Cumulative caffeine exposure predicts neurodevelopmental outcomes in premature infants.

Background: Preterm infants who receive caffeine for apnea of prematurity have improved neurodevelopmental outcomes compared to untreated infants. The optimal dosing regimen for neuroprotection is unknown. We hypothesized that higher caffeine exposure is associated with improved neurodevelopmental performance.

Methods: We quantified caffeine exposure in a previously reported cohort of 106 infants born at ≤32 gestational weeks who received brain MRIs during the neonatal hospitalization. Infants were subdivided into tertiles based on average daily caffeine exposure (ADCE). Bayley-III examinations were performed on 69 participants at 30 months corrected age. Neurodevelopmental impairment (NDI) was defined as a score of ≤85 on the Bayley-III motor, language, and/or cognitive subscales. We evaluated the relationship between caffeine exposure, neuroimaging abnormalities, and neurodevelopmental performance.

Results: Higher ADCE was associated with decreased odds of NDI (OR 0.69, 95% C.I. 0.50-0.95) but not with MRI abnormalities. High dose caffeine was associated with improved motor (mean difference 10.9, 95% C.I. 0.7-21.0), language (mean difference 15.2, 95% C.I. 3.4-27.0), and cognitive (mean difference 13.0, 95% C.I. 0.6-25.4) performance compared to low dose in multivariable analyses adjusted for gestational age and respiratory disease.

Conclusion: Higher sustained caffeine exposure during the neonatal hospitalization is associated with improved neurodevelopmental outcomes in preterm infants.

Impact: Premature infants who receive caffeine for apnea of prematurity have improved neurodevelopmental outcomes compared to untreated infants. The optimal dosing strategy for neuroprotection is unknown. We found that higher average daily exposure during the neonatal hospitalization was associated with reduced neurodevelopmental impairment at 30 months corrected age. High dose caffeine was associated with improved motor, language, and cognitive performance on the Bayley-III compared to low dose caffeine in multivariable analyses adjusted for gestational age and respiratory disease. Preterm infants may benefit from higher maintenance doses and/or from continuing caffeine beyond the period of respiratory need.