Malignancy complicating pregnancy is fortunately rare, affecting one in 1000 to one in 1500 pregnancies. Optimal treatment involves balancing the benefit of treatment for the mother while minimizing harm to the fetus. This balance is dependent on the extent of the disease, the recommended course of treatment, and the gestational age at which treatment is considered.
Both surgery and chemotherapy are generally safe in pregnancy, whereas radiation therapy is relatively contraindicated. Iatrogenic prematurity is the most common pregnancy complication, as infants are often delivered for maternal benefit. In general, however, survival does not differ from the nonpregnant population.
These patients require a multidisciplinary approach for management with providers having experience in caring for these complex patients. The aim of this review was to provide an overview for obstetricians of the diagnosis and management of malignancy in pregnancy.
Highlights
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We review the epidemiology and outcomes of malignancy in pregnancy in general.
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We provide a general overview of the treatment of malignancy in pregnancy with chemotherapy and radiation.
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The more common malignancies seen in pregnancy are reviewed in detail.
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Outcomes and survival of malignancy in pregnancy are similar to nonpregnant patients.
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Timing of delivery is dependent on the type and stage of the malignancy, and the gestational age at diagnosis.
Introduction
Cancer in pregnancy is, fortunately, rare. However, when a woman is diagnosed with cancer during her pregnancy, many complicated questions arise. The underlying dilemma to which all other questions can be traced is how best to balance the health of the mother with the health of her unborn child. Every woman, partner, and family is likely to have a different viewpoint on this underlying dilemma, making these questions, at times, extraordinarily complex. Once the diagnosis of cancer in pregnancy is established, the patient should be referred to an institution with experience in dealing with such cases, where she can receive multidisciplinary care by a team whose main objective was to guide and support care decisions that reflect the wishes of the woman and her support system.
The aim of this review was to give clinicians a framework for how to approach some of these complex issues, with a focus on how the pregnancy affects cancer progression and treatment, and, conversely, how cancer progression and treatment affect the pregnancy.
Epidemiology of cancer in pregnancy
Cancer affects approximately one in 1000 to one in 1500 pregnancies . This estimate is an increase from one in 2000 in 1964 , and it is thought to reflect not only higher rates of cancer in general but also a delay in childbearing to the third or fourth decades of life by an increasing number of women . The most common cancers that occur concurrent with pregnancy include hematologic malignancies, breast cancer, thyroid cancer, colon cancer, cervical cancer, ovarian cancer, and melanoma ( Table 1 ). Pathologic features and prognosis of patients diagnosed during pregnancy are usually comparable with age- and stage-matched nonpregnant patients .
| Type of Malignancy | Incidence in Pregnancy (per 100,000 pregnancies) | References |
|---|---|---|
| Gynecologic Malignancies | ||
| Breast | 10–35 | |
| Cervix | 10–12 | |
| Ovarian | 0.6–5.2 | |
| Other Malignancies | ||
| Hematologic (Lymphoma and Leukemia) | 13–16 | |
| Thyroid | 2–14 | |
| Melanoma | 2.8–8.7 | |
| Colon | 2.8–7.7 | |
Epidemiology of cancer in pregnancy
Cancer affects approximately one in 1000 to one in 1500 pregnancies . This estimate is an increase from one in 2000 in 1964 , and it is thought to reflect not only higher rates of cancer in general but also a delay in childbearing to the third or fourth decades of life by an increasing number of women . The most common cancers that occur concurrent with pregnancy include hematologic malignancies, breast cancer, thyroid cancer, colon cancer, cervical cancer, ovarian cancer, and melanoma ( Table 1 ). Pathologic features and prognosis of patients diagnosed during pregnancy are usually comparable with age- and stage-matched nonpregnant patients .
| Type of Malignancy | Incidence in Pregnancy (per 100,000 pregnancies) | References |
|---|---|---|
| Gynecologic Malignancies | ||
| Breast | 10–35 | |
| Cervix | 10–12 | |
| Ovarian | 0.6–5.2 | |
| Other Malignancies | ||
| Hematologic (Lymphoma and Leukemia) | 13–16 | |
| Thyroid | 2–14 | |
| Melanoma | 2.8–8.7 | |
| Colon | 2.8–7.7 | |
Diagnosis of cancer in pregnancy
Prompt diagnosis of cancer is paramount to successful treatment regardless of pregnancy status. Unfortunately, the diagnosis of cancer in pregnancy is often delayed. Diagnosis during pregnancy is complicated by the fact that many symptoms of malignancy are similar to symptoms of pregnancy, including nausea/vomiting, breast changes, abdominal pain, anemia, and fatigue. Breast changes and the gravid uterus may make the physical examination of a pregnant woman difficult. In addition, clinicians may be more hesitant to order the appropriate tests because of concerns that laboratory results may be inaccurate or that radiologic testing is harmful.
Laboratory testing
The physiologic changes of pregnancy and the accompanying alterations in commonly used laboratory values may complicate the diagnosis of malignancy ( Table 2 ). For example, hemoglobin and hematocrit levels are typically lower, and alkaline phosphatase and lactate dehydrogenase (LDH) are usually higher during pregnancy.
| Laboratory Value | Range in Pregnant Adult | Range in Non-Pregnant Adult |
|---|---|---|
| Hematology | ||
| Hemoglobin (g/dL) | 9.5–15.0 | 12–15.8 |
| Hematocrit (%) | 28.0–41.0 | 35.4–44.4 |
| Platelet (×10 9 /L) | 146–429 | 165–415 |
| White blood cell count (×10 3 /mm 3 ) | 5.6–16.9 | 3.5–9.1 |
| Blood Chemical Constituents | ||
| Albumin (g/dL) | 2.3–5.1 | 4.1–5.3 |
| Alkaline phosphatase (U/L) | 17–229 | 33–96 |
| Lactate dehydrogenase (U/L) | 78–524 | 115–221 |
Many specific tumor markers are also impacted by pregnancy, and therefore they are either not useful or are not as predictive as in the nonpregnant population. Ovarian cancer antigen 125 (CA-125) concentrations have been shown to be elevated in the first trimester with wide variation between weeks 5 and 8, normalize during the second and third trimesters, rise again immediately after delivery, also with wide fluctuations, and generally do not return to baseline until 10 weeks postpartum . More recently, the concentration of the biomarker human epididymis protein 4 (HE4) was found to be lower in pregnant women when compared with nonpregnant, premenopausal women . Other markers whose levels, and thus clinical utility, may be altered by pregnancy include human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP), and LDH . Carcinoembryonic antigen (CEA) and CA 19-9 are not affected by pregnancy .
Diagnostic imaging
Following physical examination and laboratory evaluation, imaging remains the mainstay of the diagnosis of malignancy. The imaging modalities available for diagnostic use during pregnancy include ultrasonography, X-ray and computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine studies. Importantly, most diagnostic radiologic procedures are associated with little, if any, known significant fetal risks.
Because ultrasound involves the use of sound waves and does not involve exposure to ionizing radiation, it should be used as the first-line imaging modality during pregnancy when clinically reasonable. Ultrasound has been used clinically in obstetrics for more than 50 years, and during this time there have been no reports of documented short- or long-term adverse fetal effects associated with diagnostic ultrasound procedures . Ultrasound is, however, a form of energy that can have both mechanical and thermal effects. Ultrasound should therefore be used only when clinically indicated, for the shortest amount of time, and with the lowest level of acoustic energy compatible with an accurate diagnosis .
MRI is also a safe imaging modality in pregnancy because it utilizes magnets that alter the energy state of hydrogen protons, and it is not associated with known adverse fetal effects . However, the safety of gadolinium, a paramagnetic contrast agent, has not been confirmed. Studies of its effects on human fetal development are lacking, but animal studies have demonstrated increased rates of spontaneous abortion, skeletal abnormalities, and visceral abnormalities when given at two to seven times the recommended human dose .
Ionizing radiation can theoretically result in three harmful fetal effects: cell death (and related teratogenic consequences), carcinogenesis, and genetic effects or mutations in germ cells . However, these effects are unlikely after exposure to the low radiologic doses associated with current diagnostic imaging procedures. The rad or gray (Gy) signifies the dose, or the amount of energy deposited per kilogram of tissue, with 1 Gy equal to 100 rad. The generally accepted safe range of radiation during pregnancy is <5 rad. This threshold is lower than the lowest dose believed to have biological fetal consequences, and it has not been associated with adverse fetal effects, including fetal anomalies or pregnancy loss . The most common modes of imaging and the associated fetal radiation doses are listed in Table 3 . Most radiopaque agents used with CT and other conventional radiography contain derivatives of iodine, and they have not been well studied in humans. Neonatal hypothyroidism has been reported when some iodinated agents are used after 12 weeks of pregnancy, when the fetal thyroid becomes functional and can concentrate iodine. For this reason, radiopaque contrast agents should generally be avoided unless they are essential for diagnosis .
| Procedure | Fetal Exposure |
|---|---|
| X-Ray, chest (2 view) | 0.02–0.07 mrad |
| X-Ray, abdomen (1 view) | 100 mrad |
| Mammography | 7–20 mrad |
| Barium enema or small bowel series | 2–4 rad |
| CT scan, head, or chest | <1 rad |
| CT scan, abdomen, or lumbar spine | 3.5 rad |
| CT scan, pelvis | 250 mrad |
Finally, nuclear medicine studies, such as pulmonary ventilation–perfusion, thyroid, bone, and renal scans, are performed by tagging a chemical agent with a radioisotope. The fetal exposure and therefore the safety of each of these studies depend on the physical and biochemical properties of the specific radioisotope used. Technetium Tc 99m is one of the most commonly employed isotopes, used for brain, bone, renal, and cardiovascular scans. These procedures generally result in a fetal exposure of <0.5 rad, and therefore they can be performed during pregnancy . By contrast, radioactive iodine readily crosses the placenta, and it can adversely affect the fetal thyroid if used after 12 weeks’ gestation .
Treatment of cancer in pregnancy: general principles
Surgery
Cancer surgery during pregnancy may be either diagnostic or therapeutic. When surgery is considered the optimal method for either diagnosis or treatment, it should not be significantly delayed because of the pregnancy, but, if possible without compromising care, it should be performed in the second trimester. At this time, the pregnancy is well established, but in most cases the uterus is not so large as to make surgery technically difficult. In the first trimester, although the administration of anesthesia has not been associated with an increased risk of congenital malformations, several reports have described an increased rate of miscarriage . In the third trimester, the primary concerns are caval compression, technical difficulty related to the enlarged uterus, and preterm labor, which may be due to the surgery itself, its complications (such as blood loss), or to the anesthesia. Regional anesthesia is preferred over general anesthesia because general anesthesia carries a greater risk to the mother with regard to airway management and potential aspiration . If surgery is the preferred mode of treatment, but maternal prognosis would not be affected by postponing surgical treatment, surgery should be deferred until after delivery.
Regardless of the type of surgery performed during pregnancy, fetal well-being should be assured. Before viability, this can be achieved with Doppler or ultrasound preceding and following general anesthesia. After viability, the patient should be positioned with a wedge under one hip to deflect the uterus off the vena cava, and continuous fetal monitoring should be considered . Patients should be consented, and the necessary personnel and equipment should be available for an emergent cesarean delivery if continued fetal well-being cannot be assured.
Chemotherapy
Chemotherapy is often necessary during pregnancy based on maternal disease status. Most chemotherapeutic agents are classified as pregnancy category D. Although a full discussion of individual chemotherapeutic agents is beyond the scope of this article, a few general principles will be reviewed, and selected common chemotherapeutic agents will be discussed as they pertain to individual malignancies.
The impact of chemotherapy during pregnancy is directly related to both the gestational age at exposure (fetal vulnerability) and the specific agent being used ( Fig. 1 ).
The time between conception and approximately 10 days post conception is called the “all-or-none” period, meaning that if there is exposure to a chemotherapeutic agent or any other noxious insult but the embryo survives, there will likely be no adverse effects. From 10 days post conception to 8 weeks’ gestation, the main period of organogenesis, exposure to chemotherapeutic agents can result in major congenital malformations; up to 16% of fetuses exposed to chemotherapy during the first trimester are born with a congenital malformation . Although exposure to chemotherapy in the second and third trimesters is considered relatively safe because most organs have formed, certain systems remain vulnerable (e.g., the central nervous and hematologic systems), and tissue growth may be adversely affected. Complications that have been reported after prenatal exposure in the second and third trimesters include preterm delivery, fetal growth restriction, and intrauterine fetal demise . Fortunately, available clinical data suggest that most fetuses exposed to chemotherapy starting in the second trimester do not experience significant long-term complications . However, if it is predicted that maternal survival would not be affected, the initiation of chemotherapy should be delayed if possible. Regardless of when chemotherapy is started, dose calculation should follow the standard procedures applied outside the pregnancy setting, with the acknowledgement that the pharmacokinetics of some drugs may be altered because of the pregnancy . Finally, given that there are limited data on single-agent chemotherapy, it is difficult to compare adverse outcomes in pregnancy related to single-versus multi-agent chemotherapy .
Limited data are available on the safety of administering targeted agents to pregnant patients. In addition, targeted agents are a heterogeneous group of drugs, which makes generalization difficult. For example, biologic agents such as monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus, and it has been shown that this does not take place before 14 weeks’ gestation. This suggests that exposure to monoclonal antibodies during the first trimester is unlikely to have an adverse effect, whereas second and third trimester exposure may be harmful . In general, the adverse outcome rate for monoclonal antibodies has been noted to be as high as 40% . Trastuzumab specifically has been associated with the development of oligohydramnios . Conversely, small molecule agents, such as tyrosine kinase inhibitors, can cross the placenta throughout pregnancy, and they should be avoided in the first trimester, similar to standard chemotherapy .
Radiation
There are reports of the use of radiation therapy in pregnancy without adverse fetal effects in the treatment of breast cancer, lymphoma, and brain and head and neck cancer, most likely because of the limited scatter associated with modern radiologic equipment and the ability to effectively shield the uterus . However, because high radiation exposure is associated with teratogenesis, pregnancy loss, and mental retardation and malignancy in exposed offspring, it seems reasonable to delay radiation therapy until the postpartum period if the uterus cannot be shielded or the delay would not significantly affect outcome . When advanced disease amenable to radiation is diagnosed in the first trimester, such as late-stage cervical cancer, high-dose radiation therapy may be used with the fetus in situ, knowing that treatment will cause an abortion .
Pregnancy monitoring and delivery considerations
In ongoing pregnancies, the serial assessment of fetal well-being and fetal growth is indicated regardless of whether the patient is undergoing cancer treatment or has delayed therapy until after delivery. Currently, the majority of providers taking care of pregnant women with malignancy prefer preterm delivery, despite the neonatal consequences. In one study, the induction of labor or primary cesarean delivery was performed in >70% of cases, with maternal malignancy (as opposed to an obstetrical indication) documented as the indication in 76.7% . If delivery is anticipated before 34 weeks’ gestation, antenatal steroids should be administered for fetal lung maturity. If maternal disease is stable, delivery at or beyond 37 weeks is preferred, and it is often possible.
Ideally, chemotherapy should be stopped 2–3 weeks before delivery to allow for the recovery of the fetal and maternal bone marrow. This will hopefully minimize the risk of infection and sepsis in both the mother and the baby . However, because spontaneous preterm labor can occur, especially after 34 weeks’ gestation, it is often recommended that chemotherapy not be administered beyond the 33rd week of gestation .
Some cancers can metastasize to the placenta, most commonly melanoma, leukemia, and lymphoma. The histologic evaluation of the placenta should therefore be performed following delivery to evaluate for metastatic disease in any patient with active malignancy . Cases of cancer metastasizing to the fetus have been published, but they are very rare and are limited to case reports .
For women who require chemotherapy or hormonal therapy following delivery, breast-feeding is contraindicated . The general recommendation for planning a future pregnancy is to wait for at least a 2-year disease-free interval after treatment, as this is the most likely time frame for a recurrence . However, because overall survival is predicted by the 5-year disease-free interval, patients should be encouraged to delay pregnancy for 5 years if possible.
Review of selected common malignancies
Gynecologic malignancies
Breast cancer
Breast cancer in pregnancy is fortunately rare. However, unfortunately, breast cancer in pregnancy is most often axillary lymph node-positive, and it presents with a larger primary tumor size than outside of pregnancy. Histologically, the tumors are often poorly differentiated, are more frequently estrogen and progesterone receptor-negative, and approximately 30% are HER2/neu-positive . Approximately 65–90% of pregnant patients are diagnosed with stage II or III breast cancer compared with 45–65% of nonpregnant patients, with more nonpregnant women being diagnosed with stage I disease .
The evaluation of the pregnant patient with suspected breast cancer should include a detailed physical examination of the breast and regional lymph nodes. Mammography of the breast with shielding can be done safely during pregnancy, and it has a reported accuracy of >80% . Breast and regional lymph node ultrasound can be used to assess the extent of disease and to guide biopsy . Although the preferred technique for biopsy is a core-needle biopsy, fine-needle aspiration is acceptable . Further staging should be guided by the clinical disease stage with studies tailored to minimize fetal exposure to radiation. The documentation of metastases may alter the treatment plan, and it may influence the patient’s decision regarding continuing the pregnancy.
Considerations and selection of optimal local and systemic therapy are usually similar to those in the nonpregnant population; however, the selection and timing of chemotherapy, endocrine therapy, and radiation therapy may be altered with pregnancy.
The decision to proceed to mastectomy or breast-conservation surgery should be made according to the same standards that would be applied to a nonpregnant woman, because either can be safely carried out at any time during the course of gestation . The most common procedure performed during pregnancy in the United States has been the modified radical mastectomy as there are insufficient data on which to base recommendations for the use of sentinel lymph node biopsy (SLNB) in pregnancy . It may be reasonable to proceed with SLNB in pregnant breast cancer patients in centers in which SLNB is routine practice in the nonpregnant setting; however, these decisions should be individualized. Notably, there are limited data on the use of radioactive tracer (e.g., technetium 99m sulfur colloid) in pregnancy . The use of blue dye (isosulfan blue or methylene blue dye) is discouraged during pregnancy because of the theoretical risk of fetal methemoglobinemia .
Fetal radiation exposure resulting from adjuvant breast radiation is expected to be low and below the threshold for deterministic effects of radiation if it occurs during the first or second trimesters. However, because adjuvant radiotherapy is generally not considered an urgent procedure, it may be advisable to postpone until after delivery . However, if breast-conservation surgery is performed in the first trimester, the postponement of radiotherapy until delivery could result in a delay of >6 months, which could increase the risk of local recurrence . In this situation, a multidisciplinary team should discuss the risks and benefits of the proposed surgical modality and timing of possible radiotherapy.
Indications for chemotherapy should be the same as those for nonpregnant women, taking into consideration the gestational age at diagnosis as chemotherapy should generally not be initiated in the first trimester. The largest experience with chemotherapeutic agents in pregnancy has been with anthracycline antibiotics, alkylating agents, and taxanes, and available data support their safety . Iftaxane chemotherapy is used; weekly administration of paclitaxel after the first trimester is preferred . There are only case reports of the use of trastuzumab (Herceptin) during pregnancy . The majority of these case reports noted associated oligo- or anhydramnios, and fetal renal failure was reported in one case. Therefore, it should only be administered in the postpartum period. Endocrine therapy, such as tamoxifen or aromatase inhibitors, is also contraindicated during pregnancy, and, if indicated, it should be reserved for the postpartum period.
Delivery planning should balance the optimization of maternal therapy with the fetal risks related to prematurity. For most cases, delivery can be scheduled at or near term (≥37 weeks’ gestation).
Cervical cancer
Cervical cytological abnormalities are a common occurrence in pregnancy, found in up to 5% of pregnancies . The diagnosis of invasive cervical cancer, however, is rare, and, fortunately, almost three-fourths of cases are diagnosed in the early stages . In general, cervical cancer does not adversely affect pregnancy nor does the pregnancy itself affect maternal survival .
The initial evaluation of cervical cytological abnormalities in pregnancy is well described by The American Society for Colposcopy and Cervical Pathology (ASCCP) . Briefly, women found to have low-grade lesions on cytology should be offered colposcopy. It can be done during the pregnancy or can be safely deferred until 6 weeks post partum. However, high-grade lesions require immediate evaluation by colposcopy, with biopsy to rule out invasive disease but without endocervical curettage because it is contraindicated during pregnancy. With a finding of CIN2-3, colposcopy should be performed every trimester, and additional biopsies performed if progression to malignancy is suspected. Although these lesions rarely progress, postpartum follow-up is necessary because approximately 50% of high-grade lesions will persist .
If microinvasive or invasive disease is suspected or confirmed, management with cervical conization or trachelectomy may be possible, and the patient should be referred to a gynecologic oncologist . In general, radical hysterectomy and/or pelvic radiotherapy with or without chemotherapy are the main modalities used in managing cervical cancer. In pregnancy, this therapy would result in pregnancy termination and fetal death. Patients who wish to continue the pregnancy require a modification of this standard treatment. As with other malignancies, treatment depends on the cancer stage and gestational age. In early-stage cervical cancer, definitive treatment might be delayed until after delivery, with close monitoring during pregnancy . Alternatively, for stage IA1 disease, cervical conization during the second trimester may be sufficient. For locally advanced disease (stage IB1, IB2, IIA), in patients who wish to continue the pregnancy, thorough staging is recommended. Staging can be performed radiographically with pelvic MRI; however, lymphadenectomy is still the gold standard . This procedure can be safely carried out laparoscopically, although the risk of bleeding is higher during pregnancy . If the patient needs treatment for a locally advanced or a high-risk tumor, platinum-based neoadjuvant chemotherapy can be considered. The local response rate is similar to that in nonpregnant women . In patients with stage IA1 with positive margins, IA2, IB or IIA disease, locally advanced disease, small cell histological subtype, poorly differentiated squamous or adenocarcinoma or with disease progression who do not wish to continue the pregnancy, immediate treatment with radical surgery or radiation therapy is advised .
The timing and mode of delivery in patients with cervical cancer vary by the stage of the cancer and the timing of diagnosis. With advanced disease, preterm delivery is preferred to allow for timely maternal treatment. If radical surgery is indicated based on disease stage, this can be offered at the time of a cesarean delivery. When performed in the third trimester, however, this surgery is often complicated by significant hemorrhage . With stage IA disease, vaginal delivery may be safely accomplished at or near term (≥37 weeks’ gestation) followed by definitive surgical management if needed . The patient should additionally be carefully followed up with serial examinations after vaginal delivery because tumor implantation at the episiotomy site has been described . Patients with bulky or friable stage IB disease are at risk of significant hemorrhage at the time of vaginal delivery; therefore, scheduled cesarean hysterectomy at or near term (≥37 weeks’ gestation) is prudent .
Ovarian cancer
The routine use of ultrasound during pregnancy has made the diagnosis of adnexal masses a common occurrence, with an estimated incidence of one in 600 to 1500 pregnancies . Fortunately, most are benign; only 1–3% are found to be malignant, and most are diagnosed in early stages. The most common ovarian malignancies diagnosed during pregnancy are germ cell, sex cord-stromal, or borderline tumors, and, less commonly, invasive epithelial cancers .
Approximately 70% of adnexal masses identified during pregnancy will spontaneously resolve; therefore, serial evaluation is warranted to determine the need for intervention. Masses that require surgical intervention include those that cause acute complications such as pain, hemorrhage, or torsion, and also those that are large in size (>8 cm), complex in nature, persist after 16 weeks’ gestation, or are associated with the presence of extra-ovarian disease . As described previously, the use of tumor markers may not be as helpful as in a nonpregnant patient with an ovarian mass.
Both laparoscopic surgery and open laparotomy are acceptable surgical approaches. Care should be taken to avoid rupturing the ovary. Surgical staging, with the preservation of the uterus and contralateral ovary, is advised when possible. In stage 1 or 2 disease, the preservation of the uterus with peritoneal staging should be offered as the primary surgical treatment with the removal of only suspicious lymph nodes . In patients with peritoneal spread of disease, standard surgical management includes a complete debulking surgery. This surgery will necessarily end the pregnancy because a hysterectomy is required. If stage 3 cancer is diagnosed in the first or second trimesters, this should be offered as the standard procedure. If continuation of pregnancy is elected, debulking surgery, if required, would need to be performed postpartum .
The standard chemotherapy for epithelial ovarian cancer, namely a platinum-based agent with a taxane, may be used with minimal fetal consequences in the second and third trimesters. Ovarian germ cell tumors, on the other hand, are classically treated with an etoposide-platinum-based combination (BEP or EP) . Although some reports have been published on the potential safety of this regimen in pregnancy , it remains relatively toxic. In particular, etoposide has been associated with a high incidence of fetal growth restriction and newborn complications including myelosuppression . Alternative regimens should be considered during pregnancy, and they vary by institution . Sex cord-stromal tumors should be treated as in the nonpregnant woman with either observation or a platinum-based agent based on stage . Borderline tumors generally only require observation once surgical staging has been completed .
The timing of delivery in patients with ovarian cancer is again dependent on stage and gestational age. Following surgery, early-stage disease can be delivered at or near term (≥37 weeks’ gestation) with a plan for vaginal delivery. Advanced disease may require preterm delivery and possible planned laparotomy for cesarean delivery and interval debulking .
Other malignancies
Hematologic cancer
Hematologic malignancies, including leukemia and lymphoma, account for approximately one in four of malignancies diagnosed in pregnancy .
Acute leukemia, including acute myeloid leukemia and acute lymphoid leukemia, accounts for 90% of all leukemias diagnosed during pregnancy . Presenting symptoms are typically related to pancytopenia and its complications, and they include weakness and easy fatigability, infections, and/or hemorrhagic findings such as gingival bleeding, ecchymoses, and epistaxis. Leukemia is diagnosed by bone marrow biopsy, which should not be delayed because of pregnancy if there is a high index of suspicion.
The stage at diagnosis is not affected by pregnancy, and disease course and survival are not altered in pregnant compared with nonpregnant women . Unfortunately, pregnancy seems to be adversely affected by leukemia with increased rates of preterm delivery, growth restriction, intrauterine fetal demise, and spontaneous abortion . In addition, the hematologic changes seen with acute leukemia may compound the normal physiologic changes seen in pregnancy leading to an increased risk of thrombosis, bleeding, and disseminated intravascular coagulation .
Because of the aggressive nature of these cancers, treatment should begin immediately, regardless of gestational age. This may require a recommendation of termination if leukemia is diagnosed in the first trimester or planned preterm delivery if diagnosed in the third trimester. Patients with acute myeloid leukemia should either be placed in a clinical trial for treatment or be started on cytarabine with an anthracycline antibiotic (e.g., idarubicin or daunorubicin) . Acute lymphoblastic leukemia is treated with a combination of chemotherapeutic agents plus a tyrosine-kinase inhibitor based on the cytogenetic and molecular subtype .
Lymphoma usually presents as painless lymphadenopathy. Workup should include a chest X-ray and MRI of the chest, abdomen, and pelvis, with definitive diagnosis made by lymph node biopsy . In general, survival and stage at diagnosis are not affected by pregnancy, and pregnancy is not adversely affected by the disease .
In Hodgkin lymphoma, similar to every other malignancy, treatment regimen varies by stage. Unlike leukemia, however, treatment can often be postponed until the second trimester if the disease is diagnosed in the first trimester, or it can be postponed until postpartum if the disease is diagnosed in the third trimester . Patients with higher-stage disease who need prompt treatment with chemotherapy may receive a combination of doxorubicin, vincristine, bleomycin, and dacarbazine (ABVD) starting in the second trimester . In the setting of stable or well-controlled disease, delivery is recommended at term (37 + weeks’ gestation).
Patients diagnosed with aggressive non-Hodgkin lymphoma should begin immediate chemotherapy. If the diagnosis is made in the first trimester, pregnancy termination should be considered. The combination of cyclophosphamide, hydroxydaunorubicin (aka doxorubicin or Adriamycin), oncovin (aka vincristine), and prednisone (CHOP) is the standard chemotherapy regimen regardless of pregnancy status . Several reports have shown favorable pregnancy outcomes when administration is started in the second trimester . The administration of rituximab during pregnancy in patients with B-cell lymphoma has been shown to increase the risk of B-cell depletion in the newborn .
Thyroid cancer
During pregnancy, the prevalence of thyroid nodules increases, and thyroid cancer, most commonly papillary cancers, is a relatively common cancer diagnosis . The workup of a thyroid nodule in pregnancy, which should be similar to the workup outside of pregnancy, includes a thorough history of risk factors for thyroid cancer such as radiation exposure and personal and family history of thyroid disease, familial polyposis, familial medullary carcinoma, or multiple endocrine neoplasia; a thyroid ultrasound; and serum thyroid-stimulating hormone and free thyroxine levels . Similar to the nonpregnant patient, concerning findings on ultrasound should prompt a fine-needle aspiration, which is safe in any trimester of pregnancy .
There is no difference in the survival or progression of thyroid cancer in pregnant versus nonpregnant women . In addition, pregnancy and fetal outcomes do not seem to be affected by maternal thyroid cancer .
If thyroid cancer is diagnosed, stable tumors do not require immediate surgery, and definitive treatment can be postponed until the postpartum period because delaying surgery does not appear to impact maternal outcome. However, if this management strategy is chosen, thyroid ultrasound should be performed for each trimester to assess for continued stability. An increase in the volume of 50%, an increase in tumor diameter by 20%, or other evidence of metastatic disease would require surgical intervention . Radioablative therapy is contraindicated in pregnancy and breast-feeding .
In general, delivery before term is not recommended, and it is almost never indicated. The mode of delivery should be based on obstetric indications.
Melanoma
Melanoma is one of the most common cancers diagnosed in women during their reproductive years . The diagnosis of melanoma requires a biopsy. Although an increase in pigmentation can be normal during pregnancy, biopsy should be performed if any nevus changes in color, size, or symmetry . When matched for tumor thickness and stage, there is no difference in overall survival between pregnant and nonpregnant women . Unfortunately, melanoma is often diagnosed at a later stage in pregnant women. Although outcomes are very good with stage I or II disease, outcomes are poor for both the mother and the fetus with advanced disease.
If melanoma is confirmed, staging is done with SLNB regardless of pregnancy status . Further staging with MRI or ultrasound should then be performed if there is concern for metastatic disease. Surgical management should follow standard procedures outside of pregnancy.
Chemotherapy and interferon have been used for metastatic melanoma outside of pregnancy; however, insufficient data exist to recommend their use during pregnancy . In addition, safety data are lacking on the use of newer agents such as ipilimumab or vemurafenib during pregnancy, and therefore they should be reserved for use post partum .
Following surgical treatment, delivery can be planned at or near term (≥37 weeks’ gestation) with early-stage disease. With later-stage disease, preterm delivery will likely be beneficial to maternal treatment, and the decision regarding the timing of delivery should be made in concert with the patient’s primary oncologist. Finally, melanoma more commonly metastasizes to the placenta than other cancers, so placental pathology examination to evaluate for metastatic disease is necessary . Unfortunately, fetal metastases have also been reported .
Colon cancer
Colon cancer is a relatively uncommon cancer in pregnancy. In part, this is because only 10% of colon cancers are diagnosed before the age of 50. During pregnancy, it is more common for cancers to involve the rectum, compared with outside of pregnancy where it is more common for the non-pelvic colon to be involved . There is no difference in stage at diagnosis or survival for women diagnosed with colon cancer during pregnancy versus outside of pregnancy . Colon cancer, however, has been associated with an increase in spontaneous preterm birth, although overall fetal outcomes are good .
Abdominal ultrasound can be used as a first line for diagnosis; however, as the pregnancy progresses, MRI may be necessary . Colonoscopy with biopsies as needed is safe in pregnancy . In contrast to other tumor markers, CEA levels are minimally changed during normal pregnancy, and, thus, they can be used to monitor response to treatment.
The treatment of colon cancer in pregnancy is similar to the treatment outside of pregnancy, and it is again dependent on stage. An important consideration in pregnancy is that the enlarging uterus may encroach on the surgical field, although surgical resection is often possible . When diagnosed in the third trimester, surgery may be deferred until post partum, after the pelvic vessels and the uterus have returned to nonpregnant sizes .
Chemotherapy, generally 5-fluorouracil (5-FU), may be used for higher-stage disease after the first trimester . 5-FU, however, has been associated with fetal growth restriction . Another standard regimen that includes a combination of folinic acid, 5-FU, and oxaliplatin (FOLFOX) is generally avoided in pregnancy because of limited safety data for oxaliplatin .
The timing and mode of delivery will depend on the stage and location of the cancer; however, in disease that has been treated surgically, at or near term (≥37 weeks), delivery is reasonable . Vaginal delivery may be possible; however, cesarean delivery may be preferable if a concomitant surgical resection is planned or if the vagina is obstructed by tumor .
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