clinical challenge ❖ défi clinique

MOTHEMOTHERISKRISK UPDATEUPDATE

Which drugs are contraindicated during breastfeeding? Practice guidelines

Myla E. Moretti, MSC Amy Lee, MSC Shinya Ito, MD

abstract QUESTION Many breastfeeding mothers are concerned about taking medications that might affect their babies. Are there any guide- lines on which drugs are safe?

ANSWER Only a few drugs pose a clinically significant risk to breastfed babies. In general, antineoplastics, drugs of abuse, some anticonvulsants, ergot alkaloids, and radiopharmaceuticals should not be taken, and levels of amiodarone, cyclosporine, and lithium should be monitored. résumé

QUESTION Plusieurs femmes qui allaitent sont inquiètes de prendre des médicaments qui pourraient être néfastes pour leur nourris- son. Existe-t-il des lignes directrices au sujet de l’innocuité des médicaments dans un tel cas?

RÉPONSE Il n’existe que quelques médicaments qui posent des risques cliniquement significatifs chez les enfants nourris au sein. En général, les cytotoxiques, les stupéfiants, certains anticonvulsifs, les alcaloïdes de l’ergot et les agents radiopharmaceutiques sont à proscrire et les concentrations d’amiodarone, de cyclosporine et de lithium devraient être surveillées.

here is no question that breast- considered incompatible with breast- Breastfeeding might be possible pro- T feeding is best for providing all feeding because even very low levels vided infants are closely monitored. necessary nutrients to infants for the of exposure can prove toxic. If Two cases of cisplatin excretion into first 6 months of life. Use of medica- breastfeeding is continued, drug lev- milk indicated that patients excrete tion while lactating, however, compli- els in milk and infant plasma, and this drug in varying amounts into cates the decision to breastfeed. infant hematologic parameters, must milk.4,5 The outcome of infants Fortunately, most drugs are compat- be monitored. Much research is still exposed to cisplatin through milk ible with breastfeeding and do not required in this area, and only limit- are not known. Adverse events, pose a risk to infants. While certain ed information is available on some including neutropenia6 and leukope- drugs are traditionally contraindicat- of these agents. nia,7 are reported in two infants ed for nursing mothers, many of Nine cases of infants breastfed by whose mothers used cyclophos- these restrictions are based on theo- mothers taking azathioprine (25 to phamide while breastfeeding. retical concerns only rather than on 100 mg/d) appear in the current lit- In a single report, low levels of evidence or clinical observation. In erature. All infants thrived and had doxorubicin were found in breast this update we discuss these con- no reported adverse effects. 1-3 milk5 although infant outcome was traindicated drugs in light of not known. Methotrexate is the practice guidelines of the o you have questions about the safety of drugs, chemicals, excreted into milk in mini- Motherisk Program. Dradiation, or infections in women who are pregnant or mal amounts,8 and single breastfeeding? We invite you to submit them to the Motherisk weekly doses, such as Drugs generally Program by fax at (416) 813-7562; they will be addressed in those used for rheumatoid considered incompatible future Motherisk Updates. Published Motherisk Updates are arthritis maintenance ther- with breastfeeding available on the College of Family Physicians of Canada website apy, are unlikely to pose Antineoplastics. Anti- (www.cfpc.ca). Some articles are published in The Motherisk substantial risk to babies. cancer drugs used in Newsletter and Motherisk website (www.motherisk.org) also. Use of methotrexate for chemotherapy are generally cancer chemotherapy is not

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto. Ms Moretti, Ms Lee, and Dr Ito are members of the Motherisk Team.

VOL 46: SEPTEMBER • SEPTEMBRE 2000 ❖ Canadian Family Physician • Le Médecin de famille canadien 1753 clinical challenge ❖ défi clinique

recommended for lactating moth- old.17 Heroin toxicity has been continue therapy while breastfeed- ers because we do not know how it observed in infants breastfed by ing, the drug should be monitored affects suckling infants. mothers abusing heroin, but at ther- in breast milk and infant plasma, as apeutic doses, most opioids, such as should the infant’s thyroid function. Anticonvulsants. Only a few anti- morphine, meperidine, methadone, Cyclosporine has been used suc- convulsants are excreted in high and codeine, are excreted into milk cessfully for several lactating moth- concentrations in breast milk. in only minimal amounts18,19 and are ers.3,27,28 Breast-milk levels ranged Phenobarbital, ethosuximide, and compatible with breastfeeding. widely, although infant plasma lev- primidone might result in substantial Phencyclidine, a potent hallucino- els, when detectable, were low. infant exposure.9 Close monitoring of gen, has been found in breast milk Because cyclosporine is a potent infants exposed to phenobarbital is several weeks after maternal immunosuppressant, however, it warranted because their blood levels dosing.20 This is attributable to its should be continued during breast- might approach therapeutic levels. long half-life; nursing mothers feeding only if levels in milk and Sedation has been observed, and should be encouraged to avoid it. infant serum are monitored. there is potential for withdrawal Similar to amiodarone, lithium upon weaning. Ergot alkaloids. Ergotamine thera- concentrations vary greatly in milk. py during lactation was associated Although amiodarone is contraindi- Drugs of abuse. Generally speak- with ergotism (vomiting, diarrhea, cated by many authorities because ing, all drugs of abuse should be occasional convulsions) in a 1934 infant plasma levels can reach one avoided by nursing women. In addi- publication21 but not in a more third to half of maternal levels,29 the tion to unnecessary infant exposure, recent study.22 We do not know how only reported adverse event could mothers’ ability to care for their much of this drug is excreted into not rule out possible effects of in babies while under the influence of milk. Until more data are available, utero exposure.30 Lithium is an such substances becomes an issue. other therapies should be consid- excellent example of a drug that Heavy alcohol consumption was ered for patients requiring headache requires monitoring and case-by- associated with pseudo–Cushing’s treatment. Ergonovine is known to case assessment so nursing mothers syndrome in a 4-month-old baby.10 reduce serum prolactin levels and can be successfully treated. Ethanol was also associated with might inhibit lactation.23 Cigarette smoking should be min- decreased milk intake by infants,11 Methylergonovine, used for uter- imized while breastfeeding. While altered sleep patterns,12 and slower ine involution, does not influence second-hand smoke exposure is neurologic development.13 If moth- milk supply. It is not found in clini- probably the greater concern, smok- ers drink alcohol, breastfeeding cally significant amounts in breast ing might decrease milk supply and could be withheld temporarily milk24 and can be used safely. nicotine can be measured in breast (about 2 to 3 hours per drink) to Bromocriptine effectively suppress- milk.31 ensure alcohol levels in the milk es lactation and, hence, is not com- Estrogens found in oral contra- have diminished. patible with breastfeeding. Also, it ceptives have been shown to reduce Amphetamines have been detect- could be hazardous to mothers.25 milk production in some mothers. ed in infant urine following maternal On the other hand, progestin-only therapy.14 Nothing is known about Others. Although the drugs listed contraceptives are unlikely to affect maternal amphetamine abuse and its below can be used with caution, milk supply. If estrogen-containing potential effect on nursing infants. safer alternative drugs should be contraceptives are to be used, thera- Cocaine is excreted into breast milk considered first if they exist for the py should commence only after in notable concentrations; infants particular indication. maternal milk supply is well estab- might accumulate the drug because Amiodarone excretion into milk lished, about 6 weeks after deliv- they are less able than adults to varies from person to person. ery.32 Infant weight gain can be metabolize it. Cocaine has been Nursing infants might ingest up to monitored to ensure sufficient milk detected in infant serum, and toxicity 50% of the maternal dose (on the is produced. has been reported in some basis of weight).26 Also, amiodarone Radiopharmaceuticals might infants.15,16 Infants exposed to mari- contains large amounts of iodine require temporary cessation of juana through breast milk showed a that could affect infants’ thyroid breastfeeding because radioactivity delay in motor development at 1 year glands. If the decision is made to sometimes persists in breast milk for

1754 Canadian Family Physician • Le Médecin de famille canadien ❖ VOL 46: SEPTEMBER • SEPTEMBRE 2000 clinical challenge ❖ défi clinique

hours or even days. Before proce- 5. Egan PC, Costanza ME, Dodion P, human breast milk. Acta Anaesthesiol dures, breast milk may be pumped Egorin MJ, Bachur NR. Doxorubicin and Scand 1989;33(5):426-8. and frozen to be given to infants cisplatin excretion into human milk. 19. Wojnar-Horton RE, Kristensen JH, while breastfeeding is temporarily Cancer Treat Rep 1985;69(12):1387-9. Yapp P, Ilett KF, Dusci LJ, Hackett LP. withheld. In addition, mothers should 6. Amato D, Niblett JS. Neutropenia from Methadone distribution and excretion pump and discard their breast milk cyclophosphamide in breast milk [letter]. into breast milk of clients in a methadone while the isotope is still present in Med J Aust 1977;1(11):383-4. maintenance programme. Br J Clin order to preserve milk production. 7. Durodola JI. Administration of Pharmacol 1997;44(6):543-7. Recommendations to patients should cyclophosphamide during late pregnancy 20. Kaufman KR, Petrucha RA, Pitts FN Jr, be individualized to particular agents. and early lactation: a case report. J Natl Weekes ME. PCP in amniotic fluid and Consultation with a nuclear medicine Med Assoc 1979;71(2):165-6. breast milk: case report. J Clin Psychiatry physician and reading the various lit- 8. Johns DG, Rutherford LD, Leighton PC, 1983;44(7):269-70. erature resources available33,34 will Vogel CL. Secretion of methotrexate into 21. Fomina PI. Untersuchungen uber den assist in determining the length of human milk. Am J Obstet Gynecol ubergang des aktiven Agens des breastfeeding interruption. 1972;112(7):978-80. Mutterkorns in die milch stillender 9. Nau H, Kuhnz W, Egger HJ, Rating D, Mutter. Arch Gynakol 1934;157:275-85. Conclusion Helge H. Anticonvulsants during preg- 22. Jolivet A, Robyn C, Huraux-Rendu C, As experience with lactating nancy and lactation. Transplacental, Gautray JP. Effet de derives des women’s use of drugs increases, we maternal and neonatal pharmacokinetics. alcaloides de l’ergot de siegle sur la are realizing that only a few drugs Clin Pharmacokinet 1982;7(6):508-43. secretion lactee dans le post-partum pose a clinically significant risk to 10. Binkiewicz A, Robinson MJ, Senior B. immediat [Effect of ergot alkaloid deriva- infants. This is reassuring for both Pseudo-Cushing syndrome caused by tives on milk secretion in the immediate patients and health care providers alcohol in breast milk. J Pediatr postpartum period] (Fr). J Gynecol Obstet faced with the risk-benefit dilemma. 1978;93(6):965-7. Biol Reprod (Paris) 1978;7(1):129-34. To make an informed decision, it is 11. Mennella JA, Beauchamp GK. The 23. Shane JM, Naftolin F. Effect of critical that appropriate and the transfer of alcohol to human milk. Effects ergonovine maleate on puerperal pro- most up-to-date sources be consult- on flavor and the infant’s behavior. N Engl lactin. Am J Obstet Gynecol ed when making recommendations J Med 1991;325(14):981-5. 1974;120(1):129-31. to patients requiring drug therapy 12. Mennella JA, Gerrish CJ. Effects of 24. Del Pozo E, Brun DR, Hinselmann M. while lactating. Contact the exposure to alcohol in mother’s milk on Lack of effect of methyl-ergonovine on Motherisk Program for specific infant sleep. Pediatrics 1998;101(5):E2. postpartum lactation. Am J Obstet Gynecol information. 13. Little RE, Anderson KW, Ervin CH, 1975;123(8):845-6. Worthington-Roberts B, Clarren SK. 25. Comabella M, Alvarez-Sabin J, Rovira A, References Maternal alcohol use during breast-feeding Codina A. Bromocriptine and postpartum 1. Coulam CB, Moyer TP, Jiang NS, and infant mental and motor development at cerebral angiopathy: a causal relation- Zincke H. Breast-feeding after renal one year. N Engl J Med 1989;321(7):425-30. ship? Neurology 1996;46(6):1754-6. transplantation. Transplant Proc 14. Steiner E, Villen T, Hallberg M, Rane A. 26. McKenna WJ, Harris L, Rowland E, 1982;14(3):605-9. Amphetamine secretion in breast milk. Whitelaw A, Storey G, Holt D. 2. Grekas DM, Vasiliou SS, Lazarides AN. Eur J Clin Pharmacol 1984;27(1):123-4. Amiodarone therapy during pregnancy. Immunosuppressive therapy and breast- 15. Chasnoff IJ, Lewis DE, Squires L. Am J Cardiol 1983;51(7):1231-3. feeding after renal transplantation [let- Cocaine intoxication in a breast-fed infant. 27. Flechner SM, Katz AR, Rogers AJ, Van ter]. Nephron 1984;37(1):68. Pediatrics 1987;80(6):836-8. Buren C, Kahan BD. The presence of 3. Nyberg G, Haljamae U, Frisenette-Fich C, 16. Chaney NE, Franke J, Wadlington WB. cyclosporine in body tissues and fluids Wennergren M, Kjellmer I. Breast-feeding Cocaine convulsions in a breast-feeding during pregnancy. Am J Kidney Dis during treatment with cyclosporine. baby. J Pediatr 1988;112(1):134-5. 1985;5(1):60-3. Transplantation 1998;65(2):253-5. 17. Astley SJ, Little RE. Maternal marijuana 28. Thiru Y, Bateman DN, Coulthard MG. 4. De Vries EG, van der Zee AG, Uges DR, use during lactation and infant develop- Successful breast feeding while mother Sleijfer DT. Excretion of platinum into ment at one year. Neurotoxicol Teratol was taking cyclosporin. BMJ breast milk [letter] [published erratum 1990;12(2):161-8. 1997;315(7106):463. appears in Lancet 1989;1(8641):798]. 18. Feilberg VL, Rosenborg D, Broen CC, 29. Schou M, Amdisen A. Lithium and preg- Lancet 1989;1(8636):497. Mogensen JV. Excretion of morphine in nancy. 3. Lithium ingestion by children

1756 Canadian Family Physician • Le Médecin de famille canadien ❖ VOL 46: SEPTEMBER • SEPTEMBRE 2000 clinical challenge ❖ défi clinique

breast-fed by women on lithium treatment. BMJ 1973;2(859):138. 30. Tunnessen WW Jr, Hertz CG. Toxic effects of lithium in newborn infants: a commentary. J Pediatr 1972;81(4):804-7. 31. Dahlstrom A, Lundell B, Curvall M, Thapper L. Nicotine and cotinine con- centrations in the nursing mother and her infant. Acta Paediatr Scand 1990;79(2):142-7. 32. Kelsey JJ. Hormonal contraception and lactation [review]. J Hum Lact 1996;12(4):315-8. 33. Rubow S, Klopper J, Wasserman H, Baard B, van Niekerk M. The excre- tion of radiopharmaceuticals in human breast milk: additional data and dosimetry. Eur J Nucl Med 1994;21(2):144-53. 34. Romney BM, Nickoloff EL, Esser PD, Alderson PO. Radionuclide administration to nursing mothers: mathematically derived guidelines. Radiology 1986;160(2):549-54. …

VOL 46: SEPTEMBER • SEPTEMBRE 2000 ❖ Canadian Family Physician • Le Médecin de famille canadien 1757