Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use
Abstract
:1. Introduction—Description of the Condition
- Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience devastating complications.
- Improvement in the quality of preterm neonatal care has drastically reduced mortality, but morbidity is still high in preterm babies with developmental delay, cerebral palsy, hearing and vision problems.
- Strokes which occur early during the brain development still represent a challenge in terms of learning causality and optimizing the outcomes
- Preclinical studies with optimal animal models and pharmacokinetic- pharmacodynamic modelling have demonstrated neuroprotective effects of erythropoietin
- Erythropoietin shows promise in conjunction with therapeutic hypothermia, in neonatal hypoxic-ischemic encephalopathy
- Studies on very preterm newborns treated with Epo highlighted an improved white matter development
- There is a need for optimal dose-ranging studies and tailored regimes, accounting for patients’ risk of brain damage
1.1. Neurological Impairment in Neonatal Population
1.2. Pathogenesis of Brain Damage
1.2.1. Preterm Infants and Brain Damage
1.2.2. Hypoxic Ischemic Encephalopathy
1.2.3. Perinatal and Neonatal Stroke
1.3. Erythropoietin (Epo) Actions and Neuroprotective Effects
2. Materials and Methods
2.1. Research Strategy for Study Identification
2.2. Eligibility Criteria and Study Selection
2.3. Data Extraction of the Studies
3. Results
3.1. Erythropoietin Administration in Preterm Infants
3.2. Erythropoieti Administration in HIE
3.3. Erythropoietin Administration in Neonatal Stroke
4. Discussion
4.1. Erythropoieti in Preterm Infants
4.2. Erythropoietin in HIE
4.3. Erythropoietin in Neonatal Stroke
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
1H-MRS | Proton Magnetic Resonance Spectroscopy |
AIMS | Alberta Infant Motor Scale for motor functions |
BASC2 | Behavior Assessment System for Children—2nd edition |
BBB | blood brain barrier |
BSID-II or III | Bayley Scales of Infant Development-II or III edition, composed by three scores—MDI, PDI and Infant Behavior Record |
BW | birth weight |
Darbe | darbepoetin |
DTI | Diffusion Tensor Imaging |
ELBW | Extremely Low Birth Weight |
Epo | Erythropoietin |
EpoR | Erythropoietin receptors |
GMFCS | Gross Motor Function Classification System |
HAWIK-III | Hamburg-Wechsler Intelligence Test for Children-III edition |
HIE | Hypoxic Ischemic Encephalopathy |
IQ | Intelligence Quotient |
Iv | intravenous |
IVH | Intraventricular Haemorrhage |
KABC | Kaufman Assessment Battery for Children |
MDI | Motor Development Index |
MRI | Magnetic Resonance Imaging |
NMS | Neuromuscular Function Scale |
OP | Object of Permanence |
PDI | Psychomotor Development Index |
Sc | subcutaneous |
TBSS | Tract Based Spatial Statistics |
TH | Therapeutic Hypothermia |
WIDEA | Warner Initial Developmental Evaluation |
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First Author (Year) | Target Population | Intervention | Outcomes | Findings | Ref. |
---|---|---|---|---|---|
Bierer (2006) | GA: ≤32 weeks BW 401–1000 g N = 12 | Epo 400 U/kg 3 times/week, from the 4th day of life to 35th postmenstrual week (n = 6) (n = 6 placebo) | Evaluation at 18–22 months
|
| [100] |
Brown (2009) | GA: ≤30 weeks BW < 1500 g N = 82 | Epo 3 times/weeks for 6 weeks, mean cumulative dose 3750 U/kg (range 250–400 U/kg/dose) firstly iv then sc. | Evaluation at 22 months
|
| [101] |
Neubauer (2010) | BW ≤ 1000 g N = 146 | Epo at a cumulative 8574 U/kg administered over 68 days sc or iv (n = 89) (n = 57 no treatment) | Evaluation at 10–13 years
|
| [102] |
McAdams (2013) | BW ≤ 1000 g N = 35 | Epo 500 U/kg, 1000 U/kg or 2500 U/kg once a day for the first 3 days of life (n = 17) (n = 18 no treatment) | Evaluation at 4–36 months
|
| [103] |
Ohls (2014) | BW 500–1250 g N = 80 | Darbe alfa 10 mcg/kg once a week sc (n = 27); or Epo 400 U/kg, 3 times a week sc, until 35 weeks of postnatal corrected age (n = 29) (n = 24 placebo) | Evaluation at 18–22 months:
|
| [104] |
Leuchter (2014) | GA 26–31 weeks N = 165 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 77) (n = 88 placebo) | Evaluation at term equivalent age
|
| [105] |
O’Gorman (2015) | GA 26–31 weeks N = 58 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 24) (n = 34 placebo) | Evaluation at term equivalent age
|
| [106] |
Luciano (2015) | GA ≤ 30 weeks N = 104 | Epo at a median cumulative dose of 6300 UI/Kg (6337 ± 2434 UI/Kg) for 6.9 ± 2.4 weeks, starting at age of 4 days (n = 59) (n = 49 not treated) | Evaluation at 24 months
|
| [107] |
Fauchère (2015) | GA 26–31 weeks N = 443 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 229) (n = 114 placebo) | Evaluation between 7–10 days of age
|
| [108] |
Natalucci (2016) | GA 26–31 weeks N = 450 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 225) (n = 225 placebo) | Evaluation at 2 years of corrected age
|
| [109] |
Lowe (2017) | BW 500–1250 g N = 71 | Darbe alfa 10 mcg/kg once a week sc or Epo 400 U/kg, 3 times a week sc, or placebo until 35 weeks of postnatal corrected age (n = 35) (n = 14 placebo preterm; n = 22 full term controls) | Evaluation at 3.5–4 years
|
| [98] |
Gasparovic (2018) | BW 500–1250 g N = 52 | Darbe alfa 10 mcg/kg once a week sc or Epo 400 U/kg, 3 times a week sc, until 35 weeks of postnatal corrected age (n = 15) (n = 15 placebo preterm) (n = 22 term controls) | Evaluation 4 and 6 years of age
|
| [99] |
Yang (2018) | GA < 32 weeks, BW < 1500 g N = 81 | Epo 500 U/kg dose within 72 h from birth every 48 h for 2 weeks (n = 42) (n = 39 term controls) | Evaluation at term equivalent age:
|
| [110] |
Jakab (2019) | GA 26–31 weeks N = 58 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 24) (n = 34 placebo) | Evaluation at term equivalent age:
|
| [111] |
Juul (2020) | GA 24+0–27+6 weeks N = 741 | Epo iv 1000 U/kg every 48 h for a total of six doses, followed by sc maintenance of 400 U/kg 3/week up to 32 weeks of postmenstrual age (n = 376) (n = 365 placebo) | Evaluation at 22–26 months
|
| [112] |
Natalucci (2020) | GA 26–31 weeks N = 345 | Epo 3000 IU/kg at <3 h, 12–18 h and 36–42 h after birth (n = 177) (n = 168 placebo) | Evaluation at at 5 years of age
|
| [113] |
First Author (Year) | Target Population | Intervention | Outcomes | Findings | Ref. |
---|---|---|---|---|---|
Zhu (2009) | GA > 37 weeks BW > 2500 g moderate/severe HIE N = 153 | Epo at 300 U/kg every two days for 2 weeks (n = 45) or 500 U/kg every two days for 2 weeks (n = 28) Hypotermia (n = 84) | Evaluation at 18 months
|
| [116] |
Wang (2011) | GA > 37 weeks moderate or severe HIE N = 70 | Epo 200 U/kg/dose 3 times weekly for 2–4 weeks n = 35 (n = 22 moderate and n = 13 severe) Controls n = 35 (n = 24 moderate and n = 11 severe) | Evaluation at 28 days and 3, 6 months:
|
| [120] |
Avasiloaiei (2013) | GA ≥ 37 weeks; perinatal asphyxia N = 67 | Epo 1000 U/kg per days for the first three days after birth (n = 22) Phenobarbital a 40 mg/kg single dose (n = 22) Supportive therapy (n = 23) No hypothermia was available | Evaluation at 3-6-9-12 months
|
| [117] |
El Shimi (2014) | GA ≥ 40 weeks HIEN = 45 | Epo 1500 U/kg at day 1 of life (n = 10) Moderate hypothermia (n = 10) Supportive therapy (n = 10) (n = 15 controls) | Evaluation at 3 months:
|
| [121] |
Rogers (2014) | GA ≥ 37 weeks HIE N = 24 | Epo 250 U/kg (n = 3) or 500 U/kg (n = 6) or 1000 (n = 7) or 2500 U/kg (n = 8) every 48 h for 6 times, starting from day 1 of life | Evaluation at 22 months
|
| [118] |
Wu (2016) | GA ≥ 36 weeks; moderate or severe HIEN = 50 | Hypothermia and placebo (n = 26) at day 1, 2, 3, 5 and 7 of life hypothermia and Epo (n = 24) 1000 U/kg at day 1, 2, 3, 5 and 7 of life | Evaluation at 12 months
|
| [122] |
Malla (2017) | GA ≥ 37 weeks; moderate or severe HIE | Epo 500 IU/kg on alternate days for a total of five doses with first dose < 6 h of age (n = 50) 2 mL of normal saline solution on alternate days for a total of five doses with first dose < 6 h of age (n = 50) No hypothermia was given | Evaluation at 10–14 days and 19 months
|
| [119] |
Mulkey (2017) | GA ≥ 36 weeks; moderate or severe HIEN = 24 | Hypothermia and placebo (n = 24) at day 1, 2, 3, 5 and 7 of life Hypothermia and Epo (n = 20) 1000 U/kg at day 1, 2, 3, 5 and 7 of life (n = 11 received 3 doses, n = 8 received 4 doses, n = 1 received 5 doses before MRI assessment) | O: evaluation at ≤7 days and 12 months
|
| [123] |
First Author (Year) | Target Population | Intervention | Outcomes | Findings | Ref. |
---|---|---|---|---|---|
Andropoulos (2013) | GA > 37 weeks, diagnosis of cardiac abnormalities scheduled for hypothermic cardiopulmonary bypass (CPB) for more than 60 minutes N = 42 | Epo at 1000 U/kg over 60 min 12–24 h preoperatively; immediately after CPB and 24 h after dose 2 Or Epo 500 IU/ kg preoperatively and at days 1 and 3 post-surgery every two days for 2 weeks (n = 20 placebo) | Evaluation pre and post surgery and 22 months:
|
| [126] |
Benders (2014) | Neonates with a MRI confirmed perinatal arterial ischemic stroke N = 20 | Epo 1000 U/kg immediately after MRI diagnosis and at 24 and 48 h after the first dose (n = 10) (n = 10 full term controls) | Evaluation at 3, 12 and 24 months
|
| [125] |
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Perrone, S.; Lembo, C.; Gironi, F.; Petrolini, C.; Catalucci, T.; Corbo, G.; Buonocore, G.; Gitto, E.; Esposito, S.M.R. Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use. Antioxidants 2022, 11, 652. https://doi.org/10.3390/antiox11040652
Perrone S, Lembo C, Gironi F, Petrolini C, Catalucci T, Corbo G, Buonocore G, Gitto E, Esposito SMR. Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use. Antioxidants. 2022; 11(4):652. https://doi.org/10.3390/antiox11040652
Chicago/Turabian StylePerrone, Serafina, Chiara Lembo, Federica Gironi, Chiara Petrolini, Tiziana Catalucci, Giulia Corbo, Giuseppe Buonocore, Eloisa Gitto, and Susanna Maria Roberta Esposito. 2022. "Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use" Antioxidants 11, no. 4: 652. https://doi.org/10.3390/antiox11040652
APA StylePerrone, S., Lembo, C., Gironi, F., Petrolini, C., Catalucci, T., Corbo, G., Buonocore, G., Gitto, E., & Esposito, S. M. R. (2022). Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use. Antioxidants, 11(4), 652. https://doi.org/10.3390/antiox11040652