Vitamin D supplementation in pregnant or breastfeeding women or young children for preventing asthma.

Background: Randomised controlled studies evaluating vitamin D supplementation in pregnancy or early childhood for preventing childhood asthma have yielded inconclusive results. Previous systematic reviews of vitamin D for asthma prevention focused on studies comparing vitamin D to placebo or studies intervening in pregnancy, limiting the body of evidence.

Objectives: Primary: to evaluate the efficacy of any vitamin D supplementation and high-dose vitamin D supplementation in early life, including the prenatal period, for preventing asthma in children. Secondary: to assess the efficacy of vitamin D supplementation: • for preventing asthma in children at risk of vitamin D deficiency at the start of the trial or whose mothers were at risk; • by intervention timing and the cumulative dose administered; • in preventing factors associated with early childhood asthma, including atopic dermatitis, respiratory tract infections, sensitisation to allergens, and airway inflammation.

Search methods: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and the Cochrane Airways and Skin Trial Registers. We checked the reference lists of relevant systematic reviews and meta-analyses. We contacted authors to obtain additional study information as needed. Date of last search: October 2023.

Selection criteria: We included randomised controlled studies comparing higher versus lower/standard dose vitamin D (≤ 400 international units (IU)/day) or any vitamin D versus placebo/no treatment in generally healthy pregnant or lactating women or children up to five years of age that evaluated childhood asthma, wheeze, atopic dermatitis, airway infections, allergic sensitisation, and airway inflammation. We excluded trials recruiting populations with pre-existing conditions.

Data collection and analysis: We followed standard Cochrane methodological procedures, including using Cochrane's Screen4Me workflow. We considered participants rather than events as the unit of analysis, performed fixed-effect meta-analysis, and reported risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs) for four comparisons: (1) any vitamin D versus placebo/no supplementation in pregnant or breastfeeding women; (2) any vitamin D versus placebo/no supplementation in infants or children; (3) high versus low/standard dose vitamin D in pregnant or breastfeeding women; (4) high versus low/standard dose vitamin D in infants or children. Our outcomes were: asthma, wheeze, atopic dermatitis, airway infections, allergic sensitisation, airway inflammation, and adverse events. We narratively described results that could not be meta-analysed. We used the Cochrane risk of bias tool (RoB) to assess bias in the studies. We used GRADE to assess the certainty of the evidence.

Main results: We included 18 studies involving a total of 10,611 participants, of which 16 contributed data to meta-analyses. Studies were conducted around the world, with most taking place in higher-income countries. The dose and frequency of vitamin D ranged from 200 IU/day to 100,000 IU bolus quarterly, and the duration of supplementation ranged from 28 days to two years. Comparison 1. Any vitamin D versus placebo/no supplementation in pregnant or breastfeeding women (4 studies) Compared to placebo or no supplementation, any vitamin D given to pregnant or breastfeeding women may reduce the risk of early childhood asthma (RR 0.17, 95% CI 0.05 to 0.61; 1 study, 236 participants; low-certainty evidence) and likely has little to no effect on childhood airway infections (RR 1.00, 95% CI 0.97 to 1.04; 3 studies, 1564 participants; moderate-certainty evidence). The evidence is very uncertain for wheeze, atopic dermatitis, allergic sensitisation, airway inflammation, or adverse events. Comparison 2. Any vitamin D versus placebo/no supplementation in infants or children (5 studies) Compared to placebo or no supplementation, any vitamin D given to infants or children may have little to no effect on childhood wheeze (RR 0.89, 95% CI 0.68 to 1.16; 2 studies, 431 participants; low-certainty evidence), atopic dermatitis (RR 1.01, 95% CI 0.80 to 1.28; 2 studies, 448 participants; low-certainty evidence), airway infections (RR 0.92, 95% CI 0.83 to 1.01; 2 studies, 500 participants; low-certainty evidence), allergic sensitisation (RR 2.25, 95% CI 0.60 to 8.50; 1 study, 228 participants; low-certainty evidence), or airway inflammation measured by eosinophil counts (RR 1.06, 95% CI 0.65 to 1.74; 1 study, 226 participants; low-certainty evidence). The evidence is very uncertain for asthma and adverse events. Comparison 3. High versus low/standard dose vitamin D in pregnant or breastfeeding women (4 studies) Compared to low/standard dose, high-dose vitamin D given to pregnant or breastfeeding women likely reduces the risk of childhood wheeze (RR 0.79, 95% CI 0.64 to 0.98; 3 studies, 1439 participants; moderate-certainty evidence), but likely results in little to no difference in childhood asthma, although the direction and magnitude of effect is similar to that for wheeze (RR 0.81, 95% CI 0.63 to 1.04; 2 studies, 1355 participants; moderate-certainty evidence). Compared to low/standard dose, high-dose vitamin D in pregnancy likely has little to no effect on childhood atopic dermatitis (RR 0.91, 95% CI 0.75 to 1.11; 3 studies, 1439 participants; moderate-certainty evidence), airway infections (RR 0.95, 95% CI 0.82 to 1.11; 3 studies, 1441 participants; moderate-certainty evidence), or allergic sensitisation (RR 1.01, 95% CI 0.87 to 1.18; 2 studies, 1110 participants; moderate-certainty evidence). The evidence is very uncertain for adverse events. No studies evaluated airway inflammation. Comparison 4. High versus low/standard dose vitamin D in infants or children (7 studies) Compared to low/standard dose, high-dose vitamin D given to infants or children may slightly reduce airway infections (RR 0.94, 95% CI 0.90 to 0.98; 6 studies, 2385 participants; low-certainty evidence) but may have little to no effect on atopic dermatitis (RR 0.76, 95% CI 0.55 to 1.05; 1 study, 769 participants; low-certainty evidence). The evidence is very uncertain for asthma, wheeze, allergic sensitisation, and adverse events. No studies evaluated airway inflammation.

Authors' conclusions: Evidence supporting a protective effect of vitamin D supplementation in early life, including the prenatal period, on childhood asthma is limited. Moderate-certainty evidence suggests that high-dose vitamin D in pregnancy likely helps prevent childhood wheeze. Evidence for the effects of vitamin D in early childhood on asthma or wheeze is less certain. Additional high-quality studies, especially in infants and children, are needed to establish with any certainty the effects of vitamin D supplementation on childhood asthma and associated factors.