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.