Therapeutic Hypothermia in Preterm Infants Under 36 Weeks: Outcomes and Brain MRI Findings

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Therapeutic hypothermia (TH) is the standard treatment for term neonates, but its safety and efficacy in neonates <36 weeks’ gestational age (GA) remains unclear. This study aimed to evaluate the outcomes of preterm infants with HIE treated with TH. Methods : Retrospective analysis of preterm infants (<36w’GA) treated with TH (01/2019-06/2024). Data on demographics, clinical complications, coagulation profiles, brain magnetic resonance imaging (MRI), and neurodevelopment outcomes were analyzed. Results : Seventeen patients were included (median GA 34.4w; median birth weight 2300g), 58.8% were male. Placental abruption was identified in 7 cases (41.2%), and 8 (47.1%) required advanced resuscitation. Thirteen patients (76.5%) presented anemia, 12 (70.6%) coagulopathy, 9 (52.9%) thrombocytopenia, and 9 (52.9%) acute liver failure. Hypofibrinogenemia (<1g/L) was significantly associated with severe intracranial hemorrhage (ICH) and mortality unrelated to withdrawal of care. MRI findings were classified based on the predominant lesion: I-hypoxic-ischemic injury, II-severe ICH, or III-normal/mild findings. Severe ICH was the predominant lesion in 4 cases (23.5%). White matter injury was seen in 12 (76%). Death occurred in 8 cases (47.1%), with 3 (37.5%) resulting from withdrawal of care and 5 (62.5%) from fatal complications. Of the 9 surviving patients, at 2 years, 6 (66.7%) had normal neurodevelopment, while 1 (11.1%) had severe disability. Conclusion : Coagulation abnormalities, particularly hypofibrinogenemia, significantly increase the risk of severe ICH and mortality in <36w infants treated with TH. The safety and efficacy of TH in this population require further investigation. Therapeutic Hypothermia Hypoxic-ischemic encephalopathy Premature Infant Coagulation disorders Neurodevelopmental Outcomes Figures Figure 1 Introduction Perinatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of neonatal brain injury, with therapeutic hypothermia (TH) being the gold standard treatment for newborns with moderate to severe HIE in developed countries[ 1 , 2 ]. TH has proven to be both safe and effective in reducing neurological damage and improving survival rates in term or near-term neonates[ 3 – 6 ], but data on preterm infants remains scarce[ 7 ]. Three of the pivotal randomized controlled trials (RCTs) included only newborns ≥ 36 weeks gestational age (GA)[ 3 – 5 ], and the two RCTs including neonates from 35 weeks GA did not provide subgroup analyses for those between 35.0 and 35.6 weeks[ 6 , 8 ]. In the RCTs of hypothermia versus normothermia, strict inclusion criteria were used. The reasons for excluding preterm infants from the major trials were concerns about precise diagnosis and grading of HIE[ 9 ], as well as the potential adverse effects of TH in this more vulnerable population[ 10 ]. It is well known that hypothermia in preterm infants is associated with increased mortality and morbidity[ 11 ]. However, studies in preterm animal models[ 12 , 13 ] and a pilot study in preterm neonates with necrotizing enterocolitis[ 14 ] suggested that it might be safe to offer TH to infants < 36 weeks GA. Materials and methods Medical records were reviewed retrospectively from preterm neonates born before 36 weeks GA who were admitted at Hospital Clínic Barcelona and Hospital Sant Joan de Déu (BCNatal) with a diagnosis of HIE treated with TH from January 2019 to June 2024. Pertinent demographic, clinical, laboratory, neuroimaging and neurodevelopment data were recorded. The study protocol was approved by the local research ethics committee (approval number HCB/2024/0944) and was conducted following the principles of the Declaration of Helsinki. TH criteria To initiate TH in our center, GA of at least 36 weeks is required, along with at least 1 criterion suggestive of perinatal hypoxia-ischemia and evidence of moderate-to-severe encephalopathy or seizures (Table 1 ). In the last decade, our protocol has enabled the provision of TH to neonates with GA between 34.0 and 35.6 weeks and birth weight ≥ 1800g. Compassionate use of TH is also considered for neonates of lower GA. This decision is made by the attending neonatologist following careful and individualized consideration. Table 1 Therapeutic hypothermia criteria. Criteria A, at least 1 of: - Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary pH < 7.00) - Base Deficit ≥ 16 mmol/L in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth - Apgar score of ≤ 5 at 10 minutes after birth - Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth Criteria B, at least 1 of: - Clinical or subclinical (i.e. electrographic only) seizures - Moderate-to-severe neonatal encephalopathy. Before 2021, this was based on modified Sarnat classification [ 20 ]; from 2021, it was defined as ≥ 8 points in the Neonatal Encephalopathy-Rating Scale [ 21 ] Neurological assessment To grade encephalopathy severity, we initially used García-Alix et al.’s modification of Sarnat staging[ 22 ] with altered consciousness as a key element. Since 2021, we adopted the Neonatal Encephalopathy-Rating Scale[ 23 ]. A neurological exam at admission is performed by the attending neonatologist. All infants undergo amplitude-integrated EEG (aEEG) before cooling (as part of the entry criteria), throughout cooling, and during rewarming. The aEEG trace is assessed using both voltage criteria[ 24 ] and pattern recognition[ 25 ]. Neonatal morbidities We collected data on neonatal complications and morbidities associated with hypoxic-ischemic injury or TH, including: (1) hemodynamic instability requiring ≥ 2 vasoactive agents; (2) pulmonary hypertension requiring inhaled nitric oxide; (3) respiratory distress syndrome (RDS) requiring surfactant; (4) acute kidney injury, defined as oliguria and plasma creatinine ≥ 1.50 mg/dL at 24–48 hours; (5) acute liver failure, defined as GOT ≥ 500 UI/L or GPT ≥ 150 UI/L; (6) metabolic disorders, including: hypoglycaemia 180 mg/dL and hypocalcemia < 1.10 mmol/L; (7) necrotizing enterocolitis classified as modified Bell’s staging ≥ II[ 26 ]; (8) microbiologically confirmed sepsis; (9) anemia, defined as Hb < 13 g/dL; (10) thrombocytopenia < 50/mm 3 ; (11) coagulopathy, defined as prothrombin time (PT) < 40%, and considered severe if PT < 20%; (12) hypofibrinogenemia, defined as fibrinogen < 1.0 g/L; (13) intracranial hemorrhage (ICH) including: intraventricular hemorrhage (IVH) grade ≥ 2[ 27 ], parenchymal, subarachnoid and subdural bleeds; and (14) seizures, either clinical or subclinical (electrographic only). Neuroimaging Neonatal neuroimaging was classified based on MRI. When MRI was unavailable, cranial ultrasonography (CUS) was used to assess for bleeding. CUS scans were performed at different axes of the coronal and sagittal planes through the anterior fontanel, using 5- to 12-MHz sector, microconvex or linear probes. MRI was obtained with equipment operating at 1.5 or 3 Tesla. Sagittal, axial, and coronal T1- and T2-weighted images, as well as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) maps and susceptibility-weighted imaging (SWI) were reviewed. Images were assessed for quality, normal anatomy, and acquired lesions. The basal ganglia and thalami (BGT), white matter (WM) and cortex were evaluated as described by Rutherford et al.[ 21 ]. Signal intensity was graded as mild, moderate, or severe in the BGT, and moderate or severe in the WM. Cortex involvement was defined by loss of cortical markings and highlighting. The posterior limb of the internal capsule (PLIC) was described as normal, abnormal, or not evaluable due to low postmenstrual age at the time of MRI. The cerebellum and brainstem were classified as normal, primary injury (hypoxic-ischemic damage), or secondary (hemorrhage or compression due to bleeding). The presence of ICH was recorded. Special attention was paid to the distortion or displacement of brain structures caused by ICH with mass effect. MRI findings were classified based on the predominant type of lesion into three categories: I-hypoxic-ischemic injury; II-severe intracranial hemorrhage; III-normal or mild findings. In those with hypoxic-ischemic injury, three injury patterns were identified[ 20 ]: global, BGT and WM (Table 2 ). Two expert neonatologists specialized in neuroimaging blinded to the infant’s clinical status, independently reviewed the MRI scans. Disagreements were resolved by consensus. Table 2 Classification of neuroimaging main findings according to the predominant type of injury. Predominant type of lesion Injury pattern Findings H-I Injury Global BGT WM BGT lesions and severe WM damage BGT lesions with mild or moderate WM changes Moderate WM damage only Severe ICH Hemorrhagic Severe ICH causing mass effect Normal or mild findings Normal or mild changes Mild WM changes, non-complicated ICH, or normal findings Abbreviations: BGT: basal ganglia and thalami; H-I: hypoxic-ischemic; ICH: intracranial hemorrhage; WM: white matter. Neurodevelopmental Assessment After discharge, infants enter a follow-up program. At 2 years corrected age, those with atypical neurodevelopment undergo standardized evaluation using the Bayley Scales of Infant Development III. Severe disability was defined by any of the following: Bayley III composite cognitive score 70 dB or requiring cochlear implants). Moderate disability was defined as: Bayley III composite cognitive score 70-84, cerebral palsy with GMFCS level 2, seizure disorder or moderate hearing deficit (40-70 dB). Statistical Analysis Data analysis was performed using SPSS Statistics 29.0.2.0 (IBM, Chicago, IL, USA). Demographic data, clinical features, and outcomes were summarized using descriptive statistics presented as numbers and percentages or median with interquartile range [25 th ; 75 th centile] as appropriate. Univariate analysis was performed using the Chi-squared test for categoric variables. Statistical significance was considered as a bilateral p -value less than 0.05. Results Seventeen neonates born at less than 36 weeks of gestation with HIE were included, all receiving TH started within the first 6 hours of life. Of these, 6 (35.3%) had moderate HIE, and 11 (64.7%) had severe HIE. Median GA was 34.4 weeks. Perinatal history along with neonatal characteristics and short-term outcomes are shown in Table 3. Nine patients (52.9%) presented hemodynamic instability, 14 (82.3%) required mechanical ventilation, and 9 (52.9%) received at least 2 fresh plasma transfusions. Table 3. Perinatal history, baseline neonatal and neurological characteristics, and short-term outcomes. Pregnancy and Delivery Preeclampsia 4 (25.0) Gestational diabetes 2 (12.5) Fetal isoimmunization 1 (6.3) Placental abruption 7 (41.2) Cardiotocographic abnormality 7 (41.2) Feto-maternal transfusion 3 (17.6) Emergency caesarean delivery 16 (94.1) Neonatal Characteristics and Perinatal Events Gestational age (weeks) 34.4 [34.1 – 35.2] Birth weight (grams) 2300 [2060 - 2493] Male sex 10 (58.8) Advanced resuscitation 8 (47.1) Apgar minute 1 0 [0 – 1] Apgar minute 5 2 [0 – 4] Apgar minute 10 5 [3 – 7] Umbilical artery pH 6.88 [6.56 – 6.98] pH in first blood sample 7.00 [6.81 – 7.16] Base deficit in first blood sample 20.4 [28.3 – 13.6] Lactate in first blood sample (mmol/L) 13.2 [7 – 22] Transferred from another center 5 (29.4) Neurological assessment Hours of life at the start of TH 3 [1 – 5] Moderate encephalopathy 6 (35.3) Severe encephalopathy 11 (64.7) aEEG pattern at admission Normal/discontinuous Burst – suppression Low voltage/flat trace 6 (35.3) 4 (23.5) 7 (41.2) Seizures 6 (35.3) Age at MRI (days) 4.5 [3 – 6.5] Short-term outcomes Respiratory distress syndrome 1 (5.9) Pulmonary hypertension 2 (11.8) Acute Kidney injury 5 (29.4) Acute liver failure 9 (52.9) Hypoglycemia 9 (52.9) Hyperglycemia 7 (41.2) Hypocalcemia 7 (41.2) Necrotizing enterocolitis 1 (5.9) Sepsis 0 (0) Thrombocytopenia 9 (52.9) Anemia 13 (76.5) Coagulopathy 12 (70.6) Death 8 (47.1) Values are expressed as number (%) or median [25 th - 75 th centile]. Abbreviations: aEEG: amplitude-integrated electroencephalogram; MRI: magnetic resonance imaging. Eight patients died (47%). Death following withdrawal of care due to severe hypoxic-ischemic injury with poor neurological prognosis occurred in 3 neonates (17.6%). Mortality from complications was observed in 5 cases (29.4%), 4 cases of severe ICH with mass effect, and 1 case of necrotizing enterocolitis. No differences in mortality were observed based on GA, weight, sex (71.4% males and 30% females; p=0.092), the need for advanced resuscitation, the degree of initial acidosis, the use of inotropes, mechanical ventilation, inhaled nitric oxide or insulin, the severity of HIE (1 death in moderate HIE (16.7%) and 7 in severe HIE (63.6%); p=0.064), or the presence of seizures (5 deaths in patients with no seizures (45.5%) and 3 in cases with seizures (50%); p=0.858). However, the aEEG trace at admission was associated with significantly higher mortality in those with burst-suppression, low voltage, or flat patterns (8 deaths, 72.7%), with no mortality in those with normal or discontinuous trace (p=0.004). Table 4 highlights hemostatic abnormalities as significant contributors to morbidity and mortality. Hypofibrinogenemia was strongly associated with severe ICH (p=0.01). While no significant association was found with overall mortality, subgroup analysis showed neonates with hypofibrinogenemia had a higher probability of death unrelated to therapeutic withdrawal (p=0.03). Table 4. Hemostatic disorders and the predominant type of lesion in neonatal neuroimaging. Predominant type of lesion N = 17 Mild findings (n = 4) H-I injury (n = 9) Severe ICH (n = 4) p -value Coagulopathy (PT Quick < 40%) 12 (70.6) 2 (16.7) 6 (50) 4 (33.3) 0.279 Severe Coagulopathy (PT Quick < 20%) 7 (41.3) 2 (28.6) 2 (28.6) 3 (42.9) 0.187 Thrombocytopenia (< 50.000 mm 3 ) 9 (52.9) 3 (33.3) 4 (44.4) 2 (22.2) 0.590 Hypofibrinogenemia (< 1g/L) 7 (41.3) 2 (28.6) 1 (14.3) 4 (57.1) 0.010 Values are expressed in numbers (%). Abbreviations: PT: prothrombin time. Radiological findings, grouped by predominant lesion type, are shown in Table 5. In cases of hypoxic-ischemic injury, detailed damage patterns are provided. Severe ICH was observed in 4 neonates (23.5%), while other 4 (23.5%) had no identifiable or mild lesions. Regarding the affected regions, moderate-to-severe WM injury was seen in 12 neonates (75% of cases with MRI), and BGT involvement occurred in 8 (50% of cases with MRI), with 6 classified as severe. Figure 1 exhibits representative images from our patients, illustrating the main patterns of hypoxic-ischemic and hemorrhagic lesions. Table 5. Main findings and differential patterns on neuroimaging. Predominant type of lesion N = 17 H-I Injury Global 1 BGT 1 WM 1 3 (17.6) 2 (11.8) 4 (23.5) Severe ICH 4 (23.5) Mild changes 4 (23.5) Involved regions of injury Classification N = 16 2 BGT 3 Moderate Severe 2 (12.5) 6 (37.5) PLIC 3 Abnormal Equivocal N.A. 4 6 (37.5) 1 (6.2) 9 (56) WM 3 Moderate Severe 7 (43.7) 5 (32.1) Cortex 3 Abnormal 7 (43.7) Cerebellum H-I injury Secondary injury 1 (6.2) 4 (25) Brainstem H-I injury Secondary injury 3 (18.7) 4 (25) Values are expressed in numbers (%). Abbreviations: BGT: basal ganglia and thalami; H-I: hypoxic-ischemic; ICH: intracranial hemorrhage; PLIC: posterior limb of the internal capsule; WM: white matter. 1 Based on Okereafor et al. [18] 2 One patient died due to severe intracranial hemorrhage (ICH) before MRI could be performed. Ultrasound confirmed IVH grade III with acute ventricular dilatation and intracranial hypertension. This case is included in the classification of predominant injury sites. However, since no MRI was obtained, it is not possible to determine the extent of damage in other regions. 3 Based on Rutherford et al. [19] 4 Not assessable due to the patient's postmenstrual age at the time of the MRI. Of the 9 surviving patients (52.9%), at 2-year follow-up, 6 (66.7%) had normal neurodevelopment, with 1 presenting isolated language delay according to the Bayley III test. Two patients (22.2%) showed moderate disability based on cognitive scores, one of them with a severe WM injury pattern on MRI, and the other with mild findings. Severe disability at 2 years of corrected age was observed in 1 patient (11.1%) with cerebral palsy with level 3 GMFCS and hearing loss, associated with a BGT injury pattern on the neonatal MRI. Discussion Our study shows that preterm infants undergoing TH for HIE face a high incidence of complications, primarily coagulation disorders and ICH, which may be fatal. These multifactorial coagulation abnormalities are challenging to manage, even with blood products. One in two patients does not survive, and among those who do, one in three experiences neurological sequelae. Following the demonstration that TH is associated with a reduction in death and disability at ≥18 months as well as continued neuroprotection in childhood for term and near-term neonates with HIE, the exclusion of patients with lower gestational ages began to raise clinical and ethical concerns[19, 29]. Despite the lack of trials for moderately preterm infants, the biological plausibility of its benefits, the absence of other treatments, and favorable preclinical safety data[12, 13] led several centers to adopt TH under compassionate use[30, 31]. By 2015, 22% of cooled neonates did not meet the original RCT criteria[15]. Currently, clinical practice remains highly variable for patients not meeting standard inclusion criteria[32, 33]. One of the main reasons for excluding preterm infants from the original RCTs was the concern that the risk of side effects of TH would be higher in this population[7, 10]. Evidence regarding the safety and effectiveness of TH in preterm infants comes from retrospective studies, which have yielded mixed results[15–18]. Patients in our study showed significant organ dysfunction. One potential concern is how hypothermia might affect neonates with pulmonary immaturity by reducing surfactant production[34], increasing pulmonary vascular resistance[35], and raising oxygen consumption[34]. However, in our series, only 1 patient required surfactant, and 2 required nitric oxide for pulmonary hypertension, both with good outcomes. It has also been suggested that hypothermia may suppress the immune system and increase infection risk[34], but no cases of early or late-onset sepsis were observed in our cohort. In our study, the most frequent complications were anemia and coagulopathy. The high prevalence of anemia is expected considering two factors. First, more than half of the cases were associated with a sentinel event, i.e., placental abruption or feto-maternal transfusion. Second, postnatal hemorrhagic complications likely caused acute anemia requiring transfusion. The hemostatic disorders found in our study are particularly concerning due to their high prevalence and severity. Nearly three-quarters of the cases exhibited coagulation abnormalities, with half experiencing severe coagulopathy and requiring at least 2 fresh frozen plasma transfusions. Almost half of the patients presented with some degree of ICH. Notably, severe, life-threatening ICH was the predominant finding in nearly one-quarter of the cases. Hypofibrinogenemia was associated with severe ICH and mortality unrelated to withdrawal of care. Coagulation disorders may occur in the context of perinatal hypoxia-ischemia and can be exacerbated by hypothermia and acute liver dysfunction. The effects of TH on the coagulation cascade and platelet function could increase the risk of ICH, especially in the setting of hypoxia-ischemia[36]. In the main TH RCTs, coagulopathy was reported in 14.5% to 41% of cases[3–6]. Retrospective studies of moderate-late preterm infants report coagulations abnormalities ranging from 30% to 64%[16–18]. Results on ICH in cooled preterm infants with HIE vary across different studies. In a matched retrospective study, Kim et al. reported IVH in 30% of infants at 34-35 weeks GA and 10% in those ≥36 weeks but did not describe other types of ICH[37]. Rao et al. found a 65.5% coagulopathy rate in their preterm group (34-35 weeks, n=31), with 6.7% experiencing parenchymal hemorrhage, 3.3% grade 2 IVH, and 10% subdural bleeds, while no hemorrhages occurred in the term group (n=32)[16]. In a retrospective cohort study of 30 preterm infants <36 weeks GA, Herrera et al. reported that 50% required treatment for coagulopathy, with a 38% incidence of ICH, half presenting with severe IVH or parenchymal hemorrhage[17]. In our study, 2 patients (11.7%) developed grade 2 or 3 IVH. One of them had grade 3 IVH with significant acute ventricular dilatation, leading to cerebral edema and intracranial hypertension with compression of the posterior fossa structures and brainstem. Moderate and late preterm infants have a low incidence of IVH, although precise data are lacking because routine ultrasound screening is not performed for these gestational ages. An absolute risk of 1-3% for IVH has been observed in preterm infants at 34-35 weeks[38, 39], and 9% in term neonates with HIE undergoing TH[40]. Publications concerning neuroimaging patterns of brain injury following perinatal asphyxia in moderate and late preterm neonates are scarce[41, 42], as are studies on the neuropathology of hypoxic-ischemic injury in these patients[43]. Parmentier et al. studied the findings of 119 preterm infants (24.0-36.0 weeks) with perinatal asphyxia, with early MRI (n=94) and/or MRI around term (n=66) available for review[42]. In the group of infants ≥32 weeks GA, the predominant injury patterns were hemorrhagic (11%), WM or watershed (43%), and BGT or global (28%). In our study of patients with a similar GA, a predominantly hemorrhagic pattern was seen in 23.5%, suggesting TH may potentially worsen this condition favored by asphyxia and low GA. In our cohort, BGT involvement was seen in half of the patients with MRI, similar to findings in other studies of preterm infants undergoing TH[16, 17]. However, isolated BGT injury was observed in only 12% of the total cases, compared to 56% reported by Okereafor et al. in term neonates[20]. Moderate to severe WM involvement was observed in 76% of patients with MRI, higher than the 57-67% reported in preterm infants undergoing TH[16, 17]. Predominant WM damage without BGT involvement was noted in 23.5% of cases, much higher than the 2% reported in term neonates[20]. Diffuse WM injury in preterm newborns is linked to damage to oligodendrocyte precursor cells (pre-oligodendrocytes) following hypoxia-ischemia and inflammation[44]. Moderate and late preterm infants also show WM microstructure alterations compared to term controls[45]. The higher WM injury prevalence in our cohort highlights the vulnerability of the developing WM in the immature brain to hypoxic-ischemic injury. One-quarter of patients showed no significant injury on imaging, similar to findings in preterm infants with asphyxia[42]. Thirty-five percent of the patients survived without sequelae at 2 years, while 18% did so with moderate-to-severe sequelae, comparable to outcomes in term infants with HIE treated with TH[46]. The main limitations of our study are its retrospective design, the small sample size, and the absence of a control cohort. However, the primary strength is that we have meticulously recorded all laboratory, clinical, neuroimaging, and follow-up data, allowing us to provide a comprehensive profile of our cooled preterm infants. Conclusion Our findings should raise awareness regarding coagulopathy and severe intracranial hemorrhage in late preterm infants with HIE treated with TH, and may encourage the development of specific clinical protocols for this patient group, including comprehensive coagulation assessment and proactive treatment in case of disorders. The higher prevalence of WM injury suggests that the pattern of injury in preterm patients with hypoxic-ischemic insult may differ from that in term neonates. These results underscore the need for caution when extrapolating the potential benefits of TH in preterm infants <36 weeks in the absence of robust scientific evidence. Nevertheless, the significance of our results should be confirmed by further studies, and the safety and efficacy of TH in preterm infants remain to be demonstrated in ongoing clinical trials (clinicaltrials.gov NCT01793129). Abbreviations ADC Apparent Diffusion Coefficient aEEG Amplitude-Integrated Electroencephalogram BGT Basal Ganglia and Thalami CUS Cranial Ultrasonography DWI Diffusion-Weighted Imaging GA Gestational Age GMFCS Gross Motor Function Classification System Hb Hemoglobin HIE Hypoxic-Ischemic Encephalopathy ICH Intracranial Hemorrhage IVH Intraventricular Hemorrhage MRI Magnetic Resonance Imaging PLIC Posterior Limb of the Internal Capsule PT Prothrombin Time RCT Randomized Controlled Trial RDS Respiratory Distress Syndrome SWI Susceptibility-Weighted Imaging TH Therapeutic Hypothermia WM White Matter Declarations Competing Interests The authors have no relevant financial or non-financial interests to disclose Ethics approval The study protocol was approved by the local research ethics committee (approval number HCB/2024/0944) and was conducted following the principles of the Declaration of Helsinki. This committee determined that obtaining informed consent was not required. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution P.R.L. drafted the main manuscript text. Study conception and design: P.R.L. and V.A.B. Data acquisition: P.R.L. and M.F.A. Data analysis and interpretation: P.R.L., V.A.B., and M.F.A. Critical revision of the manuscript: V.A.B. and A.A.A. All authors have read and approved the final version of the manuscript. Available data assessing the effectiveness and safety of TH in late and moderately preterm infants derive from retrospective studies with conflicting safety results[ 15 – 18 ]. Although broadening the criteria in clinical protocols to include late preterm infants to optimize outcomes is based on plausible logic[ 19 ], doing so requires careful consideration of risks and benefits. References Tagin MA, Woolcott CG, Vincer MJ et al (2012) Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy. 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Acta Paediatr Int J Paediatrics 104:138–145. https://doi.org/10.1111/apa.12784 Rao R, Trivedi S, Vesoulis Z et al (2017) Safety and Short-Term Outcomes of Therapeutic Hypothermia in Preterm Neonates 34–35 Weeks Gestational Age with Hypoxic-Ischemic Encephalopathy. J Pediatr 183:37–42. https://doi.org/10.1016/j.jpeds.2016.11.019 Herrera TI, Edwards L, Malcolm WF et al (2018) Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy. Early Hum Dev 125:1–7. https://doi.org/10.1016/j.earlhumdev.2018.08.003 Kim SH, El-shibiny H, Inder T, El-Dib M (2024) Therapeutic hypothermia for preterm infants 34–35 weeks gestational age with neonatal encephalopathy. J Perinatol 44:528–531. https://doi.org/10.1038/s41372-024-01874-x Austin T, Shanmugalingam S, Clarke P (2013) To cool or not to cool? Hypothermia treatment outside trial criteria. Arch Dis Child Fetal Neonatal Ed 98. https://doi.org/10.1136/ARCHDISCHILD-2012-302069 Okereafor A, Allsop J, Counsell SJ et al (2008) Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics 121:906–914. https://doi.org/10.1542/peds.2007-0770 Rutherford M, Counsell S, Allsop J et al (2004) Diffusion-weighted magnetic resonance imaging in term perinatal brain injury: A comparison with site of lesion and time from birth. Pediatrics 114:1004–1014. https://doi.org/10.1542/peds.2004-0222 Garcia-Alix A, Cabañas F, Pellicer A et al (1994) Neuron-specific enolase and myelin basic protein: relationship of cerebrospinal fluid concentrations to the neurologic condition of asphyxiated full-term infants. Pediatrics 93:234–240 Garcia-Alix A, Arnaez J, Arca G et al (2021) Development, Reliability, and Testing of a New Rating Scale for Neonatal Encephalopathy. J Pediatr 235:83–91e7. https://doi.org/10.1016/j.jpeds.2021.04.003 al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D (1999) Assessment of Neonatal Encephalopathy by Amplitude-integrated Electroencephalography. Pediatrics 103:1263–1271. https://doi.org/10.1542/peds.103.6.1263 Hellström-Westas L (2006) Continuous Electroencephalography Monitoring of the Preterm Infant. Clin Perinatol 33:633–647. https://doi.org/10.1016/j.clp.2006.06.003 Bell MJ, Ternberg JL, Feigin RD et al (1978) Neonatal Necrotizing Enterocolitis Therapeutic Decisions Based upon Clinical Staging. http://doi.org/10.1097/00000658-197801000-00001 Papile LA, Burstein J, Burstein R, Koffler H (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92:529–534. https://doi.org/10.1016/s0022-3476(78)80282-0 Palisano R, Rosenbaum P, Walter S et al (1997) Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 39:214–223. https://doi.org/10.1111/j.1469-8749.1997.tb07414.x Higgins RD, Shankaran S (2011) Hypothermia: novel approaches for premature infants. Early Hum Dev. https://doi.org/10.1016/J.EARLHUMDEV.2011.01.004 . 87 Suppl 1 Gancia P, Pomero G (2012) Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: New categories to be enrolled. J Maternal-Fetal Neonatal Med 25:86–88. https://doi.org/10.3109/14767058.2012.715023 Azzopardi D, Strohm B, Linsell L et al (2012) Implementation and conduct of therapeutic hypothermia for perinatal Asphyxial encephalopathy in the UK - Analysis of national data. PLoS ONE 7. https://doi.org/10.1371/journal.pone.0038504 Burnsed J, Zanelli SA (2017) Neonatal therapeutic hypothermia outside of standard guidelines: a survey of U.S. neonatologists. Acta Paediatrica. Int J Paediatrics 106:1772–1779. https://doi.org/10.1111/apa.13983 Bonifacio SL, Liu J, Lee HC et al (2024) Trends in HIE and Use of Hypothermia in California: Opportunities for Improvement. https://doi.org/10.1542/peds.2023-063032 . Pediatrics 154: Schubert A (1995) Side Effects of Mild Hypothermia. J Neurosurg Anesthesiol 7:139–147. https://doi.org/10.1097/00008506-199504000-00021 Benumof JL, Wahrenbrock EA (1977) Dependency of hypoxic pulmonary vasoconstriction on temperature. J Appl Physiol 42:56–58. https://doi.org/10.1152/jappl.1977.42.1.56 Rohrer MJ, Natale AM (1992) Effect of hypothermia on the coagulation cascade. Crit Care Med 20:1402–1405. https://doi.org/10.1097/00003246-199210000-00007 Kim SH, El-shibiny H, Inder T, El-Dib M (2024) Therapeutic hypothermia for preterm infants 34–35 weeks gestational age with neonatal encephalopathy. J Perinatol 44:528–531. https://doi.org/10.1038/s41372-024-01874-x Nakasone R, Fujioka K, Kyono Y et al (2021) Neurodevelopmental outcomes at 18 months of corrected age for late preterm infants born at 34 and 35 gestational weeks. Int J Environ Res Public Health 18:1–10. https://doi.org/10.3390/ijerph18020640 Mitha A, Chen R, Altman M et al (2021) Neonatal Morbidities in Infants Born Late Preterm at 35–36 Weeks of Gestation: A Swedish Nationwide Population-based Study. J Pediatr 233:43–50e5. https://doi.org/10.1016/j.jpeds.2021.02.066 Al Yazidi G, Boudes E, Tan X et al (2015) Intraventricular hemorrhage in asphyxiated newborns treated with hypothermia: a look into incidence, timing and risk factors. BMC Pediatr 15:106. https://doi.org/10.1186/s12887-015-0415-7 Logitharajah P, Rutherford MA, Cowan FM (2009) Hypoxic-Ischemic Encephalopathy in Preterm Infants. Antecedent Factors, Brain Imaging, and Outcome Parmentier CEJ, El Bakkali L, Verhagen EA et al (2024) Brain MRI Injury Patterns across Gestational Age among Preterm Infants with Perinatal Asphyxia. https://doi.org/10.1159/000538986 . Neonatology Laptook AR (2016) Birth Asphyxia and Hypoxic-Ischemic Brain Injury in the Preterm Infant. Clin Perinatol 43:529–545. http://doi.org/10.1016/j.clp.2016.04.010 Volpe JJ (2009) The Encephalopathy of Prematurity-Brain Injury and Impaired Brain Development Inextricably Intertwined. Semin Pediatr Neurol 16:167–178 Kelly CE, Cheong JLY, Gabra Fam L et al (2016) Moderate and late preterm infants exhibit widespread brain white matter microstructure alterations at term-equivalent age relative to term-born controls. Brain Imaging Behav 10:41–49. https://doi.org/10.1007/s11682-015-9361-0 Shankaran S, Pappas A, McDonald SA et al (2012) Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 366:2085–2092. https://doi.org/10.1056/NEJMOA1112066 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 24 Nov, 2024 Reviews received at journal 20 Nov, 2024 Reviewers agreed at journal 16 Nov, 2024 Reviewers invited by journal 16 Nov, 2024 Editor assigned by journal 14 Nov, 2024 Submission checks completed at journal 14 Nov, 2024 First submitted to journal 07 Nov, 2024 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-5412003","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381879200,"identity":"8331e4ce-83f6-4806-97bc-9fdff7f4c432","order_by":0,"name":"Paola Roca-Llabrés","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYPACGwY+ZgaGA6RoSWNgg2nhIVLLYQY2GJOgFnOxsw8f/Kg5L8/GznvwwA8GO3l7QlosZ6cbG/Ycu23YxsyXcLCHIdmwh5AWg9tpbNIMbLcT2Jh5DA4DvcNIpJZ/5+Ba7InTwth2AK4lkaAWy9lpzIa9fclAv/AYHOwxSE7uOUBAi7l0GuODH9/s5Pn5zxh/+FFhZ9veQMhheLnEaBkFo2AUjIJRgAUAAJX8NTZuR24fAAAAAElFTkSuQmCC","orcid":"","institution":"Neonatology Department. BCNatal - Barcelona Center for Maternal Fetal and Neonatal Medicine. Hospital Clínic, Universitat de Barcelona","correspondingAuthor":true,"prefix":"","firstName":"Paola","middleName":"","lastName":"Roca-Llabrés","suffix":""},{"id":381879201,"identity":"6ecf11aa-b3de-4a76-912b-b3b6dca2a573","order_by":1,"name":"Melissa Fontalvo-Acosta","email":"","orcid":"","institution":"Neonatology Department. BCNatal - Barcelona Center for Maternal Fetal and Neonatal Medicine. Hospital Sant Joan de Déu, Universitat de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Melissa","middleName":"","lastName":"Fontalvo-Acosta","suffix":""},{"id":381879202,"identity":"de62d095-2ac8-49d7-830b-51ed37b5e3bf","order_by":2,"name":"Victoria Aldecoa-Bilbao","email":"","orcid":"","institution":"Neonatology Department. BCNatal - Barcelona Center for Maternal Fetal and Neonatal Medicine. Hospital Clínic, Universitat de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Victoria","middleName":"","lastName":"Aldecoa-Bilbao","suffix":""},{"id":381879204,"identity":"bad8e76e-5815-4ead-8727-e55cf1d8081e","order_by":3,"name":"Ana Alarcón","email":"","orcid":"","institution":"Neonatology Department. BCNatal - Barcelona Center for Maternal Fetal and Neonatal Medicine. Hospital Sant Joan de Déu, Universitat de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Alarcón","suffix":""}],"badges":[],"createdAt":"2024-11-07 19:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5412003/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5412003/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05948-y","type":"published","date":"2025-01-02T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71216072,"identity":"22b416fd-9359-49d8-aa0b-8dd164d9ae13","added_by":"auto","created_at":"2024-12-12 08:44:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":473858,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative brain MRI images of different predominant types of lesion and injury patterns\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: BGT: basal ganglia and thalami; ICH: intracranial hemorrhage; MRI: magnetic resonance imaging; SI: signal intensity; WM: white matter.\u003cbr\u003e\n \u003c/em\u003e\u003cstrong\u003eA\u003c/strong\u003e: Axial T2 imaging shows severely affected BGT and WM, representing global injury pattern. \u003cstrong\u003eB\u003c/strong\u003e: Axial T1 imaging with increased SI in BGT, representing BGT injury pattern. \u003cstrong\u003eC\u003c/strong\u003e: Axial T2 imaging shows increased SI in WM, respecting BGT, in representation of WM injury pattern. \u003cstrong\u003eD\u003c/strong\u003e, \u003cstrong\u003eE\u003c/strong\u003e, \u003cstrong\u003eF\u003c/strong\u003e: Three different cases of severe ICH. \u003cstrong\u003eD\u003c/strong\u003e: Retrocerebellar subdural hematoma with mass effect and collapse of the cerebellum and fourth ventricle. \u003cstrong\u003eE\u003c/strong\u003e: Intraparenchymal hematoma in the vermis and left cerebellum with mass effect. \u003cstrong\u003eF\u003c/strong\u003e: Large subdural hematoma with midline shift, subfalcine and transtentorial herniation, and significant mass effect on the brainstem.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5412003/v1/233baff142f40551a476cab2.jpg"},{"id":73093312,"identity":"13c7f487-0ba9-4e1b-84b6-442db646a33b","added_by":"auto","created_at":"2025-01-06 16:13:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1180890,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5412003/v1/04fb07d8-ec4a-4093-a5c5-bc95bc13065d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eTherapeutic Hypothermia in Preterm Infants Under 36 Weeks: Outcomes and Brain MRI Findings\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePerinatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of neonatal brain injury, with therapeutic hypothermia (TH) being the gold standard treatment for newborns with moderate to severe HIE in developed countries[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. TH has proven to be both safe and effective in reducing neurological damage and improving survival rates in term or near-term neonates[\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], but data on preterm infants remains scarce[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Three of the pivotal randomized controlled trials (RCTs) included only newborns\u0026thinsp;\u0026ge;\u0026thinsp;36 weeks gestational age (GA)[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and the two RCTs including neonates from 35 weeks GA did not provide subgroup analyses for those between 35.0 and 35.6 weeks[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the RCTs of hypothermia versus normothermia, strict inclusion criteria were used. The reasons for excluding preterm infants from the major trials were concerns about precise diagnosis and grading of HIE[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], as well as the potential adverse effects of TH in this more vulnerable population[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It is well known that hypothermia in preterm infants is associated with increased mortality and morbidity[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, studies in preterm animal models[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and a pilot study in preterm neonates with necrotizing enterocolitis[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] suggested that it might be safe to offer TH to infants\u0026thinsp;\u0026lt;\u0026thinsp;36 weeks GA.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eMedical records were reviewed retrospectively from preterm neonates born before 36 weeks GA who were admitted at Hospital Cl\u0026iacute;nic Barcelona and Hospital Sant Joan de D\u0026eacute;u (BCNatal) with a diagnosis of HIE treated with TH from January 2019 to June 2024. Pertinent demographic, clinical, laboratory, neuroimaging and neurodevelopment data were recorded. The study protocol was approved by the local research ethics committee (approval number HCB/2024/0944) and was conducted following the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eTH criteria\u003c/h2\u003e\n \u003cp\u003eTo initiate TH in our center, GA of at least 36 weeks is required, along with at least 1 criterion suggestive of perinatal hypoxia-ischemia and evidence of moderate-to-severe encephalopathy or seizures (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In the last decade, our protocol has enabled the provision of TH to neonates with GA between 34.0 and 35.6 weeks and birth weight\u0026thinsp;\u0026ge;\u0026thinsp;1800g. Compassionate use of TH is also considered for neonates of lower GA. This decision is made by the attending neonatologist following careful and individualized consideration.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTherapeutic hypothermia criteria.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"1\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCriteria A, at least 1 of:\u003c/p\u003e\n \u003cp\u003e- Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary pH\u0026thinsp;\u0026lt;\u0026thinsp;7.00)\u003c/p\u003e\n \u003cp\u003e- Base Deficit\u0026thinsp;\u0026ge;\u0026thinsp;16 mmol/L in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth\u003c/p\u003e\n \u003cp\u003e- Apgar score of \u0026le;\u0026thinsp;5 at 10 minutes after birth\u003c/p\u003e\n \u003cp\u003e- Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCriteria B, at least 1 of:\u003c/p\u003e\n \u003cp\u003e- Clinical or subclinical (i.e. electrographic only) seizures\u003c/p\u003e\n \u003cp\u003e- Moderate-to-severe neonatal encephalopathy. Before 2021, this was based on modified Sarnat classification [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]; from 2021, it was defined as \u0026ge;\u0026thinsp;8 points in the Neonatal Encephalopathy-Rating Scale [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eNeurological assessment\u003c/h3\u003e\n\u003cp\u003eTo grade encephalopathy severity, we initially used Garc\u0026iacute;a-Alix et al.\u0026rsquo;s modification of Sarnat staging[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e] with altered consciousness as a key element. Since 2021, we adopted the Neonatal Encephalopathy-Rating Scale[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. A neurological exam at admission is performed by the attending neonatologist. All infants undergo amplitude-integrated EEG (aEEG) before cooling (as part of the entry criteria), throughout cooling, and during rewarming. The aEEG trace is assessed using both voltage criteria[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] and pattern recognition[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eNeonatal morbidities\u003c/h3\u003e\n\u003cp\u003eWe collected data on neonatal complications and morbidities associated with hypoxic-ischemic injury or TH, including: (1) hemodynamic instability requiring\u0026thinsp;\u0026ge;\u0026thinsp;2 vasoactive agents; (2) pulmonary hypertension requiring inhaled nitric oxide; (3) respiratory distress syndrome (RDS) requiring surfactant; (4) acute kidney injury, defined as oliguria and plasma creatinine\u0026thinsp;\u0026ge;\u0026thinsp;1.50 mg/dL at 24\u0026ndash;48 hours; (5) acute liver failure, defined as GOT\u0026thinsp;\u0026ge;\u0026thinsp;500 UI/L or GPT\u0026thinsp;\u0026ge;\u0026thinsp;150 UI/L; (6) metabolic disorders, including: hypoglycaemia\u0026thinsp;\u0026lt;\u0026thinsp;40 mg/dL, hyperglycaemia\u0026thinsp;\u0026gt;\u0026thinsp;180 mg/dL and hypocalcemia\u0026thinsp;\u0026lt;\u0026thinsp;1.10 mmol/L; (7) necrotizing enterocolitis classified as modified Bell\u0026rsquo;s staging\u0026thinsp;\u0026ge;\u0026thinsp;II[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]; (8) microbiologically confirmed sepsis; (9) anemia, defined as Hb\u0026thinsp;\u0026lt;\u0026thinsp;13 g/dL; (10) thrombocytopenia\u0026thinsp;\u0026lt;\u0026thinsp;50/mm\u003csup\u003e3\u003c/sup\u003e; (11) coagulopathy, defined as prothrombin time (PT)\u0026thinsp;\u0026lt;\u0026thinsp;40%, and considered severe if PT\u0026thinsp;\u0026lt;\u0026thinsp;20%; (12) hypofibrinogenemia, defined as fibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;1.0 g/L; (13) intracranial hemorrhage (ICH) including: intraventricular hemorrhage (IVH) grade\u0026thinsp;\u0026ge;\u0026thinsp;2[\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], parenchymal, subarachnoid and subdural bleeds; and (14) seizures, either clinical or subclinical (electrographic only).\u003c/p\u003e\n\u003ch3\u003eNeuroimaging\u003c/h3\u003e\n\u003cp\u003eNeonatal neuroimaging was classified based on MRI. When MRI was unavailable, cranial ultrasonography (CUS) was used to assess for bleeding. CUS scans were performed at different axes of the coronal and sagittal planes through the anterior fontanel, using 5- to 12-MHz sector, microconvex or linear probes. MRI was obtained with equipment operating at 1.5 or 3 Tesla. Sagittal, axial, and coronal T1- and T2-weighted images, as well as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) maps and susceptibility-weighted imaging (SWI) were reviewed. Images were assessed for quality, normal anatomy, and acquired lesions.\u003c/p\u003e\n\u003cp\u003eThe basal ganglia and thalami (BGT), white matter (WM) and cortex were evaluated as described by Rutherford et al.[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Signal intensity was graded as mild, moderate, or severe in the BGT, and moderate or severe in the WM. Cortex involvement was defined by loss of cortical markings and highlighting. The posterior limb of the internal capsule (PLIC) was described as normal, abnormal, or not evaluable due to low postmenstrual age at the time of MRI.\u003c/p\u003e\n\u003cp\u003eThe cerebellum and brainstem were classified as normal, primary injury (hypoxic-ischemic damage), or secondary (hemorrhage or compression due to bleeding). The presence of ICH was recorded. Special attention was paid to the distortion or displacement of brain structures caused by ICH with mass effect.\u003c/p\u003e\n\u003cp\u003eMRI findings were classified based on the predominant type of lesion into three categories: I-hypoxic-ischemic injury; II-severe intracranial hemorrhage; III-normal or mild findings. In those with hypoxic-ischemic injury, three injury patterns were identified[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]: global, BGT and WM (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTwo expert neonatologists specialized in neuroimaging blinded to the infant\u0026rsquo;s clinical status, independently reviewed the MRI scans. Disagreements were resolved by consensus.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClassification of neuroimaging main findings according to the predominant type of injury.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePredominant type of lesion\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInjury pattern\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFindings\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-I Injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlobal\u003c/p\u003e\n \u003cp\u003eBGT\u003c/p\u003e\n \u003cp\u003eWM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBGT lesions and severe WM damage\u003c/p\u003e\n \u003cp\u003eBGT lesions with mild or moderate WM changes\u003c/p\u003e\n \u003cp\u003eModerate WM damage only\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere ICH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemorrhagic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere ICH causing mass effect\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal or mild findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal or mild changes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild WM changes, non-complicated ICH, or normal findings\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: BGT: basal ganglia and thalami; H-I: hypoxic-ischemic; ICH: intracranial hemorrhage; WM: white matter.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNeurodevelopmental Assessment\u003c/em\u003e\u003cbr\u003eAfter discharge, infants enter a follow-up program. At 2 years corrected age, those with atypical neurodevelopment undergo standardized evaluation using the Bayley Scales of Infant Development III. Severe disability was defined by any of the following: Bayley III composite cognitive score \u0026lt;70, cerebral palsy with Gross Motor Function Classification System (GMFCS) levels 3-5[28], blindness, or severe hearing loss (\u0026gt;70 dB or requiring cochlear implants). Moderate disability was defined as: Bayley III composite cognitive score 70-84, cerebral palsy with GMFCS level 2, seizure disorder or moderate hearing deficit (40-70 dB).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003cbr\u003eData analysis was performed using SPSS Statistics 29.0.2.0 (IBM, Chicago, IL, USA). Demographic data, clinical features, and outcomes were summarized using descriptive statistics presented as numbers and percentages or median with interquartile range [25\u003csup\u003eth\u003c/sup\u003e; 75\u003csup\u003eth\u0026nbsp;\u003c/sup\u003ecentile] as appropriate. Univariate analysis was performed using the Chi-squared test for categoric variables. Statistical significance was considered as a bilateral \u003cem\u003ep\u003c/em\u003e-value less than 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSeventeen neonates born at less than 36 weeks of gestation with HIE were included, all receiving TH started within the first 6 hours of life. Of these, 6 (35.3%) had moderate HIE, and 11 (64.7%) had severe HIE. Median GA was 34.4 weeks. Perinatal history along with neonatal characteristics and short-term outcomes are shown in Table 3. Nine patients (52.9%) presented hemodynamic instability, 14 (82.3%) required mechanical ventilation, and 9 (52.9%) received at least 2 fresh plasma transfusions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Perinatal history, baseline neonatal and neurological characteristics, and short-term outcomes.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"378\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 378px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePregnancy and Delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003ePreeclampsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eGestational diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eFetal isoimmunization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003ePlacental abruption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eCardiotocographic abnormality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eFeto-maternal transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eEmergency caesarean delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e16 (94.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 378px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeonatal Characteristics and Perinatal Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eGestational age (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e34.4 [34.1 \u0026ndash; 35.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eBirth weight (grams)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2300 [2060 - 2493]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eMale sex\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eAdvanced resuscitation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eApgar minute 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0 [0 \u0026ndash; 1]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eApgar minute 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2 [0 \u0026ndash; 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eApgar minute 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5 [3 \u0026ndash; 7]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eUmbilical artery pH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6.88 [6.56 \u0026ndash; 6.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003epH in first blood sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7.00 [6.81 \u0026ndash; 7.16]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eBase deficit in first blood sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e20.4 [28.3 \u0026ndash; 13.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eLactate in first blood sample (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e13.2 [7 \u0026ndash; 22]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eTransferred from another center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 378px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological assessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHours of life at the start of TH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3 [1 \u0026ndash; 5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eModerate encephalopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eSevere encephalopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e11 (64.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eaEEG pattern at admission\u003c/p\u003e\n \u003cp\u003eNormal/discontinuous\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBurst \u0026ndash; suppression \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLow voltage/flat trace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (35.3)\u003c/p\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eAge at MRI (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.5 [3 \u0026ndash; 6.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 378px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eShort-term outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRespiratory distress syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003ePulmonary hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eAcute Kidney injury\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eAcute liver failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHypoglycemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHyperglycemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHypocalcemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eNecrotizing enterocolitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eSepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e13 (76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eCoagulopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eValues are expressed as number (%) or median [25\u003csup\u003eth\u003c/sup\u003e - 75\u003csup\u003eth\u003c/sup\u003e centile].\u003cem\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;Abbreviations: aEEG: amplitude-integrated electroencephalogram; MRI: magnetic resonance imaging.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEight patients died (47%). Death following withdrawal of care due to severe hypoxic-ischemic injury with poor neurological prognosis occurred in 3 neonates (17.6%). Mortality from complications was observed in 5 cases (29.4%), 4 cases of severe ICH with mass effect, and 1 case of necrotizing enterocolitis. No differences in mortality were observed based on GA, weight, sex (71.4% males and 30% females; p=0.092), the need for advanced resuscitation, the degree of initial acidosis, the use of inotropes, mechanical ventilation, inhaled nitric oxide or insulin, the severity of HIE (1 death in moderate HIE (16.7%) and 7 in severe HIE (63.6%); p=0.064), or the presence of seizures (5 deaths in patients with no seizures (45.5%) and 3 in cases with seizures (50%); p=0.858). However, the aEEG trace at admission was associated with significantly higher mortality in those with burst-suppression, low voltage, or flat patterns (8 deaths, 72.7%), with no mortality in those with normal or discontinuous trace (p=0.004).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4 highlights hemostatic abnormalities as significant contributors to morbidity and mortality. \u0026nbsp;Hypofibrinogenemia was strongly associated with severe ICH (p=0.01). While no significant association was found with overall mortality, subgroup analysis showed neonates with hypofibrinogenemia had a higher probability of death unrelated to therapeutic withdrawal (p=0.03).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Hemostatic disorders and the predominant type of lesion in neonatal neuroimaging.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 408px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePredominant type of lesion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eN = 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eMild findings\u003c/p\u003e\n \u003cp\u003e(n = 4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eH-I injury\u003c/p\u003e\n \u003cp\u003e(n = 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eSevere ICH\u003c/p\u003e\n \u003cp\u003e(n = 4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eCoagulopathy\u003c/p\u003e\n \u003cp\u003e(PT Quick \u0026lt; 40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e12 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e6 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e4 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eSevere Coagulopathy\u003c/p\u003e\n \u003cp\u003e(PT Quick \u0026lt; 20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e3 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003cp\u003e(\u0026lt; 50.000 mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e3 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e4 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.590\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eHypofibrinogenemia\u003c/p\u003e\n \u003cp\u003e(\u0026lt; 1g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e4 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are expressed in numbers (%).\u0026nbsp;\u003cbr\u003e\u003cem\u003eAbbreviations: PT: prothrombin time.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRadiological findings, grouped by predominant lesion type, are shown in Table 5. In cases of hypoxic-ischemic injury, detailed damage patterns are provided. Severe ICH was observed in 4 neonates (23.5%), while other 4 (23.5%) had no identifiable or mild lesions. Regarding the affected regions, moderate-to-severe WM injury was seen in 12 neonates (75% of cases with MRI), and BGT involvement occurred in 8 (50% of cases with MRI), with 6 classified as severe. Figure 1 exhibits representative images from our patients, illustrating the main patterns of hypoxic-ischemic and hemorrhagic lesions. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Main findings and differential patterns on neuroimaging.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"385\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 312px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePredominant type of lesion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN = 17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eH-I Injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eGlobal\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eBGT\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eWM\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 312px;\"\u003e\n \u003cp\u003eSevere ICH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 312px;\"\u003e\n \u003cp\u003eMild changes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvolved regions of injury\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClassification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003eN = 16\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eBGT\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003ePLIC\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eAbnormal\u003c/p\u003e\n \u003cp\u003eEquivocal\u003c/p\u003e\n \u003cp\u003eN.A.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eWM\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e7 (43.7)\u003c/p\u003e\n \u003cp\u003e5 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eCortex\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eAbnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e7 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eCerebellum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eH-I injury\u003c/p\u003e\n \u003cp\u003eSecondary injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eBrainstem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eH-I injury\u003c/p\u003e\n \u003cp\u003eSecondary injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3 (18.7)\u003c/p\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are expressed in numbers (%).\u0026nbsp;\u003cbr\u003e\u003cem\u003eAbbreviations: BGT: basal ganglia and thalami; H-I: hypoxic-ischemic; ICH: intracranial hemorrhage; PLIC: \u0026nbsp;posterior limb of the internal capsule; WM: white matter.\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003csup\u003e1\u003c/sup\u003e Based on Okereafor et al. [18]\u003cbr\u003e\u003csup\u003e2\u003c/sup\u003e One patient died due to severe intracranial hemorrhage (ICH) before MRI could be performed. Ultrasound confirmed IVH grade III with acute ventricular dilatation and intracranial hypertension. This case is included in the classification of predominant injury sites. However, since no MRI was obtained, it is not possible to determine the extent of damage in other regions.\u003cbr\u003e\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eBased on Rutherford et al. [19]\u003cbr\u003e\u003csup\u003e4\u003c/sup\u003e Not assessable due to the patient\u0026apos;s postmenstrual age at the time of the MRI.\u003c/p\u003e\n\u003cp\u003eOf the 9 surviving patients (52.9%), at 2-year follow-up, 6 (66.7%) had normal neurodevelopment, with 1 presenting isolated language delay according to the Bayley III test. Two patients (22.2%) showed moderate disability based on cognitive scores, one of them with a severe WM injury pattern on MRI, and the other with mild findings. Severe disability at 2 years of corrected age was observed in 1 patient (11.1%) with cerebral palsy with level 3 GMFCS and hearing loss, associated with a BGT injury pattern on the neonatal MRI.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study shows that preterm infants undergoing TH for HIE face a high incidence of complications, primarily coagulation disorders and ICH, which may be fatal. These multifactorial coagulation abnormalities are challenging to manage, even with blood products. One in two patients does not survive, and among those who do, one in three experiences neurological sequelae.\u003c/p\u003e\n\u003cp\u003eFollowing the demonstration that TH is associated with a reduction in death and disability at \u0026ge;18 months as well as continued neuroprotection in childhood for term and near-term neonates with HIE, the exclusion of patients with lower gestational ages began to raise clinical and ethical concerns[19, 29]. Despite the lack of trials for moderately preterm infants, the biological plausibility of its benefits, the absence of other treatments, and favorable preclinical safety data[12, 13] led several centers to adopt TH under compassionate use[30, 31]. By 2015, 22% of cooled neonates did not meet the original RCT criteria[15]. Currently, clinical practice remains highly variable for patients not meeting standard inclusion criteria[32, 33].\u003c/p\u003e\n\u003cp\u003eOne of the main reasons for excluding preterm infants from the original RCTs was the concern that the risk of side effects of TH would be higher in this population[7, 10]. Evidence regarding the safety and effectiveness of TH in preterm infants comes from retrospective studies, which have yielded mixed results[15\u0026ndash;18]. Patients in our study showed significant organ dysfunction.\u003c/p\u003e\n\u003cp\u003eOne potential concern is how hypothermia might affect neonates with pulmonary immaturity by reducing surfactant production[34], increasing pulmonary vascular resistance[35], and raising oxygen consumption[34]. However, in our series, only 1 patient required surfactant, and 2 required nitric oxide for pulmonary hypertension, both with good outcomes. It has also been suggested that hypothermia may suppress the immune system and increase infection risk[34], but no cases of early or late-onset sepsis were observed in our cohort.\u003c/p\u003e\n\u003cp\u003eIn our study, the most frequent complications were anemia and coagulopathy. The high prevalence of anemia is expected considering two factors. First, more than half of the cases were associated with a sentinel event, i.e., placental abruption or feto-maternal transfusion. Second, postnatal hemorrhagic complications likely caused acute anemia requiring transfusion.\u003c/p\u003e\n\u003cp\u003eThe hemostatic disorders found in our study are particularly concerning due to their high prevalence and severity. Nearly three-quarters of the cases exhibited coagulation abnormalities, with half experiencing severe coagulopathy and requiring at least 2 fresh frozen plasma transfusions. Almost half of the patients presented with some degree of ICH. Notably, severe, life-threatening ICH was the predominant finding in nearly one-quarter of the cases. Hypofibrinogenemia was associated with severe ICH and mortality unrelated to withdrawal of care.\u003c/p\u003e\n\u003cp\u003eCoagulation disorders may occur in the context of perinatal hypoxia-ischemia and can be exacerbated by hypothermia and acute liver dysfunction. The effects of TH on the coagulation cascade and platelet function could increase the risk of ICH, especially in the setting of hypoxia-ischemia[36]. In the main TH RCTs, coagulopathy was reported in 14.5% to 41% of cases[3\u0026ndash;6]. Retrospective studies of moderate-late preterm infants report coagulations abnormalities ranging from 30% to 64%[16\u0026ndash;18].\u003c/p\u003e\n\u003cp\u003eResults on ICH in cooled preterm infants with HIE vary across different studies. In a matched retrospective study, Kim et al. reported IVH in 30% of infants at 34-35 weeks GA and 10% in those \u0026ge;36 weeks but did not describe other types of ICH[37]. Rao et al. found a 65.5% coagulopathy rate in their preterm group (34-35 weeks, n=31), with 6.7% experiencing parenchymal hemorrhage, 3.3% grade 2 IVH, and 10% subdural bleeds, while no hemorrhages occurred in the term group (n=32)[16]. In a retrospective cohort study of 30 preterm infants \u0026lt;36\u0026nbsp;weeks GA, Herrera et al. reported that 50% required treatment for coagulopathy, with a 38% incidence of ICH, half presenting with severe IVH or parenchymal hemorrhage[17].\u003c/p\u003e\n\u003cp\u003eIn our study, 2 patients (11.7%) developed grade 2 or 3 IVH. One of them had grade 3 IVH with significant acute ventricular dilatation, leading to cerebral edema and intracranial hypertension with compression of the posterior fossa structures and brainstem. Moderate and late preterm infants have a low incidence of IVH, although precise data are lacking because routine ultrasound screening is not performed for these gestational ages. An absolute risk of 1-3% for IVH has been observed in preterm infants at 34-35 weeks[38, 39], and 9% in term neonates with HIE undergoing TH[40].\u003c/p\u003e\n\u003cp\u003ePublications concerning neuroimaging patterns of brain injury following perinatal asphyxia in moderate and late preterm neonates are scarce[41, 42], as are studies on the neuropathology of hypoxic-ischemic injury in these patients[43]. Parmentier et al. studied the findings of 119 preterm infants (24.0-36.0 weeks) with perinatal asphyxia, with early MRI (n=94) and/or MRI around term (n=66) available for review[42]. In the group of infants \u0026ge;32 weeks GA, the predominant injury patterns were hemorrhagic (11%), WM or watershed (43%), and BGT or global (28%). In our study of patients with a similar GA, a predominantly hemorrhagic pattern was seen in 23.5%, suggesting TH may potentially worsen this condition favored by asphyxia and low GA.\u003c/p\u003e\n\u003cp\u003eIn our cohort, BGT involvement was seen in half of the patients with MRI, similar to findings in other studies of preterm infants undergoing TH[16, 17]. However, isolated BGT injury was observed in only 12% of the total cases, compared to 56% reported by Okereafor et al. in term neonates[20].\u003c/p\u003e\n\u003cp\u003eModerate to severe WM involvement was observed in 76% of patients with MRI, higher than the 57-67% reported in preterm infants undergoing TH[16, 17]. Predominant WM damage without BGT involvement was noted in 23.5% of cases, much higher than the 2% reported in term neonates[20]. Diffuse WM injury in preterm newborns is linked to damage to oligodendrocyte precursor cells (pre-oligodendrocytes) following hypoxia-ischemia and inflammation[44]. Moderate and late preterm infants also show WM microstructure alterations compared to term controls[45]. The higher WM injury prevalence in our cohort highlights the vulnerability of the developing WM in the immature brain to hypoxic-ischemic injury.\u003c/p\u003e\n\u003cp\u003eOne-quarter of patients showed no significant injury on imaging, similar to findings in preterm infants with asphyxia[42]. Thirty-five percent of the patients survived without sequelae at 2 years, while 18% did so with moderate-to-severe sequelae, comparable to outcomes in term infants with HIE treated with TH[46].\u003c/p\u003e\n\u003cp\u003eThe main limitations of our study are its retrospective design, the small sample size, and the absence of a control cohort. However, the primary strength is that we have meticulously recorded all laboratory, clinical, neuroimaging, and follow-up data, allowing us to provide a comprehensive profile of our cooled preterm infants.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings should raise awareness regarding coagulopathy and severe intracranial hemorrhage in late preterm infants with HIE treated with TH, and may encourage the development of specific clinical protocols for this patient group, including comprehensive coagulation assessment and proactive treatment in case of disorders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe higher prevalence of WM injury suggests that the pattern of injury in preterm patients with hypoxic-ischemic insult may differ from that in term neonates.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese results underscore the need for caution when extrapolating the potential benefits of TH in preterm infants \u0026lt;36 weeks in the absence of robust scientific evidence. Nevertheless, the significance of our results should be confirmed by further studies, and the safety and efficacy of TH in preterm infants remain to be demonstrated in ongoing clinical trials (clinicaltrials.gov NCT01793129).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eApparent Diffusion Coefficient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaEEG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmplitude-Integrated Electroencephalogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBGT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBasal Ganglia and Thalami\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCranial Ultrasonography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDWI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiffusion-Weighted Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGestational Age\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGMFCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGross Motor Function Classification System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHb\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHypoxic-Ischemic Encephalopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntracranial Hemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntraventricular Hemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePLIC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePosterior Limb of the Internal Capsule\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProthrombin Time\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized Controlled Trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRespiratory Distress Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSWI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSusceptibility-Weighted Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTherapeutic Hypothermia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhite Matter\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThe study protocol was approved by the local research ethics committee (approval number HCB/2024/0944) and was conducted following the principles of the Declaration of Helsinki. This committee determined that obtaining informed consent was not required.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eP.R.L. drafted the main manuscript text. Study conception and design: P.R.L. and V.A.B. Data acquisition: P.R.L. and M.F.A. Data analysis and interpretation: P.R.L., V.A.B., and M.F.A. Critical revision of the manuscript: V.A.B. and A.A.A. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAvailable data\u003c/h2\u003e \u003cp\u003eassessing the effectiveness and safety of TH in late and moderately preterm infants derive from retrospective studies with conflicting safety results[\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although broadening the criteria in clinical protocols to include late preterm infants to optimize outcomes is based on plausible logic[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], doing so requires careful consideration of risks and benefits.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTagin MA, Woolcott CG, Vincer MJ et al (2012) Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy. 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Brain Imaging Behav 10:41\u0026ndash;49. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11682-015-9361-0\u003c/span\u003e\u003cspan address=\"10.1007/s11682-015-9361-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShankaran S, Pappas A, McDonald SA et al (2012) Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 366:2085\u0026ndash;2092. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMOA1112066\u003c/span\u003e\u003cspan address=\"10.1056/NEJMOA1112066\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Therapeutic Hypothermia, Hypoxic-ischemic encephalopathy, Premature Infant, Coagulation disorders, Neurodevelopmental Outcomes","lastPublishedDoi":"10.21203/rs.3.rs-5412003/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5412003/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: Perinatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term neonates, but its safety and efficacy in neonates \u0026lt;36 weeks’ gestational age (GA) remains unclear. This study aimed to evaluate the outcomes of preterm infants with HIE treated with TH.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Retrospective analysis of preterm infants (\u0026lt;36w’GA) treated with TH (01/2019-06/2024). Data on demographics, clinical complications, coagulation profiles, brain magnetic resonance imaging (MRI), and neurodevelopment outcomes were analyzed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Seventeen patients were included (median GA 34.4w; median birth weight 2300g), 58.8% were male. Placental abruption was identified in 7 cases (41.2%), and 8 (47.1%) required advanced resuscitation. Thirteen patients (76.5%) presented anemia, 12 (70.6%) coagulopathy, 9 (52.9%) thrombocytopenia, and 9 (52.9%) acute liver failure. Hypofibrinogenemia (\u0026lt;1g/L) was significantly associated with severe intracranial hemorrhage (ICH) and mortality unrelated to withdrawal of care. MRI findings were classified based on the predominant lesion: I-hypoxic-ischemic injury, II-severe ICH, or III-normal/mild findings. Severe ICH was the predominant lesion in 4 cases (23.5%). White matter injury was seen in 12 (76%). Death occurred in 8 cases (47.1%), with 3 (37.5%) resulting from withdrawal of care and 5 (62.5%) from fatal complications. Of the 9 surviving patients, at 2 years, 6 (66.7%) had normal neurodevelopment, while 1 (11.1%) had severe disability.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Coagulation abnormalities, particularly hypofibrinogenemia, significantly increase the risk of severe ICH and mortality in \u0026lt;36w infants treated with TH. The safety and efficacy of TH in this population require further investigation.\u003c/p\u003e","manuscriptTitle":"Therapeutic Hypothermia in Preterm Infants Under 36 Weeks: Outcomes and Brain MRI Findings","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-12 08:44:47","doi":"10.21203/rs.3.rs-5412003/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-24T09:46:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-20T11:46:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37206212563523318397710701264922504498","date":"2024-11-16T13:04:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-16T12:58:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-14T19:03:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-14T10:39:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-11-07T19:05:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4eabc7f5-6df5-4134-a441-7bd2bc45566f","owner":[],"postedDate":"December 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:02:14+00:00","versionOfRecord":{"articleIdentity":"rs-5412003","link":"https://doi.org/10.1007/s00431-024-05948-y","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2025-01-02 15:57:34","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-12-12 08:44:47","video":"","vorDoi":"10.1007/s00431-024-05948-y","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05948-y","workflowStages":[]},"version":"v1","identity":"rs-5412003","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5412003","identity":"rs-5412003","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}