Introduction

The most common malignancies presenting in pregnant women are breast, cervical, lymphoma and melanoma. The incidence of haematological malignancies in pregnancy ranges from 1 in 1000 to 1 in 10,000. Much of the management of haematological malignancies in non-pregnant women is based upon robust randomised-controlled trials. In pregnancy, before the development of national and international disease databases, the evidence basis has been limited to retrospective case studies. Management of haematological malignancies in pregnancy is complex and requires a multidisciplinary approach. The clinician and mother need to address both maternal and fetal well-being. The mother needs to be informed of the stage of disease and whether or not there is an immediate need for chemotherapy to optimise maternal outcome. The potential risks to the fetus need to be considered. In certain cases of aggressive disease presenting in the first and second trimester, the mother may need counselling to consider termination of the pregnancy. The mother should be provided with the necessary information and support to make informed decisions about the pregnancy and disease management. In cases in which the pregnancy proceeds and chemotherapy is embarked upon, the team should plan delivery between courses of chemotherapy after maternal bone-marrow reconstitution to avoid maternal and neonatal pancytopaenia. After birth of the baby, any further treatment regimens should be reviewed to consider whether breast feeding is a possibility or contraindicated.

Diagnosis and staging

Woman may present with symptoms and signs similar to those in non-pregnant women with a haematological malignancy or an abnormal blood count. Pregnancy, however, may also mask these features unless the physician remains vigilant. Bone-marrow aspirate and trephine may be carried out safely with local anaesthesia during pregnancy. Lymph-node biopsy under local or general anaesthesia, using modern anaesthetic techniques, does not pose a risk to the fetus. Lymphoma staging usually requires a computed tomography scan or positive emission tomography (PET) combined with a computed tomography scan. In pregnancy a magnetic resonance imaging (MRI) scan circumvents radiation to the fetus.

Diagnosis and staging

Woman may present with symptoms and signs similar to those in non-pregnant women with a haematological malignancy or an abnormal blood count. Pregnancy, however, may also mask these features unless the physician remains vigilant. Bone-marrow aspirate and trephine may be carried out safely with local anaesthesia during pregnancy. Lymph-node biopsy under local or general anaesthesia, using modern anaesthetic techniques, does not pose a risk to the fetus. Lymphoma staging usually requires a computed tomography scan or positive emission tomography (PET) combined with a computed tomography scan. In pregnancy a magnetic resonance imaging (MRI) scan circumvents radiation to the fetus.

Chemotherapy in pregnancy

Chemotherapy during pregnancy may harm the fetus, newborn baby or mother. Detrimental effects for the fetus or newborn baby include malformation, teratogenesis, mutations, carcinogenesis, organ toxicity and abnormal neurodevelopment. Detrimental effects to the mother include spontaneous miscarriage and potential sterility.

Virtually all chemotherapy agents can cross the placenta. Fetal toxicity depends upon the timing of treatment in relation to the phase of fetal development. In the pre-embryonic stage (conception until 17 days after conception), cells of conceptus divide rapidly, and insult has an all or nothing effect. If most cells are affected, this is likely to progress to spontaneous miscarriage; however, when a balance of cells remain to replace damaged cells, there may be no long-term effect. In the embryonic phase (3–8 weeks after conception), cells differentiate and form organ systems. Damage during this stage may result in permanent effects in an end organ. In the fetal stage (from 8 weeks after conception), growth and maturation continues. The cerebral cortex, gastrointestinal tract and renal glomeruli continue to differentiate and remain vulnerable.

In animal models, virtually all chemotherapy drugs have been associated with congenital malformations. The doses given to humans, however, are less. This makes it difficult to extrapolate results from animal models. Chemotherapy given in the first trimester increases the risk of spontaneous miscarriage and fetal death, and is associated with a 10–20% risk of malformation. This risk is reduced when single-agent chemotherapy is used and anti-metabolites are excluded. Second- and third-trimester exposure is associated with an increased risk of intrauterine fetal growth restriction (FGR), fetal death, preterm delivery, and low birth weight. data, however, do not suggest an increase in the risk of fetal malformation. In addition the limited data available on fetal exposure to chemotherapy after the first trimester suggest no increase in adverse neurodevelopment, infertility or childhood malignancy.

In view of the additional risks of chemotherapy to the fetus in the first trimester it is preferable to defer chemotherapy until the second trimester after organogenesis unless this compromises maternal outcome. Unfortunately, deferring treatment is not always an option, and the mother may be counselled to consider termination of pregnancy.

Pregnancy may alter drug metabolism owing to increased plasma volume, decreased albumin, increased hepatic, renal clearance and gastric motility, and the amniotic sac may be a third space. Studies to inform us of pregnancy-adjusted doses, however, are lacking, and standard doses of drugs should be used.

Radiotherapy

Radiotherapy during pregnancy may cause harm to the developing fetus, including organ malformation, reduced intelligence quotient, severe mental retardation and increased risk of childhood malignancy. Exposure to 0.1–0.2 Gy in the first trimester is the threshold for severe malformation. A number of case reports have been published on radiotherapy in supra diaphragmatic Hodgkin’s lymphoma. Studies using a humanoid phantom to simulate a first-trimester pregnancy and measure radiation doses to the fetus reported local field irradiation in the neck or axilla resulted in fetal doses less than 0.1 Gy. Treatment of Hodgkin’s lymphoma, however, has evolved. Women with stage I and II Hodgkin’s lymphoma are treated with combined chemotherapy followed by involved field radiotherapy. Women with stage III and IV Hodgkin’s lymphoma are treated with extended combined chemotherapy; radiotherapy is of no benefit if a complete remission is achieved. In general, radiotherapy should be reserved for cases where it is absolutely necessary, limiting whole-body fetal dose to less than 0.1 Gy.

Lymphoma

Lymphoma is the fourth most common malignancy in pregnancy, with an estimated prevalence of 1 in 1000 to 1 in 6000.

Hodgkin’s lymphoma

The peak incidence of Hodgkin’s lymphoma coincides with reproductive age. It is the most common lymphoma in pregnancy affecting 1 in 1000 to 1 in 6000 pregnancies.

Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the standard chemotherapy regimen. A systematic review identified 68 pregnancies in 67 women with Hodgkin’s lymphoma treated with chemotherapy in pregnancy. In 26 out of the 68 pregnancies, ABVD was the chemotherapy regimen given. The largest case study included 26 women treated with chemotherapy. In this study, exposure to chemotherapy was not associated with low fetal birth weight or congenital anomaly, and no late secondary effects were identified with median follow up of 18 years. Ten of the 26 pregnancies were exposed to chemotherapy in the first trimester. The systematic review summarised the outcome of the remaining 42 pregnancies. Of the 17 exposed to chemotherapy in the first trimester, six congenital abnormalities and three spontaneous miscarriages were reported. These combined results challenged the favourable outcome of the largest series and discouraged elective treatment in the first trimester. Sixteen out of the 42 pregnancies were exposed to ABVD, including two pregnancies in the first trimester, one of which reported FGR and thumb malformation. The outcome of the 14 pregnancies exposed to ABVD beyond the first trimester was good, with the exception of a third-trimester intrauterine death (IUD).

The ABVD chemotherapy regimen seems to the most commonly use. A number of reports have been published of early stage Hodgkin’s lymphoma involving the supra- diaphragmatic region treated with radiotherapy, including a study of 16 women treated in pregnancy. In all 16 pregnancies, the women delivered normal babies at term. A further 30 cases have been reported in which the fetus received between 0.02–0.5 Gy. All babies were reported to be healthy at birth, and one report included an 11-year follow up with no reported abnormalities.

When early stage disease is diagnosed in the first trimester, a watchful wait approach with regular follow up may be considered, with a plan to commence ABVD in the second trimester. This may not be feasible, however, because of disease bulk or progression, in which case termination of pregnancy should be considered followed by ABVD. In advanced-stage disease in the first trimester, delay in treatment may adversely affect maternal outcome, and termination of the pregnancy followed by ABVD should be considered. After a diagnosis of early or advanced-stage disease in the second or third trimester, ABVD is recommended. An alternative suggested approach in early stage disease limited to the supra-diaphragmatic area is radiotherapy with appropriate shielding to the abdomen and limiting whole-body fetal dose to less than 0.1 Gy. The current standard of care for early stage disease, however, is ABVD followed by involved field radiotherapy. Prognosis of pregnant women treated for Hodgkin’s lymphoma is similar to non-pregnant women.

Non Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma (NHL) is less common in pregnancy, and encompasses a heterogeneous group ranging from indolent to aggressive lymphomas.

A systematic review identified 75 pregnant women treated with systemic therapy for NHL. The largest case study included 29 pregnant women, including 20 diagnosed with diffuse large B cell lymphoma (DLBCL). Most of the women received cyclophosphamide, doxorubicin, vincristine, prednisolone and bleomycin. Dose intensity was not modified and 17 mothers received treatment in the first trimester. Chemotherapy did not adversely affect the outcome of pregnancy, and no congenital malformation was reported. The remaining cases summarised in the review included 46 woman, 15 of whom received cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) for a diagnosis of DLBCL, including four in the first trimester. Congenital malformation or fetal mortality was not reported. One of the 15 pregnancies resulted in premature delivery at 33 weeks after chemotherapy; the neonate had transient leucopaenia and enterocolitis.

The use of rituximab a CD 20 monoclonal antibody, has improved the outcome of indolent and aggressive NHL. Rituximab, in conjunction with chemotherapy, has been reported in seven women diagnosed with NHL during pregnancy. One of the women unintentionally received rituximab in the first trimester; the remaining six received it during the second trimester. One woman delivered prematurely, and the neonate had an associated transient pulmonary insufficiency. A further neonate had B-cell depletion, which resolved after 12 weeks.

Indolent NHL (i.e. follicular lymphoma) progress slowly and is not curable. A ‘watch and wait’ approach is considered before disease progression, and this should also apply in pregnancy with regular follow up. In cases of symptomatic indolent lymphoma in the first trimester of pregnancy, if possible chemotherapy should be delayed and steroids and rituximab considered. In the second and third trimester in symptomatic cases, single-agent chlorambucil, chlorambucil, vincristine and prednisolone, or CHOP may be considered. Data on fludarabine in pregnancy are lacking, and it is not recommended owing to potential teratogenicity.

In contrast to the treatment of indolent NHLs, treatment of aggressive subtypes of NHL (i.e. DLBCL, mantle cell lymphoma, mature T and natural killer cell lymphoma) needs to be started early to avoid significant disease-related morbidity and mortality. The current standard of care is CHOP with or without rituximab depending on the presence of a CD20+ tumour. When diagnosed in the first trimester, if disease burden is low, delay of treatment until the second trimester may be considered; however, in the presence of high-burden disease, the woman should be counselled to consider termination of pregnancy in view of potential teratogenicity. CHOP with or without rituximab should be commenced. It seems reasonably safe to treat aggressive lymphoma presenting in the second or third trimester with CHOP with or without cyclophosphamide, doxorubicin, vincristine, prednisolone and bleomycin rituximab.

Burkitt’s lymphoma is an aggressive NHL. Case reports of Burkitt’s lymphoma in pregnancy are limited, and typically neither the mother nor the infant survive. If the pregnancy is in the third trimester, successful delivery before or after chemotherapy has been started has been reported. Burkitt’s lymphoma has rapid tumour growth, increased central nervous system involvement, risk of relapse and high risk of tumour lysis. Treatment involves intensive combination chemotherapy with central nervous system prophylaxis. High-dose methotrexate is an essential component of Burkitt’s lymphoma protocols, and carries a high risk of teratogenicity in the first trimester and fetal myelosuppression throughout pregnancy. It is not appropriate to delay treatment after a diagnosis of Burkitt’s lymphoma. The women should be counselled about the aggressive nature of the disease, poor prognosis if not treated, and potential teratogenicity of the intensive combination chemotherapy. She should be advised to consider termination of the pregnancy up until 20 weeks gestation. If presenting in the third trimester before 32 weeks, intensive combination chemotherapy should be started, with elective delivery planned when the woman is not cytopaenic from 32 weeks onwards. In cases diagnosed from 32 weeks onwards, delivery should be expedited and treatment started. In cases presenting in the third trimester, the clinician and woman may consider omitting methotrexate until after delivery.

Acute leukaemia

The estimated incidence of acute leukaemia in pregnancy is 1 in 100,000 pregnancies. Two-thirds of acute leukaemia are myeloid and the other one-third lymphoid. Acute leukaemia is an aggressive malignancy with rapid progression. After diagnosis in pregnancy, immediate treatment is necessary regardless of gestation or delay. Modification of the standard treatment regimen may adversely affect maternal prognosis. When acute leukaemia is diagnosed in the first trimester, the woman should be advised to consider termination of the pregnancy. In addition to the treatment effects, the disease may affect perinatal outcome through its effect upon both the pregnancy and fetus (e.g. maternal anaemia, coagulopathy and decreased placental blood flow and oxygen transfer secondary to the presence of leukaemic cells).

Acute myeloid leukaemia

The standard treatment for acute myeloid leukaemia (AML) consists of induction chemotherapy with cytarabine and an anthracycline (i.e. daunorubicin) to achieve a complete response followed by high-dose cytarabine. Treatment should not be delayed as it may compromise the chance of successful remission. In most cases when AML is diagnosed in the first trimester, the pregnancy is terminated and induction chemotherapy follows. Hence data on pregnancy outcome after chemotherapy for AML in the first trimester are limited.

Four cases of limb deformities in association with cytarabine used alone or in combination during the first trimester have been reported. A systematic review identified 52 woman diagnosed with AML who received cytarabine in combination or as a single agent in the second or third trimester of pregnancy. In 26 (50%) of these pregnancies, the pregnancies and deliveries were otherwise uneventful. Six (11.5%) IUD deaths occurred, six (11.5%) premature deliveries, five (9.6%) congenital abnormalities, three cases (5.7%) of FGR and three cases (5.7%) of fetal pancytopaenia.

Daunorubicin is the most frequently used anthracyclines in AML-induction regimens outside pregnancy. A systematic review reported 34 women diagnosed with AML who received daunorubicin during the second and third trimester. Fifteen (44%) had an otherwise uneventful pregnancy and delivery. Six (17.5%) second or third trimester IUDs occurred, six (17.5%) premature deliveries, two (5.8%) congenital abnormalities, three cases (8.8%) of FGR, and three cases (8.8%) of fetal pancytopaenia.

After a diagnosis of AML in the first trimester, women should be counselled and advised to consider termination of pregnancy followed by standard induction chemotherapy. Women diagnosed in the second or third trimester should start induction chemotherapy with daunorubicin and cytarabine; fetal cardiac function and limb formation should be monitored. For supportive treatment in the event of neutropaenic sepsis or fungal infections, penicillin, cephalosporins, metronidazole, aminoglycosides and amphotericin B seem to be safe in pregnancy. Planning the timing of delivery in relation to chemotherapy should be considered to avoid maternal and neonatal neutropaenia where possible.

Acute promyelocytic leukaemia (APML) is a subtype of AML associated with the translocation (15;17). Risk of disseminated intravascular coagulation increases, and women may present with an aggressive and life-threatening form. Immediate emergency management includes blood component support, all-trans-retinoic acid (ATRA) and initiation of an anthracycline, usually idarubicin to induce remission.

All-trans-retinoic acid has been associated with cardiac and neurological malformations in up to 85% of cases if given in the first trimester. Forty-three cases of APML have been reported during pregnancy: 12 first trimester, 21 second trimester and 10 third trimester. Treatment of APML in the first trimester with ATRA alone or combination chemotherapy has been associated with an increased risk of congenital malformations and spontaneous miscarriage. Presentation and treatment in the second and third trimester, however, has been associated with a more favourable outcome.

The European Leukaemia Net advise against the use of ATRA in the first trimester. Women diagnosed with APML in the first trimester of pregnancy should be counselled to consider termination of pregnancy, with attention to reversing the coagulopathy before the termination. If termination is not acceptable, blood-component support should be continued alongside anthracycline therapy with the addition of ATRA in the second trimester. Idarubicin is more lipophilic compared with alternative anthracyclines, and leads to increased placental transfer and potential toxicity. Therefore, daunorubicin may be considered as it is known to be effective in APML, and more experience is associated with daunorubicin in AML during pregnancy.

When women present in the second or third trimester, treatment may be started immediately with ATRA and an anthracycline. Delivery may be planned after resolution of the coagulopathy and myelosuppression at an appropriate gestation. Administration of ATRA beyond the first trimester of pregnancy is considered relatively safe for mother and fetus. In view of reported reversible fetal arrhythmias and other cardiac complications at birth, referral for fetal cardiology monitoring is advisable. The European expert panel suggest the alternative approach of starting ATRA with the addition of anthracycline after delivery. There does not seem to be a difference in complete remission rate, but risk of ATRA syndrome increases. A prolonged delay in starting anthracycline may lead to ATRA resistance and increase risk of relapse. This would also not be suitable for high-risk women with hyperleukocytosis.

Acute lymphoblastic leukaemia

Only 21 studies have been published on acute lymphoblastic leukaemia (ALL) in pregnancy. In view of the aggressive nature of ALL, prompt initiation of an intensive combined chemotherapy regimen is necessary. The chemotherapy regimens used include methotrexate, which is highly teratogenic and linked with aminopterin syndrome (cranial dysostosis, micrognathia, ear anomalies).

Women presenting with ALL in pregnancy before 20 weeks should be counselled to consider termination of the pregnancy. From 20 weeks gestation, there is still a considerable risk of fetal and maternal complications. A modified treatment regimen omitting methotrexate until the third trimester should be considered, with the aim of delivering the baby after 32 weeks gestation when the mother is not pancytopaenic. Cytarabine, cyclophosphamide, vincristine, L-asparaginase and anthracyclines have all been used in pregnancy.

Myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) defined by the World Health Organization encompass the more commonly encountered essential thrombocythaemia, polycythaemia vera, primary myelofibrosis, chronic myelogenous leukaemia (CML) and the rarer entities MPN unclassified, mast cell disorders, chronic neutrophilic leukaemia and hypereosinophilic syndrome.

Chronic myelogenous leukaemia

The incidence of CML is 0.6–2 per 100,000 per year, accounting for 15% of leukaemia in adults, 10% of which occurs in women of child-bearing age.

The standard treatment is imatinib mesylate, a tyrosine kinase inhibitor that targets the BCR/ABL oncogene present in CML. Treatment with imatinib has revolutionised CML treatment: 76% of women achieve complete cytogenetic remission at 18 months. Imatinib, however, has been reported to be teratogenic in animal studies. The largest study onimatinib in pregnancy includes 180 pregnancies. Outcome data are available for 125 (69%). Of those with known outcomes, 50% delivered normal infants and 28% underwent elective termination of pregnancy. Congenital abnormalities were identified in 12 infants.

Before the introduction of imatinib, interferon-alpha or hydroxyurea were treatment options in women who were not suited to bone marrow transplant. Animal studies report hydroxyurea to be teratogenic. It also rarely leads to a cytogenetic response. Interferon-alpha, however, being a relatively large compound is unlikely to cross the placenta. Animal studies do not report interferon to be teratogenic. Interferon, however, produces a suboptimal cytogenetic response of between 10 and 38% compared with imatinib. Leukapheresis is used in cases of CML that present with symptoms of hyperleukocytosis. Leukapheresis is a temporary measure. Two cases of leukapheresis in pregnant women with CML have been reported to have favourable outcomes.

Women presenting with chronic phase CML in pregnancy may be closely monitored and started on imatinib in postpartum. In the presence of hyperleukocytosis, however, interferon-alpha should be commenced. A more challenging dilemma is in women who have achieved a cytogenetic response with imatinib and want to become pregnant. The response achieved with imatinib is dependent upon continuation of treatment, and cessation is associated with a risk of relapse. Woman should be informed of this risk. Of nine women who stopped imatinib due to pregnancy, six progressed to cytogenetic response and five lost their complete haematological response. After pregnancy, imatinib was reintroduced with a repeat response to treatment. If imatinib is discontinued, interferon-alpha should be started alongside regular disease monitoring, with the reintroduction of imatinib if disease progression occurs. Women presenting with accelerated-phase CML in the first trimester should start a tyrosine kinase inhibitor and consider termination of pregnancy. In the event of an unplanned pregnancy in a woman taking imatinib, the options include the following: termination of pregnancy; consideration of stopping imatinib and commencing IFN; or continuation of imatinib with detailed fetal scanning, with the potential to terminate the pregnancy if congenital malformation is identified.