Clinical Pharmacy

(Chapter 1)

Drug Use in Pregnancy &

Lactation

FDA Pregnancy Categories for Medication Use

A

Controlled studies in pregnancy (<1%)

Adequate studies have failed to demonstrate a risk to fetus (in first
trimester) and no evidence of risk in later trimesters; possibility of fetal
harm appears remote. Thyroid supplements (levothyroxine), vitamins (folic
acid, riboflavin; vitamins A, D, and C)

Animal studies show no risk; or human data are reassuring

Animal studies have failed to demonstrate a risk to the fetus, and there
are no adequate studies in pregnant women; or animal studies show an
adverse effect on the fetus but well-controlled studies in pregnant women
have failed to demonstrate a risk to the fetus. Acetaminophen, opioids,
penicillins,
cephalosporins,
erythromycin,
prednisone,
caffeine,
sulfonamides, cimetidine, fluoxetine, insulin, NSAIDs

FDA Pregnancy Categories for Medication Use continue

C

Human data lacking; animal studies positive or not done (66%)

Animal studies have shown an adverse effect on the fetus and there are
no adequate studies in humans, or no studies are available in either
animals or women. Potential benefits may warrant its use. Epinephrine,
phenylpropanolamine,
trimethobenzamide,
aspirin,
atropine,
promethazine, theophylline, lisinopril, potassium chloride, disulfiram,
acyclovir, propranolol

Human data show risk; benefit may outweigh

Positive evidence of human fetal risk based on adverse reaction data, but
potential benefits in serious situations may warrant its use. Warfarin,
tetracycline, phenytoin, diazepam, trimethadione, lorazepam, amitriptyline

Animal or human data positive; no benefit

Studies in animals or humans have demonstrated fetal abnormalities
and/or there is positive evidence of human fetal risk, and the risks clearly
outweigh any potential benefits. Isotretinoin, diethylstilbestrol,
phencyclidine (PCP), triazolam, X-rays, chemotherapy

Prevalence of diseases during pregnancy

Complication

Prevalence

Medication

Epilepsy

17-33%

Phenytoin (D)

Depression

14-23%

Fluoxetin (SSRI) (D),

TCAs (cause birth
defects)

RA (Prolactin proinflammator)

prevalence of RA is 4-5 times

higher in female than male

Corticosteroids (C),
Immunosuppressives,
NSAIDs

Hypertension

10% in pregnancy
Pre-eclampsia 2-8%
Eclampsia 1%

Methyldopa, labatolol,
nifedipin

GI complication

Nausea, vomiting and

dyspepsia in 50-90%

Ranitidine (B),
Omeprazole (C)

IBD

Ulcerative colitis proceed in

26% women

Mtronidazole, Cipro

UTI

Vaginal Infection 35%

Cystitis 40%
Pyelonephritis 25-30%

Oral Antibiotics

Critical periods in human fetal development (prenatal development)

The human gestation period is approximately 40 weeks from the first day of the last
menstrual period (38 weeks' post- conception) and is conventionally divided into the first,
second and third trimesters, each lasting 3 calendar months. Another method for
classifying the stage of pregnancy is according to the stage of fetal development. This is a
more useful approach when assessing the potential risks associated with drug use in
pregnancy.
Pre-embryonic stage (weeks 02 post-conception, 0-17days)
The first two weeks post-conception are regarded as the pre-embryonic stage and describe
the period up to implantation of the fertilized ovum.
Embryonic stage (weeks 3-8 post-conception, 17days to 56 days)
Organogenesis occurs predominantly during the embryonic stage and, with the exception
of the central nervous system, 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 first trimester whenever possible.
Fetal stage (weeks 938 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 central nervous
system, which can be damaged by exposure to certain drugs, for example, ethanol, at any
stage of pregnancy.

DELIVERY
Some drugs given late in pregnancy or during delivery may cause particular
problems. Pethidine, administered as an analgesic can cause fetal apnoea
(which is reversed with naloxone). Anaesthetic agents given during Caesarean
section may transiently depress neurological, respiratory and muscular functions.
Warfarin given in late pregnancy causes a haemostasis defect in the baby, and
predisposes to cerebral haemorrhage during delivery.
THE MALE
Although it is generally considered that sperm cells damaged by drugs will not
result in fertilization, the manufacturers of griseofulvin, an antifungal agent,
advise men not to father children during or for six months after treatment.
Finasteride, an antiandrogen used in the treatment of benign prostatic
hyperplasia, is secreted in semen, and may be teratogenic to male fetuses.
Drug dose during pregnancy
A threshold dose above which drug-induced malformations are more likely to
occur has now been demonstrated for certain teratogenic compounds, although
for most a safe dose has not been conclusively determined. The likelihood of a
dose relationship underlies the recommendation to use the lowest effective dose
in pregnancy. For this reason, more frequent monitoring of drug levels may be
recommended for certain drugs during pregnancy.

Drugs as teratogens
A teratogen is defined 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.
Dysmorphogenesis is structural or functional birth defects, literally means an ill-shaped or
malformed body structure.
Congenital anomalies are also known as birth defects, congenital disorders or congenital
malformations. Congenital anomalies can be defined as structural or functional nonreversible anomalies that occur during intrauterine life and can be identified prenatally, at
birth or later in life, caused by genetic predisposition (defective gene was latent but started
multiplication by stimulation) or drug exposure that adversely affect fetus development. Two
types of anomalies found, immediate and delayed.
Causes of anomalies include socioeconomic and demographic factors (about 94% of
severe congenital anomalies occur in low- and middle-income countries, where women
often lack access to sufficient, nutritious food and may have increased exposure); Genetic
factors, infection during pregnancy (syphilis and rubella); Maternal nutritional status (Iodine
deficiency, folate insufficiency, obesity and diabetes mellitus) ; Environmental factors
(certain medications, alcohol, tobacco, psychoactive drugs and radiation during
pregnancy).

Drugs as
continues

teratogens

External (immediate) congenital

anomalies
such
as
limb
abnormalities,
spina
bifida
(spinal cord defective closure)
and hydrocephalus (enlarged
skull due to blockade of CSF
pathway) may be obvious at
birth, some defects may take
many
years
to
manifest
clinically or be identified.
Examples of delayed effects of
teratogens are the behavioural
and
intellectual
disorders
associated with in utero alcohol
exposure and the development
of clear-cell vaginal cancer in
young
women
following
maternal
intake
of
diethylstilboestrol,
for
the
prevention of miscarriage and
preterm delivery.

Dru
g
eff
ect
s
on

fet

us

A. Placental Transfer of drugs

In the placenta, maternal blood is separated from fetal blood by a cellular

membrane. Most LMW drugs with a molecular weight of less than 1000 can cross
the placenta. This is usually by passive diffusion down the concentration gradient,
but can involve active transport. However, LMW drugs have limited transfer eg.
Heparin.
The rate of diffusion depends first on the concentration of free drug (i.e. nonprotein bound) on each side of the membrane, and second on the lipid solubility of
the drug, which is determined in part by the degree of ionization. Diffusion occurs
if the drug is in the unionized state.
Weakly basic drugs entrapped in fetal circulation due to lower pH than maternal
plasma.
Some drugs are metabolized by the fetus/plasma
Placental function is also modified by changes in blood flow. This may be the
mechanism which causes the small reduction in birth weight following treatment of
the mother with atenolol in pregnancy.
Occasional drug delivery is to treat fetal disorders. Eg. Flecainide is given to
resolve fetal tachycardia
The fetal BBB is not developed until the second half of pregnancy, and the
susceptibility of the central nervous system (CNS) to developmental toxins may
be partly related to this. The human placenta possesses multiple enzymes that
are primarily involved with endogenous steroid metabolism, but which may also
contribute to drug metabolism and clearance.

Fetal and newborn plasma proteins appear to bind ampicillin and benzylpenicillin with
less affinity and salicylates with greater affinity, than maternal proteins. Maternal
albumin gradually decreases during pregnancy and fetal albumin concentrations
increase, so different fetal: maternal albumin concentrations occur at different stages
of pregnancy. The degree of protein binding of any drug is an important determinant
of its movement across the placenta. Drugs which are highly protein bound tend to
achieve higher maternal and lower fetal concentrations.
B. Pharmacological effects
Pharmacological effects are usually dose related and to some extent predictable.
Drugs may adversely affect the fetus via effects on the maternal circulation or they
may cross the placenta and exert a direct pharmacological effect on the fetus.
Corticosteroids in high doses (eg. Prednisolone more than 10mg daily) causes fetal
renal suppression i. e. reduce Na+ reabsorption and K+/H+ secretion.
Maternal treatment with anti hypertensive drugs cause fetal hypoxia secondary to
maternal hypertension.
The capacity of the neonate to eliminate drugs is reduced, and this can result in
significant accumulation of some drugs, leading to toxicity. Neonatal withdrawal may
require treatment.
If a pregnant woman takes paroxetine, echocardiography should be done to evaluate
the fetus's heart because paroxetine appears to be associated with an increased
incidence of congenital cardiac anomalies.

C. Idiosyncratic effects
Idiosyncratic drug effects in the fetus and neonate are possible but occur rarely
compared with pharmacological effects. Some effects of drugs are less
predictable and unrelated to dose. These idiosyncratic effects are caused by~
Fetal genetic predisposition (defective gene complexity)
Unknown threshold dose for individual which leads to dysmorphogenecity.
Idiosyncratic drug effects leads to major irreversible congenital anomaly so lower
effective doses are suggested.
D. Timing of drug 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 trimesters may be variable.
For example, folic acid antagonists, for example, trimethoprim, are 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. 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.

Timing of drug exposure continues

Phenobarbital cause congenital anomaly in 1st trimester and cause neonatal
bleeding if given in 3rd trimester. Women who are taking more than one drug for
seizure control, Phenobarbital also exerts withdrawal effects in the baby. Exposure
in any trimester may be due to the fact that it reduces the efficiency of birth control
pills.
The external genitalia also continue to form from the seventh week until term, and
consequently, danazol (x), which has weak androgenic properties used to treat
endometrosis and fibrocytic breast disease. If therapy is intiated during
menstruation, test should be performed and non-hormonal cotraceptive should be
performed. It may cause virilisation of a female fetus if given in any trimester after
the eighth week of pregnancy (when the androgen receptors begin to form).
Conversely, due to anti androgenic property spiranolactone and cyproterone
acetate cause feminization of male fetus. Women take them to counteract male
hormones (testosterone) on skin. But it is not suitable for men skin. They are
combinely used to skip menstruation and pregnancy, treatment not necessary for
post menopausal women.

Timing of drug exposure continues

Drugs that interfere with this process can cause gross structural defects if given
during organogenesis (e.g. thalidomide phocomelia). Thalidomide was unusual
in the way in which a very small dose predictably produced serious
malformations.
The non-steroidal anti-inflammatory drugs (NSAIDs) are another important group
of drugs that may cause problems specifically in the third trimester. These drugs
inhibit prostaglandin synthesis in a dose-related fashion and, when given late in
pregnancy, may result in premature closure of the fetal ductus arteriosus,
bleeding disorder, delayed purturition and fetal renal impairment. NSAIDs should
therefore be avoided during the third trimester.
Diethylstilbestrol, an association was reported between adenocarcinoma of the
vagina in girls in their late teens whose mothers had been given diethylstilbestrol
during the pregnancy. Exposure to stilbestrol in utero has also been increased
rates of ectopic pregnancy and premature labor.
Sulphonamides and thiazides at 3rd trimester cause neonatal hemolysis and
thrombocytopenia respectively.

Further examples include the angiotensin-converting enzyme (ACE) inhibitors, which

if given in the second and third trimesters can result in fetal renal dysfunction and
subsequent oligohydramnios, that is, reduced amniotic fluid volume.
In fetogenic stage
Drugs used to treat maternal hyperthyroidism can cause fetal and neonatal
hypothyroidism.
Tetracycline antibiotics inhibit growth of fetal bones and stain teeth.
Aminoglycosides cause fetal 8th nerve damage.
Opioids and cocaine taken regularly during pregnancy can lead to fetal drug
dependency.
Warfarin can cause fetal intracerebral bleeding.
Indometacin, a potent inhibitor of prostaglandin synthesis, is used under specialist
supervision to assist closure of patent ductus arteriosus in premature infants.
Anticonvulsants may possibly be associated with mental retardation.
Cytotoxic drugs can cause intrauterine growth retardation and stillbirth.

E. Drug dosing during pregnancy

Drug dose should be tapered to the lowest effective dose either before
conception or during 1st trimester. Eg. Doses of antipsychotic and
antidepressants should be reduced as the term approaches cause they have
potential to cause neonatal withdrawal effects. But some pharmacokinetic
changes may demand dose increase. Pregnancy itself can cause a temporary
worsening or improvement of some diseases and in that way influence drug
dosages.
Maternal pharmacokinetic changes
A. Absorption
Gastric and intestinal emptying time increases by 3040% in the second and
third trimesters and could be important in delaying absorption and time to onset
of action for some drugs. There is also a reduction in gastric acid secretion in
the first and second trimesters and an increase in mucus secretion. As a
consequence of the increase in gastric pH, the ionization, 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
anesthetics, bronchodilators, pollutants, cigarette smoke and other volatile
drugs.

Maternal pharmacokinetic changes .

B. Clearance
Within the first few weeks of pregnancy, the glomerular filtration rate (GFR)
increases by approximately 50% within 1st few weeks of pregnancy and remain
raised until after delivery. 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. Lithium and
antibiotics dose should be increased because of their unchanged clearance. The
following drugs have shown pregnancy-induced increases of 2065% on their
renal elimination:
Ampicillin, Cefuroxime, Ceftazidime, Cefazolin, Pipericillin, Atenolol, Sotalol,
Digoxin, Lithium, Dalteparin sodium, Enoxaparin sodium
Hepatic clearance of many drugs increased during pregnancy possibly due to
enzyme induction by endogenous progesterone. For this increased metabolism
of methadone and phenytoin requires higher maintenance dose. Conversely
theophylline metabolism decrease so revised reduced maintenance dose is
required.

Maternal pharmacokinetic changes .

C. Volume of 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 flow increases by up to 50% at the end of the first trimester and uterine
blood flow increases and peaks at term (3642 L/h). There is also a mean
increase of 8 L in body water (60% to placenta, fetus and amniotic fluid and 40%
to maternal tissues). As a consequence, there may be increased dosage
requirements for some drugs to achieve the same therapeutic effect, provided
these effects are not offset by other pharmacokinetic changes. Both the total
plasma and the free-drug concentrations of phenytoin, carbamazepine and
valproic acid decrease during pregnancy, but the free-drug fraction (ratio of free
to total plasma concentration) may increase.

Maternal pharmacokinetic changes .

D. Protein Binding
Albumin is the main plasma protein responsible for binding acidic drugs such as
phenytoin and salicylates, whilst 1-acid glycoprotein predominantly binds basic
drugs, including -blockers and opioid analgesics. As pregnancy progresses, the
plasma volume increases at a greater rate than the increase in albumin which
results in hypoalbuminaemia. In addition, steroid and placental hormones
occupy the protein- binding sites. This leads to an increase in the fraction of
unbound drug. Clinical effect is related to the concentration of unbound drug,
which usually remains unchanged even though the total (bound plus unbound)
plasma concentration is decreased. Thus, a fall in the total plasma concentration
does not usually require an increase in dose. The 1-acid glycoprotein
concentrations remain the same as those in non-pregnancy.
Phenytoin is bound to albumin and exhibits the effects described earlier, but the
situation is further complicated by increased hepatic metabolism that may
necessitate a dose increase.

Effects of drugs on neonates

Capacity of drug elimination is minimal in fetus or neonate which results
significant drug accumulation and toxicity. So at the end stage drug dose should
be low as possible.
Dose of antidepressants or neuroleptics should be slowly reduced close to
purturition to minimize neurological disturbance (toxicity) and to minimize
withdrawal effects. This is very much distressing and symptoms often require
sedative treatment. Morphine oral solution is used to wean baby off methadone
Tapering of the dose is not always practical for methadone and lithium which
actually need to increase to maintain symptom control of mother.

Drugs in lactation
Breast milk is the best form of nutrition for young infants. It provides all the
energy and nutrients required for the first 6 months of life. The WHO and
UNICEF recommend exclusive breastfeeding for this period. Benefits of
breastfeeding include protection of the infant against gastric, respiratory and
urinary tract infections and reduction in rates of obesity juvenile-onset
diabetes and atopic disease . Adults who were breastfed as infants often have
lower blood pressure and lower cholesterol levels. Maternal benefits include
reduced risk of developing pre-menopausal breast cancer and delayed
resumption of menstrual cycle. Breastfeeding also strengthens the mother
infant bond.
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
contraceptives are preferred.
Drugs may occasionally be used therapeutically for their effect on lactation.
Dopamine agonists such as cabergoline decrease milk production.

Drugs in lactation
Breast milk is the best form of nutrition for young infants. It provides all the
energy and nutrients required for the first 6 months of life. The WHO and
UNICEF recommend exclusive breastfeeding for this period. Benefits of
breastfeeding include protection of the infant against gastric, respiratory and
urinary tract infections and reduction in rates of obesity juvenile-onset
diabetes and atopic disease . Adults who were breastfed as infants often have
lower blood pressure and lower cholesterol levels. Maternal benefits include
reduced risk of developing pre-menopausal breast cancer and delayed
resumption of menstrual cycle. Breastfeeding also strengthens the mother
infant bond.
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
contraceptives are preferred.
Drugs may occasionally be used therapeutically for their effect on lactation.
Dopamine agonists such as cabergoline decrease milk production.

Preconception advice
Epilepsy is an example, in which, if continued drug treatment is necessary,
attempts are made to stabilise treatment with a single drug at the lowest effective
dose. It is also important to note that many pregnant women become
less adherent to their drug therapy out of concern about possible harm to their
infant. In many cases, such as asthma, inflammatory bowel disease, epilepsy,
inadequate treatment of the underlying disease may be more detrimental to the
motherfetus pair than the drugs used to treat the condition.
All women planning a pregnancy should be offered general advice to minimise the
risk of congenital anomalies. This includes avoidance of recreational drugs,
natural or herbal remedies, alcohol, smoking, vitamin A products, minimisation of
caffeine consumption and beginning daily supplementation with at least 400 cg of
folic acid to reduce the risk of neural tube defects. It is recommended that the daily
dose of folic acid be increased to around 45 mg daily in women who have
epilepsy or who have had a previous child with a neural tube defect. Some
infectious diseases may carry important fetal consequences if contracted during
pregnancy. For example, rubella infection in the first 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.

Post-conception advice
It is important to draw distinction between advice given to women preconceptually and that provided to a pregnant woman who has already been
exposed to a drug. In the former setting, it may be recommended that an
alternative preparation be considered or that a drug treatment be stopped
where clinically appropriate. This advice often hinges on the lack of definitive
safety data and does not automatically 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 normal baby is the most likely
outcome, or where appropriate be offered additional prenatal investigation to
screen for congenital malformation where the risk to fetus is considered to be
significant.

Case Presention
Case 1.
A woman is 6 weeks' pregnant and has been diagnosed with
depression that warrants pharmacological intervention. She
wishes to recommence venlafaxine, which has been helpful in the
past. She 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 her to commence venlafaxine?
3. Is there any risk from the ethanol ingestion?

What are the safest antidepressants in the first trimester

of pregnancy?
Tricyclic antidepressants (TCAs) have been extensively used in
pregnancy and are generally regarded as safe. For this reason,
past practice was to recommend that TCAs should be used
preferentially for the treatment of depression in pregnancy when
considering teratogenic risk to the fetus. TCAs are, however,
associated with side effects including risk of maternal
cardiotoxicity, particularly in overdose. Further, available data on
TCA use in pregnancy do not prove that they are less teratogenic
than other antidepressant classes such as S NRIs and SS RIs.
An antidepressant other than TCAs may therefore be appropriate for
use in pregnancy, and the risks and benefits for each should be
considered and ideally discussed with the patient on a case-bycase basis.

Is it reasonable for her to commence venlafaxine?

Experience with the use of venlafaxine and many other antidepressants, for
example, 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 antidepressants, then venlafaxine may
be considered the most appropriate choice of antidepressant for that
woman. I n this case, any potential risks associated with venlafaxine are
likely to be less than those associated with inadequately treated
depression.
Is there any risk from the ethanol ingestion?
Ethanol is a human teratogen. Fetal alcohol spectrum disorders are
characterised by low birth weight, facial dysmorphogenesis and delayed
development. A safe limit for alcohol consumption in pregnancy has not
been defined, and it is possible that very low amounts of alcohol may
produce subtle effects on the fetus. Therefore, the best practice is to avoid
all alcohol exposure in pregnancy. I n this case, the mother ingested
ethanol at the time of conception. S he should be reassured that this is
regarded as a relatively safe period and is not expected to adversely affect
the fetus . However, further ethanol ingestion should be avoided.

Case 2.
A 30-year-old woman with epilepsy is currently taking valproic acid
1500 mg daily. She wishes to conceive but is concerned about the
possibility of birth defects due to valproate exposure in pregnancy.
Her seizures have been difficult to control with alternative
anticonvulsants.
Questions
1. What are the risks associated with valproate treatment in
pregnancy?
2. How can these risks be minimised?

What are the risks associated with valproate treatment in

pregnancy?
Valproate is a human teratogen, with early first-trimester exposure
associated with a 12% risk of neural tube defects, as well as
other malformations such as orofacial clefts. Valproate has also
been associated with neonatal complications such as seizures. I t
is frequently advised that valproate is avoided in pregnancy and
that the valproate dose should be gradually tapered and
discontinued prior to conception. However, this is not a realistic
option for many women with epilepsy. I n fact, seizures may lead
to greater problems such as maternalfetal injury, miscarriage or
hypoxia.

How can these risks be minimised?

The patient should be reassured that most pregnancies in women with epilepsy
end with a healthy baby without malformations. Concern about the risk of
fetal abnormalities may result in reduced adherence, which may have
greater maternalfetal risk than the drug itself. As the patient is not yet
pregnant, this is an optimal time for her current drug regime to be reviewed
and optimised by a neurologist or health professional with expertise in
managing women with epilepsy during pregnancy. There is some evidence
to suggest that higher doses/concentrations of valproate are associated with
greater risk of malformations. Where valproate remains the drug of choice,
the lowest effective dose should be used throughout pregnancy. Monitoring
free valproate concentrations may be useful in pregnancy, perhaps with the
view to maintaining those concentrations shown to be effective in the nonpregnant stage. However, doses should be adjusted based on clinical need
and not concentrations alone. Women with epilepsy should be commenced
on high-dose folic acid 45 mg daily pre-conceptually. They should also be
offered the option of prenatal diagnostic techniques that screen for neural
tube defects such as ultrasound and serum -fetoprotein..

Case 3.
A 2-day-old full-term infant has excessive shrill crying, is jittery
is feeding poorly. The medical team cannot find any cause for these
effects. The mother is worried that they may be due to paroxetine
exposure via breast milk and wonders whether St John's wort would be
a safer alternative. She has taken paroxetine 20 mg daily throughout
pregnancy, and this has been continued after delivery.
You note from a specialist textbook that the likely infant
exposure is about 2% of the weight-adjusted maternal dose.
Questions
1. What is the most likely drug-related explanation?
2. Is it safe for the mother to continue to take paroxetine whilst
breastfeeding?
3. Is S t John's wort a reasonable alternative?

What is the most likely drug-related explanation?

The most likely explanation is a neonatal withdrawal syndrome from
SS RI use near term. S ymptoms typically occur 12 h5 days after
birth. The adult half-life of paroxetine is about 24 h, but this is
much longer in a neonate. There will be a gradual decline in
paroxetine plasma levels in the neonate after delivery. Drug
exposure in pregnancy is much greater than exposure via milk.
There may be some overlap of symptoms resulting from drug
transfer into breast milk and from in utero exposure agitation,
jitteriness, hypotonia and gastro-intestinal symptoms. However,
sedation has only been reported after drug exposure via breast
milk. Paroxetine is one of the preferred SS RIs in breastfeeding as
the half-life is shorter than most members of the group and the
incidence of reported adverse effects is low.

Is it safe for the mother to continue to take paroxetine whilst

breastfeeding?
The mother should be reassured that the effects are not due to the
transfer of excessive amounts of paroxetine into milk. Withdrawal
symptoms usually settle after a few days, whereas adverse effects
due to the drug via milk will remain with continued exposure. If
symptoms persist, further medical advice should be sought.
Is S t John's wort a reasonable alternative?
Herbal remedies are often perceived as safe as they are natural.
In general, there is a lack of data to support the safe use of herbal
remedies in lactation, and their use should be avoided. If a
pharmacological treatment is indicated, then a drug for which data
in lactation is available, for example, paroxetine should be used.

Case 4.
A 20-year-old female medical student attended her GP requesting a course of Septrin
(co-trimoxazole) for cystitis. She tells her GP that her last menstrual bleed was
about six weeks earlier. She did not think she was at risk of pregnancy as her
periods had been irregular since stopping the oral contraceptive one year previously
due to fears about thrombosis, and her boyfriend used a condom. Physical
examination, which did not include a vaginal examination, was normal. Urinalysis
was 1 positive for blood and a trace of protein.
Question
Why should the GP not prescribe co-trimoxazole for this patient?
Answer. Until proven otherwise, it should be assumed that this woman is pregnant. Cotrimoxazole (a combination of sulfamethoxazole and trimethoprim) has been
superseded by trimethoprim alone as a useful drug in lower urinary tract infection
(UTI). The sulfamethoxazole does not add significant antibacterial advantage in
lower UTI, but does have sulphonamide-associated side effects, including the rare
but life-threatening StevensJohnson syndrome. Both sulfamethoxazole and
trimethoprim inhibit folate synthesis and are theoretical teratogens. If pregnancy is
confirmed (urinary frequency is an early symptom of pregnancy in some women,
due to a progesterone effect) and if the patient has a lower UTI confirmed by pyuria
and bacteria on microscopy whilst awaiting culture and sensitivity results, amoxicillin
is the treatment of choice. Alternatives include an oral cephalosporin or
nitrofurantoin. Note that lower urinary tract infection in pregnancy can rapidly
progress to acute pyelonephritis

Case 5.
A breastfeeding mother returned to see her midwife 4 weeks after delivery of a full-term
healthy infant. She is complaining of bilateral nipple pain during and after
breastfeeding, a problem that was constant for the past 4 days. She was advised to
use miconazole cream 2% to the nipples after each feed. This provided initial relief
but symptoms returned after a few days. She was given a course of fluconazole 200
mg daily for 14 days for a presumed candidal infection but expressed concern that the
medication might affect the infant..
Question
Is this regimen safe to use in lactation?
Ans. Topical miconazole is effective in treating superficial candidal infections, but oral
therapy with fluconazole is needed when the infection spreads to the milk ducts.
Assuming a mean fluconazole milk level of 2.3 mg/L, an infant weight of 4 kg and a
milk intake of 150 mL/kg/day: The estimated daily infant intake via milk will be 2.3
0.15 4 = 1.38 mg or 0.345 mg/kg/day. This represents 10.35% of the weightadjusted dose for a 60-kg woman taking 200 mg of fluconazole daily and 5.75% of the
paediatric dose of 6 mg/kg/day. The mother may be reassured that the amount of
drug reaching the infant via milk is only a small fraction of the dose that would be
used to treat an infection in the infant.
What other therapeutic measures should be taken?
Ans. Candidal infections are easily passed between the mother and the infant, and both
should receive treatment. Infants can be treated with nystatin suspension or oral
miconazole gel. The latter is not suitable for young infants under 4 months because of
the risk of choking on the viscous formulation, and care is still needed with older
infants

Case 6.
A mother who wishes to give up smoking seeks advice on the safety of nicotine
replacement therapy (NRT) whilst breastfeeding. She is currently in the latter stages
of pregnancy but does not wish to use these products until after delivery and has not
been successful in significantly reducing her smoking without aids.
Question
1. What effect is smoking likely to have on breastfeeding?
Ans. Women who smoke during pregnancy are less likely to breastfeed and more likely to
wean their infants earlier. Nicotine reduces basal prolactin levels which may lead to a
decrease in milk supply. I t also causes adrenaline release which may inhibit the
release of oxytocin and affect the milk let-down reflex. Tobacco smoke may produce
breathing difficulties and other problems in infants. Maternal smoking is a major factor
for sudden infant death syndrome (SI DS) and breastfeeding provides significant
protection.
2. Can NRT be used safely whilst breastfeeding?
Ans. Ideally, breastfeeding mothers should stop smoking, preferably by using nonpharmacological methods. I f this is not possible, most authorities advise that the
amount of nicotine passing into milk after use of NRT is very much smaller than that
after smoking and less harmful than the second-hand smoke an infant might breathe
if the mother continues to smoke. NRT products are devoid of tars, carbon monoxide
and respiratory irritants found in cigarettes. Where the infant has breathing difficulties,
NRT should be avoided. Other members of the household who smoke should also be
encouraged to give up smoking.

Question
3. If so, which products are preferred?
Ans. Women who smoke during pregnancy are less likely to breastfeed and
more likely to wean their infants earlier. Nicotine reduces basal prolactin levels
which may lead to a decrease in milk supply. I t also causes adrenaline release
which may inhibit the release of oxytocin and affect the milk let-down reflex.
Tobacco smoke may produce breathing difficulties and other problems in infants.
Maternal smoking is a major factor for sudden infant death syndrome (SI DS)
and breastfeeding provides significant protectionBreast milk levels of nicotine
after use of a 21-mg transdermal patch are roughly equivalent to smoking 17
cigarettes a day. Maternal plasma levels of nicotine after using a nicotine spray
are about one-third those of smokers and levels after using
a gum are variable but can be similar to those seen after smoking. I f possible,
nicotine patches should be avoided during breastfeeding because they provide a
continuous (but low) passage of nicotine into breast milk. If patches are used,
they should be removed at night time to decrease nocturnal exposure. For
shorter-acting preparations (e.g. gums, lozenges), it is best to breastfeed
immediately before use and allow a 23 hour period before resumption of
breastfeeding to minimise infant exposure..