Educational Aims
The reader will come to appreciate:
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The administration of vitamin D to mothers at-risk of preterm delivery and increased lung function, decreased respiratory distress, TTN, and RDS in newborns.
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The potential benefit of vitamin D injections to infants to reduce the need for non-invasive and mechanical ventilation, need treatment with surfactant.
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The need to measure vitamin D levels in newborns and mothers and identify cases of vitamin D deficiency and the possibility of timely intervention to minimize the risk of respiratory distress in infants.
Abstract
Introduction
Respiratory distress (RD) is the most common cause of admission to the Neonatal Intensive Care Unit (NICU). The role of Vitamin D in the development and fortification of fetal pulmonary architecture and the synthesis of surfactants is well-documented. While different serum levels of 25-hydroxyvitamin D (Vit. D) have been studied for their diagnostic significance in RD, there is limited research on how it specifically affects the development of respiratory problems in infants and their mothers. The purpose of the present study is a systematic review and meta -analysis to evaluate the correlation between serum levels of Vit. D in mothers and newborns with RD, and to determine the impact of treating either population on the clinical outcomes of afflicted infants.
Methods
A comprehensive literature search was conducted across various databases, including PubMed, ScienceDirect, Cochrane Library, ISI, and Google Scholar, using a combination of keywords such as RD, diagnosis, vitamin D, mothers, infants, vitamin D supplementation, Respiratory distress syndrome(RDS), and Transient Tachypnea of Newborn (TTN). The search was carried out until March 2024.The level of vitamin D in both mothers and their infants was systematically extracted and analyzed to determine the diagnostic efficacy of Vit. D levels. The mean difference (MD) was calculated along with a 95% confidence interval to determine the association between the Vit. D levels in newborns and their mothers and the likelihood of RD, RDS and TTN in infants. To assess potential publication bias, a funnel plot was generated and Egger’s regression test was applied, utilizing a random-effects model.
Results
Initially a total of 298 relevant articles was retrieved. Among them, 17 articles with a total of 1,582 infants (745 cases and 837 healthy controls) met the criteria as eligible studies. Of these six were prospective cohort studies, four retrospective case-control studies, four randomized controlled trials (RCTs), and three descriptive-analytical studies. The meta -results revealed a significant association between Vit. D levels and risk of RD in infants (MD = 6.240, 95 %CI: 4.840–7.840, P < 0.001) and mothers (MD = 8.053, 95 %CI: 4.920–11.186, P < 0.001). Furthermore, a strong association was found for risk of RDS (MD = 5.493, 95 %CI: 3.356–7.631, P < 0.001) in infants and TTN (MD = 6.672, 95 %CI: 4.072–9.272, P < 0.001), (MD = 8.595, 95%CI: 4.604-12.586, P < 0.001) both in infants and mothers. Administering 50,000 units of vitamin D to mothers (MD = 8.595, 95 %CI: 4.604–12.586, P < 0.001) prior to childbirth was observed to reduce the likelihood of RD in newborns by 64 % (RR = 0.36, 95 %CI: 0.23–0.57, P < 0.001). Supplemental vitamin D provided to infants was associated with several clinical benefits.
Conclusion
Our meta -results indicated a significant correlation between serum levels of Vit. D and the risk of RD, RDS and TTN in infants. Prophylactic maternal administration of vitamin D plays a protective role against neonatal RD. Additionally, providing vitamin D to premature infants has shown a significant impact in reducing the incidence of respiratory complications.
Introduction
Vitamin D is crucial in maintaining the equilibrium of calcium and phosphorus ions in the body, as well as regulating bone metabolism. 25-hydroxyvitamin D (Vit. D) possesses anti-proliferative, pro-apoptotic and immune-modulating properties. The presence of Vit.D receptors, particularly notable in the fetal lung towards the latter stages of pregnancy, underscores its impact on the lung’s structural and functional evolution, including the differentiation of cells and the synthesis and release of surfactant—a substance vital for breathing . Additionally, it was found that the active form of Vit.D plays a crucial role in enhancing the production of surfactant by type II lung cells . These type II alveolar cells could be key mediators for the regulatory effects of Vit.D. In the context of fetal development, a lack of Vit.D can lead to a deficit in alveolar surfactant, which in turn can impair the proper development of pulmonary structure and function . Vitamin D insufficiency is prevalent among expectant mothers and infants . Maternal blood levels exclusively determine the Vit.D concentration in the developing fetus. Importantly, the fetal levels of Vit.D are typically around two-thirds to three-fourths of those found in the mother .
Notably, preterm infants exhibit lower vitamin D levels in comparison to their term counterparts, attributed to the reduced transfer of vitamin D stores through the placenta. Therefore, premature babies need more vitamin D . Research reveals a striking rate of vitamin D insufficiency, with findings that 79 % of infants were deficient . Insufficient levels of Vitamin D in pregnant women have been linked with the incidence of preterm births . The results of a study showed that vitamin D deficiency(VDD) was seen in 89 % of premature infants . Respiratory distress (RD) is common soon after birth and is usually caused by abnormal respiratory function during the transitional phase from fetal to neonatal life .
Last literature demonstrated that one of the chief contributors to respiratory problems in term and near- term newborns is Transient Tachypnea of the Newborn (TTN), accounting for about one-third to one-half of all infant’s RD cases . Several studies have noted a correlation between vitamin D deficiency(VDD) in both mothers and babies with TTN, suggesting a potential link that merits further investigation. Addressing this nutritional shortfall could be an important step in reducing RD incidences in newborns . Insufficient vitamin D levels at birth have been linked to a greater likelihood of premature newborns developing Respiratory distress syndrome (RDS) Proactively managing and ensuring sufficient vitamin D levels in infant may mitigate the risk of RDS . There is a noted decrease in RDS occurrences as the gestational age at the time of delivery increases, with a reported incidence of 97 % at 23 weeks of pregnancy, decreasing to 65 % at 28 weeks of pregnancy .
Since each study individually may have conclusions with limited statistical power due to small sample size and methodological limitations, the existing systematic review and meta -analysis comprehensively investigated the relationship between maternal and infant vitamin D levels and the incidence of RD. Considering that the systematic review and meta -analysis study to determine the serum level of Vit.D in the diagnosis of RD, the effect of treatment of the mother or the infant on the incidence or clinical course of RD and especially on the two common causes of respiratory distress (RDS, TTN) in infants has not been done, the aim of the this systematic review and meta -analysis of RD is evaluate to the serum level of Vit.D in mother and infants and the effect of mother or infants treatment on the clinical course of baby with RD.
Materials and methods
Study search strategy
This comprehensive systematic review and meta -analysis was conducted in adherence to the stipulations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . To collate relevant literature, a meticulous search was initiated across various electronic databases, including PubMed, Science Direct, Cochrane Library, ISI Web of Science, and Google Scholar. The search terms including RD, incidence, vitamin D, mothers, infants, vitamin D supplementation, RDS, and TTN, were used individually or in combination to retrieve related articles up to March 2024. Additionally, to ensure a comprehensive collection, the reference list of all identified articles was also examined to uncover any potential studies of interest. As the present analysis was constructed on the foundation of data extracted from pre-existing published literature, the need for ethical approval or patient consent was deemed non-applicable.
Criteria for study selection
Criteria for selecting the subjects were as follows; 1) Research studies examining the correlation between serum Vit.D levels among mothers and infants, particularly in cases with and without various forms of infant RD, such as RDS and TTN. 2) Investigations focusing exclusively on infant populations or those that include both infants and their mothers. 3) Research requiring a diagnostic correlation between RD and serum Vit.D levels. 4) Studies provided with enough data for calculating related effect size. 5) Exploration of vitamin D supplementation practices during the gestational period. 6) Examination of the administration of vitamin D supplementation to infants. 7) Analysis of the implications of maternal vitamin D supplementation on neonatal RD outcomes. 8) Evaluation of the effect of infant vitamin D supplementation on the progression and management of RD.
Criteria for exclusion were as follow: 1) Research pertaining to the adult population. 2) Studies using animal models. 3) Instances where full-text articles are unavailable. 4) Narrative or systematic reviews. 5) Correspondences such as letters to the editor or case reports. 6) Information sourced exclusively from medical websites.7) Academic dissertations or theses.
Data collection and quality evaluation
The process of data collection was meticulously conducted independently by two separate researchers (BH and ZHM), using a detailed checklist. In term of discrepancy, the issues were adjudicated through mutual agreement with a third expert (HMM). The data compiled from each paper included the principal author’s name, publication year, origin country, study design, cohort size, numbers of participants in case and control groups, gestational duration, site of sample collection, average maternal and neonatal vitamin D serum concentration along with its standard deviation. The Newcastle-Ottawa Scale (NOS), with a range of 0–9 points, was the tool used for the assessment of the methodological quality of the studies in question. Studies that scored equal to or higher than 5 points were deemed high-quality and thus were incorporated into the analysis.
Statistical analysis
The data were analyzed via specialized meta -analysis software packages, including OpenMeta and Comprehensive Meta-Analysis (CMA) (Biostat, Englewood, NJ). The association between serum vitamin D levels in newborn and their mothers were assessd by determining the mean difference (MD) and a 95 % confidence interval. Cochran Q test and the I 2 index was used to calculate the level of heterogeneity across the included studies. In case of I 2 more than 50 % and a p-value less than 0.05 the MD was calculated using a random effects models, otherwise a fixed effect model was implemented .
In order to identify the sources of heterogeneity, subgroup analysis and sensitivity analysis were conducted. These methodologies provide a deeper understanding of the data and ensure the reliability of the conclusions drawn from the statistical assessment . Begg’s funnel plots and Egger’s regression tests were also applied to evaluate the potential publication bias. The mean and standard deviation of vitamin D levels in infants diagnosed with RDS and TTN, the vitamin D concentration data were analyzed using SPSS software, version 26. This calculation factored in the number of infants in each group, resulting in a weighted mean and standard deviation for both the control and the case groups involved in the study. A p-value less tha 0.05 was considered as a significant level.
Results
Study selection process
The flow diagram of study selection is presented in Fig. 1 . The preliminary search yielded 298 articles, each of which was evaluated for its relevancy to the research question. During the review process, 96 articles were excluded due to duplication or irrelevance based on titles and abstracts. A further 79 articles were eliminated due to the incomplete details regarding methodology, study design, or population focus. Ultimately, a total of 17 studies was elligible to the investigation of the association between serum vitamin D levels and RD risk, and these were subjected to comprehensive analysis as depicted in Fig. 1 .
Study characterization
This research provides a comprehensive review and analysis of literature examining the association between the incidence of RD and serum vitamin D levels. The descriptive summary of all relevant studies is presented in (Table 1) . Only English-language publications in up to March 2024 were enrolled in this study. The study encompasses 17 eligible articles that collectively involve 1582 infants, with 745 cases presenting with RD and 837 healthy controls.
The body of research splits into various subcategories with respect to vitamin D and respiratory distress. Specifically, 17 articles focus on the serum vitamin D levels in infants with versus those without RD, and 10 articles scrutinize these levels in mothers of infants from both groups. Additionally, 7 articles evaluate vitamin D serum levels in infants related to TTN, and 6 articles explore this factor in mothers of newborns with and without TTN. Further, 6 articles investigate serum vitamin D levels in newborns concerning RDS, while 2 articles delve into the maternal serum vitamin D correlation with RDS.
The geographical distribution of the investigations showed that the studies originate from several countries; Iran leads with 7 studies, representing 41.18 % of the total, followed by Turkey with 4 studies accounting for 23.53 %. There are 2 studies each from India (5.89 %) and Egypt (11.76 %), one from China (5.89 %), and 2 from Korea (11.76 %).
The selection of 17 scrutinized articles encompasses diverse research methodologies including 6 prospective cohort studies, 4 cases of retrospective case-control research, 4 randomized controlled trials (RCTs), and 3 descriptive-analytical studies. This multifaceted approach provides a comprehensive perspective on the assessment of vitamin D serum levels as they relate to RD conditions in infants and their mothers.
Table 1 . Characteristics of the studies reviewed in the meta -analysis.
| Respiratory Problems | Neonatal Vit.D mean ± SD | Maternal Vit.D mean ± SD | ||
|---|---|---|---|---|
| Case | Control | Case | Control | |
| RD | 14.87 ± 6.78 | 21.10 ± 9.99 | 15.30 ± 6.99 | 23.33 ± 11.12 |
| TTN | 10.53 ± 5.68 | 17.71 ± 9.13 | 15.24 ± 5.09 | 23.34 ± 10.18 |
| RDS | 16.92 ± 6.52 | 23.60 ± 8.87 | 18.78 ± 10.66 | 23.20 ± 9.94 |
A) Association between maternal or neonatal serum levels of Vit. D levels and the risk of RD in infants
A meta -analysis incorporating data from 17 studies was conducted to determine the MD in serum vitamin D concentrations among infant afflicted with RD including RDS, TTN, and other RD etiologies compared to those without such conditions. Thorough statistical analysis, focusing on the occurrence of these conditions, assessed the serum vitamin D levels across both cohorts. The findings of this comprehensive review highlighted a notable disparity in serum vitamin D levels between infants suffering from RD and their healthy counterparts. This disparity points to a significant association between low serum vitamin D concentrations and the heightened risk of developing RD in the infant’s population, as depicted in Figs. 2 and 3 . The results underscore the potential importance of serum vitamin D as a biomarker for respiratory health in infants (MD = 6.240, 95 %CI: 4.840–7.840, P < 0.001).
Publication Bias: According to a visual assessment of Begg’s funnel plot and reviewing the outcomes of Egger’s regression test, it was determined that there was no evidence of publication bias in the research involving the studied infants (P = 0.163) ( Fig. 4 ).
A systematic review was conducted encompassing data from 10 distinct studies, focusing on the average serum vitamin D concentrations and standard deviations. This information was aggregated to compute the MD, serving as a proxy for the differential in serum vitamin levels between mothers of infants experiencing RD and those without. The comprehensive analysis of the data revealed a marked discrepancy in the vitamin D serum concentrations among the two groups of mothers. These findings underscore a significant correlation between maternal serum vitamin D status and the incidence of RD in newborns (MD = 8.053, 95 %CI: 4.920–11.186, P < 0.001) ( Figs. 5 and 6 ).
Publication Bias: Through reviewing the Begg’s funnel plot and analyzing the outcomes of the Egger’s regression test, no evident publication bias was detected within the researched cohort of participating mothers, as indicated by a statistical non-significance (P = 0.528) ( Fig. 7 ).
