Pediatric Annals

Drugs and Chemicals Excreted in Breast Milk

Jay M Arena, MD

Abstract

Unbelievable as it may seem, available information derived from clinical and laboratory research about the excretion of chemicals and drugs in breast milk is scanty, almost nonexistent. And this despite the fact that all products ingested by the mother are excreted in the milk in some form.1

There are a number of factors that apparently play a part in this paucity of information. It is almost impossible to carry out experimental observations on nursing mothers. The studies on animals are complicated. And there is great difficulty in extrapolating the data from animal to human studies.

Fortunately, not all drugs are able to pass into the mother's milk in significant amounts.2"4 Some do, and in proportions that can jolt the baby. How much depends on a number of factors. The excretion of some chemicals into the breast milk may be considerable, whereas with others only minute amounts may be found. The passage of a drug across the membrane between plasma and milk is influenced by its pKa, or degree of ionization (i.e., the pH at which equal concentrations of the acid and basic forms of a substance, usually a buffer, are present); its solubility in fats and water; and the poorly understood transport mechanism. Ionized forms pass only slowly into these secretions. The concentration of acidic compounds in milk is lower than that in plasma. Nonelectrolytes - such as ethanol, urea, and antipyrine - readily enter milk and reach the same concentration as in plasma, independently of the pH of the milk (Table 1).

One of the most searching projects about drugs and breast milk was reported from Copenhagen in 1966 by Rasmussen.5 He studied the passage of drugs from blood plasma to milk in goats and cows while almost constant plasma levels were maintained by continuous intravenous infusion. Each of the drugs tested - sulfonamides, antibiotics, barbiturates, antipyrine, ethanol, and urea - exhibited a constant ratio between the concentration in ultrafiltrate of milk and ultrafiltrate of blood plasma. This ratio was found to be independent of both the plasma level and the volume of milk produced during the experimental period. Therefore, the passage can be considered to have taken place by diffusion.

If not all drugs ingested by the nursing nother are excreted in her milk, most are- but usually in insignificant amounts. Occasionally, however, these drugs can be dangerous to the nursing infant. For example, methemoglobin was found in a newborn infant whose mother was treated with phenytoin sodium (Dilantin) for epilepsy.6 This baby did well on donor's breast milk. But when put on his own mother's milk again - while she was still taking Dilantin - the infant became drowsy and developed a grayish-blue discoloration.

However, in another report of several epileptic nursing women taking phenytoin sodium breast milk and colostrum were tested and found to contain lower concentrations than maternal plasma, and an increase in the maternal plasma did not raise the amount of phenytoin sodium in breast milk. There were no discernible effects produced in the nursing infants in this report. In 1956, a number of breast-fed infants died in southeast Turkey when their mothers were poisoned by eating seed wheat treated with hexachlorobenzene, a fungistatic agent. Investigation of the Turkish incident revealed a porphyrin in the urine of affected persons. It is assumed that hexachlorobenzene or one of its metabolites was excreted in the mother's milk and poisoned the infants.

Table

1. Arena, J. Contamination of the ideal food. Nutr. Today (Winter, 1970), 2-8.

2. Catz, C, and Giacoia, G. Drugs and breast milk. Pediatr. Clin. North Am. 19 (1972), 151-166.

3. Knowles, J. Excretion…

Unbelievable as it may seem, available information derived from clinical and laboratory research about the excretion of chemicals and drugs in breast milk is scanty, almost nonexistent. And this despite the fact that all products ingested by the mother are excreted in the milk in some form.1

There are a number of factors that apparently play a part in this paucity of information. It is almost impossible to carry out experimental observations on nursing mothers. The studies on animals are complicated. And there is great difficulty in extrapolating the data from animal to human studies.

Fortunately, not all drugs are able to pass into the mother's milk in significant amounts.2"4 Some do, and in proportions that can jolt the baby. How much depends on a number of factors. The excretion of some chemicals into the breast milk may be considerable, whereas with others only minute amounts may be found. The passage of a drug across the membrane between plasma and milk is influenced by its pKa, or degree of ionization (i.e., the pH at which equal concentrations of the acid and basic forms of a substance, usually a buffer, are present); its solubility in fats and water; and the poorly understood transport mechanism. Ionized forms pass only slowly into these secretions. The concentration of acidic compounds in milk is lower than that in plasma. Nonelectrolytes - such as ethanol, urea, and antipyrine - readily enter milk and reach the same concentration as in plasma, independently of the pH of the milk (Table 1).

One of the most searching projects about drugs and breast milk was reported from Copenhagen in 1966 by Rasmussen.5 He studied the passage of drugs from blood plasma to milk in goats and cows while almost constant plasma levels were maintained by continuous intravenous infusion. Each of the drugs tested - sulfonamides, antibiotics, barbiturates, antipyrine, ethanol, and urea - exhibited a constant ratio between the concentration in ultrafiltrate of milk and ultrafiltrate of blood plasma. This ratio was found to be independent of both the plasma level and the volume of milk produced during the experimental period. Therefore, the passage can be considered to have taken place by diffusion.

If not all drugs ingested by the nursing nother are excreted in her milk, most are- but usually in insignificant amounts. Occasionally, however, these drugs can be dangerous to the nursing infant. For example, methemoglobin was found in a newborn infant whose mother was treated with phenytoin sodium (Dilantin) for epilepsy.6 This baby did well on donor's breast milk. But when put on his own mother's milk again - while she was still taking Dilantin - the infant became drowsy and developed a grayish-blue discoloration.

However, in another report of several epileptic nursing women taking phenytoin sodium breast milk and colostrum were tested and found to contain lower concentrations than maternal plasma, and an increase in the maternal plasma did not raise the amount of phenytoin sodium in breast milk. There were no discernible effects produced in the nursing infants in this report. In 1956, a number of breast-fed infants died in southeast Turkey when their mothers were poisoned by eating seed wheat treated with hexachlorobenzene, a fungistatic agent. Investigation of the Turkish incident revealed a porphyrin in the urine of affected persons. It is assumed that hexachlorobenzene or one of its metabolites was excreted in the mother's milk and poisoned the infants.

Table

TABLE 1DRUGS EXCRETED IN BREAST MILK

TABLE 1

DRUGS EXCRETED IN BREAST MILK

ANTIBIOTICS AND THE NURSING MOTHER

Since antibiotics are perhaps the most widely used group of drugs in human and veterinary medicine today, they present a particular problem. Antibiotics found in milk are more of an animal than a human problem, since the marketing of milk containing penicillin is prohibited by federal regulation, but because of the treatment of mastitis and other infections in cows with penicillin, residue of this antibiotic in milk occasionally reaches the consumer. In human beings, following the intramuscular injection of 100,000 units of penicillin to nursing mothers, concentrations of penicillin in their milk of 0.015-0.06 U. /ml. (equivalent to serum levels of 0.5-2.0 U. /ml.) have been observed.7 Concentrations of streptomycin in milk of puerperal women are insignificant following intramuscular injection, but they may persist for some time (Table 2).

Levels of novobiocin ranging from 0.36 to 0.54 percent have been observed in breast milk six to 30 hours after an initial oral dose of 500 mg., followed by 250 mg. every six hours. Corresponding blood levels ranged from 1.2 to 5.2 mg. /100 ml. in the mother, determined two hours after administration of the drug.

The administration of 1.0 gm. of oxacillin (Prostaphlin) orally to nursing mothers did not result in a measurable amount of the drug in their breast milk within three and three-quarters hours after ingestion. Five mothers given 500 mg. of tetracycline hydrochloride orally four times daily for three days following premature rupture of their membranes exhibited serum values of 0.9-3.2 mg. /ml. Values in their milk ranged from 20 to 90 percent of serum values, with an average of 70 percent. Levels in the infants' serum were less than 0.07 mg. /ml., which is insufficient to treat an infection.

The concentration of chloramphenicol in breast milk is approximately 50 percent of that in the serum. Blood levels of 26-49 mg. /ml. and milk levels of 16-25 mg. /ml. (half of the blood level) have been found in women treated for scrub typhus in Malaya.

Among other antibacterial agents, sulfanilamide and sulfapyridine in doses of 2 and 3 gm. per day produced milk levels of 3-13 mg./ 100 ml. The in milk are approximately equal to those in the maternal serum. When 3 gm. of nonabsorbable sulfathiazole was administered to one group, the milk contained only 0.5 mg. /100 ml.

Isoniazid appears in breast milk in approximately the same concentration as it does in the maternal serum.8 A linear relationship exists between the dose of isonicotinic acid hydrazide administered and the milk serum concentrations.8 Rifampin, used in the treatment of tuberculosis, diffuses readily in breast milk.

SECRETION OF RADIOACTIVE ISOTOPES IN BREAST MILK

As much as 27 percent of a 10-30-millicurie tracer dose of radioactive iodine administered to a lactating woman may cross the plasma-milk barrier.9 The major portion will appear in milk within the first 24 hours, with smaller traces persisting for several days. This is enough to produce a significant suppressive effect on the infant's developing thyroid gland; therefore breast feeding should be discontinued for a week. Thiouracil given to a lactating woman appears in her milk in a higher concentration than in her blood or urine and could produce goiter in the nursing infant.

If techniques using "technetium are required in nursing mothers, a breast pump should be used for at least three days after the administration of the isotope.10 Studies in a 24-year-old nursing mother undergoing a brain scan showed that a significant amount of radioactive isotope remained in the breast milk for at least 24 hours after administration, and small amounts were detectable after 46 hours. By the third day, no radioactivity was detected in the milk.

OTHER MEDICATIONS INGESTED BY THE NURSING MOTHER

Atropine is contraindicated for nursing mothers because it decreases milk production and may cause intoxication of the infant. However, only minute amounts of atropine (less than 0.1 mg. /100 ml. have been detected in milk when therapeutic doses of 600 mg. were taken orally (not parenterally) by lactating women.

Bromides, diazepam (Valium), anthraquinones (cascara, senna, aloe, danthron [Dorbane]), metronidazole (Flagyl), and ergot ingested by the mother are excreted in her milk and may give rise to symptoms in the infant when large doses - above the average or usual - have been prescribed. Some of these compounds are detoxified by the same mechanism that conjugates free bilirubin and would be particularly hazardous for the icteric nursing infant.

Table

Table 2ANTIMICROBIALS IN BREAST MILK

Table 2

ANTIMICROBIALS IN BREAST MILK

On the other hand, only small amounts - when average normal doses are taken - of morphine, codeine, glutethimide, scopolamine, Phenolphthalein, sulfonamides, antibiotics, nitrofurantoin, tolbutamide (Orinase), mandelic acid, iodides, quinine, salicylates, and many of the psychotherapeutic drugs are found in milk. Hence, these drugs are not ordinarily contraindicated for the nursing mother, except when they are prescribed in unusually large dosage - as might be the case of the nursing mother with rheumatoid arthritis who takes very large doses of salicylates each day. Caffeine may pass into milk but does not seem to affect the baby; about 1 percent of that ingested is found in the infant. A recent report from England has shown that oral anticoagulants (warfarin) taken by the nursing mother were not detectable in the infant's blood or maternal breast milk, indicating that mothers taking warfarin may safely breastfeed their infants.

It is well documented that reserpine in the parturient woman causes severe and sometimes serious nasal stuffiness and blockage in her newborn. If the mother continues to take this drug, it could produce the symptoms in the nursing infant.

Breast feeding alone cannot provide the optimal amount of fluoride for prevention of dental caries.11 It has been demonstrated that lactating women who were drinking water containing 0.55 ppm of fluoride have a level of only a little above 0.1 ppm in their breast milk. Infants, on the other hand, absorb iron more efficiendy from human milk than from cow's milk.

ALCOHOL, TOBACCO, AND MARIJUANA

In regard to alcohol, moderate amounts (say, one or two cocktails a day) are not harmful to the nursing mother or infant.12 Barbiturates in usual doses excreted in breast milk have never been found to affect the nursing infant. 1S

Cigarette smoking raises a question for the lactating mother deserving of special attention. Smoking may reduce the volume of milk excreted, and that is a problem in itself. Lactating women who smoke from 10 to 20 cigarettes a day pass along 0.4-0.5 mg. of nicotine in each liter of milk.14 By Clark's rule, this is the equivalent of 6-7.5 mg. of nicotine in the adult. While this is but one-tenth of the lethal dose, 4 mg. taken orally has been known to produce alarming symptoms in adults. This is, of course, less than the heavysmoking mother passes on to her infant. I have already mentioned the fact that, all other factors being comparable, women who smoke excessively have smaller babies than nonsmokers.

The most active component of marijuana, tetrahydrocannabinol (THC), is fat-soluble, and it is likely to appear in breast milk.15 However, the long-range effects on the infant of this toxin have not yet been documented. In the marijuana smoker the pulse rate, blood pressure, and blood sugar levels all rise. The eyes are reddened, and the urge to urinate increases. This is a clear pattern of pansystemic intoxication.16 What can this potent drug do to a 10-pound baby even in minuscule amounts? Animal (rat) experiments at Duke University have clearly indicated that THC inhibits the secretion of luteinizing hormone, which interferes with conception in some animals.

ORAL CONTRACEPTIVES

Oral contraceptives pose a special problem of their own for the nursing mother.17 Little is known about the excretion of hormones in milk. The excretion in milk of ingested thyroid drugs has not been well documented. Studies18 of lactating rats given cortisone revealed a significant retardation of growth and development in litters suckled by rats receiving 20 mg. of cortisone per day, but valid human data are lacking. It is reasonable to expect that the continued use of such hormone combinations as the oral contraceptives would have unbalancing effects on the developing endocrine system of a suckling baby. For one thing, from a practical standpoint, oral contraceptives - that is, progestin-estrogen combinations of drugs - might inhibit lactation.19 Gynecomastia has been reported in one nursing male infant whose mother was taking combined estrogens.20 The Jong-range effects of oral contraceptives on a nursing infant could be considerable.

ENVIRONMENTAL POLLUTANTS AFFECTING BREAST MILK

Finally, the nursing mother, like everyone else, is exposed to environmental toxicants. The fact that DDT is present in all human milk - and breast milk contains more DDT than does cow's milk - has been recognized for years.21 However, there has been no increase in these worldwide values, even though many studies show considerable variations in their reports. Significant amounts of lead have been found in bulk-pasteurized milk and in canned milk products. Breast milk, on the other hand, contains little or no detectable lead.

Human breast milk also contains cadmium, but to a minimal degree. Animal studies show cadmium to be selectively retained within mammary tissue and thus prevented from incorporation in milk. Methyl mercury is excreted in breast milk and may produce symptoms (Minamata disease in Japan). Polychlorinated biphenyls (PCBs) have wide industrial uses, and PCB contamination is found to be almost universal, including presence in human adipose tissue, brain and liver, and human milk. Little is known about the toxic effects of PCBs in breast milk at present, however.22

CONCLUSION

Nearly all compounds ingested by the lactating mother are excreted in her milk to some degree in some form. In most instances they are excreted in such small amounts as to be barely detectable; when this is the case, there is no significant hazard.

The following substances should be avoided while breast-feeding: any drug or chemical taken in excessive amounts, diuretics (although chlorothiazide appears to be a safe diuretic for the nursing mother), atropine, reserpine, steroids, radioactive preparations, hallucinogens, bromides, diazepam, antithyroid drugs, anthraquinones, dihydrotachysterol, antimetabolites, and (perhaps) oral contraceptives.

Breast feeding is contraindicated in mothers with illnesses that require large doses of any drug and also in those using a new and unusual drug. These limitations, however, should in no way discourage the majority of mothers requiring medication who want to breast-feed. When the possibility of potential harm for the nursing infant exists, the offending drug can usually be discontinued or reduced in dosage or the chemical removed from the mother's immediate environment.

The cytomegalic and other viruses have been found recently in breast milk. The significance, if any, of this is as yet unclear.

REFERENCES

1. Arena, J. Contamination of the ideal food. Nutr. Today (Winter, 1970), 2-8.

2. Catz, C, and Giacoia, G. Drugs and breast milk. Pediatr. Clin. North Am. 19 (1972), 151-166.

3. Knowles, J. Excretion of drugs in milk - a review. /. Pediatr. 66 (1965), 1068-1082.

4. O'Brien, T. Excretion of drugs in human milk. At». J. Hosp. Pharm. 31 11974), 844-854.

5. Rasmussen, F. Studies on the Mammary Excretion and Absorption of Drugs. Copenhagen: C. Fr. Martenson, 1966.

6. Mirkin, B. L. Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism and possible teratogenic effects. J. Pediatr. 78 (1971), 329-337.

7. Lipman, A. Antimicrobial agents in breast milk. Mod. Med. 45 (1977), 89.

8. Berlin, CM., and Lee, C. Isoniazid and acctylisoniazid disposition in human milk, saliva, and plasma. Fed. Proc. 38 (1979), 426.

9. Nurnberger, C, and Lipscomb, A. Transmission radioiodine (I"1) to infants through human maternal milk. J. A.M. A. ISO (1952), 1398-1400.

10. Wyburn, J. R. Human breast milk excretion of radionuclides following administration of radiopharmaceuticals. /. Nucl. Med. 17 (1976), 1055.

11. Stone, O., and Willis, C. The effect -of stannous fluoride and stannous chloride on inflammation. Toxic Appi. Pharmacol. 13 (1968), 332-338.

12. Kesäniemi, Y. Ethanol and acetaldehyde in the milk and peripheral blood of lactating women after ethanol administration. J. Obstet. Gynec. Br. Comm. 81 (1974), 84-86.

13. Burler, T. C, Mah afee, C, and WaddeJl, W. J. Phénobarbital· studies of elimination, accumulation, tolerance, and dosage schedules. /. Pharmacol. Exp. Ther. Ill (1954)^425-435.

14. American Academy of Pediatrics Committee on Environmental Hazards. Effects of cigarette-smoking on fetus and child. Pediatrics 57 (1976), 411-413.

15. Krenz, D., and Axelrod, J. Deita-9-tetrahydrocannabínol localization in body fat. Science 179 (1973), 391-392.

16. Nahas, G., and Paton, W. (eds.): Marijuana: Chemistry, Biochemistry and Cellular Effects. New York: Springer- Verlag, 1976.

17. Barsivala, V., and Virkar, K. The effect of oral contraceptives on concentrations of various components of human milk. Contraception 7 (1973), 307-312.

18. Mercier-Parot, L. Disturbance in postnatal development of rats after maternal administration of cortisone. Comp. Rend. 240 (1955), 2259.

19. Kora, S. Effect of oral contraceptives on lactation. Fértil. Steril. 20 (1969), 419-423.

20. Curtis, E. M. Oral contraceptive feminization of a normal male infant. Obstet. Gynecol. 23 (1964), 295.

21. Bakken, A., and Seip, M. Insecticides in human breast milk. Acta. Pediatr. Scand. 65 (1976), 535-539.

22. Poland, R. L., and Cohen, S. N. The contamination of the food chain in Michigan with PBB: the breast-feeding question. In Schwarz, R. H., and Yaffee, S. J. (eds.): Drugs and Chemical Risks to the Fetus and Newborn. New York: Alan R. Liss, 1980, pp. 129-137.

TABLE 1

DRUGS EXCRETED IN BREAST MILK

Table 2

ANTIMICROBIALS IN BREAST MILK

10.3928/0090-4481-19801201-05

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