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482
A. R. Mair et al.
Framework/RPS%20English%20Competency%20
Framework%203.pdf?ver=mctnrKo4YaJDh2nA8N5
G3A%3d%3d
75. National Institute for Health and Care Excellence,
N.Medicines optimisation: the safe and effective use
of medicines to enable the best possible outcomes;
2015. https://www.nice.org.uk/guidance/ng5
76. BMJ.BMJ Best Practice; 2022. https://bestpractice.
bmj.com/info/
Further Reading
Hilmer SN, Agency for Clinical Innovation NSW
Optimising Medication Management for Frailty
Reference Group. Medication review for people liv-
ing with frailty | Agency for Clinical Innovation
(nsw.gov.au); https://aci.health.nsw.gov.au/networks/
frailty-taskforce/resources/medication-review
Mair A, Wilson M, Dreischulte T. Addressing the chal-
lenge of polypharmacy. Annu Rev Pharmacol Toxicol.
2020;60:661–81. https://doi.org/10.1146/annurevpharmtox- 010919-023508 .
Mair A, Alonso A, International Organisation of
Integrated Care. Polypharmacy and integrated
care. In: Handbook of integrated care. 2nd ed.
Springer; 2020. 978-3-030-69261-2. https://doi.
org/10.1007/978- 3- 030- 69262- 9_27.
Patient Shared Decision Making App for Polypharmacy
Reviews 2018. Effective prescribing and therapeutics & digital health & care innovation centre (DHI).
Polypharmacy: manage medicines (version 3.0.3)
[Mobile app]; 2020.
Safe Prescribing andDrug Use
inPregnancy andBreastfeeding
HedvigNordeng, EvaJirsová, andOlavSpigset
21
Abstract
This chapter focuses on the special challenges related to pharmacovigilance and drug
safety for pregnant and breastfeeding women.
It takes the reader through the principles of
drug safety and pharmacotherapy among
pregnant and breastfeeding women and presents examples relevant for clinical practice. It
also addresses how evidence on drug safety
specic to pregnant and breastfeeding women
is generated and how drug safety in these
populations is surveyed (i.e., perinatal
pharmacovigilance).
H. Nordeng (*)
PharmacoEpidemiology and Drug Safety Research
Group, Department of Pharmacy, Faculty of
Mathematics and Natural Sciences, University of
Oslo, Oslo, Norway
e-mail: h.m.e.nordeng@farmasi.uio.no
E. Jirsová
Pharmacovigilance Department, State Institute for
Drug Control, Prague, Czech Republic
O. Spigset
Department of Clinical and Molecular Medicine,
Faculty of Medicine and Health Sciences, Norwegian
University of Science and Technology,
Trondheim, Norway
Department of Clinical Pharmacology, St. Olav
University Hospital, Trondheim, Norway
Keywords
Pregnancy · Breastfeeding · Teratology
Malformation · Breast milk · Perinatal
pharmacovigilance
Learning Objectives
• Describe principles of
– Pharmacological treatment in pregnancy
and breastfeeding
– Drug teratogenicity
– Drug transfer into breast milk
• Give examples of
– Teratogenic drugs and drugs increasing the
risk of pregnancy complications
– Drugs that should be avoided when breast-
feeding and the reason why
• Reect on
– How benets are weighted against risks of
drug use among pregnant and breastfeeding women, and how a balanced benet–
risk assessment should be presented to the
woman
– Why the product label can differ from clin-
ical guidelines
• Describe
– How evidence specic to pregnant and
breastfeeding women is generated
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_21
483
484
– How surveillance of drug safety in these
populations is undertaken (i.e., perinatal
pharmacovigilance)
• Know
– Which questions are important for causal-
ity assessments of new signals of drug
teratogenicity
Key Points
• Few drugs are proven teratogens and
strictly contraindicated in pregnancy.
• Prescribing during pregnancy is often
challenging due to missing and/or
inconsistent information.
• Teratogenicity of a drug depends on several factors other than its mechanism of
action, such as dose, administration
form, duration of exposure, timing in
pregnancy, and genetic susceptibility.
Teratogenic effects include birth defects,
embryo-fetal death, growth retardation,
functional defects (e.g., reduced cognition), or impaired health in offspring
later in life (e.g., cancer).
• Therapeutic drug monitoring (TDM) is
recommended for certain drugs that commonly require dose adjustments in pregnancy. This is because physiological
changes in pregnancy affect pharmacokinetics and pharmacodynamics.
• Most women who use a drug may breastfeed, because the benets of breastfeeding outweigh or exceed the disadvantage
of drug exposure to the infant. In most
cases, the drug amount transferred to the
breast milk is too small to exert any clinically important effects on the infant.
Often, the combination of available
information and clinical experience is
sufcient to provide specic advice.
• Adverse drug reactions in infants via
breast milk exposure are rare and depend
on several factors related to the pharmacodynamic (e.g., inherent toxicity) and pharmacokinetic properties of the drug, the
dose and treatment duration as well as
maternal-infant characteristics (e.g.,
H. Nordeng et al.
genetic polymorphisms, infant age, prematurity, health status of the infant), and
extent of breastfeeding.
• Surveillance of drug safety in pregnancy
and breastfeeding starts prior to marketing authorization and continues throughout the entire drug lifecycle. Perinatal
pharmacoepidemiologic studies are
essential in the postmarketing setting.
1 Introduction
Avoiding all drugs in pregnancy and during
breastfeeding is unrealistic and may even be dangerous. Untreated diabetes, epilepsy, severe mental illnesses, and infections in pregnancy are
examples where the underlying disease in itself
may be more harmful to the woman and the fetus/
infant than the drug and thus require treatment.
Consequently, we need to know which drugs are
safe and how drugs are used by pregnant and
breastfeeding women. Moreover, health care professionals need to know how to nd and interpret
available scientic data.
The prevalence of drug use in pregnancy
ranges from approximately 25–99% with analgesics, anti-infectives, antacids, antiemetics, and
respiratory drugs being most frequently used [1].
By far, paracetamol (acetaminophen) is the most
commonly used over-the-counter (OTC) drug
during pregnancy, used by almost half of all pregnant women. Similarly, drug use is common
among breastfeeding women, with analgesics,
anti-infectives, and oral contraceptives as the
most frequently used.
Pregnant and breastfeeding women generally
tolerate drugs as well as nonpregnant individuals.
Drugs should only be prescribed in the lowest
effective dose, when clinically needed and
according to prescribing guidelines. The information needs in pregnant women, however, are
different, often with questions related to pregnancy and their disease, ranging from their ability to become pregnant, how symptoms of the
underlying disease might change during
pregnancy, how the disease and the use of medi-
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
485
cines may affect their unborn or breastfed child,
and their ability to breastfeed and care for their
baby. Studies show that both pregnant women
and health care professionals tend to overestimate risks of drugs when used in pregnancy [2,
3]. In many countries, Teratology Information
Services (TIS) provide the public and health professionals with tailor-made information on drug
risks in pregnancy or breastfeeding. An overview
of TIS centers members of the European Network
of Teratology Information Services (ENTIS) can
be found at www.entis- org.eu.
2 Drugs inPregnancy
2.1 Principles ofPharmacological
Management ofPregnant
Women
Pregnancy may affect the woman’s disease and
vice versa; the disease may impact a woman’s
pregnancy by, for example, increasing the risk of
pregnancy complications or adverse pregnancy
outcomes [4]. Disorders like migraine and some
rheumatic diseases tend to improve in some
patients during pregnancy, potentially due to high
estrogen and progesterone levels. Other diseases
including cardiovascular and mental health disorders, and diseases with episodic manifestations
(e.g., systemic lupus erythematosus, multiple
sclerosis), may worsen, relapse, or are when the
woman becomes pregnant. Some disorders
increase the risk of pregnancy complications in
themselves. A well-known example is diabetes.
Poor glucose control during pregnancy increases
the risk of birth defects, macrosomia (birth
weight >4500 g), miscarriage, and stillbirths,
among others. Acute conditions (e.g., infections)
and pregnancy-related ailments (e.g., nausea)
may also require pharmacological treatment. In
sum, pharmacological treatment in pregnancy
may help prevent birth defects and other adverse
maternal-fetal health outcomes, as well as help to
avoid impaired maternal-fetal health [4].
Decisions about pharmacological treatment
with drugs during pregnancy require an individual benet–risk assessment. Such an assessment
should be based upon factors including the wom-
an’s prior treatment response, severity of disorder, risk of relapse, and the availability of data on
drug effects in pregnancy. Drugs’ adverse drug
reaction (ADR) proles should also be considered as these may be particularly unfavorable for
the pregnant woman (Box 21.1). Women with
chronic disease and pregnancy-related complications should be followed-up by multidisciplinary
teams of health care professionals in pregnancy.
Box 21.1 Unfavorable Adverse Drug
Reaction Proles for Drugs When Used in
Pregnant Women
• Nausea → worsening of nausea and
vomiting in pregnancy (many
antidepressants)
• Metabolic impairment (e.g., reduced
glucose tolerance)→gestational diabetes, gestational hypertension, preeclampsia (some antipsychotics, especially
olanzapine, clozapine, and quetiapine)
• Weight gain → excessive weight gain in
pregnancy* → gestational diabetes
(some antipsychotics including olanzapine, clozapine, and quetiapine)
• Sedation → excessive tiredness (rstgeneration antihistamines, hypnotics)
• Hemorrhage → increased blood loss at
delivery (nonsteroidal anti- inammatory
drugs; NSAIDs)
*Most pregnant women gain approxi-
mately 10–12kg in pregnancy, putting on
most of the weight after week 20
Generally, the most restrictive prescribing is
recommended during the rst trimester, when the
bases for the organs are formed. In the fetal period
(second and third trimesters), some drugs may
negatively impact fetal growth and functional
maturation and should therefore also be avoided
after the rst trimester [e.g., tetracyclines, angiotensin-converting enzyme (ACE) inhibitors]. In
addition, some drugs may cause pharmacological
effects in the newborn when given shortly before
labor (e.g., sedatives, anesthetics), and some
486
drugs might also cause withdrawal symptoms in
the newborn (e.g., opioids, benzodiazepines).
2.1.1 Therapeutic Drug Monitoring
Physiological changes in pregnancy may lead to
altered pharmacokinetics resulting in difculty in
predicting the appropriate drug dosage.
Pharmacokinetic changes are mainly due to altered
metabolic activity in the liver with increased (most
common) or decreased drug metabolism and
enhanced renal excretion due to increased renal
perfusion. Other physiological changes include
increased uid volume and decreased plasma
albumin concentration, which may also to some
extent impact the plasma concentrations of drugs.
These changes may appear already during the rst
trimester but are often most pronounced in the second and third trimesters.
For drugs with a broad therapeutic range,
these changes have no or little clinical signicance (e.g., for commonly used antibiotics). For
other drugs, an increased dosage could be necessary to ensure adequate treatment effect (see list
of examples below). When available, therapeutic
drug monitoring (TDM) is commonly recommended for such drugs to optimize drug dosing
regimens in pregnancy.
Examples of drugs where monitoring in pregnancy is generally recommended:
• Anticonvulsants, e.g., lamotrigine
• Antiretroviral drugs, e.g., HIV drugs
• Opioids, e.g., methadone
Because of individual differences, it is advisable to monitor the plasma concentration of the
drug at baseline (prior to pregnancy) as well as
several times in pregnancy, depending on the
woman’s clinical symptoms and the previously
measured plasma levels.
Within the rst week or so after birth, the
woman’s drug elimination returns to baseline
state, and consequently, doses that have been
increased during pregnancy must be reduced
again to avoid risk of overdose and adverse drug
reactions.
Box 21.2 summarizes the prescribing principles in pregnancy.
H. Nordeng et al.
Box 21.2 Principles of Drug Prescribing in
Pregnancy
• Offer counseling to all women with
chronic disorders before pregnancy
• Ensure that women with chronic disorders are followed-up by the appropriate
specialists during pregnancy. The pattern and the severity of the underlying
disease may change
• Perform a benet–risk assessment on an
individual patient basis and prescribe a
drug in pregnancy only if the expected
benets outweigh the potential risks to
the mother and child
• Avoid known human teratogens
• Be aware that some teratogenic drugs
should be stopped long before conception. The length of this period varies
depending on the specic drug
• Communicate clearly and ensure that
the woman is informed of known benets and risks of both taking and not taking the drug
• Use the lowest effective dose for the shortest required duration—bear in mind that
effective is more important than lowest
• Prefer nonpharmacological treatments,
if available and effective (e.g., for the
treatment of nausea and vomiting in
pregnancy)
• Prefer topical administration over systemic administration when possible
(e.g., for asthma, allergy, and dermatological disorders)
• Monitor effect and adverse drug reactions closely and consider the need for
therapeutic drug monitoring, as changes
in drug metabolism and excretion during
pregnancy may require dose adjustments
• Ensure that patients treated with drugs
with unfavorable adverse drug reactions
related to pregnancy (e.g., nausea,
weight gain, metabolic effects) are specically monitored for pregnancyrelated complications
• Remember that absence of information for
a drug does not imply that the drug is safe
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
487
2.2 Birth Defects andOther
Adverse Pregnancy Outcomes
2.2.1 Birth Defects
Every pregnancy starts out with a 2–4% risk of
resulting in a major birth defect (a congenital malformation) [5]. This is called the background risk.
Birth defects can occur during any stage of pregnancy, but the vast majority originate in the rst
trimester (Fig.21.1). Some birth defects (e.g., cleft
lip) are clearly visible at birth, whereas others (e.g.,
heart defects, vision and hearing impairments) are
detected through examinations or tests, such as
echocardiography or visual and auditory tests.
Birth Defect
Abnormality that arises because of an
abnormal developmental process during
intrauterine life. Birth defects are also
known as congenital abnormalities or congenital malformations. They can be dened
as structural anomalies (e.g., limb reduction) or functional anomalies (e.g., hearing
impairments). Broadly, congenital refers to
the existence at or before birth.
About 80% of birth defects have unknown etiology. Among the remaining 20% with known
etiology, almost all are due to genetic or chromosomal abnormalities. Notably, less than 1% of all
birth defects are due to teratogenic agents, making teratogenicity of drugs rare in clinical practice [6]. Of note, medications that are suspected
teratogens based on animal studies are generally
contraindicated in humans, making them rarely
used. In such situations, it is difcult (both ethically and practically) to study them and determine their safety in humans.
Other common adverse pregnancy outcomes
include miscarriage, premature delivery, and
low birth weight (Fig. 21.1). In Europe, the
estimated background risk of miscarriages in
clinically recognized pregnancies is 10–20%
[7], while approximately 6–8% of infants are
born prematurely (<37 completed gestational
weeks) and 4–8% are born with a low birth
weight (<2500 g) [8].
2.2.2 Passage ofDrugs Through
thePlacenta
There is a close connection between the woman’s blood and fetal blood through the placenta.
Even though a “placenta barrier” with drug
transporters and metabolic enzymes exists, most
drugs have the ability to cross the placenta to the
fetus via passive diffusion if administered in
sufciently high doses for a sufciently long
duration. The exceptions are drugs with very
high molecular weights [above a few thousand
Dalton (Da)], such as insulin and heparin, which
do not cross the placenta this way. In principle,
any drug that reaches the fetal circulation has
the biological potential to affect fetal
development.
Some substances can be transferred to the
fetus via active transport mechanisms across the
placenta. An example is antibodies of immunoglobulin G (IgG) type that passes from the mother
to the fetus via pinocytosis toward the end of
pregnancy. Such active transfer of maternal IgG
antibodies gives the infant passive immunity and
protects it against various infectious diseases in
the rst 6 months of life. For example, if the
mother has been vaccinated or has had COVID- 19
and has SARS-CoV-2 antibodies, she will transfer these to the fetus. Maternal pertussis vaccination in pregnancy uses this principle to protect
the newborn against pertussis. Of note, other
immunoglobulins, mainly of IgM type, do not
pass the placental barrier.
The fetus itself metabolizes drugs to a very
small degree, but excretes drugs mainly via the
placenta.
2.2.3 Teratogenicity
A teratogen is generally dened as a substance
that causes birth defects or can disturb the development of an embryo or fetus. Examples of teratogenic effects are birth defects, fetal death (i.e.,
miscarriage or stillbirth), growth retardation, and
functional defects later in life [9]. As of today,
only 30–40 drugs have been proved to be major
teratogens in humans (Table21.1).
488
y
Sensitivity to
congenltal anomal
Early embryonic period
H. Nordeng et al.
Organogenesis
Embryonic period Foetal period
Tr imester 1
Zygote
Conception
divisions
Implantation
Weeks from
conception
Weeks from
LMP
0213243546576879810911101211
Conceptus
loss
Anomaly
LOW
teratogen
susceptibility
Sensitivity to teratogens by organ
Highly sensitive to teratogens
Less sensitive to teratogens
Conceptus loss
Early susceptibility to later preterm birth
Other
Foetal growth restriction
adverse
outcomes
Miscarriage
Interrupted placental development
Major
birth defects
Central nervous system
Vertebrae and cranium
Heart
Arms
Renal/urinary system
Ears
Eyes
Legs
Palate
Tr imester 2
13
16
18
Tr imester 3
22–36
24–38
38 / Term
40 / Term
Functional defects and
minor morphological
abnormalities
Gut
Teeth
External genitalia
Still-birth
Preterm birth
Low birth weight / Small-for-gestational age
Fig. 21.1 Risk of birth defects and other adverse outcomes
vary by timing in pregnancy
LMP last menstrual period. In teratology, weeks are numbered from the time of conception, whereas in obstetrics,
Teratogen
An agent that causes birth defects or can
disturb the structural or functional development of an embryo or fetus.
The timing and duration of drug use are of
great importance in relation to the risk for fetal
harm (Fig. 21.1). For example, neural tube
defects do not occur after week 6, i.e., after clo-
weeks are numbered from the rst day of the last menstrual
period. (Figure created with BioRender.com. Adapted
from Moore KL: The Developing Human: Clinically
Oriented Embryology, fourth ed. Saunders, 1988. Elsevier)
sure of the neural tube. Use of tetracyclines will
not affect dental and skeletal development before
the fourth month of pregnancy, only by later use,
as these organs form later in fetal life.
Drugs have been linked to six main distinct
teratogenic mechanisms [10]:
• Folate antagonism (carbamazepine, methotrexate, phenytoin, trimethoprim, valproic acid)
• Neural crest cell disruption (retinoic acid, tretinoin, isotretinoin)
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
Table 21.1 Examples of known human teratogens that increase the risk of structural malformations [5, 9]
Drug Main identied malformation(s) Risk
Diethylstilbestrol
(DES)
Isotretinoin CVD, ear anomalies, skeletal defects,
Lithium CVD (Ebstein’s anomaly) 5% risk of CVD (~10 times increased risk of
Methotrexate Skeletal defects 5% overall risk of malformations
Misoprostol
Mycophenolate Facial defects, CVD, cleft lip ~10–20% overall risk of malformations. 40–50%
Phenytoin Facial defects, cognitive dysfunction,
Thalidomide Limb anomalies (phocomelia), CVD 20–30% malformation risk after exposure on days
Valproic acid NTD, neurodevelopmental impairments 1–2% risk of NTD.Risk of neurodevelopmental
Warfarin Multiple malformations, “fetal warfarin
CVD cardiovascular defects, IQ intelligence quotient, NTD neural tube defects
a
Baseline risk of malformations: any malformation: 2–4%, NTD: 0.1%, CVD: 1% (Ebstein’s anomaly 1in 20,000),
Moebius syndrome 1in 50,000–100,000
b
Misoprostol in combination with mifepristone is used to induce miscarriage and is 95% effective when used in the rst
9 weeks of pregnancy
b
Vaginal and cervical cancer, genital
defects
cognitive dysfunction
Facial defect: Moebius syndrome
(paralysis of sixth and seventh cranial
nerves), limb defects
“fetal hydantoin syndrome”
syndrome”
a
~40% risk of genital defects
~40% overall risk of malformations
Ebstein’s anomaly)
~30 times increased risk of Moebius syndrome
risk of miscarriage
5–10% risk for “fetal hydantoin syndrome” ~7 times
increased risk for cognitive dysfunction
34–50 of gestation
delays, including reduced IQ.Dose-dependent with
highest risks with doses >700mg/day
Up to 25% risk of “fetal warfarin syndrome”
489
• Endocrine disruption [cytotoxic agents, sex
hormones, diethylstilbestrol (DES)]
• Oxidative stress (thalidomide, phenytoin, valproic acid, antiarrhythmic agents, chemotherapeutic agents)
• Vascular disruption (misoprostol, ergotamine,
thalidomide)
• Specic receptor- or enzyme-mediated teratogenesis, e.g.,
– Inhibitors of enzymes or receptors of the
renin–angiotensin system (ACE inhibitors
and angiotensin II receptor antagonists)
– Inhibitors of cyclooxygenase [nonsteroidal
anti-inammatory drugs (NSAIDs)]
Many drugs classied as teratogens are asso-
ciated with several of these mechanisms.
2.2.4 Harmful Eects Beyond
theFirst Trimester
Some medications can disrupt normal fetal development if used in the second or third trimester of
pregnancy. Some well-known examples are ACE
inhibitors, angiotensin II receptor antagonists,
and NSAIDs.
ACE inhibitors and angiotensin II receptor
antagonists may impair the blood ow to the
placenta and can cause low levels of amniotic
uid surrounding the fetus. This can induce poor
lung development, poor growth, poor development of the skull bones, problems with the development of the kidneys, and, in the most severe
cases, death of the developing fetus.
NSAIDs are from gestational week 20 associated with fetal renal dysfunction leading to oligohydramnios (low level of amniotic uid). When
used in the third trimester of pregnancy, NSAIDs
may induce premature closure of the ductus arteriosus (a blood vessel essential for fetal blood
circulation), which may result in persistent pulmonary hypertension in the newborn.
Some medicines should not be used close to
delivery because they may affect the delivery or
the newborn (e.g., NSAIDs). Moreover, newborns
may develop respiratory, suckling, or other motor
problems or show signs of withdrawal reactions
490
H. Nordeng et al.
if the woman has used benzodiazepines or opioids close to delivery.
The central nervous system is vulnerable to
neurotoxic drugs throughout pregnancy (Fig.21.1).
Behavioral teratology focuses on neurotoxicity
induced during development of the brain and has
received increasing attention in the last decade.
Adverse neurodevelopmental outcomes include,
for example, behavioral disorders (e.g., ADHD),
cognitive impairment, and delayed language and
motor development. These are outcomes that are
essential for children’s daily lives, and as such,
important outcomes in pregnancy safety studies.
2.2.5 Medication andImpaired
Fertility
Medicines can impair fertility through a variety
of mechanisms. For example:
Altering hormone levels: Some drugs, such
as hormonal contraceptives, can alter the levels
of sex hormones, which can disrupt the normal
menstrual cycle and make it more difcult to
conceive. Drugs that raise prolactin levels (e.g.,
metoclopramide, most antipsychotics, and some
antidepressants) can affect ovulation, thereby
reducing fertility.
Damaging reproductive tissues: Cytotoxic
drugs, for example, cisplatin, can damage the
function of the ovaries or testes, thereby impairing fertility.
Disrupting sperm production: Certain
drugs, such as anabolic steroids, can reduce
sperm production or impair sperm motility.
Affecting implantation: Some drugs, such as
NSAIDs, can impair implantation of the fertilized egg in the uterus, making it more difcult to
achieve pregnancy.
3 Drug Safety During
Breastfeeding
Human milk represents the ideal primary source
of nutrients for infants and offers also other
health advantages to both mother and child.
Given the range of benets of breastfeeding, the
World Health Organization (WHO) recommends
that children should be exclusively breastfed for
the rst 6 months of life. As the infant should not
unnecessarily be denied the benets of breastfeeding, health care professionals should tailor
pharmacological treatment and support women
who wish to breastfeed whenever possible.
In clinical practice, prescribers need to weigh
the potential risk to the infant of drug exposure
through the milk against the disadvantage of not
being breastfed. Other options, such as not initiating or stopping pharmacotherapy might be even
more harmful, taking into account the risk for the
mother and thereby indirectly also for the infant if
the mother is not receiving adequate treatment.
The lack of knowledge on drug safety during
breastfeeding among health care professionals
may result in unnecessary cessation of breastfeeding in women who need to take drugs.
Despite the lack of clinical studies, the sum of
available information in combination with clinical experience will in most cases be sufcient to
provide specic advice about the use of drugs
during breastfeeding [11–13].
Specic questions to clarify the benet–risk
ratio of using drugs when breastfeeding are given
in Table21.2.
Answers to these questions require knowledge
about principles for transfer of drugs to breast
milk and the situations in which this transfer may
entail a risk of adverse effects in breastfed infants.
They also often depend on the individual
maternal- child characteristics.
Any drug used by the mother must pass several steps to exert an effect in a breastfed infant
(Fig.21.2). In reality, most drugs are transferred
to breast milk in amounts well below a level
expected to exert any pharmacological effect on
the breastfed infant [11, 12]. Nevertheless, during long-term maternal treatment, particularly
when the infant is premature or newborn, also
low doses ingested via breast milk may exert a
pharmacological effect to the infant due to immature elimination pathways causing accumulation
of the drug.
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
491
Table 21.2 Questions that should be asked to clarify the
benet–risk ratio of using a drug when breastfeeding
Drug factors:
• Is the drug formally contraindicated during
breastfeeding?
• Have any adverse effects been previously reported
in breastfed infants?
• What can the safety prole of the drug tell us
about the potential to cause ADRs relevant for
infants?
• How much drug will the infant ingest via breast
milk (i.e., are there data on the relative infant dose
[RID], the levels in breast milk, and/or plasma
levels in the infant available)?
• If levels in breast milk are known, how does the
drug dose ingested via breast milk compare to a
therapeutic dose for infants?
• If data are missing, what breast milk exposure
could be expected based on pharmacokinetic
characteristics (e.g., molecular weight,
bioavailability, elimination half-life)?
• Are there any alternative drugs that would be safer
for the infant?
Maternal factors:
• What are the mother’s breastfeeding intentions?
• How necessary is the drug for the mother?
• What is the mother’s drug dose, the frequency of
administration, the duration of treatment, and the
route of administration?
Infant factors:
• How old is the infant?
• Was the infant born prematurely?
• Is the infant fully breastfed?
• Is the infant healthy?
The steps that the drug has to pass in order to
exert an effect in the infant are the following
(Fig.21.2):
Step 1: The drug must be absorbed systemically in the woman to achieve a certain plasma
concentration. Drugs taken orally or injected are
those that are most often found in the milk. Many
locally acting drugs (dermatological preparations, inhalational drugs, eye drops, nasal sprays,
vaginal suppositories, etc.) will in general not be
detectable in the woman’s plasma in signicant
concentrations, and thereby neither in the milk.
Step 2: Most drugs transfer between maternal
plasma and breast milk based on the principles of
passive diffusion through lipid membranes and will
therefore follow a gradient from a high to a low
concentration of free (unbound) drug (Fig. 21.3).
Passive diffusion from plasma to milk (and vice
versa) depends on the pharmacokinetic (PK) properties of the substance: The drugs that most easily
diffuse into breast milk have high concentrations in
maternal plasma, are fat-soluble, have relatively
low molecular weights (<500 Dalton), and relatively low plasma protein binding.
It is a common misconception that the drug
remains in the milk and that the women therefore
should pump out and discard milk after having
taken a drug that may affect her infant. The breast
is not a reservoir where substances may accumulate, like the urinary bladder, but rather a compartment in dynamic equilibrium with maternal
plasma. As the drug is gradually eliminated by
the woman and the maternal plasma concentration of the drug declines, it will diffuse from
breast milk back to the maternal plasma. Pumping
and discarding milk is therefore necessary only
in exceptional cases, for example, when the
mother uses a contraindicated drug over a short
period and needs to pump herself to maintain lactation and avoid breast engorgement.
For drugs with short elimination half-lives, the
time interval between drug intake and breastfeeding is a key determinant for the drug concentration in the milk. When the concentration reaches
its peak level in the plasma, it will, with a short
delay, also reach its highest level in the milk.
As an example, the hypnotic drug zolpidem
(elimination half-life 0.8–4 h) is rapidly eliminated from maternal plasma/milk. Consequently,
the risk of adverse effects in the infant can be
reduced by breastfeeding at times when the concentration in breast milk is at its lowest level.
This can generally be achieved, e.g., by taking
the daily dose in the evening and avoiding breastfeeding during the night.
Step 3: At a given drug concentration in milk,
the amount of milk that the infant ingests at that
time will be decisive for the drug dose to the
infant. Standard milk volumes used in calculations of drug intake via milk amount to 30mL/kg
body weight in a meal and 150 mL/kg body
weight in a day.
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