Antineoplastic drugs

2.13.1

Malignancy and pregnancy

Currently available evidence indicates that previous chemotherapy for cancer does not measurably increase the rate of spontaneous abortion or stillbirths in subsequent pregnancies ( ). Similarly, malformations, genetic defects, and chromosomal anomalies do not appear to be more frequent than expected among the children of cancer survivors who were previously treated with chemotherapy ( ). Some kinds of cancer chemotherapy may reduce subsequent fertility, depending on the drugs administered, their dose, and the duration of therapy, as well as on the age of the patient at the time of treatment ( ).

Generally, radiotherapy much earlier in life does not cause permanent infertility in either men or women. Neither does it increase the risk of birth defects or genetic disease in children born of subsequent pregnancies. An exception may be prior irradiation of the ovaries and/or uterus, which has been associated with an elevated risk of infertility or premature menopause. One study has also shown increased rates of premature births, growth retardation, and stillbirths and perinatal deaths among infants of women who had previously received such therapy ( ). Tissue damage after irradiation of the uterus was suspected as the cause, especially if the radiotherapy took place before menarche.

Malignant illness during pregnancy is rare, occurring in 0.2–1 per 1000 pregnancies. Breast cancer, lymphomas, melanomas and ovarian cancer are seen most often ( , ). There is no clear evidence that pregnancy itself influences the prognosis for a cancer.

If malignant disease is diagnosed in the first trimester, many couples choose to terminate the pregnancy, owing to the potential teratogenic risk of the expected therapy. There is, therefore, the least experience with maternal treatment early in pregnancy, but it is clear from documented cases that chemotherapy does not usually lead to major fetal malformations that are apparent at birth ( ). Moreover, intellectual development does not usually seem to be impaired, although available studies are very limited in terms of the number of patients and range of chemotherapeutic treatments included ( , ).

Only a few antineoplastic medications (for example, anthracyclines or trastuzumab ) have been reported to produce specific adverse fetal pharmacologic effects. Multiple agent chemotherapy in the second or third trimester may lead to growth retardation or transient bone marrow depression with fetal anemia, leucopenia or thrombocytopenia, but intrauterine death appears to be infrequent. Premature delivery of a pregnant woman who has cancer may be undertaken once fetal lung maturity has been achieved in order to have a “free hand” to provide maternal treatment without exposing the fetus to potentially toxic substances.

2.13.2

Breast cancer

Breast cancer is one of the most frequently diagnosed malignancies in pregnancy. Breast cancer in pregnancy is increasing because the incidence of breast cancer increases with age, and older women are becoming pregnant more often in industrialized nations. However, the increase in breast cancer during pregnancy appears to be greater than expected as a result of increased maternal age alone ( ).

Large population-based registry studies ( , ) and series including 100 or more women who received various chemotherapeutic regimens for breast cancer have been reported ( , , ), and the results of these and many smaller clinical studies have recently been reviewed ( , , , ). In general, these studies show similar, or only slightly worse, survival for women who are treated for breast cancer during pregnancy when other prognostic factors are taken into consideration.

Most of the reported experience is with treatment after the first trimester of pregnancy. Breast cancer chemotherapy generally seems to be well tolerated by the fetus in the second and third trimesters, at least in terms of serious adverse outcomes that are apparent in infancy, if premature delivery can be avoided ( , ) (see the individual medications detailed below). Treatment with trastuzumab is an apparent exception – there is a substantial risk of fetal renal dysfunction with trastuzumab therapy during the second half of pregnancy (see discussion below). Surgical treatment of breast cancer can undertaken at any point in pregnancy, with maternal risks that are similar to those in nonpregnant women and fetal risks that are similar to those associated with other kinds of surgery ( , ).

2.13.3

Vinca alkaloids and analogs

Vinca alkaloids are cytotoxic agents that disrupt microtubule formation. They have many effects on cellular activities, including inhibition of mitotic spindle formation and mitotic arrest. Vinblastine and vincristine are natural alkaloids, while vindesine , vinorelbine and vinflunine are semisynthetic derivatives.

At least 16 infants have been reported whose mothers were treated with vinblastine , usually in combination with other cytotoxic agents, during the first trimester of pregnancy ( , ). In most cases, the child appeared normal at birth, although instances of cleft lip and palate, foot malformations, hydrocephalus, thumb anomaly, and atrial septal defect have been described ( , , , , , ). More than 50 children whose mothers received cancer chemotherapy that included vinblastine during the second or third trimester of pregnancy have been reported ( , ). Most of these infants appeared normal at birth, but fetal growth retardation and transient anemia have been described.

At least 57 infants without congenital anomalies and at least seven children with malformations have been reported after maternal vincristine therapy during the first trimester of pregnancy ( , ). Two of the children had cleft lip and palate, but the malformations were different in all of the others. In each of these cases, the mother was also treated with other chemotherapeutic agents. More than 160 apparently normal children have been reported after maternal vincristine treatment later in pregnancy ( , ), but premature delivery, fetal growth retardation and neonatal bone marrow suppression have also been observed ( , , , , ).

Three of 10 children born to women who were treated with vinorelbine and other chemotherapeutic drugs during the first trimester were reported to have malformations ( ) – one child with atrial septal defect ( ), one with hydrocephalus ( ), and one with cleft palate and tracheoesophageal fistula ( ). At least 16 infants, most of whom appeared to be healthy, have been reported after maternal treatment with vinorelbine later in pregnancy ( , ).

One normal infant whose mother was treated with vindesine during the third trimester of pregnancy has been reported ( ). There is, as yet, no reported experience with vinflunine treatment during pregnancy.

2.13.4

Podophyllotoxin derivatives

Etoposide and teniposide are semisynthetic alkaloids that inhibit DNA synthesis by blocking topoisomerase.

Reports describe five apparently healthy children whose mothers were treated with etoposide and other cancer chemotherapeutic agents during the first trimester of pregnancy and more than 40 infants whose mothers were treated with etoposide in combination with other drugs later in pregnancy ( , , , , ). Most of these children appeared normal, but transient neonatal anemia, pancytopenia or hair loss was sometimes seen ( , , , ). A premature infant, whose mother was treated with etoposide, bleomycin and cisplatin in the 26th/27th week of pregnancy developed cerebral atrophy ( ). The glandular hypospadias observed in a boy whose mother was treated after the 21st week of gestation with etoposide, bleomycin, and cisplatin ( ) was unrelated to the treatment, which occurred after formation of the penile urethra was completed.

Only three reports of infants born after maternal treatment with teniposide during pregnancy are available ( , , ); all involved combination therapy in the second or third trimester of pregnancy. Two of the children appeared normal; the outcome in the third case was said to be “adverse” but was not described further.

2.13.5

Nitrosourea alkylators

A child with microphthalmia was born to a woman who was treated with carmustine (BCNU), dacarbazine , cisplatin , and tamoxifen during the first and second trimesters of pregnancy ( ). Two other women who were treated with the same combination of drugs beginning at the 23rd week of gestation have been reported. One had a child with atrial septal defect, strabismus and a nevus ( ), and the other woman had a healthy child ( ).

Only two infants have been reported whose mothers were treated with lomustine (CCNU) during the first trimester of pregnancy, and both had cleft lip and palate ( , ). The therapy also included other anticancer agents in both cases.

One normal infant whose mother was treated with nimustine during the second half of pregnancy has been reported ( ). No information is available on the outcomes of pregnancies in which the mother was treated with bendamustine .

2.13.6

Nitrogen mustard analog alkylators

Chlorambucil blocks the initiation of DNA replication. There are at least eight reports on its use in the first trimester of pregnancy ( , ). In two cases, the fetus was found to have unilateral renal agenesis. Chlorambucil was the only drug used to treat one of these mothers ( ); the other woman had also been treated with prednisone for autoimmune disease ( ). A woman with severe dermatosclerosis who had been treated with chlorambucil during the first trimester of pregnancy had an infant with multiple cardiovascular malformations who died on the third day of life ( ). In another case, the fetus had retinal defects ( ). Few cases have been described in which the mother was treated with chlorambucil beginning later in pregnancy, but all of the infants were reported to be normal ( ).

An extremely rare but characteristic pattern of malformations has been reported in at least 12 children whose mothers were treated with cyclophosphamide during the first trimester of pregnancy ( ). The most frequently described features of this cyclophosphamide embryopathy included growth retardation, developmental delay, microcephaly and major malformations of the distal limbs in association with minor anomalies of the ears, nose, jaw and midface ( , , , , , ). The frequency of this embryopathy among infants whose mothers were treated with cyclophosamide during the first trimester of pregnancy is unknown, but most infants born to women who are treated with cyclophosphamide early in pregnancy appear normal at birth ( , ). Maternal treatment with cyclophosphamide later in pregnancy has not been associated with an increased risk of fetal malformations, although oligohydramnios, premature delivery and neonatal bone marrow suppression are unusually frequent ( , ).

Ifosfamid and trofosfamid are structurally similar to cyclophosphamide. Ten infants whose mothers were treated with ifosfamid in combination with other cancer chemotherapeutic agents during pregnancy have been reported ( ), but only one of these women was treated during the first trimester ( ). None of the infants had major malformations. However, nine of these children were born prematurely, and oligohydramnios and fetal growth retardation were frequent.

reported a child whose mother was treated with trofosfamid , etoposide and idarubicin during the second half of pregnancy. The baby was born without malformations and showed normal neurological development to age 2 years.

There are only three reports of maternal melphalan treatment in the first trimester of pregnancy, resulting in two miscarriages and one early therapeutic abortion ( , ). A mother who was treated in the first trimester with bendamustine gave birth to a healthy child ( ). There is no experience in pregnancy with estramustine .

2.13.7

Other alkylating agents

Busulfan exerts its alkylating effect specifically on the bone marrow and is, therefore, used in preparation for bone marrow transplantation. At least 49 pregnancies, among them at least 31 with use during the first trimester, have been reported ( , , ). At least six of these children or fetuses had malformations, but they differed in each case.

Malformations have been reported in two of 9 children born to women who were treated with dacarbazine during the first trimester of pregnancy ( , ). One child had microphtalmia with associated visual impairment ( ), and another had metacarpal agenesis and hypoplasia of the thumb ( ). Most infants born to women treated with dacarbazine later in pregnancy appear healthy at birth, although premature delivery and fetal growth retardation are frequent ( , ).

Four infants whose mothers were treated with mechlorethamine ( nitrogen mustard ) and other cytotoxic agents during the first trimester of pregnancy had major congenital anomalies, including oligodactyly in two cases ( , ) hydrocephalus in one ( ), and renal hypoplasia in another ( ). At least a dozen infants without major birth defects have also been described following maternal mechlorethamine therapy in the first trimester, and a similar number have been reported following maternal exposure that did not begin before the second or third trimester ( , ).

Five of 15 infants born to women who were treated with procarbazine during the first trimester of pregnancy were reported to have major malformations ( , ). Four of these infants are described in the previous paragraph because their mothers were also treated with mechlorethamine ( , , , ). Another infant with cleft lip and palate has been described whose mother was not treated with mechlorethamine but who did receive other chemotherapeutic agents as well as probarbazine early in pregnancy ( ).

Three apparently normal infants born to women who were treated with temozolomide during the second or third trimester of pregnancy have been reported ( , , ). There is no reported experience with thiophosphamide or treosulfan treatment during pregnancy.