Identifying Human Teratogens: An Update

A human teratogen is an agent that alters the growth or structure of the developing embryo or fetus, thereby causing birth defects. The first human teratogen identified in 1941 by an ophthalmologist, Norman Gregg, was maternal rubella infection in pregnancy, which produced a triad of defects (cataracts, heart malformations, and deafness) in the infants.1 Following the identification of thalidomide, an antinauseant, as a major human teratogen causing severe birth defects in 1961,2 research in teratology began to expand and there was increased awareness of the possible teratogenic impact of maternal exposures during pregnancy. Several factors that determine the teratogenicity of an exposure have been set forth as the principles of teratology byWilson,3 guiding researchers in the study and understanding of teratogenic agents. These include, but are not limited to, the following: Abnormal development produced by a teratogenic exposure is manifested as death, malformation(s), growth retardation, or a functional disorder. These include neurologic impairments, such as mental retardation, and long-term effects on cognition and behavior that may appear later in childhood. A second principle of teratology states that susceptibility to teratogenesis varies with the developmental stage at the time of exposure, and a third claims that manifestations of abnormal development depend on dose and duration of a teratogenic exposure. These indicate that not all exposures deemed as teratogenic are actually teratogenic all the time; the timing and dose of a particular exposure during pregnancy often determine the kind and extent of its teratogenic potential. The embryonic period, during which organogenesis takes place, occurs between implantation at around 14 days to around 60 days postconception. This is usually the most sensitive period to teratogenesis when exposure to a teratogenic agent has the greatest likelihood of producing a malformation. For example, administration ofmanyestablishedmajor teratogenic drugs, such as isotretinoin, valproic acid, warfarin, or high-dose methotrexate, in specific gestational windows in the first trimester is associated with a high risk of having a baby with a congenital malformation, but the risk significantly decreases in the second or third trimesters of pregnancy. In some cases, several periods of susceptibility may exist for a single organ, such as in the case of craniosynostosis, an abnormality that occurs as a result of premature fusing of cranial sutures. Also, for some teratogens, a level of exposure exists below which probably no demonstrated harmful embryonic effect occurs, such as in the case of methotrexate, a folic acid antagonist.4 Another teratology principle states that susceptibility to a teratogenic exposure also depends on the fetal and maternal genotype. Genetic predisposition to the effects of several teratogenic exposures has been intensively studied. For example, embryonic exposure to cigarette smoke has been established as a risk factor for orofacial clefts5 and gastroschisis,6 but even higher risks were found for cleft palate among the offspring of maternal smokers in the presence of a rare transforming growth factor α (TGFA) genotype7 or a variation in the nitric oxide synthase (NOS3) gene in the infant.8 The genetic basis underlying susceptibility to fetal alcohol syndrome and abnormal glucose metabolism-induced birth defects have also been linked to certain maternal and fetal gene variants.9 Specifically with regard to drug metabolism, genetic variation in maternal metabolism of certain antiepileptic medications may predispose her infant to the development of birth defects.9,10 Experimental animal teratology studies performed on rodents are critical in determining the risk or safety in pregnancy of a particular agent, and are usually used by industry and regulatory agencies as a first step before a specific agent is approved for marketing, such as in the case of medications. However, it is sometimes difficult to extrapolate results from available animal studies to humans in part due to the relevance of the dose utilized and in part due to species differences in response to amedication. Experimental teratology studies or randomized controlled trials in human pregnancy are rarely permitted because of ethical reasons.