TERATOLOGY

TERATOLOGY

Teratology is the study of abnormal fetal development. Major birth defects occur in approximately 3% of all deliveries. A teratogenic agent, which can be identified in less than 50% of the cases, is any chemical (drug), infection, physical condition, or deficiency that, on fetal exposure, can alter fetal morphology or subsequent function. Teratogenicity appears to be related to genetic predisposition (both maternal and embryonic), the developmental stage of the fetus at the time of exposure, and the route and length of administration of the teratogen. Because any woman in her reproductive years may be pregnant, all women should be warned of any teratogenic potential associated with a drug. In cases of known ter-atogens, women and their physicians have a responsibility to effectively prevent pregnancy.

A. Genetic Susceptibility

Species differences in response to teratogens have been demonstrated. Human newborns exposed to the tranquilizer thalidomide in utero demonstrated major malformation of the arms (phocomelia), whereas laboratory animals (rats) showed no effect at similar doses. Animal studies, although helpful, do not always reliably predict the response in humans.

B. Developmental Stage At Time Of Exposure 

Susceptibility of the conceptus to teratogenic agents depends on the developmental stage at the time of exposure.

• Resistant period. From day 0 to day 11 of gestation (postovulation), the fetus exhibits the “all or noneâ€‌ phenomenon with regard to major anomalies; that is, it will either be killed by the insult or survive unaffected. This is the period of predifferentiation when the aggregate of totipotential cells can recover from an injury and continue to multiply.
• Maximum susceptibility (embryonic period). From days 11 to 57 of gestation, the fetus is undergoing organ differentiation and, at this time, is most susceptible to the adverse effects of teratogens. The particular malformation depends on the time of exposure. After a certain time in organogenesis, it is thought that abnormal embryogenesis can no longer occur. For example, because the neural tube closes between days 22 and 28 postconception (5 weeks after the last menstrual period), a teratogen must be active before or during this period to initiate development of a neural tube defect (e.g., spina bifida or anencephaly).
• Lowered susceptibility (fetal period). After 57 days (8 weeks) of gestation, the organs have formed and are increasing in size. A teratogen at this stage may cause a reduction in cell size and number, which is manifested by:
1. Growth retardation
2. Reduction of organ size
3. Functional derangements of organ systems

C. Administration Of Teratogen

The route and length of administration of a teratogen alter the type and severity of the malformation produced. Abnormal developments increase in frequency and degree as the dosage increases. Agents may be less teratogenic if systemic blood levels are reduced by the route of administration (e.g., poor gastrointestinal antibiotic absorption may account for lower blood levels in pregnancy).

D. Definition

Teratogenicity of an agent or factor is defined by the following criteria:

• Presence of the agent during the critical period of development when the anomaly is likely to appear. Malformations are caused by intrinsic problems within the developing tissues at a specific time in organogenesis.
• Production of the anomaly in experimental animals when the agent is administered during a stage of organogenesis similar to that of humans. Teratogenicity may not become apparent for several years; for example, in utero exposure to diethylstilbestrol is known to cause genital tract abnormalities, such as adenosis and carcinoma, but these abnormalities may not become apparent until the reproductive years.
• Ability of the agent to act on the embryo or fetus either directly or indirectly through the placenta. For example, heparin is not teratogenic because, unlike warfarin, it cannot cross the placenta because of its large molecular weight.

E. Structural Defects

These defects have been categorized into three groups 

• Malformations are morphologic defects of an organ or other part of the body resulting from an abnormality in the process of development in the first trimester. This leads to incomplete or aberrant morphogenesis (e.g., ventricular septal defect).
• Deformations are abnormal forms, shapes, or positions of a body part caused by constraint within the uterus, usually occurring in the second or third trimester. An example is clubfeet from oligohydramnios.
• Disruptions are defects from interference with a normally developing organ system, usually occurring later in gestation (i.e., in the second or third trimester, after organogenesis). An example is amniotic band syndrome.

TERATOGENIC AGENTS

A. Ionizing Radiation

1.            Acute high dose (more than 250 rad). The dose of radiation and the gestational age during exposure are predictive of the adverse neonatal effects: microcephaly, mental retardation, and growth retardation. For example, the in utero victims of the atomic explosions in Hiroshima and Nagasaki have suffered from both birth defects and leukemia. However, follow-up studies have shown that most children with these adverse effects were those exposed before 15 weeks' gestation, during the period of organogenesis, whereas most of the children exposed during the third trimester had growth retardation but normal intelligence.

a.   Time of exposure. Fetal effects depend on the 

    gestational age (postovulation) at the time of 

    exposure.

-          At 2 to 4 weeks, either the fetus is normal or 

     a spontaneous abortion occurs.

-        At 4 to 12 weeks, microcephaly, mental 

     retardation, cataracts, growth retardation, or

     microphthalmia may occur.

-        At 12 to 16 weeks, mental retardation or 

     growth retardation occurs.

-        After 20 weeks, the effects are the same as 

     with postnatal exposure and include hair loss, skin

    lesions, and bone marrow suppression.

b.       Dose effect

-      After exposure to less than 5 rad, and probably

    less than 10 rad, an adverse fetal outcome is

    unlikely to result.

-     After exposure to 10 to 25 rad, some adverse

    fetal effects may result.

-    After exposure to more than 25 rad, classic fetal

   effects, including growth retardation, structural 

   malformations, and fetal resorption, may be 

   detected. At this level of exposure, elective 

   abortion should be offered as an option.

2.      Chronic low dose

• In diagnostic radiation, the dose to the conceptus should be calculated by the hospital's radiation biologist. Such a dose rarely adds up to significant exposure, even if several radiographic studies are performed.
• Associated risk of teratogenicity

         -    The mutagenic effects of radiation, if present, have
            proved to be very small. The estimated risk of leukemia
            for children exposed in utero to radiation during maternal 
            radiographic pelvimetry increases from 1 in 3000 among 
            unexposed children to 1 in 2000.
        -  The results of several studies provide no conclusive 
           evidence linking preconception low-dose radiation 
          exposure with an increased risk of delivering an infant
          with a chromosomal abnormality.

3.      Radioactive iodine. Radiation exposure from radioisotopes administered internally for organ visualization is roughly equal to that of radiographic procedures; however, after the 10th week of gestation, fetal thyroid development can be retarded in addition to any adverse effects of radiation.

B. Drugs And Medications

In the United States, surveys show that 45% to 95% of pregnant women ingest either over-the-counter or prescription drugs other than iron and vitamins during their pregnancy. Many are taken before a woman realizes that she is pregnant or are taken without the advice of a physician. The prohibition of all medications during pregnancy is impossible and is likely to be more harmful to the patient. However, the issue of whether a medication is harmful to the fetus is raised in most pregnancies. Physicians caring for women of childbearing age should be aware of potential teratogenicity of medications and should be able to address questions arising from the accidental or intentional ingestion of drugs during pregnancy.

• Approximately 3% to 5% of newborns have congenital malformations caused by a host of environmental and genetic factors, most of which are unable to be identified. Drugs and medications account for less than 1% of these malformations.
• Access to the fetoplacental unit is critical in the causation of developmental anomalies. Factors affecting access of the drug or medication to the fetus include:

1. Maternal absorption
2. Drug metabolism
3. Protein binding and storage
4. Molecular size (molecules with a molecular weight of more than 1000 daltons do not cross the placenta easily)
5. Electrical charge
6. Lipid solubility

• Animal research can help identify teratogenic potential, but results may be misleading because of species variation.

1.  The most striking example is thalidomide, in which exposure in the animals tested (mice and rats) failed to produce limb defects but caused severe limb reduction defects in humans, monkeys, and rabbits. Although the thalidomide-associated embryopathy led to the belief that human teratogenicity could not be predicted by animal studies, it is erroneous.
2. Every drug found to be teratogenic in humans has subsequently been shown to cause similar defects in animals, although species variation exists. It is worth noting that drugs that cause teratogenesis in animals often do so at much higher doses than used clinically in humans, where similar outcomes are not seen. Of the 1600 drugs that have been tested in animals, about one-half cause congenital anomalies; however, there are only 30 documented human teratogens.

• Human research. Case reports once suggested that drugs such as warfarin, diethylstilbestrol, and isotretinoin were teratogenic. Other studies have led to the “mislabelingâ€‌ of safe drugs (e.g., Bendectin). Pharmaceutical companies also play a role in the identification of teratogens by participating in postmarketing surveillance studies. To learn more about the teratogenic effects of certain drugs, women can call centers that monitor exposure to prescription and over-the-counter medications.

1.  Formal epidemiologic studies are designed to assess whether mothers who took a drug during pregnancy have larger numbers of malformed children than those who did not (cohort studies) or whether mothers of children with a specific malformation took the drug more often than mothers of children without the malformation (case-control studies). Long-term studies are also important; it is becoming increasingly clear that adverse effects of drugs on neurodevelopmental behavior may be more serious than structural defects.
2. Difficulties occur with the study of teratogens. Because most malformations occur rarely, large sample sizes of exposed individuals are necessary. Maternal illnesses that require the use of medications may be a confounding factor in the study of the teratogenicity of any drug used to treat that disorder. Recall bias also confounds the study of drugs and their potential teratogenic affects, because women whose children have abnormalities are much more likely to recall an exposure (especially in case-control studies).

• Risk factors for adverse fetal effects have been assigned to all drugs based on the teratogenic risk that the drug poses to the fetus. The Food and Drug Administration has proposed the following classification scheme, which is generally accepted by manufacturers and authors (see chapter 4).
• Known teratogenic drugs. The list of proven teratogens is surprisingly short. Certain commonly used agents should be avoided even while a patient is trying to conceive. These include the vitamin A isomer isotretinoin or doses of vitamin A higher than 8000 IU daily; alcohol; excess caffeine; and some of the sex steroids. The live virus vaccines, such as rubella, should never be prescribed if a patient is possibly pregnant or planning to conceive within 1 month. However, if the aforementioned drugs are inadvertently given, the outcome is still usually favorable.
• A dose threshold is a theoretic dose for each teratogen below which no adverse effects have been noted.
• “Recreationalâ€‌ drugs (see Chapter 8). Because most recreational drugs are taken with other agents, such as alcohol or tranquilizers, the precise effect is difficult to ascertain. Listed below are commonly used drugs and their potential effects.

1. Alcohol. Consumption of alcohol in pregnancy is the most common known teratogenic cause of mental retardation. Both abortion and stillbirth are increased in heavy drinkers. Fetal alcohol syndrome, which manifests as mental retardation, growth retardation, abnormal facies, ocular and joint anomalies, and cardiac defects, has been associated with the ingestion of 1 oz or more of absolute alcohol per day.
2. Marijuana. There is no evidence that smoking marijuana is teratogenic, although the adverse effects of smoking in pregnancy should not be overlooked (see Chapter 8).
3.  Heroin has not been shown to cause birth defects, but the drugs that are often taken with heroin are associated with congenital anomalies. The principal adverse fetal effect in heroin addicts is severe neonatal withdrawal, causing death in 3% to 5% of neonates. Methadone is used to replace heroin, and, although it is not teratogenic, it is associated with severe neonatal withdrawal.
4.  Phencyclidine (PCP), or “angel dust,â€‌ is a hallucinogenic agent associated with facial abnormalities in a small percentage of exposed infants.
5. Cocaine is rapidly becoming the most abused drug in pregnancy, second only to alcohol. One study showed an increased risk of congenital malformations, stillbirths, and low-birth-weight infants in cocaine users. A clear causal relationship exists between cocaine use and abruptio placentae because of the drug's vasoconstrictive properties

• Cancer chemotherapy. Although there is a high incidence of fetal loss, including spontaneous abortion and stillbirth, the incidence of congenital malformations is surprisingly low.

1. When cancer chemotherapy is administered during the first trimester of pregnancy, there are varied and unpredictable effects, ranging from severe deformity to no abnormality. The fetal heart, neural tube, and limbs are affected during early organogenesis, with the palate and ears being susceptible later in organogenesis.  
2. After the period of organogenesis (weeks 2 to 8 postconception), there is less teratogenic risk from chemotherapy in pregnancy, though intrauterine growth restriction, stillbirth, preterm delivery, and low-birth-weight infants are possible with second- and/or third-trimester exposure. Even after organogenesis, the fetal eyes, genitalia, hematopoietic system, and CNS remain vulnerable to continued exposure (Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy

source : NMS Obstetrics and Gynecology, 6th Edition