BREASTFEEDING 2001, PART II:

THE MANAGEMENT OF BREASTFEEDING 0031-3955/01 $15.00 + .00

XENOBIOTICS AND
BREASTFEEDING
Cynthia R. Howard, MD, MPH, and Ruth A. Lawrence, MD

Breastfeeding is vital to the health and well-being of mothers and infants.

It is acknowledged by the American Academy of Pediatrics (AAP), the American
College of Obstetricians and Gynecologists, the American Academy of Family
Physicians, the Institute of Medicine of the National Academy of Sciences, and
the World Health Organization as the optimal way to nourish an infant.32,n.63,74.75
Concerns about the safety of breastfeeding, however, commonly arise around
the issue of maternal drug use and subsequent risks for the nursing infant.
Pediatricians often are asked to assess the safety of not only over-the-counter and
prescription medications but also herbal remedies and relatively contraindicated
substances, such as tobacco and alcohol. Which drugs are safe during breastfeed-
ing? When medications are needed, how maya physician select an effective
drug while minimizing exposure for the nursing infant? This article provides
guidance for pediatricians about these issues.

PREVALENCE OF DRUG USE DURING BREASTFEEDING

Prescription and Nonprescription Drugs

Medication and drug use during lactation is common.' In a study of 14,000

pregnant or breastfeeding women, most (79%) used at least one medication,
with an average of 3,3 different drugs used during the course of breastfeeding."
Little information exists regarding the use of herbal remedies and teas during
breastfeeding. Calls to lactation-consultation services, however, are increasingly

From the Divisions of General Pediatrics (CRH) and Neonatology (RAL), Departments of
Pediatrics (CRH, RAL) and Obstetrics and Gynecology (RAL), University of Rochester
School of Medicine and Dentistry; the Mother-Baby Unit, Rochester General Hospital
(CRH); and The Breastfeeding and Human Lactation Study Center, Strong Memorial
Hospital (RAL), Rochester, New York

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 48 • NUMBER 2 • APRIL 2001 485

486 HOWARD & LAWRENCE

common, and one third to one half of adults in the United States, Canada, and
Australia use complementary and alternative medical care that may include the
use of herbal rernedies.> 36

Alcohol, Tobacco, and Illicit Drugs

Few sources of nationally representative data exist regarding the prevalence

of alcohol, tobacco, and illicit drug use during breastfeeding. Substance use
during pregnancy is highly correlated with continued use during lactation.
Among smoking women, less than one third of those who quit smoking during
pregnancy remain abstinent." Although the clinician might expect the rate of
breastfeeding initiation to be low among substance-using women, data from the
1988 National Maternal Infant Health Survey indicate that women with moder-
ate alcohol use « 6 drinks/wk) and marijuana or hashish use are equally or
more likely to choose to breastfeed. These data indicate a tendency toward
shorter breastfeeding duration in women who used tobacco, marijuana, and
cocaine, but infants were breastfed and exposed to these drugs through breast
milk for substantial time periods (2-3 mo)." Breastfeeding may be important in
supporting abstinence for mothers with a history of substance use. Evidence
shows that, for mothers who quit smoking during pregnancy, breastfeeding may
enhance their resolve for continued abstinence."

ADVISING BREASTFEEDING MOTHERS

Infants rarely experience severe adverse effects because of medications in

breast milk. In a study of 838 infants exposed to medications through breast
milk." no infants experienced a reaction requiring medical attention or
breastfeeding cessation, but 11% experienced minor reactions. Analgesics, antibi-
otics, antihistamines, and sedatives were the most commonly used medications,
with 20% of mothers exposed to more than one medication. The rate of adverse
reactions was slightly higher when multiple medications were used (15.7%
versus 10.1%) (Table 1). These data indicate that, for most drugs, short-term
clinical effects are insubstantial and breastfeeding should be continued. Transient
and minor effects pharmacologically consistent with the drug in question may
be expected in many as 11% of nursing infants.
Safety concerns may cause a woman to be noncompliant with therapy or to
wean her infant prematurely. In a prospective study of 203 women who con-
sulted a breastfeeding information service and were reassured that continued
breastfeeding was safe during antibiotic therapy," 15% did not initiate therapy,
and 7% discontinued breastfeeding. A careful discussion of the indications for
drug therapy and of the safety and importance of continued breastfeeding may
help to avert such problems.
Although the medicinal properties of herbs have been documented for
centuries, scientific investigations of therapeutic effects are limited. Even less is
known about the presence of pharmacologically active substances in breast milk.
Table 2 lists some of the concerns presented by the therapeutic use of herbs.
The US Food and Drug Administration categorizes approximately 250 herbs,
including chamomile, garlic, ginger, ginseng, and valerian, as generally recog-
nized as safe." Teas that are considered safe during lactation include chicory,
orange spice, peppermint, raspberry, red bush tea, and rose hips.?" Mother's
milk tea, a blend of plants recommended for generations as a galactagogue,
 Table 1. INCIDENCE OF ADVERSE REACTION IN BREASTFED INFANTS ACCORDING TO CATEGORY OF MATERNAL MEDICATION

Minor Adverse Reactions

Components of Minor Adverse Reactions (No. of Infants)
Maternal Drug Exposure No. of Infantsl
Group Total No. Percentage Diarrhea Drowsiness InitabiIity Miscellaneous

Including multiple exposures"

Antibiotics 32/166 19.3 21 2 5 4
Analgesics 22/196 11.2 3 11 4 4
Antihistamines 8/85 9.4 1 1 6 0
Sedatives 3/42 7.1 0 2 1 0
Miscellaneoust 43/435 9.9 13 8 14 8
Excluding multiple exposures
Antibiotics 22/119 18.5 14 0 4 4
Analgesics 13/134 9.7 0 7 3 3
Antihistamines 7/60 11.7 0 1 6 0
Sedatives 1/29 3.4 0 1 0 0
Miscellaneoust 25/330 7.6 3 4 10 8

"Note that sums of number of infants with adverse reactions (108) and total numbers of infants (924) are greater than those in text (those with adverse outcomes per
total numbers 94/838) owing to overlapping exposures.
tSevera1 combination drugs are included in this group.
From Ito S, B1ajchman A, Stephenson M, et a1: Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol
168:1393-1399, 1993; with permission.

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i Table 2. HERBS AND US FOOD AND DRUG ADMINISTRATION (FDA)-APPROVED DRUGS: SIMILARITIES AND DIFFERENCES

Factor Legal Medications (FDA-Approved) Herbal Therapies

Mechanism Biochemical Biochemical

Origins 25% Plant origin Raw plants
Efficacy Evidence required, but not always based on Proof not required
well-controlled trials
Safety Must be well studied, within acceptable limits, Evidence of safety not required and often unavailable
and detailed on drug label or insert
Burden of proof with FDA to show herbal therapies unsafe
Dose Established, usually by dose-response studies Some guidelines exist, usually based on historical precedent or tradition,
occasionally based on dose-response in clinical trials
Standardized products are preferential and available for some herbs (e.g., garlic,
ginkgo, St. John's wort, saw palmetto, and valerian)
Not necessarily standardized by content of active ingredients, which are often
unknown
Pharmacokinetics Usually well characterized Rarely known
Potency Standardized Varies with genetics, growing conditions, time harvested, plant part used,
preparation, and storage
Proof of purity Required Varies greatly
High potential for contamination; history of case reports
Identification Some confusion possible with coexistence of Problematic, beginning with misidentification of plants at harvesting
generic and multiple trade names Products should be labeled with and chosen by scientific name (genus species,
e.g. Echinacea purpurea is the most used and studied; Echinacea
species-many of its common names are shared by other plants)
Quality control Required Not required
Improving with self-regulation by herb industry
Cost Wide range Highly variable
Elevated for patented drugs Extracts are the most concentrated and cost-effective
Insurance coverage Often Rarely

From O'Hara M, Kiefer 0, Farrell K, et al: A review of 12 commonly used medicinal herbs. Archives of Family Medicine 7:523-536, 1998; Copyright 1998, American
Medical Association.
 XENOBIOTICS AND BREASTFEEDING 489

contains several ingredients that are pharmacologically active and may affect
the infant. The tea is a blend of fennel seeds, coriander seeds, chamomile
flowers, lemongrass, borage leaves, blessed thistle leaves, star anise, comfrey
leaves, and fenugreek seeds (Table 3).40
Advising women with a history of illicit drug use about breastfeeding is
difficult. Street drugs lack pharmacologic standardization and may be contami-
nated with other active agents, bacteria, heavy metals, or pesticides. The possibil-
ity of polysubstance use also must be assessed.s- 27, 53 In the case of a woman
with an ongoing drug problem, the risks posed to the infant outweigh the
benefits of breastfeeding. For a woman in treatment for substance abuse and
who remains abstinent, breastfeeding support, close monitoring of the mother
for relapse and the infant for adequate weight gain, and frank discussions with
the mother about the risks posed to the infant by exposure to illicit substances
through breast milk are essential. For other relatively contraindicated substances,
such as nicotine and alcohol, limited use may be compatible with continued
breastfeeding because the benefits outweigh the risks.

MATERNAL, INFANT, AND DRUG FACTORS

THAT INFLUENCE THE SAFETY OF
DRUG USE DURING LACTATION

Human milk contains a mixture of maternal and transferred substances,

and most drugs administered to the mother find their way into milk. Drugs
given to nursing mothers, however, generally reach infants in much smaller
amounts than do drugs given to pregnant women reaching the fetus.

Maternal Factors

Several maternal factors influence drug passage into milk and infants'
response to drugs in breast milk, including:
Renal and hepatic metabolism
Dose and duration of therapy
Route of administration
Maternal metabolism substantially may reduce serum concentrations of a
drug. Conditions that alter a mother's ability to excrete or metabolize a drug
(e.g., pregnancy) are likely to result in greater exposure for the infant." The
dosage and duration of therapy also are important determinants of the safety.
Dosages of some medications vary over a wide range, depending on the indica-
tion for therapy. Often, low doses or short-duration therapy with even contrain-
dicated drugs (e.g., radiopharmaceuticals) may require only a temporary inter-
ruption of breastfeeding. Oral bioavailability of the drug also has an important
role in determining safety. Drugs that must be administered parenterally because
of poor oral bioavailability may not be orally bioavailable in infants (e.g., insulin,
aminoglycoside antibiotics, and magnesium sulfate). Also, the effect of a drug
on the milk supply is an important consideration (Table 4).

Infant Factors

Several infant factors influence drug passage into milk and infants' response
to drugs in breast milk, including:
Il:oo
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Table 3. POSSIBLE INGREDIENTS AND EFFECTS OF MOTHER'S MILK TEA

Plant Constituents Effects Toxicity

Fennel seed Volatile oil, anisic acid
Coriander seed Volatile oil, coriandrol
Chamomile flower Volatile oil, bitter glycoside
Lemongrass Lemon flavor
Borage leaf Volatile oil, tannin, mineral acids
Blessed thistle leaf Volatile oil, bitter principle
Star anise Volatile oil, anethole, resin, tannin
Comfrey leaf (Symphytum officinale) Protein, vitamin BIz, tannin, allantoin,
choline, pyrrolizidine alkaloids
Fenugreek seed (Greek hayseed) (coffee Mucilage, trigonelline, Physterols,
substitute and natural dye) celery flavor
Other beverages
Coffee plant Volatile oil, caffeine, tannin
Blue cohosh Saponin, glucoside that affects
muscles
Weak diuretic stimulant eNS disturbances
Increases flow of saliva and gastric
juice
Sudorific, antispasmodic, used to Vomiting and vertigo
lighten hair
Diuretic, sudorific, euphoric Possible
Aperitif, galactagogue, diaphoretic Strongly emetic
Stimulant, mild expectorant
Used as mucilage to knit bones, weak Vena-occlusive
sedative, demulcent, astringent disease, hepatotoxic
Digestive tonic, uterine stimulant, Hypoglycemia, can
galactagogue, reduces blood sugar induce labor
Stimulant, diuretic, coloring Insomnia, restlessness
Oxytocic, potent, acts on voluntary Irritant, causes pain in
and involuntary muscles fingers and toes

From Lawrence RA, Lawrence RM: Drugs in breast milk. In Lawrence RA, Lawrence RM (eds): Breastfeeding: A Guide for the Medical Profession, ed 5. St. Louis, CV
Mosby, 1999, P 375; with permission.
 XENOBIOTICS AND BREASTFEEDING 491

Table 4. DRUGS THAT DECREASE MILK VOLUME

Drug Generic Name

Levodopa Antihistamines (numerous)

Phenelzine Pyridoxine
Tranylcypromine Prostaglandin E2
Ergocryptine Estrogens (numerous)
Barbiturates (numerous) Androgens (numerous)
Apomorphine Bromocriptine
Alcohol (excessive)

Adaptedfrom Riordan JM: Drugs and breastfeeding. In Riordan JM, Auerbach KG (eds): Breastfeed-
ing and Human Lactation, copyright 1999: Jones and Bartlett Publishers, Sudbury MA. uruno.ibpub.com.
Reprinted with permission.

Age of the infant

Absorption of drug
Renal and hepatic metabolism
Quantity of breast milk consumed
Safety record of drug in infants
Information about the dosage, safety, or pharmacokinetics of new medica-
tions in infants often is unavailable. Also lacking are studies of long-term
exposure. When selecting therapies for lactating mothers, drugs that are proved
safe in infancy are preferable to those for which information is limited. An
infant's ability to metabolize and excrete particular drugs changes with age.
Drug absorption and metabolism are affected by an infant's higher stomach pH,
increased tendency for reflux, variable gastric emptying and prolonged intestinal
transit time, lower intestinal absorptive surface, and reduced hepatic and pancre-
atic enzyme activity. Hepatic metabolic capacity matures over the first several
weeks of life, whereas renal glomerular filtration rates mature over 2 to 5
months. 10. 35 The reduced ability to metabolize drugs is magnified in preterm, ill,
and low birth weight infants. 4. 10
Other age-related toxicities may occur because of an infant's enhanced
ability to absorb large and complex substances, including high molecular weight
drugs.v " Similarly, drugs that bind to albumin may cause bilirubin to be
displaced in jaundiced neonates. Age also affects the quantity of breast milk and
the amount of drug consumed. In later infancy, breast milk is a less substantial
portion of the diet. Exclusively breastfed neonates are likely to be exposed to
larger amounts of drug through breast milk. An infant's suckling pattern also
may affect exposure to drugs." For medications with shorter half-lives, adminis-
tering a dose after breastfeeding may decrease exposure." This strategy works
best in older infants, who nurse less frequently than do neonates, who nurse 8
to 12 times per day.
Non-dose-related toxicities, including potential allergic sensitization and
antibiotic-induced changes to the gastrointestinal flora, are important considera-
tions. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency are
susceptible to hemolytic anemia caused by small amounts of some drugs in
breast milk (e.g., sulfonamides).

Drug Factors
Several infant factors influence drug passage into milk and infants' response
to drugs in breast milk, including:
492 HOWARD & LAWRENCE

pKa
Solubility in water and lipids
Protein binding
Size of molecule
Oral bioavailability
Non-dose-related toxicity
Effect on breast milk supply
The pH of the drug, size of the molecule, protein binding, solubility in
lipids and water, and diffusion rate all influence how much drug passes from
the maternal serum into milk (Table 5). High molecular weight drugs are less
readily transferred. Water-filled membranal pores permit the movement of small
molecular weight « 200) drugs into milk." Larger molecules must transit the
outer lipid membranes of the cell and diffuse across the aqueous interior to pass
into the milk."
In the maternal serum, the protein-bound component of a drug serves as a
reservoir (inactive) in equilibrium with the free drug. Protein-binding capacity
is much higher in plasma than milk, and protein-bound drugs tend to remain
in the serum rather than passing into milk.v "
Nonionized drugs in plasma are excreted in milk in greater amounts than
are ionized compounds. Blood plasma and interstitial fluids are slightly alkaline
(pH 7.4), whereas milk is typically slightly acidic relative to plasma (pH 7.1;
range, 6.7-7.4). Weak acids, thus, are ionized to a greater extent in the plasma
and pass less easily into milk, whereas weak bases pass more readily into
milk. 4,41,47
The alveolar epithelium of the breast is a lipid barrier to the transfer of
drugs into milk. Water-soluble drugs and ions are inhibited, whereas un-ionized
and lipid soluble drugs pass through this barrier more easily.v "
Some drugs in free solution also may pass into the alveolar milk directly
through the spaces between the mammary alveolar cells. The intercellular junc-
tions are relatively open at delivery and tighten as lactation is established. The
amount of drug that passes into milk on postpartum day 1 may be higher than
later in lactation, Because milk volume is low, the dose to the infant, however,
may be insignificant."
The risk that a drug poses depends on several factors: (1) the route by
which the mother is exposed and her absorption, metabolism, and excretion of
the drug; (2) the dosing pattern (e.g., single versus long-term dosing); (3) the
pharmacokinetics of the drug; and (4) the physiologic maturity of the infant.

Table 5. PREDICTED DISTRIBUTION RATIOS OF DRUG CONCENTRATIONS

IN MILK AND PLASMA

Substance Milk-to-Plasma Ratio

Highly lipid-soluble drugs =1

Highly protein-bound drugs in maternal serum <1
Small (mol wt <200) water-soluble drugs =1
Weak acids :51
Weak bases ~1
Actively transported drugs >1

From Gaginella TS: US Pharmacist 3:39,1978; with permission.

 XENOBIOTICS AND BREASTFEEDING 493

METHODS OF ESTIMATING DRUG EXPOSURE

FOR INFANTS
Infant Dose

The amount of drug to which an infant is exposed during breastfeeding

may be estimated by several methods. The dose may be calculated as:

Infant dose = (drug concentration in milk) X (milk volume consumed)

For more concerning exposures, peak milk levels adjusted for maternal dose
and a large volume of milk (190-230 mL/kg/ d) may be assumed in estimating
an infant's dose.': 16, 26

Milk-to-Plasma Ratios

The milk-to-plasma ratio often is used as an index of drug transfer to breast

milk. The ratio is calculated as:

Milk-to-plasma ratio = (unbound drug in milk)/(drug in plasma)

and is helpful in estimating relative amounts of drug in breast milk; a high
milk-to-plasma ratio indicates more drug in the milk. Ratios of greater than 1,
however, may be associated with low amounts of drug in milk if the plasma
levels are low. Using the milk to plasma ratio and the drug concentration in
plasma, an estimate of drug concentration in milk may be made:

Drug concentration in milk = (maternal plasma concentration)

X (milk-to-plasma ratio)
Peak or mean levels may be used to calculate worst case or average concentra-
tions of drugs in milk.

Percentage of Dose

Sources sometimes provide estimates of the percentage of maternal dose

received by the infant through milk. Because this method assumes adult capabili-
ties for absorption, excretion, and metabolism, it is less useful than estimates of
the percentage of the usual infant dose for a medication.

MINIMIZING INFANT DRUG EXPOSURE

Several approaches have been suggested to minimize infant drug exposure.

Table 6 illustrates an approach adapted from that used by Well Start Interna-
tional. The steps should be implemented sequentially..

SOURCES OF INFORMATION ABOUT SPECIFIC DRUGS AND

LACTATION

Although it is beyond the scope of this article to provide detailed informa-

tion about the excess of drugs to which mothers may be exposed, several
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Table 6. MINIMIZING INFANT EXPOSURE TO MEDICATIONS

Primary
Considerations Secondary Considerations Additional Information

Choice to treat Is the drug necessary or can it be eliminated?
When is therapy needed? Can it be delayed
until weaning?
When therapy is Among therapeutic choices which poses the
needed least risk to infant?
Is there a route of administration that will
minimize maternal serum drug
concentrations?
Can doses to the mother be timed to provide
lower drug exposure to the infant?
When a contraindicated Is the required course of therapy short enough
medication must be that temporary cessation of breastfeeding
used could be considered?
Does maternal health necessitate the use of a
medication that is too toxic for
breastfeeding to be safe?
Local decongestant for URI symptoms versus a multidrug cold preparation
Can diagnostic, elective surgical procedures or therapy be delayed until the
infant is weaned?
Within a class of medication is there one that passes minimally into breast
milk and has no active metabolites?
Locally applied versus systemic administration
Serum concentrations peak from 1-3 h after an oral dose; can the mother
avoid nursing during peak serum concentrations (e.g., nurse before the
dose)? Can the medication be dosed at the time of the infant's longest
sleep period?
Mothers can express milk before an anticipated short course of therapy and
feed the infant expressed milk during therapy. Milk expression during
therapy should continue to maintain the mother's milk supply.
Elimination is drug specific. For highly toxic medications feedings
should be withheld for 4-5 half-lives (94% or 97% elimination)
It is in the best interest of the mother and infant that breastfeeding be
discontinued (e.g., antineoplastic agents)
 XENOBIOTICS AND BREASTFEEDlNG 495

comprehensive sources of information about drugs in breast milk are avail-

able.",19,28,40 The AAP also periodically publishes lists of drugs categorized
according to the risks that they pose to nursing infants." Many poison control
centers offer information about drug passage into breast milk The Lactation
Study Center at the University of Rochester (1-716-275-0088) welcomes inquiries
from physicians and maintains a computerized database of information on drugs
and lactation. Although information about herbs and breastfeeding is limited."
several books'» 21, 65 and online resources 1, 2 provide clinical information about
herbs.

DRUGS THAT MAY BE OF CONCERN DURING LACTATION

Because of their toxicity, high excretion into breast milk, or clinical effects
on infants, a few drugs should not be used during lactation or used with
extreme caution. In general, drugs of abuse are considered contraindicated
during breastfeeding (Table 7). Also, antineoplastic agents are generally incom-
patible with breastfeeding because of potential adverse, dose-dependent and
dose-independent effects on infants, Mothers who are given radiopharmaceuti-
cals should not breastfeed until the radioactivity in the milk clears. Consultation
with a nuclear medicine physician helps to select an agent with the shortest
excretion time."
Some agents may be contraindicated because of the effect on milk supply
(see Table 4). Bromocryptine, one therapeutic use of which is lactation suppres-
sion, is incompatible with lactation.'? Estrogen-containing oral contraceptives
also reduce milk production. Progestin-only oral contraceptives, however, have
no or only minimal effects on the milk supply (Table 8).40 Other agents, including
nicotine" and alcohol in sufficient doses." may decrease milk supply.

Anticonvulsants

Most anticonvulsants are excreted into breast milk in insignificant

amounts.v' 59, 72 Phenobarbital, ethosuximide, and primidone, however, may re-
sult in greater exposures for nursing infants. 37-39, 48, 52 Phenobarbital levels may
reach the lower range of therapeutic levels, and breastfed infants who are
exposed to this drug must be monitored closely."

Psychoactive Drugs

Because of the potential for antidepressants to affect infants' developing

CNSs, the AAP classifies antidepressants as medications whose effects during
breastfeeding are unknown but may be of concern." The decision to treat a
breastfeeding woman with antidepressants must entail a case-specific risk-
benefit assessment. For mother-infant couplets who continue to breastfeed while
undergoing antidepressant therapy, careful monitoring is vital. In a critical
review of the published literature on antidepressant use during breastfeeding,
Wisner et aF3 recommended the use of the following drugs: amitriptyline,
nortriptyline, desipramine, clomipramine, dothiepin, or sertraline. Based on
serum levels in infants, these investigators suggested that infants more than 10
weeks of age were at low risk for adverse effects from tricyclic antidepressants
(TCAs).
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Table 7. SPECIFIC DRUGS IN BREAST MILK

Oral
AAP Availability Protein Milk-Plasma Max in Milk
Drug Rating (%) Bound (%) Ratio (mglL) Comments

Antidepressants
Alprazolam None 92 ± 17 71 ± 3 Excreted into Withdrawal symptoms seen in an infant when
human milk mother stopped drug.
Amitriptyline 4 48 ± 11 98.8 ± 0.8 0.5-1.69 0.15 Galactorrhea or prolactin increase reported.
Not detected in infant's urine or serum
(limit 5 ng/mL). Peak in milk 1.5 h.
Clomipramine None 36-68 96.5-98.6 0.76-1.62 0.624
Desipramine 4 33-68 86.55 ± 4.45 0.4-1.2 0.328 Neither drug nor metabolite recovered from infant's
serum or urine. 5%-10% of whites poor
metabolizers.
Diazepam 4 100 ± 14 90-98 0.1-2.7 0.6 Chronic use not recommended. Infant sedation if fed
4 h but not 8 h after dose. In milk: 1.7%-3.8% of
therapeutic pediatric dose.
Dothiepin 4 - 0.33-1.59 0.475 Drug not detected in infant's serum.
Fluoxetine 4 > 60-80 80-95 0.29-0.88 0.181 Twelve case reports during breastfeeding. One report
of colic symptoms in infant. No adverse reactions
otherwise. May accumulate.
Imipramine 4 19-68 85-95 0.08-1.0 1 Desipramine is active metabolite. Reported to cause
galactorrhea and prolactin increase. Clinically
insignificant levels in breast milk.
Lithium 1 95 ± 5 0 0.24-0.66 4 Infant's serum level 10%-50% of mother's. Cyanosis,
poor muscle tone and ECG changes seen in
infants.
Lorazepam 4 64-109 91 ± 2 0.148-0.257 0.082 Infant toxicity observed at times. Longer half-life in
neonates.
 Nortriptyline None 46-59 92 ± 2 0.6-3.71 0.404 Minimal level found in breastmilk. 5%-10% of
whites poor metabolizers. Not detected in infant
serum.
Paroxetine None - 95 1
Sertraline None 98-99 - Extensive first pass metabolism. Metabolite 10%
activity. Drug usually not recovered from infant's
serum, metabolite found in low levels.
Drugs of Abuse
Amphetamine 2 > 95 15 2.8-7.5 0.138 Concentrated in milk, infant's urinary excretion is
0.001%-0.003% of mother's, causes stimulation
(jittery, irritability, sleeplessness) in infants.
Cocaine 1 and 2 30-40 91 >1 Significant No drug and metabolite in milk after 36 h or infant's
amounts serum after 60 h. Potential for significant toxicity.
in milk
Ethanol 6 90 ± 10 - 0.777-1.41 5600 Ethanol's metabolite is acetaldehyde, does not
appear in milk; high amounts may suppress
lactation. In milk: peak occurs 0.5-1.0 h. Milk may
smell of alcohol.
Heroin 2 - - Excreted into milk in sufficient amounts to cause
addiction.
Marijuana 2 >1 - Availability of the metabolite if marijuana is smoked
is 2%-50%; risks for passive exposure exist; in
laboratory animals, structural changes have been
documented in nursling's brain.
Phencyclidine 1 72 Excreted into In animal studies, the milk-plasma ratio>10; in one
human milk mother, 40 d after her last dose, 3.9 ng/mL was
found in the milk.
Table continued on following page

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~ Table 7. SPECIFIC DRUGS IN BREAST MILK (Continued)
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Oral
AAP Availability Protein Milk-Plasma Max in Milk
Drug Ratingt (%) Bound (%) Ratio (mgll) Comments

Others
Aspirin" 5 58.5 ± 12.5 49-70 0.03-1.0 42.6 High first pass metabolism. In milk: 0.06%-25.0% of
newborn therapeutic dose, peak 6 ± 3 h.
Caffeine 6 99 ± 14 29 ± 14 0.48-0.9 28.6 In milk: peak 0.5-2.0 h, average amount 0.846 mg/L,
half-life 6.1 ± 4.4 h; ability to metabolize caffeine
developed 3.0-4.5 months; after one cup of coffee,
caffeine is not found in the infant's urine.
Isoniazid" 6 90 0 0.5-3 16.6 In milk 6.3%-25.0% of therapeutic dose.
Levothyroxine* None 50-80 0.43 May increase milk production.
Metronidazole 4 80-100 <1-20 0.45-1.8 60 In milk: 1.3%-75.0% newborn therapeutic dose. AAP
oral; advises mother take 2 g orally, discard milk for
intravaginal 12-24 h.
19-81;
ointment
3-10
Nicotine 2 30->90 4.9 ± 2.8 0.3-9.6 0.6 In milk: peak 0.165 h; half-life 1.53 ± 0.25 h. May
suppress lactation. Decreased response of prolactin
and oxytocin to suckling. Active metabolite,
cotinine, excreted into milk.
Propylthiouracil* 6 78 ± 15 80 0.1-0.77 0.9 In milk: peak 1.5 h. In infant, get baseline levels of
T3, T4, TSH before and 6 weeks after mother
starts taking medication.
Tetracycline* 6 72.5 ± 22.5 20-75 0.2-1.5 8 In infant: Drug absorption negligible, undetected in
serum. In milk: probably chelated by calcium.

"Considered to be compatible with breastfeeding but often mistaken as posing a risk to breastfed infants.
tAAP ratings for maternal drug use during breastfeeding: I, drugs that are contraindicated; 2, drugs of abuse that are contraindicated; 3, radioactive compounds that
require temporary cessation of breastfeeding; 4, drugs whose effect on nursing infants is unknown but may be of concern; 5, drugs that have been associated with significant
effects on some nursing infants and should be given to nursing mothers with caution; 6, usually compatible with breastfeeding.
AAP = American Academy of Pediatrics.
Adapted from The Lactation Study Center, Rochester, NY; additional data from Lawrence RA, Friedman LR: Study Group on Human Lactation and Breastfeeding, The
University of Rochester, Rochester, NY.
 XENOBIOTICS AND BREASTFEEDING 499

Table 8. EFFECTS OF CONTRACEPTIVE AGENTS ON MILK YIELD

AND INFANT DEVELOPMENT

Agent Milk Yield Effect on Infant

Combined estrogen/progestin Moderate inhibitory effect Slower weight gain

Progestin only
Minipill (norethindrone
[Micronor, Nor-QD])
Other products
Injectable depot
medroxyprogesterone acetate
(DMPA), Depo-Provera and
norethindrone enanthate
(NET-ED, NORISTERAT)
Levonorgestrel (Norplant System)
Vaginal rings containing natural
hormone progesterone
Shorter breastfeeding No long-term effects
Milk concentration
unchanged
Small amount of steroid in
milk
No effect on volume No effect on weight gain
No effect on duration No reported long-term
effects
Breastfeeding lasts longer No long-term effects
? change in milk: protein
increased, fat decreased
Steroid present in milk
No effect Normal growth
Small amount of steroid in No long-term effects
milk
No significant differences No effects on growth
Long-term effects under
study

Modified from Winikoff B, Smeraro P, Zimmerman M: Contraception During Breastfeeding: A

Clinician's Source Book. New York, Population Council, 1987.

Tricyclic antidepressants in maternal dosages of as much as 150 mg per day

for amitriptyline, as much as 300 mg per day for desipramine, as much as 200
mg per day for imipramine, or as much as 125 mg per day for nortriptyline have
not caused observable effects in breastfed infants.v" 14.57,58,69 Many investigators,
however, recommend against the use of these agents because of the potential
for long-term effects on infants' neurologic development. When the TCAs are
used, infant exposure may be minimized by using a secondary amine (i.e.,
nortriptyline or desipramine) and by giving the drug as a single dose at bedtime,
substituting nighttime breastfeedings if possible.'
Fluoxetine and sertraline, widely used selective serotonin reuptake inhibi-
tors, pass into breast milk in small amounts." 45, 60, 76 There is one case report of
a mother taking 20 mg per day of fluoxetine whose infant exhibited colic
symptoms and attained therapeutic serum levels of the drug and its metabolite."
Other reports suggest few symptoms in exposed infants." Information about the
effects of other drugs in this class on breastfed infants is limited.
Despite the risks of lithium use during pregnancy and lactation," some
investigators believe that the evidence to date indicates beneficial effects for
mother and infant from continued breastfeeding," whereas others call for its
cautious use in some circumstances.' Concentrations in infants have been mea-
sured at one tenth to one half of mothers' serum levels." The effects of such
levels on infants are unknown. Lithium therapy after delivery or when a
breastfeeding infant is several months of age greatly decreases the risk to the
infant. These infants must be monitored carefully."
Long-term benzodiazepine therapy should be avoided if possible during
500 HOWARD & LAWRENCE

breastfeeding, especially in the neonatal period. The short-acting agents oxaze-

pam and lorazepam seem to be preferable when this class of drugs is used
during breastfeeding.' The use of benzodiazepines during breastfeeding is proba-
bly safe if limited to short courses of therapy,"

Anti-Infective Agents

Most anti-infective agents are compatible with breastfeeding. Metronidazole

is present in milk at levels equal to those in serum. Estimated infant doses are
0.4% to 36.0% of the maternal dose." Because of the theoretic risk for carcinoge-
nicity and the relatively high infant plasma concentrations, it is prudent to avoid
the use of metronidazole during nursing, especially of neonates. For some
therapeutic purposes, a single, 2-g dose may suffice. An alternative feeding
method should be used for 24 hours while pumping and discarding the
milk.": 24. 40. 41 After 6 months of age, infants metabolize metronidazole well and
may be given the drug directly.
Breastfeeding is contraindicated during maternal chloramphenicol therapy."
Breast milk levels are too low to cause"gray baby syndrome,'?" but idiosyncratic
bone marrow suppression may occur,"

Drugs of Possible Concern

Caffeine
Average caffeine content in the usual servings of some common beverages
is coffee, 66 to 146 mg; nonherbal tea, 20 to 46 mg; and caffeinated soft drinks,
32 to 65 mg. 12• 15 Maternal consumption of one or two caffeine-containing bever-
ages per day is not associated with unacceptable levels of caffeine in human
milk." Caffeine may accumulate if an infant receives frequent doses. Cases of
caffeine excess in breastfed infants have been reported." Irritability and poor
sleeping patterns have been observed in infants during periods of heavy mater-
nal caffeine use."

Nicotine
The active ingredient of cigarettes is nicotine, one of the drugs that the AAP
lists as contraindicated during lactation." This recommendation is controversial,
however, and the Institute of Medicine does not consider infrequent cigarette
smoking a contraindication to breastfeeding.F- 40 Infants raised in households
with smokers, regardless of feeding method, have nicotine and cotinine (an
active metabolite of nicotine) in their urine, but breastfed infants have higher
levels." Smoking is associated with shortened duration of breastfeeding and
decreased milk volume." 32. 44. 46. 67 One study" showed a strong correlation with
infantile colic in addition to the known associations with sudden infant death
syndrome, otitis media, and lower respiratory tract infections. Mothers should
not smoke while nursing or in their infants' presence. Although no published
reports associate nicotine from human milk with infant health problems, it is
advisable for mothers to avoid smoking for 2.5 hours before a feeding and to
avoid smoking in their infants' presence.v
 XENOBIOTICS AND BREASTFEEDING 501

Alcohol
High amounts of maternal alcohol consumption may suppress lactation."
Two studies have shown that the milk-ejection reflex may be at least partially
blocked by maternal alcohol intake.": 32, 68 No effect of ethanol intake was ob-
served at doses of less than 0.5 g/kg of maternal weight. The AAP considers
maternal ethanol use to be compatible with breastfeeding, although it recognizes
that adverse effects may occur." The Institute of Medicine recommends con-
sumption be limited to no more than 0.5 g per day per kilogram of maternal
body weight." Alcohol consumption in excess of 0.5 g/kg may be harmful to
infants in part because of a potential for reduced milk volume. For an average
woman weighing 60 kg (132 lb), an ethanol dose of 0.5 g/kg is approximately
60 to 70 mL of liquor, 240 mL of wine, or 355 mL (two cans) of beer.

SUMMARY

Breastfeeding provides important benefits to mothers and infants and

should be encouraged strongly as the optimal feeding choice for most infants,
In assessing the effects of maternal medication on breastfeeding, clinicians must
weigh the many benefits of breastfeeding for mothers and infants against the
risk for exposing infants to a drug as it is present in breast milk. With regard to
most medications, continued breastfeeding despite drug exposure is advanta-
geous to mothers and infants.

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Address reprint requests to

Cynthia R. Howard, MD, MPH
Department of Pediatrics
Rochester General Hospital
1425 Portland Avenue
Rochester, NY 14621

e-mail: cindy.howard@viahealth.org