Association between maternal vitamin D supplementation during pregnancy and the risk of acute respiratory infections in offspring: a systematic review and meta-analysis.

Abstract

Background
Acute respiratory infections (ARIs) are a leading cause of mortality in infants. Vitamin D supports innate antimicrobial effector mechanisms in leucocytes and respiratory epithelium. Maternal vitamin D supplementation during pregnancy has been proposed as a preventive strategy, however, an up-to-date synthesis of available data from randomised controlled trials (RCTs) has not been conducted.

Methods
We conducted a systematic review and meta-analysis of aggregate data from RCTs of maternal vitamin D supplementation for prevention of ARIs in offspring. Data were analysed using a random-effects model. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and the ClinicalTrials.gov from database inception to 5th August 2025. No language restrictions were imposed. Double-blind RCTs of maternal vitamin D supplementation, with placebo or lower-dose vitamin D control, were eligible if approved by Research Ethics Committee and if ARI incidence in offspring was collected prospectively and pre-specified as an efficacy outcome. Sub-group analyses were done to determine whether effects of maternal vitamin D supplementation on offspring ARI risk varied according to maternal baseline circulating 25-hydroxyvitamin D (25 [OH]D) concentrations (<25 nmol/L, 25–49.9 nmol/L, 50–74.9 nmol/L, or ≥75 nmol/L). The study was registered with PROSPERO, CRD42024527191.

Findings
Our search identified 405 unique studies, of which 4 RCTs (3678 participants) were eligible and included. For the primary comparison of any maternal vitamin D supplementation vs. placebo, the intervention did not significantly affect overall ARI risk in offspring (incidence rate ratio [IRR] 1.01, 95% CI 0.98–1.03, P = 0.66; 4 studies; I2 14.5%, absolute effects from GRADE assessment: 0.05 higher rate in vitamin D arm; moderate quality finding). Pre-specified subgroup analysis did not reveal evidence of effect modification by maternal baseline vitamin D status: <25 nmol/L group: IRR 1.12, 95% CI 0.98–1.27 (607 participants in 4 studies, I2 47.8%) vs. 25–49.9 nmol/L group: IRR 1.04, 95% CI 0.96–1.13 (1154 participants in 4 studies, I2 68.5%) vs. 50–74.9 nmol/L group: IRR 1.00, 95% CI 0.93–1.08 (789 participants in 4 studies, I2 64.9%) vs. ≥75 nmol/L group: IRR 0.97, 95% CI 0.89–1.06 (505 participants in 4 studies, I2 47.6%). A funnel plot did not indicate the presence of publication bias or small-study effects (P = 0.71, Egger's test).

Interpretation
Our analysis of current data does not support routine antenatal vitamin D supplementation for the prevention of ARI in offspring. Key limitations of the study were the administration of a low dose vitamin D standard-of-care in some populations which may have attenuated effects of the intervention, and heterogeneity in ARI case definitions which may have introduced misclassification bias. Targeted supplementation in deficient populations may warrant further investigation.

Funding
None.

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Identifiers

ORCID for Cyrus Cooper: orcid.org/0000-0003-3510-0709

ORCID for Stefania D'angelo: orcid.org/0000-0002-7267-1837

ORCID for Nicholas Harvey: orcid.org/0000-0002-8194-2512

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