Teratology, Teratogens, and Fetotoxic Agents 235 teratogen may be deined as any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Thus, a teratogen may be a medication or other chemical substance, a physical or environmental factor such as heat or radiation, a maternal metabolite as in diabetes or phenylketonuria, or an infection such as cytomegalovirus. Even obesity is considered a teratogen (Stothard, 2009; Waller, 2007).
Strictly defined, a teratogen causes only structural abnormalities. A hadegen-after the god Hades-is an agent that interferes with organ maturation and function, and from a population-based review of 270,878 births.
pregnancy risk "undetermined" for more than 95 percent of these agents (Adam, 2011).
he study of birth defects and their etiology is termed teratology, derived from the Greek teratos, meaning monster. A
TABLE 12-2. Criteria for Determining Teratogenicity
Essential Criteria: 1.
Careful delineation of clinical cases, particularly if there is a speciic defect or syndrome 2.
Proof that exposure occurred at critical time during development (see Fig. 12-2) 3.
Consistent indings by at least two epidemiological studies with: a.
exclusion of bias, b.
adjustment for confounding variables, c.
adequate sample size (power), d.
prospective ascertainment if possible, and e.
relative risk (RR) of 3.0 or greater, some recommend RR of 6.0 or greater
For a rare environmental exposure associated with a rare defect, at least three reported cases. This is easiest if defect is severe
Ancillary Criteria: 4.
The association is biologically plausible 5.
Teratogenicity in experimental animals is important but not essential 6.
The agent acts in an unaltered form in an experimental model
Data from from Shepard 1994, 2002a.
term teratogen is used to refer to all three types of agents.
The guidelines shown in Table 12-2 were proposed by Shepard (1994) as a framework for discussion and have proven useful for more than 25 years. Although each individual criterion is not required to establish teratogenicity, the following tenets must be considered (Shepard, 2002a): • The defect has been completely characterized. This is preferably done by a geneticist or dysmorphologist because various genetic and environmental factors may produce similar anomalies. It is easiest to prove causation when a rare exposure produces a rare defect, when at least three cases with the same exposure have been identified, and when the defect is severe.
• he agent must cross the placenta. Although almost all drugs cross the placenta, transport must be of suicient quantity to directly inluence embryonic or fetal development or to alter maternal or placental metabolism to exert an indirect efect. Placental transfer depends on maternal metabolism; on speciic characteristics of the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism, such as by the cytochrome P 450 enzyme system. In early pregnancy, the placenta also has a relatively thick membrane that slows difusion.
• Exposure must occur during a critical developmental period.
o Thepreimplantation period is the 2 weeks between fertilization and implantation and is known as the "all or none" period. As the zygote undergoes cleavage, an insult damaging a large number of cells typically causes embryonic death. However, if only a few cells are injured, compensation may be possible and allow normal development (Clayton-Smith, 1996). From animal data, insults that appreciably diminish the cell number in the inner cell mass may produce a dose-dependent diminution in body length or size (Iahnaccone, 1987).
Fertilization to bilaminar disc formation