Pregnancy outcomes in myeloproliferative neoplasms: A Mayo Clinic report on 102 pregnancies (2020)

To the Editor: Over the past five decades, 361 (12%) of 3023patients with myeloproliferative neoplasms (MPN), seen at the Mayo Clinic, were age 40 years or younger; specific diagnosis in approximately half of these patients was essential thrombocythemia (ET).1 True incidence of pregnancy in MPN is difficult to ascertain since most data is derived from retrospective series. However, it is known that among the MPNs, pregnancy occurs most frequently in ET, followed by polycythemia vera (PV) but is extremely rare in the context of primary myelofibrosis (PMF).2 In ET the live birth rate is highly variable ranging from 50% to 75% primarily due to first trimester fetal loss. Predictors of fetal loss including the role of the JAK2V617F mutation remain debatable.2-5 The current study aims to: (a) provide an accurate description of pregnancy outcomes including fetal and maternal complications in MPN, (b) evaluate trends in outcomes over the last decade, and (c) identify predictors of fetal loss, particularly the impact of driver mutations (JAK2, CALR, MPL) and treatments in ET. After institutional review board approval, we utilized our institutional MPN database to identify 152, 36, and 26 women aged <50 years with ET, PV and PMF, respectively. A comprehensive obstetric history of pregnancies occurring after MPN diagnosis was recorded. Fetal outcomes were characterized as live birth, first/second trimester loss, or stillbirth. Maternal complications included pre-eclampsia, placental abruption, thrombosis and hemorrhage occurring up to 6 weeks postpartum. Trends in pregnancy outcomes over the last decade were computed with the year 2008 as a cut-off. JMP Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all statistical analysis. A total of 95 pregnancies occurred in 55 of 152 (36%) women with ET; half (n = 27) had more than one pregnancy (two pregnancies (n = 17), three pregnancies (n = 7), four pregnancies (n = 3). Note, 21 women had pregnancies prior to ET diagnosis, of which eight (38%) experienced one or more fetal loss. Median age at first pregnancy post ET diagnosis was 29 years (range, 20-36 years), with median leukocyte count of 9 × 109/L (range, 3.9-19.8 × 109/L) and platelet count of 849 × 109/L (range; 252-1998 × 109/L). Seven women (13%) were active smokers, with diabetes mellitus, hypertension and hyperlipidemia in one woman each. International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) categories were computable for 40 women; low (n = 20), intermediate (n = 14), and high risk (n = 6). Among 34 women with known driver mutational status, 45% were JAK2V617F mutated (n = 18), 30% CALR mutated (n = 12) and the remainder triple negative. A group of 33(60%) women were on aspirin therapy during first pregnancy, additionally 13 patients were receiving cytoreductive therapy (interferon (n = 8), anagrelide (n = 3), with one woman each on hydroxyurea and radioactive phosphorus). Five women received anticoagulation with low molecular weight heparin. Live births for first pregnancy after ET diagnosis, were noted in 34 women (62%) with the remainder experiencing fetal loss predominantly in the first trimester. Maternal complications in 24% women included post-partum hemorrhage (n = 5), venous thromboembolism (n = 3), preeclampsia (n = 3) and placental abruption (n = 2). On the other hand only four (7%) fetal complications arose; two intrauterine growth retardation and pre-term births each. We recommend referring to Table 1 for details on clinical parameters and pregnancy outcomes in ET. Twenty seven women underwent a second pregnancy, of which 22 (81%) were live births. First trimester loss occurred in five of 27 second pregnancies (19%); all of whom had experienced antecedent pregnancy fetal loss. Six of 10 (60%) of third pregnancies were fetal losses (first trimester (n = 4), second trimester (n = 1), still birth (n = 1)). It is noteworthy that five of six third pregnancy fetal losses coincided with first pregnancy (P = .58), and four with second pregnancy loss (P = .34). An encouraging trend in pregnancy outcomes over the preceding decade was observed with increasing live birth rates of 76% post 2008 as opposed to 63% prior to 2008 (P = .34). As expected, this trend aligned with a significant reduction in both maternal/fetal complications after 2008 (5% vs 34%) (P = .007). Subsequently, we interrogated pregnancies in ET to identify disease features predictive of fetal loss and learnt that first pregnancy fetal loss was highly predictive of second pregnancy loss (P = .004). On the other hand, aspirin use during pregnancy was a preventive measure with fetal loss rates with or without aspirin of 27% vs 60% respectively (P = .02). Other factors such as maternal age > 30 years (P = .8), leukocytosis (P = .85), thrombocytosis (P = .41), JAK2 mutation (P = .62), CALR mutation (P = .28), prior thrombosis (P = .3), IPSET thrombosis (P = .63), fetal loss prior to ET (P = .53), anticoagulation use,P = .88), or cytoreductive therapy (P = .72) did not impact outcomes. With regards to PV, 4 of 36 (11%) women; median age 29.7 years, median hemoglobin 17.4 g/dL, leukocyte count 12 × 109/L, and platelet count 703 × 109/L with one or more pregnancies were studied. Patient one had venous thrombosis after diagnosis that was managed with aspirin, enoxaparin and hydroxyurea. She experienced an uncomplicated first pregnancy save for emergent Cesarean section for fetal distress resulting in a live birth. Patient two had a successful pregnancy while on aspirin, despite a history of two spontaneous miscarriages. Patient three, without prior thrombosis or fetal loss, delivered a live fetus by Cesarean section complicated by post-partum pulmonary embolism, treated with aspirin, enoxaparin and phlebotomies. Her subsequent pregnancy was uncomplicated on aspirin and enoxaparin. Patient four without prior thrombosis or hemorrhage had an uneventful first pregnancy on aspirin. Two women with PMF aged 26 and 28 years with elevated platelet counts of 1205 × 109/L and 784 × 109/L respectively, CALR mutated had a successful pregnancy each while on aspirin. In summary, the largest analysis of pregnancies in MPN from a single institution highlights substantial progress in pregnancy complications over the last decade with improving trends in live birth rates being consistent with a multi-center Italian cohort of 122 pregnancies (76% vs 75.4% live birth rates respectively).3, 6 Salient findings include the protective effect of aspirin on fetal loss and concordance of first and second pregnancy losses, which have been partially endorsed by a recent contemporary series from Harvard on 130 pregnancies. The study showed adverse impact of prior fetal loss (OR 8.82, P = .023) with a trend toward improved outcomes with aspirin use (OR 0.33, P = .12).7 Our discrepant observations regarding the lack of impact of JAK2, CALR mutations, or interferon use on outcomes warrant further collaborative investigations.3, 4 Lastly, the current series serves as a valuable resource for reproductive counseling of young women with MPN. The authors declare no potential conflict of interest.