about choline intake and epigenetic regulation in fetal and neonatal brains. Many animal studies have been conducted to elucidate importance of adequate choline intake during pregnancy and lactation period for epigenetic regulation. Please cite some papers on animal experiments and summarize the information.

Response: Thank you for your suggestion. In response, we have incorporated an additional section in the paper titled "Maternal choline intake and fetal epigenetic regulation". This section provides a comprehensive overview of the influence of choline on fetal epigenetic regulation, as well as a summary of animal studies.

Please see line 277-360.

 

Choline is widely contained in foods as some forms: glycerophosphocholine, free choline and phosphatidylcholine. In line 220-222, they speculated about the difference in dietary effect between the choline forms. Please discuss about the variations in the dietary effect among choline supplements.

Response: A further section has been added to the paper, entitled "Choline supplements", in which the differences in the effects of choline-containing supplements are discussed.

Please see line 474-518.

 

Line 268-270, It is not clear why pregnant women who consumed 480 mg of choline per day showed significantly lower concentrations of: DMG (down 38%), sarcosine (down 49%), and betaine (down 55%). What they compared with in this study? Why adequate choline intake (480 mg) decreased the choline concentrations?

Response: We are grateful for bringing this to our attention. In fact, we did not present this study in an entirely transparent manner. We have revised this section of the paper (line 432-445) to explain more clearly what the authors were comparing in this study and to provide a rationale for why a reduction in choline metabolites was observed with a choline intake of 480 mg.

 

We made our best efforts to improve the manuscript and we hope we have met your expectations. Thank you once again for your constructive comments.

 

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors The adjustments were made and it seems appropriate to accept the article in its final version

Reviewer 2 Report

Comments and Suggestions for Authors

The Authors have satisfactorily addressed the rewiewer's concerns.

Reviewer 3 Report

Comments and Suggestions for Authors

This review was improved very well according to the suggestions.