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Teratogenic Agents


Teratogenic Agents
A teratogenic agent is a chemical, physical, or biologic agent that produces abnormalities during embryonic or fetal development. Maternal disease or altered metabolic state also can affect the development of the embryo or fetus. Theoretically, teratogenic agents can cause birth defects in three ways:


       By direct exposure of the pregnant woman and the embryo or fetus to the agent
     Through exposure of the soon-to-be-pregnant woman to an agent that has a slow clearance rate, such that a teratogenic dose is retained during early pregnancy
   As a result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a woman’s (or a man’s) reproductive cells

For discussion purposes, teratogenic agents have been divided into three groups: radiation, drugs and chemical substances, and infectious agents. Chart 7.1 lists commonly identified agents in each of these groups.


Radiation
Heavy doses of ionizing radiation are teratogenic and mutagenic and have the capacity to effect inheritable changes in genetic materials. Specifically, excessive levels of radiation have been shown to cause microcephaly, skeletal malformations, and mental retardation. There is no evidence that diagnostic levels of radiation (e.g., from a chest x-ray) cause congenital abnormalities. Additionally all efforts to shield the fetus are taken when possible. In situations where a study is necessary for the woman’s health, the benefits to her of having proper diagnostic imaging outweigh potential theoretical risks to the fetus. Administration of therapeutic doses of radioactive iodine (131I) during the 13th week of gestation, the time when the fetal thyroid is beginning to concentrate iodine, has been shown to interfere with thyroid development.

Chemicals and Drugs
Environmental chemicals and drugs can cross the placenta and cause damage to the developing embryo and fetus. It has been estimated that only 2% to 3% of developmental defects have a known drug or environmental origin. Some of the bestdocumented environmental teratogens are the organic mercurials, which cause neurologic deficits and blindness. Certain fish and water sources may be contaminated by mercury. The precise mechanisms by which chemicals and drugs exert their teratogenic effects are largely unknown. They may produce cytotoxic (cell-killing), antimetabolic, or growth-inhibiting effects to the embryonic and fetal development.
Drugs top the list of chemical teratogens, probably because they are regularly used at elevated doses. Many drugs can cross the placenta and expose the fetus to both the pharmacologic and teratogenic effects. Factors that affect placental drug transfer and drug effects on the fetus include the rate at which the drug crosses the placenta, the duration of expo- sure, and the stage of placental and fetal development at the time of exposure. Lipid-soluble drugs tend to cross the placenta more readily and enter the fetal circulation. The molecular weight of a drug also influences the rate and amount of drug transferred across the placenta. Drugs with a molecular weight of less than 500 can cross the placenta easily, depending on lipid solubility and degree of ionization; those with a molecular weight of 500 to 1000 cross the placenta with more difficulty; and those with molecular weights of more than 1000 cross very poorly.
Several medications have been considered teratogenic. However, perhaps the best known of these drugs is thalidomide, which has been shown to give rise to a full range of malformations, including phocomelia (i.e., short, flipper-like appendages) of all four extremities. Other drugs known to cause fetal abnormalities are the antimetabolites used in the treatment of cancer, the anticoagulant drug warfarin, several of the anticonvulsant drugs, ethyl alcohol, and cocaine. Some drugs affect a single developing structure; for example, propylthiouracil can impair thyroid development and tetracycline can interfere with the mineralization phase of tooth development. More recently, vitamin A and its derivatives (the retinoids) have been targeted for concern because of their teratogenic potential. Concern over the teratogenic effects of vitamin A derivatives arose with the introduction of the acne drug isotretinoin (Accutane).
In 1983, the U.S. Food and Drug Administration established a system for classifying drugs according to probable risks to the fetus. According to this system, drugs are put into five categories: A, B, C, D, and X. Drugs in category A are the least dangerous, and categories B, C, and D are increasingly more dangerous. Those in category X are contraindicated during pregnancy because of proven teratogenicity. The law does not require classification of drugs that were in use before 1983.
Because many drugs are suspected of causing fetal abnormalities, and even those that were once thought to be safe are now being viewed critically, it is recommended that women in their childbearing years avoid unnecessary use of drugs. This pertains to nonpregnant women as well as preg- nant women because many developmental defects occur early in pregnancy. As happened with thalidomide, the damage to the embryo may occur before pregnancy is suspected or confirmed. A drug that is often abused and can have deleterious effects on the fetus is alcohol.

Fetal Alcohol Syndrome. The term fetal alcohol syndrome (FAS) refers to a group of physical, behavioral, and cognitive fetal abnormalities that occur secondary to drinking alcohol while pregnant.  It has been estimated that approximately 0.5 to 2.0 cases per 100 live births have FAS.33 Alcohol, which is lipid soluble and has a molecular weight between 600 and 1000, passes freely across the placental barrier. Concentrations of alcohol in the fetus are at least as high as in the mother. Unlike other teratogens, the harmful effects of alcohol are not restricted to the sensitive period of early gestation but extend throughout pregnancy.
Fetal Alcohol Syndrome

Alcohol has widely variable effects on fetal development, ranging from minor abnormalities to FAS. There may be prenatal or postnatal growth retardation; CNS involvement, including neurologic abnormalities, developmental delays, behavioral dysfunction, intellectual impairment, and skull and brain malformation; and a characteristic set of facial features that include small palpebral fissures (i.e., eye openings), a thin vermilion border (upper lip), and an elongated, flattened midface and philtrum (i.e., the groove in the middle of the upper lip)  (Fig. 7.13). The facial features of FAS may not be as apparent in the newborn but become more prominent as the infant develops. As the children grow into adulthood, the facial features  become  more  subtle,  making  diagnosis of FAS in older people more difficult. Each of these defects can vary in severity, probably reflecting the timing of alcohol consumption in terms of the period of fetal development, amount of alcohol consumed, and hereditary and environmental influences.
The criteria for FAS diagnosis require the documented presence of three of the following findings:

   Three facial abnormalities (smooth philtrum, thin vermilion border on the upper lip, and small palpebral fissures)
     Growth deficits (prenatal or postnatal height or weight, or both, below the 10th percentile)
   CNS abnormalities (e.g., head circumference below the 10th percentile, global cognitive or intellectual deficits, motor functioning delays, problems with attention or hyperactivity)

The amount of alcohol that can be safely consumed during pregnancy is unknown. Even small amounts of alcohol consumed during critical periods of fetal development may be teratogenic. For example, if alcohol is consumed during the period of organogenesis, a variety of skeletal and organ defects may result. If alcohol is consumed later in gestation, when the brain is undergoing rapid development, there may be behavioral and cognitive disorders in the absence of physical abnormalities. Chronic alcohol consumption throughout pregnancy may result in a variety of effects, ranging from physical abnormalities to growth retardation and compromised CNS functioning. Evidence suggests that short-lived high concentrations of alcohol, such as those that occur with binge drinking, may be particularly significant, with abnormalities being unique to the period of exposure.33 Because of the possible effect on the fetus, it is recommended that women abstain completely from alcohol during pregnancy.
Infectious Agents
Many microorganisms cross the placenta and enter the fetal circulation, often producing multiple malformations. The acronym TORCH stands for toxoplasmosis, other, rubella (i.e., German measles), cytomegalovirus, and herpes, which are the agents most frequently implicated in fetal anomalies. Other infections include varicella–zoster virus infection, listeriosis, leptospirosis, Epstein-Barr virus infection, tuberculosis, and syphilis. Human immunodeficiency virus (HIV) and human parvovirus (B19) have been suggested as additions to the list. The TORCH screening test examines the infant’s serum for the presence of antibodies to these agents. However, the titers for serum antibodies against the TORCH agents in the mother and newborn usually are not diagnostic, and the precise cause of the disorder often remains uncertain.
Infections with the TORCH agents are reported to occur in 1% to 5% of newborn infants and are among the major causes of neonatal morbidity and mortality. Common clinical and pathologic manifestations include growth retardation and abnormalities of the brain (microcephaly, hydrocephalus), eye, ear, liver, hematopoietic system (anemia, thrombocytopenia), lungs (pneumonitis), and heart (myocarditis, congenital heart disorders). These manifestations vary among symptomatic newborns, how-ever, and only a few present with multisystem abnormalities.
Toxoplasmosis is a protozoal infection caused by Toxoplasma gondii, which can be deleterious to pregnant woman and the unborn fetus. The domestic cat can carry the organism, excreting the protozoa in its feces. It has been suggested that pregnant women should avoid contact with excrement from the family cat. The introduction of the rubella vaccine has virtually eliminated the congenital rubella syndrome in most developed countries. Rubella remains endemic in many developing countries, however, where it is the major preventable cause of hearing impairment, blindness, and adverse neurodevelopmental outcome. The epidemiology of cytomegalovirus infection is largely unknown. Some infants are severely affected at birth, and others, although having evidence of the infection, have no symptoms. In some symptom-free infants, brain damage becomes evident over a span of several years. There also is evidence that some infants contract the infection during the first year of life, and in some of them the infection leads to retardation a year or two later. Herpes simplex virus type 2 infection is considered to be a genital infection and usually is transmitted through sexual contact. The infant acquires this infection in utero or in passage through the birth canal.