Malignant Diseases and Pregnancy

Key Abbreviations

α-Fetoprotein	AFP
β–Human chorionic gonadotropin	β-hCG
Carcinoembryonic antigen	CEA
Complete hydatidiform mole	CHM
Computed tomography	CT
Fine-needle aspiration	FNA
Food and Drug Administration	FDA
Gestational trophoblastic disease	GTD
Gray	Gy
Hodgkin lymphoma	HL
Magnetic resonance imaging	MRI
Non-Hodgkin lymphoma	NHL
Partial hydatidiform mole	PHM

The diagnosis of cancer for anyone is understandably frightening. The juxtaposition of a new life and possible maternal death can present numerous emotional and ethical conflicts to the patient, her family, and her physicians. To deal with cancer in the context of pregnancy is particularly burdensome because the patient may have to balance competing maternal and fetal interests. On occasion, a pregnant woman may be required to make decisions affecting her life or longevity versus the life or the well-being of her unborn. Cancer in pregnancy complicates the management of both the cancer and the pregnancy. Diagnostic and therapeutic interventions must carefully address the associated risks to both the patient and the fetus. Informed decisions require evaluation of a number of factors, and with counseling, these considerations are the foundation on which treatment decisions are made. There has been an evolution in the philosophy of management from one of total disregard of the pregnancy with frequent immediate termination to a more thoughtful approach in which management decisions consider both maternal and fetal outcomes so as to limit risk of death or morbidity to both.

It is estimated that 20% to 30% of malignancies occur in women younger than 45 years of age. Although cancer is the second most common cause of death for women in their reproductive years, only approximately 1 in 1000 pregnancies is complicated by cancer. Because there are no large prospective studies that address cancer treatment in pregnancy, physicians tend to base treatment strategies on small retrospective studies or anecdotal reports that occasionally present conflicting information. Although several options of management may be available, a successful outcome is dependent on a multidisciplinary team approach. The management plan must be formulated within a medical, moral, ethical, legal, and religious framework that is acceptable to the patient and guided by communication and educational resources of the health care team.

Delays in diagnosis of the cancer during pregnancy are common for various reasons, including the following: (1) many of the presenting symptoms of cancer are often attributed to the pregnancy; (2) many of the physiologic and anatomic alterations of pregnancy can compromise physical examination; (3) serum tumor markers, such as β–human chorionic gonadotropin (β-hCG), α-fetoprotein (AFP), and CA-125, are increased during pregnancy; and (4) our ability to optimally perform either imaging studies or invasive diagnostic procedures may be altered during pregnancy. Because the gestational age is significant when evaluating the risks of treatments and needs for delivery, it is important to determine gestational age accurately. An early ultrasound evaluation is important to ensure accurate dating.

The malignancies most commonly encountered in the pregnant patient are breast cancer, cervical cancer, and melanoma. The frequencies of cancer complicating pregnancy have increased, which may be attributable to the trend to delay childbearing. Before specific malignancies are discussed later, some general principles of management/treatment are reviewed.

Surgery and Anesthesia

Surgery may be required for the diagnostic or therapeutic management of malignancy in pregnancy. Prior to surgery, perioperative cautions include attention to the relative safety of all drugs administered. There is no evidence that there are significant risks of anesthesia independent of coexisting disease; however, the use of local or regional anesthesia should be considered to limit systemic exposure to medications. If surgery is being performed after 20 weeks of gestation, positioning should allow for lateral displacement of the uterus to minimize compression of the vena cava. In addition, careful monitoring of maternal hemodynamic parameters is imperative because the placenta lacks the ability to autoregulate blood flow, and perfusion is determined primarily by maternal blood pressure. Continuous or intermittent fetal monitoring should be used in cases in which extrauterine survival is possible, and a perinatal team should be readily available to intervene should there be evidence of persistent fetal distress.

Although surgery may be safely performed during all three trimesters, the second trimester is preferred for patients requiring an abdominal or pelvic procedure to limit the risk of first-trimester pregnancy loss and preterm labor while allowing for adequate visualization of the abdominal anatomy . Data suggest pregnant patients may safely undergo laparoscopic surgery during pregnancy, although there are no randomized controlled trials comparing approaches. It is recommended that the duration of surgery be minimized, the pneumoperitoneum be kept at a maximum intraabdominal pressure of 10 to 13 mm Hg, and an open entry technique (Hasson technique) be utilized to gain access to the peritoneal cavity. If oophorectomy or ovarian cystectomy is required in the first trimester, thus compromising the corpus luteum, progesterone supplementation is recommended.

Radiation Therapy

Ionizing radiation is a known teratogen, and the developing pregnancy is particularly sensitive to its effects. Critical factors include gestational age, radiation field extent, and the fetal dose. In general, the potential effects of radiation exposure in pregnancy include pregnancy loss, congenital malformations, intellectual disability, and cancer induction. Risk is thought to arise if exposed to radiation greater than the threshold dose of 0.1 to 0.2 Gray (Gy); thus the recommended limit in pregnancy is 0.05 Gy. Exposure to ionizing radiation greater than this threshold dose during the first 2 weeks after conception results in an “all or none” phenomenon. If the pregnancy survives, it will likely be normal. During organogenesis and early fetogenesis, doses greater than 0.20 Gy are considered teratogenic and increase the risk of miscarriage. During late gestation, radiation may cause specific organ damage, such as mental retardation, skeletal anomalies, and ophthalmologic abnormalities. Reports have indicated that radiation exposure in utero increases the risk of childhood malignancy (although the lifetime cancer risks from prenatal radiation exposure are not yet known) and may impact fertility. It is important to remember that these data are conflicting and are extrapolated from the general health side effects of atomic bombs. For these reasons, radiation therapy should be postponed until the postpartum period and consideration should be given to suitable alternative therapies, such as surgery or chemotherapy. If delay of therapy is not possible, termination of the pregnancy may be required.

Chemotherapy During Pregnancy

Pharmacology of Chemotherapy During Pregnancy

The pharmacokinetics of chemotherapeutic agents can be influenced by the physiologic changes of pregnancy, which may ultimately impact the efficacy of systemic therapy. In brief, decreased gastrointestinal (GI) motility and delayed gastric emptying may alter absorption of orally administered medications. Blood volume expansion occurs early in pregnancy and continues well into the third trimester. This volume expansion combined with the enhanced renal clearance and faster hepatic metabolism in pregnancy may reduce active drug concentrations. Plasma albumin decreases in pregnancy, increasing the amount of unbound active drug, whereas estrogen exposure during pregnancy increases other plasma proteins that might decrease active drug fractions. Lastly, amniotic fluid may act as a pharmacologic third space, potentially increasing maternal and/or fetal toxicity due to delayed elimination and increased exposure. Because pharmacologic studies in pregnancy are lacking, we currently assume initial drug doses are similar to those prescribed in the nonpregnant patient, and adjustments to dose are based on toxicity on a case-by-case basis.

Classification of Chemotherapy Agents

Antimetabolites

Antimetabolites inhibit cellular metabolism by acting as false substrates during DNA or RNA synthesis. This drug class includes methotrexate, 5-fluorouracil, gemcitabine, capecitabine, cytarabine, and 6-mercaptopurine. Methotrexate is a folic acid antagonist that has been used for the treatment of malignancy, autoimmune disorders, and ectopic pregnancy. Folate antagonists are believed to be among the most teratogenic antineoplastic drugs. Exposure to high-dose methotrexate during the first trimester of pregnancy has been associated with miscarriage, skeletal abnormalities, and central nervous system defects. In the second and third trimesters, methotrexate has been associated with low birthweight and neonatal myelosuppression. The use of low-dose methotrexate for systemic diseases (e.g., rheumatic disease and psoriasis) has a lower teratogenic potential based on available data, although reports of severe congenital abnormalities do exist.

Data regarding the use of the other antimetabolites during the first trimester are limited. In addition, these drugs are often used in combination with other agents, making it challenging to interpret the drug-specific risk of congenital malformations or other pregnancy complications. Skeletal abnormalities, cardiac defects, intrauterine death, and growth restriction have been reported.

Alkylating Agents

Alkylating agents bind to DNA, resulting in DNA cross-links and, ultimately, strand breaks; these were among the first agents applied to the treatment of cancer. Examples of alkylating agents include cyclophosphamide, ifosfamide, chlorambucil, and dacarbazine. Most of the alkylating agents have demonstrated some teratogenic potential when administered in the first trimester, including but not limited to GI, genitourinary, ocular, and skeletal abnormalities. In the second and third trimesters, alkylating agents have been shown to be acceptably safe.

Antitumor Antibiotics

This class of chemotherapeutic agents is generally derived from microorganisms and includes anthracyclines (doxorubicin, epirubicin, and daunorubicin), bleomycin, dactinomycin, and mitomycin C. Antitumor antibiotics appear to be associated with a relatively low risk of teratogenicity, although cases have been reported. Due to the relatively high molecular weight of anthracyclines (with exception of idarubicin) and high plasma protein binding, they presumably have low transplacental passage, which may explain the low rate of teratogenicity. Anthracycline tolerability is limited by cardiotoxicity (cardiomyopathy, congestive heart failure); thus there has been concern regarding the potential fetal cardiac risk when used during pregnancy. Many series fail to demonstrate significant cardiotoxicity in offspring; however, longer-term follow-up will be required to exclude this possibility.

Vinca Alkaloids

Vinca alkaloids prevent the formation of microtubules and, thus, halt mitosis in the M phase of the cell cycle. Vincristine and vinblastine, although potent teratogens in animals, do not appear to be as teratogenic in humans. Although reports of early exposure were associated with congenital anomalies, these were all multidrug regimens with other potential teratogenic agents, including antimetabolites and alkylating agents. Further studies are required; however, exposure later in gestation appears well tolerated.

Platinum Agents

The use of platinum agents in pregnancy has been described with limited complications. A review on the use of platinum agents in pregnancy included 43 patients exposed to platinum-based chemotherapy. Of these, only two had first-trimester platinum exposure. Only three fetal abnormalities were identified and included one case each of ventriculomegaly, hearing impairment, and microphthalmos. Another review of 48 women receiving platinum therapy for cervical cancer in pregnancy found no congenital malformations; however, approximately one-third of the neonates had morbidity following delivery, including anemia, respiratory distress syndrome, hypoglycemia, hypotension, and tachycardia.

Taxane Agents

Taxane chemotherapy is used for the management of multiple malignancies, including breast, ovarian, and cervical cancer. Experience with use in pregnancy is growing, although still limited. As with the other chemotherapeutic agents listed previously, taxanes are often used in combination with other drugs, making interpretation of the potential toxicities somewhat challenging. Available data suggest use in pregnancy, particularly after the first trimester, is relatively low risk.

Targeted Therapies

Tamoxifen, a selective estrogen receptor modular used in estrogen-positive breast cancer, is contraindicated in pregnancy due to the risk of adverse fetal outcomes, including craniofacial malformations and ambiguous genitalia. Trastuzumab, a monoclonal antibody used for the treatment of HER2-positive breast cancer and advanced uterine serous carcinomas, is not recommended in pregnancy due to its association with oligohydramnios (>70% with exposure in the second or third trimester). Rituximab, an anti-CD20 antibody that is used for the treatment of some autoimmune disorders and hematologic malignancies, has been associated with transient neonatal lymphopenia, and further studies are necessary to determine an accurate safety profile. Tyrosine kinase inhibitors (e.g., imatinib, erlotinib, and dasatinib) have been associated with congenital anomalies, spontaneous abortion, low birthweight, and premature delivery. The antiangiogenic agents (bevacizumab, sunitinib, and sorafenib) are not recommended for use in pregnant women. The recent evolution in immunotherapies, including adoptive T-cell transfer and immune checkpoint modulators, is altering the cancer treatment landscape. Little is currently known how these therapies could affect the pregnant patient or the fetus. Altering the immune interface between mother and fetus is an area of great importance, and future evaluation of these therapies will elucidate safety outcomes.

Drug Effects on the Embryo, Fetus, and Neonate

Although data on chemotherapy administration during pregnancy are somewhat limited, literature reviews and descriptive cohort studies provide us with some information regarding the potential pregnancy complications. The risk associated with chemotherapy administration during pregnancy depends on the drugs used and the gestational age during which the embryo or fetus is exposed. Although the placenta does act as a filter, most cytotoxic agents cross the placenta and, therefore, have the potential to impact the developing pregnancy. Exposure during the first 4 weeks of gestation (or up to 2 weeks post conception) most often results in an “all or none” phenomena with pregnancy loss or no adverse effect. Excluding the intentional use of abortifacients, it is difficult to clearly demonstrate that the use of chemotherapy results in an increase in the clinically recognized spontaneous abortion rate over the expected 15% to 20%.

Teratogenicity is the main concern when treating pregnant women with chemotherapy and is influenced by many factors, including the timing of exposure, the dose administered, the extent of placental transfer, and the duration of exposure. All drugs undergo animal teratogenicity testing, and based on these results, the drugs are assigned risk categories ( Table 55.1 ) by the US Food and Drug Administration (FDA). Based on this system, most chemotherapeutic agents are rated as C, D, or X. However, animal teratogenicity testing cannot always be reliably extrapolated to humans, and the data in humans are limited. The risk of congenital malformations is estimated to be 10% to 25% (compared with the baseline risk of 3% to 4%) when chemotherapy is administered in the first trimester during organogenesis. Notably, the risk is higher with multidrug therapy than with monotherapy. Because detailed ultrasonography may fail to identify subtle anatomic but serious functional abnormalities, patients should be appropriately counseled and may consider the option of pregnancy termination if first-trimester chemotherapy is planned or administered. The risk of teratogenicity during the second and third trimesters is significantly reduced and is likely no different from that for pregnant women who are not exposed to chemotherapy.

TABLE 55.1

Food and Drug Administration Risk Categories for Drug Use During Pregnancy

From Amant F, Han SN, Gziri MM, et al. Chemotherapy during pregnancy. Curr Opin Oncol. 2012;24:580–586.

Category	Definition
A	Controlled studies have failed to demonstrate risk to the fetus in first trimester (no risk in late trimesters).
B	Animal studies have failed to identify a risk to the fetus but no adequate or well-controlled studies in pregnant women.
C	Animal studies have shown an adverse effect on the fetus and no well-controlled studies in humans, but potential benefit may warrant use of the drug despite potential risks.
D	There is evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefit may warrant use the drug despite potential risks.
X	Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of fetal risk based on adverse reaction data; risks of the drug clearly outweigh any possible benefit.

Administration of cytotoxic chemotherapy in the second and third trimesters has been associated with intrauterine growth restriction, neonatal myelosuppression, hearing loss, low birthweight, need for NICU admission, and intrauterine fetal demise. It is, of course, challenging to discern the direct effect of the drugs from that of the maternal morbidity associated with the malignancy and its treatment. For example, chemotherapy-induced nausea and vomiting may also affect fetal growth and birthweight. Although recommendations vary based on cancer type, treatments rendered, and extent of disease, iatrogenic preterm delivery should be avoided when possible. In one series, it was reported that 61% of cancer in pregnancy cases were delivered prior to 37 weeks, significantly higher than the approximately 8% rate reported in the general population. Another report of 180 pregnancies affected by cancer reported that the mean gestational age at delivery was 36.2 (± 2.9) weeks, with 8% occurring before 32 weeks, with approximately 90% of preterm inductions performed for maternal cancer (88%) compared with obstetrical indications (12%). In this series, more than 50% of neonates required neonatal intensive care, with prematurity as the most common indication. Therefore the consequences of iatrogenic premature delivery must be weighed against continued cancer treatment during the pregnancy and consultation with maternal-fetal medicine and neonatology teams should be initiated as soon as possible.

Additional factors must be considered in the peripartum period. First, administration of chemotherapy in late gestation should allow for an interval of at least 3 weeks prior to delivery. This will minimize the risk of transient neonatal myelosuppression or maternal hematologic toxicities, which may result in complications such as sepsis, bleeding, and death. Secondly, because most antineoplastic agents can be found in breast milk, breastfeeding is contraindicated.

When assessing neonatal outcomes, the rates of major and minor malformations were comparable with the general population. However, based on limited retrospective reports, fetal exposure to cytotoxic chemotherapy has raised concerns regarding late-onset adverse effects such as neurodevelopmental delay, abnormal cardiac structure and function, compromised fertility, and childhood malignancy. In regard to functional outcomes, a case-control study of 129 children born to women with cancer during pregnancy, with 96% exposed to chemotherapy in utero, were compared with controls based on gestational age. The investigators found that there were no differences in birthweight, cognitive, cardiac, or general development between the two groups. Other studies have reported similar outcomes in cognitive skills and academic achievement. However, a recent study noted that, although cognitive skills and academic achievement are similar, children who were exposed to in utero chemotherapy may have a higher rate of behavioral problems. However, further studies of the impact of cancer therapies on the developing fetus and neonate are required.

Cancer During Pregnancy

Although most cancers have been diagnosed during pregnancy or the peripartum period, the most common malignancies are discussed later. Table 55.2 provides an overview of these cancers, symptoms, and challenges of diagnosis in pregnancy.

TABLE 55.2

Overview of Symptoms and Challenges of Diagnosis of Common Cancers in Pregnancy

Cancer	Symptoms	Confounding Changes Associated With Pregnancy	Diagnosis
Breast	Painless or persistent lump Bloody nipple discharge	Nipple enlargement Serosanguinous nipple discharge Breast tenderness and engorgement	Mammogram Ultrasound/MRI Breast biopsy
Lymphoma	Enlarged lymph nodes Night sweats Pruritus Weight loss	Skin changes/pruritus	Lymph node biopsy
Leukemia	Anemia Thrombocytopenia/bleeding Fatigue	Fatigue Anemia	Complete blood count, bone marrow biopsy
Melanoma	Irregular or hyperpigmented lesion	Hyperpigmentation	Biopsy of lesion
Cervix	Abnormal Pap test Vaginal bleeding Vaginal discharge	Cervical eversion Hyperemia Mucous discharge	Colposcopy Cervical biopsy
Ovary	Abdominopelvic pain Mass on ultrasound	Functional cysts Theca-lutein cysts	Ultrasound/MRI
Gastric	Nausea/vomiting Abdominal pain Indigestion	Nausea/vomiting Indigestion	Upper endoscopy
Colorectal	Rectal bleeding Anemia Altered bowel movements	Hemorrhoids/rectal bleeding Anemia Constipation	Colonoscopy
Central nervous system	Persistent headaches, nausea/vomiting, visual changes	Nausea/vomiting Headaches	MRI brain Eye exam

MRI , Magnetic resonance imaging.

Breast Cancer

The estimated number of breast cancer cases in women in the United States exceeds 260,000 cases, with approximately 40,000 deaths each year. Although the lifetime risk of developing breast cancer is 1 in 8, the risk is 1 in 52 for women 49 years or younger. Each year, this results in approximately 10% of premenopausal breast cancers being diagnosed in women who are pregnant or within 1 year after delivery, which equates to 1 per 3000 to 10,000 live births. The average age of women diagnosed with breast cancer is between 33 to 38 years of age; approximately 30% have a genetic predisposition, 50% are high-grade tumors, and 20% present with metastatic disease.

Diagnosis and Staging

Because the breast changes become more pronounced in later pregnancy, it is important to perform a thorough breast examination at the initial visit. Breast abnormalities should be evaluated in the same manner as if the patient were not pregnant. The most common presentation of breast cancer in pregnancy is a painless lump discovered by the patient. Despite the striking physiologic breast changes of pregnancy, including nipple enlargement and increased glandular tissue resulting in engorgement and tenderness, a newly found or persistent breast mass should be evaluated promptly. Diagnostic delays, which are commonly 3 to 7 months or longer, are often attributed to physician reluctance to evaluate breast complaints or abnormal findings in pregnancy and may increase the risk of nodal involvement and advanced disease.

Although bilateral serosanguinous nipple discharge may be normal in late pregnancy, less common presentations such as bloody nipple discharge should be evaluated with mammography and ultrasound. In cases of mastitis or breast abscesses, or evaluation of breast edema or inflammation, a skin biopsy should be considered to evaluate for inflammatory breast cancer.

Mammography with abdominal protection should be performed and has a sensitivity that ranges from 63% to 78%. Although the radiation exposure to the fetus is negligible, the hyperproliferative changes in the breast during pregnancy are characterized by increased tissue density, making interpretation more difficult. Breast ultrasound has a high sensitivity and specificity and can distinguish between solid and cystic masses, can assess for axillary metastases, and allows for simultaneous biopsy, making it the preferred imaging modality for pregnant women. Magnetic resonance imaging (MRI) without gadolinium has also been used; however, there are limited data on its accuracy in this population. Percutaneous biopsy is recommended for any lesion that does not meet criteria for a simple cyst. Fine-needle aspiration (FNA) of a mass for cytologic study may be used but is often misleading due to changes in the breast during pregnancy. For breast masses, a core needle biopsy is the preferred method for histologic diagnosis.

Before proceeding with treatment, staging should be undertaken. All draining lymph nodes should be evaluated. Sentinel lymph node biopsy with the use of technetium 99m–labeled sulfur colloid appears safe in pregnancy, although the use of blue dye should be avoided. The contralateral breast must also be carefully assessed. Laboratory tests should include baseline liver function tests and serum tumor markers (CA 15-3, CA 27.29, and CEA). A chest radiograph (with abdominal shielding) is indicated, and if metastatic disease is suspected, further imaging with a liver ultrasound can be performed. Bone scans and computed tomography (CT) scans are generally not recommended, and if bone metastases are suspected, site-specific radiographs or PET MRI may be considered. However, in an asymptomatic patient with normal blood tests, further imaging is not necessary.

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