Special Issues in Pregnancy

Fetal Development and Physiology

The three phases of fetal development are implantation, organogenesis, and growth. The implantation phase lasts from conception to 2 weeks. Exposure to chemotherapy at this stage usually results in an all-or-none phenomenon—that is, spontaneous abortion or no sequelae. Organogenesis occurs between 2 and 7 to 12 weeks. Noxious stimuli at this time may lead to organ dysgenesis, resulting in fetal malformation or death. The growth phase occurs from the second trimester to term. During this time, toxic stimuli to the mother and fetus may result in fetal growth retardation, which can be associated with abnormal brain development and subsequent learning difficulties. However, as will be discussed, fetal growth retardation has not been demonstrated to be a significant clinical concern in women receiving chemotherapy during the second and third trimesters.

Because most chemotherapy drugs are uncharged, lipophilic, of low molecular weight, and minimally protein bound, they cross the placenta to the fetal circulation. The placenta is the primary portal of exit of waste products and toxins from the fetus. However, in general, the metabolites are more polar than the parent compound, might not cross the placenta as easily, and hence may accumulate in fetal tissues or amniotic fluid. The fetal liver can metabolize drugs as early as 7 to 8 weeks of pregnancy, but the extent to which the fetal liver and kidneys participate in drug elimination is minimal.

Maternal Physiology: Relevance to Chemotherapy and Surgery

Pregnancy induces several important physiologic changes that cause significant alterations in the metabolism and efficacy of commonly used medications ( Box 61.1 ). However, few data exist to guide physicians in adjustment of drug regimens (see the section on chemotherapy dosage).

Physiologic changes in pregnancy also affect surgical treatment and planning. Pregnancy is accompanied by increased plasma volume and dilutional anemia, reduced mean arterial pressure, increased oxygen consumption, and a narrow respiratory reserve. Cardiac output is increased by 30% to 50% as early as the second trimester, but in the supine position the gravid uterus can compress the inferior vena cava, resulting in decreased venous return and reduction in cardiac output. Fetal development or viability may be jeopardized by hypotension and hypoxemia. Nevertheless, surgery can usually be performed safely during pregnancy; a small but increased risk of low birth weight and spontaneous abortion occurs, but there is no increased risk of fetal malformation.

Diagnostic Radiology for Staging

The practitioner who is responsible for the radiologic examination must take all reasonable steps beforehand to advise the pregnant patient of the potential risks to the embryo or fetus that are associated with in utero exposure. A tally of total radiation dose received during pregnancy should be kept.

Radiation can be divided into ionizing and nonionizing radiation. Ionizing radiation can penetrate tissue and damage cellular DNA, resulting in mutation and ultimately affecting the development and viability of the fetus. Numerous studies of radiation exposure after the atomic bomb detonations in Japan confirmed that this effect is dependent on radiation dose and stage of fetal development at the time of exposure ( Table 61.1 ). Fetal abnormalities associated with exposure to excessive ionizing radiation include microcephaly, eye malformation, and growth retardation. The American College of Obstetricians and Gynecologists recommendations for imaging during pregnancy state that 5-cGy exposure to the fetus is not associated with any increased risk of fetal loss or birth defects. Radiation exposure is well below this amount for most procedures except for the maximum dose with computed tomography (CT) scanning of the abdomen and pelvis ( Table 61.2 ). A more relevant concern is an increased risk of childhood cancer. After a gestational age of 3 to 4 weeks, the number of excess cancer cases (leukemia and solid tumors) up to age 15 years after radiation in utero is estimated to be 1 in 17,000 per 0.1 cGy. The baseline cancer risk in the first 15 years is about 1 in 650, and thus fetal doses of 2.5 cGy will approximately double the risk; however, this represents an excess lifetime fatal cancer risk of less than 0.5%.

Teratogenicity of Chemotherapy

The US Food and Drug Administration (FDA) has defined risk categories for all drugs based in part on the evidence in animals of fetal harm. Most chemotherapeutic agents are category D, for which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Extrapolation of teratogenic and mutagenic effects of chemotherapeutic agents from animals to human organogenesis is difficult, however, because of differences in susceptibility among species. The timing of fetal drug exposure is critical. Administration of drugs within 1 week of conception may result in a spontaneous abortion or a healthy fetus. During the first trimester, when organogenesis occurs, drugs may produce congenital malformations and/or result in spontaneous abortion. Other factors that may influence the probability of teratogenesis include the frequency of drug administration, duration of exposure, synergistic effects of multiple drugs, use of radiation, and individual genetic susceptibility.

Most human data about chemotherapy during pregnancy involve small series or case reports, which are prone to reporting bias. Specific or systemic information about the teratogenicity of individual cytotoxics or modern multiagent chemotherapy regimens is limited, particularly in the first trimester. Many reported malformations have occurred after exposure to multiple agents, making it difficult to assign blame to a single causative agent. It is important to note that the overall incidence of major congenital malformations with chemotherapy use after the first trimester is approximately 3% (close to the risk in the general population), although the incidence of minor malformations may be as high as 9%, and 10% to 15% of all pregnancies result in a miscarriage or spontaneous abortion. Extrapolation from older data also might not be appropriate, because many of these drugs (e.g., alkylating agents such as nitrogen mustard and busulfan and antimetabolites such as aminopterin) are now rarely used. Limited experience in the first trimester with regimens such as Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) and cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisolone (CHOP) suggests low rates of teratogenicity. In the second and third trimesters, drugs very rarely cause significant malformations but could impair fetal growth and development. The current available literature suggests that chronic prenatal chemotherapy exposure does not result in learning or behavioral problems (also known as functional teratogenesis ). Overall, the use of systemic antineoplastic therapy alone appears to be accompanied by significantly lower risk than is commonly appreciated.

Specific Chemotherapy Drugs

Table 61.3 details the available experience with some of the more commonly used chemotherapy drugs in animals and at various stages of human pregnancy, together with the FDA category. The recommendations are those published by Briggs and colleagues, with some additional comments from the authors. The choice of chemotherapy agents should be based on the most current literature.