Clinical Pharmacokinetics

, Volume 41, Issue 8, pp 559–579

Treatment of Epilepsy in Women of Reproductive Age

Pharmacokinetic Considerations
Review Article Special Populations


Although epilepsy affects men and women equally, there are many women’s health issues in epilepsy, especially for women of childbearing age. These issues, which include menstrual cycle influences on seizure activity (catamenial epilepsy), interactions of contraceptives with antiepileptic drugs (AEDs), pharmacokinetic changes during pregnancy, teratogenicity and the safety of breastfeeding, challenge both the woman with epilepsy and the many healthcare providers involved in her care. Although the information in the literature on women’s issues in epilepsy has grown steeply in recent years, there are many examples showing that much work is yet to be done. The purpose of this article is to review these issues and describe practical considerations for women of childbearing age with epilepsy. The article addresses the established or ‘first-generation’ AEDs (phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide and valproic acid) and the ‘second-generation’ AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide).

Although a relationship between hormones and seizure activity is present in many women, good treatment options for catamenial epilepsy remain elusive. Drug interactions between enzyme-inducing AEDs and contraceptives are well documented. Higher dosages of oral contraceptives or a second contraceptive method are suggested if women use an enzyme-inducing AED. Planned pregnancy and counselling before conception is crucial. This counselling should include, but is not limited to, folic acid supplementation, medication adherence, the risk of teratogenicity and the importance of prenatal care. AED dosage adjustments may be necessary during pregnancy and should be based on clinical symptoms, not entirely on serum drug concentrations.

Many groups have turned their attention to women’s issues in epilepsy and have developed clinical practice guidelines. Although the future holds promise in this area, many questions and the need for progress remain.


  1. 1.
    Epilepsy Foundation of America. Epilepsy: a report to the nation [online]. Available from URL: [Accessed 2002 May 30]
  2. 2.
    Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia 2000; 41: 321–51CrossRefGoogle Scholar
  3. 3.
    Foldvary N. Treatment issues for women with epilepsy. Neurol Clin 2001; 19: 409–25PubMedCrossRefGoogle Scholar
  4. 4.
    Krauss GL, Brandt J, Campbell M, et al. Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians. Neurology 1996; 46: 1534–9PubMedCrossRefGoogle Scholar
  5. 5.
    Morrell MJ, Sarto GE, Shafer PO, et al. Health issues for women with epilepsy: a descriptive survey to assess knowledge and awareness among healthcare providers. J Womens Health Gend Based Med 2000; 9: 959–65PubMedCrossRefGoogle Scholar
  6. 6.
    Crawford P, Lee P. Gender difference in management of epilepsy: what women are hearing. Seizure 1999; 8: 135–9PubMedCrossRefGoogle Scholar
  7. 7.
    Fairgrieve SD, Jackson M, Jonas P, et al. Population based, prospective study of the care of women with epilepsy in pregnancy. BMJ 2000; 321: 674–5PubMedCrossRefGoogle Scholar
  8. 8.
    de Kloet ER, Joels M. Brain corticosteroid receptors and neurotransmission. In: Fuxe K, Agnati LF, editors. Volume transmission in the brain: novel mechanisms for neural transmission. New York: Raven Press, 1991: 213–24Google Scholar
  9. 9.
    McEwen BS. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991; 12: 141–7PubMedCrossRefGoogle Scholar
  10. 10.
    Belelli D, Lan NC, Gee KW. Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci Biobehav Rev 1990; 14: 315–22PubMedCrossRefGoogle Scholar
  11. 11.
    Lambert JJ, Peters JA, Cottrell GA. Actions of synthetic and endogenous steroids on the GABAA receptor. Trends Pharmacol Sci 1987; 8: 224–7CrossRefGoogle Scholar
  12. 12.
    Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992; 38: 379–95PubMedCrossRefGoogle Scholar
  13. 13.
    Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992; 6: 2311–22PubMedGoogle Scholar
  14. 14.
    Majewska MD, Harrison NL, Schwartz RD, et al. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986; 232: 1004–7PubMedCrossRefGoogle Scholar
  15. 15.
    Harrison NL, Majewska MD, Harrington JW, et al. Structure-activity relationships for steroid interaction with the gamma aminobutyric acidA receptor complex. J Pharmacol Exp Ther 1987; 241: 346–53PubMedGoogle Scholar
  16. 16.
    Gee KW, Bolger MB, Brinton RE, et al. Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther 1988; 246: 803–12PubMedGoogle Scholar
  17. 17.
    McAuley JW, Kroboth PD, Stiff DD, et al. Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents. Pharmacol Biochem Behav 1993; 45: 77–83PubMedCrossRefGoogle Scholar
  18. 18.
    Jung-Testas I, Hu ZY, Baulieu EE, et al. Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 1989; 125: 2083–91PubMedCrossRefGoogle Scholar
  19. 19.
    Robel P, Jung-Testas I, Hu ZY, et al. Neurosteroids: biosynthesis and metabolism in cultured rodent glia and neurons. In: Costa E, Paul SM, editors. Neurosteroids and brain function. New York: Thieme Medical Publishers, Inc., 1991: 147–54Google Scholar
  20. 20.
    Myslobodsky MS. Pro- and anti-convulsant effects of stress: the role of neuroactive steroids. Neurosci Biobehav Rev 1993; 17: 129–39PubMedCrossRefGoogle Scholar
  21. 21.
    Backstrom T, Gee KW, Lan N, et al. Steroids in relation to epilepsy and anesthesia. Ciba Found Symp 1990; 153: 225–30PubMedGoogle Scholar
  22. 22.
    Laidlaw J. Catamenial epilepsy. Clin Aspects 1956; 1: 1235–7Google Scholar
  23. 23.
    Hogskilde S, Wagner J, Carl P, et al. Anticonvulsive properties of pregnanolone emulsion compared with althesin and thiopentone in mice. Br J Anaesth 1988; 61: 462–7PubMedCrossRefGoogle Scholar
  24. 24.
    Belelli D, Bolger MB, Gee KW. Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur J Pharmacol 1989; 166: 325–9PubMedCrossRefGoogle Scholar
  25. 25.
    Landgren S, Aasly J, Backstrom T, et al. The effect of progesterone and its metabolites on the interictal epileptiform discharge in the cat’s cerebral cortex. Acta Physiol Scand 1987; 131: 33–42PubMedCrossRefGoogle Scholar
  26. 26.
    Kokka N, Sapp DW, Witte U, et al. Sex differences in sensitivity to pentylenetetrazol but not in GABAA receptor binding. Pharmacol Biochem Behav 1992; 43: 441–7PubMedCrossRefGoogle Scholar
  27. 27.
    Cramer JA, Mattson RH. Hormones and epilepsy. In: Wyllie E, editor. The treatment of epilepsy: principles and practices. Philadelphia: Lea & Febiger, 1993: 686–91Google Scholar
  28. 28.
    Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia 1993; 34: 827–31PubMedCrossRefGoogle Scholar
  29. 29.
    Mattson RH, Cramer JA, Caldwell BV, et al. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology 1984; 34: 1255–8PubMedCrossRefGoogle Scholar
  30. 30.
    Morrell MJ. Hormones and epilepsy through the lifetime. Epilepsia 1992; 33 Suppl. 4: S49–61PubMedCrossRefGoogle Scholar
  31. 31.
    Herzog AG. Reproductive endocrine considerations and hormonal therapy for women with epilepsy. Epilepsia 1991; 32 Suppl. 6: S27–33PubMedCrossRefGoogle Scholar
  32. 32.
    Herzog AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology 1995; 45: 1660–2PubMedCrossRefGoogle Scholar
  33. 33.
    Yerby MS, Friel PN, McCormick K. Antiepileptic drug disposition during pregnancy. Neurology 1992; 42 Suppl. 5: 12–6PubMedGoogle Scholar
  34. 34.
    Yerby MS. Treatment of epilepsy during pregnancy. In: Wyllie E, editor. The treatment of epilepsy: principles and practices. Philadelphia: Lea & Febiger, 1993: 844–57Google Scholar
  35. 35.
    McAuley JW, Moore JL, Long L, et al. Characterizing cyclical seizures in an outpatient epilepsy clinic [abstract]. Epilepsia 1996; 37 Suppl. 5: 94Google Scholar
  36. 36.
    Hopkins A. Epilepsy, menstruation, oral contraception and pregnancy. In: Hopkins A, Shorvon S, Cascino G, editors. Epilepsy. New York: Demos, 1995: 521–33Google Scholar
  37. 37.
    Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997; 38: 1082–8PubMedCrossRefGoogle Scholar
  38. 38.
    Murri L, Galli R. Catamenial epilepsy, progesterone and its metabolites. Cephalalgia 1997; 17 Suppl. 20: 46–7PubMedGoogle Scholar
  39. 39.
    Galli R, Luisi M, Pizzanelli C, et al. Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase. Epilepsia 2001; 42: 216–9PubMedGoogle Scholar
  40. 40.
    Wrighton SA, Stevens JC. The human hepatic cytochrome P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 1–21PubMedCrossRefGoogle Scholar
  41. 41.
    Backstrom T, Jorpes P. Serum phenytoin, phenobarbital, carbamazepine, albumin; and plasma estradiol, progesterone concentrations during the menstrual cycle in women with epilepsy. Acta Neurol Scand 1979; 59: 63–71PubMedCrossRefGoogle Scholar
  42. 42.
    Kharasch ED, Russell M, Garton K, et al. Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Anesthesiology 1997; 87: 26–35PubMedCrossRefGoogle Scholar
  43. 43.
    Kirkwood C, Moore A, Hayes P, et al. Influence of menstrual cycle and gender on alprazolam pharmacokinetics. Clin Pharmacol Ther 1991; 50: 404–9PubMedCrossRefGoogle Scholar
  44. 44.
    Jochemsen R, van der Graaff M, Boeijinga JK, et al. Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam. Br J Clin Pharmacol 1982; 13: 319–24PubMedCrossRefGoogle Scholar
  45. 45.
    Kashuba ADM, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998; 34: 203–18PubMedCrossRefGoogle Scholar
  46. 46.
    Kumar N, Behari M, Ahuja GK, et al. Phenytoin levels in catamenial epilepsy. Epilepsia 1988; 29: 155–8PubMedCrossRefGoogle Scholar
  47. 47.
    Shavit G, Lerman P, Korczyn AD, et al. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 1984; 34: 959–61PubMedCrossRefGoogle Scholar
  48. 48.
    Backstrom T. Epileptic seizures in women related in plasma estrogens and progesterone during the menstrual cycle. Acta Neurol Scand 1976; 54: 321–47PubMedCrossRefGoogle Scholar
  49. 49.
    Backstrom T, Zetterlund B, Blom S, et al. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 1984; 69: 240–8PubMedCrossRefGoogle Scholar
  50. 50.
    Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999; 52: 1917–8PubMedCrossRefGoogle Scholar
  51. 51.
    Monaghan EP, Navalta LA, Shum L, et al. Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia 1997; 38: 1026–31PubMedCrossRefGoogle Scholar
  52. 52.
    Laxer K, Blum D, Abou-Khalil BW, et al. Assessment of ganaxolone’s anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group. Epilepsia 2000; 41: 1187–94PubMedCrossRefGoogle Scholar
  53. 53.
    Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 1998; 51 Suppl. 4: S21–7PubMedCrossRefGoogle Scholar
  54. 54.
    Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980; 21: 261–71PubMedCrossRefGoogle Scholar
  55. 55.
    Morrell MJ. Sexual dysfunction in epilepsy. Epilepsia 1991; 32 Suppl. 6: S38–45PubMedCrossRefGoogle Scholar
  56. 56.
    Cramer JA, Jones EE. Reproductive function in epilepsy. Epilepsia 1991; 32 Suppl. 6: S19–25PubMedCrossRefGoogle Scholar
  57. 57.
    Rosciszewska D, Buntner B. Urinary excretion of 17-hydroxycorticosteroids and 17 ketosteroids in women with epileptic seizures during the premenstrual period. Neurol Neurochir Pol 1975; 9: 305–9PubMedGoogle Scholar
  58. 58.
    Herzog AG, Seibel MM, Schomer DL, et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origins. Arch Neurol 1986; 43: 341–6PubMedCrossRefGoogle Scholar
  59. 59.
    Bilo L, Meo R, Nappi C, et al. Reproductive endocrine disorders in women with primary generalized epilepsy. Epilepsia 1988; 29: 612–9PubMedCrossRefGoogle Scholar
  60. 60.
    Murialdo G, Galimberti CA, Gianelli MV, et al. Effects of valproate, phenobarbital, and carbamazepine on sex steroid setup in women with epilepsy. Clin Neuropharmacol 1998; 21: 52–8PubMedGoogle Scholar
  61. 61.
    Stoffel-Wagner B, Bauer J, Flugel D, et al. Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medications. Epilepsia 1998; 39: 1164–73PubMedCrossRefGoogle Scholar
  62. 62.
    Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329: 1383–8PubMedCrossRefGoogle Scholar
  63. 63.
    Nalin A, Galli V, Ciccarone V, et al. Antiepileptic drugs and puberty. Brain Dev 1988; 10: 192–4PubMedCrossRefGoogle Scholar
  64. 64.
    Cook JS, Bale JF, Hoffmann RJ. Pubertal arrest associated with valproic acid therapy. Pediatr Neurol 1992; 8: 229–31PubMedCrossRefGoogle Scholar
  65. 65.
    Kollipara S, Connors MH. Hypothalamic effects of sodium valproate [letter]. J Pediatr 1983; 103: 501PubMedGoogle Scholar
  66. 66.
    Isojarvi JI, Rattya J, Myllyla VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43: 446–51PubMedCrossRefGoogle Scholar
  67. 67.
    Bauer J, Jarre A, Klingmuller D, et al. Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy Res 2000; 41: 163–7PubMedCrossRefGoogle Scholar
  68. 68.
    Markus R, Goulding PJ. Valproate, polycystic ovary syndrome and the need for a prospective study. Seizure 2000; 9: 235–6CrossRefGoogle Scholar
  69. 69.
    Isojarvi JI, Pakarinen AJ, Rautio A, et al. Serum sex hormone levels after replacing carbamazepine with oxcarbazepine. Eur J Clin Pharmacol 1995; 47: 461–4PubMedCrossRefGoogle Scholar
  70. 70.
    Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hips fractures in white women. Study of Osteoporotic Fracture Research Group. N Engl J Med 1995; 332: 767–73PubMedCrossRefGoogle Scholar
  71. 71.
    Hahn TJ. Bone complications of anticonvulsants. Drugs 1976; 12: 201–11PubMedCrossRefGoogle Scholar
  72. 72.
    Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med 1986; 59: 569–77PubMedGoogle Scholar
  73. 73.
    Stephen JL, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure 1999; 8: 339–42PubMedCrossRefGoogle Scholar
  74. 74.
    Feldkamp J, Becker A, Witte OW, et al. Long-term anticonvulsant therapy leads to low bone mineral density: evidence of direct effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol Diabetes 2000; 108: 37–43PubMedGoogle Scholar
  75. 75.
    Valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy X-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994; 9: 631–7PubMedCrossRefGoogle Scholar
  76. 76.
    Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127: 256–62PubMedCrossRefGoogle Scholar
  77. 77.
    Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between age 6 and 12 years. Clin Pediatr 1999; 38: 93–8CrossRefGoogle Scholar
  78. 78.
    Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease: new perspectives based on the Framingham study. Ann Intern Med 1979; 90: 85–91PubMedGoogle Scholar
  79. 79.
    Bush TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem 1988; 34: B60–70PubMedGoogle Scholar
  80. 80.
    Jacobs DRJ, Mebane IL, Bangdiwala SI, et al. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women. The follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol 1990; 131: 32–47PubMedGoogle Scholar
  81. 81.
    Muuronen A, Kaste M, Nikkila EA, et al. Mortality from ischaemic heart disease among patients using anticonvulsive drugs: a case control study. Br Med J 1985; 291: 1481–3CrossRefGoogle Scholar
  82. 82.
    Reddy MN. Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy. Proc Soc Exp Biol Med 1985; 180: 359–63PubMedGoogle Scholar
  83. 83.
    Louma PV, Sotaniemi EA, Peklonen RO, et al. Plasma high-density lipoprotein cholesterol and hepatic cytochrome P450 concentrations in epileptics undergoing anticonvulsant treatment. Scand J Clin Lab Invest 1980; 40: 163–7CrossRefGoogle Scholar
  84. 84.
    Calandre EP, Rodriguez-Lopez C, Blazquez A, et al. Serum lipids, lipoproteins and apoliproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital. Acta Neurol Scand 1991; 83: 250–3PubMedCrossRefGoogle Scholar
  85. 85.
    Verrotti A, Domizio S, Angelozzi B, et al. Changes in serum lipids and lipoproteins in epileptic children treated with anti-convulsants. J Paediatr Child Health 1997; 33: 242–5PubMedCrossRefGoogle Scholar
  86. 86.
    Eiris JM, Lojo S, Del Rio MC, et al. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995; 45: 1155–7PubMedCrossRefGoogle Scholar
  87. 87.
    Isojarvi JI, Pakarinen AJ, Myllyla VV. Serum lipid levels during carbamazepine medication: a prospective study. Arch Neurol 1993; 50: 590–3PubMedCrossRefGoogle Scholar
  88. 88.
    Luoma PV, Myllyla VV, Hokkanen E. Relationship between plasma high-density lipoprotein cholesterol and anticonvulsant levels in epileptics. J Cardiovasc Pharmacol 1982; 4: 1024–7PubMedCrossRefGoogle Scholar
  89. 89.
    Wallace RB, Hunninghake DB, Reiland S, et al. Alterations of plasma high-density lipoprotein cholesterol levels associated with consumption of selected medications. The Lipid Research Clinics Program Prevalence Study. Circulation 1980; 62 Suppl. 4: 77–82Google Scholar
  90. 90.
    Luoma PV, Myllyla VV, Sotaniemi EA, et al. Plasma high-density lipoprotein cholesterol in epileptics treated with various anticonvulsants. Eur Neurol 1980; 19: 67–72PubMedCrossRefGoogle Scholar
  91. 91.
    Nikkila EA, Kaste M, Ehnholm C, et al. Elevation of high-density lipoprotein in epileptic patients treated with phenytoin. Acta Med Scand 1978; 204: 517–20PubMedCrossRefGoogle Scholar
  92. 92.
    Luoma PV, Reunanen MI, Sotaniemi EA. Changes in serum triglyceride and cholesterol levels during long-term phenytoin treatment for epilepsy. Acta Med Scand 1979; 206: 229–31PubMedCrossRefGoogle Scholar
  93. 93.
    Back DJ, Breckenridge AM, Crawford FE, et al. An investigation of the pharmacokinetics of ethynlestradiol in women using radioimmunoassay. Contraception 1979; 20: 263–73PubMedCrossRefGoogle Scholar
  94. 94.
    Fotherby K, Akpoviroro J, Abdel-Rahman HA, et al. Pharmacokinetics of ethynyloestradiol in women for different populations. Contraception 1981; 23: 487–96PubMedCrossRefGoogle Scholar
  95. 95.
    Bolt WH, Kappus H, Bolt HM. Ring A oxidation of 17α-ethynylestradiol in man. Horm Metab Res 1974; 6: 432PubMedCrossRefGoogle Scholar
  96. 96.
    Crawford P, Chadwick DJ, Martin C, et al. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990; 30: 892–6PubMedCrossRefGoogle Scholar
  97. 97.
    Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523–31PubMedCrossRefGoogle Scholar
  98. 98.
    Eldon MA, Underwood BA, Randinitis EJ, et al. Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol. Neurology 1998; 50: 1146–8PubMedCrossRefGoogle Scholar
  99. 99.
    Holdich T, Whiteman P, Orme M, et al. Effect of lamotrigine on the pharmacology of the combined oral contraceptive pill 9 [abstract]. Epilepsia 1991; 32 Suppl. 1: 96CrossRefGoogle Scholar
  100. 100.
    Dooley M, Plosker GL. Levetiracetam. A review of its adjunctive use in the management of partial onset seizures. Drugs 2000; 60: 871–93PubMedCrossRefGoogle Scholar
  101. 101.
    Klosterskov Jensen P, Saano V, Haring P, et al. Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 1992; 33: 1149–52PubMedCrossRefGoogle Scholar
  102. 102.
    Back DJ, Bates M, Bowden A, et al. The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy. Contraception 1980; 22: 495–503PubMedCrossRefGoogle Scholar
  103. 103.
    Mengel HB, Houston A, Back DJ. An evaluation of the interaction between tiagabine and oral contraceptives in female volunteers. J Pharm Med 1994; 4: 141–50Google Scholar
  104. 104.
    Rosenfeld WE, Doose DR, Walker SA, et al. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38: 317–23PubMedCrossRefGoogle Scholar
  105. 105.
    Crawford P, Chadwick D, Cleland P, et al. The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids. Contraception 1986; 33: 23–9PubMedCrossRefGoogle Scholar
  106. 106.
    Bartoli A, Gatti G, Cipolli G, et al. A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers. Epilepsia 1997; 38: 702–7PubMedCrossRefGoogle Scholar
  107. 107.
    Haukkamaa M. Contraception by norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception 1986; 33: 559–65PubMedCrossRefGoogle Scholar
  108. 108.
    Odlind V, Olsson SE. Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with norplant implants. Contraception 1986; 33: 257–61PubMedCrossRefGoogle Scholar
  109. 109.
    Dansky LV. The teratogenic effects of epilepsy and anticonvulsant drugs. In: Hopkins A, Shorvon S, Cascino G, editors. Epilepsy. New York: Demos, 1995: 535–55Google Scholar
  110. 110.
    Yerby MS, Leavitt A, Erickson DM, et al. Antiepileptics and the development of congenital anomalies. Neurology 1992; 42 Suppl. 5: 132–40PubMedGoogle Scholar
  111. 111.
    Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42 Suppl. 5: 149–60PubMedGoogle Scholar
  112. 112.
    Shinnar S, Berg AT. Withdrawal of antiepileptic drugs. Curr Opin Neurol 1995; 8: 103–6PubMedCrossRefGoogle Scholar
  113. 113.
    Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: a guideline for discontinuing antiepileptic drugs in seizure-free patients: summary statement. Neurology 1996; 47: 600–2CrossRefGoogle Scholar
  114. 114.
    Betts T, Fox C. Proactive pre-conception counselling for women with epilepsy: is it effective? Seizure 1999; 8: 322–7PubMedCrossRefGoogle Scholar
  115. 115.
    Yerby MS, Friel PN, McCormick K, et al. Pharmacokinetics of anticonvulsants in pregnancy: alternations in plasma protein binding. Epilepsy Res 1990; 5: 223–8PubMedCrossRefGoogle Scholar
  116. 116.
    Lander CM, Eadie MJ. Plasma antiepileptic drug concentrations during pregnancy. Epilepsia 1991; 32: 257–66PubMedCrossRefGoogle Scholar
  117. 117.
    Koup JR, Rose JQ, Cohen ME. Ethosuximide pharmacokinetics in a pregnant patient and her newborn. Epilepsia 1978; 19: 533–9CrossRefGoogle Scholar
  118. 118.
    Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997; 38: 1039–41PubMedCrossRefGoogle Scholar
  119. 119.
    Nau H, Kuhnz W, Egger HJ, et al. Anticonvulsants during pregnancy and lactation: transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982; 7: 508–43PubMedCrossRefGoogle Scholar
  120. 120.
    Chang SW, da Silva JH, Kuhl DR. Absorption of rectally administered phenytoin: a pilot study. Ann Pharmacother 1999; 33: 781–6PubMedCrossRefGoogle Scholar
  121. 121.
    Graves NM, Kriel RL, Jones-Saete C, et al. Relative bioavailability of rectally administered carbamazepine suspension in humans. Epilepsia 1985; 26: 429–33PubMedCrossRefGoogle Scholar
  122. 122.
    Margarit MV, Rodriguez IC, Cerezo A. Rectal bioavailability of water-soluble drugs: sodium valproate. J Pharm Pharmacol 1991; 43: 721–5PubMedCrossRefGoogle Scholar
  123. 123.
    Birnbaum AK, Kriel RL, Im Y, et al. Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally. Pharmacotherapy 2001; 21: 158–62PubMedCrossRefGoogle Scholar
  124. 124.
    Perucca E, Crema A. Plasma protein binding of drugs in pregnancy. Clin Pharmacokinet 1982; 7: 336–52PubMedCrossRefGoogle Scholar
  125. 125.
    Chen SS, Perucca E, Lee JN, et al. Serum protein binding and free concentration of phenytoin and phenobarbitone in pregnancy. Br J Clin Pharmacol 1982; 13: 547–52PubMedGoogle Scholar
  126. 126.
    Patel IH, Levy RH. Valproic acid binding to human serum albumin and determination of free fractions in the presence of anticonvulsants and free fatty acids. Epilepsia 1979; 20: 85–90PubMedCrossRefGoogle Scholar
  127. 127.
    Dickinson RG, Hooper WD, Wood B, et al. The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin. Br J Clin Pharmacol 1989; 28: 17–27PubMedCrossRefGoogle Scholar
  128. 128.
    Hauser WA, Hesdorffer DC. Pregnancy and teratogenesis. In: Hauser WA, editor. Epilepsy: frequency, causes, and consequences. New York: Demos, 1990: 147–56Google Scholar
  129. 129.
    Yerby MS. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 2000; 5 Suppl. 1: S21–31Google Scholar
  130. 130.
    Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Baltimore: Williams & Wilkins, 1994Google Scholar
  131. 131.
    Samren EB, van Duijn Cai, Koch S, et al. Maternal use of anti-epileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997; 38: 981–90PubMedCrossRefGoogle Scholar
  132. 132.
    Oakeshott P, Hunt G. Valproate and spina bifida [letter]. Lancet 1989; I: 611CrossRefGoogle Scholar
  133. 133.
    Samren EB, van Duijn CM, Christiaens GC, et al. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999; 46: 739–46PubMedCrossRefGoogle Scholar
  134. 134.
    Kaneko S, Battino D, Andermann E, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999; 33: 145–58PubMedCrossRefGoogle Scholar
  135. 135.
    Battino D, Kaneko S, Andermann E, et al. Intrauterine growth in the offspring of epileptic women: a prospective multicenter study. Epilepsy Res 1999; 36: 53–60PubMedCrossRefGoogle Scholar
  136. 136.
    Canger R, Battino D, Canevini MP, et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999; 40: 1231–6PubMedCrossRefGoogle Scholar
  137. 137.
    Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344: 1132–8PubMedCrossRefGoogle Scholar
  138. 138.
    Jick S, Terris BZ. Anticonvulsants and congenital malformations. Pharmacotherapy 1997; 17: 561–4PubMedGoogle Scholar
  139. 139.
    Olafsson E, Hallgrimsson JT, Hauser WA, et al. Pregnancies of women with epilepsy: a population-based study in Iceland. Epilepsia 1998; 39: 887–92PubMedCrossRefGoogle Scholar
  140. 140.
    Hvas CL, Henriksen TB, Ostergaard JR, et al. Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birth-weight. Br J Obstet Gynaecol 2000; 107: 896–902CrossRefGoogle Scholar
  141. 141.
    Albunyan M, Abo-Talib Z. Outcome of pregnancies in epileptic women: a study in Saudi Arabia. Seizure 1999; 8: 26–9CrossRefGoogle Scholar
  142. 142.
    Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996; 75: 517–20PubMedCrossRefGoogle Scholar
  143. 143.
    Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000; 37: 489–97PubMedCrossRefGoogle Scholar
  144. 144.
    Kozma C. Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 2001; 98: 168–75PubMedCrossRefGoogle Scholar
  145. 145.
    Holmes LB, Rosenberger PB, Harvey EA, et al. Intelligence and physical features of children of women with epilepsy. Teratology 2000; 61: 196–202PubMedCrossRefGoogle Scholar
  146. 146.
    Finnell RH, Buehler BA, Kerr BM, et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992; 42 Suppl. 5: 25–31PubMedGoogle Scholar
  147. 147.
    Raymond GV, Buehler BA, Holmes LB. Placental epoxide hydrolase activity: correlation with features of fetal anticonvulsant syndrome [abstract]. Teratology 1992; 45: 461Google Scholar
  148. 148.
    Kerr BM, Rettie AE, Eddy AC, et al. Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation. Clin Pharmacol Ther 1989; 46: 82–93PubMedCrossRefGoogle Scholar
  149. 149.
    Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 1992; 42 Suppl. 5: 17–24PubMedGoogle Scholar
  150. 150.
    Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992; 42 Suppl. 5: 32–42PubMedGoogle Scholar
  151. 151.
    MRC Vitamin Study Research Group. Prevention of neural tube defect: results of the Medical Research Council vitamin study. Lancet 1991; 338: 131–7CrossRefGoogle Scholar
  152. 152.
    Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000; 343: 1608–14PubMedCrossRefGoogle Scholar
  153. 153.
    Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 1996; 37 Suppl. 6: S36–44CrossRefGoogle Scholar
  154. 154.
    Reiff-Eldridge R, Heffner CR, Ephross SA, et al. Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am J Obstet Gynecol 2000; 182: 159–63PubMedCrossRefGoogle Scholar
  155. 155.
    Kondo T, Kaneko S, Amano Y, et al. Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy. Epilepsia 1996; 37: 1242–4PubMedCrossRefGoogle Scholar
  156. 156.
    Lumley J, Watson L, Watson M, et al. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. The Cochrane Database of Systematic Reviews. Available in the Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 2: CD001056. Oxford: Oxford Update Software, 2000Google Scholar
  157. 157.
    Craig J, Morrison P, Morrow J, et al. Failure of periconceptual folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valproate. Seizure 1999; 8: 253–4PubMedCrossRefGoogle Scholar
  158. 158.
    Thorp JA, Gaston L, Caspers DR, et al. Current concepts and controversies in the use of vitamin K. Drugs 1995; 49: 376–87PubMedCrossRefGoogle Scholar
  159. 159.
    Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343: 118–26PubMedCrossRefGoogle Scholar
  160. 160.
    American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93: 137–50Google Scholar
  161. 161.
    Begg EJ, Atkinson HC, Duffull SB. Prospective evaluation of a model for the prediction of milk: plasma drug concentrations from physiochemical characteristics. Br J Clin Pharmacol 1992; 33: 501–5PubMedCrossRefGoogle Scholar
  162. 162.
    Notarianni LJ, Belk D, Aird SA, et al. An in vitro technique for the rapid determination of drug entry into breast milk. Br J Clin Pharmacol 1995; 40: 333–7PubMedCrossRefGoogle Scholar
  163. 163.
    Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Saf 2000; 22: 425–40PubMedCrossRefGoogle Scholar
  164. 164.
    Bar-Oz B, Nulman I, Koren G, et al. Anticonvulsants and breastfeeding: a critical review. Paediatr Drugs 2000; 2: 113–26PubMedGoogle Scholar
  165. 165.
    Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate and during lactation. Epilepsia 2000; 41: 709–13PubMedCrossRefGoogle Scholar
  166. 166.
    Rambeck B, Kurlemann G, Stodieck SR, et al. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997; 51: 481–4PubMedCrossRefGoogle Scholar
  167. 167.
    Shafer PO. Counseling women with epilepsy. Epilepsia 1998; 39 Suppl. 8: S38–44PubMedCrossRefGoogle Scholar
  168. 168.
    Schachter SC, Cantrell DT, Krishnamurthy KB. The brainstorms woman: epilepsy in our lives. Philadelphia: Lippincott Williams and WilkinsGoogle Scholar
  169. 169.
    Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: management issues for women with epilepsy (summary statement). Epilepsia 1998; 39: 1226–31CrossRefGoogle Scholar
  170. 170.
    ACOG educational bulletin. Seizure disorders in pregnancy. Number 231, 1996 Dec. Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1997; 56: 279–86CrossRefGoogle Scholar
  171. 171.
    Scottish Obstetric Guidelines and Audit Project. The management of pregnancy in women with epilepsy. Aberdeen: Scottish Programme for Clinical Effectiveness in Reproductive Health. Available from: [Accessed 2002 May 30]
  172. 172.
    Wiebe S. Managing women with epilepsy: guideline producers now need to pay attention to implementation [editorial]. BMJ 2000; 320: 3–4PubMedCrossRefGoogle Scholar
  173. 173.
    Russell AJ, Macpherson H, Cairnie V, et al. The care of pregnant women with epilepsy: a survey of obstetricians in Scotland. Seizure 1996; 5: 271–7PubMedCrossRefGoogle Scholar
  174. 174.
    The North America Registry for Epilepsy and Pregnancy. A unique public/private partnership of health surveillance. Epilepsia 1998; 39: 793–8CrossRefGoogle Scholar
  175. 175.
    Fox C, Betts T. How much risk does a woman with active epilepsy pose to her newborn child in the puerperium?. A pilot study. Seizure 1999; 8: 367–9Google Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.The Ohio State University College of PharmacyColumbusUSA
  2. 2.University of Washington College of PharmacySeattleUSA

Personalised recommendations