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Figure 10.2 Examples of high and low clearance drugs and their percent relative infant dose
(%RID). Drug A (clearance of 7 mL per kg per minute) and Drug B (clearance of 0.7 mL per kg per
minute) are assumed to have the same therapeutic plasma concentration (1 mg per L). Therapeutic doses
to achieve the target concentration at steady state are 600 mg per day for Drug A and 60 mg per day for
Drug B. Because maternal plasma concentrations are the same (1 mg per L) for both drugs, their milk
concentrations become equal under a given MP ratio. There are three different scenarios of MP ratio
(i.e., 0.2, 1, and 5), and each of these scenarios lead to three scenarios of infant dose for both Drug A
and Drug B. Derived %RID are shown at the bottom of the figure, demonstrating that %RID of Drug A
(high clearance drug) does not exceed a threshold of 10% even at an MP ratio of as high as 5. This is in
sharp contrast with Drug B (low clearance drug). (Adapted from Ito S. Emerging research paradigm for
infant drug exposure through breast milk. Curr Pharm Des 2019;25:528–533.)
These concepts, including Equation (3), are based on CL in the mother,
and RID estimation in a clinical setting often uses mother’s dose (MoD) in the
absence of neonatal therapeutic dosing recommendations. If infant drug
clearance per body weight is markedly lower than that of an adult (e.g., liver
dysfunction or renal failure), then this must be further taken into account, when
RID is interpreted as a risk assessment tool for dose-dependent effects.
EFFECTS OF DRUG ON LACTATION
Some drugs may affect lactation by changing prolactin secretion. As
previously described, dopamine is an important inhibitory factor of the
release of prolactin. As a result, dopamine agonists such as bromocriptine and
ergotamine diminish breast milk production, while dopamine antagonists,
including domperidone and some antipsychotics, stimulate prolactin
production and thus increase milk volume. Indeed, domperidone is sometimes
used as a galactogogue.
ADVERSE EFFECTS OF DRUG IN M ILK
Infants may experience adverse effects from maternal medication used in
breastfeeding. Such cases are rare but reported, although causality assessment
is difficult. Because RID is relatively low for most drugs, acute toxicity is
unlikely for otherwise healthy infants. However, if infant drug clearance is
low and its age-dependent development is compromised, even small doses
through milk may cause accumulation over time. Table 10.7 presents drug
groups and infant factors, which necessitate an even more cautious approach
in the risk assessment, compared to other medications and healthy infants.
TABLE 10.7
Particularly important is maternal use of opioids because their profiles of
adverse effects include serious events such as respiratory depression.
74
Main Factors That Re quire Cautious Risk–Benefit Ass e s s me nt during
Breastfee ding
Maternal medications
Radioactive compounds. Duration of breastfeeding interruption depends on dose and
elimination half-life of the compounds. Because of thyroid accumulation, radioactive iodine needs
particular caution.
Cancer chemothe rapy. Amount excreted into milk may be small, and/or gastrointestinal
absorption may be marginal, but human data are often lacking. Each drug needs careful risk
analysis in the context of individual circumstances.
Opioids. Although a short-term use for 2–3 days is usually acceptable, its serious toxicity profiles
including respiratory depression justify close monitoring of infant conditions. In an unsupervised
outpatient setting, maternal regular use of opioids for more than 2–3 days is not recommended.
The U.S. Food and Drug Administration (FDA) advises against the use of codeine and tramadol
for breastfeeding women, partly because their metabolism depends on highly polymorphic
CYP2D6 causing wide individual variations in plasma (and milk) concentration profiles.
74
Infant factor
Dysfunction of drug-eliminating organs of infant. Reduced function of liver and kidney, two
major drug-eliminating organs, may decrease clearance of drug, posing a risk of drug
accumulation over time.
Neonates. More than half of reported toxicity involves neonates with neurologic or
gastrointestinal symptoms.
108
RESOURCES
There are a variety of resources available that provide information on the use
of drugs in lactation. In general, product monographs contain limited
information, because pregnant and lactating women are usually excluded from
clinical trials. Fortunately, regulatory bodies increasingly acknowledge the
importance of this information. As a result, the U.S. Food and Drug
Administration (FDA) introduced the Pregnancy and Lactation Labeling Rule
(PLLR) in 2014, which outlines how available information should be
presented and updated in product monographs.89 Several databases are
available in printed and digital formats to guide clinicians in determining drug
safety during lactation. LactMed is the largest online database that contains
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lactation safety data on approximately 1,500 drugs and substances. The
database, which is supported by the National Institute of Health (NIH), is
constantly updated and can be accessed online free of charge
(https://www.ncbi.nlm.nih.gov/books/NBK501922/).
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Karel Allegaert
Johannes N. van den Anker
C H A P T E R
11
Principles of Neonatal Pharmacology
INTRODUCTION
Pharmacotherapy is a very powerful intervention to improve outcomes in
neonates.1 Prescription of a given drug should result in a safe and effective
intervention to treat or prevent a specific disease or risk in an individual
patient or population, while avoiding disproportional side effects. Clinical
pharmacology supports these aims in predicting drug-related effects and side
effects, driven by pharmacokinetics (PK) and pharmacodynamics (PD). The
dynamic changes related to maturation and growth in newborns result in a
unique setting with extensive variability.2 Nonmaturational changes (e.g.,
disease characteristics, drug–drug interactions, pharmacogenetics) further add
to this variability.
1,2
Consequently, neonates are a particularly vulnerable
subgroup, covering the time interval from birth up to 28 days of postnatal life,
although this definition has been adapted to the maturational age of 44 weeks’
postmenstrual age (term-equivalent age + 4 weeks) to cover the subpopulation
of preterm neonates.
3
Unfortunately, the potential impact of drugs to improve outcome in
neonates is still underexplored. A recent meta-analysis (2015) confirmed that
off-label drug prescription remains common practice (90%) in neonates,
4,5
despite legal initiatives to stimulate pediatric studies, and additional
initiatives like the Food and Drug Administration Safety and Innovation Act
(FDASIA) to stimulate drug research in neonates.3 Compared to adults,
available information to make informed decisions on pharmacotherapy
(choice, dose, indication) in neonates is much more limited.
6