Chemotherapy in pregnancy

13.1.1

Maternal outcomes

Maternal outcomes subsequent to a cancer diagnosis during pregnancy are comparable to those of nonpregnant women when adjusted for equal treatment, age, stage at diagnosis, and other cancer-specific risk factors [ ]. Treatment, including systemic therapy, should be offered as clinically appropriate. Delays in initiation of treatment may lead to inferior oncologic outcomes.

13.1.2

Obstetric outcomes

In a large cohort of 1170 women treated with chemotherapy during pregnancy, 88% had a successful live birth and 48% of pregnancies resulted in preterm birth. The majority of the preterm births were iatrogenic (88%) [ ].

13.1.3

Fetal outcomes

The low molecular weight of most chemotherapeutic agents allows them to cross the placenta, and most are known to have teratogenic potential. Chemotherapy poses the greatest risks for the developing fetus early in pregnancy. Depending on the type of cancer and the stage of diagnosis, chemotherapy may need to be administered without delay and pregnancy termination may either be recommended, or the inevitable outcome of treatment. When the fetus is exposed to the cytotoxic effects of chemotherapy during the first trimester, pregnancy will likely end in spontaneous abortion, major malformations, and fetal loss [ ]. Organogenesis, the critical time of organ formation from 2 to 8 weeks following conception, represents the time when the cardiac and central nervous systems are especially susceptible to insult. However, even following organogenesis, injury may still occur to the eyes, gonads, and central nervous and hematopoietic systems as these organ systems continue to mature over the course of a pregnancy [ ]. Treatment with chemotherapy in the second and third trimesters is generally thought to be safer but can be associated with intrauterine growth restriction and low birth weight infants. However, longitudinal follow-up is lacking [ ]. In one study of 796 singleton pregnancies exposed to chemotherapy, 21% of infants were small for gestational age and 41% required admission to neonatal intensive care after birth, primarily due to prematurity [ ]. In this same cohort, 4% of infants were born with a congenital malformation.

13.2.1

Antimetabolites

Antimetabolites are characterized by their inhibitory activity during DNA or RNA synthesis. Examples include methotrexate, 5-fluorouracil, thioguanine, cytarabine, cladribine, cladribine, fludarabine, mercaptopurine, pemetrexed, and gemcitabine. Perhaps due to its long history as a chemotherapeutic agent, methotrexate has been used for many illnesses, including acute myeloid leukemia, non-Hodgkin's lymphoma (NHL), osteosarcoma, head and neck cancer, and breast cancer [ , ]. It is known to be an abortifacient and a teratogen. In a review of 42 cases of methotrexate exposure, 23 cases in the first trimester found no abnormalities [ ]. Previous reports noted associations with cognitive defects, craniosynostosis, hypertelorism, micrognathia, and limb deformities [ ]. It is likely that there is a critical dose above which teratogenicity or spontaneous abortion occurs. Methotrexate used in low doses in rheumatologic disease has not been demonstrated to increase rates of fetal malformation or induce spontaneous abortions [ ].

5-Fluorouracil was associated with multiple fetal anomalies in a patient who received chemotherapy for colon cancer beginning at 12 weeks' gestation [ ]. 5-Fluorouracil is often used in combination with cyclophosphamide and doxorubicin for the treatment of breast cancer. Generally, first trimester exposure should be avoided if possible.

Cytarabine is typically used in combination with other agents such as vincristine, tioguanine, or doxorubicin to treat acute leukemia. There are reports of limb malformations after first trimester exposure, either alone or in combinations for the aforementioned agents [ , ]. In a report of 89 cases, intrauterine fetal distress (IUFD) was noted to have occurred in 6% and neonatal deaths in two [ ]. Cause of death was not identified in these cases. Cytarabine and daunorubicin were used in four cases. Cytarabine and tioguanine were used in five of the six intrauterine fetal demises. The effects of underlying maternal leukemia may also have contributed to the complications [ ].

A case report of 6-mercaptopurine given for treatment of acute monocytic leukemia in pregnancy during the first trimester and again in the third trimester was associated with the birth of a premature infant but no malformations were noted [ ]. As with methotrexate, much of the recent data regarding the thioprine class of chemotherapeutic agents come from the autoimmune literature where this class of medication is commonly used as immunomodulators. Mercaptopurine has been used in combination with azathioprine in patients with inflammatory bowel disease (IBD), which is estimated to affect 1.4 million Americans, with a peak onset at 15–30 years of age [ ]. A retrospective cohort study by Francella identified 15 patients who remained on 6-mercaptopurine/azathioprine for their entire pregnancy for the treatment of IBD. The authors reported that previous data showed a 3.9% congenital anomaly rate for the aforementioned agents, while their study found a 2.5% rate for one case of a congenital anomaly, compared to 4% in the control group [ ]. There was no difference in spontaneous abortion rates, major or minor malformations, neonatal infection rates, or prematurity.

13.2.2

Alkylating agents

Alkylating agents are commonly used to treat breast cancer, acute leukocytic leukemia, and lymphoma. Cyclophosphamide is contraindicated in the first trimester due to significant malformations including absent toes, eye abnormalities, low-set ears, and cleft palate [ ]. Again, much of the data surrounding the use of cyclophosphamide come from the literature regarding rheumatologic diseases. A case report of a mother who was prescribed cyclophosphamide for systemic lupus erythematosus and had exposure to the agent throughout her entire first trimester resulted in an infant with multiple physical anomalies similar to those findings from animal studies, raising the question of a cyclophosphamide phenotype [ ]. In utero exposure during the first trimester may be associated with the cyclophosphamide phenotype characterized as growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. Cyclophosphamide use has been reported as safe during the second and third trimesters.

Chlorambucil has been reported to cause cleft palate, skeletal dysplasias, and renal aplasia when administered in the first trimester [ ]. A case report of a 36-year-old patient who received chlorambucil to treat her chronic lymphocytic leukemia until her pregnancy was diagnosed at 20 weeks' gestation described no associated fetal malformations or major abnormalities [ ]. In a series of 15 pregnant patients with Hodgkin's lymphoma (HL), one patient who received chemotherapy with chlorambucil during the latter half of her pregnancy delivered a full-term infant [ ].

Dacarbazine is an alkylating agent with little data in humans. In high doses, it is known to be teratogenic in rats [ ]. Dacarbazine has emerged as an agent used in combination with tamoxifen, carmustine, and cisplatin for the treatment of metastatic melanoma during pregnancy. It is also used as part of the ABVD regimen for lymphoma [ ]. Dipaola et al. published a case report of a patient who received two cycles of this combination therapy for melanoma prior to delivery of her healthy infant at 30 weeks' gestation [ ]. No skeletal defects or cleft palate was observed as had been previously described with dacarbazine. The placental tissue was notable for invasion of malignant melanoma into the intervillous spaces; however, the fetus did not have metastatic disease.

Busulfan use in pregnancy was associated with no anomalies during the first trimester [ ]. It was associated with malformations in two cases with second trimester use: in one case, unilateral renal agenesis was noted after combination of busulfan and allopurinol, and in the other case, pyloric stenosis occurred after single therapy [ ].