Study on the Role of TNF-α Protein in the Pathogenesis of Recurrent Miscarriage

Recurrent spontaneous abortion (RSA) refers to the loss of three or more fetuses before 28 weeks of gestation. Since the risk of subsequent abortion after two miscarriages is similar to that after three, Chinese experts recommend evaluation after two occurrences. Approximately 5% of women of reproductive age experience two or more miscarriages, while about 1% experience three or more. The pathogenesis of RSA is complex and multifactorial, involving genetic factors, anatomical abnormalities of the reproductive tract, infections, endocrine dysfunction, and immune abnormalities. With advancing research, immune dysfunction has increasingly been recognized as a significant cause of RSA.

As the fetus carries paternal antigens that are partially foreign to the maternal immune system, pregnancy can be viewed as a semi-allogeneic transplant process. Successful pregnancy relies on maternal immune tolerance toward the embryo. Fine regulation of immune cells and cytokines is crucial for maintaining normal pregnancy. The relationship between Th1/Th2 cytokine balance and RSA has attracted widespread attention. Current evidence suggests that Th1-dominant immunity may lead to miscarriage, while Th2-dominant immunity supports successful pregnancy. Th1 cytokines (e.g., TNF-α and interleukin-2) primarily mediate cellular immune responses, whereas Th2 cytokines (e.g., interleukin-4, interleukin-5, and interleukin-10) mainly mediate humoral immunity. The balance between these cytokines determines whether pregnancy is maintained or terminated.

TNF-α, a major Th1 cytokine, plays vital regulatory roles in normal pregnancy. During physiological pregnancy, decidual TNF-α modulates trophoblast growth and differentiation while promoting progesterone and human chorionic gonadotropin synthesis. It also stimulates cytotrophoblasts to produce urokinase-type plasminogen activator, facilitating extracellular matrix degradation and placental implantation. At appropriate concentrations, TNF-α positively regulates trophoblast invasiveness, promotes placental vascular remodeling, and is essential for pregnancy maintenance. Moderate TNF-α expression is critical for successful embryo implantation and normal placental development.

Elevated TNF-α concentrations may induce miscarriage through multiple pathways. In uterine smooth muscle, TNF-α promotes contractions that may expel the embryo. For embryonic development, excessive TNF-α induces necrosis and impairs normal growth. In the vascular system, TNF-α stimulates thrombus formation in fetal blood supply systems, compromising placental perfusion. Both domestic and international studies demonstrate significantly higher serum levels of Th1 cytokines (including TNF-α and interleukin-2) in RSA patients compared to normal women, suggesting their pathogenic role. Research also reveals elevated TNF-α expression in decidual tissue, supporting the hypothesis that TNF-α activates endothelial procoagulants, triggering thrombosis, inflammation, and trophoblast apoptosis—ultimately leading to RSA.

Current clinical practice employs empirical immunomodulatory drugs for RSA treatment. Lymphocyte immunotherapy reduces Th1/Th2 ratios (including interferon-γ/interleukin-10 and TNF-α/interleukin-10 ratios), with successful cases showing decreased cytokine levels. Patients treated with dydrogesterone exhibit lower serum interleukin-4 and TNF-α levels compared to placebo groups, alongside significantly reduced recurrence rates. These findings implicate TNF-α as an inflammatory mediator in RSA pathogenesis, suggesting that targeted intervention may improve pregnancy outcomes. However, large-scale randomized controlled trials are needed to validate the efficacy and safety of these treatments.

TNF-α exerts biological effects by binding two receptor types: TNFR1 and TNFR2. Ubiquitously expressed TNFR1 activation induces apoptosis and inflammatory responses. In RSA pathology, high TNF-α concentrations bind trophoblast-surface TNFR1, activating caspase cascades that induce trophoblast apoptosis and placental insufficiency. TNF-α also activates vascular endothelial cells, increasing adhesion molecule expression and promoting leukocyte infiltration and inflammatory cytokine release, exacerbating placental inflammation. Furthermore, TNF-α inhibits trophoblast migration and invasiveness, impairing placental vascular remodeling and contributing to embryonic maldevelopment and miscarriage. Elucidating these molecular mechanisms provides theoretical foundations for TNF-α-targeted therapies.

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