General commentary on drug therapy and drug risk during lactation

3.1

The advantages of breastfeeding versus the risks of maternal medication

No discussion of the risks of maternal medications can be undertaken without an understanding of the benefits of being breastfed for the child. Advantages to breastfeeding have been recognized in general terms for decades. However, new information and evidence-based studies following breastfed infants for months and even years have identified many additional advantages and protections provided by human milk and the process of breastfeeding.

The nutrient advantages can be simply stated by “species specificity” (see Table 3.1 ). The nutrient needs of the human infant are specifically met by the nutrient content of human milk. The most dramatic evidence of this is demonstrated by the comparative advantages to brain growth, visual acuity, auditory acuity, and scores on developmental tests related to infants who are exclusively breastfed, compared to infants who receive traditional formulas. These data are substantiated by multiple studies in both premature and full-term infants. Along with the ideal nutrients, such as omega-3 fatty acids, whey protein, and high levels of lactose, the energy for the brain, are the presence of enzymes and ligands that facilitate the digestion and absorption of nutrients, including the micronutrients.

The other well-documented advantages of human milk are the infection-protection qualities that protect the breastfed infant from respiratory infections, otitis media, gastrointestinal infections, and even urinary tract and meningeal infections and necrotizing enterocolitis (NEC) ( ). The study of the immunologic properties of human milk has shown that infants who are exclusively breastfed for at least 4 months have a reduced risk of childhood onset diabetes, Crohn’s disease, celiac disease, and childhood-onset cancers – especially leukemia. Hundreds of articles testing the allergy protection of human milk have shown a clear advantage in being breastfed for potentially allergic children ( ).

There are many advantages to breastfeeding for the mother herself. The process facilitates a rapid recovery postpartum, with a reduced loss of blood and prompt involution of the uterus to its pre-pregnant state. Further breastfeeding prevents postpartum depression ( ), and reduces the long-term risk of obesity and osteoporosis for the nursing mother. Studies of specific diseases show that there is a reduced risk of breast cancer and ovarian cancer for women who breastfeed ( ). Finally, the special relationship between mother and infant that develops while the infant suckles at the breast has always been a prime reason to breastfeed.

Determining the risk–benefit ratio of maternal medication for a given infant, requires taking all of the tremendous advantages under consideration and understanding the specific risk of the medication to a given child. For example, if the child is in a developing country where the risk of dying of an infectious disease in the first year of life is 50% for those infants who receive formula, then the risk of a maternal medication is relatively insignificant by comparison.

The World Health Organization (WHO) and the Innocenti Declaration state clearly the importance of infants being breastfed. The Innocenti Declaration was reaffirmed in 2006 at its fifteenth-year anniversary, once again urging exclusive breastfeeding for the first 6 months of life followed by continued breastfeeding with the addition of solid foods through to 12 months of age, and for as long thereafter as mother and child wish.

The incidence of breastfeeding decreased significantly throughout the 1970s and 1980s and is now slowly increasing worldwide because of a vigorous effort on the part of many supportive organizations to reverse the trend of bottle feeding. The most extensive program is the Baby Friendly Hospital Initiative (BFHI), which was begun by the United Nations International Children’s Emergency Fund (UNICEF). The BFHI has spread throughout most of the developing world, but has been slowly accepted in Western cultures. BFHI requires that all hospitals have a breastfeeding policy and that all staff be thoroughly trained in the introduction and management of breastfeeding. In addition to adequate training of the staff, all infants should be put to breast within the first hour of life. It is also required that dummies or pacifiers not be provided to breastfeeding infants, and that BFHI hospitals pay for any formula utilized, accept no free samples, and distribute no free samples to their patients.

While encouraging mothers and babies to breastfeed in the hospital, support needs to be provided at home as well by the mother’s physician, the pediatrician, the nurse midwife, and office staff, as well as licensed, board-certified lactation consultants. With respect to medications, however, proper information is essential. Many mothers are told to wean because of the medication that they must take. This is actually very rarely necessary. The information available to the practitioner, however, may often be incorrect. Package inserts and the physician’s desk reference, for instance, almost always suggests that the drug is not recommended during lactation, not because there is negative information but because the manufacturer has not provided any studies or information that would permit them to say it is safe. This may also lead to poor compliance – that is, the mothers do not follow medical advice. In a prospective study carried out at a counseling center among 203 breastfeeding mothers who were prescribed an antibiotic compatible with breastfeeding, 15% of the women did not take the medication prescribed and 7% stopped breastfeeding ( ). It therefore becomes the responsibility of the practitioner, using relevant medical literature, to adequately inform the breastfeeding mother, and to determine whether the drug will enter the milk in a relevant quantity or present any problems for the child. The AAP Committee on Drugs ( ) has published a new statement proclaiming that “The benefits of breastfeeding outweigh the risk of exposure to most therapeutic agents via human milk.”

3.2

The passage of medications into the mother’s milk

It is important to be aware of the characteristics of the drug itself, the ability of a given mother to absorb, metabolize, and excrete the medication, and the infant’s ability to absorb, detoxify, and excrete the agent. The infant’s age influences the latter ability, and no decision can be made about a given drug without knowing the age of the infant.

The significant characteristics of the drug include the route of administration, the absorption rate, the half-life or peak serum time, the dissociation constant, and the volume of distribution. The passage of a drug is influenced by the size of the molecule, its ionization, and the pH of the substrate (plasma 7.4, milk 6.8), the solubility in water and in lipids, and the protein binding. The distribution of a compound may follow one of several pathways ( Figure 3.1 ).

The solubility of a drug is important because the alveolar and epithelial layer of the breast is a lipid barrier that is most permeable in the first few days of lactation, when colostrum is being produced. The solubility of a compound in water and in lipid is a determining factor for its transfer throughout lactation (see Table 3.2 ).

Drugs pass into milk by five identified pathways: (1) simple diffusion, (2) carrier mediated diffusion, (3) active transport, (4) pinocytosis, and (5) reverse pinocytosis. If it is assumed that the body is a single compartment and the blood is distributed in the compartment uniformly, then an important characteristic of the drug is the volume of distribution (Vd) which can be calculated as the quotient of the total amount of drug in the body/concentration of drug in the plasma. Thus, drugs with a large volume of distribution do not get into the milk in any amount as compared to drugs with a low volume of distribution which pass into the milk from the plasma in greater amounts.

3.3

Infant characteristics

In addition to the parameters of the drug and the dose in mother’s serum, and the amount in the milk, the characteristics of the infant are essential. The most important is the age and maturity of the infant, because the infant’s ability to absorb, metabolize, and excrete the drug are dependent on this. Therefore, medications in the milk are of greater concern in the first weeks of life than with a month or a year of age. For example, when a mother is taking a medication that is poorly excreted by a neonate, such as aminophylline, it may be well excreted by a 1-year-old and is not accumulated.

Absorption from the infant’s gastrointestinal tract is dependent on the bioavailability of the drug, the effect of gastric pH and gastric enzymes, and the presence of food, which may impair absorption. Obviously, drugs in breast milk are present with food. If a medication can be given directly to an infant (for example, acetaminophen ), it can be given to the nursing mother. Infants tolerate acetaminophen very well, detoxifying it in the sulfhydryl pathway rather than the glucuronidase pathway.

Infants’ liver and kidneys are immature at birth. Thus, a drug that depends on liver metabolism, such as sulfadiazine , will compete with the bilirubin metabolism. A drug such as aspirin competes for albumin-binding sites in the infant, displacing bilirubin in the first month of life. However, clinical relevance may be questionable, due to the small amounts of a drug transferred via breast milk. In the case of aspirin, it is salicylic acid that passes into the milk and not acetyl-salicylic acid; thus, it does not interfere with platelets in the infant.

Renal excretion is also immature early in life and a drug that depends on renal excretion, such as caffeine , theophylline , and some antibiotics, will accumulate in the infant in the first weeks and months of life but will gradually be better tolerated as the infant excretes it more effectively. These same drugs when given to an infant directly are given less frequently (daily instead of twice daily) in the first week of life.