Introduction
Infections in early childhood remain a leading global cause of child mortality, where pre- and postnatal environmental exposures seem to be crucial for development.

Objectives
To investigate whether an urbanized environment at birth was associated with risk of infections and to understand the potential underlying mechanisms.

Methods
The children from the COPSAC2010 mother-child cohort were monitored with daily dairy cards during the first 3 years with parental registrations of any infection symptom. Rural and urban environments were based on the CORINE land cover database. The airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling was performed at pregnancy week 24 and 2-3 days after birth.

Results
Among 663 children, we found a mean (SD) of 16.3 (8.4) of all infection episodes mainly respiratory. Children living urban vs rural had increased risk of infections: 17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05-1.26), p=0.002. Urbanization resulted in a different airway immune profile, which increased risk of infections, principal component 1 (PC1): 1.03 (1.00-1.06), p=0.038 and PC2: 1.04 (1.01-1.07), p=0.022. Further, urbanization resulted in different maternal and child metabolomic profiles, which increased risk of infections: 1.26 (1.09-1.44), p=0.001 and 1.33 (0.99-1.82), p=0.065. The urbanization effect on infection risk was mediated through the airway immune profile and borderline mediated through the maternal metabolomic profile.

Conclusions
Urbanized living at birth was associated with increased risk of infections in childhood until age 3 years and explained through altered airway immune and metabolomic profiles.