PONE-D-25-11614

Maternal obesity and prenatal alcohol exposure are associated with child development: Results from the Safe Passage Study

PLOS ONE

Dear Dr. Sania,

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.

Please submit your revised manuscript by Oct 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Emma K. Kalk

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2.  Thank you for stating the following financial disclosure:

“This research was supported by grants UH3OD023279, U01HD055154, U01HD045935, U01HD055155, and U01AA016501, issued by the Office of the Director of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders. Ayesha Sania was supported by a career development award from the Fogarty International Center at the NIH (1K01TW012425-01A1). The opinions expressed in this paper are those of the authors and do not necessarily represent the official views of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Development, or Fogarty International Center, the National Institute on Alcohol Abuse and Alcoholism, or the National Institute on Deafness and Other Communication Disorders.”

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

3. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

We will update your Data Availability statement on your behalf to reflect the information you provide.

4. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Many thanks for your submission. Please will you address the Reviewers' Comments below and in the attached PDF.

Apologies for the delay.

[Note: HTML markup is below. Please do not edit.]

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

**********

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

**********

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 study aimed to evaluate cognitive, motor, and language development of 1-year old children by using the Mullen Scales of Early Learning in a prospective cohort study of mother-infant dyads from Northern Plains (NP), USA and Cape Town (CT), South Africa. The relative contributions of prenatal alcohol use, maternal socioeconomic, and nutritional status were investigated within each study site.

The study presents the results of original research. Strengths include the prospective design, the large study sample, inclusion of both high- and low-income settings and measurements by trained assessors using standardized methods. Limitations include assessors not blinded (?) to predictor variables and the short duration of follow-up. I think these should be addressed in the Discussion section.

I have some detailed comments that follow below:

ABSTRACT

1. In the abstract, data from Northern Plains (NP) are presented first, however results starts with Cape Town (CT). I would consistently refer to CT first, then NP – throughout the abstract and manuscript

2. In the abstract, only prenatal alcohol use, maternal socioeconomic and nutritional status are mentioned in the first paragraph, while prenatal and delivery factors are mentioned in the second paragraph, perhaps mention the three main statistical models, i.e. maternal (or prenatal) factors, pregnancy complications and child factors?

INTRODUCTION

1. I was surprised about the potential positive effects of alcohol on cognition in high income settings, and I think the phrasing of the sentence could be misleading, even though the authors explain that it may be an effect of socioeconomic status. There are other references stating the harmful effects of alcohol also in high-income settings, for instance:

a. Hoyme HE, Kalberg WO, Elliott AJ, Blankenship J, Buckley D, Marais AS et al. Updated clinical guidelines for diagnosing fetal Alcohol Spectrum disorders. Pediatrics. 2016;138(2).

b. Lange S, Probst C, Gmel G, Rehm J, Burd L, Popova S. Global prevalence of fetal alcohol spectrum disorder among children and youth: a systematic review and Meta-analysis. JAMA Pediatr. 2017;171(10):948–56.

c. Jacobson JL, Akkaya-Hocagil T, Ryan LM, Dodge NC, Richardson GA, Olson HC, et al. Effects of prenatal alcohol exposure on cognitive and behavioral development: findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts. Alcohol Clin Exp Res. 2021;45(10):2040–58

METHODS

2. Page 7, line 173-175: Are maternal socioeconomic indicators included in both Model 1 and 2?

3. Where the trained assessors performing the Mullen blinded to the predictive factors? That would be a strength that could be emphasized. In case they were not blinded this potential bias should be discussed in Discussion

RESULTS

4. I would be consistent throughout the manuscript starting with the CT results

5. Page 8, line 198-199: Perhaps use the abbreviations CT and NP once they are introduced?

6. I was also curious to know which factors contributed the most to developmental outcomes, the mother or the child factors – perhaps this could be discussed in the Discussion

DISCUSSION

7. Also here I would be consistent starting with CT

8. I would address limitations such as assessors not being blinded to predictors (if that was the case) and the limited follow-up period of 1 year – as children are in continuous development, and 1 year is too early to determine any long-term effects

FIGURES AND TABLES

9. Is there a typo in Table 1: Northern Plaines? (should be Northern Plains)

Reviewer #2: SUMMARY:

This is a secondary analysis of a large cohort study of mother-infant dyads in two areas with high rates of maternal alcohol use. It assesses infant developmental outcomes at 1 year of age in relation to a variety of demographic, prenatal and perinatal exposures using multiple logistic regression analysis controlling for various confounding variables in 3 categories. A number of known demographic and perinatal risk factors for poor developmental outcomes were confirmed to be present in both cohorts. There were many differences in exposures between the Cape Town and Northern Plains sites, though the sites were not compared statistically, with the analysis being conducted internally for each site. For example prenatal alcohol and smoking exposures were much more common in the Cape Town site, and obesity more common in the Northern Plains site. High and ongoing prenatal alcohol exposure with associated with poor developmental outcome in the CT site but not the NP site, whereas the reverse was true for maternal obesity. Prenatal smoking exposure was not associated with poor developmental outcome. The authors concluded that risk factors could potentially be used to identify infants for early developmental interventions, but that these should context specific given the differences found between sites.

MAJOR COMMENTS:

The study is a well designed large cohort study. The cohort, studies methods and primary outcomes have been described in other articles. The findings presented in this paper do not appear to have been published elsewhere and are interesting in themselves. It is stated (line 106) that a subset of women enrolled before 24 weeks were randomly selected for further procedures. Please indicate briefly the process of selection.

At the beginning of the introduction it is mentioned that early cognitive... development is a key determinant of future educational and income achievement (line 54-55). It is not discussed how best to measure this and it should be discussed to what extent developmental outcomes at 1 year are sufficient for this purpose.

The introduction mentions that PAE is more risky in low income settings (line 69) than high income settings and various potential protective factors in high income settings are mentioned. The role of additional risk factors in low income settings should also be mentioned e.g. binge drinking is known to be a common pattern in South Africa.

In the methods section on Study Populations (line 96-109), little background is given regarding the nature of the two study sites. Some further context would help readers to interpret the article e.g. are the residential areas urban vs rural, how do SES generally compare to average in each country?

3750 infants were selected for further procedures (line 106), and 2868 (line 193) were included in this study (i.e. 24% dropouts). Please specify the reasons for dropouts per study site.

The manner in which alcohol and smoking exposures were stratified was described in a previous paper by Dukes et al (2017) and is statistically sophisticated. It allows for assessment of longitudinal drinking and smoking practices through pregnancy, but makes it less obvious to the reader how risky is the drinking at any particular timepoint. Details of drinking and smoking are describe for the cohort as a whole in supplementary table 1. It would be helpful to include rates of binge drinking per trimester, since binge drinking is a specific risk for adverse outcomes of PAE. This could be included in Supplementary Table 1 and/or text, and does not require additional statistical analysis. Given that the analyses are done for the two sites independently, Supplementary Table 1 should give drinking and smoking for the two sites separately. Also, given that substance exposures are a particular point of interest for the Safe Passage study it should be stated why other drug use is not included in the analysis.

On lines 145-6, it is stated that the standard number of drinks of alcohol consumed per day of pregnancy was estimated. This is expressed in Supplementary table 1 as the drinks/trimester. Therefore perhaps better to state here also drinks/trimester rather than drinks/day.

Figures 1-10 outline neurodevelopmental outcomes at each site by risk factor. These are presented as SMDs with 95% CIs. P-values are not included, and should be included. The risk factors included vary considerably between figures - please indicate in the text why this is the case and try to standardize as much as possible which variables are included, and try to at least include smoking in all figures given that it is a stated point of interest.

It is stated in the text (line 217) that in CT probable depression was associated with lower gross motor scores than no depression. It think this should be tempered with a statement that there was a big group with major depression and this was not associated with lower gross motor score (so there is not apparent "dose-response" effect).

In the discussion, it is mentioned that multiple factors classically associated with child development showed similar effects across sites (lines 269-272). Child sex should be included on the list (as an aside, the effect of child sex seems particular large in the CT site, though this is probably hard to interpret). You end up proposing variables to identify infants for early intervention - should child sex be one of these?

In relation to the fact that PAE affected developmental outcome in CT but not NP you indicate (line 287) that residual confounding is unlikely due to a uniform set of confounding variables being assessed. Is it not possible that unmeasured confounder/s could have affected results? (e.g. drug use, for argument sake). In addition, there is evidence that the blood alcohol concentration is an important determinant of risk related to PAE - BAC is determined not just by the level of alcohol consumption but also by volume of distribution/body size (women in NP were bigger - likely reducing effect of PAE), and drinking behavior that was not described (e.g. binges). It would therefore be appropriate to add some further nuance to the discussion of dietary deficiencies (line 289-295).

Maternal obesity was associated with developmental outcome in NP but not CT. It is suggest that this may be due to lower levels of obesity in CT or due to measurement error in CT due to maternal weight being measured on average at 20 weeks vs 16 weeks (average gestations at enrollment) (lines 304-308). I find this unconvincing - a considerable number of individuals in CT measured as obese, and the 4 week difference does not feel obviously sufficient to mask an effect. It seems equally plausible that other explanations are possible (though speculative) e.g. in an environment where dietary deficiencies are more common obesity may be associated with less deficiency of specific nutrients.

The fact that this is a secondary analysis means there should be some caution about the results. This is especially true given the large number of statistical comparisons and the lack of statistical adjustment for this. For example it is not obvious why pre-eclampsia would be associated with a better receptive language score in CT (figure 2), or why resuscitation at birth would be associated with better outcome in NP (figure 7) and this result could perhaps be the result of multiple comparisons? The role of multiple comparisons should be noted in the limitations, which should be stated in more detail. The use of developmental outcomes at 1 year is an imperfect proxy for long term development (outcome at 3 or 5 years of age would be better) - this is also a limitation to be mentioned.

MINOR:

A few typographical errors are highlighted in the uploaded pdf.

**********

6. 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

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Maternal obesity and alcohol_Safe Passage_typos.pdf

Maternal obesity and prenatal alcohol exposure are associated with child development: Results from the Safe Passage Study

PONE-D-25-11614R1

Dear Dr. Sania,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Emma K. Kalk

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: