Management of haematological malignancy in pregnancy
Introduction
Haematological malignancies are rare in pregnancy, with an incidence that ranges from 1:1000 to 1:10,000. This is a diverse group which presents several diagnostic and therapeutic dilemmas to the clinician, as both the maternal and fetal well-being need to be addressed.
Management is complex and requires multidisciplinary input. The mother needs to be informed about the disease progression, the requirement for immediate treatment, and the effect of delay in treatment to enable her to make an informed decision about continuation of pregnancy.Diagnosis
Symptoms and signs of haematological malignancy are similar to non-pregnant women. Bone marrow aspiration (57) and lymph node biopsy under local or general anaesthetic may safely be performed in pregnancy (58). Magnetic resonance imaging without contrast can also safely be used and carries no radiation risk to the fetus.
Chemotherapy in pregnancy
All chemotherapeutic agents can cross the placenta (59) and can cause a spectrum of effects ranging from teratogenesis, carcinogenesis, and organ toxicity to abnormal neurodevelopment. This risk is reduced when single-agent chemotherapy is used (60, 61).
The effect on the fetus is determined by the gestation at exposure to treatment and the stage of fetal development:
• Pre-embryonic stage (from conception to 17 days post conception): exposure has little or no effect.
• Embryonic stage (3-4 weeks post conception): exposure may result in permanent damage to an end organ.
• Fetal stage (from 8 weeks post conception): exposure may result in damage to the cerebral cortex, gastrointestinal tract, and renal glomeruli.
• Second and third trimester: exposure carries an increased risk of fetal growth restriction, intrauterine fetal death, preterm labour, and low birth weight (62). There is no associated increased risk, however, of neurodevelopmental delay or childhood malignancy (63, 64).
Radiotherapy in pregnancy
Radiotherapy in pregnancy can cause a number of significant adverse effects on the fetus. It can cause organ malformation, reduced intelligence quotient, developmental delay, severe intellectual disability, and an increased risk of childhood cancer (65). Treatment with radiotherapy should therefore be reserved for cases where it is essential, and to limit the total amount the fetus is exposed to less than 0.1 Gy.
Hodgkin's lymphoma in pregnancy
Lymphoma is the fourth commonest malignancy in pregnancy; Hodgkin’s is the commonest lymphoma in pregnancy, with an estimated prevalence of 1:1000 to 1:6000 (66).
The standard treatment regimen is a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
In early disease diagnosed in the first trimester, treatment may be delayed to the second trimester to avoid the teratogenic side effects of drugs. In advanced disease in the first trimester, termination of pregnancy is recommended followed by ABVD. In early disease limited to the supradiaphragmatic area in the first trimester, radiotherapy with abdominal shielding and a fetal dose of less than 0.1 Gy may be an alternative option. The prognosis of pregnant women with Hodgkin’s lymphoma is similar to nonpregnant women (67).
Non-Hodgkin's lymphoma in pregnancy
Non-Hodgkin’s lymphoma is less common in pregnancy; it consists of two types; indolent lymphomas and aggressive lymphomas.
• Indolent lymphoma (follicular): this progresses slowly and is incurable; expectant management is recommended unless the patient is symptomatic, in which single-agent chemotherapy may be used; preferably in the second or third trimester.
• Aggressive lymphoma (diffuse large B-cell lymphoma, mantle cell lymphoma, mature T and natural killer cell lymphoma): these require treatment due to their aggressive nature. Counselling about termination of pregnancy is recommended if diagnosed in the first trimester. Treatment may be given safely in the second and third trimesters, and early delivery may be considered if the patient is diagnosed from 32 weeks of gestation onwards.
Acute leukaemia
Acute leukaemia occurs in 1:100,000 pregnant women (68). The majority, two-thirds of cases, are myeloid, and one-third are lymphoid leukaemias. This is an aggressive malignancy and treatment should not be delayed or modified due to pregnancy (69).
• Acute myeloid leukaemia: the standard treatment is using a combination of cytarabine and an anthracycline. Treatment should not be delayed due to pregnancy as this will minimise the chance of remission. Women should be counselled about termination if diagnosed in the first trimester followed by chemotherapy (70). If diagnosed in the second or third trimester, standard chemotherapy should be given with increased fetal surveillance due to the risk of limb anomalies and cardiac arrhythmias (71).
• Acute lymphocytic leukaemia: this is a very aggressive type of leukaemia and any delay in treatment will affect survival. All treatment protocols contain methotrexate which is highly teratogenic. Therefore, if acute lymphocytic leukaemia is diagnosed before 20 weeks, women should be counselled and offered termination of pregnancy. If it is diagnosed after 20 weeks’ gestation, treatment could be given with the omission of methotrexate until the third trimester, elective early delivery from 32 weeks, and continuing treatment postnatally.
Myeloproliferative neoplasms
These encompass essential thrombocythaemia, polycythaemia vera, primary myelofibrosis, chronic myelogenous leukaemia (CML), and the rarer types; myeloproliferative neoplasm unclassified, mast cell disorders, chronic neutrophilic leukaemia and hypereosinophilic syndrome.
• Chronic myelogenous leukaemia: the incidence is 0.6- 2 per 100,000 per year, chronic myelogenous leukaemia accounts for 15% of leukaemia in adults, 10% of which occurs in women of reproductive age (72). Standard treatment is with imatinib mesylate which may be teratogenic; women should be counselled and offered termination depending on the gestation at diagnosis. In women who present in the chronic phase of chronic myelogenous leukaemia, treatment may be delayed until after delivery.
• Philadelphia-negative myeloproliferative neoplasms: these are essential thrombocythaemia, polycythaemia vera, and primary myelofibrosis, and collectively they occur in about 6-9 per 100,000. Essential thrombocythaemia has a peak incidence in women of reproductive age, and 15% of patients diagnosed with polycythaemia are less than 40 years of age. There is a high risk of thrombosis with this condition in pregnancy, which may also lead to microthrombi at the placental bed, placental insufficiency, PET, stillbirth, preterm labour and low birth weight.
Treatment options include aspirin, heparin, venesection, and cytoreductive agents such as interferon-alpha.