The growth and developmental outcomes of Hypoxic Ischemic Encephalopathy; Population-based study from 2010 to 2019

The growth and developmental outcomes of Hypoxic Ischemic Encephalopathy; Population-based study from 2010 to 2019 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article The growth and developmental outcomes of Hypoxic Ischemic Encephalopathy; Population-based study from 2010 to 2019 Joonsik Park, Sook Hyun Park, Chloe Kim, So Jin Yoon, Joo Hee Lim, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2629230/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Dec, 2023 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. Using a national dataset, we determined the trends of HIE prevalence, the use of therapeutic hypothermia (TH), mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE (International Classification of Diseases-10 code: G93.1) between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 23.7 per 10,000 birth without significant change during the period. The mortality among all term infants with HIE was 4.6% (range: 3.1–6.2%). TH was performed in approximately 6.7% of infants with HIE and the annual variation was large, ranging from 2.4–12.5%. Infants with TH showed significantly higher mortality, nitric oxide usage, and invasive ventilator usage than those without TH. Infants with TH also showed significantly poorer outcomes including delayed development, cerebral palsy (CP), sensorineural hearing loss and seizure compared to infants without TH (p < 0.0001). With increasing application of TH, mortality and developmental outcomes among infants with HIE has been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed. Health sciences/Medical research Health sciences/Medical research/Paediatric research hypoxic ischemic encephalopathy therapeutic hypothermia mortality developmental outcomes Figures Figure 1 Figure 2 Introduction Hypoxic Ischemic Encephalopathy (HIE), caused by impaired cerebral blood flow and oxygen delivery to the brain, is a serious birth complication affecting term infants.[ 1 ] Despite advances in obstetric care, HIE continues to affect 1.5 infants per every 1,000 births worldwide and accounts for a large disease burden in the developed country.[ 2 ] Since approved by the United States (US) Food and Drug Administration in 2005, therapeutic hypothermia (TH) has been the standard treatment for neonates at gestational age (GA) of 35 weeks or more with moderate to severe HIE within the first six hours after birth.[ 3 ] In the US, 2.4 per 1000 birth is diagnosed with HIE and TH is applied to 10.9% of those with HIE.[ 4 ] In the United Kingdom (UK), 1.2-3.0 per 1,000 birth is diagnosed with HIE and TH is applied to 41–67%, with 0.98 death per 1,000 noted.[ 5 , 6 ] In Sweden, 1.4 per 1000 births has HIE and 47% had TH.[ 7 ] Clinical trials have shown that TH reduces the risk of death in infants with HIE compared to control groups (10% vs of 20–30%).[ 5 , 6 , 8 ] In Korea, TH has been adopted as standard therapy since 2012 and is covered under national insurance.[ 9 ] A single center from Korea reported that 10% of infants die and 42% have abnormal neurological outcomes among the infants diagnosed with HIE who undergo TH.[ 10 ] To the best of our knowledge, no population-based national data about HIE and TH have been reported in Korea. The use of TH for newborns with HIE has been shown to significantly improve neurodevelopmental outcomes. Results from a Cochrane Review stated that hypothermia at 33–34 °C for 72 hours reduced death or major neurodevelopmental disability among survivors at 18 or 24 months of age. In particular, TH decreased the risk of neuromotor and developmental delay and that of cerebral palsy among the survivors.[ 8 ] TH has also been shown to have neuroprotective effect in children aged 6–7 years.[ 11 ] Data from the Total Body Hypothermia for Neonatal Encephalopathy trial showed more children in the cooled group than the control group survived with an intelligence quotient of greater than 85.[ 12 ] Furthermore, more children in the cooled group demonstrated normal neurological exams and fewer had cerebral palsy. MRI results have also shown a lower incidence of brain injury (66% in non-cooled population vs 36% in cooled population).[ 13 ] Despite receiving TH, up to 29% of neonates with HIE still develop adverse outcomes.[ 14 ] The outcomes of HIE included high mortality or severe disabilities, such as mental retardation, epilepsy, and cerebral palsy in 40–60% of such infants. [ 15 – 17 ] To optimize the benefits of TH, further investigations are needed to determine the timing, duration and patient characteristics for case selection. Epidemiological studies can help to improve the quality of care for newborns with HIE and inform clinical decision-making. We aimed to determine the trends of HIE prevalence, TH application, mortality, and the associated outcomes from 2012 to 2019 in Korea using a population-based national database. Methods Patients and data source This study analyzed the data of term infants diagnosed with HIE (International Classification of Diseases-10 code: G93.1) between 2012 and 2019 from the National Health Insurance Service (NHIS) database. Healthcare claims data, such as diagnostic codes, costs of diagnostic tests, and administered procedures, for almost all Korean residents are linked to the National Health Screening Program for infants and children database. Information on birth weight was obtained by the ICD-10 codes input by the hospital or by a questionnaire administered as part of the Infant Health Screening Program. Preterm infants, those with low birth weight, and those with ICD-10 codes P07.29, P07.39, and P07.00 ~ 19, were excluded. We used birth certificate data from Statistics Korea to estimate the prevalence of HIE and the incidence of TH ( https://kosis.kr/statisticsList ). The National Health Screening Program for infants and children in Korea was launched in 2007 to monitor current health issues. It has since been a successful part of the primary clinical service.[ 18 ] The program provides population surveillance that includes medical history, physical examination, anthropometric measurements, screening for visual acuity, developmental screening via the Korean Developmental Screening Test (K-DST), oral examination, and questionnaires on anticipatory guidance. The study population of infants had their first visits at 4–6 months of age, second visits at 9–12 months, third visits at 18–24 months, fourth visits at 30–36 months, fifth visits at 42–48 months, and sixth visits at 54–60 months. All the check-ups were based on the chronological age, not the corrected age. The K-DST is a screening test that verifies whether infants have achieved normal neurodevelopmental status in six domains (gross/fine motor, cognition, communication, social interaction, and self-control).[ 19 ] Tests were administered according to the child’s corrected age at the time of the clinic visits. Results were categorized into four groups based on standard deviation (SD) scores (a score below − 2 SD = “further evaluation”, between − 2 and − 1 SD = “follow-up test”, between − 1 and 1 SD = “at peer-level”, and above 1 SD = “at a high-level”). For children in the follow-up test group, short-term checkups were recommended. To screen for developmental delays, scores below − 1 SD were set as a critical cutoff and indicated that these infants require further evaluation and follow-up tests. Additionally, there were some positive responses to questions that were considered as red flags for clinically significant neurodevelopmental disorders, such as cerebral palsy, language delay, and autism spectrum disorders, and these infants were referred to medical specialists. The complications associated with HIE were identified using ICD-10 codes input by the hospital including delayed development (DD) (R62.9), cerebral palsy (CP) (G80), autism spectrum disorders (ASD) (F84.9), sensorineural hearing loss (SNHL)(H90.5), attention deficit hyperactivity disorder (ADHD)(F90.0), Blindness (H54.0) and Seizure disorder (G40 or R56.8). Statistical analyses Baseline infant characteristics were expressed as percentages for categorical variables. The cohort was stratified according to birth year. A χ2test was used to compare the neonatal characteristics and complications between the groups. Logistic regression models were used to determine the significant changes in the incidence of complications, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each risk factor associated with mortality and morbidity. The Cochran-Armitage trend test was used to test for linear trend. All analyses were performed using SAS v 9.4 (SAS Institute, Cary, North Carolina). A p -value < 0.05 was considered statistically significant. Ethics statement This study used NHIS-NSC data (NHIS-2022–1-120) maintained by the NHIS. The authors declare no conflicts of interest with NHIS. In this study, all identifiable variables, including claim-, individual-, and organizational-level identification numbers, were randomly re-generated by the NHIS database to protect patient privacy. The study protocol was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University School of Medicine (IRB No. 3-2021-0221). Informed consent was waived by Yonsei University School of Medicine owing to the retrospective study design All methods were performed in accordance with the relevant guidelines and regulations. Data availability The dataset analyzed in this study are not publicly available due to the policy of Research of Korea Centers for Disease Control and Prevention. However, dataset is available from the corresponding author on reasonable request. Results According to the birth statistics, 3,188,372 live births occurred between 2012-2019. In total, 6,994 infants were diagnosed with HIE. Of these, 470 infants were treated for TH during the study period. The HIE incidence in term infants was 2.4 per 1,000 births (range:1.9 to 2.7), which did not change significantly during the study period. A 4.6% mortality was noted among the term infants with HIE and this was maintained between 3.1% to 6.2% during the eight years included in this study. TH was performed on approximately 6.7% of infants with HIE but the annual rate varied widely from 2.4% to 12.5%. Mortality among the infants with TH showed significant reduction. (Fig 1) Among the 6,994 term infants diagnosed with HIE, NO therapy and invasive ventilation were applied to 61 infants (0.9%) and 486 infants (6.9%) respectively, and anti-epileptic drugs were administered to 287 infants (4.1%). CP was diagnosed in 526 infants (7.5%), delayed development in 823 infants (11.8%), autism spectrum disorders in 96 infants (1.4%), SNHL in 212 infants (3.0%), blindness in seven infants (0.1%), and seizures in 84 infants (1.2%). The combined outcome which included CP, delayed development, SNHL, or blindness affected 1122 infants (16.0%). Infants with HIE and TH showed significantly higher mortality than those with HIE but without TH, and the mortality was significantly higher at all ages after birth, regardless of the nitric oxide and/or invasive ventilator usage (p<0.0001). Infants with HIE and TH also showed significantly higher morbidities including DD, CP, SNHL, and seizures compared to infants with HIE and without TH (p<0.0001). (Table 1) Table 1. Demographic characteristics and developmental outcomes among infants with hypoxic ischemic encephalopathy Total HIE without TH (n=6524) HIE with TH (n=470) OR (95% CI) P value Mortality <1 month 81(1.2%) 54 27 7.30(4.56/11.71) <.0001 1-12 month 119(1.7%) 84 35 6.17(4.11/9.26) <.0001 ≥1 year 121(1.7%) 73 48 10.05(6.89/14.66) <.0001 Total 321(4.6%) 211 110 9.14(7.09/11.78) <.0001 Nitric oxide therapy 61(0.9%) 39(0.6%) 22(4.7%) 8.17(4.80/13.89) <.0001 Invasive ventilator 486(6.9%) 399(6.1%) 87(18.5%) 33.13(22.80/48.13) <.0001 Anti-epileptic drug Total 1377(19.7%) 1077(16.5%) 300(63.8%) 8.93(7.31/10.89) <.0001 First prescription 287(4.1%) 218(3.3%) 69(14.7%) 4.98(3.73/6.65) <.0001 Delayed development 823(11.8%) 726(11.1%) 97(20.6%) 2.08(1.64/2.63) <.0001 Cerebral palsy 526(7.5%) 453(8.3%) 73(15.5%) 2.47(1.89/3.22) <.0001 Autism spectrum disorders 96(1.4%) 89(1.4%) 7(1.5%) 1.09(0.50/2.37) 0.8218 SNHL 212(3%) 186(2.8%) 26(5.5%) 2.03(1.33/3.10) 0.0010 Blindness 7(0.1%) 6(0.1%) 1(0.2%) 1.02(0.80/1.32) 0.4816 ADHD 84(1.2%) 80(1.2%) 4(0.9%) 0.69(0.25/1.89) 0.4733 Seizure 1785(25.5%) 1538(23.6%) 247(52.6%) 3.59(2.97/4.34) <.0001 CP or Delayed development or SNHL or Blindness 1122(16%) 981(15%) 141(30%) 2.42(1.97/2.98) <.0001 CP or Delayed development or SNHL or blindness or mortality 1351(19.3%) 1122(17.2%) 229(48.7%) 4.58(4.78/5.54) <.0001 Abbreviations: HIE hypoxic ischemic encephalopathy; TH therapeutic hypothermia; OR odds ratio; CI confidence interval; SNHL sensorineural hearing loss; ADHD attention deficit hyperactivity disorder; CP cerebral palsy The CP incidence significantly decreased in the 453 infants with HIE and without TH. The results showed a decreasing trend from 6.8% to 4.3% during the study period. (P= 0.0031 z=2.9601) The CP incidence among the 73 infants with HIE and hypothermia showed no significant differences over the eight years. (Table 2) Table 2. Trends of developmental outcomes among infants with hypoxic ischemic encephalopathy Total (n=6994) [2012-2019] P value* 2012-2015 (n=4022) 2016-2019 (n=2972) P value** Delayed development 823(11.8%) [8.4 - 8.8%] 0.2244 459(11.4%) 364(12.2%) <0 .001 Cerebral palsy 546(7.8%) [7.0 - 5.3%] 0.0464 320(8.0%) 226(7.6%) <0.001 Autism spectrum disorder 96(1.4%) [1.3 - 0.3%] 0.0043 70(1.7%) 26(0.9%) 0.426 SNHL 209(3.0%) [3.9 - 2.9%] 0.0667 135(3.4%) 74(2.5%) 0.057 Blindness 1(0.0%) [0.0 - 0.1%] 0.0924 0(0.0%) 1(0.0%) ADHD 84(1.2%) [3.1 – 0.0%] <0.001 81(2.0%) 3(0.1%) 0.772 Seizure 1785(25.5%) [19.2 – 19.0%] <0.001 948(23.6%) 837(28.2%) <0 001 Mortality 321(4.6%) [3.4 – 3.1%] 0.179 179(4.5%) 142(4.8%) 0.002 * The Cochran-Armitage trend test was used ** χ2test was used Abbreviations: SNHL sensorineural hearing loss; ADHD attention deficit hyperactivity disorder Based on the data from the disability identification system, brain lesion disorder was the most common disability in infants with HIE (5.7% in the HIE and without TH group vs 14.7% in the HIE with TH group; p<0.0001), followed by auditory disorder, intellectual disorder, and language disorder. (Supplement Table. 1) The growth outcomes of 2045 infants with HIE (6.9%) showed a weight of <10 percentile, 1777 infants (7.3%) showed a height of <10 percentile, and 2263 infants (9.2%) showed a head circumference (HC) of <10 percentile. There were significant variations in weight <10 percentile (1.9%-9.4%), height <10 percentile (3.2%-8.8%), and HC <10 percentile (6.2%-9.8%) during the study period. Poor growth of infants with HIE, with and without TH, is shown in Fig. 2. The head circumference (HC) was significantly different in the at 6 m onth, 12month and 24 month of age. In contrast, weight (WT) showed a significant difference only in the first test, while height (HT) was not significantly different between the two groups in any of the tests. Although infants with TH demonstrated poorer conditions than those without TH, catch-up growth in HT, WT, and HC at 18 months was evident. Poor developmental outcomes between infants with HIE, with and without TH, are shown in Fig. 2d. Infants in the HIE with TH group required more “refer to specialized test” (7.0% vs 4.4%) and also more “closed serial test follow-up” (13.2% vs 10.9%). Exclusively, during the 2 nd (p<0.001) and 3 rd (p=0.038) tests, significantly poor developmental outcomes were demonstrated in the HIE with TH group. In total, 4.6% of infants with HIE required “refer to specialized test” and 10.6% required “closed serial test follow-up”. “Refer to specialized test” (2.7%-8.6%) and “closed serial test follow up” (5.4%-23.8%) varied significantly during the study period. The comparison of growth outcomes between infants with and without CP is shown in Table 3. Poor growth at the 2nd, 3rd, and 4 th tests was significantly associated with an increased risk of CP regardless of TH. Table 3. Comparisons of poor growth outcome at 12, 24 and 36 month of age between infants with and without cerebral palsy adjusted with therapeutic hypothermia CP (n=536 ) No-CP (n=6458 ) OR (95%CI) P value HT below 10p at 12month 38(20.5%) 222(4.8%) 5.03(3.427-7.383) <.0001 WT below 10p at 12month 45(24.3%) 210(4.5%) 6.793(4.713-9.793) <.0001 HC below 10p at 12month 69(37.3%) 221(26.5%) 11.368(8.176-15.805) <.0001 HT below 10p at 24month 35(22.6%) 226(4.9%) 5.537(3.707-8.272) <.0001 WT below 10p at 24month 47(30.3%) 303(6.6%) 6.274(4.362-9.024) <.0001 HC below 10p at 24month 62(40%) 296(6.4%) 9.542(6.768-13.454) <.0001 HT below 10p at 36month 42(27.6%) 219(5.5%) 6.512(4.446-9.539) <.0001 WT below 10p at 36month 57(37.5%) 301(7.6%) 7.467(5.261-10.599) <.0001 HC below 10p at 36month 71(46.7%) 359(9%) 8.835(6.306-12.38) <.0001 Abbreviations: CP cerebral palsy; OR Odds ratio; CI confidence interval; HT Height; WT weight; HC head circumference ; p percentile Discussion This population-based nationwide study showed that the HIE prevalence in term infants in Korea is similar to that in other developed countries at 2.4 per 1000 live births. However, the use of TH for infants with HIE was lower in Korea at only 6.7%, although an increasing trend over the years was observed. Infants with HIE had a mortality of 4.6%. An increased risk for CP was identified among infants with HIE at <10 percentiles in their HT, WT, and HC. The worldwide incidence of HIE varies between 1–3 per 1,000 live births in developed countries and 2.3 to 30.6 per 1000 live births in the developing countries.[20-22] The Korean incidence of 2.4/1000 live births is similar to the HIE incidence in UK (2.63 in 1990s, 2.96 per 1,000 live births in the 2010s) which showed no significant changes over time.[5,23] Providing better access to medical and antenatal care in developing countries may reduce the incidence of HIE.[20] In contrast, in developed countries, significant improvement in the incidence is not usually observed once maternal care has settled down. Our results elucidated that the incidence of HIE in Korea has not changed over eight years. The mortality rate for newborns with HIE can vary depending on the severity of the condition and the availability of appropriate medical care. The UK study reported decreased mortality in infants with HIE who had undergone TH (12.9% to 6.7% from 2010 to 2017).[6, 24] A study from Spain reported 21% mortality which remained relatively constant during the study period from 2010 to 2019.[25] In Canada, 27% mortality in infants with HIE was noted during the study period (1988 to 2015).[26] In this study, we noted a mortality of 4.6% in Korea during the study period of eight years, which did not decline significantly over time. Of note, the diagnosis of HIE may be overestimated due to the retrospective ICD-10 code analysis. TH is effective in reducing the mortality of infants with moderate to severe HIE.[4] TH can reduce the mortality rate for newborns with HIE by 10%-20% compared to control groups that did not utilize TH.[27] In this study, it was impossible to compare the incidence due to the observational nature of the study. However, the mortality rate among infants with HIE and TH significantly declined from 40% to 16.9% during the eight years. TH was first introduced as standard therapy for moderate to severe HIE in Korea in the 2010s.[9] The use of TH in infants with HIE has remained under 10%, except for the year 2018. TH is broadly applied in up to 40.5% of all infants with HIE in the UK and 21.1% of the infants in the US.[5,28] The reasons for a significantly lower rate of TH in Korea are as follows: missed or underestimation of moderate to severe HIE as mild to no HIE, the ideal time point for the diagnosis of HIE passed, inability to transport the infant within the therapeutic window, or an active decision not to offer intensive care and lack of facilities or experienced TH specialist. Opportunities to explore practice-site variations and to develop quality improvement interventions to assure consistent evidence-based care of term infants with HIE and the appropriate application of TH for eligible newborns should be considered.[29] It is encouraging to note that developmental outcomes including CP as a consequence of HIE has decreased significantly in recent years in Korea. We assume that improvements in neonatal care and developmental follow-up protocols have led to better outcomes over time in addition to application of TH. Although CP and other developmental outcomes has not decreased significantly in the HIE with TH group, these results shows the active application of TH is promising for better outcomes. HIE with TH group to be affected by serious medical conditions compared to the HIE without TH group. The severe baseline medical status may be associated with severe HIE, requiring TH. Significantly higher mortalities and morbidities requiring invasive ventilators and anti-epileptic medication were found among HIE infants with TH than those without TH. The occurrence of PPHN was between 13% and 25% in asphyxiated hypothermic infants,[30,31] which is clearly higher than the incidence in the general population (2/1000 live births) . [32,33] Also, neonates with hypothermia showed a 2.5 times higher risk of PPHN than in controls (23% vs 11%).[34] In this study, 4.7% of infants with HIE and TH required nitric oxide treatment compared with 0.6 % of infants with HIE and without TH, which means it is 8.8 times more common. TH significantly reduced the combined rate of death and severe disability in three trials that evaluated 18 month outcomes (risk ratio: 0.81, P=0.002).[35] Hypothermia in survivors showed severe disability (28.1%), cerebral palsy (26.4%), deafness (4.7%) and mental and the psychomotor developmental index of less than 70 (26.5% and 26.2% respectively) with significant reduction of the rates compared to normothermia. We found 21% of DD, 16% of CP, 5.5% of SNHL was shown among the HIE infants treated with TH. Children with HIE scored significantly lower than typically developing children in terms of fine motor skills, executive functions, memory, and language. Children with HIE treated with TH may not be as ‘school-ready’ as their typically developing classmates, and may benefit from long-term medical follow-up until school commencement.[36] According to the National Health Screening Program for infants and children, we found that infants with HIE tended to have poor growth. This disparity is more evident in infants with HIE and TH, probably because of the seriousness of the HIE than in infants without TH. An HC of under the 10 percentile was significantly higher in the HIE with TH group than in the HIE without TH group until the fourth test, which corresponded to a chronological age of 30 months. This may be attributed to infants with developmental problems being less likely to engage in general screening at the appropriate age. The adaptation of TH in patients with mild HIE has been a point of contention in developed countries. Despite the known adverse effects associated with TH, it continues to be used for infants with mild HIE and late preterm infants for example 36% infants with mild HIE underwent TH safely in the 2010s in the UK.[5] In Korea, TH is currently not used as a standard therapy for infants with mild HIE as per the National Health Insurance Guidelines. However it is promising in the future. The strength of this study is the use of data from nationwide databases, which encompassed all live births and affected patients included in the study period. Long-term growth and developmental screening data until six years old were also analyzed. The study has some limitations. The study contains weaknesses inherent to an observational study. National claim data did not include individual patient medical information. The severity of HIE is indistinguishable. The analyses relied on the accuracy of the included ICD codes and labeling error could not be identified and corrected. The KDST was used as a developmental screening tool but the Bayley Scales of Infant Development was not used as a diagnostic tool. The association of outborn birth status with mortality and morbidity was not evaluated. With increasing TH application, neurodevelopmental outcomes showed decreasing trends, however still remained in Korea. Further efforts and earlier interventions to improve the developmental and growth outcomes of infants with HIE are warranted. Declarations Funding This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711138055, KMMDF_PR_20200901_0057) Competing interests The authors declare no competing interests. Data availability statement format guidelines The datasets generated during and/or analysed during the current study are not publicly available due to NHIS Database policy, but are available from the corresponding author on reasonable request References Allen, K. A. & Brandon, D. H. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments. Newborn Infant Nurs Rev 11 , 125-133, doi:10.1053/j.nainr.2011.07.004 (2011). Shankaran, S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr 27 , 152-157, doi:10.1097/mop.0000000000000199 (2015). 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). Smith, J., Wells, L. & Dodd, K. The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. Bjog 107 , 461-466, doi:10.1111/j.1471-0528.2000.tb13262.x (2000). Shipley, L., Gale, C. & Sharkey, D. Trends in the incidence and management of hypoxic-ischaemic encephalopathy in the therapeutic hypothermia era: a national population study. Arch Dis Child Fetal Neonatal Ed 106 , 529-534, doi:10.1136/archdischild-2020-320902 (2021). Hage, L. 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. Arch Dis Child Fetal Neonatal Ed 106 , 501-508, doi:10.1136/archdischild-2020-319685 (2021). Torn, A. E., Lampa, E., Wikstrom, A. K. & Jonsson, M. Hypoxic ischemic encephalopathy in offspring of immigrant women in Sweden: A population-based cohort study. Acta Obstet Gynecol Scand 100 , 2285-2293, doi:10.1111/aogs.14234 (2021). Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013 , Cd003311, doi:10.1002/14651858.CD003311.pub3 (2013). Sung, I. K. Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy in Newborn Infants. Neonatal Medicine 24 , doi:10.5385/nm.2017.24.4.145 (2017). Chun, M.-K., Sung, H.-J., Park, J.-H., Lim, G.-Y. & Kim, S.-Y. Predictors of Neurodevelopmental Outcomes in Newborns Undergoing Hypothermia Therapy. Neonatal Med 26 , 17-23, doi:10.5385/nm.2019.26.1.17 (2019). Azzopardi, D. et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 371 , 140-149, doi:10.1056/NEJMoa1315788 (2014). Azzopardi, D. et al. The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr 8 , 17, doi:10.1186/1471-2431-8-17 (2008). Rao, R. et al. Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children's Hospital Neonatal Consortium. Am J Perinatol 39 , 319-328, doi:10.1055/s-0040-1716341 (2022). Shankaran, S. 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 318 , 57-67, doi:10.1001/jama.2017.7218 (2017). Pierrat, V. et al. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. Arch Dis Child-Fetal 90 , 257-261, doi:10.1136/adc.2003.047985 (2005). Hoehn, T. et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation 78 , 7-12, doi:10.1016/j.resuscitation.2008.04.027 (2008). Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365 , 663-670, doi:10.1016/S0140-6736(05)17946-X (2005). Moon, J. S. Review of National Health Screening Program for Infant and Children in Korea. J Korean Med Assoc 53 , 377-385, doi:DOI 10.5124/jkma.2010.53.5.377 (2010). Moon, J. S., Lee SY, Eun BL, Kim SW, Kim YK, Shin SM, Lee HK, Chung HJ. One-year evaluation of the national health screening program for infants and children in Korea. Korean Journal of Pediatrics 53 , 307-313 (2010). Kurinczuk, J. J., White-Koning, M. & Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 86 , 329-338, doi:10.1016/j.earlhumdev.2010.05.010 (2010). Lawn, J. E. et al. Two million intrapartum-related stillbirths and neonatal deaths: where, why, and what can be done? Int J Gynaecol Obstet 107 Suppl 1 , S5-18, S19, doi:10.1016/j.ijgo.2009.07.016 (2009). Namusoke, H., Nannyonga, M. M., Ssebunya, R., Nakibuuka, V. K. & Mworozi, E. Incidence and short term outcomes of neonates with hypoxic ischemic encephalopathy in a Peri Urban teaching hospital, Uganda: a prospective cohort study. Matern Health Neonatol Perinatol 4 , 6, doi:10.1186/s40748-018-0074-4 (2018). Evans, K., Rigby, A. S., Hamilton, P., Titchiner, N. & Hall, D. M. The relationships between neonatal encephalopathy and cerebral palsy: a cohort study. J Obstet Gynaecol 21 , 114-120, doi:10.1080/01443610020025967 (2001). Shipley, L., Mistry, A. & Sharkey, D. Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis. Arch Dis Child Fetal Neonatal Ed 107 , 6-12, doi:10.1136/archdischild-2020-320966 (2022). Vega-Del-Val, C. et al. Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia. Neonatology 118 , 685-692, doi:10.1159/000518654 (2021). Ravichandran, L. et al. Incidence, Intrapartum Risk Factors, and Prognosis of Neonatal Hypoxic-Ischemic Encephalopathy Among Infants Born at 35 Weeks Gestation or More. J Obstet Gynaecol Ca 42 , 1489-1497, doi:10.1016/j.jogc.2020.04.020 (2020). Shankaran, S. et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353 , 1574-1584, doi:10.1056/NEJMcps050929 (2005). Acun, C. et al. Trends of Neonatal Hypoxic Ischemic Encephalopathy Prevalence and Associated Risk Factors in the United States 2010-2018. Am J Obstet Gynecol , doi:10.1016/j.ajog.2022.06.002 (2022). Kracer, B., Hintz, S. R., Van Meurs, K. P. & Lee, H. C. Hypothermia therapy for neonatal hypoxic ischemic encephalopathy in the state of California. J Pediatr 165 , 267-273, doi:10.1016/j.jpeds.2014.04.052 (2014). Shankaran, S. et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 122 , e791-798, doi:10.1542/peds.2008-0456 (2008). Yum, S. K. et al. Therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy and reversible persistent pulmonary hypertension: short-term hospital outcomes. J Matern Fetal Neonatal Med 31 , 3108-3114, doi:10.1080/14767058.2017.1365123 (2018). Walsh-Sukys, M. C. et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatrics 105 , 14-20, doi:DOI 10.1542/peds.105.1.14 (2000). Szakmar, E., Jermendy, A. & El-Dib, M. Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy (vol 39, pg 763, 2019). J Perinatol 39 , 891-891, doi:10.1038/s41372-019-0371-4 (2019). Joanna, R. G. V. et al. Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: a frequent and perilous combination. J Matern Fetal Neonatal Med 35 , 4969-4975, doi:10.1080/14767058.2021.1873941 (2022). Edwards, A. D. 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-Brit Med J 340 , doi:ARTN c363 10.1136/bmj.c363 (2010). Edmonds, C. J., Cianfaglione, R., Cornforth, C. & Vollmer, B. Children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia are not as school ready as their peers. Acta Paediatr 110 , 2756-2765, doi:10.1111/apa.16002 (2021). Additional Declarations No competing interests reported. Supplementary Files SupplementTable1.docx Cite Share Download PDF Status: Published Journal Publication published 28 Dec, 2023 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Major revision 30 Aug, 2023 Reviews received at journal 24 Aug, 2023 Reviewers agreed at journal 15 Aug, 2023 Reviews received at journal 13 Aug, 2023 Reviewers agreed at journal 16 Jul, 2023 Reviewers agreed at journal 12 Jul, 2023 Reviewers invited by journal 12 Jul, 2023 Editor assigned by journal 29 Jun, 2023 Editor invited by journal 23 Mar, 2023 Submission checks completed at journal 23 Mar, 2023 First submitted to journal 25 Feb, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies 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-2629230","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":185817389,"identity":"ba90a134-786b-4d82-a3de-3d074a6ba2d0","order_by":0,"name":"Joonsik Park","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joonsik","middleName":"","lastName":"Park","suffix":""},{"id":185817390,"identity":"a0221602-b4d9-48b3-bd7f-06d6b1f09d15","order_by":1,"name":"Sook Hyun Park","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sook","middleName":"Hyun","lastName":"Park","suffix":""},{"id":185817391,"identity":"9b1bb12b-f842-4663-89ee-41f357bacde4","order_by":2,"name":"Chloe Kim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chloe","middleName":"","lastName":"Kim","suffix":""},{"id":185817392,"identity":"8952f753-f779-4d8e-83f4-5857ae6e9ca5","order_by":3,"name":"So Jin Yoon","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"So","middleName":"Jin","lastName":"Yoon","suffix":""},{"id":185817394,"identity":"0ffe18d0-08da-4eee-92ea-c664a3154359","order_by":4,"name":"Joo Hee Lim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joo","middleName":"Hee","lastName":"Lim","suffix":""},{"id":185817396,"identity":"c61a4c7d-8c76-4adc-a869-c0edfce82061","order_by":5,"name":"Jung Ho Han","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jung","middleName":"Ho","lastName":"Han","suffix":""},{"id":185817398,"identity":"b6bd413c-aa76-444f-a38e-0cdb6f2d439a","order_by":6,"name":"Jeong Eun Shin","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeong","middleName":"Eun","lastName":"Shin","suffix":""},{"id":185817399,"identity":"2d1401dd-b90d-41ce-b9fc-cd97cd6c5092","order_by":7,"name":"Ho Seon Eun","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ho","middleName":"Seon","lastName":"Eun","suffix":""},{"id":185817403,"identity":"4880e885-c544-4e2a-94e4-7dd4f25e457f","order_by":8,"name":"Min Soo Park","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Min","middleName":"Soo","lastName":"Park","suffix":""},{"id":185817407,"identity":"388f612b-f8e4-4848-b905-0b1417fc29ac","order_by":9,"name":"Soon Min Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAq0lEQVRIiWNgGAWjYFAC5gYGhgoGBgMStDACtZwhWQtjGyla5KcdbHzwcd7hxO38Bxg//CBGi8HtxGbDmdsOJ+6ckcAs2UOUFunENmleoJYNNxgYpIlz2OzE9t9/5wC1nD/A/JsoLQy3E9uYGRuAWg4ksBFnC8gvkj3H0o033EhssyTKL/Kzkw9++FFjLbvh/OHDN4gKMShoZoDEKQmgjiTVo2AUjIJRMMIAABcdOKh/VbeQAAAAAElFTkSuQmCC","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Soon","middleName":"Min","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2023-02-26 02:29:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2629230/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2629230/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-023-50187-0","type":"published","date":"2023-12-28T15:00:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":34780645,"identity":"62cddf49-73fe-4910-9138-e3bb9832a2d5","added_by":"auto","created_at":"2023-03-24 15:12:00","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":365333,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of hypoxic ischemic encephalopathy and the use of therapeutic hypothermia (A), and mortality (B) from 2012 to 2019. Abbreviations: HIE hypoxic ischemic encephalopathy; TH therapeutic hypothermia\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2629230/v1/34c7188d4b046a0e888b52fc.jpeg"},{"id":34780646,"identity":"642ca200-5fe6-4956-a7ed-8cc0a1346ef0","added_by":"auto","created_at":"2023-03-24 15:12:00","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103479,"visible":true,"origin":"","legend":"\u003cp\u003eComparisons of growth and developmental outcomes between Infants with and without therapeutic hypothermia. (A) Weight below10 percentile (B) Height below 10 percentile (C) Head circumference below 10 percentile (D) The abnormal developmental screening outcome using Korean Developmental Screening Test\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2629230/v1/26872d9bf64b960625263ae9.jpeg"},{"id":49028159,"identity":"44347010-84bd-45bf-84e7-86706445ca4d","added_by":"auto","created_at":"2024-01-01 15:03:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":373387,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2629230/v1/de06aade-b787-4906-8c6d-a8f624796590.pdf"},{"id":34780644,"identity":"5967e18a-24b6-4dbc-8e2f-2e1e2b9ffca9","added_by":"auto","created_at":"2023-03-24 15:12:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14761,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2629230/v1/efa3499e8bf9d57d52792a1e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The growth and developmental outcomes of Hypoxic Ischemic Encephalopathy; Population-based study from 2010 to 2019","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypoxic Ischemic Encephalopathy (HIE), caused by impaired cerebral blood flow and oxygen delivery to the brain, is a serious birth complication affecting term infants.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Despite advances in obstetric care, HIE continues to affect 1.5 infants per every 1,000 births worldwide and accounts for a large disease burden in the developed country.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSince approved by the United States (US) Food and Drug Administration in 2005, therapeutic hypothermia (TH) has been the standard treatment for neonates at gestational age (GA) of 35 weeks or more with moderate to severe HIE within the first six hours after birth.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In the US, 2.4 per 1000 birth is diagnosed with HIE and TH is applied to 10.9% of those with HIE.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] In the United Kingdom (UK), 1.2-3.0 per 1,000 birth is diagnosed with HIE and TH is applied to 41–67%, with 0.98 death per 1,000 noted.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] In Sweden, 1.4 per 1000 births has HIE and 47% had TH.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Clinical trials have shown that TH reduces the risk of death in infants with HIE compared to control groups (10% vs of 20–30%).[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] In Korea, TH has been adopted as standard therapy since 2012 and is covered under national insurance.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] A single center from Korea reported that 10% of infants die and 42% have abnormal neurological outcomes among the infants diagnosed with HIE who undergo TH.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] To the best of our knowledge, no population-based national data about HIE and TH have been reported in Korea.\u003c/p\u003e \u003cp\u003eThe use of TH for newborns with HIE has been shown to significantly improve neurodevelopmental outcomes. Results from a Cochrane Review stated that hypothermia at 33–34 °C for 72 hours reduced death or major neurodevelopmental disability among survivors at 18 or 24 months of age. In particular, TH decreased the risk of neuromotor and developmental delay and that of cerebral palsy among the survivors.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] TH has also been shown to have neuroprotective effect in children aged 6–7 years.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Data from the Total Body Hypothermia for Neonatal Encephalopathy trial showed more children in the cooled group than the control group survived with an intelligence quotient of greater than 85.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Furthermore, more children in the cooled group demonstrated normal neurological exams and fewer had cerebral palsy. MRI results have also shown a lower incidence of brain injury (66% in non-cooled population vs 36% in cooled population).[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDespite receiving TH, up to 29% of neonates with HIE still develop adverse outcomes.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] The outcomes of HIE included high mortality or severe disabilities, such as mental retardation, epilepsy, and cerebral palsy in 40–60% of such infants. [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] To optimize the benefits of TH, further investigations are needed to determine the timing, duration and patient characteristics for case selection. Epidemiological studies can help to improve the quality of care for newborns with HIE and inform clinical decision-making.\u003c/p\u003e \u003cp\u003eWe aimed to determine the trends of HIE prevalence, TH application, mortality, and the associated outcomes from 2012 to 2019 in Korea using a population-based national database.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003ePatients and data source\u003c/h2\u003e\n\u003cp\u003eThis study analyzed the data of term infants diagnosed with HIE (International Classification of Diseases-10 code: G93.1) between 2012 and 2019 from the National Health Insurance Service (NHIS) database. Healthcare claims data, such as diagnostic codes, costs of diagnostic tests, and administered procedures, for almost all Korean residents are linked to the National Health Screening Program for infants and children database. Information on birth weight was obtained by the ICD-10 codes input by the hospital or by a questionnaire administered as part of the Infant Health Screening Program. Preterm infants, those with low birth weight, and those with ICD-10 codes P07.29, P07.39, and P07.00\u0026thinsp;~\u0026thinsp;19, were excluded. We used birth certificate data from Statistics Korea to estimate the prevalence of HIE and the incidence of TH (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kosis.kr/statisticsList\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe National Health Screening Program for infants and children in Korea was launched in 2007 to monitor current health issues. It has since been a successful part of the primary clinical service.[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e] The program provides population surveillance that includes medical history, physical examination, anthropometric measurements, screening for visual acuity, developmental screening via the Korean Developmental Screening Test (K-DST), oral examination, and questionnaires on anticipatory guidance. The study population of infants had their first visits at 4\u0026ndash;6 months of age, second visits at 9\u0026ndash;12 months, third visits at 18\u0026ndash;24 months, fourth visits at 30\u0026ndash;36 months, fifth visits at 42\u0026ndash;48 months, and sixth visits at 54\u0026ndash;60 months. All the check-ups were based on the chronological age, not the corrected age. The K-DST is a screening test that verifies whether infants have achieved normal neurodevelopmental status in six domains (gross/fine motor, cognition, communication, social interaction, and self-control).[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] Tests were administered according to the child\u0026rsquo;s corrected age at the time of the clinic visits. Results were categorized into four groups based on standard deviation (SD) scores (a score below \u0026minus;\u0026thinsp;2 SD = \u0026ldquo;further evaluation\u0026rdquo;, between \u0026minus;\u0026thinsp;2 and \u0026minus;\u0026thinsp;1 SD = \u0026ldquo;follow-up test\u0026rdquo;, between \u0026minus;\u0026thinsp;1 and 1 SD = \u0026ldquo;at peer-level\u0026rdquo;, and above 1 SD = \u0026ldquo;at a high-level\u0026rdquo;). For children in the follow-up test group, short-term checkups were recommended. To screen for developmental delays, scores below \u0026minus;\u0026thinsp;1 SD were set as a critical cutoff and indicated that these infants require further evaluation and follow-up tests. Additionally, there were some positive responses to questions that were considered as red flags for clinically significant neurodevelopmental disorders, such as cerebral palsy, language delay, and autism spectrum disorders, and these infants were referred to medical specialists. The complications associated with HIE were identified using ICD-10 codes input by the hospital including delayed development (DD) (R62.9), cerebral palsy (CP) (G80), autism spectrum disorders (ASD) (F84.9), sensorineural hearing loss (SNHL)(H90.5), attention deficit hyperactivity disorder (ADHD)(F90.0), Blindness (H54.0) and Seizure disorder (G40 or R56.8).\u003c/p\u003e\n\u003ch2\u003eStatistical analyses\u003c/h2\u003e\n\u003cp\u003eBaseline infant characteristics were expressed as percentages for categorical variables. The cohort was stratified according to birth year. A \u0026chi;2test was used to compare the neonatal characteristics and complications between the groups. Logistic regression models were used to determine the significant changes in the incidence of complications, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each risk factor associated with mortality and morbidity. The Cochran-Armitage trend test was used to test for linear trend. All analyses were performed using SAS v 9.4 (SAS Institute, Cary, North Carolina). A \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\n\u003ch2\u003eEthics statement\u003c/h2\u003e\n\u003cp\u003eThis study used NHIS-NSC data (NHIS-2022\u0026ndash;1-120) maintained by the NHIS. The authors declare no conflicts of interest with NHIS. In this study, all identifiable variables, including claim-, individual-, and organizational-level identification numbers, were randomly re-generated by the NHIS database to protect patient privacy. The study protocol was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University School of Medicine (IRB No. 3-2021-0221). Informed consent was waived by Yonsei University School of Medicine owing to the retrospective study design All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eThe dataset analyzed in this study are not publicly available due to the policy of Research of Korea Centers for Disease Control and Prevention. However, dataset is available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAccording to the birth statistics, 3,188,372 live births occurred between 2012-2019. In total, 6,994 infants were diagnosed with HIE. Of these, 470 infants were treated for TH during the study period. The HIE incidence in term infants was 2.4 per 1,000 births (range:1.9 to 2.7), which did not change significantly during the study period. A 4.6% mortality was noted among the term infants with HIE and this was maintained between 3.1% to 6.2% during the eight years included in this study. TH was performed on approximately 6.7% of infants with HIE but the annual rate varied widely from 2.4% to 12.5%. Mortality among the infants with TH showed significant reduction. (Fig 1)\u003c/p\u003e\n\u003cp\u003eAmong the 6,994 term infants diagnosed with HIE, NO therapy and invasive ventilation were applied to 61 infants (0.9%) and 486 infants (6.9%) respectively, and anti-epileptic drugs were administered to 287 infants (4.1%). CP was diagnosed in 526 infants (7.5%), delayed development in 823 infants (11.8%), autism spectrum disorders in 96 infants (1.4%), SNHL in 212 infants (3.0%), blindness in seven infants (0.1%), and seizures in 84 infants (1.2%). The combined outcome which included CP, delayed development, SNHL, or blindness affected 1122 infants (16.0%). Infants with HIE and TH showed significantly higher mortality than those with HIE but without TH, and the mortality was significantly higher at all ages after birth, regardless of the nitric oxide and/or invasive ventilator usage (p\u0026lt;0.0001). Infants with HIE and TH also showed significantly higher morbidities including DD, CP, SNHL, and seizures compared to infants with HIE and without TH (p\u0026lt;0.0001). (Table 1)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Demographic characteristics and developmental outcomes among infants with hypoxic ischemic encephalopathy\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHIE without TH\u003c/p\u003e\n \u003cp\u003e(n=6524)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHIE with TH\u003c/p\u003e\n \u003cp\u003e(n=470)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\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 rowspan=\"4\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e81(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.30(4.56/11.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e1-12 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e119(1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.17(4.11/9.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge;1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e121(1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.05(6.89/14.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e321(4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.14(7.09/11.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eNitric oxide therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e61(0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39(0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22(4.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.17(4.80/13.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eInvasive ventilator\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e486(6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e399(6.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e87(18.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33.13(22.80/48.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eAnti-epileptic drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1377(19.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1077(16.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e300(63.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.93(7.31/10.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFirst prescription\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e287(4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e218(3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e69(14.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.98(3.73/6.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eDelayed development\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e823(11.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e726(11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e97(20.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.08(1.64/2.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eCerebral palsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e526(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e453(8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73(15.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.47(1.89/3.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eAutism spectrum disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e96(1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e89(1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7(1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.09(0.50/2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8218\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eSNHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e212(3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e186(2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26(5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.03(1.33/3.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eBlindness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7(0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6(0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1(0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.02(0.80/1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4816\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eADHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e84(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4(0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69(0.25/1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4733\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eSeizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1785(25.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1538(23.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e247(52.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.59(2.97/4.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eCP or Delayed development or SNHL or Blindness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1122(16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e981(15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e141(30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.42(1.97/2.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eCP or Delayed development or SNHL or blindness or mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1351(19.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1122(17.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e229(48.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.58(4.78/5.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: HIE hypoxic ischemic encephalopathy; TH therapeutic hypothermia; OR odds ratio; CI confidence interval; SNHL sensorineural hearing loss; ADHD attention deficit hyperactivity disorder; CP cerebral palsy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe CP incidence significantly decreased in the 453 infants with HIE and without TH. The results showed a decreasing trend from 6.8% to 4.3% during the study period. (P= 0.0031 z=2.9601) The CP incidence among the 73 infants with HIE and hypothermia showed no significant differences over the eight years. (Table 2)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Trends of developmental outcomes among infants with hypoxic ischemic encephalopathy\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.286189683860233%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003eTotal (n=6994) [2012-2019]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e2012-2015 (n=4022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e2016-2019 (n=2972)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\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 width=\"28.286189683860233%\"\u003e\n \u003cp\u003eDelayed development\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e823(11.8%)\u003c/p\u003e\n \u003cp\u003e[8.4 - 8.8%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.2244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e459(11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e364(12.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e\u0026lt;0\u003c/p\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eCerebral palsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e546(7.8%)\u003c/p\u003e\n \u003cp\u003e[7.0 - 5.3%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.0464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e320(8.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e226(7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eAutism spectrum disorder\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e96(1.4%)\u003c/p\u003e\n \u003cp\u003e[1.3 - 0.3%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.0043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e70(1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e26(0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e0.426\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eSNHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e209(3.0%)\u003c/p\u003e\n \u003cp\u003e[3.9 - 2.9%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.0667\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e135(3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e74(2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eBlindness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e1(0.0%)\u003c/p\u003e\n \u003cp\u003e[0.0 - 0.1%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.0924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e1(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eADHD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e84(1.2%)\u003c/p\u003e\n \u003cp\u003e[3.1 \u0026ndash; 0.0%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e81(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e3(0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eSeizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e1785(25.5%)\u003c/p\u003e\n \u003cp\u003e[19.2 \u0026ndash; 19.0%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e948(23.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e837(28.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e\u0026lt;0\u003c/p\u003e\n \u003cp\u003e001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.286189683860233%\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.3044925124792%\"\u003e\n \u003cp\u003e321(4.6%)\u003c/p\u003e\n \u003cp\u003e[3.4 \u0026ndash; 3.1%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.980033277870216%\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e179(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973377703826955%\"\u003e\n \u003cp\u003e142(4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.482529118136439%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* The Cochran-Armitage trend test was used\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e**\u0026nbsp;\u0026chi;2test was used\u003c/p\u003e\n\u003cp\u003eAbbreviations: SNHL sensorineural hearing loss; ADHD attention deficit hyperactivity disorder\u003c/p\u003e\n\u003cp\u003eBased on the data from the disability identification system, brain lesion disorder was the most common disability in infants with HIE (5.7% in the HIE and without TH group vs 14.7% in the HIE with TH group; p\u0026lt;0.0001), followed by auditory disorder, intellectual disorder, and language disorder. (Supplement Table. 1)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe growth outcomes of 2045 infants with HIE (6.9%) showed a weight of \u0026lt;10 percentile, 1777 infants (7.3%) showed a height of \u0026lt;10 percentile, and 2263 infants (9.2%) showed a head circumference (HC) of \u0026lt;10 percentile. There were significant variations in weight \u0026lt;10 percentile (1.9%-9.4%), height \u0026lt;10 percentile (3.2%-8.8%), and HC \u0026lt;10 percentile (6.2%-9.8%) during the study period. Poor growth of infants with HIE, with and without TH, is shown in Fig. 2. The head circumference (HC) was significantly different in the at 6\u003csup\u003e\u0026nbsp;m\u003c/sup\u003eonth, 12month and 24 month of age. In contrast, weight (WT) showed a significant difference only in the first test, while height (HT) was not significantly different between the two groups in any of the tests. Although infants with TH demonstrated poorer conditions than those without TH, catch-up growth in HT, WT, and HC at 18 months was evident. Poor developmental outcomes between infants with HIE, with and without TH, are shown in Fig. 2d. \u0026nbsp;Infants in the HIE with TH group required more \u0026ldquo;refer to specialized test\u0026rdquo; (7.0% vs 4.4%) and also more \u0026ldquo;closed serial test follow-up\u0026rdquo; (13.2% vs 10.9%). Exclusively, during the 2\u003csup\u003end\u003c/sup\u003e (p\u0026lt;0.001) and 3\u003csup\u003erd\u003c/sup\u003e (p=0.038) tests, significantly poor developmental outcomes were demonstrated in the HIE with TH group. In total, 4.6% of infants with HIE required \u0026ldquo;refer to specialized test\u0026rdquo; and 10.6% required \u0026ldquo;closed serial test follow-up\u0026rdquo;. \u0026ldquo;Refer to specialized test\u0026rdquo; (2.7%-8.6%) and \u0026ldquo;closed serial test follow up\u0026rdquo; (5.4%-23.8%) varied significantly during the study period.\u003c/p\u003e\n\u003cp\u003eThe comparison of\u0026nbsp;growth\u0026nbsp;outcomes between infants with and without CP is shown in Table 3.\u0026nbsp;Poor growth at the 2nd, 3rd, and 4\u003csup\u003eth\u003c/sup\u003e tests was significantly associated with an increased risk of CP regardless of TH.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Comparisons of poor growth outcome at 12, 24 and 36 month of age between infants with and without cerebral palsy adjusted with therapeutic hypothermia\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003eCP (n=536 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003eNo-CP (n=6458 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003eOR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHT below 10p at 12month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e38(20.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e222(4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e5.03(3.427-7.383)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eWT below 10p at 12month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e45(24.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e210(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e6.793(4.713-9.793)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHC below 10p at 12month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e69(37.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e221(26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e11.368(8.176-15.805)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHT below 10p at 24month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e35(22.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e226(4.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e5.537(3.707-8.272)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eWT below 10p at 24month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e47(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e303(6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e6.274(4.362-9.024)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHC below 10p at 24month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e62(40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e296(6.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e9.542(6.768-13.454)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHT below 10p at 36month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e42(27.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e219(5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e6.512(4.446-9.539)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eWT below 10p at 36month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e57(37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e301(7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e7.467(5.261-10.599)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.084033613445378%\"\u003e\n \u003cp\u003eHC below 10p at 36month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\"\u003e\n \u003cp\u003e71(46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.478991596638654%\"\u003e\n \u003cp\u003e359(9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.058823529411764%\"\u003e\n \u003cp\u003e8.835(6.306-12.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.092436974789916%\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CP cerebral palsy; OR Odds ratio; CI confidence interval; HT Height; WT weight; HC head circumference ; p percentile\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u0026nbsp;This population-based nationwide study showed that the HIE prevalence in term infants in Korea is similar to that in other developed countries at 2.4 per 1000 live births. However, the use of TH for infants with HIE was lower in Korea at only 6.7%, although an increasing trend over the years was observed. Infants with HIE had a mortality of 4.6%. An increased risk for CP was identified among infants with HIE at \u0026lt;10 percentiles in their HT, WT, and HC.\u003c/p\u003e\n\u003cp\u003eThe worldwide incidence of HIE varies between 1\u0026ndash;3 per 1,000 live births in developed countries and 2.3 to 30.6 per 1000 live births in the developing countries.[20-22]\u0026nbsp;The Korean incidence of 2.4/1000 live births is similar to the HIE incidence in UK (2.63 in 1990s, 2.96 per 1,000 live births in the 2010s) which showed no significant changes over time.[5,23]\u0026nbsp;Providing better access to medical and antenatal care in developing countries may reduce the incidence of HIE.[20]\u0026nbsp;In contrast, in developed countries, significant improvement in the incidence is not usually observed once maternal care has settled down. Our results elucidated that the incidence of HIE in Korea has not changed over eight years.\u003c/p\u003e\n\u003cp\u003eThe mortality rate for newborns with HIE can vary depending on the severity of the condition and the availability of appropriate medical care.\u0026nbsp;The UK study reported decreased mortality in infants with HIE who had\u0026nbsp;undergone TH (12.9% to 6.7% from 2010 to 2017).[6,\u0026nbsp;24]\u0026nbsp;A study from Spain reported 21% mortality which remained relatively constant during the study period from 2010 to 2019.[25]\u0026nbsp;In Canada, 27% mortality in infants with HIE was noted during the study period (1988 to 2015).[26]\u0026nbsp;In this study, we noted a mortality of 4.6% in Korea during the study period of eight years, which did not decline significantly over time. Of note, the diagnosis of HIE may be overestimated due to the retrospective ICD-10 code analysis.\u003c/p\u003e\n\u003cp\u003eTH is effective in reducing the mortality of infants with moderate to severe HIE.[4]\u0026nbsp;TH can reduce the mortality rate for newborns with HIE by 10%-20% compared to control groups that did not utilize TH.[27]\u0026nbsp;In this study, it was impossible to compare the incidence due to the observational nature of the study. However, the mortality rate among infants with HIE and TH significantly declined from 40% to 16.9% during the eight years.\u003c/p\u003e\n\u003cp\u003eTH was first introduced as standard therapy for moderate to severe HIE in Korea in the 2010s.[9]\u0026nbsp;The use of TH in infants with HIE has remained under 10%, except for the year 2018.\u0026nbsp;TH\u0026nbsp;is broadly applied in up to 40.5% of all infants with HIE in the UK and\u0026nbsp;21.1% of the infants in the US.[5,28]\u0026nbsp;The reasons for a significantly lower rate of TH in Korea are as follows: missed or underestimation of moderate to severe HIE as mild to no HIE, the ideal time point for the diagnosis of HIE passed,\u0026nbsp;inability to transport the infant within the therapeutic window, or an active decision not to offer intensive care\u0026nbsp;and lack of facilities or experienced TH specialist. Opportunities to\u0026nbsp;explore practice-site variations and to develop quality improvement interventions to assure consistent evidence-based care of term infants with HIE and the appropriate application of TH for eligible newborns should be considered.[29]\u003c/p\u003e\n\u003cp\u003eIt is encouraging to note that developmental outcomes including \u0026nbsp;CP as a consequence of HIE has decreased significantly in recent years in Korea. We assume that improvements in neonatal care and developmental follow-up protocols have led to better outcomes over time in addition to application of TH. Although CP and other developmental outcomes has not decreased significantly in the HIE with TH group, these results shows the active application of TH is promising for better outcomes.\u003c/p\u003e\n\u003cp\u003eHIE with TH group to be affected by serious medical conditions compared to the HIE without TH group. The severe baseline medical status may be associated with severe HIE, requiring TH. Significantly higher mortalities and morbidities requiring invasive ventilators and anti-epileptic medication were found among HIE infants with TH than those without TH.\u0026nbsp;The occurrence of PPHN was between 13% and 25% in asphyxiated hypothermic infants,[30,31]\u0026nbsp;which is clearly higher than the incidence in the general population (2/1000 live births)\u003cs\u003e.\u003c/s\u003e [32,33]\u0026nbsp;Also,\u0026nbsp;neonates with hypothermia\u0026nbsp;showed a 2.5 times\u0026nbsp;higher risk of PPHN than in controls\u0026nbsp;(23% vs 11%).[34]\u0026nbsp;In this study, 4.7% of infants with\u0026nbsp;HIE and TH required nitric oxide treatment compared with 0.6 % of infants with HIE and without TH, which means it is 8.8 times more common.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTH significantly reduced the combined rate of death and severe disability in three trials that evaluated 18 month outcomes (risk ratio: 0.81, P=0.002).[35]\u0026nbsp;Hypothermia in survivors showed severe disability (28.1%), cerebral palsy (26.4%), deafness (4.7%) and mental and the psychomotor developmental index of less than 70 (26.5% and 26.2% respectively) with \u0026nbsp;significant reduction of the rates compared to normothermia.\u0026nbsp;We found 21% of DD, 16% of CP, 5.5% of SNHL was shown among the HIE infants treated with TH.\u0026nbsp;Children with HIE scored significantly lower than typically developing children in terms of fine motor skills, executive functions, memory, and language. Children with HIE treated with TH may not be as \u0026lsquo;school-ready\u0026rsquo; as their typically developing classmates, and may benefit from long-term medical follow-up until school commencement.[36]\u003c/p\u003e\n\u003cp\u003eAccording to the National Health Screening Program for infants and children, we found that infants with HIE tended to have poor growth. This disparity is more evident in infants with HIE and TH, probably because of the seriousness of the HIE than in infants without TH. An HC of under the 10 percentile was significantly higher in the HIE with TH group than in the HIE without TH group until the fourth test, which corresponded to a chronological age of 30 months. This may be attributed to infants with developmental problems being less likely to engage in general screening at the appropriate age.\u0026nbsp;The \u0026nbsp;adaptation of TH in patients with mild HIE has been a point of contention in developed countries. Despite the known adverse effects associated with TH, it continues to be used for infants with mild HIE and late preterm infants for example 36% infants with mild HIE underwent TH safely in the 2010s in the UK.[5]\u0026nbsp;In Korea, TH is currently not used as a standard therapy for infants with mild HIE as per the National Health Insurance Guidelines.\u0026nbsp;However it is promising in the future.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strength of this study is the use of data from nationwide databases, which encompassed all live births and affected patients included in the study period. Long-term growth and developmental screening data until six years old were also analyzed.\u003c/p\u003e\n\u003cp\u003eThe study has some limitations. The study contains weaknesses inherent to an observational study. National claim data did not include individual patient medical information. The severity of HIE is indistinguishable. The analyses relied on the accuracy of the included ICD codes and labeling error could not be identified and corrected. The KDST was used as a developmental screening tool but the Bayley Scales of Infant Development was not used as a diagnostic tool.\u0026nbsp;The association of outborn birth status with mortality and morbidity was not evaluated.\u003c/p\u003e\n\u003cp\u003eWith increasing TH application, neurodevelopmental outcomes showed decreasing trends, however still remained in Korea. Further efforts and earlier interventions to improve the developmental and growth outcomes of infants with HIE are warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health \u0026amp; Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711138055, \u0026nbsp; KMMDF_PR_20200901_0057)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement format guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are not publicly available due to NHIS Database policy, but are available from the corresponding author on reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAllen, K. A. \u0026amp; Brandon, D. H. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments. \u003cem\u003eNewborn Infant Nurs Rev\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 125-133, doi:10.1053/j.nainr.2011.07.004 (2011).\u003c/li\u003e\n\u003cli\u003eShankaran, S. Therapeutic hypothermia for neonatal encephalopathy. \u003cem\u003eCurr Opin Pediatr\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 152-157, doi:10.1097/mop.0000000000000199 (2015).\u003c/li\u003e\n\u003cli\u003eAmerican Academy of Pediatrics. \u0026amp; American College of Obstetricians and Gynecologists. \u003cem\u003eGuidelines for perinatal care\u003c/em\u003e. 7th edn, (American Academy of Pediatrics ;American College of Obstetricians and Gynecologists, 2012).\u003c/li\u003e\n\u003cli\u003eSmith, J., Wells, L. \u0026amp; Dodd, K. The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. \u003cem\u003eBjog\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 461-466, doi:10.1111/j.1471-0528.2000.tb13262.x (2000).\u003c/li\u003e\n\u003cli\u003eShipley, L., Gale, C. \u0026amp; Sharkey, D. Trends in the incidence and management of hypoxic-ischaemic encephalopathy in the therapeutic hypothermia era: a national population study. \u003cem\u003eArch Dis Child Fetal Neonatal Ed\u003c/em\u003e \u003cstrong\u003e106\u003c/strong\u003e, 529-534, doi:10.1136/archdischild-2020-320902 (2021).\u003c/li\u003e\n\u003cli\u003eHage, L.\u003cem\u003e et al.\u003c/em\u003e 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. \u003cem\u003eArch Dis Child Fetal Neonatal Ed\u003c/em\u003e \u003cstrong\u003e106\u003c/strong\u003e, 501-508, doi:10.1136/archdischild-2020-319685 (2021).\u003c/li\u003e\n\u003cli\u003eTorn, A. E., Lampa, E., Wikstrom, A. K. \u0026amp; Jonsson, M. Hypoxic ischemic encephalopathy in offspring of immigrant women in Sweden: A population-based cohort study. \u003cem\u003eActa Obstet Gynecol Scand\u003c/em\u003e \u003cstrong\u003e100\u003c/strong\u003e, 2285-2293, doi:10.1111/aogs.14234 (2021).\u003c/li\u003e\n\u003cli\u003eJacobs, S. E.\u003cem\u003e et al.\u003c/em\u003e Cooling for newborns with hypoxic ischaemic encephalopathy. \u003cem\u003eCochrane Database Syst Rev\u003c/em\u003e \u003cstrong\u003e2013\u003c/strong\u003e, Cd003311, doi:10.1002/14651858.CD003311.pub3 (2013).\u003c/li\u003e\n\u003cli\u003eSung, I. K. Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy in Newborn Infants. \u003cem\u003eNeonatal Medicine\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, doi:10.5385/nm.2017.24.4.145 (2017).\u003c/li\u003e\n\u003cli\u003eChun, M.-K., Sung, H.-J., Park, J.-H., Lim, G.-Y. \u0026amp; Kim, S.-Y. Predictors of Neurodevelopmental Outcomes in Newborns Undergoing Hypothermia Therapy. \u003cem\u003eNeonatal Med\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 17-23, doi:10.5385/nm.2019.26.1.17 (2019).\u003c/li\u003e\n\u003cli\u003eAzzopardi, D.\u003cem\u003e et al.\u003c/em\u003e Effects of hypothermia for perinatal asphyxia on childhood outcomes. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e371\u003c/strong\u003e, 140-149, doi:10.1056/NEJMoa1315788 (2014).\u003c/li\u003e\n\u003cli\u003eAzzopardi, D.\u003cem\u003e et al.\u003c/em\u003e The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. \u003cem\u003eBMC Pediatr\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 17, doi:10.1186/1471-2431-8-17 (2008).\u003c/li\u003e\n\u003cli\u003eRao, R.\u003cem\u003e et al.\u003c/em\u003e Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children\u0026apos;s Hospital Neonatal Consortium. \u003cem\u003eAm J Perinatol\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 319-328, doi:10.1055/s-0040-1716341 (2022).\u003c/li\u003e\n\u003cli\u003eShankaran, S.\u003cem\u003e et al.\u003c/em\u003e 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. \u003cem\u003eJAMA\u003c/em\u003e \u003cstrong\u003e318\u003c/strong\u003e, 57-67, doi:10.1001/jama.2017.7218 (2017).\u003c/li\u003e\n\u003cli\u003ePierrat, V.\u003cem\u003e et al.\u003c/em\u003e Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. \u003cem\u003eArch Dis Child-Fetal\u003c/em\u003e \u003cstrong\u003e90\u003c/strong\u003e, 257-261, doi:10.1136/adc.2003.047985 (2005).\u003c/li\u003e\n\u003cli\u003eHoehn, T.\u003cem\u003e et al.\u003c/em\u003e Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. \u003cem\u003eResuscitation\u003c/em\u003e \u003cstrong\u003e78\u003c/strong\u003e, 7-12, doi:10.1016/j.resuscitation.2008.04.027 (2008).\u003c/li\u003e\n\u003cli\u003eGluckman, P. D.\u003cem\u003e et al.\u003c/em\u003e Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e365\u003c/strong\u003e, 663-670, doi:10.1016/S0140-6736(05)17946-X (2005).\u003c/li\u003e\n\u003cli\u003eMoon, J. S. Review of National Health Screening Program for Infant and Children in Korea. \u003cem\u003eJ Korean Med Assoc\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 377-385, doi:DOI 10.5124/jkma.2010.53.5.377 (2010).\u003c/li\u003e\n\u003cli\u003eMoon, J. S., Lee SY, Eun BL, Kim SW, Kim YK, Shin SM, Lee HK, Chung HJ. One-year evaluation of the national health screening program for infants and children in Korea. \u003cem\u003eKorean Journal of Pediatrics\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 307-313 (2010).\u003c/li\u003e\n\u003cli\u003eKurinczuk, J. J., White-Koning, M. \u0026amp; Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. \u003cem\u003eEarly Hum Dev\u003c/em\u003e \u003cstrong\u003e86\u003c/strong\u003e, 329-338, doi:10.1016/j.earlhumdev.2010.05.010 (2010).\u003c/li\u003e\n\u003cli\u003eLawn, J. E.\u003cem\u003e et al.\u003c/em\u003e Two million intrapartum-related stillbirths and neonatal deaths: where, why, and what can be done? \u003cem\u003eInt J Gynaecol Obstet\u003c/em\u003e \u003cstrong\u003e107 Suppl 1\u003c/strong\u003e, S5-18, S19, doi:10.1016/j.ijgo.2009.07.016 (2009).\u003c/li\u003e\n\u003cli\u003eNamusoke, H., Nannyonga, M. M., Ssebunya, R., Nakibuuka, V. K. \u0026amp; Mworozi, E. Incidence and short term outcomes of neonates with hypoxic ischemic encephalopathy in a Peri Urban teaching hospital, Uganda: a prospective cohort study. \u003cem\u003eMatern Health Neonatol Perinatol\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 6, doi:10.1186/s40748-018-0074-4 (2018).\u003c/li\u003e\n\u003cli\u003eEvans, K., Rigby, A. S., Hamilton, P., Titchiner, N. \u0026amp; Hall, D. M. The relationships between neonatal encephalopathy and cerebral palsy: a cohort study. \u003cem\u003eJ Obstet Gynaecol\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 114-120, doi:10.1080/01443610020025967 (2001).\u003c/li\u003e\n\u003cli\u003eShipley, L., Mistry, A. \u0026amp; Sharkey, D. Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis. \u003cem\u003eArch Dis Child Fetal Neonatal Ed\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 6-12, doi:10.1136/archdischild-2020-320966 (2022).\u003c/li\u003e\n\u003cli\u003eVega-Del-Val, C.\u003cem\u003e et al.\u003c/em\u003e Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia. \u003cem\u003eNeonatology\u003c/em\u003e \u003cstrong\u003e118\u003c/strong\u003e, 685-692, doi:10.1159/000518654 (2021).\u003c/li\u003e\n\u003cli\u003eRavichandran, L.\u003cem\u003e et al.\u003c/em\u003e Incidence, Intrapartum Risk Factors, and Prognosis of Neonatal Hypoxic-Ischemic Encephalopathy Among Infants Born at 35 Weeks Gestation or More. \u003cem\u003eJ Obstet Gynaecol Ca\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 1489-1497, doi:10.1016/j.jogc.2020.04.020 (2020).\u003c/li\u003e\n\u003cli\u003eShankaran, S.\u003cem\u003e et al.\u003c/em\u003e Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e353\u003c/strong\u003e, 1574-1584, doi:10.1056/NEJMcps050929 (2005).\u003c/li\u003e\n\u003cli\u003eAcun, C.\u003cem\u003e et al.\u003c/em\u003e Trends of Neonatal Hypoxic Ischemic Encephalopathy Prevalence and Associated Risk Factors in the United States 2010-2018. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e, doi:10.1016/j.ajog.2022.06.002 (2022).\u003c/li\u003e\n\u003cli\u003eKracer, B., Hintz, S. R., Van Meurs, K. P. \u0026amp; Lee, H. C. Hypothermia therapy for neonatal hypoxic ischemic encephalopathy in the state of California. \u003cem\u003eJ Pediatr\u003c/em\u003e \u003cstrong\u003e165\u003c/strong\u003e, 267-273, doi:10.1016/j.jpeds.2014.04.052 (2014).\u003c/li\u003e\n\u003cli\u003eShankaran, S.\u003cem\u003e et al.\u003c/em\u003e Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e122\u003c/strong\u003e, e791-798, doi:10.1542/peds.2008-0456 (2008).\u003c/li\u003e\n\u003cli\u003eYum, S. K.\u003cem\u003e et al.\u003c/em\u003e Therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy and reversible persistent pulmonary hypertension: short-term hospital outcomes. \u003cem\u003eJ Matern Fetal Neonatal Med\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 3108-3114, doi:10.1080/14767058.2017.1365123 (2018).\u003c/li\u003e\n\u003cli\u003eWalsh-Sukys, M. C.\u003cem\u003e et al.\u003c/em\u003e Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e105\u003c/strong\u003e, 14-20, doi:DOI 10.1542/peds.105.1.14 (2000).\u003c/li\u003e\n\u003cli\u003eSzakmar, E., Jermendy, A. \u0026amp; El-Dib, M. Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy (vol 39, pg 763, 2019). \u003cem\u003eJ Perinatol\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 891-891, doi:10.1038/s41372-019-0371-4 (2019).\u003c/li\u003e\n\u003cli\u003eJoanna, R. G. V.\u003cem\u003e et al.\u003c/em\u003e Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: a frequent and perilous combination. \u003cem\u003eJ Matern Fetal Neonatal Med\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 4969-4975, doi:10.1080/14767058.2021.1873941 (2022).\u003c/li\u003e\n\u003cli\u003eEdwards, A. D.\u003cem\u003e et al.\u003c/em\u003e Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. \u003cem\u003eBmj-Brit Med J\u003c/em\u003e \u003cstrong\u003e340\u003c/strong\u003e, doi:ARTN c363 10.1136/bmj.c363 (2010).\u003c/li\u003e\n\u003cli\u003eEdmonds, C. J., Cianfaglione, R., Cornforth, C. \u0026amp; Vollmer, B. Children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia are not as school ready as their peers. \u003cem\u003eActa Paediatr\u003c/em\u003e\u003cstrong\u003e110\u003c/strong\u003e, 2756-2765, doi:10.1111/apa.16002 (2021).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"hypoxic ischemic encephalopathy, therapeutic hypothermia, mortality, developmental outcomes","lastPublishedDoi":"10.21203/rs.3.rs-2629230/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2629230/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDespite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. Using a national dataset, we determined the trends of HIE prevalence, the use of therapeutic hypothermia (TH), mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE (International Classification of Diseases-10 code: G93.1) between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 23.7 per 10,000 birth without significant change during the period. The mortality among all term infants with HIE was 4.6% (range: 3.1\u0026ndash;6.2%). TH was performed in approximately 6.7% of infants with HIE and the annual variation was large, ranging from 2.4\u0026ndash;12.5%. Infants with TH showed significantly higher mortality, nitric oxide usage, and invasive ventilator usage than those without TH. Infants with TH also showed significantly poorer outcomes including delayed development, cerebral palsy (CP), sensorineural hearing loss and seizure compared to infants without TH (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). With increasing application of TH, mortality and developmental outcomes among infants with HIE has been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.\u003c/p\u003e","manuscriptTitle":"The growth and developmental outcomes of Hypoxic Ischemic Encephalopathy; Population-based study from 2010 to 2019","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-24 15:11:55","doi":"10.21203/rs.3.rs-2629230/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-08-30T11:01:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-24T11:09:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0c6021b9-114d-45c0-8afc-3fcbc69c5132","date":"2023-08-16T02:29:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-13T15:17:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"027cc1d9-ff7a-4215-a41a-521366dc4800","date":"2023-07-16T11:38:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d83dfd13-7425-4aa7-aa53-97bab875dab5","date":"2023-07-12T13:56:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-12T07:49:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-06-29T15:12:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-03-23T06:57:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-03-23T06:53:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-02-26T02:15:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"37d33054-a710-4a93-9685-fb7cc06cf002","owner":[],"postedDate":"March 24th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":20139056,"name":"Health sciences/Medical research"},{"id":20139057,"name":"Health sciences/Medical research/Paediatric research"}],"tags":[],"updatedAt":"2024-01-01T15:01:39+00:00","versionOfRecord":{"articleIdentity":"rs-2629230","link":"https://doi.org/10.1038/s41598-023-50187-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2023-12-28 15:00:36","publishedOnDateReadable":"December 28th, 2023"},"versionCreatedAt":"2023-03-24 15:11:55","video":"","vorDoi":"10.1038/s41598-023-50187-0","vorDoiUrl":"https://doi.org/10.1038/s41598-023-50187-0","workflowStages":[]},"version":"v1","identity":"rs-2629230","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2629230","identity":"rs-2629230","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}