Background
Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and long-term disabilities in children [
1‐
4]. In spite of significant improvements in obstetric and neonatal care, HIE continues to occur in developed countries, with a disproportionately high burden persisting in low- and middle- income countries. HIE occurs in 1 to 3 per 1000 live births in high income countries, and up to 20 per 1000 live births in low and middle-income countries [
1,
3‐
5]. There are 15–18 million live births in China each year, and the incidence of neonatal HIE is estimated to be 3–6 per 1000 live births [
6]. Neonatal HIE accounts for 15.2% of mortality under the age of five [
7]. Improving survival and long-term neurodevelopmental outcomes of infants with HIE have a significant impact on national and global public health.
Therapeutic hypothermia (TH) for infants with moderate-severe HIE improves survival and decreases long-term disability in infancy and up to mid-childhood [
8‐
16]. TH has become the standard of care in developed countries [
17]. To standardize HIE diagnosis and implement evidence-based management of neonatal HIE in China, national guidelines have been published, including “Diagnosis of Hypoxic-ischemic Encephalopathy in Term Infants” [
18] (hereinafter referred to as HIE diagnosis guideline), “Guideline of Evidence-based Treatment for Hypoxic-ischemic Encephalopathy in Term Infants” [
19] (hereinafter referred to as HIE treatment guideline, Additional file
1), and “Protocol of Hypothermia Treatment for Hypoxic-ischemic Encephalopathy in Neonates” [
20] (hereinafter referred to as TH protocol).
Standardization is essential to assure the efficacy and safety of TH in clinical practice and ultimately improve patient outcomes. Since the publications of the national HIE guidelines, many hospitals have implemented TH. However, there has been no report regarding standardization of HIE management and clinical adoption of TH in different types of hospitals throughout China. We conducted a nationwide survey to investigate the current status of neonatal HIE diagnosis, TH, and other HIE treatments, and long-term neurodevelopmental follow-up programs for infants who have survived HIE.
Discussion
This is the first national survey of neonatal HIE diagnosis and treatment conducted in China. The respondents were mainly senior pediatricians and neonatologists working in Level III hospitals across the country. Thus, findings from our survey provide a good representation of the current status of neonatal HIE diagnosis and treatment in China.
The 2005 updated Chinese national HIE diagnosis guideline [
18] requires meeting all of the following four criteria: (1) history of perinatal hypoxic-ischemic events and evidence of fetal distress, (2) Apgar scores at 1 and 5 min of </= 3 and </=5, respectively, and or arterial blood gas pH </= 7, (3) evidence of encephalopathy, and (4) exclusion of other causes for encephalopathy. Our survey found that 96% of respondents used clinical manifestations of encephalopathy as HIE diagnostic criteria, but only 68% used arterial blood analysis as a diagnostic indicator. Physicians who were aware of the HIE diagnostic criteria were more likely to use arterial blood gas. This demonstrates that more education is needed to emphasize the value of cord blood gas analysis in providing essential evidence of acute hypoxic-ischemic insults to the fetus during labor and delivery. Additionally, placing designated blood gas analyzers may facilitate the utilization of blood gas by labor and delivery departments that have thousands of deliveries each year. The HIE diagnostic guideline also recommends using EEG/aEEG and brain imaging (preferably MRI when available) to obtain information on brain injury and prognosis. In our survey, only 56% of hospitals utilized EEG/aEEG, and 73% used brain MRI, which represents an significant opportunity to improve HIE diagnosis and prognosis [
21‐
23].
International multicenter randomized clinical trials (RCT) and subsequent meta-analysis have demonstrated that TH is effective and safe for treating neonates with moderate and severe HIE [
8‐
13]. In developed countries, much effort has been devoted to disseminating and standardizing TH in clinical practice [
24‐
29], leading to TH becoming the standard of care in clinical practice. The implementation of TH in developing countries faces multiple challenges [
30‐
32]. While data from low-resource settings is limited, a recent systemic review showed that hypothermia efficacy was not associated with countries’ income levels [
33]. TH was recommended by the Chinese national guidelines a decade ago, it was implemented only in 54% of the surveyed hospitals, and only 60% of the Level III hospitals that routinely treat critically ill neonates offered the therapy. Awareness of the HIE treatment guideline and TH protocol was only 63 and 78%, respectively. Furthermore, awareness of the guidelines was not associated with a higher rate of TH.
It is worthwhile noticing that the TH rate in general hospitals (43%) was significantly lower than that in maternity and infant hospitals (67%) and children’s hospitals (77%). This difference demonstrates that hospitals specializing in women’s and children’s services place a higher priority on implementing novel neonatal therapies (like TH) and support such efforts with necessary funding and resources.
Thirty-nine percent of the respondents listed reduction in HIE cases in recent years as a reason for not providing TH. In the past decades, China has made remarkable progress in maternal and child health. Between 1990 and 2018, the national neonatal mortality rate has decreased from 30 to 4 deaths per 1000 live births, and the under-5 mortality rate decreased from 54 to 8.5 per 1000 live births [
34]. National birth-asphyxia-related infant mortality has been reduced significantly since the launch of China’s Neonatal Resuscitation Program (NRP) in 2004 [
35]. Despite this progress, HIE affects as many as 100,000 newborns each year in China and remains the leading national cause of mortality and morbidities in children under-5 years of age [
7]. In our survey, 74% of hospitals treated more than 10 cases of HIE annually, but just 54% of the hospitals provided TH, the only proven therapy for neonatal HIE. Given the high rates of mortality and morbidity associated with HIE, every affected newborn should have the opportunity to benefit from TH treatment.
Thirty percent of survey respondents expressed a lack of training in TH and concerns about the safety of hypothermia treatment. This finding, together with the observation of low awareness of the HIE guidelines, highlights a significant need for a national education program like NRP, that provides organized education and training in TH throughout the county. Another 31% of respondents cited the high cost of cooling devices and treatment. While hospital funding in China has improved dramatically in recent years, this has brought up the need for more financial investment in lifesaving therapies in neonatal critical care. In addition, financial reimbursement to the hospitals for providing TH therapy remains to be established.
The Chinese TH protocol [
20] follows the published patient selection criteria and cooling methods used in multicenter RCTs [
8‐
10]. Our survey showed that only 27% of the cooling hospitals were in full compliance with published TH protocol. Only 31% followed the recommended patient selection criteria, which reflects the lack of standardization in HIE diagnosis. Compliance issues were also found in cooling procedures, including the timing of TH initiation, cooling temperature, and cooling duration. Similar practice variations have been reported by a recent study in Brazil [
32]. Standardization in the health care setting has been shown to improve safety and patient outcomes [
36]. While current recommended TH protocols are being optimized through more clinical trials [
37,
38], standardization is a crucial component of TH dissemination to assure its efficacy and safety in clinical practice.
Despite TH therapy, up to 55% of children with HIE die or suffer severe long-term neurological abnormalities [
13], emphasizing the need for further research for new treatments. Multicenter RCTs are investigation the neuroprotective effects of erythropoietin, allopurinol, xenon, melatonin, and topiramate when administrated alone or as adjuvants to TH [
39‐
43]. Our survey found that 81% of the hospitals used one or more putative neuroprotective agents, including erythropoietin, ganglioside, rat nerve growth factor, citicoline, and cerebrolysin [
44‐
48]. Clinical trials conducted in China and meta-analyses of these studies showed that ganglioside, the most commonly used agent in our survey, was safe and effective in reducing neurological sequelae of HIE [
45]. However, the trials had significant heterogeneities in study design, patient population selection, and outcome evaluation. Most of the studies lack data on long-term follow-up. Rat nerve growth factor, citicoline, and cerebrolysin were mainly evaluated by pre-clinical investigations and limited clinical studies [
46‐
48]. Their neuroprotective effect remains to be demonstrated by multicenter RCTs.
Long-term neurodevelopmental follow-up is an essential component of care for children affected by HIE, which allows early identification of and intervention for abnormal development. Our survey showed that 91% of hospitals had a long-term follow-up program; more than half of them used the Bayley III scale. Nationwide standardization in timing and method of neurodevelopmental assessment remains to be established.
This study has several limitations. We were not able to provide the overall rate of HIE, percentage of HIE infants who received TH, and complications of TH because many of the surveyed hospitals did not have a database for their HIE cases. This is due to the fact that majority of the survey hospitals were lack of database to track HIE infants. Establishing a national neonatal registry is essential for providing epidemiological data on neonatal HIE incidence, treatments, and outcomes [
24]. This survey mainly reflects the knowledge of providers who practice in Level III hospitals. However, many babies are delivered in Level I and II hospitals. Future surveys should include providers in Level I and II hospitals to assess their abilities to timely identify at-risk newborns, stabilize, and transfer these infants to cooling centers [
22]. as many of the survey hospitals were lack of a database tracking HIE cases.
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