PONE-D-22-10468Maternal dietary folate intake with folic acid supplement use and childhood wheeze and eczema in the Japan Environment and Children's StudyPLOS ONE

Dear Dr. Araki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Numerous advantages of the authors’ manuscript over the studies so far published include the largest-ever sample size and the full consideration of potential confounders, which was highly appreciated by Reviewer 3. Taken together, I would like to encourage the authors to revise the manuscript while making clearer the following points that the three reviewers have kindly raised. Let me summarize as follows.

1. Perhaps the significance of the findings is more strongly upheld if the authors discuss more on the rationale of, and the consequences of, the adjustment for numerous covariates (Reviewer 1). Confounding by maternal education and smoking may be of a particular relevance with this regard considering the points addressed in the paper recommended by Reviewer 2.

2. Please rephrase the hypothesis the authors posed; “maternal intake of supplement along with dietary folate intake” is a bit too vague. I suppose that, because of this unclarity, Reviewer 1 has felt that readers are not carefully guided to the analysis plan. Also, the additional analysis (LL. 234 and onward) sounds abrupt to me as this analysis was not originally planned.

3. Please re-check the consistency and clarity of the text (Reviewer 2). An example include “however” in LL 225 and “however” in the following sentence.

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We look forward to receiving your revised manuscript.

Kind regards,

Kenji J Tsuchiya, MD, PhD

Academic Editor

PLOS ONE

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2. You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

3.  One of the noted authors is a group or consortium "Japan Environment and Children’s Study (JECS) Group". In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The long effect of maternal intake of dietary folate and folic acid supplement on health of offspring is worthy of assessment because folic acid supplement has become popular for pregnant women around the world. Unfortunately, the evidence from the population remains limited. This study focused on maternal dietary folate intake with folic acid supplement use and childhood wheeze and eczema, and found something interesting. However, some technical issues should be addressed further.

1. It is unclear why the authors selected wheeze and eczema as indicator for allergy. Maybe more review should be included in the part of introduction.

2. An important technical flaw is that authors did not provide strategy of statistical analysis for data in details. If possible, add it please.

3. Due to lots of potential confounders, how did authors consider them? It could be one of limitation of this study.

4. The data used here was from a cohort project. Lots of participants were excluded due to various reasons. Is there any difference between the participants included and those excluded? If yes, whether is the association biased? Maybe something more should be done about this issue.

5. In this study, whether or not other allergens during childhood are considered, which could confound this association between maternal folate or folic acid and allergy of offspring. Pls say something more in discussion.

6. Conclusion should be done with caution because of confounders and weak association from the table 4.

Reviewer #2: In general, this is a good manuscript aiming to understand the relationship between folic acid intake, wheeze and eczema. The authors used data from nearly 100,000 mother-child pairs whose folic acid intake was self-reported. This is a main limitiation of the study that should be stressed.

Please give more details on the instrument for dietary data collection (FFQ)

Please consider, if possible, the adherence to recommendation on folic acid use during pregnancy. Have the authors information on the timing of folic acid intake (before pregnancy or after the conception). This is also important to understand the effect of the duration of folic acid intake. (please consider the following 10.3390/ijerph17020638).

I would also suggest a double-check of the text for revising minor errors and typos.

Reviewer #3: This is an excellent work. The authors found that high maternal intake of dietary folate was a risk factor for wheeze and eczema in children at 2 years of age, but folic acid supplements were not associated with wheeze and eczema in the offspring. The strength of this work is the nationwide birth cohort study with huge sample with 84,361 mothers and 85,114 children. Some minor suggestions or comments are as follows:

1. TITLE. I suggest the authors to modify the current title to a more accurate and attractive one such as "Maternal dietary folate intake with folic acid supplement use and wheeze and eczema in children aged 2 years in Japan: A nationwide cohort study".

2. About the limitations in DISCUSSION. Another two aspects should be mentioned:

(1) The authors didn't consider the indoor and outdoor environmental factors. The authors mentioned "These factors (covariates) were selected based on previous studies that reported an association between folic acid intake during pregnancy and allergies in offspring", but the environmental factors have been widely considered to be the risk factors for childhood allergic sympotms/diseases. Some references include:

-- Onset and remission of childhood wheeze and rhinitis across China - associations with early life indoor and outdoor air pollution. Environment International 2019, 123: 61-69.

-- Preconceptional, prenatal and postnatal exposure to outdoor and indoor environmental factors on allergic diseases/symptoms in preschool children. Chemosphere 2016, 152: 459-467

(2) As the authors mentioned in ABSTRACT that "The study does not provide evidence that pregnant women should be denied folic acid intake owing to the increased risk early onset allergies in offspring", further/future studies focusing on the its association with allergic diseases, asthma or rhinitis, in elder preschool children aged 3-6 years are necessary to confirm the conclusions of the present work.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Maternal dietary folate intake with folic acid supplements and wheeze and eczema in children aged 2 years in the Japan Environment and Children’s Study

PONE-D-22-10468R1

Dear Dr. Araki,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kenji J Tsuchiya, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you very much for addressing all the questions and comments the reviewers have raised. They are satisfied with your replies.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: This manuscript was improved according to the reviewers' comments. The quality is now fine. I suggest to accept this work for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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