Deficient syncytiotrophoblast tumour necrosis factor-alpha characterizes failing first trimester pregnancies in a subgroup of recurrent miscarriage patients

Pregnancy failure in mice has been associated with increased placental concentrations of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). To investigate the role of uterine TNF-alpha in human first trimester miscarriage, we have collected human decidual and trophoblast tissue from women (i) undergoing surgical termination of pregnancy (n = 27), (ii) undergoing a sporadic miscarriage (n = 20) and (iii) with a history of recurrent pregnancy loss [>3 consecutive pregnancy losses (n = 26)] undergoing a further miscarriage. Formalin fixed tissues were examined for TNF-alpha mRNA (in-situ hybridization) and protein (immunohistochemistry). In decidua from all three groups, TNF-alpha protein and mRNA were co-localized to the decidual stroma, the luminal surface of some maternal vessels and to the glandular epithelium. Chorionic villi from the normal pregnancy and the sporadic miscarriage group exhibited co-localized TNF-alpha protein and mRNA in the syncytiotrophoblast and cytotrophoblast. In the recurrent miscarriage group, however, 63.6% of the biopsies showed positive immunostaining in only the cytotrophoblast, compared with 4.0% of women undergoing surgical termination of pregnancy and 0.0% of women with a sporadic failed pregnancy (P < 0.001). TNF-alpha mRNA was also localized exclusively to this layer. This may be a secondary effect caused by a different mechanism of pregnancy loss unique to this subgroup.