Infants with hypoxic-ischemic encephalopathy (HIE) are at high risk for neurodevelopmental impairment, despite current standards of care. Adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognized as a neurorestorative agent, but, to date, has not been used in infants. Herein, the investigator describes a clinical trial with the aim of demonstrating the safety and feasibility of metformin use to improve neurodevelopmental outcomes in infants with HIE.

Inclusion Criteria:

• <6 months old at time of enrollment, and able to initiate study drug between 3 and 6 months old.
• Born > 35 weeks gestational age with a clinical diagnosis of HIE at birth, who receive therapeutic hypothermia.
• Post-hypothermia brain MRI with evidence of hypoxic-ischemic brain injury, based on the neuroradiology clinical report. Specifically, participants must have had evidence of a lactate peak by magnetic resonance spectroscopy and/or signal abnormalities by conventional (T1 and/or T2) or diffusion-weighted images consistent with hypoxic-ischemic pattern of injury.
• English- or Spanish-speaking families, as the parents/guardians will be responsible for documenting dose administrations and adverse events.

Exclusion Criteria:

• Known genetic or chromosomal disorder, and in the presence of congenital or acquired liver or kidney disease that might, in the opinion of the Principal Investigator (PI) or delegate, affect drug metabolism.
• Maternal use of metformin while actively breastfeeding.
• Infant weight below the 10th percentile based on WHO growth charts at the time of study drug initiation.
• Normal post-hypothermia brain MRI, without evidence of ischemic brain injury, based on the neuroradiology clinical report.
• Concomitant use of the following drugs: anti-diabetic drugs (insulin, sulfonylureas), steroids, diuretics (furosemide, chlorothiazide, spironolactone), diazoxide, beta blockers, ACE inhibitors, angiotensin II blockers, calcium channel blockers (including nifedipine), phenytoin, valproic acid, topiramate, cimetidine, corticosteroids, thyroid medications, sympathomimetics, carbonic anhydrase inhibitors, or any antibiotics.
• Any condition or diagnosis, that could in the opinion of the PI or delegate, interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk.