Gebelikte Epilepsi Tedavisinde Yeni Nesil Antiepileptik İlaçlar
Year 2014,
Volume: 11 Issue: 3, 297 - 303, 15.12.2014
Nilgün Erten
,
Züleyha Erişgin
Abstract
Epilepsi toplumda sık görülen bir hastalıktır. Hem anne hem de bebeğin hayatını ilgilendiren gebelik
sürecinde, epilepsi gibi kronik bir hastalığın takibi ayrı bir önem taşımaktadır. Bu yazıda; gebelikte epilepsi
hastalığının seyri, tedavide yeni nesil antiepileptik ilaçların kullanımı, bu ilaçların fetus üzerine etkileri ve
farmakokinetiklerindeki değişikliklere değinilmiştir.
References
- 1) Adab N, Tudur Smith C, Vinten J, Williamson PR,
Winterbottom JB. Common antiepilepticdrugs in
pregnancy in women with epilepsy. Cochrane Database
SystRev. 2004(3):CD004848.
2) Brosh K, Matok I, Sheiner E, Koren G, Wiznitzer A,
Gorodischer R, et al.Teratogenicdeterminants of firsttrimester exposure to antiepileptic medications. J Popul
Ther Clin Pharmacol2011;18:e89–98.[Epub March 21,
2011].
3) Crawford P. Epilepsy and pregnancy: good
management reduces therisk. Prof Care Mother Child
.1997;7(1):17-8.
4) Thomas SV. Managing epilepsy in pregnancy. Neurol.
India. 2011;59(1): 59-65.
5) Thomas SV, Sindhu K, Ajaykumar B, Devi PB,
Sujamol J. Maternaland obstetric outcome ofwomen with
epilepsy. Seizure. 2009;18(3):163–166.
6) Mawer G, Briggs M, Baker GA, Bromley R, Coyle H,
Eatock J, et al. Pregnancy with epilepsy: Obstetric and
neonatal outcomeof a controlled study. Seizure.
2010;19(2):112–119.
7) Rauchenzauner M, Ehrensberger M, Prieschl M,
Kapelari K, Bergmann M, Walser G, et al. Generalized
tonic-clonic seizures and antiepileptic drugs during
pregnancy-a mater of importance fort he baby? J Neurol.
2013;260(2):484-488.
8) Cassina M, Dilaghi A, Gianantonio ED, Cesari E, Santis MD, Mannaioni G, et al. Pregnancy outcome in women
exposed to antiepileptic drugs: teratogenic role of
maternal epilepsy and its pharmacolojic treatment.
Reproductive toxicology. 2013 Aug;39:50-7.
9) Lima DC, do Vale TG, Arganaraz GA, Varella VPP,
Filho RF, Cavalheiro EAet al. Behavioral evaluation of
adult rat exposed in utero to maternal epileptic seizures.
Epilesy and Behavior. 2010;18(1-2):45-49.
10) Hossain MA. Molecular mediators of
hypoxic–ischemic injury and implications forepilepsy in
t h e d e v e l o p i n g b r a i n . E p i l e p s y Be h a v
2005;7(2):204–13.
11) Kulaga S, Sheehy O, Zargarzadeh AH, Moussally K,
Be´rard A. Antiepileptic drug use duringpregnancy:
Perinatal outcomes. Seizure. 2011;20(9):667–672.
12) Ikonomidoua C, Turski L. Antiepileptic drugs and
brain development. Epilepsy Research. 2010;88(1): 11-
22.
13) Diaz HS, Smith CR, Shen A, Mittendorf R, Hauser
WA, Yerby M, et al. Are newer antiepileptic drugs
associated with improved safety in pregnancy compared
to older antiepileptic drugs? Epilepsy Currents. 2013;
13(1):15-16.
14) Meador KJ. Neurodevelopmental effects of
antiepileptic drugs. Curr Neurol. Neurosci
Rep2002;2(4):373–8.
15) Martinez FM, Pena MP, Pe´ rez Lopez-Fraile I,
Castro Vilanova MD, EscartinSA, Martin MM, et al.
Malformations and fetal death in the Spanish
antiepilepticdrug and pregnancy registry: results at 6
years. Neurologia 2009;24(6):360–5.
16) Lowe SA. Anticonvulsants and drugs for
neurological disease. Best Practice & ResearchClinical
Obstetrics and Gynaecology. 2001; 15(6): 863-876.
17) Arne Reimers, Eylert Brodtkorb. SecondGeneration Antiepileptic Drugs andPregnancy: A Guide
for Clinicians. Expert Rev Neurother. 2012;12(6):707-
717.
18) Reimers A, Helde G, Bråthen G, Brodtkorb E.
Lamotrigine and its N 2-glucuronideduring pregnancy:
the significance of renal clearance and estradiol.
Epilepsy Res.2011;94(3),198–205.
19) Anderson GD. Pregnancy-induced changes in
pharmacokinetics: a mechanistic-basedapproach. Clin.
Pharmacokinet.2005; 44(10):989-1008.
20) Brodtkorb E, Reimers A. Seizure control and
pharmacokinetics of antiepileptic drugsin pregnant
women with epilepsy. Seizure. 2008;17(2),160-5.
21) Meador KJ, Baker GA, Browning N, Cohen MJ,
Clayton-Smith J, Kalayjian LA, et al. Foetalantiepileptic
drug exposure and verbal versus non-verbal abilities at
three years of age.Brain. 2011; 134(Pt 2),396–404.
22) Wilson RD, Davies G, Désilets V, Reid GJ, Summers
A, Wyatt P, et al. The use of folicacid for the prevention
of neural tube defects and other congenital anomalies. J
ObstetGynaecolCan. 2003;25(11):959–73.
23) Chen L, Liu F, Yoshida S, Kaneko S. Is breastfeeding of infants advisable for epileptic motherstaking
antiepileptic drugs? Psychiatry Clin. Neurosci.
2010;64(5):5–468.
24) Ohman I, Vitols S, Tomson T. Lamotrigine in
pregnancy: pharmacokinetics during delivery, inthe
neona te , and during lact ation. Epil epsi a .
2000;.41(6):6–713
25) Ohman I, Vitols S, Tomson T. Pharmacokinetics of
gabapentin during delivery, in the neonatalperiod, and
lactation: does a fetal accumulation occur during
pregnancy? Epilepsia. 2005;46(10):10–1624
26) Blackburn ST. Renal function in the neonate. J.
Perinat. Neonatal Nurs. 1994;8(1):1–47.
27) Galanti M, Newport JD, Pennell PB, Titchner D,
Newmanb M,et al. Postpartum depression in women
with epilepsy: Influence of antiepileptic drugs in a
p r o s p e c t i v e st u d y. Ep i l e p s y & Be h a v i o r.
2009;16(3):426–430.
28) Saramma PP, Sarma PS, Thomas SV. Women with
epilepsy have poorer knowledge and skills inchild rearing
than women without epilepsy. Seizure. 2011;20(7):575-9.
29) Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout
D, Sabers A, et al. Dose-dependent risk of malformations
with antiepileptic drugs: an analysis of data from the
EURAP epilepsy and pregnancy registry. Lancet Neurol.
2011;10(7):7–617
30) Reiff-Eldridge R, Heffner CR, Ephross SA.
Monitoring pregnancy outcomes after prenatal
drugexposure through prospective pregnancy registries: a
pharmaceutical company commitment.American Journal
of Obstetrics and Gynecology. 2000;182(1 pt 1):159–163
31) Petrenaite V, Sabers A, Hansen-Schwartz J.
Individual changes in lamotrigine plasmaconcentrations
during pregnancy. Epilepsy Res. 2005;65(3):3–188.
32) Ohman I, Beck O, Vitols S, Tomson T. Plasma
concentrations of lamotrigine and its 2-N-glucuronide
metabolite during pregnancy in women with epilepsy.
Epilepsia. 2008; 49(6):6–1080
33) Sabers A. Algorithm for lamotrigine dose adjustment
before, during, and after pregnancy. ActaNeurol. Scand.
2012;126(1):1-4.
34) Miyagi SJ, Collier AC. Pediatric development of
glucuronidation: the ontogeny of hepaticUGT1A4. Drug
Metab. Dispos. 2007;35(9):9–1592.
35) Nordmo E, Aronsen L, Wasland K, Småbrekke L,
Vorren S. Severe apnea in an infant exposedto lamotrigine
i n b r e a s t m i l k . A n n . P h a r m a c o t h e r .
2009;43(11):11–1897.
36) Perucca E and Johannessen SI. The ideal
pharmacokinetic properties of an antiepileptic drug:how
close does levetiracetam come? Epileptic Disord.
2003;5(1):17–S26.
37) Vajda FJ, Graham J, Roten A, Lander CM, O'Brien TJ,
Eadie M. Teratogenicity of the newerantiepileptic drugs--
the Australian experience. J Clin Neurosci.
2012;19(1):57-9.
38) Kim J, Kondratyev A, Gale K. Antiepileptic DrugInduced Neuronal Cell Death in theImmature Brain:
Effects of Carbamazepine, Topiramate, and
Levetiracetam as Monotherapy versusPolytherapy.
JPharmacol Exp Ther. 2007;323(1):165–73.
39) Patsalos PN. Pharmacokinetic profile of
levetiracetam: toward ideal characteristics.
Pharmacol.Ther. 2000;85(2):2–85.
40) López-Fraile IP, Cid AO, Juste AO, Modrego PJ.
Levetiracetam plasma level monitoring duringpregnancy,
delivery, and postpartum: clinical and outcome
implications. Epilepsy Behav. 2009;15(3):372-5.
41) Tomson T, Palm R, Källén K, Ben-Menachem E,
Söderfeldt B, Danielsson B, et al. Pharmacokinetics of
levetiracetam during pregnancy, delivery, in the
n e o n a t a l p e ri o d , a n d l a c t a ti o n . Ep il e p si a .
2007;48(6):1111-6.
42) Westin AA, Reimers A, Helde G, Nakken KO,
Brodtkorb E. Serum concentration/dose ratio
oflevetiracetam before, during and after pregnancy.
Seizure.2008;17(2):192-8.
43) Johannessen SI, Helde G, Brodtkorb E.
Levetiracetam concentrations in serum and in breastmilk
at birth and during lactation. Epilepsia.2005;46(5):775-7.
44) Flesch G. Overview of the clinical pharmacokinetics
of oxcarbazepine. Clin. Drug Investig.2004;
24(4):185–203.
45) Almeida L, Soares-da-Silva P. Eslicarbazepine
a c e t a t e (BIA 2 - 0 9 3 ). Ne u r o t h e r a p e u t i c s.
2007;4(1):88–96.
46) Christensen J, Sabers A, Sidenius P. Oxcarbazepine
concentrations during pregnancy: aretrospective study in
patients with epilepsy. Neurology.2006;67(8):1497-9.
47) Wegner I, Edelbroek P, de Haan GJ, Lindhout D,
Sander JW. Drug monitoring of lamotrigineand
oxcarbazepine combination during pregnancy.Epilepsia.
2010;51(12):2500–2.
48) Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure
deterioration in women treated withoxcarbazepine during
pregnancy. Epilepsy Res. 2009; 84(2–3):245–9.
49) Bülau P, Paar WD, von Unruh GE. Pharmacokinetics of
oxcarbazepine and 10-hydroxy-carbazepine in the newborn
child of an oxcarbazepine-treated mother. Eur. J. Clin.
Pharmacol.1988; 34(3):311–3.
50) Lutz UC, Wiatr G, Gaertner HJ, Bartels M.
Oxcarbazepine treatment during breastfeeding: acase
report. J. Clin. Psychopharmacol. 2007;27(6):6–732.
51) Bennett GD, Amore BM, Finnell RH, Wlodarczyk B,
Kalhorn TF, Skiles GL, et al. Teratogenicity of
carbamazepin-10, 11-epoxide and oxcarbazepine in the
SWVMouse.J Pharmacol Exp Ther. 1996; 279 (3):1237-42.
52) Erisgin Z. Sıçanlarda intrauterin oxcarcazepin ve
gabapentin uygulamasının postnatal dönemdesubstantia
nigradaki nöron sayısına etkileri. Ondokuz Mayıs
Üniversitesi Sağlık Bilimleri Enstitüsü,Samsun, Doktora
Tezi, 2012.
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The Usage Of New Generation Antiepileptic Drugs During The Pregnancy
Year 2014,
Volume: 11 Issue: 3, 297 - 303, 15.12.2014
Nilgün Erten
,
Züleyha Erişgin
Abstract
Epilepsy is a common disease in the community. Chronic illness, such as epilepsy that has been concerning
the lives of both mother and baby during pregnancy, following-up is getting more important. In this paper, the
course of epilepsy during pregnancy, usage of new- generation antiepileptic drugs for treatment of epilepsy,
the effects of these drugs on the fetus and changes of pharmacokinetic are mentioned.
References
- 1) Adab N, Tudur Smith C, Vinten J, Williamson PR,
Winterbottom JB. Common antiepilepticdrugs in
pregnancy in women with epilepsy. Cochrane Database
SystRev. 2004(3):CD004848.
2) Brosh K, Matok I, Sheiner E, Koren G, Wiznitzer A,
Gorodischer R, et al.Teratogenicdeterminants of firsttrimester exposure to antiepileptic medications. J Popul
Ther Clin Pharmacol2011;18:e89–98.[Epub March 21,
2011].
3) Crawford P. Epilepsy and pregnancy: good
management reduces therisk. Prof Care Mother Child
.1997;7(1):17-8.
4) Thomas SV. Managing epilepsy in pregnancy. Neurol.
India. 2011;59(1): 59-65.
5) Thomas SV, Sindhu K, Ajaykumar B, Devi PB,
Sujamol J. Maternaland obstetric outcome ofwomen with
epilepsy. Seizure. 2009;18(3):163–166.
6) Mawer G, Briggs M, Baker GA, Bromley R, Coyle H,
Eatock J, et al. Pregnancy with epilepsy: Obstetric and
neonatal outcomeof a controlled study. Seizure.
2010;19(2):112–119.
7) Rauchenzauner M, Ehrensberger M, Prieschl M,
Kapelari K, Bergmann M, Walser G, et al. Generalized
tonic-clonic seizures and antiepileptic drugs during
pregnancy-a mater of importance fort he baby? J Neurol.
2013;260(2):484-488.
8) Cassina M, Dilaghi A, Gianantonio ED, Cesari E, Santis MD, Mannaioni G, et al. Pregnancy outcome in women
exposed to antiepileptic drugs: teratogenic role of
maternal epilepsy and its pharmacolojic treatment.
Reproductive toxicology. 2013 Aug;39:50-7.
9) Lima DC, do Vale TG, Arganaraz GA, Varella VPP,
Filho RF, Cavalheiro EAet al. Behavioral evaluation of
adult rat exposed in utero to maternal epileptic seizures.
Epilesy and Behavior. 2010;18(1-2):45-49.
10) Hossain MA. Molecular mediators of
hypoxic–ischemic injury and implications forepilepsy in
t h e d e v e l o p i n g b r a i n . E p i l e p s y Be h a v
2005;7(2):204–13.
11) Kulaga S, Sheehy O, Zargarzadeh AH, Moussally K,
Be´rard A. Antiepileptic drug use duringpregnancy:
Perinatal outcomes. Seizure. 2011;20(9):667–672.
12) Ikonomidoua C, Turski L. Antiepileptic drugs and
brain development. Epilepsy Research. 2010;88(1): 11-
22.
13) Diaz HS, Smith CR, Shen A, Mittendorf R, Hauser
WA, Yerby M, et al. Are newer antiepileptic drugs
associated with improved safety in pregnancy compared
to older antiepileptic drugs? Epilepsy Currents. 2013;
13(1):15-16.
14) Meador KJ. Neurodevelopmental effects of
antiepileptic drugs. Curr Neurol. Neurosci
Rep2002;2(4):373–8.
15) Martinez FM, Pena MP, Pe´ rez Lopez-Fraile I,
Castro Vilanova MD, EscartinSA, Martin MM, et al.
Malformations and fetal death in the Spanish
antiepilepticdrug and pregnancy registry: results at 6
years. Neurologia 2009;24(6):360–5.
16) Lowe SA. Anticonvulsants and drugs for
neurological disease. Best Practice & ResearchClinical
Obstetrics and Gynaecology. 2001; 15(6): 863-876.
17) Arne Reimers, Eylert Brodtkorb. SecondGeneration Antiepileptic Drugs andPregnancy: A Guide
for Clinicians. Expert Rev Neurother. 2012;12(6):707-
717.
18) Reimers A, Helde G, Bråthen G, Brodtkorb E.
Lamotrigine and its N 2-glucuronideduring pregnancy:
the significance of renal clearance and estradiol.
Epilepsy Res.2011;94(3),198–205.
19) Anderson GD. Pregnancy-induced changes in
pharmacokinetics: a mechanistic-basedapproach. Clin.
Pharmacokinet.2005; 44(10):989-1008.
20) Brodtkorb E, Reimers A. Seizure control and
pharmacokinetics of antiepileptic drugsin pregnant
women with epilepsy. Seizure. 2008;17(2),160-5.
21) Meador KJ, Baker GA, Browning N, Cohen MJ,
Clayton-Smith J, Kalayjian LA, et al. Foetalantiepileptic
drug exposure and verbal versus non-verbal abilities at
three years of age.Brain. 2011; 134(Pt 2),396–404.
22) Wilson RD, Davies G, Désilets V, Reid GJ, Summers
A, Wyatt P, et al. The use of folicacid for the prevention
of neural tube defects and other congenital anomalies. J
ObstetGynaecolCan. 2003;25(11):959–73.
23) Chen L, Liu F, Yoshida S, Kaneko S. Is breastfeeding of infants advisable for epileptic motherstaking
antiepileptic drugs? Psychiatry Clin. Neurosci.
2010;64(5):5–468.
24) Ohman I, Vitols S, Tomson T. Lamotrigine in
pregnancy: pharmacokinetics during delivery, inthe
neona te , and during lact ation. Epil epsi a .
2000;.41(6):6–713
25) Ohman I, Vitols S, Tomson T. Pharmacokinetics of
gabapentin during delivery, in the neonatalperiod, and
lactation: does a fetal accumulation occur during
pregnancy? Epilepsia. 2005;46(10):10–1624
26) Blackburn ST. Renal function in the neonate. J.
Perinat. Neonatal Nurs. 1994;8(1):1–47.
27) Galanti M, Newport JD, Pennell PB, Titchner D,
Newmanb M,et al. Postpartum depression in women
with epilepsy: Influence of antiepileptic drugs in a
p r o s p e c t i v e st u d y. Ep i l e p s y & Be h a v i o r.
2009;16(3):426–430.
28) Saramma PP, Sarma PS, Thomas SV. Women with
epilepsy have poorer knowledge and skills inchild rearing
than women without epilepsy. Seizure. 2011;20(7):575-9.
29) Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout
D, Sabers A, et al. Dose-dependent risk of malformations
with antiepileptic drugs: an analysis of data from the
EURAP epilepsy and pregnancy registry. Lancet Neurol.
2011;10(7):7–617
30) Reiff-Eldridge R, Heffner CR, Ephross SA.
Monitoring pregnancy outcomes after prenatal
drugexposure through prospective pregnancy registries: a
pharmaceutical company commitment.American Journal
of Obstetrics and Gynecology. 2000;182(1 pt 1):159–163
31) Petrenaite V, Sabers A, Hansen-Schwartz J.
Individual changes in lamotrigine plasmaconcentrations
during pregnancy. Epilepsy Res. 2005;65(3):3–188.
32) Ohman I, Beck O, Vitols S, Tomson T. Plasma
concentrations of lamotrigine and its 2-N-glucuronide
metabolite during pregnancy in women with epilepsy.
Epilepsia. 2008; 49(6):6–1080
33) Sabers A. Algorithm for lamotrigine dose adjustment
before, during, and after pregnancy. ActaNeurol. Scand.
2012;126(1):1-4.
34) Miyagi SJ, Collier AC. Pediatric development of
glucuronidation: the ontogeny of hepaticUGT1A4. Drug
Metab. Dispos. 2007;35(9):9–1592.
35) Nordmo E, Aronsen L, Wasland K, Småbrekke L,
Vorren S. Severe apnea in an infant exposedto lamotrigine
i n b r e a s t m i l k . A n n . P h a r m a c o t h e r .
2009;43(11):11–1897.
36) Perucca E and Johannessen SI. The ideal
pharmacokinetic properties of an antiepileptic drug:how
close does levetiracetam come? Epileptic Disord.
2003;5(1):17–S26.
37) Vajda FJ, Graham J, Roten A, Lander CM, O'Brien TJ,
Eadie M. Teratogenicity of the newerantiepileptic drugs--
the Australian experience. J Clin Neurosci.
2012;19(1):57-9.
38) Kim J, Kondratyev A, Gale K. Antiepileptic DrugInduced Neuronal Cell Death in theImmature Brain:
Effects of Carbamazepine, Topiramate, and
Levetiracetam as Monotherapy versusPolytherapy.
JPharmacol Exp Ther. 2007;323(1):165–73.
39) Patsalos PN. Pharmacokinetic profile of
levetiracetam: toward ideal characteristics.
Pharmacol.Ther. 2000;85(2):2–85.
40) López-Fraile IP, Cid AO, Juste AO, Modrego PJ.
Levetiracetam plasma level monitoring duringpregnancy,
delivery, and postpartum: clinical and outcome
implications. Epilepsy Behav. 2009;15(3):372-5.
41) Tomson T, Palm R, Källén K, Ben-Menachem E,
Söderfeldt B, Danielsson B, et al. Pharmacokinetics of
levetiracetam during pregnancy, delivery, in the
n e o n a t a l p e ri o d , a n d l a c t a ti o n . Ep il e p si a .
2007;48(6):1111-6.
42) Westin AA, Reimers A, Helde G, Nakken KO,
Brodtkorb E. Serum concentration/dose ratio
oflevetiracetam before, during and after pregnancy.
Seizure.2008;17(2):192-8.
43) Johannessen SI, Helde G, Brodtkorb E.
Levetiracetam concentrations in serum and in breastmilk
at birth and during lactation. Epilepsia.2005;46(5):775-7.
44) Flesch G. Overview of the clinical pharmacokinetics
of oxcarbazepine. Clin. Drug Investig.2004;
24(4):185–203.
45) Almeida L, Soares-da-Silva P. Eslicarbazepine
a c e t a t e (BIA 2 - 0 9 3 ). Ne u r o t h e r a p e u t i c s.
2007;4(1):88–96.
46) Christensen J, Sabers A, Sidenius P. Oxcarbazepine
concentrations during pregnancy: aretrospective study in
patients with epilepsy. Neurology.2006;67(8):1497-9.
47) Wegner I, Edelbroek P, de Haan GJ, Lindhout D,
Sander JW. Drug monitoring of lamotrigineand
oxcarbazepine combination during pregnancy.Epilepsia.
2010;51(12):2500–2.
48) Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure
deterioration in women treated withoxcarbazepine during
pregnancy. Epilepsy Res. 2009; 84(2–3):245–9.
49) Bülau P, Paar WD, von Unruh GE. Pharmacokinetics of
oxcarbazepine and 10-hydroxy-carbazepine in the newborn
child of an oxcarbazepine-treated mother. Eur. J. Clin.
Pharmacol.1988; 34(3):311–3.
50) Lutz UC, Wiatr G, Gaertner HJ, Bartels M.
Oxcarbazepine treatment during breastfeeding: acase
report. J. Clin. Psychopharmacol. 2007;27(6):6–732.
51) Bennett GD, Amore BM, Finnell RH, Wlodarczyk B,
Kalhorn TF, Skiles GL, et al. Teratogenicity of
carbamazepin-10, 11-epoxide and oxcarbazepine in the
SWVMouse.J Pharmacol Exp Ther. 1996; 279 (3):1237-42.
52) Erisgin Z. Sıçanlarda intrauterin oxcarcazepin ve
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