PRESCRIBING IN PREGNANCY
THE USE OF CHEMOTHERAPEUTIC AGENTS DURING PREGNANCY Joel I. Sorosky, MD, Anil K. Sood, MD, and Thomas E. Buekers, MD
Cancer complicating pregnancy is uncommon, with an incidence of approximately 1 per 1000 pregnancies. The American College of Obstetricians and Gynecologists estimates that approximately 3500 cases of cancer occur in pregnant women annually in the United States.25The most common malignancies encountered during pregnancy, in descending order, are cervical, breast, melanoma, ovarian, thyroid, leukemia, lymphoma, and colorectal. Pregnancy per se does not increase the risk of malignancy. The incidence of specific malignancies during pregnancy parallels that of nongravid women of comparable age. The incidence of cancer complicating pregnancy may increase as child-bearing is delayed to later in life. For women with breast cancer, ovarian cancer, leukemia, and lymphomas, chemotherapy may have a major role in treatment? Chemotherapy may be given for a variety of indications (Table 1).Appropriate use of chemotherapeutic agents requires knowledge of the mechanism of action, effect on the cell cycle phase, and toxicity. Unfortunately, there are no large prospective series that address chemotherapy use during pregnancy and, thus, most physicians are forced to formulate treatment regimens based on small retrospective studies or case reports. The ultimate decision to delay or initiate chemotherapy during pregnancy is difficult and must take into account the emotional, religious, social, and moral needs of the mother and family. The primary concern of pregnant
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa . OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 24 * NUMBER 3 * SEPTEMBER 1997
Table 1. INDICATIONS FOR CHEMOTHERAPY Adjuvant therapy Neoadjuvant therapy Definitive therapy Palliative therapy
Following surgery or radiation therapy for small volume disease undetectable by the usual clinical and radiologic methods To shrink tumors before definitive surgery or radiation therapy As primary disease treatment To provide relief without expectation for cure
women with cancer is “living to see my child grow However, the necessity of using therapeutic maternal doses of chemotherapeutic agents must be balanced against the risks to the fetus. The effects of chemotherapy on the developing fetus must be balanced in turn against the effects of the maternal illness on the fetus. The potential exists for a conflict. Because the incidence of carcinoma requiring chemotherapy during pregnancy is small, few individuals or institutions will attain sufficient experience with this clinical scenario. This review offers clinicians useful information upon which to advise their patients. This is particularly important because information in the older literature may be of limited relevance as lower doses of single agent chemotherapy were commonly used.I9 MATERNAL PHYSIOLOGIC CONSIDERATIONS
The physiologic changes associated with pregnancy directly affect the dosing and toxicity of chemotherapeutic agents. The increase in renal blood flow, glomerular filtration rate, and creatinine clearance may increase the clearance of drugs excreted by the kidneys. Amniotic fluid may act as a physiologic third space, potentially increasing the toxicity of particular agents (e.g., methotrexate) by delaying elimination. The physiologic increase in body water with the increase in plasma volume may alter the volume of drug distribution. Virtually all chemotherapeutic agents cross the placenta. Placental transfer of maternal substances to the fetus is usually established by the fifth week of life. Placental transfer favors the uptake of nonionized lipophilic molecules with a molecular weight of less than 1000 daltons and a low degree of protein binding7 Similarly, animal studies suggest that almost all chemotherapeutic agents are teratogenic, with the most sensitive time corresponding to the period of organogenesis. PRINCIPLES OF CHEMOTHERAPY
Chemotherapeutic drugs are classified by their mechanism of action, with different classes of drugs affecting different phases of the cell cycle. There are four active phases of the cell cycle: GI, S, GZ,M, and one resting
THE USE OF CHEMOTHERAPEUTIC AGENTS DURING PREGNANCY
phase, Go. A cell spends most of its time in the GI phase preparing for DNA synthesis. The primary function in GI is synthesis of protein and RNA. Chromosomal doubling occurs during the S phase. During the GZ phase, the mitotic apparatus is formed to prepare for the M phase. Mitosis occurs during the M phase. PRINCIPLES OF CHEMOTHERAPY ADMINISTRATION DURING PREGNANCY
All chemotherapeutic agents are theoretically teratogenic and mutagenic. Their use may result in fetal malformations, fetal growth restriction, spontaneous abortion, or fetal death. It is important to differentiate teratogenic and mutagenic effects from those related to a suboptimum intrauterine environment or those resulting from a maternal toxicity such as neutropenia, infection, thrombocytopenia, or myocardial toxicity.I4 Chemotherapeutic agents act on rapidly proliferating cells and are, therefore, potentially dangerous to fetal tissue. The effects of chemotherapy on the fetus are influenced by the particular drug, timing of exposure, duration of exposure, frequency of exposure, and ability of the l7 There may be increased toxicity when drug to cross the pla~enta.~, chemotherapy is administered with radiation therapy. Maternal factors that can affect fetal drug exposure include decreased serum albumin levels, which increase free drug concentration; obesity, which causes maternal sequestration of lipid soluble drugs; and expanded plasma volume, which reduces peak drug concentration^.^ During early fetal development and organogenesis, the stem cell population is limited. Anatomic defects may result from the destruction of or damage to small numbers of stem cells. Most of the knowledge regarding the effects of antineoplastic agents in pregnancy have been extrapolated from animal studies and case reports. Animal studies suggest a high morbidity probability, but they do not consistently predict results in humans. The first trimester is the most critical with respect to exposure to chemotherapy. The blastocyst is resistant to teratogens in the first 2 weeks of life. If it is not destroyed by exposure to a teratogen, a surviving blastocyst will not manifest any abnormalities from a chemotherapeutic agent. The third to the eighth week of development, 5 to 10 weeks of gestational age, is the period of maximal susceptibility to teratogenic insult. With the exception of brain and gonadal tissue, organogenesis is complete by 13 weeks of gestation. If chemotherapy induces severe damage early in gestation, spontaneous abortion results., If, however, sublethal damage occurs between the second and tenth weeks of development, teratogenesis may occur. After organogenesis is complete, the risk of developing birth defects induced by chemotherapy is decreased and intrauterine growth restriction becomes the dominant effect.15Approximately 10% to 20% of infants exposed to cytotoxic agents during the first trimester have major malfor-
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mations as compared to a rate of 3% in the general population.1° The underlying rate of spontaneous abortion and birth defects in the general population are large enough to potentially confound data from a small series. Generally, chemotherapy should be delayed until after the first trimester. From the data available, chemotherapy administered after organogenesis does not appear to have significant teratogenic risk; however, central nervous system development is not complete and chemotherapy may affect fetal growth and development. Chemotherapy also may induce myelosuppression in the fetus and newborn infant. The Toronto Leukemia Study Group has reported that one third of all infants exposed in utero had pancytopenia at birth.20Aviles and Niz reported on 17 children delivered of mothers with acute leukemia treated during pregnancy and concluded that chemotherapy did not have a major impact upon later development.2 They subsequently reported on 43 children born to mothers with hematologic malignancies who received chemotherapy during pregnancy. Nineteen of the mothers received treatment in the first trimester. No physical, neurologic, psychologic, hematologic, or cytogenetic defects were f0und.l Premature birth and low birth weight for gestational age are probably the most common complications and are most likely ~nderreported.~
CHEMOTHERAPY PRIOR TO DELIVERY
Chemotherapy administered near term or prior to preterm delivery requires careful planning and coordination. The mother may have agentspecific adverse side effects, such as pancytopenia, if chemotherapy is administered several weeks prior to delivery. The optimal time for delivery is when the mother is neither neutropenic nor thrombocytopenic. Ideally, myelosuppressive chemotherapy should be avoided 3 weeks prior to intended delivery. Timing of delivery may also affect the neonate because the placenta acts as both a vehicle for drug delivery to the fetus and a route of drug excretion. Chemotherapy administered shortly before delivery may not have been eliminated from the fetus by the time of delivery, and prolonged drug levels may persist in the newborn who now lacks the placental route of excretion. The newborn, particularly the preterm newborn, may not be able to metabolize and excrete certain drugs. Chemotherapeutics may not be excreted because the neonatal liver and kidneys have a limited ability to metabolize agents such as the vinca alkaloids or cyclophosphamide.
The common agents used in the management of malignancies during pregnancy and their side effects are shown in Table 2.
THE USE OF CHEMOTHERAPEUTIC AGENTS DURING PREGNANCY
Table 2. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS AND COMMON SIDE EFFECTS Agent Alkylating Agents Busulfan Chlorambucil Cyclophosphamide Antibiotics Doxorubicin Dactinomycin Mitomycin Bleomycin Vinca Alkaloids Vincristine Vinblastine Antimetabolites Methotrexate 5-Fluorouracil Cytosine arabinoside Taxanes Taxol Miscellaneous Cisplatin Hexalen Etoposide
Side Effects Bone marrow depression, pulmonary fibrosis Bone marrow depression Alopecia, bone marrow depression, hemorrhagic cystitis Alopecia, bone marrow depression, cardiomyopathy, radiation recall Alopecia, bone marrow depression, stomatitis Bone marrow depression Pneumonitis and pulmonary fibrosis Neurotoxicity, constipation Bone marrow depression, stomatitis, neurotoxicity Bone marrow depression, stomatitis Bone marrow depression, diarrhea Bone marrow depression, stomatitis Alopecia, bone marrow suppression, hypersensitivity reactions Renal toxicity, oto- and neurotoxicity Bone marrow depression, neurotoxicity Alopecia, bone marrow depression
Alkylating agents such as busulfan, chlorambucil, cyclophosphamide, and nitrogen mustard are associated with an increased incidence of congenital anomalies if administered during the first trimester. The chlorambucil syndrome is characterized by renal aplasia, cleft palate, and skeletal abnormalities after first trimester exposure. The rate of fetal malformation has recently been reported to be 14% when these agents are administered during the first trimester. When administered later in pregnancy, the incidence of malformations decreased to 4%.” Case reports describe cisplatin administration during the second and third trimester without adverse neonatal outcomes.13 Antibiotics
In humans, none of the chemotherapeutic antibiotics have been associated with birth defects.22Turchi and Villasis reviewed 28 cases of anthracycline exposure in pregnancy.24Twenty-three women were exposed to doxorubicin and five were exposed to daunorubicin. Four women received doxorubicin in addition to other agents during the first
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trimester without any malformations in the neonate. There were two maternal and fetal deaths, two spontaneous abortions, and one pregnancy was terminated. Bleomycin .has been administered to the mother without adverse fetal effects.I3,l5 Bleomycin may also cause maternal pulmonary toxicity. If women who received bleomycin prior to or during pregnancy require a general anesthetic during pregnancy, oxygen levels should be administered at room air concentration. The use of increased oxygen levels to improve fetal well-being may cause significant maternal pulmonary toxicity. Actinomycin D has been administered during the second and third trimester without congenital malformations.1°
Vinca Alkaloids Vinca alkaloids are agents that inhibit spindle formation by binding to tubulin and preventing cell division during the M phase. Although vincristine and vinblastine have caused malformations in animals, no reports have yet described fetal malformation in humans. Schapira and Chudley reported no malformations in 10 neonates with first trimester exposure.21Gililland and Weinstein reported no congenital malformations in 11neonates, 3 of whom were exposed during the first trimester.'"
Antimetabolites The folic acid antagonists are the agents most commonly associated with birth defects.' The aminopterin syndrome is characterized by cranial dysostosis, hypertelorism, anomalies of the external ears, micrognathia, and cleft palate after first trimester exposure. Methotrexate, a folic acid antagonist, is a human teratogen and an abortifacient. Infants of women who received methotrexate for malignancy during the first trimester had multiple birth defects, including cranial defects and malformed extremities. Eight normal neonates were delivered to seven women receiving methotrexate in combination with other chemotherapy during the first trimester. Of eight women taking methotrexate during pregnancy for rheumatoid arthritis, five delivered term infants without obvious malformations and three spontaneously aborted.12 Cytosine arabinoside is an analog of the nucleoside deoxycytidine and is phosphorylated to Ara-cytosine triphosphate. Caligiuri and Mayer reported six patients with first trimester exposure to cytosine arabinoside, either alone or in combination with other agents. There were four normal infants and two with congenital malformation^.^ 5-fluorouracil (5-FU) is a pyrimidine antagonist. Case reports exist of congenital anomalies in neonates exposed to 5-FU during the first trirne~ter.~~
THE USE OF CHEMOTHERAPEUTIC AGENTS DURING PREGNANCY
To date there are no published reports of paclitaxel (taxol) administered during pregnancy. Paclitaxel is teratogenic in animals.26
A combination of chemotherapeutic agents that have been used effectively as single agents is commonly used for the treatment of many cancers. The rate of fetal malformations associated with combination chemotherapy is similar to the rate observed with single agent chemotherapy. NATIONAL REGISTRY
In 1985 the National Cancer Institute established a national registry for in utero exposure to chemotherapeutic agents.I8 Of the first 210 cases studied, 29 were abnormal outcomes with a total of 52 birth defects. Although extensive generalization is not possible because of the small number of birth defects, the data are reassuring in that only two abnormal outcomes were associated with exposure after the first trimester. Because the data are voluntarily reported, there is a potential for bias. The true number of drug exposures is not known and the registry may reflect bias in that only adverse outcomes have been reported or, conversely, only normal outcomes have been reported.
The delayed effects of in utero exposure to chemotherapeutic agents are less well documented than the immediate birth defects. Chemotherapy-induced second malignancies, impaired growth and development, intellectual impairment, and infertility have been reported.27Clear cell vaginal carcinoma in daughters of women taking diethylstilbestrol (DES) serves as a reminder for both the difficulty and the necessity of longterm follow-up. BREAST-FEEDING
Many chemotherapeutic agents, including hydroxyurea, cyclophosphamide, cisplatin, doxorubicin, and methotrexate can be found in breast milk. Breast-feeding is, therefore, contraindicated in women receiving ~hemotherapy.~,
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SUMMARY The information available concerning the effects of chemotherapy administered during pregnancy is limited and consists of case reports and small series. A registry has been established at the National Cancer Institute, but there are currently only several hundred cases of neonates exposed to chemotherapy registered. All clinicians who care for women receiving chemotherapy during pregnancy should report those experiences to the National Cancer Institute to increase the data base. When chemotherapy is used during the embryogenesis period in the first trimester there is an increased rate of spontaneous abortion and major birth defects. The most toxic chemotherapeutic agents administered during pregnancy are methotrexate and aminopterin and should be avoided when possible, particularly during the first trimester. Pregnancy-related physiologic changes should be kept in mind when dosing and administering cytotoxic chemotherapy. The risk of fetal malformation when chemotherapy is administered during the second and third trimesters is probably not greater than background rate, but there may be a greater risk of stillbirth, fetal growth restriction, premature birth, and maternal and fetal myelo~uppression.~~ Breastfeeding should be avoided in women receiving chemotherapy.
References 1. Aviles A, Diaz-Magneo JC, Talavera A, et al: Growth and development of children of mothers treated with chemotherapy during pregnancy: Current status of 43 children. Am J Hematol 36243, 1991 2. Aviles A, Niz J: Long-term follow-up of children born to mothers with acute leukemia during pregnancy. Med Pediatr Oncol 163, 1988 3. Bandyk EA, Gilmore MA. Perceived concerns of pregnant women with breast cancer treated with chemotherapy. Oncol Nurs Forum 22:975, 1995 4. Ben-Baruch G, Menczer J, Goshen R, et al: Cisplatin excretion in human milk. J Natl Cancer Inst 84:451, 1992 5. Caligiuri MA, Mayer RJ: Pregnancy and leukemia. Semin Oncol 16:388, 1989 6. Doll RC, Ringenberg QS, Yarbo JW: Management of cancer during pregnancy. Arch Intern Med 14:2058, 1988 7. Doll RC, Ringenberg QS, Yarbo JW: Antineoplastic agents and pregnancy. Semin Oncol 16337, 1989 8. Egan PC, Costanza M, Dadion P, et al: Doxorubicin and cisplatin excretion into human breast milk. Cancer Treat Rep 69:1387, 1985 9. Garber JE: Long-term follow-up of children exposed in utero to antineoplastic agents. Semin Oncol 16437, 1989 10. Gililland J, Weinstein L The effects of cancer chemotherapeutics agents on the developing fetus. Obstet Gynecol Sum 386, 1983 11. Glantz J C Reproductive toxicology of alkylating agents. Obstet Gynecol SUIT49:709, 1994 12. Kozlowski RD, Steinbrunner JV,MacKenzie AH, et al: Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 8859, 1990 13. Malone JM, Gershenson DM, Creasy RK, et a1 Endodermal sinus tumor of the ovary associated with pregnancy. Obstet Gynecol 68:865, 1986
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14. Mulvihill JJ, McKeen EA, Rosner F, et a1 Pregnancy outcome in cancer patients. Cancer 60:1143, 1987 15. Nettleton J, Long, Kuban D, et al: Breast cancer during pregnancy: Quantifying the risk of treatment delay. Obstet Gynecol 87414, 1996 16. Ortega J: Multiple agent chemotherapy including bleomycin in non-Hodgkins’s lymphoma during pregnancy. Cancer 40:282?, 1977 17. Petrek JA: Pregnancy-associated breast cancer. Semin Surg Oncol 7306, 1991 18. Randall T National registry seeks scarce data on pregnancy outcomes during chemotherapy. JAMA 269:323, 1993 19. Reichman BS, Green KB: Breast cancer in young women: Effect of chemotherapy on ovarian function, fertility, and birth defects. Monogr Natl Cancer Inst 16125, 1994 20. Reynoso EE, Shepherd FA, Messner HA, et al: Acute leukemia during pregnancy: The Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098, 1987 21. Schapira DV, Chudley AE: Successful pregnancy following continuous treatment with combination chemotherapy before conception and throughout pregnancy. Cancer 542300, 1983 22. Schardein JL: Cancer chemotherapeutics agents. In Schardein JL (ed): Chemically Induced Birth Defects, 2nd ed. New York, Marcel Dekker Inc 1993, p 457 23. Stephens JD, Golbus MS, Miller TR, et al: Multiple congenital anomalies in a fetus exposed to 5-flurouracil during the first trimester. Am J Obstet Gynecol 137746, 1980 24. Turchi JJ, Villasis C: Anthracyclines in the treatment of malignancy in pregnancy. Cancer 61:435,1988 25. Waalen J: Pregnancy poses tough questions for cancer treatment. J Natl Cancer Inst 83:900, 1991 26. Weibe VJ, Sipila PEH Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol 16:75, 1994 27. Zemlickis D, Lishner M, Degendorfer P, et al: Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 152:573, 1992
Address reprint requests to Joel I. Sorosky, MD Associate Professor Division of Gynecologic Oncology Department of Obstetrics and Gynecology The University of Iowa Hospitals and Clinics 200 Hawkins Drive Iowa City, IA 52242