Chapter 32: Neoplasia During Pregnancy

Cancer complicates ~1 in every 1000 pregnancies. Of all the cancers that occur in women, less than 1% complicate pregnancies. The four cancers that most commonly complicate pregnancies are cervical cancer, breast cancer, melanoma, and lymphomas (particularly Hodgkin’s lymphoma); however, virtually every form of cancer has been reported in pregnant women (Table 32-1). In addition to cancers developing in other organs of the mother, gestational trophoblastic tumors can arise from the placenta. The problem of cancer in a pregnant woman is complex. One must take into account (1) the possible influence of the pregnancy on the natural history of the cancer, (2) effects on the mother and fetus of complications from the malignancy (e.g., anorexia, nausea, vomiting, malnutrition), (3) potential effects of diagnostic and staging procedures, and (4) potential effects of cancer treatments on both the mother and the developing fetus. Generally, the management that optimizes maternal physiology is also best for the fetus. However, the dilemma occasionally arises that what is best for the mother may be harmful to the fetus, and what is best for the fetus may compromise the ultimate prognosis for the mother. The best way to approach management of a pregnant woman with cancer is to ask, “What would we do for this woman in this clinical situation if she was not pregnant? Now, which, if any, of those plans need to be modified because she is pregnant?”

Pregnancy is associated with a number of physiologic changes that frequently result in symptoms that may make it difficult to recognize symptoms or physical findings suggestive of a neoplasm. Increased sensitivity of central chemoreceptors to Pco₂ drives an increase in minute ventilation that many women perceive as dyspnea at rest or with minimal exertion. The combination of increased total body water, decreased colloid oncotic pressure, and some obstruction of venous return from the lower extremities causes demonstrable dependent edema in more than 50% of pregnant women. Decreased gastrointestinal motility due to high serum progesterone levels and mechanical compression from an enlarging uterus cause early satiety, gastroesophageal reflux, nausea, vomiting, and constipation. Hemorrhoids develop and often bleed. Breasts enlarge and increase in density and “lumpiness.” These changes may result in delayed recognition and more advanced disease at diagnosis.

Physiologic changes in the maternal immune system necessary to facilitate retention of the fetal semi-allograft raise concerns that the relationship of a cancer with its host may be altered to the detriment of the maternal host. One half of all the genes necessary to create a new individual by sexual reproduction come from each parent. This provides the opportunity for many antigenic differences between the conceptus and the mother. Mammalian placentation has been a very successful method of reproduction, but it has necessitated some combination of both fetal and maternal evolutionary immune adaptations. These mechanisms are incompletely understood and remain an area of active investigation. It does seem likely, however, that this has been accomplished without a general, nonspecific blunting of the maternal immune response, which would be maladaptive to the mother. The multiple mechanisms likely include some “masking” of fetal antigens from recognition by the maternal immune system, blunting the maternal inflammatory response locally at the placental–maternal interface and induction of fetal-specific maternal immune tolerance to avoid rejection. Attention has turned to a subset of CD4+ induced, peripherally produced regulatory T cells that express the X chromosome encoded transcription factor Foxp3 (so-called Tregs). When these Foxp3 cells develop centrally in the thymus, they are termed “Tregs.” When Foxp3-expressing cells develop peripherally, they are called “Pregs.” These regulatory cells suppress the immune response against “self ” and foreign antigens. They seem to be capable of suppressing the maternal response to paternal antigens expressed by the fetus and creating memory cells that retain tolerance to the same paternal antigens in subsequent pregnancies. Unfortunately, in a mouse model, the interleukin (IL) 10 produced by these cells enhanced susceptibility to infection by Listeria and Salmonella, while ironically not proving essential for retaining the fetal graft. Undoubtedly much remains to be learned about this critical immune balance.

RADIATION IN PREGNANCY

Exposure of developing fetuses to ionizing radiation may cause adverse fetal effects; awareness among physicians of this potential toxicity has resulted in a disproportionate aversion to diagnostic imaging in pregnancy. First, it must be stated that there are very useful imaging modalities (i.e., ultrasound and magnetic resonance imaging [MRI]) that do not use any ionizing radiation and are not associated with any demonstrable adverse fetal effects. There are three potential adverse fetal effects of ionizing radiation: teratogenesis (induction of anatomic birth defects), mutagenesis, and carcinogenesis. The fetus is most sensitive to teratogenesis during organogenesis in the first trimester. The dose of ionizing radiation necessary to induce birth defects in human fetuses is derived from studies of the survivors of the atomic bomb explosions and by extrapolation from controlled experiments in nonhuman mammals. From these data sources, it is clear that a minimum of 5 rem and more likely greater than 10 rem exposure is needed to induce birth defects in the first trimester. The fetal doses of radiation associated with some common diagnostic radiologic procedures are displayed in Table 32-2. The data in Table 32-2 show that no single procedure or selective combination of diagnostic procedures will exceed the very conservative 5 rem teratogenic threshold. Teratogenic effects later in pregnancy are largely limited to microcephaly and require exposures exceeding 25 rem. The reason for the disproportionate concern about radiation exposure and birth defects is that 2.5% of all fetuses are affected with birth defects without radiation exposure and, therefore, 2.5% of women undergoing any diagnostic imaging procedure will deliver malformed fetuses. Spontaneous mutations occur relatively infrequently, and high doses of radiation (>150 rem) are required to cause a demonstrable increase in that rate. The magnitude of the risk of carcinogenesis in offspring exposed as fetuses to diagnostic doses of radiation has been very difficult to measure due to the relative rarity of cancer in children and the long duration of follow-up that might credibly be needed to see the effect. The inconsistent results and small effect sizes observed from diagnostic exposures make it likely that, if there is an effect, it is very small and, if there is not a significant effect, it will be impossible to prove that fact to everyone’s satisfaction. No imaging using ionizing radiation should be done without a compelling reason and due consideration to obtaining the necessary information by other imaging modalities. Exposure to diagnostic and therapeutic radionuclides, especially radioactive iodine, poses unique risks, but a full discussion of these is beyond the scope of this chapter. Radiation therapy uses radiation doses three orders of magnitude greater than diagnostic procedures, entails substantial risks if the fetus is in the radiation field, and is rarely appropriate in pregnancy. Finally, although difficult to prove, it is likely that more harm has come to pregnant women from failing to perform appropriate diagnostic procedures than has been done to their offspring from performing appropriate diagnostic procedures.

CHEMOTHERAPY IN PREGNANCY

There are a number of reasons why it is impossible to make many definitive statements regarding the safety and efficacy of chemotherapy in pregnancy. All of the available data in the literature are published as case reports or case series. The quality and completeness of the data are inconsistent and often poor. Reports may come from medical oncologists, obstetricians, pediatricians, or other treating physicians familiar with the information important to the report from their own perspective but missing information important for other specialty areas. Reports frequently lack critical details of drug administration, such as dose, duration, cumulative dose, and timing of exposure in gestation, and outcomes, including birth weight and gestational age at delivery, indication for or cause of premature delivery, and follow-up of offspring beyond the immediate neonatal period. There are a wide variety of agents available to treat cancer, and they are usually used in combinations. This results in the fact that every patient is almost unique (an experiment of one) in the combination of agents, doses, durations, and gestational ages of administration, making it very difficult to attribute what benefit or toxicity accrues to which agent. Fortunately, cancer in pregnant women is sufficiently rare that it takes quite a while to accumulate enough information for any one agent or combination of agents to be confident about what toxicities (including congenital malformations) are truly associated with which agents. There is such rapid progress in cancer chemotherapy that by the time there may seem to be enough information about the agents currently in use to use them intelligently and counsel patients meaningfully, the cancer community has moved on to newer, more efficacious, and hopefully less toxic agents for which there is little or no experience in pregnancy. Finally, for obvious reasons, there are no untreated controls for comparison. It may be very difficult to sort out the maternal consequences (nausea, vomiting, fever, weight loss, dehydration) that might result directly from the malignancy and cause adverse pregnancy outcomes from some of the toxicities of the chemotherapeutic agents used to treat the malignancy.

Generally, toxic chemotherapy should be avoided during pregnancy, if at all possible. It should virtually never be given in the first trimester. However, a variety of single agents and combinations have been given in the second and third trimesters, without a high ­frequency of toxic effects to the pregnancy or the fetus, but data on safety are sparse. Maternal factors that may influence the pharmacology of chemotherapeutic agents include the 50% increase in plasma volume, altered absorption and protein binding, increased glomerular filtration rate, increased hepatic mixed function oxidase activity, and third space created by amniotic fluid. The fetus is protected from some agents by placental expression of drug efflux pumps, but decreased fetal hepatic mixed function oxidase and glucuronidation activity may prolong the half-life of agents that do cross the placenta. A database on the risks associated with individual chemotherapy agents is available on the Internet (http://ntp.niehs.nih.gov/ntp/ohat/cancer_chemo_preg/chemopregnancy_monofinal_508.pdf).

Optimal management strategies have not been developed based on prospective clinical trials. Management of a malignancy complicating pregnancy will be critically determined by the gestational age when the malignancy is diagnosed and the anticipated natural history of the lesion, if left untreated. On one extreme, if the malignancy is slowly progressive, the patient is near her delivery date, and waiting until delivery to begin treatment would not be anticipated to compromise maternal prognosis, then treatment could be delayed until after delivery to avoid fetal exposure to chemotherapy. If there is a greater sense of urgency to begin definitive treatment to avoid compromising maternal prognosis, and the patient is beyond 24 weeks of gestation but remote from her delivery date, then treatment (surgical, medical, or both) might be initiated during pregnancy and plans made to deliver the fetus early to avoid exposure to more chemotherapy than absolutely necessary. Finally, if the patient is in her first trimester and toxic chemotherapy must be initiated promptly to avoid a very poor maternal outcome, then it may be necessary to consider therapeutic abortion to avoid maternal disaster and fetal survival with injury resulting in long-term morbid sequelae. No two cases are precisely alike, and inevitably, decision making must be individualized, preferably with consultation with a multidisciplinary team including medical oncology, surgical oncology if appropriate, maternal–fetal medicine, neonatology, and anesthesia. Pregnancy appears to have little or no impact on the natural history of malignancies, despite the hormonal influences. Spread of the mother’s cancer to the fetus (so-called vertical transmission) is exceedingly rare.

The incidence of cervical cancer in pregnant women is roughly comparable to that of age-matched controls who are not pregnant. Invasive cervical cancer complicates about 0.45 in 1000 live births, and carcinoma in situ is seen in 1 in 750 pregnancies. About 1% of women diagnosed with cervical cancer are pregnant at the time of diagnosis. Early signs of cervical cancer include vaginal spotting or discharge, pain, and postcoital bleeding, which are also common features of pregnancy. Early visual changes in the cervix related to invasive cancer can be mistaken for cervical decidualization or ectropion (columnar epithelium on the cervix) due to pregnancy. Women diagnosed with cervical cancer during pregnancy report having had symptoms for 4.5 months on average.

Approximately 95% of all cervical cancer is caused by human papillomavirus (HPV) infections, with types 16 and 18 accounting for about 70% of cervical cancer. The rate of carriage of these serotypes is highest among women in their early twenties and can be reduced with the use of vaccination before exposure. Women generally tend to clear the infection by age 30, with the risk of cervical cancer being highest among those who fail to clear the infection. Screening is recommended at the first prenatal visit and 6 weeks postpartum. The rate of cytologic abnormalities on Pap smear in pregnant women is about 5–8% and is not much different than the rate in nonpregnant women of the same age.

In 2012, several sets of recommendations were published for screening for cervical cancer: one by the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP); a second by the U.S. Preventive Services Task Force (USPSTF); and a third by the American College of Obstetricians and Gynecologists (ACOG). Although the details of the recommendations for screening and management of abnormal results differ slightly among the three sets of guidelines, there is general consensus that cytology screening should start at age 21 and continue every 3 years through age 29. After age 30, cytology screening frequency may be reduced to every 5 years if accompanied by co-testing for HPV. Recommendations for management of abnormal cytology findings are complex and determined by the degree of abnormality of the cytology finding (e.g., atypical squamous cells of undetermined significance; atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; low-grade squamous intraepithelial lesion; or high-grade squamous intraepithelial lesion), the HPV status of the patient, the age of the patient, and whether this is the first abnormal finding or a persistent abnormality. A full discussion of all the treatment recommendations based on these factors is beyond the scope of this chapter. Some of the diagnostic procedures recommended for evaluation of nonpregnant women are contraindicated in pregnancy, and the indications for some procedures are modified in the setting of pregnancy. Suffice it to say that the evaluation of women with abnormal cervical cytology in pregnancy should be referred to knowledgeable and experienced gynecologists or gynecologic oncologists.

Cervical intraepithelial neoplasia is a slowly progressive lesion and has a low risk of progression to invasive cancer during pregnancy (~0.4%), and many low-grade lesions (36–70%) regress spontaneously. Accordingly, some physicians defer definitive diagnostic procedures in pregnant women until 6 weeks postpartum unless they are at high risk for invasive disease. If invasive disease is suspected and the pregnancy is between 16 and 20 weeks, a cone biopsy may be performed to make the diagnosis and may be curative for some lesions; however, the procedure may cause heavy bleeding due to the increased vasculature in the gravid cervix and increases the risk of premature rupture of membranes and preterm labor two- to threefold. Cone biopsy should not be done within 4 weeks of delivery. The only indication for therapy of cervical neoplasia in pregnant women is the documentation of invasive cancer.

Management of invasive disease is guided by the stage of disease, the gestational age of the fetus, and the desire of the mother to have the baby. If the disease is in early stage and the pregnancy is desired, it is safe to delay treatment regardless of gestational age until fetal maturity allows for safe delivery. Abortion followed by definitive therapy is recommended for women with advanced, but potentially curable, cancer in the first or second trimester (Chap. 46). If the disease is in an advanced stage in early pregnancy and the patient declines pregnancy termination to permit prompt definitive therapy, she must be informed of the fact that the maternal safety of delaying therapy is unproven. In women in the third trimester with advanced disease, the mother should be treated with betamethasone to accelerate fetal lung maturation and the baby should be delivered at the earliest possible gestational age followed immediately by stage-appropriate therapy. Most women with invasive cancer have early-stage disease. If the disease is microinvasive, vaginal delivery can take place and be followed by definitive treatment, usually conization. If a lesion is visible on the cervix, delivery is best done by caesarian section and followed by radical hysterectomy.

Breast cancer complicates approximately 1 in 3000 to 10,000 live births. About 5% of all breast cancers occur in women age 40 years or younger. Among all premenopausal women with breast cancer, 25–30% were pregnant at the time of diagnosis. It has been recognized for some time that breast cancer associated with pregnancy generally seems to have a poorer prognosis for both overall survival and progression-free survival. The definition of pregnancy-associated breast cancer (PABC) has differed in various publications, but a generally accepted definition is breast cancer diagnosed during pregnancy or within 1 year of delivery. There are likely several reasons for the observation of the poorer prognosis. Breast cancers diagnosed during pregnancy are often diagnosed at a later stage of disease and so have a poorer outcome. The late diagnosis is often due to the fact that early physical signs of the disease are missed or attributed to the changes that occur in the breast normally as a function of pregnancy. However, a discreet breast mass in a pregnant woman should never be assumed to be normal. Another reason is the more aggressive behavior of the cancer possibly related to the hormonal milieu (estrogen increases 100-fold; progesterone increases 1000-fold) of the pregnancy. However, about 70% of the breast cancers found in pregnancy are estrogen receptor–negative. About 28–58% of the tumors express HER2, a biologically more aggressive breast cancer subset. Another factor is that aggressive, definitive chemotherapy and radiation therapy are often delayed due to concerns about the consequences of those treatments for the fetus. Younger women with breast cancer have a higher likelihood of having mutations in BRCA1 or BRCA2.

Differences in presentation between PABC and breast cancers diagnosed in nonpregnant women are shown in Table 32-3. About 20% of breast cancers are detected in the first trimester, 45% in the second trimester, and 35% in the third trimester. Some argue that stage for stage, the outcome is the same for breast cancer diagnosed in pregnant and nonpregnant women. Primary tumors in pregnant women are 3.5 cm on average, compared to <2 cm in nonpregnant women. A dominant mass and a nipple discharge are the most common presenting signs, and they should prompt ultrasonography and breast MRI exam (if available) followed by lumpectomy if the mass is solid and aspiration if the mass is cystic. Mammography is less reliable in pregnancy due to the increased breast density. Needle aspirates of breast masses in pregnant women are often nondiagnostic or falsely positive. Even in pregnancy, most breast masses are benign (~80% are adenoma, lobular hyperplasia, milk retention cyst, fibrocystic disease, fibroadenoma, or other rarer entities).

Many studies comparing outcomes among women with PABC to those of nonpregnant women have small sample sizes, and there is considerable heterogeneity among the study results, but a formal meta-analysis including multiple adjustments and sensitivity analyses confirms the clinical impression of poorer outcomes for women with PABC. The hazard ratios were 1.44 for poorer overall survival and 1.60 for poorer disease-free survival.

Although having had a pregnancy is a protective factor against breast cancer in women in general, it is questionable as to whether it retains its protective effect in carriers of BRCA1 and BRCA2 mutations. Cullinane et al. (Int J Cancer 117:988, 2005) found a statistically insignificant difference (odds ratio 0.94) in breast cancer risk among BRCA1 carriers who had ever been pregnant versus those who never had a pregnancy. Stratifying the risk of breast cancer according to the number of prior pregnancies versus no pregnancies, no statistically significant protective trend was observed. For BRCA2 carriers, there was a marginally statistically significant increased risk of breast cancer among women with prior pregnancies. In an international study with more than 65,000 person-years of observation (Andrieu J: Natl Cancer Inst 98:535, 2006), there was no significant effect in either direction of pregnancy on breast cancer risk for carriers of either mutation. Staging the axillary lymph nodes is currently somewhat controversial. Sentinel lymph node sampling is not straightforward in pregnant women. Blue dye has been carcinogenic in rats, and fetuses cannot be shielded from administered radionuclides. For this reason, many surgeons favor axillary node dissection to stage the nodes. Largely due to the typical delay in diagnosis, axillary nodes are more often positive in pregnant than in nonpregnant women.

As with other types of cancer in pregnant women, counseling following diagnosis in the first trimester should include a discussion of pregnancy termination to allow definitive therapeutic intervention at the earliest possible time without the potential for permanent injury to a surviving fetus. While definitive local surgery can safely be performed in the first trimester, radiation therapy and chemotherapy are considerably more risky. Delay in administration of systemic therapy can increase the risk of axillary spread. In the second and third trimesters, chemotherapy (particularly anthracycline-based combinations) is both safe and effective (Chap. 38). Lumpectomy followed by adjuvant chemotherapy is frequently used; fluorouracil and cyclophosphamide with either doxorubicin or epirubicin have been given without major risk to the fetus. Taxanes and gemcitabine are also beginning to be used; however, safety data are sparse. Methotrexate and other folate antagonists are to be avoided because of effects on the fetal nervous system. Myelotoxic therapy is generally not administered after 33 or 34 weeks of gestation to allow 3 weeks off therapy before delivery for recovery of blood counts. Endocrine therapy and trastuzumab are unsafe during pregnancy. Experience with lapatinib is anecdotal, but no fetal malformations have been reported. Antiemetics and colony-stimulating factors are also considered safe. Women being treated into the postpartum period should not breast-feed their babies because of excretion of cancer chemotherapy agents, particularly alkylating agents, in milk.

Subsequent pregnancies following gestational breast cancer do not appear to influence relapse rate or overall survival. A meta-analysis found that pregnancy in breast cancer survivors was associated with a reduced the risk of dying from breast cancer by as much as 42%. This finding, however, is heavily confounded by the “healthy survivor effect”; women with more extensive or advanced disease are more likely to avoid pregnancy.

Speculation about melanoma occurring during pregnancy based largely on anecdotal evidence and small case series concluded that it occurred with increased frequency, was more aggressive in its natural history, and was caused in part by the hormonal changes that also produced hyperpigmentation (so-called melasma) during pregnancy. However, more complete epidemiologic data suggest that melanoma is no more frequent in pregnant women than in nonpregnant women in the same age group, that melanoma is not more aggressive during pregnancy, and that hormones seem to have little or nothing to do with the etiology. Pregnant and nonpregnant women do not differ in the location of primary tumor, depth of primary tumor, tumor ulceration, or vascular invasion.

Suspicious lesions should be looked for and managed definitively with excisional biopsy during pregnancy. Wide excision with sampling of regional lymph nodes is warranted. If lymph nodes are involved, the course of action is less clear. Several agents have demonstrated some activity in melanoma, but none have been used during pregnancy. Adjuvant interferon α is toxic, and its safety in pregnancy has not been documented. Agents active in advanced disease include dacarbazine, IL-2, ipilimumab (antibody to CTLA-4), and in those with BRAF mutation V600E, a BRAF kinase inhibitor. In the setting of metastatic disease, abortion may be indicated so that systemic therapy can be initiated as soon as possible (Chap. 34).

Melanoma is one of the very few cancers that are well documented to metastasize transplacentally to the fetus, where it seems to have a predilection for the head and neck. It has a very grave prognosis in the offspring. Fortunately, transplacental spread is rare.

Pregnancy subsequent to the diagnosis and treatment of melanoma is not associated with an increased risk of melanoma recurrence.

(See Chap. 16) Hodgkin’s disease occurs mainly in the age range that coincides with child-bearing. However, Hodgkin’s disease is not more common in pregnant than nonpregnant women. Hodgkin’s disease is diagnosed in approximately 1 in 6000 pregnancies. It generally presents as a nontender lymph node swelling, most often in the left supraclavicular region. It may be accompanied by B symptoms (fever, night sweats, unexplained weight loss). Excisional biopsy is the preferred diagnostic procedure because fine-needle aspiration cannot reveal the architectural framework that is an essential component of Hodgkin’s disease diagnosis. The stage at presentation appears to be unaffected by pregnancy. Women diagnosed in the second and third trimester can be treated safely with combination chemotherapy, usually doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In general, the patient in the first trimester is asymptomatic, and a woman with a desired pregnancy can be followed until the second or third trimester when definitive multiagent chemotherapy can be safely given. Radiation therapy is not given during pregnancy and is not necessary for optimal management of the pregnant patient. If symptoms requiring treatment appear during the first trimester, anecdotal evidence suggests that Hodgkin’s disease symptoms can be controlled with weekly low-dose vinblastine. Such an approach has been safely used to avoid termination of pregnancy. Pregnancy does not have an adverse effect on treatment outcome.

Non-Hodgkin’s lymphomas are more unusual in pregnancy (approximately 0.8 per 100,000 pregnancies), but are usually tumors with an aggressive natural history, such as diffuse large B cell lymphoma, Burkitt’s lymphoma, or peripheral T cell lymphoma. Diagnosis relies on an excisional biopsy of a tumor mass, not fine-needle aspiration. Staging evaluation is generally limited to ultrasound or MRI examinations. Diagnosis in the first trimester should prompt termination of the pregnancy followed by definitive treatment with combination chemotherapy, because aggressive lymphomas are not likely to be held at bay with single-agent chemotherapy. Women diagnosed in the second or third trimesters can be treated with standard chemotherapy, such as with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The experience with rituximab in this setting is anecdotal. However, infants born of mothers who have received rituximab may have transient delay in B cell development that typically normalizes by 6 months. The treatment outcome is similar in lymphomas diagnosed in pregnant and nonpregnant women of the same clinical stage.

(See Chap. 50) Thyroid cancer, along with melanomas, brain tumors, and lymphomas, are cancers that are increasing in incidence in the general population. Thyroid cancers are rising faster among women in North America than the other increasing tumor types. The Endocrine Society has developed practice guidelines to inform the management of patients with thyroid disease during pregnancy (http://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/Thyroid-Exec-Summ.pdf). Thyroid nodules 1 cm or larger are approached by fine-needle aspiration. If a malignancy is diagnosed, surgery is generally recommended in the second and third trimesters. However, surgical complications appear to be twice as common when the patient is pregnant. Because the growth of thyroid tumors is often indolent, surgery can safely be postponed until after the first trimester. Patients with follicular cancer or early papillary cancer can be observed until the postpartum period. The fetal thyroid begins trapping iodine by 12 weeks of gestation and does so with very high avidity. Even small doses of radioactive iodine given during pregnancy can completely ablate the fetal thyroid with serious consequences for the fetus and should be avoided throughout pregnancy. Radioactive iodine can be safely administered after delivery. Patients with a history of thyroid cancer who become pregnant should be maintained on thyroid hormone replacement during pregnancy because of the adverse impact of maternal hypothyroidism on the fetus. Women who are breast-feeding should not be treated with radioactive iodine, and women treated with radioactive iodine should not become pregnant for 6–12 months after treatment.

The assessment of thyroid function during pregnancy is challenging because of the physiologic changes that occur during pregnancy. Women who have previously been treated for thyroid cancer are at risk of hypothyroidism. The demand for thyroid hormone increases during pregnancy, and doses to maintain normal function may increase by 30–50%. Total T₄ levels are higher during pregnancy, but target therapeutic levels also increase (Table 32-4). It is recommended that the upper and lower limits of the laboratory range be multiplied by 1.5 in the second and third trimester to establish a pregnancy-specific normal range. The target thyroid-stimulating hormone (TSH) level is <2.5 mIU/L.

(See Chap. 46) Gestational trophoblastic disease encompasses hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and assorted miscellaneous and unclassifiable trophoblastic tumors. Moles are the most common, occurring in 1 in 1500 pregnancies in the United States. The incidence is higher in Asia. In general, if the serum level of β-human chorionic gonadotropin (β-hCG) returns to normal after surgical removal (evacuation) of the mole, the illness is considered gestational trophoblastic disease. By contrast, if the β-hCG level remains elevated after mole evacuation, the patient is considered to have gestational trophoblastic neoplasia. Choriocarcinoma occurs in 1 in 25,000 pregnancies. Maternal age >45 years and prior history of molar pregnancy are risk factors. A previous molar pregnancy makes choriocarcinoma about 1000 times more likely to occur (incidence 1–2%).

Hydatidiform moles are characterized by clusters of villi with hydropic changes, trophoblastic hyperplasia, and absence of fetal blood vessels. Invasive moles are distinguished by invasion of the myometrium. Placental site trophoblastic tumors are composed mainly of cytotrophoblast cells arising at the site of placental implantation. Choriocarcinomas contain anaplastic trophoblastic tissue with both cytotrophoblast and syncytiotrophoblast features and no identifiable villi.

Moles can be partial, typically associated with fetal tissue, or complete, typically not associated with any fetal or embryonic tissue. Partial moles have a distinct molecular origin and usually are smaller tumors with less hydropic villi and considerably less potential for persistent or malignant disease. Partial moles result from fertilization of an egg by two sperm, resulting in diandric triploidy. Complete moles usually have a 46,XX genotype; 95% develop by a single male sperm fertilizing an empty egg and undergoing gene duplication (diandric diploidy); 5% develop from dispermic fertilization of an empty egg (diandric dispermy).

Women with molar gestations often present with first-trimester bleeding, disproportionately high serum β-hCG levels for menstrual age, unusually large uterine size for menstrual age, hyperemesis gravidarum, theca lutein cysts in the ovaries (due to β-hCG stimulation), and hyperthyroidism (due to cross-reactivity of β-hCG and TSH) and may develop preeclampsia before 20 weeks of menstrual age. Pelvic ultrasound imaging of complete moles shows absence of fetal parts, an enlarged echo-bright, hydropic placenta in an enlarged uterus, and enlarged multicystic ovaries. If the diagnosis is uncertain at the initial examination and the pregnancy is desired, then a serum β-hCG level should be obtained and the examination repeated in a week. If no embryo is seen within 7–10 days and the serum β-hCG is elevated, then this is a nonviable pregnancy that should be evacuated. Diagnosis of partial molar pregnancies can be more difficult because an embryo or fetus with visible heart motion is usually present, and the hydropic changes in the placenta, uterine enlargement, and elevations of β-hCG are not usually as dramatic. Although an embryo or fetus is present, it rarely grows normally with normal anatomy, and repeated ultrasound examinations usually make the diagnosis. Amniocentesis will also make the diagnosis by demonstration of triploidy.

Patients with molar pregnancies require prompt uterine evacuation with suction curettage, which may be complicated by very heavy bleeding. Following evacuation of complete moles, approximately 20% will result in persistent, invasive, or metastatic disease. Partial moles are considerably less likely (<5%) to result in persistent disease. Patients should be monitored with serial determinations of serum β-hCG until the values fall below the lower limit of the assay and remain low for at least 6 months. Patients should be advised not to become pregnant for at least 12 months.

A variety of criteria have been used to make the diagnosis of postmolar gestational trophoblastic disease, but current consensus guidelines as adopted by the International Federation of Gynecology and Obstetrics are listed below:

1. A β-hCG level plateau of four values plus or minus 10% recorded over a 3-week duration (days 1, 7, 14, and 21)

2. A β-hCG level increase of more than 10% in three values recorded over a 2-week duration (days 1, 7, and 14)

3. Persistence of detectable β-hCG for more than 6 months after molar evacuation

About half of choriocarcinomas develop after a molar pregnancy, and half develop after ectopic pregnancy or, rarely, after a normal full-term pregnancy. Disease is classified as stage I if it is confined to the uterus, stage II if disease is limited to genital structures (~30% have vaginal involvement), stage III if disease has spread to the lungs but no other organs, and stage IV if disease has spread to liver, brain, or other organs.

Patients without widely metastatic disease are generally managed with single-agent methotrexate (either 30 mg/m² IM weekly until β-hCG normalizes or 1 mg/kg IM every other day for four doses followed by leucovorin 0.1 mg/kg IV 24 h after methotrexate), which cures >90% of patients. Patients with very high β-hCG levels, presenting >4 months after a pregnancy, with brain or liver metastases, or failing to be cured by single-agent methotrexate are treated with combination chemotherapy. Etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA-CO) is the most commonly used regimen, producing long-term survival in >80% of patients. Brain metastases can usually be controlled with brain radiation therapy. The vast majority of choriocarcinomas can be cured with chemotherapy alone. Hysterectomy is reserved for women who have completed their child-bearing, women with chemotherapy-resistant disease in the uterus, and women with rare placental site trophoblastic tumors confined to the uterus because these tumors are less reliably sensitive to chemotherapy. Women cured of trophoblastic disease who have not undergone hysterectomy do not appear to have increased risk of fetal abnormalities or maternal complications with subsequent pregnancies.