MATERNAL DRUG USAGE AND

FETAL TERATOGENESIS

Teratology is the study of abnormal prenatal development. A teratogenic exposure is one that can cause an embryo or fetus to develop abnormally and affect prenatal development by either:

· altering gene expression

· programmed cell death (apoptosis)

· affecting cell migration or proliferation, histogenesis, synthesis or function of proteins or nucleic acids.

Some teratogenic exposures act directly on the embryo, whereas others act through intermediates produced by maternal metabolism.

The stage of pregnancy during which an exposure occurs is extremely important:

· The first 2 weeks after conception is sometimes referred to as the "all-or-none" period, because toxic exposures during this time usually kill the embryo or produce no permanent effect if the embryo survives (1). Toxic exposures are unlikely to cause malformations, because the cells of the conceptus are pluripotent at this stage i.e. cells that are killed by an exposure can be replaced by other cells. However, if too many cells are damaged or die, the embryo will not survive. However, some mutagenic treatments during the preimplantation period produce malformations in rodent experiments, so the "all-or-none" rule does not always hold (2).

· Organogenesis (18–60 days post conception in humans) is the time during which the embryo is most sensitive to many teratogenic exposures and when most structural anomalies are produced. The fetal period is marked by rapid growth and maturation as well as active cell growth, proliferation and migration, particularly in the central nervous system. Teratogenic exposures during this period may cause fetal growth retardation, death or central nervous system dysfunction that may not be apparent until later childhood.

• Anticonvulsants (valproic acid, phenytoin, trimethadione) (1,2).
• Folic acid antagonists (methotrexate) (3).
• Anticoagulants (warfarin) (4).
• Fluorinated glucocorticoids (tiamcinolone) (5).
• Antineoplastic chemotherapeutic agents (6).
• Alcohol abuse - virtually all fetuses with fetal alcohol syndrome will be symmetrically growth retarded (may be severe) (7).
• Retinoic acid embryopathy.
• Lithium – In the 1970’s an international registry of 225 children who were exposed to lithium in utero reported an incidence of CHD that included six children (2.7%) with Ebstein’s anomaly (a four-hundred fold higher value than the unexposed population) (8,9). This was a biased study and more recent epidemiological studies suggest that the risk of CHD is actually much lower tan originally reported. In a prospective cohort study of 148 women, no significance in the rate of CHD was proved for mothers taking lithium versus the control population (0.9% versus 0.8%). Ebstein’s anomaly was the cardiac malformation in the lithium treated pregnant women (10,11). Case control studies in fetuses with Ebstein’s anomaly and animal studies have however failed to demonstrate teratogenicity of lithium in therapeutic doses (12).
• Non-steroidal anti-inflammatory drugs – they are reversible, competitive inhibitors of prostaglandin synthesis, and can alleviate prostaglandin-induced uterine contractions. An important side effect is premature constriction of the ductus arteriosus, which can lead to congestive cardiac failure and hydrops in the fetus, or pulmonary hypertension in the neonate. Prenatal exposure to indomethicin has been associated with the development of persistent pulmonary hypertension in the neonate(13). Ductus closure in the fetus may lead to increased right ventricular afterload, tricuspid regurgitation, right-to-left shunting, and rarely congestive heart failure. On the discovery of ductal constriction in utero, the drug should be withdrawn, and immediate delivery if patency is not restored. Although non steroidals can cross the placenta, several studies have failed to demonstrate teratogenicity (14).
• Beta –mimetics. They are the second most common tocolytic agents used in the USA (15). Examples include ritrodine and terbutaline. They easily cross the placenta and have been associated with significant fetal cardiovascular complications, fetal hyperglycemia, hyperinsulinemia and intraventricular hemorrhage (16,17).

Fetal arrhythmias have been reported in association with beta- mimetrics (18).

Agents known to cause small for gestational age perinates:

• Heroin (may be as high as 70% and as high as 30% in mothers using methadone) (19,20).
• Cocaine (30% of cases) (21).

Agents suspected (but not proven) to increase the risk of IUGR:

• Heavy metals.
• Organic solvents.
• Insecticides.
• Anesthetic gas.
• Caffeine (in huge doses).
• Organic solvents.
• Gasoline sniffing.
• Heavy cannabis abuse.

Mercury and fish consumption

Some predatory fish accumulate particularly high levels of mercury that can be toxic, particularly to developing fetuses (22). Recent case reports of toxic exposure (23) and research suggesting that groups at risk may be unaware of past advisories (24) reinforce the need to highlight limiting the intake of contaminated species (25).

The toxin:

· Elemental mercury from rocks and soil exists naturally in background levels in lakes and streams but is concentrated in the environment by emissions from hydroelectric projects, the burning of garbage and fossil fuels, and industrial pulp and paper and mining processes (24).

· Microorganisms in lake and stream sediments convert elemental mercury to organic methylmercury, which binds tightly to the proteins in fish tissue and is concentrated in fish higher up the food chain.

· When ingested by humans, methylmercury is easily absorbed and retained by the body; it has a half-life in blood of about 44 days, which makes blood tests useful measures of acute exposure (26).

· It concentrates in new hair, and consecutive hair segments indicate a person's exposure history (26).

· Methylmercury is eliminated fecally as inorganic mercury (27).

· Methylmercury is a potent neurotoxin, causing axonal demyeliniation (28). Adults can experience symptoms months after an acute exposure consisting of ataxia, blurred vision, hearing deficits and paraesthesias (7). Fetuses are particularly sensitive to methylmercury, as shown by the more than 1400 infants from the Minimata area of Japan who were acutely exposed in utero when their mothers ate fish contaminated by a factory discharge. The children, often normal at birth, developed abnormal reflexes, problems with suckling and swallowing, gait, speech, and mental retardation (24). The effects of chronic, low-level exposure, typical of many Aboriginal populations in Canada (29) is less clear. There is no effective treatment for methylmercury exposure.

Health Canada judges 0.5 parts per million (ppm) to be the limit for total mercury content in commercial fish (22,25) The consumption of mussels, pollock, salmon, scallops, shrimp and sole — the majority of aquatic species consumed in Canada — are not of concern. Fish with a total mercury content between 0.5 and 1.5 ppm include fresh and frozen tuna (but not canned tuna, which consists of smaller, shorter-lived species with lower mercury levels), swordfish and shark (22,31).

Mercury levels in freshwater fish varies, but in general bass, pike, muskellunge and walleye have high levels and should be eaten in moderation (30).

REFERENCES

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