Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344647
Source of Support: None, Conflict of Interest: None
Keywords: Anti-epileptic drugs, neonatal seizures, neonates
Neonates are prone to seizures due to their juvenile brain; any hindrance can cause long-term impairment., Effective management of seizures is a neurological emergency. WHO guidelines recommend phenobarbitone as the first-line and phenytoin as the second-line drug. Levetiracetam and phenobarbitone are administered as first-line agents for neonatal seizure management, but their comparative efficacy is unknown.
Due to the lack of established guidelines for treatment, this study was conducted to perceive the efficacy of anti-epileptics. The utilization of AEDs was assessed and correlated with their efficacy. Hypoxic-ischemic encephalopathy was the major etiology identified; other associated etiologies were also examined.
A retrospective cohort study was conducted for a period of 1 year which included neonates admitted from Jan 2014 to July 2018. Ethical clearance was obtained from the lEC of the hospital. The data were collected from inpatient medical records and the hospital's online database using a case report form (CRF).
Neonates diagnosed with neonatal seizure and/or HIE (ICD-10-P-90 and ICD-10-P-91.60) (male and female) who were admitted at the study site from 2014 (Jan) to 2018 (July) were included. In other words, the 267 neonates in our study were either diagnosed with NS or status epilepticus to meet the primary objective. Neonates with HIE were also included in the study to determine its etiology and association with NS. Patients with incomplete records were excluded from the study.
Method of data collection
Detailed history of the neonates, that is, age at admission, birth weight, admission weight, history, and type of seizure, was recorded. The natal and post-natal history of the babies were collected. All available information regarding maternal medical and medication history were also recorded. Relevant laboratory investigations, such as complete blood count, blood glucose levels, serum calcium levels, serum electrolytes, and CSF analysis, were recorded in the study. Hypoglycemia was marked when glucose levels were <45 mg/kg in mature neonates. Calcium levels of <7.5 mg/dl indicated hypocalcemia. CSF analysis with CSF sugar less than serum sugar level, elevated protein levels, and CSF leukocytes more than 20 with predominant neutrophils were indicated as an abnormality.
The data were analyzed using Statistical Package for Social Sciences (IBM SPSS version 20.0). P < 0.001 is considered as statistically significant. All the categorical variables are expressed in proportion and analyzed by Chi-Square test. Continuous variables were expressed in terms of mean ± SD, and analysis was carried out by independent t test.
The etiology of HIE was checked by assessing categorical variables using the Chi Square formula and binary logistic regression. The association of HIE and neonatal seizures was measured using the Chi-square formula.
General descriptive data
A total of 267 neonate's patient data were observed during the study, among which the majority were male (168, 62.9%). The mean and standard deviation of age (in days) of the study patients included was 4.17 ± 5.729. Out of 267 cases, 152 (56.9%) neonates had the diagnosis of only seizures, 38 (14%) with HIE, and 77 (28.8%) diagnosed with both neonatal seizures and HIE. The comorbidities (possible etiology) observed in subjects with seizures were metabolic abnormalities, infectious diseases, CNS abnormalities, respiratory disorders, HIE, hematologic abnormalities, and congenital malformations. Electroencephalogram was done for most of the neonates (191, 71.5%) and cessation seizures were confirmed clinically.
Most babies (51.68%) had their first seizure episode within 24–48 h of life [Table 1]. The electroencephalography investigations for most babies were normal (as EEG was performed 24 h after a seizure due to unavailability of bedside EEG at the hospital) and 157 (58.8%) subjects were admitted for less than 10 days. The electrolyte abnormalities were monitored by recording hypoglycemia, hypocalcemia, and hypomagnesemia. Hyponatremia, hypernatremia, and hyperkalemia were included as the electrolyte abnormalities. However, hyperkalemia did not cause a seizure in most neonates.
Utilization pattern of anti-epileptics drugs (2014–2018 (July))
When the frequency of overall drug utilization throughout the years was assessed, phenobarbitone was administered to 129 neonates, making this the commonly used anti-epileptic drug, especially in the year 2016. Phenytoin was the intermediately used drug and levetiracetam was the least used drug throughout. The utilization pattern of anti-epileptic drugs as first, second-, and third-line agents was observed. Phenobarbitone was commonly administered as a first-line agent along with phenytoin as a second-line agent. The drug least used as a first-line agent was phenytoin. There was a sudden rise in levetiracetam exposure to 23% in the year 2016 [Table 2].
Determination of the efficacy of AED (s) for neonatal seizures (a comparative observation)
The AEDs were compared based on their main outcomes, and phenobarbitone was prescribed in the highest number of cases where seizures were resolved within 24 h (97, 75.1%). It also had the least cases of seizure recurrences (53, 41.1%) and readmission (20, 15.5%). Phenytoin was the second-best first-line agent, making levetiracetam the least efficient first-line agent given its poor outcomes. Thus, we observed phenobarbitone as the most efficient first-line AED.
A second-line AED is required in a scenario where the first-line AED fails to effectively control seizures. When the efficacy of drugs as a second-line agent was compared, phenytoin manifested as the best choice. It had the least seizure recurrence (4, 8.51%), readmissions (7, 14.8%), and fastest resolution in 24 h (25, 53.1%). In contrast, levetiracetam proved itself as the worst second-line agent [Table 3].
The efficacy of AEDs as a third-line agent was also assessed and compared. Levetiracetam and phenytoin were the prominently observed third-line agents in this study. Levetiracetam was the better third-line choice with the fastest recovery in 48 h (6, 60%) and least admissions (2, 20%).
Determination of association between hypoxic-ischemic encephalopathy and neonatal seizures
A highly significant association was found between HIE and neonatal seizures with P < 0.05; it was determined statistically by applying Chi-square formula (df = 1, P < 0.05).
Etiology of HIE
The possible etiology of HIE was remarked using Chi-square formula (df = 1, P < 0.05) and binary logistic regression, for the association of HIE and the neonatal factors and maternal medical history.
We observed that metabolic abnormalities and birth asphyxia and PV leakage in mothers were significant etiologies of HIE, with P < 0.05.
Newborns have a juvenile brain, which may be one of the many reasons why a coexisting etiology (HIE, Intracranial hemorrhage, sepsis, etc.) may cause a seizure.
The efficacy of antiepileptic drugs was assessed by comparing three main outcomes of each AEDs. The main variables that were measured to evaluate the AEDs were the time taken to resolve seizure, seizure recurrence, and readmission. The AED that took the shortest time to resolve a seizure, yielded the least cases of seizure recurrence after administration, and required the least readmissions was considered most efficient.
Phenobarbitone was extensively prescribed as a first-line drug in 2014, with a gradual decrease especially in 2017 and higher in 2018. The explanation as to why it was commonly prescribed was obtained when its efficacy was observed. It was the fastest to resolve seizures with lease recurrences and readmissions. These outcomes were the best when compared with levetiracetam and phenytoin. Phenobarbitone was the second-best when used as a second-line agent and was never administered as a third-line agent in our study.
Ahmad et al. conducted a retrospective cohort study among 9134 neonates who were diagnosed with seizures. There was a 98% phenobarbitone exposure observed, making it the commonly used AED during the study period. However, the study had stated a lot of safety concerns based on a single-center review, which established an association between phenobarbitone use, worsened 24-month cognitive/motor scores, and cerebral palsy.
Torolira et al. also confirmed that phenobarbitone had revealed widespread neonatal injury during a study on rat pups. A study by Gowda et al. concluded that there were 10 adverse events reported with phenobarbitone and none for levetiracetam group among 122 neonates. Long-term effects and possible adverse reactions of phenobarbitone use must be addressed and not just the anticonvulsant properties.
Levetiracetam had contractual changes in its use as a first-line agent. Its poor efficacy could explain the reduced utilization [Table 3]. In the present study, levetiracetam was observed as an efficient third-line agent. However, its minimized use at the hospital could predispose these results when observed therapeutic outcomes were statistically determined. Neubauer et al. concluded that it is an effective adjunctive AED (second or third-line agent) for seizure control in newborns. Randomized controlled trials conducted by Sharpe et al. revealed that phenobarbitone was more effective than levetiracetam along with higher levels of adverse effects. The trial recommended using higher doses of levetiracetam to reach desired therapeutic goals. A study conducted by Dias et al. observed that levetiracetam is a better alternative to phenobarbitone in neonates where NS is associated with HIE. Neonates diagnosed with HIE may be phenobarbitone resistant, leaving levetiracetam as the better first-line drug in such scenarios.
In contrast, a study was conducted by Grinspan et al. on the comparative effectiveness of levetiracetam and phenobarbitone in the management of neonatal seizures. It concluded that levetiracetam had the least monotherapy failure and had less developmental delay, whereas neonates treated with phenobarbitone had a much greater number of monotherapy failures and poorer cognitive outcomes in otherwise healthy subjects, further reminding the necessity for clinical trials to generate systematic guidelines to treat neonatal seizures and unravel the dilemma.
The use of levetiracetam in a study conducted by Ahmad et al, showed an increase from 1.43% to 14.3%. This is because of its newly found benefits in monotherapy and as a second-line drug. An association between levetiracetam use in each population and worsened cognitive and motor scores was observed. However, it was lesser than the reports obtained from phenobarbitone safety studies.
Phenytoin was least prescribed as a first-line drug throughout the study, but was the commonly administered second-line agent, which was justified by its efficacy as the latter. Phenytoin exposure was seen in neonates diagnosed with seizures and HIE. Based on the pharmacokinetics of phenytoin, Neubauer et al. suggested its use for acute management and long-term maintenance.
Painter et al. compared the effectiveness of phenobarbitone and phenytoin in neonatal seizures. They concluded that both drugs had equal effectiveness but are still not adequately competent AEDs. In contrast, Pathak et al. conducted an open clinical trial and concluded that phenobarbitone was more efficacious than phenytoin in treating neonatal seizures.
In many subjects, midazolam was coadministered with phenobarbitone, probably for its dual advantage as an AED and as a sedative for investigational procedures. In a study by Kang et al., midazolam and levetiracetam were administered to neonates diagnosed with refractory seizures and HIE.
Dao et al. did a study that reported a few adverse reactions only when midazolam was coadministered with phenobarbitone; when higher than necessary doses were administered, neonates were to be found in serious conditions, such as malformations and brain hemorrhage. However, no serious adverse reactions were reported in the present study.
The association of HIE and neonatal seizure was observed among subjects. As a result, we witnessed a significant association between HIE and NS. In a population study, Ronen et al. observed neonatal seizures that were triggered by HIE. Kang et al. conducted a study that strongly stated that HIE is a crucial etiology since it may lead to a comorbidity.
When levetiracetam was administered prophylactically to neonatal rats diagnosed with HIE, a significant improvement in hypoxic activity was observed. In a study by Mruk et al., levetiracetam showed a direct disease-modifying effect on HIE, reducing the risk of developing seizures. Early diagnosis and specific treatment are important as most neonates with HIE are phenobarbitone resistant. Study findings by Kossoff showed that there is a twofold risk of developing seizures in neonates diagnosed with severe HIE. Neonatal seizure occurs in approximately 1–2 per 1000 live births according to a study by Silverstein et al., thereby emphasizing the importance of quick HIE management and prevention in order to prevent seizures.
Birth asphyxia, metabolic acidosis, and maternal para-valvular leakage were concluded as significant etiologies of HIE. In a study by Thornberg et al., the incidence of birth asphyxia with HIE in neonates was estimated as 1.8 per 1000 live births, thus indicating that birth asphyxia is an important etiology of HIE. Metabolic abnormalities such as hypoglycemia and hypocalcemia were confirmed as possible etiology of HIE in a study by Hahn et al. According to a study conducted by Itoo et al., maternal factors can trigger HIE in neonates.
To conclude, phenobarbitone was most utilized and observed as an efficient anti-epileptic drug for neonatal seizures. Levetiracetam was the least used and the least efficient AED. Phenytoin was the best second-line drug and the second-best AED in the study. HIE was observed to commonly cause seizures, making its prevention and effective management more crucial.
Lack of clinical studies focusing on long-term side effects, follow-up, and missing data are the limitations of this study. The safety of the AEDs was not assessed in the neonatal population due to lack of follow-up as this was conducted retrospectively. Owing to limitations in this study, there is an alarming need for standardized clinical trials in order to establish thorough evidence-based guidelines for the treatment of neonatal seizures.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]