Abstract
Objective:
Compare neurodevelopment after levetiracetam (LEV) and phenobarbital (PB) for neonatal seizures.
Study design:
Retrospective study of infants who received antiepileptic drugs (AEDs) for neonatal seizures. Effect of cumulative exposure to LEV and PB on outcomes of death, cerebral palsy (CP) and Bayley Scales of Infant Development (BSID) scores were evaluated at 24 months corrected age. Analyses were adjusted for number of electrographic seizures and gestational age.
Result:
In 280 infants with comparable seizure etiology and cranial imaging results, increased exposure to PB was associated with worse BSID cognitive and motor scores (8.1- and 9-point decrease per 100 mg kg−1; P=0.01). The effect was less with LEV (2.2- and 2.6-point decrease per 300 mg kg−1 LEV (P=0.01)). CP probability increased by 2.3-fold per 100 mg kg−1 PB and was not associated with increasing LEV.
Conclusion:
Increased exposure to PB is associated with worse neurodevelopmental outcomes than LEV. Prospective studies of outcomes of neonatal exposure to AEDs are essential.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Moster D, Wilcox AJ, Vollset SE, Markestad T, Lie RT . Cerebral palsy among term and postterm births. JAMA 2010; 304 (9): 976–982.
Saigal S, Doyle LW . An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008; 371 (9608): 261–269.
Yeargin-Allsopp M, Van Naarden Braun K, Doernberg NS, Benedict RE, Kirby RS, Durkin MS . Prevalence of cerebral palsy in 8-year-old children in three areas of the United States in 2002: a multisite collaboration. Pediatrics 2008; 121 (3): 547–554.
Perez A, Ritter S, Brotschi B, Werner H, Caflisch J, Martin E et al. Long-term neurodevelopmental outcome with hypoxic-ischemic encephalopathy. Journal of Pediatrics 2013; 163 (2): 454–459.
Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW et al. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation 2012; 126: 1143–1172.
Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292 (19): 2357–2365.
Long A, Moran P, Robson S . Outcome of fetal cerebral posterior fossa anomalies. Prenat Diagn 2006; 26 (8): 707–710.
Gillam-Krakauer M, Carter BS . Neonatal hypoxia and seizures. Pediatr Rev 2012; 33 (9): 387–397.
Sivaswamy L . Approach to neonatal seizures. Clin Pediatr (Phila) 2012; 51 (5): 415–425.
van Rooij LGM, Hellstrom-Westas L, de Vries LS . Treatment of neonatal seizures. Semin Fetal Neonatal Med 2013; 18 (4): 1–7.
Cilio MR, Ferriero DM . Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med [Internet]. 2010; 15 (5): 293–298.
Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341 (7): 485–489.
Castro Conde JR, Hernández Borges AA, Doménech Martínez E, González Campo C, Perera Soler R . Midazolam in neonatal seizures with no response to phenobarbital. Neurology 2005; 64 (5): 876–879.
Löscher W, Rogawski MA . How theories evolved concerning the mechanism of action of barbiturates. Epilepsia 2012; 53 (Suppl 8): 12–25.
Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002; 99 (23): 15089–15094.
Sulzbacher S, Farwell JR, Temkin N, Lu AS, Hirtz DG . Late cognitive effects of early treatment with phenobarbital. Clin Pediatr (Phila) 1999; 38 (7): 387–394.
Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB . Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322 (6): 364–369.
Park S-P, Kwon S-H . Cognitive Effects of Antiepileptic Drugs. J Clin Neurol 2008; 4 (3): 99.
Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR . Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011; 26 (4): 465–470.
Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J . Levetiracetam: Safety and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011; 15 (1): 1–7.
Silverstein FS, Ferriero DM . Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008; 39 (2): 77–79.
Lee C-Y, Chen C-C, Liou H-H . Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus. Br J Pharmacol 2009; 158 (7): 1753–1762.
Yan H-D, Ishihara K, Seki T, Hanaya R, Kurisu K, Arita K et al. Inhibitory effects of levetiracetam on the high-voltage-activated L-type Ca2+ channels in hippocampal CA3 neurons of spontaneously epileptic rat (SER). Brain Res Bull 2013; 90: 142–148.
Yang X-F, Weisenfeld A, Rothman SM . Prolonged exposure to levetiracetam reveals a presynaptic effect on neurotransmission. Epilepsia 2007; 48 (10): 1861–1869.
Meehan AL, Yang X, Yuan L-L, Rothman SM . Levetiracetam has an activity-dependent effect on inhibitory transmission. Epilepsia 2012; 53 (3): 469–476.
Brunquell PJ, Glennon CM, DiMario FJ, Lerer T, Eisenfeld L . Prediction of outcome based on clinical seizure type in newborn infants. Pediatr 2002; 140 (6): 707–712.
Voress JMT . Developmental Assessment of Young Children. PRO-ED: Austin, TX, 1998.
Albers C GA . Test review: Bayley Scales of Infant and Toddler Development, Third Edition. J Psychoeduc Assess 2007; 25 (2): 180–190.
Kuban K, Allred E, O'Shea M, Paneth N, Pagano M, Leviton A . An algorithm for identifying and classifying cerebral palsy in young children. J Pediatr. 2008 153 4: 466–472.
Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 2007; 109: 8–14.
Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH . Content validity of the expanded and revised Gross Motor Function Classification System. Dev Med Child Neurol 2008; 50 (10): 744–750.
Kim J-S, Kondratyev A, Tomita Y, Gale K . Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia 2007; 48 (s5): 19–26.
Forcelli PA, Janssen MJ, Vicini S, Gale K . Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol 2012; 72 (3): 363–372.
Shankaran S . Neurodevelopmental outcome of premature infants after antenatal phenobarbital exposure. Am J Obstet Gynecol 2002; 187 (1): 171–177.
Shankaran S, Papile LA, Wright LL, Ehrenkranz RA, Mele L, Lemons JA et al. The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants. N Engl J Med 2000; 337 (7): 466–471.
Ries M . Cognitive effects of “older” anticonvulsants in children with epilepsy: a review and critique of the literature. J Pediatr Pharmacol Ther 2003; 8 (2): 115–131.
Kilicdag H, Daglıoglu K, Erdogan S, Guzel A, Sencar L, Polat S et al. The effect of levetiracetam on neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury. Early Hum Dev 2013; 89 (5): 355–360.
Stienen MN, Haghikia A, Dambach H, Thöne J, Wiemann M, Gold R et al. Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation. Br J Pharmacol 2010; 162 (2): 491–507.
Talos DM, Chang M, Kosaras B, Fitzgerald E, Murphy A, Folkerth RD et al. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res 2012; 73 (1): 24–30.
Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J, Baker GA et al. Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology 2011; 76 (4): 383–389.
Tulloch JK, Carr RR, Ensom MHH . A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther 2012; 17 (1): 31–44.
Merhar SL, Schibler KR, Sherwin CM, Meinzen-Derr J, Shi J, Balmakund T et al. Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr 2011; 159 (1): 152–153.
Cormier J, Chu CJ . Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. Neuropsychiatr Dis Treat 2013; 9: 295.
Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B . Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol 2011; 44 (4): 265–269.
Oztekin O, Kalay S, Tezel G, Akcakus M, Oygur N . Can we safely administer the recommended dose of phenobarbital in very low birth weight infants? Childs Nerv Syst 2013; 29 (8): 1353–1357.
Touw DJ, Graafland O, Cranendonk A, Vermeulen RJ, Van Weissenbruch MM . Clinical pharmacokinetics of phenobarbital in neonates. Eur J Pharm Sci 2000; 12 (2): 111–116.
Acknowledgements
We thank Matthew Marshall for programming the data extraction from the pharmacy database. Study data were collected and managed using REDCap electronic data capture tools hosted at Vanderbilt University, supported by grant 1 UL1 RR024975 from NCRR/NIH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Journal of Perinatology website
Supplementary information
Rights and permissions
About this article
Cite this article
Maitre, N., Smolinsky, C., Slaughter, J. et al. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol 33, 841–846 (2013). https://doi.org/10.1038/jp.2013.116
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2013.116
Keywords
This article is cited by
-
Levetiracetam versus Phenobarbitone for Management of Neonatal Seizures: A Systematic Review and Meta-analysis
Indian Journal of Pediatrics (2023)
-
Seizure burden in preterm infants and smaller brain volume at term-equivalent age
Pediatric Research (2022)
-
Association between anti-seizure medication and outcomes in infants
Journal of Perinatology (2022)
-
Neurocognitive Effects of Antiseizure Medications in Children and Adolescents with Epilepsy
Pediatric Drugs (2021)
-
Efficacy of levetiracetam as first-line therapy for neonatal clinical seizures and neurodevelopmental outcome at 12 months of age
Acta Neurologica Belgica (2021)