Antineoplastic agents and pregnancy.

The data presented are based on a search of the English-language literature of cancer in pregnancy from 1971 through January 1989. In addition, a search of the Englishlanguage literature of antineoplastic agents from 1975 through January 1989 was made. Pregnancy associated with cancer is relatively uncommon, but the decision to initiate chemotherapy in such patients may be extremely difficult for everyone involved because of the possible deleterious effects on the offspring. In pregnancy, there is a considerable increase in the amount of total body water. Plasma volume increases by approximately 50 per cent, resulting in a larger dilutional space for water-soluble drugs. The albumin concentration decreases and plasma proteins are increased due in part to high estrogen levels. Antineoplastic drugs compete for binding sites on albumin and other plasma proteins. Such changes affect drug distribution and, thus, plasma drug concentration is likely to be greatest for drugs of low-lipid solubility that are tightly bound to plasma protein. A increased distribution volume will decrease the peak concentration of a drug following bolus administration, and the half-life will be longer unless drug metabolism or excretion is also increased. In addition, hepatic oxidation by the mixed function oxidase system is more rapid during pregnancy; there is an increase in renal plasma flow, glomerular filtration rate, and creatinine clearance. Such changes could lead to an increased clearance of drugs from the body. Given the altered physiologic state of pregnancy, there are inadequate pharmacokinetic studies to determine whether present dosages of antineoplastic agents used in the nonpregnant woman are appropriate in pregnancy. It is unlikely that such data will ever become available. In its absence, it must be assumed that drug dosage used in the nonpregnant state is adequate in pregnancy. During the first trimester, chemotherapeutic agents should be avoided. If this option is not feasible then one needs to decide whether treatment can safely be postponed until the second trimester or later. Several reviews have confirmed the observation that the phase of embryonic organogenesis of the first trimester is the critical period for teratogenesis. The folic acid antagonists aminopterin and methotrexate have been reported more frequently than any other agent to be associated with fetal abnormalities when given in the first trimester. If chemotherapy must be given, the folicacid antagonists should be avoided. Alkylating agents appear to be less potent teratogens than antimetabolites, with six cases of fetal malformations reported among 50 patients at risk. Four of these six mothers also had received radiation therapy. Alkylating agents, in contrast to methotrexate, are frequently key ingredients in curative or significantly palliative therapeutic regimens. Although vinblastine is highly teratogenic in animal models, there has been only one reported abnormality observed in the offspring of 14 women treated with vinblastine in the first trimester. Therefore, the use of vinblastine in the first trimester may be relatively safe. There are no data on the closely related alkaloid, vincristine. The vinca alkaloids, like the alkylating agents, are frequently included in curative regimens. The apparent rate of fetal malformation associated with the combination chemotherapy is similar to that observed with single agents. If one excludes the folate antagonists and concomitant use of radiation, then the incidence declines to 6 per cent for single agents. In contrast to these first trimester findings, there is no evidence of an increased risk of teratogenicity associated with the administration of cytotoxic drugs in the second and third trimesters. In 150 cases treated with chemotherapy during the last two trimesters of pregnancy, there have been four reported cases of birth defects. Delivery should be planned when maternal Mood counts are optimal. A complete blood count should be obtained on the newborn and examination for congenital malformations and organ dysfunction should be performed. Breast feeding is contraindicated as antineoplastic agents administered systemically may reach significant levels in milk.