No evidence for increased prevalence of <i>JAK2</i> V617F in women with a history of recurrent miscarriage

Abstract

Myeloproliferative neoplasms (MPNs) have been associated with increased rates of pregnancy complications. Women with essential thrombocythaemia (ET) (Griesshammer et al, 1998), and, much less frequently, polycythaemia vera (PV)(Robinson et al, 2005), present at a childbearing age and it has been reported that up to a third of MPN pregnancies may fail as first trimester miscarriages (Elliott & Tefferi, 2003). A recent study has demonstrated that the JAK2 V617F mutation, seen in nearly all PV cases and half of those with ET, was detectable in a significantly greater proportion of women with a first unexplained pregnancy loss compared to controls, although the overall incidence was low (1·06% of women with a first unexplained pregnancy loss vs. 0·2% in controls, P < 0·001) (Mercier et al, 2007). We hypothesized that JAK2 V617F may be further enriched in women who had multiple miscarriages (Passamonti et al, 2007). We studied peripheral blood leucocyte DNA from women who had suffered at least three consecutive spontaneous early miscarriages (<10 weeks gestation) or at least one late pregnancy loss (>10 weeks) by a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) assay with a sensitivity of detection of 1%JAK2 V617F (Jones et al, 2005). None of the women had evidence of an MPN. We calculated that 381 individuals had to be enrolled in this study to attain 95% power to exclude a JAK2 V617F positivity rate of 1% at the α = 0·05 level. The observed incidence of JAK2 V617F mutated cases was compared to an incidence of 1% using the Clopper-Pearson exact test. Statistical analysis was performed using PASS, version 2008 (NCSS, Kaysville, UT, USA) and stata, version SE/10 (STATA Corp, College Station, TX, USA). Significance was defined as P-value <0·05; P-values were two-tailed. The study was approved by the Internal Review Boards of the participating Institutions and informed consent was provided according to the Declaration of Helsinki. Of the 389 cases, 92% had a history of early miscarriage and 14·1% of late miscarriage (6·1% had experienced both). Detailed clinical information was available for 230 (59%) cases: the mean age was 36 years (range: 20–50 years) and the median number of miscarriages was 3 (range: 3–7). Factors known to be associated with recurrent miscarriages, such as antiphospholipid syndrome, maternal infections, diabetes, uterine abnormalities and parental chromosomal abnormalities, were excluded. The JAK2 V617F mutation was not detected in any case, yielding a 95% confidence interval for the prevalence of the mutation ranging from 0 to 0·009 and excluding a 1% prevalence of JAK2 V617F in this population (P = 0·038). Our study therefore demonstrated no enrichment of JAK2 V617F (estimated prevalence <1%) among unselected women with a history of recurrent miscarriage. Although we cannot exclude the possibility of a small, significant excess of JAK2 V617F over background levels, our findings indicate that a latent maternal JAK2 V617F-positive MPN is an unlikely cause of miscarriage. This work was supported by the grant PENED03ED934/2003 to DL from the Secretariat for Research and Technology of the Greek Ministry of Development.