TERATOGENICITY AND DRUGS THAT AFFECT THE FETUS (Part One)

TERATOGENICITY

A teratogen is any agent (virus, chemical, drug, environmental, physical, or radiation) that causes malformations in the embryo or fetus.

Biologically, a teratogen is any medication or substance that is capable of interfering in embryonic or fetal development, causing birth defects.

The term comes from Greek, teratos – monster.

Approximately 65% of birth defects have an unknown etiology, 4-5% are caused by teratogenic agents and less than 1% are caused by medications.

CRITERIA FOR ASSESSING TERATOGENIC POTENTIAL

1. The defect must be fully assessed (this is done by a geneticist).
2. The agent must cross the placental barrier (a sufficient amount of the agent must cross to act directly or indirectly on fetal development).
3. Exposure must occur during a critical period of development (exposure in the first 8 weeks causes embryopathy, affecting organogenesis and as a result we have serious structural malformations; after 8 weeks causes fetopathy and consequently affects the functional development and maturation of organs).
4. There must be a biological link between the causative agent and the malformation.
5. The suspected teratogen must cause defects in animals.

CLASSIFICATION OF TERATOGENS

• Category A: Studies in pregnant women have not shown an increased risk for fetal anomalies if administered in the first, second, or third trimester of pregnancy. Less than 1% of medications fall into this category if taken according to recommended doses, e.g., prenatal multivitamins, calcium supplements, levothyroxine.
• Category B: Animal studies show no impact on fertility and on the fetus. In humans, there are no complete data in the first trimester of pregnancy and no risk data in the last trimester of pregnancy. E.g., antibiotics such as penicillin, macrolides, or cephalosporin.
• Category C: Animal studies have shown their teratogenic effect and there are no complete data and studies in pregnant women. Included are medications used to treat serious medical conditions, e.g., albuterol in bronchial asthma, B-blockers and Ca-blockers in hypertension, lamivudine and zidovudine in viral infections.
• Category D: Includes medications that cause serious fetal damage when administered to a pregnant woman. E.g., valproic acid, lithium, carbamazepine, azathioprine, phenytoin.
• Category X: Medications that are contraindicated in a pregnant woman, who may be pregnant or who plans a pregnancy soon as they may cause fetal damage. E.g., rubella vaccine, retinoids, statins.

COUNSELING FOR TERATOGENIC EXPOSURE

Part of routine prenatal care and preconception counseling should be the assessment of exposure to medications and teratogenic agents.

Counseling includes: exposure to agents, their dosage, timing of exposure, duration of exposure, possible teratogenic risks, fetal genetic damage.

Counseling includes assessing the risk versus the benefit of their use. Some maternal diseases are more dangerous for the mother and fetus if not treated compared to the risks posed by the use of these medications.

TERATOGENIC MECHANISM OF ACTION

The mechanism of teratogenic action is related to the disruption of the physiological process that leads to anomalies in cell differentiation, alteration of tissue growth, and cell death.

• Disruption of folic acid metabolism: folic acid is essential in the production of methionine which is required for the production of proteins, lipids, and myelin. Its deficiency leads to neural tube defects, cardiac defects, cleft palate, and even Down syndrome.
• Fetal genetic alterations: mutations in certain genes when interacting with environmental factors lead to various fetal deformations.
• Paternal exposure: exposure to teratogenic agents within 2 months, 64 days, before conception leads to chromosomal anomalies or genetic mutations in sperm. During intercourse, toxic substances from seminal fluid directly contact the fetus. Exposure of male reproductive cells to these agents can lead to alterations in gene expression.

EXAMPLES OF TERATOGENIC AGENTS

1 - ALCOHOL

Ethyl alcohol is one of the most powerful known teratogenic agents.

It is one of the most common non-genetic causes of mental retardation.

It is one of the preventable causes of birth defects.

Unfortunately, fetal alcohol syndrome is not diagnosed prenatally, in some cases we may have major anomalies or fetal growth retardation that suggest it.

Fetal alcohol syndrome (FAS) presents a wide spectrum of fetal defects related to alcohol consumption.

The dose that causes the syndrome is unknown as any amount, even minimal, of alcohol can lead to such a syndrome.

Using alcohol during pregnancy leads to its dependency syndrome in the baby at birth. These signs appear within a few hours and last up to 18 months after birth.

• central nervous system (small head, cerebral anomalies, complete or partial lack of brain development, small jaw...).
• eyes (strabismus, ptosis, retinal vascularization anomalies, hypoplasia of the optic nerve)
• ears (malformed ears, hearing disorders).
• heart (atrial and ventricular septum defects, defects in the large vessels)
• chest defects (diaphragmatic and umbilical hernia)
• kidneys (hypoplastic or aplastic kidney, horseshoe kidney, ureteral duplication)
• skeletal (scoliosis, ligament contractures, vertebral defects, radioulnar synostosis)
• incomplete genital development
• mental, motor, and developmental retardation
• poor coordination
• hyperactivity in childhood

Diagnosis: the mother's history; the appearance of the child.

Treatment: specific medications for alcohol dependency syndrome; there is no treatment for birth defects and mental retardation.

Prevention: discontinue the use of alcohol from the moment a pregnancy is planned.