THERAPEUTICS
Drugs in Pregnancy and
48 Lactation
Paula Russell, Laura Yates, Peter Golightly and Sarah Fenner
Key points
Drugs in pregnancy
• Assess risk/benefit ratio for the mother–fetus pair.
• Avoid non-essential drugs.
• Where drug treatment is clinically indicated, select an effective
agent with the best safety profile.
• Use the lowest effective dose for the shortest possible time.
• Provide timely and accurate counselling to help avoid
unfounded maternal fears about drug safety that may other-
wise result in non-adherence with drug therapy or unnecessary
pregnancy termination.
• Teratogenic risks of a drug may vary with each trimester of
exposure.
• Drug exposure in the second and third trimesters may also
result in fetal harm.
Drugs in lactation
• Avoid unnecessary use of drugs.
• Maternal therapy only rarely constitutes a reason to avoid
breastfeeding.
• Assess the risk/benefit ratio for both mother and infant.
• Monitor the infant for unusual signs or symptoms.
• Avoid use of new drugs if there is a therapeutic equivalent for
which data on use in lactation are available.
Drugs in pregnancy
The use of both prescription and over-the-counter drugs in
pregnancy presents a number of challenges to those asked to
provide advice to women either pre-conceptually or during
pregnancy. This is in part due to the fact that no two cases are
the same, and that each enquiry ideally requires an individual
risk assessment that takes into account what is known about
the drug and its effects on the developing fetus, as well as the
woman’s personal medical and family history. It is now well
recognised that most medicines and/or their metabolites readily
cross the placenta, and that some are teratogenic, resulting in
harm to the fetus. Robust scientiic human data on the effects
of many drugs, particularly newer preparations, are, however,
frequently lacking.
It is therefore generally accepted that maternal pharmacother-
apy should be avoided if not necessary, or minimised where the
maternal condition allows. Nevertheless, it has been estimated
820 that more than 80% of expectant mothers take three or four drugs
at some stage of pregnancy (Headley et al., 2004), with a signii-
cant number of women taking medication at the time their preg-
nancy is detected. Indications for drug use range from chronic
illnesses, such as epilepsy and depression, to those commonly
associated with pregnancy, such as nausea and vomiting and uri-
nary tract infections.
Approximately 2–3% of all live births are associated with a
congenital anomaly. Although exogenous factors such as drugs
may account for only 1–5% of these (affecting <0.2% of all live
births), given that drug-associated malformations are largely pre-
ventable, they remain an important consideration.␣
Drugs as teratogens
A teratogen is deined as any agent that results in structural or
functional abnormalities in the fetus, or in the child after birth,
as a consequence of maternal exposure during pregnancy.
Examples of drugs that are known to be human teratogens are
listed in Box 48.1. The teratogenic mechanism for most drugs
remains unclear but may be due to the direct effects of the drug
on the fetus and/or as a consequence of indirect physiological
changes in the mother or fetus. Perhaps the best known and most
widely studied teratogen is thalidomide, a mild sedative that
was widely marketed as a remedy for pregnancy-related nau-
sea and vomiting. In 1961 thalidomide was withdrawn from the
UK market after numerous reports of severe anatomical birth
defects in infants of mothers who took the drug in early preg-
nancy. Whereas external congenital anomalies such as limb
abnormalities, spina biida and hydrocephalus may be obvious
at birth, some defects may take many years to manifest clinically
or be identiied. Examples of delayed effects of teratogens are
the behavioural and neurodevelopmental disorders associated
with in utero sodium valproate exposure and the development of
clear-cell vaginal cancer in young women after maternal intake
of diethylstilboestrol, used irst in the 1930s for the prevention
of miscarriage and preterm delivery (Herbst et al., 1971).
Critical periods in human fetal development
The human gestation period is approximately 40 weeks from the
irst day of the last menstrual period (38 weeks post-conception)
and is conventionally divided into the irst, second and third
trimesters, each lasting 3 calendar months. Another method

Box 48.1 Examples of drugs considered to be human
teratogens
Angiotensin-converting enzyme inhibitors
Androgens
Carbamazepine
Carbimazole
Cytotoxics (some)
Danazol
Diethylstilboestrol
Ethanol
Lithium
Methotrexate
Misoprostol
Mycophenolate mofetil
Tetracyclines
Thalidomide
Valproic acid
Vitamin A and derivatives, e.g. isotretinoin
Warfarin
for classifying the stage of pregnancy is according to the stage
of embryo-fetal development. This is a more useful approach
when assessing the potential risks associated with drug use in
pregnancy.
Pre-embryonic stage: weeks 0–2 post-conception
The irst 2 weeks post-conception are regarded as the pre-
embryonic stage and describe the period up to implantation
of the fertilised ovum. Teratogenic exposure during the pre-
embryonic stage, sometimes referred to as the ‘all-or-nothing’
period, is thought to carry a low risk of fetal harm, with most expo-
sures leading either to death of the embryo or complete recovery and
normal development of the fetus. Fetal malformations after drug
exposure during this period are therefore thought to be unlikely,
but robust scientiic data to support a low risk of adverse fetal out-
come are lacking. Risk to the fetus may also be increased where
the half-life of the drug is suficient to extend exposure into the
embryonic stage. A good example of the latter is isotretinoin and
related vitamin A derivatives that have half-lives up to a week,
and which when used systemically, for example, for the treat-
ment of acne and psoriasis, are recognised teratogens (Nulman
et al., 1998).␣
Embryonic stage: weeks 3–8 post-conception
Organogenesis occurs predominantly during the embryonic
stage and, with the exception of the central nervous system
(CNS), eyes, teeth, external genitalia and ears, is complete
by the end of the 10th week of pregnancy. Exposure to drugs
during this critical period therefore represents the greatest
risk of major birth defects. For this reason, women are often
advised to avoid or minimise all drug use in the irst trimester
whenever possible. It is important to bear in mind, however,
that very few drugs are in fact proven teratogens, and that
exposure in the second and third trimesters may still result in
fetal harm.␣
DRUGS IN PREGNANCY AND LACTATION 48
Fetal stage: weeks 9–38 post-conception
During the fetal stage, the fetus continues to develop, grow
and mature and, importantly, remains susceptible to some drug
effects. This is especially true for the CNS, which can be dam-
aged by exposure to certain drugs, for example, ethanol, at
any stage of pregnancy. The external genitalia also continue
to form from the seventh week until term; consequently, dan-
azol, which has weak androgenic properties, can cause virilisa-
tion of a female fetus if given in any trimester after the eighth
week of pregnancy when the androgen receptors begin to form
(Rosa, 1984).
Further examples include the angiotensin-converting
enzyme inhibitors, which if given in the second and third tri-
mesters can result in fetal renal dysfunction and subsequent
oligohydramnios, that is, reduced amniotic luid volume
(Sedman et al., 1995). The non-steroidal anti-inlammatory
drugs (NSAIDs) are another important group of drugs that may
cause problems, speciically in the third trimester. These drugs
inhibit prostaglandin synthesis in a dose-related fashion and,
when given late in pregnancy, may result in premature clo-
sure of the fetal ductus arteriosus and fetal renal impairment
(Koren et al., 2006). NSAIDs should therefore be avoided dur-
ing the third trimester.␣
Principles of teratogenesis
In 1959 James Wilson, co-founder of The Teratology Society,
proposed several principles of teratogenesis that have since
been expanded and modiied but remain fundamental in assess-
ing whether a drug or chemical exposure during pregnancy
is likely to be associated with reproductive or developmen-
tal toxicity. A basic understanding of these factors is essential
to both the interpretation of preclinical (animal) reproductive
toxicity studies and to enable accurate risk assessment in clini-
cal practice. A subset of Wilson’s principles is discussed as
follows.
Timing of exposure
The stage of pregnancy at which a drug exposure occurs is
key to determining the likelihood, severity or nature of any
adverse effect on the fetus. Risk both between and within tri-
mesters may be variable. For example, folic acid antagonists
such as trimethoprim have been associated with an increased
risk of neural tube defects if exposure occurs before neural
tube closure (third to fourth week post-conception), but not
after this period (Hernandez-Diaz et al., 2001). It has also been
suggested that trimethoprim should be avoided after 32 weeks’
gestation in view of the theoretical risk of severe jaundice in
the neonate as a result of bilirubin displacement from protein
binding, although clinical evidence to support this is lacking
(Dunn, 1964). Unfortunately, the precise period of teratogenic
risk is known for very few substances. One drug for which this
period has been established is thalidomide, where exposure
between days 20 and 36 post-conception is associated with a
high risk of congenital malformation (Lenz, 1988; Newman,
1986).␣ 821
 48 THERAPEUTICS

Drug dose Table 48.1 Examples of drugs with pharmacological effects

on the fetus or neonate
A threshold dose above which drug-induced malformations or
other adverse effects are more likely to occur has now been dem- Possible adverse
onstrated for certain teratogenic compounds, although for most a Drug pharmacological effect Notes
‘safe dose’ has not been conclusively determined. The likelihood
Angiotensin- Fetal and neonatal hy- Monitor fetus if
of a dose relationship underlies the recommendation to use the
converting poxia, hypotension, renal long-term therapy
lowest effective dose in pregnancy. For this reason more frequent enzyme dysfunction, oligohydram- in the second or
monitoring of drug levels may be recommended for certain drugs inhibitors nios and intra-uterine third trimester
during pregnancy.␣ growth retardation

β-Blockers, Neonatal bradycardia, Neonatal symptoms

Species e.g. atenolol hypotension and hyper- are usually mild and
glycaemia improve within
Teratogenicity of a drug may be species dependent. Interestingly, 48 h; no
preclinical thalidomide studies in mice and rats did not result long-term effects
in congenital malformation in the offspring (Breitkreutz and
Anderson, 2008; Miller et al., 2009; Vorhees et al., 2001). Birth Benzodiaz- ‘Floppy infant syndrome’ Risk if regular use in
defects or other adverse reproductive outcomes observed in ani- epines Withdrawal reactions third trimester
mal studies cannot therefore be simply extrapolated to the human Neonatal observa-
tion recommended
situation. Further, the drug dose and route of administration used
in early animal studies may not be comparable with clinical use Corticosteroid Fetal adrenal suppression Dependent on
in humans.␣ (high dose) dose and treatment
interval
Genotype and environmental interaction Non-steroidal Premature closure of the Avoid repeated use
Not all fetuses exposed to known teratogenic drugs show evi- anti- ductus arteriosus (affect- after week 28; if
inflammatory ing fetal circulation) and unavoidable, fetal
dence of having been affected in utero. It remains undetermined
drugs fetal renal impairment circulation moni-
whether this variable susceptibility to teratogenic drugs is a (decreased urine output) tored regularly
result of genetic differences in the exposed mothers, the fetal
genotype, modifying environmental factors or a combination of Opioids Neonatal withdrawal Risk if used long-
all three. Malformations are reported to occur in only 20–50% symptoms term
of infants born to mothers exposed to thalidomide during the Respiratory depression Risk if used near
period of greatest risk of embryopathy, that is, days 20–36 post- term
fertilisation (Lenz, 1966; Newman, 1985). Similarly, maternal
Phenothi- Neonatal withdrawal and Observation for at
treatment with systemic isotretinoin during the irst trimester azines transient extrapyramidal least 48 h;
results in fetal malformation in only 18–35% of the live born symptoms symptoms may last
infants, with a further 30% of children exhibiting developmental for several weeks
delay in the absence of physical deformity (Benke, 1984; Braun
et al., 1984; Hill, 1984).␣ Tricyclic and Neonatal withdrawal Risk if used long-
selective sero- symptoms term and/or near
tonin reuptake term; observation
Pharmacological effect inhibitor anti- for at least 48 h
depressants
Pharmacological effects on the fetus are by far the most common
drug effects during pregnancy, and the consequences are often Adapted from Schaefer et al. (2014).
minor and reversible compared with the idiosyncratic effects
that can lead to major irreversible anomalies. Pharmacological
effects are usually dose related and to some extent predict- The capacity of the neonate to eliminate drugs is reduced,
able. Drugs may adversely affect the fetus via effects on the and this can result in signiicant accumulation of some drugs,
maternal circulation, or they may cross the placenta and exert leading to toxicity. Neonatal withdrawal effects may require
a direct pharmacological effect on the fetus. Equally, drugs are treatment.
sometimes administered to pregnant women to treat fetal dis- Idiosyncratic drug effects in the fetus and neonate are possible
orders; for example, lecainide has been used to resolve fetal but occur rarely compared with pharmacological effects.␣
tachycardia.
The neonate can also be adversely affected by maternal drug
Maternal pharmacokinetic changes
therapy (Table 48.1). It is generally only at birth that signs of
fetal distress are observed due to in utero drug exposure or the Physiological changes in pregnancy induce profound changes to
effects of abrupt discontinuation of the maternal drug supply. the pharmacokinetic properties of many drugs. These changes,
822
 DRUGS IN PREGNANCY AND LACTATION 48
peaks at term (36–42 L/h). There is also a mean increase of 8 L in
Table 48.2 Summary of pharmacokinetic changes during
body water (60% to placenta, fetus and amniotic luid and 40% to
pregnancy
maternal tissues). As a consequence, there may be increased dos-
Change during pregnancy age requirements for some drugs to achieve the same therapeutic
effect, provided these effects are not offset by other pharmaco-
Absorption kinetic changes. Both the total plasma and the free-drug concen-
Gastro-intestinal motility ↓
trations of phenytoin, carbamazepine and valproic acid decrease
during pregnancy, but the free-drug fraction (ratio of free to total
Lung function ↑ plasma concentration) may increase (Pavek et al., 2009).
Protein binding. Albumin is the main plasma protein respon-
Skin blood circulation ↑ sible for binding acidic drugs such as phenytoin and salicylates,
whereas α1-acid glycoprotein predominantly binds basic drugs,
Distribution
including β-blockers and opioid analgesics. As pregnancy pro-
Plasma volume ↑ gresses the plasma volume increases at a greater rate than the
increase in albumin which results in hypoalbuminaemia. In addi-
Body water ↑ tion, steroid and placental hormones occupy the protein-binding
sites. This leads to an increase in the fraction of unbound drug.
Plasma protein ↓ Clinical effect is related to the concentration of unbound drug,
which usually remains unchanged even though the total (bound
Fat deposition ↑
plus unbound) plasma concentration is decreased. Thus, a decline
Metabolism in the total plasma concentration does not usually require an
increase in dose. The α1-acid glycoprotein concentrations remain
Liver activity ↑↓ the same as those in non-pregnancy.
Excretion
Phenytoin is bound to albumin and exhibits the effects
described earlier, but the situation is further complicated by
Glomerular filtration ↑ increased hepatic metabolism that may necessitate a dose
increase. Consequently, therapy can only be reliably guided by
Renal tubule secretion ↑ clinical assessment or measurement of unbound rather than total
Adapted from Schaefer et al. (2014).
plasma concentration.␣

summarised in Table 48.2, affect absorption, distribution, metabolism,
and excretion of drugs, and may also affect their pharmacodynamic
properties. Some of the changes that occur in maternal organ systems
are secondary to pregnancy-induced hormonal changes, whereas
others occur to support the pregnant woman and the developing fetus.
Absorption
Gastric and intestinal emptying time increases by 30–40% in the sec-
ond and third trimesters (Pavek et al., 2009) and could be important
in delaying absorption and time to onset of action for some drugs
(Loebstein et al., 1997). There is also a reduction in gastric acid
secretion in the irst and second trimesters, and an increase in mucous
secretion. As a consequence of the increase in gastric pH, the ionisa-
tion, and hence absorption, of weak acids and bases can be affected.
Cardiac output and respiratory volume increase during pregnancy,
leading to hyperventilation and increased pulmonary blood perfusion.
These changes cause higher pulmonary absorption of anaesthetics,
bronchodilators, pollutants, cigarette smoke and other volatile drugs.␣
Distribution
The volume of distribution of drugs may be altered because of
an increase of up to 50% in blood (plasma) volume and a 30%
increase in cardiac output. Renal blood low increases by up to 50%
at the end of the irst trimester, and uterine blood low increases and
Metabolism
The metabolic activity of cytochrome P450 isoenzymes CYP3A4,
CYP2D6, CYP2A6 and CYP2C9 and uridine 5′-diphosphate
glucuronosyltransferase (UGT) isoenzymes (UGT1a1, UGT1A4
and UGT2B7) is increased during pregnancy. Drugs metabolised
by these isoenzymes may therefore require dose adjustment. This
may decrease the amount of the drug available for transfer across
the placenta, and thereby inluence fetal exposure. In contrast,
the metabolic activity of CYP1A2 and CYP2C19 is decreased
during pregnancy, and drugs metabolised by these isoenzymes
may need dose reduction to minimise toxicity. These changes
and their extent depend on the stage of pregnancy, so there may
be clinically signiicant changes in drug concentrations between
trimesters (Table 48.3) (Anderson, 2005; Deligiannidis et al.,
2014). In general the effects on individual drugs are inconsistent
and dificult to predict, but knowledge of the effect of pregnancy
on isoenzymes may inform decisions about possible monitoring
and/or dose alterations.␣
Excretion
Within the irst few weeks of pregnancy the glomerular iltration
rate (GFR) increases by approximately 50%. Consequently, those
drugs which are excreted primarily unchanged by the kidneys,
for example, lithium, digoxin and penicillin, show enhanced
elimination and lower steady-state concentrations. The following
823
 48 THERAPEUTICS

and maternal proteins. For example, fetal and newborn plasma

Table 48.3 Summary of pregnancy-induced effects on
proteins appear to bind ampicillin and benzylpenicillin with
hepatic metabolism of some drugs
less afinity and salicylates with greater afinity than maternal
Effect on clearance proteins. Maternal albumin gradually decreases during preg-
nancy and fetal albumin concentrations increase, so different
Drugs/ First Second Third fetal/maternal albumin concentrations occur at different stages
Isoenzyme probes trimester trimester trimester
of pregnancy. The degree of protein binding of any drug is an
CYP1A2 Caffeine ↓ 33% ↓ 50% ↓ 65% important determinant of its movement across the placenta.
Drugs that are highly protein bound tend to achieve higher
CYP2A6 Nicotine ND ↑ 54% maternal and lower fetal concentrations. Drugs with very large
(combined molecular weights such as insulin and heparin have negligible
data) transfer. Lipophilic, un-ionised drugs cross the placenta more
CYP2C9 Phenytoin No effect No effect ↑ 20%
easily than polar drugs, and weakly basic drugs may become
‘trapped’ in the fetal circulation because of the slightly lower pH
CYP2C19 Proguanil ND ↓ 50% ↓ 50% compared with maternal plasma.
Some other factors such as enzymes or drug eflux transporters
CYP2D6 Dextro- in the placenta may facilitate or restrict the transfer of a drug to
methorphana ND ND ↑ 50% the fetus. The inluence of transporter activity on placental trans-
Metoprolol
fer is increasingly recognised. For example, the accumulating
CYP3A4 Cortisola
evidence about transport mechanisms operating at the placental
ND ND ↑ Variableb barrier is expected to be useful in developing techniques to con-
Nifedipine
trol fetal and placental transfer of antiviral drugs, thus achieving
UGT1A4 Lamotrigine ↑ 200% ↑ 200% ↑ 300% maximum therapeutic beneit while minimising potential fetal
monother- toxicity (Tomi et al., 2011).␣
apy
Polytherapy ↑ 65% ↑ 65% ↑ 90%
Maternal pharmacodynamic changes
UGT2B7 Morphine ND ND ↑ Variableb
(limited Pharmacodynamic changes in pregnancy are less well stud-
data) ied than pharmacokinetic changes, but increases in blood pres-
sure and blood glucose associated with corticosteroids may be
aDextromethorphan and cortisol used as probes of CYP2D6 and CYP3A4
activity.
more common in pregnancy. It is thought that impairment of
bExtent variable depending on the drug studied. cell-mediated immunity affects the eficacy of vaccination, par-
ND, Not detectable. ticularly late in pregnancy. Sensitivity to the bradycardic effects
Adapted from Anderson (2005). of β-receptor blocking drugs such as propranolol may also be
increased in pregnancy (Rubin et al., 1987). There is currently
not a good understanding of pharmacodynamic changes and their
clinical implications in pregnancy.␣

drugs have shown pregnancy-induced increases of 20–65% on

Drug dosing in pregnancy
their renal elimination (Anderson, 2005):
• ampicillin, As a general principle, the dose of a drug given at any stage of
• cefuroxime, pregnancy should be as low as possible to minimise potential
• ceftazidime, toxic effects to the fetus. Drug therapy that is considered essential
• cefazolin, can be tapered to the lowest effective dose either before concep-
• piperacillin, tion (ideally) or at the time the pregnancy is diagnosed. Where
• atenolol, drug exposure during the third trimester is predicted to have an
• sotalol, adverse effect on the neonate postpartum, consideration may
• digoxin, be given to slowly reducing the dose towards term to minimise
• lithium, the risks to the baby. Such decisions are, however, not always
• dalteparin sodium, straightforward. Recommendations to wean an expectant mother
• enoxaparin sodium.␣ off antidepressants and antipsychotics to reduce the likelihood
of neonatal withdrawal syndrome (characterised by jitteriness,
altered muscle tone, poor feeding and irritability) and, in the case
Fetal–placental transfer
of the selective serotonin reuptake inhibitors (SSRIs), avoid the
Most drugs have a molecular weight less than 600 and diffuse possible increased risk of persistent pulmonary hypertension of
easily across the placenta to enter the fetal circulation to some the newborn are now being challenged. Not only are there insuf-
extent. In general, the fetal/maternal drug concentration ratio is icient data to conclusively demonstrate neonatal beneit or an
824 less than 1. Drugs differ in the extent to which they bind to fetal optimal time of weaning, but also the increased risk of psychiatric

problems and relapse in the mother’s immediate postpartum
period needs to be taken into account.
Many physiological changes occur during pregnancy that
may affect the way the body handles drugs. Knowledge of these
changes can allow some prediction of the impact on pharma-
cotherapy while remaining aware that there is variability in the
extent of these changes during the pregnancy and high inter-
individual variability. The need for changes in dosages is inlu-
enced by whether the drug is excreted unchanged by the kidneys
or which metabolic isoenzymes are involved in its elimination.
Women who are taking drugs with enhanced clearance and for
which a good correlation between plasma levels and therapeu-
tic effect exists should have their plasma concentrations closely
monitored and dose adjusted to reduce the risk of suboptimal
therapy, for example, with phenytoin, carbamazepine, lithium
and digoxin. Similarly, highly protein-bound drugs may require
free-drug concentration monitoring. However, there is no clear
guidance for adjusting doses during pregnancy, and for most
drugs, the concentration of free drug, and therefore the effect of
that drug, is unchanged.
Pregnancy itself can cause a temporary worsening or
improvement of some diseases and in that way inluence drug
dosages.␣
Drug selection in pregnancy
Although there are few, if any, drugs for which safe use in preg-
nancy can be absolutely assured, only a handful of drugs in cur-
rent clinical use have been conclusively shown to be teratogenic.
In general, drugs that have been used extensively in pregnant
women without apparent problems are recommended in prefer-
ence to new drugs for which there is less experience of use. For
example, methyldopa is used rarely to treat hypertension in the
non-pregnant state but has historically been preferred in preg-
nancy because of a long history of safe use (National Institute
for Health and Care Excellence [NICE], 2011). However, older
drugs may be less effective in terms of controlling maternal ill-
ness and are often associated with an increased side-effect risk
proile.
In most cases the decision whether to commence or continue
with a medication in pregnancy will depend on the risk–beneit
analysis for that speciic mother–infant pair. A frequent error
made by health professionals was to apply the recently discon-
tinued US Food and Drug Administration (FDA) pregnancy risk
categories (A [no demonstrable risk]; B, C, D and X [teratogenic
agents that are considered to be completely contraindicated in
pregnancy]) when considering whether to prescribe a drug in
pregnancy. It is now widely accepted that these categories were
oversimpliied and of little practical help in a clinical setting.
More detailed information sheets containing a summary of the
fetal risks and the additional maternal factors that need to be taken
into consideration are now being used. Consideration also needs
to be given to the quality and quantity of both human and animal
data, the study design, dose exposure and any reported congenital
malformations and/or adverse events (see http://www.fda.gov for
up-to-date information).
It is worth noting that standard literature sources often contain
unhelpful information such as ‘do not use in pregnancy unless
DRUGS IN PREGNANCY AND LACTATION 48
the beneits outweigh the risks’. This is understandable from a
medico-legal point of view but offers little in terms of risk assess-
ment. The primary literature is frequently inadequate because
ethical and legal restraints mean that randomised controlled trials
are rarely undertaken in pregnant women. Often the only informa-
tion that is available is conined to retrospective studies, voluntary
reporting schemes and/or animal studies. The rate of anomalies
in retrospective studies and voluntary reporting databases may
be erroneously elevated due to preferential reporting of abnor-
mal outcomes. Individual case reports are also dificult to inter-
pret because the denominator of drug exposure is unknown, and
an abnormal outcome may be coincidental to the drug exposure.
More recently, prospective controlled trials have been utilised
where the pregnancy outcomes of a deined cohort of women
exposed to the drug are compared with outcomes of a matched
control group. Complete follow-up of each pregnancy and postna-
tal monitoring is an essential feature of this type of investigation.␣
Pre-conception advice
Drug use during the irst trimester, in particular, the embryonic
stage, carries the greatest risk of malformation because this
is when the fetal organs are being formed. Ideally all unneces-
sary drug therapy should be discontinued prior to conception.
However, inadvertent drug exposure frequently occurs, because
approximately half of all pregnancies are unplanned. It is thus
critical to make careful drug choices when prescribing for women
of reproductive potential.
Women with chronic illnesses who require drug treatment
should be offered specialist counselling before conception, and
the options explored to reduce or change drug therapy to a safer
agent if necessary. It is also important to note that many preg-
nant women become less adherent to their drug therapy out of
concern about possible harm to their infant. In many cases, such
as asthma, inlammatory bowel disease and epilepsy, inadequate
treatment of the underlying disease may be more detrimental to
the mother–fetus pair than the drugs used to treat the condition.
It is thus essential that women of reproductive potential are given
clear and up-to-date information so that unrealistic fears about
the risks to their baby do not result in unnecessary pregnancy
termination or disease relapse.
All women who are planning a pregnancy should be offered
general advice to minimise the risk of congenital anomalies. This
includes avoidance of recreational drugs, ‘natural’ or herbal rem-
edies, alcohol, smoking and vitamin A products; minimisation of
caffeine consumption; and beginning daily supplementation with
at least 400 micrograms of folic acid to reduce the risk of neural
tube defects (NICE, 2014). It is recommended that the daily dose
of folic acid be increased to around 5 mg daily in women who
have epilepsy (NICE, 2016) or who have had a previous child
with a neural tube defect (NICE, 2014). Some infectious diseases
may carry important fetal consequences if contracted during
pregnancy. For example, rubella infection in the irst 20 weeks
of pregnancy is associated with an increased risk of miscarriage
and a syndrome comprising problems such as deafness, cardiac
defects and mental retardation in more than 20% of pregnancies.
Women who lack immunity to rubella should be immunised prior
to conception.␣ 825
 48 THERAPEUTICS
Post-conception advice
It is important to draw distinction between advice given to women
pre-conceptually and that provided to a pregnant woman who has
already been exposed to a drug. In the former setting, it may be rec-
ommended that an alternative preparation be considered or that a
drug treatment be stopped where clinically appropriate. This advice
often hinges on the lack of deinitive safety data and does not auto-
matically translate to exposure to that drug in pregnancy being an
indication for discontinuing the drug, additional fetal monitoring
or termination of the pregnancy on the basis of the exposure. Any
change to the woman’s medication should be based on a careful and
individual risk assessment, and include a discussion with the woman
to provide her with accurate, up-to-date, evidence-based advice. In
many such cases the woman can be reassured that a healthy baby is
the most likely outcome, or where appropriate be offered additional
prenatal investigation to screen for congenital malformation where
the risk to the fetus is considered to be signiicant.␣
Teratology information services and pregnancy
registries
It is dificult to keep up to date with the published literature.
There is an increasing need for summary documents that include
and critically appraise all available data, and which enable health-
care providers to have a balanced and informed discussion with
patients regarding the risks and beneits of a certain therapy in
pregnancy. This is evidenced by the ongoing debate surrounding
the teratogenic potential of various antidepressants with conlict-
ing opinion even amongst experts in the ield.
Teratology Information Services have been established in sev-
eral countries across the world and provide evidence-based, up-
to-date information and individual case-based risk assessments.
In addition to reviewing published literature on drugs, teratology
services also have access to specialist online databases and dis-
cussion forums. A number routinely collect pregnancy outcome
data on the women about whom they receive an enquiry, to enable
surveillance for potential teratogens.
For some new drugs, pregnancy registries have been initiated
that record all reported drug exposures and follow up the out-
come of the pregnancy. These registries are cumulative and work
on the basis that speciic anomalies would be identiied relatively
quickly, and that there will eventually be suficient statistical
power to detect the magnitude of any increased risk relative to the
general population. These registries may be held by a Teratology
Information Service or by independent groups with an interest in
a deined area. The 2009 A/H1N1 inluenza pandemic provided
an example of teratology services across the globe responding
to the urgent need for safety data by establishing registries on
antiviral and pandemic vaccine exposure during the pandemic.␣
Drugs in lactation
Breast milk is the best form of nutrition for young infants. It pro-
vides all the energy and nutrients required for the irst 6 months of
life. The World Health Organization (WHO, 2001) and the United
Nations Children’s Fund recommend exclusive breastfeeding
826
for this period. Beneits of breastfeeding include protection of
the infant against infectious diseases (gastro-intestinal, upper
and lower respiratory tract, otitis media and urinary tract) and
reduction in rates of obesity, types 1 and 2 diabetes, inlamma-
tory bowel disease, childhood leukaemia, asthma, coeliac disease
and atopic disease (Eidelman and Schanler, 2012; Kramer and
Kakuma, 2012). There is evidence to show that adults who were
breastfed as infants have a predisposition to lower blood pres-
sure and cholesterol levels (Horta et al., 2007). Maternal beneits
include reduced risk of development of postpartum depression,
cardiovascular disease, diabetes (Eidelman and Schanler, 2012),
premenopausal breast and ovarian cancer, and delayed resump-
tion of menstrual cycle (Department of Health, 2003; Eidelman
and Schanler, 2012). Breastfeeding strengthens the mother–
infant bond.
There are few contraindications to breastfeeding; these include
galactosaemia in an infant and active untreated tuberculosis and
HIV infection in developed countries. However, in the devel-
oping world, where mortality is increased in non-breastfeeding
infants from a combination of malnutrition and infectious dis-
eases, breastfeeding may outweigh the risk of acquiring HIV
infection from human milk.
Reasons for early discontinuation of breastfeeding include prob-
lems latching, sore/cracked nipples, engorgement, inconvenience
(return to work, feeding in public, lifestyle choices), concerns
about inadequate lactation and nutritional adequacy, personal ill-
ness and medication, and infant factors (Li et al., 2008).
Breastfeeding mothers frequently require treatment with pre-
scription medicines or may self-medicate with over-the-counter
preparations, nutritional supplements or herbal medicines. It is
important for health professionals to understand the principles of
safe use of medications during lactation to provide appropriate
advice.
There are two main goals to consider when formulating advice
for nursing mothers. These are to protect the infant from mater-
nal drug-related adverse effects and to allow, whenever possible,
necessary maternal medication (Berlin et al., 2009).
Transfer of drugs into breast milk
Most drugs pass into breast milk to some degree, although
transfer is usually low. The drug ‘dose’ ingested by the infant
via breast milk only rarely causes adverse effects. Examples of
adverse effects observed in breastfed infants exposed to com-
monly used medicines via breast milk are given in Table 48.4.
These examples are of reports that are considered to have a high
probability of a direct association between infant exposure in
breast milk and maternal ingestion, although not all of these are
proven to be directly caused by the drug ingested via breast milk.
There are a signiicant number of reports of possible adverse reac-
tions in breastfed infants due to maternal medication in which the
association is less clear, unsubstantiated or anecdotal (Anderson
et al., 2003, 2016).
Almost all drugs enter milk by passive diffusion of unionised,
unbound drug through the lipid membranes of the alveolar cells
of the breast, according to the pH partitioning theory. Several
factors inluence the rate and extent of passive diffusion.
 DRUGS IN PREGNANCY AND LACTATION 48
Milk differs from blood in that it has a lower pH (7.2 vs. 7.4),
Table 48.4 Adverse reactions reported in breastfed infants
less buffering capacity and higher fat content. The following drug
(Anderson et al., 2003, 2016)
parameters affect the extent of transfer into milk:
Drug Adverse reaction • pKa: This is a measure of the fraction of the drug that is ion-
ised at a given pH, for example, physiological pH. Highly
Acebutolol Hypotension, bradycardia, tachypnoea ionised drugs tend not to concentrate in milk. For basic drugs
(e.g. erythromycin), a greater fraction will be ionised at an
Aspirin Metabolic acidosis, thrombocytopenic
purpura acidic pH, so the milk compartment will tend to ‘trap’ weak
bases. In contrast, acidic drugs (e.g. penicillins) are more ion-
Atenolol Bradycardia, cyanosis, hypotension ised at higher pH values and will be ‘trapped’ in the plasma
compartment. Drugs with higher pKa values generally have
Ciprofloxacin Pseudomembranous colitis higher milk/plasma ratios.
• Protein binding: Drugs that are highly bound to plasma pro-
Codeine Apnoea, bradycardia, death
teins (e.g. warfarin) are likely to be relatively retained in
Cyclophosphamide Neutropenia, thrombocytopenia maternal plasma because there is a lower total protein content
in the milk. High protein binding essentially restricts the drug
Dapsone Haemolytic anaemia to the plasma compartment because only the free fraction of
the drug crosses the biological membrane. Milk concentra-
Diazepam Lethargy, sedation, poor suckling tions of highly protein-bound drugs are usually low.
• Lipophilicity: The alveolar epithelium of the breast is a lipid
Doxepin Sedation and respiratory arrest
barrier. Transfer of water-soluble drugs and ions is inhibited
Erythromycin Pyloric stenosis by this barrier. CNS active drugs usually have the characteris-
tics required to pass into milk.
Fluoxetine Colic, irritability, sedation • Molecular weight: Drugs with low molecular weights (<200)
readily pass into milk through small pores in the cell walls of
Indometacin Seizures alveolar cells. Drugs with higher molecular weights cross cell
membranes by dissolving in the lipid layer which may sub-
Lamotrigine Apnoea, cyanosis
stantially reduce milk concentrations. Proteins such as heparin
Lithium Cyanosis, lethargy, T-wave abnormalities, or insulin with very large molecular weights greater than 6000
thyroid-stimulating hormone elevation are virtually excluded from milk.
The proile of a drug that passes minimally into milk would
Mesalazine Watery diarrhoea therefore be an acidic drug that is highly protein bound and has
low-to-moderate lipophilicity (e.g. most NSAIDs). In contrast, a
Naproxen Prolonged bleeding, haemorrhage, weakly basic drug that has low plasma protein binding and is rel-
anaemia
atively lipophilic will achieve higher concentrations in the milk
Oxycodone Sedation, hypothermia, poor feeding compartment (e.g. sotalol).
In the irst few days of life, large gaps exist between the
Paroxetine Agitation, feeding difficulty alveolar cells. These permit enhanced passage of drugs into
milk. By the end of the irst week these gaps close under the
Phenindione Postoperative haemorrhage inluence of prolactin (Lawrence and Lawrence, 2016). There
is greater passage of drugs into colostrum (early milk) than in
Phenytoin Methaemoglobinaemia
mature milk because the former contains more protein and less
Sulfasalazine Bloody diarrhoea fat. There is also some variation in fat and protein content of
milk between the beginning and end of a feed, but these changes
Theophylline Irritability, poor sleep have less inluence on drug passage than the physicochemical
properties of the drug.␣
Topiramate Diarrhoea

Yellow fever vaccine Fever, irritability, convulsions, meningo-
encephalitis
These include maternal plasma level, physiological differences
between plasma and milk, and the physicochemical properties
of the drug. Differences in composition between blood and milk
determine which physicochemical characteristics inluence
diffusion.
Milk/plasma concentration ratio
Several methods have been proposed to determine the amount
of drug transferred to breast milk. The milk/plasma (M/P) ratio
is often used as a measure of the extent of drug transfer into
breast milk. It is usually obtained from case reports or small
clinical studies and may be based on paired concentrations or
full area under the concentration–time curve (AUC) analysis.
M/P ratios that are based on a pair of milk and plasma sam-
ples collected simultaneously may be inaccurate because they
827
 48 THERAPEUTICS
a 20
75
Concentration
50
b
25
Milk
Plasma
0 Time (hours)
0 6 12 18
Time (hours)
Fig. 48.1 Diagrammatic representation of a drug concentration–
time profile in the maternal plasma and milk phases after a single oral
dose. The points a, b and c illustrate simultaneous sampling times
from both phases. Sampling at (a) would yield an estimated milk/
plasma (M/P) ratio of 0.2, at (b) a value of 1.0, and at (c) a value of
9.3. All can be misleading. The true M/P ratio calculated by the area
under the concentration–time curve method is 1.2 when extrapolated
to infinity.
assume that the concentrations of drug in milk and plasma are
in parallel, which may not be the case. It is better to collect
multiple samples of plasma and milk across a dosing interval,
or until the drug is cleared from both phases after a single dose,
for determination of a M/P ratio based on the respective AUCs
(M/PAUC). Fig. 48.1 demonstrates the markedly different esti-
mates of M/P ratio that can be obtained via both sampling meth-
ods. The true M/P ratio may vary signiicantly during the same
episode of breastfeeding.
If human-derived M/P ratios are lacking for a particular drug,
it may be possible to predict the extent of transfer using known
physicochemical properties, for example, pKa, and a published
predictive model (Atkinson and Begg, 1990; Begg et al., 1992;
Zhao et al., 2006). M/P ratios obtained from animal studies
should not be used for clinical decision making because they may
not correlate well with human M/P ratios.
Studies in humans demonstrate that most drugs have an
M/P ratio less than 1.0, with the range of reported ratios
being from around 0.1–5.0. It is often thought that drugs with
high M/P ratios (e.g. 5.0) are unsafe because the concentra-
tion in milk exceeds that in plasma, while those with low
ratios (<1.0) are believed to be safe. This is not always the
case because the M/P ratio often fails to correlate with the
‘dose’ of drug the infant ingests via milk. The amount of drug
transferred into milk is principally determined by the mater-
nal plasma level. Thus, even where the M/P ratio is high, if
the maternal plasma level is low, drug transfer is still low.
Therefore, the M/P ratio must never be used as the sole mea-
sure of drug safety in breastfeeding. However, it can be used
to estimate the ‘dose’ ingested via milk, which is a better pre-
dictor of safety.␣
Calculating the infant ‘dose’ ingested via milk
Infant plasma drug levels are the most accurate indicator of drug
828 exposure, but these are seldom available.
Cumulative infant dose
10
c
0
0 4 8 12 16 20 24
24
Fig. 48.2 The cumulative dose received by the infant is plotted
against time. The arrows represent the maternal dose times. This type
of study is undertaken by the mother expressing all the milk, from
both breasts, at usual feeding times. An aliquot of milk is taken and
assayed for the drug. The volume of milk is measured, and the total
amount of drug at each time is calculated as the product of concen-
tration and volume. This type of study must be undertaken at steady
state.
When using quantitative data from milk analyses, the most
accurate estimation of the infant ‘dose’ is from studies in which
the milk is collected over a complete dose interval at steady state
and the total dose is calculated (Fig. 48.2). Unfortunately, these
studies are seldom performed. Therefore, information must be
obtained from less than ideal conditions.
If the M/P ratio is known from published studies, the likely
infant dose (Dinf) can be calculated as follows, with some
assumptions:
= × ×
where Cpmat is the average maternal plasma concentration, and
the M/PAUC should be used in preference to a ratio based on paired
concentrations when available. The volume of milk ingested
(Vmilk) is not known but is generally assumed to be around 150 mL
of milk per kilogram of body weight per day. The above equation
simpliies if the actual milk concentration data are available:
= ×
The likely infant plasma drug concentration (Cpinf) can be cal-
culated by:
= ×
where F is oral availability and Clinf is the infant clearance.
Unfortunately, neither F nor Clinf is known accurately for infants,
so estimation of the likely steady-state average plasma drug con-
centration will be very approximate. Weight-adjusted Clinf values
(i.e. L/h/kg) are often signiicantly less than adult values in the
early stages of life (Table 48.5).
Given the dificulty in estimating infant plasma drug concen-
trations, the relative infant dose (RID), for example, compared
with a therapeutic infant dose, is often used as a surrogate of
exposure. To give some basis for comparison, the likely infant
dose from milk can be compared with an infant therapeutic dose.
This is reasonable for drugs such as paracetamol that are usually
administered to infants, but is unsuitable for drugs such as anti-
depressants that are not. In the absence of a clearly deined range

Table 48.5 Approximate drug clearance by age as percentage
of maternal value (Begg, 2000)
Post-conceptual age (weeks) Approximate drug clearance (%)
24–28 5 •
28–34 10
34–40 33
40–44 50
44–68 66
>68 100
of infant doses, the weight-adjusted maternal dose expressed
as a percentage (% dose) is widely used to indicate infant drug
exposure.
( )
( )= × maternal therapy with drugs with similar side-effect proiles,
( )
Dinf represents dose in infant via milk, and Dmat represents dose
in mother.
For the great majority of drugs, this calculation yields infant
doses in the order of 0.1–5.0% of the weight-adjusted maternal
dose expressed as a percentage (% dose). It is generally thought
that RID values of less than 10% of the maternal dose are prob-
ably safe. However, the inherent toxicity of the drug should be
taken into account when using this igure.
To calculate the daily infant drug intake via milk, the standard
milk intake of 150 mL/kg/day is multiplied by the concentration
of the medication in milk. Some authors use the peak concentra-
tion in milk to indicate the maximum infant intake.
Estimated daily infant intake = drug concentration in milk
micrograms/day micrograms/L × 0. 15 ×
infant weight kg ␣ infant born at 28 weeks will have a gestational age of 30 weeks.
Variability
To further complicate matters, there will be signiicant variabil-
ity between and within individuals in the values used to estimate
infant exposure (i.e. Dinf, F, Clinf, where Dinf is itself a function of
the estimated parameters Cpmat, M/P and volume of milk). Some
of this variability will change over time because of developing
organ function in the maturing baby, and some will be unex-
plained variability. In addition to this pharmacokinetic variabil-
ity, there will be variability in response of the infant to any given
concentration of the drug. It is fortunate that most drugs seem to
fall readily into a safe range (RID <10%) based on expected expo-
sure. However, care should be taken when using these values to
assess drug safety in lactation, when variability in the estimates of
the parameters used may impact on the accuracy of prediction of
their safety. This is especially true for those circumstances when
initial estimates of these parameters are less precise, for example,
in neonates.␣
DRUGS IN PREGNANCY AND LACTATION 48
Box 48.2 Factors that affect infant risk from maternal therapy
• Drug adverse reaction profile
• Relative infant dose
• Oral bioavailability
Active metabolites
• Half-life
• Gestational age of the infant
• Full maternal drug regimen
• Pharmacogenetic factors
Assessing the risk to the infant
Many factors must be considered when assessing the risk of
maternal drug therapy to the breastfeeding infant (Box 48.2).
Pharmacokinetic and pharmacodynamic factors
Inherent toxicity of the drug will be a main factor in determin-
ing infant safety. Thus, antineoplastic drugs, radionuclides and
iodine-containing compounds would be of concern. Multiple
for example, psychotropic drugs or anticonvulsants, is likely to
increase the risk to the infant. Oral bioavailability is an indicator
of the drug’s ability to reach the systemic circulation after oral
administration. Drugs with a low oral bioavailability are either
poorly absorbed from the gastro-intestinal tract, broken down in
the gut or undergo extensive ‘irst-pass’ metabolism in the liver
before entering plasma.
The presence of active metabolites (e.g. desmethyldiazepam)
may prolong infant drug exposure and lead to drug accumulation,
especially where drug clearance is low, such as in the neonatal
period. Similarly, drugs with long half-lives (e.g. luoxetine) may
be problematic at this time. Drug clearance by the infant does not
reach adult values until 6–7 months (see Table 48.5). A premature
infant of 30 weeks’ gestational age has a drug clearance value of
about 10% of the maternal value. It is important to distinguish
between gestational age and time after delivery. A 2-week-old
The maternal drug regimen can affect infant risk. Single doses
or short courses seldom present problems, whereas chronic ther-
apy can be problematic. Topical or inhalation therapy usually
results in much lower plasma drug levels and, therefore, lower
passage into milk. Multiple maternal medications increase the
risk to the infant.␣
Pharmacogenetic factors
Recently, attention has been focused on the possible role of phar-
macogenetic factors in affecting the safety of breastfed infants
exposed to drugs via milk (Madadi et al., 2009). Sedation (and
one death) occurred in infants of mothers with rare genotypes of
cytochrome P450 CYP2D6. leading to ultrarapid metabolism of
codeine to morphine. The incidence of these genotypes varies
amongst different populations. The overall percentage of Western
Europeans with the CYP2D6 ultrarapid metaboliser phenotype is
5.4% (Ingelman-Sundberg, 2005). Higher percentages have been
reported in populations from northeast Africa and the Middle East.␣ 829
 48 THERAPEUTICS

Reducing risk to the breastfed infant Box 48.3 Measures to ensure the safety of the breastfed infant

A number of strategies may be adopted to reduce the risk of drug-

• Avoid unnecessary maternal drug use.
related side effects in the breastfed infant. One technique that has • Seek professional advice on the suitability of over-the-counter
been recommended for reducing infant exposure is to give the mater- products.
nal dose immediately after the infant has been fed with the aim of • Avoid herbal products because of lack of data to support
avoiding feeding at peak milk concentrations. However, this is often safe use.
impractical, especially where young infants are feeding frequently • Assess the risk/benefit ratio for both mother and infant.
up to 2 hourly. In addition, accurate data on times of peak levels in • Use the minimum clinically effective dose for the shortest
possible time.
milk are often unavailable, and it cannot be assumed that times of • Review maternal therapy towards the end of pregnancy.
peak milk levels mirror those in plasma. This technique should be • Choose a drug regimen and route of administration which
used selectively, where the drug has a short half-life and where peak presents the minimum of drug to the infant via breast milk.
and trough levels are predictable (e.g. antibiotics, anaesthetics). • Avoid drugs known to cause serious toxicity in adults or
Where a single dose of a drug known to be hazardous is given children.
to a breastfeeding mother, for example, a radiopharmaceutical, • Monitor the infant for unusual signs or symptoms.
• Avoid new drugs if there is a therapeutic equivalent with data
it will usually be possible to resume breastfeeding after a suit-
to support safe use in lactation.
able washout period, calculated as ive times the half-life. Where • Recognise risk factors, e.g. prematurity, infant
the half-life is very long, the washout period necessary to avoid morbidity and multiple maternal medications.
hazardous exposure to the infant may exceed the period of sus-
tainable lactation.
Breastfeeding mothers should be advised to avoid self-medi-
cation. Where drug use is clearly indicated, the lowest effective Table 48.6 Examples of commonly used drugs thought to be
dose should be used for the shortest possible time. Use of topical safe for use in breastfeeding mothers of full-term,
healthy infants
therapy, such as eye/nasal drops for hay fever, would reduce drug
exposure in comparison with oral antihistamines. Drug groups Individual drugs
The maternal regimen should be simpliied wherever possible.
A review of therapy before delivery will help reduce risks to the Antacids Cetirizine
neonate. New drugs are best avoided if a therapeutic equivalent is Bulk laxatives Chloroquine/proguanil
available for which data on safe use in lactation exists. All infants Cephalosporins Clotrimazole
Contrast media Cromoglycate
exposed to drugs via breast milk should be monitored for any
Inhaled medications (e.g. Diclofenac
untoward effects. Measures to ensure the safety of the breastfed salbutamol, beclometasone) Fluconazole
infant are summarised in Box 48.3. Insulins Heparin (including low
Some commonly used drugs thought to be safe to use in moth- Penicillins molecular weight)
ers of full-term, healthy infants are listed in Table 48.6.␣ Progestogen-only contracep- Ibuprofen
tives Iron supplements
Topical formulations (except Loratadine
Special situations when applied to breast) Lactulose
Vaccines (except yellow fever) Levothyroxine
Neonates and premature infants Vitamins (except high-dose Nystatin
A and D) Omeprazole
Neonates and premature infants are at greater risk of develop- Paracetamol
ment of adverse effects after exposure to drugs via breast milk. Paroxetine/sertraline
Gastric emptying time is signiicantly prolonged and, in some Warfarin
cases, may alter absorption kinetics. Protein binding is decreased This table is to be used as a guide only. Expert advice is required when the
and values for total body water are higher than for adults. Renal maternal dose is high and if the infant is premature, has renal or hepatic
function is limited because the kidney is anatomically and func- disease, or has glucose-6-phosphate dehydrogenase deficiency.
tionally immature (van den Anket, 1996). The neonate’s capacity
to conjugate drugs in the liver is often deicient.␣
Breastfeeding should be avoided or a safer alternative chosen
if the infant has a known or suspected G6PD deiciency and
Glucose-6-phosphate dehydrogenase deficiency
the mother is taking drugs that have been reported to cause
Infants with glucose-6-phosphate dehydrogenase (G6PD) oxidative stress (e.g. nitrofurantoin, dapsone).␣
deiciency are susceptible to adverse effects even when only
small amounts of certain drugs are present in milk. G6PD is Allergy
an enzyme present in erythrocytes that is responsible for main-
taining the antioxidant compound glutathione in its active The theoretical possibility exists for an allergic reaction in an
form. Deiciency of this enzyme makes the erythrocyte more infant exposed to a drug in breast milk. Even minimal exposure
susceptible to oxidative stress, resulting in haemolysis. Only to the drug could cause an allergic response. However, in prac-
830 small amounts of drug are needed to cause such a reaction. tice, such reactions are rare, and only if the infant has already

experienced an allergic reaction to a particular drug should
maternal use be discouraged or breastfeeding avoided.␣
Recreational drug use
Accurate background data of maternal use of recreational drugs
may be dificult to obtain. Usage may be chronic or sporadic.
The role of the healthcare professional in ensuring the safety of
the breastfed infant is important, and the advice should be that
substances such as cannabis, LSD and cocaine should be avoided
whilst breastfeeding.
Signiicant amounts of alcohol pass into milk, although it is
not normally harmful to the infant if the quantity and duration of
intake are limited. The occasional consumption of a small alco-
holic beverage is acceptable if breastfeeding is avoided for about
2 hours after the drink. Chronic or heavy consumers of alcohol
should not breastfeed. High intakes of alcohol decrease milk let-
down and disrupt nursing until maternal levels decrease. Heavy
maternal use may cause infant sedation, luid retention and hor-
mone imbalances in breastfed infants.
Nicotine has been suggested to decrease basal prolactin produc-
tion, although effects may be variable. Ideally mothers should be
encouraged not to smoke whilst breastfeeding. Nicotine and its
metabolite, cotinine, are both present in milk. Undertaking smok-
ing cessation with a nicotine patch is a safer option than continued
smoking. Whilst transdermal nicotine patches produce a sustained
lower nicotine plasma level, nicotine gums produce large varia-
tions in peak levels. A 2- to 3-hour washout period is recom-
mended before breastfeeding after maternal use of a nicotine gum.
Caffeine appears in breast milk rapidly after maternal intake.
Fussiness, jitteriness and poor sleep patterns have been reported
in infants of mothers with very high caffeine intakes equivalent
to about 10 or more cups of coffee daily. Preterm and newborn
infants metabolise caffeine very slowly and are at increased risk
of adverse effects.␣
Drug effects on lactation
Drugs that affect dopamine activity are the main cause of
effects on milk production, mainly mediated by effects on
prolactin. Early postpartum use of oestrogens may reduce the
volume of milk, but the effect is variable and depends on the
dose and the individual response. Progestogen only contracep-
tives are preferred.
Drugs may occasionally be used therapeutically for their effect
on lactation. Dopamine agonists such as cabergoline decrease
milk production and this effect may be utilised, for example, after
an infant death. Dopamine agonists should not be used routinely
for relief of the symptoms of postpartum pain or engorgement
that can be managed with simple analgesics or breast support.
Dopamine antagonists such as domperidone may be used in
cases of inadequate lactation that have not responded to irst-line
methods such as improved technique or milk expression by hand
or pump. However, a European and UK regulatory review has
recommended restricted use of domperidone because of the risk
of cardiac adverse effects (Medicines and Healthcare Products
Regulatory Agency, 2014). The use of domperidone to enhance
lactation is not speciically covered by the review because it is
DRUGS IN PREGNANCY AND LACTATION 48
an unlicensed (‘off-label’) indication. However, it is appropriate
for the recommendations from the review to apply to its use as
a galactagogue. Because there are limited alternative options for
the stimulation of lactation, the use of domperidone can be con-
sidered provided non-pharmacological options have been unsuc-
cessful. A maternal dosage of 30 mg daily for 1 week should not
usually be exceeded, and it should not be used if the mother or
infant:
• has conditions where cardiac conduction is, or could be,
impaired;
• has underlying cardiac diseases such as congestive heart
failure;
• is receiving other medications known to prolong QT interval
or are potent CYP3A4 inhibitors;
• has severe hepatic impairment.
If treatment is still required after 1 week, the risks of continuing
domperidone must be considered carefully. Alternatively, meto-
clopramide can be used; however, only for up to 5 days because
of the risk of neurological side effects (European Medicines
Agency, 2013).
Other drugs may affect lactation as an unwanted side effect, for
example, diuretics causing dehydration. When these are used on a
long-term basis, infant weight gain should be monitored.␣
Case studies
Case 48.1
Ms LP is 6 weeks’ pregnant and has been diagnosed with depres-
sion that warrants pharmacological intervention. She wishes to
recommence venlafaxine, which has been helpful in the past. Ms
LP is also anxious that the ethanol she consumed around the time
of conception may have harmed her baby.
Questions
1. What are the safest antidepressants in the first trimester of
pregnancy?
2. Is it reasonable for Ms LP to commence venlafaxine?
3. Is there any risk from the ethanol ingestion?␣
Answers
1. The concept of ‘safe’ needs to take into account the risks of
inadequate treatment of the mother, as well as those to the fetus
through in utero exposure to a particular antidepressant. Choice
of antidepressant in pregnancy will therefore depend on the
severity of the maternal depression, the presence of associated
symptoms such as anxiety or obsessive-compulsive behaviors,
availability and suitability of non-pharmaceutical interventions
and, finally, any prior treatment regimens that have been suc-
cessfully or unsuccessfully used. SSRIs are currently the most
commonly prescribed antidepressant group and the most stud-
ied in pregnancy. However, human pregnancy data will vary for
individual SSRIs. Although not without risk to the fetus, SSRIs are
generally prescribed as first-line therapy in preference to tricy-
clic antidepressants which carry a higher risk of maternal toxicity,
especially in overdose, and which are less well studied in human
pregnancy. 831
 48 THERAPEUTICS
2. Experience with the use of venlafaxine and many other antide-
pressants (e.g. moclobemide) in pregnancy is limited. However,
in some instances it may be necessary to use an agent such as
venlafaxine. For example, if the mother had a history of severe
depression that did not respond to multiple trials of other anti-
depressants, then venlafaxine may be considered the most
appropriate choice of antidepressant for that woman. In this
case any potential risks associated with venlafaxine are likely to
be less than those associated with inadequately treated depres-
sion. Discussion of the available data and its limitations with Ms
LP is, however, necessary to enable her to make an informed
decision.
3. Ethanol is a human teratogen. Fetal alcohol spectrum disorders
are characterised by low birth weight, facial dysmorphogenesis
and/or delayed development. A ‘safe limit’ for alcohol con-
sumption in pregnancy has not been defined, and best prac-
tice is therefore to avoid all alcohol exposure in pregnancy. In
this case Ms LP ingested ethanol at the time of conception. She
should be reassured that this is regarded as a relatively low-risk
period for fetal harm, but that further ethanol ingestion should
be avoided.␣
Case 48.2
A 30-year-old woman with epilepsy, Ms AD, is currently taking val-
proic acid 1500 mg daily. She wishes to conceive but is concerned
about the possibility of birth defects caused by valproate expo-
sure in pregnancy. Ms AD’s seizures have been difficult to control
with alternative anticonvulsants.
Questions
1. What are the risks associated with valproate treatment in
pregnancy?
2. What advice should Ms AD be given?␣
Answers
1. Valproate is a human teratogen which has been associated with
both structural and lasting neurodevelopmental effects. These
may include neural tube defects, craniofacial anomalies such as
cleft lip and palate, heart defects, autism, attention deficit hyper-
activity disorder and learning difficulties. Recommendations
from a European-wide review in 2014 (European Medicines
Agency, 2014) advise against valproate use in female children, in
female adolescents, in women of childbearing potential and in
pregnant women unless other treatments are ineffective or not
tolerated. Women of childbearing potential in whom valproate
treatment is considered necessary for the treatment of epilepsy
are advised to remain on effective contraception during treat-
ment. The MHRA has produced a number of guidance docu-
ments for healthcare professionals in the UK, including an openly
accessible toolkit for women (https://www.gov.uk/government/-
publications/toolkit-on-the-risks-of-valproate-medicines-in-
female-patients).
2. It is imperative that Ms AD be advised to request referral to,
or review by, a neurologist, ideally with expertise in the treat-
ment of women with epilepsy who become pregnant, and that
she continues to use effective contraception until the risks
and options available to her have been fully reviewed and
discussed. New anticonvulsant therapies that do not appear
to carry the same risks as valproate may have become avail-
able since Ms AD was last reviewed. Valproate teratogenicity
appears to increase with increasing dose. Although no ‘safe
832
dose’ has been defined, if this patient needs to remain taking
valproate, it may be possible to gradually reduce her daily dose
under specialist review. General preconception advice could be
given, that is, commence folic acid, optimise weight and gen-
eral health, etc. It is important that Ms AD understands that
folic acid 5 mg daily is advised for all women with epilepsy
who are planning a pregnancy (NICE, 2016), but that at pres-
ent there is no evidence that it prevents or reduces the risk
of birth defects or neurodevelopmental impairment caused by
valproate.␣
Case 48.3
A mother, Ms TF, with a history of depression has relapsed and
requires treatment with an antidepressant. Ms TF is fully breast-
feeding a 2-week old, full-term, fit and healthy baby. In the past
she has taken fluoxetine, but stopped this when she found out she
was pregnant.
Questions
1. What is the antidepressant of choice during breastfeeding?
2. Ms TF has responded well to fluoxetine previously, so can this be
used during breastfeeding?
3. What are the potential risks of using fluoxetine?␣
Answers
1. Sertraline and paroxetine are the preferred SSRIs for use during
breastfeeding because they have shorter half-lives, lower pas-
sage into milk and a larger evidence base compared with the
other SSRIs. However, it is important that Ms TF has an antide-
pressant that works for her, so choice of agent should primarily
be based on suitability for the patient rather than safety during
breastfeeding.
2. If a woman has been successfully treated with an SSRI during
pregnancy and requires continued therapy in the postnatal period
there is no need to change therapy, provided the infant is full
term, fit and healthy, and can be adequately monitored. Although
fluoxetine is not a preferred SSRI during lactation, due to its long
half-life, because it has proved effective for Ms TF in the past,
the balance of benefit to risk will favour use of fluoxetine in this
mother.
3. Because fluoxetine has a very long half-life there is a risk of accu-
mulation and, therefore, adverse effects in the breastfed baby. The
baby should be monitored for drowsiness, poor feeding, irritability
and behavioural effects.␣
Case 48.4
A mother, Ms CG, is breastfeeding her 20-day-old, full-term, fit
and healthy baby. She has postpartum hypertension and has been
started on labetalol.
Labetalol does not control Ms CG’s hypertension and she is
started on nifedipine.
Questions
1. Comment on the suitability of labetalol as a suitable β-blocker for
use during breastfeeding.
2. Are there any monitoring requirements?
3. Can Ms CG still continue to breastfeed?␣

Answers
1. In general, β-blockers that are considered to pose less risk to a
breastfeeding infant have, or are predicted to have, lower levels
in breast milk, due to a high degree of plasma protein binding,
low lipid solubility and a short half-life, and relatively low renal
excretion. The risks of available β-blockers vary widely due to
these features. Although propranolol is considered to be the
β-blocker of choice in breastfeeding, because clinical properties
of β-blockers vary widely, propranolol may not always be a suitable
clinical choice. Metoprolol and labetalol are also considered to
pose low risk. Labetalol would be suitable to use in this situation,
with appropriate monitoring.
2. The breastfed infant should be monitored for signs of β-blockade,
especially bradycardia. Also consider monitoring for hypotension
and hypoglycaemia.
3. Because there will be low levels of nifedipine in breastmilk,
amounts ingested by the baby will be small. Nifedipine, includ-
ing modified-release preparations, is considered compatible
with breastfeeding. Therefore, Ms CG can continue to breast-
fed, but the risk of additive adverse effects in the baby must be
remembered.␣
Case 48.5
A breastfeeding mother, Ms SV, returned to see her midwife
4 weeks after delivery of a full-term, healthy infant. She is com-
plaining of bilateral nipple pain during and after breastfeeding, a
problem that was constant for the past 4 days. Ms SV was advised
to use miconazole cream 2% to the nipples after each feed. This
provided initial relief, but symptoms returned after a few days.
Acknowledgements
The contributions of Stephen B. Duffull, Sharon J. Gardiner, David K. Woods and Elena Grant to previous versions of this chapter which
appeared in earlier editions of the textbook are gratefully acknowledged.
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DRUGS IN PREGNANCY AND LACTATION 48
She was given a course of fluconazole 200 mg daily for 10 days
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