Chapter 183. Environmental Causes of Birth Defects

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

Timing of Exposure

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.

Dose of the Agent

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.

Route of Exposure

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.

Duration of Exposure

Since functional as well as structural development of the fetus can be affected by some teratogens, the duration of ...