1932
0

Annual Review of Physiology

Volume 87, 2025

Preterm Brain Injury: Mechanisms and Challenges

Abstract

Preterm fetuses and newborns have a high risk of neural injury and impaired neural maturation, leading to neurodevelopmental disability. Developing effective treatments is rather challenging, as preterm brain injury may occur at any time during pregnancy and postnatally, and many cases involve multiple pathogenic factors. This review examines research on how the preterm fetus responds to hypoxia-ischemia and how brain injury evolves after hypoxia-ischemia, offering windows of opportunity for treatment and insights into the mechanisms of injury during key phases. We highlight research showing that preterm fetuses can survive hypoxia-ischemia and continue development in utero with evolving brain injury. Early detection of fetal brain injury would provide an opportunity for treatments to reduce adverse neurodevelopmental outcomes, including cerebral palsy. However, this requires that we can detect injury using noninvasive methods. We discuss how circadian changes in fetal heart rate variability may offer utility as a biomarker for detecting injury and phases of injury.

Keyword(s): biomarkers, circadian, fetus, hypoxia-ischemia, neuroprotection, preterm
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022724-104754
2025-02-10
2025-06-23
Loading full text...

Full text loading...

/deliver/fulltext/physiol/87/1/annurev-physiol-022724-104754.html?itemId=/content/journals/10.1146/annurev-physiol-022724-104754&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Inder TE, Volpe JJ, Anderson PJ. 2023.. Defining the neurologic consequences of preterm birth. . N. Engl. J. Med. 389::441–53
     [Crossref] [Google Scholar]
  2. 2.
    Laptook AR. 2016.. Birth asphyxia and hypoxic-ischemic brain injury in the preterm infant. . Clin. Perinatol. 43::529–45
     [Crossref] [Google Scholar]
  3. 3.
    Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, et al. 2013.. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. . Pediatr. Res. 74::50–72
     [Crossref] [Google Scholar]
  4. 4.
    Dhillon SK, Lear CA, Galinsky R, Wassink G, Davidson JO, et al. 2018.. The fetus at the tipping point: modifying the outcome of fetal asphyxia. . J. Physiol. 596::5571–92
     [Crossref] [Google Scholar]
  5. 5.
    Lear BA, Lear CA, Dhillon SK, Davidson JO, Bennet L, Gunn AJ. 2022.. Is late prevention of cerebral palsy in extremely preterm infants plausible?. Dev. Neurosci. 44::177–85
     [Crossref] [Google Scholar]
  6. 6.
    Gunn AJ, Thoresen M. 2019.. Neonatal encephalopathy and hypoxic-ischemic encephalopathy. . Handb. Clin. Neurol. 162::217–37
     [Crossref] [Google Scholar]
  7. 7.
    Gale C, Statnikov Y, Jawad S, Uthaya SN, Modi N. 2018.. Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database. . Arch. Dis. Child. Fetal Neonatal Ed. 103::F3016. . 2021.. Arch. Dis. Child. Fetal Neonatal Ed. 106::e14
     [Google Scholar]
  8. 8.
    Logitharajah P, Rutherford MA, Cowan FM. 2009.. Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging, and outcome. . Pediatr. Res. 66::222–29
     [Crossref] [Google Scholar]
  9. 9.
    Back SA. 2015.. Brain injury in the preterm infant: new horizons for pathogenesis and prevention. . Pediatr. Neurol. 53::185–92
     [Crossref] [Google Scholar]
  10. 10.
    Steinmetz JD, Seeher KM, Schiess N, Nichols E, Cao B, et al. 2024.. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. . Lancet Neurol. 23::344–81
     [Crossref] [Google Scholar]
  11. 11.
    Manuck TA, Rice MM, Bailit JL, Grobman WA, Reddy UM, et al. 2016.. Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. . Am. J. Obstet. Gynecol. 215::103.e1–14
     [Crossref] [Google Scholar]
  12. 12.
    Chalak LF, Rollins N, Morriss MC, Brion LP, Heyne R, Sanchez PJ. 2012.. Perinatal acidosis and hypoxic-ischemic encephalopathy in preterm infants of 33 to 35 weeks’ gestation. . J. Pediatr. 160::388–94
     [Crossref] [Google Scholar]
  13. 13.
    Salhab WA, Perlman JM. 2005.. Severe fetal acidemia and subsequent neonatal encephalopathy in the larger premature infant. . Pediatr. Neurol. 32::25–29
     [Crossref] [Google Scholar]
  14. 14.
    Schmidt JW, Walsh WF. 2010.. Hypoxic-ischemic encephalopathy in preterm infants. . J. Neonatal-Perinatal Med. 3::277–84
     [Crossref] [Google Scholar]
  15. 15.
    Gopagondanahalli KR, Li J, Fahey MC, Hunt RW, Jenkin G, et al. 2016.. Preterm hypoxic-ischemic encephalopathy. . Front. Pediatr. 4::114
     [Crossref] [Google Scholar]
  16. 16.
    Reiss JD, Peterson LS, Nesamoney SN, Chang AL, Pasca AM, et al. 2022.. Perinatal infection, inflammation, preterm birth, and brain injury: a review with proposals for future investigations. . Exp. Neurol. 351::113988
     [Crossref] [Google Scholar]
  17. 17.
    Bennet L, Dhillon S, Lear CA, van den Heuij L, King V, et al. 2018.. Chronic inflammation and impaired development of the preterm brain. . J. Reprod. Immunol. 125::45–55
     [Crossref] [Google Scholar]
  18. 18.
    Reid SM, Hinwood GL, Guzys AT, Hunt RW, Reddihough DS. 2024.. Neonatal well-being and timing of brain injury in persons with cerebral palsy born at term or late preterm. . Dev. Med. Child Neurol. 66::892–901
     [Crossref] [Google Scholar]
  19. 19.
    Nakao M, Nanba Y, Okumura A, Hasegawa J, Toyokawa S, et al. 2023.. Fetal heart rate evolution and brain imaging findings in preterm infants with severe cerebral palsy. . Am. J. Obstet. Gynecol. 228::583
     [Crossref] [Google Scholar]
  20. 20.
    Fortin O, Husein N, Oskoui M, Shevell MI, Kirton A, Dunbar M. 2024.. Risk factors and outcomes for cerebral palsy with hypoxic-ischemic brain injury patterns without documented neonatal encephalopathy. . Neurology 102::e208111
     [Crossref] [Google Scholar]
  21. 21.
    Garfinkle J, Wintermark P, Shevell MI, Oskoui M. 2017.. Children born at 32 to 35 weeks with birth asphyxia and later cerebral palsy are different from those born after 35 weeks. . J. Perinatol. 37::963–68
     [Crossref] [Google Scholar]
  22. 22.
    Counsell SJ, Arichi T, Arulkumaran S, Rutherford MA. 2019.. Fetal and neonatal neuroimaging. . Handb. Clin. Neurol. 162::67–103
     [Crossref] [Google Scholar]
  23. 23.
    Gunn AJ, Bennet L. 2016.. Timing still key to treating hypoxic ischaemic brain injury. . Lancet Neurol. 15::126–27
     [Crossref] [Google Scholar]
  24. 24.
    Levison SW, Rocha-Ferreira E, Kim BH, Hagberg H, Fleiss B, et al. 2022.. Mechanisms of tertiary neurodegeneration after neonatal hypoxic-ischemic brain damage. . Pediatr. Med. 28:(5):28
     [Crossref] [Google Scholar]
  25. 25.
    Bennet L, Booth L, Gunn AJ. 2010.. Potential biomarkers for hypoxic-ischemic encephalopathy. . Semin. Fetal Neonatal Med. 15::253–60
     [Crossref] [Google Scholar]
  26. 26.
    Bax M, Nelson KB. 1993.. Birth asphyxia: a statement. . Dev. Med. Child. Neurol. 35::1022–24
     [Crossref] [Google Scholar]
  27. 27.
    Koehler RC, Yang ZJ, Lee JK, Martin LJ. 2018.. Perinatal hypoxic-ischemic brain injury in large animal models: relevance to human neonatal encephalopathy. . J. Cereb. Blood Flow Metab. 38::2092–111
     [Crossref] [Google Scholar]
  28. 28.
    Gunn AJ, Bennet L. 2009.. Fetal hypoxia insults and patterns of brain injury: insights from animal models. . Clin. Perinatol. 36::579–93
     [Crossref] [Google Scholar]
  29. 29.
    Mallard C, Hagberg H. 2007.. Inflammation-induced preconditioning in the immature brain. . Semin. Fetal Neonatal Med. 12::280–86
     [Crossref] [Google Scholar]
  30. 30.
    Lear CA, Wassink G, Westgate JA, Nijhuis JG, Ugwumadu A, et al. 2018.. The peripheral chemoreflex: indefatigable guardian of fetal physiological adaptation to labour. . J. Physiol. 596::5611–23
     [Crossref] [Google Scholar]
  31. 31.
    Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, Mercuri E, Cowan FM. 2013.. Antepartum and intrapartum factors preceding neonatal hypoxic-ischemic encephalopathy. . Pediatrics 132::e952–59
     [Crossref] [Google Scholar]
  32. 32.
    Pacora P, Romero R, Jaiman S, Erez O, Bhatti G, et al. 2019.. Mechanisms of death in structurally normal stillbirths. . J. Perinat. Med. 47::222–40
     [Crossref] [Google Scholar]
  33. 33.
    Lear CA, Westgate JA, Ugwumadu A, Nijhuis JG, Stone PR, et al. 2018.. Understanding fetal heart rate patterns that may predict antenatal and intrapartum neural injury. . Semin. Pediatr. Neurol. 28::3–16
     [Crossref] [Google Scholar]
  34. 34.
    King VJ, Bennet L, Stone PR, Clark A, Gunn AJ, Dhillon SK. 2022.. Fetal growth restriction and stillbirth: biomarkers for identifying at risk fetuses. . Front. Physiol. 13::959750
     [Crossref] [Google Scholar]
  35. 35.
    Russ JB, Ostrem BEL. 2023.. Acquired brain injuries across the perinatal spectrum: pathophysiology and emerging therapies. . Pediatr. Neurol. 148::206–14
     [Crossref] [Google Scholar]
  36. 36.
    Hayes DJL, Warland J, Parast MM, Bendon RW, Hasegawa J, et al. 2020.. Umbilical cord characteristics and their association with adverse pregnancy outcomes: a systematic review and meta-analysis. . PLOS ONE 15::e0239630
     [Crossref] [Google Scholar]
  37. 37.
    Einspieler C, Prayer D, Marschik PB. 2021.. Fetal movements: the origin of human behaviour. . Dev. Med. Child Neurol. 63::1142–48
     [Crossref] [Google Scholar]
  38. 38.
    Shelley HJ. 1961.. Glycogen reserves and their changes at birth and in anoxia. . Br. Med. Bull. 17::137–43
     [Crossref] [Google Scholar]
  39. 39.
    Bennet L. 2017.. Sex, drugs and rock and roll: tales from preterm fetal life. . J. Physiol. 595::1865–81
     [Crossref] [Google Scholar]
  40. 40.
    Gunn AJ, Quaedackers JS, Guan J, Heineman E, Bennet L. 2001.. The premature fetus: Not as defenseless as we thought, but still paradoxically vulnerable?. Dev. Neurosci. 23::175–79
     [Crossref] [Google Scholar]
  41. 41.
    Jensen A. 1996.. The brain of the asphyxiated fetus—basic research. . Eur. J. Obstet. Gynecol. Reprod. Biol. 65::19–24
     [Crossref] [Google Scholar]
  42. 42.
    Lear BA, Lear CA, Dhillon SK, Davidson JO, Gunn AJ, Bennet L. 2023.. Evolution of grey matter injury over 21 days after hypoxia-ischaemia in preterm fetal sheep. . Exp. Neurol. 363::114376
     [Crossref] [Google Scholar]
  43. 43.
    Drury PP, Bennet L, Booth LC, Davidson JO, Wassink G, Gunn AJ. 2012.. Maturation of the mitochondrial redox response to profound asphyxia in fetal sheep. . PLOS ONE 7::e39273
     [Crossref] [Google Scholar]
  44. 44.
    Bennet L, Roelfsema V, Dean JM, Wassink G, Power GG, et al. 2007.. Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 292::R1569–76
     [Crossref] [Google Scholar]
  45. 45.
    Drury PP, Davidson JO, van den Heuij LG, Wassink G, Gunn ER, et al. 2014.. Status epilepticus after prolonged umbilical cord occlusion is associated with greater neural injury in fetal sheep at term-equivalent. . PLOS ONE 9::e96530
     [Crossref] [Google Scholar]
  46. 46.
    Lear CA, Koome ME, Davidson JO, Drury PP, Quaedackers JS, et al. 2014.. The effects of dexamethasone on post-asphyxial cerebral oxygenation in the preterm fetal sheep. . J. Physiol. 592::5493–505
     [Crossref] [Google Scholar]
  47. 47.
    Giussani DA. 2016.. The fetal brain sparing response to hypoxia: physiological mechanisms. . J. Physiol. 594::1215–30
     [Crossref] [Google Scholar]
  48. 48.
    Wassink G, Bennet L, Booth LC, Jensen EC, Wibbens B, et al. 2007.. The ontogeny of hemodynamic responses to prolonged umbilical cord occlusion in fetal sheep. . J. Appl. Physiol. 103::1311–17
     [Crossref] [Google Scholar]
  49. 49.
    Kiserud T, Jauniaux E, West D, Ozturk O, Hanson MA. 2001.. Circulatory responses to maternal hyperoxaemia and hypoxaemia assessed non-invasively in fetal sheep at 0.3–0.5 gestation in acute experiments. . Br. J. Obstet. Gynaecol. 108::359–64
     [Google Scholar]
  50. 50.
    Cheung CY. 1990.. Fetal adrenal medulla catecholamine response to hypoxia-direct and neural components. . Am. J. Physiol. 258:: R1340–46
     [Google Scholar]
  51. 51.
    Booth LC, Malpas SC, Barrett CJ, Guild SJ, Gunn AJ, Bennet L. 2012.. Renal sympathetic nerve activity during asphyxia in fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 303::R30–38
     [Crossref] [Google Scholar]
  52. 52.
    Hunter CJ, Bennet L, Power GG, Roelfsema V, Blood AB, et al. 2003.. Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep. . Stroke 34::2240–45
     [Crossref] [Google Scholar]
  53. 53.
    Lear CA, Beacom MJ, Dhillon SK, Lear BA, Mills OJ, et al. 2023.. Dissecting the contributions of the peripheral chemoreflex and myocardial hypoxia to fetal heart rate decelerations in near-term fetal sheep. . J. Physiol. 601::2017–41
     [Crossref] [Google Scholar]
  54. 54.
    Mallard EC, Gunn AJ, Williams CE, Johnston BM, Gluckman PD. 1992.. Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep. . Am. J. Obstet. Gynecol. 167::1423–30
     [Crossref] [Google Scholar]
  55. 55.
    Keunen H, Blanco CE, van Reempts JL, Hasaart TH. 1997.. Absence of neuronal damage after umbilical cord occlusion of 10, 15, and 20 minutes in midgestation fetal sheep. . Am. J. Obstet. Gynecol. 176::515–20
     [Crossref] [Google Scholar]
  56. 56.
    Mallard EC, Williams CE, Johnston BM, Gluckman PD. 1994.. Increased vulnerability to neuronal damage after umbilical cord occlusion in fetal sheep with advancing gestation. . Am. J. Obstet. Gynecol. 170::206–14
     [Crossref] [Google Scholar]
  57. 57.
    Quaedackers JS, Roelfsema V, Heineman E, Gunn AJ, Bennet L. 2004.. The role of the sympathetic nervous system in postasphyxial intestinal hypoperfusion in the pre-term sheep fetus. . J. Physiol. 557::1033–44
     [Crossref] [Google Scholar]
  58. 58.
    van den Heuij LG, Fraser M, Miller SL, Jenkin G, Wallace EM, et al. 2019.. Delayed intranasal infusion of human amnion epithelial cells improves white matter maturation after asphyxia in preterm fetal sheep. . J. Cereb. Blood Flow Metab. 39::223–39
     [Crossref] [Google Scholar]
  59. 59.
    Lear BA, Lear CA, Davidson JO, Sae-Jiw J, Lloyd JM, et al. 2021.. Tertiary cystic white matter injury as a potential phenomenon after hypoxia-ischaemia in preterm f sheep. . Brain Commun. 3::fcab024
     [Crossref] [Google Scholar]
  60. 60.
    George S, Gunn AJ, Westgate JA, Brabyn C, Guan J, Bennet L. 2004.. Fetal heart rate variability and brain stem injury after asphyxia in preterm fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 287::925–33
     [Crossref] [Google Scholar]
  61. 61.
    Bennet L, Roelfsema V, Pathipati P, Quaedackers JS, Gunn AJ. 2006.. Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep. . J. Physiol. 572::141–54
     [Crossref] [Google Scholar]
  62. 62.
    Bennet L, Dean JM, Wassink G, Gunn AJ. 2007.. Differential effects of hypothermia on early and late epileptiform events after severe hypoxia in preterm fetal sheep. . J. Neurophysiol. 97::572–78
     [Crossref] [Google Scholar]
  63. 63.
    Dean JM, George SA, Wassink G, Gunn AJ, Bennet L. 2006.. Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep. . Neuropharmacology 50::491–503
     [Crossref] [Google Scholar]
  64. 64.
    Dean JM, Gunn AJ, Wassink G, George S, Bennet L. 2006.. Endogenous α2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep. . Neuroscience 142::615–28
     [Crossref] [Google Scholar]
  65. 65.
    Dhillon SK, Gunn ER, Pedersen MV, Lear CA, Wassink G, et al. 2023.. Alpha-adrenergic receptor activation after fetal hypoxia-ischaemia suppresses transient epileptiform activity and limits loss of oligodendrocytes and hippocampal neurons. . J. Cereb. Blood Flow Metab. 43::947–61
     [Crossref] [Google Scholar]
  66. 66.
    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, et al. 1998.. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. . BMJ 317::1549–53
     [Crossref] [Google Scholar]
  67. 67.
    Bennet L, Westgate JA, Liu YC, Wassink G, Gunn AJ. 2005.. Fetal acidosis and hypotension during repeated umbilical cord occlusions are associated with enhanced chemoreflex responses in near-term fetal sheep. . J. Appl. Physiol. 99::1477–82
     [Crossref] [Google Scholar]
  68. 68.
    Wibbens B, Bennet L, Westgate JA, De Haan HH, Wassink G, Gunn AJ. 2007.. Preexisting hypoxia is associated with a delayed but more sustained rise in T/QRS ratio during prolonged umbilical cord occlusion in near-term fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 293::R1287–93
     [Crossref] [Google Scholar]
  69. 69.
    Gardner DS, Fletcher AJ, Bloomfield MR, Fowden AL, Giussani DA. 2002.. Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus. . J. Physiol. 540::351–66
     [Crossref] [Google Scholar]
  70. 70.
    Pulgar VM, Zhang J, Massmann GA, Figueroa JP. 2007.. Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion. . Brain Res. 1176::18–26
     [Crossref] [Google Scholar]
  71. 71.
    Westgate JA, Wassink G, Bennet L, Gunn AJ. 2005.. Spontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep. . Am. J. Obstet. Gynecol. 193::1526–33
     [Crossref] [Google Scholar]
  72. 72.
    Lear CA, Georgieva A, Beacom MJ, Wassink G, Dhillon SK, et al. 2023.. Fetal heart rate responses in chronic hypoxaemia with superimposed repeated hypoxaemia consistent with early labour: a controlled study in fetal sheep. . Br. J. Obstet. Gynaecol. 130::881–90
     [Crossref] [Google Scholar]
  73. 73.
    Amaya KE, Matushewski B, Durosier LD, Frasch MG, Richardson BS, Ross MG. 2016.. Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses. . Am. J. Obstet. Gynecol. 214::270
     [Crossref] [Google Scholar]
  74. 74.
    Wassink G, Bennet L, Davidson JO, Westgate JA, Gunn AJ. 2013.. Pre-existing hypoxia is associated with greater EEG suppression and early onset of evolving seizure activity during brief repeated asphyxia in near-term fetal sheep. . PLOS ONE 8::e73895
     [Crossref] [Google Scholar]
  75. 75.
    Takahashi N, Nishida H, Arai T, Kaneda Y. 1995.. Abnormal cardiac histology in severe intrauterine growth retardation infants. . Pediatr. Int. 37::341–46
     [Crossref] [Google Scholar]
  76. 76.
    Dimasi CG, Darby JRT, Morrison JL. 2023.. A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth. . J. Physiol. 601::1319–41
     [Crossref] [Google Scholar]
  77. 77.
    McIntire DD, Bloom SL, Casey BM, Leveno KJ. 1999.. Birth weight in relation to morbidity and mortality among newborn infants. . N. Engl. J. Med. 340::1234–38
     [Crossref] [Google Scholar]
  78. 78.
    Wolf H, Arabin B, Lees CC, Oepkes D, Prefumo F, et al. 2017.. A longitudinal study of computerised cardiotocography in early fetal growth restriction. . Ultrasound Obstet. Gynecol. 50::71–78
     [Crossref] [Google Scholar]
  79. 79.
    Dhillon SK, Gunn AJ, Jung Y, Mathai S, Bennet L, Fraser M. 2015.. Lipopolysaccharide-induced preconditioning attenuates apoptosis and differentially regulates TLR4 and TLR7 gene expression after ischemia in the preterm ovine fetal brain. . Dev. Neurosci. 37::497–514
     [Crossref] [Google Scholar]
  80. 80.
    van den Heuij LG, Mathai S, Davidson JO, Lear CA, Booth LC, et al. 2014.. Synergistic white matter protection with acute-on-chronic endotoxin and subsequent asphyxia in preterm fetal sheep. . J. Neuroinflammation 11::89
     [Crossref] [Google Scholar]
  81. 81.
    Ahearne CE, Chang RY, Walsh BH, Boylan GB, Murray DM. 2017.. Cord blood IL-16 is associated with 3-year neurodevelopmental outcomes in perinatal asphyxia and hypoxic-ischaemic encephalopathy. . Dev. Neurosci. 39::59–65
     [Crossref] [Google Scholar]
  82. 82.
    Steinborn A, Günes H, Röddiger S, Halberstadt E. 1996.. Elevated placental cytokine release, a process associated with preterm labor in the absence of intrauterine infection. . Obstet. Gynecol. 88::534–39
     [Crossref] [Google Scholar]
  83. 83.
    Lear CA, Lear BA, Davidson JO, Sae-Jiw J, Lloyd JM, et al. 2023.. Tumour necrosis factor blockade after asphyxia in foetal sheep ameliorates cystic white matter injury. . Brain 146::1453–66
     [Crossref] [Google Scholar]
  84. 84.
    Lin CY, Chang YC, Wang ST, Lee TY, Lin CF, Huang CC. 2010.. Altered inflammatory responses in preterm children with cerebral palsy. . Ann. Neurol. 68::204–12
     [Crossref] [Google Scholar]
  85. 85.
    Zareen Z, Strickland T, Fallah L, McEneaney V, Kelly L, et al. 2021.. Cytokine dysregulation in children with cerebral palsy. . Dev. Med. Child Neurol. 63::407–12
     [Crossref] [Google Scholar]
  86. 86.
    Iwata O, Iwata S, Bainbridge A, De Vita E, Matsuishi T, et al. 2008.. Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome. . Brain 131::2220–26
     [Crossref] [Google Scholar]
  87. 87.
    Leaw B, Nair S, Lim R, Thornton C, Mallard C, Hagberg H. 2017.. Mitochondria, bioenergetics and excitotoxicity: new therapeutic targets in perinatal brain injury. . Front. Cell. Neurosci. 11::199
     [Crossref] [Google Scholar]
  88. 88.
    Blumberg RM, Cady EB, Wigglesworth JS, McKenzie JE, Edwards AD. 1997.. Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain. . Exp. Brain Res. 113::130–37
     [Crossref] [Google Scholar]
  89. 89.
    Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, et al. 1994.. Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. . Pediatr. Res. 36::699–706
     [Crossref] [Google Scholar]
  90. 90.
    Penrice J, Lorek A, Cady EB, Amess PN, Wylezinska M, et al. 1997.. Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet. . Pediatr. Res. 41::795–802
     [Crossref] [Google Scholar]
  91. 91.
    Bainbridge A, Tachtsidis I, Faulkner SD, Price D, Zhu T, et al. 2014.. Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy. . Neuroimage 102::173–83
     [Crossref] [Google Scholar]
  92. 92.
    Kaynezhad P, Mitra S, Bale G, Bauer C, Lingam I, et al. 2019.. Quantification of the severity of hypoxic-ischemic brain injury in a neonatal preclinical model using measurements of cytochrome-c-oxidase from a miniature broadband-near-infrared spectroscopy system. . Neurophotonics 6::045009
     [Crossref] [Google Scholar]
  93. 93.
    Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, et al. 1989.. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. . Pediatr. Res. 25::445–51
     [Crossref] [Google Scholar]
  94. 94.
    van Bel F, Dorrepaal CA, Benders MJ, Zeeuwe PE, van de Bor M, Berger HM. 1993.. Changes in cerebral hemodynamics and oxygenation in the first 24 hours after birth asphyxia. . Pediatrics 92::365–72
     [Crossref] [Google Scholar]
  95. 95.
    Hope PL, Costello AM, Cady EB, Delpy DT, Tofts PS, et al. 1984.. Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants. . Lancet 2::366–70
     [Crossref] [Google Scholar]
  96. 96.
    Puka-Sundvall M, Gajkowska B, Cholewinski M, Blomgren K, Lazarewicz JW, Hagberg H. 2000.. Subcellular distribution of calcium and ultrastructural changes after cerebral hypoxia-ischemia in immature rats. . Dev. Brain Res. 125::31–41
     [Crossref] [Google Scholar]
  97. 97.
    Nair S, Leverin AL, Rocha-Ferreira E, Sobotka KS, Thornton C, et al. 2022.. Induction of mitochondrial fragmentation and mitophagy after neonatal hypoxia-ischemia. . Cells 11::1193
     [Crossref] [Google Scholar]
  98. 98.
    Gilland E, Puka-Sundvall M, Hillered L, Hagberg H. 1998.. Mitochondrial function and energy metabolism after hypoxia-ischemia in the immature rat brain: involvement of NMDA-receptors. . J. Cereb. Blood Flow Metab. 18::297–304
     [Crossref] [Google Scholar]
  99. 99.
    Winter JD, Tichauer KM, Gelman N, Thompson RT, Lee TY, St. Lawrence K. 2009.. Changes in cerebral oxygen consumption and high-energy phosphates during early recovery in hypoxic-ischemic piglets: a combined near-infrared and magnetic resonance spectroscopy study. . Pediatr. Res. 65::181–87
     [Crossref] [Google Scholar]
  100. 100.
    Harvey-Jones K, Lange F, Verma V, Bale G, Meehan C, et al. 2023.. Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy. . Pediatr. Res. 94::1675–83
     [Crossref] [Google Scholar]
  101. 101.
    Bennet L, Booth LC, Drury PP, Quaedackers JS, Gunn AJ. 2012.. Preterm neonatal cardiovascular instability: Does understanding the fetus help evaluate the newborn?. Clin. Exp. Pharmacol. Physiol. 39::965–72
     [Crossref] [Google Scholar]
  102. 102.
    Wikström S, Hövel H, Hansen Pupp I, Fellman V, Hüppi PS, et al. 2018.. Early electroencephalography suppression and postnatal morbidities correlate with cerebral volume at term-equivalent age in very preterm infants. . Neonatology 113::15–20
     [Crossref] [Google Scholar]
  103. 103.
    Costa FG, Hakimi N, Van Bel F. 2021.. Neuroprotection of the perinatal brain by early information of cerebral oxygenation and perfusion patterns. . Int. J. Mol. Sci. 22::5389
     [Crossref] [Google Scholar]
  104. 104.
    Murphy E, Healy DB, Chioma R, Dempsey EM. 2023.. Evaluation of the hypotensive preterm infant: Evidence-based practice at the bedside?. Children 10::519
     [Crossref] [Google Scholar]
  105. 105.
    Karlsson BR, Grogaard B, Gerdin B, Steen PA. 1994.. The severity of postischemic hypoperfusion increases with duration of cerebral ischemia in rats. . Acta Anaesthesiol. Scand. 38::248–53
     [Crossref] [Google Scholar]
  106. 106.
    Jensen EC, Bennet L, Hunter CJ, Power GC, Gunn AJ. 2006.. Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep. . J. Physiol. 572::131–39
     [Crossref] [Google Scholar]
  107. 107.
    Michenfelder JD, Milde JH, Katusić ZS. 1991.. Postischemic canine cerebral blood flow is coupled to cerebral metabolic rate. . J. Cereb. Blood Flow Metab. 11::611–16
     [Crossref] [Google Scholar]
  108. 108.
    Quaedackers JS, Roelfsema V, Heineman E, Gunn AJ, Bennet L. 2004.. The role of the sympathetic nervous system in post-asphyxial intestinal hypoperfusion in the preterm sheep fetus. . J. Physiol. 557:(Part 3):1033–44
     [Crossref] [Google Scholar]
  109. 109.
    Dean JM, Gunn AJ, Wassink G, Bennet L. 2006.. Transient NMDA receptor-mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep. . Exp. Physiol. 91::423–33
     [Crossref] [Google Scholar]
  110. 110.
    Dean JM, George S, Naylor AS, Mallard C, Gunn AJ, Bennet L. 2008.. Partial neuroprotection with low-dose infusion of the α2-adrenergic receptor agonist clonidine after severe hypoxia in preterm fetal sheep. . Neuropharmacology 55::166–74
     [Crossref] [Google Scholar]
  111. 111.
    Yawno T, Yan EB, Hirst JJ, Walker DW. 2011.. Neuroactive steroids induce changes in fetal sheep behavior during normoxic and asphyxic states. . Stress 14::13–22
     [Crossref] [Google Scholar]
  112. 112.
    Nguyen P, Yan EB, Castillo-Melendez M, Walker DW, Hirst JJ. 2004.. Increased allopregnanolone levels in the fetal sheep brain following umbilical cord occlusion. . J. Physiol. 560::593–602
     [Crossref] [Google Scholar]
  113. 113.
    Rajaram A, Milej D, Suwalski M, Kebaya L, Kewin M, et al. 2022.. Assessing cerebral blood flow, oxygenation and cytochrome c oxidase stability in preterm infants during the first 3 days after birth. . Sci. Rep. 12::181
     [Crossref] [Google Scholar]
  114. 114.
    Abbasi H, Drury PP, Lear CA, Gunn AJ, Davidson JO, et al. 2018.. EEG sharp waves are a biomarker of striatal neuronal survival after hypoxia-ischemia in preterm fetal sheep. . Sci. Rep. 8::16312
     [Crossref] [Google Scholar]
  115. 115.
    Pavlidis E, Lloyd RO, Mathieson S, Boylan GB. 2017.. A review of important electroencephalogram features for the assessment of brain maturation in premature infants. . Acta Paediatr. 106::1394–408
     [Crossref] [Google Scholar]
  116. 116.
    Tich SN, d'Allest AM, Villepin AT, de Belliscize J, Walls-Esquivel E, et al. 2007.. Pathological features of neonatal EEG in preterm babies born before 30 weeks of gestational age. . Neurophysiol. Clin. 37::325–70
     [Crossref] [Google Scholar]
  117. 117.
    Northington FJ, Zelaya ME, O'Riordan DP, Blomgren K, Flock DL, et al. 2007.. Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. . Neuroscience 149::822–33
     [Crossref] [Google Scholar]
  118. 118.
    Ten VS, Stepanova AA, Ratner V, Neginskaya M, Niatsetskaya Z, et al. 2021.. Mitochondrial dysfunction and permeability transition in neonatal brain and lung injuries. . Cells 10::569
     [Crossref] [Google Scholar]
  119. 119.
    Cappellari AM, Palumbo S, Margiotta S. 2023.. Questions and controversies in neonatal seizures. . Children 11::40
     [Crossref] [Google Scholar]
  120. 120.
    Weeke LC, van Ooijen IM, Groenendaal F, van Huffelen AC, van Haastert IC, et al. 2017.. Rhythmic EEG patterns in extremely preterm infants: classification and association with brain injury and outcome. . Clin. Neurophysiol. 128::2428–35
     [Crossref] [Google Scholar]
  121. 121.
    Glass HC, Shellhaas RA, Tsuchida TN, Chang T, Wusthoff CJ, et al. 2017.. Seizures in preterm neonates: a multicenter observational cohort study. . Pediatr. Neurol. 72::19–24
     [Crossref] [Google Scholar]
  122. 122.
    Shah DK, Zempel J, Barton T, Lukas K, Inder TE. 2010.. Electrographic seizures in preterm infants during the first week of life are associated with cerebral injury. . Pediatr. Res. 67::102–6
     [Crossref] [Google Scholar]
  123. 123.
    Leth H, Toft PB, Herning M, Peitersen B, Lou HC. 1997.. Neonatal seizures associated with cerebral lesions shown by magnetic resonance imaging. . Arch. Dis. Child. Fetal Neonatal Ed. 77::F105–10
     [Crossref] [Google Scholar]
  124. 124.
    Bennet L, Galinsky R, Draghi V, Lear CA, Davidson JO, et al. 2018.. Time and sex dependent effects of magnesium sulphate on post-asphyxial seizures in preterm fetal sheep. . J. Physiol. 596::6079–92
     [Crossref] [Google Scholar]
  125. 125.
    Gonzalez H, Hunter CJ, Bennet L, Power GG, Gunn AJ. 2005.. Cerebral oxygenation during post-asphyxial seizures in near-term fetal sheep. . J. Cereb. Blood Flow Metab. 25::911–18
     [Crossref] [Google Scholar]
  126. 126.
    Lear CA, Davidson JO, Dhillon SK, King VJ, Lear BA, et al. 2020.. Effects of antenatal dexamethasone and hyperglycemia on cardiovascular adaptation to asphyxia in preterm fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 319::R653–65
     [Crossref] [Google Scholar]
  127. 127.
    Kelly CE, Shaul M, Thompson DK, Mainzer RM, Yang JY, et al. 2023.. Long-lasting effects of very preterm birth on brain structure in adulthood: a systematic review and meta-analysis. . Neurosci. Biobehav. Rev. 147::105082
     [Crossref] [Google Scholar]
  128. 128.
    Yamaguchi K, Lear CA, Beacom MJ, Ikeda T, Gunn AJ, Bennet L. 2018.. Evolving changes in fetal heart rate variability and brain injury after hypoxia-ischaemia in preterm fetal sheep. . J. Physiol. 596::6093–104
     [Crossref] [Google Scholar]
  129. 129.
    Lumbers ER, Gunn AJ, Zhang DY, Wu JJ, Maxwell L, Bennet L. 2001.. Nonimmune hydrops fetalis and activation of the renin-angiotensin system after asphyxia in preterm fetal sheep. . Am. J. Physiol. Regul. Integr. Comp. Physiol. 280::R1045–51
     [Crossref] [Google Scholar]
  130. 130.
    Gunn AJ, Maxwell L, de Haan HH, Bennet L, Williams CE, et al. 2000.. Delayed hypotension and subendocardial injury after repeated umbilical cord occlusion in near-term fetal lambs. . Am. J. Obstet. Gynecol. 183::1564–72
     [Crossref] [Google Scholar]
  131. 131.
    Munshi UK, Brown MM, Tauber KA, Horgan MJ. 2022.. Early troponin I levels in newborns undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy and residual encephalopathy at discharge. . Am. J. Perinatol. 39::1083–88
     [Crossref] [Google Scholar]
  132. 132.
    Tan S. 2014.. Fault and blame, insults to the perinatal brain may be remote from time of birth. . Clin. Perinatol. 41::105–17
     [Crossref] [Google Scholar]
  133. 133.
    Nakao M, Nanba Y, Okumura A, Hasegawa J, Toyokawa S, et al. 2022.. Correlation between fetal heart rate evolution patterns and magnetic resonance imaging findings in severe cerebral palsy: a longitudinal study. . Br. J. Obstet. Gynaecol. 129::1574–82
     [Crossref] [Google Scholar]
  134. 134.
    Nakao M, Okumura A, Hasegawa J, Toyokawa S, Ichizuka K, et al. 2020.. Fetal heart rate pattern in term or near-term cerebral palsy: a nationwide cohort study. . Am. J. Obstet. Gynecol. 223::907
     [Crossref] [Google Scholar]
  135. 135.
    Jonsson M, Ågren J, Nordén-Lindeberg S, Ohlin A, Hanson U. 2014.. Neonatal encephalopathy and the association to asphyxia in labor. . Am. J. Obstet. Gynecol. 211::667
     [Crossref] [Google Scholar]
  136. 136.
    Pereira S, Patel R, Zaima A, Tvarozkova K, Chisholm P, et al. 2022.. Physiological CTG categorization in types of hypoxia compared with MRI and neurodevelopmental outcome in infants with HIE. . J. Matern. Fetal Neonatal Med. 35::9675–83
     [Crossref] [Google Scholar]
  137. 137.
    Martinez-Biarge M, Groenendaal F, Kersbergen KJ, Benders MJ, Foti F, et al. 2016.. MRI based preterm white matter injury classification: the importance of sequential imaging in determining severity of injury. . PLOS ONE 11::e0156245
     [Crossref] [Google Scholar]
  138. 138.
    Sarkar S, Shankaran S, Barks J, Do BT, Laptook AR, et al. 2018.. Outcome of preterm infants with transient cystic periventricular leukomalacia on serial cranial imaging up to term equivalent age. . J. Pediatr. 195::59–65.e3
     [Crossref] [Google Scholar]
  139. 139.
    Pierrat V, Duquennoy C, van Haastert IC, Ernst M, Guilley N, de Vries LS. 2001.. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. . Arch. Dis. Child. Fetal Neonatal Ed. 84::F151–56
     [Crossref] [Google Scholar]
  140. 140.
    Salas J, Tekes A, Hwang M, Northington FJ, Huisman T. 2018.. Head ultrasound in neonatal hypoxic-ischemic injury and its mimickers for clinicians: a review of the patterns of injury and the evolution of findings over time. . Neonatology 114::185–97
     [Crossref] [Google Scholar]
  141. 141.
    Kersbergen KJ, Benders MJ, Groenendaal F, Koopman-Esseboom C, Nievelstein RA, et al. 2014.. Different patterns of punctate white matter lesions in serially scanned preterm infants. . PLOS ONE 9::e108904
     [Crossref] [Google Scholar]
  142. 142.
    Geddes R, Vannucci RC, Vannucci SJ. 2001.. Delayed cerebral atrophy following moderate hypoxia-ischemia in the immature rat. . Dev. Neurosci. 23::180–85
     [Crossref] [Google Scholar]
  143. 143.
    Northington FJ, Chavez-Valdez R, Martin LJ. 2011.. Neuronal cell death in neonatal hypoxia-ischemia. . Ann. Neurol. 69::743–58
     [Crossref] [Google Scholar]
  144. 144.
    Baburamani AA, Supramaniam VG, Hagberg H, Mallard C. 2014.. Microglia toxicity in preterm brain injury. . Reprod. Toxicol. 48::106–12
     [Crossref] [Google Scholar]
  145. 145.
    Molloy EJ, El-Dib M, Juul SE, Benders M, Gonzalez F, et al. 2023.. Neuroprotective therapies in the NICU in term infants: present and future. . Pediatr. Res. 93::1819–27
     [Crossref] [Google Scholar]
  146. 146.
    Seron-Ferre M, Mendez N, Abarzua-Catalan L, Vilches N, Valenzuela FJ, et al. 2012.. Circadian rhythms in the fetus. . Mol. Cell. Endocrinol. 349::68–75
     [Crossref] [Google Scholar]
  147. 147.
    Lear CA, Lear BA, Davidson JO, King VJ, Maeda Y, et al. 2024.. Dysmaturation of sleep state and electroencephalographic activity after hypoxia-ischaemia in preterm fetal sheep. . J. Cereb. Blood Flow Metab. 44::1376–92
     [Crossref] [Google Scholar]
  148. 148.
    Bennet L, Walker DW, Horne RSC. 2018.. Waking up too early—the consequences of preterm birth on sleep development. . J. Physiol. 596::5687–708
     [Crossref] [Google Scholar]
  149. 149.
    Lear CA, Maeda Y, King VJ, Dhillon SK, Beacom MJ, et al. 2024.. Circadian patterns of heart rate variability in fetal sheep after hypoxia-ischaemia: a biomarker of evolving brain injury. . J. Physiol. 602::655369
     [Crossref] [Google Scholar]
  150. 150.
    Beacom MJ, Frasch MG, Lear CA, Gunn AJ. 2024.. Monitoring chaos at the cot-side. . Pediatr. Res. 96::281–82
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-physiol-022724-104754
Loading
Preterm Brain Injury: Mechanisms and Challenges
Annual Review of Physiology 87, 79 (2025); https://doi.org/10.1146/annurev-physiol-022724-104754
/content/journals/10.1146/annurev-physiol-022724-104754
/content/journals/10.1146/annurev-physiol-022724-104754
Loading

Data & Media loading...

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error