DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1846 In pregnant women, the placenta provides a barrier
for the transfer of certain drugs from the mother to the
fetus (e.g., drug transporters expel toxic natural products
and related drugs from the placenta, aromatase converts
maternal androgen to estrogens); however, many compounds
can freely cross the placental barrier and access
the fetal circulation. The teratogenic effects of thalidomide
on limb formation, alcohol on development of the
CNS and cognition, and diethystilbestrol (DES) on genital
development in males and females and on the subsequent
development of vaginal and cervical carcinomas
in female offspring are stark reminders of the dangers of
fetal exposure to drugs. In the clinical setting, there is no
direct method for determining fetal exposure to a drug.
Drug concentration over time in the mother’s systemic
circulation is the major determinant of this exposure, but
other contributing factors include the size, solubility, ionization,
and protein binding of the drug; its active transport
into and out of the placental circulation; and the rate
of fetal clearance, which includes first-pass metabolism
by the placenta.
Based on the relative paucity of human data on
the teratogenic effects of drugs and the limited reliability
of animal models, a fundamental tenet in treating
pregnant women is to minimize, whenever possible, the
exposure of mother and fetus to drugs; when necessary,
one should preferentially use those drugs that have the
best record of safety in pregnant women without
adverse developmental effects on the fetus. Of equal
importance, substances of abuse (e.g., cigarettes, alcohol,
illegal drugs) should be avoided and, whenever
possible, eliminated before conception. In addition, all
pregnant women should take a multivitamin containing
400 μg of folic acid daily to diminish the incidence of
neural tube defects. The greatest concern is during the
period of organogenesis in the first trimester, when a
number of the most vulnerable tissues are formed.
Cancer chemotherapy drugs cannot be given with reasonable
safety during the first trimester, but most cytotoxics
may be administered without teratogenic effects
and with maintenance of pregnancy in the third
trimester (see Chapters 61-63).
Drugs that are used to promote fertility are a special
case, since they, by nature of their use, will be present
in the mother at the time of conception. Fortunately,
available evidence largely supports the safety of fertility
agents for fetal development, although there have been
data suggesting increased risk with certain agents (e.g.,
neural tube defects and hypospadias associated with
clomiphene; Elizur and Tulandi, 2008).
The FDA assigns different levels of risk to drugs
for use in pregnant women, as listed in Table 66–5.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Table 66–5
FDA Use-in-Pregnancy Ratings
Category A: Controlled studies show no risk.
Adequate, well-controlled studies in pregnant women
have failed to demonstrate a risk to the fetus in any
trimester of pregnancy.
Category B: No evidence of risk in humans. Adequate,
well-controlled studies in pregnant women have not
shown an increased risk of fetal abnormalities despite
adverse findings in animals, or, in the absence of adequate
human studies, animal studies show no fetal risk. The
chance of fetal harm is remote, but remains a possibility.
Category C: Risk cannot be ruled out. Adequate, wellcontrolled
human studies are lacking, and animal studies
have shown a risk to the fetus or are lacking as well.
There is a chance of fetal harm if the drug is administered
during pregnancy, but the potential benefits may
outweigh the potential risk.
Category D: Positive evidence of risk. Studies in
humans, or investigational or post-marketing data, have
demonstrated fetal risk. Nevertheless, potential benefits
from the use of the drug may outweigh the potential
risk. For example, the drug may be acceptable if needed
in a life-threatening situation or serious disease for
which safer drugs cannot be used or are ineffective.
Category X: Contraindicated in pregnancy. Studies in
animals or humans, or investigational or post-marketing
reports, have demonstrated positive evidence of fetal
abnormalities or risk that clearly outweighs any possible
benefit to the patient.
Certain drugs are so toxic to the developing fetus that they
must never be administered to a pregnant woman (category
X); in some cases (e.g., thalidomide, retinoids), the
potential for fetal harm is so great that multiple forms of
effective contraception must be in place before the drug
is initiated. For other drugs, the risk of adverse effects on
the fetus may range from category A (drugs that have not
been proven to have adverse effects on the fetus despite
adequate investigation) to category C (drugs with risks
that sometimes may be justified based on the severity of
the underlying condition (e.g., hydralazine for pregnancy-induced
hypertension, β adrenergic receptor
agonists for premature labor; see “Pregnancy-Induced
Hypertension/Pre-eclampsia” and “Tocolytic Therapy for
Established Preterm Labor”). Unfortunately, the FDA listings
may be overly simplistic or outdated for a given drug;
for example, oral contraceptives are listed as category X,
even though considerable data now indicate that birth
defects are not increased in women taking oral contraceptives
at the time of conception.