Timing of Cow's Milk or Cow's Milk Formula Introduction to the Infant Diet and Atopic Risk in Children: a Systematic Review and Meta-analysis

Infant feeding is an important early-life exposure that may influence the development of atopic disease. The optimal timing of introduction of food allergens, including cow's milk (CM), is not known. This study aims to systematically review the evidence describing the effects of timing of CM or cow's milk formula (CMF) introduction to the infant diet on the development of atopic diseases during childhood. Pubmed, Embase, CINAHL, Cochrane CENTRAL, and CNKI were searched through May 30, 2019. Study screening and data extraction by two reviewers followed the PRISMA statement. Data were extracted independently in duplicate, and meta-analyses were performed by pooling unadjusted and adjusted odds ratio (OR) separately. Heterogeneity was explored using I2 and publication bias by funnel plots and Begg's tests. In total, 45 studies from 20 countries were included. Meta-analyses using adjusted data showed that no associations were observed between early introduction of CM or CMF and the risk of asthma (< 4 vs. ≥ 4 months: OR 1.16, 95% confidence interval (CI) 0.89, 1.51), wheeze (< 6 vs. ≥ 6 months: OR 1.15, 95% CI 0.85, 1.56), and eczema or atopic dermatitis (< 6 vs. ≥ 6 months: OR 0.96, 95% CI 0.65, 1.41). Overall, quite little high-quality evidence was identified to allow for definitive conclusions on the association between early CM or CMF introduction and risk of allergic diseases. Our meta-analysis on this topic highlights the specific gaps in information for public recommendations regarding CM or CMF feeding practice in an early stage of life, particularly before 3 months of age.