Cisplatin has been used in the treatment of a variety of solid tumors, including those of the urogenital system. As a result of poor placental transfer of cisplatin, the developing embryo may be protected from exposure to this agent, but toxic effects on the more developed fetus are possible (Kopf-Maier 1983).
At present, there is only one case report on multiple chemotherapy using cisplatin, cyclophosphamide, and doxorubicin in the first trimester (Kim 1996). A young pregnant woman received two cycles in weeks 7 and 12 respectively. In week 25, a boy was delivered by emergency cesarean section, weighing 1020 g; he showed blepharophimosis, microcephaly, and enlarged lateral ventricles on both sides. His mother and the baby were diagnosed with a balanced autosomal translocation. Ultrasound scans of the skull showed no alterations up to the thirtieth postnatal day. Jacobs (1980) describes an externally normal looking fetus following exposure to cisplatin after week 12 of pregnancy.
There are about 28 publications about treatment during the second and third trimesters, administered as mono-drug Lherapy as well as multi-agent chemotherapy. Han (2005) reports two cases with apparently normal outcome after therapy with cisplatin, etoposide, and bleomycin. Ferrandina (2005) describes a healthy male premature baby after prenatal exposure to six cycles of cisplatin. Tomlinson (1997) reports a normal pregnancy using cisplatin and cyclophosphamide, and gives a summary on nine further cases, including a premature birth with neutropenia and reversible hair loss from day 10 onwards which had been exposed to cisplatin, bleomycin, and etoposide until 6 days prior to birth. At the age of 1 year, the child was apparently normal except for a moderate sensineural hearing loss bilaterally (Raffles 1989; see also case description in section 2.13.4). One case report describes a premature infant that developed cerebral atrophy with enlargement of the cerebral ventricles; its mother had received 100mg/m2 etoposide for 5 days in week 26/27, in combination with bleomycin and cisplatin, to treat an ovarian tumor (Elit 1999). In a series of cases reported by Peres (2001), a stillbirth occurred at week 26 of pregnancy without malformations. The mother had received cisplatin and etoposide in week 22 as treatment for non-Hodgkin's lymphoma. All other children were healthy, but two had intrauterine growth restriction (Caluwaerts 2006, Ohara 2000, di Paolo 1997, Giacaionc 1996, Hoffmann 1995, Henderson 1993).
One study found that animals prenatally exposed to cisplatin had an increased risk of tumor formation in various tissues. Although it is not known whether this finding has relevance for the use of cisplatin in the clinical setting, the authors recommend that infants exposed to this agent during gestation should be monitored for preneoplastic and neoplastic lesions in later life (Diwan 1993).
Carboplatin is related to cisplatin. In a case report involving fetal exposure to cisplatin between 20 and 30 weeks' gestation, and carboplatin between 31 and 36 weeks' gestation, no adverse effects on fetal development were detected (Henderson 1993). Another case report with carboplatin exposure between 17 and 33 weeks' gestation also describes a healthy infant (Mendez 2003).
There is no information on the use of oxaliplatin during pregnancy.
Hydroxycarbarnide, also called hydroxyurea, reduces the synthesis of DNA. Currently, hydroxyurea is used in the management of chronic granulocytic leukemia, in polycythemia vera and thrombocythemia, and in cases of sickle cell anemia. To date, there are more than 25 reported cases of treatment with hydroxycarbarnide during pregnancy. One apparently normal fetus was eiectively aborted in the midtrimester, and one woman delivered a stillborn male infant without gross abnormalities (Celiloglu 2000, Byrd 1999). There were no gross structural malformations among the live births whose mothers had predominantly been treated during the first trimester (Merlob 2005, Pata 2004, Thauvin-Robinet 2001, Wright 2001, Diav-Citrin 1999). There are case reports of successful therapy with hydroxyurea in the second or third trimester, when therapy of chronic granulocytic leukemia during pregnancy was necessary (Ault 2006).
Anagrelide is used for the treatment of essential thrombo-cythaemia. It inhibits phosphodiesterase III and acts during the postmitotic phase of megakaryocyte development. Thus, the number of thrombocytes is selectively reduced. It is not cytotoxic or mutagenic. The findings during pregnancy are limited to approximately ten reports, in which no teratogenic effects were noticed (at Kindi 2005A, Doubek 2004, T1S Berlin data).
Tretinoin or ail-trans-retinoic acid (ATRA), is used orally as an antineoplastic in the treatment of acute promyelocyte leukemia. Most human reproductive studies on retinoids focus on the potent teratogenic effect of isotretinoin (an isomer of tretinoin), which is used in the oral therapy of cystic acne and is easily converted to tretinoin. Defects of the central nervous system, branchial arches, and cardiovascular system were observed. There are 22 case reports that include the use of systemic tretinoin (45 mg/m2 per day) for the treatment of acute promyclocytic leukemia during pregnancy. Only one of these exposures occurred during the first trimester (during the sixth week of gestation). No congenital abnormalities were observed in any of the exposed newborns. If problems in newborn babies arose, they were usually due to the premature birth and of a transient nature. There are also reports of growth restriction and fetal arrhythmia as well as cardiac arrest with successful recovery (Takitani 2005, Consoli 2004, Carradice 2002, Fadilah 2001, Tcrada 1997). A female full-term, who as a fetus had been exposed to ATRA and idarubicin from week 15 on, showed an atrial septal defect and a slight dilatative cardiomyopathy of the right ventricle, which regressed completely after 1-2 months. The hemodynamically insignificant atrial septal defect was still detectable (Siu 2002). For further details on retinoids, see Chapter 2.17.
There are no data available on the tolerance during pregnancy for arnsacrine or rniltefosin, which is also used against leishmaniosis.
The same is true for pentostatin, mitoguazone, and the topoiso-merase inhibitors irinotecan and topotecan, for the photosensitizing agents temoporfin and porfimer-sodium, and for bexaroten, an agonist of the retinoid X receptor. Likewise, concerning pcrnetrexed (an inhibitor of thymidylate synthesis) and mitotane, there are no data available concerning the use during pregnancy.
Imatinib, a protein tyrosine kinase inhibitor, is used for the therapy of chronic granulocytic leukemia. There arc only a few case reports about its use during pregnancy, and these prove neither its safety nor its teratogenicity. There were 11 pregnant patients on imatinib, of whom all but one took it until pregnancy was recognized: two had spontaneous abortions, one decided to have a therapeutic abortion, and eight pregnancies were carried to term, resulting in the birth of nine babies, of which one had a hypospadia that was surgically corrccted (Ault 2006, Ali 2005). There are four case reports describing imatinib exposure throughout pregnancy. All babies were without congenita! malformations, but two of them were small for gestational age (A1 Kindi 2005B, Prabhasch 2005). Hensley (2003) described two healthy infants, a boy with hypospadia, and two induced abortions due to deformities (hydrocephalus, heart defect). Another case report with exposure to imatinib until week 7 concerns a girl with pyloric stenosis (Heartin 2004). Choudhary (2006) reported on a woman who inadvertently took imatinib until 6 weeks after gestation, and delivered a dead fetus with meningocele at the thirty-fourth week of pregnancy.
Erlotinib is a newly licensed cytotoxic drug for the treatment for non-small-cell lung cancer. Altretamine is an oral drug used to treat ovarian cancer, which was approved by the FDA in 1990. There are no data concerning the use during pregnancy.
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