FIGURE 12-2 Timing of organogenesis during the embryonic period. (Reproduced with permission from Salder W: Langman's Medical
Embryology, 6th ed. Baltimore, Williams & Wilkins; 1990.)
The embyonic period extends from the second through the eighth week postconception. It encompasses organogenesis and is thus the most crucial period with regard to structural malformations. Critical developmental periods for each organ system are illustrated in Figure 12-2.
heetal period, which is beyond 8 weeks postconception, is characterized by continued maturation and unctional development. During this time, certain organs remain vulnerable.
• A biologically plausible association is supportive. Because birth defects and medication exposures are both common, they may be temporally but not causally related.
• Epidemiological indings must be consistent. Because initial evaluation of teratogen exposure is often retrospective, it may be hampered by recall bias, inadequate reporting, and incomplete assessment of the exposed population. Potential confounding factors include varying dosages, concomitant drug therapy, and comorbid maternal disease(s). Familial and environmental variables can also inluence development of birth defects. hus, an important criterion for teratogenicity is that two or more high-quality epidemiological studies report similar findings. Finally, a relative risk of 3.0 or reater is generally considered necessary to support the hypothesis, whereas a lesser risk is interpreted with caution (Khoury, 1992).
• he suspected teratogen causes a defect in animal studies. his criterion is not obligatory. In fact, the Teratology Society (2005) states that establishment of causation in teratology-related litigation requires human data.
Failure to employ these tenets and criteria has contributed to erroneous conclusions regarding the safety of some widely used drugs. he poster child for this is the medicolegal iasco surrounding Bendectin. This antiemetic was a combination of doxylamine and pyridoxine, with or without dicyclomine, and was safe and efective for nausea and vomiting in early pregnancy. More than 30 million women used this drug worldwide, and the 3-percent congenital anomaly rate among exposed fetuses was not diferent from the background rate (McKeigue, 1994). Despite considerable evidence that this combination of an antihistamine and a B-vitamin is not teratogenic, Bendectin was the target of numerous lawsuits, and the inancial burden of defending these forced its withdrawal from the marketplace. As a consequence, hospitalizations for hyperemesis doubled (Koren, 1998). Ironically, the combination of doxylamine and pyridoxine was subsequently remarketed under the brand name Diclegis and was approved by the FDA in 2013.
he study of medication safetyor teratogenicity-in pregnant women is fraught with complications. First, animal studies are considered necessary but insuicient. For example, thalidomide is harmless in sveral animal species but resulted in phocomelia in thousands of children born across Europe in the late 1950s and early 1960s. Second, medications are rarely approved by the FDA for a pregnancy-related indication. Instead, pregnant women are considered a special population and summarily excluded from medication trials. Last, drug concentration and thus embyo-fetl exposure are afected by pregnancy physiology. hese include changes in volume of distribution, cardiac output, gastrointestinal absorption, hepatic metabolism, and renal clearance. In the absence of research trials, counseling is based on case reports or series, casecontrol studies, cohort studies, and pregnancy registry data.