Vitamin D Supplementation in Pregnant Women or Infants for Preventing Allergic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Allergic diseases represent a significant global health burden, arising from the interplay between genetic susceptibility and environmental factors. The prevalence of these conditions is approximately 10% in infants without a family history of allergies and 20% to 30% in those with an allergic first-degree relative. Environmental factors, including vitamin D status, have been increasingly recognized as influential in the onset of allergic diseases. Low vitamin D levels during early life have been associated with increased risks of asthma, eczema, food allergy, wheezing, allergic rhinitis, and respiratory infections. Vitamin D, obtained from sunlight exposure and dietary sources, plays a complex role in immune modulation, affecting both innate and adaptive immune systems. Given its widespread deficiency, particularly among pregnant women, vitamin D supplementation has been proposed as a potential strategy for preventing allergic diseases in offspring. However, the efficacy of such supplementation remains unclear.

This systematic review and meta-analysis aimed to evaluate the effectiveness of vitamin D supplementation in pregnant women, infants, or children for the primary prevention of allergic diseases. The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered with the International Prospective Register of Systematic Reviews (CRD42020167747). The review included randomized controlled trials (RCTs) published up to March 1, 2020, sourced from MEDLINE (PubMed), EMBASE (OVID), and the Cochrane Central Register of Controlled Trials. The search strategy employed keywords related to pregnancy, lactation, infants, children, vitamin D, and allergic diseases. Studies were selected based on predefined inclusion criteria, focusing on RCTs involving healthy pregnant women, lactating females, or children up to 5 years of age, with specified vitamin D supplementation protocols and outcomes related to asthma, wheezing, eczema, allergic rhinitis, lower respiratory tract infections (LRTIs), or food allergy.

The initial search yielded 1251 studies, of which seven RCTs met the inclusion criteria. These trials were conducted in various countries, including the UK, New Zealand, Denmark, Finland, and the USA, and involved diverse populations. The studies varied in terms of the timing, dosage, and duration of vitamin D supplementation, as well as the follow-up periods, which ranged from 6 months to 6 years. The included RCTs evaluated the effects of vitamin D supplementation on allergic outcomes such as asthma, wheezing, eczema, allergic rhinitis, LRTIs, and food allergy. The risk of bias in the included trials was assessed using the Cochrane Collaboration’s tool, with most studies deemed to have a low risk of bias across key domains.

The meta-analysis revealed that vitamin D supplementation in pregnant women or infants did not significantly reduce the risk of developing allergic diseases. Specifically, the pooled risk ratios (RRs) for asthma or wheezing were 1.01 (95% CI: 0.81–1.26) for pregnant women, 1.00 (95% CI: 0.70–1.43) for infants, and 0.35 (95% CI: 0.10–1.25) for combined supplementation in pregnant women and infants. Similarly, no significant effects were observed for eczema (RR: 0.92, 95% CI: 0.79–1.06), allergic rhinitis (RR: 0.93, 95% CI: 0.78–1.11), LRTIs (RR: 0.97, 95% CI: 0.85–1.11), or food allergy. Sensitivity analyses confirmed the robustness of these findings.

The results of this review are consistent with previous studies suggesting that vitamin D supplementation may not be effective in the primary prevention of allergic diseases. However, several factors may have influenced these outcomes. First, the timing and duration of supplementation varied across studies, with some trials initiating vitamin D supplementation during the second trimester of pregnancy and others during infancy. Early lung development, which begins in the second trimester, may be a critical window for vitamin D’s effects, and initiating supplementation earlier in pregnancy could yield different results. Second, the dosage of vitamin D supplementation ranged from 400 IU/day to 200,000 IU/day, and it is possible that lower doses may not have achieved sufficient serum 25-hydroxyvitamin D levels to exert protective effects. Third, the populations studied varied in terms of baseline vitamin D status and genetic susceptibility to allergic diseases, which could have influenced the outcomes.

Despite the null findings, the role of vitamin D in immune modulation and lung development cannot be dismissed. Animal and laboratory studies have demonstrated that vitamin D influences lung structure and function, as well as immune responses. Vitamin D receptors are present on immune cells and in the airways, and vitamin D has been shown to modulate inflammation and regulate immune system development. These biological mechanisms suggest that vitamin D could still play a role in allergic disease prevention, but further research is needed to identify the optimal timing, dosage, and target populations for supplementation.

This systematic review has several strengths, including a comprehensive search strategy, adherence to PRISMA guidelines, and the inclusion of only RCTs to minimize confounding. However, there are limitations to consider. The heterogeneity in study designs, populations, and intervention protocols may have affected the results. Additionally, some studies included populations at high risk of allergic diseases due to family history, while others included average-risk populations, which could have influenced the outcomes. The lack of long-term follow-up in some trials also limits the ability to assess the sustained effects of vitamin D supplementation.

In conclusion, this meta-analysis found no significant evidence to support the use of vitamin D supplementation in pregnant women or infants for the primary prevention of allergic diseases. Future research should focus on identifying specific phenotypes of asthma and allergic diseases that may respond to vitamin D supplementation, as well as exploring the optimal timing and dosage of supplementation. Long-term follow-up studies are also needed to evaluate the sustained effects of vitamin D on allergic outcomes. Until more definitive evidence is available, vitamin D supplementation should be guided by individual needs and clinical considerations, particularly for bone health.

doi.org/10.1097/CM9.0000000000001951

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