Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis

Ivain, Phoebe; Montaldo, Paolo; Khan, Aamir; Elagovan, Ramyia; Burgod, Constance; Morales, Maria Moreno; Pant, Stuti; Thayyil, Sudhin

doi:10.1038/s41372-021-01132-4

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…Future research exploring the origins and timing of birth-related brain injury might help to develop effective neuroprotective interventions. Neuroregenerative therapies such as erythropoietin 31 might be more effective in these settings than therapies with an acute neuroprotective effect alone.…”

Section: Discussionmentioning

confidence: 99%

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh

Thayyil

Pant

Montaldo

et al. 2021

The Lancet Global Health

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Summary Background Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia. Methods We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18–22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , NCT02387385 . Findings We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention. Interpretatio...

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Section: Discussionmentioning

confidence: 99%

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh

Thayyil

Pant

Montaldo

et al. 2021

The Lancet Global Health

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185

149

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“…Hypoxia–ischemia (HI) before, during or around the time of birth is the primary cause of hypoxic–ischemic encephalopathy (HIE), which occurs in approximately 2/1000 live births in high resource settings and approximately 26/1000 live births in low resource settings [ 1 ], and is associated with a high rate of mortality and morbidity in survivors, including lifelong physical and mental disabilities [ 2 , 3 ]. Therapeutic hypothermia (TH) is now established as a neuroprotective treatment for term infants with moderate to severe HIE in high resource settings [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia–Ischemia in Near-Term Fetal Sheep

Davidson

Heuij

Dhillon

et al. 2022

IJMS

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Background: Hypoxic–ischemic encephalopathy (HIE) around the time of birth results from loss of oxygen (hypoxia) and blood supply (ischemia). Exogenous infusion of multi-potential cells, including human amnion epithelial cells (hAECs), can reduce hypoxic–ischemic (HI) brain injury. However, there are few data on treatment of severe HI in large animal paradigms at term. The aim of the current study was to determine whether infusion of hAECs early after injury may reduce brain damage after ischemia in near-term fetal sheep. Methods: Chronically instrumented fetal sheep (0.85 gestation) received 30 min of global cerebral ischemia followed by intravenous infusion of hAECs from 2 h after the end of ischemia (ischemia-hAEC, n = 6) or saline (ischemia-vehicle, n = 7). Sham control animals received sham ischemia with vehicle infusion (sham control, n = 8). Results: Ischemia was associated with significant suppression of EEG power and spectral edge frequency until the end of the experiment and a secondary rise in cortical impedance from 24 to 72 h, which were not attenuated by hAEC administration. Ischemia was associated with loss of neurons in the cortex, thalamus, striatum and hippocampus, loss of white matter oligodendrocytes and increased microglial numbers in the white matter, which were not affected by hAEC infusion. Conclusions: A single intravenous administration of hAECs did not reduce electrographic or histological brain damage after 30 min of global cerebral ischemia in near-term fetal sheep.

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“…Given the sub-acute nature of brain injury in LMICs [ 5 ], it is likely that drugs with neuroregenerative properties are more effective than acute neuroprotective therapies, until the underlying mechanisms are known. A recent systematic review of five small studies of erythropoietin monotherapy in LMICs, involving 348 neonates from tertiary neonatal intensive care units, showed a significant reduction in death or disability (RR 0.56; 95 % CI, 0.42–0.75), when administered within 24 h after birth [ 72 ]. Erythropoietin monotherapy needs to be evaluated in well designed and adequately powered randomized control trials in LMICs before clinical use, irrespective of the results of high-income country erythropoietin trials where erythropoietin is evaluated as an adjunct to cooling therapy, particularly as cerebral iron depletion may negate the effects of erythropoietin neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

Need for more evidence in the prevention and management of perinatal asphyxia and neonatal encephalopathy in low and middle-income countries: A call for action

Krishnan

Kumar

Variane³

et al. 2021

Seminars in Fetal and Neonatal Medicine

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Although low- and middle-income countries (LMICs) shoulder 90 % of the neonatal encephalopathy (NE) burden, there is very little evidence base for prevention or management of this condition in these settings. A variety of antenatal factors including socio-economic deprivation, undernutrition and sub optimal antenatal and intrapartum care increase the risk of NE, although little is known about the underlying mechanisms. Implementing interventions based on the evidence from high-income countries to LMICs, may cause more harm than benefit as shown by the increased mortality and lack of neuroprotection with cooling therapy in the hypothermia for moderate or severe NE in low and middle-income countries (HELIX) trial. Pooled data from pilot trials suggest that erythropoietin monotherapy reduces death and disability in LMICs, but this needs further evaluation in clinical trials. Careful attention to supportive care, including avoiding hyperoxia, hypocarbia, hypoglycemia, and hyperthermia, are likely to improve outcomes until specific neuroprotective or neurorestorative therapies available.

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Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis

Cited by 18 publications

References 35 publications

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh

Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia–Ischemia in Near-Term Fetal Sheep

Need for more evidence in the prevention and management of perinatal asphyxia and neonatal encephalopathy in low and middle-income countries: A call for action

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