Erythropoietin (EPO) is a promising neuroprotective drug. We investigated whether EPO has beneficial effects on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE).
We retrospectively reviewed the data of 56 infants with HIE born at or after 35 weeks of gestation who were admitted to Inha University Hospital between 2012 and 2021. Patients were divided into two groups based on EPO use and compared. In the EPO group, patients were administered 1,000 U/kg of EPO on days 1, 2, 3, 5, and 7, starting within 24 hours after birth. The primary outcome was death or neurodevelopmental impairment (NDI) at the age of 12 months.
EPO was administered to 38 infants, and 18 did not receive EPO. Only 37.5% of patients with HIE (21/56) and 60% of patients with moderate-to-severe HIE (21/35) received therapeutic hypothermia. Among all patients with HIE, death or NDI (21.1 % vs. 50.0%; odds ratio [OR], 0.09; 95% confidence interval [CI], 0.01 to 0.78;
EPO administration significantly reduced mortality and NDI in infants with HIE. EPO can be considered an adjunctive therapeutic agent for neonatal HIE.
Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and neurodevelopmental impairment (NDI) [
Recently, erythropoietin (EPO) has been highlighted as a promising neuroprotective agent in neonatal HIE. In a hypoxic state, EPO production increases in brain cells, which plays an important role in neuroprotection and neuroregeneration in the central nervous system [
The time has come to discuss the use of EPO for neonatal HIE in the real clinical situation in Korea. Therefore, we investigated whether EPO administration has a beneficial effect on mortality and neurodevelopmental outcomes in newborns with HIE.
We retrospectively reviewed the data of infants with HIE born at a gestational age of ≥35 weeks who were admitted to the neonatal intensive care unit (NICU) of Inha University Hospital from 2012 to 2021. The inclusion criterion for HIE was altered levels of consciousness with perinatal asphyxia. Altered consciousness was defined as having at least one of the following: lethargy, stupor, coma, hyperalert state, hypotonia, abnormal reflexes including oculomotor or pupillary abnormalities, absent or weak suck, or clinical seizures [
Baseline characteristic data, including sex, gestational age, birth weight, delivery type, birthplace, Apgar scores, initial results of capillary or venous gas analysis, serum lactic acid, and lactate dehydrogenase, were collected. HIE was classified as mild, moderate, or severe based on the modified Sarnat and Sarnat staging [
Variables are expressed as median (interquartile range [IQR]) or number (%). We compared both groups using the Mann-Whitney U-test for continuous variables and Fisher’s exact test for categorical variables, as appropriate. Statistical analysis was performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05.
Of the 56 patients with HIE, 38 received EPO, and 18 did not (
Of the 35 included patients with moderate-to-severe HIE, 24 and <36 weeks of gestation (n=3). Brain ultrasonography was performed for all included patients. Brain MRI was performed in 46 patients (82%) on the median of 5 days (IQR, 4 to 7) of life. In the group comparison, although there were no differences in gestational age, birth weight, sex, maternal age, and mode of delivery, the Apgar score at 1 minute was lower (median 3 [IQR, 1 to 5] vs. 5 [IQR, 3 to 6],
Therapeutic hypothermia is the only proven treatment to reduce mortality and neurodevelopmental disabilities in patients with HIE. However, many infants with HIE have poor prognoses even after hypothermia treatment [
EPO is a glycoprotein that is primarily responsible for red blood cell production [
This study has some limitations. First, the data were collected from a single center and analyzed retrospectively. Second, the number of patients was small, especially for moderate-to-severe HIE. This might lower the power to prove the benefit of EPO on death or NDI in patients with moderate-to-severe HIE. Larger prospective studies should address this issue. Third, we included all patients with HIE, from mild to severe cases, rather than including only patients with moderate-to-severe HIE who received therapeutic hypothermia. As reported in this study, a significant number of neonatal HIE cases were not clinically indicated for therapeutic hypothermia. Because this study was not a randomized controlled study, we aimed to reflect real clinical situations. Fourth, EPO was administered off-label at the attending clinician’s discretion and not as per planned protocols. However, we decided to use EPO based on convincing evidence of the effectiveness of EPO for neonatal HIE, and EPO has been safely used for decades in infants. During the discussion with parents on EPO administration, every parent agreed to the off-label use of EPO, which could be beneficial in such a desperate state of their baby. Additionally, since off-label use of EPO is not costly, it is not a significant financial burden for most parents in Korea. We believe that now is not the time to discuss whether EPO should be used for neonatal HIE, but to determine the most effective dose, starting point, frequency, and length of EPO treatment for infants with HIE.
To our knowledge, this is the first study to investigate the clinical benefits of EPO administration for neonatal HIE in Korea. We demonstrated that EPO significantly reduced brain injuries in imaging studies and death or long-term NDI in neonatal HIE. We also found that a significant proportion of neonatal HIE cases were not clinically indicated for therapeutic hypothermia for various reasons. EPO can be valuable and, in some cases, the only treatment option to promote neuroprotection, especially for these infants. In conclusion, EPO is a promising therapeutic agent for neonatal HIE. Further large-scale prospective studies are required to address detailed guidelines for the optimal use of EPO for neonatal HIE.
The study was approved by the Institutional Review Board of Inha University Hospital (IRB no. 2022–05–017). The requirement for informed consent was waived by the board due to the retrospective nature of this study.
No potential conflict of interest relevant to this article was reported.
Conception and design: J.L.
Acquisition, analysis, or interpretation of data: S.J.B., J.L., G.W.J., Y.H.J.
Drafting the work or revising: S.J.B., J.L.
Final approval of the manuscript: All authors read and approved the final version of the manuscript.
This work was supported by a 2022 Inha University Hospital Research Grant.
None
Study participants. Abbreviations: EPO, erythropoietin; HT, hypothermia.
Comparisons of Neonates with Hypoxic-Ischemic Encephalopathy
Variable | Total HIE (n=56) |
Moderate-to-severe HIE (n=35) |
|||||
---|---|---|---|---|---|---|---|
EPO (n=38) | Control (n=18) | EPO (n=24) | Control (n=11) | ||||
Gestational age (wk) | 38+1 (37–39+5) | 38+1 (37+4–39+4) | 0.654 | 38+2 (36+3–39+5) | 39+3 (38+0–40+1) | 0.186 | |
Birth weight (g) | 3,300 (2,275–3,480) | 3,020 (2,710–3,275) | 0.247 | 3,345 (2,658–3,500) | 3,160 (3,020–3,485) | 0.930 | |
Sex, boy:girl | 22:16 (57.9:42.1) | 11:7 (61.1:38.9) | 0.819 | 13:11 (54.2:45.8) | 5:6 (50:60) | 0.725 | |
Born outside | 25 (65.8) | 15 (83.3) | 0.218 | 16 (66.7) | 9 (81.8) | 0.447 | |
Cesarean section | 30 (78.9) | 10 (55.6) | 0.112 | 19 (79.2) | 6 (54.5) | 0.227 | |
Maternal age (yr) | 36 (30–38) | 34 (31–35) | 0.337 | 35 (31–37) | 34 (32–36) | 0.636 | |
Apgar score 1 min | 3 (1–5) | 5 (3–6) | 0.031 | 2 (1–4) | 5 (3–5) | 0.049 | |
Apgar score 5 min | 6 (3–7) | 7 (5–9) | 0.098 | 5 (2–6) | 6 (4–8) | 0.236 | |
Initial blood gas analysis | |||||||
pH | 7.03 (6.91–7.13) | 7.16 (7.00–7.21) | 0.067 | 6.95 (6.82–7.09) | 7.09 (6.88–7.18) | 0.248 | |
pCO2 (cmH2O) | 69.7 (64.8–86.5) | 58.8 (33.5–68.5) | 0.009 | 80.6 (67.3–97.3) | 51.3 (23.5–76.3) | 0.025 | |
base deficit (mEq/L) | 14.1 (9.1–19.8) | 14.0 (4.0–20.6) | 0.745 | 16.3 (10.3–20.4) | 19.0 (15.6–22.0) | 0.394 | |
Serum lactic acid (mmol/L) | 8.9 (6.0–12.8) | 5.2 (4.5–6.2) | 0.115 | 12.6 (6.2–13.3) | 4.7 (2.1–6.9) | 0.025 | |
Serum LDH (U/L) | 643 (455–879) | 847 (608–1,155) | 0.181 | 632 (465–943) | 1,066 (912–1,244) | 0.047 | |
HIE stage | 0.904 | 0.709 | |||||
Mild | 14 (36.8) | 7 (38.9) | - | - | |||
Moderate | 17 (44.7) | 7 (38.9) | 17 (70.8) | 7 (63.6) | |||
Severe | 7 (18.4) | 4 (22.2) | 7 (29.2) | 4 (36.4) | |||
Seizure | 20 (52.6) | 8 (44.4) | 0.775 | 19 (79.2) | 8 (72.7) | 0.685 | |
Hypothermia | 19 (50) | 4 (22.2) | 0.080 | 17 (70.8) | 4 (36.4) | 0.073 | |
Brain injury on imaging | 16 (42.1) | 15 (83.3) | 0.004 | 13 (54.2) | 10 (90.9) | 0.034 | |
Death | 6 (15.8) | 4 (22.2) | 0.711 | 6 (25.0) | 4 (36.4) | 0.689 | |
NDI | 5 (13.2) | 6 (33.3) | 0.126 | 5 (20.8) | 5 (45.5) | 0.146 | |
Death or NDI | 8 (21.1) | 9 (50.0) | 0.041 | 9 (37.5) | 8 (72.7) | 0.050 |
Values are expressed as median (interquartile range) or number (%).
Abbreviations: HIE, hypoxic-ischemic encephalopathy; EPO, erythropoietin; LDH, lactate dehydrogenase; NDI, neurodevelopmental impairment.
Multivariable Logistic Regression Analysis
Variable | Total HIE |
Moderate-to-severe HIE |
||
---|---|---|---|---|
OR (95% CI) | OR (95% CI) | |||
Brain injury on imaging | 0.16 (0.03–0.92) | 0.040 | 0.04 (0.002–0.70) | 0.027 |
Death or NDI | 0.09 (0.01–0.78) | 0.029 | 0.32 (0.03–3.70) | 0.360 |
Adjusted for Apgar score 1 and 5 minutes, pH and pCO2 of initial blood gas analysis, and hypothermia;
Adjusted for Apgar score 1 minute, pCO2 of initial blood gas analysis, serum lactic acid and lactate dehydrogenase, and hypothermia.
Abbreviations: HIE, hypoxic-ischemic encephalopathy; OR, odds ratio; CI, confidence interval; NDI, neurodevelopmental impairment.