Temporal dynamics of neonatal hypoxic–ischemic encephalopathy injuries on magnetic resonance imaging

Abstract

Moderate to severe perinatal hypoxic–ischemic encephalopathy occurs in ~1 to 3/1000 live births in high-income countries and is associated with a significant risk of death or neurodevelopmental disability. Detailed assessment is important to help identify high-risk infants, to help families, and to support appropriate interventions. A wide range of monitoring tools is available to assess changes over time, including urine and blood biomarkers, neurological examination, and electroencephalography. At present, magnetic resonance imaging is unique as although it is expensive and not suited to monitoring the early evolution of hypoxic–ischemic encephalopathy by a week of life it can provide direct insight into the anatomical changes in the brain after hypoxic–ischemic encephalopathy and so offers strong prognostic information on the long-term outcome after hypoxic–ischemic encephalopathy. This review investigated the temporal dynamics of neonatal hypoxic-ischemic encephalopathy injuries, with a particular emphasis on exploring the correlation between the prognostic implications of magnetic resonance imaging scans in the first week of life and their relationship to long-term outcome prediction, particularly for infants treated with therapeutic hypothermia. A comprehensive literature search, from 2016 to 2024, identified 20 pertinent articles. This review highlights that while the optimal timing of magnetic resonance imaging scans is not clear, overall, it suggests that magnetic resonance imaging within the first week of life provides strong prognostic accuracy. Many challenges limit the timing consistency, particularly the need for intensive care and clinical monitoring. Conversely, although most reports examined the prognostic value of scans taken between 4 and 10 days after birth, there is evidence from small numbers of cases that, at times, brain injury may continue to evolve for weeks after birth. This suggests that in the future it will be important to explore a wider range of times after hypoxic–ischemic encephalopathy to fully understand the optimal timing for predicting long-term outcomes.

Introduction

Perinatal hypoxic-ischemic encephalopathy (HIE) is caused by lack of oxygen and hypotension leading to hypoperfusion around the time of birth (Stevenson et al., 2017; Russ et al., 2021; Molloy et al., 2023). Moderate to severe HIE can lead to death or survival with neurological damage, motor, behavioral, and language impairments, including cerebral palsy (Lai and Yang, 2011; Glass, 2018; Ristovska et al., 2022). The precise evolution of injury, particularly in the early stages of life after birth is in many cases only partially understood (Dijkhuizen et al., 1998; Kristián, 2004; Huang and Castillo, 2008; Goldman et al., 2022).

A wide spectrum of monitoring tools, including electroencephalography (EEG) (Obeid et al., 2017; Leen et al., 2019; Troha Gergeli et al., 2022), amplitude-integrated EEG (aEEG) (Steiner et al., 2022), cranial ultrasound (cUS) (Cizmeci et al., 2024), urine tests (Bersani et al., 2022), and blood tests (Martinello et al., 2017; She et al., 2023), are used to monitor the evolution of brain injury and to assess the long-term prognosis. Among these, magnetic resonance imaging (MRI) has particular value as it can directly assess changes in brain anatomy, and so non-invasively evaluate the pattern and severity of brain damage at specific times (Sanchez Fernandez et al., 2017) and their association with long-term outcomes (Twomey et al., 2010; Goergen et al., 2014; Obeid et al., 2017; Bobba et al., 2023). Different patterns of hypoxia–ischemia can lead to selective injury of the basal ganglia and thalami (Logitharajah et al., 2009) or of watershed regions such as the parasagittal cortex, or in the most severe cases, pancerebral injury (Gopagondanahalli et al., 2016).

Specific MRI sequences, including T1-weighted, T2-weighted, and diffusion-weighted imaging (DWI) have demonstrated utility in identifying specific types of injuries associated with HIE (Parmentier et al., 2022). The T1-weighted MRI sequence T1 provides the best view of tissue anatomy, while water (cerebrospinal fluid) is bright in T2 (Miller et al., 2003; Soun et al., 2017). DWI visualizes changes in the diffusion of water, for example, the reduced diffusion during cell swelling due to cell energy failure (Chenevert et al., 2006). Other sequences such as diffusion tensor imaging and arterial spin labeling (ASL) offer unique strengths in identifying ischemic biomarkers (Aracki-Trenkic et al., 2020; DiBella et al., 2022; Parmentier et al., 2022). For instance, a study using ASL MRI in a small cohort of 28 HIE-affected neonates treated with therapeutic hypothermia (TH) showed increased cerebral blood flow in the basal ganglia, thalami, and temporal lobes on day 4 compared to day 11 of life, highlighting the changes of perfusion over time in infants with HIE (Proisy et al., 2019).

Susceptibility-weighted imaging (SWI) is valuable for detecting blood oxygen changes and vascular abnormalities, such as hemorrhage and cerebral vascular malformations (Parmentier et al., 2022). Moreover, the severity of brain injury on DWI and ASL MRI correlates with EEG changes within the first day of life in neonates treated with TH for HIE and with mortality (P < 0.001), suggesting its potential as a prognostic tool (Obeid et al., 2017). Key questions in the field include the effects of the timing of MRI scans after HIE on their prognostic value (Charon et al., 2016; O’Kane et al., 2021) and of the first successful therapy for HIE, TH (Charon et al., 2016; O’Kane et al., 2021; Li et al., 2022; Shipley et al., 2022).

This systematic review critically examines recent studies of the effect of the timing of MRIs after TH for HIE on their prognostic value. By concentrating on “timing-focused” clinical MRI studies conducted alongside TH, we aimed to improve the understanding of outcome prediction for neonates affected by HIE.

Methods

For this literature review, we queried Google Scholar, Scopus, and PubMed. The search, conducted from November 2023 to January 2024, used the keywords “Hypoxic Ischemic Encephalopathy,” “HIE,” magnetic resonance imaging,” and “MRI” to identify relevant studies. We included manuscripts that were published in English in peer-reviewed journals globally from 2016 onwards and directly related to the paper’s focus.

Studies were chosen if they specifically addressed “timing” or established connections between MRI and other prognostic tools (e.g., EEG) or TH. Through an initial screening of abstracts, 49 papers were identified. Upon a thorough review, 20 articles were found to meet the specified scope for this review. In case of thematic overlap, the study with the highest quality and relevance was prioritized for inclusion. Multiple studies covering similar topics were included if they contributed valuable insights, ensuring a comprehensive review that closely aligned with our paper’s objectives. All selected papers were accessible online through these databases.

Results

Timing of magnetic resonance imaging scans

The studies summarized in Additional Table 1 address the role of timing in MRI-based assessments of HIE. While the optimal timing for prognostic MRI remains unknown, multiple studies (Charon et al., 2016; Shetty et al., 2019; O’Kane et al., 2021; Li et al., 2022; Troha Gergeli et al., 2022) highlight that the timing of MRI scans significantly affects the rate of detection of brain injuries and their prognostic values. Li et al. (2022) found that 61% of infants in their cohort exhibited brain injuries on MRI scans conducted around five days of age, with milder injuries observed in those scanned later (≤ 8 days). Troha Gergeli et al. (2022) similarly reported that MRI at 5 days after birth offered superior prognostic accuracy for long-term outcomes compared to other diagnostic methods, such as EEG. These findings indicate that MRI is a reliable technique for predicting long-term outcomes at 5 years.

Table 1.

MRI-based studies identified in this systematic review

Study	Research details	Scan time	Aim	Key findings
Shetty, 2019	• MRI: T1, T2-relaxation under spin tagging (TRUST) • Scanner: 3 Tesla Philips • 9 infants underwent TH • 6 Males, 3 Females • Infants age: 39±1.4 wk of gestation • Early scans at 18-24 h after initiating TH (23.5±5.2 h after birth), second scans at 5-6 d age post-TH	1d	To assess the feasibility of TRUST MRI for measuring venous oxygen saturation within 18-24 h after initiation of TH in neonates with moderate-to-severe HIE. Additionally, to provide a framework to compare parameters between early and post-hypothermia MRIs for providing insight into neonatal cerebral oxygen metabolism noninvasively.	• Results indicated values akin to healthy neonates in cerebral metabolic rate of oxygen, suggesting clinical potential, but noted reduced oxygen extraction fraction and cerebral metabolic rate of oxygen in severe HIE cases, hinting at injury severity markers. • Suggests need for larger prospective studies to validate findings
Li, 2022	• MRI’s: T1,T2,DWI • Scanner: 3 & 1.5 Tesla from GE, Siemens, and Philips • 142 infants with mild HIE, majority underwent TH • 91 Males, 51 Female • Infants age: ≥36 wk of gestation • Scans at ≤8 d of age	5d (median)	To investigate the timing and patterns of brain injury in newborn infants with mild HIE. Utilizing neonatal brain MRIs scored by two reviewers, the study sought to delineate the severity and timing of brain injury, specifically focusing on acute, subacute, and chronic lesions in this population.	• 61% of infants showed brain injury on MRI, with common injuries including watershed, deep grey, and punctate white matter lesions. 37% of infants had subacute lesions, emphasizing the need to address both acute and subacute injury mechanisms in developing neuroprotective therapies for mild HIE • The group that received TH observed a significantly lower frequency of watershed injury despite injury rates being the.
Negro, 2018	• MRI: T1, T2 weighted spin echo, DWI, ADC • Scanner: not specified • 80 infants, underwent TH • 43 Male, 37 Female • Infants age: 39.8 wk (SD 1.4) • Scans at 5 ± 3 d postnatal age	5d (median)	To evaluate the predictive capacity of a default panel of oxidative stress biomarkers for early identification of infants at high risk of HIE and their validation through correlation with MRI findings. Also to assess correlation of a range of biomarkers including Advanced Oxidation Protein Products (AOPP), Non-Protein-Bound Iron (NPBI), and F2-isoprostanes (F2-IsoPs) in blood samples with MRI scores for brain injury severity.	The potential of early oxidative stress biomarkers in blood samples, particularly AOPP, in identifying infants at risk of brain damage, offering avenues for early intervention to enhance long-term outcomes in neonatal HIE.
Wu, 2023a	• MRI; T1, T2, DWI, MRS • Scanner: 3 Tesla at 17 sites different vendors • 451 infants underwent TH • Gender ratio: not specified • Infants age: ≥36 wk of gestation • Scans at 4-6 d of age	5 days (median)	To investigate the association between neonatal brain MRI and MRS findings in infants with HIE and their neurodevelopmental outcomes at 2 yr of age.	• Severe brain injury on MRI were strongly associated with worse neurodevelopmental outcomes in HIE infants at 2 yr of age, associated with increased risk of death or neurodevelopmental impairment. • Mild or moderate brain injury on MRI showed comparable outcomes to those without apparent injury • MRI findings have limitations in discerning milder forms of impairment alone
Cizmeci, 2024	• MRI: T1, T2, DWI, proton & voxel point-resolved spectroscopy • Scanner: 1.5 Tesla SIGNA, GE Healthcare • 149 infants, undergoing TH • Gender ratio: not specified • Infants age: ≥35 wk of gestation • cUS: first 48-72 h of life • Scans within the first 7 d after birth	<7 days	To compare early cUS and post-rewarming brain MRI results in newborns with HIE and correlate these neuroimaging results with neurodevelopmental outcomes at 18 mon of age.	• severe HIE was associated with higher rates of abnormal white matter and deep grey matter hyper-echogenicity on cUS within the first 48 h after birth compared to mild HIE. • Severely abnormal brain MRI was significantly associated with adverse outcomes, with a 19.9-fold increased risk compared to infants with normal brain MRI. • The study highlights the complementary role of early cUS as a predictive tool for identifying brain injury, particularly in neonates with severe HIE, aiding in prognostication and clinical decision-making
Steiner, 2022	• MRI: T1, T2, DWI, single-voxel spectroscopy • Scanner: 1.5 Tesla Philips Healthcare • 56 patients: moderate to severe HIE, and TH for 72 h • 25 Male, 31 Female • Infants age: between 33.3 to 41.43 wk of gestation • aEEG and NIRS recorded for 102 h commencing with TH • Scans at a median of 8 d	8d (median)	To assess the predictive capability of combined neurophysiological including aEEG and Near-infrared spectroscopy (NIRS) with MRI for long-term prognosis at 2 years age in neonates with HIE.	Combined aEEG and MRI parameters showed superior predictive power for long-term outcome compared to individual measures. However, NIRS parameters did not effectively differentiate between favorable and adverse outcomes.
Bersani, 2022	• MRI: T1, T2 • Scanner: 1.5-T scanner (vendor not specified) • 74 perinatal asphyxia or intraventricular hemorrhage infants underwent TH • 28 Males, 46 Females • Infants age: >36 wk of gestation • Scans between 7 to 10 d from birth	7-10 d	To assess the predictive capacity of urinary S100B concentrations in infants with HIE receiving TH, compared to brain MRI patterns.	• Significant correlation found between elevated urinary S100B levels, particularly at the first void, and brain lesion severity on MRI • Early urinary S100B measurements (i.e., high S100B levels) are reliable predictors of brain injury, validated by MRI. • Supports potential inclusion in clinical protocols for identifying suitable candidates for TH treatment.
Sarioglu, 2022	• MRI:T1,T2,DWI, spin echo, ADC • Scanner: 1.5 Tesla Philips • 68 Neonates • 43 Males, 25 Females • Infants age: ≥37 wk of gestation • Scans at 5.9± 1.5 d from birth	<10 days	To evaluate the efficacy of the MRI-based texture analysis (TA) of the basal ganglia and thalami in differentiating moderate-to-severe HIE from mild HIE in neonates.	MRI-based TA of the basal ganglia and thalami allows for accurate diagnosis of moderate-to-severe HIE.
Chang, 2020	• MRI: DWI • Scanner: 3 Tesla Siemens Healthcare • 107 infants • 46 Males, 61 Females • Infants age: ≥35 wk of gestation • Scans within 10 d of life post TH	<10 days	To assess the distribution and burden of MRI changes as prognostic indicators of neurodevelopmental outcomes at 18-24 months in infants with HIE treated with TH, focusing on lesion volume, count, and location, particularly in the basal ganglia and thalamus.	• A significant association between abnormal neurodevelopmental outcomes at 18–24 months and greater involvement of total lesion count, increased size, and wider extension of injury in areas such as the basal ganglia and thalamus, as well as a trend towards more abnormal scans in brain MRI. • Utility of MRI assessments in guiding prognostication and early interventions for HIE infants, particularly in identifying those at risk for long-term disabilities.
Im, 2024	• MRI: T2, FLAIR • Scanner: not specified • 240 infants, 157 with HIE • 50 HIE Males, 107 Females • Infants age: ≥35 wk of gestation • Scans at a mean 10 d of life	>10 days (13.9 ± 4.9 days)	To evaluate volumetric brain changes in HIE-impacted infants, particularly focusing on brain stem volume reduction and ventricular enlargement as potential biomarkers for severe HIE and adverse long-term neurodevelopmental outcomes at 18-24 months.	• Infants with TH-treated HIE, despite clinically manifested normal neurodevelopment at 18-24 months, exhibited a significant reduction in brainstem volume and an increase in ventricle size. • Authors indicate the necessity for extended follow-up into school age to monitor potential developmental delays. • Brainstem volume reduction and ventricular enlargement identified as predictive markers for adverse outcomes, irrespective of therapeutic interventions.
O'Kane, 2021	• MRI: T1, T2, ADC images • Scanner: 3 Tesla GE Healthcare • 49 infants underwent TH. • 25 Male, 24 Female • Infants age: ≥35 wk' gestation • Early scans at <7 d (range 2-6d) and ≥7 days (range 7-25 d)	Early: 4 days Late: 10 days (medians)	To assess the agreement in brain injury findings between early and late MRI in newborn infants with HIE treated with TH and to compare the predictive ability of early versus late MRI for early neurodevelopmental outcomes at 15-30 months of age.	• Near-perfect agreement between early and late MRI. • Early MRI tended to identify severe injury more frequently than late MRI. • Early MRI scores showed greater consistency in predicting adverse outcomes compared to late MRI scores. • A single MRI conducted within the first week after birth is not only adequate but possibly more reliable for assessing brain injury and offering prognostic insights in this vulnerable population.
Charon, 2016	• MRI: T1, ADC • Scanner: 1.5 Tesla Siemens Healthcare • 38 infants undergone TH • 30 Male, 8 Female • Infants age: 36-41 wk + 6 d • Early scans at 4 days (2-6 d), late under 11 (7-25 d)	Early: 4 days Late: 11 days (medians)	To evaluate and compare the prognostic efficacy of early (≤ 6 d) and late (≥ 7 d) MRI in predicting adverse outcomes at 2 yr of age in term neonates with HIE treated with whole-body hypothermia.	• Early and late MRIs exhibited 100% sensitivity for adverse outcomes, with early MRI demonstrating higher specificity (96.3%) and positive predictive value (83.3%) compared to late MRI. • ADC measurements can make minimal contributions to prognostication beyond visual analysis. • Early MRI can guide post-hypothermia intensive care decisions, but caution is needed as normal early MRI results require subsequent late MRI evaluation for subtle injuries.
Trivedi, 2017	• MRI: T1,T2,DWI • Scanner: 1.5 & 3 Tesla Siemens Healthcare • 57 infants, underwent TH • 28 Males, 29 Females • Infants age: ≥35 wk of gestation • Early scans at 4±2 d, late 10±2 d	Early: 4 d Late: 10 d (medians)	To establish the validity of a qualitative MRI injury scoring system, weighted for deep nuclear grey matter injury and conducted within recommended time frames, through its association with neurodevelopmental outcomes at 18-24 mon in neonates with moderate to severe HIE treated with TH.	• Qualitative MRI injury scoring system can predict neurodevelopmental outcomes in moderate to severe HIE neonates at 18-24 mon. • Higher MRI injury scores are linked to worse cognitive, motor, and language outcomes. • Watershed injury also associated with poorer cognitive outcomes.
Beck, 2022	• MRI:T1,T2,DWI • Scanner: not specified • 520 infants • 78 Males, 242 Females • Infants age: ≥36 wk of gestation • Early scans at < 6 d, late scans 6-12 d	Early: <6 d Late: 6-12 d	To provide a comprehensive characterization of brain injuries in neonatal encephalopathy resulting from HI events through a descriptive analysis of MRI data from infants affected by HIE.	• Early MRI examinations, particularly within the first six days of life, identified a higher incidence of brain injuries, suggesting its potential utility for timely assessment and management of affected newborns. • Basal ganglia, white matter, and cortical injuries were predominant in neonatal encephalopathy, with the thalamus and periventricular white matter being the most affected sublocations.
Troha Gergeli, 2022	• MRI: T1,T2,DWI • Scanner: 1.5 & 3 Tesla Siemens Healthcare • 50 infants with moderate to severe HIE, Follow up at 5 yr • TH initiated under 6 h old • 26 Male, 24 Female • Infants age: ≥36 wk of gestation • MRI scans at 5.7±2.6 d, range 4 to 17 d • EEG at 14.3±7.2 d of age to minimize effects of drugs	6d (median)	To evaluate the predictive value of commonly used diagnostic methods in neonates with HIE treated with hypothermia, specifically assessing short-term neurodevelopmental outcome at 18 mon and long-term neurological outcome at 5 yr.	• MRI, especially with DWI within the first postnatal week, is the most accurate predictor of long-term neurological outcome in HIE infants treated with hypothermia. • EEG conducted around the second or third postnatal week also shows valuable prognostic accuracy for outcomes.
Proisy, 2019	• MRI: T1-weighted, T2-weighted, DWI, ADC • Scanner: 1.5 Tesla Siemens Healthcare • 28 infants with an acute perinatal event • TH initiated under 6 h old • 16 Male, 12 Female • Infants age: ≥36 wk of gestation • Early scans as close as possible to d 4 and late scans as close as possible to d 11 of life.	6 days (median)	To assess cerebral blood flow (CBF) alterations between d 4 of life and d 11 of life in neonates with HIE treated with hypothermia. Secondary objectives included comparing CBF values across different brain regions and between neonates with abnormal and normal findings on MRI.	• Significantly higher CBF values in basal ganglia and thalami and temporal lobes on d 4 compared to d 11. • Neonates with abnormal MRI findings displayed hyper-perfusion in cortical grey matter on d 4. • No significant CBF differences between normal and abnormal MRI neonates on d 11. • Early ASL imaging detects cerebral perfusion abnormalities in HIE neonates. • ASL imaging is useful for monitoring HIE evolution in neonates undergoing hypothermia.
Obeid, 2017	• MRI: T1-weighted, T2-weighted, DWI, ASL • Scanner: 1.5 Tesla GE Healthcare • 41 infants with moderate to severe HIE • TH initiated under 6 h old • 23 Male, 18 Female • Infants age: 39 weeks of gestation (range: 36-41 wk) • MRIs as soon as possible following rewarming, 3-6 d of life • EEG recordings started at 7 h (range 3-18 h)	4 days (median)	To investigate the utility of EEG recordings within the first day of life in newborns undergoing TH for HIE as a predictive tool for the severity of brain injury on MRI and mortality.	• Severity of EEG findings in the first day of life during TH correlates with brain injury on MRI post TH. • EEG findings correlate with mortality rates. • Early EEG assessment aids clinical decision-making
Jain, 2017	• MRI: T1, T2, DWI • Scanner: not specified • 78 infants, undergoing TH • Gender ratio: not specified • EEG: within the first 24 h of life, average 8.5 h of life • Infants age: not specified • Scans from the 2nd wk of life	7-14 days (within)	To evaluate and compare early EEG power and aEEG as predictors of MRI injury in neonatal HIE, with the goal of identifying infants at high risk for adverse outcomes despite receiving TH.	• Total EEG power shortly after TH initiation predicts moderate-severe MRI injury in encephalopathic infants. • Infants with EEG power below a certain threshold have higher odds of MRI injury. • EEG power could be useful for early stratification and identifying candidates for additional therapeutic interventions.

ADC: Apparent diffusion coefficient; aEEG: amplitude-integrated electroencephalography; AOPP: advanced oxidation protein products; ASL: arterial spin labeling; CBF: cerebral blood flow; cUS: cranial ultrasound; DWI: diffusion-weighted imaging; EEG: electroencephalography; F2- IsoPs: F2-isoprostanes; FLAIR: fluid-attenuated inversion recovery; GE: general electric (scanner vendor); HIE: hypoxic-ischemic encephalopathy; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NIRS: near-infrared spectroscopy; NPBI: non-protein-bound iron; S100B: S100 calcium binding protein B; SD: standard deviation; TA: texture analysis; TH: therapeutic hypothermia; TRUST: T2-relaxation under spin tagging.

Magnetic resonance imaging timing and therapeutic hypothermia

Several studies explored interactions between the timing of MRIs and TH (Charon et al., 2016; Shetty et al., 2019; O’Kane et al., 2021; Li et al., 2022). Charon et al. (2016) demonstrated that early MRI scans (≤ 6 days) using apparent diffusion coefficient (ADC) values had higher specificity and positive predictive value for adverse outcomes at 2 years of age in neonates treated with whole-body hypothermia, compared to later scans (7–25 days: median 10 days). O’Kane et al. (2021) compared early (< 7 days) and late (≥ 7 days) MRIs, and found overall agreement between the two, but with lower injury scores on the later MRIs. Examples of early and late scans from O’Kane et al. (2021) and Charon et al. (2016) are presented in Figures 1–3. Similarly, Li et al. (2022) also reported that early MRI scans within the first 8 days, particularly in infants treated with TH, provided more accurate prognostic information, notably a reduced incidence of watershed injury in infants who received TH. A recent study suggests that the optimal timing of MRI is between 4 to 6 days of life, before pseudo-normalization of DWI sequences (Machie et al., 2024). These reports suggest that if an early MRI is performed during hypothermia (within 1–3 days), a follow-up scan after rewarming is appropriate, as early imaging may not reveal the full extent of brain injury (Wisnowski et al., 2021; Machie et al., 2024). This two-step approach helps ensure a more accurate assessment of injury progression.

Figure 1.

Representative cases of T1, T2, and diffusion tensor imaging images with differing scores between early and later scans.

In patient A, the basal ganglia score has increased on day 4 (score = 3, indicating signal abnormalities in both the thalamus [white arrow] and basal ganglia [black arrow]) compared to day 10 (score = 1, indicating signal abnormality limited to the thalamus [white arrow]). Similarly, in patient B, basal ganglia injury has been more prominent on day 5 (score = 4, indicating extensive involvement with signal abnormalities in the thalamus and basal ganglia [white arrows] and white matter tracts [black arrows]) compared to day 9 (score = 2, indicating reduced signal abnormalities in the thalamus and basal ganglia [white arrows]). Reprinted with permission from O’Kane et al. (2021). ADC: Apparent diffusion coefficient.

Figure 3.

Exemplar case.

Caption as cited in the reference: (A–D) Female neonate, born at 39 weeks of gestation, who exhibited normal early magnetic resonance imaging (MRI), abnormal late MRI (moderate central lesions) and a favorable outcome. (A, B) Normal early imaging (day 5) at the level of the basal ganglia with axial diffusion-weighted imaging (A), and axial T2-weighted imaging (B); posterior limb of internal capsule signal intensity was normal (arrows). (C, D) Late imaging (day 12) at the same level with mild hyperintensity on axial T1-weighted images within the thalami (bottom arrows) and normal hyperintensity within the posterior limb of internal capsule (top arrows) (C) and axial T2-weighted images with hyperintensity within the thalami (bottom arrows) and the posterior part of the lentiform nuclei (top arrows) (D). Reprinted with permission from Charon et al. (2016).

Figure 2.

Exemplar case.

Caption as cited in the reference: (A–F) Male neonate, born at 4 weeks and 6 days of gestation exhibited diffuse injuries on early magnetic resonance imaging (MRI) on day 4 (A–C) and late MRI on day 9 (D–F) and a favorable outcome as shown by normal neurological assessment at 23 months and a global developmental quotient of 97. (A, B) Early diffusion-weighted imaging and corresponding apparent diffusion coefficient maps with hyperintensity in the hippocampi (bottom arrows), the thalami (top arrows) (A), and the perirolandic, frontal and parietal white matter (arrows) (B). (C) Axial T1-weighted imaging with hyperintensity in the bilateral insular cortex (arrows). (D) Axial T2-weighted images on late MRI with mild hyperintensity in the thalami (arrows). (E, F) Axial T1-weighted images on late MRI with normal hyperintensity within the posterior limb of internal capsule (arrows), mild intraventricular hemorrhage in the left occipital ventricular horn (*) (E) and hyperintensity within the insular cortex (arrows) (F). Reprinted with permission from Charon et al. (2016).

These findings collectively suggest that early MRI scans at 4 to 6 days of life are critical for assessing the neuroprotective effects of TH and for informing prognosis in HIE.

Alternative imaging techniques

Beyond conventional MRI sequences, some studies (Ancora et al., 2013) have explored less-utilized methods, including T2-relaxation under spin tagging (TRUST) scanning (Shetty et al., 2019), proton and voxel point-resolved spectroscopy (Cizmeci et al., 2024), single voxel spectroscopy (Steiner et al., 2022), FLAIR (Im et al., 2024), spin echo (Negro et al., 2018; Sarioglu et al., 2022), and apparent diffusion coefficient (Charon et al., 2016; O’Kane et al., 2021; Sarioglu et al., 2022). These methods have demonstrated potential in the diagnosis and prognostic assessment of HIE, suggesting that they could complement traditional MRI. For example, T2-relaxation under spin tagging scanning, particularly in very early MRI scans (< 1 day), has shown promise for non-invasive assessment of cerebral oxygen metabolism in HIE (Shetty et al., 2019), potentially revealing subtle differences in injury severity that could inform therapeutic decision-making early in the neonate’s care.

Overall, the evidence reviewed here highlights the complex interplay between MRI timing, specific MRI techniques, underlying HIE-related brain injury, and therapeutic interventions like TH, which collectively influence how quickly neonatal HIE evolves and its ultimate prognosis. The findings across these studies address the necessity of timely and precise diagnostic approaches to enhance prognostic accuracy and improve outcomes for infants with HIE.

Discussion

Evolution of brain injury post–hypoxic-ischemic encephalopathy and the role of magnetic resonance imaging

It is well established that brain injury following perinatal HIE evolves over hours, days, and weeks, necessitating careful assessment at multiple time points (Wachtel et al., 2019). MRI is now indispensable in evaluating the extent and localization of HIE-induced injuries, despite challenges such as cost and timing. This review addresses the critical connection between the timing of MRI scans after birth and the evolution of injury, highlighting variability in MRI timing across studies, which reflects the nuanced progression of HIE in the early stages (Steiner et al., 2022; Troha Gergeli et al., 2022). This variability exposes gaps in the literature that hinder a holistic understanding of the progression of HIE when relying solely on MRI (Bersani et al., 2022; Steiner et al., 2022; Troha Gergeli et al., 2022; Cizmeci et al., 2024).

Optimal magnetic resonance imaging timing and its controversies

This analysis suggests that while the optimal timing for prognostic MRI remains unclear, meaningful biomarkers can be captured within the first week of life. Despite this, there is still a lack of consensus on precise timing due to disparate scan times across studies (Parmentier et al., 2022). The studies reviewed here reported a wide range of timing, from as early as 23.5 ± 5.2 hours after birth (Shetty et al., 2019) to as late as 25 days (Charon et al., 2016; O’Kane et al., 2021). While there is general agreement that infants should receive at least one scan within the first week, the diversity in scan times reflects the complex considerations in clinical practice. Parmentier et al. (2022) advocate for MRI within 4–5 days post-birth, whereas guidelines from organizations such as the American Academy of Neurological Practice recommend a broader range of 2–8 days (Sanchez Fernandez et al., 2017), while the American College of Obstetricians and Gynecologists suggests imaging within the first 24–96 hours plus follow-up at 10 days (Schendel, 2014; Parmentier et al., 2022). Beck et al. (2022) emphasize that scans taken before and after 6 days can help to measure the evolution of injury over time.

Advanced imaging modalities and their prognostic value

Advanced imaging modalities such as diffusion tensor imaging, ASL, and magnetic resonance spectroscopy (MRS) have helped augment our understanding of the pathophysiology of HIE (Parmentier et al., 2022; Troha Gergeli et al., 2022). MRS is used to directly measure key brain metabolites (Sijens et al., 2017; Barta et al., 2018). Elevated lactate and reduced N-acetylaspartate levels in the first 2–9 days post-birth are associated with worse neurological outcomes, particularly cognitive and motor deficits (Sijens et al., 2017; Barta et al., 2018, 2022; Hung et al., 2024). Regarding mild HIE, while basal ganglia and thalamus N-acetylaspartate concentrations and Lactate/N-acetylaspartate peak area ratios are well-established MRS biomarkers for predicting 2-year outcomes in moderate and severe HIE (Lally et al., 2019), but a recent study shows that whole-body hypothermia may not significantly improve these biomarkers (Chalak et al., 2024). These findings highlight the potential of MRS to help improve understanding of the mechanisms of injury.

Early versus late magnetic resonance imaging scans: correlation with long-term outcomes

Studies comparing early MRI scans (typically ≤ 5 days) with late scans (usually 8–15 days) have confirmed a strong correlation between early and late imaging. These comparisons demonstrate 100% sensitivity and negative predictive value, with high specificity and positive predictive values—96.3% and 83.3% for early MRI, and 89.3% and 70% for late MRI, respectively (Charon et al., 2016). Additionally, there is substantial agreement between early and late watershed and basal ganglia/watershed scores, with a kappa value exceeding 0.883 (AUC: 0.8, P < 0.001) (O’Kane et al., 2021). Moreover, qualitative MRI injury scores observed in T1-weighted, T2-weighted, and DWI sequences repeatedly imaged within the first 6 days and around 10 days of life can provide predictive insights into neurodevelopmental outcomes at 18–24 months, particularly in the cognitive, motor, and language domains (Trivedi et al., 2017). Typically, DWI abnormalities peak around 3–5 days after birth showing delayed onset of the peak of mitochondrial failure and cell death (Parmentier et al., 2022; Troha Gergeli et al., 2022). A review by Bano et al. (2017) suggests that while early DWI is effective in detecting white matter injury, it may yield false negative results within the first 24 hours after birth. Recent research suggests that while early DWI MRI can reveal initial injury, the full extent of the damage may only become evident weeks later in some cases, highlighting the importance of later MRIs for accurately assessing the injury’s scope and its potential neurodevelopmental impact (Sotelo et al., 2024). While most studies suggest that early scans can serve as better predictors of long-term outcomes, there is evidence that some abnormalities found on late scans were not visible on early scans. This strongly suggests that there is a need for further investigation into the late progression of brain injury after HIE (Charon et al., 2016; O’Kane et al., 2021; Beck et al., 2022). Therefore, there are still challenges in accurately defining the severity and progression of HI injuries given the lack of systematic timing of MRI acquisition (Laptook et al., 2021).

Suggestion for the definition of “early” versus “late” scans

Based on this analysis, we propose adopting the terms “very early” (≤ 1 day), “early” (< 7 days), and “late” (≥ 7 days) MRI scans as standardized definitions to enhance consistency in future studies on HIE.

Predictive potential of multimodal approaches

The combination of neurophysiological monitoring and neuroimaging may improve prediction outcomes in neonates with HIE. EEG recordings within the first 24 hours after birth, combined with MRI acquired at 8 days in neonates with moderate to severe HIE, offered superior sensitivity and specificity compared to single-parameters for outcomes assessed at 2 years of age (Steiner et al., 2022). Additionally, early EEG findings (3–18 hours post-birth) in neonates treated with therapeutic hypothermia for HIE strongly correlate (P < 0.001) with the severity of brain injury observed in DWI and ASL MRI scans conducted shortly after rewarming (4–5 days post-birth) (Obeid et al., 2017). This suggests the potential of early EEG assessment to identify infants with HIE who will develop brain injury on MRI and/or have a high risk of death (Obeid et al., 2017). Another study has focused on the relationship between the size, volume, and location of lesions on MRI on day 5 of life in infants with mild HIE (Machie et al., 2021).

Emerging magnetic resonance imaging techniques and prognostic tools

Recent advances in MRI-based texture analysis show potential for diagnosing moderate-to-severe HIE in neonates by analyzing specific texture parameters from apparent diffusion coefficient, T1-weighted, and T2-weighted sequences acquired within the first 10 days after birth (Sarioglu et al., 2022). Additionally, newer imaging sequences such as susceptibility-weighted imaging (Haller et al., 2021; Parmentier et al., 2022) and FLAIR (Im et al., 2024) may have greater sensitivity for predicting subsequent brain lesions at later ages of 5 months to 2.5 years compared to conventional MRI (Bano et al., 2017). These technical developments highlight the importance of the continued development of MRI as a diagnostic tool in clinical practice (Sarioglu et al., 2022). We suggest that future efforts should specifically investigate the value of novel MRI sequences at different times after neonatal HIE to identify the optimal timing for capturing HIE-related markers in imaging and potential trajectories.

Limitations and future directions

The present review has highlighted the substantial challenges and limitations for studies on MRI imaging and HIE progression, including the difficulty of performing scans on high-risk infants requiring intensive care, and constraints on access to expensive MRI machines (Wu et al., 2023b). Moreover, the variability in scan times for different sequences makes it difficult to compare their optimal timing (Parmentier et al., 2022; Troha Gergeli et al., 2022). For example, the literature suggests that T1 and T2 images should be acquired in the second half of the week after birth, whereas DWI should be performed between 3–5 days of life (Troha Gergeli, 2022). Other research suggests that while MRI provides more comprehensive insights compared to cranial ultrasound, these neuroimaging techniques are not yet at a stage where we can use them to confidently exclude infants from follow-up (Wu et al., 2023a). There is also evidence that despite the wealth of information provided by neuroimaging in neonates affected by HIE, the clarity of the insights derived from these images may not always be sufficient to guide appropriate interventions (Peeples, 2018).

The key limitation of this analysis is the inconsistent timing of scans between studies. We suggest that a key area of future research should be to understand how the timing of MRI acquisition affects the appearance of injury, as this could enhance its prognostic value, particularly in cases of mild HIE where the definition is still the subject of debate (Li et al., 2022). Leveraging advancements in computer vision and machine learning technologies, for improved data acquisition, processing, and analysis, could further facilitate the automated detection of subtle image features and temporal variations in MRI data associated with neonatal HIE and outcomes. Additionally, exploring the potential benefits of combining MRI data with other prognostic tools, such as EEG, may offer valuable insights for optimizing clinical management.

Conclusion

In conclusion, while MRI remains a pivotal tool for understanding the evolution of HIE-related injuries, this systematic review highlights limitations in the literature, particularly concerning the variable timings of scans and the challenges associated with conducting studies in high-risk infants. These limitations emphasize the need for future “timing-focused” clinical or pre-clinical MRI studies, commencing as early as possible within a “day range” from birth, to offer a more comprehensive understanding of the later progression of brain injury after HIE and its correlation with outcomes. Nonetheless, this review supports the greater prognostic value of MRI within the first week of life in most cases compared to later scans. Its value may be increased by integrating it with other prognostic tools, such as EEG and cranial ultrasound to provide a more holistic perspective on HIE evolution and to enhance diagnostic accuracy. The ongoing advancements in imaging sequences, machine learning algorithms, and interdisciplinary approaches will undoubtedly contribute to refining our understanding of HIE and its evolving nature, enabling more accurate prognostication and informed therapeutic interventions. Overall, while MRI is a powerful tool for assessing HIE in neonates, further research across a broader range of times after HIE and the severity of HIE is needed to refine imaging protocols, the optimal timing of scans, and to enhance prognostic accuracy.

Additional files:

Additional file 1: Open peer review report 1 ^{(85.9KB, pdf)} .

Additional Table 1: MRI-based studies identified in this systematic review.

Funding Statement

Funding: This work was supported by a grant from the Health Research New Zealand (HRC) 22/559 (to AJG and LB).

Data availability statement:

All relevant data are within the manuscript and its Additional files.