2133 Vinca alkaloids and structural analogs

Vinblastine is an alkaloid derived from the periwinkle plant. Like the related vincristine, it inhibits cell division by interfering with the mitotic spindle. There are more than 15 case reports concerning the use of vinblastine during the first trimester, mostly in combination with other cytostatic drugs. In most cases, the coursc of pregnancy was apparently norma! (Aviles 1991). However, there are also reports of children with malformations: a child with hydrocephalus after intrauterine exposure to vinblastine alone in week 3; a second with cleft palate whose mother had received vincristine and other cytostatic drugs from week 9 until delivery, following treatment with vinblastine until week 6; and a spontaneous miscarriage shortly after injection of vinblastine in week 6 (Mulvihill 1987). There is also a report of a spontaneous miscarriage of a male fetus with only four toes on each foot and syndactyly in week 24 of pregnancy (Garrett 1974), as well as a male infant delivered at 37 weeks weighing only 1900 g with a defect of the atrial septum who died of respiratory distress syndrome and whose mother had been treated with vincristine and vinblastine (Thomas 1976). The mothers of these latter four children had received vinblastine in combi nation with several other agents. There are some reports with normal outcome after exposure during the second and third trimesters (Doll 1989).

There are more than 20 case reports regarding apparently normal children following vincristine therapy during the first trimester (for an overview, see Schardein 2000 and www.motherisk.org), However, there are also reports of an aborted fetus with renal aplasia after combination therapy (Mennuti 1975); the newborn cited above (Thomas 1976) who had a defect an atrial septal defect and died of respiratory distress syndrome; a child with cleft palate after vincristine treatment until week 6 followed by vinblastine and other cytostatic drugs (Mulvihill 1987); and a woman receiving combination therapy for Hodgkin's disease during the first trimester whose hydrocephalic child died four hours after birth (Zemlicki 1992). Furthermore, there are reports about apparently normal pregnancies after exposure during the second and/or third trimesters, but also reports of neonatal pancytopenia (Pizzuto 1980) and intrauterine growth retardation.

Three children aged 2 and 3 years whose mothers were treated for breast cancer with vinorelbine plus 5-fluorouracil during the second and third trimesters developed normally (Cuvier 1997). Another pregnancy with vinorelbine and trastuzumab (see section 2.13.16) in the third trimester was complicated by an oligohydramnios, which was thought more likely to be a side effect of trastuzumab (Fanale 2005).

At present, there are no reports available on vindesine.

2.13.4 Podophyllotoxin derivatives

There are at least 13 case reports on etoposide (Han 2005, Rodriguez 1995, Arango 1994, Horbelt 1994, Brunet 1993), including two reports describing Lhe delivery of healthy children after exposure during the first trimester (Avilcs 1991). Development of these two children was normal up to the ages of 3 and 8, respectively.

Transient pancytopenia was reported in some children following exposure during the second/third trimester (Hsu 1995, Murray 1994). One case report describes a premature baby that developed cerebral atrophy with enlargement of the cerebral ventricles; its mother had been treated for an ovarian tumor and received 100mg/m2 etoposide for 5 days in week 26/27 in combination with bleomycin and cisplatin (Flit 1999). Another premature baby (gestational age 27 weeks) whose mother had received multi-agent chemotherapy with etoposide, bleomycin, and cisplatin in week 26, developed severe leukopenia and anemia postnatally on day 3. At the age of 10 days, the infant was noted to be losing her scalp hair and there was an associated rapid loss of lanugo. Hair growth recovered after 12 weeks. Re-examination after a year showed normal neurodevelopmental progress, but there was moderate sensorineural hearing loss bilaterally (Rattles 1989).

Teniposide is a semi-synthetic derivative of podophyllotoxin that inhibits topoisomerasc, preventing DNA synthesis and cell entry into the prophase. An apparently healthy baby was born to a woman who received teniposide and other chemotherapeutic agents during the second half of pregnancy (Lowenthal 1982).

2.13.5 Nitrogen mustard agents

Streptozocin is a nitrosourea marketed for the treatment of metastatic islet cell carcinoma of the pancreas. Because of its diabetogenic effect in animals (Tuch 1993), concern was raised about human use of the drug. However, experimental animal diabetes induced by streptozocin seems not to occur in humans. Human fetal pancreatic islet cells appear to be resistant to streptozocin toxicity in comparison to rat fetal islet cells (Tuch 1989). There has been a single report of a human pregnancy in which streptozocin was used. No adverse effect was observed (Schapira 1984).

Carmustine is a nitrosourea that alkylates nucleic acids. One normal infant who had been exposed to this drug during early pregnancy was reported by Schardein (2000). No other reports are available.

Fotemustine, lomustine, nimustine, and semustine block DNA replication. No information is available about use of these drugs in pregnancy.

2.13.6 Nitrogen mustard analogs

Chlorambucil blocks the initiation of DNA replication. Two fetuses aborted after maternal treatment in the first trimester were found to have unilateral renal agenesis (Steege 1980, Shotton 1963). One of these was a twin pregnancy, where only one of the twins was affected. A third aborted fetus after intrauterine exposure in the first trimester showed retinal defects (Rugh 1965). Several normal pregnancies have also been reported (Jacobs 1981).

Cyclophosphamide is an alkylating agent used in cancer chemotherapy and as an immunosuppressant for the treatment of, for example, lupus erythematodes. Animal studies using rats, mice, rabbits, monkeys, and chicken showed malformations of the CNS, the craniofacial area and the skeleton (cf. Enns 1999).

Knowledge regarding the treatment of pregnant women with cyclophosphamide during the first trimester is based on a small cases series (Aviles 1991) and retrospective case reports. In total, there are reports on more than 30 women treated during the first trimester, including one twin pregnancy: 17 children were healthy or without congenital malformations (Fernandez 2006, Peres 2001, Aviles 1991, Pizzuto 1980), 11 fetuses and children had major or minor malformations (Paskulin 2005, Paladini 2004, Vaux 2003, Giannakopoulou 2000, Enns 1999, Mutchinick 1992, Kirshon 1988, Murray 1984, Toledo 1971, Greenberg 1964), two pregnancies ended in spontaneous miscarriage (Clowse 2005), and in two other pregnancies the fetuses died in weeks 25/26 (Peres 2001. Ba-Thike 1990). Furthermore, a boy who was born with multiple malformations developed thyroid cancer at 11 years of age and a neuroblastoma at age 14; at the age of 16 a metastasizing papillary thyroid carcinoma was diagnosed. His twin sister was healthy (Zemlickis 1993).

To date, in the TIS Berlin, five pregnancies with exposure during the first trimester have been prospectively analyzed; one ended in spontaneous abortion, one was terminated during the second trimester at the mother's request, despite apparently normal detailed ultrasound findings, and three children were born healthy.

Recently, a special cyclophosphamide embryopathy {Enns 1999) or cyclophosphamide-methotrexatc-cytarabine embryopathy (Vaux 2003) has been proposed; characteristics include craniofacial abnormalities along with eye and ear malformations, limb defccts, and growth retardation. Nine of the cases described above do at least partially follow this pattern, including those where the mothers had received cyclophosphamide as the only cytotoxic drug in connection with systemic lupus erythematosus.

Treatment with cyclophosphamide during the second and third trimesters may result in pancytopenia and reduced birth weight of newborns. There is also a higher incidence of premature births (Kerr 2005). Numerous case studies have reported an apparently normal outcome of the pregnancies, even in cases of malign illness (Hahn 2006, Ring 2005, Koseuglu 2001, Luisiri 1997, Oates 1990). In two patients with lupus who received cyclophosphamide during the second trimester due to the severity of the disease, the pregnancies ended in late abortion (Clowse 2005).

Ifosfamid and trofosfamid arc structurally similar to cyclophosphamide, There is one case report of a healthy infant whose mother was treated with ifosfamid and other agents during the third trimester of pregnancy because of Ewing's sarcoma (Merimsky 1999).

Chromosomal abnormalities have been identified after treatment of humans with melphalan, often years after therapy has been completed (Mamuris 1989, Lambert 1984). This agent is believed to be associated with secondary malignancies. There is only one case report, describing a miscarriage that occurred in a woman who was treated with melphalan without other cancer chemotherapeutic agents during the first trimester of pregnancy (Zemlickis 1992).

There is one case report of a healthy child whose mother was treated with bendamustin in the first trimester of pregnancy (cited in Schardein 2000).

Pregnancies exposed to estramustifl have not been described.

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