role in mediating retinoid-induced toxicity. The details of this mechanism are beyond the scope of this chapter and the reader is directed toward a recent review for elucidation (30).

Topical application has the benefit of a significantly better adverse effect profile. The most common sequelae are mucocutaneous effects, characterized by skin and mucosal dryness (xerosis, cheilitis, conjunctivitis), desquamation, erythema, and pruritus. These effects typically start after several days of therapy, peak within the first few weeks, then wane as tolerance develops (31). They are easily treatable—frequent application of emollients and other precautionary measures (such as avoidance of harsh soaps, astringents, abrasives, and excessive bathing) will ameliorate the situation. The mucocutaneous effects are dose dependent and reversible upon discontinuation of the retinoid.

Teratogenicity, well documented as the most serious side effect of oral retinoids (32), is logically the potential concern with topical retinoids. With oral retinoids, most aromatic retinoids cross the placenta; in utero exposure results in limb and craniofacial deformities, as well as cardiovascular and central nervous system abnormalities. Systemic absorption of topical retinoids, however, is thought to be negligible (33). A large retrospective study of birth defects in offspring born to mothers exposed to topical tretinoin (all-trans-retinoic acid) during pregnancy has demonstrated no significant risk (34). Animal studies by Willhite et al. (35) support these data, suggesting that the drug would not be expected to cross the placenta unless present at extremely high concentrations. Even in light of this evidence, many clinicians feel strongly about avoiding topical retinoids in pregnancy (36).

Reports of enhanced photocarcinogenicity in experimental mice exist (37), but no evidence exists of a comparable process with humans (38). Conversely, topical retinoids appear to have a protective effect against ultraviolet-induced premalignant and malignant lesions. However, skin treated with topical retinoids is more reactive to chemical and physical stresses (including ultraviolet light), because of the thinner horny layer and amplified vasculature. The concomitant use of sunscreens is therefore a necessary precaution.

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