Biological Pathways Linking Integrated Interventions to Infant Growth in the first 6 months of life: Findings from a Mediator Analysis of the WINGS Randomized Controlled Trial

Background Growth faltering during infancy remains a major public health concern in low- and middle-income countries. We examined whether birth size, infant gut microbiome, growth and inflammatory biomarkers, and breast milk macro and micronutrients mediated the effects of an integrated intervention package on infant growth at 6 months of life. Methods This mediation analysis was nested within the Women and Infants Integrated Interventions for Growth Study (WINGS), a factorial randomized controlled trial conducted in urban low- and middle-income communities in Delhi, India. The intervention package included nutrition, health, water, sanitation and hygiene (WASH), and psychosocial support delivered during the preconception, pregnancy, and early childhood. The analysis included 296 mother-infant dyads from the group received intervention from preconception throughout pregnancy and childhood and the group received routine care. Using a counterfactual causal mediation framework, we assessed the mediating roles of birth size, infant biomarkers at 3 months; insulin-like growth factor-1 [IGF-1], C-reactive protein [CRP], and Bifidobacterium breve species, and breast milk biomarkers at three months (vitamin B12 and total protein). Outcomes included length-for-age z-score (LAZ), weight-for-age z-score (WAZ), weight-for-length z-score (WLZ) at 6 months, and changes in these anthropometric indices between 3 and 6 months. Multiple mediators were evaluated simultaneously using parametric regression models adjusted for maternal height, maternal body mass index, family possess below poverty line card, and place of birth. Results The intervention package significantly improved WAZ at 6 months (total effect 0.31; 95% CI 0.04-0.58). This effect was significantly mediated through birth size; reduction of small for gestational age (SGA) (average causal mediation effect 0.15; 95% CI 0.04-0.28), accounting for approximately 44% of the total effect. Conclusions Improved fetal growth, reflected by reduced SGA, was the principal biological pathway through which the integrated intervention package mediated infant growth at six months.