How I treat myeloproliferative neoplasms in pregnancy

The classical BCR-Abl1–negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are associated with a risk of thrombosis, bleeding, and transformation to acute leukemia, as are the rarer entities prefibrotic PMF and MPN unclassified or not otherwise specified. In 2022, new diagnostic criteria for these entities were separately described by the World Health Organization¹ and International Consensus Criteria,² and although there are minor nuances between the diagnostic criteria, they are essentially sufficiently similar in MPN at least to avoid clinical management issues. It has been suggested that, over time, there has been an increase in diagnosis of these conditions due to the advances in molecular diagnostics and increasing availability as well as sensitivity of such tests. ET, PV, and PMF are more commonly diagnosed in the older population; however, they can occur at any age. With the aging pregnant population as well as the increased ability to test and diagnose these conditions, an increasing number of pregnant patients with MPN are being encountered.^3,4 Furthermore, intriguing recent data also suggest that patients with MPN may harbor driver mutations, in particular, JAK2V617F, from an early age, perhaps having the mutation for several decades (sometimes since early childhood), suggesting that, if widespread, genetic screening is introduced, even more young patients with these mutations will be identified.^5,6 

Pregnancy is a prothrombotic state in the general population, and thrombosis is a leading cause of maternal mortality.^7,8 Pregnant patients with MPN have a further increased risk of maternal and fetal morbidity and mortality due to thrombosis, preeclampsia, placental dysfunction, and intrauterine growth restriction. It is, therefore, prudent that this group of patients be regularly monitored throughout their pregnancy by a hematologist and obstetrician, including imaging of uterine artery by Doppler ultrasonography, following, where possible, an evidence-based approach. To date, the available interventions for reducing the risk of these complications include venesection, aspirin, heparin, and interferon or a combination of these as well as obstetric interventions such as early delivery. There are no randomized clinical trials reported for patients with MPN relating to pregnancy, but there have been a series of case reports, systematic reviews, large collaborative studies, population registry-based studies, and 1 prospective UK study. This literature has been summarized in a recent review,⁹ and for reference, we have updated and collated these data into a table (Table 1).

Here, we describe how we manage MPNs in pregnancy in our hospital by using a case-based approach and referencing the relevant clinical data summarized earlier, following an algorithm that is illustrated in Figure 1; some of this is based upon national guidance and data from the United Kingdom.

A woman aged 22 years with a diagnosis of JAK2 V617F ET 2 years ago visits the clinic and asks advice regarding contraception and future pregnancy planning. She initially presented with migraine-like symptoms and a platelet count of 650 × 10⁹/L. Her current platelet count is 689 × 10⁹/L; she takes regular aspirin and does not require any cytoreductive therapy at present.

Locally, our practice is to recommend avoiding estrogen and suggest progesterone-only pill, implant, depot, Mirena coil, or barrier contraception in this circumstance. We would also generally review the diagnosis and ensure the migraine symptoms are under control. If additional or different drugs are being used for the migraine this should be reviewed potentially with the help of a pharmacist and/or neurology consultation. Thinking forward, we also give broader health education to patients regarding their general fitness that is helpful for their disease management (vascular risk) and future pregnancy (eg, avoiding obesity). Obstetric outcome does worsen with age, so it is helpful to advise, when possible, to consider early completion of family.³² 

With regard to future pregnancy, this patient currently would be regarded as having low-risk ET (regardless of which current risk stratification is used) and a low-risk pregnancy; thus, aspirin 75 mg once daily should be continued ante natally and postpartum; low molecular weight heparin (LMWH) (weight-based dose, once-daily thromboprophylaxis) should be offered for 6 weeks postpartum. The patient would have routine scanning and placental flow testing at 20 weeks with escalation if abnormalities were detected here based on Saving Babies Lives version 3.³⁰ Women with MPN follow the local protocol for women with a diagnosis of antiphospholipid syndrome or systemic lupus erythematosus (additional scan at 32 and 26 weeks) and escalate to more frequent scan intervals according to prior obstetric history and current pregnancy indications. Care would also be escalated if additional factors increasing the risk of thrombosis occurred such as immobility or hyperemesis.³¹ ET is heterogeneous with regard to driver mutation, and there is currently some controversy in the field as to whether patients who have JAK2, CALR, CMPL, or lack any of these driver mutations (designated “triple negative”) should be managed differently, for example, the International Prognostic Score Essential Thrombocythemia (IPSET) score differentiates these patients.³³ Currently, we do not adjust pregnancy management based on driver mutation.

With regard to higher doses of aspirin, more studies in the background population are suggesting a benefit with regard to early onset preeclampsia prevention. When higher dose aspirin is offered to prevent early onset preeclampsia, the practice is to provide this from 13 to 36 weeks at night.^34-36 Our local approach for pregnancy in MPN considers that the majority of these women are already taking 75 mg, and recent studies do not suggest an increase in the incidence of preeclampsia compared with that in the background population.⁴ When an individual’s risk of preeclampsia is considered more likely, with 2 moderate or 1 high-risk factor (according to national guidance³⁷), the dose is increased to 150 mg from 13 weeks and then reduced to 75mg from 37 weeks; however, when the woman has a bleeding phenotype, targeting biophysical profiling with an early uterine artery Dopplers at 13 weeks and angiogenic markers is a considered approach in keeping with personalized medicine (to support maintaining 75 mg when biophysical profiling does not support the risk of early onset preeclampsia).

In the MPN field, there are trends to introduce cytoreductive treatment in what might conventionally be regarded as low-risk disease; a specific example of this is a patient with low-risk PV who might receive treatment with either interferon or hydroxycarbamide to manage with frequent venesections of disease-related symptoms.^38,39 Whether cytoreductive drugs introduced in these circumstances should continue during pregnancy needs to be discussed and will be based on a reassessment of the disease and maternal wishes; hydroxycarbamide should be changed to interferon before conception (ideally 3 months is recommended for parents of either sex).⁴⁰ 

Two years later, this patient attends postfertility investigations that identified poor sperm motility and now plans in vitro fertilization (IVF). Her platelet count is 698 × 10⁹/L, and no other interim changes have occurred.

Essentially, now the question is, Would the need for IVF change the management plan? Although there are no data available regarding fertility treatment specifically in women with MPN, American Society of Hematology guidelines on venous thromboembolism (VTE) management in pregnancy do not recommend LMWH for unselected women undergoing assisted reproductive therapy. However, similar to the absence of data regarding assisted reproductive therapy in women with MPN, the panel noted the absence of data specific to women with a history of VTE or thrombophilia. It was agreed that most panel members would consider provision of prophylaxis during assisted reproduction to women who would qualify for antepartum prophylaxis on the basis of their VTE history or high-risk thrombophilia; however, in the absence of data, the panel was not able to make an evidence-based recommendation for these subgroups.⁴¹ In our local practice, we would regard women embarking on IVF to be at higher risk of thrombosis, and they are offered weight-based, once-daily LMWH thromboprophylaxis from the time of hormone replacement therapy in the majority of cases, and this continues throughout pregnancy because the risk associated with IVF remains an antenatal risk factor. This approach is individualized and a shared decision-making process, taking into account the IVF protocol, complications, and other thrombotic and bleeding risk factors. Care is also taken with regard to the timing of LMWH, and an interval of 12 hours is recommended before oocyte collection. Note, we would only recommend LMWH and continue aspirin; this is not an indication for cytoreductive therapy. Otherwise, our standard algorithm of monitoring and appropriate escalation would be followed.

Six months later, the patient attends pregnant with twins (dichorionic). She is well, the platelet count is 742 × 10⁹/L, and the twins were conceived via IVF.

In this situation, we would already be following the practice outlined earlier, and in addition, because of the twin pregnancy, we would escalate the dose of aspirin to 150 mg once daily (2 moderate risk factors of preeclampsia: first, pregnancy age >40 years and second, multiple pregnancy according to National Institute of Clinical Excellence and Effectiveness guidelines).³⁷ Uterine artery Dopplers (for placental sufficiency) and fetal growth are all carefully monitored every 4 weeks.

A 34-year-old woman diagnosed with JAK2 V617F–positive ET attends clinic for advice regarding future pregnancies. G1P1, took aspirin in previous pregnancy, and delivered at 36 weeks after the documentation of deterioration in growth scans. Fetal birth weight was 2100 g, and the infant is currently well.

This patient’s prior pregnancy provides clear evidence of deterioration in growth scans, and an infant small for gestational age indicates placental insufficiency. No additional or alternative reason for this was identified. Local practice is to define prior poor pregnancy outcome in MPN according to the following criteria adopted and adapted from the revised classification criteria for antiphospholipid syndrome:⁴² 

• Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal abnormalities excluded.

• One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks gestation.

• One or more premature births of a morphologically normal fetus before 34 weeks gestation because of eclampsia, severe preeclampsia, or recognized placental insufficiency.

• A significant antepartum or postpartum hemorrhage (requiring red cell transfusion).

Furthermore, as described in Figure 1, our generally accepted features of placental insufficiency include the following:³¹ 

• Abnormal or nonreassuring fetal surveillance tests.

• Abnormal Doppler flow velocity wave forms analysis suggestive of fetal hypoxemia.

• Oligohydramnios.

• Postnatal birth weight less than the 10th percentile for gestational age.

With this information, we gauge that this patient’s next pregnancy will be high risk with regard to pregnancy outcome (Figure 1). We would recommend the addition of LMWH and a cytoreductive agent (interferon). Interferon has been shown to be associated with improved pregnancy outcome.⁴³ Regarding the choice of interferon, most experience is with interferon alfa, specifically, pegylated interferon alfa 2a.^44,45 However, more recently, a different formulation of interferon has been approved for use in PV, and unlike pegylated interferon alfa 2a, ρ-pegylated interferon alfa 2b is not actively contraindicated in pregnancy, and we have published some data attesting to its safety.⁴⁶ The target of interferon is to normalize the blood count, and the best approach, we believe, is to begin this before pregnancy at a low dose to gradually allow the patient to accommodate (45 μg for alternate weeks would be usual for pegylated interferon alfa 2a). Before commencing this agent, we arrange a retinal scan and autoimmune and thyroid screen. As indicated, this pregnancy would have more intense scrutiny and growth scans and placentation.

A pregnant 26-year-old woman diagnosed with PV after an investigation of menorrhagia and epistaxis 4 years ago is referred for an opinion at 9 weeks gestation. She has no prior obstetric history, and her current management is low-dose aspirin and venesection. Blood results are white cell count, 8.1 × 10⁹/L; hemoglobin, 150 g/L; hematocrit, 0.49; and platelet count, 567 ×10⁹/L.

For this patient with no history of thrombotic events or pregnancy complications, there is no indication for antenatal LMWH prophylaxis; LMWH should, however, be administered for 6 weeks postpartum. Aspirin should be continued throughout pregnancy, usually at a dose of 75 mg. However, the patient’s current packed cell volume of hematocrit or hematocrit level is outside the appropriate range for the first trimester, and venesection should be considered if tolerated. Some additional points are worth considering for patients with PV in pregnancy, and these are the normal range for hematocrit, tolerance of venesection, iron supplementation, variant allele frequency (VAF) monitoring, and ruxolitinib therapy (the latter is also relevant for patients with myelofibrosis).

Progressively, during pregnancy, the normal range for hematocrit drops due to hemodilution; thus, it is important to adjust the target range for venesection accordingly. This should be done with reference to normal gestation specific ranges; broadly, in our practice, the target hematocrit would be ∼0.37.^9,22 Concerning venesection, this is an unusual requirement during pregnancy but is sometimes needed, for example, for a newly diagnosed patient whose disease is not well controlled or when inappropriate iron supplementation has been given. When venesection is required, the volume and requirement of fluid supplementation should be tapered according to the individual's previous tolerance and gestation. In our experience, it is extremely rare to require this procedure beyond ∼20 weeks gestation. Iron supplementation is frequently given in pregnancy, especially, for patients with borderline anemia or features suggesting the presence of iron deficiency, for example, microcytosis. We are always very cautious to educate patients regarding the need to avoid iron supplementation unless the advice of the hematologist has been taken into account; because, in a routinely venesected patient with PV, supplementation with iron, even at lower than standard doses, may result in a significant rise in hematocrit. Lastly, concerning monitoring of the VAF for JAK2 V617F, this is increasingly of interest in PV especially given the finding on a recent prospective study,⁴⁷ albeit in patients requiring drugs in the second-line setting who generally would have a higher event rate. There is no current evidence for considering the impact of JAK2 VAF or, indeed, if any change of this would be anticipated in pregnancy. Our current recommendation, therefore, is not to change the patient's management based on this assay. Finally, ruxolitinib is a drug frequently used in the second-line setting in PV and increasingly being tested in the front line.⁴⁸ There is inadequate literature to advice regarding this drug in females and males considering conception, and therefore, our practice is to avoid its use

A 32-year-old woman was diagnosed with CALR type 1–positive PMF (International Prognostic Scoring System [IPSS], low-risk) 3 years ago after a hepatic vein thrombosis and attends clinic to discuss treatment options regarding future pregnancies. She has 1 healthy daughter aged 5 years delivered by cesarean section following a trial of labor that failed to progress. Her current medications are aspirin, warfarin, and hydroxycarbamide, and her blood count was as follows: hemoglobin, 110 g/L; packed cell volume of hematocrit, 0.35; platelet count, 147 ×10⁹/L; and white cell count, 7.6 × 10⁹/L.

We specifically chose to discuss this particular patient who is high risk for pregnancy. First, because of her underlying disease, PMF, which is an uncommon condition in young females of childbearing potential, but nonetheless, there is available literature (Table 1), and this case is a good example. In addition, this is a patient with splanchnic vein thrombosis (specifically hepatic vein thrombosis). This event would render the patient at high risk in a future pregnancy but also gives us the opportunity to discuss our approach to management of such patients who can be complicated and whose clinical course requires careful and close working with colleagues in gastroenterology and hepatology. Jointly, we closely monitored this patient and had a proactive plan with regard to monitoring for raised portal pressure and discussing nuances for the management of pregnancy and labor with specific regard to her underlying liver disease. This is absolutely critical because these patients can have high tendency to have repeated thromboses despite adequate treatment with cytoreductive therapy and anticoagulation.⁴⁹ Once the plan has been discussed and agreed with these colleagues, we would proceed to switch from hydroxycarbamide to interferon and, when the patient is pregnant, from warfarin to a twice daily intermediate dose of LMWH. Previous obstetric history is favorable, but she will require close monitoring and a plan for delivery specifically with regard to anticoagulation; in the postpartum period, her anticoagulation will need to be maintained in a therapeutic dose range. Because myelofibrosis carries the worst prognosis of MPN, it is worth noting that the medical literature does not suggest that the disease either progresses or regresses during pregnancy, and there is likely no impact of pregnancy itself on disease outcome. Sometimes, for these patients with myelofibrosis, a specific plan does need to be made if they have massive splenomegaly and are considering pregnancy again.

In this article, we have explored our own approach to the management of pregnancy in MPN; some of this is evidence-based and some is local practice (eg, risk-assessment has very little evidence base); some of the evidence-based is borrowed from other prothrombotic conditions. The MPN field has evolved significantly, largely driven by the description of specific mutations notably affecting JAK2 and CALR, which can lead to very different disease behaviors, for example, specifically in ET. We have tried to reflect nuances and changes in practice, for example, discussion of JAK2 molecular monitoring and the use of ruxolitinib, for example, in pregnancy. We can be certain that in this field in which there are also many investigational agents, we will continue to grow, evolve, and change over time. A good example of that is the development of CALR-directed immunotherapeutics, which, if successful, could completely change the way CALR-mutated disease is managed and bring different challenges specifically with regard to pregnancy. These are, of course, all changes to come in the future; however, meanwhile, we would wish to highlight the need for international collaboration with regard to sharing data and collecting outcomes for patients with MPN, specifically, with regard to pregnancy. Of course, there is also much to learn from the obstetric field in which other noninvasive scanning methods such as the use of MRI might be helpful to predict patients at risk of an adverse outcome at an earlier stage.

The main message of our article is that patients with MPN who are either contemplating pregnancy or currently pregnant should be examined, ideally, in a multiprofessional setting by clinicians who are experienced for both their MPN and, when appropriate, disease-related complications (we have given the example of gastroenterology/hepatology). These patients often require meticulous management and a shared approach with the patients and other professionals in decision-making. Modern approaches to collating large data sets, and advances in genomic and image-related prediction should help us to move forward with better evidence in the future.

Contribution: S.R., M.R., and C.H. conceived and jointly wrote the paper and approved the final version.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Claire Harrison, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom; email: claire.harrison@gstt.nhs.uk.