Introduction

It’s now well known that human milk is the best nutrition for infants. The benefits are simply enormous and supported by a world of excellent literature. Further, it is becoming more and more apparent that breastfeeding has long-lasting health benefits for the mom. However, the use of medications in breastfeeding mothers is often controversial and is steeped with misinformation in the healthcare field. This book has for many years been the primary source for drug information and in breastfeeding mothers. The truth is, most drugs simply don’t enter milk in levels that are hazardous to a breastfed infant. The problem, however, is determining which drugs are safe and which are hazardous.

Because so few clinicians understand lactational pharmacology, the number of women who are advised to discontinue breastfeeding in order to take a medication is still far too high. Fortunately, many mothers are now becoming aware of the enormous benefits of breastfeeding and simply refuse to follow some of the advice given by their healthcare professionals. They seek out the information on their own and invariably find this book or my websites.

Because almost all mothers will ingest medications during the early neonatal period, it is not surprising that one of the most common questions encountered in pediatrics concerns the use of various drugs in the breastfeeding mother. Unfortunately, most healthcare professionals simply review the package insert or advise the mother not to breastfeed without having done a thorough study of the literature to find the true answer. Discontinuing breastfeeding is often the wrong decision, and most mothers could easily continue to breastfeed and take the medication without risk to the infant. Even the FDA has recognized this and now recommends drug manufacturers carry out studies to determine milk levels of their drug.

It is generally accepted that all medications transfer into human milk to some degree, although it is almost always quite low. Only rarely does the amount transferred into milk produce clinically relevant doses in the infant. Ultimately, it is the clinician’s responsibility to review the research and make a clear decision as to whether the mother should continue to breastfeed.

However, once medications transfer into human milk, other kinetic factors are involved. One of the most important is the oral bioavailability of the medication to the infant. Numerous medications are either destroyed in the infant’s gut, fail to be absorbed through the gut wall, or are rapidly picked up by the liver. Once in the liver, they are either metabolized or stored, but often never reach the mother’s plasma.

Drugs normally enter milk by passive diffusion, driven by equilibrium forces between the maternal plasma compartment and the maternal milk compartment. They pass from the maternal plasma through capillaries into the lactocytes lining the alveolus. Medications must generally pass through both bilayer lipid membranes of the alveolar cell to penetrate milk; although early on, they may pass between the alveolar cells (first 72 hours postpartum). During the first three days postpartum, large gaps between the alveolar cells exist. These gaps permit enhanced access into the milk for most drugs, many immunoglobulins, maternal living cells (lymphocytes, leukocytes, macrophages), and other maternal proteins. By the end of the first week, the alveolar cells swell under the influence of prolactin and subsequently close the intracellular gaps thus reducing the transcellular entry of most maternal drugs, proteins, and other substances into the milk compartment. While it is generally agreed that medications penetrate into milk at higher levels during the colostral period, nevertheless, the absolute dose transferred during the colostrum period is still low due to the minimal volume of colostrum (30-100 mL/day) for the first few days postpartum.

In most instances, the most important determinant of drug penetration into milk is the mother’s plasma level. Almost without exception, as the level of the medication in the mother’s plasma rises, the concentration in milk increases as well. Drugs enter and exit milk as a function of the mother’s plasma level. As soon as the maternal plasma level of a medication begins to fall, equilibrium forces drive the medication out of the milk compartment back into the maternal plasma for elimination. Maternal plasma levels are almost always directly related to the maternal drug dose. Higher doses produce higher plasma levels, and therefore higher milk levels. It is always recommended to use drug doses evaluated in lactation studies. We often see doses up to five times higher than those researched, limiting the generalizability of the findings.

In some instances, drugs may be trapped in milk (ion trapping) due to the lower pH of human milk (7.2). Drugs with a high pKa may become trapped in the milk compartment due to ion trapping. This is important in weakly basic drugs, such as the barbiturates (drugs with high pKa).

There are some known cellular pumping systems that actively pump drugs into milk. The most important is iodine. The iodine pump is the same as found in everyone’s thyroid gland. Its purpose is to make sure the infant receives iodine to maintain thyroxine production.

The iodides, such as ¹³¹I or any “ionic” form of iodine, concentrate in milk due to this pump. Thus iodides, particularly radioactive ones, should be avoided as their milk concentrations are exceedingly high. Two other physicochemical factors are important in evaluating drugs in breastfeeding mothers—the degree of protein binding and lipid solubility. Drugs that are very lipid soluble penetrate into milk in higher concentrations almost without exception. Of particular interest are the drugs that are active in the central nervous system (CNS). CNS-active drugs invariably have the unique characteristics required to enter milk. Therefore, if a drug is active in the central nervous system, significant levels in milk can be expected; although, the amounts still are often subclinical. Many of the neuroactive drugs produce Relative Infant Doses of >5%. Protein binding also plays an important role. Drugs circulate in the maternal plasma, either bound to albumin or freely soluble in the plasma. It is the free component (unbound fraction) that transfers into milk, while the bound fraction stays in the maternal circulation. Therefore, drugs that have high maternal protein binding (warfarin, most NSAIDs) have low milk levels simply because they are bound in the plasma compartment and can’t get out.

Once a drug has entered the mother’s milk and has been ingested by the infant, it must traverse through the infant’s GI tract prior to absorption. Some drugs are poorly stable in this environment due to the proteolytic enzymes and acids present in the infant’s stomach. This includes the aminoglycoside family, omeprazole, and large peptide drugs, such as heparin, and most of the new monoclonal antibodies. Other drugs are poorly absorbed by the infant’s gastrointestinal tract and do not enter the infant’s blood stream. Thus, oral bioavailability is a useful tool to estimate just how much of the drug will be absorbed by the infant. Many drugs are sequestered in the liver (first pass) and may never actually reach the plasma compartment. Absorption characteristics such as these ultimately tend to reduce the overall effect of many drugs in breastfed infants. There are certainly exceptions to this rule, and one must always be aware that the action of a drug in the GI tract can be profound, producing diarrhea, constipation, and occasionally syndromes such as pseudomembranous colitis.

One of the more popular methods for estimating risk to the infant is the Relative Infant Dose (RID). The RID is calculated by dividing the infant’s dose via milk (mg/kg/day) by the mother’s dose in mg/kg/day. The RID gives the clinician a feeling for just how much medication the infant is exposed to on a weight-normalized basis. However, many authors calculate the infant dose without normalizing for maternal and infant weight, so be cautious. An RID has other limitations as well. It estimates infant exposure, but does not consider infant absorption. The RID also does not consider a comparative maternal dose. For example, a mother who doubles her dose still doubles the estimated exposure (Absolute Infant Dose or AID) to the infant as the RID stays the same.

Lastly, it is very important to always evaluate the infant’s ability to handle small amounts of medications. Some infants, such as premature or unstable infants, may not be suitable candidates for certain medications. But remember that early postpartum (and in late stage lactation), the amount of milk produced (30-100 mL/day) is so low that the clinical dose of drug transferred is often low, so even premature neonates would receive only a limited amount from the milk.

General Suggestions for the Clinician

Determine if the drug is absorbed from the GI tract. Many drugs, such as the aminoglycosides, vancomycin, cephalosporin antibiotics (third generation), magnesium salts, monoclonal antibodies, and large protein drugs (heparin), are so poorly absorbed that it is unlikely the infant will absorb significant quantities. At the same time, observe for GI side effects from the medication trapped in the GI compartment of the infant (e.g. diarrhea).

Review the Relative Infant Dose (RID) and compare that to the pediatric dose if known. Most older RIDs were derived using the C_max (highest milk concentration of the drug) that were published. In current research projects, we always calculate the average (C_ave) milk level throughout the dosing schedule. This estimate provided and average exposure rather than just the highest. we no longer use the milk/plasma ratio as it is virtually worthless unless you know the maternal plasma level. It does not provide the clinician with information as to the average amount of drug transferred to the infant via milk. Even if the drug has a high milk/plasma ratio, if the maternal plasma level of the medication is very small (such as with ranitidine), then the absolute amount (dose) of a drug delivered to the infant will still be quite small and often subclinical. Also consider the doses used in milk research versus the maternal dose being used in practice. Some drugs are used at significantly higher doses, and will result in a higher absolute amount of drug delivered to the infant.

Be cautious of drugs (or their active metabolites) that have long pediatric half-lives as they can continually build up in the infant’s plasma over time. The barbiturates, benzodiazepines, and meperidine are classic examples where higher levels in the infant can and do occasionally occur. Interestingly, the SSRI family have long half-lives, but are not retained in the infant’s plasma.

If you are provided a choice, choose drugs that have higher protein binding because they are generally sequestered in the maternal circulation and do not transfer readily into the milk compartment or the infant. Remember, it’s the free drug that transfers into the milk compartment. Without doubt, the most important parameter that determines drug penetration into milk is plasma protein binding. Choose drugs with high protein binding.

Although not always true, we have generally found centrally active drugs (anticonvulsants, antidepressants, antipsychotic) frequently penetrate milk in higher (not necessarily “high”) levels simply due to their physicochemistry. If the drug in question produces sedation, depression, or other neuroleptic effects in the mother, it may produce similar effects in the infant. Thus, with CNS-active drugs, one should always check the data in this book closely and monitor the infant routinely.

For radioactive compounds, we have gathered much of the published data in this field into several tables. The Nuclear Regulatory Commission recommendations are quite good, but they differ from some published data. They can be copied and provided to your radiologist. They are available from the Nuclear Regulatory Commission’s web page address in the appendix. With radioisotopes, we recommend you routinely call the InfantRisk Center for advice. Some are quite dangerous.

Use the Relative Infant Dose. In general, a Relative Infant Dose of <10% is considered safe, and its use is becoming increasingly popular by numerous investigators. But this depends on the drug. With risky anticancer drugs, a much lower RID is should be used in your evaluation of risk.

Most importantly, it is rare that a breastfeeding mother needs to discontinue breastfeeding just to take a medication. It is simply not acceptable for the clinician to stop lactation merely because of heightened anxiety or ignorance on their part. The risks of formula feeding are significant and should not be trivialized. Few drugs have documented side effects in breastfed infants, and we know most of these.

The following review of drugs is a thorough review of what has been published and what we presently know about the use of medications in breastfeeding mothers.

The authors make no recommendations as to the safety of these medications during lactation in clinical practice, but only review what is currently published in the scientific literature. Individual use of medications must be left up to the judgement of the physician, the patient, and other healthcare consultants.