Vitamin D in Breastfed Infants: Systematic Review of Alternatives to Daily Supplementation

Abstract

Daily oral vitamin D supplementation (400 IU) is recommended for breastfeeding infants (≤1 y). Recent studies have examined alternative approaches to preventing vitamin D deficiency in this population. This systematic review and meta-analysis aimed to estimate the effects of maternal postpartum (M-PP) or infant intermittent (I-INT) vitamin D supplementation on infant 25-hydroxyvitamin D [25(OH)D] concentrations in comparison to routine direct infant daily (I-D) oral supplementation (400 IU). MEDLINE, MEDLINE In-Process, Embase, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to December 2018. Inclusion criteria consisted of published, peer-reviewed, vitamin D intervention trials involving lactating women and/or exclusively or partially breastfed term infants. Two reviewers independently extracted study characteristics (e.g., sample size, intervention dose, and duration and mode of administration) and related biochemical and clinical outcomes. Of 28 included trials, 5 randomized controlled trials were incorporated in meta-analyses examining infant 25(OH)D. Overall, M-PP supplementation resulted in modestly lower infant 25(OH)D compared with I-D supplementation (weighted mean difference = -8.1 nmol/L; 95% CI: -15.4, -0.9; I2 = 45%; P = 0.14; 3 trials), but the 2 most recent trials found M-PP to achieve similar infant 25(OH)D as I-D. Comparison of I-INT with I-D was confined to 2 trials with contradictory findings, and it was considered inappropriate for pooled analysis. Meta-analysis was therefore limited by a small number of eligible trials with variable quality of analytically derived 25(OH)D data and inconsistent reporting of safety outcomes, including effects on calcium homeostasis. Considering all 28 included trials, this systematic review highlights M-PP and I-INT regimens as plausible substitutes for routine daily infant vitamin D supplementation, but evidence remains too weak to support a policy update. Dose-ranging, adequately powered trials are required to establish the efficacy, safety, and feasibility of alternative strategies to prevent vitamin D deficiency in breastfeeding infants. This review was registered with PROSPERO as CRD42017069905.

Keywords: 25-hydroxyvitamin D; micronutrient supplementation; rickets; vitamin D; vitamin D supplementation.

FIGURE 1

PRISMA flow diagram for screening and selection of studies for systematic review and meta-analysis of maternal postpartum or infant intermittent vitamin D supplementation. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

FIGURE 2

Risk of bias among trials included in the systematic review conducted using the Cochrane Risk Assessment Tool. Bias assessment was evaluated based on the primary outcome of maternal or infant achieved 25-hydroxyvitamin D concentrations or related metabolites following intervention.

FIGURE 3

WMDs and 95% CIs for infant circulating 25-hydroxyvitamin D (25(OH)D) concentrations (nmol/L) in response to maternal postpartum vitamin D supplementation compared to direct infant supplementation with 400 IU/d, calculated from a random-effects model using inverse variance weights. Test for heterogeneity: χ² = 5.47, df = 3 (P = 0.14), I² = 45.2%. Test for overall effect: z = 2.19 (P = 0.028). ¹Mothers of the control group received 400 IU/d vitamin D-3.

FIGURE 4

Mean attained infant 25(OH)D concentrations in response to maternal supplementation with vitamin D (diamonds) compared with placebo (circles) in order of vitamin D dose provided. Adjoining line represents the difference in mean attained 25(OH)D between the intervention and the placebo group following maternal vitamin D supplementation. Included trials were limited to those in which a placebo or null intervention group acted as a direct comparison to the trial arm involving maternal postpartum vitamin D supplementation. 25(OH)D, 25-hydroxyvitamin D.