The myeloproliferative neoplasms (MPNs), previously known as the myeloproliferative disorders, are generally indolent stem cell malignancies, characterized by a propensity to thrombotic or hemorrhagic events and, less frequently, transformation to myelofibrosis or acute myeloid leukemia. The MPNs defined by the World Health Organization (WHO) encompass the more commonly encountered essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), and the rarer entities MPN unclassified, MPN syndromes overlapping with myelodysplasia, mast cell disorders, chronic neutrophilic leukemia, and hypereosinophilic syndrome. The combined incidence of ET, PV, and PMF is approximately 6 in 100,000 to 9 in 100,000, with a peak frequency between 50 and 70 years. However, for ET in particular there is a second peak in women of reproductive age, and 15% of patients with PV are younger than 40 years at the time of diagnosis. Thus these diseases are encountered in women of reproductive potential, and may indeed be diagnosed in pregnancy or during investigation of recurrent pregnancy loss or infertility. Historical case reports of pregnancy and retrospective case series, albeit likely to be subject to reporting bias, suggest significant maternal morbidity and poor fetal outcome. Pregnancy in these conditions is clearly complicated, and a proportion of women with MPN will require disease-specific intervention in pregnancy.

Pathogenesis of MPN

MPNs result from the transformation of a hemopoietic progenitor cell, characterized by overproduction of mature blood cells. In 2005, 4 groups simultaneously reported the discovery of a point mutation in exon 14 of Janus Kinase 2 (JAK2V617F), where phenylalanine is substituted by valine, which enables constitutive activation of JAK 2. Both wild-type and mutant JAK2 bind to the intracytoplasmic tail of many common hemopoietic cytokine receptors, which include those cognate receptors for erythropoietin, thrombopoietin (TPO), and granulocyte colony stimulating factor. When the ligand binds to one of these receptors, phosphorylation of JAK2 and the receptor itself occurs, initiating signaling via the JAK-STAT, MAPK, and PI3K pathways. This process is independent of the presence of ligand receptor interaction in the presence of JAK2V617F ( Fig. 1 ). The JAK2V617F mutation is present in 95% of patients with PV and 50% of patients with ET or myelofibrosis. Many of the remaining patients with JAK2V617F-negative PV have a mutation in exon 12. A proportion of patients with ET or myelofibrosis have one of several mutations of the transmembrane domain of the TPO receptor cMPL, which also causes constitutive activation. All these mutations have been shown to produce an MPN-like phenotype in murine models.

The role of JAK2 in the signalling pathway and the erythropoietin receptor. In the absence of erythropoietin, the erythropoietin receptor binds JAK2 as an inactive dimer ( A ). The binding of erythropoietin induces conformational change in the erythropoietin receptor and phosphorylation of JAK2 and the cytoplasmic tail of the receptor ( B ) leading to signalling through the Janus kinases and signal transducers and activators of transcription (JAK-STAT), phosphatidylinositol 3 kinase (PI3K) and RAS and mitogen activated protein kinase (RAS-MAPK). In cells with JAK2 V617F the signalling pathways are constitutively increased even in the absence of erythropoietin ( C ). ( Adapted from Campbell PJ, Green A. The mechanisms of disease. The Myeloproliferative Disorders. The New England Journal of Medicine 2006;355:2452–66.)