Teratogenicity Of Chemotherapeutic Agents

All chemotherapeutic agents are theoretically teratogenic and mutagenic. Fetal malformation, intrauterine growth retardation (IUGR), spontaneous abortion, and fetal death may occur. The teratogenicity of any particular drug depends on the timing of exposure, the total dose, and the drug characteristics on placental transfer. Drugs with high lipid solubility, low molecular weight, and decreased plasma protein binding have greater tendency for placental transfer from mother to fetus.

Chemotherapeutic agents cause cell death through several different mechanisms. They act on rapidly proliferating cells and thereby are potentially harmful to fetal tissues. Normal fetal cells undergo rapid growth with multiple cell divisions during the first trimester, especially during organogenesis (2-11 weeks of gestation). With the exception of brain and gonadal tissues, organogenesis is accomplished by 12 weeks of gestation. Therefore, if chemotherapy is administered during the first trimester, there is a high risk of fetal death due to immaturity of all fetal tissues.922 During organogenesis, drug-induced teratogenesis can also manifest with major or minor abnormalities of organ systems without fetal death.

If chemotherapy causes severe damage early in gestation, spontaneous abortion often occurs. If sublethal damage occurs during organogenesis, malformation can result. Once organ development is complete, the rate of cell division decreases and the rate of cell injury and congenital malformations due to chemotherapy equals the risk in the general population (3%).2324 Although the available data suggests that chemotherapy administration after organogenesis does not appear to cause significant teratogenicity, one needs to take into account that central nervous system development is not complete and fetal growth and development may still be affected.

Doll et al.9 reported on 139 cancer patients treated with various chemotherapeutic agents during the first trimester; the rate of fetal malformations was 17%. In 45 of these patients exposed to two or more agents concurrently, 16% had infants with malformations. If patients who received folate antagonists and radiation therapy were excluded, the malformation rate dropped to 6%.

The Toronto Leukemia Study Group reported that one-third of all infants exposed to chemotherapy in utero had pancytopenia at birth.25 Aviles and Niz26 reported on 17 infants delivered to mothers with acute leukemia treated during pregnancy. They concluded that chemotherapy did not have a major impact on later development. Garber27 also reported on 43 children born to mothers with hematologic malignancies who underwent chemotherapy during pregnancy. Nineteen of the mothers received treatment during the first trimester. No physical, neurologic, psychologic, hema-tologic, or cytogenetic defects were detected.

Cytarabine is a significant chemotherapeutic agent in leukemia. Wagner et al.28 treated a patient for ALL, with relapse of disease on maintenance therapy, who acquired a second complete remission. The patient was on maintenance therapy with cytarabine when she conceived. Her three cytarabine cycles may have coincided with normal limb bud development, as her infant had a malformed right hand and bilateral femur, tibiofibular and foot defects, as well as bilateral external ear abnormalities.28

Another woman with AML conceived while undergoing treatment with cytarabine and oral thiogua-nine.29 She continued this treatment until her term delivery. The neonate had upper and lower distal limb abnormalities, especially of his hands. The patient was continued on the same medications and again conceived 2-4 weeks after her last dose of chemotherapy. This infant was born without any abnormalities.29

Caligiuri and Mayer23 reported on leukemic pregnant patients treated with cytarabine as either a single agent or in combination. Eighteen of these women gave birth to normal offsprings, and five pregnancies ended in elective abortions. Another AML patient was 20 weeks pregnant when treated with cytarabine and daunoru-bicin; she received reinduction with mitoxantrone and cytarabine. She subsequently underwent consolidation therapy with one cycle of cytarabine and idarubicin between weeks 29 and 30. Two days later she delivered a stillborn but phenotypically normal infant.30

The use of anthracyclines with combination chemotherapy has been reported by Turchi and Villasis in 20 pregnant patients.31 Among the 20 patients treated, no fetal malformations resulted, but there was one maternal-fetal death, one therapeutic abortion, one spontaneous abortion, and four neonatal problems (marrow hypoplasia, pneumothorax, sepsis, and poly-cythemia) that all resolved.31 In the infant who developed polycythemia, the maternal course was complicated by relapsed null-cell ALL on maintenance folate antimetabolites, requiring reinduction chemotherapy, pulmonary infiltrates requiring mechanical ventilation, and prolonged bone marrow aplasia. The infant was born at 36 weeks' gestation, weighed 2400 g, and poly-cythemia resolved with normal marrow function.32

APL has been reported in approximately 10% of cases of leukemia in pregnancy, similar to the percentage in nonpregnant leukemic patients. In 1995, Hoffman et al.33 published a case report and a review of the English literature that compiled 24 cases of APL occurring in pregnant patients. Ten of these patients received an anthra-cycline with or without cytarabine or another agent for induction therapy. Three fetuses were exposed in the first trimester, with one spontaneous abortion, and five were exposed in the second trimester; the seven live neonates were normal. Two patients were treated in the third trimester, with one intrauterine death at 29 weeks' gestation.33

Requena et al.34 described two patients with APL treated with cytarabine, thioguanine, daunorubicin, and mitoxantrone during the second trimester. Both women delivered normal neonates, though one infant was intubated for a total of 7 minutes. Takatsuki et al.35 evaluated two APL patients who were both given a non-ATRA chemotherapy regimen. One patient received combination chemotherapy with daunorubicin at 14 weeks, when she presented with APL and DIC; intrauterine fetal death occurred (IUFD) at 19 weeks. The other patient was diagnosed with APL and DIC at 29 weeks of gestation. Combination chemotherapy including daunoru-bicin produced a complete remission, and the patient successfully delivered a normal infant.35

The advent of ATRA brought unknown risks to pregnant patients with APL. Another vitamin A derivative, 13-ris-retinoic acid, causes a specific retinoic embryopathy when taken in the first trimester.3 Therefore, ATRA would be suspected of causing a similar set of deformities. Three of the patients described by Hoffman et al.33 received ATRA between gestational weeks 30 and 32; they delivered a total of four normal, but premature, neonates. One patient was diagnosed with relapsed APL in the first trimester and treated with ATRA. Her infant was premature, but healthy at 15 months of age33 Giagounidis et al.36 reviewed 13 cases of APL in pregnancy treated with ATRA and did not find any fetal malformations attributed to ATRA. Several reports of fetal outcomes of pregnant patients who received ATRA are illustrated in Table 106.2.37-47

With the exception of the folate antimetabolites, ter-atogenicity cannot be completely attributed to one single

Table 106.2 Pregnancy outcomes of 11 patients with APL who received ATRA during gestation
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