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.
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.
