2138 Cytotoxic anthracydine antibiotics

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Daunorubicin interferes with DNA synthesis. The molecular size and relative hydrophilia of daunorubicin considerably restrict and delay its transfer to the placenta. According to Germann (2004), the concentrations in fetal tissues are between 100-fold and a 1000fold lower than in adult and tumor tissues, respectively.

In his review, Briggs (2005) describes 29 pregnant women, of whom 4 had been exposed during the first trimester (Feliu 1988, Alegre 1982). The 22 children born alive did not show any malformations. In 2 of these children, transient neutropenia was observed at the age of 2 months. Re-examination of 13 children of this group when aged between 6 months and 9 years demonstrated that their development was normal. Zuazu (1991) describes two other pregnancies exposed during the first trimester; one ended in a spontaneous miscarriage 20 days after the end of multi-agent chemotherapy, and the other proceeded to delivery of a healthy premature baby in week 34. Artlich (1994) describes a patient who underwent treatment with daunorubicin and cytarabine at the time of conception, and received cytarabine and thioguanine 5 weeks later. The child had craniosynostosis and radial aplasia. When administered during the second/third trimester, daunorubicin may occasionally elicit myelo-suppression.

Doxorubicin, also called adriamycin, has been described in numerous pregnancies, including at least 12 where it was administered during the first trimester (Garcia 1981, Blatt 1980, Hassenstein 1978). A child whose mother had received simultaneously cyclophosphamide and cobalt irradiation treatment of t he left axilla and supraclavicular region, during weeks 8-13, showed anal atresia with rectovaginal fistula (Murray 1984). Kim (1996) describes a premature baby with blepharophimosis, microcephaly, hydrocephalus, and a balanced autosomal translocation inherited from the mother, who had received two cycles of cyclophosphamide, doxorubicin, and cisplatin during the first trimester. The other newborns did not show any anomalies.

In a review, Germann (2004) analyzed 160 case reports published between 1976 and 2001; 50 cases involved daunorubicin and 99 cases involved doxorubicin. Some of these have been quoted above. About 30 of the 160 patients received treatment during the first trimester and gave birLh to 20 healthy children; 3 newborn infants showed malformations.

A case report (Nakajima 2004) showed again that cytotoxic therapy (doxorubicin and ifosfamide) during the second/third trimester may lead to healthy but growth-restricted children. This applies also to a study of 57 pregnant breast cancer patients who were treated with FAC (5-fIuorouracil, doxorubicin, cyclophosphamide) (Hahn 2006). However, doxorubicin is known to have cardiotoxic side effects: there are three case reports of young pregnant women who had received doxorubicin treatment in their childhood or youth and, although their cardiac function appeared normal prior to pregnancy, they were decompensating at the end of pregnancy (Pan 2002).

There are at least 20 case reports on epirubicin in combination therapy, including two exposures during the first trimester which ended in spontaneous miscarriage. Regarding the other pregnancies, there was 1 abortion, 1 stillbirth and 1 child who died shortly after birth. Furthermore, there were cases of intrauterine growth restriction, premature births, and a transient leukopenia (Ring 2005, Gadducci 2003, Giacalone 1999, Müller 1996, Goldwasser 1995).

Placental transfer of epirubicin is low but slightly higher than that of doxorubicin (Gaillard 1995).

Five ease reports describe combination therapy with idarubicin after the first trimester (Claahsen 1998, Reynoso 1994). In the first case, fetal death occurred after the beginning of the therapy, whereas the second report describes birth of a growth-restricted but otherwise healthy baby. The third child was born in week 28 and suffered from acute cardiac failure lasting for 3 days, which the authors attributed to idarubicin (Achtari 2000). Furthermore, transient dilated cardiomyopathy was reported in two other children (Niedermeier2005, Siu 2002). One of these children also displayed a moderate-sized membranous ventricular septal defect, short digits and limbs, acrocyanosis, a shallow sacral dimple, and a prominent frontal skull with mild macrognathia which cannot be explained by exposure to idarubicin and cytarabine exclusively during the second and third trimesters (Niedermeier 2005). Although idarubicin is less car-diotoxic than traditional anthracyclines, its higher lipophilicity makes placental transfer easier. This could explain why the fetuses described in the few reports available frequently showed cardiac complications.

For mitoxantrone, four case reports are available. One of these describes a pregnancy with idarubicin exposure in combination with other drugs, which resulted in fetal death (Reynoso 1994). An apparently normal newborn was reported after intrauterine exposure to chemotherapy in weeks 24-34 (Azuno 1995). Giacalone (1999) reports a healthy child and a growth-restricted infant after therapy during the second trimester. Mitoxantrone has immunomodulatory properties, and is therefore used for certain forms of multiple sclerosis.

Nothing is known about the effects of the treatment of pregnant women with aclarubicin and pirarubicin.

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