Drug Safety

, Volume 22, Issue 6, pp 425–440

Anticonvulsant Use During Lactation

Review Article

Abstract

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested.

Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects.

In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.

References

  1. 1.
    Dewey KG, Heinig MJ, Nommsen-Rivers LA. Differences in morbidity between breast-fed and formula-fed infants. J Pediatr 1995; 126: 696–702PubMedCrossRefGoogle Scholar
  2. 2.
    Ford K, Labbok M. Breast-feeding and child health in the United States. J Biosoc Sci 1993; 25: 187–94PubMedCrossRefGoogle Scholar
  3. 3.
    Wright AL, Holberg CJ, Martinez FD, et al. Breast-feeding and lower respiratory tract illness in the first year of life. BMJ 1989; 299: 946–9PubMedCrossRefGoogle Scholar
  4. 4.
    Pisacane A, Graziano L, Mazzarella G, et al. Breast-feeding and urinary tract infection. J Pediatr 1992; 120: 87–9PubMedCrossRefGoogle Scholar
  5. 5.
    Saarinen UM, Kajosaari M, Backman A, et al. Prolonged breastfeeding as prophylaxis for atopic disease. Lancet 1979; II: 163–8CrossRefGoogle Scholar
  6. 6.
    Hahn-Zoric M, Fulconis F, Minoli I, et al. Antibody responses to parenteral and oral vaccines are impaired by conventional and low protein formulas as compared to breast-feeding. Acta Paediatr Scand 1990; 79: 1137–42PubMedCrossRefGoogle Scholar
  7. 7.
    Byers T, Graham S, Rzepka T, et al. Lactation and breast cancer: evidence for a negative association in premenopausal women. Am J Epidemiol 1985; 121: 664–74PubMedCrossRefGoogle Scholar
  8. 8.
    Borgeoise BF. Antiepileptic drug, learning and behavior in childhood epilepsy. Epilepsia 1998; 39: 913–21CrossRefGoogle Scholar
  9. 9.
    Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525–38PubMedCrossRefGoogle Scholar
  10. 10.
    Bertilsson L. Geographic/interracial differences in polymorphic drug oxidation. Clin Pharmacokinet 1995; 29: 192–209PubMedCrossRefGoogle Scholar
  11. 11.
    Casey C, Hambridge KM. Nutritional aspects of human lactation. In: Neville MC, Neifert MR, editors. Lactation. physiology, nutrition and breast-feeding. New York: Plenum Press, 1983: 199–248Google Scholar
  12. 12.
    Öhman R, Hägg S, Carleborg L, et al. Excretion of paroxetine in breast milk. J Clin Psychiatry 1999; 60: 519–23PubMedCrossRefGoogle Scholar
  13. 13.
    Prentice A, Prentice AM, Whitehead RG. Breast-milk fat concentrations of rural African women. Short-term variations within individuals. Br J Nutr 1981: 45: 483–94PubMedCrossRefGoogle Scholar
  14. 14.
    Bennett PN. Drugs and human lactation. 2nd ed. Amsterdam: Elsevier, 1996Google Scholar
  15. 15.
    Wilson JT, Brown DJ, Hinson JL, et al. Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs. Ann Rev Pharmacol Toxicol 1985; 25: 667–89CrossRefGoogle Scholar
  16. 16.
    Anderson PO. Drugs and breast-feeding. Semin Perinatol 1979; 3: 271–8PubMedGoogle Scholar
  17. 17.
    Morselli PL. Clinical pharmacokinetics in neonates. Clin Pharmacokinet 1976; 1: 81–9PubMedCrossRefGoogle Scholar
  18. 18.
    Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Clin Pharmacokinet 1980; 5: 485–527PubMedCrossRefGoogle Scholar
  19. 19.
    Hardman JG, Limbird LE, editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 1712–92Google Scholar
  20. 20.
    Andre M, Vert P. Anticonvulsants in the newborn infant. In: Yaffe SJ, Aranda JV, editors. Pediatric pharmacology. 2nd ed. Philadelphia: W.B. Saunders, 1992: 183–92Google Scholar
  21. 21.
    Scheyer RD, Cramer JA. Pharmacokinetics of antiepileptic drugs. Semin Neurol 1990; 10: 414–21PubMedCrossRefGoogle Scholar
  22. 22.
    Bülau P, Paar WD, von Unruh GE. Pharmacokinetics of oxcarbazepine and 10-hydroxy-oxcarbazepine in the newborn child of an oxcarbazepine-treated mother. Eur J Clin Pharmacol 1988; 34: 311–3PubMedCrossRefGoogle Scholar
  23. 23.
    Gourley GR, Arend RA. β-glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. Lancet 1986; I: 644–6CrossRefGoogle Scholar
  24. 24.
    Blumer JL, Reed MD. Principles of neonatal pharmacology. In: Yaffe SJ, Aranda JV, editors. Pediatric pharmacology. 2nd ed. Philadelphia: W. B. Saunders, 1992: 164–77Google Scholar
  25. 25.
    Kuhnz W, Jäger-Roman E, Rating D, et al. Carbamazepine and carbamazepine-10, 11-epoxide during pregnancy and postnatal period in epileptic mothers and their nursed infants. Pharmacokinetics and clinical effects. Pediatr Pharmacol 1983; 3: 199–208Google Scholar
  26. 26.
    Froescher W, Eichelbaum M, Niesen M, et al. Carbamazepine levels in breast milk. Ther Drug Monitor 1984; 6: 266–71CrossRefGoogle Scholar
  27. 27.
    Pynnönen S, Kanto J, Sillanpää M, et al. Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk. Acta Pharmacol Toxicol 1977; 41: 244–53CrossRefGoogle Scholar
  28. 28.
    Pynnönen S, Sillanpää M. Carbamazepine and mother’s milk. Lancet 1975; II: 563CrossRefGoogle Scholar
  29. 29.
    Niebyl JR, Blake DA, Freeman JM, et al. Carbamazepine levels in pregnancy and lactation. Obstet Gynecol 1979; 53: 139–40PubMedGoogle Scholar
  30. 30.
    Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979; 7: 624–7PubMedCrossRefGoogle Scholar
  31. 31.
    Kaneko S, Suzuki K, Sato T, et al. The problems of antiepileptic medication in the neonatal period: is breast feeding advisable? In: Janz D, Bossi L, Dam M, et al., editor. Epilepsy, pregnancy and the child. New York: Raven Press, 1981: 343–8Google Scholar
  32. 32.
    Kok THH, Taitz LS, Bennet MJ, et al. Drowsiness due to clemastine transmitted in breastmilk. Lancet 1982; I: 914–5CrossRefGoogle Scholar
  33. 33.
    Brent NB, Wisner KL. Fluoxetine and carbamazepine concentrations in a nursing mother/infant pair. Clin Pediatr (Phila) 1998; 37: 41–4CrossRefGoogle Scholar
  34. 34.
    Wisner KL, Perel JM. Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs. J Clin Psychopharmacol 1998; 18: 167–9PubMedCrossRefGoogle Scholar
  35. 35.
    Koup JR, Rose JQ, Cohen ME. Ethosuximide pharmacokinetics in a pregnant patient and her newborn. Epilepsia 1978; 19: 535–9PubMedCrossRefGoogle Scholar
  36. 36.
    Rane A, Tunell R. Ethosuximide in human milk and in plasma of a mother and her nursed infant. Br J Clin Pharmacol 1981; 12: 855–8PubMedCrossRefGoogle Scholar
  37. 37.
    Kuhnz W, Koch S, Jakob S, et al. Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. Br J Clin Pharmacol 1984; 18: 671–7PubMedCrossRefGoogle Scholar
  38. 38.
    Söderman P, Rane A. Ethosuximide and nursing [abstract no. 513]. 3rd World conference on Clinical Pharmacology and Therapeutics; 1986 Jul 27-Aug 1; Stockholm, 182Google Scholar
  39. 39.
    Kuhnz W, Koch S, Helge H, et al. Primidone and phenobarbital during lactation period in epileptic women: total and free drug serumlevels in the nursed infants and their effects on neonatal behavior. Dev Pharmacol Ther 1988; 11: 147–54PubMedGoogle Scholar
  40. 40.
    Westerink D, Glerum JH. Separation and microdetermination of phenobarbital and phenytoin in human milk [in Dutch]. Pharm Weekbl 1965; 100: 577–83PubMedGoogle Scholar
  41. 41.
    Nau H, Jesdinsky D, Wittfoht W. Microassay for primidone and its metabolites phenylethylmalondiamide, phenobarbital and p-hydroxyphenobarbital in human serum, saliva, breast milk and tissues by gas chromatography-mass spectrometry using selected ion monitoring. J Chromatogr 1980; 182: 71–9PubMedCrossRefGoogle Scholar
  42. 42.
    Söderman P, Elwin C-E, Liden A. Excretion in milk and blood levels of primidone and phenobarbital in mother and child during primidone treatment [abstract no. 519]. 3rdWorld conference on Clinical Pharmacology and Therapeutics; 1986 Jul 27-Aug 1; Stockholm, 183Google Scholar
  43. 43.
    Steen B, Rane A, Lönnerholm G, et al. Phenytoin excretion in human breast milk and plasma levels in nursed infants. Ther Drug Monit 1982; 4: 331–4PubMedCrossRefGoogle Scholar
  44. 44.
    Rane A, Garle M, Borgå O, et al. Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clin Pharmacol Ther 1974; 15: 39–45PubMedGoogle Scholar
  45. 45.
    Shimoyama R, Ohkubo T, Sugawara K, et al. Monitoring of phenytoin in human breast milk, maternal plasma and cord blood plasma by solid-phase extraction and liquid chromatography. J Pharm Biomed Anal 1998; 17: 863–9PubMedCrossRefGoogle Scholar
  46. 46.
    Mirkin BL. Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects. J Pediatr 1971; 78: 329–37PubMedCrossRefGoogle Scholar
  47. 47.
    Von Unruh GE, Froescher W, Hoffman F, et al. Valproic acid in breast milk. How much is really there? Ther Drug Monit 1984; 6: 272–6CrossRefGoogle Scholar
  48. 48.
    Dickinson R, Harland R, Lynn R, et al. Transmission of valproic acid (Depakene) across the placenta: half life of the drug in mother and baby. J Pediatr 1979; 94: 832–5PubMedCrossRefGoogle Scholar
  49. 49.
    Alexander FW. Sodium valproate and pregnancy [letter]. Arch Dis Child 1979; 54: 240PubMedCrossRefGoogle Scholar
  50. 50.
    Nau H, Rating S, Koch S, et al. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother’s milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981; 219: 768–77PubMedGoogle Scholar
  51. 51.
    Nau H, Helge H, Luck W. Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites. J Pediatr 1984; 104: 627–34PubMedCrossRefGoogle Scholar
  52. 52.
    Bardy A, Granström ML, Hiilesmaa VK. Valproic acid and breastfeeding. In: Janz D, Bossi L, Dam M, et al., editors. Epilepsy, pregnancy and the child. New York: Raven Press, 1982: 359–60Google Scholar
  53. 53.
    Philbert A, Pedersen B, Dam M. Concentration of valproate during pregnancy, in the newborn and in breast milk. Acta Neurol Scand 1985; 72: 460–3PubMedCrossRefGoogle Scholar
  54. 54.
    Tsuru N, Maeda T, Tsuruoka M. Three cases of delivery under sodium valproate-placental transfer, milk transfer and probable teratogenicity of sodium valproate. Jpn J Psychiatry Neurol 1988; 42: 89–96PubMedGoogle Scholar
  55. 55.
    Rane A, Bertilsson L, Palmér L. Disposition of placentally transferred carbamazepine in the newborn. Eur J Clin Pharmacol 1975; 8: 283–4PubMedCrossRefGoogle Scholar
  56. 56.
    Frey B, Schubiger G, Musy JP. Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-feeding. Eur J Pediatr 1990; 150: 136–8PubMedCrossRefGoogle Scholar
  57. 57.
    Merlob P, Mor N, Litwin A. Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breastfeeding. Ann Pharmacother 1992; 26: 1563–5PubMedGoogle Scholar
  58. 58.
    American Academy of Pediatrics, Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93: 137–15Google Scholar
  59. 59.
    Frensdorf W. Uebergang von Luminal in die Milch. Munch Med Wschr 1926; 73: 322–3Google Scholar
  60. 60.
    Tyson RM, Schrader EA. Pearlmann HH. Drugs transmitted through breastmilk. J Pediatr 1938; 13: 86–90CrossRefGoogle Scholar
  61. 61.
    Juul S. Barbiturate poisoning via breast milk? [in Danish]. Ugeskr Laeger 1969; 131: 2257–8PubMedGoogle Scholar
  62. 62.
    Finch E, Lorber J. Methemoglobinemia in the newborn: probably due to phenytoin excreted in milk. J Obstet Gynecol Br Emp 1954; 61: 833–4CrossRefGoogle Scholar
  63. 63.
    Knott C, Reynolds F, Clayden G. Infantile spasms on weaning from breast milk containing anticonvulsants. Lancet 1987; II: 272–3CrossRefGoogle Scholar
  64. 64.
    Brodie MJ. Management of epilepsy during pregnancy and lactation. Lancet 1990; 336: 426–7PubMedCrossRefGoogle Scholar
  65. 65.
    Dillon AE, Wagner CL, Wiest D, et al. Drug therapy in the nursing mother. Obstet Gynecol Clin North Am 1997; 24: 675–96PubMedCrossRefGoogle Scholar
  66. 66.
    Nau H, Kunz W, Egger HJ, et al. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982; 7: 508–43PubMedCrossRefGoogle Scholar
  67. 67.
    Stahl MMS, Neiderud J, Vinge E. Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid. J Pediatr 1997; 130: 1001–3PubMedCrossRefGoogle Scholar
  68. 68.
    Goldberg HL. Psychotropic drugs in pregnancy and lactation. Int J Psychiatry Med 1994; 24: 129–47PubMedCrossRefGoogle Scholar
  69. 69.
    Söderman P, Matheson I. Clonazepam in breast milk. Eur J Pediatr 1988; 147: 212–3PubMedCrossRefGoogle Scholar
  70. 70.
    Fisher JB, Edgren BE, Mammel MC, et al. Neonatal apnea associated with maternal clonazepam therapy: a case report. Obstet Gynecol 1985; 66(3 Suppl.): 34S–5SPubMedGoogle Scholar
  71. 71.
    Erkkola R, Kanto J. Diazepam and breastfeeding. Lancet 1972; I: 1235–6CrossRefGoogle Scholar
  72. 72.
    Wesson DR, Camber S, Harkey M, et al. Diazepam and desmethyldiazepam in breast milk. J Psychoactive Drugs 1985; 17: 55–6PubMedCrossRefGoogle Scholar
  73. 73.
    Brandt R. Passage of diazepam and desmethyldiazepam into breast milk. Arzneimittelforschung 1976; 26: 454–7PubMedGoogle Scholar
  74. 74.
    Sundsbak HP, Bredesen JE. Diazepam in breast milk [letter in Norwegian]. Tidsskr Nor Laegeforen 1980; 100: 582Google Scholar
  75. 75.
    Dusci LJ, Good SM, Hall RW, et al. Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam. Br J Clin Pharmacol 1990; 29: 123–6PubMedCrossRefGoogle Scholar
  76. 76.
    Cole AP, Hailey DM. Diazepam and active metabolite in breastmilk and their transfer to the neonate. Arch Dis Child 1975; 50: 741–2PubMedCrossRefGoogle Scholar
  77. 77.
    Whitelaw AG, Cummings AJ, McFadyen IR. Effect of maternal lorazepam on the neonate. Br Med J Clin Res Ed 1981; 282: 1106–8PubMedCrossRefGoogle Scholar
  78. 78.
    Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985; 57: 1042–3PubMedCrossRefGoogle Scholar
  79. 79.
    Matheson I, Lunde PK, Bredesen JE. Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects. Br J Clin Pharmacol 1990; 30: 787–93PubMedCrossRefGoogle Scholar
  80. 80.
    Patrick MJ, Tilstone WJ, Reavey P. Diazepam and breast feeding. Lancet 1972; 1: 542–3PubMedCrossRefGoogle Scholar
  81. 81.
    Data on file; Schering Plough, January 18, 1993Google Scholar
  82. 82.
    Schmidt D, Krämer G. The new anticonvulsant drugs: implications for avoidance of adverse effects. Drug Saf 1994; 11: 422–31PubMedCrossRefGoogle Scholar
  83. 83.
    Data on file; Parke Davies, protocol 945–196-0Google Scholar
  84. 84.
    Tomson T, Öhman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997; 38: 1039–41PubMedCrossRefGoogle Scholar
  85. 85.
    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
  86. 86.
    Berry DJ. The disposition of lamotrigine throughout pregnancy [abstract no. 90]. In: Sixth international congress of therapeutic drug monitoring and clinical toxicology: 1999 Sept 13-17: Cairns. Ther Drug Monit, 1999; 21: 478CrossRefGoogle Scholar
  87. 87.
    Öhman I, Tomson T, Vitols S. Lamotrigine (LTG) pharmacokinetics during delivery and lactation [abstract no. 201]. In: Sixth international congress of therapeutic drug monitoring and clinical toxicology: 1999 Sept 13-17: Cairns. Ther Drug Monit 1999; 21: 478CrossRefGoogle Scholar
  88. 88.
    Tran A, O’Mahoney T, Rey E, et al. Vigabatrin: placental transfer in vivo and excretion into breast milk of the enantiomers. Br J Clin Pharmacol 1998; 45: 409–11PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Division of Clinical PharmacologyNorrland University HospitalUmeåSweden
  2. 2.Department of Clinical PharmacologyRegional and University HospitalTrondheimNorway

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