Abstract
I
Area Under the Curve
The standard method of quantifying drug passage into breastmilk is the administration of a drug to a nursing mother and obtaining several timed breastmilk samples over a time period, usually 1 day or one dosage interval. After plotting these measured values on a graph versus time, the area under the milk concentration–time curve (AUC) can be measured. This value is not too clinically meaningful in itself, but it is a measure of the overall exposure of the infant to the drug. The AUC is clinically most useful for calculating the average drug concentration in breastmilk, which is obtained by dividing the AUC by the total time over which the samples were collected.
Estimated Infant Dosage
The average milk concentration calculated as mentioned can be used to calculate the average daily dosage of a drug that the infant received as follows:
Infant daily dosage = drug concentration in milk × daily volume of milk ingested.
The average drug concentration (as calculated) is usually used in the calculation, yielding the average infant dosage. Sometimes the highest measured concentration in breastmilk is used instead. This provides the maximum dosage that the infant would be exposed to.
Milk Volume
In the calculation mentioned, the daily milk intake is assumed to be 150 mL/kg for an exclusively breastfed infant. But in reality, milk intake is not a constant value, but varies with the age of the infant. 1 The volume of colostrum is only 13–17 mL/kg on day 1. By day 7, average milk intake is about 160 mL/kg/day. A maximum value of 170–180 mL/kg/day occurs around 28 days of age. It then slowly drifts lower, reaching the 150 mL/kg mark during the second month. By 56 days of age, the value has decreased to 130 mL/kg/day, at 90 days of age the value is about 120 mL/kg/day, and at 6 months of age, the value for exclusive breastfeeding is only about 110 mL/kg/day. Of course, if a mother is not exclusively breastfeeding, these values (and consequently, the drug dosage) would be lower for her infant.
Nevertheless, the value of 150 mL/kg/day is well established in the pharmacokinetic literature and it does provide a standard by which the infant dosages of drugs in breastmilk can be compared with each other. However, it is important to remember that for an individual infant, the volume of milk ingested can be quite different from this value.
M/P Ratio
If maternal plasma drug concentrations are measured during the collection of milk samples, one can calculate the AUC of the drug in maternal plasma similarly to the AUC in breastmilk. Then, the milk-to-plasma (M/P) ratio can be calculated. It is the ratio of the AUC of the drug in breastmilk divided by the AUC of the drug in the maternal plasma. The M/P ratio can be used to predict breastmilk concentrations based on actual or expected maternal plasma drug concentration with dosage regimens other than the one used to calculate the M/P ratio:
Milk drug concentration = M/P × maternal plasma concentration
Two points about the M/P ratio are worth noting. First, simultaneous measurements of one milk and one maternal plasma drug concentration usually do not provide an accurate value for the M/P ratio because drug levels in maternal plasma and breastmilk do not rise and fall in parallel. Most importantly from a clinical perspective, the M/P ratio does not predict the safety of a drug during breastfeeding. 2 Although some authors have stated that an M/P ratio less than 1 is safe to use and those with an M/P ratio greater than 1 are not, there is no basis for this assertion and many exceptions can be found. The M/P ratio is merely a starting point for further calculations such as that mentioned. LactMed does not usually report the M/P ratio of drugs in the database because of its lack of clinical meaning.
Relative Infant Dosage
Because many drugs do not have established infant dosages, the World Health Organization (WHO) Working Group and others proposed calculation of a value initially called the weight-adjusted percentage of the maternal dosage, now more commonly called the RID3,4:
The WHO Working Group proposed that drugs with an RID greater than 10% of the lowest end of the weight-adjusted (i.e., mg/kg) maternal or infant dosage might not be safe and those with an RID greater than 25% should be avoided in nursing mothers. However, no empiric evidence was used to define these breakpoints.
Although the RID and its breakpoints are currently fairly well accepted as measures of safety of medication use during breastfeeding, they have numerous important shortcomings. One problem with the RID is that the dosage of the drug given to the mother can vary over a range. As the maternal dosage increases, so does the infant's dosage from the drug in breastmilk, but the RID usually does not change. So, the RID falls short of predicting drug safety during breastfeeding for drugs with a wide dosage range, especially those with an RID near the 10% cutoff.
The RID does not take the infant's age into account. In addition to the variability of the daily milk volume already discussed, the continuously maturing infant metabolic and excretory pathways create a situation in which the age of the infant has a great effect on the infant's drug exposure. Analyses of adverse drug reaction reports in breastfed infants have found that about two-thirds of adverse reactions occur during the first month postpartum and more than three-quarters occur in the first 2 months.5,6
Other potential pitfalls of the RID include the possibility of differences in bioavailability and enterohepatic recirculation of the drug in neonates and infants compared with adults. The RID also completely lacks any consideration of the inherent toxicity of the medication.
Fortunately, most drugs have an RID that is not near the level of concern. In one evaluation by members of the WHO Working Group, 47% of 205 drugs in the Group's book had an RID of less than 1%, 75% of drugs had an RID of less than 5%, and 87% had an RID of less than 10%. 7
The RID is reported in LactMed when it can be calculated. Occasionally, authors use a volume other than 150 mL/kg/day in their calculations, and their RID value is adjusted to this milk intake value.
I/M Plasma Concentration Ratio
Infant plasma concentrations are occasionally reported, and they can be used to calculate the ratio of the infant plasma drug concentration to the maternal plasma drug concentration. As with the RID, a drug that produces a steady-state infant plasma concentration greater than 25% of the lower end of the therapeutic concentration range was considered to be unacceptable by the WHO Working Group, again with no empiric evidence. 3
Recently, the American Academy of Pediatrics used this method to assess the safety of psychotropic drugs during lactation. 8 The document listed 13 psychoactive drugs reported to have infant plasma concentrations greater than 10% of maternal plasma concentrations. Drugs were placed on the list if only one infant had ever been reported with an infant/maternal plasma ratio greater than 10%. For example, the references listed for sertraline reported a total of four infants with a infant/maternal plasma ratio greater than 10%, whereas a broader look at the literature in LactMed indicates that 119 other infants have been reported with plasma concentration ratios less than 10%. 9 The average infant/maternal plasma concentration ratio of all these reports is about 1%. 9 Moreover, most recent expert reviews consider sertraline to be the antidepressant of choice during breastfeeding.10–13 Clearly, both the ratio and how it is interpreted are important.
Some drugs with relatively high infant plasma drug concentrations have been found, preliminarily at least, not to be harmful to infant development. That is to say, the benefits of breastfeeding outweigh possible adverse developmental outcomes. A good example is lamotrigine. Breastfed infants whose mothers are taking lamotrigine have relatively high plasma lamotrigine levels, averaging 30–35% of maternal serum levels, and infant plasma levels up to 50% of maternal levels have been reported. In one follow-up study, breastfed infants exposed to lamotrigine in breastmilk had slightly higher IQs and enhanced verbal abilities when compared with nonbreastfed infants at 6 years of age. 14
Another potential problem with the infant/maternal plasma concentration ratio relates to the time of infant sampling if the mother was taking the drug during pregnancy. In general, much more drug is passed to the infant transplacentally than through breastmilk. Therefore, obtaining infant blood samples too soon after delivery can reflect transplacental passage rather than breastmilk transfer.
LactMed reports any measured infant plasma drug concentrations that are reported in the published articles. Occasionally, infant urine drug or metabolite concentrations are reported, but their meaning is unclear other than to document that the drug was absorbed and excreted by the infant.
Summary
A number of mathematical measurements have been proposed to determine the safety of drug use during breastfeeding. None of them is absolutely foolproof for numerous reasons. Drugs have different degrees of toxicity that cannot be quantified easily. The breastfed infant is continually changing in milk intake and maturation of drug elimination pathways. These can be estimated, but usually not exactly quantified for a given infant. Pharmacogenetic differences between individuals can also play a role in infant susceptibility to drug effects. Finally, not all adverse drug reactions are related to dose. Allergic reactions can occur with tiny amounts of drug in breastmilk. Fortunately, most drugs have a wide margin of safety during breastfeeding. The few long-term follow-up studies that are available tend to confirm this view.
Footnotes
Disclosure Statement
No competing financial interests exist.