A teratogen is any environmental influence that adversely affects the normal development of the fetus.
Description
Abnormal fetal development may result from exposure to a teratogen. There are four different teratogen categories: physical agents (radiation and hyperthermia), metabolic conditions affecting the mother, infection, and drugs (like thalidomide) and alcohol.
Women whose body temperature is raised while pregnant may have abnormalities result in their fetus. The rise in body temperature can be caused by infection or by spending time in hot areas such as a sauna or hot tub.
Ionizing radiation-mutagens versus teratogens
Any outside agent (like radiation) interfering with the process of development is considered a teratogen. Development is the process in which a tiny mass of undifferentiated cells (the embryo) multiplies and differentiates into the kidney, liver, heart, bone, muscles, and so on. Mutagens, however, are agents that directly affect and disrupt DNA, the genetic blueprint of an organism. Some agents, like radiation, are mutagens and teratogens. Ionizing radiation can cause defects either in development or it can damage DNA directly.
Metabolic disease
Infants of women with metabolic disorders have increased risks for abnormalities. Diabetic women, for example, are three to four times more likely to have fetuses with congenital abnormalities than infants of mothers without diabetes. The metabolic disease of the mother can have genetic or other causes.
Infection
There are a number of known infectious organisms which are teratogenic to the fetus, some of which cause damage directly, and some of which damage the fetus by causing a fever and raising the temperature of the mother.
Thalidomide
A dramatic example of a teratogen is thalidomide. In the early 1960s it was shown that more than 7,000 women who took the anti-nausea drug thalidomide during their pregnancy had children with very short or absent arms and legs. Other abnormalities were also seen in the children, such as the absence of ears, as well as heart and intestinal malformations. Affected infants were born to women who took thalidomide during the critical time period, also known as the period of susceptibility.
Period of susceptibility
Thalidomide also teaches the importance of timing in the action of teratogens. Only a small amount of thalidomide was necessary to cause birth defects, but it had to be taken between 34 and 50 days after conception in order to harm the embryo. The time when teratogens can act, in this case from day 34 to day 50 after conception, is called the period of susceptibility. Since organ development in the unborn child occurs at different times, it was shown that taking thalidomide on different days caused the infants to have a variety of defects (heart vs. ears vs. limb formation). Drugs very often affect specific parts of the process of development. Before, or after, the processes take place, the drug will have no effect. Of course many teratogens, like thalidomide, work on a number of different developmental processes at different times (sometimes they are consecutive times, or they may be non-consecutive: for example from days 16 to 20 and days 24 to 48). The period of susceptibility of the child to most teratogens is between the third and eighth week after conception.
Dose and duration
The most common teratogen, alcohol, illustrates the important concept that the dose of a teratogen (for example, the number of alcoholic drinks a mother has) and duration of exposure to a teratogen (for example, the number of days a mother drinks alcohol) both play an important role in the effect of a teratogen. Alcohol can have a wide range of effects on a fetus, from no mental change or very mild mental changes (usually a small dose of alcohol) to full-blown fetal alcohol syndrome, in which the infant is severely retarded. Even two glasses of alcohol can be teratogenic to a fetus, but the mental retardation and characteristic facial changes seen in full-blown fetal alcohol syndrome generally requires the mother to drink 2-3 oz of alcohol per day for a sustained period of time (the exact amount of time is not known) during pregnancy. Thus, dose and duration help determine the severity of a teratogen's effects.
Other factors that affect teratogens
Although the dose and duration are important in determining how much of an effect alcohol will have on the fetus, other factors have an impact, too. When normal mice and mutant mice are given the same dose of a particular teratogen, the mutant mice are affected much more severely. This means that in humans, the genetic makeup of the fetus helps determine to what extent the teratogen will affect the fetus. A baby with one particular set of genes might be severely affected by the mother drinking one glass of alcohol, while another fetus may be unaffected by the first or even second glass of alcohol. The outcome of teratogens probably depends on a combination of factors: the mother's condition (genetic or otherwise), the genetic background of the fetus, and the dose and duration of the teratogen. However, the importance of each factor probably varies greatly from teratogen to teratogen and from individual to individual.
Although the discussion of these teratogenic concepts has revolved around examples from the category of drugs and alcohol, the concepts may be applied to any of the categories of teratogens.
Demographics
Exact numbers of infants affected by teratogens are difficult to estimate. Langman's Medical Embryology states 4-6% of all infants will have major developmental or genetic abnormalities. This source estimates that of the children with major abnormalities, 10% can be attributed to teratogens, 20-25% can be attributed to genetic and environmental influences, and 40-60% of the abnormalities are due to unknown causes (possibly teratogenic). That means as many as 95% of all major birth disorders may involve teratogens.
Diagnosis
The diagnosis varies from teratogen to teratogen. Some genetic diseases and teratogens can present with the same abnormalities and symptoms. If the gene causing the disorder has been isolated and is well understood, the difference between a genetic and a teratogenic disorder may be established. Many abnormalities in children go unexplained. In these cases, teratogen exposure should be considered.
Treatment, prevention, and the period of susceptibility
Treatment options and how well they work vary widely according to the teratogen. The best course is to prevent teratogen exposure, or reduce the exposure as much as possible. Prevention is complicated because very often women may not realize they are pregnant until the middle of the period of susceptibility. Substances that are not harmful to an adult, like the derivatives of retinoic acid found in a number of skin creams, alcohol, and many prescription drugs, can be extremely harmful to the fetus. Retinoic acid, for example, has a period of susceptibility from days 20-35 after conception—a time when many women might not realize they are pregnant.
Thus, women who are engaging in activities that can lead to pregnancy and want to avoid any potential damage to their fetus should attempt to avoid teratogenic substances (including a large number of over-the-counter, prescription, and illegal drugs). Alternatively, women can also prevent most damage to the fetus by closely monitoring their pregnancy status and avoiding teratogens as soon as pregnancy occurs.
Gilbert, Scott F. Developmental Biology. Sunderland, MA: Sinauer Associates, 1994, pp. 633-645.
Sadler, T.W. Langman's Medical Embryology. Baltimore, Williams and Williams, 1995, pp. 122-143.
PERIODICALS
Incardona, J.P., and H. Roelink. "The Role of Cholesterol in Shh Signaling and Teratogen-induced Holoprosencephaly." Cellular and Molecular Life Sciences 57, no. 12 (November 2000): 1709-19.
Machado, A.F., et al. "Teratogenic Response to Arsenite During Neurulation: Relative Sensitivities of C57BL/6J and SWV/Fnn Mice and Impact of the Splotch Allele." Toxicological Sciences 51, no. 1 (September 1999): 98-107.
Sampson, P.D., et al. "On Categorization in Analyses of Alcohol Teratogenesis." Environmental Health Perspectives 108, Supplement 3 (June 2000): 421-428.
