BCG vaccination and first hospitalization in children younger than 5 years: a nationwide cohort study in Portugal.

BACKGROUND: The BCG, used to prevent tuberculosis, has been associated with beneficial non-specific effects (NSEs), including reduced childhood morbidity and mortality. In Portugal, universal neonatal BCG vaccination was discontinued in 2016 and replaced by a selective, risk-based strategy. This policy transition resulted in substantial variation in BCG vaccination status and provides an opportunity to examine the association between BCG vaccination and hospitalization in children.

OBJECTIVE: The primary objective was to estimate the association between BCG vaccination and the risk of first hospitalization, with secondary analyses examining cause-specific hospitalizations.

METHODS: We conducted a nationwide retrospective cohort study including all children younger than 5 years born in mainland Portugal between July 1, 2010 and June 30, 2021. Data were obtained from linked national health registries. Follow-up began at day seven of life and continued until first hospitalization, age 5 years, or end of study. BCG vaccination was categorized according to age at vaccination (unvaccinated, 7-90 days, 3-12 months, and 1-5 years) and Cox proportional hazards models were used to estimate hazard ratios for first hospitalization. Kaplan-Meier curves were used to describe cumulative incidence. Models were adjusted for sex, birth year, birth season, comorbidities, and child health surveillance visits. Cause-specific analyses and hospitalization duration (≥3 days) were also examined. Sensitivity analyses addressed calendar-period effects, geographic adjustment, and adjustment for child health surveillance visits.

RESULTS: Among 544,794 children, 66.5% received BCG vaccination. Over 1,781,194 child-years of follow-up, 169,286 first hospitalizations were recorded. After adjustment, associations between BCG vaccination and first hospitalization varied according to age at vaccination. Compared with unvaccinated children, adjusted hazard ratios for first hospitalization were 0.15 (95% CI: 0.14-0.16) for vaccination between 7-90 days, 0.16 (95% CI: 0.15-0.16) for vaccination between 3-12 months, and 0.42 (95% CI: 0.41-0.43) for vaccination between 1-5 years. Similar associations were observed for respiratory, other medical, and neurological hospitalizations. For respiratory hospitalizations, adjusted hazard ratios were 0.56 (95% CI: 0.51-0.61), 0.57 (95% CI: 0.55-0.59), and 0.81 (95% CI: 0.78-0.83) for vaccination at 7-90 days, 3-12 months, and 1-5 years, respectively. Most hospitalizations were short, with stays lasting ≥3 days occurring slightly less frequently among BCG-vaccinated than unvaccinated children (7.1% vs 8.0%).

CONCLUSIONS: BCG vaccination was associated with a lower hazard of first hospitalization in this setting, particularly among children vaccinated during early infancy. However, given the observational design and the selective vaccination strategy implemented after 2016, these associations should not be interpreted as evidence of a causal protective effect. The variation in effect estimates according to age at vaccination and hospitalization outcome highlights the potential influence of contextual factors, healthcare utilization, and residual confounding.