Volumetric changes in brain MRI of infants with abnormal development who had Hypoxic-ischemic Encephalopathy and underwent therapeutic hypothermia

Volumetric changes in brain MRI of infants with abnormal development who had Hypoxic-ischemic Encephalopathy and underwent therapeutic hypothermia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Volumetric changes in brain MRI of infants with abnormal development who had Hypoxic-ischemic Encephalopathy and underwent therapeutic hypothermia Soo-Ah Im, Sae-Yun Kim, Hyun Mi Kang, Young-Ah Youn This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3310053/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Background Hypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40–60% of long-term morbidity. MRI is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18–24 months among HIE infants. Methods We retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for TH were a gestational age ≥ 35 weeks, a birth weight ≥ 1,800 g, and the presence of ≥ moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18–24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III. Results The study recruited a total of 240 infants between 2013 to 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded among the 107 TH-treated HIE infants. We grouped according to brain MRI findings; 33.6% (36/107) infants had normal or minimal lesions of brain MRI and 66.4% (71/107) had abnormal MRI findings. At 18–24 months, 31 of 107 infants (29.0%) had delayed neurodevelopment and 76 of 107 infants (71.0%) were normal in their neurodevelopmental stages. When comparing brain volumes between the normal control infants (n = 83) and the abnormal ND group at the corrected 18–24 months of age (n = 31) in the 107 TH -treated HIE group, abnormal ND group exhibited a significant reduction in brain stem volume and larger ventricular volume (p < 0.001). This observation was consistent when we regrouped the HIE infants according to severe brain MRI group who did not receive TH due to contraindications. Conclusion In addition to location of brain injury in MRI assessment, brain stem volume reduction accompanied by larger ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term neurodevelopmental outcomes among HIE infants who were treated with TH. MRI-volumetry hypothermia hypoxia-ischemia long-term outcomes seizures Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Hypoxic-ischemic encephalopathy (HIE) in neonates after perinatal asphyxia affects 1–8 per 1,000 live births and results in 15%~25% mortality; among infants who survive, 25% have permanent neurological sequelae [ 1 , 2 ]. Severe HIE has been implicated in cognitive, motor, behavior, and/or language impairments, which account for approximately 20% of life-long disabilities, such as cerebral palsy [ 3 ]. Currently, magnetic resonance imaging (MRI) allows observation of primary structural brain injury patterns and secondary sequelae in HIE patients, which is the standard of care imaging choice. Specifically, MRI can noninvasively detect perinatally acquired cerebral lesions associated with HIE and characterize lesion severity [ 4 – 7 ],which can be used to prognosticate patients and provide treatment [ 8 , 9 ]. Qualitative volumetric MRI studies have helped elucidate the potential short-term effects of hypothermia on the extent and pattern of cerebral injury following HIE and may predict the adverse neurodevelopmental (ND) outcomes[ 10 – 11 ]..The MRI National Institute of Child Health and Human Development (NICHD) is presently the most commonly used scoring system for HIE evaluation and has been shown to be a predictor for death and disability at 18–22 months following TH for HIE patients [ 12 ]. The NICHD score assesses the deep location of lesions in the basal ganglia, thalamus, and posterior limb of the internal capsule [ 13 ], which have been associated to abnormal motor outcomes [ 14 ]. Further, Miller et al. 6 observed that HIE patients with lesions in the basal ganglia and thalamus demonstrate the greatest impairment of motor and cognitive outcomes associated with cerebral palsy at 30 months. In addition to the location of injury assessment, brain MRI volume change can also be a marker of long-term neurological outcomes[ 6 , 14 ]. Therefore, it is possible that there is a similar relationship between disability and HIE lesion counts and volume for HIE patients. The purpose of this study is to evaluate changes in brain volume on MRI as a prognostic indicator of severe HIE and adverse ND outcomes among infants treated with therapeutic hypothermia (TH). Furthermore, the study additionally evaluated the location of injuries in correlation to adverse ND among HIE infants treated with TH. Materials and Methods 2.1. Subject Selection After approval of the institutional review board of Seoul St. Mary’s Hospital, The Catholic University of Korea (Seoul, Korea), we retrospectively identified a cohort of HIE patients between June 2013 and March 2017. Inclusion criteria were gestational age ≥ 35 weeks with a birth weight of ≥ 1,800 g who underwent TH. All patients received the same TH protocol, which is detailed in Appendix 1 . Exclusion criteria were HIE infants who were older than 6 h at the time of the assessment or those with other major congenital abnormalities, syndromes, or metabolic diseases. Infants with a birth weight of ≤ 1,800 g, a gestational age of ≤ 35 weeks of gestational age, overt bleeding, signs of infection, or those requiring ≥ 60% oxygen support, which may suggest persistent pulmonary hypertension, were also excluded from this study. The perinatal history and delivery events were recorded for all patients. At 18 ~ 24 months, infants returned for follow-up evaluations, at which time they completed the cognitive, language, and motor composites of the Bayley Scales of Infant and Toddler Development III and were evaluated by certified examiners. Children were considered as having developmental delay (DD) or abnormal development if their score was < 85. If the score was ≥ 85, their ND stage was normal. The study was approved by the Ethics Committee of Seoul St. Mary’s Hospital, The Catholic University of Seoul, Korea. The study recruited a total of 240 infants between 2013 to 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications (Ex. admitted after 6 hours of life, overt bleeding, signs of infection, or those requiring ≥ 60% oxygen support. etc). As a normal control group, normal born infants performed brain MRI for more detailed evaluation of possible anomaly (Ex,sellar abnormality in perinatal sonogram), cephalhematoma, asymmetric ventricle size…etc. Accordingly, the normal brain MRI were collected in 83 infants ( Fig. 1 ). 2.2. Imaging Methods and 3D Image assessment The brain MRI was performed on all 240 infants within at least 10 days of life (For the TH received infants, the brain MRI was performed after they were rewarmed and extubated from the ventilator which was also within a week of life). The MRI was categorized according to patterns of structural injury. One independent radiologist (ISA) was masked to the treatment and outcomes of the infants and reviewed the images for quality and acquired lesions. One specialized radiologist reviewed all images and classified them independently without knowing the clinical outcomes. For quantitative assessment (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume), MR images were uploaded to dedicated 3D workstation (Aquarius iNtuition, TeraRecon Inc., Durham, NC). Axial FLAIR and T2 MR images (Figs 2,3) were annoated by a technician (TE) using a previously described 3D program and the results were reviewed and confirmed by a pediatric radiologist (ISA). They were blinded to the clinical outcomes. Based on these annotations, volume metrics were extracted. The measured shape was confirmed by reconstruction in 3D, and an example is shown in Figs 4~7 . 2.4. Statistical Analysis Continuous variables are expressed as the means ± standard deviation (SD) and were compared with Student’s t -test. Continuous variables are displayed as the median with the interquartile range when variables were not normally distributed, and they were compared using the Wilcoxon rank sum test. All inferential statistical analyses were 2-tailed, with statistical significance defined as values of p <0.05. Statistical analyses were performed with SAS v9.4. Lesion feature calculations were performed using Python 3.5 programming language. Results 3.1. Demographic Characteristics of 107 TH-treated HIE infants Among the recruited 240 infants (83 normal control infants, 107 TH-treated HIE infants and 37 HIE infants who did not receive TH due to contraindications), we primarily evaluated the 107 TH-treated HIE infants. The TH-treated HIE group initially started with 120 infants; however, of these infants, two died before further studies (e.g., brain images) were performed. Another 11 patients were excluded in this study because brain MRI were not available for further analysis. As a result, 107 infants were analyzed for brain images as a TH treated HIE group (Fig 1) . Clinical evaluation was further proceeded among the 107 TH-treated HIE infants. We grouped according to brain MRI findings; 33.6% (36/107) infants had normal or minimal lesions of brain MRI and 66.4% (71/107) had abnormal MRI findings. At 18-24 months, those infants were evaluated for the ND assessment of the Bayley Scales of Infant and Toddler Development III by certified examiners; 31 of 107 infants (29.0%) had delayed ND and 76 of 107 infants (71.0%) were normal in their ND stages as in Fig 1. Descriptive clinical characteristics of abnormal vs normal brain MRI and abnormal vs normal ND groups were further assessed among the 107 TH-treated HIE infants as presented in Table 1 and 2. Generally, clinical characteristics were similar between the normal and abnormal MRI groups except for clinical and electro-graphical seizures ( p <0.001) which were significantly higher in the abnormal MRI group along with higher usage of seizure medication. Furthermore, a lower initial pH <7.0 was more common in the abnormal brain MRI group ( Table 1 ). When we regrouped the 107 TH-treated HIE infants according to long-term ND outcomes, we observed that 31 out of 107 infants (29.0%) showed delayed ND as shown in ( Table 2 ). The clinical characteristics were also similar as presented in Table 1 with significant increase in the occurrence of clinical seizures. 3.2 MRI NICHD Scoring System for ND Outcome at 18-24 Months At 18-24 months, 71.0% (76/107) of infants showed normal ND stages, 29.0% (31/107) exhibited abnormal ND stages. According to MRI NICHD Scoring System, more lesions involved in the basal ganglia and thalamus, or posterior limb of internal capsule as grouped in stages 2A and 2B, were significantly associated with abnormal ND outcomes at 18~24 months of age ( p <0.001). Ten (32.26%) infants in the abnormal ND group were in stage 2 A, involving BGT, PLIC, or ALIC involvement or watershed infarction without additional cerebral lesions. The stage 2B was only found in the abnormal ND group. The most severe stage for cerebral hemispheric devastation, stage 3, was not found in either group in this study ( Table 3 ). 3.3. Comparison of brain volumetric MRI findings; 107 TH -treated HIE group, 37 HIE group without TH and normal control group We compared the brain volumes between the normal control infants (n=83) and the abnormal ND group at the corrected 18-24 months of age (n=31) among the 107 TH -treated HIE group. The group with abnormal neurodevelopmental outcomes exhibited a significant reduction in brain stem volume and larger ventricular volume (p< 0.001) (Table 4). This observation was consistent when we regrouped the HIE infants according to severe brain MRI group who did not receive TH due to contraindications (Table 5). Discussion HIE in term or near-term infants occurs in 1-6/1000 live births which is often attributed due to perinatal hypoxic-ischemia[15]. More than half of untreated infants suffering from moderate to severe HIE are at risk of death or major disability. TH is reported to reduce the HIE induced mortality and adverse neurodevelopmental outcome targeting early mechanisms of injury by reducing cerebral metabolism, excitotoxic neurotransmitter accumulation, ATP depletion, oxygen and nitrogen free radical release, and lipid peroxidation of cell membranes [16-17]. With a growing interest in neuroprotection, as TH for HIE infants, it has become increasingly interested in the long-term neurodevelopmental outcomes among neonatal HIE survivors who can either have a normal long-term neurodevelopment or carry the most severe form of HIE as cerebral palsy (CP), resulting a wide variation of outcomes. MRI is a noninvasive method which is usually performed before discharge to visually assess perinatally acquired cerebral lesions associated with HIE[4,7], and the patterns and severity of lesions possibly providing a guide for detecting adverse outcomes[12,14]. In this study, we initially observed the relationship between an abnormal signal intensity in the basal ganglia and thalamus location which was a powerful predictor of severe HIE and adverse ND outcomes at 18~24 months of age (Table 3). We observed that more involvement of injury in areas of basal ganglia, thalamus defined as deep brain lesions according to MRI NICHD Scoring System were significantly associated with abnormal ND at 18–24 months of age. Many studies report that lesions in the basal ganglia and thalamus are usually consistent with a severe HIE, which may be graded as a severe acute hypoxic-ischemic insult [8,18]. Moderate and severe lesions in the basal ganglia and thalamus and severe white matter lesions are further associated with cerebral palsy [19]. Additionally, the correlation between the specific injury location and development of infantile spasms [20] was also studied, which emphasized the importance of the brain injury location. The thalamus and basal ganglia are known to mediate motor processes and have been found to be vulnerable to hypoxic ischemic injury in infants [21,22]. With greater involvement of the basal ganglia and thalamus and a trend towards more-abnormal scans, a worse prognosis can be prepared for in advance [23]. During the perinatal period, there are dynamic changes in thalamocortical efferent fiber organization and cortical lamination, including rapid axonal growth [24]. This makes the thalamus and connecting white matter projections particularly vulnerable to injury suggesting abnormal development may correlate to the brain lesions [25]. In addition to studying the location of injury , we sought the brain volume as quantitative assessment (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) on MR images in relation to abnormal ND among HIE infants. The significant reduction in brain stem volume and enlarged ventricular volume on MRIs scanned at a mean 10 days of life in HIE neonates compared to normal control infants were manifested in severe HIE and abnormal ND group. Other investigators have also reported reduced volumes of these subcortical regions in preterm infants who are at risk of adverse ND, compared to age-matched, term-born controls[26]. Grinberg et. al [27] also found that all brain volumes measured were smaller in the cytomegalovirus-infected group and that there was a correlation between smaller cerebellar volume and lower adaptive behavior score at later life of 7 years of age. Brain volume loss occur incrementally in healthy individuals as part of physiological aging. However, pathological cause such as toxins accumulated in older participants may accelerate the brain volume loss throughout their life[28]. Chard et.al [29] additionally manifested patients having multiple sclerosis (MS) showed more dramatic brain volume loss per year between 0.50% and 1.35% while physiological volume loss per year is reported between 0.1% and 0.3[30]. The local volumes of the hippocampi and the lateral ventricles have been shown to be early biomarkers of Alzheimer disease [31]. Brain stem volume reduction as in our study can also indicate abnormal ND at 18-24 months of age. The significant change in brain stem volume can potentially serve as a potential marker for delayed neurodevelopmental outcomes. Meanwhile, enlarged ventricle size is often associated with adverse ND outcomes. Dimitrova et. al [32] studied 275 preterm brain imaging. He noted that increased ventricular volume was significantly related to poorer motor and language scores at 18 months. Significantly reduced brain total tissue volume was often accompanied by enlarged ventricles. Among preterm babies, lower gestational age at birth, lower birthweight, longer requirement for respiratory support, and longer total parental nutrition were related to reduced total brain tissue volume and enlarged ventricles in preterm cohorts. Our study also showed significantly enlarged ventricle volume accompanied by smaller brain stem volume in both severe brain MRI group and abnormal ND group which demonstrated that volumetric brain MRI study is a feasible and reliable surrogate measure to predict long-term neurodevelopmental outcomes. As regard to volumetric measures, more brain volume involvement of injury can be well associated with worse 12-month neurodevelopmental outcomes [23]. Markus et al reported that these volumetric measures were correlated with neurological outcome [33]. Andronikou et al demonstrated regional cortical volume loss in mild and severe partial-prolonged hypoxic ischemic injury [34]. We also observed that in addition to more involvement of injury in areas of basal ganglia, thalamus according to MRI NICHD Scoring System, more extensive involvement were significantly associated with abnormal ND at 18–24 months of age. The characteristic study volume features in brain MRI of HIE can be of value in the communication of severity of HIE insult. Those volume assay can be handled and viewed in more detail in future studies. This study had some limitations. Several factors may have contributed to a potential selection bias in our review: first, this was a retrospective study design, which might be unable to fully confirm the examined relationships; second, the gray and white matter volumes were not distinguished and quantified, which limits the potential to reveal more detailed information about segmental brain volumes; third, many clinical conditions of the neonates may have comingled; and fourth, hidden disabilities may subsequently have become apparent at a later life, and many infants might have important developmental lags that were not classified as impairments. Despite the limitations, scanning speed of detecting abnormalities combined with an analysis of lesion location and volume changes can assist clinicians in predicting disabilities in HIE infants in the future. Conclusion In addition to location of brain injury in MRI assessment, brain stem volume reduction in HIE infants accompanied by enlarged ventricular volume may serve as a biomarker indicating severe HIE and adverse long-term neurodevelopmental outcomes at 18-24 months of age among HIE infants who were treated with TH. Both location of brain injury and brain stem volume reduction may be helpful in the prognostication of high risk HIE infants. In future studies, longer-term data of HIE infants including unreported milder disabilities such as attention deficit disorders in the school-aged years are also warranted. Declarations Availability of Data and Materials: The datasets used during the current study are available from the corresponding author upon request. Medical records are available in the Archive of the Department of Pediatrics of the Seoul St. Mary’s Hospital. Ethics Approval Consent to Participate : For this retrospective study, a formal consent was waived due to chart review in this study; any personal data was protected. The ethical approval was obtained from the Catholic University of Korea, Seoul St. Mary’s Hospital, Institutional Review Board. All methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to Participate: We, each author listed on the manuscript, have seen and approved the submission of this version of the manuscript and take full responsibility for the manuscript. We have no conflicts of interest to declare. Consent for Publication: Not applicable. Authors’ Contributions: All Authors have made a substantial contribution: YYA designed the patient study; YYA and ISA conducted the research. KSY and KHM helped with the research. YYA wrote the paper and ISA had primary responsibility for final content. YYA did the statistical analysis. All authors read and approved the final manuscript. Acknowledgement: Emi Tomita, a technician from Artificial Intelligence Research Center, JLK Inc, helped with measuring volumetric brain MRI study using 3D computer program. Funding: We have no financial relationship with any organization. No honorarium, grant, or other form of payment was received to produce this manuscript. We do not have any sources of financial assistance or potential conflicts of interest. Competing Interests: The authors declare that they have no competing interests. References Finer NN, Robertson CM, Richards RT, et al. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome. J Pediatr 1981;98:112–17. Nelson, K. B. Neonatal encephalopathy: etiology and outcome. Dev Med Child Neurol 2005; 47, 292. Badawi, N. Felix JF, Kurinczuk JJ, et al. Cerebral palsy following term newborn encephalopathy: a population-based study. Dev Med Child Neurol 2005;47:293-298. 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Clinical characteristics of abnormal brain MRI group among therapeutic hypothermia (TH)-treated newborns ( n =107) Normal brain MRI ( n =36) Abnormal brain MRI ( n =71) p value Gestational age, weeks 40.1 (39.1~40.4) 39.4 (38.2~40.0) 0.051 Birth weight, g 3260 (2965~3530) 3200 (2990~3435) 0.051 Delivery mode, emergent C/S 22 (26.5) 9 (25.7) 0.113 Apgar score at 1 min 4.86 (2.58) 4.83 (2.11) 0.939 Apgar score at 5 min 7.07 (1.88) 6.61 (2.00) 0.225 Outborn, n (%) 14 (32.6) 20 (26.7) 0.639 Male, n (%) 18 (41.9) 28 (37.3) 0.772 MAS, n (%) 7 (16.3) 7 (9.3) 0.408 SGA, n (%) 4 (9.3) 6 (8.0) 1.000 Fetal heart deceleration 31 (72.1) 63 (84.0) 0.191 Emergent call 37 (86.0) 65 (86.7) 1.000 Initial pH 8.88 (5.71) 6.58 (4.36) 0.023 LDH (initial) 1219.72 (496.54) 1207.12 (485.95) 0.893 CPK (initial) 1067.40 (962.94) 920.16 (765.30) 0.366 Sarnat Stage on day 1 0.59 -Stage 2 35 (81.4) 55 (73.3) -Stage 3 6 (14.0) 16 (21.3) Sarnat stage on day 4 0.548 -Stage 2 6 (14.0) 7 (9.3) -Stage 3 1 (2.3) 4 (5.3) Clinical seizures 22 (61.1) 64 (90.1) 0.001 Abnormal aEEG 0.001 -moderately abnormal 13 (36.1) 45 (60.0) -severely abnormal 2 (4.8) 2 (2.7) AED, phenobarbital 30 (83.3) 69 (97.2) 0.029 AED, keppra 16 (37.2) 35 (46.7) 0.421 AED, phenytoin 9 (20.9) 7 (9.3) 0.136 Ventilator care, days 3.90 (3.73) 3.74 (4.52) 0.841 Full feeding (100 ml/kg/day) 8.43 (4.28) 8.43 (5.03) 0.997 Hospital days 13.40 (5.67) 13.91 (7.52) 0.700 Complications - coagulation disorder￥ 18 (41.9) 25 (33.8) 0.500 - PPHN 4 (9.3) 7 (9.3) 1.000 AEP refer 7 (16.2) 10 (13.3) 0.088 Death 1 (2.3) 1 (1.3) 1.000 Abbreviations: TH, therapeutic hypothermia; MRI, magnetic resonance imaging; C/S, cesarean section; NSD, normal spontaneous delivery; MAS, meconium aspiration syndrome; SGA, small for gestational age; BE, base excess; LDH, lactate dehydrogenase; CPK, creatine phosphokinase, aEEG, amplitude-integrated electroencephalogram; AED, antiepileptic drug; PPHN, persistent pulmonary hypertension; AEP, auditory evoked potential. Table 2. Clinical characteristics associated to abnormal neurodevelopmental outcome of TH treated newborns at corrected age of 18~24 months ( n =107) Normal neurodevelopment ( n =76) Abnormal neurodevelopment ( n =31) p value Gestational age, weeks 39.9 (38.8~40.2) 39.3 (38.2~40.0) 0.072 Birth weight, g 3230 (3030~3510) 3200 (2955~3370) 0.153 Delivery mode, emergent C/S 22 (26.5) 9 (25.7) 0.113 Apgar score at 1 min 4.90 (2.39) 4.69 (2.03) 0.638 Apgar score at 5 min 6.81 (2.01) 6.71 (1.87) 0.815 Male, n (%) 35 (42.2) 11 (31.4) 0.376 Clinical seizure 55 (73.3) 31 (96.9) 0.011 Ventilator care, days 3.86 (4.82) 3.66 (2.06) 0.822 Full feeding (100 cc/kg/day) 8.53 (5.28) 8.18 (3.14) 0.724 Hospital days 13.80 (7.62) 13.54 (4.82) 0.857 Abbreviations: TH, therapeutic hypothermia Table 3. MRI findings associated to abnormal neurodevelopment among TH treated HIE infants according to the MRI NICHD Score ( n =107) MRI NICHD Score, n (%) Normal neurodevelopment (n=76) Abnormal neurodevelopment (n=31) p-value 0 30(39.47) 5(16.13) < 0.001 1A 31(40.79) 5(16.13) < 0.001 1B 8(10.53) 7(22.58) < 0.001 2A 7(9.21) 10(32.26) < 0.001 2B 0(0) 4(12.90) < 0.001 3 0(0) 0(0) Abbreviations: MRI, magnetic resonance imaging; TH, therapeutic hypothermia; HIE, hypoxic ischemic encephalopahty MRI were classified according to the NICHD pattern for brain injury: score of 0 for normal MRI; 1A fo r minimal cerebral lesions only; 1B for more extensive cerebral lesions without basal ganglia and thalamus (BGT), or posterior limb of internal capsule (PLIC) or anterior limb of internal capsule (ALIC) involvement and no area of watershed infarction; 2A for any BGT, PLIC, or ALIC involvement or watershed infarction without any cerebral lesions; 2B for any BGT, PLIC, or ALIC involvement or watershed infarction with additional cerebral lesions; and 3 for cerebral hemispheric devastation Table 4. Comparison of brain volumes between the normal control infants (n=83) vs. abnormal ND TH treated HIE group (n=31) Normal control ( n =83) Abnormal ND (TH group) ( n =31) p value Intracranial, total, ml 402.85 ±84.0 377.9 ±37.7 0.115 Ventricle, ml 5.3±2.5 7.0 ±2.5 0.001 Brainstem, ml 6.54 ±1.2 5.6 ± 0.7 <0.001 Cerebellar, ml 23.9± 9.3 21.1± 3.8 0.110 Cerebrum, ml 402.85 ±84.0 351.1± 34.9 0.131 Abbreviations: ND, neurodevelopment; TH, therapeutic hypothermia; HIE, hypoxic ischemic encepalopathy Table 5. Comparison of brain volumes between the normal control vs. Severe HIE in MRI group (No TH) Normal control ( n =83) Severe HIE MRI group no TH ( n =37) p value Intracranial, total, ml 402.85 ±84.0 381.5 ±39.4 0.144 Ventricle, ml 5.3±2.5 6.6 ±2.4 0.006 Brainstem, ml 6.54 ±1.2 5.7 ± 0.6 <0.001 Cerebellar, ml 23.9± 9.3 21.6± 3.2 0.140 Cerebrum, ml 372.6 ± 74.4 354.2± 34.9 0.163 Abbreviations: HIE, hypoxic ischemic encepalopathy; MRI, magnetic resonance imaging; TH, therapeutic hypothermia; Supplementary Files Appendix1.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major revision 08 Oct, 2023 Reviewers agreed at journal 15 Sep, 2023 Reviewers invited by journal 06 Sep, 2023 Editor assigned by journal 01 Sep, 2023 First submitted to journal 31 Aug, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3310053","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":231334835,"identity":"a4efed72-0094-470e-8a32-961ad2aab3e2","order_by":0,"name":"Soo-Ah Im","email":"","orcid":"","institution":"The Catholic University Seoul Saint Mary's Hospital Department of Radiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Soo-Ah","middleName":"","lastName":"Im","suffix":""},{"id":231334836,"identity":"d2b3f786-5d85-4de0-b8bc-32054b95e53c","order_by":1,"name":"Sae-Yun Kim","email":"","orcid":"","institution":"Kangnam Saint Mary's Hospital: The Catholic University of Korea Seoul St Mary's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sae-Yun","middleName":"","lastName":"Kim","suffix":""},{"id":231334837,"identity":"c77cd0cb-340d-4ec0-92a8-c927b55bac70","order_by":2,"name":"Hyun Mi Kang","email":"","orcid":"","institution":"The Catholic University Seoul Saint Mary's Hospital Department of Radiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hyun","middleName":"Mi","lastName":"Kang","suffix":""},{"id":231334838,"identity":"df923851-65fe-44ba-8258-2b6d947cf3d9","order_by":3,"name":"Young-Ah Youn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACPgYG9p8fKmwSwLyEAiK0sAGxtMSZNKgWA6gQIS0SvG2HIVoYiNLC3vzAQILtfB7/7O7EDw8MGPL45RsIaOE5ZpBQwHO7WOLO2c0SQIcVS7YRsgWo7ICExO3Ehhu5G0BaEjccI6RF/vnHBh6Dc4nzb+Ru/gHSsp+gFgkeYwaehAOJG27kboPYQtD7PDllzBIHkhM3ArVYJBhIJM44loBfCz/78W2MH//ZJc4DOuzmjwqbxP7mAwSsQQMSpCkfBaNgFIyCUYAdAAAf2UMwDXBQsQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9083-2414","institution":"Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Young-Ah","middleName":"","lastName":"Youn","suffix":""}],"badges":[],"createdAt":"2023-08-30 11:50:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3310053/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3310053/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":42943388,"identity":"65ceb08e-0646-44b0-982e-77ae7f9fb682","added_by":"auto","created_at":"2023-09-11 14:29:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25725,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of study.\u003c/p\u003e\n\u003cp\u003eAbbreviation: TH, therapeutic hypothermia; HIE, hypoxic–ischemic encephalopathy; MRI, magnetic resonance imaging; ND; neurodevelopment.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/73487fcac2b4e3cc134ca32b.png"},{"id":42943391,"identity":"0c227bd8-303b-49a4-bc3f-7940f4fe08c4","added_by":"auto","created_at":"2023-09-11 14:29:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":111297,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntracranial and ventricle marking\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/fbfdabad763e02565829cdd7.png"},{"id":42945083,"identity":"b441257f-8129-4810-af11-73a28eee6e12","added_by":"auto","created_at":"2023-09-11 14:37:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":100380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBrainstem and cerebellar marking\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/001da54317e7be17eaf1880d.png"},{"id":42945748,"identity":"436a813e-5890-4962-88bc-2fe345e05499","added_by":"auto","created_at":"2023-09-11 14:45:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":130458,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e3D intracranial volume\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/720a474651b037714f1ba84c.png"},{"id":42943384,"identity":"493c0017-0173-4c3a-81a9-e64270ba7b91","added_by":"auto","created_at":"2023-09-11 14:29:26","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":103504,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e3D ventricle volume\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/93607ee0cf9151c1a81875c0.png"},{"id":42945084,"identity":"5c5fd74d-ef18-4796-8780-b4ae5a8bb2cb","added_by":"auto","created_at":"2023-09-11 14:37:26","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":104440,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e3D brain stem volume\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/d194e36ab0691cd299a9b6dd.png"},{"id":42943389,"identity":"45cbd0d4-b760-43c8-bf8e-e46c16783780","added_by":"auto","created_at":"2023-09-11 14:29:26","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":107844,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e3D cerebellar volume\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/e6a13c1f4431ee9eebe82931.png"},{"id":42945780,"identity":"8556dad3-97af-47cd-b671-973b6fa25612","added_by":"auto","created_at":"2023-09-11 14:45:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1474660,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/3fc4ee0d-df95-4d5f-b94f-1309adb50d3a.pdf"},{"id":42943385,"identity":"bae7748f-fa31-47ed-9882-148c688d6a4a","added_by":"auto","created_at":"2023-09-11 14:29:26","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35270,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3310053/v1/a82f910e9d3feaed010582cb.docx"}],"financialInterests":"","formattedTitle":"Volumetric changes in brain MRI of infants with abnormal development who had Hypoxic-ischemic Encephalopathy and underwent therapeutic hypothermia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypoxic-ischemic encephalopathy (HIE) in neonates after perinatal asphyxia affects 1\u0026ndash;8 per 1,000 live births and results in 15%~25% mortality; among infants who survive, 25% have permanent neurological sequelae [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Severe HIE has been implicated in cognitive, motor, behavior, and/or language impairments, which account for approximately 20% of life-long disabilities, such as cerebral palsy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, magnetic resonance imaging (MRI) allows observation of primary structural brain injury patterns and secondary sequelae in HIE patients, which is the standard of care imaging choice. Specifically, MRI can noninvasively detect perinatally acquired cerebral lesions associated with HIE and characterize lesion severity [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e],which can be used to prognosticate patients and provide treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Qualitative volumetric MRI studies have helped elucidate the potential short-term effects of hypothermia on the extent and pattern of cerebral injury following HIE and may predict the adverse neurodevelopmental (ND) outcomes[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]..The MRI National Institute of Child Health and Human Development (NICHD) is presently the most commonly used scoring system for HIE evaluation and has been shown to be a predictor for death and disability at 18\u0026ndash;22 months following TH for HIE patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The NICHD score assesses the deep location of lesions in the basal ganglia, thalamus, and posterior limb of the internal capsule [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which have been associated to abnormal motor outcomes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Further, Miller et al.\u003csup\u003e6\u003c/sup\u003e observed that HIE patients with lesions in the basal ganglia and thalamus demonstrate the greatest impairment of motor and cognitive outcomes associated with cerebral palsy at 30 months.\u003c/p\u003e \u003cp\u003eIn addition to the location of injury assessment, brain MRI volume change can also be a marker of long-term neurological outcomes[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, it is possible that there is a similar relationship between disability and HIE lesion counts and volume for HIE patients.\u003c/p\u003e \u003cp\u003eThe purpose of this study is to evaluate changes in brain volume on MRI as a prognostic indicator of severe HIE and adverse ND outcomes among infants treated with therapeutic hypothermia (TH). Furthermore, the study additionally evaluated the location of injuries in correlation to adverse ND among HIE infants treated with TH.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Subject Selection\u003c/h2\u003e \u003cp\u003e After approval of the institutional review board of Seoul St. Mary\u0026rsquo;s Hospital, The Catholic University of Korea (Seoul, Korea), we retrospectively identified a cohort of HIE patients between June 2013 and March 2017. Inclusion criteria were gestational age\u0026thinsp;\u0026ge;\u0026thinsp;35 weeks with a birth weight of \u0026ge;\u0026thinsp;1,800 g who underwent TH. All patients received the same TH protocol, which is detailed in \u003cspan refid=\"Sec4\" class=\"InternalRef\"\u003e\u003cb\u003eAppendix 1\u003c/b\u003e\u003c/span\u003e. Exclusion criteria were HIE infants who were older than 6 h at the time of the assessment or those with other major congenital abnormalities, syndromes, or metabolic diseases. Infants with a birth weight of \u0026le;\u0026thinsp;1,800 g, a gestational age of \u0026le;\u0026thinsp;35 weeks of gestational age, overt bleeding, signs of infection, or those requiring\u0026thinsp;\u0026ge;\u0026thinsp;60% oxygen support, which may suggest persistent pulmonary hypertension, were also excluded from this study. The perinatal history and delivery events were recorded for all patients. At 18\u0026thinsp;~\u0026thinsp;24 months, infants returned for follow-up evaluations, at which time they completed the cognitive, language, and motor composites of the Bayley Scales of Infant and Toddler Development III and were evaluated by certified examiners. Children were considered as having developmental delay (DD) or abnormal development if their score was \u0026lt;\u0026thinsp;85. If the score was \u0026ge;\u0026thinsp;85, their ND stage was normal. The study was approved by the Ethics Committee of Seoul St. Mary\u0026rsquo;s Hospital, The Catholic University of Seoul, Korea.\u003c/p\u003e \u003cp\u003eThe study recruited a total of 240 infants between 2013 to 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications (Ex. admitted after 6 hours of life, overt bleeding, signs of infection, or those requiring\u0026thinsp;\u0026ge;\u0026thinsp;60% oxygen support. etc).\u003c/p\u003e \u003cp\u003eAs a normal control group, normal born infants performed brain MRI for more detailed evaluation of possible anomaly (Ex,sellar abnormality in perinatal sonogram), cephalhematoma, asymmetric ventricle size\u0026hellip;etc. Accordingly, the normal brain MRI were collected in 83 infants \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e\u003cp\u003e2.2. Imaging Methods and 3D Image assessment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe brain MRI was performed on all 240 infants within at least 10 days of life (For the TH received infants, the brain MRI was performed after they were rewarmed and extubated from the ventilator which was also within a week of life). The MRI was categorized according to patterns of structural injury. One independent radiologist (ISA) was masked to the treatment and outcomes of the infants and reviewed the images for quality and acquired lesions. One specialized radiologist reviewed all images and classified them independently without knowing the clinical outcomes. For quantitative assessment (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume), MR images were uploaded to dedicated 3D workstation (Aquarius iNtuition, TeraRecon Inc., Durham, NC). Axial FLAIR and T2 MR images \u003cstrong\u003e(Figs 2,3)\u003c/strong\u003e were annoated by a technician (TE) using a previously described 3D program and the results were reviewed and confirmed by a pediatric radiologist (ISA). They were blinded to the clinical outcomes. Based on these annotations, volume metrics were extracted. The measured shape was confirmed by reconstruction in 3D, and an example is shown in \u003cstrong\u003eFigs 4~7\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4. Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables are expressed as the means \u0026plusmn; standard deviation (SD) and were compared with Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test. Continuous variables are displayed as the median with the interquartile range when variables were not normally distributed, and they were compared using the Wilcoxon rank sum test.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eAll inferential statistical analyses were 2-tailed, with statistical significance defined as values of \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05. Statistical analyses were performed with SAS v9.4. Lesion feature calculations were performed using Python 3.5 programming language.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1.\u003c/strong\u003e \u003cstrong\u003eDemographic Characteristics of 107\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTH-treated HIE\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003einfants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the recruited 240 infants (83 normal control infants, 107\u0026nbsp;TH-treated HIE\u0026nbsp;infants and 37 HIE infants who did not receive\u0026nbsp;TH due\u0026nbsp;to contraindications), we primarily evaluated the 107\u0026nbsp;TH-treated HIE\u0026nbsp;infants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;TH-treated HIE\u0026nbsp;group initially started with 120 infants; however, of these infants, two died before further studies (e.g., brain images) were performed.\u0026nbsp;Another 11 patients were excluded in this study because brain MRI were not available for further analysis. As a result, 107 infants were analyzed for brain images as a TH treated HIE group\u0026nbsp;\u003cstrong\u003e(Fig 1)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical evaluation was further proceeded among the 107\u0026nbsp;TH-treated HIE\u0026nbsp;infants. We grouped according to brain MRI findings;\u0026nbsp;33.6% (36/107) infants had normal or minimal lesions of brain MRI and 66.4% (71/107) had abnormal MRI findings. At 18-24 months, those infants were evaluated for the ND assessment of the Bayley Scales of Infant and Toddler Development III by certified examiners; 31 of 107 infants (29.0%) had delayed ND and 76 of 107 infants (71.0%) were normal in their ND stages as in \u003cstrong\u003eFig 1.\u003c/strong\u003e Descriptive clinical characteristics of abnormal vs normal brain\u0026nbsp;MRI and abnormal vs normal ND groups were further assessed among the 107\u0026nbsp;TH-treated HIE\u0026nbsp;infants\u0026nbsp;as\u0026nbsp;presented in \u003cstrong\u003eTable 1 and 2.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenerally, clinical characteristics were similar between the normal and abnormal MRI groups\u0026nbsp;except for\u0026nbsp;clinical and electro-graphical seizures (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001) which were significantly higher in the abnormal MRI group along with higher usage of seizure medication. Furthermore, a lower initial pH \u0026lt;7.0 was more common in the abnormal brain MRI group (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWhen we regrouped the 107\u0026nbsp;TH-treated HIE\u0026nbsp;infants\u0026nbsp;according to long-term\u0026nbsp;ND outcomes, we observed that 31 out of 107 infants (29.0%) showed delayed ND as shown in (\u003cstrong\u003eTable 2\u003c/strong\u003e). The clinical characteristics were also similar as presented in Table 1 with significant increase in the occurrence of clinical seizures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 MRI NICHD Scoring System for ND Outcome at 18-24 Months\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 18-24 months, 71.0% (76/107) of infants showed normal ND stages, 29.0% (31/107) exhibited abnormal ND stages. According to MRI NICHD Scoring System, more lesions involved in the basal ganglia and thalamus, or posterior limb of internal capsule as grouped in stages 2A and 2B, were significantly associated with abnormal ND outcomes at 18~24 months of age (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001).\u0026nbsp;Ten (32.26%)\u0026nbsp;infants in the abnormal ND group were in stage 2 A, involving\u0026nbsp;BGT, PLIC, or ALIC involvement or watershed infarction without additional cerebral lesions.\u0026nbsp;The stage 2B was only found in the abnormal ND group. The most severe stage\u0026nbsp;for cerebral hemispheric devastation, stage 3, was not found in either group in this study\u0026nbsp;(\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Comparison of brain volumetric MRI findings; 107\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTH -treated HIE\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003egroup, 37 HIE group without TH and normal control group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe compared the brain volumes between the normal control infants (n=83) and the abnormal ND group at the corrected 18-24 months of age (n=31) among the 107 TH -treated HIE\u0026nbsp;group.\u0026nbsp;The group with abnormal neurodevelopmental outcomes exhibited a significant reduction in brain stem volume and larger ventricular volume\u0026nbsp;(p\u0026lt; 0.001) \u003cstrong\u003e(Table 4).\u0026nbsp;\u003c/strong\u003eThis observation was consistent\u0026nbsp;when we regrouped the HIE infants according to severe brain MRI group who did not receive TH due to contraindications\u0026nbsp;\u003cstrong\u003e(Table 5).\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHIE in term or near-term infants occurs in 1-6/1000 live births which is often attributed due to perinatal hypoxic-ischemia[15].\u0026nbsp;More than half of untreated infants suffering from moderate to severe HIE are at risk of death or major disability. TH is reported to reduce the HIE induced mortality and adverse neurodevelopmental outcome targeting early mechanisms of injury by reducing cerebral metabolism, excitotoxic neurotransmitter accumulation, ATP depletion, oxygen and nitrogen free radical release, and lipid peroxidation of cell membranes [16-17].\u0026nbsp;With a growing interest in neuroprotection, as TH for HIE infants, it has become increasingly interested in the long-term neurodevelopmental outcomes among neonatal HIE survivors who can either have a normal long-term neurodevelopment or carry the most severe form of HIE as cerebral palsy (CP), resulting a wide variation of outcomes. MRI is a noninvasive method which is usually performed before discharge to visually assess perinatally acquired cerebral lesions associated with HIE[4,7],\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand the patterns and severity of lesions possibly providing a guide for detecting adverse outcomes[12,14].\u003c/p\u003e\n\u003cp\u003eIn this study, we initially observed the relationship between\u0026nbsp;an abnormal signal intensity in the basal ganglia and thalamus location which was a powerful predictor of\u0026nbsp;severe HIE and adverse ND outcomes at 18~24 months of age (Table 3). We observed that\u0026nbsp;more involvement of injury in areas of basal ganglia, thalamus defined as deep brain lesions according to MRI NICHD Scoring System\u003cem\u003e\u0026nbsp;\u003c/em\u003ewere significantly associated with abnormal ND at 18\u0026ndash;24 months of age.\u0026nbsp;Many studies report that lesions in the basal ganglia and thalamus are usually consistent with a severe HIE, which may be graded as a severe acute hypoxic-ischemic insult\u0026nbsp;[8,18].\u0026nbsp;Moderate and severe lesions in the basal ganglia and thalamus and severe white matter lesions are further associated with cerebral palsy\u0026nbsp;[19].\u0026nbsp;Additionally, the correlation between the specific injury location and development of infantile spasms [20] was also studied, which emphasized the importance of the brain injury location. The thalamus and basal ganglia are known to mediate motor processes and have been found to be vulnerable to hypoxic ischemic injury in infants [21,22].\u0026nbsp;With greater involvement of the basal ganglia and thalamus\u0026nbsp;and a trend towards more-abnormal scans, a worse prognosis can be prepared for in advance [23].\u0026nbsp;During the perinatal period, there are dynamic changes in thalamocortical efferent fiber organization and cortical lamination, including rapid axonal growth [24].\u0026nbsp;This makes the thalamus and connecting white matter projections particularly vulnerable to injury suggesting abnormal development may correlate to the brain lesions [25].\u003c/p\u003e\n\u003cp\u003eIn addition to studying the location of injury , we sought\u0026nbsp;the\u0026nbsp;brain volume\u0026nbsp;as quantitative assessment (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) on\u0026nbsp;MR images in relation to abnormal ND among HIE infants. The\u0026nbsp;significant reduction in brain stem volume and enlarged ventricular volume\u0026nbsp;on MRIs scanned at a mean 10 days of life in HIE neonates compared to normal control infants\u0026nbsp;were manifested\u0026nbsp;in severe HIE and abnormal ND group.\u0026nbsp;Other investigators have also reported reduced volumes of these subcortical regions in preterm infants who are at risk of adverse ND, compared to age-matched, term-born controls[26].\u0026nbsp;Grinberg et. al [27]\u0026nbsp;also found that all brain volumes measured were smaller in the cytomegalovirus-infected group and that there was a correlation between smaller cerebellar volume and lower adaptive behavior score at later life of 7 years of age.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBrain volume loss occur incrementally in healthy individuals as part of physiological aging. However, pathological cause such as toxins accumulated in older participants may accelerate the brain volume loss throughout their life[28].\u0026nbsp;\u0026nbsp;Chard et.al\u0026nbsp;[29]\u0026nbsp;additionally manifested patients having multiple sclerosis (MS) showed more dramatic brain volume loss per year between 0.50% and 1.35% while physiological volume loss per year is reported between 0.1% and 0.3[30].\u0026nbsp;The local volumes of the hippocampi and the lateral ventricles have been shown to be early biomarkers of Alzheimer disease\u0026nbsp;[31].\u0026nbsp;Brain stem volume reduction as in our study can also indicate abnormal ND at 18-24 months of age.\u0026nbsp;The significant change in brain stem volume can potentially serve as\u0026nbsp;a potential marker for delayed neurodevelopmental outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeanwhile, enlarged ventricle size is often associated with adverse ND outcomes. Dimitrova et. al [32]\u0026nbsp;studied 275 preterm brain imaging. He noted that increased ventricular volume was significantly related to poorer motor and language scores at 18 months. Significantly reduced brain total tissue volume was often accompanied by enlarged ventricles. Among preterm babies, lower gestational age at birth, lower birthweight, longer requirement for respiratory support, and longer total parental nutrition were related to reduced total brain tissue volume and enlarged ventricles in preterm cohorts. Our study also showed significantly enlarged ventricle volume accompanied by smaller brain stem volume in both severe brain MRI group and abnormal ND group which demonstrated that volumetric brain MRI study is a feasible and reliable surrogate measure to predict long-term neurodevelopmental outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs regard to volumetric measures, more brain volume involvement of injury can be well associated with worse 12-month neurodevelopmental outcomes [23].\u0026nbsp;Markus et al reported that these volumetric measures were correlated with neurological outcome [33].\u0026nbsp;Andronikou et al demonstrated regional cortical volume loss in mild and severe partial-prolonged hypoxic ischemic injury [34].\u0026nbsp;We also observed that in addition to\u0026nbsp;more involvement of injury in areas of basal ganglia, thalamus according to MRI NICHD Scoring System, more extensive involvement\u003cem\u003e\u0026nbsp;\u003c/em\u003ewere significantly associated with abnormal ND at 18\u0026ndash;24 months of age.\u0026nbsp;The characteristic study volume features in brain MRI of HIE can be of value in the communication of severity of HIE insult. Those volume assay can be handled and viewed in more detail in future studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study had some limitations. Several factors may have contributed to a potential selection bias in our review: first, this was a retrospective study design, which might be unable to fully confirm the examined relationships; second, the gray and white matter volumes were not distinguished and quantified, which limits the potential to reveal more detailed information about segmental brain volumes; third, many clinical conditions of the neonates may have comingled; and fourth, hidden disabilities may subsequently have become apparent at a later life, and many infants might have important developmental lags that were not classified as impairments. Despite the limitations, scanning speed of detecting abnormalities combined with an analysis of lesion location and volume changes can assist clinicians in predicting disabilities in HIE infants in the future.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn addition to location of brain injury in MRI assessment, brain stem volume reduction in HIE infants accompanied by enlarged ventricular volume may\u0026nbsp;serve as a biomarker indicating severe HIE and adverse long-term neurodevelopmental outcomes at 18-24 months of age among HIE infants who were treated with TH.\u0026nbsp;Both location of brain injury and brain stem volume reduction may be helpful in the prognostication of high risk HIE infants.\u0026nbsp;In future studies, longer-term data of HIE infants including unreported milder disabilities such as attention deficit disorders in the school-aged years are also warranted.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials:\u0026nbsp;\u003c/strong\u003eThe datasets used during the current study are available from the corresponding author upon request. Medical records are available in the Archive of the Department of Pediatrics of the Seoul St. Mary\u0026rsquo;s Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval Consent to Participate\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eFor this retrospective study, a formal consent was waived due to chart review in this study; any personal data was protected. The ethical approval was obtained from the Catholic University of Korea, Seoul St. Mary\u0026rsquo;s Hospital, Institutional Review Board.\u0026nbsp; All methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u0026nbsp;\u003c/strong\u003eWe, each author listed on the manuscript, have seen and approved the submission of this version of the manuscript and take full responsibility for the manuscript.\u0026nbsp;We have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eNot\u0026nbsp;applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions:\u0026nbsp;\u003c/strong\u003eAll Authors have made a substantial contribution: YYA designed the patient study; YYA and ISA conducted the research. KSY and KHM helped with the research. YYA wrote the paper and ISA had primary responsibility for final content. YYA did the statistical analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003e Emi Tomita, a technician from Artificial Intelligence Research Center, JLK Inc, helped with measuring volumetric brain MRI study using 3D computer program.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eWe have no financial relationship with any organization.\u0026nbsp;No honorarium, grant, or other form of payment was received to produce this manuscript.\u0026nbsp;We do not have any sources of financial assistance or potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFiner NN, Robertson CM, Richards RT, et al. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome. J Pediatr 1981;98:112\u0026ndash;17.\u003c/li\u003e\n\u003cli\u003eNelson, K. B. Neonatal encephalopathy: etiology and outcome. \u003cem\u003eDev Med Child Neurol\u003c/em\u003e 2005; 47, 292.\u003c/li\u003e\n\u003cli\u003eBadawi, N. Felix JF, Kurinczuk JJ,\u003cem\u003e et al.\u003c/em\u003e Cerebral palsy following term newborn encephalopathy: a population-based study. \u003cem\u003eDev Med Child Neurol\u003c/em\u003e 2005;47:293-298. \u003c/li\u003e\n\u003cli\u003eHaataja, L.\u003cem\u003e \u003c/em\u003eE Mercuri, A Guzzetta\u003cem\u003e,et al.\u003c/em\u003e Neurologic examination in infants with hypoxic-ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings. \u003cem\u003eJ Pediatr\u003c/em\u003e 2001;138: 332-337.\u003c/li\u003e\n\u003cli\u003eSie, L. T., M S van der Knaap, J Oosting,\u003cem\u003e et al.\u003c/em\u003e MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. \u003cem\u003eNeuropediatrics\u003c/em\u003e 2000; 31:128-136.\u003c/li\u003e\n\u003cli\u003eMiller, S. P.\u003cem\u003e \u003c/em\u003eRamaswamy V, Michelson D,\u003cem\u003e et al.\u003c/em\u003e Patterns of brain injury in term neonatal encephalopathy. \u003cem\u003eJ Pediatr\u003c/em\u003e 2004;146: 453-460.\u003c/li\u003e\n\u003cli\u003eAzzopardi, D. \u0026amp; Edwards, A. D. Magnetic resonance biomarkers of neuroprotective effects in infants with hypoxic ischemic encephalopathy. \u003cem\u003eSemin Fetal Neonatal Med\u003c/em\u003e 2010;15: 261-269.\u003c/li\u003e\n\u003cli\u003eOkereafor, A. Allosop J, Counsell SJ,\u003cem\u003e et al.\u003c/em\u003e Patterns of brain injury in neonates exposed to perinatal sentinel events. \u003cem\u003ePediatrics\u003c/em\u003e 2008;121: 906-914.\u003c/li\u003e\n\u003cli\u003eMercuri, E. L Haataja, A Guzzetta,\u003cem\u003e et al.\u003c/em\u003e Visual function in term infants with hypoxic-ischaemic insults: correlation with neurodevelopment at 2 years of age. \u003cem\u003eArch Dis Child Fetal Neonatal Ed\u003c/em\u003e 1999; 80: F99-104.\u003c/li\u003e\n\u003cli\u003eInder TE, Hunt RW, Morley CJ, Coleman L, Stewart M, Doyle LW, Jacobs SE. Randomized trial of systemic hypothermia selectively protects the cortex on MRI in term hypoxic-ischemic encephalopathy. J Pediatr. 2004; 145(6):835\u0026ndash;837.\u003c/li\u003e\n\u003cli\u003eRutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, Thoresen M. Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics. 2005; 116(4):1001\u0026ndash;1006.\u003c/li\u003e\n\u003cli\u003eShankaran S, Barnes PD, Hintz SR, et al. Brain injury following trial of hypothermia for neonatal hypoxic\u0026ndash; ischemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2012; 97(6): F398\u0026ndash;F404. \u003c/li\u003e\n\u003cli\u003eCowan F, Rutherford M, Groenendaal F,\u003cem\u003e et al.\u003c/em\u003e Origin and timing of brain lesions in term infants with neonatal encephalopathy. \u003cem\u003eLancet\u003c/em\u003e 2003;361: 736-742.\u003c/li\u003e\n\u003cli\u003eRutherford MA, Pennock JM, Counsell SJ,\u003cem\u003e et al.\u003c/em\u003e Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. \u003cem\u003ePediatrics\u003c/em\u003e 1998; 102: 323-328.\u003c/li\u003e\n\u003cli\u003eVolpe JJ. Neurology of the newborn. Chicago: Saunders; 2001.\u003c/li\u003e\n\u003cli\u003eGonzalez FF, Ferriero DM.Therapeutics for neonatal brain injury. Pharmacol Ther 2008; 120:43\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eYu L, Derrick M, Ji H, Silverman RB, Whitsett J, Vasquez-Vivar J, Tan S: Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole. Dev Neurosci 2011;33:312\u0026ndash;319.\u003c/li\u003e\n\u003cli\u003eShankaran, S. McDonald S, Laptook A,\u003cem\u003e et al.\u003c/em\u003e Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. \u003cem\u003eJ Pediatr 2015;\u003c/em\u003e 167: 987-993.\u003c/li\u003e\n\u003cli\u003eMercuri, E.\u003cem\u003e et al.\u003c/em\u003e Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging. \u003cem\u003ePediatrics\u003c/em\u003e 106, 235-243, doi:10.1542/peds.106.2.235 (2000).\u003c/li\u003e\n\u003cli\u003eThoresen, M. Patient selection and prognostication with hypothermia treatment. \u003cem\u003eSemin Fetal Neonatal Med\u003c/em\u003e 15, 247-252, doi:10.1016/j.siny.2010.05.008 (2010).\u003c/li\u003e\n\u003cli\u003eBall, G., Boardman, J.P., Aljabar, P., et al.The influence of preterm birth on the developing thalamocortical connectome. Cortex 2012; a journal devoted to the study of the nervous system and behavior. \u003c/li\u003e\n\u003cli\u003eNossin-Manor R., et al. Deep gray matter maturation in very preterm neonates: regional variations and pathology-related age-dependent changes in magnetization transfer ratio. Radiology 2012; 263 (2), 510\u0026ndash;517.\u003c/li\u003e\n\u003cli\u003eSarah B. Mulkey. Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy\u003c/li\u003e\n\u003cli\u003eKostovic I, Jovanov-Milo sevi c N, Rado \u0026acute; s M, Sedmak G, Benjak V, ˇ Kostovic-Srzenti \u0026acute;c M, Vasung L, \u0026acute; Culjat M, Rado s M, H\u0026uuml;ppi P et al. Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches. Brain Struct Funct.2014;219:231\u0026ndash;253.\u003c/li\u003e\n\u003cli\u003eBall G, Pazderova L, Chew A, Tusor N, Merchant N, Arichi T, Allsop JM, Cowan FM, Edwards AD, Counsell SJ. Thalamocortical connectivity predicts cognition in children born preterm. Cereb Cortex. 2015; 25:4310\u0026ndash;4318.\u003c/li\u003e\n\u003cli\u003eSrinivasan, L., et al., Quantification of deep gray matter in preterm infants at term-equivalent age using manual volumetry of 3-Tesla magnetic resonance images. Pediatrics 2007; 119 (4), 759\u0026ndash;765\u003c/li\u003e\n\u003cli\u003eGrinberg A, Katorza E, Ber R, Mayer A and Lipitz S. Volumetric MRI Study of the Brain in Fetuses with Intrauterine Cytomegalovirus Infection and Its Correlation to Neurodevelopmental Outcome. AJNR Am J Neuroradiol 40:353\u0026ndash;58\u003c/li\u003e\n\u003cli\u003eOpfer R, Ostwaldt AC, Sormani MP et.al. Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSLda longitudinal brain volumetry study in healthy adults Neurobiology of Aging 2018;65: 1-6.\u003c/li\u003e\n\u003cli\u003eChard, D., Miller, D. et. Al. Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging. J. Neurol. Sci. 2009; 282, 5-11.\u003c/li\u003e\n\u003cli\u003eTakao, H., Hayashi, N., Ohtomo, K., et.al. A longitudinal study of brain volume changes in normal aging. Eur. J. Radiol. 2012; 81:2801-2804.\u003c/li\u003e\n\u003cli\u003eCoup\u0026eacute;, P., Eskildsen, S. F., Manj\u0026oacute;n, J. V., Fonov, V., Collins, D. L., and ADNI. Simultaneous segmentation and grading of anatomical structures for patient\u0026rsquo;s classification: application to Alzheimer\u0026rsquo;s disease. Neuroimage 2012; 59: 3736\u0026ndash;3747.\u003c/li\u003e\n\u003cli\u003eDimitrova R., Arulkumaran S, Carney O, Chew A, Falconer S, Ciarrusta J et. al. Cerebral Cortex, August 2021;31: 3665\u0026ndash;3677.\u003c/li\u003e\n\u003cli\u003eMarkus R, Reutens DC, Kazui S, et al. Hypoxic tissue in ischemic stroke: persistence and clinical consequences of spontaneous survival. Brain 2004; 127, 1427-1436.\u003c/li\u003e\n\u003cli\u003eAndronikou S, Simpson E, Klemm M, et al. Technical report: 3D printing of the brain for use as a visual-aid tool to communicate MR imaging features of hypoxic ischemic injury at term with non-physicians. Child\u0026apos;s Nervous System 2018; 34:1573\u0026ndash;1577.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Clinical characteristics of abnormal brain MRI group among therapeutic hypothermia (TH)-treated newborns (\u003cem\u003en\u003c/em\u003e=107)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.688311688311686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"24.18831168831169%\"\u003e\n \u003cp\u003eNormal brain MRI (\u003cem\u003en\u003c/em\u003e=36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.92207792207792%\" colspan=\"2\"\u003e\n \u003cp\u003eAbnormal brain MRI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(\u003cem\u003en\u003c/em\u003e=71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2012987012987%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eGestational age, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e40.1 (39.1~40.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e39.4 (38.2~40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eBirth weight, g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e3260 (2965~3530)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e3200 (2990~3435)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eDelivery mode, emergent C/S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e22 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eApgar score at 1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e4.86 (2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e4.83 (2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.939\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eApgar score at 5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e7.07 (1.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e6.61 (2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.225\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eOutborn, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e14 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e20 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.639\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eMale, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e18 (41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e28 (37.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eMAS, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e7 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e7 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eSGA, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e6 (8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eFetal heart deceleration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e31 (72.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e63 (84.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.191\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eEmergent call\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e37 (86.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e65 (86.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eInitial pH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e8.88 (5.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e6.58 (4.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eLDH (initial)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e1219.72 (496.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e1207.12 (485.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eCPK (initial)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e1067.40 (962.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e920.16 (765.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.366\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eSarnat Stage on day 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-Stage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e35 (81.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e55 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-Stage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e6 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e16 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eSarnat stage on day 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.548\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-Stage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e6 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e7 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-Stage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e4 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eClinical seizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e22 (61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e64 (90.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eAbnormal aEEG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-moderately abnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e13 (36.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e45 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e-severely abnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e2 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eAED, phenobarbital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e30 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e69 (97.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eAED, keppra\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e16 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e35 (46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.421\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eAED, phenytoin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e9 (20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e7 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eVentilator care, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e3.90 (3.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e3.74 (4.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.841\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eFull feeding (100 ml/kg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e8.43 (4.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e8.43 (5.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.997\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eHospital days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e13.40 (5.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e13.91 (7.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.700\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eComplications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e- coagulation disorder￥\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e18 (41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e25 (33.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003e- PPHN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e7 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eAEP refer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e7 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e10 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7479674796748%\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.15447154471545%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.21951219512195%\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: TH, therapeutic hypothermia; MRI, magnetic resonance imaging; C/S, cesarean section; NSD, normal spontaneous delivery; MAS, meconium aspiration syndrome; SGA, small for gestational age; BE, base excess; LDH, lactate dehydrogenase; CPK, creatine phosphokinase, aEEG, amplitude-integrated electroencephalogram; AED, antiepileptic drug; PPHN, persistent pulmonary hypertension; AEP, auditory evoked potential.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Clinical characteristics associated to abnormal neurodevelopmental outcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eof TH treated newborns\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eat corrected age of 18~24 months (\u003cem\u003en\u003c/em\u003e=107)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.85064935064935%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.051948051948052%\"\u003e\n \u003cp\u003eNormal neurodevelopment (\u003cem\u003en\u003c/em\u003e=76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.22077922077922%\" colspan=\"2\"\u003e\n \u003cp\u003eAbnormal\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eneurodevelopment\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.876623376623376%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eGestational age, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e39.9 (38.8~40.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e39.3 (38.2~40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.072\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eBirth weight, g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e3230 (3030~3510)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e3200 (2955~3370)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eDelivery mode, emergent C/S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e22 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eApgar score at 1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e4.90 (2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e4.69 (2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.638\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eApgar score at 5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e6.81 (2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e6.71 (1.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eMale, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e35 (42.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e11 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.376\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eClinical seizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e55 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e31 (96.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eVentilator care, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e3.86 (4.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e3.66 (2.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.822\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eFull feeding (100 cc/kg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e8.53 (5.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e8.18 (3.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.724\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eHospital days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e13.80 (7.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e13.54 (4.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.857\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: TH, therapeutic hypothermia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTable 3. MRI findings associated to abnormal neurodevelopment among TH treated HIE infants according to\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ethe MRI NICHD Score (\u003cem\u003en\u003c/em\u003e=107)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;MRI NICHD Score,\u0026nbsp;\u003c/strong\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003cp\u003eneurodevelopment\u003c/p\u003e\n \u003cp\u003e(n=76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003eAbnormal neurodevelopment\u003c/p\u003e\n \u003cp\u003e(n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e30(39.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e5(16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e1A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e31(40.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e5(16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e1B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e8(10.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e7(22.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e2A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e7(9.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e10(32.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e4(12.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.7109634551495%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.259136212624586%\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: MRI, magnetic resonance imaging; TH, therapeutic hypothermia; HIE, hypoxic ischemic encephalopahty\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI were classified according to the NICHD pattern for brain injury: score of 0 for normal MRI; 1A fo\u003c/strong\u003e\u003cstrong\u003er minimal cerebral lesions only; 1B for more extensive cerebral lesions without basal ganglia and thalamus (BGT), or posterior limb of internal capsule (PLIC) or anterior limb of internal capsule (ALIC) involvement and no area of watershed infarction; 2A for any BGT, PLIC, or ALIC involvement or watershed infarction without any cerebral lesions; 2B for any BGT, PLIC, or ALIC involvement or watershed infarction with additional cerebral lesions; and 3 for cerebral hemispheric devastation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTable 4. Comparison of brain volumes between the normal control\u0026nbsp;infants\u0026nbsp;(n=83) vs. abnormal\u0026nbsp;ND TH treated HIE group (n=31)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"24.227642276422763%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal control\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e=83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.96747967479675%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eND\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(TH group)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eIntracranial, total, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e402.85\u0026nbsp;\u0026plusmn;84.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e377.9\u0026nbsp;\u0026plusmn;37.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eVentricle, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e5.3\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e7.0\u0026nbsp;\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eBrainstem, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e6.54 \u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e5.6 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eCerebellar, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e23.9\u0026plusmn; 9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e21.1\u0026plusmn; 3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eCerebrum, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e402.85\u0026nbsp;\u0026plusmn;84.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e351.1\u0026plusmn; 34.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ND, neurodevelopment; TH, therapeutic hypothermia; HIE, hypoxic ischemic encepalopathy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eComparison of brain volumes between the normal control vs. Severe HIE in MRI group (No TH)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"24.227642276422763%\"\u003e\n \u003cp\u003eNormal control\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e=83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.96747967479675%\" colspan=\"2\"\u003e\n \u003cp\u003eSevere HIE MRI group\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eno TH (\u003cem\u003en\u003c/em\u003e=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eIntracranial, total, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e402.85\u0026nbsp;\u0026plusmn;84.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e381.5\u0026nbsp;\u0026plusmn;39.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eVentricle, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e5.3\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e6.6\u0026nbsp;\u0026plusmn;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eBrainstem, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e6.54 \u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e5.7 \u0026plusmn; 0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eCerebellar, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e23.9\u0026plusmn; 9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e21.6\u0026plusmn; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.91056910569106%\"\u003e\n \u003cp\u003eCerebrum, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.317073170731707%\" colspan=\"2\"\u003e\n \u003cp\u003e372.6 \u0026plusmn; 74.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.878048780487806%\"\u003e\n \u003cp\u003e354.2\u0026plusmn; 34.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.894308943089431%\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: HIE, hypoxic ischemic encepalopathy; MRI, magnetic resonance imaging; TH, therapeutic hypothermia;\u003cstrong\u003e\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"MRI-volumetry, hypothermia, hypoxia-ischemia, long-term outcomes, seizures","lastPublishedDoi":"10.21203/rs.3.rs-3310053/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3310053/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40\u0026ndash;60% of long-term morbidity. MRI is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18\u0026ndash;24 months among HIE infants.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for TH were a gestational age\u0026thinsp;\u0026ge;\u0026thinsp;35 weeks, a birth weight\u0026thinsp;\u0026ge;\u0026thinsp;1,800 g, and the presence of \u0026ge;\u0026thinsp;moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18\u0026ndash;24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study recruited a total of 240 infants between 2013 to 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded among the 107 TH-treated HIE infants. We grouped according to brain MRI findings; 33.6% (36/107) infants had normal or minimal lesions of brain MRI and 66.4% (71/107) had abnormal MRI findings. At 18\u0026ndash;24 months, 31 of 107 infants (29.0%) had delayed neurodevelopment and 76 of 107 infants (71.0%) were normal in their neurodevelopmental stages. When comparing brain volumes between the normal control infants (n\u0026thinsp;=\u0026thinsp;83) and the abnormal ND group at the corrected 18\u0026ndash;24 months of age (n\u0026thinsp;=\u0026thinsp;31) in the 107 TH -treated HIE group, abnormal ND group exhibited a significant reduction in brain stem volume and larger ventricular volume (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This observation was consistent when we regrouped the HIE infants according to severe brain MRI group who did not receive TH due to contraindications.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn addition to location of brain injury in MRI assessment, brain stem volume reduction accompanied by larger ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term neurodevelopmental outcomes among HIE infants who were treated with TH.\u003c/p\u003e","manuscriptTitle":"Volumetric changes in brain MRI of infants with abnormal development who had Hypoxic-ischemic Encephalopathy and underwent therapeutic hypothermia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-11 14:29:21","doi":"10.21203/rs.3.rs-3310053/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-10-08T16:24:45+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-09-15T10:47:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-09-06T14:06:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-09-01T04:26:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2023-08-31T08:51:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0cc23161-9fcb-4bb4-8e7a-c9c108f37d74","owner":[],"postedDate":"September 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2023-10-08T20:24:57+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-11 14:29:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3310053","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3310053","identity":"rs-3310053","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}