Will high dose erythropoietin (Epo) protect extremely premature babies from brain injury?
Determining whether high-dose erythropoietin (Epo) will improve survival and decrease the neurocognitive and developmental problems common among extremely premature infants is the key question Seattle Children’s neonatologist Dr. Sandra (Sunny) Juul hopes to answer with a large clinical trial.
Some 400,000 infants are born prematurely in the United States each year. Approximately 50,000 are born at 28 weeks gestation or less, and nearly half the babies born at less than 28 weeks will either die or have moderate or severe neurodevelopmental impairment.
“There’s a great deal of preclinical evidence that Epo improves brain development and protects the brain from injury by aiding in the development of neurons and also by decreasing inflammation,” says Juul. “Recent clinical trials have proven that higher doses of Epo are safe. Now we want to know what impact it can have on a child’s future.”
The Preterm Epo Neuroprotection (PENUT) trial will enroll a total of 940 infants born between 24 and 28 weeks gestation at 18 centers across the United States. Babies will be assessed at 2 years of age with a standardized neurological exam to see whether Epo treatment improves their motor and cognitive function. Juul hopes to secure funding in the future to follow participants into their school years.
A $9 million grant from the National Institute of Neurological Disorders and Stroke supports this double-blind, randomized study, which began enrolling patients in December 2013. As of January 23, 2015, 346 patients have been enrolled.
We want to give premature babies a much greater chance at reaching their full potential.
-Dr. Sandra Juul
Epo’s multiple benefits
Juul, a pioneer in neonatal neuroprotection research, has led the way in examining the potential benefit of Epo for the past two decades. Her interest in the hormone began when she learned that Epo receptors are present on mouse neurons, and then she started looking into what more this could mean. Juul has been instrumental in establishing that Epo also stimulates brain development and can protect the brain from injury.
Epo is most commonly used to treat anemia in preemies. It increases red blood cell production, which improves the circulation of oxygen to all the tissues. Participants in the PENUT study will be enrolled immediately after delivery (within the first 24 hours). They will be given 1,000 units/kilo of Epo every other day for six doses – a little more than double the dose usually given to treat anemia – followed by a smaller maintenance dose three times a week until they are 32 weeks gestational age.
Epo appears to have multiple benefits, which is important because neonatal brain injury is complex. “If you want something to work, it has to work in a lot of different ways,” says Juul who recently became the new division chief of Neonatology at Seattle Children's Hospital.
There are receptors for Epo on neurons, so a damaged neuron with Epo present is much more likely to repair itself and survive; in the absence of Epo it’s more likely to die.
Epo also protects oligodendrocytes, a vulnerable population of cells that are just developing between 24 to 32 weeks. Damage to oligodendrocytes increases white matter injury.
“So that’s why we give a high dose early on when the brain is very vulnerable and then long-term therapy while the oligodendrocytes are at risk,” says Juul.
Results from her years of previous research lead Juul to be optimistic about the trial. If her hypothesis proves true, and Epo works as well as she hopes, thousands of babies could be spared neurological injury.
“We want to give premature babies a much greater chance at reaching their full potential,” says Juul.