Exposure of a conceptus to teratogenic or mutagenic agents can have adverse results depending on the type, dose, and route of exposure and the stage of pregnancy. One tenet of teratology is the “all-or-none” phenomenon, the concept that embryonic exposure before organogenesis results in either no adverse embryonic outcome or in embryonic death. This principle has guided genetic counseling of pregnant women who had an inadvertent exposure in the very early stages of pregnancy, often before they knew they were pregnant. Interruption of pregnancy has been averted because of the reassuring nature of this concept. This review reevaluates the data that led to the all-or-none theory and the appropriateness of using it for genetic counseling in clinical practice.
Ionizing radiation and nonionizing radiation have been studied extensively for their effects on the developing embryo and fetus. Older and more recent studies in rats and mice have reported that ionizing radiation in the preimplantation and preorganogenesis stages increased the risk of embryonic death. The rates of malformations in the surviving fetuses and control subjects at term were similar, indicating that the induced malformations tended to be lethal.
The adverse effects of chemicals and radiation on the preimplantation zygote and embryo can also originate from the mother. Studies on the effects of mitomycin C showed that the placenta and implantation site were the most affected tissues and that the malformations were a product of a maternal toxic effect. Such findings were not apparent when the embryo was the target of the teratogen. Studies of ethylene oxide, methylnitrosourea, ethylnitrosourea, triethylene melamine, and glycidol in mice found high rates of mortality, congenital anomalies, peri-implantation losses, and midgestational and late gestational deaths, and a significant increase in external defects, retarded ossification, and skeletal anomalies. The mechanisms causing these mutagenic malformations did not seem to be maternally induced. Reciprocal zygote transfer experiments in mice eliminated maternal toxicity as the mechanism for the fetal anomalies.
The effects of mutagens and teratogens on the developing embryo or fetus are dose-dependent and stage-specific. The germ cell stage is less sensitive than the zygote stage, which is less sensitive than the period of organogenesis. The predominant effect is death or a stage-specific increase in the LD50. Multiple agents cause changes in the zygote that result in deleterious effects in the embryo. Yet, some teratogens are inactive in the zygote. Exposure of gametes produces low rates of some anomalies, whereas exposure during organogenesis causes a wider array of agent-specific malformations.
Most studies on mutagens/teratogens have been performed in model systems, with doses many times the human dose or exposure. Using malformations as an end point can be a problem because mutagens that produce malformations, when compared with humans, are either sporadic in nature or due to polygenic factors. These types of defects have high background rates in humans, making a link between a preimplantation or zygotic exposure and effects in humans difficult.
Some mutagens cause chromosome breaks, translocations, deletions, and point mutations, but outcomes on human gametes from environmental exposure are unknown. The small numbers of exposed individuals make epidemiologic studies in humans difficult. The inaccuracies in human pregnancy dating make extrapolation from animal studies to human pregnancy almost impossible. Without additional evidence to the contrary, and given that many women are exposed to medications or environmental agents before learning of their pregnancies, it is wise to counsel pregnant women using the all-or-none hypothesis to avoid needless interruption of pregnancy based on an unfounded fear of an adverse outcome.
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA