Clinical analysis of lamotrigine-related embryo damage and abortion_Journal of Epilepsy

Authors：

 GUYixue ¹ , YANYin ² ,  WANGXuefeng ¹

1. Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
2. Department of Nerology, Chongqing Ninth People's Hospital, Chongqing 400700, China;

Corresponding author：

WANGXuefeng, Email: xfyp@163.com

Keywords：

Lamotrigine; Pregnancy; Embryo damage; Abortion; Epilepsy; Safety profile

DOI：

10.7507/2096-0247.20150006

Video：

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Objective To discuss the risk of abortion related to lamotrigine (LTG) and its safety profile during pregnancy. Methods Retrospectively studied pregnant women in our epilepsy clinics who took LTG from 2011 to 2015 as monotherapy and experienced embryo damage or abortion. Here, we present an extensive review of related literatures regarding possible mechanisms, clinical features and safty of LTG during pregnancy. Results In our study, fourty-five pregnancies were administered monotherapy LTG, and three of these patients suffered embryo damage. Conclusions Although LTG is considered safe for pregnant women and the embryo or fetus,it also has risk of embryo damage or abortion, which should be carefully considered before prescription. Using monotherapy and the lowest effective drug dose, monitoring LTG serum concentrations during pregnancy, supplementing folate administration before and after conception and conducting regular prenatal diagnostic tests might reduce the risk of abortion.

Citation： GUYixue, YANYin, WANGXuefeng. Clinical analysis of lamotrigine-related embryo damage and abortion. Journal of Epilepsy, 2015, 1(1): 37-42. doi: 10.7507/2096-0247.20150006 Copy

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2.	Veiby G, Daltveit AK, Schjolberg S, et al. Exposure to antiepileptic drugs in utero and child development:a prospective population-based study. Epilepsia, 2013, (54):1462-1472.
3.	Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic drug exposure:fetal death and malformations. Neurology, 2006, 67(22):407-412.
4.	Man SL, Petersen I, Thompson M, et al. Antiepileptic drugs during pregnancy in primary care:a UK population based study. PLoS One, 2012,7(2):e52339.
5.	Sabers A, Dam M, B AR-H, et al. Epilepsy and pregnancy:lamotrigine as main drug used. Acta Neurol Scand, 2004,109(78):9-13.
6.	Polifka JE, Friedman JM. Medical genetics:Clinical teratology in the age of genomics. CMAJ, 2002,167(4):265-273.
7.	Bech BH, Kjaersgaard MI, Pedersen HS, et al. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth:population based cohort study. BMJ, 2014, 349(16):g5159.
8.	Tennis P, Eldridge RR. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia, 2002,43(7):1161-1167.
9.	Miskov S, Gjergja-Juraski R, Cvitanovic-Sojat L, et al. Prospective surveillance of Croatian pregnant women on lamotrigine monotherapy——aspects of pre-pregnancy counseling and drug monitoring. Acta Clin Croat, 2009,48(12):271-281.
10.	Ornoy A. Neuroteratogens in man:an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol, 2006, 22(7):214-226.
11.	Iqbal MM, Gundlapalli SP, Ryan WG, et al. Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants. South Med J, 2001,94(30):304-322.
12.	Forges T, Monnier-Barbarino P, Alberto JM, et al. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update, 2007, 13(6):225-238.
13.	Matte JJ, Girard CL, Brisson GJ. Folic acid and reproductive performances of sows. J Anim Sci, 1984,59(1):1020-1025.
14.	Tremblay GF, Matte JJ, Dufour JJ, et al. Survival rate and development of fetuses during the first 30 days of gestation after folic acid addition to a swine diet. J Anim Sci, 1989, 67(15):724-732.
15.	Gaskins AJ, Rich-Edwards JW, Hauser R, et al. Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Obstet Gynecol, 2014, 124(60):23-31.
16.	Marsh ED, Brooks-Kayal AR, Porter BE. Seizures and antiepileptic drugs:does exposure alter normal brain development? Epilepsia, 2006, 47(2):1999-2010.
17.	Katz I, Kim J, Gale K, et al. Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther, 2007,322(120):494-500.
18.	Forcelli PA, Janssen MJ, Vicini S,et al. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol, 2012, 72(20):363-372.
19.	Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann NY Acad Sci, 2003, 993(371):103-114.
20.	Farber NB, Jiang XP, Heinkel C, et al. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry, 2002,7(2):726-733.
21.	Etemad L, Moshiri M, Moallem SA. Epilepsy drugs and effects on fetal development:Potential mechanisms. J Res Med Sci, 2012, 17(4):876-881.
22.	Maggs JL, Naisbitt DJ, Tettey JN, et al. Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem Res Toxicol, 2000, 13(5):1075-1081.
23.	Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia, 1984, 25(11):77-83.
24.	Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res, 2010,91(4):161-165.
25.	Hill M, Vrbikova J, Zarubova J, et al. The steroid metabolome in lamotrigine-treated women with epilepsy. Steroids 2011,760(221):1351-1357.
26.	Majewska M, Lee HY, Tasaki Y, et al. Is cortisol a modulator of interferon tau action in the endometrium during early pregnancy in cattle? J Reprod Immunol, 2012, 93(14):82-93.
27.	Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation:a case report. Epilepsia, 1997,38(16):1039-1041.
28.	Petrenaite V, Sabers A, Hansen-Schwartz J. Individual changes in lamotrigine plasma concentrations during pregnancy. Epilepsy Res, 2005,65(15):185-188.
29.	Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology, 2003,61(15):S35-42.
30.	Ohman I, Beck O, Vitols S, et al. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia, 2008,49(17):1075-1080.
31.	Reimers A, Ostby L, Stuen I,et al. Expression of UDP-glucuronosyltransferase 1A4 in human placenta at term. Eur J Drug Metab Pharmacokinet, 2011,35(21):79-82.
32.	Battino D, Tomson T, Bonizzoni E, et al. Seizure control and treatment changes in pregnancy:observations from the EURAP epilepsy pregnancy registry. Epilepsia, 2013,54(17):1621-1627.
33.	Brent RL. Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures. Teratology, 1999,59(24):182-204.
34.	Practice parameter:management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 1998,51(17):944-948.
35.	Harden CL, Pennell PB, Koppel BS,et al. Practice parameter update:management issues for women with epilepsy——focus on pregnancy (an evidence-based review):vitamin K, folic acid, blood levels, and breastfeeding:report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology, 2009,73(16):142-149.
36.	ACOG educational bulletin. Seizure disorders in pregnancy. Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet, 1997, 56(20):279-286.
37.	Guidelines for the care of women of childbearing age with epilepsy. Commission on Genetics, Pregnancy, and the Child, International League Against Epilepsy. Epilepsia, 1993,34(7):588-589.

1. Fairgrieve SD, Jackson M, Jonas P, et al. Population based, prospective study of the care of women with epilepsy in pregnancy. BMJ, 2000, 321(22):674-675.
2. Veiby G, Daltveit AK, Schjolberg S, et al. Exposure to antiepileptic drugs in utero and child development:a prospective population-based study. Epilepsia, 2013, (54):1462-1472.
3. Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic drug exposure:fetal death and malformations. Neurology, 2006, 67(22):407-412.
4. Man SL, Petersen I, Thompson M, et al. Antiepileptic drugs during pregnancy in primary care:a UK population based study. PLoS One, 2012,7(2):e52339.
5. Sabers A, Dam M, B AR-H, et al. Epilepsy and pregnancy:lamotrigine as main drug used. Acta Neurol Scand, 2004,109(78):9-13.
6. Polifka JE, Friedman JM. Medical genetics:Clinical teratology in the age of genomics. CMAJ, 2002,167(4):265-273.
7. Bech BH, Kjaersgaard MI, Pedersen HS, et al. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth:population based cohort study. BMJ, 2014, 349(16):g5159.
8. Tennis P, Eldridge RR. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia, 2002,43(7):1161-1167.
9. Miskov S, Gjergja-Juraski R, Cvitanovic-Sojat L, et al. Prospective surveillance of Croatian pregnant women on lamotrigine monotherapy——aspects of pre-pregnancy counseling and drug monitoring. Acta Clin Croat, 2009,48(12):271-281.
10. Ornoy A. Neuroteratogens in man:an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol, 2006, 22(7):214-226.
11. Iqbal MM, Gundlapalli SP, Ryan WG, et al. Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants. South Med J, 2001,94(30):304-322.
12. Forges T, Monnier-Barbarino P, Alberto JM, et al. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update, 2007, 13(6):225-238.
13. Matte JJ, Girard CL, Brisson GJ. Folic acid and reproductive performances of sows. J Anim Sci, 1984,59(1):1020-1025.
14. Tremblay GF, Matte JJ, Dufour JJ, et al. Survival rate and development of fetuses during the first 30 days of gestation after folic acid addition to a swine diet. J Anim Sci, 1989, 67(15):724-732.
15. Gaskins AJ, Rich-Edwards JW, Hauser R, et al. Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Obstet Gynecol, 2014, 124(60):23-31.
16. Marsh ED, Brooks-Kayal AR, Porter BE. Seizures and antiepileptic drugs:does exposure alter normal brain development? Epilepsia, 2006, 47(2):1999-2010.
17. Katz I, Kim J, Gale K, et al. Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther, 2007,322(120):494-500.
18. Forcelli PA, Janssen MJ, Vicini S,et al. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol, 2012, 72(20):363-372.
19. Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann NY Acad Sci, 2003, 993(371):103-114.
20. Farber NB, Jiang XP, Heinkel C, et al. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry, 2002,7(2):726-733.
21. Etemad L, Moshiri M, Moallem SA. Epilepsy drugs and effects on fetal development:Potential mechanisms. J Res Med Sci, 2012, 17(4):876-881.
22. Maggs JL, Naisbitt DJ, Tettey JN, et al. Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem Res Toxicol, 2000, 13(5):1075-1081.
23. Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia, 1984, 25(11):77-83.
24. Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res, 2010,91(4):161-165.
25. Hill M, Vrbikova J, Zarubova J, et al. The steroid metabolome in lamotrigine-treated women with epilepsy. Steroids 2011,760(221):1351-1357.
26. Majewska M, Lee HY, Tasaki Y, et al. Is cortisol a modulator of interferon tau action in the endometrium during early pregnancy in cattle? J Reprod Immunol, 2012, 93(14):82-93.
27. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation:a case report. Epilepsia, 1997,38(16):1039-1041.
28. Petrenaite V, Sabers A, Hansen-Schwartz J. Individual changes in lamotrigine plasma concentrations during pregnancy. Epilepsy Res, 2005,65(15):185-188.
29. Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology, 2003,61(15):S35-42.
30. Ohman I, Beck O, Vitols S, et al. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia, 2008,49(17):1075-1080.
31. Reimers A, Ostby L, Stuen I,et al. Expression of UDP-glucuronosyltransferase 1A4 in human placenta at term. Eur J Drug Metab Pharmacokinet, 2011,35(21):79-82.
32. Battino D, Tomson T, Bonizzoni E, et al. Seizure control and treatment changes in pregnancy:observations from the EURAP epilepsy pregnancy registry. Epilepsia, 2013,54(17):1621-1627.
33. Brent RL. Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures. Teratology, 1999,59(24):182-204.
34. Practice parameter:management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 1998,51(17):944-948.
35. Harden CL, Pennell PB, Koppel BS,et al. Practice parameter update:management issues for women with epilepsy——focus on pregnancy (an evidence-based review):vitamin K, folic acid, blood levels, and breastfeeding:report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology, 2009,73(16):142-149.
36. ACOG educational bulletin. Seizure disorders in pregnancy. Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet, 1997, 56(20):279-286.
37. Guidelines for the care of women of childbearing age with epilepsy. Commission on Genetics, Pregnancy, and the Child, International League Against Epilepsy. Epilepsia, 1993,34(7):588-589.

Journal of Epilepsy

Clinical analysis of lamotrigine-related embryo damage and abortion

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