Purinederived antimetabolites purine antagonists

6-Mercaptopurine is a purine analog, which acts as an inhibitor of nucleic acid synthesis (cf. azathioprine = AZA, a pro-drug of 6-MP). Until now, no specific malformation syndrome has been described. 6-MP is also used as an immunosuppressive, for example for chronic inflammatory bowel disease (IBD). The plasma half-lives of 6-MP and AZA of 1-3 hours are short, but the half-life of the cytostatic active metabolite, the thioguanine nucleotide, is 3-13 days. The mode of action and metabolic transformation of 6-MP vary inter-individually, and involve the enzyme thiopurine-methyltrans-ferase, TPMT, the activity of which is genetically determined. AZA and 6-MP are able to cross the placenta (Polifka 2002).

In one report, more than 60 of over 100 pregnant women who were exposed during the first trimester took 6-MP in connection with IBD {Francella 2003). frequently in combination with prednisolone; a small group took it continuously throughout the entire pregnancy. The majority of the children of the pregnant women receiving 6-MP described in this and other publications were born without anomalies (Moskowitz 2004, Polifka 2002, Aviles 1990, Dara 1981, Pizzuto 1980). Some infants and fetuses showed malformations such as Polydactyly (Mulvihill 1987), hypospadia (Sosa Munoz 1983), hydrocephalus (Francella 2003), hypoplasia of the lung, malformations of the urinary bladder and urethra (Norgârd 2003), cleft palate, and facial dysmorphism (Tegay 2002). It is not possible to deduce a significant teratogenic potential from these reports. There is overlap between the therapeutic dose ranges of the two major indications for treatment, IBD and leukemia. The indication in itself is therefore not a distinguishing feature in terms of potential teratogenicity.

Thioguanine is a purine analog that produces single-strand breaks in mammalian DNA. Schardein (2000) collected five cases of thioguanine exposure during early pregnancy, of which none resulted in a child with anomalies. In another case report, an infant exposed to thioguanine and cytarabine during the sixth week postconception was born with craniosynostosis and radius aplasia, as well as digital defects (Schafer 1981). Probably, cytarabine was the substance causing the malformations. Artlich (1994) also reports on a malformed child after intrauterine exposure during the first trimester (see cytarbine; section 2.13.12). 6-Thioguanine is also indicated for Crohn's disease. De Boer (2005) described two patients with Crohn's disease treated with Iow-dosc 6-thioguanine throughout pregnancy who delivered healthy babies. Significantly lower levels of 6-thioguaninenucleotides were found in the erythrocytes of the infants compared to the mother (ratio 1 : 12).

A woman with hairy cell leukemia diagnosed at 10 weeks' gestation who deferred therapy with cladribine until 6 months after giving birth, when she stopped nursing, had an uneventful pregnancy outcome (Alothman 1994).

No information is available on use of fludarabine during pregnancy.

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