Introduction
Perinatal brain injury is a major cause of neurological disability in both premature and term infants1 and may include disorders of hearing, vision, speech, motor function, intellectual disability, and seizures. Therefore, preventive and restorative strategies for perinatal brain injury are critically needed to minimize adverse neurological sequelae. In this review, we discuss the established and emerging interventions for perinatal neuroprotection in term and preterm infants.
Prevention of preterm delivery
Prematurity is the leading cause of morbidity and mortality in childhood within the developed world2. Preterm birth (and low birth weight independently) is a leading risk factor for cerebral palsy (CP) and associated neurologic impairments and neurosensory disabilities3,4. Therefore, prevention of preterm delivery is a crucial strategy for perinatal neuroprotection.
Antenatal steroids
A Cochrane systematic review including 30 studies (7774 women and 8158 infants) mostly from high-income countries found that treatment with antenatal corticosteroids (dexamethasone or betamethasone) as compared with placebo or no treatment is associated with a reduction in perinatal death (relative risk [RR] 0.72, 95% confidence interval [CI] 0.58 to 0.89), neonatal death (RR 0.69, 95% CI 0.59 to 0.81), and intraventricular hemorrhage (IVH) (RR 0.55, 95% CI 0.40 to 0.76)5. Treatment with corticosteroids was associated with less developmental delay in childhood, although the data were deemed insufficient.
Antenatal steroids promote lung maturation6, thereby stabilizing respiratory and hemodynamic system. In addition, they stabilize germinal matrix vasculature7,8 and exert vasoconstrictive effects on fetal cerebral blood flow, thereby offering protection against IVH and hypercapnia-induced vasodilatation9,10.
Antenatal corticosteroid administration in women at risk of preterm birth is the standard of care. However, further research is warranted to support this practice in lower-income settings and high-risk obstetric groups.
Magnesium sulfate
Several randomized controlled trials (RCTs) have demonstrated the neuroprotective effects of antenatal magnesium sulfate in preterm infants11–15. A recent meta-analysis that included the above-mentioned trials concluded that antenatal magnesium sulfate given prior to preterm birth for fetal neuroprotection (4448 babies) prevents CP (mild, moderate, and severe) and reduces the combined risk of fetal/infant death or CP (RR 0.86, 95% CI 0.75 to 0.99)16. This benefit was seen independently of reason for preterm birth with similar effects across a range of preterm gestational ages. (It should be noted that the trials included in this analysis included women at less than 33 weeks’ gestation.) These results were consistent with previous meta-analyses that found that magnesium sulfate administered to women at high risk of delivery before 34 weeks of gestation reduced the risk of CP and rate of gross motor dysfunction17–19. Antenatal magnesium sulfate is also associated with reduced cerebellar hemorrhage on magnetic resonance imaging (MRI) in preterm newborns20. However, long-term follow-up has not demonstrated improved neurological, cognitive, behavioral, or functional outcomes in school age for children of women receiving magnesium sulfate for preterm delivery (<30 weeks)21,22.
Based on the above data, antenatal magnesium remains the standard of care for women at less than 32 weeks’ gestation who are at risk for imminent delivery. Evidence for effectiveness between 34 to 37 weeks remains to be established.
Recent studies have also demonstrated improvements in short-term neurological outcomes after postnatal magnesium sulfate infusion. Two small RCTs using postnatal magnesium sulfate infusion (250 mg/kg per day) for 3 days in term neonates with severe birth asphyxia resulted in an improved survival with normal results of cranial computed tomography and electroencephalography in the treated group compared with the control group23,24. However, no significant neurodevelopmental improvement was noted at 6 months25. A prospective observational study, however, reported normal neurodevelopmental outcomes at 18 months in 73% of infants with moderate to severe hypoxic ischemic encephalopathy (HIE) treated with magnesium sulfate (in combination with dopamine) within 6 hours of birth26. A multicenter RCT of therapeutic hypothermia plus magnesium sulfate versus hypothermia alone of term and near term newborn infants born at, at least 35 weeks (the Mag Cool Study) with a clinical diagnosis of moderate or severe HIE found no differences in the short-term adverse outcomes (death, seizures, and intracranial hemorrhage) between the two groups27.
The mechanism underlying the neuroprotective effects of magnesium sulfate is not well elucidated. It is widely accepted that magnesium prevents excitotoxic damage through N-Methyl-d-aspartic acid (NMDA) receptor blockade28. Moreover, magnesium has anti-inflammatory properties29 and reduces the production of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha30. Animal models have also demonstrated that magnesium sulfate changes expression of several genes, thereby altering the mitochondrial and metabolic substrate of the immature brain and reducing vulnerability to hypoxia31. Therefore, magnesium-induced preconditioning of the brain via development of mitochondrial resistance and suppression of inflammation likely contributes to its mechanism of perinatal protection32.
As advances in neonatal care enable increased survival of infants of 22 to 23 weeks’ gestational age, studies will need to be carried out in this population to determine the effectiveness of interventions.
Delayed umbilical cord clamping
Delayed cord clamping is typically defined as a lapse of at least 30 to 60 seconds before clamping the umbilical cord after delivery. In term infants, a meta-analysis of 15 trials involving a total of 3911 women and infant pairs found no significant differences between early (<60 seconds) and late (>60 seconds) clamping in terms of neonatal mortality (RR 0.37, 95% CI 0.04 to 3.41) or for most other neonatal morbidity outcomes33. However, mean birth weight was significantly higher in the late cord clamping group, and infants in the early cord clamping group were more likely to be iron-deficient at 3 to 6 months (RR 2.65, 95% CI 1.04 to 6.73).
In preterm infants, a 2012 meta-analysis of 15 studies (738 infants born at between 24 and 36 weeks’ gestation) found that delaying cord clamping for 30 to 180 seconds was associated with less IVH (RR 0.59, 95% CI 0.41 to 0.85), decreased need for transfusions for anemia (RR 0.61, 95% CI 0.46 to 0.81), and lower risk for necrotizing enterocolitis compared with immediate clamping34. However, there were no clear differences in severe (grade 3 or 4) IVH and periventricular leukomalacia. A later trial comparing immediate with delayed cord clamping for 30 seconds among preterm neonates born at between 24 and 34 weeks of gestation found a lower rate of IVH among neonates in the delayed cord clamp group compared with neonates in the immediate clamp group but this was not statistically significant35. A trial assessing the effects of delayed cord clamping in 208 preterm (<32 weeks’ gestation) infants on neonatal and 18-month motor outcomes found that although delayed cord clamping did not alter the incidence of IVH in preterm infants, it improved motor function at 18 to 22 months’ corrected age (odds ratio 0.32, 95% CI 0.10 to 0.90)36. More recently, a meta-analysis of 18 RCTs comparing delayed versus early clamping in 2834 infants born at less than 37 weeks’ gestation found that delayed clamping (30 seconds to more than 120 seconds) reduced hospital mortality (RR 0.68, 95% CI 0.52 to 0.90); however, delayed cord clamping did not reduce the incidence of intubation for resuscitation, mechanical ventilation, IVH, or brain injury37. Maternal postpartum hemorrhage or the need for maternal blood transfusion was not impacted by delayed clamping.
As a result, the American College of Obstetricians and Gynecologists recommends a delay in umbilical cord clamping for at least 30 to 60 seconds after birth in vigorous term and preterm infants38. This has been endorsed by the American Academy of Pediatrics, and recent Neonatal Resuscitation Program guidelines recommend delayed umbilical cord clamping for at least 30 to 60 seconds for most vigorous term and preterm infants39,40.
It has been postulated that delayed cord clamping allows improved cardiovascular transition with resultant improved cerebral autoregulation41. Also, delaying clamping for at least 60 seconds may increase the number of infants breathing before the cord is clamped and this may decrease need for invasive mechanical ventilation and endotracheal intubation37. Animal data suggest that timing cord clamping on the basis of the infant’s physiology may optimize the potential benefits and that delayed cord clamping may be of greatest benefit to apneic infants42–44.
Non-steroidal anti-inflammatory drugs
Indomethacin, a non-selective cyclo-oxygenase (COX) inhibitor was shown to reduce the incidence of IVH in preterm infants (RR 0.66, 95% CI 0.53 to 0.82)45. A meta-analyses of 19 large RCTs found that prophylactic indomethacin in preterm infants did not improve mortality or long-term developmental outcomes46. However, pooled data from recent observational studies suggest that the use of prophylactic indomethacin may be associated with a small reduction in mortality risk, particularly in infants with birth weights above the 10th percentile47.
Ibuprofen is another non-selective COX inhibitor but has not been shown to prevent IVH in premature infants48.
Indomethacin promotes maturation of the cerebral vasculature49; blunts cerebral vascular responses caused by hypoxia, hypercapnia, hypertension, and asphyxia50,51; and improves cerebral vascular autoregulation52, all of which may contribute to a reduction of IVH.
Prophylactic indomethacin administration continues to be used in many centers across the United States despite conflicting evidence. Well-designed contemporary studies are required to guide clinical practice.
Therapeutic hypothermia
Multiple RCTs of therapeutic hypothermia in term newborns have demonstrated that hypothermia (33–35 °C) for 72 hours starting within about 6 hours of birth is associated with improved survival and decreased neurological impairment53–59. A meta-analysis60 of 11 of these trials involving 1505 term and late preterm infants with moderate or severe encephalopathy found that therapeutic hypothermia resulted in decreased death or major disability by 18 to 24 months of age (RR 0.75, 95% CI 0.68 to 0.83), as well as decreased mortality (RR 0.75, 95% CI 0.64 to 0.88), and reduced neurodevelopmental disability in survivors (RR 0.77, 95% CI 0.63 to 0.94). Subgroup analysis revealed that infants with severe encephalopathy demonstrated significant reduction in mortality but no significant reduction in major disability, although there was a trend toward improvement (RR 0.75, 95% CI 0.50 to 1.12), and the lack of significance was attributed to the small number of infants in this category. There was no significant reduction in death or moderate to severe disability at 6 to 7 years of age among those that underwent hypothermia, but there was a clinically important trend toward improvement (RR 0.81, 95% CI 0.64 to 1.04) and a significant reduction in death at 6 to 7 years of age. The CoolCap trial, for instance, found that the measured outcome at 18 months was strongly associated with overall functional scores at 7 to 8 years of age, supporting a sustained treatment effect of therapeutic hypothermia61. The NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) trial found no significant reduction in the combined outcome of death or an IQ score of less than 70 at 6 to 7 years in the hypothermia group; however, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors62.
The above-mentioned meta-analysis also demonstrated a significant reduction in CP in the hypothermia groups (RR 0.66, 95% CI 0.54 to 0.82)60. Therapeutic hypothermia was also associated with significant reduction in the presence of abnormal findings on MRI60, in particular in the basal ganglia or thalamus, white matter, and abnormal posterior limb of the internal capsule63. A retrospective cohort study of 224 neonates found that therapeutic hypothermia in moderate encephalopathy was associated with reduced seizures (RR 0.43, 95% CI 0.30 to 0.61)64.
It remains to be seen whether the therapeutic window for hypothermia may extend beyond 6 hours. A multicenter RCT spanning 8 years and including term infants with moderate or severe HIE found that hypothermia initiated at 6 to 24 hours after birth compared with non-cooling resulted in a 76% probability of any reduction in death or disability at 18 to 22 months65. The neuroprotective mechanisms of hypothermia include reduced concentrations of free creatine, lactate, NAA, and neurotransmitters such as glutamate, glutamine, GABA, and aspartate and increased concentration of taurine and phosphocreatine. Animal models have also demonstrated that hypothermia reduces synthesis of free radicals and nitric oxide and suppression of microglial activation66. Overall, hypothermia attenuates cellular energy demand and secondary energy failure67.
Although therapeutic hypothermia is now the standard of care for term and late preterm infants with moderate/severe HIE, future directions include investigating the neuroprotective mechanism in infants with mild encephalopathy and in preterm infants. There is recent evidence to suggest that mild HIE is associated with disability68. In addition, the combination of hypothermia with other therapeutic agents such as those described below is being investigated.
Recombinant human erythropoietin
Several studies suggest that erythropoietin, either alone or in combination with hypothermia therapy, improves neurodevelopmental outcomes and is safe. A case control study in Egypt with 45 neonates with mild to moderate HIE found that neonates that received human recombinant erythropoietin 2500 IU/kg subcutaneously daily for 5 days had decreased serum nitrous oxide concentrations, fewer seizures, improved electroencephalogram backgrounds, and favorable neurologic outcomes at 6 months of age. An RCT in China in 167 term neonates with moderate to severe hypoxia-ischemia demonstrated that erythropoietin monotherapy 300 to 500 IU/kg reduced disability at 18 months in infants with moderate but not severe injury69. A trial in India in 100 term neonates with moderate or severe HIE found that erythropoietin 500 U/kg monotherapy given within 6 hours of birth resulted in significant reduction of death or moderate or severe disability at 19 months of age (RR 0.57, 95% CI 0.38 to 0.85) and lower risk of CP in survivors (RR 0.52, 95% CI 0.25 to 1.03). A phase II, multicenter, double-blinded controlled trial in the Unites States (NEATO) in term newborns with moderate to severe HIE found that multiple doses of erythropoietin (1000 U/kg) given intravenously for 7 days was associated with reduced severity of brain injury on neonatal MRI, specifically in the subcortical region, and improved motor function at 1 year among infants undergoing therapeutic hypothermia70. Phase III trials are under way to determine whether high-dose erythropoietin in conjunction with hypothermia in infants with moderate/severe HIE reduces the combined outcome of death or neurodevelopmental disability and improves neurodevelopmental outcomes at 2 years of age, without significant adverse effects, when compared with hypothermia alone71. A pilot prospective study of nine patients who met criteria for hypothermia suggests that combination therapy with 300 U/kg erythropoietin every other day for 2 weeks, 250 mg/kg magnesium sulfate for 3 days, and therapeutic hypothermia is feasible in newborns with HIE. Phase II and II studies are needed to investigate the neuroprotective effect of this strategy.
However, it should be noted that a recent mouse model study suggested that, when used immediately after the insult, erythropoietin may not be beneficial in situations of extreme oxidative stress and may, in fact, worsen the injury72.
Preliminary data also suggest a benefit of erythropoietin in preterm infants. A retrospective analysis73 of neurodevelopmental outcome data from extremely-low-birth-weight infants given 500 to 2500 U/kg erythropoietin × 3 doses in a phase I/II trial74 found that erythropoietin administration correlated with improvement of cognitive and motor scores. A study of 102 infants reported improved cognitive scores at 18 to 22 months in preterm infants that received low doses of erythropoietin (400 U/kg, 3×/week subcutaneously) or darbepoetin (10 μg/kg, 1×/week subcutaneously)75. In a large multicenter placebo-controlled randomized trial in Switzerland of very preterm infants (born at between 26 and 32 weeks), there were no significant differences in neurodevelopmental outcomes at 2 years between those that received prophylactic early high-dose erythropoietin for neuroprotection and those that received placebo76. However, subgroup analyses revealed that high-dose erythropoietin administration was associated with reduced brain injury, improved white matter development in the major white matter tracts, and an increase of local structural connectivity strengths77–79. A large RCT of 800 infants of not more than 32 weeks’ gestational age demonstrated that repeated low-dose erythropoietin (500 IU/kg) reduced risk of long-term neurological disability in very preterm infants at 18 months of age (RR 0.40, 95% CI 0.27 to 0.59)80. A meta analyses of four RCTs including 1133 preterm infants showed that prophylactic erythropoietin improved neurocognition at 18 to 24 months’ corrected age but had no significant effect on motor development, hearing, or vision81.
A recent Cochrane review of 34 studies spanning 22 countries enrolling 3643 infants, gestational age of less than 37 weeks and/or birth weight of less than 2500 g concluded that early treatment with erythropoiesis-stimulating agents significantly decreased rates of IVH, periventricular leukomalacia, and necrotizing enterocolitis82. It also found a reduction in any neurodevelopmental impairment at 18 to 22 months in the erythropoietin group compared with the placebo group (typical RR 0.62, 95% CI 0.48 to 0.80), but the quality of evidence was deemed to be low.
Further trials are needed to determine optimal dosing strategy and long-term assessment of developmental outcomes. The Phase 3 Preterm Erythropoietin Neuroprotection (PENUT) trial (ClinicalTrials.gov Identifier: NCT01378273) randomly assigned 941 preterm infants between 24 and 27 weeks’ gestation to receive erythropoietin 1000 U/kg or placebo given intravenously every 48 hours for six doses, followed by 400 U/kg or sham injections three times a week through 32 weeks postmenstrual age83. Results are pending publication. Other trials using erythropoietin in preterm or very preterm infants (ClinicalTrials.gov Identifiers: NCT02550054 and NCT02076373) are under way to assess neurodevelopmental outcomes84,85.
The neuroprotective and neuroregenerative effects of erythropoietin are likely related to its anti-inflammatory86, anti-excitotoxic, anti-oxidant87, and anti-apoptotic effects on neurons and oligodendrocytes and regenerative effects of oligodendrogenesis, neurogenesis, and angiogenesis88–92.
Melatonin
Data from animal studies suggest a role of melatonin in perinatal neuroprotection93–97. In a randomized controlled pilot study of 45 newborns, 30 of whom had HIE, melatonin administration together with hypothermia was associated with fewer seizures, fewer white matter abnormalities on MRI, and better mortality rate at 6 months without developmental or neurological abnormalities98. A phase II multi-center double-blinded randomized placebo-controlled trial (Mint study) evaluating the neuroprotective effect of intravenous melatonin in 58 preterm infants born at less than 31 weeks’ gestation found no difference in white matter fractional anisotropy99. The PREMELIP study aimed to assess the neuroprotective effect of melatonin administered in the immediate prepartum period in very preterm infants (<28 weeks’ gestation) using MRI but was terminated100. The “Protect Me Trial”, which aims to evaluate the effect of maternal melatonin supplementation in pregnancies with early-onset fetal growth restriction on neurodevelopmental outcomes at 2 years of age, is under way101.
Melatonin’s neuroprotective effects are likely due to its antioxidant102,103, anti-inflammatory94,96,104, and anti-apoptotic94,105 effects, which may protect against free radical–induced damage incurred during times of increased oxidative stress perinatally106.
Xenon
Xenon has demonstrated neuroprotection in animal models of moderate HIE and this effect is enhanced when combined with cooling107,108. However, a single phase II trial randomly assigning 92 newborns with moderate to severe HIE to either cooling plus xenon or cooling alone did not show significant differences between magnetic resonance biomarkers of brain damage or in occurrence of seizures during primary hospitalization56. Long-term neurodevelopmental outcomes were not reported. However, this study was limited by delay before starting xenon (median of 11 hours). Thus, current evidence is inadequate to determine whether xenon therapy for newborns with HIE is effective109.
Xenon’s neuroprotective effects are thought to be related to its inhibition of NMDA subtype of the glutamate receptor, a key step in the neurotoxic cascade, and activation of two species of potassium channels which have been linked to neuroprotection110.
Topiramate
Topiramate has demonstrated neuroprotective effects in animal models of transient global cerebral ischemia, ischemic stroke, and neonatal hypoxic ischemic cerebral injury111–113. A phase II trial in term newborns with moderate to severe HIE treated with hypothermia showed that treatment with topiramate was safe but that, compared with cooling alone, it did not improve death or neurological disability114. There was a reduction in the prevalence of epilepsy observed in the topiramate group. The neuroprotective properties of topiramate are presumed to be due to AMPA and kainate receptors inhibition115, blockade of sodium116 and high voltage-activated calcium currents, and inhibitory effect on mitochondrial permeability transition pores117,118.
Allopurinol
A 2012 Cochrane review including 114 infants in three trials found no clear differences in severe neurodevelopmental disability or death among survivors at 18 months or at 4 to 8 years after allopurinol versus placebo (RR 0.78, 95% CI 0.56 to 1.08)119. In addition, a follow-up study of two of the trials included in the above review found no differences in mortality or developmental disability at the age of 4 to 8 years in the overall group of asphyxiated infants; however, a subgroup revealed significantly less severe adverse outcome in the allopurinol-treated moderately asphyxiated infants compared with controls (RR 0.40, 95% CI 0.17 to 0.94)120,121. A more recent follow-up study of 222 women in labor with suspected fetal hypoxia randomly assigned to receive allopurinol or placebo demonstrated that allopurinol administration does not improve long-term developmental and behavioral outcome at 5 years of age121,122. Currently, a multicenter European trial (ClinicalTrials.gov Identifier: NCT03162653) is under way to evaluate whether early postnatal allopurinol in addition to standard of care reduces the incidence of death or severe neurodevelopmental impairment at 24 months of age in newborns with HIE123.
Allopurinol, a xanthine oxidase inhibitor, preserves NMDA receptor integrity and prevents adenosine degradation and oxygen radical formation and this potentially confers neuroprotection in HIE124.
Autologous cord blood cell therapy
Preclinical evidence is emerging to support the use of cord-derived mesenchymal stromal cells (MSCs) for regeneration and repair of injured immature brain125,126. Animal models suggest that exogenous administration of MSCs significantly reduces brain injury and post-hemorrhagic hydrocephalus after IVH by protecting against inflammation, gliosis, and apoptosis of the injured brain127–129.
Limited clinical data exist suggesting that the use of autologous cord blood cells for perinatal/preterm brain injury is safe and feasible130–132. Further clinical trials are under way to evaluate safety and efficacy of autologous cord blood cells for neonatal brain injury133–138.
MSCs are thought to restore neurological injury by differentiation to neuronal cells or, more importantly, via secretion of paracrine factors such as insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF), which augment neuronal and glial cell proliferation and survival139,140. These transplanted MSCs secrete the paracrine factors at variable levels in response to cues from the local substrate141. Moreover, MSCs are shown to secrete anti-inflammatory cytokines127.
Vitamin E
A meta-analysis of 26 randomized clinical trials found that vitamin E supplementation in preterm infants (gestational age less than 37 weeks or birth weight less than 2500 g) reduced the risk of intracranial hemorrhage but increased the risk of sepsis142. Currently, there are no data to support the use of vitamin E for perinatal neuroprotection.
Creatine
Animal experiments demonstrate that, when given as a supplement to the mother’s diet during pregnancy, creatine protects the fetal brain against hypoxic insult at term143–145. Further trials are needed to evaluate the effect of antenatal creatine supplementation on neuroprotection of the fetus.
Creatine is involved with cellular energy production but also has demonstrated antioxidant actions146, stabilization of lipid membranes147, and interactions with glutamate and GABAA receptors148 that diminish excitotoxicity145,149.
Conclusions
Recent clinical and laboratory advances in neuroprotection of the developing brain suggest that there is a cascade of biochemical events that can be partially disrupted, leading to reduced brain injury. Brain cooling and blockade of NMDA glutamate receptors are two of the earliest interventions that showed an ability to reduce brain injury and these interventions can be synergistic. Cooling has been shown to reduce brain injury in human term infants by impeding the cascade of injury, especially the events in the mitochondria. Magnesium has shown neuroprotective activity in numerous studies, several possibly by anti-inflammatory and anti-glutamate effects. Anti-erythropoietin protective effects have also been identified. Recent advances in perinatal neuroprotection are growing briskly as we identify more potential therapeutic targets.
F1000 recommendedReferences
- 1.
Volpe JJ:
Perinatal brain injury: from pathogenesis to neuroprotection.
Ment Retard Dev Disabil Res Rev.
2001; 7(1): 56–64. PubMed Abstract
| Publisher Full Text
- 2.
Blencowe H, Cousens S, Oestergaard MZ, et al.:
National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.
Lancet.
2012; 379(9832): 2162–72. PubMed Abstract
| Publisher Full Text
- 3.
Himpens E, van den Broeck C, Oostra A, et al.:
Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: a meta-analytic review.
Dev Med Child Neurol.
2008; 50(5): 334–40. PubMed Abstract
| Publisher Full Text
- 4.
Doyle LW, Casalaz D, Victorian Infant Collaborative Study Group:
Outcome at 14 years of extremely low birthweight infants: a regional study.
Arch Dis Child Fetal Neonatal Ed.
2001; 85(3): F159–64. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 5.
Roberts D, Brown J, Medley N, et al.:
Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
Cochrane Database Syst Rev.
2017; 3: CD004454. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 6.
Massaro D, Teich N, Maxwell S, et al.:
Postnatal development of alveoli. Regulation and evidence for a critical period in rats.
J Clin Invest.
1985; 76(4): 1297–305. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 7.
Xu H, Hu F, Sado Y, et al.:
Maturational changes in laminin, fibronectin, collagen IV, and perlecan in germinal matrix, cortex, and white matter and effect of betamethasone.
J Neurosci Res.
2008; 86(7): 1482–500. PubMed Abstract
| Publisher Full Text
- 8.
Vinukonda G, Dummula K, Malik S, et al.:
Effect of prenatal glucocorticoids on cerebral vasculature of the developing brain.
Stroke.
2010; 41(8): 1766–73. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 9.
Schwab M, Roedel M, Anwar MA, et al.:
Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow.
J Physiol.
2000; 528(Pt 3): 619–32. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 10.
Cambonie G, Mesnage R, Milési C, et al.:
Betamethasone impairs cerebral blood flow velocities in very premature infants with severe chronic lung disease.
J Pediatr.
2008; 152(2): 270–5. PubMed Abstract
| Publisher Full Text
- 11.
Mittendorf R, Dambrosia J, Pryde PG, et al.:
Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants.
Am J Obstet Gynecol.
2002; 186(6): 1111–8. PubMed Abstract
| Publisher Full Text
- 12.
Crowther CA, Hiller JE, Doyle LW, et al.:
Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial.
JAMA.
2003; 290(20): 2669–76. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 13.
Magpie Trial Follow-Up Study Collaborative Group: The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months.
BJOG.
2007; 114(3): 289–99. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 14.
Marret S, Marpeau L, Zupan-Simunek V, et al.:
Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial*.
BJOG.
2007; 114(3): 310–8. PubMed Abstract
| Publisher Full Text
- 15.
Rouse DJ, Hirtz DG, Thom E, et al.:
A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy.
N Engl J Med.
2008; 359(9): 895–905. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 16.
Crowther CA, Middleton PF, Voysey M, et al.:
Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis.
PLoS Med.
2017; 14(10): e1002398. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 17.
Doyle LW, Crowther CA, Middleton P, et al.:
Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.
Cochrane Database Syst Rev.
2009; (1): CD004661. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 18.
Conde-Agudelo A, Romero R:
Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis.
Am J Obstet Gynecol.
2009; 200(6): 595–609. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 19.
Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network:
Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.
Obstet Gynecol.
2009; 114(2 Pt 1): 354–64. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 20.
Gano D, Ho ML, Partridge JC, et al.:
Antenatal Exposure to Magnesium Sulfate Is Associated with Reduced Cerebellar Hemorrhage in Preterm Newborns.
J Pediatr.
2016; 178: 68–74. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 21.
Doyle LW, Anderson PJ, Haslam R, et al.:
School-age outcomes of very preterm infants after antenatal treatment with magnesium sulfate vs placebo.
JAMA.
2014; 312(11): 1105–13. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 22.
Chollat C, Enser M, Houivet E, et al.:
School-age outcomes following a randomized controlled trial of magnesium sulfate for neuroprotection of preterm infants.
J Pediatr.
2014; 165(2): 398–400.e3. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 23.
Ichiba H, Tamai H, Negishi H, et al.:
Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia.
Pediatr Int.
2002; 44(5): 505–9. PubMed Abstract
| Publisher Full Text
- 24.
Bhat MA, Charoo BA, Bhat JI, et al.:
Magnesium sulfate in severe perinatal asphyxia: a randomized, placebo-controlled trial.
Pediatrics.
2009; 123(5): e764–9. PubMed Abstract
| Publisher Full Text
- 25.
Gathwala G, Khera A, Singh J, et al.:
Magnesium for neuroprotection in birth asphyxia.
J Pediatr Neurosci.
2010; 5(2): 102–4. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 26.
Ichiba H, Yokoi T, Tamai H, et al.:
Neurodevelopmental outcome of infants with birth asphyxia treated with magnesium sulfate.
Pediatr Int.
2006; 48(1): 70–5. PubMed Abstract
| Publisher Full Text
- 27.
Rahman SU, Canpolat FE, Oncel MY, et al.:
Multicenter randomized controlled trial of therapeutic hypothermia plus magnesium sulfate versus therapeutic hypothermia plus placebo in the management of term and near-term infants with hypoxic ischemic encephalopathy (The Mag Cool study): A pilot study.
J Clin Neonatol.
2015; 4(3): 158–163. Publisher Full Text
- 28.
Nowak L, Bregestovski P, Ascher P, et al.:
Magnesium gates glutamate-activated channels in mouse central neurones.
Nature.
1984; 307(5950): 462–5. PubMed Abstract
| Publisher Full Text
- 29.
Burd I, Breen K, Friedman A, et al.:
Magnesium sulfate reduces inflammation-associated brain injury in fetal mice.
Am J Obstet Gynecol.
2010; 202(3): 292.e1–9. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 30.
Aryana P, Rajaei S, Bagheri A, et al.:
Acute Effect of Intravenous Administration of Magnesium Sulfate on Serum Levels of Interleukin-6 and Tumor Necrosis Factor-α in Patients Undergoing Elective Coronary Bypass Graft With Cardiopulmonary Bypass.
Anesth Pain Med.
2014; 4(3): e16316. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 31.
Koning G, Lyngfelt E, Svedin P, et al.:
Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia-ischemia.
Int J Dev Neurosci.
2018; 70: 56–66. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 32.
Koning G, Leverin AL, Nair S, et al.:
Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection.
J Cereb Blood Flow Metab.
2019; 39(6): 1038–55. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 33.
McDonald SJ, Middleton P, Dowswell T, et al.:
Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.
Cochrane Database Syst Rev.
2013; (7): CD004074. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 34.
Rabe H, Diaz-Rossello JL, Duley L, et al.:
Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
Cochrane Database Syst Rev.
2012; (8): CD003248. PubMed Abstract
| Publisher Full Text
- 35.
Elimian A, Goodman J, Escobedo M, et al.:
Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial.
Obstet Gynecol.
2014; 124(6): 1075–9. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 36.
Mercer JS, Erickson-Owens DA, Vohr BR, et al.:
Effects of Placental Transfusion on Neonatal and 18 Month Outcomes in Preterm Infants: A Randomized Controlled Trial.
J Pediatr.
2016; 168: 50–5.e1. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 37.
Fogarty M, Osborn DA, Askie L, et al.:
Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis.
Am J Obstet Gynecol.
2018; 218(1): 1–18. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 38.
Committee on Obstetric Practice: Committee Opinion No. 684: Delayed Umbilical Cord Clamping After Birth.
Obstet Gynecol.
2017; 129(1): e5–e10. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 39.
Weiner GM, Zaichkin J, Kattwinkel J:
Textbook of Neonatal Resusciation (NRP). Itasca, IL: American Academy of Pediatrics. 2016. Reference Source
- 40.
Delayed Umbilical Cord Clamping After Birth.
Pediatrics.
2017; 139(6): pii: e20170957. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 41.
Vesoulis ZA, Liao SM, Mathur AM:
Delayed cord clamping is associated with improved dynamic cerebral autoregulation and decreased incidence of intraventricular hemorrhage in preterm infants.
J Appl Physiol (1985).
2019; 127(1): 103–10. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 42.
Hooper SB, Te Pas AB, Lang J, et al.:
Cardiovascular transition at birth: a physiological sequence.
Pediatr Res.
2015; 77(5): 608–14. PubMed Abstract
| Publisher Full Text
- 43.
Bhatt S, Alison BJ, Wallace EM, et al.:
Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs.
J Physiol.
2013; 591(8): 2113–26. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 44.
Polglase GR, Dawson JA, Kluckow M, et al.:
Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs.
PLoS One.
2015; 10(2): e0117504. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 45.
Fowlie PW, Davis PG:
Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis.
Arch Dis Child Fetal Neonatal Ed.
2003; 88(6): F464–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 46.
Fowlie PW, Davis PG, McGuire W:
Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.
Cochrane Database Syst Rev.
2010; (7): CD000174. PubMed Abstract
| Publisher Full Text
- 47.
Jensen EA, Foglia EE, Schmidt B:
Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies.
Semin Perinatol.
2018; 42(4): 228–34. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 48.
Dani C, Bertini G, Pezzati M, et al.:
Prophylactic ibuprofen for the prevention of intraventricular hemorrhage among preterm infants: a multicenter, randomized study.
Pediatrics.
2005; 115(6): 1529–35. PubMed Abstract
| Publisher Full Text
- 49.
Ment LR, Stewart WB, Ardito TA, et al.:
Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup.
Stroke.
1992; 23(8): 1132–7. PubMed Abstract
| Publisher Full Text
- 50.
Coyle MG, Oh W, Stonestreet BS:
Effects of indomethacin on brain blood flow and cerebral metabolism in hypoxic newborn piglets.
Am J Physiol.
1993; 264(1 Pt 2): H141–9. PubMed Abstract
| Publisher Full Text
- 51.
Ballabh P:
Pathogenesis and prevention of intraventricular hemorrhage.
Clin Perinatol.
2014; 41(1): 47–67. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 52.
Van Bel F, Bartelds B, Teitel DF, et al.:
Effect of indomethacin on cerebral blood flow and oxygenation in the normal and ventilated fetal lamb.
Pediatr Res.
1995; 38(2): 243–50. PubMed Abstract
| Publisher Full Text
- 53.
Eicher DJ, Wagner CL, Katikaneni LP, et al.:
Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.
Pediatr Neurol.
2005; 32(1): 11–7. PubMed Abstract
| Publisher Full Text
- 54.
Shankaran S, Laptook AR, Ehrenkranz RA, et al.:
Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
N Engl J Med.
2005; 353(15): 1574–84. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 55.
Gluckman PD, Wyatt JS, Azzopardi D, et al.:
Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
Lancet.
2005; 365(9460): 663–70. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 56.
Azzopardi DV, Strohm B, Edwards AD, et al.:
Moderate hypothermia to treat perinatal asphyxial encephalopathy.
N Engl J Med.
2009; 361(14): 1349–58. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 57.
Zhou WH, Cheng GQ, Shao XM, et al.:
Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China.
J Pediatr.
2010; 157(3): 367–72, 372.e1-3. PubMed Abstract
| Publisher Full Text
- 58.
Simbruner G, Mittal RA, Rohlmann F, et al.:
Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT.
Pediatrics.
2010; 126(4): e771–e778. PubMed Abstract
| Publisher Full Text
- 59.
Jacobs SE, Morley CJ, Inder TE, et al.:
Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial.
Arch Pediatr Adolesc Med.
2011; 165(8): 692–700. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 60.
Jacobs SE, Berg M, Hunt R, et al.:
Cooling for newborns with hypoxic ischaemic encephalopathy.
Cochrane Database Syst Rev.
2013; 69(1): CD003311. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 61.
Guillet R, Edwards AD, Thoresen M, et al.:
Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy.
Pediatr Res.
2012; 71(2): 205–9. PubMed Abstract
| Publisher Full Text
- 62.
Shankaran S, Pappas A, McDonald SA, et al.:
Childhood outcomes after hypothermia for neonatal encephalopathy.
N Engl J Med.
2012; 366(22): 2085–92. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 63.
Rutherford M, Ramenghi LA, Edwards AD, et al.:
Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial.
Lancet Neurol.
2010; 9(1): 39–45. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 64.
Orbach SA, Bonifacio SL, Kuzniewicz MW, et al.:
Lower incidence of seizure among neonates treated with therapeutic hypothermia.
J Child Neurol.
2014; 29(11): 1502–7. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 65.
Laptook AR, Shankaran S, Tyson JE, et al.:
Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.
JAMA.
2017; 318(16): 1550–60. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 66.
Si QS, Nakamura Y, Kataoka K:
Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide.
Neuroscience.
1997; 81(1): 223–9. PubMed Abstract
| Publisher Full Text
- 67.
Wisnowski JL, Wu TW, Reitman AJ, et al.:
The effects of therapeutic hypothermia on cerebral metabolism in neonates with hypoxic-ischemic encephalopathy: An in vivo 1H-MR spectroscopy study.
J Cereb Blood Flow Metab.
2016; 36(6): 1075–86. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 68.
Chalak LF, Nguyen KA, Prempunpong C, et al.:
Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months.
Pediatr Res.
2018; 84(6): 861–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 69.
Zhu C, Kang W, Xu F, et al.:
Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy.
Pediatrics.
2009; 124(2): e218–26. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 70.
Wu YW, Mathur AM, Chang T, et al.:
High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial.
Pediatrics.
2016; 137(6): pii: e20160191. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 71.
PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns. Reference Source
- 72.
Sheldon RA, Windsor C, Lee BS, et al.:
Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice.
Dev Neurosci.
2017; 39(1–4): 228–37. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 73.
McAdams RM, McPherson RJ, Mayock DE, et al.:
Outcomes of extremely low birth weight infants given early high-dose erythropoietin.
J Perinatol.
2013; 33(3): 226–30. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 74.
Juul SE, McPherson RJ, Bauer LA, et al.:
A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety.
Pediatrics.
2008; 122(2): 383–91. PubMed Abstract
| Publisher Full Text
- 75.
Ohls RK, Kamath-Rayne BD, Christensen RD, et al.:
Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo.
Pediatrics.
2014; 133(6): 1023–30. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 76.
Natalucci G, Latal B, Koller B, et al.:
Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial.
JAMA.
2016; 315(19): 2079–85. PubMed Abstract
| Publisher Full Text
- 77.
Leuchter RH, Gui L, Poncet A, et al.:
Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.
JAMA.
2014; 312(8): 817–24. PubMed Abstract
| Publisher Full Text
- 78.
O’Gorman RL, Bucher HU, Held U, et al.:
Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants.
Brain.
2015; 138(Pt 2): 388–97. PubMed Abstract
| Publisher Full Text
- 79.
Jakab A, Ruegger C, Bucher HU, et al.:
Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.
Neuroimage Clin.
2019; 22: 101806. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 80.
Song J, Sun H, Xu F, et al.:
Recombinant human erythropoietin improves neurological outcomes in very preterm infants.
Ann Neurol.
2016; 80(1): 24–34. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 81.
Fischer HS, Reibel NJ, Bührer C, et al.:
Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis.
Pediatrics.
2017; 139(5): pii: e20164317. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 82.
Ohlsson A, Aher SM:
Early erythropoiesis-stimulating agents in preterm or low birth weight infants.
Cochrane Database Syst Rev.
2017; 11: CD004863. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 83.
Juul SE, Mayock DE, Comstock BA, et al.:
Neuroprotective potential of erythropoietin in neonates; design of a randomized trial.
Matern Health Neonatol Perinatol.
2015; 1: 27. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 84.
Erythropoietin in Premature Infants to Prevent Encephalopathy.Reference Source
- 85.
Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants. Reference Source
- 86.
Villa P, Bigini P, Mennini T, et al.:
Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.
J Exp Med.
2003; 198(6): 971–5. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 87.
Kumral A, Gonenc S, Acikgoz O, et al.:
Erythropoietin increases glutathione peroxidase enzyme activity and decreases lipid peroxidation levels in hypoxic-ischemic brain injury in neonatal rats.
Biol Neonate.
2005; 87(1): 15–8. PubMed Abstract
| Publisher Full Text
- 88.
Rangarajan V, Juul SE:
Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection.
Pediatr Neurol.
2014; 51(4): 481–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 89.
Juul SE, Pet GC:
Erythropoietin and Neonatal Neuroprotection.
Clin Perinatol.
2015; 42(3): 469–81. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 90.
Wang L, Zhang Z, Wang Y, et al.:
Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats.
Stroke.
2004; 35(7): 1732–7. PubMed Abstract
| Publisher Full Text
- 91.
Osredkar D, Sall JW, Bickler PE, et al.:
Erythropoietin promotes hippocampal neurogenesis in in vitro models of neonatal stroke.
Neurobiol Dis.
2010; 38(2): 259–65. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 92.
Gonzalez FF, Larpthaveesarp A, McQuillen P, et al.:
Erythropoietin increases neurogenesis and oligodendrogliosis of subventricular zone precursor cells after neonatal stroke.
Stroke.
2013; 44(3): 753–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 93.
Miller SL, Yan EB, Castillo-Meléndez M, et al.:
Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion.
Dev Neurosci.
2005; 27(2–4): 200–10. PubMed Abstract
| Publisher Full Text
- 94.
Welin AK, Svedin P, Lapatto R, et al.:
Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion.
Pediatr Res.
2007; 61(2): 153–8. PubMed Abstract
| Publisher Full Text
- 95.
Lekic T, Manaenko A, Rolland W, et al.:
Neuroprotection by melatonin after germinal matrix hemorrhage in neonatal rats.
Acta Neurochir Suppl.
2011; 111: 201–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 96.
Watanabe K, Hamada F, Wakatsuki A, et al.:
Prophylactic administration of melatonin to the mother throughout pregnancy can protect against oxidative cerebral damage in neonatal rats.
J Matern Fetal Neonatal Med.
2012; 25(8): 1254–9. PubMed Abstract
| Publisher Full Text
- 97.
Miller SL, Yawno T, Alers NO, et al.:
Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction.
J Pineal Res.
2014; 56(3): 283–94. PubMed Abstract
| Publisher Full Text
- 98.
Aly H, Elmahdy H, El-Dib M, et al.:
Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study.
J Perinatol.
2015; 35(3): 186–91. PubMed Abstract
| Publisher Full Text
- 99.
Merchant N, Azzopardi D, Counsell S, et al.:
O-057 Melatonin As A Novel Neuroprotectant In Preterm Infants – A Double Blinded Randomised Controlled Trial (mint Study).
Arch Dis Child.
2014; 99(Suppl 2 ): A43.2–A43. Publisher Full Text
- 100.
Therapeutic Effects of Maternal Melatonin Administration on Brain Injury and White Matter Disease. Reference Source
- 101.
Palmer KR, Mockler JC, Davies-Tuck ML, et al.:
Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction.
BMJ Open.
2019; 9(6): e028243. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 102.
Gitto E, Romeo C, Reiter RJ, et al.:
Melatonin reduces oxidative stress in surgical neonates.
J Pediatr Surg.
2004; 39(2): 184–9; discussion 184–9. PubMed Abstract
| Publisher Full Text
- 103.
Reiter RJ, Tan DX, Fuentes-Broto L:
Melatonin: a multitasking molecule.
Prog Brain Res.
2010; 181: 127–51. PubMed Abstract
| Publisher Full Text
- 104.
Fulia F, Gitto E, Cuzzocrea S, et al.:
Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin.
J Pineal Res.
2001; 31(4): 343–9. PubMed Abstract
| Publisher Full Text
- 105.
Yawno T, Castillo-Melendez M, Jenkin G, et al.:
Mechanisms of melatonin-induced protection in the brain of late gestation fetal sheep in response to hypoxia.
Dev Neurosci.
2012; 34(6): 543–51. PubMed Abstract
| Publisher Full Text
- 106.
Wilkinson D, Shepherd E, Wallace EM:
Melatonin for women in pregnancy for neuroprotection of the fetus.
Cochrane Database Syst Rev.
2016; 3: CD010527. PubMed Abstract
| Publisher Full Text
- 107.
Ma D, Hossain M, Chow A, et al.:
Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia.
Ann Neurol.
2005; 58(2): 182–93. PubMed Abstract
| Publisher Full Text
- 108.
Thoresen M, Hobbs CE, Wood T, et al.:
Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia.
J Cereb Blood Flow Metab.
2009; 29(4): 707–14. PubMed Abstract
| Publisher Full Text
- 109.
Rüegger CM, Davis PG, Cheong JL:
Xenon as an adjuvant to therapeutic hypothermia in near-term and term newborns with hypoxic-ischaemic encephalopathy.
Cochrane Database Syst Rev.
2018; 8: CD012753. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 110.
Bantel C, Maze M, Trapp S:
Noble gas xenon is a novel adenosine triphosphate-sensitive potassium channel opener.
Anesthesiology.
2010; 112(3): 623–30. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 111.
Edmonds HL Jr, Jiang YD, Zhang PY, et al.:
Topiramate as a neuroprotectant in a rat model of global ischemia-induced neurodegeneration.
Life Sci.
2001; 69(19): 2265–77. PubMed Abstract
| Publisher Full Text
- 112.
Schubert S, Brandl U, Brodhun M, et al.:
Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets.
Brain Res.
2005; 1058(1–2): 129–36. PubMed Abstract
| Publisher Full Text
- 113.
Yang Y, Shuaib A, Li Q, et al.:
Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization.
Brain Res.
1998; 804(2): 169–76. PubMed Abstract
| Publisher Full Text
- 114.
Filippi L, Fiorini P, Catarzi S, et al.:
Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.
J Matern Fetal Neonatal Med.
2018; 31(8): 973–80. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 115.
Ängehagen M, Rönnbäck L, Hansson E, et al.:
Topiramate reduces AMPA-induced Ca2+ transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures.
J Neurochem.
2005; 94(4): 1124–30. PubMed Abstract
| Publisher Full Text
- 116.
Zona C, Ciotti MT, Avoli M:
Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells.
Neurosci Lett.
1997; 231(3): 123–6. PubMed Abstract
| Publisher Full Text
- 117.
Filippi L, Fiorini P, Daniotti M, et al.:
Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).
BMC Pediatr.
2012; 12: 144. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 118.
Kudin AP, Debska-Vielhaber G, Vielhaber S, et al.:
The mechanism of neuroprotection by topiramate in an animal model of epilepsy.
Epilepsia.
2004; 45(12): 1478–87. PubMed Abstract
| Publisher Full Text
- 119.
Chaudhari T, McGuire W:
Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy.
Cochrane Database Syst Rev.
2008; (2): CD006817. PubMed Abstract
| Publisher Full Text
- 120.
Kaandorp JJ, van Bel F, Veen S, et al.:
Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials.
Arch Dis Child Fetal Neonatal Ed.
2012; 97(3): F162–6. PubMed Abstract
| Publisher Full Text
- 121.
Kaandorp JJ, Benders MJ, Schuit E, et al.:
Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.
Arch Dis Child Fetal Neonatal Ed.
2015; 100(3): F216–F223. PubMed Abstract
| Publisher Full Text
- 122.
Klumper J, Kaandorp JJ, Schuit E, et al.:
Behavioral and neurodevelopmental outcome of children after maternal allopurinol administration during suspected fetal hypoxia: 5-year follow up of the ALLO-trial.
PLoS One.
2018; 13(8): e0201063. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 123.
Maiwald CA, Annink KV, Rüdiger M, et al.:
Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).
BMC Pediatr.
2019; 19(1): 210. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 124.
Rodríguez-Fanjul J, Durán Fernández-Feijóo C, Lopez-Abad M, et al.:
Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: Is it a gender question?
PLoS One.
2017; 12(9): e0184643. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 125.
Li J, Yawno T, Sutherland A, et al.:
Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells.
Exp Neurol.
2016; 283(Pt A): 179–87. PubMed Abstract
| Publisher Full Text
- 126.
Drommelschmidt K, Serdar M, Bendix I, et al.:
Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.
Brain Behav Immun.
2017; 60: 220–32. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 127.
Wagenaar N, Nijboer CH, van Bel F:
Repair of neonatal brain injury: Bringing stem cell-based therapy into clinical practice.
Dev Med Child Neurol.
2017; 59(10): 997–1003. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 128.
Ahn SY, Chang YS, Sung DK, et al.:
Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage.
Stroke.
2013; 44(2): 497–504. PubMed Abstract
| Publisher Full Text
- 129.
Mukai T, Mori Y, Shimazu T, et al.:
Intravenous injection of umbilical cord-derived mesenchymal stromal cells attenuates reactive gliosis and hypomyelination in a neonatal intraventricular hemorrhage model.
Neuroscience.
2017; 355: 175–87. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 130.
Cotten CM, Murtha AP, Goldberg RN, et al.:
Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy.
J Pediatr.
2014; 164(5): 973–979.e1. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 131.
Sun JM, Grant GA, McLaughlin C, et al.:
Repeated autologous umbilical cord blood infusions are feasible and had no acute safety issues in young babies with congenital hydrocephalus.
Pediatr Res.
2015; 78(6): 712–6. PubMed Abstract
| Publisher Full Text
- 132.
Kotowski M, Litwinska Z, Klos P, et al.:
Autologous cord blood transfusion in preterm infants - could its humoral effect be the kez to control prematurity-related complications? A preliminary study.
J Physiol Pharmacol.
2017; 68(6): 921–7. PubMed Abstract
| F1000 Recommendation
- 133.
Ahn SY, Chang YS, Sung SI, et al.:
Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial.
Stem Cells Transl Med.
2018; 7(12): 847–56. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 134.
Efficacy and Safety of Pneumostem® for IVH in Premature Infants (Phase 2a). Reference Source
- 135.
Neonatal Hypoxic Ischemic Encephalopathy : Safety and Feasibility Study of a Curative Treatment With Autologous Cord Blood Stem Cells. Reference Source
- 136.
A Multi-site Study of Autologous Cord Blood Cells for Hypoxic Ischemic Encephalopathy. Reference Source
- 137.
Neuroprotective Effect of Autologous Cord Blood Combined With Therapeutic Hypothermia Following Neonatal Encephalopathy. Reference Source
- 138.
Autologous Cord Blood and Human Placental Derived Stem Cells in Neonates With Severe Hypoxic-Ischemic Encephalopathy. Reference Source
- 139.
Ahn SY, Chang YS, Sung DK, et al.:
Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats.
Cell Transplant.
2017; 26(1): 145–56. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 140.
van Velthoven CT, Kavelaars A, van Bel F, et al.:
Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain.
Brain Behav Immun.
2011; 25(7): 1342–8. PubMed Abstract
| Publisher Full Text
- 141.
Murphy MB, Moncivais K, Caplan AI:
Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine.
Exp Mol Med.
2013; 45: e54. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 142.
Brion LP, Bell EF, Raghuveer TS:
Vitamin E supplementation for prevention of morbidity and mortality in preterm infants.
Cochrane Database Syst Rev.
2003; 16(4): CD003665. PubMed Abstract
| Publisher Full Text
- 143.
Ireland Z, Dickinson H, Snow R, et al.:
Maternal creatine: does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)?
Am J Obstet Gynecol.
2008; 198(4): 431.e1–6. PubMed Abstract
| Publisher Full Text
- 144.
Ireland Z, Castillo-Melendez M, Dickinson H, et al.:
A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia.
Neuroscience.
2011; 194: 372–9. PubMed Abstract
| Publisher Full Text
- 145.
Dickinson H, Ellery S, Ireland Z, et al.:
Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy.
BMC Pregnancy Childbirth.
2014; 14: 150. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 146.
Guimarães-Ferreira L, Pinheiro CH, Gerlinger-Romero F, et al.:
Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle.
Eur J Appl Physiol.
2012; 112(11): 3905–11. PubMed Abstract
| Publisher Full Text
- 147.
Tokarska-Schlattner M, Epand RF, Meiler F, et al.:
Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects.
PLoS One.
2012; 7(8): e43178. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 148.
Peña-Altamira E, Crochemore C, Virgili M, et al.:
Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation.
Brain Res.
2005; 1058(1-2): 183–8. PubMed Abstract
| Publisher Full Text
- 149.
Beal MF:
Neuroprotective effects of creatine.
Amino Acids.
2011; 40(5): 1305–13. PubMed Abstract
| Publisher Full Text
Comments on this article Comments (0)