Medications, Herbal Preparations, and Natural Products in Breast Milk

Risk Categories

The AAP Committee on Drugs published a list of drugs and other chemicals that transfer into human breast milk. The list, which was last updated in 2013, is divided into those that are contraindicated, those that require temporary interruption of breastfeeding, and those that are compatible with breastfeeding. ¹⁰ Concern about the issue of drugs in breast milk has spread. That classification is different from the previously used FDA Pregnancy Categories of Risk, which separates medications based on the amount and quality of available studies in pregnant women and animals (A, B, C, D, X) and not on either incidence of reactions or the potential severity of risk. ¹¹ The FDA has new labeling rules for medications, the Pregnancy and Lactation Labeling Rule of 2014. ⁹ The database and book authored by Dr. Thomas Hale and his team use a lactation risk classification (LRC) based on their assessment of the risk data (L1=compatible with breastfeeding, L2=probably compatible, L3=probably compatible [individualized assessment of the benefits versus risk needed], L4=possibly hazardous, L5=hazardous). ¹² All of these risk categorization strategies are oversimplifications. The decision about the use of a medication, herb, or product by a lactating woman necessitates an individualized risk–benefit assessment for the mother and the infant based on the available information, with the mother/parents included in that information review and the decision-making.

Extent of Medication Use in Lactation

A study of more than 14,000 pregnant women in 148 hospitals in 22 countries revealed that 79% of women received an average of 3.3 drugs. ¹⁰ The drugs most often given were analgesics and anesthetics. Of the 91% of women who initiated breastfeeding, 36% received methylergonovine, and 5% received antibiotics. Another study of 885 women 3 to 5 months postpartum in Oslo showed that breastfeeding women took fewer medications (daily dose/1000 women/day) than nonbreastfeeding women. ¹³ The most common medication in the latter group was oral contraceptives. Colds, dyspepsia, hemorrhoids, and breast infections were the disorders identified in this study that precipitated the use of albuterol (salbutamol), clemastine fumarate (Tavist), dexchlorpheniramine maleate (cold preparations), phenylpropanolamine hydrochloride (Comtrex, Dimetane), cromolyn sodium, and methotrimeprazine hydrochloride (levomepromazine).

A more recent systematic review of breastfeeding practices and postpartum women’s use of medicines included 20 studies (cohort and cross-sectional) from nine countries. ³ The proportion of women using ≥1 medicine during lactation ranged from 34% to 100%. The three largest reviews included studies from Sweden ( n =102,995), Norway ( n =106,329), and Denmark ( n =15,756) in which the percentages of medication use were 51%, 57% and 34%, respectively. In the four registered databases, from Norway, Sweden, the Netherlands, and Denmark, the most commonly documented medications were oral contraceptives and systemic antibiotics, whereas in the other studies, analgesics/antipyretics, nonsteroidal antiinflammatory drugs, and antibiotics were the most common (without including iron, vitamins, and minerals). Long-term use of medications for chronic illnesses in Norway, Sweden, and the Netherlands in the first 3 months postpartum included cardiovascular medications, thyroid therapy, antiasthma, antidepressants/antipsychotics, medications for diabetes, and antileptics. In five smaller studies from Brazil and Canada, breastfeeding appeared to be affected by postpartum medication use by the mothers, including noninitiation of breastfeeding or stopping breastfeeding earlier than intended. ³

Consulting Reliable Information on Humans

No substitute exists for specific knowledge about the individual medications and their use in lactation. It is equally inappropriate to discontinue breastfeeding when it is not medically necessary as it is to continue breastfeeding while taking contraindicated drugs.

Consideration of the pharmacokinetics contributes to the understanding of the potential problems involved. Given the limited data available in humans, some reported data have been extrapolated from experiments performed on cows, goats, and rodents. Bovine experiments have been conducted using continuous infusions, which provide data on the passage of a drug into milk under certain pH and plasma levels. Animal studies are not particularly useful because there is so much variability in the protein and fat composition of different species’ milk and the existence of active transport systems in different species. Human pharmacokinetic studies are necessary to quantify the amount of drug that passes to human milk. ¹⁴ Medical professionals should not try to “oversimplify” the data but can consult with local pharmacologists knowledgeable in medications and lactation or available hotlines and support groups for assistance. (See Chapter 25, Appendix G for some of these resources.)

Protein Binding

Drugs entering the circulation become protein bound or remain free in the circulation. The protein-bound component of the drug serves as an inactive reservoir for the drug that is in equilibrium with the free drug. Most drugs enter the mammary alveolar cells in the unbound form ( Fig. 11.1 ).

At term, plasma proteins may be reduced and the fatty acid and hypoprotein fraction slightly increased in the mother, which results in the displacement of some drugs from plasma proteins. During the early postpartum period, for 5 to 7 weeks, the free fraction of some drugs increases and therefore more readily crosses into milk (e.g., salicylate, phenytoin, diazepam).

Relative Concentration in Plasma Versus Milk

For most drugs, a higher concentration will be found in the plasma than in the milk. Only the small free fraction of a drug can cross the biologic membrane. The total concentration in milk is only minimally influenced by the binding of drugs to milk proteins (milk protein concentration is 0.9% in mature milk). Only those drug molecules that are free in solution can pass through the endothelial pores, either by diffusion or by reverse pinocytosis. Pinocytosis is the process whereby drug molecules dissolved in the interstitial fluid attach to receptors located at the surface of the cell membrane. The cell membrane invaginates at the site of the drug attachment, bringing the drug into the cell. The membrane is pinched off, and the drug, surrounded by membrane, remains in the cell. Then the membrane is dissolved, leaving the drug molecule free in the cell.

Reverse pinocytosis is the process by which the apical membrane evaginates after fusion of the intracellular membrane-bound secretion granules with the plasma membrane. The granules include lipids, proteins, lactose, drug molecules, and other cellular constituents. The evagination of the plasma membrane is pinched off and released into the alveolar lumen. Within the extravascular space, the drug may be bound to proteins in the interstitial fluid. Some agents in free solution can pass into the alveolar milk directly by way of the spaces between the mammary alveolar cells. These paracellular areas account for a major portion of the fluid changes across the epithelium. These spaces between adjacent alveolar cells serve to carry water-soluble drugs from the tissue into the milk.

The intercellular junctions are “open” at delivery as lactation is being established and gradually “tighten” over the next few days. The amount of drug passed into milk on day 1 is greater than on day 3 or later. The composition of the milk changes from colostrum to mature milk, altering the amount of protein and fat, which can also influence drug levels in the milk. It is always important to know when plasma and milk samples were measured in relationship to the onset of lactation. Furthermore, some studies have been done on nonlactating women by pumping enough milk to measure the drug. These “weaning samples” do not reflect the normal physiology of lactation and therefore provide only misinformation.

Ionization

Drugs that are nonionized are excreted in the milk in greater amounts than are ionized compounds. Depending on the pH of the solvent and the drug dissociation constant (p K _a ), many weak electrolytes are more or less ionized in solution. Blood plasma and interstitial fluid are slightly alkaline (pH 7.4). Drugs that are weak acids are ionized to a greater extent in alkaline solution and are more extensively bound to protein. The amount of drug excreted from plasma (pH 7.4) to milk (pH 6.8 to 7.3, average 7.0) depends on the pH of the compound. Thus a weakly acidic compound has a higher concentration in plasma than in milk. Conversely, weakly alkaline compounds are in equal or higher levels in the milk than in the plasma.

Passage of Molecules Into Milk Depends on Size

The passage of molecules into the milk also depends on the size of the molecule, or the molecular weight (mol wt, in daltons). Water-filled membranous pores permit the movement of molecules of less than 100 mol wt. Because of action similar to the limitation of transport of certain large-molecular-weight chemicals across the placenta, insulin and heparin are not found in human milk either, presumably because of the molecules’ large size.

Half-Life of a Medication

The half-life (T _1/2 ) of a medication is the amount of time it takes for half of the drug to be removed from the body by the various metabolic processes and is most often measured as the time it takes for the plasma level to drop by one-half at steady state (plasma half-life). A shorter drug half-life is preferred because there would likely be less exposure of the infant to the drug, and it might be possible to dose the medication to limit the infant’s drug exposure in the milk.

Mechanisms of Transport

Drugs pass into milk by simple diffusion, carrier-mediated diffusion, or active transport, as follows:

• Simple diffusion: Concentration gradient decreases

• Carrier-mediated diffusion: Concentration gradient decreases

• Active transport: Concentration gradient increases

• Pinocytosis: Active membrane transport into the cell via receptors

• Reverse pinocytosis: Active membrane transport out of the cell

Nonelectrolytes such as ethanol, urea, and antipyrine enter the milk by diffusion through the lipid membrane barrier and may reach the same concentrations in the milk as in the plasma, regardless of the pH. The main entrance site of molecules is at the basement luminal membrane, where water-soluble materials pass through the alveolar pores. Nonionized drugs cross the membrane more easily than ionized ones because of the structure of the membrane. The nonionized drugs pass through the membrane by diffusion. When simple diffusion takes place, the M/P ratio is 1.0. Passive diffusion provides the same ratio regardless of the plasma concentrations of the drug or the volume of milk secreted. Different M/P ratios depend on the binding to protein and are a measure of the protein-free fraction. The dissimilar ratios for the sulfa drugs (see Table 11.1 ) partly result from the difference in protein binding and partly from ionization.

Large molecules depend on their lipid solubility and ionization to cross the membrane because they pass in a lipid-soluble, nonionized form. The M/P ratio is determined when equilibrium exists in the amount of nonionized drug in the aqueous phase on both sides of the membrane. When drugs are only partially ionized, the nonionized fraction determines the concentration that crosses the membrane. The drugs for which the nonionized fraction is not very lipid soluble will pass only in a limited degree into breast milk.

Passive drug transport may occur in the form of facilitated diffusion . The active compound is transported across the cell membrane by a carrier enzyme or protein. The gradient is toward a lesser or equal concentration in both simple diffusion and facilitated diffusion and is controlled by chemical activity gradients. Facilitated diffusion usually involves water-soluble substance too large to pass through the membrane pores.

Active transport mechanisms provide a process whereby the gradient is “uphill,” or higher, in the milk. The process is similar to facilitated diffusion except that metabolic energy is required to overcome the gradient. Examples of substances actively transported include glucose, amino acids, calcium, magnesium, and sodium. Pinocytosis and reverse pinocytosis, as described previously, are involved in the transport of very large molecules and proteins. Chloride ions are secreted into milk via an active apical membrane pump, whereas sodium and potassium diffuse by electrical gradient. Because the level of sodium is kept low, an active return of sodium may occur into the plasma, referred to as a reverse pump . Retrograde diffusion, the passage of a drug back into the maternal bloodstream from the milk, is another mechanism influencing the level of drug in the milk. The same variable affecting the drug’s diffusion into the milk will affect its passage back into the plasma. Drugs with a shorter half-life will demonstrate greater variations in drug level within the milk as a result of retrograde diffusion. ¹⁴

Volume of Distribution

The volume of distribution ( V _d ) is calculated as follows:

The absorption and elimination are considered to be exponential or first-order kinetics. A two-compartment model of drug kinetics considers the phase of decreasing drug concentration as the drug distributes into the tissues. Initially, concentrations fall rapidly as the drug distributes, then first-order elimination follows. When considering the pharmacokinetics of drugs in breast milk, one must also consider that elimination in the breast is by two potential routes: excreted with the milk to the infant and back-diffusion into the plasma to reequilibrate with the falling level in the plasma.

Milk-to-Plasma Ratio

By definition, the M/P ratio is the concentration of a drug in the mother’s milk divided by its concentration in the mother’s plasma at the same time. A higher M/P ratio indicates that a higher amount of drug will reach the milk for a given concentration. The overall amount of drug reaching the milk is primarily determined by the concentration of the drug in the plasma. If choosing between two drugs with different M/P ratios, then the drug with the lower M/P ratio is less likely to reach the milk than the one with the higher M/P ratio given the same plasma concentrations of the drugs.

Mode of Administration of the Drug

The concentration of the drug in the circulation of the mother depends on the mode of administration: oral, IV, IM, or TDDS. Absorption through the skin, the lungs (inhalants), or vaginally may also need to be considered.

The levels in the blood depend on the route of administration. The curves produced by bolus IV medication peak high and early and taper sharply, thus making avoiding peak plasma levels more feasible. Absorption from IM dosing is less rapid but follows a similar but less sharp curve. Oral dosing depends on other factors, such as whether the medication is taken between or during meals. Depending on the curve of uptake and removal of drug from the plasma, the area under the curve varies. Single doses are simple area-under-the-curve calculations, but calculations for multiple doses or chronic use vary with the steady state of the drug in the body. The mode of administration is important in determining the overall bioavailability of a drug. TDDS patches are constructed to deliver the medication at a constant rate continuously over a period of time.

The TDDS depends on absorption of the drug through the skin at a steady rate; it has become a significant route of administration for certain medications. The delivery rate is determined by diffusion of the drug from the reservoir matrix through the epidermis. This method offers some advantages, including convenience of dosing, reduced dosing frequency, ease of reaching a steady state, increased patient compliance, avoidance of first-pass hepatic biotransformation, avoidance of peaks and valleys in blood levels, and reduction of side effects through heightened selectivity of drug action. ¹⁶ The level in the plasma remains constant during the drug’s anticipated life span while the patch is in place. The technology is limited to drugs with low molecular weight that are hydrophilic and can diffuse through the stratum corneum. The top molecular weight is 500 daltons. For patient compliance and economics, the patch size is limited to 50 cm in diameter. Occasional patients experience skin irritation. Currently, patches are limited to drugs that are potent in small amounts and highly diffusible through the skin. To maintain a constant rate, a surplus of the drug must be present, often 20 to 30 times the amount that will be absorbed during the time of application. The potential for toxicity is great. If a patch is utilized while lactating, it should be applied and covered so that a nursing infant cannot accidentally get to it. TDDS patches are available for scopolamine, nicotine, clonidine, fentanyl, and other drugs ( Table 11.3 ).

A summary of the steps in the passage of drugs into breast milk follows:

• 1.

  Mammary alveolar epithelium represents a lipid barrier with water-filled pores and is most permeable for drugs during the colostral phase of milk secretion (first week postpartum).

• 2.

  Drug excretion into milk depends on the drug’s degree of ionization, molecular weight, solubility in fat and water, and the relation of the pH of plasma (7.4) to the pH of milk (7.0).

• 3.

  Drugs preferably enter mammary cells basally in the nonionized, nonprotein-bound form by diffusion or active transport.

• 4.

  Water-soluble drugs of less than 200 mol wt pass through water-filled membranous pores.

• 5.

  Drugs leave mammary alveolar cells apically by diffusion or active transport.

• 6.

  Drugs may enter milk via spaces between mammary alveolar cells.

• 7.

  Most ingested drugs appear in milk; drug amounts in milk usually do not exceed 1% of ingested dosage, and levels in the milk are independent of milk volume.

• 8.

  Drugs are bound much less to milk proteins than to plasma proteins.

• 9.

  The drug-metabolizing capacity of mammary epithelium is not understood.

Absorption from Gastrointestinal Tract

Although concern surrounds the amount of a given agent in the breast milk, of greater importance is the amount absorbed into an infant’s bloodstream. No accurate way exists to predict this because numerous factors affect absorption from the gastrointestinal (GI) tract and the metabolic and elimination processes acting on the drug in an infant’s bloodstream. The tolerance of the chemical to the pH of the stomach and the enzymatic activity of the intestinal tract are additional significant factors. The volume of milk consumed is a factor as well. Some drugs are not well absorbed with food (see later discussion of food–drug interactions). The oral bioavailability of a compound is a major factor relative to the exposure of an infant to a drug.

Infant’s Ability to Detoxify and Excrete Agent

Any drug given to an infant by any route has to be evaluated according to the infant’s ability to detoxify or conjugate the chemical in the liver and excrete it in the urine or eliminate it in stool. Some compounds that appear in milk at very low levels are not well excreted by infants and therefore can accumulate in infants’ systems to the point of toxicity.

Drugs that depend on the liver for conjugation, such as acetaminophen, are theoretic risks because of the limited reserve of the neonatal hepatic detoxification system. When actual measurements were made of neonates given acetaminophen, they were noted to handle it well because they conjugate it in the sulfhydryl system as an alternative pathway, which is used only to a small extent in adult metabolism of acetaminophen. When a single dose of a drug is given to a mother and the level is measured in her milk and in her infant, it does not give a clear picture of the potential for accumulation in the infant’s system. The competition for binding a drug to protein is also important. Some drugs, such as sulfadiazine, compete for binding sites that might normally bind bilirubin in the first week or so of life. This puts an infant in jeopardy of kernicterus at a given bilirubin level because of an increase in the fraction of bilirubin left unbound for lack of binding sites.

The Maturity of Infant in Early Life

The maturity of an infant at birth is an extremely important factor during the first few months of life; thus the gestational age at birth should be established. Clearly, the less mature the infant, the less well tolerated drugs are, not only because of the immaturity of the organ systems but also because of differences in body composition ( Fig. 11.2 ). The less mature an infant, the greater the water content of the body and the proportion of extracellular water. Although the percentage of body weight that is protein is similar for all newborns (i.e., 12%), the absolute amount of protein for binding is less the smaller an infant is. The amount of body fat is also low, by percentage of body weight and in absolute values. The distribution of highly lipid-soluble drugs therefore will be more apt to deposit in the brain of a 1000-g infant with 3% body fat by weight than in a 3500-g full-term infant with 12% body fat. This may explain the more sedating effect of a drug on the central nervous system (CNS) of a smaller, younger, and less mature infant. The relative lack of plasma protein-binding sites in a small, premature infant compared with a more mature, older infant results in more free (unbound) active drug in circulation. Complications of premature birth, such as acidosis and hypoxia, also contribute to the unavailability of albumin-binding sites and thus result in more unbound drug.

The inability of the liver to metabolize drugs effectively results in the accumulation of some compounds that might be readily cleared by an older infant. At about 42 weeks’ conceptual age, an infant’s liver is able to metabolize most drugs competently. Renal clearance similarly is less effective with decreasing maturity, which increases the risk for drug accumulation. The need to dose a premature infant less frequently is common to many drugs, such as antibiotics, caffeine, and theophylline, and confirms that a small, premature infant does not clear drugs well.

Metabolic Problems in Early Life

Special problems in neonates, in addition to the presence of jaundice or low serum albumin, may require special consideration. Low Apgar scores at birth, signifying some degree of stress, hypoxia, or acidosis, may alter binding-site availability but may also alter the metabolism and excretion of a drug. Continuing respiratory distress requiring ventilatory support, sepsis, and renal failure demand special consideration when determining if a sick neonate can receive the mother’s milk when she is being treated with certain medications. Prescribing for such a mother should be done in consultation with the neonatologist if the woman is providing milk for her infant.

Age

The age of an infant makes a difference in the total volume of milk consumed; in an older child (already taking complementary foods), the child’s diet includes other food items so that milk does not compose the total intake. Age can influence the pH of the stomach, the amount of catabolic enzymes in intestinal secretions, and the integrity of the mucosal barrier, thus affecting drug ionization, metabolism, and absorption. Age influences the infant’s ability to metabolize drugs more effectively; for example, sulfa drugs can be given to infants after the first month of life, whereas they may cause toxicity in the first month of life. The age of the child also must be taken into consideration with regard to the volume of breast milk ingested per feeding and per day, with a greater volume of milk leading to greater exposure. The usual estimate of intake for an exclusively breastfed infant is 150 mL/kg per day. The agent may appear in low levels in a mother’s serum, but mammary blood flow during lactation is 500 mL/min, and a mother produces between 60 and 300 mL of milk per hour. Even an agent that appears in minimal concentrations in the milk may present a significant problem when one considers that 1000 mL of milk may be consumed in a day by an older infant. Even though the volume is low during the colostral phase of lactation, the breast itself is more permeable to drugs; therefore a higher concentration of drug may enter the colostrum. The immaturity of the infant’s developing organs may predispose those organs to greater sensitivity/toxicity to certain medications.

Prolonged Therapeutic Use

If a medication will have to be taken for weeks or months, as with cardiovascular drugs, the drug has a greater potential impact than when taken only for a few days. If the drug exposure has already occurred for 9 months in utero, some think it is less of an issue during lactation; however, the presence of the drug in the milk may compound the problem.

To determine the dose delivered to an infant, the following formula is used:

The average daily dose the infant receives can also be calculated, as follows:

There is variability in the daily milk intake for an exclusively breastfed infant because of the age of the child, the child’s nutritional needs, and the growth and age of the child. ¹⁹ The routinely accepted value for daily milk intake of an exclusively breastfed infant is 150 mL/kg per day, which can be used for estimates.

It has been recommended by Ito and by Hale that the calculation be the relative infant dose (RID), which is the weight-adjusted percentage of the maternal dosage. ¹² , ²⁰ It is commonly calculated as follows:

The WHO Working Group on Drugs and Human Lactation and others recommend that the RID be less than 10% of the lower dose of the weight-adjusted maternal or infant dosage. They also state that an RID of greater than 25% is enough to proscribe the use of the medication in a lactating mother. There are no published data to justify these specific cutoff values. There are a number of variables that compound the use of the RID in predicting drug safety in lactating women—for example, a mother’s daily dose can vary significantly, the infant’s postnatal age will influence the infant’s milk intake and the enterohepatic circulation of the drug, the drug’s bioavailability in the infant compared with an adult, the existence of active metabolites of a drug, and the fact that the RID may also be reported as a range of percentages. Although there are limitations to the use of RID to predict the safety of medication use during breastfeeding, an appropriately calculated and reported RID can be useful when it is low and is thoughtfully combined with other important drug information for lactating women and infants.

Sensitization

Is sensitization a risk, even in the small dosages of a drug that might pass into the milk? This question arises most frequently with the use of antibiotics, and the use of penicillin is most frequently questioned. Certainly, if a family has a strong history of drug sensitization, it should be considered. In that case, however, it should be questioned for a mother as well. Whether infants are put at risk for developing resistant strains of bacteria in their systems by small amounts of antibiotics in their feedings is a serious question. It is not a question that has been adequately addressed in the literature. It is as pertinent for the dairy and meat industries as for the humans who consume the food products that have a small amount of antibiotics because of administration to livestock.

Oral Bioavailability

The dose of a drug delivered via milk to an infant is significantly affected by oral bioavailability, which is the percentage of the drug absorbed into the infant’s system via the gut.

Oral bioavailability is the rate and extent to which an active drug is absorbed and enters the general circulation. Absolute oral bioavailability compares the oral route with the IV route. To reach the general circulation, an oral dose must pass through the wall of the gut, liver, or mucosa of the upper respiratory tract. ²¹ First-pass metabolism or elimination in the tissues of these three organs may reduce a drug’s bioavailability. It is possible for a drug to be 100% absorbed and be destroyed or eliminated and have 0% bioavailability because it is so rapidly metabolized.

If a compound is poorly absorbed, it is of less concern than one with 100% bioavailability. Most drugs administered by injection (e.g., insulin, heparin, gentamicin) only are not orally bioavailable.

Food–Drug Interactions

When drugs are taken with meals, numerous opportunities exist for food–drug interactions to occur. ²² Because a breastfed infant receives all maternal medications excreted in the milk “with food,” this is an important consideration in the discussion of drugs in milk. The effects of food may reduce GI absorption or irritation. Mechanisms of food–drug interactions can be summarized as follows. ²²

Physiologic

• 1.

  Changes in gastric emptying

• 2.

  Increased intestinal motility

• 3.

  Increased splanchnic blood flow

• 4.

  Increased bile, acid, and enzyme secretion

• 5.

  Induction and inhibition of drug metabolism

• 6.

  Competition in active transport

Physiochemical

• 7.

  Food as a mechanical barrier to absorption

• 8.

  Altered dissolution of drugs

• 9.

  Chelation and adsorption

Pharmacodynamic

• 10.

  Altered enzyme activity

• 11.

  Changes in homeostasis

Factors Favoring the Safe Maternal Use of a Medication During Lactation

There are a number of factors favoring the maternal use of a medication, drug, or product during lactation once it is clear that that the mother has an appropriate diagnosis and indication for the use of the medication.

• 1.

  Pediatric approved use of the medication—The medication is safely used in infants and children with a known dose range.

• 2.

  Favorable safety profile—There is a documented side-effect profile from appropriate studies of medication use in children and/or published information regarding the medication’s safe use during lactation. Or the agent is listed in the generally recognized as safe (GRAS) listing maintained by the FDA.

• 3.

  There is evidence that the medication has little or no effect on the mother’s milk supply or breastfeeding.

• 4.

  The medication has low or no oral bioavailability

• 5.

  Low or very low RID: <10%, <5%, or <1%.

• 6.

  The medication has specific characteristics that are likely to lead to a lower amount of the drug in breast milk, such as shorter half-life, high protein binding, and high molecular weight. There are no or limited active metabolites that could add to the amount of active drug in the milk or affect the mother or infant.

• 7.

  There is adequate information about the potentially exposed infant, including age, size/weight, and amount of milk ingested daily, and no significant conditions affecting excretion, metabolism, or probable sensitivity to the medication

• 8.

  Additional precautions for the use of herbal product include the following: (1) know the chemical substances contained in the herb and their reported effects; (2) consider products from known, reliable sources; (3) use a “pure” form of the herb, not a mixture of herbs; (4) use the lowest dose necessary; and (5) consult a herbalist, lactation consultant, or physician knowledgeable about the herb’s use during lactation before use.

Minimizing The Effect of Maternal Medication

If a mother truly needs a specific medication and the hazards to the infant are minimal, the following important adjustments can be made to minimize the effects:

• 1.

  Do not use the long-acting form of the drug because the infant may have more difficulty renally excreting such an agent or detoxifying it in the liver. Accumulation of the drug or an active metabolite in the infant is then a genuine concern.

• 2.

  Schedule doses so that the smallest possible amount gets into the milk. Check the usual absorption rates and peak blood levels of the drug. Having a mother take the medication immediately after breastfeeding is usually the safest time for the infant with most, but not all, drugs.

• 3.

  Watch the infant for any unusual signs or symptoms, such as a change in feeding pattern or sleeping habits, fussiness, or a rash, whenever the mother takes medication.

• 4.

  When possible, choose the drug that produces the least amount in the milk (e.g., sulfonamides; see Tables 11.1 and 11.2 ).

Drugs in Lactation Resources

The Breastfeeding and Human Lactation Study Center at the University of Rochester continually updates its database on drugs, medications, and contaminants in human milk. (See Chapter 25 .) More than 4000 references pertain to drugs in the database. In addition, other drugs typically used by women in their childbearing years for which there are no specific milk levels are listed with their oral bioavailability for infants, peak serum time in the mothers, volume of distribution for the drugs, and other pharmacologic information (pH, solubility, protein binding, metabolism) obtained from a host of resources. With this information, a physician should be able to determine relative risk and thus select the best compound and adjust the dose and the time of, and association to, the breastfeeding.

The Breastfeeding and Human Lactation Center is available during limited hours (8 am to 4 pm EST, Monday to Friday) to address more complex questions (585-275-0088).

LactMed is an extensive database (Drugs and Lactation Database) maintained and updated frequently by the National Library of Medicine and the professional contributors. It can be accessed at http://www.ncbi.nlm.nih.gov/pubmed/30000282 . ⁴

E-Lactancia is a database resource maintained by the Association for Promotion and Cultural and Scientific Research of Breastfeeding in Spain ( http://www.e-lactancia.org ). ²⁵

The Infant Risk Center is a website and call center resource at the University of Texas Tech University Health Science Center connected with Dr. Thomas Hale and his team (available at www.infantrisk.com and 806-352-2519). ²⁶

Mother to Baby is the database and call center established in 2013 by the Organization of Teratology Information Specialists (OTIS) as the public face for the organization’s research and information service to mothers, families, and professionals concerning questions about pregnancy and lactation. OTIS was established in 1987 to connect world-renowned experts in the field of birth defects research to the general public. The Mother to Baby Organization answers questions and concerns related to pregnancy and lactation about the risks of medications, chemicals, herbal products, illicit drugs, diseases, and more via e-mail, telephone, and open chat ( https://mothertobaby.org , 866-626-6847).

Analgesics

Analgesia is an essential consideration for the mother in the peripartum and postpartum period through the duration of lactation. Pharmacologic and nonpharmacologic pain relief during labor and the postpartum period can improve overall maternal and infant outcomes by relieving suffering but may have consequences for breastfeeding. The Academy of Breastfeeding Medicine (ABM) has published an evidence-based clinical protocol on peripartum analgesia and anesthesia for the breastfeeding mother. ²⁷ There is a second clinical protocol from the ABM addressing analgesia and anesthesia for the breastfeeding mother outside the immediate postpartum period. ²⁸ Benoit et al. have summarized the evidence for breastfeeding as analgesia for infants. ²⁹ Physicians can familiarize themselves with the guidelines published by the ABM and then refer to the databases, Infantrisk.com and LactMed, to review up-to-date information on specific agents being considered for use in a lactating mother. Refer to Chapter 15 , Medical Complications of Mothers, for specific medical conditions.

Anesthesia

The ABM’s clinical protocols on anesthesia in the peripartum period and beyond provide appropriate evidence-based guidance on the use of anesthesia for breastfeeding mothers. ²⁷ , ²⁸ There is a review of obstetrical anesthesia from the anesthesiologist’s perspective written by Lim et al. for additional reference. ³⁰

Antibiotics

Antibiotics are one of the most frequently utilized medications during lactation, along with analgesics and vitamins. The majority of antibiotics have recommended uses in infants and children for their own diagnosed infections and can be safely given to breastfeeding mothers. ³¹ , ³² Exposure of infants to antibiotics in any form raises concerns for sensitization, changes in intestinal flora (diarrhea or altered intestinal microbiome), and the development of drug-resistant microorganisms. Data are conflicting concerning early life antibiotic exposure and downstream effects of alteration of the infant’s intestinal microbiome (obesity, adiposity, inflammatory bowel disease, autism, or other nervous system effects). Van Wattum et al., in their systematic review, reported on a comparison of the absolute infant dose as a percentage of the therapeutic infant dose for 20 different antibiotics. The absolute infant dose for metronidazole was just over 10% of the therapeutic infant dose, vancomycin and azithromycin were approximately 6%, and the other 17 antibiotics were less than 4%. ³² The low levels of absolute infant dose from breastfeeding are highly unlikely to cause a problem for breastfeeding infants, whether they also are receiving the same antibiotic or not. Specifically, lactating mothers can use the penicillins, cephalosporins, vancomycin, and aminoglycosides without concerns relative to their infants. The notable exceptions to the apparent safety of antibiotics and breastfeeding include sulfonamide exposure in an infant less than 4 weeks of age because of concern for interference with bilirubin binding to albumen, tetracycline-related medications because of teeth staining and abnormal bone growth with prolonged exposure, chloramphenicol in infants related to “gray baby” syndrome or idiosyncratic bone marrow suppression, and erythromycin or azithromycin because of its association with pyloric stenosis when administered to infants in the first 4 to 6 weeks of life. For these antibiotics, a specific risk–benefit assessment should be reviewed with the mother. Chloroquine, gentamicin, streptomycin, and rifampin are reported by the AAP to be safe because they are not excreted in milk. ¹⁰

Anticholinergics

Anticholinergic drugs include atropine, scopolamine (hyoscine), and synthetic quaternary ammonium derivatives, some of which are available in over-the-counter medications. Some atropine does enter the milk. There are very limited data on their use during lactation. Infants are particularly sensitive to these drugs; therefore infant monitoring should include drowsiness, insomnia, dry and hot skin, dry mouth, increased heart rate, and constipation or urinary retention. The quaternary anticholinergics, however, should not appear in milk to any degree because, as anions, they do not pass into the relatively acidic milk. Mepenzolate methylbromide (Cantil) does not appear in milk.

Scopolamine is available by dermal patch for motion sickness and causes maternal mucous membrane dryness, which could affect milk production because it restricts the secretions of other secretory glands. Only a small amount appears in milk. The AAP rates it and atropine as category 6, drugs usually compatible with breastfeeding, and Hale ranks atropine as L3 (no data—probably compatible). For the scopolamine patch, which provides a constant level of drug, there are no data on its transfer into breast milk, but it is poorly orally bioavailable. Pressure-point wristbands are reported to be effective for motion sickness in pregnancy and lactation and contain no medication.

Gastrointestinal Medications