The word teratogen derives from the Greek word teratos, which had a double meaning of both prodigy and demon. The Greek term also referred to any natural phenomenon that evoked fascination and horror. Today, it has a much more precise medical meaning, describing any environmental agent, contaminant, or chemical that causes fetal abnormalities during pregnancy.
Historical Background and Scientific Foundations
Fetal abnormalities were traditionally thought to be a sign of divine displeasure, that all was not right with the world. The Tablet of Nineveh written in Babylonia nearly 4,000 years ago listed 62 malformations and interpretations of different birth defects. A child born without a right hand, for example, presaged an earthquake. This connection between birth defects and messages from God became particularly pronounced during the Wars of Religion in the sixteenth and seventeenth centuries. For example, the theologian Martin Luther (1483–1546) asserted that a deformed child was the sign of the imminent collapse of the Roman Catholic Church.
On the other hand, the Bible also focused upon maternal responsibility for fetal viability. Thus by the medieval era, it was commonly believed that fetal deformities could not only be a sign from God, but could also be due to maternal failings. Birth defects were assumed to result from a variety of causes, such as coitus between people of different races, possession by the devil, or sex with animals. It was also postulated that the thoughts of pregnant women could be imprinted on the developing fetus. So, if a woman unduly thought about cherries, perhaps due to a food craving, the baby could be born with cherry shaped and colored birthmarks. The Roman naturalist and physician Pliny the Elder (23–79) thus advised women that during pregnancy, they should not look at animals in order to avoid the abnormal development of their developing child.
It was not until systematic study of embryology took place in the nineteenth century that the true causes of birth defects and the role of teratogens were beginning to be understood. In 1822, Etienne Geoffroy Saint-Hilaire (1772–1844) published the second volume to his major work, Philosophie Anatomique. Utilizing studies in comparative anatomy, he argued that birth defects were due to an interruption to fetal development. Geoffrey, in a later collaboration with his son, reproduced deformities in chicken eggs with mixed success, but their work did help to put an end to the idea of material imagination.
Researcher Camille Dareste (1822–1899) also argued that birth defects were due to incomplete embryonic development, and he realized that external agents—teratogens—could be a factor in deformities. He thus used different teratogenic agents to reproduce the abnormalities in chicks that he had observed in nature. As the historian Jean-Louis Fischer indicated, to transform embryos experimentally, Dareste exposed them to teratogens such as varnish, electricity, or different chemicals, as well as lowering incubation temperatures for several hours during early development.
Charles R. Stockard (1879–1939), a zoologist at Cornell Medical College, continued Dareste’s research in the same spirit, demonstrating how different ionic concentrations could produce abnormalities in minnow embryos. Stockard later did experimental tests to reveal the effects of alcohol on the fetal development of guinea pigs. His results seemed to indicate that maternal exposure to alcohol fumes could cause fetal abnormality and an increase in stillbirths. Stockard’s research indirectly led to the discovery of Fetal Alcohol Syndrome (FAS) in 1973. American physician Sterling Clarren confirmed the teratogenic affects of alcohol on fetal development, and as additional scientists have demonstrated, FAS is the leading known cause of mental retardation in the western world.
The latter part of the twentieth century saw the discovery of many teratogens. In 1941, Sir Norman Gregg (1892–1968) discovered the human rubella virus as the first human teratogen; exposure in utero led to heart defects and congenital cataracts. Later experimental findings connecting exposure to mercury to teratogenic effects raised awareness about in utero exposure to chemicals in the environment.
Though some of the effects of teratogens were discovered through animal studies in the laboratory, most teratogens are discovered empirically when there is a sudden or increased occurrence of a particular birth defect. The spike in occurrences of phocomelia, a previously rare disorder resulting in shortened limbs due to the lack or malformation of long bones, led to the identification of a chemical isomer of thalidomide as a human teratogen. Thalidomide was given to expecting mothers
WORDS TO KNOW
EMBRYOLOGY: The study of early development in living things.
PHOCOMELIA: A birth defect in which the upper portion of a limb is absent or poorly developed, so that the hand or foot attaches to the body by a short, flipperlike stump.
to quell morning sickness during the first trimester when the embryo was vulnerable to limb abnormalities. Though the compound thalidomide in itself is safe, the medicine given to mothers was contaminated with its chemical isomer, its molecular mirror image.
The following postulates, a modern modification of Robert Koch’s postulates of disease, are generally used to determine if an agent is a human teratogen. These postulates include the necessity of demonstrating a direct statistical correlation between the occurrence of teratogens and fetal abnormality. The correlation must be reproduced in experiments using animals. Increased doses or exposure to the teratogen should cause an increase in teratogenic effects, and the suggested effect must be scientifically and biologically plausible.
Impacts and Issues
Increased awareness of teratogens has also led to several epidemiological techniques to identify them in the environment and in medications.
Monitoring birth defects and developmental disabilities in a given population can lead to a “case-control” study in which parents of the children with abnormalities as well as control groups are interviewed. Drugs given in pregnancy are also now subject to continuous monitoring to identify teratogens, and as a result, the U.S. Food and Drug Administration (FDA) in the 1980s created five drug categories to designate the safety of medications for use during pregnancy. Despite the fact that few drugs have been demonstrated to cause birth defects, it is important for a pregnant woman to discuss any medication she is taking with her physician, including over-the-counter medications, herbal remedies, or vitamins.
Longitudinal studies involving a large population, in which children and their parents are interviewed from birth until adulthood, can make connections between environment and potential teratogens. In Denmark, investigators studied the risks of mumps-measles-rubella (MMR) vaccines causing autism. Cross-referencing immunization records of children with those later diagnosed with autism demonstrated that the rate of autism was the same in vaccinated and non-vaccinated groups.
There was thus no increased risk of autism involved with MMR vaccination, and the MMR vaccine was therefore determined not to be a teratogen. As Jose F. Cordero indicated, in the United States, the large population and privacy concerns would have made such a study impossible. Epidemiologists must always consider patient confidentiality when engaging in studies to identify teratogens.
In 2004, the U.S. Environmental Protection Agency (EPA) issued recommendations for women of childbearing age concerning the levels of methylmercury in fish and shellfish. Methylmercury is a known teratogen, and occurs naturally and also makes its way into rivers and oceans when mercury is released as an industrial pollutant. Once in the water, mercury converts to methylmercury and is absorbed by fish. Although the EPA suggested that fish are an important part of a nutritious diet, the agency recommends that pregnant women and young children avoid eating fish such as shark, king mackerel, swordfish, and tilefish that contain higher amounts of methylmercury. Salmon, shrimp, canned light tuna, and catfish are among the suggested alternatives that have low levels of methylmercury, although the suggested amount of consumption is six ounces per week for tuna and 12 ounces of these fish overall per week. Finally, the EPA recommends that only six ounces of fish caught by family or friends from local waters be consumed per week, and that children receive smaller portions.
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Anna Marie E. Roos