Association Between Caffeine Citrate Initiation Within the First 2 h of Life and Respiratory Outcomes in Very Preterm Infants: A Single-Center Observational Cohort Study

Background/Objectives: Caffeine citrate is widely used in very preterm infants, but whether initiation during the first postnatal hours is independently associated with respiratory outcomes remains uncertain. We evaluated the association between caffeine initiation within versus after the first 2 h of life and respiratory outcomes in infants born at <32 weeks’ gestation. Methods: This single-center observational cohort study included 84 infants born at <32 weeks’ gestation and with a birth weight of ≤1500 g who received caffeine citrate within the first 24 h of life. The 2 h threshold represented the unit’s protocol-defined target for caffeine loading rather than a biologically validated cutoff. The primary outcome was bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age. Secondary outcomes included BPD or death, moderate/severe BPD or death, respiratory support requirements, and neonatal morbidities. Conventional multivariable logistic regression and expanded gestational age- and birth weight-based propensity score models with stabilized inverse probability of treatment weighting (IPTW) were used. The expanded propensity score models incorporated maternal, placental, perinatal, and early respiratory variables, including first-hour invasive mechanical ventilation and surfactant administration within the first hour. Results: Caffeine was initiated within the first 2 h in 41 infants and after the first 2 h in 43 infants. BPD occurred in 10/41 (24.4%) and 24/40 (60.0%) infants, respectively, while BPD or death occurred in 10/41 (24.4%) and 27/43 (62.8%), respectively. In expanded IPTW analyses, caffeine initiation after the first 2 h remained associated with BPD in both the gestational age-based model (OR 3.40, 95% CI 1.22–9.48) and the birth weight-based model (OR 3.23, 95% CI 1.16–9.00). Corresponding ORs for BPD or death were 3.89 (95% CI 1.41–10.71) and 3.68 (95% CI 1.34–10.12). Additional adjustment for residual imbalance in pretreatment respiratory support produced similar estimates. Conclusions: Caffeine initiation after the first 2 h of life was associated with higher odds of BPD and BPD or death. These findings support further investigation of very early caffeine timing but do not establish a causal effect because of the observational design, modest sample size, and potential residual confounding.