Cyclophosphamide, methotrexate, and cytarabine embropathy: is apoptosis the common pathway?

Background: Cyclophosphamide (CP) is an alkylating agent primarily used for the treatment of autoimmune disease and cancer. The purpose of this article is two-fold: first, to indicate that CP is a recognized human teratogen based on the features seen in a child prenatally exposed to this agent, as well as features seen in the previously reported cases; second, to suggest a common pathway to explain the similarity in the pattern of malformation seen in infants prenatally exposed to CP, in infants prenatally exposed to methotrexate (MTX), and in infants prenatally exposed to cytosine arabinoside (CA).

Methods: Case report and review of the literature of an infant prenatally exposed to CP during the first trimester with a specific pattern of malformation. Features are compared to seven previous reports.

Results: A common pattern of malformation is delineated including growth deficiency, hypoplasia of the calvarial and facial bones, and oligodactyly.

Conclusions: The finding of a similar pattern of malformation among eight infants prenatally exposed to CP suggests that CP is a human teratogen. MTX and CA produce similar patterns of malformation in prenatally exposed infants despite very different pharmocologic profiles and metabolism. We speculate that the phenotype is a consequence of apoptosis in certain cells which are susceptible to the effects of the teratogen at specific stages of development.