PRINCIPLES OF TERATOLOGY
TIMING OF EMBRYONIC AND FOETAL DEVELOPMENT
- The time from conception until implantation known as the "all or none" period, when insults to the embryo are likely to result in death of the conceptus and miscarriage (or resorption), or in intact survival. At this stage, the embryo is undifferentiated and repair and recovery are possible through multiplication of the still totipotential cells to replace those which have been lost. Exposure of embryos to teratogens during the preimplantation stage usually does not cause congenital malformations, unless the agent persists in the body beyond this period.
- The embryonic period, from 18 to 54-60 days after conception is the period when the basic steps in organogenesis occur. This is the period of maximum sensitivity to teratogenicity since not only are tissues differentiating rapidly but damage to them becomes irreparable. Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. Since teratogens are capable of affecting many organ systems, the pattern of anomalies produced depends upon which systems are differentiating at the time of teratogenic exposure.
- The foetal phase, from the end of the embryonic stage to term, is the period when growth and functional maturation of organs and systems already formed occurs. Teratogen exposure in this period will affect foetal growth (e.g., intrauterine growth retardation), the size of a specific organ, or the function of the organ, rather than cause gross structural anomalies. The term foetal toxicity is commonly used to describe such an effect. Of particular interest is the potential effect of psychoactive agents (e.g., antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system, which has led to a new field of behavioural teratology.
EVALUATION OF DRUGS FOR POTENTIAL TERATOGENICITY IN HUMANS
- A recognizable pattern of anomalies.
- A statistically higher prevalence of a particular anomaly in patients exposed to an agent than in appropriate controls.
- Presence of the agent during the stage of organogenesis of the affected organ system.
- Decreased incidence of the anomaly in the population prior to the introduction of the agent.
- Production of the anomaly in experimental animals by administering the agent in the critical period of organogenesis.
TABLE 1 - USE-IN-PREGNANCY RATING (US FDA, '79)
TABLE 2 - AMALGAMATION OF CRITERIA FOR PROOF OF HUMAN TERATOGENICITY*
PROVEN TERATOGENIC DRUGS IN HUMANS
The foetal alcohol syndrome is a clinical pattern of anomalies characterized by intrauterine growth retardation which commonly continues postnatally. These include: microcephaly, developmental delay, and dysmorphic facies consisting of low nasal bridge, midface hypoplasia, long featureless philtrum, small palpebral fissures and thin upper lip. Cleft palate and cardiac anomalies may also occur. Full expression of this syndrome occurs with chronic daily ingestion of at least 2 grams alcohol per kilogram (eight drinks per day). The full syndrome is present in about one third of these mothers and partial effects occur in approximately three quarters of offspring.
Misoprostol is a synthetic prostaglandin E1 analogue, prescribed for duodenal and gastric ulceration, also used as an abortifacient by women in Brazil. A Brazilian case-series suggested an association between first trimester exposure to misoprostol and limb defects with or without Moebius' sequence. The association was further supported by a case-control study comparing the frequency of misoprostol use during the first trimester by mothers of 96 infants with Moebius' syndrome and mothers of infants with neural tube defects. Among the mothers of infants with Moebius' syndrome, 49% had used misoprostol, as compared with 3% of the mothers of infants with neural tube defects (odds ratio, 29.7; 95% confidence interval 11.6 to 76.0). Despite the strong association between misoprostol exposure during the first trimester and Moebius' syndrome, its absolute teratogenic risk is probably not high.
POSSIBLE TERATOGENIC DRUGS IN HUMANS
First trimester exposure to diazepam has been associated in small studies with a small increase in the incidence of cleft lip and palate. Larger studies did not confirm the association.