Correspondence

JAK2 V617F Mutation in Unexplained Loss of First Pregnancy

N Engl J Med 2007; 357:1984-1985November 8, 2007

Article

To the Editor:

Unexplained pregnancy loss is a common health problem. Meta-analyses and reviews1 suggest that disorders promoting venous thrombosis, collectively termed “thrombophilias,” contribute to the pathogenesis of fetal loss. The high variability among studies with respect to the associated risk between such disorders and unexplained pregnancy loss suggests the existence of underlying risk modifiers.

The V617F mutation of the Janus kinase 2 (JAK2) gene has been detected in most patients with polycythemia vera and in half of those with essential thrombocythemia.2 Pregnant women with polycythemia vera or essential thrombocythemia have reduced rates of live birth, with spontaneous loss being the most frequent fetal complication.3 The JAK2 V617F mutation has also recently been associated with splanchnic thrombosis.4

We searched for the JAK2 V617F mutation in 3496 pairs of women who were enrolled in a matched case–control study of unexplained pregnancy loss in the Nimes Obstetricians and Haematologists study of first pregnancy involving 32,683 patients.5 Excluded from the Nimes study were data for women who had a personal or family history of thrombotic events, who had antiphospholipid antibodies, or who had any chromosomal, hormonal, anatomic, or infectious explanation for pregnancy loss. A total of 431 patients had had embryonic loss before 10 weeks of gestation, and 3065 patients had had fetal loss at 10 or more weeks of gestation. Women were screened by means of a nested allele-specific polymerase-chain-reaction assay performed on DNA extracted from circulating leukocytes. Multiparametric conditional logistic-regression analysis was performed.

We detected heterozygosity for the JAK2 V617F mutation in very few women; however, the mutation occurred more frequently in patients with pregnancy loss (1.06%) than in control subjects (0.20%) (Table 1Table 1Frequency of Three Gene Mutations among 3496 Pairs of Primigravidas with Unexplained Pregnancy Loss and Control Subjects.). The mutation was significantly associated with the risk of fetal loss, which occurred in 23 case subjects as compared with 5 control subjects (odds ratio, 4.63; 95% confidence interval [CI], 1.76 to 12.2; P=0.002), and with the risk of embryonic loss, which occurred in 14 case subjects as compared with 2 control subjects (odds ratio, 7.20; 95% CI, 1.63 to 31.9; P=0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (3.25% vs. 0.75%, P<0.001). The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene and the 20210A mutation in the prothrombin gene (Table 1).

We reviewed data from the patients with the JAK2 V617F mutation for other risk factors for pregnancy loss, such as diabetes mellitus, hypertension, advanced maternal age, prepregnancy obesity, and socioeconomic factors. One patient was over 35 years of age; another had a low level of education and had had deficient prenatal care. In all women with the mutation, the clinical examination and complete blood count were normal.

We conclude that the JAK2 V617F mutation, which occurs in 0.20% of normal primigravidas between the ages of 21 and 36 years who live in the Mediterranean region of southern Europe, is associated with an increased risk of pregnancy loss.

Eric Mercier, Pharm.D., Ph.D.
Géraldine Lissalde-Lavigne, M.D., Ph.D.
Jean-Christophe Gris, M.D., Ph.D.
Groupe Hospitalo-Universitaire Caremeau, F-30029 Nîmes, France
jean.christophe.gris@chu-nimes.fr

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   Marie-Cécile Valera, Olivier Parant, Christophe Vayssiere, Jean-François Arnal, Bernard Payrastre. (2011) Essential thrombocythemia and pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 158:2, 141-147
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   Kh. Dhanachandra Singh, Muthusamy Karthikeyan, Palani Kirubakaran, Selvaraman Nagamani. (2011) Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors. Journal of Molecular Graphics and Modelling 30, 186-197
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   S. Rabhi, H. Khibri, R. Berrady, L. Lamchachti, M. Lahlou, Z. Khammar, M. Ouazzani, S. Tizniti, S. A. Ibrahimi, W. Bono. (2011) Syndrome de Budd-Chiari primaire: à propos de quatre observations et revue de la littérature. Journal Africain d'Hépato-Gastroentérologie 5:2, 80-85
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   Claire N. Harrison, Susan E. Robinson. (2011) Myeloproliferative Disorders in Pregnancy. Hematology/Oncology Clinics of North America 25:2, 261-275
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   E. GRANDONE, D. COLAIZZO, G. TISCIA, P. VERGURA, F. CAPPUCCI, L. GRECO, M. MARGAGLIONE, P. MARTINELLI, . (2011) Impact of common thrombophilias and JAK2 V617F on pregnancy outcomes in unselected Italian women. Journal of Thrombosis and Haemostasis 9:3, 496-501
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   S. P. KAANDORP, M. N. LAUW, C. E. VAN DER SCHOOT, M. GODDIJN, F. VAN DER VEEN, H. R. KOENE, B. J. BIEMOND, S. MIDDELDORP. (2010) Prevalence of JAK2V617F mutation in women with unexplained recurrent miscarriage. Journal of Thrombosis and Haemostasis 8:12, 2837-2839
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   Ramzi R. Finan, Fekriya E. Mustafa, Intissar Al-Zaman, Samira Madan, Abdalla A. Issa, Wassim Y. Almawi. (2010) SHORT COMMUNICATION: STAT3 Polymorphisms Linked with Idiopathic Recurrent Miscarriages. American Journal of Reproductive Immunology 63:1, 22-27
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   Alessandro M. Vannucchi. (2010) JAK2 Mutation and Thrombosis in the Myeloproliferative Neoplasms. Current Hematologic Malignancy Reports 5:1, 22-28
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   J. Martínez-Serra, E. Maffiotte, A. Gutierrez, M.A. Durán, J.C. Amat, J. Besalduch. (2009) New real-time PCR-based method for the joint genotyping of JAK2 (V617F) with inherited thrombophilic F5 and F2 mutations. Clinica Chimica Acta 410:1-2, 59-63
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    Paola Guglielmelli, Cinzia Fatini, Meri Lenti, Alberto Bosi, Alessandro M. Vannucchi. (2009) JAK2V617F mutation screening in patients with retinal vein thrombosis or recurrent fetal loss. Thrombosis Research 124:3, 377-378
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    Alessandro M Vannucchi, Paola Guglielmelli, Lisa Pieri, Elisabetta Antonioli, Alberto Bosi. (2009) Treatment options for essential thrombocythemia and polycythemia vera. Expert Review of Hematology 2:1, 41-55
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    Dominique-Charles Valla. (2009) Primary Budd-Chiari syndrome. Journal of Hepatology 50:1, 195-203
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