++
The definition of a teratogenic agent (an exposure, external
to the fetal genome, that induces structural or functional alterations
during prenatal development) suggests that the clinicians’ first
encounter may be well after the exposure has occurred. Knowledge
of the principles of teratology can direct diagnostic and treatment
approaches to a child with dysfunction or dysmorphology of unknown
etiology and can be instrumental in guiding initial evaluations
as well as physician–patient–parent interactions.
++
In weighing the possibility that a teratogen is responsible for
a child’s condition or defect, one of the most important
factors to consider is background risk. Every pregnancy
carries an approximate 3% risk that the fetus will be affected
with a major, life-affecting defect. Although this level of risk
can be increased by maternal teratogenic exposure, it cannot be
decreased. A common misconception is that a majority of birth defects
are the result of teratogenic exposure. However, teratogens cause
only about 3% of the clinically significant congenital
structural defects in humans. Because no teratogen affects all exposed fetuses,
there is probably an interaction between genes and environment necessary
to create teratogenicity.
++
To determine risk, the following factors must be assessed:
++
- Timing of exposure
- Dose of the agent
- Route
- Duration of exposure
- Confounders
- Species susceptibility
- Clinical sonsistency
++
The time frame at which an exposure occurs during the pregnancy
is, arguably, the most important factor to consider when determining teratogenicity.
Contemporary understanding of embryology and embryopathy guides
this principle. For example, teratogenic exposure between days 15
and 28 after fertilization can be the cause of a neural tube defect,
because during this time neural tube closure occurs in the embryo.
Parallels can be drawn between teratogenic exposure and development
of virtually any other major organ or system. Thus, knowing that
the mother was exposed during a critical time for induction of the
child’s anomaly is vital when evaluating a child for possible
teratogenic effects.
++
Fortunately, threshold levels have been estimated for most known
human teratogens. For example, the dosage of methotrexate required for
therapeutic treatment of rheumatoid arthritis and psoriasis is considerably
below that which could induce fetal defects.
++
Most agents are transmitted to the fetus indirectly, through
maternal blood. Therefore, in order for the fetus to be affected,
an agent must have access to maternal blood. The amount of fetal
exposure to compounds concentrated in maternal blood is, therefore,
dependent on maternal blood levels. Isotretinoin, a known teratogen,
is directly absorbed into the maternal bloodstream, whereas tretinoin,
a topical vitamin A congener, has minimal maternal systemic absorption
and is not associated with an increased risk for birth defects.
++
Since functional as well as structural development of the fetus
can be affected by some teratogens, the duration of ...