Drugs in breast milk: A scientific explanation

Drugs in breast milk: A scientific explanation

OBJECTIVES Based on the content of the article, you will be able to: 1. Describe the physiology of lactation. 2. List factors that influence breast mi...

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OBJECTIVES Based on the content of the article, you will be able to: 1. Describe the physiology of lactation. 2. List factors that influence breast milk production. 3. List selected medications that are known to be contraindicated for use by lactating women. 4. Calculate the amount of a drug that is likely to be transferred from maternal plasma to breast milk. See page 236 for instructions.

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reast-feeding in the United States has increased over the past 25 years (Hoekelman, 1992; Martinez, & Krieger, 1985; Wright, Rice, & Wells, 1996). This has occurred because women and their health care providers are better educated about the benefits of breast-feeding, but the incidence of breastfeeding appears higher in hospitals that have positive breast-feeding practices (Wright et al., 1996). For example, 63% of all newborn infants were breast-fed in a breastfeeding-friendly hospital before discharge versus 52% where hospital practices were not specified (Hoekelman, 1992; Martinez & Krieger, 1985; Wright et al., 1996). The incidence of total breast-feeding dropped to 15.9% at 4 months of age and to 28.1% for infants who were breast- and bottle-fed at the same age (Wright et al., 1996). Reported benefits for breast-fed infants include increased bonding

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with their mothers, nutritional advantages, and protection against infections such as gastrointestinal illness and respiratory infections including otitis media (Lawrence, 1989; Sagraves, Kamper, & Doerr, 1996). Many of these positive effects are associated with the presence of immunologic factors in human milk (Lawrence, 1989; Sagraves et al., 1996). Conflicting data exist about a positive association between breast-feeding and the incidence of urinary tract infections, bacteremia and meningitis, allergies, obesity, and anemia in infants (Kovar, Serdula, Marks, & Fraser, 1984). Because some women who wish to breast-feed have acute or chronic health probReprint requests: Rosalie Sagraves, PharmD, Chicago, IL 60612. J Pediatr Health Care. (1997). Copyright

lems that may require medication use to improve maternal wellbeing, health care professionals may need to make decisions about maternal medication use. For example, a health care provider may need to evaluate a specific medication or pharmaceutical classes of drugs to determine product safety in an infant when used by a lactating woman, whether nursing should be interrupted during maternal medication use, or whether an alternative medication should be recommended.

PHYSIOLOGY OF LACTATION Health care providers should have an appreciation of the lactation

FCCP, College of Pharmacy,

University

of Illinois at Chicago,

II, 230-237.

0 1997 by the National Association

of Pediatric Nurse Associates

& Practitioners.

0891.5245/97/$5.00+025/8/83857

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process to better understand how medications are distributed to human milk. Physiologically, women’s breasts are prepared for lactation through mammogenesis (development and maturation of the breasts that begins embryonically and ends with pregnancy), lactogenesis (milk secretion that begins during pregnancy and increases at the time of delivery), and galactopoiesis (establishment of lactation) (Lawrence, 1989). During pregnancy the development and maturation of mammary tissue is under the control of placental lactogen, prolactin, and chorionic gonadotropin, whereas the formation of ducts and lobular growth in the breasts are under the influence of increased estrogen and progesterone concentrations. The role of prolactin in the production of human milk is not totally understood, but it is vital to this process (Lawrence, 1989). It appears that prolactin stimulates the production and secretion of breast milk, whereas oxytocin stimulates the contraction of the myoepithelial cells that surround breast alveoli. Milk then goes into the ducts to be ejected. Thereafter, the “letdown reflex” occurs, and milk is expelled from the breast. Adrenocorticotropic hormone, cortisol, growth hormone, insulin, and thyroxin are needed for milk production and secretion, but their roles are not totally understood (Lawrence, 1989; Wilson, 1981). Maternal medication use can alter milk production by affecting hormones that control the lactation process. For example, bromocriptine decreases prolactin secretion, whereas the ingestion of an amphetamine, methyldopa, a phenothiazine, or theophylline may have the opposite effect (Wilson, 1981). Anxiety, stress, and pain inhibit the ejection of milk by decreasing oxytocin concentration. Breast milk production ranges from 600 to 1000 ml per day, with the maximum daily milk volume

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BOX BREAST

1 EXOGENOUS

INFLUENCES

l l l l

OF

MILK

Maternal l

ON THE PRODUCTION

Amount of subcutaneous fat Nutritional status Single versus multiple births Return of menses Stress

Infant l l l l l

Age Body weight Sucking pattern Stress Behavior

Data from Wilson, J.T. (1981). Drugs in breast milk. Australia: ADIS Press.

occurring at approximately 0600 and the lowest between 1800 and 2200 (Jelliffe & Jelliffe, 1978; Wilson, 1981). Other milk volume alterations are related to the amount of time a woman spends in nursing her infant and infant-dependent factors such as an increased need for nutrition as the infant grows and matures. Marked alterations in cardiac output and blood flow to a mother’s breasts during lactation also can affect the volume of milk produced. For example, maternally ingested drugs that can reduce blood flow (e.g., those with vasoconstrictor properties) can potentially decrease milk volume (Kirksey & Groziak, 1984). Similarly, milk production can be adversely affected by maternal stress, anxiety, or pain. Blood flow to the breasts can diminish as menses returns. The composition of breast milk is physiologically unique for the young of each species, but it also changes with time to meet the nutritional needs of an infant as he or she grows and matures. The breast-fed infant receives “colos&urn” during the first week of life. This clear yellow-colored fluid is high in protein but low in fat and carbohydrate (lactose) content compared with “mature milk.” Colostrum also contains high concentrations of immunoglobulins such as secretory immunoglobulin A. During the first month after birth there is a shift in milk compo-

sition from colostrum to that of mature milk. This shift primarily involves a decrease in protein and increases in lactose and fat. The milk produced during this shift in milk composition is termed “transitional milk.” Mature milk is an emulsion that is 88% to 95% water with protein and carbohydrate found in its aqueous portion (Murray & Seger, 1994). Fat makes up the remainder of the emulsion. Approximately 0.9% of mature human milk is protein, of which 60% is whey (e.g., lactalbumin and lactoferrin) and the remainder casein (Murray & Seger, 1994). Lactose comprises approximately 7% of the milk content and fat 3.8% (Murray & Seger, 1994). The fat and lactose content of human milk varies with the letdown reflex, maternal nutrition, and whether fore or hind milk (i.e., fore milk occurs at the beginning of a nursing session and hind milk at the end) is analyzed. It has also been shown that the fat content is highest at the midpoint of the nursing interval. At that time breast milk changes from a thin, clear to a thick, creamy fluid. The concentration of a maternally used medication in breast milk is influenced by milk production and changes in fat and other milk constituents with the age of the infant and within the nursing period. Exogenous influences may also affect breast milk production (Box 1).

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MECHANISM AND DETERMINANTS GOVERNING DRUG EXCRETION IN HUMAN MILK After a drug is ingested orally, applied topically, or received intravenously or intramuscularly, it enters the maternal circulatory system, from which it is transported to other parts of the woman’s body including her breasts. Most drugs are transported from the maternal circulation into breast milk by passive diffusion. Fat-soluble drugs that are un-ionized easily cross semipermeable lipid membranes to gain access to human milk by passive diffusion (Wilson, 1981). A few water-soluble compounds such as ethanol and lithium that have a low molecular weight (MW) diffuse into human milk through small water-filled pores. Other factors that affect the excretion of a drug into breast milk may be categorized as maternal, breast, and infant. Maternal factors include the dose, frequency, and route of maternal drug administration and the pharmacokinetics and pharmacodynamits of the drug in the lactating woman. One must remember that during pregnancy and the initial postpartum period, a woman’s body undergoes dramatic physiological changes. Therefore the pharmacokinetics of a drug administered to a lactating woman may be much different immediately after birth than several weeks or months later, when the physiological effects of pregnancy have waned. Some of these changes include a decline in the maternal blood volume after birth after it was increased during pregnancy by up to 40%, a change in cardiac output, which can be increased as much as 30% during pregnancy, and an increasing albumin concentration that declines during pregnancy (Cheek & Gutsche, 1987; Nation, 1980.)

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Volume

11 Number

5

In addition, drug elimination changes dramatically in the immediate postpartum period. Alterations in renal function (e.g., renal blood flow, glomerular filtration rate, creatinine clearance) during pregnancy affect the cIearance of renally eliminated drugs (Nation, 1980). After delivery, maternal renal function returns to prepregnancy levels. Blood flow increases to the breasts after birth. In addition, changes in the composition of breast milk from the immediate postpartum period through the weaning process may markedly affect drug excretion into breast milk. Therefore drug concentrations in maternal blood and milk weeks or months after birth may not be applicable to the early postpartum period. Later during the weaning process, marked changes in the composition of breast milk may affect drug excretion and change drug concentrations in breast milk. Breast factors that affect the ability of a drug to gain access into breast milk include blood flow to the breasts, pH of maternal plasma and milk, drug ionization, protein binding in breast milk, drug metabolism in breast milk, and the possible reabsorption of a drug or metabolites from breast milk back into the maternal circulation. In addition, it is important to know whether we are talking of drug passage into colostrum, transitional milk, or mature milk, because the percentage of the drug present in breast milk varies with milk composition. The amount of drug transferred from maternal plasma to breast milk and the rate at which this process occurs depends on drug characteristics such as MW, maternal plasma and breast milk protein binding, lipid solubility, pKa, which helps determine the ionization of a drug at specific plasma and milk pHs, and the difference in pH between maternal plasma and

breast milk. Typically a low-molecular weight, unionized, lipid-soluble basic compound that has low plasma protein binding can cross into human milk with relative ease (Wilson, 1981). Based on MW alone, most drugs can cross biologic membranes into breast milk to some degree, with only high MW drugs such as heparin (MW approximately 15,000) being too large to cross. Medications that are highly protein-bound in plasma are restricted from leaving the maternal plasma for breast milk. In addition, the lipid solubility of a drug helps determine its ability to penetrate a semipermeable lipid membrane. The parent drug, more than its metabolites, is likely to be transferred from the maternal plasma to breast milk, because its metabolites are usually polar, ionized compounds that poorly cross biologic membranes. Henderson-Hasselbach equations for acidic and basic substances can be used to determine the milk/ plasma (M/P) ratio for free un-ionized drugs based on the pKa of the drug and the pHs of maternal plasma and milk (Wilson, 1981). Acidic Drug:

Basic Drug: Mu,pu

= 1 + 10’ph-pH-’ 1 + [email protected]~-P%)’

where MuiPu is the ratio of an unionized drug in maternal milk versus plasma pHm = pH of milk pHP = pH of plasma. The pH of human milk (range, 6.35 to 7.65; average, 7.2) is more acidic than maternal plasma. Based on Henderson-Hasselbach equations, the M/P ratio for the free unbound portion of a basic drug should theoretically be >l, whereas the M/I’ ratio for the free unbound portion of an acidic drug (e.g., acetaminophen) should be
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Begg, & Darlow, 1988; Wilson, 1981). For example, a basic drug such as erythromycin attains a higher concentration in breast milk than acidic drugs because it has a higher rate of entry and a lower propensity to be reabsorbed back into maternal plasma (Briggs, 1995). Most drugs have M/P ratios of 0.5 to 1, which suggests that less than 1% of a maternal dose is available for absorption by her infant (Murray & Seger, 1994). Lipid-soluble drugs such as diazepam and phenytoin concentrate in the lipid phase of human milk. Therefore when a drug concentration or M / I’ ratio is determined for a highly lipid-soluble drug, it must be noted whether whole or only the lipid portion of the milk was used to determine the drug concentration (Atkinson et al., 1988). Infant factors that should be considered when determining the amount of maternal drug that is available for absorption by abreastfed infant include sucking pattern, number of daily feedings, time he or she spends nursing, milk volume consumed per feeding, theoretic absorption of the drug by the infant, and the pharmacokinetics of the drug in infants (Wilson, 1981). The amount of drug absorption from ingested breast milk depends on the infant’s gastric pH, gastric emptying time, intestinal transit time, and bile acid and pancreatic enzyme production. If absorbed, the effect of the drug on the neonate will depend on the dose absorbed and the pharmacokinetics and pharmacodynamics of the drug in infantsterm and premature.

METHODS TO ESTIMATE THE CONCENTRATIONS OF DRUGS IN BREAST MILK AND POTENTIAL INFANT DRUG EXPOSURE Information about drugs in breast milk and their availability for ingestion by breast-feeding infants

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BOX 2

QUESTIONS

THAT

NEED TO BE ADDRESSED BEFORE BEGINNING DRUG THERAPY IN A NURSING

MOTHER

1. Is the drug necessary? 2. How long will the mother need the drug and at what doses? 3. IS the selected drug commonly used for treating pediatric patients? 4. Are there any known toxicities from the drug that have been reported in nursing infants? 5. Are there any long-term effects that have been reported to occur in nursing infants or children? 6. Is there any information known about drug concentrations in breast milk? 7. What is known about the pharmacokinetics of the drug in nursing women, women in general, or in men? 8. Can the drug be absorbed by a breast-feeding infant? If so, what pharmacokinetic information is known about the drug in infants? 9. Are there alternative drugs that might be used by the mother that do not appear in breast milk, are found in breast milk in lower concentrations, or produce fewer adverse effects in infants who are breast-fed? 10. Can the drug have an effect on the mother’s milk supply?

is not easily available for all drugs. Therefore health care providers must evaluate the available literature and use equations, known maternal milk and plasma concentrations for specific drugs, and physiochemical models to estimate drug concentrations in breast milk.

An M/P ratio is often used to estimate the amount of maternal drug that may be delivered to her breastfeeding infant. Two common ways to determine a M/P ratio are the point method and the area under the curve method. With the point method an M/P ratio is determined by dividing the amount of drug in breast milk at a particular time by the amount of drug in the same individual’s plasma at the same time. This method may not be accurate because the drug concentration versus time profile in the maternal milk and plasma may not always be parallel. For example, milk concentrations may lag behind plasma concentrations. This method can be used to estimate the concentration of drug in maternal milk at the time the peak plasma concentration occurs, if the time that this peak occurs is known (Anderson, 1991; Atkinson et al., 1988). This method can also be used to determine the concentration of a drug in breast milk before the next maternal dose, if milk and plasma concentrations are obtained before maternal dosing and an M/P ratio for the drug is known. An M / P ratio determined with the area under the curve for milk and plasma concentrations versus time curves is more accurate. It can be used to help predict an average drug concentration in breast milk at steady-state (Anderson, 1991). Equation 1 can be used to help determine the concentration of a drug in breast milk. Equation 1 (Atkinson et al., 1988). Ca, = Gatema, p~asma x Ml P ratio Cd = milk concentration C maternalplasma= maternal plasma concentration

Equation 2 is useful in estimating the percentage of a maternal drug dose that potentially could be ingested by the breast-feeding infant. To do this estimation, the volume of milk ingested and the maternal milk concentration at a

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BOX 3 DRUGS CONTRAINDICATED Amphetamine* l Bromocriptine l Cocaine* l Cyclophosphamide . Cyclosporine l Doxorubicin l Ergotamine

. Heroin* . Lithium l Marijuana* l Methotrexate l Nicotine from cigarette smoking l Phencyclidine (PCP)* l Phenindione

l

*Substance

WHEN BREAST-FEEDING

particular point in time must be known. Atkinson et al. (1988) used 150 ml/ kg/ day as the typical volume of milk ingested by a breastfeeding infant. Equation 2 (Atkinson et al., 1988).

based on physical and chemical properties of various drugs. For more information about modeling, the reader can turn to the following references: l

c,, xv,, x 100 D maternal Cmilk= concentration in

% maternal dose =

maternal milk Vmilk = volume of maternal milk D mat-TId = maternal drug dose

Equation 3 may be used to estimate the dose that an infant can ingest if the mother’s steady-state plasma concentration for the drug can be calculated atid if an M/P ratio determined by the area under the curve method is known. For milk volume 150 ml/kg / day can be used as the typical volume ingested (Atkinson et al., 1988). Equation 3 (Atkinson et al., 1988). Dose = C, x x/I / PnUc x V,,

C,, = maternal steady-state plasma concentration M / PAUc= milk to plasma ratio calculated using areasunder the concentration versus time curves for maternal milk and plasma V,,k = volume of maternal milk

inml/kg/day Mathematic models have been developed to help predict the transport of drugs into breast milk

Volume

11 Number

SHOULD BE USED CAUTIOUSLY BY NURSING MOTHERS l l l l l

of abuse.

Data from Briggs, C.C. (1995). Drugs in pregnancy and lactation. In Y.L. Young & M.A. Koda-Kimble (Eds.), Applied therapeutics (6th ed.). Vancouver, WA: Applied Therapeutics, Inc., 45-l -39; American Academy of Pediatrics Committee on Drugs. (1994). Transfer of drugs and other chemicals into human milk. Pediatrics, 93, 137-150; and Murray, L., & Seger, D. (1994). Drug therapy during pregnancy and lactation. Emergency Medicine Clinics of North America, 72, 129-149.

2 34

BOX 4 DRUGS THAT

5

l

l

Atkinson, H.C., & Begg, E.J. (1988). The binding of drugs to major human milk whey proteins. British Journal of Clinical Pharmacology, 26,107-109. Atkinson, H.C., Begg, E.J., & Darlow, B.A. (1988). Drugs in human milk: Clinical pharmacokinetic considerations. Clinical Pharmacokinetics, 14,217-240. Fleishaker, J.C., Desai, N., & McNamara, l?J. (1987). Factors affecting the milk-to-plasma drug concentration ratio in lactating women: Physical interactions with protein and fat. Journal of Pharmaceutical Sciences,76,189-193.

HOW TO MINIMIZE DRUG EXPOSURE IN A BREASTFED INFANT In most cases maternal drug use poses little risk to a nursing infant, and there is rarely a need to temporarily suspend or discontinue breast-feeding because of a woman’s need to use a medication. A risk associated with the ingestion of a particular drug by an infant may be reduced by altering the nursing schedule. If a lactating

l

5-Aminosalicylic Aspirin Clemastine Phenobarbital Primidone Sulfasalazine

acid

Data from American Academy of Pediatrics Committee on Drugs. (1994). Transfer of drugs and other chemicals into human milk. Pediatrics, 93, 137-150.

woman needs drug therapy, the following may be considered to help minimize an infant’s intake of a drug being used by his or her mother (Anderson, 1991). 1. When possible, select a route for maternal drug administration other than the oral route to minimize infant exposure (e.g., use a topical drug or inhaled product). 2. If possible, select a drug that does not easily distribute into breast milk (i.e., select a drug from a particular class that has the lowest concentration in breast milk or is the least toxic to an infant). 3. Possibly, the lactating woman can take the drug in a single daily dose so that there is more knowledge about drug peaks and troughs. 4. If multiple doses are needed, the lactating woman should try to adjust the infant’s feeding schedule so feedings occur at troughs rather than peak drug concentrations. 5. Monitor the breast-feeding infant for signslsymptoms of drug toxicity. 6. lf there is concern about infant toxicity, infant serum or urine drug concentrations may be obtained, if possible, for the drug in question. 7. lf a short course of an undesirable drug is necessary for maternal well-being, breast-feeding might

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l

BOX 5 DRUGS/CHEMICALS THAT REQUIRE NURSING TO BE TEMPORARILY STOPPED l l

l

Metronidazole Radiopharmaceuticals

Adapted from Briggs, C.G. (1995). Drugs in pregnancy and lactation. In Y.L. Young & M.A. Koda-Kimble (Eds.), Applied therapeutics (6th ed.). Vancouver, WA: Applied Therapeutics, Inc., 45-l -39; and American Academy of Pediatrics Committee on Drugs. (1994). Transfer of drugs and other chemicals into human milk. Pediatrics, 93, 137-150.

l

l

Atkinson, H.C., Begg, E.J., & Darlow, B.A. (1988). Drugs in human milk: Clinical pharmacokinetic considerations. Clinical Pharmacokinetics, 14,217-240. Begg E.J., & Atkinson, H.C. (1993). Modeling of the passage of drugs into milk. Pharmacology and Therapeutics, 59,301-310. Briggs, G.G., Freeman, R.K., & Yaffe, S.J.(1994). Drugs in pregnancy and lactation (3rd ed.). Baltimore: Williams &Wilkins. Wilson, J.T. (1981). Drugs in breast milk. Auckland, New Zealand: ADIS Press.

Hoekelman,

R.A. (1992).

breast-feeding

D.B., & Jelliffe,

Boxes 2 to 5 address drug-use considerations and drugs that lactating women should avoid or use with caution. For additional information about the transfer of medications into breast milk, the reader may wish to turn to the following articles and textbooks. l

l

American Academy of Pediatrics Committee on Drugs (1994). Transfer of drugs and other chemicals into human milk. Pediatrics, 93,137-150. Anderson, P.0. (1991). Drug use during breast-feeding. Clinical Pharmacy, 10,594-624.

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American

and composition

poorly

nourished

view.

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and

other

(1994).

chemicals

Pediatrics,

Commit-

Transfer into

human

Drug

use

milk.

93,137-150.

Anderson,

P.O.

Clinical

during

Kirksey,

H.C.,

Phurmacy,

& Begg,

of drugs

whey

proteins.

10,

Atkinson,

Begg,

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E.J., & Darlow,

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considerations.

(Eds.),

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Therapeutics, T.G.,

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&

Levinson

In

(1987).

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plasma

drug

tating

women:

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Vancouver,

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during

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&

Kovar,

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of risks Review

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(1984).

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between

and

feeding

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of the epi-

for an association

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infant

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in the U.S. Pedi-

L., & Seger, D. (1994).

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pregnancy

and

obstetrics

Williams

& Wilkins.

N., & McNamara, affecting

concentration Physical

protein and fat. Journal Sciences, 76,189-193.

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therapy

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kinetics

in child-

12,129-149. Nation,

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In T.R. CovingWashington

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tion. Wilson,

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be interruptedforfour orfive drug half-lives (give the infant previously expressedbreast milk during this time period); then resume breast-feeding. The woman can pump her breasts during the time she is taking the medication and discard her milk. Pumping the breasts will help prevent breast engorgemen t and maintain breast milk flow. 8. May be able to delay starting maternal drug therapy if the infant is to be weaned soon.

rates.

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