Caffeine May Help to Prevent Cerebral Palsy, UCSF Study Finds

A few doses of caffeine during the perinatal period may help prevent cerebral palsy and related neurodevelopmental disorders that are rooted in lack of oxygen to the brain near the time of birth, a new UC San Francisco study found.

Cerebral palsy is the most common motor disability in childhood, and the most common lifelong physical disability in the world. While a million people in the U.S. have cerebral palsy, 95% of cases occur in low- to middle-income countries. 

About 1 in 10 cases of cerebral palsy are caused by lack of oxygen to the brain around the time of birth, commonly called birth asphyxia or hypoxic-ischemic encephalopathy.   

Researchers at UCSF used large animal models to see if caffeine could mitigate the effect of birth asphyxia when delivered to the mother once intravenously, then again to the offspring shortly after birth. 

“Caffeine has previously proven to be safe in stimulating the respiratory centers of preterm babies and helping them remember to breathe,” said Emin Maltepe, MD, PhD, neonatologist at UCSF Benioff Children’s Hospital and senior author of the study, which appears Oct. 21 in Stroke.

“It easily crosses the blood-brain barrier and is a potent antioxidant and anti-inflammatory molecule,” added Jana Mike, MD, PhD, a Benioff Children’s Hospital pediatric intensivist and the first author of the study. 

A better treatment for lower-income countries

Thirty pregnant animals received either a single intravenous dose of one gram of caffeine, which is equal to about 10 cups of coffee, or a placebo. After birth, their offspring received a dose of 20 mg/kg of caffeine, followed by 10 mg/kg per day for two days; the others received the placebo. 

Systemic inflammation, measured by cytokine levels, was significantly lower in the offspring that received caffeine, as was the level of injury to gray and white matter in the brain. Motor activity levels, including eating and moving around, were higher for the offspring that received caffeine. Importantly, there was no harm to the mothers or their offspring from the caffeine. 

“We’re excited about the potential this brings for preventing long-term disability in babies with birth asphyxia, particularly in less-resourced countries where the current treatment is less effective and the need for prenatal treatment is greatest,” Maltepe said.  

The current standard of care is to cool a hypoxic newborn’s body to a target temperature for 72 hours then slowly rewarm it. It is only modestly effective in high-income countries, and it is often ineffective or contraindicated in lower- and middle-income countries. This could be because brain hypoxia occurs earlier in gestation, possibly due to the inability of the placenta to provide enough nourishment to the developing fetus.

South Asian researchers have developed an algorithm to identify women whose pregnancies are at higher risk for brain hypoxia and thus may be candidates for perinatal caffeine treatment, Maltepe said. Clinical trials are in the planning stages to test the use of caffeine in humans in several countries where cooling is not available, as well as in those like South Africa, where it is.   

A new approach to pediatric therapies 

The current study was led by the UCSF-based Initiative for Pediatric Drug and Device Development, or iPD3, created seven years ago with a goal of testing and translating therapies specifically for children. Often, pediatric therapies are just scaled-down versions of therapies that were created for adults, Maltepe noted. 

The iPD3’s charge, put forth by its funder the Bill and Melinda Gates Foundation, was to review research on existing drugs with neuroprotective effects to find one that could be tested for treating birth asphyxia in less-resourced countries.  

“We reviewed over 1,000 drugs, taking an unbiased, agnostic look at potential therapies for this patient population,” Maltepe said. “I didn’t expect caffeine to be the frontrunner, but it was the most effective of all the ones we examined, and significantly more effective than the current standard of care. It’s exciting to see the iPD3 approach bear fruit.”

Additional co-authors: Yasmine White, MD, Janice Ha, Ariana Iranmahboub, Cheryl Hawkins, MD, Rachel S. Hutchings, Christian Vento, Hadiya Manzoor, PhD, Janel Long-Boyle, PharmD, PhD, Jeffrey R. Fineman, MD, Donna M. Ferriero, MD, MS, of UCSF; Aijun Wang, Brian D. Goudy, MD, Payam Vali, MD, Satyam Lakshminrusimha, MBSS, of UC Davis; and Jogarao VS Gobburu, PhD, MBA, University of Maryland, Baltimore.

Funding: Bill and Melinda Gates Foundation; National Institutes of Health [R35-5R35NS097299 (DF), R01 HD072455 (EM), K08NS125042 (JKM)]. 

Disclosures: None.     

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