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Association Between Caffeine Citrate Initiation Within the First 2 h of Life and Respiratory Outcomes in Very Preterm
Halil Ugur Hatipoglu1, Birgul Livaoglu Say2, Nurdan Uras3
1Department of Pediatrics, University of Health Sciences, Haseki Training and Research Hospital, Istanbul 34270, Türkiye.
Insights
Starting caffeine citrate treatment for very preterm infants within the first two hours of life was linked to better respiratory outcomes. Delaying caffeine initiation increased the risk of bronchopulmonary dysplasia (BPD) or death.
Area of Science:
- Neonatology
- Pediatric Respiratory Medicine
- Clinical Pharmacology
Background:
- Caffeine citrate is a standard treatment for apnea of prematurity in very preterm infants.
- The optimal timing for initiating caffeine citrate therapy remains unclear.
- Early postnatal respiratory support strategies are critical for preterm infant outcomes.
Purpose of the Study:
- To investigate the association between early (within 2 hours) versus late (after 2 hours) caffeine citrate initiation and respiratory outcomes.
- To evaluate the impact of caffeine timing on bronchopulmonary dysplasia (BPD) and mortality in infants born before 32 weeks' gestation.
Main Methods:
- Single-center observational cohort study of 84 infants born at <32 weeks' gestation.
- Comparison of respiratory outcomes based on caffeine initiation within or after the first 2 postnatal hours.
- Utilized multivariable logistic regression and propensity score modeling (IPTW) to adjust for confounding factors.
Main Results:
- Infants initiated on caffeine after 2 hours had significantly higher rates of BPD (60.0% vs 24.4%) and BPD or death (62.8% vs 24.4%).
- Propensity score analyses (IPTW) showed that late caffeine initiation was independently associated with increased odds of BPD (OR 3.40) and BPD or death (OR 3.89).
- Adjustments for early respiratory support did not alter these associations.
Conclusions:
- Initiating caffeine citrate therapy after the first 2 postnatal hours is associated with adverse respiratory outcomes, including higher rates of BPD and mortality.
- These findings suggest that very early caffeine administration may be beneficial for preterm infants.
- Further research is needed to confirm causality due to the observational nature of the study.
Abstract:
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.