Abstract
Objective
To assess long‐term safety of antiseizure medication (ASM) discontinuation after resolution of acute provoked neonatal seizures and prior to hospital discharge.
Methods
Prospective, observational, comparative effectiveness cohort study of neonates with acute provoked seizures born from July 2015 to March 2018, and followed until September 2024, at nine U.S. Neonatal Seizure Registry centers with Level IV neonatal intensive care units and Level IV pediatric epilepsy programs. Duration of ASM treatment was quantified as (1) discontinuation before discharge from the neonatal seizure admission or (2) maintenance at the time of hospital discharge. Outcomes were adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined among enrolled participants by a logistic regression model including seizure etiology, gestational age, therapeutic hypothermia, worst electroencephalography (EEG) background, days of EEG seizures, and discharge neurological exam (all p ≤ .1 in a joint model, except etiology, which was included for face validity). The primary outcome was non‐inferiority of cognition (Wechsler Preschool and Primary Scale of Intelligence assessed at age 5–6 years). Secondary outcomes were non‐inferiority of functional development (Vineland Adaptive Behavior Scale, 3rd Edition, assessed at 3–8 years) and post‐neonatal epilepsy (assessed at 1–8 years).
Results
Among 284 children with at least one follow‐up, outcomes were similar in the discontinued vs maintained ASM groups for full‐scale IQ at age 5 years (adjusted difference +10 points), functional development at ages 3–8 years (adjusted difference 0 points), and post‐neonatal epilepsy at ages 1–8 years (adjusted hazard ratio .93, 95% confidence interval [CI] .48–1.80).
Significance
Prolonged administration of ASM for several months after resolution of acute provoked neonatal seizures may expose infants to unnecessary medications. These results provide additional evidence for safety of discontinuing ASM for most neonates soon after the resolution of acute provoked seizures—a practice that is recommended in the International League Against Epilepsy (ILAE) guideline for neonatal seizure management.
Keywords: antiseizure medication (ASM), electroencephalography (EEG), epilepsy, hypoxic–ischemic encephalopathy (HIE), neonatal encephalopathy, neonatal seizures, neurocritical care, seizure
Key points.
Discontinuation of antiseizure medication (ASM) after resolution of acute provoked neonatal seizures is safe to age 2 years, but long‐term data have been lacking.
Prolonged administration of ASM for several months after resolution of acute provoked neonatal seizures may expose infants to unnecessary medications.
Neonates with acute provoked seizures whose ASMs were discontinued after seizure resolution and prior to hospital discharge have similar long‐term cognitive outcomes, functional development, and epilepsy rates up to age 8 years compared with those whose ASMs are maintained, even after adjustment for propensity to continue treatment.
It is safe to discontinue ASMs soon after resolution of acute provoked neonatal seizures.
1. INTRODUCTION
Acute provoked neonatal seizures are self‐limited but leave survivors with a long‐term risk for post‐neonatal epilepsy. 1 , 2 , 3 Although acute neonatal seizures are almost always followed by a latent, seizure‐free period of months to years, infants are often maintained on antiseizure medications (ASMs) for months to years due to clinician and parent concern about the risks of continued seizures and early‐life epilepsy. 4 , 5
We and others previously showed that ASM discontinuation soon after resolution of acute neonatal seizures does neither impair neurodevelopment nor increase the risk of epilepsy. 5 , 6 , 7 , 8 , 9 , 10 We also showed that early discontinuation of ASM dramatically reduces exposure to phenobarbital, a medication that is potentially neurotoxic 11 and associated with impaired cognition when used for long durations. 12 , 13 In 2023, the International League Against Epilepsy (ILAE) adopted guidelines to support discontinuation of ASM following cessation of acute provoked neonatal seizures, regardless of electroencephalography (EEG) or magnetic resonance imaging (MRI) findings. 14
Despite growing evidence that it is a safe practice, discontinuing ASMs soon after resolution of acute provoked neonatal seizure has not been adopted uniformly, and some have maintained that this approach is not justified. 15 Of note, few prior studies follow children beyond infancy.
We aimed to determine childhood outcomes after provoked neonatal seizures. We hypothesized that, after adjusting for propensity to maintain ASM at discharge from the neonatal seizure admission, infants whose ASMs were discontinued would not have worse cognition, worse functional neurodevelopment, or higher risk of post‐neonatal epilepsy compared with those who were maintained on ASM at discharge.
2. METHODS
This was a prospective, observational, multicenter comparative effectiveness study of infants with acute provoked neonatal seizures born from July 2015 to March 2018, and enrolled at nine Neonatal Seizure Registry centers (NCT02789176). Patient inclusion, enrollment, and follow‐up to age 2 years has been described previously. 5 The protocol received approval from a central institutional review board based at the University of California San Francisco and each central IRB relying site. Eligible families were invited to re‐enroll and complete additional serial assessments when the child was 3‐ 8‐years‐old (NCT04337697, enrollment from June 2020 to December 2023). Participating families provided written, informed consent.
2.1. Childhood follow‐up (ages 3–8 years)
The primary outcome was the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), which was administered in person between the ages of 5 and 6 years by a trained psychologist or psychometrist at each site. Parents also completed the online rating form for the Vineland Adaptive Behavior Scales, 3rd Edition (Vineland‐3) at enrollment and again at age 5–6 years. A clinical research coordinator collected epilepsy diagnosis 16 by parent interview and corroborated diagnoses by medical record review at every follow‐up.
2.2. Propensity score adjustment
Propensity adjustment was used to improve causal inference and to address confounding by indication in estimating the effect of discontinuing compared with maintaining ASM prior to hospital discharge by accounting for covariates that predicted treatment duration. Detailed explanation of the propensity score is available in Glass et al. 5 Briefly, backward stepwise regression and machine learning methods were used to build the propensity model. The final model included gestational age, worst EEG background during the first 24 h of recording, number of calendar days with EEG seizures, treatment with therapeutic hypothermia, and discharge neurological examination (all with significance at p ≤ .1), as well as seizure etiology (which was retained for face value). Study center was not included in the propensity adjustment given that treatment variability by study center was the basis for comparison between otherwise similar clinical scenarios.
We adopted a non‐inferiority design, setting the margin at 1.25 standard deviations (SD) of the WPPSI‐IV and Vineland‐3 scores (−19 points) based on similar methods for the infant outcome study. 5
For WPPSI‐IV and Vineland‐3, we conducted a linear mixed‐model analysis with random effects for intercepts and time and using restricted maximum likelihood fitting and Kenward–Roger degree of freedom adjustments. Mixed‐model analyses using maximum likelihood methods provide some protection against bias due to differential loss to follow‐up. ASM at discharge and propensity (categorized as quintiles) were included as the sole predictors in the regression models. Because the Vineland‐3 was administered more than once, the model for Vineland‐3 included a time point variable as well as interaction between ASM at discharge and time point, with a plan to retain if results indicated differential effects based on timing of testing. We calculated 90% confidence intervals (CIs) with non‐inferiority established if the adjusted CI lay within the non‐inferiority range defined and provided the p‐value for superiority. For epilepsy, we calculated odds ratios for post‐neonatal epilepsy and hazard ratios for time to epilepsy diagnosis with 95% CIs.
Multiple imputation including children lost to follow‐up was completed using SAS PROC MI and PROC MIANALYZE with 10 imputations generated for each model using the Markov Chain Monte Carlo method. Analyses were conducted in SAS (Cary, NC).
3. RESULTS
From the original 303 participants enrolled in the initial study, 284 children were evaluated at least once between ages 1 and 8 years and were included in the epilepsy analysis, whereas 187 children were re‐evaluated between 3 and 8 years and are included in the WPPSI‐IV and Vineland‐3 analyses (Figure S1). Table 1 shows the clinical characteristics of children by enrollment status in the 3‐ to 8‐year follow‐up study.
TABLE 1.
Characteristics of newborns with acute provoked seizures and anti‐seizure medications (ASMs) by discontinued or maintained ASM at hospital discharge and enrollment status in the childhood follow‐up study.
| Total N = 303 | Not enrolled 3–8 year follow‐up N = 116 | Enrolled 3–8 year follow‐up N = 187 | Discontinued ASM N = 109 | Maintained ASM N = 194 | |
|---|---|---|---|---|---|
| Clinical characteristics | |||||
| Gestational age at birth a , no. (%) | |||||
| <28 weeks | 9 (3%) | 3 (3%) | 6 (3%) | 5 (5%) | 4 (2%) |
| 28–<32 weeks | 6 (2%) | 3 (3%) | 3 (2%) | 3 (3%) | 3 (2%) |
| 32–<37 weeks | 35 (12%) | 15 (13%) | 20 (11%) | 7 (6%) | 28 (14%) |
| ≥37 weeks | 253 (84%) | 95 (82%) | 158 (84%) | 94 (86%) | 159 (82%) |
| Male, no. (%) | 170 (56%) | 68 (59%) | 102 (55%) | 59 (54%) | 111 (57%) |
| 5‐min Apgar score, median (IQR) | 8 (5, 9) | 8 (5,9) | 7 (4,9) | 6 (4, 9) | 8 (6, 9) |
| Seizure etiology a , No. (%) | |||||
| Hypoxic‐ischemic encephalopathy | 130 (43%) | 44 (38%) | 86 (46%) | 58 (53%) | 72 (37%) |
| Ischemic stroke | 79 (26%) | 32 (28%) | 47 (25%) | 22 (20%) | 57 (29%) |
| Intracranial hemorrhage | 55 (18%) | 26 (22%) | 29 (16%) | 17 (16%) | 38 (20%) |
| Other b | 39 (13%) | 14 (12%) | 25 (13%) | 12 (11%) | 27 (14%) |
| Worst EEG background (1st 24 h at study center) a , no. (%) | |||||
| Normal | 25 (8%) | 13 (11%) | 12 (6%) | 14 (13%) | 11 (6%) |
| Mild/moderately abnormal | 199 (66%) | 72 (62%) | 127 (68%) | 75 (69%) | 124 (64%) |
| Severely abnormal (burst suppression, depressed/ undifferentiated, flat tracing) | 53 (17%) | 23 (20%) | 30 (16%) | 14 (13%) | 39 (20%) |
| Status epilepticus at onset of recording | 24 (8%) | 7 (6%) | 17 (9%) | 6 (6%) | 18 (9%) |
| Cannot assess | 2 (1%) | 1 (1%) | 1 (<1%) | 0 (0%) | 2 (1%) |
| Days of EEG seizures a , median (IQR) | 1 (1, 2) | 1 (1,2) | 1 (1,2) | 1 (1,2) | 2 (1, 2) |
| Initial loading ASM, no. (%) | |||||
| Phenobarbital | 273 (90%) | 108 (93%) | 165 (88%) | 96 (88%) | 177 (91%) |
| Levetiracetam | 17 (6%) | 6 (5%) | 11 (6%) | 3 (3%) | 14 (7%) |
| Fosphenytoin | 3 (1%) | 0 (0%) | 3 (2%) | 2 (2%) | 1 (<1%) |
| No loading dose | 10 (3%) | 2 (2%) | 8 (4%) | 8 (7%) | 2 (1%) |
| Complex medical diagnosis (congenital heart disease, ECMO, congenital diaphragmatic hernia), no. (%) | 36 (12%) | 15 (13%) | 21 (11%) | 8 (7%) | 28 (14%) |
| Therapeutic hypothermia a , no. (%) | 86 (28%) | 25 (22%) | 61 (33%) | 44 (40%) | 42 (22%) |
| Abnormal neurologic exam at discharge a , no. (%) | 96 (32%) | 40 (34%) | 56 (30%) | 20 (18%) | 76 (39%) |
Abbreviations: ASM, antiseizure medication; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalogram; IQR, interquartile range; NICU, neonatal intensive care unit.
Included in the final propensity model.
meningitis/encephalitis (n = 24), hypoglycemia (n = 4), kernicterus (n = 1), etiology not determined (n = 10).
ASMs were maintained upon discharge from the neonatal seizure admission in 178 of 284 (63%) for a median duration of 4.2 (interquartile range [IQR] 2.8–8) months. ASMs were discontinued prior to hospital discharge in 106 of 284 (37%) at a median of 6 (IQR 3–11) days. Among newborns maintained on ASMs, 152 of 178 (85%) were prescribed phenobarbital (monotherapy or as part of polytherapy).
Likelihood of enrollment in the childhood follow‐up study was not different among children maintained on ASMs (117/194, 60%) compared with discontinued prior to hospital discharge from the neonatal admission (70/109, 64%, p = .50).
3.1. Cognition
Mean WPPSI‐IV full‐scale IQ (FSIQ) scores were 14 points (16%) higher for children whose ASMs were discontinued (99 23) than for children who were maintained on ASM upon discharge (85 25, p = .004; Figure 1). The propensity adjusted average difference was +10 points, 90% lower margin +1 point, which met our a priori non‐inferiority limit of −19 points. The adjusted significance for superiority was p = .06.
FIGURE 1.
(A) WPPSI full‐scale IQ at age 5–6 years by ASM maintenance strategy and stratified by quintile of propensity to be maintained on ASMs at discharge from the neonatal seizure admission where “1” reflects the lowest propensity to be maintained on ASM and “5” the highest propensity. (B) Vineland‐3 Adaptive Behavior Composite at ages 3–8 years by ASM maintenance strategy and stratified by propensity score quintile. ASM Anti‐seizure medication; IQ Intelligence quotient; WPPSI Wechsler Preschool and Primary Scale of Intelligence.
3.2. Functional neurodevelopment
The interaction between ASM continuation and annual assessment time point was not significant (p = .83) and, therefore, not included in the model. Vineland‐3 scores were, on average, 7 points (8%) higher for children whose ASMs were discontinued prior to hospital discharge compared with children maintained on ASMs upon discharge (94 2 vs 87 2, p = .03; Figure 1b). The propensity adjusted average difference was 0 points, 90% lower margin −5 points, which met our a priori non‐inferiority limit of −19 points. The adjusted significance for superiority was p = .99.
3.3. Epilepsy
Figure 2 shows the unadjusted epilepsy‐free survival over time by ASM discontinuation approach. Children who developed epilepsy had a younger gestational age at birth and higher likelihood of abnormal EEG background, three or more days of seizures, deep gray injury on MRI, and abnormal neurologic examination at discharge. There was no difference in epilepsy diagnosis by neonatal seizure etiology (see Numis et al., Epilepsia 2025). 3 Among children whose ASM were discontinued, 14 of 284 (13.2%) developed epilepsy, with a cumulative incidence of 12.9% (95% confidence interval [CI] = 5.0%–20.7%). Among children whose ASMs were maintained, 38 of 284 (21.3%) developed epilepsy with a cumulative incidence of 26.5% (95% confidence interval [CI] = 18.5%–34.5%). Age at epilepsy diagnosis was not significantly associated with ASM discontinuation approach in either unadjusted (hazard ratio [HR] .58, 95% CI .31–1.07) or adjusted analyses (HR .93, 95% CI .48–1.80).
FIGURE 2.
Unadjusted epilepsy‐free survival among 284 infants with acute provoked neonatal seizures.
Multiple imputations to account for children lost to follow‐up had no effect on the results.
4. DISCUSSION
In this prospective, observational, multi‐center follow‐up to our comparative effectiveness study of neonates with acute provoked seizures designed to assess for non‐inferiority of short ASM treatment duration, discontinuing medication after resolution of acute seizures and before hospital discharge did not adversely affect cognition, functional development, or incidence of epilepsy during early childhood (through age 8 years). These results extend our 2‐year study showing that discontinuation of ASMs before hospital discharge is safe 5 and provides additional support for the ILAE recommendation that “following cessation of acute provoked seizures without evidence for neonatal‐onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings.” 14
Adjusted FSIQ at age 5 to 6 years showed a trend toward significantly higher IQ in the children whose ASMs were discontinued prior to hospital discharge (adjusted difference +10 points, p = .06). Phenobarbital is known to affect cognition when given for long durations, 12 and we previously reported that the median duration of phenobarbital administration was 4 months (IQR, 3–8 months) among children whose ASMs were maintained compared with 6 days (IQR 3–11 days) among those in the early discontinuation group. 5 It is clear that short duration phenobarbital is the most effective approach for treatment of acute provoked neonatal seizures 14 , 17 ; our results should not be interpreted as a concern about this evidence‐based practice. Although we interpret our current results with caution given the non‐inferiority study design, our data support the notion that prolonged use of phenobarbital should be avoided.
Although we present a large cohort with up to 8 years of follow‐up, the study has several limitations. First, the study was initially designed for 2‐year follow‐up. 5 This current article reports data from NCT04337697, which involved re‐enrollment for in‐person assessments, was initiated at the onset of the coronavirus disease 2019 (COVID‐19) pandemic, and was designed to capture outcome for each child at age 5 to 6 years over the study period. 18 , 19 As a result, the sample size for follow‐up drops significantly after age 2 years and again after 5 years. Nonetheless, children who did or did not enroll in the follow‐up study were similar, and it is notable that there was no differential loss by ASM discontinuation status; therefore it is unlikely that the results we report are due to bias. Second, the newborns in this study were treated with phenobarbital. It is not known whether treatment with other ASMs would yield similar results. However, the results strongly support the notion that prolonged ASM treatment is not necessary after resolution of acute provoked seizures.
Careful distinction between provoked seizures and neonatal‐onset epilepsy is critical. Neonates with clinical findings that suggest epilepsy (e.g., no clear history of acute brain injury, seizures that continue for more than 3 days, EEG background evolution that is inconsistent with a clinical history of acute brain injury, classic sequential or tonic seizure semiology, family history of neonatal seizures, or brain malformation) require genetic evaluation. 20 Neonates with epilepsy usually require continued ASMs, whereas ASMs can be safely discontinued prior to hospital discharge for neonates with acute provoked seizures.
5. CONCLUSIONS
Prolonged ASM treatment following acute provoked neonatal seizures does not benefit neurodevelopment or prevent epilepsy. Continuing ASMs for neonates with acute provoked seizures unnecessarily prolongs exposure to potentially harmful medications and is associated with higher rates of parental symptoms of anxiety and depression. 21 Implementation studies are needed to optimize and adopt this safe practice, which drastically reduces infant exposure to ASMs and medicalization of infants, most of whom will have typical development in childhood. 18
AUTHOR CONTRIBUTIONS
Hannah C. Glass: Conceptualization, Funding Acquisition, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation (lead). Adam L Numis: Conceptualization, Methodology, Visualization, Writing – Review & Editing. Janet S. Soul: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Courtney J. Wusthoff: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Monica E. Lemmon: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Catherine J. Chu: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Shavonne L. Massey: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Cameron Thomas: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Tayyba Anwar: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Madison M. Berl: Conceptualization, Methodology, Writing – Review & Editing. Jennifer Larson: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Julie Sturza: Data Curation, Formal Analysis, Software, Validation, Writing – Review & Editing. Elizabeth E. Rogers: Conceptualization, Methodology, Writing – Review & Editing. Linda S. Franck: Conceptualization, Methodology, Writing – Review & Editing. Charles E. McCulloch: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing. Renée A. Shellhaas: Conceptualization, Funding Acquisition, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation.
FUNDING INFORMATION
The Patient Centered Outcomes Research Institute (2015C2‐1507‐31187) and NIH/NINDS (R01NS111166) supported this study.
CONFLICT OF INTEREST STATEMENT
Hannah C. Glass has received payment for expert testimony and consults for Dompé Therapeutics. Adam L Numis declares no conflicts of interest. Janet S. Soul had an investigator‐initiated research grant from UCB (ended 12/2022) and receives royalties as a peer reviewer for UpToDate. Courtney J. Wusthoff serves as associate editor for the Journal of Clinical Neurophysiology, has received payment as a consultant for Persyst, and has received payment for expert testimony. Monica E. Lemmon has received payment for expert testimony. Catherine J. Chu, consults for Ovid Pharmaceuticals, Biogen, Ionis Pharmaceuticals, Stoke Pharmaceuticals, and Sensorium Therapeutics, and has a sponsored research award from Novartis, and receives research support from National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH). Shavonne L. Massey declares no conflicts of interest. Cameron Thomas has received payment for legal consulting. Tayyba Anwar declares no conflicts of interest. Madison M. Berl serves as associate editor for Neuropsychology Review. Jennifer Larson has received payment for expert testimony. Julie Sturza declares no conflicts of interest. Elizabeth E. Rogers declares no conflicts of interest. Linda S. Franck declares no conflicts of interest. Charles E. McCulloch declares no conflicts of interest. Renée A. Shellhaas serves as president of the Pediatric Epilepsy Research Foundation, receives royalties from UpToDate for authorship of topics related to neonatal seizures, and is a consultant for The Epilepsy Study Consortium.
ETHICS STATEMENT
The protocol received approval from a central institutional review board based at the University of California San Francisco and each relying site. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
PATIENT CONSENT STATEMENT
Participating families provided written, informed consent.
Supporting information
Figure S1.
ACKNOWLEDGMENTS
The Patient Centered Outcomes Research Institute (2015C2‐1507‐31187) and National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS; R01NS111166) supported this study but did not participate in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Glass HC, Numis AL, Soul JS, Wusthoff CJ, Lemmon ME, Chu CJ, et al. Long‐term safety of early discontinuation of antiseizure medication after resolution of acute provoked neonatal seizures. Epilepsia. 2026;67:2836–2844. 10.1002/epi.70192
Clinical trial registration: NCT04337697.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.