Dear Dr. Ayehu,

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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?

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Reviewer Comments

First, I would like to commend the authors for selecting the topic of dehydration in preterm neonates admitted to a NICU. This is an important subject due to its high frequency and association with significant morbidity and mortality, which are even more pronounced in developing countries. The topic is sparsely addressed in the literature and clearly required considerable effort from the research team in both data collection and interpretation.

I have read the manuscript thoroughly and identified certain inconsistencies and points of uncertainty, which I have listed below:

1. A critical concern relates to the definition of dehydration used for data collection, as it serves as the foundation for the entire statistical analysis. The methodology does not clearly define “dehydration” in a detailed manner. It appears from the text that dehydration was defined as a 20% loss of birth weight in the first week and a 10% loss after the first week, but other clinical signs and criteria associated with dehydration are mentioned, making it unclear how these were used in conjunction with weight loss. It would be ideal if the authors clearly stated the definition, for example: “dehydration was defined as a weight loss combined with at least one of the following clinical signs”; or “dehydration was defined as weight loss and all clinical signs listed”; or “dehydration was defined as weight loss and two or more clinical signs,” etc. Additionally, I would like to review the data collection form used, as this would help clarify the approach. This point needs to be rewritten to eliminate ambiguity, as it critically affects the rest of the analysis.

2. I recommend including a reference for the definition of dehydration in preterm infants, if available. The text should state clearly whether the definition was based on a prior published article, another author’s experience (with a cited source), or created exclusively for this study.

3. Another point for review is the measurement unit for dehydration. When comparing rates across studies, it is crucial to ensure that comparable units are used. In the literature I reviewed — including articles cited by the authors — dehydration incidence is highly variable due to differing definitions and objectives (e.g., dehydration in exclusively breastfed infants versus dehydration due to excessive fluid loss). Units of measurement also vary (percentage of dehydrated patients, dehydrated patients per 1,000 live births, dehydrated patients per 1,000 exclusively breastfed neonates, etc.). I could not find any publication using the same measurement (dehydration per 1,000 patient days) as used in this study. This discrepancy complicates direct comparisons with existing data. Additionally, inconsistencies arise in the text when the authors compare their results with the literature using differing units. For example, lines 238–239 seem to imply that an incidence of 41 per 1,000 patient days is equivalent to 41%, which is incorrect.

More generally, when the authors cite literature about dehydration definitions, two key studies are mentioned, yet reference 11 is not cited in the section dealing with definitions and comparisons. Upon review, I found that:

• In the Netherlands study (Reference 11), dehydration was defined as weight loss >10% of birth weight combined with a serum sodium ≥150 mEq/L. To minimize bias related to low intake and weight loss due to infection, neonates with UTIs and GERD were excluded.

• In the California study (Reference 22), dehydration was defined as either: (a) a serum sodium ≥150 mEq/L, and/or (b) weight loss ≥12%.

In lines 281–282, I could not locate the cited California reference (22), and the Netherlands reference is not mentioned (although I assume it is Reference 11). The Dutch article uses dehydration incidence per 100,000 exclusively breastfed neonates, while the Californian reference uses an incidence of 2.1 per 1,000 live births. These differing units must be clearly explained in the text, making it evident that the objectives and patient populations differ from those of the present study (dehydration in preterm neonates in a NICU). Additionally, it would be helpful to compare the current results with those from other studies using the same metric (dehydration per 1,000 patient days).

4. The results section contains inconsistencies between data presented in tables and those stated in the conclusion. For example, on line 266, an odds ratio (OR) of 3.38 suggests that incubators are a risk factor for dehydration. However, in the abstract, an OR of 0.19 is stated, implying a protective effect. This discrepancy must be resolved.

Moreover, upon closer inspection of the tables, it is unclear how bed types were classified. The text mentions incubators, radiant warmers, common cribs, and phototherapy units. However, it is ambiguous whether “common cribs” means a regular hospital crib or a bed adjacent to the mother. Additionally, why was phototherapy treated as a bed category, given that it can be administered in any of these environments? This may introduce confounding, as dehydration attributed to an incubator might, in fact, relate to phototherapy exposure.

Importantly, the results and tables do not assess gestational age as a potential risk factor for dehydration. According to literature, extremely preterm neonates have dehydration rates as high as 40%; moreover, the smallest and most premature infants are generally placed in incubators, which may justify the higher dehydration rate observed (if accurately presented). Similar inconsistencies arise in the assessment every four hours: line 268 mentions dehydration risk 1.6 times higher when assessment every four hours was not performed, whereas the abstract suggests that assessment every four hours was protective (OR = 0.31).

5. In the limitations section, it is worth reinforcing the potential for bias. Even if the dehydration definition is deemed adequate, using 20% weight loss in the first week as a threshold appears too high. The usual range of weight loss in preterm infants is 10–15%; >15% is generally significant, making the dehydration threshold too specific and potentially underestimating its true incidence. Other authors (e.g., the article cited as Reference 22) have used >12% as the dehydration cutoff.

Moreover, nutritional intake and weight gain were not assessed. Inadequate weight gain can result from malnutrition (or sepsis/infection), yielding apparent dehydration due to low intake and complicating the differentiation between dehydration and malnutrition. Another consideration is the timing of admission (average of four hours). Infants admitted later may present more dehydrated, and comparing neonates admitted within the first hour versus those admitted later could justify a portion of the dehydration outcomes observed.

6. The discussion on dehydration associated with neonatal asphyxia is superficial and lacks a cited reference. The authors mention that incubators used for asphyxiated neonates may cause dehydration, but this contradicts the common clinical picture of SIADH, which is associated with fluid retention rather than dehydration. This point should be clarified.

Similarly, the role of maternal hypertension as a risk factor for dehydration is insufficiently explained and lacks supporting references. The latest meta analysis of maternal risk factors for dehydration (DOI:10.34763/jmotherandchild.20232701.d-24-00007) does not include maternal hypertension per se, suggesting that its role may be related to prematurity and its associated complications, rather than an independent risk.

7. Statistical inconsistencies should be revisited. In the tables, certain results (e.g., dehydration in neonates <1,500 g versus 1,500–2,500 g) appear inconsistent or unexpected. According to the data, 51 of 96 neonates weighing <1,500 g developed dehydration (around 53%), yielding a nonsignificant result. Meanwhile, 142 of 238 neonates weighing 1,500–2,500 g (around 60%) reportedly have an OR of 1.38 (0.48–3.98), p = 0.56. This inconsistency warrants rechecking for errors.

8. According to the STROBE checklist, the article generally satisfies the requirements for an observational cohort study, with a robust methodological design, appropriate statistical analyses, and well contextualized discussion. Minor improvements could be made in terms of conflict of interest declarations and statements of funding.

9. The reference list requires thorough review for accuracy and duplication. I noticed redundancies (e.g., References 2 and 17, and 6 and 18 are identical). Additionally, some formatting inconsistencies must be corrected (e.g., the term “request PDF” on line 395).

10. Finally, I recommend submitting the manuscript for review by an academic or scientific language editor. While the text is generally intelligible, a review for formal academic English (e.g., replacing “person days” with “patient days”) would further improve its quality and readability. Services such as the American Manuscript Editors or similar platforms can be helpful.

Thank you for submitting this important contribution. I am available for any further questions or clarification.

Reviewer #2: Authors have highlighted common causes of dehydration in developing countries except preterm with surgical conditions presenting with dehydration, which is also a major cause of poor outcome in preterm.

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Reviewer #1: Yes:  Marcos Alves Pavione

Reviewer #2: No

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Attachments

Attachment

Submitted filename: PONE-D-25-27567_reviewer.pdf

Dear Dr. Ayehu,

Please submit your revised manuscript by Sep 26 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.

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• 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 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,

Ricardo Q. Gurgel, PhD

Academic Editor

PLOS ONE

Journal Requirements:

1. 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. 

2. 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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #1: First, I would like to congratulate the authors for their effort in implementing the suggested revisions in a timely manner and for their maturity in recognizing that the critiques were constructive, aiming to make the manuscript more scientifically robust.

Following the revisions, the main points were adequately addressed, and there is a substantial improvement in both the clarity of the text and the comprehensibility of the information. At this stage, only a few minor corrections remain, mostly related to writing style, as outlined below:

1. Although marked as addressed, the term person-days was not replaced by patient-days, which is the correct term for this statistical measure. In some parts of the manuscript, person-days remains, whereas in others it was replaced with preterm-days, which is not used in the literature (e.g., lines 37 and 241). I suggest standardizing to patient-days throughout the text.

2. In line 38, parentheses appear duplicated.

3. Two abbreviations appear in the text without prior full spelling: TBW (line 71) and ANC (line 220).

4. The term mensuration should be replaced with menstrual in line 169.

5. To maintain uniformity of reporting, the percentage of hypothermic cases should be included (lines 228–229).

6. In the limitations section, it is important to add the justification for not using gestational age, as explained in the response letter to the editor.

7. Finally, in the section on justifications for dehydration in the context of neonatal asphyxia, the rationale still does not adequately align with the physiology of dehydration in asphyxia.

Below, I provide a review text that may be used to strengthen the explanation:

Justification for Increased Dehydration in Neonates with Neonatal Asphyxia

The increased dehydration observed in neonates with neonatal asphyxia can be explained by the pathophysiology of the hypoxic–ischemic insult and its renal, hemodynamic, and metabolic repercussions.

1. Redistribution of Blood Flow (“Centralization”)

During asphyxia, there is intense sympathetic activation and a rise in catecholamines. Cardiac output is redistributed to vital organs (brain, heart, adrenal glands), with peripheral vasoconstriction and reduced renal and splanchnic blood flow. This renal hypoperfusion impairs the ability to concentrate urine and retain sodium and water, contributing to increased urinary losses during the post-reperfusion phase.

2. Hypoxic–Ischemic Renal Injury

Asphyxia may cause acute tubular injury (acute tubular necrosis) and nephron dysfunction. Typical alterations include urinary loss of sodium (natriuresis) and chloride, in addition to impaired tubular water reabsorption. This leads to osmotic diuresis and hyponatremia, increasing fluid deficit.

3. Hormonal Alterations

Hypoxia reduces both secretion and responsiveness to vasopressin (ADH) and to the renin–angiotensin–aldosterone system in the initial phase. Tubular resistance to ADH promotes free water loss, while reduced aldosterone activity increases sodium loss, further aggravating dehydration.

4. Increased Metabolic Demand After Reperfusion

Following resuscitation, a hypermetabolic state develops due to systemic inflammatory response and tissue repair. This increases heat production, oxygen consumption, and fluid requirements, accelerating the onset of a negative fluid balance.

5. Additional Losses

Newborns with asphyxia often require mechanical ventilation (sometimes with suboptimal heating and humidification) or phototherapy, both of which increase insensible water loss. Metabolic acidosis may also promote compensatory diuresis.

Pathophysiological Summary

Neonatal asphyxia induces blood flow centralization and hypoxic–ischemic tubular injury, leading to natriuresis and impaired urine concentration. Combined with hormonal dysregulation and increased insensible losses, these changes predispose affected neonates to more rapid and severe dehydration compared to those without asphyxia.

References

1. Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, Kent AL. Neonatal acute kidney injury. Pediatrics. 2015;136(2):e463–e473.

2. Jetton JG, Askenazi DJ. Update on acute kidney injury in the neonate. Curr Opin Pediatr. 2012;24(2):191–196.

3. Perlman JM, Tack ED, Martin T, Shackelford G, Amon E. Acute systemic organ injury in term infants after asphyxia. Am J Dis Child. 1989;143(5):617–620.

4. Kaur S, Jain S, Saha A, Chawla D, Parmar VR, Basu S. Incidence and predictors of acute kidney injury in term neonates with perinatal asphyxia. J Clin Neonatol. 2017;6(4):231–235.

5. Guignard JP, Drukker A. Why do newborn infants have a high plasma creatinine? Pediatrics. 1999;103(4):e49.

6. World Health Organization. Neonatal emergency protocols. Geneva: WHO; 2023.

I remain at your disposal for any further clarification.

Reviewer #2: (No Response)

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Reviewer #1: Yes:  Marcos Alves Pavione

Reviewer #2: Yes:  Samuel Wabada, Department of Surgery, division of Paediatric Surgery, University of Maiduguri, Borno State, Nigeria

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Incidence and predictors of dehydration among preterm neonates admitted to neonatal intensive care unit of Southern Ethiopia hospitals: a Prospective follow-up study

PONE-D-25-27567R2

Dear Dr. Ayehu

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.

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