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Home , Placental insufficiency, Polycythemia, Stillbirth

Myeloproliferative Disorders • Research Paper The management and outcome of 18 in women with vera

Susan Robinson Background and Objectives. (PV) is rare in women of childbearing Susan Bewley age with only 20 previous pregnancies reported. Beverley J. Hunt Deepti H. Radia Design and Methods. We report a series of 18 pregnancies (19 ) in eight Claire N. Harrison women with PV managed prior to or following implementation of management guide- lines tailored to PV in , and review the literature. Results. Seven of these pregnancies were managed by standard antenatal care (group A) without specific attention to the women’s PV. All remaining 11 pregnancies (group B) were managed following a formal protocol and received tailored management prin- cipally comprising tight control of the by venesection, and the use of inter- feron a in three patients, in addition to aspirin 75 mg, and prophylactic low molecular weight heparin (LMWH). Each pregnancy was monitored with uterine artery Doppler examinations and regular fetal scanning. In group A (n=7) there was one , which required delivery at 34 weeks due to , three first trimester , two and one combined and neonatal death () associated with placental dysfunction. All 11 patients in group B received aspirin and post-partum LMWH; four also received venesection (during pregnancy), three interfer- on-a and three antenatal LMWH. There were ten live births, nine at term, one first trimester and no intrauterine growth retardation. Intepretation and Conclusions. Pregnancy in PV without meticulous attention to hema- tocrit is associated with poor fetal outcome. Aggressive intervention with control of hematocrit, aspirin and some LMWH appears to be associated with significantly better outcome (p=0.0017). Key words: pregnancy, polycythemia vera. Haematologica 2005; 90:1477-1483 ©2005 Ferrata Storti Foundation

From the Department of (SR, BJH, DHR, CNH); Women’s olycythemia vera (PV) is a clonal volume, high resistance circulation to a Health Services, St Thomas’ Hospital myeloproliferative disorder of high volume, low resistance circulation. (SB), Guy’s and St Thomas’ NHS hematopoietic stem cells, character- Failure of conversion can be detected by P 3 Foundation Trust, London, UK. ized by an increase in red cell production. uterine artery Doppler scanning and may The mean age of diagnosis is 60 years, but be the earliest marker of placental dysfunc- Correspondence: Claire N. Harrison, Department of 15% of cases are diagnosed in people tion. When compared to normal fetuses, Hematology, St Thomas’ Hospital, under 40 years old. The incidence in those with intrauterine growth retardation Guy’s and St Thomas’ NHS women increases during the reproductive (IUGR) have been shown to have a four- Foundation Trust, London, UK. years (from 0.04 per 100,000 in those aged fold reduction in uteroplacental E-mail: 4 [email protected] 20-34 years to 0.25 per 100,000 in those flow. Other severe pregnancy complica- aged 35-39 years) and peaks at 65-69 years tions such as and pre- (1.84 per 100,000).1 Clinical complications are also associated with utero- include venous and arterial , placental dysfunction. hemorrhage, and in the long-term, trans- Placental dysfunction is known to occur formation to myelofibrosis or acute in some other acquired and inherited caus- myeloid . es of . Antiphospholipid Normal uterine blood flow and adequate syndrome is perhaps the best example of placental growth are key to a successful an acquired thrombophilia in which an pregnancy outcome. In the first and early active intervention leads to improved preg- part of the second trimester of pregnancy nancy outcome.5,6 the embryonic trophoblast invades the The most extensive literature relating to endometrial capillaries and then the spiral pregnancy in myeloproliferative diseases arteries2 and the develops. The exists for essential thrombocythemia (ET) consequences are conversion from a low with over 280 pregnancies reported in 147

haematologica/the hematology journal | 2005; 90(11) | 1477 | S. Robinson et al. patients. There have been a number of reviews that PV who attend this clinic and are attempting to con- have analyzed these cases7-10 and demonstrate signifi- ceive, or are known to be pregnant, are reviewed by cant fetal complications. Overall there is a successful a consultant with a specialist interest in myeloprolif- live birth rate of 50-57%. First trimester loss is the most erative disorders and an obstetrician experienced in common in 26-36%; the expected rate of the management of high-risk pregnancies. Further spontaneous in pregnancy is 15-20% and patients from colleagues at other hospitals are three or more losses occur in 1-2%.11,12 Late pregnancy referred for specialist advice regarding pregnancy and loss is also more prevalent in ET; 5-9.6% of pregnancies are either managed locally with monthly specialist end in this way among women with ET compared to review or in complex cases followed up and delivered 0.5% for the normal population.12,13 Furthermore, in ET within our institution. pregnancies IUGR occurs in 4-5.1%, preterm delivery Our protocol for the management of pregnancy in ET in 5.6-8%, and placental abruption in 2.8%. Placental and PV24 states that if any of the following factors were thrombosis has been documented in ET pregnancies present then the pregnancy was considered at high risk complicated by late fetal loss,14 pre-term delivery14 and of complication to the and/or : previous IUGR.15 Maternal complications are relatively rare and venous or arterial thrombosis or hemorrhage attributed no fatal events have been documented. Thrombosis is to myeloproliferative disease; previous pregnancy com- most common and usually minor, but major thrombot- plication (>3 first trimester losses or >1 second or third ic events have also been reported including cerebral trimester pregnancy loss, birth weight <5th centile for sinus thrombosis, deep vein thrombosis and transient gestation, intrauterine death or stillbirth, stillbirth and ischemic attacks.8,10 The apparent low risk of maternal pre-eclampsia {necessitating preterm delivery <37 complications should be considered in context as the weeks}), or development of any such complication in majority of these patients would be viewed as low risk the index pregnancy; or count rising to 9 for general ET management, suggesting that pregnancy >1,500¥10 /L. Preconception planning included cessa- does increase the risk of thrombosis as would be antic- tion of possible teratogenic , advice on a ipated. Disappointingly, the literature on ET does not wash-out period, and precise control of PCV pre-preg- facilitate identification of risk factors for pregnancy- nancy. Interferon-a was commenced in those with a related events nor does it indicate a clear therapeutic disease-related prior reason for cytotoxic therapy or in strategy. high-risk pregnancies (as defined above). The target However, given the expanding literature on PCV was initially less than 0.45 though this was subse- antithrombotic therapy in successful pregnancy man- quently modified to be compatible with a mid-gesta- agement in both antiphospholipid syndrome and/or tion appropriate range. All patients received aspirin (75 inherited thrombophilia, it would appear logical to mg) and prophylactic LMWH for six weeks post-par- offer similar therapeutic strategies in ET. Therapeutic tum. Treatment details are provided in Table 1. Uterine options in ET also include cytoreductive drugs such as artery Doppler studies were performed at 20 and 24 hydroxyurea (also known as ), ana- weeks3 in all pregnancies to obtain an assessment of grelide and interferon-a. Based on an uncontrolled ret- placental function. If bilateral notching was detected rospective analysis of 25 ET patients it appears that then escalation of therapy including the addition of interferon-a therapy reduced both ET complications antioxidant vitamins C and E and dose escalation of during pregnancy and also apparently improved preg- LMWH was considered (the former now in the context nancy outcome.10,16-22 It has also been suggested that of the Vitamins in Pregnancy-VIP-randomized con- treatment with hydroxyurea facilitated successful preg- trolled trial). It was advised that fetal growth monitor- nancy outcome in one patient with a history of two ing was performed at least every 4 weeks, or more fre- stillbirths in the third trimester.23 This suggests that quently according to the progress of the pregnancy. In cytoreductive therapy might potentially protect against view of the known associations of thrombophilia with fetal loss, but with such small numbers such a conclu- pregnancy morbidity25 and risks of venous thrombosis, sion remains unproven. a comprehensive thrombophilia profile for all patients We report the outcome of 18 pregnancies in eight was obtained, usually preconception. women with PV seen in our institution. A detailed Data were compiled retrospectively from medical review of the literature on pregnancy in PV is present- and obstetric records. Further information was request- ed in the discussion. ed from patients, referring institutions and physicians, in particular with reference to previous pregnancies. Details of diagnosis, thrombophilia screening, previous Design and Methods obstetric history, hematologic indices, treatment and outcome of each of the 18 pregnancies were collected Our Hematology department has a specialist for data analysis. The patients were divided into group myeloproliferative clinic. Patients with a diagnosis of A, comprising patients who received standard antena-

| 1478 | haematologica/the hematology journal | 2005; 90(11) Pregnancy in polycythemia vera

Table 1. Details of 18 pregnancies in polycythemia vera.

Patient Pregnancy Age Treatment IUGR Outcome (years) Group

1 1 17 Prediagnosis TOP 2 20 Prediagnosis Yes IUGR, Elective Cesarean section 3 21 Prediagnosis SVD FT 4 24 Prediagnosis SVD FT 5 32 B Query PE 8/40 Venesection SVD FT Fragmin 5000u bd s/c 8/40 onwards

2 1 34 A Yes Hypertensive, , emergency CS 34/40 (1504 g) IUGR. Placental insufficiency, infarcted small placenta

3 1 36 A Misc (1st trimester) 2 38 B SVD FT

4 1 18 Prediagnosis TOP 2 20 Prediagnosis Yes 30/40 SVD Pre-eclampsia (1362g) IUGR 3 21 Prediagnosis TOP fetal abnormality 4 23 A Misc 7/40 5 23 A Misc 11/40 6 24 B Elective CS 38/40 7 28 B Misc (1st trimester) 830B IFNa preconception Elective CS 38/40 Enoxaparin 40 mg od post partum 3600g

5 1 30 A Yes Pre-eclampsia, IUGR, oligohydramnios, SB 25/40 (450g) 2 31 A Yes Pre-eclampsia, IUGR 25/40. 1, IUD Twin 2, Neonatal death 337B IFNa SVD FT Enoxaparin 40 mg od until 20/40 then bd Vit C & E 61 32 B Venesection SVD FT (3900g) 2 37 B Elective CS FT (4200g) 7 1 31 B 33/40 SVD Venesection 2 33 B SVD FT IFNa Venesection

8 1 29 A IUD 29/40 placental 2 31 B SVD 38/40 3500g IFNa Enoxaparin 40 mg od until 20/40 then bd

Group A standard antenatal care. Group B managed according to protocol. TOP: termination of pregnancy; SB: stillbirth; SVD: spontaneous vaginal delivery; FT: full term; IUGR: intrauterine growth restriction; IUD: intrauterine death; CS: Cesarean section; Misc: miscarriage; PE: pulmonary ; IFNa : interferon a; LMWH: low molecular weight heparin. tal care with no manipulation of blood counts (either by venesection or cytotoxic therapy), no heparin or Results aspirin, and group B, comprising the patients treated according to our protocol. The results were compared We identified 18 pregnancies (19 fetuses) occurring according to management in pregnancy and to those in eight women age 17-38 years with a diagnosis of cases reported in the literature. Fisher’s exact test was PV according to World Health Organization criteria. used with Unistat 5.0 (London) software. None of these patients had a recognized throm-

haematologica/the hematology journal | 2005; 90(11) | 1479 | S. Robinson et al. bophilic abnormality other than PV. The data from although three resulted in early neonatal death reduc- this case series are summarized in Table 1 and con- ing the overall success rate to 8/20 (40%) healthy firm a significant fetal morbidity in PV with only 11 neonates. The treatments these patients received dur- live births, four first trimester losses, three stillbirths ing pregnancy were highly varied. Only 10 of the 20 and one neonatal death. Overall there were three pregnancies received some PV-related management, cases of IUGR and three premature births at 34, 36 with two receiving aspirin during pregnancy and 6 and 26 weeks. Maternal morbidity in this case series weeks of heparin post-partum, mirroring our active was minor. One patient had an unconfirmed pul- therapy. Most of these patients were managed before monary embolus at eight weeks (suggestive history 1983 and the PCV was not aggressively controlled. but inconclusive ventilation perfusion scan), and there Historical management perhaps reflects the level of were three cases of pre-eclampsia (patient #4, and knowledge at that time, since the Polycythaemia Vera two early pregnancies of patient #5 in the standard Study Group, which significantly informed manage- care group A). ment of this disease, was only founded in 1967, and ten In group A there was only one live birth in a preg- of these pregnancies predate 1968. nancy complicated by placental insufficiency and The 18 pregnancies reported here significantly IUGR, and seven fetal deaths comprising three first expand the available literature in this field and we have trimester losses, one neonatal death and three still- been able to compare maternal and obstetric outcome births (two of which were complicated by IUGR and before and after introduction of a well-defined preg- one by ). By contrast, there was nancy management protocol already presented in detail only one unsuccessful outcome in the actively man- elsewhere.24 Overall there were 11 live births, four first aged pregnancies (group B). Nine out of ten live births trimester losses, three stillbirths and one neonatal death were full term. The difference in rates of live births (19 fetuses), three cases of IUGR and three premature between these two groups was statistically significant births at 34, 36 and 26 weeks. Maternal morbidity in (p=0.0017, Fisher’s exact test) despite the small num- this case series was minor. One patient had an uncon- bers involved. Unfortunately analysis of the influence firmed pulmonary embolus at eight weeks (suggestive of prior pregnancy events, platelet counts or packed history but inconclusive ventilation perfusion scan), cell volume (PCV) on pregnancy outcome was limited and there were three cases of pre-eclampsia. by patient numbers. Subanalysis suggests that those patients treated accord- Pregnancies occurring prior to a diagnosis of PV ing to our protocol had a significantly better outcome were considered separately (Table 1), but a significant (1/7 vs 10/11 live births, p=0.0017) although the num- incidence of complications is also apparent. There bers involved are small. were seven pregnancies prior to PV diagnosis. Two When our own case series is combined with histori- out of four live births were complicated by IUGR (one cal cases, there is a live birth rate of 22/38 (57%), of the two also had pre-eclampsia) necessitating early although the rate of surviving neonates is only 19/38 delivery and the other two live births were uncompli- (50%). In common with ET, first trimester loss is the cated; there were three elective terminations of preg- most frequent complication (8/38, 21%), followed by nancy. Blood counts available for these pregnancies late pregnancy loss and IUGR (6/38,15%) and preterm were normal. delivery (5/38,13%). If all 38 pregnancies including lit- erature review cases and the present case series are assigned to either group A or group B according to Discussion review of management in individual cases (Table 2), the analysis of the benefits of active management versus Pregnancy is a prothrombotic state and confers a traditional antenatal care still suggest active individual- greater risk of venous thromboembolism especially in ly tailored management (control of PCV<0.45, aspirin patients with thrombophilia for whom there is also evi- and post-partum LMWH; group B) is of statistically sig- dence of an increased risk of adverse pregnancy out- nificant benefit (p=0.012, Fisher’s exact test) come. For patients with PV thrombotic events (both The possibility that our management strategy venous and arterial) dominate the clinical phenotype improves pregnancy outcome is confounded by small and are the significant predictors of prognosis.26 The numbers, and the fact that comparisons are made with risks associated with pregnancy in PV are unclear. The historical controls (previous literature and pregnancies previous literature (excluding three texts with insuffi- in case series group A). It is likely that the major com- cient detail)27-29 comprises nine reports of 20 pregnan- ponent of this improvement is related to meticulous cies,30-38 with no author reporting more than two attention to the PCV with a contribution from daily patients or four pregnancies. The obstetric outcome aspirin and post-partum LMWH. Furthermore the sig- and complications documented in these papers are out- nificant literature favoring active antithrombotic thera- lined in Table 2. There were 11/20 (55%) live births py in improving fetal outcome in pregnancies affected

| 1480 | haematologica/the hematology journal | 2005; 90(11) Pregnancy in polycythemia vera

Table 2. Reported cases of pregnancy in patients with polycythemia vera.

Author No. of No. of Previous Previous Treatment Treatment Treatment High MaternalLive Pregnancy Misc Still IUGR Live Live pts. Pregnancies thrombosis hemorrage pre- during group risk outcome birth loss 1st birth birth birth pregnancy pregnancy total total trimester premature FTD delivery <37/40

Crowley 1 1 No No Aspirin + Aspirin + A No Death* 0 1 1 0 0 0 0 1987 dipyrimadole dipyrimadole TOP Centrone 1 3 No No Nil Nil A No Alive 1 2 2 0 0 0 1 Ferguson 1 2 No No Venesection Nil A No Alive 2 0 0 0 0 0 2 1983 PET PET Ruch 1 2 Superficial No Venesection None A No Alive 1 1 0 1@35/40 1 0 1 1964 thrombophlebitis and 32P PET & PET Subtil 1 3 No No Venesection Aspirin, B No Alive PE 1 2 0 *** 2 2 1 0 2001 heparin** post partum @24 & 32/40 venesection 28/40 Hochman 1961 1 4 Yes, CVA No Venesection Nil A Yes Alive PET 2 2 0 2 (5+7 0 1@7 0 TBI prior to months) months third pregnancy PET PET 1@8 months

Harris 2 2@ No No Nil Nil A No Alive PPH 2@ 000002 1967 Ruggeri 1 2 No No Venesection Heparin 3/52 A No Alive, 1 1 1 0 0 0 1 2001 + aspirin post partum PE 24/7 post partum Pata 1 1 No No Hydroxyurea Hydroxyurea A No Alive 1 0 0 0 0 0 1 2004 9/40 then nil Current 8 18 Yes No Venesection, Varied: A=7 10/18 Alive 11 7 4 2 3 1 9 series (1 twin) (1 patient) Aspirin, Venesection, B=11 PET in 1 34/40IUGR see Table 1 Interferon, Aspirin, 1 36/40 Hydroxyurea Interferon LMWH, 1 vitamin C+E 26/40NND Total 18 38 1 CVA None 1 thrombophlebitis 1 death 22 16 8 7 66 17 4 PET 3 NND 2 PE 1 PPH

Misc: miscarriage; IUGR: intra-uterine growth retardation; FTD: full term delivery; NND: neonatal death; TOP: termination of pregnancy; PPH: post partum hemorrhage; PET: pre-eclampsia; LMWH: low molecular weight heparin. Treatment: group A standard antenatal care, group B PV specific therapy.* the patient died with evidence of deep vein thrombosis, pulmonary emboli, saggital sinus thrombosis, and disseminated intravascular coagulation. ** aspirin and post-partum heparin in second pregnancy, LMWH and aspirin throughout third pregnancy. *** multiple placental infarcts in first, and abnormal Doppler waveforms and severe IUGR in third pregnancy, @one singleton and one twin pregnancy (this patient had previously had a twin pregnancy terminating in intrauterine death at 22 weeks, followed by two normal pregnancies and then the diagnosis of PV). by inherited thrombophilia and anti-phospholipid syn- and three cases of pre-eclampsia, all in pregnancies not drome may have some relevance to fetal outcome in intensively managed for PV (group A). PV.39-41 The ECLAP study42 supports the widespread use of Maternal morbidity due to thrombotic and low-dose aspirin in PV. The safety of aspirin in preg- problems were notable in the previous reports with one nancy is substantiated by the CLASP study.43 The death due to disseminated intravascular coagulation pathogenesis of thrombosis in PV is not identical to and venous thromboembolism after an elective termi- that in other prothrombotic states and is due in the nation of pregnancy; two post-partum pulmonary most part to blood rheology as determined by PCV emboli, and one large post partum haemorrhage. In the and to a lesser extent, by leukocyte adhesion, platelet current series the only maternal morbidity was a possi- activation, and platelet – leukocyte aggregates.44,45 In ble but unconfirmed pulmonary embolus (patient 1) the absence of antithrombotic therapies specifically

haematologica/the hematology journal | 2005; 90(11) | 1481 | S. Robinson et al. targeted to these areas it seems reasonable to utilize tion is the root cause and that free radicals produced aspirin and LMWH as adjuncts to strict control of the by the placenta cause the maternal signs of pre- PCV. Indeed, whether the use of LMWH added to eclampsia by activating maternal endothelium.51 Thus aspirin is of benefit to fetal outcome in PV is uncertain the logic of using antioxidants is that they will bind to from an analysis of this case series. However, LMWH the free radicals, preventing maternal signs. There is has been shown to be superior to aspirin in improv- currently no clear evidence for the role of antioxidant ing fetal outcome in women with a previous pregnan- vitamins in patients with myeloproliferative diseases cy loss and thrombophilia (, protein S (patient #5 was the only patient who received antiox- and prothrombin gene mutation),40 supporting our idant vitamins) and the present protocol includes par- decision to use LMWH in high risk pregnancies not ticipation in the VIP multicenter study).51 just in patients with prior thrombotic events. Interestingly, the pregnancies documented prior to a More speculative elements of our protocol are the diagnosis of PV in our patients also appear to have use of interferon-a and/or the antioxidant vitamins C had a poor outcome which may reflect pre-clinical and E. Interferon-a was introduced based on reports disease with masking of abnormal blood counts by of its successful use in ET.10 For those PV patients who the known hematologic effects of pregnancy. It is require cytoreduction prior to conception the choice well known that patients with PV and other myelo- of interferon-a is logical as it is the cytoreductive drug proliferative diseases have an increased risk of that appears least harmful to the fetus. More contro- thrombosis prior to diagnosis.52 Hence careful review versial is the use of interferon-a for patients (such as of the blood count in any woman with a pregnancy patients #5 and #8) whose disease might not warrant complication is appropriate to exclude a myeloprolif- cytoreduction but who have had significant prior seri- erative disorder. ous pregnancy complications. Here therapy is based In conclusion, pregnant women with PV have an upon the suggestion that thrombosis underpins the increased risk of fetal loss through all trimesters, utero-placental dysfunction that resulted in past preg- IUGR, prematurity and poor fetal outcome. This nancy complications. This was documented on histo- largest series of patients to date supports the use of logical examination of the placenta. In the non-preg- therapies tailored according to previous disease and nant state control of myeloproliferation or cytoreduc- prior pregnancy complications. As PV is a rare clini- tion for PV has been documented to reduce the inci- cal condition international and prospective collabora- dence of thrombosis significantly46-48 hence supporting tion is required to investigate this matter further. the aggressive control of PCV (with either interferon- or venesection) and platelet count in such patients. SR: gathered all the patients’ data, performed the historical a search and wrote the first draft of the manuscript; SB: designed the Interest in the use of anti-oxidants in pregnancies at new management protocol, managed patients with the new proto- high risk of pre-eclampsia is derived from the col, and substantially edited the manuscript; BH: designed the new Vitamins In Pre-eclampsia study. This double-blind, management protocol, managed patients with the new protocol, and edited the manuscript; DR: managed patients with the new proto- randomized study showed that supplementation col and edited the manuscript; CH: stimulated the data collection, with antioxidant vitamins C (1000 mg/day) and E designed the new management protocol, managed patients with the (400 IU/day) reduced the incidence of pre-eclampsia new protocol, and helped with drafting the manuscript. The authors 49,50 declare that they have no potential conflict of interest. significantly in the treated arm. A larger multi-cen- The authors wish to acknowledge Drs. Andrew Mumford, ter study on the use of anti-oxidants in the treatment Marilyn Pocock, John Duncan, and Professor Sam Machin for of pre-eclampsia is currently underway.51 The biolog- referring patients and providing data in relation to previous preg- nancies in some patients and Kiran Palmer for help with the statis- ical basis for their possible benefit relates to a two- tical analysis. stage theory, which suggests that placental dysfunc- Manuscript received June 25, 2005. Accepted August 24, 2005.

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haematologica/the hematology journal | 2005; 90(11) | 1483 |