Efficacy of Lactose-Free Versus Standard Formula in Managing Infantile Colic: A Meta-analysis of Randomized Controlled Trials

Abstract

Background: Infantile colic is a common, self-limited syndrome characterized by excessive crying in early infancy. A lactose-related mechanism—via osmotic load and colonic fermentation—has been proposed, motivating the use of lactose-modifying strategies (oral lactase, lactose-free hydrolysate formulas, and reduced-lactose “comfort” formulas).

Objective: To assess the efficacy and safety of lactose-modifying interventions versus control (placebo or standard cow’s milk formula) for established infantile colic.

Methods: Randomized controlled trials enrolling term infants ≤5–6 months with colic diagnosed by Wessel or Rome criteria were eligible. Interventions included lactase supplementation (β-galactosidase added to expressed breast milk or formula immediately before feeds) and formula changes affecting lactose exposure (lactose-free extensively/casein-hydrolyzed formulas or reduced-lactose formulas, sometimes with additional compositional changes). The primary outcome was treatment effectiveness (trial-defined responders: ≥50% reduction in crying/fussing or <3 h/day) at ~1–4 weeks. Random-effects meta-analysis (REML) pooled log risk ratios (lnRR); heterogeneity (I², τ²), small-study bias (Egger/Kendall), and sensitivity analyses (excluding cross-over trials; excluding probiotic-containing formulas) were prespecified. Secondary outcomes were crying/fussing minutes/day, adverse events (AEs), and short-term growth.

Results: Ten trials were included across Europe, South Asia, and Australia. The pooled lnRR for treatment success was 0.259 (SE 0.138), corresponding to RR ≈ 1.30 (95% CI 0.99–1.70; p = 0.060). Heterogeneity was negligible (τ² = 0.000; I² = 0%). Funnel-plot symmetry and formal tests suggested no small-study effects. Subgroup patterns indicated more consistent short-term benefit with lactase supplementation (notably at 2–3 weeks), probable short-term improvement with lactose-free hydrolysate versus standard formula, and mixed findings for reduced-lactose formulas incorporating other compositional changes.

Conclusions: Lactose-modifying strategies yield a small-to-moderate, clinically plausible increase in short-term response among infants with colic, with the clearest signal for oral lactase. Benefits of formula changes appear greatest when lactose is fully removed (hydrolysates) and are inconclusive when lactose is only reduced within multi-component “comfort” formulas.