Incidence of Neonatal Seizures in China Based on Electroencephalogram Monitoring in Neonatal Neurocritical Care Units

Key Points Question What is the incidence of neonatal seizures in China, and what are the implications for neonatal neurocritical care units based on continuous video electroencephalography monitoring? Findings This cross-sectional study involving 20 310 high-risk neonates in China found an incidence of seizures in 16.9% of cases, with acute neonatal encephalopathy being the most common cause. Meaning The findings of this study highlight the need to expand neonatal neurocritical care units and provide important insights into the incidence of neonatal seizures in China, emphasizing the significant burden they pose to high-risk infants.


Introduction
Advancements in neonatal critical care techniques have contributed to a further reduction in global neonatal mortality rates. 1 However, it is accompanied by the potential for severe neurological complications in a subset of treated neonates, who often develop brain injury or encephalopathy.
Seizures are the most common manifestation of neonatal brain injury, with approximately 20% later evolving into epilepsy or neurobehavioral developmental disorders. 2 The incidence of neonatal seizures varies, ranging from approximately 0.95 to 5.0 per 1000 live births. 3 This rate is affected by factors such as gestational age, etiology, and medical center. 3 With respect to etiology, neonates with hypoxic-ischemic encephalopathy exhibit the highest incidence of seizures. 4,5 However, the incidence of neonatal seizures varies across different regions of the world, and large-scale data on the local incidence of neonatal seizures in China have yet to be reported.
Neonatal convulsive seizures often prove challenging to identify based solely on clinical observations, with roughly half or more being subclinical in nature. [6][7][8] The American Clinical Neurophysiology Society (ACNS) states that continuous electroencephalography (cEEG) monitoring is the criterion standard for detecting seizures in high-risk neonates. 9 Early detection of neonatal seizures may help prevent or reduce brain injuries and fatalities, and timely intervention could improve neurodevelopmental outcomes for nearly half of neonates with seizures by decreasing cerebral palsy, intellectual disability, and epileptic encephalopathy. 10 Early electrophysiological evaluation is increasingly favored for newborns at high risk of brain injury, owing to the growing body of evidence supporting better seizure control and potentially improved outcomes. 11 In 2009, the Children's Hospital of Fudan University established the first neonatal neurocritical care unit in China. 12

Study Design
This large cross-sectional multicenter study was conducted in the NICUs of 7 tertiary medical centers.
The study is registered on ClinicalTrials.gov (NCT02552511) and adheres to the guidelines of the Declaration of Helsinki. 13 The Ethics Committee of the Children's Hospital of Fudan University reviewed the study's content. The parents or guardians of included newborns provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Sample Size Estimation
Sample size estimation was calculated using PASS 2008 version 8.0.3 (NCSS). The incidence of seizures in the NICU ranged from 0.95 to 5.0 per 1000 live births. We conservatively selected an incidence of 0.95 per 1000 live births for neonatal seizures. Assuming an allowable error of 1.0% and a 2-sided significance level of .05, a minimum of 3303 neonates with seizures would be needed.
Consequently, each hospital required approximately 472 neonates with seizures.

Monitoring Criteria of CNNCCN and cEEG Monitoring Standards
Neonates at high risk for seizures, requiring cEEG monitoring per ACNS guidelines, 9 were eligible for the study. All included newborns were no older than 28 days of age. The parents or guardians of eligible newborns were approached and provided consent. The definition and inclusion criteria for high-risk infants were referenced from the neonatal population recommended for monitoring by ACNS. 9,15 These inclusion criteria were specifically targeted at neonates at a high risk of seizures (eTable 1 in Supplement 1). Neonates with scalp injuries, scalp infections, or scalp bleeding, which could lead to delayed EEG monitoring, were excluded from the study. Further details can be found in the study flowchart (Figure 1). Monitoring standards of cEEG can be seen in eTable 2 in Supplement 1.

cEEG Monitoring Process
The cEEG recordings were performed using the Nicolet Monitor (Natus) video EEG system, with 32 gold-over-silver scalp cup electrodes positioned according to the International 10-20 system.
Considering the small scalp area of neonates, which limits the placement of too many electrodes, and their delicate skin, which may lead to scalp injuries or pressure sore infections, we followed the

Etiology Clarification
The team carried out a systematic and in-depth evaluation of each possible cause of seizures in newborns, with each cause following specific diagnostic criteria (eTable 3 in Supplement 1). When evaluating acute neonatal encephalopathy (ANE), the research team carefully analyzed the relationship between other causes and ANE. If a particular cause was found to be closely related to ANE, it was considered the main cause. After ruling out all other causes, ANE was confirmed as the diagnosis. Furthermore, for infants whose causes could not be confirmed, the team made an etiological diagnosis through multidisciplinary discussion. Seizures that could not be confirmed to be caused by these causes were marked as unknown etiology.

Baseline Data Collection
Data were collected between January 1, 2017, and January 31, 2020. Baseline information and clinical

Definition and Diagnosis of Seizures
Neonatal seizures are identified by at least 10 seconds (or shorter if associated with clinical changes) of paroxysmal, abnormal, and sustained ictal rhythm, which is a repetitive and evolving pattern with a minimum amplitude of 2 microvolts, as observed in the cEEG. 9,15 Neurophysiologists will only diagnose seizures when abnormal motor events are associated with abnormal electrical activity on the EEG. To compare the association between PMA and seizure burden with prognosis, the team referred to the seizure burden grouping by the Neonatal Seizure Registry group 16 and combined it with the postintervention status to categorize the seizure burden into 3 groups: mild, moderate, and severe. Mild refers to fewer than 7 seizures during the monitoring period and seizures that can be effectively controlled after the initial use of medication. Moderate refers to more than 7 seizures or frequent recurrences during the monitoring period, but the seizures can still be controlled after using multiple single or combined medications. Severe refers to a continuous state of seizures during the monitoring period or multiple long-lasting seizures that are difficult to control through medical treatment.

Report of cEEG Monitoring Results
Each research center is outfitted with at least 2 fixed reporting staff members who each have more than 5 years of EEG interpretation experience. This arrangement guarantees they can alternate shifts to meet the requirement of 24-hour coverage. A chief neurophysiologist, with more than 10 years of experience, is responsible for reviewing these reports to ensure their accuracy. Before the commencement of the study, all neurophysiologists responsible for reporting underwent uniform training and education and secured EEG reporting qualifications issued by the China Anti-Epilepsy Association. Additionally, the study established regular review and quality control mechanisms, which included the evaluation of randomly selected cEEG reports by an independent review team, and regular consistency checks.

Statistical Analysis
The data were analyzed between January 2021 and January 2022. Data analysis was conducted using Stata version 13.0 (StataCorp). Clinical variables are presented as number and percentages, with mean and SD for continuous variables or median with ranges for ordinal variables. Group comparisons of quantitative data were achieved by 2 independent sample t tests. The betweengroup comparison of qualitative data was done using the χ 2 test. P < .05 was considered statistically significant, and all tests were 2-tailed.

Results
Overall, 20 310 neonates were recruited (10 495    A total of 7.8% of neonates with seizures (267) died during hospitalization (Figure 4)   Across all etiologies, the number of neonates with seizures decreased as the seizure burden increased, but the mortality rate rose with the severity of the seizure burden ( Figure 4). This pattern was evident in both preterm and full-term infants. Although the number of deaths among preterm infants with moderate-to-severe seizure burden was lower than in full-term infants, the mortality

Discussion
Seizures are the most prevalent neurological symptom in newborns with acute brain injury. 17 cEEG monitoring serves as the criterion standard for seizure detection. 18,19 Over the past decade, as cEEG has been increasingly adopted for neurocritical monitoring in China, 20 a growing number of thirdlevel NICUs have provided newborns with the opportunity to receive brain protection upon admission. In 2011 and 2013, 9,15 the ACNS successively released guidelines and consensus on newborn brain monitoring, providing a harmonized reference and management standard for newborn brain monitoring worldwide. As a result, the Children's Hospital of Fudan University spearheaded the formation of the CNNCCN, which established the first neonatal neurocritical care unit in China. 21 Encompassing more than 20 000 cases of newborn seizures, this study represents the most extensive multicenter observational investigation in China, boasting the largest sample size reported to date of which we are aware. The present study unveils the cross-sectional data of newborn seizures collected over a 2-year span.
In this study, seizures were detected in 3423 high-risk infants (16.9%), which aligns with international data. 5,22,23 The incidence of neonatal seizures varies among studies due to factors such as sample size, location, and the level of research institutions involved. [24][25][26][27] The global incidence of neonatal seizures is not uniform, with higher rates observed in low-resource countries than in highresource countries and in low-income countries compared with high-income countries. 28 Studies focusing on newborns of less than 28 weeks of gestation are very limited. 33 To our knowledge, our research represents the largest cross-sectional study to date in China concerning extremely preterm infants. Past research indicates that the incidence of seizures in preterm infants in the NICU is 2 to 10 times higher than in full-term infants. 27,34 This might be higher than our research findings. The discrepancy could be related to sample size, as we have data for each gestational age group, with the rates for each group relatively stable. Furthermore, we found that the mortality rate was higher for preterm infants with seizures, with the rate increasing as gestational age decreased. 35 Extremely preterm infants face a 20% to 50% risk of experiencing seizures, [36][37][38][39][40][41][42] and the incidence of cognitive and motor disorders also significantly increases. 43 These findings underscore the importance of early identification and management of neonatal seizures in preterm infants, given the heightened risk of adverse outcomes for extremely preterm infants. This indicates that preterm infants remain a high-risk group for brain injury in the NICU, and that brain protection strategies should be implemented during the perinatal period to improve postnatal neurodevelopmental outcomes in this population.
Perinatal environmental factors still remain the most common causes of seizures in high-risk infants. 5 The etiology of seizures is closely linked with the burden and mortality rate of critically ill newborns. Although genetic syndromes, CNS malformations, and inborn errors of metabolism accounted for merely 12.5% of all seizure cases, these infants experienced severe seizure burdens and a high rate of early death. Critically ill infants with these 3 major etiologies often face severe metabolic disorders, uncontrolled seizures, progressively worsening brain damage, or death during treatment, with a poor long-term prognosis. 44 Therefore, we emphasize the need for heightened clinical vigilance for these types of patients. Prompt activation of genetic or other auxiliary tests should be initiated as soon as suspicion arises, aiming to secure time for intervention and treatment to improve prognosis.

Limitations
This study has limitations. First, we lacked long-term outcome data and control data for high-risk infants not monitored with cEEG due to early funding constraints. We aim to create a large cEEG monitoring cohort for comparison. Second, we may have missed seizure cases without clinical symptoms by stopping monitoring after 4 hours. Despite ACNS recommendations of at least 24 hours of monitoring, implementing such continuous, large-scale monitoring was challenging. Future research might investigate the optimal cEEG monitoring duration. Furthermore, variability in cEEG analysis and reporting levels was expected despite our training measures, emphasizing the importance of experienced neurophysiologists and adherence to ACNS guidelines. 45 Future studies could potentially involve a larger neonatal population and long-term follow-up.

Conclusion
This cross-sectional study highlights the considerable burden that neonatal seizures pose to high-risk infants in China, especially those born preterm or with congenital conditions. Improvements in prenatal and neurocritical care, optimization of treatments for medically refractory seizures, and expanded access to early diagnosis and coordinated care for complex conditions could help address excess morbidity and mortality.