Background: Acute hypoxia-ischemia during birth can result in significant encephalopathy. The associated oxidative and metabolic stress, mitochondrial dysfunction and cell death are a result of cellular energy failure and reperfusion injury. Creatine is an intracellular metabolite required to sustain ATP to meet metabolic demand during oxygen deprivation. Supplementary creatine has been proposed as a prophylactic treatment during pregnancy to prevent or ameliorate the effects of hypoxia-ischemia at birth on the neonate. We hypothesize that creatine can prevent hypoxia-related neuropathology by buffering intracellular ATP levels, thereby reducing reactive oxygen species (ROS) production and associated neuropathology.
Methods: Chronically instrumented fetal sheep (118 days gestation) were implanted with brain microdialysis probes and a silastic umbilical cord cuff. Creatine (6mg/kg/h) or saline (9mg/kg/h) was infused IV to the fetus from 122 to 134 days gestation. On day 131, each fetus was exposed to 10 minute umbilical cord occlusion (UCO; n=8 creatine, n=7 saline) or no occlusion (control; n=7 creatine, n=6 saline) and 72 h of reperfusion. Cerebral microdialysis fluid was collected at 1 h intervals from 130 to 134 days gestation and analysed for hydroxyl radical (OH•) production using HPLC and the fluorescent terepthalic acid trapping method.
Results: UCO caused immediate and similar respiratory acidosis, hypotension and bradycardia in both saline- and creatine-infused fetuses. However, creatine infusion resulted in significantly lower OH• production levels between 0-72 hours post-UCO compared to saline-infused fetuses (31.43 ± 1.515 vs 39.96 ± 2.831 μM.h; AUC ± SEM, p=0.0088).
Conclusions: Systemic creatine pretreatment reduced the overall cerebral production of cytotoxic OH• resulting from global fetal hypoxia-ischemia; whether this reduction corresponds to a reduction in neuropathology mediated by oxidative stress is now being examined. This animal-based research supports the use of creatine supplementation during human pregnancy to reduce intrapartum hypoxia/asphyxia neuropathology.