(Table of Contents-Lesson 2)
(Next) (Glossary)
Teratogen refers to any agent that causes a structural
abnormality following fetal exposure during pregnancy. Seldom,
if ever, have teratogens been identified following designed epidemiologic
studies. Usually an increased prevalence of a particular birth
defect leads to the discovery of a teratogenic agent. For instance,
Minamata disease, an encephalopathy that mimics cerebral palsy,
was first recognized in towns surrounding Minamata Bay in postwar
Japan. This localized area of increased prevalence led
to an investigation that pointed to methyl mercury, which was
discharged into the bay by a local factory, as the offending agent.
Ingestion of contaminated fish during pregnancy was the primary
cause for this devastating condition. Similar results followed
the ingestion of grain laced with methyl mercury, which was used
as a fungicide, in Mexico and Iraq.
The sudden appearance of several cases of a rare disorder
can also raise suspicions of teratogenicity. Cases of phocomelia
in the early 1960's in Germany and Australia led to the identification
of thalidomide as a human teratogen. Thalidomide was used to treat
morning sickness, resulting in exposure at the stage in development
when the embryo is most vulnerable, the first trimester.
Teratogenic agents include: infectious agents (rubella,
cytomegalovirus, varicella, herpes simplex, toxoplasma, syphilis,
etc.); physical agents (ionizing agents, hyperthermia); maternal
health factors (diabetes, maternal PKU); environmental chemicals
(organic mercury compounds, polychlorinated biphenyl or PCB, herbicides
and industrial solvents); and drugs (prescription, over- the-counter,
recreational). It may appear as though there are more suspected
teratogens than were apparent a generation ago. This may be because
there has been an increase in the number of synthetic chemical
compounds in use or possibly the clinical recognition of subtle
malformations as teratogenic effects. Examples of the latter would
be fetal alcohol syndrome, fetal hydantoin syndrome, fetal trimethadione
syndrome, fetal warfarin syndrome and smoking associated with
low birth weight infants.
There are no absolute teratogens; however, many agents
can exhibit teratogenic effects under certain circumstances. The
dose and the time of exposure to a particular agent often determines
the severity of the damage and the type of defect that occurs.
The dose response is obvious: the greater the dose, the
greater the effect. The time of exposure is another important
concept, as certain stages of embryonic and fetal development
are more vulnerable than others. In general, the embryonic stage
(first trimester) is more vulnerable than the fetal period (second
and third trimesters). Thalidomide provides a classic example.
The critical period of exposure is during organogenesis (the formation
of the organs) from the 35th-48th day after the last menstrual
period. The specificity of the malformations is linked to the
time of exposure: 35-37 days, no ears; 39-41 days, no arms; 41-43
days, no uterus; 45-47 days, no tibia; and 47-49 days, triphalangeal
thumbs.
The types or severity of abnormalities caused by a teratogenic
agent is also dependent on the genotype of the pregnant woman
and the genotype of the fetus (genetic susceptibility).
For example, variation in maternal metabolism of a particular
drug will determine what metabolites the fetus is exposed to and
the duration of exposure. Differences in placental membranes,
placental transport and biotransformation all affect fetal exposure.
The genetic susceptibility of the fetus to a particular teratogenic
agent will also have an effect on the final outcome.
Absolute risk refers to the rate of occurrence of an abnormal
phenotype among individuals exposed to the agent. Chronic alcoholic
mothers, for instance, have a 45% chance of having an infant with
fetal alcohol syndrome. Relative risk refers to the ratio
of the rate of the condition among the exposed and the nonexposed.
A relative risk of 2 means that smokers have twice the risk of
having a low birth weight baby as nonsmokers. Keep in mind that
a high relative risk may indicate a low absolute risk if the condition
is rare. For a rare condition with an incidence of 1 in 100,000,
a high relative risk of 10 still leads to a very low absolute
risk of 1 in 10,000. Finally, attributable risk is the
rate of the condition that can be attributed to exposure to the
agent. Ninety percent of phocomelia patients have a history of
thalidomide exposure in utero.
It goes without saying that some pregnant women need to be on
medication. However, there are strategies to prevent or decrease
the risk of fetal abnormalities: the use of the lowest dose possible,
the avoidance of combination drug therapies (for the treatment
of seizure disorders), the use of a different agent (heparin instead
of coumadin for thrombophlebitis), the avoidance of first trimester
exposures (preconception diabetes or PKU control), and folic acid
supplementation. Reassurance of a low risk or negligible risk,
by itself, is often welcome.
The public awareness of hazardous agents in the home and the workplace,
and awareness of the teratogenic potential of drugs or medications
during pregnancy has led to the establishment of teratogen information
services in most states or regions of the country. This has been
facilitated by the availability of national databases (Reprotox,
TERIS), the teratology society organizations (OTIS-Organization
of Teratogen Information Services) and the birth defect/genetics
centers in most states.
SUMMARY
Teratogens, agents that cause fetal injury with exposure during
pregnancy, are found at home or the workplace. The effect is related
to type of agent, dose and duration and time of exposure. The
first half of pregnancy is the most vulnerable. Public awareness
is essential for prevention.