The present systematic review and meta-analysis demonstrated that prenatal vitamin D was unsuccessful to affect the respiratory and allergy related outcomes in children including RTI, asthma, wheezing, Eczema, allergy, IgE significantly. In addition, subgroup analyses further indicated that vitamin D supplementation during pregnancy, when compared specifically to placebo, was associated with a higher incidence of RTI.
Pooled analyses of 13 RCTs demonstrated that prenatal vitamin D was not associated with statistically significant changes in the risk of RTI in children and the CI does not include thresholds considered clinically meaningful, suggesting any true effect is likely small. Likewise, available body of evidence does not support the protective role of prenatal vitamin D supplementation against childhood RTIs. It is worth noting that, the results of publication bias using Egger’s and Begg’s tests were non-significant which suggests the robustness of results. In line with our meta-analyses results which included three high quality studies [17,18,19,20,21,22], Ganmaa et al. demonstrated that vitamin D supplementation had no significant effects on the risk of acute respiratory infections and tuberculosis in children [25]. However, a systematic review demonstrated that baseline status of vitamin D affecting the infection risk [26]. Experimental and clinical work has proposed that vitamin D may influence respiratory outcomes by supporting alveolar maturation, promoting vascular growth, and modulating inflammatory pathways, potentially lowering the risk of bronchopulmonary dysplasia and respiratory distress syndrome [27]. In addition, it has been shown that reduced expression of surfactant-associated proteins and increased synthesis of collagen in vitamin D deficient animal models are associated with respiratory function inversely [28, 29]. Accordingly, vitamin D deficiency may contribute to reduced alveolar density, thickened airway muscle, and narrowed tracheal diameter, which may reduce lung compliance, and elevate the risk of respiratory diseases [30, 31]. Also, vitamin D deficiency may trigger immune developments through elevated neutrophil and eosinophil activity in the respiratory system [32]. In addition, prenatal vitamin D may not provide effective immunomodulatory benefits alone to cause a decline in RTI incidence in offspring. Although prenatal vitamin D supplementation can usually maintain adequate maternal levels, current evidence suggests it offers little protection against RTI in children. However, the variability in supplementation dosage and duration of vitamin D status may have contributed to the inconsistency in the results across studies. Moreover, RTI incidence may be affected by several confounding factors such as genetic susceptibility, and environmental exposures which could overshadows any effect of prenatal vitamin D level.
Also, prenatal exposure to vitamin D was not effective to reduce the risk of asthma significantly. However, it seems that clinically important effect cannot be ruled out. Moreover, I2 indicates substantial heterogeneity, confirmed by the wide CI and likely opposite effect directions across studies. It seems that prediction interval would span both benefit and harm. This finding is consistent with previous studies. Vitamin D has been known for immunomodulatory effects through regulating T-helper (Th1/Th2) balance, promoting regulatory T-cell development. However, the asthma is a multifactorial health condition, and is affected by several factors. In this context, postnatal vitamin D may play a crucial role to exert beneficial effects on the risk of asthma. However, previous studies have demonstrated that maternal vitamin D supplementation during pregnancy contribute to increased level of vitamin D in cord blood. While it decreases within first year postpartum [18]. The probable mechanism for elevated maternal vitamin D levels is attributed to increased CYP27B1 activity. This enzyme and vitamin D receptor are expressed by both decidual and trophoblast cells which suggesting the immunomodulatory properties of vitamin D [33]. Likewise, it seems that post term vitamin D supplementation may have regulatory effects on wheezing and asthma prevention [33, 34]. Nonetheless, the baseline maternal level of vitamin D appears to have an important effect on the observed outcomes related to asthma. Evidence suggests that vitamin D supplementation may have more pronounced effect in asthma among vitamin D deficient population, while it may be less evident in mothers with normal level of vitamin D.
Moreover, wheezing as a respiratory-related outcome was not associated with the prenatal vitamin D in our pooled analyses in the children. Although the findings are inconclusive, the CIs still allows for the possibility of a clinically meaningful benefit. The limited number of studies should be taken into consideration when evaluating publication bias. Wheezing is a frequent feature of early asthma and may present as either a temporary or persistent condition. Its expression is strongly shaped by environmental factors such as tobacco smoke, air pollution, and viral infections, which may obscure any potential effect of prenatal vitamin D. In addition to respiratory outcomes, allergic values such as eczema, allergy, and IgE were not affected by prenatal vitamin D exposure among offspring. These findings indicate that prenatal exposure of vitamin D may not be considered as a preventive strategy on the development of atopic diseases in childhood. Nevertheless, in clinical view, the substantial clinically meaningful effects are unlikely too. Allergen exposure may induce immune responses and inflammatory signaling pathways which affect the respiratory health. It has been suggested that allergic responses are mediated by a type 2 helper T cell (Th2)-driven immune reaction [35, 36].
Overall, the results of RTI, eczema, and allergic conditions, were consistent, with narrow CIs near the null effect with lower I², suggesting a little heterogeneity across included studies. For asthma and IgE positivity, the wide CIs, substantial I² level, and opposing study effects indicated inconsistency; prediction intervals would likely span both benefit and harm, which reduce certainty.
The strengths of this study are: (1) a systematic review and meta-analysis of the relationship between vitamin D supplementation during pregnancy and different outcomes, providing a reliable assessment based on the available data; (2) the inclusion of multiple RTI studies, which improves the robustness of the findings, which reduces bias and makes them more generalizable. However, there are limitations to this study. First, the generalizability of the results may be limited by the high variability of some results, which may be due to differences in the characteristics of the subjects, the vitamin D baseline level, and the dose of supplementation in the different studies. Secondly, the short follow-up periods included in the studies may not adequately reflect the long-term effects of the supplementation. Furthermore, for results with a relatively low incidence, e.g., asthma and some allergic conditions, the statistical power of the pooled data (seven studies) may be limited. Likewise, the results should be interpreted with caution. In addition, lower number of included studies for asthma, wheezing, eczema, allergy, and Ig E, limited the publication bias analyses using egger’s and Begg’s tests. Moreover, the timing of vitamin D supplementation in pregnancy was not clearly specified in the included studies which represents a limitation affecting the interpretation of the results.
link