Neonatal Antiepileptic Medication Treatment Patterns: A Decade of Change

Abstract

Objective This study aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period.

Study Design We analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression.

Results A total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p = 0.015) and continuation at discharge (90.6 to 68.6%, p <0.001). Levetiracetam (7.9 to 39.6%, p < 0.001) initiation within the neonatal period and continuation at discharge (9.4 to 49.8%, p < 0.001) increased. Neonates born at ≥ 37 weeks' gestation and those diagnosed with intraventricular hemorrhage, ischemic/thrombotic stroke, other hemorrhagic stroke, and hypoxic ischemic encephalopathy (HIE) had a higher probability of anticonvulsant administration. The most prevalent diagnosis was HIE (n = 2,223, 44.4%).

Conclusion Phenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes.

Keywords

anticonvulsant - antiepileptic - fosphenytoin - hypoxic-ischemic encephalopathy - levetiracetam - neonatal - phenobarbital - phenytoin - seizures

Publication History

Received: 07 March 2019

Accepted: 26 August 2019

Article published online:
10 October 2019

• References

• 1 Glass HC, Shellhaas RA, Wusthoff CJ. et al; Neonatal Seizure Registry Study Group. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr 2016; 174: 98-103
• 2 Uria-Avellanal C, Marlow N, Rennie JM. Outcome following neonatal seizures. Semin Fetal Neonatal Med 2013; 18 (04) 224-232
• 3 Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004; (04) CD004218
• 4 Blume HK, Garrison MM, Christakis DA. Neonatal seizures: treatment and treatment variability in 31 United States pediatric hospitals. J Child Neurol 2009; 24 (02) 148-154
• 5 Ahmad KA, Desai SJ, Bennett MM. et al. Changing antiepileptic drug use for seizures in US neonatal intensive care units from 2005 to 2014. J Perinatol 2017; 37 (03) 296-300
• 6 Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Child Neurol 2013; 28 (03) 351-364
• 7 Bartha AI, Shen J, Katz KH. et al. Neonatal seizures: multicenter variability in current treatment practices. Pediatr Neurol 2007; 37 (02) 85-90
• 8 Shellhaas RA, Chang T, Wusthoff CJ. et al; Neonatal Seizure Registry Study Group. Treatment duration after acute symptomatic seizures in neonates: a multicenter cohort study. J Pediatr 2017; 181: 298-301
• 9 Evans D, Levene M. Neonatal seizures. Arch Dis Child Fetal Neonatal Ed 1998; 78 (01) F70-F75
• 10 Low E, Boylan GB, Mathieson SR. et al. Cooling and seizure burden in term neonates: an observational study. Arch Dis Child Fetal Neonatal Ed 2012; 97 (04) F267-F272
• 11 Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr 2013; 163 (02) 465-470
• 12 Guidotti I, Lugli L, Guerra MP. et al. Hypothermia reduces seizure burden and improves neurological outcome in severe hypoxic-ischemic encephalopathy: an observational study. Dev Med Child Neurol 2016; 58 (12) 1235-1241
• 13 Zou GY, Donner A. Extension of the modified Poisson regression model to prospective studies with correlated binary data. Stat Methods Med Res 2013; 22 (06) 661-670
• 14 Williams RL. A note on robust variance estimation for cluster-correlated data. Biometrics 2000; 56 (02) 645-646
• 15 Shankaran S, Laptook AR, Ehrenkranz RA. et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353 (15) 1574-1584
• 16 Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; (01) CD003311
• 17 Massaro AN, Murthy K, Zaniletti I. et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group. J Perinatol 2015; 35 (04) 290-296
• 18 El-Dib M, Soul JS. The use of phenobarbital and other anti-seizure drugs in newborns. Semin Fetal Neonatal Med 2017; 22 (05) 321-327
• 19 Bittigau P, Sifringer M, Genz K. et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002; 99 (23) 15089-15094
• 20 Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol 2013; 33 (11) 841-846
• 21 Painter MJ, Scher MS, Stein AD. et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341 (07) 485-489
• 22 Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy - where to from here?. Front Neurol 2015; 6: 198
• 23 Barks JD, Liu YQ, Shangguan Y, Silverstein FS. Phenobarbital augments hypothermic neuroprotection. Pediatr Res 2010; 67 (05) 532-537
• 24 Sarkar S, Barks JD, Bapuraj JR. et al. Does phenobarbital improve the effectiveness of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy?. J Perinatol 2012; 32 (01) 15-20
• 25 Manthey D, Asimiadou S, Stefovska V. et al. Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol 2005; 193 (02) 497-503
• 26 Talos DM, Chang M, Kosaras B. et al. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res 2013; 73 (01) 24-30
• 27 Kilicdag H, Daglıoglu K, Erdogan S. et al. The effect of levetiracetam on neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury. Early Hum Dev 2013; 89 (05) 355-360
• 28 McHugh DC, Lancaster S, Manganas LN. A systematic review of the efficacy of levetiracetam in neonatal seizures. Neuropediatrics 2018; 49 (01) 12-17
• 29 Glass HC. Neonatal seizures: advances in mechanisms and management. Clin Perinatol 2014; 41 (01) 177-190
• 30 Zeller B, Giebe J. Pharmacologic management of neonatal seizures. Neonatal Netw 2015; 34 (04) 239-244
• 31 Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed 2017; 102 (04) F346-F358
• 32 Fisher BT, Lindenauer PK, Feudtner C. In-hospital databases. In: Strom B, Kimmel SE, Hennessy S. eds. Pharmacoepidemiology. Oxford: John Wiley & Sons, Ltd; 2012: 244-258
• 33 Boylan GB, Kharoshankaya L, Wusthoff CJ. Seizures and hypothermia: importance of electroencephalographic monitoring and considerations for treatment. Semin Fetal Neonatal Med 2015; 20 (02) 103-108