Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis

Abstract

This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg^-1) vs. high dose (>10 mg·kg^-1 caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1-5 years), middle childhood (6-11 years) and adolescence (12-19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection.

Fig. 2. Forest plots of the neonatal/infant primary outcome, and critical and selected important secondary outcomes.

^aApnea results are presented as a dichotomous measure (for caffeine vs placebo comparison) or a continuous measure (for high vs low-dose comparison), based on how apnea was measured in the majority of studies in each comparison. The forest plot for the alternate measure for each comparison is presented in Fig. 3. ^bDeath before one year of age was also considered a critical outcome, but only 1 study reported this measure (in the low vs. high-dose comparison). This data is included in Fig. 3, with other secondary outcomes.

Fig. 3

Forest plots of additional neonatal/infant secondary outcomes.