Drugs in Pregnancy

and Lactation
The pregnant woman is perhaps the last true
therapeutic orphan. Because of the ethical,
medicolegal, and fetal safety concerns regarding
pregnant women, few pharmacokinetic,
pharmacodynamic, or clinical trials are conducted
during pregnancy. The majority of drugs that are
marketed, therefore, carry the following statement
in their labeling:

There are, however, no adequate and well-

controlled studies in pregnant women.
Because animal reproductive studies are not
always predictive of human response, this
drug should be used during pregnancy only if
clearly needed. [Zinacef (cefuroxime)
labeling; PDR; 2005. p. 1678]
Drug use during pregnancy and lactation requires
special
consideration because both the mother and the
fetus or nursing infant are affected. Few drugs
are considered safe, and drug use is
generally contraindicated. However, >80%
of women are exposed to substances, such as
medication during their pregnancies. Many pregnant or
lactating women take drugs for various reasons,
including
acute disorders that may or may not be
associated with pregnancy,
chronic disorders that require continued
treatment during pregnancy or lactation, and
 habitual use of nontherapeutic drugs (eg,
alcohol, tobacco, others).
Consideration in Pregnancy

There are are two considerations regarding

drug use in pregnant women:

 The effect of the drug on the pregnancy,

fetus or neonate

 Effect of the pregnancy on drug handling

Pregnancy stages
Pregnancy: Physiologic and Pharmacokinetic Changes

As pregnancy evolves, profound changes occur in

physiology, including fluid and tissue composition.

Absorption

Despite reduced gastrointestinal motility, there appears

to be no major defect in drug absorption except that slow
gastric emptying delays the appearance in the plasma of
orally administered drugs, especially during labour.
Absorption from an intramuscular site is likely to be
efficient because vasodilatation increases tissue
perfusion.
Pregnancy: Physiologic and
Pharmacokinetic Changes
Distribution
Total body water increases by up to 8 L, creating a
larger space within which water-soluble drugs may
distribute. Plasma albumin (normal 33-55 g/L)
declines by some 10 g/L from haemodilution. While
this gives scope for increased free concentration of
drugs that normally bind to albumin, unbound drug is
also available to distribute, be metabolised and
excreted. A useful general guide during pregnancy is
to maintain concentrations at the lower end of the
recommended range. Body fat increases by about 4
kg and provides a reservoir for lipid-soluble drugs.
Drugs that are distributed to fatty tissues tend to
linger in the body because they are slowly released
from storage sites into the bloodstream.
Metabolism
Hepatic metabolism increases, although not
blood flow to the liver. There is increased
clearance of drugs such as phenytoin and
theophylline, whose elimination depends on liver
enzyme activity. Drugs that are so rapidly
metabolised that elimination depends on
delivery to the liver, i.e. on hepatic blood flow,
have unaltered clearance, e.g. pethidine.

Elimination
Renal plasma flow almost doubles and there is
more rapid loss of renally excreted drugs, e.g.
amoxicillin, the dose of which should be doubled
for systemic infections (but not for urinary tract
infections as penicillins are highly concentrated
in the urine).
Placental Drug Transfer

The placenta is the functional unit between the fetal

and the maternal blood supply. There is no mixing of
the two systems, but exchange of nutrients, oxygen,
and waste products occurs primarily via
 Passive diffusion.
 Facilitated diffusion
 Active transport
Factors affecting placental drug transfer
 Molecular weight
 Drug pKa
 Lipid solubility
 Ionization
 Protein binding
 Chemical Structure
 Physical characteristics of the placenta
 Maternal pharmacokinetic changes
Teratogenic drugs
A substance, organism, physical agents or
deficiency state capable of inducing
abnormal structure or function such as:
 Gross structural abnormalities
 Functional deficiencies
 Intrauterine growth restriction
 Behavioral aberrations
 Demise
Drug teratogenicity is most likely to occur when
drugs are
taken during the first trimester of pregnancy,
when fetal organs are formed
Teratogenic Factors
 Timing of exposure
 Developmental stage during
exposure
 Maternal dose and duration
 Maternal pharmacokinetics
 Genetic factors/phenotypes
 Interactions between agents
FDA Pregnancy Categories
 Category A
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there
is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
Category B
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled
studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other
than a decrease in fertility) that was not confirmed in controlled studies in women in the first
trimester (and there is no evidence of a risk in later trimesters).
Category C
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal
or other) and there are no controlled studies in women, or studies in women and animals are not
available. Drugs should be given only if the potential benefit justifies the potential risk to the
fetus.
Category D
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may
be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a
serious disease for which safer drugs cannot be used or are ineffective).
Category X
Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence
of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant
women clearly outweighs any possible benefit. The drug is contraindicated in women who are or
may become pregnant.
 Problems with the current system

The current system was created in 1979 and

has not been revised since its inception. With
many agents there is a paucity of human data,
despite the fact the drug may carry a category
B rating. Most newly marketed agents will be
placed in category C, amid other agents with
little data in humans or animals. This is the
most difficult category to assess. Al though
there may be case reports of drug exposures,
these tend to bias information toward fetal
risk; most publish only outcomes with
potential drug-related effects. Few drugs will
ever be assigned a category A status because
large, randomized, well -control led trials are
rarely conducted in pregnant women.
Examples of teratogenic agents.
 DRUG EXCRETION IN BREAST
MILK
Today, large number of women choose to breast -
feed their infants. It is important to understand the
principles of drug excretion in breast milk and
specific information on the various medications to
minimize risks from drug effects in the nursing
infant .

Most drugs cross into breast milk via passive diffusion

along a concentration gradient formed by the un-
ionized drug content on each side of the membrane.

It is possible to calculate the dose an infant receives

if the breast milk concentration is known. A typical
infant drinks 150 mL/kg per day. Multiplying the
average concentration by the breast milk volume
consumed will give the total daily exposure.
The drug and its environment influence the rate
and extent of drug passage into the breast milk.

 Molecular weight . Drugs weighing < 200 D

across into milk easily.
 pH gradient. Human milk is more acidic than
plasma.
 Drug pKa. Only the un-ionized form of a drug
is able to pass through the lipid membrane.
 Plasma protein binding. The free fraction of
a drug is available to pass into the breast milk.
 Lipid solubility. Lipid solubility is necessary
Drugs affecting hormonal influence of breast milk
production
The primary hormone responsible for controlling
breast milk production is prolactin. A decrease in milk
production may result in diminished weight gain in
the nursing infant , the need for supplementation, or
premature cessation of breast - feeding.
 Drugs that decrease serum prolactin levels.
 Ergot alkaloids
 L-dopa
 Bromocriptin

 Drugs that increase serum prolactin levels.

 Methyldopa
 Haloperidol
 Phenothiazines
 Metoclopramide
In assessing the safety of an agent during breast-
feeding, several considerations should be addressed:

 Inherent toxicity of the drug

 Drug safety data in infants

 Amount of drug ingested

 Duration of therapy

 Age of the infant or degree of prematurity

 Drug pharmacokinetics in the mother and child

Factors to minimize drug exposure to the
infant .