Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

Yoo Jinie Kim; Gina Lim; Ran Lee; Sochung Chung; Jae Sung Son; Hye Won Park

doi:10.1371/journal.pone.0279064

. 2023 Jan 26;18(1):e0279064. doi: 10.1371/journal.pone.0279064

Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

Yoo Jinie Kim ¹, Gina Lim ², Ran Lee ^1,³, Sochung Chung ^1,³, Jae Sung Son ^1,³, Hye Won Park ^1,^3,^*

Editor: Roberta Hack Mendes⁴

PMCID: PMC9879443 PMID: 36701289

Abstract

Background

Methods

We searched PubMed, EMBASE, and the Cochrane Library up through July 20, 2021. The search terms were ‘premature infant’, ‘vitamin D’, and ‘respiratory distress syndrome’. We retrieved randomized controlled trials and cohort and case-control studies. For statistical analysis, we employed the random-effects model in Comprehensive Meta-Analysis Software ver. 3.3. We employed the Newcastle-Ottawa Scales for quality assessment of the included studies.

Results

A total of 121 potentially relevant studies were found, of which 15 (12 cohort studies and 3 case-control studies) met the inclusion criteria; the studies included 2,051 preterm infants. We found significant associations between RDS development in such infants and vitamin D deficiency within 24 h of birth based on various criteria, thus vitamin D levels < 30 ng/mL (OR 3.478; 95% CI 1.817–6.659; p < 0.001), < 20 ng/mL (OR 4.549; 95% CI 3.007–6.881; p < 0.001), < 15 ng/mL (OR 17.267; 95% CI 1.084–275.112; p = 0.044), and < 10 ng/ml (OR 1.732; 95% CI 1.031–2.910; p = 0.038), and an even lower level of vitamin D (SMD = –0.656; 95% CI –1.029 to –0.283; p = 0.001).

Conclusion

Although the vitamin D deficiency definitions varied and different methods were used to measure vitamin D levels, vitamin D deficiency or lower levels of vitamin D within 24 h of birth were always associated with RDS development. Monitoring of neonatal vitamin D levels or the maintenance of adequate levels may reduce the risk of RDS.

Introduction

Vitamin D participates in mineral-ion homeostasis (e.g., calcium and phosphorus) and bone metabolism [1]. Apart from these classical functions, a role for vitamin D in lung development has been demonstrated by several studies (including animal works) [1–12]. Vitamin D regulates cell proliferation/differentiation, apoptosis, and angiogenesis in the lungs [6] and elsewhere in the body [1]. A recent meta-analysis found an association between the vitamin D level within 24 h of birth and the risk of bronchopulmonary dysplasia (BPD) in premature neonates [13].

Vitamin D receptors are expressed mainly in the lung during late pregnancy [2]; vitamin D thus affects lung functional and anatomical development, including cell differentiation and surfactant synthesis/secretion [3, 5, 14]. Animal studies performed by Nguyen et al. [7–9] and Marin et al. [2, 10] using rat models revealed high-level expression of vitamin D receptor on type II alveolar cells at the end of gestation, when alveolar cell differentiation and surfactant synthesis commence [2, 10]. Rehan et al. [3] reported that the active form of vitamin D enhanced surfactant synthesis by type II pulmonary cells. Surfactant phospholipid and protein B synthesis increased in human pulmonary cancer cell lines. Such laboratory-based work raised the question of whether the respiratory distress syndrome (RDS) risk is increased in preterm neonates with vitamin D deficiencies in clinical settings.

Several clinical studies have described low vitamin D levels in preterm infants who suffered from RDS [15, 16]. However, Matejek et al. [17] found no association between vitamin D deficiency and RDS. Given such conflicting evidence, we performed a systematic review and meta-analysis to explore whether vitamin D deficiency or the vitamin D level measured within 24 h of birth was associated with an increased risk of RDS.

Methods

Search strategy and study selection

This meta-analysis was reported based the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations [18, 19] (S1 Table). We searched PubMed, EMBASE, and the Cochrane Library using the following search terms: [‘premature infant’ or preterm or newborn or neonate or ‘low birth weight infant’ or ‘very low birth weight infant’ or ‘extremely low birth weight infant’] and [‘Vitamin D’ or ‘25-hydroxyvitamin D’ or 25-hydroxyergocalciferol or ergocalciferol or cholecalciferol or hydroxycholecalciferol or calcifediol or dihydroxycholecalciferol or 25(OH)D or 1,25(OH)2-vitD], and [‘respiratory distress syndrome’ or RDS or ‘hyaline membrane disease’ or ‘transient tachypnea’ or ‘pulmonary surfactants’]. Additionally, we manually checked all reference lists in an effort to identify additional relevant studies. The last search was performed on July 20, 2021. We did not place any restrictions, including on language.

We initially reviewed the titles and abstracts of the articles, and then reviewed the full-text articles. The reviews were performed independently by two reviewers (HW Park and Y Kim) using criteria that we determined before the review process for inclusion in the meta-analysis. Any disagreement during the process was resolved by the third author (R Lee).

Inclusion and exclusion criteria

We chose to include studies that satisfied the following criteria. Study design: A randomized controlled trial, or a cohort study (prospective or retrospective), or a case-control study; Patients and interventions (exposures): Newborns for whom vitamin D levels were known; Outcome: RDS. We excluded case reports, case series, editorials, review articles, and letters. Articles with inadequate or irrelevant data for analysis were also excluded after reading the full text.

Outcomes

The primary outcome was neonatal RDS diagnosed via chest radiographic findings and clinical presentations (e.g., tachypnea, nasal flaring, chest retraction, and cyanosis) within hours of birth.

Data extraction

We extracted the data from all included studies via full text review. Two authors (Y Kim and HW Park) reviewed and extracted data using a pre-prepared form. The data were the first author, publication year, study period, study design, study location, study population, sample size, method of vitamin D measurement, definition of vitamin D deficiency, diagnostic criteria for RDS, sample size, number of patients diagnosed with RDS or vitamin deficiency, and vitamin D levels or odds ratios of RDS if vitamin D was deficient for RDS, when possible. If there were any discrepancies during the review process with two authors (YJ Kim and HW Park), we discussed these with the third reviewer (R Lee) and we reviewed the study again.

Study quality assessment

We (Y Kim and HW Park) also separately assessed the quality of included studies using the Newcastle–Ottawa Scale (NOS) [20]. Disparities in the assessment were resolved through discussion with the third author (R Lee). This scale is composed of three domains that explore selection, comparability, and outcome. The three domains contain a total of eight items. We gave one star to an item that met the criteria, except for comparability (two stars). The score range is 0–9, and the total score indicates the methodological quality of the study; ≤ 3 is low, 4–5 is moderate, and ≥ 6 is high. The scores of each study for each items of NOS are provided in the S2 Table.

Data synthesis and statistical analyses

We performed this meta-analysis to calculate a pooled estimate of odds ratio (OR) for the association between vitamin D deficiency and the occurrence of RDS. We performed the analysis separately when studies reported more than one result based on different definitions of vitamin D deficiency; we thus kept the statistical assumption of the independence of an effect.

We used the I² statistic to evaluate statistical heterogeneity; the value is expressed as the percentage of total variation across studies. If the I² value is greater than 50%, this indicates the presence of significant heterogeneity across the studies. We performed our analysis conservatively; based on estimation of the between-study variations in effect size, we used a random-effects model, which yields wider CIs than a fixed-effects model [21]. We also conducted sensitivity analyses to evaluate the effect of each study on the robustness of the combined estimates and contribution to the pooled OR. A cumulative analysis was conducted by adding one study at a time, by year of publication, to evaluate temporal trends.

To detect publication bias, the Begg and Mazumdar rank-correlation test and Egger’s regression test were used. Publication bias was also evaluated based on the distribution of the effect sizes against the standard errors on a graphically displayed funnel plot. We detected publication bias by inspecting the funnel plot. Asymmetry of the funnel plot or a P-value < 0.05 in the Begg and Mazumdar rank-correlation test or Egger’s regression test were taken to indicate the presence of publication bias. The current meta-analysis was conducted using Comprehensive Meta-Analysis software version 3.3 (Biostat Inc., Englewood, NJ, USA).

Results

Literature search and study selection

We show the flow of study selection and exclusion in Fig 1. In total, 38 duplicates were removed from the 121 studies retrieved in the initial search, including the manual search. During review of abstracts and titles, 48 studies were removed, leaving 35 studies. After full-text review, 20 studies were excluded for the reasons described in Fig 1, leaving 15 studies for meta-analysis.

Characteristics of the included studies

The characteristics of the 15 studies [5, 11, 15–17, 22–31] included in this meta-analysis are shown in Table 1. When evaluating the association between vitamin D deficiency and RDS, 2,051 infants were included. The mean birth weight of the study population in the 15 included studies was 1,833.2 g (standard error 143.91), and the mean gestational age of the infants at birth was 32.0 weeks (standard error 0.90); one study [26] did not describe gestational age at birth.

Table 1. Characteristics of studies included in the meta-analysis.

Studies	Study design	Nation	Study population	Time of vitamin D measurement	Methods of measurement of vitamin D	Definition of vitamin D deficiency (serum 25(OH)D level)	NOS
Ataseven et al. [22]	prospective cohort	Turkey	GA 29–35 weeks	< 24 h after birth	LC-MS	severe: <10 ng/mL moderate: 10–20 ng/mL mild: 20–30 ng/mL	8
Fettah et al. [23]	prospective cohort	Turkey	GA < 32 weeks	soon after birth (cord)	ELISA	<15 ng/mL	7
Onwuneme et al. [24]	prospective cohort	Ireland	GA <32 weeks or BW <1,500g	< 24 h after birth	chemiluminescence	<12 ng/mL	5
Yu et al. [15]	retrospective cohort	China	GA<32 weeks	<24 h after birth	chemiluminescence	<20 ng/ml	8
Mohamed et al. [25]	prospective case–control	Egypt	GA <34 weeks	< 24 h after birth	ELISA	<20 ng/ml	5
Yang et al. [26]	retrospective cohort	China	GA <37 weeks	1^st sampling after birth	automatic biochemical analyzer	measured value^*	4
Boskabadi et al. [27]	prospective case-control	Iran	GA < 34 weeks and BW < 2,000g	NA	ELISA	severe: <10 ng/mL moderate: 10–20 ng/mL mild: 20–30 ng/mL	7^†
Kazzi et al. [28]	prospective cohort	USA	Preterm infants and BW ≤1,250 g	< 24 h after birth	LC-MS	≤10 ng/mL	5
Kim et al. [29]	retrospective cohort	Korea	BW <1,500 g	< 24 h after birth	LC-MS and chemiluminescence	severe: <10 ng/mL deficiency: 10–20 ng/mL insufficiency: 20–30 ng/mL	8
Treiber et al. [30]	prospective cohort	Slovenia	newborn	soon after birth (cord)	chemiluminescence	severe deficiency: <10ng/mL deficiency: 10–20 ng/ml insufficiency: 20–30 ng/ml	4
Ardastani et al. [5]	prospective cohort	Iran	GA 28–37 weeks and BW ≥1,000 g	soon after birth (cord) or <24h after birth	ELISA	severe deficiency: <10ng/mL deficiency: 10–20 ng/ml inadequate: 20–30 ng/ml	7
Matejek et al. [17]	prospective cohort	Czech	BW <1,500 g	soon after birth (cord)	LC-MS	<10 ng/mL	7
Al-Beltagi et al. [31]	prospective case-control	Egypt	Preterm infants	soon after birth (cord)	ELISA	measured value^*	5^†
Dogan et al. [16]	prospective cohort	Turkey	GA ≤32 weeks	< 6 h after birth	LC-MS	severe: <5 ng/mL moderate: 5–15 ng/mL mild:15–30 ng/mL	7
Zhang et al. [11]	prospective cohort	China	GA< 32 week	< 24 h after birth	chemiluminescence	severe deficiency: <10ng/mL deficiency: 10–20 ng/ml insufficiency: 20–30 ng/ml	7

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* The measured value of vitamin D was used in the analysis

^† The two case-control studies were assessed using the Newcastle-Ottawa Scale for quality assessment of case-control studies; the other studies were assessed using the Newcastle-Ottawa Scale for the assessment of cohort studies

Abbreviations: GA, gestational age at birth; BW, birth weight; g, gram; NOS, Newcastle–Ottawa Scale, LC-MS, liquid chromatography-tandem mass spectrometry; ELISA, enzyme linked immunosorbent assay

The definition of vitamin D deficiency in each study is shown in Table 1. The occurrence rates of RDS are presented by reference to the severity of vitamin D deficiency. Thus, we used the various levels in meta-analysis: a vitamin D level below 30 ng/ml in two studies [5, 27], 20 ng/ml in six studies [11, 15, 25, 27, 29, 30], 15 ng/ml in two studies [16, 23], and 10 ng/ml in nine studies [11, 17, 22, 24, 25, 28–30, 32].

The scores on the Newcastle–Ottawa Scale for quality assessment of all studies are shown in Table 1.

Pooled meta-analysis results

There were significant associations between vitamin D deficiency and RDS, regardless of the definition of vitamin D deficiency; thus at cut off values of 30 ng/ml, 20 ng/ml, 15 ng/ml, and 10 ng/ml.

Vitamin D deficiency defined using a cut off value of 30 ng/ml was associated with RDS (OR 3.478; 95% CI 1.817–6.659; p < 0.001; Fig 2A) in the random-effects model analysis. Among the included studies, there was no significant heterogeneity (p = 0.517; I² = 0%). No single study affected the pooled result on sensitivity analysis (S1-1 Fig in S1 Fig) or cumulative analysis (S1-2 Fig in S1 Fig). Publication bias was not assessed since only two studies were included.

Vitamin D deficiency defined as a vitamin D level of less than 20 ng/ml was also associated with RDS (OR 4.549; 95% CI 3.007–6.881; p < 0.001; Fig 2B) in the random-effects model analysis. There was no significant heterogeneity (p = 0.983; I2 = 0%) among the included studies. No single study affected the result of the sensitivity analysis (S2-1 Fig in S2 Fig) or cumulative analysis (S2-2 Fig in S2 Fig). In the process of funnel plot inspection (S2-3 Fig in S2 Fig), asymmetry was detected, but there was no evidence of publication bias in either the Begg and Mazumdar rank-correlation test (p = 0.452) or Egger’s regression test (p = 0.131).

Vitamin D deficiency defined as a vitamin D level of less than 15 ng/ml was associated with RDS (OR 17.267; 95% CI 1.084–275.112; p = 0.044; Fig 2C) in the random-effects model analysis. There was significant heterogeneity (p = 0.006; I² = 86.8%) between the included studies (n = 2). We performed sensitivity analysis and cumulative analysis, but only two studies were included. We could not assess publication bias because of the small sample size.

Vitamin D deficiency defined as a vitamin D level of less than 10 ng/ml was also associated with RDS (OR 1.732; 95% CI 1.031–2.910; p = 0.038; Fig 2D) in the random-effects model analysis. There was heterogeneity (p = 0.014; I² = 58.12%) among the included studies, and some studies affected the results of sensitivity analysis (S3-1 Fig in S3 Fig) and cumulative analysis (S3-2 Fig in S3 Fig). In the process of funnel-plot inspection, the presence of publication bias was not clear (S3-3 Fig in S3 Fig). In both the Begg and Mazumdar rank-correlation test (p = 0.118) and Egger’s regression test (p = 0.156), there was no evidence of publication bias.

A lower level of vitamin D was also associated with RDS (SMD = -0.656; 95% CI -1.029 to -0.283; p = 0.001; Fig 3) in the random-effects model. On assessment of heterogeneity, there was significant heterogeneity among studies (p < 0.001; I² = 83.50%), but the result of sensitivity analysis (S4-1 Fig in S4 Fig) or cumulative analysis (S4-2 Fig in S4 Fig) showed no significant change in the pooled results. On inspection of the funnel plot, we could not distinguish the presence of publication bias (S4-3 Fig in S4 Fig). Thus, we performed the Begg and Mazumdar rank-correlation test (p = 0.368) and Egger’s regression test (p = 0.202), which showed no publication bias.

Discussion

We found that vitamin D deficiency (defined using all existing criteria) was significantly associated with RDS development. Moreover, a lower level of vitamin D within 24 h of birth was associated with RDS. Thus, vitamin D deficiency may be a risk factor for RDS.

RDS reflects impaired or delayed surfactant synthesis and secretion, triggering pulmonary atelectasis and respiratory distress in preterm infants. The incidence of RDS decreases with increasing gestational age at birth, from 97% at 23 weeks of gestation to 65% at 28 weeks [33], 10.5% at 34 weeks, and 0.3% at 38 weeks [34]. The administration of antenatal corticosteroids to the mother and exogenous instillation of surfactant soon after birth are established preventative strategies for RDS [35]. The methods and timing of surfactant therapy have changed over the past decade. A thin catheter is used for prophylactic treatment of babies at high risk of RDS. Rescue therapy increasingly features early, nasal, continuous positive airway pressure and antenatal steroids [36].

In the clinical setting, vitamin D deficiency is frequently observed in pregnant women and infants [37–39]. Vitamin D deficiency in pregnant women is associated with preterm birth [40–42]. Moreover, vitamin D levels are lower in preterm infants than in term infants because less stored vitamin D is transferred transplacentally, and preterm infants have higher vitamin requirements [43]. Vitamin D levels at birth were lower in neonates born at less than 28 weeks of gestation [39], and vitamin D deficiency was more prevalent in neonates born at less than 32 weeks of gestation [38] than in more mature neonates. The vitamin D level of the fetus depends entirely on maternal circulation of vitamin D, and the level of 25(OH)D in the fetus is about two-thirds to three-quarters of the maternal level [44]. Levels measured within 24 h after birth (before supplementation), or in cord blood, correlate well with the levels in the mother and the fetus. The concentration of 25-(OH)D in blood is widely used as a biomarker reflecting vitamin D status because of the long half-life of 25-(OH)D [1, 45]. Most of the studies in this meta-analysis obtained vitamin D levels on the first day of life, but two studies did not describe the exact times of vitamin D measurements [26, 27].

No consensus definition of vitamin D deficiency has been established; studies have used different cutoff values when defining vitamin D deficiency [46]. The Institute of Medicine Committee and the American Academy of Pediatrics [47, 48] recommend that vitamin D levels should be maintained above 12 ng/ml (close to 20 ng/ml) for normal bone accretion in infants less than 1 year of age. In the study by Holick [1], a vitamin D level above 20 ng/ml was recommended.

Various hormones, including corticosteroids and thyroid hormones, are involved in surfactant synthesis [23]. Vitamin D, a steroid hormone, plays roles in surfactant synthesis and lung maturation [2, 3, 5, 11, 12]. Moreover, vitamin D deficiency itself has been associated with an increased need for assisted ventilation and a longer duration of ventilator support in preterm infants [24], and with development of BPD [13] as well as RDS. An adequate vitamin level may help to reduce the risk of RDS, BPD, and the need for ventilator support.

Limitation of the study

There are several limitations to our study. First, each study used different diagnostic criteria when defining vitamin D deficiency, and small numbers of studies were thus included in the meta-analyses for the different cutoff values. This may have influenced the pooled effect. We were not able to assess the publication bias of studies with cutoff values of less than 30 ng/ml in terms of vitamin D deficiency. Second, various methods of measuring vitamin D levels in the blood have been used. Immunoassays such as enzyme-linked immunosorbent assays (ELISAs) and chemiluminescence assays, and liquid chromatography tandem mass spectrometry (LC-MS), were used to assess vitamin D status (Table 1). LC-MS is the gold standard method for 25-(OH)D measurement [43, 49]. Immunoassays yield higher vitamin D levels [43], and the performance thereof is not as good as that of LC-MS, especially at low vitamin D concentrations (< 8 ng/mL) [50]. The variabilities of vitamin D levels in this range seldom affect the identification of a vitamin D deficiency. Third, we could not control for any effect(s) of gestational age and/or the use of antenatal corticosteroids on RDS development; we could work only with the data from the included studies. Lastly, we found both heterogeneity and effects of individual studies on the results of sensitivity analysis and cumulative analysis for vitamin D deficiency < 10 ng/ml. Neonates included in the group with vitamin D >10 ng/ml could also have been affected by vitamin D deficiency (< 30 ng/ml or < 20 ng/ml). The use of different measuring methods for vitamin D could be why heterogeneity was present and the robustness of the sensitivity and cumulative analyses varied.

Conclusion

This meta-analysis demonstrated an association between vitamin D deficiency or the vitamin D level within 24 h after birth, and the risk of RDS. In this meta-analysis, the included studies described the risk of RDS at various levels of vitamin D, thus vitamin D levels below 30 ng/ml, 20 ng/ml, 15 ng/ml, and 10 ng/ml respectively. Monitoring of neonatal vitamin D levels soon after birth and of maternal vitamin D levels during pregnancy, and maintaining adequate vitamin D levels, may help to reduce the risk of respiratory morbidities including RDS and BPD [13] in preterm infants. Although, there is no consensus regarding what constitutes vitamin D deficiency or good vitamin D supplementation, vitamin D deficiency based on a level below 30 ng/ml showed an increased risk of RDS development in this meta-analysis. Thus, we cautiously assume that the optimal level of 25(OH)D should be higher than 30 ng/ml.

Supporting information

S1 Table. PRISMA checklist.

(DOC)

Click here for additional data file.^{(71KB, doc)}

S2 Table. The quality assessment of included study using the Newcastle-Ottawa Scale.

(DOCX)

Click here for additional data file.^{(17.7KB, docx)}

S1 Fig. Sensitivity analysis (1–1), and cumulative analysis (1–2) for the relationship between vitamin D deficiency defined using a cut off value of 30 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(37.4KB, zip)}

S2 Fig. Sensitivity analysis (2–1), cumulative analysis (2–2), and funnel plot (2–3) for the relationship between vitamin D deficiency defined using a cut off value of 20 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(203.1KB, zip)}

S3 Fig. Sensitivity analysis (3–1), cumulative analysis (3–2), and funnel plot (3–3) for the relationship between vitamin D deficiency defined using a cut off value of 10 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(286.1KB, zip)}

S4 Fig. Sensitivity analysis (4–1), cumulative analysis (4–2), and funnel plot (4–3) for the relationship between vitamin D level and RDS.

(ZIP)

Click here for additional data file.^{(197.8KB, zip)}

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

All authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0279064.r001

Decision Letter 0

Roberta Hack Mendes

22 Sep 2022

PONE-D-21-40028Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysisPLOS ONE

Dear Dr. Park,

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: Yes

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5. Review Comments to the Author

Reviewer #1: Thank you to the authors for this interesting study with results that can be applied to clinical practice. Overall, I couldn’t identify major changes that are needed. However I believe that two confusion biases might be addressed: gestational age and corticoid use during pregnancy. Please refer to the full review for details.

Reviewer #2: Abstract:

• The abstract is exemplary –a comprehensive but concise summary of background methods, results, and interpretation.

Introduction:

• The Introduction is very short – some material in the Discussion may be more useful in the Introduction to provide context for the study (see below).

• I think the Introduction does not strongly state what this meta-analysis can add to the existing body of knowledge and how it will be useful – it would be good to add a sentence on this.

Methods:

• “This meta-analysis was performed based on the reporting guidelines for systematic reviews and meta-analyses”: The PRISMA guidelines do not provide guidance on how to perform a review, only how it should be reported/written up. For this reason, I would recommend changing the phrasing to “This meta-analysis is reported in accordance with the reporting guidelines…” I would also name PRISMA specifically.

• The text states that two reviewers independently carried out screening, extraction, and quality assessment. For extraction, it is stated that discrepancies were resolved by discussion with a third reviewer. It would be good to clarify if this was the case for screening and quality assessment also.

• A fuller description of the Newcastle-Ottawa Scale would be helpful for readers who are unfamiliar with it, to clarify what each of the scales measure. A brief description of each scale would suffice.

• “We performed this meta-analysis to calculate a pooled estimate of how vitamin deficiency affected the occurrence of RDS”: The rest of the paper examines the association between VDD and RDS, without specifying that one causes the other or affects the other. I would change the phrasing in this sentence to refer to association, rather than one affecting the other, for consistency and to accurately describe the analysis.

Results:

• The findings are presented very clearly; the tables and figures are uniformly excellent and easy to read.

• First paragraph and Figure 1 refer to a “manual search”. What did the manual search involve? This should be explained in the Methods section. It would be good practice for a review to include forward and backward citation chasing (i.e. screening of papers that cite the included studies and screening of reference lists of included studies) – if this has been carried out, it’s an important part of the search strategy and should be mentioned.

• The meta-analysis appears to be appropriate. Stratifying studies by levels of VDD is appropriate, rather than combining all studies in a large meta-analysis. The difference in measurement methods is an important limitation but is duly noted in the limitations section.

• My only critique of the figures would be the labels for the forest plots. The meaning of the labels “Favours VDD” or “Favours RDS” with the + and – symbols isn’t very clear – these should be changed or explained in a note below each figure in a full sentence (e.g. “Favours VDD (+) = favours the existence of a positive association, such that greater VDD was associated with higher risk of RDS” or similar).

• It might be useful to include the full breakdown of scores (at an item level or scale level) for the quality assessment in the supplementary material. This provides greater transparency and justification for the scores presented in Table 1, and also allows the reader to quickly see what issues were examined in the quality assessment if they are not familiar with the tool.

Discussion:

• The information in the first three paragraphs is useful context and might be more useful in the introduction – presenting the existing evidence for a link between VDD and RDS and the basis for why this meta-analysis was carried out. The Discussion should primarily focus on the findings from this meta-analysis and comment only briefly how they fit into the existing research (as is done in the last sentence of paragraph 3 in the Discussion) – setting up the existing research should be done in the Introduction. Note that this is based on the conventions and journals I’m used to – if this journal has other standards for the different sections of the paper, feel free to disregard this comment.

• In paragraph 4, it is probably unnecessary to cite the statistics again – the details are in the Results section and the Discussion can focus on the broader picture and what those findings mean.

• The Discussion generally establishes the implications of the findings of the meta-analysis very well, without overstating. The section on limitations is thoughtful and state not only what the limitations were, but also what the impact of those limitations may have been on the findings.

General comments:

• The entire paper is extremely well-written; it is very concise but the methods are presented in comprehensive detail, the flow of ideas is logical, the results are presented with great clarity and are easy to follow, tables and figures are used extremely well, and the supplementary material is useful. I hope that my comments are helpful to refine the article and extend my best wishes to the authors.

• I will note that my expertise is in systematic reviews, not vitamin deficiency or respiratory medicine. For this reason my review focuses primarily on the methods and presentation of the findings. I have probably missed some nuances in the interpretation of the findings and how they stack up against existing work in the field, and perhaps some further limitations of the article that should be addressed by other peer reviewers with more specific knowledge of the area.

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Reviewer #1: Yes: Taciane Alegra

Reviewer #2: No

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Attachment

Submitted filename: My review_130922.pdf

Click here for additional data file.^{(59.5KB, pdf)}

Attachment

Submitted filename: PRISMA_2020_abstract_checklist.pdf

Click here for additional data file.^{(47.8KB, pdf)}

PLoS One. 2023 Jan 26;18(1):e0279064. doi: 10.1371/journal.pone.0279064.r002

Author response to Decision Letter 0

14 Oct 2022

Answer for editor’s comments:

We have highlighted all of the revisions in yellow.

#1. Abstract

I believe it can be improved to synthesize the study better. Remember that most people will read the full text only if the abstract is interesting enough to call their attention. For example, some phrases from the introduction are better written than from the abstract and could be used to improve it.

� As you recommended, we have made the Abstract more interesting.

I also suggest adding that authors performed the meta-analysis model the reviewers used to synthesize the data, instead of citing which software they had used.

� As you recommended, we have added text to the Abstract:

“For statistical analysis, we employed the random-effects model in Comprehensive Meta-Analysis Software ver. 3.3.”

In addition to that, I believe that the PRISMA 2020 checklist for abstracts could be used as a guide to improve the abstract.

� We followed the PRISMA 2020 Abstract checklist. The details follow.

Title: Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

Background (objectives): Growing evidence suggests an association between the vitamin D levels and respiratory outcomes of preterm infants. The objective of this systematic review and meta-analysis was to explore whether premature neonates with a vitamin D deficiency have an increased risk of respiratory distress syndrome (RDS).

Methods

Eligibility criteria: The search terms were ‘premature infant’, ‘vitamin D’, and ‘respiratory distress syndrome’. We retrieved randomized controlled trials and cohort and case-control studies.

Information sources: We searched PubMed, EMBASE, and the Cochrane Library up through July 20, 2021.

Risk of bias: We employed the Newcastle-Ottawa Scales for quality assessment of the included studies.

Synthesis of results: For statistical analysis, we employed the random-effects model in Comprehensive Meta-Analysis Software ver. 3.3.

Results

Included studies: A total of 121 potentially relevant studies were found, of which 15 (12 cohort studies and 3 case-control studies) met the inclusion criteria; the studies included 2,051 preterm infants.

Synthesis of results: We found significant associations between RDS development in such infants and vitamin D deficiency within 24 h of birth based on various criteria, thus vitamin D levels < 30 ng/mL (OR 3.478; 95% CI 1.817–6.659; p < 0.001), < 20 ng/mL (OR 4.549; 95% CI 3.007–6.881; p < 0.001), < 15 ng/mL (OR 17.267; 95% CI 1.084–275.112; p = 0.044), and < 10 ng/ml (OR 1.732; 95% CI 1.031–2.910; p = 0.038), and an even lower level of vitamin D (SMD = –0.656; 95% CI –1.029 to –0.283; p = 0.001).

Discussion

Limitation of evidence: Although the vitamin D deficiency definitions varied and different methods were used to measure vitamin D levels, vitamin D deficiency or lower levels of vitamin D within 24 h of birth were always associated with RDS development.

Interpretation: Monitoring of neonatal vitamin D levels or the maintenance of adequate levels may reduce the risk of RDS.

#2. Introduction

The authors wrote “The level of vitamin D within 24 h of birth is associated with the risk of BPD in preterm infants [3]”, what gives an impression that this is well established in the literature, followed by: “Previous studies raised the possibility that the risk of respiratory distress syndrome (RDS) is increased in vitamin D-deficient preterm neonates, but the clinical relevance remains uncertain.” showing that this matter is controversial. Please, could the authors correct this disagreement? Also, could please authors provide citations to support the last quote?

� As suggested by the Editor, we have corrected (and provide more details on) the “disagreement” issue.

#3. Results

1) Manual search - Could the authors please provide details about it? Does it mean that they searched the references?

� We have added about it as follow;

Additionally, we manually checked all reference lists in an effort to identify additional relevant studies.

2) In the flow chart (Fig 1) it is described that 2 articles were excluded due to “inadequate data for analysis” and 12 because “irrelevant data for analysis.” However, it was described in the methods that inclusion and exclusion criteria were based on design of the study, not on outcomes. So, please clarify that in the text.

� We now write:

“Study design: A randomized controlled trial, or a cohort study (prospective or retrospective), or a case-control study; Patients and interventions (exposures): Newborns for whom vitamin D levels were known; Outcome: Respiratory distress syndrome (RDS).”

Outcome:

“The primary outcome was neonatal RDS diagnosed via chest radiographic findings and clinical presentations (e.g., tachypnea, nasal flaring, chest retraction, and cyanosis) within hours of birth.”

3) Regarding the 2 papers that had “inadequate data for analysis”, were they incomplete? Did the reviewers try to contact the study authors?

1) “25-OH Vitamin D deficiency in preterm babies: Incidence and association with morbidities” (Köksal et al.; poster below)

� This study did not compare the RDS incidence between infants with severe and moderate vitamin D deficiencies. The authors wrote: “There was no difference in RDS between severe and moderate vitamin D deficiency cases.” Thus, we excluded the poster.

2) “The potential effects of vitamin D deficiency on respiratory distress syndrome among preterm infants: (Al-Matary et al.)

� This paper included data on vitamin D deficiency, but the focus was on the surfactant doses for the vitamin D-deficient and normal groups, not the incidence of RDS. Thus, we excluded the paper.

� We did contact both authors by sending e-mails, but received no replies.

4) Besides that, the primary outcome isn’t clear in the text, although one can infer that it is “respiratory distress syndrome”. It would be reasonable to state it clearly in the text, as the authors could study other outcomes linked to that (like death or need of surfactant treatment, for example).

� We now describe the outcomes separately, as follows:

Outcomes

The primary outcome was neonatal RDS diagnosed via chest radiographic findings and clinical presentations (e.g., tachypnea, nasal flaring, chest retraction, and cyanosis) within hours of birth.

#4. Characteristics of included studies

1) Regarding weight and gestational age, besides the mean, could authors please provide either standard deviation or the range for those data? They are relevant for clinicians reading the paper.

� We have added the standard errors for gestational age and birth weight:

The mean birth weight of the study population in the 15 included studies was 1,833.2 g (standard error 143.91), and the mean gestational age of the infants at birth was 32.0 weeks (standard error 0.90); one study [28] did not describe gestational age at birth.

2)Table 1

- “Newcastle-Ottawa Scale for case-control study was used for study quality assessment, others used one for cohort study” - I couldn’t understand this phrase, could you please rephrase it?

� We were seeking to state that different forms of the Newcastle-Ottawa scale were used (based on the type of study); thus, we have rephrased the sentence:

The two case-control studies were assessed using the Newcastle-Ottawa Scale for quality assessment of case-control studies; the other studies were assessed using the Newcastle-Ottawa Scale for the assessment of cohort studies

- In the line explaining the study of Kim et. al, could you please correct the format of the column with vitamin D deficiency definition? So it is in the same pattern as the others.

� As recommended, we have changed the format of the column that lists the definitions of vitamin D deficiency in the line explaining the study of Kim et al. as follow;

“severe: <10 ng/mL, deficiency: 10―20 ng/mL, insufficiency 20-30 ng/mL”

#5. Discussion

BPD is used in the text, but the authors didn’t make it clear that it refers to Bronchopulmonary dysplasia. Please add it on page 1, when the term first appears.

� As recommended, we now mention that BPD refers to bronchopulmonary dysplasia (first paragraph on page 1).

After reading the paper, two potential confusion biases still were not clear to me.

1. Influence of the gestational age - As the authors stated: “The incidence of RDS decreases with increasing gestational age at birth, from 97% at 23 weeks of gestation to 65% at 28 weeks [42], 10.5% at 34 weeks, and 0.3% at 38 weeks of gestation”. Thus, we know that gestational age itself can be a protective factor for developing RDS. Did the reviewers perform any subgroup analysis regarding gestational age? Would it be possible with the data available? Could vitamin D deficiency play different roles in different patient subsets?

� We could not divide the studies by gestational age; thus, a subgroup analysis was not possible. This is a limitation of meta-analyses such as our study, and could be explored in future studies. We have added this as a limitation.

2. Corticoid administration during pregnancy -there is evidence showing that corticosteroid administration in preterm pregnancies can result in lower incidence of RDS. Did the studies included in the meta-analysis have controlled this factor? Did the reviewers consider that while doing the analysis? I believe both biases are relevant and should - at least - be cited in the discussion.

� We also could not control for this factor because we could work only with the data from the included studies. We have added this as a limitation.

Answer for Reviewer #1 comments:

Thank you to the authors for this interesting study with results that can be applied to clinical practice. Overall, I couldn’t identify major changes that are needed. However, I believe that two confusion biases might be addressed: gestational age and corticoid use during pregnancy. Please refer to the full review for details.

� We could not control for any effects of gestational age or antenatal steroid use on the development of RDS because we could work only with the data from the included studies. This is a limitation of meta-analyses. We have added this limitation.

Answer for Reviewer #2 comments:

# Abstract:

The abstract is exemplary –a comprehensive but concise summary of background methods, results, and interpretation.

� We have revised the Abstract.

Growing evidence suggests an association between the vitamin D levels and respiratory outcomes of preterm infants. The objective of this systematic review and meta-analysis was to explore whether premature neonates with a vitamin D deficiency have an increased risk of respiratory distress syndrome (RDS). We searched PubMed, EMBASE, and the Cochrane Library up through July 20, 2021. The search terms were ‘premature infant’, ‘vitamin D’, and ‘respiratory distress syndrome’. We retrieved randomized controlled trials and cohort and case-control studies.

For statistical analysis, we employed the random-effects model in Comprehensive Meta-Analysis Software ver. 3.3. We employed the Newcastle-Ottawa Scales for quality assessment of the included studies. A total of 121 potentially relevant studies were found, of which 15 (12 cohort studies and 3 case-control studies) met the inclusion criteria; the studies included 2,051 preterm infants. We found significant associations between RDS development in such infants and vitamin D deficiency within 24 h of birth based on various criteria, thus vitamin D levels < 30 ng/mL (OR 3.478; 95% CI 1.817–6.659; p < 0.001), < 20 ng/mL (OR 4.549; 95% CI 3.007–6.881; p < 0.001), < 15 ng/mL (OR 17.267; 95% CI 1.084–275.112; p = 0.044), and < 10 ng/ml (OR 1.732; 95% CI 1.031–2.910; p = 0.038), and an even lower level of vitamin D (SMD = –0.656; 95% CI –1.029 to –0.283; p = 0.001). Although the vitamin D deficiency definitions varied and different methods were used to measure vitamin D levels, vitamin D deficiency or lower levels of vitamin D within 24 h of birth were always associated with RDS development. Monitoring of neonatal vitamin D levels or the maintenance of adequate levels may reduce the risk of RDS.

# Introduction:

• The Introduction is very short – some material in the Discussion may be more useful in the Introduction to provide context for the study (see below).

• I think the Introduction does not strongly state what this meta-analysis can add to the existing body of knowledge and how it will be useful – it would be good to add a sentence on this.

� We have revised and added the statement on introduction (below).

Vitamin D participates in mineral-ion homeostasis (e.g., calcium and phosphorus) and bone metabolism [1]. Apart from these classical functions, a role for vitamin D in lung development has been demonstrated by several studies (including animal works) [1-12]. Vitamin D regulates cell proliferation/differentiation, apoptosis, and angiogenesis in the lungs [6] and elsewhere in the body [1]. A recent meta-analysis found an association between the vitamin D level within 24 h of birth and the risk of bronchopulmonary dysplasia (BPD) in premature neonates [13].

Vitamin D receptors are expressed mainly in the lung during late pregnancy [2]; vitamin D thus affects lung functional and anatomical development, including cell differentiation and surfactant synthesis/secretion [3, 5, 14, 15]. Animal studies performed by Nguyen et al. [7-9] and Marin et al. [2, 16] using rat models revealed high-level expression of vitamin D receptor on type II alveolar cells at the end of gestation, when alveolar cell differentiation and surfactant synthesis commence [2, 16]. Rehan et al. [3] reported that the active form of vitamin D enhanced surfactant synthesis by type II pulmonary cells. Surfactant phospholipid and protein B synthesis increased in human pulmonary cancer cell lines. Such laboratory-based work raised the question of whether the respiratory distress syndrome (RDS) risk is increased in preterm neonates with vitamin D deficiencies in clinical settings.

Several clinical studies have described low vitamin D levels in preterm infants who suffered from RDS [17, 18]. However, Matejek et al. [19] found no association between vitamin D deficiency and RDS. Given such conflicting evidence, we performed a systematic review and meta-analysis to explore whether vitamin D deficiency or the vitamin D level measured within 24 h of birth was associated with an increased risk of RDS..

# Methods:

� We have revised the text:

“This meta-analysis was reported based the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations”

� We have revised the description of screening, data extraction, and quality assessment as follows:

In the “Search strategy and study selection” section:

“We initially reviewed the titles and abstracts of the articles, and then reviewed the full-text articles. The reviews were performed independently by two reviewers (HW Park and Y Kim) using criteria that we determined before the review process for inclusion in the meta-analysis. Any disagreement during the process was resolved by the third author (R Lee).”

In the “Data extraction” section:

“If there were any discrepancies during the review process with two authors (YJ Kim and HW Park), we discussed these with the third reviewer (R Lee) and we reviewed the study again.”

In the “Study quality assessment” section:

“We (Y Kim and HW Park) also separately assessed the quality of included studies using the Newcastle–Ottawa Scale (NOS) [22]. Disparities in the assessment were resolved through discussion with the third author (R Lee).”

� We have added the items included in the Newcastle-Ottawa Scales and we now describe the quality assessment results in detail in the Supplementary Material (S2 Table)

� We now mention the manual search in the Methods:

“We performed this meta-analysis to calculate a pooled estimate of odds ratio (OR) for the association between vitamin D deficiency and the occurrence of RDS.”

# Results:

• The findings are presented very clearly; the tables and figures are uniformly excellent and easy to read.

� We have explained about manual search in Method section as follow;

Additionally, we manually checked reference lists to identify relevant studies for this meta-analysis.

� We have revised the existing text and added new text as follows:

Second, various methods of measuring vitamin D levels in the blood have been used. Immunoassays such as enzyme-linked immunosorbent assays (ELISAs) and chemiluminescence assays, and liquid chromatography tandem mass spectrometry (LC-MS), were used to assess vitamin D status (Table 1). LC-MS is the gold standard method for 25-(OH)D measurement [45, 51]. Immunoassays yield higher vitamin D levels [45], and the performance thereof is not as good as that of LC-MS, especially at low vitamin D concentrations (< 8 ng/mL) [52]. The variabilities of vitamin D levels in this range seldom affect the identification of a vitamin D deficiency.

� We have removed the figure labels. A positive OR means that vitamin D deficiency was associated with a risk of RDS.

� We have added the items included in the Newcastle-Ottawa Scales and we now describe the detailed results of our quality assessment in the S2 Table (in addition to the total scores in Table 1).

# Discussion:

� We have changed both the Introduction and Discussion. Some findings mentioned in the Discussion are now addressed in the Introduction to support the aim of the study.

� We have removed the statistical details from the Discussion.

The revision reads:

“We found that vitamin D deficiency (defined using all existing criteria) was significantly associated with RDS development. Moreover, a lower level of vitamin D within 24 h of birth was associated with RDS. Thus, vitamin D deficiency may be a risk factor for RDS.”

� We appreciate the kind comments that we received.

Attachment

Submitted filename: Answers for reviewers comments -submit2.docx

Click here for additional data file.^{(701.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0279064.r003

Decision Letter 1

Roberta Hack Mendes

1 Dec 2022

Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

PONE-D-21-40028R1

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PLoS One. doi: 10.1371/journal.pone.0279064.r004

Acceptance letter

Roberta Hack Mendes

4 Dec 2022

PONE-D-21-40028R1

Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

Dear Dr. Park:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. PRISMA checklist.

(DOC)

Click here for additional data file.^{(71KB, doc)}

S2 Table. The quality assessment of included study using the Newcastle-Ottawa Scale.

(DOCX)

Click here for additional data file.^{(17.7KB, docx)}

S1 Fig. Sensitivity analysis (1–1), and cumulative analysis (1–2) for the relationship between vitamin D deficiency defined using a cut off value of 30 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(37.4KB, zip)}

S2 Fig. Sensitivity analysis (2–1), cumulative analysis (2–2), and funnel plot (2–3) for the relationship between vitamin D deficiency defined using a cut off value of 20 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(203.1KB, zip)}

S3 Fig. Sensitivity analysis (3–1), cumulative analysis (3–2), and funnel plot (3–3) for the relationship between vitamin D deficiency defined using a cut off value of 10 ng/ml and RDS.

(ZIP)

Click here for additional data file.^{(286.1KB, zip)}

S4 Fig. Sensitivity analysis (4–1), cumulative analysis (4–2), and funnel plot (4–3) for the relationship between vitamin D level and RDS.

(ZIP)

Click here for additional data file.^{(197.8KB, zip)}

Attachment

Submitted filename: My review_130922.pdf

Click here for additional data file.^{(59.5KB, pdf)}

Attachment

Submitted filename: PRISMA_2020_abstract_checklist.pdf

Click here for additional data file.^{(47.8KB, pdf)}

Attachment

Submitted filename: Answers for reviewers comments -submit2.docx

Click here for additional data file.^{(701.4KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting information files.

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PERMALINK

Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis

Yoo Jinie Kim

Gina Lim

Ran Lee

Sochung Chung

Jae Sung Son

Hye Won Park

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Search strategy and study selection

Inclusion and exclusion criteria

Outcomes

Data extraction

Study quality assessment

Data synthesis and statistical analyses

Results

Literature search and study selection

Fig 1. Flow chart of study selection process.

Characteristics of the included studies

Table 1. Characteristics of studies included in the meta-analysis.

Pooled meta-analysis results

Fig 2. Meta-analysis for the association between vitamin D deficiency and respiratory distress syndrome according to the definition of vitamin D deficiency.

Fig 3. Meta-analysis for the association between vitamin D level and respiratory distress syndrome.

Discussion

Limitation of the study

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Roberta Hack Mendes

Roles

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Decision Letter 1

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