The effects of caffeine following hypoxic-ischemic encephalopathy: A systematic review of animal studies

Background: Caffeine is believed to be neuroprotective in preterm and term infants, despite the conflicting data on its effects on the developing brain in animal models. We aimed to conduct a systematic review with meta-analysis assessing the effects of caffeine on the prevention and treatment of neurological morbidity caused by hypoxic-ischemic encephalopathy (HIE) in preclinical studies. Methods: Randomized and non-randomized control studies in animal models of HIE reporting caffeine administration within the first ten days of life were included. Primary outcomes were behavioral tests that served as surrogates for cognition, memory, motor coordination, and gait; secondary outcomes pertained to structural neurologic changes. Screening for inclusion, risk of bias and data extraction were performed independently by two authors. Results: Seven studies met inclusion: 5 studies were conducted in rats and 2 in mice. All studies were performed in full-term animals, and the majority of studies used animals of both sexes (5/7). In six studies, caffeine was administered intraperitoneally to the pups, while in the remaining study, it was delivered via the drinking water of the lactating dams. The doses of caffeine ranged from 5 to 20 mg/kg; in one study, caffeine dosage was 0.3 mg/L in the drinking water of lactating dam. The mortality rate was reported only in three studies. Caffeine had a positive effect on overall functional outcome (SDM 0.92(95%CI 0.25 to 1.59)). Animals treated with caffeine performed better on Morris water maze and rotarod tests (SDM −1.39(95%CI −0.36 to −2.41)) and (SDM 1.03(95%CI 0.03 to 2.04)), respectively. Caffeine treated animals performed worse on open field test compared to the controls (SDM −1.11(95%CI −3.01 to 0.80)). The overall quality of the included studies was limited. Conclusions: Early caffeine exposure in preclinical rodent models of HIE is associated with improved selective functional and neurological outcomes, although the certainty of the evidence is limited. To validate the therapeutic efficacy of caffeine as a neuroprotective adjuvant, there is a need to explore its effects in larger animal models, which will help guide the design of relevant clinical trials.