Perinatal Acidosis and Hypoxic-Ischemic Encephalopathy in Preterm Infants of 33 to 35 Weeks’ Gestation

doi:10.1016/j.jpeds.2011.09.001

The Journal of Pediatrics

Volume 160, Issue 3, March 2012, Pages 388-394

Presented in part at the Pediatric Academic Societies’ Meeting, May 5 to 8, 2007, Toronto, Canada (abstract 751111).

https://doi.org/10.1016/j.jpeds.2011.09.001 Get rights and content

Objectives

To determine the frequency of hypoxic-ischemic encephalopathy (HIE) in preterm infants of 33 to 35 weeks’ gestational age on the basis of physiological screening for perinatal acidosis and neurological assessment of encephalopathy and to correlate neurodevelopmental outcomes with brain magnetic resonance imaging findings.

Study design

This retrospective cohort study included all inborn infants of 33 to 35 weeks’ gestation admitted to the neonatal intensive care unit at Parkland Memorial Hospital with perinatal acidosis from October 2005 to September 2008. Their medical records were reviewed, and pertinent data were recorded.

Results

Of 1305 newborns, 2.5% (n = 33) had perinatal acidosis, and 27% (n = 9) of these had HIE (2, mild; 4, moderate; 3, severe). Persistence of metabolic acidosis on the first arterial blood gas obtained in the first hour of age was significantly associated with HIE (P < .005). Magnetic resonance imaging results were abnormal in 3 of 4 infants with moderate HIE and in both survivors with severe HIE. Death or disability occurred in no infants with mild or moderate HIE, but in all infants with severe HIE.

Conclusion

Screening criteria for HIE that use biochemical and neurological assessments as performed in term newborns can be applied to preterm infants of 33 to 35 weeks’ gestation.

Section snippets

Methods

This retrospective cohort study included all inborn infants of 33 to 35 weeks’ gestation who were admitted to the neonatal intensive care unit (NICU) at Parkland Memorial Hospital (PMH) with perinatal acidosis from October 2005 to September 2008. These infants were identified by review of a prospective neonatal database and resuscitation registry⁸ and included all admissions to the PMH NICU with perinatal acidosis. Umbilical cord arterial blood was routinely sampled on all deliveries at PMH

Results

In 1305 newborns admitted to the PMH NICU at 33 to 35 weeks’ gestation, biochemical screening was performed on umbilical cord blood (n = 1275) or a blood sample obtained within 1 hour of birth (n = 30). Thirty-three newborns (2.5%) were identified with perinatal acidosis that was detected in 32 of the infants with umbilical cord blood sampling. In one newborn, acidosis was detected on the first arterial blood gas within 1 hour of age (Figure; Table I). Overall, 22 of those 33 newborns (67%) met the

Discussion

This retrospective study examined how the biochemical screening criteria and neurological assessment for HIE that are used in full-term infants to assess their eligibility for hypothermia therapy apply to the preterm infant of 33 to 35 weeks’ gestation.¹ Overall, 2.5% of these preterm newborns met physiological screening criteria for perinatal acidosis, and 27% of them had neurological signs of moderate to severe HIE on the first day of age. This finding is similar to that seen in term

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Cited by (62)

miR-200b-3p antagomir inhibits neuronal apoptosis in oxygen-glucose deprivation (OGD) model through regulating β-TrCP
2023, Brain Research
Hypoxia-ischemic brain damage (HIBD) is a primary cause of morbidity and disability in survivors of preterm infants. We previously discovered that miR-200b-3p plays an important role in HIBD via targeting Slit2. This study was designed to identify novel targets of miR-200b-3p and investigate the relationship between miR-200b-3p and its downstream effectors.
Cultured primary rat hippocampal neurons were used in the model of oxygen-glucose deprivation (OGD) and RT-qPCR was utilized to detect the alterations of miR-200b-3p in these cells following the OGD. Our study found that the expression of miR-200b-3p was up-regulated in neurons post OGD. Bioinformatics analysis identified that β transducin repeat-containing protein (β-TrCP) is a target gene of miR-200b-3p, and our luciferase reporter gene assay confirmed that miR-200b-3p can interact with β-TrCP mRNA. Hypoxia-ischemic brain damage was induced in three-day-old SD rats and inhibition of miR-200b-3p by injection of antagomir into bilateral lateral ventricles enhanced β-TrCP expression at both the mRNA and protein levels in rats' brains. TUNEL staining and CCK-8 assays found that the survival of hippocampal neurons in the miR-200b-3p antagomir group was improved significantly (p＜0.05), whereas apoptosis of neurons in the miR-200b-3p antagomir group was significantly decreased (p＜0.05), as compared with the OGD group. However, silencing of β-TrCP by β-TrCP siRNA impaired the neuroprotective effect of miR-200b-3p antagomir. H&E staining showed that miR-200b-3p attenuated the pathological changes in the hippocampal region of rats with HIBD.
Our study has demonstrated that β-TrCP is a target gene of miR-200b-3p and that inhibition of miR-200b-3p by antagomir attenuates hypoxia-ischemic brain damage via β-TrCP.
RNA-seq Analysis Reveals Potential Molecular Mechanisms of ZNF580/ZFP580 Promoting Neuronal Survival and Inhibiting Apoptosis after Hypoxic-ischemic Brain damage
2022, Neuroscience
Citation Excerpt :
Neonatal hypoxic-ischemic brain damage (HIBD) can lead to infant death and long-term neurological dysfunction. The morbidity (0.3%∼0.7%), mortality (40%), and disability (30%) are all higher (Chalak et al., 2012; Hagberg et al., 2015; Rocha-Ferreira et al., 2015; Ziemka-Nalecz et al., 2017). With recent improvements in obstetric and neonatal health care, the mortality from HIBD has been significantly reduced; however, the surviving HIBD patients may suffer from neurological defects, such as cerebral palsy, epilepsy and cognitive impairments (Douglas-Escobar and Weiss, 2015; Driscoll et al., 2018), which results in a heavy burden to families and society.
Neonatal hypoxic-ischemic brain damage (HIBD) is one of the main causes of neonatal acute death and chronic nervous system impairment, but still lacks effective treatments. ZNF580/ZFP580, reported in our previous studies, may be a newly identified member of the Krüppel-like factor (KLF) family, and has anti-apoptotic effects during ischemic myocardial injury. In the present study, we showed that the expression levels of both ZFP580/ZNF580 mRNA and protein increased significantly in neonatal HIBD rats and oxygen-glucose deprivation (OGD) SH-SY5Y cell models. ZNF580 overexpression promoted neuron survival and suppressed neuron apoptosis after OGD in neuron-like SH-SY5Y cells, while interference with ZNF580 resulted in the opposite results. RNA-seq analysis identified 248 differentially-expressed genes (DEGs) between ZNF580 overexpression SH-SY5Y cells and interference-expressed SH-SY5Y cells. Gene Ontology functional enrichment analysis showed that these DEGs played significant roles in the growth, development, and regeneration of axons, DNA biosynthetic processes, DNA replication, and apoptosis. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that these DEGs were found in some pathways, including ferroptosis, glutamatergic synapses, protein processing in the endoplasmic reticulum, estrogen signaling pathways, the TGF-beta signaling pathway, and the longevity regulating pathway. The qRT-PCR validation results were consistent with RNA-seq results, which showed that HSPA5, IGFBP3, NTN4, and KLF9 increased in ZNF580-overexpressed SH-SY5Y cells and decreased in interference-expressed SH-SY5Y cells, when compared with normal cells. Together, the results suggested that ZNF580 targeted these genes to inhibit neuronal apoptosis.
Unanswered questions regarding therapeutic hypothermia for neonates with neonatal encephalopathy
2021, Seminars in Fetal and Neonatal Medicine
Therapeutic hypothermia (TH) is now well established to improve intact survival after neonatal encephalopathy (NE). However, many questions could not be addressed by the randomized controlled trials. Should late preterm newborns with NE be cooled? Is cooling beneficial for mild NE? Is the current therapeutic time window optimal, or could it be shortened or prolonged? Will either milder or deeper hypothermia be effective? Does infection/inflammation exposure in the perinatal period in combination with NE offer potentially beneficial preconditioning or might it obviate hypothermic neuroprotection? In the present review, we dissect the evidence, for whom, when and how can TH best be delivered, and highlight areas that need further research.
Sex-related differences in arterial spin-labelled perfusion of metabolically active brain structures in neonatal hypoxic–ischaemic encephalopathy
2021, Clinical Radiology
Citation Excerpt :
The watershed pattern has a greater association with a mild degree of injury, and central grey nuclei involvement is associated with moderate to severe HIE. The central grey nuclei pattern is correlated with worse neurodevelopmental outcomes.34–38 Here, male HIE neonates had relative hypoperfusion in the thalamus.
To investigate the sex-related differences in arterial spin-labelled (ASL) perfusion of metabolically active brain structures in neonatal hypoxic–ischaemic encephalopathy (HIE).
Seventy-three term neonates were identified for a retrospective case–control study following an institutional review board (IRB) approved protocol. The cerebral pulsed arterial spin labelling values were compared by permutation test to identify metabolically active brain structures with significant perfusion changes between 10 male controls and eight female controls, and between 31 HIE males and 24 HIE females.
In the perfusion comparison between HIE male and female neonates, significantly lower perfusion was found in the thalamus in males (p=0.02). The other brain clusters, including basal ganglia, hippocampus cluster, cingulate gyrus cluster, brainstem cluster, sensorimotor cortex cluster, and cerebellum and peduncle cluster, demonstrated no significant differences between HIE males and females. In the perfusion comparison between male and female controls, there were no significant perfusion changes in those brain clusters.
Brain perfusion in neonatal HIE differs between males and females in the thalamus, a metabolically active region within neonates, with males demonstrating lower perfusion. This difference in perfusion may reflect sex-related disparities in response to and recovery from hypoxic–ischaemic events.
lncRNA NEAT1 Binds to MiR-339-5p to Increase HOXA1 and Alleviate Ischemic Brain Damage in Neonatal Mice
2020, Molecular Therapy Nucleic Acids
Citation Excerpt :
Hypoxic-ischemic brain damage (HIBD) is a major cause of fatality and morbidity.3,4 Studies have revealed that approximately 7 per 1,000 preterm newborns and 3 per 1,000 term newborns are reported to suffer from HIBD.5,6 However, only about 60% of patients survive during the neonatal phase, whereas approximately 30% fall victim to subsequent long-term neurological disabilities, including visual difficulties and learning deficiencies caused by impaired brain development.1,7
Hypoxic-ischemic brain damage (HIBD) is a major cause of fatality and morbidity in neonates. However, current treatment approaches to alleviate HIBD are not effective. Various studies have highlighted the role of microRNAs (miRNAs) in various biological functions in multiple diseases. This study investigated the role of miR-339-5p in HIBD progression. Neonatal HIBD mouse model was induced by ligation of the right common carotid artery. Neuronal cell model exposed to oxygen-glucose deprivation (OGD) was also established. The miR-339-5p expression in mouse brain tissues and neuronal cells was quantified, and the effects of miR-339-5p on neuronal cell activity and apoptosis induced by hypoxia-ischemia were explored. The overexpression or knockdown of long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in hippocampal neurons was used to determine the effect of lncRNA NEAT1 on the expression of miR-339-5p and homeobox A1 (HOXA1) and apoptosis. Short hairpin RNA targeting lncRNA NEAT1 and miR-339-5p antagomir were used in neonatal HIBD mice to identify their roles in HIBD. Our results revealed that miR-339-5p was downregulated in neonatal HIBD mice and neuronal cells exposed to OGD. Downregulated miR-339-5p promoted neuronal cell viability and suppressed apoptosis during hypoxia-ischemia. Moreover, lncRNA NEAT1 competitively bound to miR-339-5p to increase HOXA1 expression and inhibited neuronal cell apoptosis under hypoxic-ischemic conditions. The key observations of the current study present evidence demonstrating that lncRNA NEAT1 upregulated HOXA1 to alleviate HIBD in mice by binding to miR-339-5p.
Key roles of glial cells in the encephalopathy of prematurity
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: L.C. is supported by the National Center for Research Resources (grants KL2RR024983 and UL1 RR024982). The authors declare no conflicts of interest.

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Original ArticlePerinatal Acidosis and Hypoxic-Ischemic Encephalopathy in Preterm Infants of 33 to 35 Weeks’ Gestation

Objectives

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

Lancet Neurol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Pediatr

Pediatr Neurol

Semin Pediatr Neurol

Am J Obstet Gynecol

Early Hum Dev

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy

N Engl J Med

Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study

Arch Neurol

Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome

Arch Dis Child Fetal Neonatal Ed

Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems

AJNR Am J Neuroradiol

Original Article
Perinatal Acidosis and Hypoxic-Ischemic Encephalopathy in Preterm Infants of 33 to 35 Weeks’ Gestation