Hypoxic-Ischemic Encephalopathy (HIE) is among the most critical complications affecting full-term or near-term newborns[1]. It results from a disruption in cerebral blood flow and oxygen supply to the brain, leading to significant neurological damage[2]. Globally, an estimated 1.2 million newborns are affected annually, with about 96% of these cases occurring in low and middle-income countries[3]. Moderate-to-severe HIE in term and late preterm infants remains a significant cause of neonatal mortality, acute brain injury, and long-term neurodevelopmental disorders[4]. Outcomes are often poor, with 40% to 60% of affected infants either succumbing to the condition or surviving with disabilities such as cerebral palsy, epilepsy, or intellectual impairment[5]. Mortality rates for infants with moderate HIE are estimated at 10%, while those with severe HIE can be as high as 85%. Neurological impairment affects approximately 30% of moderate cases and up to 75% of severe cases[6]. A mild reduction in brain temperature (by 2-4°C), initiated within six hours of birth, provided significant neuroprotection in animal models[7]. The neuroprotective mechanism of therapeutic hypothermia is multifactorial and attributable to broad inhibitory activity against a variety of harmful cellular processes. Therapeutic hypothermia works by suppressing multiple damaging cellular processes and has become the standard of care for neonates at ≥35 weeks of gestation with moderate to severe HIE, provided it is started within six hours of birth[8]. Whole body TH is the established treatment for newborns diagnosed with moderate to severe HIE. TH decreases rates of mortality and neurodevelopmental disability by protecting the brain from secondary energy failure if started within 6 hours of life. Currently, the International Liaison Committee on Resuscitation recommends TH only for term or near-term infants with moderate to severe encephalopathy[9]. The therapy involves cooling either whole-body or selective head cooling for a duration of 72 hours to achieve neuroprotection[10]. As of 2023, TH is widely recognized as an effective intervention and should be administered whenever clinically indicated. However, even with TH, up to 29% of affected neonates continue to experience adverse neurodevelopmental outcomes[11]. Aim and Objectives To evaluate the clinical efficacy of therapeutic hypothermia in neonates diagnosed with hypoxic-ischemic encephalopathy and to assess neurodevelopmental outcomes at 6 months of age in neonates who have undergone therapeutic hypothermia, as follow-up at JLN Hospital & Rajkiya Mahila Chikitsalya, Ajmer, Rajasthan.

This prospective, observational, hospital-based cross-sectional study was planned to evaluate the clinical outcomes of neonates with Hypoxic-Ischemic Encephalopathy undergoing therapeutic hypothermia, specifically assessing its effectiveness in reducing mortality and long-term neurodevelopmental impairments. The study was conducted over a period from October 2023 to September 2024 at the Department of Paediatrics, JLN Medical College & Associated Group of Hospitals, Ajmer, Rajasthan, following approval from the institutional Ethical Committee. A sample size of 130 inborn babies with moderate or severe encephalopathy were enrolled using a purposive sampling technique. Inclusion Criteria Neonates greater than 34 weeks gestation or with a birth weight greater than 2000g who presented with evidence of moderate or severe neonatal encephalopathy and met at least one of the following criteria were included: • A sentinel event prior to delivery (such as uterine rupture, profound bradycardia, or cord prolapse) • Low Apgar scores (less than 5 at 10 minutes of life) • Prolonged resuscitation at birth (chest compressions and/or intubation and/or mask ventilation at 10 minutes) • Severe acidosis (pH < 7.0 from umbilical arterial or arterial blood within 60 minutes of birth) • Abnormal base excess (<-10 mEq/L from umbilical arterial or arterial blood within 60 minutes of birth) Written informed consent was obtained from the parents for the child's participation. Exclusion Criteria Infants with the following conditions were excluded: • Gestational age less than 34 weeks or birth weight less than 2000g • Severe congenital anomalies, genetic syndromes, or established metabolic disorders • Major intracranial hemorrhage or septicemia • Significant bleeding diathesis • Age older than 6 hours before the initiation of hypothermia treatment • Only evidence of mild neonatal encephalopathy • Lack of parental consent for participation Methodology Newborns with moderate/severe encephalopathy (per Thompson score) received 72 hours of whole-body cooling using the PCM-based MiraCradle to maintain a core rectal temperature of 33.5°C ± 0.5°C. Temperature and vital signs were continuously and frequently monitored. Supportive care, including seizure management (phenobarbitone first-line), followed standard protocols. After 72 hours, or for major adverse events/exclusion discovery, controlled rewarming was performed at 0.2°C-0.5°C per hour until the temperature reached 36.5°C. Statistical Analysis The collected data was entered into a Microsoft Excel sheet by the investigator on the same day to minimize any potential data entry bias. Continuous or quantitative data were summarized using mean and standard deviation. The difference between two means was assessed using Student's t-test. Discrete or qualitative data were presented as proportions, and the significance of differences in proportions was evaluated using the chi-square test. A 95% confidence level was maintained for all statistical analyses.

Table 1: Demographic and Maternal-Obstetric Characteristics Demographic and Clinical Characteristics Number (%) (n=130) Sex Male 81 (62.3%) Female 49 (37.7%) Type of Delivery Normal Vaginal 61 (46.9%) LSCS 49 (37.7%) Forceps 11 (8.5%) Breech 9 (6.9%) Maternal Complications Pregnancy-Induced Hypertension (PIH) 17 (13.1%) Antepartum Hemorrhage (APH) 13 (10.0%) Thyroid Disorder 1 (0.8%) Diabetes 11 (8.5%) Intrapartum Complications Fetal Heart Rate Decelerations 87 (66.9%) Cord Prolapse 30 (23.1%) Uterine Rupture 21 (16.2%) Maternal Pyrexia 15 (11.5%) Shoulder Dystocia 14 (10.8%) Maternal Hemorrhage 8 (6.2%) Table 2: APGAR Scores, Resuscitation, and Clinical Seizures Clinical Parameters Number (n=130) Percentage APGAR Score (At 10 min) <5 108 83.1 >5 22 16.9 Resuscitation Required at 10 Minutes Yes 118 90.8 No 12 9.2 Clinical Seizure Yes 73 56.2 No 57 43.8 Table 3: HIE Severity and Anticonvulsant Use Clinical Parameter Number (n=130) Percentage Severity of Hypoxic-Ischemic Encephalopathy (HIE) Moderate 87 66.9 Severe 43 33.1 Number of Anticonvulsants 1 49 67.1 >2 24 32.9 Table 4: Trend in Thompson Score During Therapeutic Hypothermia Thompson Score Assessment Mean + SD Prior to Cooling 14.74 + 2.23 Day 1 14.38 + 2.18 Day 2 12.65 + 2.35 Day 3 9.53 + 2.79 Table 5: Adverse Events Observed During NICU Stay Adverse Events Number (%) Intracranial Hemorrhage (USG) 11 (8.5%) Pulmonary Hemorrhage 4 (3.1%) Persistent Pulmonary Hypertension of Newborn (PPHN) 16 (12.3%) Acute Kidney Injury (AKI) 29 (22.3%) Coagulopathy 25 (19.2%) Thrombocytopenia 42 (32.3%) Sepsis 38 (29.2%) Table 6: Neonatal Outcome Neonatal Outcome Number (%) During Treatment at Health Facility Died Before Discharge 16 (12.3%) Discharged 114 (87.7%) During Follow-up Period of 3 Months Died 4 (3.51%) Survived 110 (96.49%) During Follow-up Period of 6 Months Died 8 (7.27%) Survived 102 (92.73%) Table 7: Amiel Tison Score - Neurodevelopmental Assessment Neurodevelopmental Status Number (%) At the Time of Discharge Normal 92 (70.8%) Moderately Abnormal 29 (22.3%) Severely Abnormal 9 (6.9%) At 3 Months Follow-up Normal 69 (62.7%) Moderately Abnormal 28 (25.5%) Severely Abnormal 13 (11.8%) At 6 Months Follow-up Normal 60 (58.8%) Moderately Abnormal 30 (29.4%) Severely Abnormal 12 (11.8%)

The present study was conducted with the primary objective of evaluating the clinical efficacy of therapeutic hypothermia in neonates with moderate to severe HIE and assessing their neurodevelopmental outcomes till six months of age. The study was hospital-based, prospective, and observational in design and carried out in the Department of Paediatrics at JLN Medical College & Associated Group of Hospitals, Ajmer, Rajasthan over a 12-month period from October 2023 to September 2024. A total of 130 neonates who met the eligibility criteria were included using purposive sampling. Gender Distribution and Obstetric Factors A male predominance was observed, with 62.3% of neonates being male, consistent with reports by Wang Z et al[12] who reported 64.5% male predominance. Normal vaginal delivery was the most common mode (46.9%), followed by cesarean section (37.7%) and instrumental deliveries (15.4%). Pregnancy-induced hypertension (13.1%) was the most frequent maternal complication followed by antepartum hemorrhage (10%) and gestational diabetes (8.5%). The most common intrapartum complication was fetal heart rate deceleration (66.9%), which indicates acute fetal distress and a high likelihood of hypoxic injury[12]. Other complications like cord prolapse (23.1%) and uterine rupture (16.2%) are obstetric emergencies associated with sudden interruption of oxygen supply. Maternal pyrexia (11.5%) may also indicate intrauterine infection, which could exacerbate neonatal brain injury. Clinical Presentation In our study, the majority (83.1%) of neonates had APGAR scores ≤5 at 10 minutes, indicating persistent low vitality and severe birth asphyxia. Resuscitation was required up to 10 minutes of life in 90.8% of neonates, correlating with the high rate of low APGAR scores. This suggests that most neonates experienced severe perinatal stress and required advanced resuscitative efforts, a known risk factor for HIE. Clinical seizures were observed in 56.2% of neonates, with 67.1% managed with a single anticonvulsant and 32.9% requiring two or more anticonvulsants. The presence of seizures indicates significant brain injury, commonly involving the cortex and subcortical structures. HIE Severity and Thompson Score In our study, the majority of neonates (66.9%) had moderate HIE, while 33.1% had severe HIE. The mean Thompson score was 14.74 before the initiation of cooling and gradually declined to 9.53 by day 3 of life. This downward trend reflects progressive neurological recovery and is consistent with the expected response to therapeutic hypothermia. Adverse Events Several adverse events were observed in neonates undergoing therapeutic hypothermia, with thrombocytopenia (32.3%) and sepsis (29.2%) being the most frequently reported complications[13]. Other significant issues included acute kidney injury in 22.3% and coagulopathy in 19.2% of neonates. Less frequent but severe complications such as persistent pulmonary hypertension of the newborn (12.3%), intraventricular hemorrhage (8.5%), and pulmonary hemorrhage (3.1%) were also noted. One of the more serious complications observed was PPHN, present in 12.3% of our neonates, similar to previous reports where the incidence ranged from 13% to 25% in asphyxiated neonates treated with hypothermia[14]. Moreover, studies indicate that neonates receiving TH have about 2.5 times higher risk of PPHN compared to those not treated with cooling[15]. Park J et al[16] found that 4.7% of neonates undergoing TH required inhaled nitric oxide therapy. Persistent pulmonary hypertension is closely linked to perinatal asphyxia, and elevated body temperature during rewarming may lead to hemoconcentration, increased blood viscosity, and narrowing of pulmonary blood vessels[17]. Clinical Outcomes and Efficacy Shankaran S et al[18] reported no increase in moderate or severe disabilities at 18-22 months among cooled infants. In fact, the rates of disabling cerebral palsy were lower (19% in the TH group vs. 30% in controls) and the proportion of infants with Mental Development Index <70 was also reduced (25% vs. 39%). In the present study, 87.7% of neonates were successfully discharged, while 12.3% died during treatment. Therapeutic hypothermia works best when initiated within the first six hours of life, often referred to as the "therapeutic window." If cooling is delayed beyond this window, its neuroprotective effect is significantly reduced[19]. This often results in cerebral palsy and other neurological sequelae, making early and precise identification of severity essential for effective intervention. Catherine RC et al[23] found that neonates treated with hypothermia had better survival, fewer neurological abnormalities, and a higher rate of normal neurodevelopmental outcomes at both discharge and 6-18 months follow-up. Similarly, Weng B et al[24] concluded that TH significantly reduced mortality and serious disability in neonates with moderate to severe HIE, emphasizing that TH is safe when administered with close monitoring and appropriate laboratory support. Jacobs SE et al[25] demonstrated through meta-analysis that therapeutic hypothermia significantly reduces both death and disability in HIE, with more favorable outcomes in moderate HIE cases. According to Thoresen et al[26], beginning hypothermia before the third hour of life may offer even better protection to the brain. Long-term Follow-up and Neurodevelopmental Outcomes In our study, the follow-up of neonates who had undergone therapeutic hypothermia showed encouraging results. At the 3-month follow-up, 110 (96.49%) survived and 4 out of 114 neonates (3.51%) died. By the 6-month follow-up, among these 110 neonates, 8 (7.27%) more had died, resulting in an overall survival rate of 92.73% at six months. Most neonates survived and remained stable during the early months of life, reflecting the long-term neuroprotective effects of TH. Edwards AD[27] reported a meta-analysis of three major trials which showed that TH significantly reduced the combined rate of death and severe disability by 19%, with a risk ratio of 0.81 (P = 0.002) at 18 months of age. Similarly, Weng B et al[24] reported that no increase in moderate or severe disability was observed at 18-22 months in infants treated with TH. Saraswat D et al[22] conducted a 12-month follow-up using the Hammersmith Infant Neurological Examination, where 36 babies showed normal neurological outcomes, 3 had psychomotor delay, and only 1 required long-term anticonvulsant therapy. In the present study, neurodevelopmental assessment using the Amiel-Tison scoring system revealed that 70.8% of neonates had no impairment at baseline, while 22.3% had moderately abnormal impairment and 6.9% had severe impairment. At the 3-month follow-up (n = 110), the proportion of neonates with no neurodevelopment impairment declined slightly to 62.7%, while 25.5% had moderate and 11.8% had severe impairment. By 6 months (n = 102), the rate of normal neurodevelopment status further decreased to 58.8%, with an increase in moderate impairment to 29.4%, and no change in severe impairment (11.8%). This trend suggests that while TH offers neuroprotection, neurological deficits may become more apparent over time, especially in moderate to severe HIE cases. Wang Z et al[12] reported a lower incidence of brain injury in the TH group (16%) compared to the non-TH group (43%), reinforcing the effectiveness of TH in reducing neurological damage in HIE neonates. Similarly, Gagne-Loranger et al[28] found a reduction in brain injury rates in mild HIE neonates who received TH (31%) versus those who did not (40%). Currently, most guidelines recommend TH for neonates ≥36 weeks gestation, initiated within 6 hours of life[29]. However, emerging evidence also supports the benefit of starting TH between 6 to 24 hours, as demonstrated in a multicenter randomized controlled trial which found reduced risk of death or disability in this delayed initiation group compared to no cooling[30]. Furthermore, the duration of hypothermia appears to impact the outcome. A 72-hour cooling protocol has been found to be more effective than 48 hours in improving oxidative balance, lowering neuron-specific enolase levels, and promoting better neurobehavioral development[31]. Tagin MA et al[32] also reported that TH is effective in reducing both mortality and major disability at 18 months in neonates with moderate or severe HIE. Importantly, TH increased survival without raising the rate of major disability, indicating that the therapy does not simply prolong survival but actually contributes to better neurodevelopment outcomes.

The study concludes that therapeutic hypothermia is an effective intervention in improving survival and early neurodevelopment in neonates with moderate to severe HIE. However, the presence of moderate to severe impairment in a significant proportion of cases at 6-month follow-up underlines the need for long-term developmental monitoring and early rehabilitation.

[1] Schiariti V, Klassen AF, Hoube JS, et al. Perinatal characteristics and parents' perspective of health status of NICU graduates born at term. J Perinatol. 2008;28:368–376. [2] Allen KA, Brandon DH. Hypoxic ischemic encephalopathy: pathophysiology and experimental treatments. Newborn and Infant Nursing Reviews. 2011;11(3):125-33. [3] Lee AC, Kozuki N, Blencowe H, et al. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatric Research. 2013;74(1):50-72. [4] Lemyre B, Chau V. Hypothermia for newborns with hypoxic-ischemic encephalopathy. Paediatr Child Health. 2018;23(4):285-291. [5] Pierrat V, Haouari N, Liska A, et al. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005;90(3):F257-F261. [6] Bonifacio SL, Hutson S. The term newborn: evaluation for hypoxic-ischemic encephalopathy. Clinics in Perinatology. 2021;48(3):681-95. [7] Gunn AJ, Gunn TR, Gunning MI, et al. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics. 1998;102(5):1098–106. [8] American Academy of Pediatrics & American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care. 7th edn. American Academy of Pediatrics/American College of Obstetricians and Gynecologists, 2012. [9] Perlman JM, Davis P, Wyllie J, Kattwinkel J. Therapeutic hypothermia following intrapartum hypoxia-ischemia. An advisory statement from the Neonatal Task Force of the International Liaison Committee on Resuscitation. Resuscitation. 2010;81(11):1459-61. [10] Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Current Treatment Options in Neurology. 2012 Dec;14:608-19. [11] Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA. 2017 Jul 4;318(1):57-67. [12] Wang Z, Zhang D, Zhang P, et al. Safety and efficacy of therapeutic hypothermia in neonates with mild hypoxic-ischemic encephalopathy. BMC Pediatrics. 2023;23(1):530. [13] Magalhaes M, Rodrigues FP, Chopard MR, et al. Neuroprotective body hypothermia among newborns with hypoxic ischemic encephalopathy: three-year experience in a tertiary university hospital. A retrospective observational study. Sao Paulo Medical Journal. 2014;133:314-9. [14] Yum SK, et al. Therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy and reversible persistent pulmonary hypertension: Short-term hospital outcomes. J Matern Fetal Neonatal Med. 2018;31:3108–3114. [15] Joanna RGV, et al. Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: A frequent and perilous combination. J Matern Fetal Neonatal Med. 2022;35:4969–4975. [16] Park J, Park SH, Kim C, et al. Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy. Scientific Reports. 2023 Dec 28;13(1):23100. [17] Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic–ischemic encephalopathy. The Journal of Pediatrics. 2003;143(5):625-9. [18] Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. New England Journal of Medicine. 2005;353(15):1574-84. [19] Cornette L. Therapeutic hypothermia in neonatal asphyxia. Facts Views Vis Obgyn. 2012;4(2):133–139. [20] Shankaran S, et al. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Engl J Med. 2005;353:1574–1584. [21] Hage L, Jeyakumaran D, Dorling J, et al. Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the National Neonatal Research Database. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2021;106(5):501-8. [22] Saraswat D, Aradhya G, Chaitali R, Guruprasad G. Therapeutic hypothermia in asphyxiated neonates, using phase change material (Mira Cradle): experience from neonatal intensive care unit of tertiary care centre South India. Int J Pediatr Res. 2019;6(12):606-612. [23] Catherine RC, Ballambattu VB, Adhisivam B, Bharadwaj SK, Palanivel C. Effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy—a randomized controlled trial. Journal of Tropical Pediatrics. 2021 Feb 1;67(1):fmaa073. [24] Weng B, Yan C, Chen Y, Gong X, Cai C. Efficiency evaluation of neuroprotection for therapeutic hypothermia to neonatal hypoxic-ischemic encephalopathy. Frontiers in Neuroscience. 2021 Sep 28;15:668909. [25] Jacobs SE, et al. Hypothermia: a systematic review and meta-analysis of clinical trials. Arch Dis Child Fetal Neonatal Ed. 2010. [26] Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatal. 2013;104(3). [27] Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010;340:c363. [28] Gagne-Loranger M, Sheppard M, Ali N, et al. Newborns referred for therapeutic hypothermia: association between initial degree of encephalopathy and severity of brain injury. Am J Perinatol. 2016;33(2):195–202. [29] Beck J, Debillon T, Guellec I, et al. Healthcare organizational factors associated with delayed therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: the LyTONEPAL cohort. Eur J Pediatr. 2023;182:181–90. [30] Laptook AR, Shankaran S, Tyson JE, et al. Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy: a randomized clinical trial. J Am Med Assoc. 2017;318:1550–60. [31] Yang T, Li S. Efficacy of different treatment times of mild cerebral hypothermia on oxidative factors and neuroprotective effects in neonatal patients with moderate/severe hypoxic-ischemic encephalopathy. J Int Med Res. 2020;48:300060520943770. [32] Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Archives of Pediatrics & Adolescent Medicine. 2012 Jun 1;166(6):558-66.