FIGURE 59–1 Schematic diagram of critical periods of human development. (Reproduced, with permission, from Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988. © Elsevier.) has been shown to have important differentiation-directing actions in normal tissues. Several vitamin A analogs (isotretinoin, etretinate) are powerful teratogens, suggesting that they alter the normal processes of differentiation. Finally, deficiency of a critical substance appears to play a role in some types of abnormalities. For example, folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects (see Box, page 599).
Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol spectrum disorder (see Chapter 23). In this syndrome, the central nervous system, growth, and facial development may be affected.
2. Defining a teratogen—To be considered teratogenic, a candidate substance or process should (1) result in a characteristic set of malformations, indicating selectivity for certain target organs; (2) exert its effects at a particular stage of fetal development, eg, during the limited time period of organogenesis of the target organs (Figure 59–1); and (3) show a dose-dependent incidence. Some drugs with known teratogenic or other adverse effects in pregnancy are listed in Table 59–1. Teratogenic effects are not limited only to major malformations, but also include intrauterine growth restriction (eg, cigarette smoking), miscarriage (eg, alcohol), stillbirth (eg, cigarette smoke), and neurocognitive delay (eg, alcohol, valproic acid).
In addition to teratogenic drugs, teratogenicity can be induced by a large group of infectious pathogens, including viruses such as rubella, cytomegalovirus, herpes, and recently, Zika virus. Similarly, numerous chemicals, such as heavy metals (eg, mercury, lead) and environmental factors (eg, radiation, hyperthermia) can damage the fetus. It is important to consider these nondrug factors in the differential diagnosis of drug-induced adverse fetal effects.
The widely cited US Food and Drug Administration (FDA) system for teratogenic potential (Table 59–2) has been an attempt to quantify teratogenic risk from A (safe) to X (definite human teratogenic risk). This system has been criticized as inaccurate and impractical. For example, several drugs have been labeled “X” despite extensive opposite human safety data (eg, oral contraceptives). Diazepam and other benzodiazepines are labeled as “D” despite lack of positive evidence of human fetal risk. The FDA has recently changed its system from the A, B, C grading system to narrative statements that summarize evidence-based knowledge about each drug in terms of fetal risk and safety.