Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns

Abstract

Background: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.

Methods: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.

Results: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).

Conclusions: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Figure 1.. Trial Enrollment and Follow-up.

HIE denotes hypoxic–ischemic encephalopathy.

Figure 2.. Forest Plot of Death or Any Neurodevelopmental Impairment, with Stratification According to Sex and the Severity of Encephalopathy.

A cognitive score of less than 90 on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), corresponds to 0.67 SD below the mean, with higher scores indicating better performance. Gross Motor Function Classification System (GMFCS) levels range from 0 (normal) to 5 (most impaired).

Figure 3.. Adverse Events and Serious Adverse Events.

Intracranial hemorrhage was defined as intraparenchymal or intraventricular blood seen on ultrasonography or MRI of the head. Cardiac compromise was defined as an elevated troponin level or decreased cardiac function on echocardiography. Thrombocytopenia was defined as a platelet count of less than 100,000 per cubic millimeter. Neutropenia was defined as an absolute neutrophil count of less than 1500 per cubic millimeter. Acute kidney injury was defined as a plasma creatinine level of more than 1.5 times the baseline level. Acute liver injury was defined as a serum aspartate aminotransferase level of more than 200 U per liter or a serum alanine aminotransferase level of more than 100 U per liter.