Does Therapeutic Hypothermia have a Role in Management of the Late Preterm Infant with Hypoxic-Ischemic Encephalopathy?

April 2026

Introduction

This Commentary was provoked by recent reports concerning the potential value (or lack thereof) for therapeutic hypothermia (TH) in treatment of late preterm (LPT) infants with hypoxic-ischemic encephalopathy (HIE).^1,2 A recent randomized clinical trial (RCT) suggested that TH in this context is not an effective therapeutic approach and may be harmful (see later).¹ The report prompted a recent review that criticized the statistical analyses in the RCT and provided new data (see later).²

In the following, I will review briefly the neurological outcome among LPT infants, the contribution of HIE to this outcome, the neuropathology underlying subsequent neurological deficits in the LPT infant, the impact of TH on the occurrence of these deficits, the experimental work suggesting benefit for TH, and the implications of the latter work for subsequent management.

Neurological Outcomes of LPT Infants

The importance of the issue of subsequent neurological deficits and causes thereof among LPT infants relates both to the relatively large number of affected infants and to the role of HIE in causation. In the US, approximately 280,000 infants are born LPT yearly and account for approximately 75% of all preterm births.³ This large group is vulnerable to neurological disability. Indeed, approximately 4% of even “healthy” LPT infants (discharged from birth hospital within 3 days of birth) later exhibit developmental delay or disability.⁴ Many studies have described the subsequent neurodevelopmental deficits in LPT infants.^5-10 Although the specific deficits are not marked, they involve learning disturbances, behavioral issues, and psychiatric disturbance. Major motor disturbances occur in approximately 1%. However, among the subset of LPT infants with HIE, rates of disability are considerably higher (see later).

Contribution of HIE to Neurological Outcome in LPT Infants

As noted earlier, neurodevelopmental deficits are relatively common in LPT infants. In the context of this Commentary, it is important to address the relative contribution of HIE to these deficits. Although LPT infants with HIE commonly exhibit subsequent neurodevelopmental impairments and imaging evidence of brain injury (see later), HIE may not be the most common cause for these impairments among all LPT infants. Although more data are needed, large epidemiological studies indicate that other frequent precedents are respiratory abnormalities (e.g., respiratory distress syndrome), metabolic disturbances (e.g., hypoglycemia, hyperbilirubinemia), and infections (e.g., bacterial sepsis), among others.¹¹ Smaller cohort studies confirm these correlates.^12,13 Nonetheless, HIE is a relatively common, readily defined precedent identifiable in the early postpartum period, with consistent imaging correlates of brain injury and impaired outcome (see later). (Recognize, also, that the precedents just noted not infrequently complicate the clinical course of the infant with HIE.)

Neuropathology Underlying the Neurological Deficits in LPT Infants

Although available information from neuropathological studies and from imaging of living infants does not demonstrate unequivocally all of the anatomical abnormalities underlying the neurological deficits seen later in LPT infants, several conclusions seem warranted. As might be expected, neuropathological information is much less abundant than that available from imaging studies.

Neuropathological Studies

The most detailed analysis of the neuropathology of LPT infants (n=16) was reported by Haynes et al.¹⁴ Although the neonatal causes of the neuropathology were multiple, varying degrees of hypoxemia and ischemia predominated. The principal injury occurred in cerebral white matter and consisted in approximately 65% of cases of periventricular leukomalacia (PVL) (focal areas of necrosis and diffuse white matter gliosis). The areas of necrosis were noncystic, generally 1 mm or less, and likely often below the resolution of conventional MRI scanners. There was associated reactive astrogliosis and activated microgliosis. These cellular elements are injurious via release of cytokines and generation of reactive oxygen and nitrogen species.¹⁵ The principal cellular target, the pre-myelinating O4-postive oligodendrocyte, which is highly sensitive to reactive oxygen and nitrogen species generated with hypoxic and related insults, comprises approximately 60% of the oligodendroglial lineage in the LPT period.¹⁴ (The next phase in progression of the oligodendroglial lineage, the O1-positive or “immature” oligodendrocyte, which is somewhat less sensitive to injury by reactive oxygen and nitrogen species, comprises the remaining developing cerebral white matter oligodendrocytes in the LPT infant.)

Neuronal and axonal injury was noted neuropathologically in an appreciable minority of LPT cases and was confined principally to the thalamus and hippocampus.¹⁴ As with white matter injury, the gray matter lesions in LPT infants also included a brisk reactive astrogliosis and activated microgliosis.¹⁶ Notably, however, because conventional neuropathology cannot detect the hallmarks of neuronal maturation, e.g., axonal, dendritic and synaptic development, all very active in the LPT period,¹⁷ impaired neuronal development could not be assessed. Indeed, as will be noted later, considerable imaging evidence supports such impairment subsequently in LPT infants.

Worthy of emphasis, the neuroinflammatory response with reactive astrocytes and activated microglia in both cerebral white matter and gray matter, with their injurious effects just noted, likely persist for many weeks following the initial insults.^16,17 In addition to disrupting development of pre-oligodendrocytes and neuronal-axonal structures, when in inflammatory mode these important glia are diverted from their usual developmental roles as mediators of normal oligodendroglial, neuronal, axonal and vascular development during the LPT period.^18,19

Imaging Studies

Studies of LPT infants with MRI techniques support the neuropathological studies indicative of cerebral white matter injury and/or impaired development in LPT infants.^20-26 Because quantitative diffusion-based analyses were not available in most reports, impairments of white matter development were more difficult to identify than white matter injury. However, multiple microstructural and functional MRI studies do support the notion of not only white matter injury but also impaired white matter development in LPT infants.^20,21,27,28

Advanced MRI methods suggest that, although white matter injury and impaired development are a prominent feature of the neuropathology of the LPT infant, disturbance of cerebral cortical development is likely also of major importance. Thus, multiple studies utilizing MRI methods have shown in such infants smaller cerebral cortical volumes, impaired cortical gyral development, and altered cortical connectivity.^20,22,27-33

The particular vulnerability of cerebral cortex in the LPT infant likely relates to the rapidity and complexity of its development during the LPT period (see earlier). This development has been demonstrated both in anatomic and imaging studies.¹⁷ Anatomic data at the macroscopic level show that over the last six weeks of gestation the brain must gain fully 35% of its overall weight observed at term.¹⁴ At the microscopic level, numerous dramatic changes occur. Most prominent are the elaboration of dendritic and axonal ramifications, onset of synaptogenesis, a marked increase in cortical surface area, and rapid gyral development.^17,34 Advanced MRI studies of fetuses and of premature infants have corroborated the LPT period as the time of extraordinarily rapid growth of cerebral cortex, with the latter the primary driver of the overall increase in cerebral volume.^35-40 Notably, diffusion-based measurements of cerebral cortex implicate cortical dendritic growth, a key feature of neuronal maturation, as the principal driver of the increases in cortical gray matter.³⁸ Moreover, longitudinal studies of cortical gray matter growth rate show a three-fold increase after onset of the LPT period.⁴⁰

What are the implications of rapid cerebral cortical development in the LPT infant? Beyond the scope of this Commentary is the large and relevant clinical and experimental literature supportive of the general notion that preterm birth and exposure to multiple deleterious postnatal insults can lead to impaired brain maturation¹⁷ and that early preterm injury to cerebral white matter appears to be a central initiator of the impairment. However, in experimental models, impaired cerebral cortical maturation (reduced dendritic arbor, decreased synaptic density), without overt white matter injury, may occur after such events as mild or transient hypoxemia.⁴¹ Similarly, work in developing rats shows similar impairments in the presence of perinatal stress.⁴² A minority of LPT infants do have increased likelihood of such factors, as well as difficulties with resuscitation at birth, respiratory distress, hypoglycemia, hyperbilirubinemia and feeding difficulties.⁴ Thus, the time period of the LPT infant appears to be characterized by a unique vulnerability of its rapid and diverse cerebral cortical development, as well as the recognized vulnerability of its developing cerebral white matter.

Effect of Neonatal Hypothermia on Subsequent Outcomes in LPT Infants

Clinical Studies Addressing the Impact of TH on LPT Infants with HIE

A large number of retrospective, cohort studies of LPT infants with HIE managed with TH have been reported (see, for examples,^23-25,43-45). This work has been effectively reviewed recently by El-Dib and coworkers (see for details²). The principal conclusion from the work is that TH is feasible in the LPT infant but, in comparison to term infants treated with TH, the LPT infants exhibit a higher incidence of such complications as coagulopathy, metabolic disturbances, and hemodynamic instability, among others. Principal neonatal MRI findings in the LPT infants have included especially evidence of injury to cerebral white matter (65-75%), cerebral cortex and deep nuclear gray matter, findings consistent with neuropathological data (see earlier). Of particular importance, when compared to term infants treated with TH for HIE, LPT infants, similarly treated, especially those at 35 weeks gestational age, had variable outcomes. Thus, based on this previous work, conclusions concerning feasibility and benefit of TH in the LPT infant with HIE required a randomized controlled trial.

On this background, Faix et al.¹ carried out a randomized controlled trial that investigated the efficacy and safety of TH in 168 preterm infants born between 33 and 35-6/7 weeks gestational age with moderate to severe HIE. The primary outcome (death or disability, moderate or severe, at 18 to 22 months corrected age) occurred in 29/83 (35%) hypothermic infants and in 20/69 (29%) normothermic infants. Death occurred in 20% of hypothermic infants versus 12% of normothermic infants. The authors concluded that in this gestational age range, TH at <6 hours for HIE did not reduce the primary outcome of death or disability at 18-22 months corrected age. Moreover, Bayesian analysis suggested a 74% probability of increased risk for death or disability in the TH group. The study investigators thus further concluded that TH not only did not offer benefit but may increase harm in preterm infants of 33 to 35 weeks gestational age. Notably, treatment effects were not rigorously analyzed across the gestational age range. For example, especially noteworthy in the context of this Commentary, at 35-0/7 to 35-6/7 weeks gestational age, there was no apparent difference between hypothermic and normothermic infants in rates of death or moderate/severe disability.¹ El-Dib et al. emphasized such difficulties with the work as relatively small sample sizes, wide confidence intervals, use of Bayesian analysis, and unequal assignment of important outcome-determining risks among groups, among other difficulties, etc.² Of particular note, the possibility that more of the TH group experienced fetal inflammation, which is associated with a blunted response to TH (see later), was suggested by a two-fold higher proportion of premature rupture of membranes >18 hours in the TH group (31% vs 16%).² The TH group also had higher incidence of chest compressions in the delivery room and lower 10-minute Apgar scores.

Interestingly, the authors of the review article of El-Dib et al.² presented their collective experience with the use of TH in LPT infants with HIE. Of the 373 infants so treated at 35 weeks gestational age, there were 49 deaths (13.1%), compared to 17.9% (5/28) in the RCT of Faix et al. (At 34 weeks gestational age, the collective experience was 14.3% deaths versus 30.0% in the RCT.) El-Dib et al. concluded that “there appears to be insufficient evidence at this time to revise international, national or institutional guidelines that currently include 35 weeks GA in TH protocols.”²

Experimental Work Indicative of Benefit for TH in LPT Infants with HIE

Considerable experimental work suggests that TH in the context of HIE in the LPT infant is beneficial.⁴⁶ In a classic study, Gunn and coworkers subjected preterm fetal sheep to complete umbilical cord occlusion followed by cerebral TH from 90 min to 70 hours after the end of occlusion.⁴⁶ TH was associated with a significant reduction in (1) loss of early differentiating oligodendrocytes (equivalent in this study to both pre-myelinating, O4+ OLs and immature OLs) which populate the cerebral white matter in the LPT human infant (see earlier), as well as (2) neuronal loss in hippocampus and basal ganglia. However, it is notable that, unlike in the human premature infant,⁴² cell proliferation in cerebral white matter did not recover in the fetal sheep model.⁴⁶ To the extent that this lack of recovery involves pre-OLs is of concern, because proliferation of pre-OLs post insult and their subsequent differentiation to mature myelin-producing OLs is a critical aspect of recovery in more prolonged preterm models and, likely, in human infants.^{15,17,42,47,48} (That the fetal sheep studies⁴⁶ were not prolonged enough to observe later proliferation of pre-OLs seems possible.) Importantly, a marked reduction in microglia and suppression of its apoptotic-inducing caspase-3 were identified and were consistent with previously documented benefit of TH in suppression of apoptotic events and local inflammation.⁴⁶

Of major potential clinical relevance, subsequent experimental work with the preterm hypoxic-ischemic fetal sheep model has shown the critical importance of persistent neuroinflammation (mediated by astrogliosis and microgliosis) in the genesis of white matter injury and the value of inhibition thereof in protection.^49-51 The latter agents utilized include insulin-like growth factor-1, TNF-alpha blockade with etanercept, and necrostatin-1s. (It is beyond the scope of this Commentary to review the studies in detail here.) Nonetheless, the findings are consistent with the notion that post-hypoxic-ischemic neuroinflammation, untreated, is critical in the genesis of brain injury in an excellent preterm model. This phenomenon may underlie the prolonged loss of neurons after hypoxia-ischemia in neonatal rats⁵² and perhaps the disturbances of neuronal and oligodendroglial maturation described earlier in LPT infants.

Conclusions

This important clinical issue involves a very large number of LPT infants with HIE. I suggest the following tentative conclusions.

First, brain injury in the LPT infant is common and, based on neuropathology and imaging, affects both developing OLs and neurons, with associated neuroinflammation.

Second, in experimental studies of HIE in LPT models, TH is beneficial for prevention or minimization of adverse cellular outcomes.

Third, results of human studies of LPT infants with HIE managed with TH are not entirely consistent concerning benefit, although it is apparent that respiratory and other systemic complications of prematurity in the youngest infants can be critical in determining neurological outcomes. Concerns about the conclusions of the recently published RCT¹ were discussed earlier.

Fourth, “real-world” experience (not derived from controlled studies) raises the possibility of value for TH in LPT infants at 35 weeks gestational age. In my view, the data do suggest that a randomized controlled study of 35-week LPT infants with HIE (1) caused by a definable peripartum insult, e.g., a sentinel event, and (2) absent signs of overt fetal/peripartum inflammation would be valuable for patient selection in subsequent studies. Infants with HIE and a background of intrauterine or peripartum infection may be associated with blunted benefit from TH.^53-55 In the interim, if current data in a given institution indicate no harm from TH in this gestational age range, continuation of the practice seems reasonable. (Of course, careful discussion with parents concerning risks/benefits is appropriate, as suggested in a recent statement from the American Academy of Pediatrics.⁵⁶)

Fifth, and perhaps most important, experimental studies in late preterm models suggest that prolonged post-insult neuroinflammation is important in determining neurological outcome and that novel interventions directed at the cellular mediators of this inflammation (especially microglia) could be central to optimal outcomes following hypoxia-ischemia (see earlier). Recent experimental studies of such interventions (see earlier) provide good examples of promising approaches for potential future clinical application.^18,19,57

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

1. Faix RG, Laptook AR, Shankaran S, et al. Whole-Body Hypothermia for Neonatal Encephalopathy in Preterm Infants 33 to 35 Weeks’ Gestation: A Randomized Clinical Trial. JAMA Pediatr 179:396-406, 2025. DOI: 10.1001/jamapediatrics.2024.6613
2. El-Dib M, Abdelgadir D, Ahmad KA, et al. Benefits and risks of therapeutic hypothermia for hypoxic-ischemic encephalopathy in late preterm infants. Pediatr Res, 2025. DOI: 10.1038/s41390-025-04428-9
3. Hamilton BE, Martin JA, Osterman MJK. Births: Provisional data for 2019 Hyattsville MD: National Center for Health Statistics; 2020 May. Available from: https://www.cdc.gov/nchs/data/vsrr/vsrr-8-508.pdf.
4. Huff K, Rose RS, Engle WA. Late Preterm Infants: Morbidities, Mortality, and Management Recommendations. Pediatr Clin North Am 66:387-402, 2019. DOI: 10.1016/j.pcl.2018.12.008
5. Martinez-Nadal S, Bosch L. Cognitive and Learning Outcomes in Late Preterm Infants at School Age: A Systematic Review. Int J Environ Res Public Health 18, 2020. DOI: 10.3390/ijerph18010074
6. Vohr BR. Neurodevelopmental outcomes of extremely preterm infants. Clin Perinatol 41:241-55, 2014. DOI: 10.1016/j.clp.2013.09.003
7. Cheong JL, Doyle LW, Burnett AC, et al. Association Between Moderate and Late Preterm Birth and Neurodevelopment and Social-Emotional Development at Age 2 Years. JAMA Pediatr 171:e164805, 2017. DOI: 10.1001/jamapediatrics.2016.4805
8. Woythaler M. Neurodevelopmental outcomes of the late preterm infant. Semin Fetal Neonatal Med 24:54-9, 2019. DOI: 10.1016/j.siny.2018.10.002
9. You J, Shamsi BH, Hao MC, et al. A study on the neurodevelopment outcomes of late preterm infants. BMC Neurol 19:108, 2019. DOI: 10.1186/s12883-019-1336-0
10. Favrais G, Saliba E. Neurodevelopmental outcome of late-preterm infants: Literature review. Arch Pediatr 26:492-6, 2019. DOI: 10.1016/j.arcped.2019.10.005
11. Mitha A, Chen R, Altman M, et al. Neonatal Morbidities in Infants Born Late Preterm at 35-36 Weeks of Gestation: A Swedish Nationwide Population-based Study. J Pediatr 233:43-50 e5, 2021. DOI: 10.1016/j.jpeds.2021.02.066
12. Williams LZJ, McNamara D, Alsweiler JM. Intermittent Hypoxemia in Infants Born Late Preterm: A Prospective Cohort Observational Study. J Pediatr 204:89-95 e1, 2019. DOI: 10.1016/j.jpeds.2018.08.048
13. Martinez-Nadal S, Demestre X, Schonhaut L, et al. Impact of neonatal morbidity on the risk of developmental delay in late preterm infants. Early Hum Dev 116:40-6, 2018. DOI: 10.1016/j.earlhumdev.2017.11.001
14. Haynes RL, Sleeper LA, Volpe JJ, Kinney HC. Neuropathologic studies of the encephalopathy of prematurity in the late preterm infant. Clin Perinatol 40:707-22, 2013. DOI: 10.1016/j.clp.2013.07.003
15. Back SA, Volpe JJ. Encephalopathy of Prematurity: Pathophysiology. Chapter 19. In: Volpe JJ, Inder TE, Darras BT, De Vries LS, du Plessis AJ, Ferriero DM, Perlman JM, editors. Volpe’s Neurology of the Newborn. 7th ed. Philadelphia PA: Elsevier; 2025. p. 523-46.
16. Pierson CR, Volpe JJ. Hypoxic-Ischemic Encephalopathy in the Term Infant: Neuropathology. Chapter 22. In: Volpe JJ, Inder T, Darras BT, de Vries LS, du Plessis AJ, Ferriero DM, Perlman JM, editors. Volpe’s Neurology of the Newborn. 7th ed. Philadelphia PA: Elsevier; 2025. p. 619-31.
17. Volpe JJ. Dysmaturation of Premature Brain: Importance, Cellular Mechanisms, and Potential Interventions. Pediatr Neurol 95:42-66, 2019. DOI: 10.1016/j.pediatrneurol.2019.02.016
18. Volpe JJ. Microglia: Newly discovered complexity could lead to targeted therapy for neonatal white matter injury and dysmaturation. J Neonatal Perinatal Med 12:239-42, 2019. DOI: 10.3233/NPM-190303
19. Fleiss B, Van Steenwinckel J, Bokobza C, et al. Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries. Biomolecules 11:99, 2021. DOI: 10.3390/biom11010099
20. Degnan AJ, Wisnowski JL, Choi S, et al. Alterations of resting state networks and structural connectivity in relation to the prefrontal and anterior cingulate cortices in late prematurity. Neuroreport 26:22-6, 2015. DOI: 10.1097/WNR.0000000000000296
21. Kelly CE, Cheong JL, Gabra Fam L, et al. Moderate and late preterm infants exhibit widespread brain white matter microstructure alterations at term-equivalent age relative to term-born controls. Brain Imaging Behav 10:41-9, 2016. DOI: 10.1007/s11682-015-9361-0
22. Cheong JLY, Thompson DK, Olsen JE, Spittle AJ. Late preterm births: New insights from neonatal neuroimaging and neurobehaviour. Semin Fetal Neonatal Med 24:60-5, 2019. DOI: 10.1016/j.siny.2018.10.003
23. Rao R, Trivedi S, Vesoulis Z, et al. Safety and Short-Term Outcomes of Therapeutic Hypothermia in Preterm Neonates 34-35 Weeks Gestational Age with Hypoxic-Ischemic Encephalopathy. J Pediatr 183:37-42, 2017. DOI: 10.1016/j.jpeds.2016.11.019
24. Binet L, Debillon T, Beck J, et al. Effect of gestational age on cerebral lesions in neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 109:562-8, 2024. DOI: 10.1136/archdischild-2023-326131
25. Roca-LLabres P, Fontalvo-Acosta M, Aldecoa-Bilbao V, Alarcon A. Therapeutic hypothermia in preterm infants under 36 weeks: Case series on outcomes and brain MRI findings. Eur J Pediatr 184:113, 2025. DOI: 10.1007/s00431-024-05948-y
26. Kose Cetinkaya A, Buyuktiryaki M, Sari FN, et al. Higher mean platelet volume is associated with pulmonary hemorrhage in very low birth weight infants. Minerva Pediatr (Torino) 77:143-7, 2025. DOI: 10.23736/S2724-5276.21.06320-5
27. Walsh JM, Doyle LW, Anderson PJ, et al. Moderate and late preterm birth: effect on brain size and maturation at term-equivalent age. Radiology 273:232-40, 2014. DOI: 10.1148/radiol.14132410
28. Wu X, Wei L, Wang N, et al. Frequency of Spontaneous BOLD Signal Differences between Moderate and Late Preterm Newborns and Term Newborns. Neurotox Res 30:539-51, 2016. DOI: 10.1007/s12640-016-9642-4
29. Munakata S, Okada T, Okahashi A, et al. Gray matter volumetric MRI differences late-preterm and term infants. Brain Dev 35:10-6, 2013. DOI: 10.1016/j.braindev.2011.12.011
30. Kim DJ, Davis EP, Sandman CA, et al. Longer gestation is associated with more efficient brain networks in preadolescent children. Neuroimage 100:619-27, 2014. DOI: 10.1016/j.neuroimage.2014.06.048
31. Rogers CE, Barch DM, Sylvester CM, et al. Altered gray matter volume and school age anxiety in children born late preterm. J Pediatr 165:928-35, 2014. DOI: 10.1016/j.jpeds.2014.06.063
32. Cheong JL, Thompson DK, Spittle AJ, et al. Brain Volumes at Term-Equivalent Age Are Associated with 2-Year Neurodevelopment in Moderate and Late Preterm Children. J Pediatr 174:91-7 e1, 2016. DOI: 10.1016/j.jpeds.2016.04.002
33. Brumbaugh JE, Conrad AL, Lee JK, et al. Altered brain function, structure, and developmental trajectory in children born late preterm. Pediatr Res 80:197-203, 2016. DOI: 10.1038/pr.2016.82
34. Kinney HC. The near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. Semin Perinatol 30:81-8, 2006. DOI: 10.1053/j.semperi.2006.02.006
35. Andescavage NN, du Plessis A, McCarter R, et al. Complex Trajectories of Brain Development in the Healthy Human Fetus. Cereb Cortex 27:5274-83, 2017. DOI: 10.1093/cercor/bhw306
36. Huppi PS, Warfield S, Kikinis R, et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann Neurol 43:224-35, 1998. DOI: 10.1002/ana.410430213
37. Kapellou O, Counsell SJ, Kennea N, et al. Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth. PLoS Med 3:e265, 2006. DOI: 10.1371/journal.pmed.0030265
38. Ball G, Srinivasan L, Aljabar P, et al. Development of cortical microstructure in the preterm human brain. Proc Natl Acad Sci U S A 110:9541-6, 2013. DOI: 10.1073/pnas.1301652110
39. Moeskops P, Benders MJ, Kersbergen KJ, et al. Development of Cortical Morphology Evaluated with Longitudinal MR Brain Images of Preterm Infants. PLoS One 10:e0131552, 2015. DOI: 10.1371/journal.pone.0131552
40. Matthews LG, Walsh BH, Knutsen C, et al. Brain growth in the NICU: critical periods of tissue-specific expansion. Pediatr Res 83:976-81, 2018. DOI: 10.1038/pr.2018.4
41. Dean JM, McClendon E, Hansen K, et al. Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 5:168ra7, 2013. DOI: 10.1126/scitranslmed.3004669
42. Murmu MS, Salomon S, Biala Y, et al. Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy. Eur J Neurosci 24:1477-87, 2006. DOI: 10.1111/j.1460-9568.2006.05024.x
43. Herrera TI, Edwards L, Malcolm WF, et al. Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy. Early Hum Dev 125:1-7, 2018. DOI: 10.1016/j.earlhumdev.2018.08.003
44. Kim SH, El-Shibiny H, Inder T, El-Dib M. Therapeutic hypothermia for preterm infants 34-35 weeks gestational age with neonatal encephalopathy. J Perinatol 44:528-31, 2024. DOI: 10.1038/s41372-024-01874-x
45. Moran P, Sullivan K, Zanelli SA, Burnsed J. Single-Center Experience with Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy in Infants with <36 Weeks’ Gestation. Am J Perinatol 41:1680-7, 2024. DOI: 10.1055/a-2251-6317
46. Bennet L, Roelfsema V, George S, et al. The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep. J Physiol 578:491-506, 2007. DOI: 10.1113/jphysiol.2006.119602
47. Buser JR, Maire J, Riddle A, et al. Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 71:93-109, 2012. DOI: 10.1002/ana.22627
48. Back SA. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331-49, 2017. DOI: 10.1007/s00401-017-1718-6
49. Wassink G, Cho KHT, Mathai S, et al. White matter protection with insulin-like growth factor-1 after hypoxia-ischaemia in preterm foetal sheep. Brain Commun 6:fcae373, 2024. DOI: 10.1093/braincomms/fcae373
50. Lear BA, Lear CA, Dhillon SK, et al. Delayed necrostatin-1s infusion attenuates cystic white matter injury in preterm fetal sheep. Neurotherapeutics 23:e00775, 2026. DOI: 10.1016/j.neurot.2025.e00775
51. Lear CA, Lear BA, Davidson JO, et al. Tumour necrosis factor blockade after asphyxia in foetal sheep ameliorates cystic white matter injury. Brain 146:1453-66, 2023. DOI: 10.1093/brain/awac331
52. McNally MA, Lau LA, Granak S, et al. Ongoing loss of viable neurons for weeks after mild hypoxia-ischaemia. Brain Commun 7:fcaf153, 2025. DOI: 10.1093/braincomms/fcaf153
53. Osredkar D, Sabir H, Falck M, et al. Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury. Dev Neurosci 37:390-7, 2015. DOI: 10.1159/000430860
54. Osredkar D, Thoresen M, Maes E, et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 85:567-72, 2014. DOI: 10.1016/j.resuscitation.2013.12.006
55. Falck M, Osredkar D, Maes E, et al. Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent. Dev Neurosci 39:238-47, 2017. DOI: 10.1159/000455838
56. Zanelli SA, Wusthoff CJ, Lucke AM, et al. Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Clinical Report. Pediatrics 157, 2026. DOI: 10.1542/peds.2025-073627
57. Gressens P. Inflammation and the Newborn Brain. Chapter 17. In: Volpe JJ, Inder TE, Darras BT, de Vries LS, du Plessis AJ, Ferriero DM, Perlman JM, editors. Volpe’s Neurology of the Newborn. 7th ed. Philadelphia PA: Elsevier; 2025. p. 494-505.