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492
the infant
Step 5Step 4Step 3Step 2Step 1
H. Nordeng et al.
Effect in
Drug
concentation in
the infant plasma
tract
Drug concentation
in the infant digestive
Drug
breast milk
concentation in
The infant’s
health condition
Pharmacodynamic
factors
Excretion
Metabolism
Distribution
Bio-availability
Ingested volume
of breast milk
Drug toxicity
Drug
concentration in
maternal plasma
ernal
ug dose
Molecule size
Plasma protein
Distribution
Bio-availability
binding
Fat solubility
Acid-base conditions
Excretion
Metabolism
Fig. 21.2 Pharmacological pathway for infant drug exposure via breast milk. (Figure created with BioRender.com)
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
493
Milk (lumen)
Tight junctions
Gap junctions
Transporters
Luminal epithelial cells
Myoepithelial cells
Basal membrane
Alveoli
containing milk
Tr anscellular
transport
Blood
Paracellular
transport
Fig. 21.3 Transport of drug to breast milk
The mammary epithelium consists of lobes, containing
alveoli and milk ducts. The luminal epithelial cells secrete
milk into the lumen of the alveolus. The surrounding
myoepithelial cells contract under the stimulation of oxytocin and cause excretion of the milk into the ducts.
Transport of drug to breast milk is possible via passive or
active transport mechanisms. Transcellular transport
implies crossing of cell membranes, whereas paracellular
transport occurs via the conned spaces between cells.
(Figure created with BioRender.com)
494
H. Nordeng et al.
Step 4: The drug must subsequently be
absorbed from the infant’s digestive tract before
it can enter the bloodstream. A high molecule
weight restricts this absorption, and drugs which
are proteins, such as insulin, will be degraded in
the gastrointestinal tract. Drugs that are not at all
or very poorly absorbed from infant’s gastrointestinal tract would not cause any systemic
effects in the infant. However, they could have
local effects in the gut leading, e.g., to gastrointestinal discomfort or diarrhea.
Step 5: In addition to the amount ingested via
breast milk, factors such as the duration of treatment, infant age, and the infant’s health condition
need to be considered. Because neonates and
infants in the rst months of life, and in particular
premature infants, have an immature liver and
kidney function, they eliminate drugs at a lower
rate than older children and adults. Hepatic function gradually matures during the rst months of
life, and after about 3–4 months of age, the metabolic capacity reaches adult levels. In contrast,
renal function is not fully developed until the
infant is 6–9months old. Therefore, drugs with a
high degree of renal elimination, such as lithium,
are of particular concern related to accumulation
in young infants.
In addition to the pharmacokinetic aspects,
premature or seriously ill infants will often be
more sensitive than healthy infants and have a
lower tolerance to the pharmacological action
of drugs, including possible unfavorable
effects.
3.1 Infant Dose
In scientic literature and clinical guidelines, it is
common to express infant exposure as the infant’s
weight-adjusted relative dose (relative infant
dose, RID), which is the calculated dose the infant
ingests per kilogram bodyweight in relation to the
maternal dose per kilogram bodyweight (see Case
Example 2 Lamotrigine during breastfeeding).
Infant exposure is regarded as minimal when the
relative dose is below 2%, small when the relative
dose is 2–5%, moderate when the relative dose is
5–10%, and high when the relative dose is above
10% [11, 12]. With relative doses above 10%, it is
generally considered that a risk of pharmacological effects in the infant does exist, if the infant is
fully breastfed [11, 12]. Comparing the drug dose
ingested via breast milk to the therapeutic dose
for infants will help evaluating the risk of effects
in the breastfed infant (Table21.2).
3.2 Evidence ofAdverse Eects
Adverse effects in breastfed infants caused by
maternal drug treatment are rare. Moreover, in
about 80% of the cases with adverse effects, the
infant was younger than 2 months of age [14].
This is in accordance with the expected gradual
maturation of hepatic and renal function during
the rst months of life and clearly illustrates that
infant age is a critical factor to take into account
when assessing the individual infant risk.
Breastfeeding is contraindicated only for a few
drugs. Examples of such drugs include cytotoxic
agents, radiopharmaceuticals, iodine-based X-ray
contrast uids, and gold compounds. Some drugs
are contraindicated because they may interfere
with milk production or the process of lactation.
Examples are dopamine agonists (cabergoline,
bromocriptine) as they inhibit prolactin secretion;
in fact, such drugs are used therapeutically to
inhibit lactation when breastfeeding is contraindicated (e.g., due to maternal HIV infection) or after
stillbirth.
It is far more common to advise caution with
the use of a drug during breastfeeding (on the basis
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
of the pharmacological effects or the drugs’ ability
to pass into the breast milk) and a careful followup of the infant. Examples include long- term use
of antipsychotics, opioids, benzodiazepines, and
several antiepileptics. This approach is generally
considered more appropriate than refraining from
initiating breastfeeding or weaning for precautionary reasons (see Box 21.3 Principles of drug prescribing during breastfeeding). Most commonly,
ADRs in a breastfed infant will develop gradually.
Therefore, it is important to inform the mother
Box 21.3 Principles of Drug Prescribing
During Breastfeeding
The principles of drug prescribing during
pregnancy apply also during breastfeeding
(e.g., benet–risk assessment, use of low-
est effective dose, preferred nonpharmaco-
logical options, or local administration
forms). There are, however, some addi-
tional prescribing principles during breast-
feeding that are important to know:
about which symptoms to observe for. If symptoms possibly indicating ADRs occur in the infant,
a change in drug, a decrease in dose, or interrupted
breastfeeding is warranted.
The most frequently reported ADRs in
breastfed infants are sedation, sleepiness, poor
feeding, failure to thrive, irritation, crying, gastrointestinal effects, and rash. In a few specic
cases, hematotoxicity (e.g., thrombocytopenia
and leukopenia) or hepatotoxicity has been
reported [11, 12]. For some drugs, a potential
effect on growth and maturation (e.g., for corticosteroids) or neurodevelopmental disorders
(e.g., for some antiepileptics) has been proposed, but not demonstrated in humans.
Breastfed newborns with suspected ADRs will
also often have been exposed in utero, making it
possible that symptoms are related to pregnancy
exposures rather than drug exposure in breast
milk.
Mixed nutrition (i.e., partial breastfeeding)
may be suggested in some situations to reduce
the infant’s drug dose per day. These situations
could occur when the woman uses a drug that
could potentially affect the infant over a longer
period while breastfeeding an infant younger
than 3 months of age.
Box 21.3 provides an overview of the principles that are important to take into account before
prescribing drugs to breastfeeding patients.
• If the medication has been prescribed to
a woman during pregnancy, it can most
likely also be used during breastfeeding
• Before prescribing, ensure that you
know the woman’s breastfeeding
intentions
• Acknowledge the benets of breastfeeding for the mother and child.
Recommending weaning without clear
evidence, just to be “on the safe side,” is
poor practice
• Prefer drugs with a low relative infant
dose (RID) and avoid drugs with a high
RID (>10%)
• Be most restrictive with prescribing
psychotropic medications to breastfeeding women with infants less than
3 months, as they account for most
reported ADRs in breastfed infants
• Ensure that breastfeeding women using
medications where infant follow-up is
recommended know which symptoms
to monitor for (e.g., drowsiness, poor
feeding, rash, bruising, and diarrhea)
• Avoid prescribing drugs with high toxicity to breastfeeding women. If prescribing requires breastfeeding
interruption, ensure the woman knows
when she can reinitiate breastfeeding
after the last drug intake
495
496
4 Regulatory Perinatal
Pharmacovigilance
Information about drug safety is often limited or
missing at the time of marketing authorization,
especially in the areas of pregnancy and breastfeeding. This lack of data has also had an impact
on the information in the drug labels. A review
of the labels of 213 drugs approved by the
U.S. Food and Drug Administration (FDA)
between 2003 and 2012 found that 98% of the
drugs had missing information about safety in
pregnancy [15]. There were no data on breastfeeding in 48% of the labels, animal milk data
were available in 43% of the labels, whereas
breast milk data from humans were available in
less than 5% of the labels [15]. On average, it
took 27years to obtain data on safety in pregnancy [16].
Note: All drug labels [called Summary of
product characteristics (SmPC) in European
countries] have a specic section where data
on pregnancy and breastfeeding, as well as animal reproductive toxicity data, are summarized. The SmPC is updated by the marketing
authorization holders when signicant new
information becomes available as per the
guidelines of the regulatory agencies. See an
example in Box 21.4.
Box 21.4 Example of a Summary of Product
Characteristics (SmPC) Document for the
SARS-CoV-2 (COVID-19) Virus Vaccine
Comirnaty (last revised March 2023, www.
medicines.org.uk)
Pregnancy
A large amount of observational data
from pregnant women vaccinated with
Comirnaty during the second and third trimester have not shown an increase in
adverse pregnancy outcomes. While data
on pregnancy outcomes following vaccination during the rst trimester are presently
limited, no increased risk for miscarriage
H. Nordeng et al.
has been seen. Animal studies do not indicate direct or indirect harmful effects with
respect to pregnancy, embryo/fetal development, parturition, or postnatal development. Comirnaty can be used during
pregnancy.
Breastfeeding
No effects on the breastfed newborn/
infant are anticipated since the systemic
exposure of breastfeeding women to
Comirnaty is negligible. Observational
data from women who were breastfeeding
after vaccination have not shown a risk for
adverse effects in breastfed newborns/
infants. Comirnaty can be used during
breastfeeding.
Fertility
Animal studies do not indicate direct or
indirect harmful effects with respect to
reproductive toxicity.
In the European Union (EU), pharmaceutical
companies have since 2012 been required to have
an RMP to ensure that more information is collected in the postmarketing setting (see Chap. 6).
If data on safety in pregnancy or breastfeeding
are missing, suspected, or identied, the RMP
will reect measures considered necessary to
identify, characterize, and/or minimize the drugs’
important risks for pregnant and breastfeeding
woman, women of childbearing age, and fathers
to be (when paternal exposures should be
avoided). When major risks with use in pregnancy have been identied, a set of risk minimization measures (RMMs) are required to avoid
exposure in utero, including, if relevant, a pregnancy prevention program (PPP). A PPP includes
a range of RMMs to minimize the risk of pregnancy during drug exposure. The most commonly used additional RMMs are educational
materials to health care professionals and
patients, contraceptive requirements, and pregnancy testing. However, PPPs vary between the
different teratogenic products. See some examples in Table21.3.
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
Educational material and forms (for HCPs
and patients)
a
Supply
restrictions
a
Pregnancy
testing
497
Contraception,
men
Contraception,
women
Yes Yes – Regularly Yes Yes
Contraindication in the
SmPC PPP
Table 21.3 Examples of drugs with proven teratogenicity according to additional RMMs (as of July 2022, www.medicines.org.uk)
For epilepsy: exception
Thalidomide Yes Yes Yes Ye s Monthly Yes Yes
Valproic acid For bipolar disorder: yes
Yes Yes Ye s Initially – Ye s
b
b
possible
Isotretinoin Ye s Ye s Yes – Monthly Yes Yes
Mycophenolate Yes. Exception possible
Fingolimod Yes – – – Regularly – Ye s
Brentuximab No – Ye s Ye s – – Ye s
If no suitable alternative treatment exists
Controlled access at prescribing level to ensure that a pregnancy test is carried out and negative results are veried by the health care professional before drug prescription
RMMs risk minimization measures, SmPC summary of product characteristics, PPP pregnancy prevention program, HCP health care professional
a
b
498
H. Nordeng et al.
In the USA, the FDA can request a risk evaluation and mitigation strategy (REMS, see denition) from the pharmaceutical company if there is
a concern related to teratogenicity of a prescription medication. One example is The iPLEDGE®
REMS, which is a safety program to manage the
risk of isotretinoin’s teratogenicity and to minimize fetal exposure (https://ipledgeprogram.
com/). A recent study based on data from the
FDA’s REMS database with information up to
09/2021 found that 11 out of 61 REMS programs
(18%) had been requested to minimize teratogenic
risks for ten drugs (ambrisentan, bosentan, isotretinoin, lenalidomide, macitentan, mycophenolate,
phentermine–topiramate, pomalidomide, riociguat, thalidomide) [17]. This study showed,
however, signicant variation in requirements
related to the use of contraceptives and pregnancy
testing [17].
These measures aim to ensure that health care
professionals and patients have information
available to make informed decisions about drug
use in pregnancy and during breastfeeding.
PPP: Pregnancy Prevention Program: a set
of risk minimization measures put in place
by the European Medicines Agency to
reduce risk of exposure to medical prod-
ucts during pregnancy that are teratogenic
or have an adverse neurological effect on
the child in utero.
REMS: Risk Evaluation and Mitigation
Strategy: a drug safety program that the
U.S.Food and Drug Administration (FDA)
requires for certain medications with seri-
ous safety concerns to help ensure the ben-
ets of the medication outweigh its risks.
Teratogenicity is a common reason for the
FDA to request a REMS.
5 Generating Evidence
onDrug Safety
A wide variety of studies are used to generate
evidence relevant for pregnant and breastfeeding women. Considering all available evidence
from different elds (triangulation) can
strengthen causal inference and support clinical
recommendations.
Animal studies: Before a drug is approved
and introduced into clinical practice it has to be
tested for teratogenicity on at least two different
mammalian species, of which typically one is a
rodent [18]. This is based on the expectation that
animal exposure would predict human experience. While this has worked in some important
cases (e.g., isotretinoin), it has failed in others
(e.g., thalidomide, as it was only tested in one
species, rats). On the other hand, all established
human teratogens have been teratogenic in at
least one animal species. For example, whereas
thalidomide was found not to be teratogenic in
rodents, it was later proven teratogenic in rabbits
and nonhuman primates. Notably, the dosage
used in animals is usually much higher than used
in humans, which may lead to false-positive ndings. On the other hand, some species may eliminate drugs at a considerably higher rate than in
humans, causing false-negative ndings if the
dose is not sufciently high. One illustrating
example is the discussion related to corticosteroid treatment regarding local vs. systemic
administration, dose–effect relationships when
used systemically, and the possible risk of cleft
lip and palate [19]. In conclusion, interspecies
differences may lead to both false-negative and
false-positive conclusions. Moreover, animal
studies are often not suited to reveal (long-term)
effects related to, e.g., behavioral teratogenicity
or certain maternal effects such as preeclampsia.
Studies on drug passage into animal breast
milk are also performed during drug development. These, however, cannot be used to inform
safety or transfer to breast milk in humans, as no
clear correlation between drug dose in animal
and human milk is known.
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
499
Case reports and case studies: Several human
teratogens have been identied through small
case studies. If a certain drug has a high rate of
specic, otherwise rare, birth defect(s), case
reports can be extremely useful. Teratogenicities
of thalidomide, warfarin, isotretinoin, and mycophenolate were all discovered this way (see Sect.
2.2.3). Analyses of suspected adverse reactions
based on spontaneous reports are routinely done,
in the EU through the EudraVigilance system
[20], and globally by the Uppsala Monitoring
Centre (UMC) for the WHO [21]. UMC stores
all reports of suspected adverse reactions to
medicinal products in the database, VigiBase
[21].
Randomized controlled trials (RCTs). RCTs
often exclude pregnant women due to ethical
and/or legal concerns of harmful fetal exposure.
The COVID-19 pandemic, however, represented
a shift with that respect, demonstrating how
RCTs including pregnant and breastfeeding
women using COVID-19 vaccines could be performed in a robust and ethical way. The example
below is one of the rst RCTs specically focusing on pregnant women.
Example: Study to Evaluate the Safety,
Tolerability, and Immunogenicity of SARS CoV-2
RNA Vaccine Candidate (BNT162b2) Against
COVID-19in Healthy Pregnant Women 18Years
of Age and Older. This study is a Phase 2/3, ran-
domized, placebo-controlled, observer-blind
study evaluating the safety, tolerability, and
immunogenicity of 30μg of BNT162b2 or placebo administered in 2 doses, 21days apart, in
approximately 350 healthy pregnant women
18 years of age or older vaccinated at
24–34weeks’ gestation [22].
Epidemiological studies: Epidemiological
studies are central in the evaluation of drug safety
in pregnancy. Typically, drug safety studies aim
to investigate associations between in utero exposures to specic drugs and pregnancy outcomes,
such as malformations, stillbirths, birth weight,
or even sometimes long-term development in
children. In practice, rigorously designed and
well-conducted pharmacoepidemiological studies provide the best feasible way of evaluating
whether drug use during pregnancy has adverse
effects on the developing fetus in the postmarketing setting.
Epidemiological studies, however, are subject
to inherent limitations, given their nonrandomized design. Often confounding by the maternal
underlying indication for drug use, concomitant
drug treatment, socio-economic and lifestyle risk
factors cannot be ruled out. Moreover, misclassication of drug exposure, confounders, and/or
pregnancy outcomes may occur and bias the effect
estimates. Issues that are particularly relevant to
drug safety studies in pregnancy are sample size
(i.e., rare exposures and outcomes), errors in measurement of drug use in relation to timing in pregnancy, and lack of information about the validity
of the pregnancy outcome studied. History has
shown us that several drugs such as the antiemetic
Bendectin (pyridoxine/doxylamine) [23] have
falsely been labeled as teratogens due to signals in
epidemiological studies [24]. Moreover, conicting results, such as for antidepressants and child
neurodevelopment, make evidence-based benet–
risk assessments particularly challenging.
In recent years, increasing attention has been
given to analyzing large databases like prescription databases, claims databases, or medical
records databases compiled for administrative
purposes by health authorities or medical reimbursement organizations. These registries are
based upon prescriptions dispensed from pharmacies or from submitted drug refund claims.
Their main strengths are their size and the fact
that they do not depend on recall of drug use.
Furthermore, after initial establishment, drug
registries are relatively inexpensive. Prescription
(or more strictly, pharmacy lling) registries are
found in North America and in a large number of
European countries and are used in recent large
initiatives to increase the knowledge about drug
safety in pregnancy and breastfeeding (e.g., the
IMI ConcePTION project, www.imi- conception.
eu). The prescription registry must be linked to a
birth registry or other data sources where pregnancies can be identied. Prescription registries,
however, often fail to include over-the-counter
and herbal drugs, and in some countries, also
500
H. Nordeng et al.
nonrefundable prescription drugs. Moreover,
issuance of a prescription or a lling at a pharmacy does not guarantee actual use due to an
often unknown degree of nonadherence.
Although birth defects are the adverse pregnancy outcome most focused on when studying
drug safety, there are several other adverse pregnancy outcomes that can take place. Some examples are summarized here:
• During pregnancy
– Spontaneous abortions (e.g., mycopheno-
late, misoprostol)
– Intrauterine growth restriction or small-for-
gestational age (e.g., beta-blockers,
immunosuppressants)
– Prematurity (e.g., statins, immuno-
suppressants)
– Stillbirths (e.g., warfarin)
– Gestational diabetes (e.g., antipsychotics
including olanzapine, clozapine, and
quetiapine)
– Hypertension/preeclampsia (serotonin and
noradrenalin reuptake inhibitors)
• At or after delivery
– Postpartum hemorrhage (e.g., NSAIDs)
– Neonatal side effects (e.g., CNS depression
and poor suckling due to sedatives)
– Withdrawal reactions in the neonate (e.g.,
opioids and benzodiazepines)
• Long term
– Impaired neurodevelopment (e.g., valproic
acid)
5.1 Causality Assessment
ofSafety Signals inPregnancy
performed by the competent medicines agencies.
In the EU, the Pharmacovigilance Risk
Assessment Committee (PRAC) at the European
Medicines Agency (EMA) is responsible for
assessing and monitoring the safety of human
medicines. In 2022, a topiramate referral was initiated at the request of the French medicines
agency, under Article 31 of Directive 2001/83/EC
[25] (see Box 21.5).
Box 21.5 Topiramate (Safety) Referral
The European Medicines Agency’s
(EMA’s) Safety Committee (PRAC) started
a review of topiramate and the risk of neurodevelopmental disorders in children
whose mothers were taking this drug during pregnancy. The review was triggered by
an epidemiological study which suggested
a possible increase in the risk of neurodevelopmental disorders, in particular autism
spectrum disorders and intellectual disability, in children whose mothers were taking
topiramate during pregnancy. The study
was based on data from several nordic registries (Denmark, Finland, Iceland,
Norway, and Sweden) and included information from more than 24,000 children
exposed in utero to at least one antiepileptic drug. Of these children, 471 were
exposed to topiramate alone, including 246
children born to mothers who had epilepsy
[26]. The PRAC started reviewing the
study results as part of a Safety Signal
Assessment in July 2022.
Perinatal pharmacovigilance includes detection
and assessment of risks of drugs in pregnancy
and breastfeeding. Safety signals or concerns can
arise from nonclinical or clinical data/studies
throughout the lifecycle of the drug. Interpreting
these data, including performing causality assessments and deciding on risk-proportionate measures, is an important regulatory activity
Box 21.6 provides an overview of questions
that may aid causality assessments of signals of
drug teratogenicity. Jointly, these questions may
help to answer the question: Does the total weight
of the evidence support a causal association? If
the answer to the question is “yes,” then a decision about the appropriate risk-proportionate
measures needs to be taken.
21 Safe Prescribing andDrug Use inPregnancy andBreastfeeding
501
Box 21.6 Questions That May Aid Causality
Assessments When Drug Teratogenicity Is
Suspected
1. Strength: How strong is the effect? The
stronger the association [i.e., the higher
effect estimate, e.g., relative risk (RR),
odds ratio (OR), or hazard ratio (HR)], the
more likely it is to be causal. Statistical signicance should not be mistaken for evidence of a substantial association, and
precision should not be mistaken for
validity.
2. Biological plausibility: Does the
association make biological sense? A biological mechanism to support the association makes it more likely that it is causal.
3. Specicity/pattern of birth defects:
Is there a specic syndrome or pattern of
malformation? Teratogens induce specic
malformations rather than a general
increase in all types of birth defects.
4. Analogy: If the drug has the same
mechanism of action or is in the same class
as a known teratogen, it is more likely that
a similar nding is causal.
5. Consistency: Is there consistency
across human studies? Associations should
be consistent across time and in different
populations, using different methods.
6. Temporal relationship: Did the
exposure occur when the birth defect could
originate? (e.g., sensitive time periods for
fetal development). The cause must come
before the effect.
7. Biological gradient: Is there a dose–
response relationship? Teratogenic effects
are usually dose-dependent. A conrmed
dose–response relationship increases the
chance that the association is causal.
8. Animal studies: Is there any supportive evidence from animal studies?
Teratogenicity in animals is important, but
not essential.
9. Alternative explanations: Can there
be alternative explanations for the nding?
Other plausible explanations should be
ruled out. This includes genetic/chromosomal disorders. For epidemiological studies, bias and confounding by, e.g., the
underlying maternal condition, lifestyle,
and health-related factors should be
considered.
Epidemiological studies (i.e., drug utilization
studies) have also an important role in evaluating
the impact of regulatory actions on prescribing
practices to pregnant and breastfeeding women.
Such studies have also been able to provide
important information on whether regulatory risk
mitigation measures [e.g., Pregnancy Prevention
Programs (Guideline on good pharmacovigilance
practices (GVP): Module XVI Addendum III—
Pregnancy prevention programme and other pregnancy-specic risk minimisation measures, [27,
28]) or clinical guidelines] are being followed.
Example: A study that examined trends in
valproic acid use among women of childbearing
potential in Ireland following two regulatory
warnings in 2014 and 2018 found no evidence of
change after the 2014 intervention [29]. A numerically small, but statistically signicant decline in
the use of valproic acid was observed after the
2018 intervention (p=0.03), which the authors
attributed to the introduction of new contraindication measures in 2018.
5.2 Breastfeeding Studies
Historically, surveillance of spontaneous reports
and published cases has been the main pharmacovigilance activity to assess drug safety during
breastfeeding.
Published case reports of possible ADRs in
breastfed infants, however, often suffer from
severe methodological limitations that impair
causal inference. It is often not possible to separate potential drug effects from the infant’s
normal state or from concurrent disease.
Moreover, reports are often confounded by in
utero exposure, i.e., the breastfed infant was also
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