Volpe's View

March, 2024

PRETERM INFANTS NEED THEIR SLEEP, ESPECIALLY ACTIVE (REM) SLEEP

Introduction

A recent report¹ from a distinguished group in the field of sleep in infancy concludes that active sleep is related beneficially to cerebral white matter development in preterm infants. The findings suggest potential value of incorporating sleep monitoring into routine caregiving practices in NICU settings (see later). Recall that in the neonatal period sleep is divided generally into two main periods, quiet sleep, a precursor to non-rapid eye movement sleep, and active sleep, a precursor to rapid eye movement (REM) sleep.² In general, preterm infants, when uninterrupted, spend approximately 80-90% of the time asleep (see later), and the majority of this time is in active sleep.³

Sleep and Brain Development—Animal Studies

The possibility that altered sleep behaviors in infants could be related to impaired brain development has been raised by a variety of animal studies.^3-6 In particular, deprivation of active sleep during development has been followed by smaller brain size, reduced brain growth and subsequent alterations of brain function. At the microstructural level, depending on the model, active sleep has been associated with synaptogenesis, maintenance of dendritic spines, and strengthening of synapses.³  At the electrophysiological level, REM sleep in early development has been associated with a number of effects indicative of functional maturation of neural circuits. As summarized by Knoop et al., “During early maturation REM sleep seems to provide the stimulation needed for preliminary development and survival of sensorimotor neural networks. It does this by driving the generation of endogenous, intense and generalized neural activity across sensorimotor systems.”³ This phenomenon is reminiscent of activity-dependent differentiation of neuronal circuits in a variety of sensory systems during brain development.⁷ (Although beyond the scope of this discussion, animal studies support the notion that non-REM sleep is more important for regulating synaptic homeostasis and later brain maturation.²)

Several concerns could be raised about the animal studies. First, the models generally involved animals that are more mature than human infants.^4,5,8 Additionally, experimental paradigms often decreased active sleep by pharmacological methods and did not control for such factors as stress (as in experiments utilizing ocular deprivation). Moreover, study of brain maturation in the animal models has often not been sufficiently detailed, especially at the regional and cellular levels. Nevertheless, the findings are compelling.

Sleep and Brain Development—Human Studies

The few relevant studies in human preterm infants have been of interest but have been limited by methodological challenges. Several reports describe an association of decreased active sleep during the preterm or term period to later cognitive impairments.^9-12 Correlation with imaging markers of brain development was not reported. Moreover, the most prevalent methodologies utilized for sleep assessment, i.e., behavioral observation or polysomnography, limit daily sleep assessments to only a few minutes to hours.^13,14

Current Study

Study Design. The study that stimulated this Commentary is entitled: “Machine learning-derived active sleep as an early predictor of white matter development in preterm infants,” by Wang et al., and as noted earlier, was published in the Journal of Neuroscience (January 2024). (The senior author, Jeroen Dudink, is a well-established leader in the field.) Stimulated by the experimental and human studies reviewed earlier, this study “aimed to determine the potential of sleep as an early predictor for subsequent white matter development in preterm infants.” To overcome the deficiencies of conventional sleep studies, after an initial study of infants for multiple consecutive hours by visual sleep scoring by trained sleep observers, the group was able to utilize heart and respiratory rates as routinely monitored in the NICU to develop a machine learning-based automated sleep stage classifier. This automated classifier subsequently was applied to a cohort of 58 preterm infants to extract sleep percentage over 5-7 consecutive days from 29-32 weeks of postmenstrual age. Excluded from the cohort were infants with major congenital malformations and such overt brain injury as grade III IVH or cystic periventricular leukomalacia. Also excluded were infants on mechanical ventilation. The study infants then had an MRI scan at term equivalent age on a clinical 3-Tesla scanner to assess volumetric tissue segmentation.

Principal Finding. The results were very interesting. The infants spent most of their time asleep (mean percentage of 90% per 24 hours), and on average, time in active sleep and in quiet sleep were approximately equal.¹ Notably, higher active sleep percentage was significantly associated with larger white matter volume at term after adjusting for potential confounding covariates (standardized regression coefficient, 0.31; 95% CI, 0.09, 0.53; adjusted P-value 0.021).

Data Implications. The data raise the critical question concerning the basis for increased cerebral white matter volume in the infants with higher active sleep percentages. Cerebral white matter volume during the last 10 weeks of brain development in the premature infant increases nearly 80%, and approximately 80% of this increase is unmyelinated white matter.^15,16 The latter is composed principally of rapidly developing axons and premyelinating oligodendrocytes. Indeed, the period of observation of the sleep parameters in the study of Wang et al.,¹ 29 to 32 weeks postmenstrual age, is the time of onset of ensheathment of developing axons by immature oligodendrocytes in human cerebral white matter.¹⁷ This ensheathment is important for the subsequent development of the abundant growing axons in cerebral white matter at this time.⁷ In turn, the resulting axonal activity stimulates the further development of these ensheathing immature oligodendroglia.¹⁸ Analysis of developing cerebral white matter during this period with GAP-43, a marker of growing axons, shows marked expression in the third trimester.^19,20 Anatomical studies have elucidated the details of thalamacortical, commissural cortical and cortico-cerebral axonal development during this period.^7,21,22 Similarly, state-of-the-art diffusion-based MRI study of human fetal brain in utero shows changes consistent with exuberant axonal development during the last trimester of gestation, although the regional changes vary in magnitude and timing.²³

Notably, during the developmental period just described, accompanying these changes in cerebral white matter are increases in cerebral cortical surface area and gyrification.²⁴ Anatomical and diffusion MRI studies are indicative of marked cortical dendritic and synaptic development also during this time.⁷ Additionally, functional MRI studies show the onset of cortical neuronal activation and connectivity after visual, auditory and somatosensory stimulation at this time.²⁵ Assessment of these individual events in future studies of the role of active sleep in premature infants in subsequent brain development will be of great interest.

Which of the developmental processes just reviewed could underlie the increase in cerebral white matter volume related to time in active sleep in the study of Wang et al.?¹ Based on the likelihood that the increase in cerebral white matter volume during the 30-40 week gestational period is related largely to axonal development, an important possibility is that active sleep in some way leads to enhanced axonal development. One critical driving force for axonal development during this period from 30-40 weeks is the development of synaptic connections in cerebral cortex by terminals of axons coursing through cerebral white matter from thalamus, subplate, and other cortical sites via commissural-cortical and cortico-cortical connections (see earlier). These events are especially prominent in the period from 30-40 weeks’ gestation.⁷ Studies in animal models (see earlier) indicate that active sleep is important in synaptic development and maintenance. Taken together, the findings suggest that cerebral white matter volume may increase with active sleep because of an increase in axonal development stimulated in an activity-dependent manner by the synaptic effects of this sleep state. As noted earlier, the period of the study, 29-32 weeks postmenstrual age, is the onset of pre-oligodendroglial ensheathment of axons, a process critical for axonal function.⁷ Future studies of cerebral connectivity in the context of active sleep will be important.

Clinical Implications

The authors of the interesting report by Wang et al.¹ conclude that the discovery of a positive association between the percentage of machine learning-derived active sleep during the preterm period and white matter volume at term-equivalent age: (1) “provides new insights into the role of active sleep in early human brain development, confirming and extending findings from animal research,” and (2) “further indicates the potential benefit of integrating automated sleep monitoring into routine caregiving practices in NICU settings.”¹ I agree with both of these conclusions.

Concerning caregiving practices, a review of studies assessing interventions to promote “sleep” in NICU settings identified fourteen, of which 10 were RCT.²⁶ Approaches studied include kangaroo care, gentle human touch, different sleep surfaces, sound, cycled light, and LED light. None of the studies showed marked benefit, although methodological concerns, including the means of assessment of sleep state, render comparisons difficult. One study utilizing an instrument that creates a sound effect similar to the sound of moving fluids did show an increase in time spent in active sleep.²⁷ The authors of this review concluded that there is insufficient evidence to recommend any new intervention to promote neonatal sleep in the NICU.²⁶ However, with the recent work of Wang et al.¹ an important breakthrough may be apparent. Automated sleep monitoring in the NICU could allow caregivers to carry out various daily interventions in such a way as to safeguard active sleep and, presumably, to promote growth of cerebral white matter and the likely anatomical correlates describe earlier.

Currently, rational changes in caregiving would be difficult if sleep assessment is carried out by observation by individuals not highly trained in such assessment. REM sleep in the premature infant often can be difficult to detect because of its close resemblance to an awake state, a resemblance that results from the spontaneous activity generated during the sleep state (Jereon Dudink, personal communication). Thus, as communicated to me by Dr. Dudink, caretakers “will more likely disturb the infants during this sleep state than during quiet sleep. … Our extended monitoring indicates that sleep is disrupted many times in an NICU and that in a less intrusive environment, the duration of active sleep in preterm infants increases, underscoring the profound impact of the NICU setting on their sleep architecture.” Thus, the value for the continuous assessment of sleep state afforded by the approach described by Wang et al.¹ is particularly apparent.

A final caveat—it should be noted that the role of non-REM sleep during the preterm period in promoting brain development is unclear. Available data suggest that non-REM sleep is related more to later brain development, rather than to that occurring during the NICU period for preterm infants.³ More research is needed on the issue of non-REM sleep in preterm infants and brain development.

Conclusion

The methodological advances concerning sleep monitoring and the correlation with enhanced cerebral white matter development, as shown by MRI described here,¹ could lead to caregiving practices that enhance specific sleep behavior in the preterm infant, promote cerebral white matter development, and perhaps most importantly, improve neurological outcome. My view is that such improved sleep management, carefully devised, could prove to be a safe, readily applied, and beneficial management approach. Future research that includes assessment of cerebral cortical and white matter microstructure by advanced diffusion-based MRI methods^28,29 and of subsequent neurodevelopmental outcomes will be of particular interest.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

1. Wang X, de Groot ER, Tataranno ML, et al.: Machine Learning-Derived Active Sleep as an Early Predictor of White Matter Development in Preterm Infants. J Neurosci 44, 2024. DOI: 10.1523/JNEUROSCI.1024-23.2023
2. Lokhandwala S, Spencer RMC: Relations between sleep patterns early in life and brain development: A review. Dev Cogn Neurosci 56:101130, 2022. DOI: 10.1016/j.dcn.2022.101130
3. Knoop MS, de Groot ER, Dudink J: Current ideas about the roles of rapid eye movement and non-rapid eye movement sleep in brain development. Acta Paediatr 110:36-44, 2021. DOI: 10.1111/apa.15485
4. Frank MG, Issa NP, Stryker MP: Sleep enhances plasticity in the developing visual cortex. Neuron 30:275-87, 2001. DOI: 10.1016/s0896-6273(01)00279-3
5. Blumberg MS, Dooley JC, Tiriac A: Sleep, plasticity, and sensory neurodevelopment. Neuron 110:3230-42, 2022. DOI: 10.1016/j.neuron.2022.08.005
6. Dang-Vu TT, Desseilles M, Peigneux P, Maquet P: A role for sleep in brain plasticity. Pediatr Rehabil 9:98-118, 2006. DOI: 10.1080/13638490500138702
7. 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
8. Del Rio-Bermudez C, Blumberg MS: Sleep as a window on the sensorimotor foundations of the developing hippocampus. Hippocampus 32:89-97, 2022. DOI: 10.1002/hipo.23334
9. Arditi-Babchuk H, Feldman R, Eidelman AI: Rapid eye movement (REM) in premature neonates and developmental outcome at 6 months. Infant Behav Dev 32:27-32, 2009. DOI: 10.1016/j.infbeh.2008.09.001
10. Bennet L, Walker DW, Horne RSC: Waking up too early – the consequences of preterm birth on sleep development. J Physiol 596:5687-708, 2018. DOI: 10.1113/JP274950
11. Freudigman KA, Thoman EB: Infant sleep during the first postnatal day: an opportunity for assessment of vulnerability. Pediatrics 92:373-9, 1993.
12. Shellhaas RA, Burns JW, Hassan F, et al.: Neonatal Sleep-Wake Analyses Predict 18-month Neurodevelopmental Outcomes. Sleep 40, 2017. DOI: 10.1093/sleep/zsx144
13. Werth J, Atallah L, Andriessen P, et al.: Unobtrusive sleep state measurements in preterm infants – A review. Sleep Med Rev 32:109-22, 2017. DOI: 10.1016/j.smrv.2016.03.005
14. Georgoulas A, Jones L, Laudiano-Dray MP, et al.: Sleep-wake regulation in preterm and term infants. Sleep 44, 2021. DOI: 10.1093/sleep/zsaa148
15. 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
16. de Vries LS, Volpe JJ. Specialized neurological studies. Chapter 13. 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; in press.
17. Back SA, Luo NL, Borenstein NS, et al.: Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 21:1302-12, 2001. DOI: 10.1523/JNEUROSCI.21-04-01302.2001
18. Gibson EM, Purger D, Mount CW, et al.: Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344:1252304, 2014. DOI: 10.1126/science.1252304
19. Haynes RL, Borenstein NS, Desilva TM, et al.: Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol 484:156-67, 2005. DOI: 10.1002/cne.20453
20. Haynes RL, Volpe JJ. Organizational events. Chapter 7. 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; in press.
21. Kostovic I, Judas M, Rados M, Hrabac P: Laminar organization of the human fetal cerebrum revealed by histochemical markers and magnetic resonance imaging. Cereb Cortex 12:536-44, 2002. DOI: 10.1093/cercor/12.5.536
22. Kostovic I, Jovanov-Milosevic N: The development of cerebral connections during the first 20-45 weeks’ gestation. Semin Fetal Neonatal Med 11:415-22, 2006. DOI: 10.1016/j.siny.2006.07.001
23. Wilson S, Pietsch M, Cordero-Grande L, et al.: Development of human white matter pathways in utero over the second and third trimester. Proc Natl Acad Sci U S A 118, 2021. DOI: 10.1073/pnas.2023598118
24. 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
25. Neil JJ, Volpe JJ. Specialized neurological studies. Chapter 10. In: Volpe JJ, Inder TE, Darras BT, de Vries LS, du Plessis AJ, Neil JJ, Perlman JM, editors. Volpe’s Neurology of the Newborn. 6th ed. Philadelphia PA: Elsevier; 2015. p. 222-54.
26. van den Hoogen A, Teunis CJ, Shellhaas RA, et al.: How to improve sleep in a neonatal intensive care unit: A systematic review. Early Hum Dev 113:78-86, 2017. DOI: 10.1016/j.earlhumdev.2017.07.002
27. Loewy J, Stewart K, Dassler AM, et al.: The effects of music therapy on vital signs, feeding, and sleep in premature infants. Pediatrics 131:902-18, 2013. DOI: 10.1542/peds.2012-1367
28. Raffelt DA, Tournier JD, Smith RE, et al.: Investigating white matter fibre density and morphology using fixel-based analysis. Neuroimage 144:58-73, 2017. DOI: 10.1016/j.neuroimage.2016.09.029
29. Batalle D, O’Muircheartaigh J, Makropoulos A, et al.: Different patterns of cortical maturation before and after 38 weeks gestational age demonstrated by diffusion MRI in vivo. Neuroimage 185:764-75, 2019. DOI: 10.1016/j.neuroimage.2018.05.046

January, 2024

ERYTHROPOIETIN AND THE HEAL STUDY: TIMING ISSUES

Introduction

The recently reported studies^1-3 derived from the High-Dose Erythropoietin (EPO) For Asphyxia and Encephalopathy (HEAL) study raise two important questions relevant to timing. The first of these questions concerns the time of occurrence of the hypoxic-ischemic injury leading to hypoxic-ischemic encephalopathy (HIE), and the second, the optimal duration of treatment with EPO in the context of HIE. The HEAL study was a multicenter, double-blind, randomized, placebo-controlled trial involving 501 infants born at gestational ages of 36 weeks or more with moderate or severe HIE, to receive EPO or placebo in conjunction with standard therapeutic hypothermia (begun within 6 hours after birth and continued for 72 hours). EPO was administered before 26 hours of age and at 2, 3, 4 and 7 days of age. The primary outcome was death or neurodevelopmental impairment of any severity at 22 to 36 months of age. The incidence of death or neurodevelopmental impairment was similar in both groups (52% in the EPO group, 49% in the Placebo group).

Time of Occurrence of Hypoxic-Ischemic Injury

Concerning the time of occurrence of the hypoxic-ischemic insults leading to HIE, in the HEAL study MRI findings at a median age of approximately 5 days (4.9 days) were interpreted to indicate that brain injury was “acute only” in 23%, “subacute only” in 22%, and “acute and subacute” in 21% (chronic injury was identified in only 2%).³ Acute lesions were defined as foci of restricted diffusion (i.e., reduced ADC) with or without corresponding signal abnormalities on T1w and T2w MRI. Subacute lesions were defined as signal abnormalities on T1w and/or T2w MRI without corresponding diffusion restriction. Acute and subacute lesions were defined by MRI features of both types. The surprising finding of subacute injury in 43% of infants deserves further consideration.

The relatively high proportion of subacute injury reported in the HEAL study should be viewed in the context of (a) previous neuropathological data and (b) the MRI findings utilized to conclude injury was subacute. In general, my view is that the gold standard for assessment of timing of neonatal injury is the neuropathology, although in this era of rare postmortem studies, we must rely on less direct measures of pathology, such as neuroimaging.

Concerning neuropathological data, in the largest reported series of infants with HIE studied postmortem, all 45 infants showed cellular evidence of acutely evolving lesions thought to be of “hypoxic-ischemic origin.”⁴ (The principal neuronal changes following an acute, injurious, hypoxic-ischemic insult are, after 24 to 36 hours, marked eosinophilia of neuronal cytoplasm [“red dead neuron”], condensation [pyknosis] or fragmentation [karyorrhexis] of nuclei and cellular edema, followed in the next 72 hours by the appearance of macrophages/activated microglia and still later by hypertrophic astrocytes.⁵) In a later series, utilizing staining for different stages of activated microglia/macrophages, a similar preponderance of acute injury was observed (only two of 23 cases showed changes consistent with onset of the hypoxic-ischemic event “2-3 days before birth”).⁶

Concerning the MRI data to identify “subacute” injury in the HEAL study, diffusion measures were of central importance.³ MRI was performed at a median age of 4.9 days. Acute injury was determined by the MRI findings noted earlier. Previous work by Bednarek et al. in their landmark study of the time course of diffusion changes in HIE had shown that in infants with HIE treated with hypothermia, “pseudonormalization” occurs by approximately 10 days,⁷ as opposed to normothermic infants with HIE in whom pseudonormalization occurs by approximately 6 days.⁸ Utilizing data for hypothermic infants, as noted earlier, Wisnowski et al. found overall that in the HEAL population 23% exhibited only acute, 22% only subacute, and 21% both acute and subacute injuries.³ However, considering only the subacute injuries, it is noteworthy that of the 93 examples 83 had moderate HIE and only 10, severe HIE. This preponderance of moderate HIE in the subacute group may be important, because as reported by Bednarek et al.⁷, at five days of age, the differences between the mean diffusivity (MD) ratio of 1.0 (“pseudonormalization”) and the values obtained in the moderate HIE group are relatively small (see Fig. 2B in Bednarek et al.).⁷ The small differences raise the possibility that “subacute” injury in the HEAL study could be overestimated. Confirmation of the MRI findings reported by Wisnowski et al.³, especially in infants with moderate HIE, will be important.

Concerning the implications of “subacute injury” for timing of the injurious hypoxic-ischemic insult(s) operative in the infants with HIE, Wisnowski et al.³ “speculate that the onset of injury was likely incurred days before birth.” Although I remain uncertain about the magnitude of subacute injury in HIE, the data raise the question of what role placental factors might play in pathogenesis of such injury. In the HEAL study, a complete placental pathological examination was available for 321 of the 500 participants (64%).¹ Acute abnormalities were noted in 20%, chronic abnormalities in 21%, and both acute and chronic abnormalities in 43%. Thus, fully 84% of placentas exhibited abnormalities. Lesions considered high risk were observed in 21% of placentas, and most of these were chronic abnormalities, such as maternal vascular malperfusion, fetal vascular malperfusion, and chronic villitis. Similar lesions have been reported in smaller series of HIE.^9-13  Although histological chorioamnionitis was relatively common (39%), only 2% were accompanied by a high-grade fetal inflammatory response and therefore considered high risk.

The prominence of chronic placental abnormalities in the HEAL population is notable, particularly because such disturbances may prime the brain to sustain hypoxic-ischemic brain injury in the peripartum period.^12,14 It is noteworthy, in this regard, that the frequency of high-risk chronic abnormalities (approximately 20%) is similar to the frequency of “subacute injury” (22%) defined by the MRI studies discussed earlier.³ It would be of great interest if an analysis of the relations between specific placental findings and MRI analyses could be carried out in individual patients in the HEAL population.

Also consistent with the notion that placental factors can be important in pathogenesis of some cases of HIE and, thereby, the response to postnatal EPO is the result of an earlier EPO trial by Wu and colleagues.¹³ In those cases with available placental pathology reports (n=35), EPO was associated with less brain injury than in nontreated infants only in those whose placentas exhibited no chronic histologic abnormalities.¹³ Thus, it is possible that in the EPO-unresponsive infants overt placental disturbance led to the hypoxic-ischemic brain injury that occurred prior to the onset of EPO therapy or that was set in motion prior to the onset of EPO therapy. More data are needed concerning placental structure and physiology in pregnancy, especially in relation to neonatal HIE. Recent advances in the application of sophisticated MRI methods for such study suggest that important insights may be gained in vivo in the near future.^15,16

Timing of Treatment with EPO

The second question relating to timing from the results of the HEAL study concerns the duration of treatment with EPO. Is seven days of treatment sufficient to determine whether EPO has benefit for management of HIE? The study’s conclusion is that this duration of treatment does not lead to clear benefit re: death or neurodevelopmental impairment at 22 to 36 months of age. Should this well-designed, large study be the final word on any value of EPO in management of infants with HIE? This issue, including the risk/benefits of longer treatment, is addressed carefully by Wu et al. in the Discussion section of the article in the New England Journal of Medicine describing the trial.² (In addition to the apparent lack of benefit on outcomes, the mean number of serious adverse effects per child was higher in the EPO group than in the placebo group.) In experimental models, EPO is well-established to have benefit in neuroprotection in primary, latent, and secondary phases of hypoxic-ischemic injury occurring over the first several days after the insult.¹⁷ This neuroprotection includes antiexcitotoxic, antioxidant, and antiapoptotic effects (among others).¹⁸ Many of these beneficial effects of EPO are shared by hypothermia, and as suggested by Wisnowski et al.³, it is possible that a substantial proportion of hypoxic-ischemic lesions are treated successfully by hypothermia, thereby shifting the distribution of residual lesions apparent after hypothermia to include a higher proportion of less responsive lesions.

Of greatest importance in this context, however, EPO has been shown in experimental models to have important neurorestorative effects and, critically, such beneficial effects can be demonstrated with delayed EPO treatment. The neurorestorative potential of EPO in developing animals subjected to hypoxia-ischemia (stroke model) was shown initially by Gonzalez et al.^19,20 Treatment was begun in the days following the production of stroke. The mechanisms of benefit included stimulation of neurogenesis and diminution of reactive astrocytosis. Subsequent work with the stroke model, which included immediate and delayed EPO treatment, showed enhanced neurogenesis and oligodendrogliosis. Other studies in hypoxic-ischemic models in developing animals have shown that EPO leads to decreased microglial activation, diminished oligodendroglial injury, and improved myelination.²¹ Beneficial effects on angiogenesis have also been shown. The first demonstration of the benefit of only delayed EPO therapy involved a stroke model (P10 rats), in which EPO therapy was instituted at P17, P20 and P23, a long delay when comparing rat and human brain development.²² In neonatal brain injury, neuronal development, axonal outgrowth, and oligodendroglial development can be impaired by the prolonged action of reactive astrocytes and activated microglia.²³ At least in experimental models, EPO appears to have the potential to interrupt these effects when administered long-term, after the acute periods of injury. Clearly, because in human brain these developmental processes are occurring over many weeks to months, prolonged therapy with EPO could be needed and potentially could be beneficial. However, serious safety and risk-benefit issues require very careful consideration before controlled study of such an approach could be undertaken.

Conclusion

To conclude, the HEAL study has raised very important issues relating to timing of hypoxic-ischemic injury and timing of EPO therapy. My view is that the EPO story concerning the infant with HIE, hopefully, hasn’t finished and will add other important chapters.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

1. Chalak L, Redline RW, Goodman AM, et al.: Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr 237:190-6, 2021. DOI: 10.1016/j.jpeds.2021.06.023
2. Wu YW, Comstock BA, Gonzalez FF, et al.: Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med 387:148-59, 2022. DOI: 10.1056/NEJMoa2119660
3. Wisnowski JL, Monsell SE, Bluml S, et al.: Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial. Dev Neurosci, 2023. DOI: 10.1159/000534618
4. Cowan F, Rutherford M, Groenendaal F, et al.: Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 361:736-42, 2003. DOI: 10.1016/S0140-6736(03)12658-X
5. Kinney HC, Volpe JJ. Hypoxic-ischemic injury in the term infant: neuropathology. Chapter 18. In: Volpe JJ, inder TE, Darras BT, de Vries LS, du Plessis AJ, Neil JJ, Perlman JM, editors. Volpe’s Neurology of the Newborn. 6th ed. Philadelphia PA: Elsevier; 2018. p. 484-99.
6. Alderliesten T, Nikkels PG, Benders MJ, et al.: Antemortem cranial MRI compared with postmortem histopathologic examination of the brain in term infants with neonatal encephalopathy following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 98:F304-9, 2013. DOI: 10.1136/archdischild-2012-301768
7. Bednarek N, Mathur A, Inder T, et al.: Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. Neurology 78:1420-7, 2012. DOI: 10.1212/WNL.0b013e318253d589
8. McKinstry RC, Miller JH, Snyder AZ, et al.: A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology 59:824-33, 2002. DOI: 10.1212/wnl.59.6.824
9. Vik T, Redline R, Nelson KB, et al.: The Placenta in Neonatal Encephalopathy: A Case-Control Study. J Pediatr 202:77-85 e3, 2018. DOI: 10.1016/j.jpeds.2018.06.005
10. Harteman JC, Nikkels PG, Benders MJ, et al.: Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury. J Pediatr 163:968-95 e2, 2013. DOI: 10.1016/j.jpeds.2013.06.010
11. Mir IN, Johnson-Welch SF, Nelson DB, et al.: Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am J Obstet Gynecol 213:849 e1-7, 2015. DOI: 10.1016/j.ajog.2015.09.072
12. Volpe JJ: Placental assessment provides insight into mechanisms and timing of neonatal hypoxic-ischemic encephalopathy. J Neonatal Perinatal Med 12:113-6, 2019. DOI: 10.3233/NPM-190270
13. Wu YW, Goodman AM, Chang T, et al.: Placental pathology and neonatal brain MRI in a randomized trial of erythropoietin for hypoxic-ischemic encephalopathy. Pediatr Res 87:879-84, 2020. DOI: 10.1038/s41390-019-0493-6
14. Inder TE, Volpe JJ. Pathophysiology: general principles. Chapter 13. In: Volpe JJ, Inder TE, Darras BT, de Vries LS, du Plessis AJ, Neil JJ, Perlman JM, editors. Volpe’s Neurology of the Newborn. 6th ed. Philadelphia PA: Elsevier; 2018. p. 325-88.
15. Hutter J, Slator PJ, Jackson L, et al.: Multi-modal functional MRI to explore placental function over gestation. Magn Reson Med 81:1191-204, 2019. DOI: 10.1002/mrm.27447
16. du Plessis AJ, Volpe JJ. Placental conditions with consequences for the fetal brain. Chapter 10. 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; in press.
17. Davidson JO, Gonzalez F, Gressens P, et al.: Update on mechanisms of the pathophysiology of neonatal encephalopathy. Semin Fetal Neonatal Med 26:101267, 2021. DOI: 10.1016/j.siny.2021.101267
18. Inder TE, Volpe JJ. Hypoxic-ischemic injury in the term infant: clinical-neurological features, diagnosis, imaging, prognosis, therapy. Chapter 20. In: Volpe JJ, Inder TE, Darras BT, de Vries LS, du Plessis AJ, Neil JJ, Perlman JM, editors. Volpe’s Neurology of the Newborn. 6th ed. Philadelphia PA: Elsevier; 2018. p. 510-63.
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