Impact of mutational status on pregnancy outcome in patients with essential thrombocytemia.

Essential thrombocytemia (ET) may occur in women of childbearing age. Pregnancy may therefore be a common issue in the clinical management of young women with ET. Previous studies have shown live birth rates of 50% to 70% and spontaneous abortion rates of 25% to 50%, mostly during the first-trimester. The pathogenesis of poor pregnancy outcome has not been fully clarified. Age, parity, thrombophilia, platelet count, leukocyte count, and hemoglobin level have not been found to be predictive of pregnancy outcome in ET; however, a 3.4fold higher risk of fetal loss in women with ET than in healthy women has been shown. The effect of JAK2 V617F mutation is currently unclear, as it has been associated with an increased rate of pregnancy loss in 2 studies but not confirmed in others. Data regarding the impact of the other MPN-associated mutations are lacking. Two recent papers demonstrated that most of the patients with sporadic ET wild type for both JAK2 and MPL carry somatic mutations of CALR. The clinical course of sporadic CALR mutated patients has been shown to be more indolent than that of JAK2 mutated cases. The impact of CALR mutations on pregnancy outcome in ET remains to be clarified. In this study we aimed to investigate the correlation between mutational status and pregnancy complications. This study includes 155 pregnancies that occurred in 94 patients with ET who were diagnosed between 1982 and 2014 at the Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo Pavia, and at the First Clinical Medicine of the University of Padova, and for whom at least one DNA sample to assess mutational status was available (DNA collected between 2002 and 2014). Some of these cases (49 out of 94 patients) have been reported in our previous paper. This study was approved by the local ethics committees. The procedures followed were in accordance with the Helsinki Declaration, and samples were obtained with patients written informed consent. Diagnosis of ET was made in accordance with the criteria in use at the time of the first observation, as previously described. All patients were screened for JAK2, CALR and MPL mutations with previously reported methods. The four genotypic subgroups (JAK2 mutated, CALR mutated, MPL mutated and triple-negative patients) were compared in terms of pregnancy outcome. Pregnancy complications included fetal loss (first, second or third-trimester miscarriage), intrauterine growth retardation (IUGR), and maternal complications (including thrombosis, bleeding, preeclampsia, gestational hypertension, gestational diabetes, abruptio placentae and intrahepatic cholestasis). Categorical variables have been described as counts and relative frequencies (%) of each category. Quantitative variables have been summarized as median and range. The Fisher’s exact test was adopted to evaluate the association between categorical variables, while comparison of quantitative variables between two or more groups of patients was carried out by the non-parametric Wilcoxon rank-sum test or the Kruskal-Wallis analysis, respectively. An association between the occurrence of pregnancy complications and mutational status, year of pregnancy, age at pregnancy and use of aspirin was investigated via multivariate logistic regression, “correcting” standard errors to specify that pregnancies are independent across patients, but not within patients (repeated pregnancies in patients). Of 94 ET patients, 59 (62.8%) carried JAK2 V617F mutation, 19 (20.2%) carried CALR mutations, 2 (2.1%) carried MPL mutations, and 14 (14.9%) were triple-negative. When comparing hematological data at ET diagnosis, the hemoglobin value was the only hematological parameter that differed according to mutational status, being higher in JAK2 V617F mutated patients (median 14 g/dl, range 11.2-16) than in both CALR mutated patients (median 13 g/dl, range 11.5-14, P<0.001) and triple-negative patients (median 12.2 g/dl, range 8-14, P<0.001), thus confirming that which we previously reported. 3 pregnancies were ended by voluntary abortion and were excluded from the analysis of pregnancy outcome. Overall, 72 out of 152 pregnancies (47.4%) were complicated: 46 (30%) by fetal loss (37 during the first-trimester, 6 during the second and 3 during the third), 18 (11.8%) by maternal complications, and 13 (8.6%) by IUGR. The distribution of complications according to mutational status is reported in Table 1. We did not find a correlation between mutation status and the rate of fetal losses (Fisher’s exact test P=0.52) or