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Drugs in Pregnant and

Breastfeeding Women
Objectives
Background
• Once in the maternal circulation, drugs are
separated from the fetus by a lipid placental
membrane
• Any given drug crosses the lipid placental
membrane to a greater or lesser extent
depending on the physicochemical properties
of the molecule
• Drugs in pregnancy can be viewed from two
standpoints:
– Effect of drugs on the fetus
– Effect of pregnancy on the drug
• Drugs can influence fetal development at
three separate stages
– Fertilization and implantation (from conception to
about 17 days gestation)
– Organogenesis (18 to 55 days)
– Growth and development (56th day onward)
Effect of Drugs on the Fetus
• Influence of drugs during fertilization and
implantation period
– Interference by a drug with either of these
processes leads to failure of pregnancy at a very
early stage probably subclinical stage

– Therefore, very little is known about drug


influence at this stage
• Influence of drugs on organogenesis
– During organogenesis, the developing embryo
shows great sensitivity to the teratogenic effects of
drugs
– With drug teratogenicity it is important to
appreciate the following:
• Teratogenesis in humans is very difficult to predict from
animal studies (considerable species variation)
• Serious congenital deformities are present in 1 to 2 % of
all babies
• Therefore, a drug is identified as teratogenic if its effects
are frequent, unusual and/or serious
• A low-grade teratogen that infrequently causes minor
deformities is likely to pass unnoticed
• Influence of drugs on organogenesis
continued
– It is important to realize that even for known
teratogens, first trimester use often results in a
normal baby
– For example, phenytoin is teratogenic in about 5 %
of exposures and warfarin in up to 25 %
– So first trimester use of known teratogens is
occasionally permitted where the risks to the
mother of not using the drug outweigh the the
risks of exposure in the fetus
– For example, the use of warfarin in women with
prosthetic heart valves
• Influence of drugs on organogenesis
continued
– The greatest risk of teratogenesis occurs at a time
when a woman might not even be aware that she
is pregnant
– Only a few drugs are known definitely to be
teratogenic, but many more could be under
certain circumstances
– Therefore, when prescibing for a woman of
childbearing age, remember that she might be
pregnant
– Ask yourself if the benefits of drug use outweigh
the risks of teratogenesis (however small the risk
might be)
• Influence of drugs on growth and
development
– During this stage major body structures have been
formed and their subsequent development and
function can be affected by drug exposure
– For example:
• Antithyroid drugs cross the placenta and can cause fetal
and neonatal hypothyroidism
• Tetracyclines inhibit bone growth and discolor teeth
• ACE inhibitors can seriously damage fetal kidney
function
• Warfarin can cause bleeding into the fetal brain
• Drugs with dependence potential can result in
withdrawal symptoms in the neonate
• Effect of drugs given at the end of pregnancy
– Aspirin in analgesic doses can cause haemorrage
in the neonate

– Indomethacin (and possibly other NSAIDs) causes


premature closure of the ductus arteriosus with
resulting pulmonary hypertension

– CNS depressant drugs can cause hypotension,


respiratory depression and hypothermia in the
neonate
Effect of Pregnancy on the Drug
• The substantial physiological changes that
occur in pregnancy can influence drug
disposition (distribution and elimination)

• The effect of pregnancy on drug disposition


may be accentuated by concurrent
pathological conditions in pregnancy
• Effect of pregnancy on drug distribution
– Maternal plasma and ECF volume increase by
about 50 % by the last trimester
• This may decrease the steady-state concentration of
drugs with a small volume of distribution
– Considerable changes in protein concentration
occur during the last trimester
• Serum albumin falling by about 20 %
• α1-acid glycoprotein concentration increases by about
40 % in normal pregnancies
– This means that
• The free fraction of acidic drugs can increase
substantially and that of basic drugs can decrease
greatly in the last trimester (worse if pre-eclampsia)
• Effect of pregnancy on drug distribution
continued
– Diazepam, phenytoin and sodium valporate have
been shown to have significantly elevated free
fractions in the last trimester
• Effect of pregnancy of drug elimination
– Effective renal plasma flow doubles by the end of
pregnancy leading to increased renal clearance of
some drugs (shown to be important in few drugs)

– For example, clearance of ampicillin doubles and


the dose must also be doubled for systemic
infections
• Effect of pregnancy of drug elimination continued
– The hepatic microsomal mixed function oxidase
system undergoes induction in pregnancy (high
circulation levels of progesterone?)

– This leads to increased clearance of drugs metabolized


through this pathway

– For example, the is evidence that steady-state plasma


concentrations of phenytoin, sodium valporate
carbamazepine may be clinically significantly
decreased during the second and third trimesters

– Therefore, higher doses may be required as pregnancy


progresses with careful monitoring of drug
concentration
Drugs in Breast feeding
• Most drugs enter breast milk to a greater or
lesser extent as part of drug distribution
• However, the plasma concentration is low by
the time the drug is re-distributed to breast
milk (distribution throughout the mother’s
body)
• Therefore, the amount of drug actually
received by the breast-fed baby is usually
clinically insginificant
Drugs in Breast feeding continued
• However, certain drugs achieve sufficient
concentration in breast milk and are
sufficiently potent that they should be
avoided in breast feeding women
• Important to note that most commonly used
drugs can safely be used in breast feeding
women
• If in doubt, seek further information