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Principles of Drug Use During Lactation


It is not disputed that breastfeeding has many benefits for both mother and baby and is the optimal nutrition for infants. With an increase in education and support of breastfeeding mothers throughout the United States, the rate of breastfeeding is on the rise. The Centers for Disease Control and Prevention report an increase of breastfeeding initiation from 79% in 2011 to 81.1% in 2013, with a steady annual increase since 2008. As the incidence rises, there are more situations in which lactating women are exposed to various medications and more questions regarding the safety of these medications to the infant. Almost all medications enter the breast milk, but the amount in breast milk, and more importantly the amount absorbed by the infant, is rarely well defined. Despite this lack of information, most drugs are considered safe while breastfeeding. In the absence of specific details for a particular drug's passage into breast milk, the clinician can evaluate the physicochemical characteristics of the drug as well as the patient characteristics to determine the appropriateness of breastfeeding while the mother is taking the medication.

Passage of Exogenous Compounds From Maternal Blood to Milk

In general, drugs enter breast milk by passive diffusion. The presence and concentration of compounds in breast milk depend on a number of important factors, including the drug's molecular weight, degree of ionization, protein binding in blood, lipid solubility, and specific uptake by mammary tissue, as well as the amount and composition of the milk. The constituents of breast milk vary relative to the postpartum period and could influence drug distribution and accumulation within breast milk, depending on the drug's physiochemical characteristics. Drug characteristics that minimize the risk of transfer into breast milk are shown in Box 44.1 .

Box 44.1
Drug Characteristics That Minimize Transfer into Breast Milk

  • Molecular weight >200 daltons

  • Weakly acidic

  • High degree of protein binding

  • Water soluble

Small compounds with molecular weights of less than about 200 daltons appear freely in breast milk and are presumed to have passed through pores in the mammary alveolar cell. Large compounds such as insulin or heparin, or those that are protein bound, do not enter the milk. Intermediate-sized compounds must penetrate the lipoprotein cell membrane by diffusion or active transport. Drugs or other chemicals that are very lipid soluble readily cross the alveolar cell, and because breast milk contains a considerable amount of lipid, these compounds are trapped in the milk. In general, drugs that are not ionized at blood pH traverse the alveolar cell membrane with greater ease than highly ionized compounds. Therefore, weak acids, which are more likely to be ionized at the plasma pH of 7.4, are less likely to enter breast milk, whereas weak bases pass into breast milk more readily. Because breast milk pH is 7 or slightly less, once a weak base crosses into breast milk, it may become more ionized and trapped.

A number of important variables specific for the type of drug, age, and time after delivery or disease influence a drug's ability to penetrate into breast milk. The interrelationships between these and other variables yet to be identified are complex, making it very difficult to predict the actual amount of drug distribution into the milk. Although many investigators and clinicians have attempted to collapse the many important characteristics into one simple surrogate marker of drug penetration into breast milk—the ratio of milk to plasma protein (M/P ratio)—this parameter is overly simplistic and often misrepresents the true nature of drug distribution into breast milk. The M/P ratio is defined as the ratio of the drug concentration in breast milk to the drug concentration in maternal plasma at a simultaneous point in time after maternal drug administration. A low M/P ratio (<1) is supposed to indicate no accumulation of drug in the mother's milk. However, the M/P ratio is based on the assumption that the drug concentrations in maternal blood and milk are constant and in equilibrium at the time of sampling, which is most often not true. Based on its limitations, the M/P ratio should be used with caution, if at all, as a means of quantitating drug distribution in breast milk and infant exposure.

Alternatively, the relative infant dose (RID) can be used as a more accurate tool to estimate infant exposure to a drug if there are data available on the concentration of drug in the breast milk and volume of milk ingested by the infant (often estimated at 150 mL/kg/day). The RID can then be calculated by dividing the infant dose measured in the breast milk (mg/kg per day) by the maternal dose (mg/kg per day) and expressing it as a percentage. It has been suggested that a RID greater than 10% may be of concern; however, every drug is different and depending on the specific patient and drug characteristics, a RID greater than 10% may be acceptable.

Delivery of Compounds to and Disposition by the Infant

After ingestion of a drug via breast milk, the drug must either act locally in the infant's gut or be absorbed by the infant into systemic circulation to produce an effect. Generally, if a drug is not orally bioavailable (e.g., vancomycin), the infant will not absorb the medication, even if it is present in breast milk. However, it is possible that the bowel of a very young infant may permit the absorption of large molecules that are normally excluded. Another potential barrier to absorption is found in milk proteins that bind certain drugs and impede absorption. Unfortunately, for most drugs, the extent of oral absorption by the breastfed infant is unknown. If absorption does occur, the infant's handling of the medication is often unclear and changes with postnatal age. Ultimately, close monitoring of the infant for adverse effects associated with the maternal drug therapy is required.

Compounds in Breast Milk

Antibiotics

Fortunately, most antimicrobial agents in breast milk appear to be safe for nursing infants. Some antibiotics, particularly those with broad antimicrobial spectra, may change the infant's intestinal flora and cause diarrhea or thrush, but this quickly resolves upon discontinuation of the antibiotic and is not considered a contraindication to breastfeeding. Two antibiotic classes that are sometimes considered contraindicated in breastfeeding include sulfonamides and tetracyclines.

Sulfonamide derivatives are sometimes avoided during lactation, because they have the potential to displace bilirubin from albumin. The amounts present in breast milk, combined with the actual bioavailable dose to the infant, suggest that maternal sulfonamide administration is acceptable during breastfeeding except in neonates at high risk for hyperbilirubinemia, including extremely premature neonates or those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Tetracyclines in breast milk purportedly have the potential to cause dental staining, and many sources have suggested that women taking tetracyclines avoid breastfeeding. Closer examination of these suggestions against breastfeeding during tetracycline therapy appear to be based on theoretical grounds rather than any supporting evidence. Moreover, the bioavailability of tetracyclines under the conditions of breastfeeding suggests that the maternal administration of tetracycline and its analogues is safe and without complications in infants.

Overall, maternally administered antibiotics are considered safe for the breastfed infant, and only in rare instances should mothers requiring antibiotic therapy be recommended to discontinue breastfeeding their infant.

Anticoagulants

The use of anticoagulants may be critical to health of a mother with a history of pulmonary embolism, venous thrombosis, or other clotting disorder. Both parenteral and oral anticoagulant options are available that are compatible with breastfeeding. Heparin has a molecular weight of about 20,000 daltons and does not enter breast milk. Newer synthetic heparin has a much lower molecular weight (3000 daltons) but is still too large for passage into breast milk. Additionally, heparins are unstable in gastric contents, so any small amount that might pass into breast milk would be quickly degraded. Oral anticoagulants of the indanedione group, as well as bishydroxycoumarin and ethyl biscoumacetate, are found in milk and have been associated with infant coagulopathies. It is unknown if newer agents, including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban, transfer into breast milk, but each of these agents has at least one physicochemical property that favors transfer. Therefore, warfarin is considered the oral drug of choice, as it is a weak acid with a high degree of protein binding and it is undetectable in breast milk.

Anticonvulsants

Anticonvulsants are a common concern for breastfeeding mothers, whether being used for treatment of a seizure disorder or as a mood stabilizer. Valproic acid, lamotrigine, and topiramate are a few of the commonly used anticonvulsants. Valproic acid is known to have teratogenic potential when taken during pregnancy but is thought to be compatible with breastfeeding because of the low levels of drug transferred to milk (RID = 1.4%-1.7%). Lamotrigine and topiramate, on the other hand, are more readily transferred into breast milk, with a RID of 9.2%-18.3% and 3%-23%, respectively. Despite the fact that these drugs can be detected at significant levels in the plasma of breastfeeding infants, there are minimal reports of adverse effects in the infants. Breastfeeding while taking any of the above anticonvulsants should be encouraged, with appropriate monitoring of the infant for any signs of toxicity (e.g., apnea, sedation).

Other anticonvulsants that are less commonly used include phenytoin, phenobarbital, and lithium. Phenytoin is found in small amounts in breast milk and is considered compatible with breastfeeding. Barbiturates, including phenobarbital, appear to be safe. However, phenobarbital is metabolized much more slowly in neonates than adults; it is possible that the drug may accumulate in the breastfed infants of phenobarbital-treated mothers. These infants should be monitored for lethargy and poor weight gain.

Lithium has been contraindicated during lactation because of a few case reports that described significant cardiovascular and central nervous system signs in two infants. It would appear from a closer evaluation of these cases that transplacental exposure cannot be ruled out, and maternal drug interaction may have predisposed these infants to a level of lithium toxicity beyond what would have occurred from breastfeeding alone. As a result, breastfeeding mothers who require lithium therapy should be permitted to continue to breastfeed, with close infant monitoring that could include the measurement of blood lithium concentrations in the infant 1-2 weeks after initiating breastfeeding, renal function tests, and thyroid function tests. Consideration should be given to an alternative anticonvulsant if an adjustment in the mother's therapy is not likely to compromise her health.

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