38,219,233 Once in the milk, the proportion of ionized weak base rises in the

relatively acidic solution, and thus drug trapping occurs. Drug reabsorption has been

found for some agents, and the prevention of passage back into the plasma by

trapping may be clinically important. Lipid solubility also is determined to a large

extent by the degree of ionization because drugs with relatively high lipid solubility

exist in the nonionized form. Diffusion through lipid membranes is probably the most

important pathway for drug transfer. Although pH, pKα

, and lipid solubility are

important elements, other factors may significantly modify predictions based solely

on these chemical characteristics. Two of these other factors are protein binding and

molecular weight.

38,233 Drugs with high molecular weights such as insulin (MW

>6,000) are less likely to transfer into breast milk, whereas those less than 300

transfer more readily.

38 Highly protein-bound drugs such as glyburide (99% protein

bound) are less likely to be transferred into breast milk, although infants should still

be monitored for signs of hypoglycemia.

Table 49-6

Factors Affecting the Fate of Drugs in Milk and the Nursing Infant

Maternal Parameters

Drug dosage and duration of therapy

Route and frequency of administration

Metabolism

Renal clearance

Blood flow to the breasts

Milk pH

Milk composition

Drug Parameters

Oral bioavailability (to mother and infant)

Molecular weight

pKa

Lipid solubility

Protein binding

Infant Parameters

Age of the infant

Feeding pattern

Amount of breast milk consumed

Drug absorption, distribution, metabolism, elimination

pKa

, dissociation constant.

Source:Anderson PO. Drugs and breast milk [letter]. Pediatrics. 1995;95:957; Dillon AE et al. Drug therapy in the

nursing mother. Obstet Gynecol Clin North Am. 1997;24:675; Begg EJ et al. Studying drugs in human milk: time to

unify the approach. J Hum Lact. 2002;18:323; Bennett PN, ed. Drugs and Human Lactation. 2nd ed. New York,

NY: Elsevier; 1996; Hale TW. Medications and Mothers’ Milk. 16th ed. Amarillo, TX: Pharmasoft Medical

Publishing; 2014.

Drug transfer also is influenced by the yield of milk, which is related to blood

flow and PRL secretion.

233 Lactation is associated with a high blood flow to the

breasts, but little is known about this flow during or between feedings. The milk

yield (volume) differs slightly depending on the duration of lactation and the time of

day. A diurnal pattern has been observed, with highest yields at 6 AM and lowest

yields at 6 PM or 10 PM. The mean composition of mature human milk is

approximately 87% aqueous solution, 3.5% lipids, 8% carbohydrate (83% of which

is lactose), 0.9% protein, and 0.2% nitrogen.

233 The proportions of these components

may vary widely from woman to woman and even within the same woman. For

example, hind milk (breast milk that is expressed last and contains more fat) contains

fourfold to fivefold the fat content of foremilk (breast milk that is expressed first and

is high in water content, water-soluble vitamins, carbohydrates, and protein),

whereas colostrum (first milk, secreted late in pregnancy and in the first few days

after delivery) contains little fat. Fat content also has exhibited a diurnal variation.

After a drug reaches the milk, it equilibrates between the aqueous and lipid

phases. The nature of this equilibration can modify how much drug actually reaches

the infant. Infant feeding patterns differ significantly from one baby to another. The

time spent suckling at each breast, and the volume of milk taken in, also determine the

amount of drug ingested, especially if the drug has partitioned into one phase more so

than the other. Once the infant ingests the drug via breast milk, the pharmacologic and

adverse effects on the infant will be determined by the extent of oral bioavailability,

distribution, metabolism, and rate of elimination. These pharmacokinetic parameters

differ, depending on the infant’s age and whether he or she was born prematurely or

at term.

CASE 49-12

QUESTION 1: H.P. is a 25-year-old woman G3, P3 who recently was diagnosed with a distal deep vein

thrombosis (DVT) in her lower left extremity confirmed by a Doppler ultrasound at 5 weeks’ gestation. She has

a significant history of having multiple DVTs in her prior pregnancies, and her thrombophilia workup was

negative. During her pregnancy, she was on therapeutic low-molecular-weight heparin (LMWH) 80 mg

(weight, 76 kg) SC every 12 hours. Her dosage was increased to 100 mg SC every 12 hours after subsequent

anti-factor Xa levels were subtherapeutic. Her LMWH was discontinued 24 hours before she received an

epidural for labor pain. After delivery, H.P. is restarted on LMWH and then changed to warfarin on day 5.

H.P. also is breast-feeding. Do either of these drugs present a risk to the nursing infant?

Heparin does not cross into breast milk (see Drug Excretion in Human Milk

section) because of its high molecular weight (~12,000) and is therefore safe in

breast-feeding. Warfarin is a weakly acidic drug (pKα 5.05) that is highly ionized at

physiologic

p. 1001

p. 1002

pH (>99%) in maternal serum.

233

It also is highly protein bound (97%).

38 These

pharmacokinetic parameters make warfarin very unlikely to transfer into breast milk.

Case reports in lactating mothers confirm that warfarin is not detected in breast milk

or infant plasma.

38 The American Academy of Pediatrics (AAP) considers warfarin

compatible with breast-feeding,

92 and it is widely considered to be safe in breastfeeding.

92,235 There are no studies to guide duration of anticoagulation in women who

have had a DVT associated with pregnancy. However, most recommend

anticoagulation for at least 6 weeks postpartum, with total duration of anticoagulation

of a minimum of 6 months after the thromboembolic event.

235 H.P. can safely breastfeed her infant while she is on LMWH and warfarin.

Estimating Infant Exposure

The actual amount an infant will ingest is difficult to determine owing to varying

maternal, drug, and infant parameters. Available data generally are from single or

small numbers of case reports or pharmacokinetic studies involving few mother–

infant pairs. An M/P ratio is sometimes used alone as the basis for a

recommendation, but this should be avoided because its accuracy can be affected by

many factors such as the time of sampling after maternal ingestion (peak versus

steady state), dose, length of therapy, route of administration, and milk

composition.

233 A RID is sometimes reported in resources or literature, which is

expressed as a percentage of the maternal dose.

233 Generally, an RID of less than

10% is interpreted as an acceptable level. This must be interpreted with caution,

however, taking into account other variables such as the age and health of the infant

and the safety profile of the drug. It is also important to note that these are estimated

values, often based on data collected from one or only a few individuals. Applying

these equations using measurements specific to a woman and her infant is not

clinically practical, however. Compared with the M/P ratio, experts believe that the

RID is a better estimate of infant exposure.

Sampling during maternal peak drug concentration attempts to approximate the

highest amount of drug that can reach the infant. This assumption is inherently flawed

because peak drug concentration in the mother does not necessarily equate with peak

drug concentration in milk at that same point in time.

233,236 The amount of drug an

infant actually receives also depends on the volume of milk ingested. Even if a drug

has a high M/P ratio, the actual amount received by the infant could be low if only a

small volume of milk was consumed. Therefore, an M/P ratio describes the

likelihood of drug excretion into breast milk, but it does not indicate the level of

infant exposure. In general, drugs with lower M/P ratios (<1) are preferred over

those with higher M/P ratios (>1) during breast-feeding, but other parameters such as

maternal condition and therapeutic efficacy should be considered.

Infant exposure to a drug via ingestion of breast milk can be estimated for some

drugs. The M/P ratio is used to estimate the drug concentration in milk (Eq. 49-1) and

the dose the infant may ingest (Eq. 49-2).

233,236,237 The variables required to calculate

Equation 49-1 can be located in the published literature, but only for some drugs. The

actual volume of milk ingested by the infant is difficult to estimate, but the average

consumption is approximately 150 mL/kg/day. The estimated infant dose can then be

used to calculate an RID, which is expressed as a percentage of the maternal dose.

236

CASE 49-13

QUESTION 1: K.J., a breast-feeding, 91-kg woman, is taking hydrochlorothiazide 50 mg PO daily. The drug

has a long elimination half-life of about 12 hours. Peak milk levels of the drug occur 5 to 10 hours after a dose.

In a recent study, the drug was excreted into milk with a mean concentration of 80 ng/mL. Based only on dose,

does this drug represent a significant risk to K.J.’s nursing infant?

The maternal dose is 50 mg/91 kg = 0.55 mg/kg/day. The infant dose is calculated

to be 80 ng/mL (1 mcg/1,000 ng) (1 mg/1,000 mcg) (150 mL/kg/day), which equals

0.012 mg/kg/day. The RID equals the actual infant dose (0.012 mg/kg/day) divided

by the actual maternal dose (0.55 mg/kg/day) × 100, which equals 2.18%. Therefore,

the exposure likely does not represent a risk. K.J. can continue to take

hydrochlorothiazide while breast-feeding. The AAP classifies hydrochlorothiazide

as compatible with breast-feeding.

38,92

Reducing Risk of Exposure

If pharmacologic treatment is medically necessary for a nursing mother, every attempt

should be made to minimize infant exposure to the drug. Methods of reducing risks

have been proposed.

229,233,234 Table 49-7 summarizes critical factors that should be

considered. Except for drugs that are contraindicated during lactation, the decision to

continue or discontinue nursing while receiving medication is ultimately the

mother’s. Therefore, patient education is an integral component in this decisionmaking process. The mother should be informed of the potential risks, or lack thereof,

associated with a drug. She also should be made aware that certain risks may be

minimized by altering feeding pattern and drug administration time and by carefully

monitoring the infant for early signs of adverse effects.

Table 49-7

Reducing Risk of Infant Exposure to Drugs in Breast Milk

A drug should be used only if medically necessary, and treatment cannot be delayed until the infant is ready to be

weaned

Drug Selection

Consider whether the drug can be safely given directly to the infant

Select a drug that passes poorly into breast milk with the lowest predicted M/P ratio, and an RID <10%

Avoid long-acting formulations (e.g., sustained release)

Consider possible routes of administration that can reduce drug excretion into milk

Determine length of therapy and if possible avoid long-term use

Feeding Pattern

Avoid nursing during times of peak drug concentration

If possible, plan breast-feeding before administration of the next dose

Other Considerations

Always observe the infant for unusualsigns (e.g., sedation, irritability, rash, decreased appetite, failure to thrive)

Discontinue breast-feeding during the course of therapy if the risks to the fetus outweigh the benefits of nursing

Provide adequate patient education to increase understanding of risk factors

M/P, milk-to-plasma ratio; RID, relative infant dose.

Source: Anderson PO. Drugs and breast milk [letter]. Pediatrics. 1995;95:957; Begg EJ et al. Studying drugs in

human milk: time to unify the approach. J Hum Lact. 2002;18:323; Howard CR, Lawrence RA. Drugs and

breastfeeding. Clin Perinatol. 1999;26:447.

p. 1002

p. 1003

Table 49-8

Drugs Considered Contraindicated During Lactation

Drug or Drug Class Effects on Nursing Infants

Amphetamines

a Accumulate in breast milk and may cause irritability and poor sleep patterns

Antineoplastics Potential for immune suppression; cytotoxic effects of drugs on dividing cells

in infants unknown

2

Cocaine

a Excreted in milk; contraindicated because of CNS stimulation and intoxication

Ergotamine Potential for suppressing lactation; vomiting, diarrhea, and convulsions have

been reported.

92 Considered contraindicated by some clinicians. AAP

recommends using with caution

Heroin

a Possible addiction if sufficient amounts ingested

Immunosuppressants Potential for immune suppression

Lithium Milk and serum concentrations average 40% of maternalserum levels.

Potential for toxicity exists. Considered contraindicated by some clinicians.

AAP recommends using with caution

Lysergic acid diethylamide

(LSD)

a

Probably excreted in milk

Marijuana

a Excreted in milk

Misoprostol Excretion in milk has not been studied but contraindicated because of potential

for severe diarrhea in infant

Phencyclidine

a Potent hallucinogenic properties

Phenidone Massive scrotal hematoma and wound oozing after herniotomy in one infant;

contraindicated

Requiring Temporary Cessation of Breast-Feeding

Radiopharmaceuticals Halt breast-feeding temporarily to allow clearance of radioactivity from milk.

Suggested times for individual agents are as follows: copper-64 (

64Cu) 50

hours; gallium-67 (

67Ga) 2 weeks; indium-111 (

111

In) 20 hours; iodine-123

(

123

I) 36 hours; iodine-125 (

125

I) 12 days; iodine-131 (

131

I) 2–14 days;

radioactive sodium 96 hours; technetium-99m (

99mTc) 15 hours–3 days;

(

99mTcO4

) (

99mTc macroaggregates) 15 hours–3 days

This list is not all-inclusive. Selected drugs are listed by drug class and not by individual names.

aAll drugs of abuse are contraindicated during lactation.

Source: Briggs G et al. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 11th

ed. Philadelphia: Lippincott Williams & Wilkins; 2017; Sachs HC and the American Academy of Pediatrics

Committee on Drugs. Transfer of drugs and therapeutics into human milk. Pediatrics. 2013;132(3);e796–e809;

Hale TW. Medications and Mothers’ Milk. 16th ed. Amarillo, TX: Pharmasoft Medical Publishing; 2014.

Resources for Drugs and Lactation

Comprehensive sources reviewing drug use in lactation are available to assist

clinicians in weighing the potential risks versus benefits of mothers using

medications while breast-feeding. Table 49-8 lists some medications that are

contraindicated during lactation. The AAP Committee on Drugs periodically reviews

the transfer of drugs and other chemicals into human milk and publishes their

findings.

92 The Committee identifies drugs that should be avoided during breastfeeding, drugs that should be used with caution, drugs whose effects on infants are

unknown but of concern, and those considered usually compatible with breastfeeding. This rigorous review is an ongoing process, and new guidelines are

published every few years; therefore, the reader should locate the latest AAP

recommendations available. In addition to the AAP guidelines, several other

references also offer comprehensive information and recommendations on drug use in

lactation.

38,92,234