Why didn’t erythropoietin improve the outcome of preterm babies?

Because that is the result of a newly published RCT of erythropoietin (EPO) for neuroprotection of small preterm babies, no effect.

Natalucci G, et al. Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years. Jama. 2016;315(19):2079.

The dose regime was different to the doses used in the trials by Robin Ohls, which I discussed previously. In this new trial the EPO was started early, and at high dose, and for a short time; EPO (3000 IU/kg) was given  intravenously within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. About 450 babies of less than 32 weeks were randomized to get this dose or placebo. Babies under 26 weeks were not included. The primary outcome of the trial was the 2 year developmental screening tests, the Bayley version 2. There wasn’t a hint of a difference between the groups, with an MDI very close to 95 for each group. About 15% of each group didn’t get followed up at 2 years corrected, unlikely I think to have a substantial impact on the outcomes. There were a few protocol deviations, so they performed an Intention to treat analysis, and then also a “per-protocol” analysis, which also showed no impact of EPO on outcomes.

Why did the other studies show an effect, and not this trial? The authors suggest the following:

In the 2 smaller randomized trials, rhEPO was started later (between day 2 and 4 of life), given in lower doses (400 IU/kg), more often (3×/wk), and over a longer period (up to 35 weeks’ postmenstrual age) than in the present study. Therefore, one of the reasons for the lack of improved outcome with rhEPO in this study could be the timing of the first dose and shorter duration of rhEPO treatment.

Which is true of course, but not the only possible explanation. I think we should be very careful about the results of the 2 other trials they mention, As I noted before there were only 24 control babies reported for the 18 month follow-up, and only 14 for the pre-school follow-up. And the control babies had extremely, and unusually, poor scores on their pre-school follow-up. So I think another potential explanation would be that the results of the other trials are skewed by an unusually poor performance among the controls.

Of course it could be that the dose in this new study is too high. Maybe too much EPO is not a good idea. This observational study (Korzeniewski SJ, et al. Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates. PLoS One. 2015;10(3):e0115083.) showed that endogenous erythropoietin levels were higher in very preterm babies with poor developmental tests at 2 years (honestly, why do you need to call this “BRAIN DAMAGE”? Are you looking for more clicks?)

Or it could be that the duration was too short, and so on. But I think this study clearly shows that there is no high quality evidence that erythropoietin or its analogues are neuroprotective in the very preterm baby. The best evidence to date (this trial) shows no benefit.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

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