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Principles of drug use in pregnancy
Swansea NHS Trust
Scott Pegler
Clinical & Information Pharmacist
Swansea NHS Trust
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History
 Thalidomide: probably the most notorious
human teratogen
 Marketed as a sedative in late 1950’s
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Associated with up to 12,000 birth defects,
primarily phocomelias
Other effects included:
 facial hemangiomata, oesophageal & duodenal
atresia, teratology of Fallot, renal agenesis &
anomalies of the external ear
Thalidomide
 No malformations if taken before the 34th day
after last menstruation & usually no
malformations if taken after the 50th day
 Sensitive time period: day 35 to day 49
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Day 35 – 37: absence of ears & deafness
Day 39 – 41: absence of arms
Day 43 – 44: phocomelia with three fingers
Day 46 – 48: thumbs with three joints
 If taken throughout the sensitive period: severe
defects of the ears, arms & legs & internal
malformations often leading to early death (40%
died before their 1st birthday)
Thalidomide
 Association between thalidomide and human
teratogenicity suspected by Lenz (Germany) in
November 1961 & endorsed by a letter by
McBride to the Lancet in November 1961
 Withdrawn in Germany at the end of Nov 1961
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end of malformation ‘epidemic’ seen in July 1962 (as
predicted)
 Thalidomide continued to be sold for several
months in some countries e.g. Belgium, Brazil,
Canada, Italy & Japan
 Finally withdrawn in Japan in Sept 1962
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peak in epidemic occurred in Japan at a time when
epidemic had ended in Germany
Thalidomide
 20% of pregnancies exposed during this
period resulted in anomalies
 Administration to female rabbits did not
show any adverse effects on fertility
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There was an increase in early pregnancy
loss (equivalent to miscarriage)
There were no thalidomide-associated
malformations in surviving foetuses
Overview
 All drugs should be avoided in pregnancy unless
they are ‘essential’
 In practice, it may not be easy to know what
treatment is really necessary or whether a
particular medicine is an appropriate choice
 Requires a balanced approach:
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Being over-cautious may deny a beneficial therapy
Lack of due caution might harm babies as a consequence of
drug exposure
 Benefits of treatment need to be weighed
against the risks of giving no medication
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Note: while the benefits of Tx may be clear, the risks may be
largely unknown or unquantifiable
For minor conditions, the risks almost always outweigh the (often
trivial) benefits
The problem
 80% of women use prescribed or OTC
drugs during pregnancy
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3 – 8 different drugs (partly prescribed and
partly self-medication)
 The risks of drug use in pregnancy has
lagged far behind advances in other areas
of pharmacotherapy
 Main reasons: epidemiological difficulties
in establishing causality and ethical
barriers to prospective RCTs
Teratogenicity and drugs
 In the UK, the spontaneous malformation rate at
birth is 2-3% i.e. approximately 1 in 40 babies
will be born with a malformation
 The incidence of malformations increases to
approximately 5% by 4-5 years of age
 Drugs are thought to cause less than 1% of
malformations
 Therapeutic drugs do not appear to be a
significant cause of birth defects
 However, most birth defects have no known
cause and exposure to drugs may play a part in
some of these
Causes of developmental
disorders
• Unknown:- Spontaneous development disorders; multigenetic
conditions; combination and interactions of exogenic and endogenic
factors (65%)
• Genetic diseases:- (20%)
• Chromosomal disorders:- (5%)
• Anatomical factors:- Uterus anomalies; twin pregnancy;
oligohydramy (2%)
• Maternal conditions:- Diabetes mellitus; hypothyroidism;
phenylketonuria; cytomegaly; listeriosis; lues; rubella;
toxoplasmosis; Varicella (4%)
• Chemical and physical agents:- Medicinal products; drugs of
abuse (especially alcohol); ionizing radiation; hyperthermia;
environmental chemicals (4%)
Evaluating drug safety in
pregnancy
 Most birth defects are rare & so an increased
risk posed by a teratogen may not be easily
identified
 Most suspected teratogens cause only a
relatively small increase in baseline risk of
malformations
 Epileptic women treated with anticonvulsant
drugs have a 2-3 fold increased risk of
malformations, i.e. a 10% risk of having an
abnormal baby.
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…or at least a 90% chance of having a normal
baby
Evaluating drug safety in
pregnancy
 Epidemiological studies of drug exposure in
pregnancy require large numbers of exposed
infants to prove or disprove the teratogenic
potential of a drug – few have the statistical
power as they cannot include sufficient patients
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e.g. 1,600 live births following 1st trimester exposure
to aciclovir would need to be monitored to detect a 5fold increase in the risk of a specific defect which
occurs as frequently as 1 per 1000 live births, with an
80% power
 For these reasons, no drug is safe beyond all
doubt in early pregnancy
Evaluating drug safety in
pregnancy
 Animal studies are required before new
drugs are licensed, but it is difficult to
extrapolate findings to human pregnancy
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Drugs which produce defects in animals can
be relatively safe in humans e.g.
corticosteroids
 Of over 2,000 drugs, chemicals &
environmental agents shown to be
teratogenic in animals, less than 50 are
proven human teratogens
Some teratogenic drugs
ACE inhibitors
Renal dysfunction and hypotension in the newborn, decreased skull
ossification, hypocalvaria and renal tubular dysgenesis
Alcohol
Fetal alcohol syndrome
Aminoglycosides
Deafness, vestibular damage
Androgens (e.g. danazol)
Masculinisation of female fetus
Anti-cancer drugs
Multiple defects, abortion
Anti-thyroid drugs
Fetal goitre
Carbamazepine
Neural tube defects
Cocaine
Cardiovascular, central nervous system defects
Diethylstilboestrol
Vaginal carcinoma after in utero exposure
Lithium
Cardiovascular defects (Ebstein’s anomaly)
Phenytoin
Fetal hydantoin syndrome
Retinoids
Craniofacial, cardiac, central nervous system defects
Sodium valproate
Neural tube defects
Thalidomide
Limb-shortening defects, renal malformations, congenital heart
disease
Warfarin
Fetal warfarin syndrome
Embryo/fetotoxic risk
assessment
 Generally accepted that the predictive
value of animal studies for predicting
safety in humans is less than adequate
 With the exception of androgens, several
antimitotic drugs, sodium valproate and
vitamin A derivatives, all human teratogens
were discovered earlier in man than in
animals
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Most were case studies from alert clinicians
rather than epidemiological studies
Drugs and the fetus
 Nearly all drugs, except those with a very high
molecular weight e.g. insulin and heparin, cross
the placenta to the fetus
 Lipid-soluble un-ionised drugs cross the
placenta more rapidly than polar drugs
 In practice, all drugs should be regarded as
having the potential to affect the unborn child
 The effect of drug exposure will depend upon:
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Timing of exposure
Dosage
Concomitant maternal disease
Genetic susceptibility
Drugs and the fetus
 However, it should be remembered that:
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Teratogens do not cause defects in all fetuses
exposed at the critical period of gestation
A drug that harms a baby in one pregnancy
may have no effect in a subsequent
pregnancy in the same woman
Timing of drug exposure
 Exposure during the pre-embryonic period (until
14 days post-conception)  the ‘all or nothing
effect’
 Damage to all or most cells  death
 If only a few cells are injured  normal development
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Women with a history of drug use in the month
following their last menstrual period can often be
reassured
Limitations
 Drug must be completely eliminated before this time (not
useful for drugs with long half-life)
 Dates of conception uncertain
Timing of drug exposure
 Fetus most vulnerable to teratogens from week
3 to week 8 after conception (embryonic phase)
when major organ systems formed
 For some drugs there is a period of greatest risk
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Exposure to sodium valproate at the time the neural
tube closes (between day 17 & 30 post-conception)
may result in spina bifida
 Cleft palate develops at about 36 days postconception & so a drug exposure outside this
period is unlikely to be implicated in any a/e
Timing of drug exposure
 During the fetal period (week 9  birth)
the fetus is less susceptible to toxic
insults, although some organs (cerebellum
& urogenital structures) continue to be
formed
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Exposure is more likely to cause growth
retardation or interfere with functional
development within specific organ systems
 Danazol can cause virilisation of a female fetus
after 8 weeks gestation
 Warfarin may cause intracranial haemorrhage in
the second & third trimesters
Timing of drug exposure
 Drugs taken close to term cause
predictable pharmacological effects
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Beta-blockers can cause neonatal
hypoglycaemia
SSRIs can cause withdrawal effects after
regular in utero exposure
 Rarely, exposure can have delayed effects
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Diethylstilboestrol – synthetic oestrogen used
for threatened spontaneous abortion
 Many female fetuses exposed before the 9th week
developed vaginal or cervical cancer later in life
Dose & polypharmacy
 In general teratogenicity is dose
dependent
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Neural tube defects & sodium valproate have
shown a correlation with:
 Total daily dose
 Dose per administration
 Peak level achieved
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Dose is only a relative risk factor
Normal babies have been born to women who
have received high doses of valproate & vice
versa
Dose & polypharmacy
 Risk of malformations increases with
exposure to multiple drugs
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e.g. anti-epileptics
 4% incidence of defects for 1 drug
 23% incidence for 4+ drugs
 Potential for confounding with disease
severity can be discounted as epilepsy is
not thought to be associated with an
increase in malformation rate
 Avoid polypharmacy whenever possible
Genetic factors
 Increasing evidence (mainly from antiepileptic drugs) that genetic factors are
important determinants of teratogenic
effects
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Malformation rates may be correlated with
high levels of epoxide metabolites of
phenytoin in individuals with low activity of
epoxide hydrolase
Risk communication
 Clear distinction must be made:
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Prospective query – choice of therapy in
pregnancy (or planned pregnancy)
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is Tx really necessary?
Retrospective – communicating the
(un)safety of drugs when exposure during
pregnancy has already occurred
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Detailed risk assessment
 Health & well-being of mother (maternal history etc.)
 Drug(s) taken (when?), dose & duration
 Reason for query e.g. for reassurance vs. help with
interpretation of an abnormal scan etc.
Pregnancy resources
 Summary of Product Characteristics
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Often very general, outdated or misleading
thus preventing clinician making an
individualised decision with their patient
Commonly written to protect the manufacturer
from potential liability
“Contraindicated in pregnancy”
 Is the drug embryo- or fetotoxic or did the clinical
trials simply exclude pregnant women?
Pregnancy resources
 Individual risk vs. population risk
 Consider a drug with a relative risk of
causing a malformation of 1.2
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The risk for an individual is very small
To a drug company, the same risk implies an
extra 400 malformed children per 100,000
exposed pregnancies (with a background rate
of 2%)
Pregnancy resources
 BNF
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Appendix provides brief information on drugs which
may have harmful effects, together with trimester of
risk
Drugs not listed cannot be assumed to be safe!
 UK Medicines Information Centres
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Access numerous independent resources, specialist
textbooks & databases e.g. ReproTox
UKMi Centres also have links with NTIS (National
Teratology Information Service) which in turn has links
with NPIS (National Poisons Information Service) &
ENTIS (European Network of Teratology Information
Services)
Principles of prescribing
in pregnancy
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Consider non-drug treatments
Avoid all drugs in 1st trimester if possible
Avoid drugs known to have harmful effects
Avoid new drugs where possible
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More experience with ‘older drugs’ – greater evidence
of safety, but can’t assume they are necessarily safe
 Avoid polypharmacy
 Use the lowest effective dose for the shortest
duration possible & review regularly
 Consider the need for dosing changes & TDM
due to the effect of pregnancy on drug handling
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Changes in serum albumin & total body water
Thank you
Any questions?
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