Immune System and Miscarriage
Women with recurrent miscarriage have enhanced pro-inflammatory immune system
T cells are involved in chronic inflammatory processes and Treg cells are possibly the most important immune regulators. We aimed to investigate peripheral blood T and Treg cells in women with idiopathic recurrent miscarriage. METHODS: The study design is a cross-sectional evaluation of Th1, Th2, T and Treg cells in women with idiopathic miscarriage and age-matched parous controls. RESULTS: TNF-α-/IL-10 T cell ratio was higher in women with recurrent miscarriage than controls. Levels of T cells and the T/Treg cell ratio were increased, whereas Treg cell levels were decreased in women with recurrent miscarriage, compared with controls. Levels of T cells were correlated with TNF-α-producing T cells, and with ratios of TNF-α/IL-10 and IFN-γ/IL-10. Furthermore, the ratio of T cells to Treg cells showed a positive correlation with TNF-α-producing T cells and IFN-γ-producing T cells as well as a ratio of IFN-γ/IL-10-producing T cells. CONCLUSIONS: Enhanced pro-inflammatory immune responses with suppressed immune regulation may be an important immune mechanism involved in recurrent miscarriage.
Lower levels of antioxidants and higher inflammation found in recurrent miscarriage
Reduced glutathione, glutathione reductase, glutathione peroxidase, catalase, superoxide dismutase, nitric oxide, malondialdehyde and TNF-alpha were assayed in women suffering unexplained first-trimester miscarriages. RESULTS: We observed that the antioxidant levels measured were significantly lower in unexplained recurrent miscarriage than in the control group. Higher TNF-alpha, malondialdehyde and nitric oxide production were detected in recurrent miscarriage groups compared to controls. Having 3 to 5 miscarriages was associated with significantly higher levels of antioxidants and lower levels of TNF-alpha compared to levels in women with more than 5 miscarriages. CONCLUSIONS: Impaired antioxidant defense and an increase in oxidative reactive species may be responsible for recurrent miscarriage due to possible damage produced by their generation. In addition, the level of TNF-alpha apparently contributes to the pathogenesis of unexplained recurrent miscarriage.
Inflammation related to immunity factors are found in recurrent miscarriage
IVIG and TNF inhibitors improve pregnancy outcome in recurrent miscarriage
The purpose of this study was to investigate whether treatment with tumor necrosis factor (TNF) inhibitors combined with intravenous immunoglobulin (IVIG) increases live birth rates among women with recurrent miscarriage concurrently treated with anticoagulants. RESULTS: The live birth rate was 19% in patients treated with anticoagulants, 54% in patients treated with anticoagulants and IVIG, and 71% in patients treated with anticoagulants, IVIG and TNF inhibitors (Enbrel or Humira). There was significant improvement in pregnancy outcome in group II versus group I and in group III versus group I. The live birth rate in group III compared to group II was not significantly different. Side effects of anticoagulants, IVIG and TNF inhibitor treatment were minimal in these patients, and no birth defects were identified in their offspring. CONCLUSION: In women with recurrent miscarriage, addition of either IVIG or a TNF inhibitor + IVIG to the anticoagulant regimen appears to improve live birth rates compared to the treatment with anticoagulant alone.
Immune receptors lower in recurrent miscarriage; progesterone therapy restores them
Levels of soluble TNF-R1 and TNF-R2 in normal pregnancy were elevated when compared with non-pregnant normal women and pregnant recurrent miscarriage women. Levels of late activated CD8+ T-lymphocytes in normal pregnancy were decreased but no changes were detected in recurrent miscarriage women. After progesterone therapy (i.m. injections of 2.5% oil solution) in recurrent miscarriage women elevation of sTNF-R1 and sTNF-R2 to normal pregnancy ranges was observed. No changes in levels of late activated CD8+ T-lymphocytes after progesterone treatment were detected. CONCLUSIONS: Elevation of levels of sTNF-R1, sTNF-R2 and decrease of late activated cytotoxic T-lymphocytes are pronounce markers of normal human pregnancy. In recurrent miscarriage women there are no elevation of sTNF-R1 and sTNF-R2 levels during pregnancy. This deficiency may be restored by progesterone treatment.
NK cell activity higher in those suffering from infertility
NK-cell activity of the infertile group (40.2%) was significantly higher than the control group (31.5%). The increased NK-cell activity was not associated with age, infertile duration, depression scores, treated hyperprolactinemia, or treated endometriosis.
Stress induces miscarriage by reducing immunosuppressive activity
Stress is known to be abortogenic in animals and humans. An increased decidual release of cytokines such as TNF-alpha and reduction in TGF-beta 2-related immunosuppressive activity has been proposed as the triggering mechanism. Uterine mast cells show activation as reflected by degranulation after stress exposure of pregnant mice and mast cells might be the cellular link between the neurotransmitter substance P and increase in decidual TNF-alpha release that leads to miscarriage.
Women who miscarry may have an inappropriate immune response to progesterone and estrogen
In a longitudinal prospective study, the wheal and flare reaction (allergic reaction) after intradermal injection of estradiol and progesterone was compared in 29 women with recurrent miscarriage to the response in 10 healthy women. Estrogen hypersensitivity was found in 23 patients, and progesterone hypersensitivity in 20 patients. No patient in the control group demonstrated sex hormone hypersensitivity. CONCLUSION: Recurrent miscarriage may be associated with inappropriate local immune responses to sex hormones. Further research is necessary into the mechanisms of hypersensitivity to estrogen and progesterone and their interactions with other systems.
High uterine blood flow resistance associated with miscarriage, autoimmune disease, low progesterone
In the repeat miscarriage group, the uterine blood flow resistance in the uterine artery of women with antinuclear antibodies (high in autoimmune disease) was significantly higher than that of women without antinuclear antibodies. Among women without antinuclear antibodies, the mean uterine blood flow resistance in the repeat miscarriage group (2.44) was also significantly higher than in the control group (2.19). The uterine blood flow resistance was inversely correlated with serum progesterone levels. CONCLUSIONS: Elevated uterine arterial impedance is associated with repeat miscarriage.
Th1 is dominant in women with recurrent miscarriage, improved by immunotherapy
The ratios of Th1/Th2 and Tc1/Tc2 chemokine receptors were higher in repeat miscarriage women compared to controls. The ratio of Th1/Th2 chemokine receptors was decreased in repeat miscarriage women after immunotherapy, while no significant change was identified in the Tc1/Tc2 after immunotherapy.This study indicates the Th1 dominant immune responses in circulation of repeat miscarriage women compared to controls. Moreover, lymphocyte immunotherapy might influence pregnancy outcome via a shift in the balance of the Th1/Th2 chemokine receptors.
Higher Th1/Th2 ratio found in recurrent miscarriage and infertility
Elevated Th1/Th2 cytokine ratios were reported in women with a history of recurrent miscarriage and multiple implantation failures.
Higher Th1, Lower Th2 found in threatened miscarriage
A sample of women with threatened miscarriage and healthy pregnant women (control group) was studied. Women with threatened miscarriage had significantly lower serum levels of anti-inflammatory cytokine, but levels of proinflammatory cytokines were higher in this group compared with healthy controls.
TNFalpha/IL-10 ratio higher in missed miscarriage and non-pregnant subjects
Women presenting with threatened miscarriage are at significantly increased risk of adverse pregnancy outcome and the pathophysiology of these conditions involves a change in the Th1/Th2 balance. The ratio TNFalpha/IL-10 was significantly higher and the beta-hCG levels was significantly lower in missed-miscarriage and non-pregnant subgroups than in threatened miscarriage and normal pregnant controls. Changes in levels of cytokines could help to predict and thus prevent the development of some of these complications.
No relation to Th1 and Th2 concentrations was found in threatened abortion
Mean serum concentrations of Th1- and Th2-type cytokines in women with threatened miscarriage did not differ from those in women with normal pregnancy at first and second sampling.