Azathioprine (AZA) is an immunosuppressant extensively metabolized to the purine analog 6-mercaptopurine (6 MP) (see Chapter 2.13). Azathioprine is well-absorbed from the gastrointestinal tract when given by mouth (47%), whereas 6-mercaptopurine is less well-absorbed (only 16%). Both agents are bound to plasma proteins (30%). The risk evaluation for the two agents is comparable for the immunosuppressive dose. AZA can pass through the human placenta. Dc Boer (2006) describes three patients with Crohn's disease where the thiopurine metabolites were measured in the red blood cells (RBC) of mother and infant directly after delivery. The metabolite 6-methylmercaptopurine (responsible for hepatotoxic-ity) could not be detected in the RBC in any of the three infants. The metabolite 6-thioguaninenucleotides (responsible for myelotoxicity) was found in the infants, but in lower concentrations than in their mothers.
AZA is mutagenic in bacteria tests and teratogenic in animal experiments (Poiifka 2002). However, approximately 40 studies and ease scries which total more than 1000 pregnancies and case reports involving 120 pregnancies have not demonstrated an increased malformation rate (Berkovitch 2005, Moskovitz 2004,
Armenti 2003, Francella 2003, Polifka 2002). Only Norgard (2003) concluded from 10 exposed pregnancies in the Danish Medical Rirth Registry that there was an increased risk for major malformations, for perinatal mortality, and for prematurity.
A risk of low birth weight and prematurity after in utero exposure to AZA has been reported (e.g. Berkovitch 2005). but this could be a consequence of the disease itself or of the associated therapy using glucocorticoids. Additionally, occasional leukopenia or pancytopenia has been reported. It was suggested that inhibition of neonatal hematopoiesis is predicted by whether or not maternal leukopenia is observed during the third trimester (Davison 1985).
Nulman (2004) evaluated the prenatal effects of a combination of cyclosporine and AZA on children's neurodevelopment, and compared it with unexposed children. The 20 exposed children (aged 3-13 years) were not significantly different from the unexposed regarding global, verbal, and performance IQ scores, compared with the control children. The exposed children appear to have language scores in the upper range of normal.
If the father took AZA or 6-MP at conception, no substantial risk for intrauterine development has been reported (see Chapter 1).
Recommendation. Immunosuppression with azathioprine has not been associated with an increased risk of teratogenesis in approximately 1000 cases. Its use does not require termination of pregnancy. A detailed fetal ultrasound examination should be offered to confirm normal morphologic development in cases of first-trimester exposure. If the pregnant woman suffers from leukopenia in the third trimester, dose reduction must be considered to prevent leukopenia in the newborn.
2,12.3 Cyclosporine A
Cyclosporine A (CsA) originates from fungal cultures, and is used after organ transplantation or for treating immunological diseases. It is fetotoxic in animals at high doses, but no major teratogenic effect has been demonstrated experimentally (Brown 1985, Mason 1985).
There arc more than 1000 case reports on renal and other transplant patients receiving cyclosporine who became pregnant and delivered a normal child (Ghanem 2005, Armenti 2003, Bar-Oz 2001, Rayes 1998, Wu 1998, Lamarque 1997).
Growth restriction has been observed in human pregnancies involving cyclosporine; however, several of these cases also included gestational exposure to corticosteroids, which may have contributed to stunting fetal growth In a meta-analysis, the rate of low birth weight in cyclosporine-exposed pregnancies was increased compared with the rate in pregnancies in transplanted women who were not on cyclosporine (49% versus 38%), but no increased risk of malformations or prematurity was associated with the use of CsA during pregnancy in the population studied (Bar-Oz 1999).
After Lhe first year, six infants had functional impairment of their B- and T-lymphocytes as well as natural killer cells; however, these deficits were not clinically apparent (di Paola 2000). In an earlier study by Baarsma (1993), prenatal cyclosporine was not associated with effects on the immune responses of infants up to 2 years. A cohort of 14 children exposed prenatally to cyclosporine and prednisone were followed to a mean age of 54 ± 32 months and evaluated to determine whether there were any detectable long-term immunologic and neurodevelopmental effects associated with these exposures. Test scores for this group did not differ significantly from those of a non-exposed control group (Rieder 1997). Nulman (2004) found similar results in 20 prenatally-exposed children.
In one case report (Roll 1997), a hepatoblastoma was reported in a 2-year-old who was exposed to cyclosporine (and prednisolone) throughout gestation. Although (his association may be coincidental, there is concern that chronic immunosuppressive therapy may increase the risk of tumor development in transplant patients. This case may indicate such a risk for fetuses exposed in utero.
CsA has a well-known nephrotoxic side effect, not only in transplanted kidneys but also in normal kidneys. In 26 intrauterine exposed children, there was no evidence of nephrotoxicity when they were followed to an average age of 39 months after their birth (Shaheen 1993). Similarly, no impairment of renal function at 1 to 7 years of age was found among 12 children born to women who had been treated with cyclosporine during pregnancy (Cochat 2004).
Recommendation. In more than 1000 pregnancies no substantial teratogenic effect was recognizable in human fetuses exposed to cyclosporine in utero. Its use does not require termination of pregnancy. A detailed fetal ultrasound examination should be offered to confirm normal morphologic development in case of first-trimester exposure.
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