Teratogenesis, risk

Although low risks of teratogenesis, including risk of neural tube defects have been reported for several antiepileptics it should be realized that uncontrolled epilepsy poses far more risks for the fetus. 

The consequences of discontinuing medication with subsequent psychotic relapse can be grave. Continuing maintenance medications that have been effective is appropriate. If a medication change is necessary, treatment with haloperidol is recommended because this agent has been used extensively, it has not been associated with teratogenesis, and it possesses only a small risk for EPS in the newborn. 

The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis. Because of this effect, thalidomide prescription and use is closely regulated by the manufacturer. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. Thrombosis is sufficiently frequent, particularly in the hematologic malignancy population, that most patients are placed on some type of anticoagulant when thalidomide treatment is initiated. 

In 1977, the NAS Safe Drinking Water Committee outlined four principles that it said should be useful in dealing with the assessment of hazards that involve chronic irreversible toxicity or the effects of longterm exposure (20). These principles (paraphrased as follows) were intended to apply primarily to cancer risks from substances whose mechanisms involve somatic mutations and may also be applicable to mutagenesis and teratogenesis ... 

In a review of 60 publications on metformin and pregnancy malabsorption of vitamin B12, which occurs in nonpregnant women, was thought to be a potential problem (116). The data did not suggest an increased risk of teratogenesis. 

E. Elefant and C. Roux, Risk evaluation and information about drug-induced teratogenesis, Therapie, 40 (1985) 297-300. 

When one compares the risk of caffeine as taken in one cup of coffee to that from the forest herbicide, 2,4-D, one finds that the margin of safety for teratogenesis or birth defects ranges from 5 to 16 (Table XIII). 

Safe S. 1998a. Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds. Teratogenesis Carcinog Mutagen 17 285-304. 

The two most serious toxic effects of valproic acid are hepatocellular injury (96) and teratogenesis (97). Since CYP2A6 and CYP2C9 are known to oxidize valproic acid to a 4-ene metabolite that is hepatotoxic, inducers of these isoforms, including other antiepileptic agents, are likely to increase the risk of hepatotoxicity (98). However, valproic acid also is metabolized by several other pathways that may be involved in causing its toxicities (99). 

While there is an increased risk of teratogenesis (particularly cardiovascular) from exposure to lithium in the first trimester, this risk has been overstated initially because of selection bias (482,483,485,486). Subsequently, case-control and cohort studies have substantially reduced, but not eliminated, such concerns (487). The risk of major malformations from exposure to lithium in the first trimester appears to be lower than from exposure to carbamazepine or valproate. 

The teratogenic effects of lithium have been reviewed in several articles (466,467,488) two reviews of drug-related congenital malformation briefly mentioned lithium and cardiovascular teratogenesis (480,489). The authors concluded that while the risk of cardiovascular malformation is lower than once believed, it is nevertheless increased. 

A general approach to reduce the risk of human teratogenesis includes planning for pregnancy. Prior... 

Perhaps of most concern is the possibility of teratogenesis, with the risk being greatest during the period of organ formation (organogenesis) generally considered to be... 

When used in combination with corticosteroids, cyclophosphamide is dosed at 1-3 mg/kg for oral therapy and 0.5-1.0 g/m of body surface area for intravenous therapy. The most common route of cyclophosphamide administration is intravenous, although there is little evidence that this is better than oral administration. Likewise, there is no evidence to suggest the optimal duration of treatment. Based on empirical experience, cyclophosphamide generally is dosed monthly for 6 months and then every 3 months for a period of either 2 years or for 1 year after the nephritis is in remission." " Of course, cyclophosphamide therapy is not without risk. Serious toxic effects include suppression of hematopoiesis, opportunistic infections, bladder complications (e.g., hemorrhagic cystitis and cancer), sterility, and teratogenesis. White blood cell counts must be monitored during cyclophosphamide therapy, and if the nadir is less than 1500/mm, the dose must be adjusted to keep the white cell count above 1500/mm. Nausea and vomiting associated with cyclophosphamide can be controlled with oral ondansetron plus dexamethasone. ... 

Acitretin is currently the only retinoid licensed in the United Kingdom for the treatment of psoriasis and is only available for treatment of patients in hospitals. It is given orally and has anti-inflammatory and cytostatic actions. This is useful in inflammatory psoriasis. The half-life of acitretin is about two days. However, there is a high risk of teratogenesis and women must use adequate contraception and stop treatment for two years before conception. 

A final remarkable feature of teratogenesis is the dramatic species- and strain-dependent variability in susceptibility for some xenobiotics. For example, some strains of mice are sensitive to phenytoin teratogenicity, while other strains are resistant. In the case of thalidomide, primates (including humans) and rabbits are sensitive, while all rodent (mice and rats) strains tested are resistant. These differences must be considered in the design and interpretation of data from animal studies when directed towards an evaluation of human risk. 

Mechanisms of Teratogenesis. Most toxicologists have viewed the experimental animal as a "black box" wherein one inserts test chemicals usually at high dose and observes effects out. There has recently been a call for low-dose exposure, examination of the effects and the mechanisms by which they arise and assessment of human risk of the effects seen in the test systems (30). Similarly, in teratology, the pregnant mammal has been considered a "black box" whereon exposures are done and resulting fetuses examined with little or no attention to mechanisms. 

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