Treatment of pregnant women with chemotherapy may pose a risk to the fetus, raising therapeutic, ethical, moral, and social dilemmas. Publications on this issue are limited to retrospective series and case reports, thus further complicating decision making. Diagnosis and staging are usually performed as in nonpregnant women, but procedures that expose the fetus to radiation are excluded. Chemotherapy is not recommended in the first trimester to avoid fetal malformations. Thus, the option is either treatment delay or pregnancy termination. Later in pregnancy, treatment is often initiated without delay, with no apparent evidence of teratogenicity.
The diagnosis of cancer during pregnancy is a traumatic event, posing a challenge for patients, their family, and the medical team. The need to treat the patient for a potentially lethal disease and concerns about adverse fetal outcomes raise therapeutic, ethical, moral, and social dilemmas. This “maternal-fetal conflict” must include close attention to the cultural attitudes and beliefs of patients and their family. Lymphoma is the fourth most common malignancy in pregnancy, with an estimated prevalence of 1 in 6000 pregnancies. Leukemia is estimated to occur in 1 in 100,000 pregnancies. Because of the increasing age of pregnancy in the western world, the incidence of malignancy during pregnancy is expected to increase.
Over the past few years, significant progress has been made in the treatment of patients with hematologic malignancies, including new imaging techniques and the addition of innovative drugs that increase therapeutic efficacy. Incorporation of these new tools during pregnancy is questionable in some instances and contraindicated in others due to concerns of fetal harm and the lack of safety data in human pregnancies.
The low incidence of hematologic malignancies during pregnancy precludes large prospective controlled trials, and information in this area is limited to retrospective series and case reports, which further complicates decision making. This article reviews the different therapeutic options for pregnant women with hematologic malignancy and discusses optimization of therapy for the mother, while minimizing risks to the fetus.
Diagnosis and evaluation of pregnant women with hematologic malignancy
The presenting signs and symptoms of lymphoma and leukemia during pregnancy are similar to those occurring in nonpregnant women. However, some common symptoms normally reported during pregnancy, such as fatigue and shortness of breath, or physiologic changes, such as pregnancy-associated anemia and thrombocytopenia, might delay the diagnostic workup. Avoiding imaging studies because of fetal exposure to radiation may further delay the initial diagnosis. The diagnosis of lymphoma is usually established by performing lymph node biopsy. The surgical procedure of lymph node biopsy, done under local or general anesthesia, does not seem to pose a risk to the fetus when using modern anesthetic techniques, and the rate of miscarriage is not different from that of healthy pregnant women.
Staging of a patient with lymphoma requires imaging studies, usually computed tomographic (CT) scan or positron emission tomography (PET) combined with CT scan (PET-CT). These studies are often associated with considerable doses of radiation, and although the dose is well below the teratogenic threshold, it is advisable to minimize exposing the fetus to radiation if possible. Ultrasonography and magnetic resonance imaging can be used safely, whereas reassessment with CT scan or PET-CT can be performed after delivery. Chest radiography can be safely performed using abdominal shielding. Bone marrow biopsy and aspiration, which are part of lymphoma staging and the key procedures in diagnosing leukemia, can be performed safely in pregnant women.
Chemotherapy in pregnancy
Pregnancy is associated with physiologic changes that may affect the pharmacokinetics of chemotherapeutic agents. Such changes include increased plasma volume, third spacing in the amniotic fluid, and increased renal clearance and hepatic metabolism of drugs. Because pharmacokinetic studies in pregnant women are lacking, it is unknown whether dose modification may be needed.
Teratogenicity is the main concern when treating pregnant women. Most cytotoxic agents have a molecular weight less than 400 kDa and can thus freely cross the placenta and reach the fetus. However, information regarding drug concentrations in the placenta, amniotic fluid, and fetus is limited to small studies with conflicting results. Although the information regarding the teratogenicity of specific chemotherapeutic drugs is limited, almost all cytotoxic drugs have been found to be teratogenic in animal studies ; however, doses used to treat humans are usually less than the teratogenic limit documented in animals, making it difficult to extrapolate human teratogenic thresholds from animal data. Most information regarding chemotherapy in pregnancy is from series that used multiagent protocols, and it is therefore difficult to separate the fetal effects of individual drugs.
Genetic variability probably explains some of the heterogeneity in pregnancy outcome after chemotherapy; for example, severe effects of doxorubicin (Adriamycin) were documented on a male fetus, whereas his female twin was unaffected.
The fetus is most vulnerable to teratogenic effects during organogenesis, which occurs during weeks 2 to 8 of pregnancy. Several organs, including the eyes and genitalia, as well as the hematopoietic and nervous systems, remain vulnerable after the first trimester. Treatment with combination chemotherapy during the first trimester has an estimated teratogenicity rate of 10% and 20%. This risk was found to be lower with single agent than combination therapy and decreased when antimetabolites were omitted. In addition to fetal malformations, chemotherapy during the first trimester increased the risk for spontaneous abortion and fetal death.
Chemotherapy during the second and third trimesters has been associated with increased risk of intrauterine growth retardation (IUGR), fetal death, preterm delivery, and low birth weight ; however, it is impossible to discern the direct effects of the drugs from those of maternal morbidity. Most of the available data do not show increased risk of fetal malformations during the later stages of pregnancy.
Chemotherapy in pregnancy
Pregnancy is associated with physiologic changes that may affect the pharmacokinetics of chemotherapeutic agents. Such changes include increased plasma volume, third spacing in the amniotic fluid, and increased renal clearance and hepatic metabolism of drugs. Because pharmacokinetic studies in pregnant women are lacking, it is unknown whether dose modification may be needed.
Teratogenicity is the main concern when treating pregnant women. Most cytotoxic agents have a molecular weight less than 400 kDa and can thus freely cross the placenta and reach the fetus. However, information regarding drug concentrations in the placenta, amniotic fluid, and fetus is limited to small studies with conflicting results. Although the information regarding the teratogenicity of specific chemotherapeutic drugs is limited, almost all cytotoxic drugs have been found to be teratogenic in animal studies ; however, doses used to treat humans are usually less than the teratogenic limit documented in animals, making it difficult to extrapolate human teratogenic thresholds from animal data. Most information regarding chemotherapy in pregnancy is from series that used multiagent protocols, and it is therefore difficult to separate the fetal effects of individual drugs.
Genetic variability probably explains some of the heterogeneity in pregnancy outcome after chemotherapy; for example, severe effects of doxorubicin (Adriamycin) were documented on a male fetus, whereas his female twin was unaffected.
The fetus is most vulnerable to teratogenic effects during organogenesis, which occurs during weeks 2 to 8 of pregnancy. Several organs, including the eyes and genitalia, as well as the hematopoietic and nervous systems, remain vulnerable after the first trimester. Treatment with combination chemotherapy during the first trimester has an estimated teratogenicity rate of 10% and 20%. This risk was found to be lower with single agent than combination therapy and decreased when antimetabolites were omitted. In addition to fetal malformations, chemotherapy during the first trimester increased the risk for spontaneous abortion and fetal death.
Chemotherapy during the second and third trimesters has been associated with increased risk of intrauterine growth retardation (IUGR), fetal death, preterm delivery, and low birth weight ; however, it is impossible to discern the direct effects of the drugs from those of maternal morbidity. Most of the available data do not show increased risk of fetal malformations during the later stages of pregnancy.
Long-term effects of fetal exposure to chemotherapy
Fetal exposure to chemotherapy has raised concerns regarding more subtle and late-onset adverse effects. Concerns regarding late effects include adverse neurodevelopmental outcomes, compromised fertility, and childhood malignancy. Information regarding long-term outcomes of fetal exposure to chemotherapy is very limited. A series by Aviles and Neri assessing outcomes in 84 children exposed to chemotherapy in utero, with an average follow-up period of 18.7 years, showed apparent normal neurologic development, school performance, and sexual development. And 12 of the children later became parents to normal children. The apparent risk of childhood malignancies was not increased. Another series with 111 children exposed to chemotherapy during pregnancy and followed up for 1 to 19 years showed favorable long-term outcomes. It seems that after the first trimester, exposure of the fetus to chemotherapy does not increase the risk of adverse neurodevelopment, infertility, or childhood malignancies, although this is based on limited information.
Radiotherapy in pregnancy
Fetal exposure to radiotherapy during the first trimester may be teratogenic and may increase the risk of childhood malignancy. Concerns regarding long-term neurodevelopmental outcomes exist as well. The dose of fetal exposure to radiation depends on field size and the distance from the radiation field margins to the uterus. An exposure of 0.1 to 0.2 Gy during the first trimester is considered the threshold for severe fetal malformations. For these reasons, radiotherapy during pregnancy should be limited to highly specific situations when the radiation field is far from the fetus, such as lymphoma with disease confined to the neck region, using abdominal shielding. Radiotherapy should be executed after consultation with an expert medical physicist.
Hodgkin lymphoma
Although Hodgkin lymphoma (HD) represents less then 1% of all malignancies, its first peak occurs in the third decade of life, during the reproductive age. Thus, it is the most common lymphoma diagnosed during pregnancy.
The current treatment consists of the ABVD protocol (Adriamycin, bleomycin, vinblastine, and dacarbazine) for most patients, with or without radiotherapy. More aggressive protocols such as escalated BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, prednisone, and procarbazine) are used for high-risk patients with advanced disease.
Most information regarding HD during pregnancy is derived from case reports and small series. Data regarding the use of ABVD are limited, but the available information, including a few reports of treatment during the first trimester, suggests that this protocol may be safe for use in pregnancy. However, because chemotherapy is generally considered teratogenic during the first trimester, it is recommended to defer treatment to later in pregnancy whenever possible.
In a patient with advanced disease diagnosed during the first trimester, delaying therapy may adversely affect maternal survival, and thus, treatment with combination chemotherapy is initiated, advising the family to consider pregnancy termination. In a patient diagnosed during the second or the third trimester, initiation of treatment with combination chemotherapy is commonly recommended.
Alternative approaches for the management of HD during pregnancy may include
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In women with early stage disease limited to the neck region, radiotherapy has been suggested, using proper shielding to the abdomen. However, such an option must be considered carefully because of the potentially severe adverse effects of radiotherapy to the fetus.
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Another alternative to multiagent chemotherapy is therapy with single-agent vinblastine, which is effective for HD with modest toxicity and lower likelihood of fetal adverse outcome. In a series described by Connors, 6 women were treated with single-agent vinblastine, delaying combination chemotherapy until after delivery, with favorable fetal outcome.
The prognosis of pregnant women with HD seems to be similar to that in nonpregnant women. A case-control study of 48 women with HD during pregnancy showed a 20-year survival rate comparable to that of matched control subjects.
A suggested algorithm for the management of HD in pregnancy is presented in Fig. 1 .
Non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies. The authors have divided the treatment of NHL during pregnancy according to the indolent, aggressive, and very aggressive types of NHL.
Indolent NHL
Indolent NHL, including follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and marginal zone lymphoma, is usually diagnosed at an older age, with a median age of 60 years for the diagnosis of follicular lymphoma, and is thus very uncommon during pregnancy. Consequently, there is a lack of evidence regarding optimal treatment of these malignancies.
Indolent NHL tends to progress slowly, causes few symptoms, and is considered incurable. Hence, the approach to its management is watchful waiting until symptomatic progression ( Fig. 2 ). For this reason, most women with indolent lymphoma diagnosed during pregnancy can be followed up closely without treatment, unless symptoms occur. When therapy is needed, single agent (chlorambucil) or combination chemotherapy such as CVP (cyclophosphamide, vincristine, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is used. A few case reports of women with NHL treated with these protocols during pregnancy are available in the literature, although none reported congenital anomalies, including 4 cases treated during the first trimester. Neonatal leukopenia and colitis were reported in an infant whose mother was exposed to chemotherapy in the third trimester.
An alternative approach is the use of single-agent rituximab without chemotherapy. The use of rituximab was not associated with fetal morbidity or mortality in several case reports. A neonate with transient B-cell depletion and otherwise normal development was reported.
Fludarabine is a purine analogue often used for the treatment of indolent NHL, but data regarding its effect on fetal development are lacking. In general, antimetabolites tend to be more teratogenic than other antineoplastic agents, and thus, fludarabine is not generally recommended during pregnancy.
Radiolabeled monoclonal antibodies are contraindicated during pregnancy because of the teratogenic risks from radiation exposure.
The use of amoxicillin, clarithromycin, and omeprazole for the eradication of Helicobacter pylori in patients with gastric mucosa-associated lymphoid tissue lymphoma is considered safe during pregnancy, and they may be administered without delay.
Aggressive NHL
It is the most frequently encountered group of NHL and includes diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and mature T- and natural killer–cell lymphomas.
The most common regimen used for these malignancies is CHOP, with the addition of rituximab in CD20 + tumors. As noted earlier, information regarding treatment with CHOP during pregnancy is limited to a few case reports and small series. Although no congenital anomalies have been noted using this protocol, including 4 cases of women treated during the first trimester, the numbers are too small to render an estimate of safety. Other reports describe treatment with different regimens containing alkylating agents and anthracyclines in patients with NHL, and although no fetal anomalies have been reported, there were a few cases of preterm delivery and intrauterine fetal death. The fetal safety of late trimester use of cyclophosphamide and doxorubicin is suggested by reports of pregnant women with breast cancer treated with protocols containing these agents. In 2 series of 53 pregnant women with breast cancer treated with these agents during the second and third trimesters, no fetal complications were noted.
Because of the rapidly progressive nature of aggressive NHL, treatment of pregnant women should not be delayed, and multiagent chemotherapy should be initiated promptly with CHOP, adding rituximab in DLBCL. When the disease is diagnosed during the first trimester, appropriate treatment with multiagent chemotherapy should be begun promptly, and pregnancy termination should be considered by the family because of the increased risk of fetal malformation (see Fig. 2 ). Treatment delay with close follow-up should be considered for women approaching the end of the first trimester with limited disease and low bulk. It seems safe to administer combination chemotherapy with CHOP and rituximab in the second and third trimesters, and treatment should begin soon after diagnosis.
Very Aggressive NHL
This group of diseases includes Burkitt lymphoma (BL) and precursor B- and T-cell lymphoblastic lymphoma/leukemia. These malignancies are characterized by very rapid tumor growth, high risk for central nervous system (CNS) involvement or relapse, and high risk for tumor lysis syndrome. Treatment should include intensive combination chemotherapy, with the addition of CNS prophylaxis. The information regarding treatment of BL during pregnancy is limited to only several case reports. Recent publications suggest that women treated with effective intensive modern combination chemotherapy can be cured. Information regarding fetal outcome with these intensive protocols is extremely limited. One case report described fetal death in a patient treated from the beginning of the second trimester, whereas in another patient treated during the third trimester with early planned delivery by cesarean delivery, the fetal outcome was uneventful. High-dose methotrexate, which is an essential part of the protocols for BL, is highly teratogenic and should not be used in the first trimester. Several reports regarding the use of this drug in pregnancy described fetal anomalies, as well as fetal myelosuppression. In the few case reports of BL during pregnancy, treatment with methotrexate was postponed until after delivery.
Because patients with aggressive lymphomas must be treated immediately and because of concerns for fetal harm using appropriate protocols, pregnancy termination should be discussed with the family when therapy has to commence during the first trimester (see Fig. 2 ). Because of the high toxicity of these protocols, extending the recommendation for pregnancy termination up to 20 weeks of pregnancy should be considered. When possible, early delivery should be recommended at later stages of pregnancy.
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