Alimentary TractEarly pregnancy loss in celiac women: The role of genetic markers of thrombophilia
Introduction
Celiac disease is an autoimmune disorder due to gluten intolerance that appears in genetically predisposed subjects with a prevalence, estimated by adult population screening, of about 1% in general population [1]. The clinical features of the disease vary from subclinical to overt malabsorptive syndrome. Intestinal mucosal damage generates a wide spectrum of symptoms/signs in part due to malabsorption, in part due to immunity [2]. The diagnosis is frequently delayed until adulthood and it is believed that for each celiac patient diagnosed, a several more remain undiscovered [1]. Autoimmune complications as thyroiditis [3], spondylo-arthritis [4] and insulin-dependent diabetes [5] are related to celiac disease. Many pathogenetic aspects of celiac disease are still unknown. Adverse pregnancy outcome is more frequent in celiac than in non-celiac women [6], [7]. The pathogenesis of this complication is unclear. For example, celiac women with subclinical or silent disease and no malabsorption can have pregnancy loss, whereas women with diarrhea, steatorrhea and autoimmune complications (i.e., thyroiditis) can have a normal pregnancy outcome, even before diagnosis [6]. In any case, early pregnancy loss is frequent in many other autoimmune diseases (i.e., systemic lupus erythematosus, primary biliary cirrhosis, and thyroiditis [8], [9]).
Acquired or hereditary thrombophilia have been related to adverse pregnancy outcome [10], [11]. In particular, a higher incidence of early recurrent abortion is associated with factor V Leiden [12], the methylenetetrahydrofolate reductase (MTHFR) C677T and to the prothrombin G20210A variants [13]. Finally, a higher incidence of the prothrombotic 4G allele of the PAI-1 gene and of genetic variants associated with increased FXIII activity were found to be related to early pregnancy loss [14]. However, data on the relationships between pregnancy loss and thrombophilia are conflicting [8], [9], [15], [16], [17], and some studies exclude that inherited prothrombotic factors as the deficiency of ATIII, PC and PS or factor V Leiden, the factor II G20210A and the MTHFR C677T variant are among the main causes of adverse pregnancy outcome [18], [19], [20].
To verify the role of inherited prothrombotic factors in adverse pregnancy outcome in celiac women we investigated, in celiacs with different pregnancy outcomes a group of prothrombotic gene variants.
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Patients
A single first trimester or early second trimester spontaneous abortion is considered a relatively common, sporadic event in healthy women. Therefore, evaluation and treatment of pregnancy loss can reasonably be started after two consecutive miscarriages [21]. Consequently, we examined: (i) 39 consecutive women with a new diagnosis of CD with at least two pregnancy losses within the first 3 months of pregnancy (group 1, Table 1); (ii) 72 consecutive celiac women with at least one normal
Results
Table 1 shows the number of early pregnancy losses in the 39 celiac women under study (group 1). Twenty-six women had three or more episodes, and five reported at least four early pregnancy losses. The control group consisted of 72 celiac women with at least one regular pregnancy and no pregnancy loss. The severity of mucosal damage was not different between the two groups (Marsh IIIa lesions: 8 in group 1 and 14 group 2; Marsh IIIb: 12 in group 1 and 23 in group 2; Marsh IIIc: 19 in group 1
Discussion
We studied the relationships between early pregnancy loss in celiac women and some genetic prothrombotic markers. The results, although will require confirmation in larger studies, warrant some comments. The 4G polymorphism of PAI 1 gene was significantly more frequent (both as variant genotypes and as variant allele) in celiac women with early pregnancy loss. On the contrary, plasma levels of ATIII, PC and PS activity seem to be not related to pregnancy loss in celiac women, infact the
Conflict of interest
None declared.
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