Tumor Necrosis Factor-α (TNF-α), a key pro-inflammatory cytokine, plays complex roles in immune regulation, inflammatory responses, and physiological processes of pregnancy. Abnormal elevation of TNF-α may be involved in the pathogenesis of various immune-related diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis. For pregnant patients with such diseases, TNF-α antagonists (such as infliximab, adalimumab, etanercept, and their biosimilars) have become important therapeutic options. This article will systematically elaborate on the mechanism of action, clinical efficacy, and safety of TNF-α antagonists, providing references for rational drug use in pregnancy-related scenarios.
In normal pregnancy, maternal immune tolerance to the fetus, a semi-allogeneic graft, is the core mechanism for maintaining pregnancy. It is characterized by the activation of regulatory T cells (Treg) and the dominant expression of Th2-type cytokines (such as IL-4 and IL-10) to inhibit excessive immune rejection. However, TNF-α, a typical Th1-type pro-inflammatory cytokine, when abnormally elevated, may disrupt this immune balance and induce pregnancy complications.
Studies have shown that TNF-α can affect pregnancy outcomes through multiple pathways: first, it upregulates the expression of fibrinogen-like protein 2 (fgl2), promotes thrombin synthesis and fibrin deposition, activates the complement system and neutrophils, leading to placental vascular endothelial damage and thrombosis, and increasing the risk of insufficient placental perfusion; second, it induces abnormal remodeling of uterine spiral arteries, affecting placental development; third, in patients with recurrent miscarriage, the level of TNF-α and the TNF-α/IL-10 ratio are significantly increased, and the ability of CD3+CD4+ cells to secrete TNF-α is enhanced, suggesting that TNF-α may cause fetal loss by exacerbating the inflammatory response at the maternal-fetal interface.
TNF-α antagonists exert therapeutic effects by specifically blocking the biological activity of TNF-α, with molecular mechanisms varying by drug type: infliximab is an anti-TNF-α monoclonal antibody that can directly bind to soluble and membrane-bound TNF-α, inhibiting its interaction with receptors; adalimumab is a fully human monoclonal antibody that targets similar to infliximab but with lower immunogenicity; etanercept and recombinant human tumor necrosis factor receptor II-Fc fusion protein (such as Yisaipu, Qiangke) simulate TNF-α receptors, competitively binding to TNF-α and blocking its signal transduction.
In pregnancy-related diseases, the core role of TNF-α antagonists is to restore immune balance at the maternal-fetal interface: on the one hand, reducing abnormally elevated TNF-α levels and reducing the damage of inflammatory factors to placental blood vessels; on the other hand, indirectly promoting the expression of Th2-type cytokines and enhancing the immune tolerance microenvironment, thereby reducing the risk of adverse pregnancy outcomes such as miscarriage and premature delivery.
Recurrent in vitro fertilization failure or recurrent miscarriage is closely related to immune disorders, especially when there is an imbalance of Th1/Th2 cytokines (dominance of Th1-type factors), the pregnancy success rate is significantly reduced. A study on 75 patients with recurrent in vitro fertilization failure (TNF-α/IL-10 > 30.6 and IFN-γ/IL-10 > 20.5) compared the efficacy of four intervention regimens:
Regimen 1: Intravenous immunoglobulin (IVIG) + TNF-α antagonist + aspirin + heparin
Regimen 2: IVIG + aspirin + heparin
Regimen 3: TNF-α antagonist + aspirin + heparin
Regimen 4: Aspirin + heparin
Interventions included: IVIG injection at a dose of 400mg/kg at least once, with additional injections if NK cells were elevated in early pregnancy; TNF-α antagonists were injected twice 30 days before embryo transfer (14 days apart), and repeated every 3-4 weeks according to the Th1/Th2 ratio. The results showed that the clinical pregnancy rate (80%) and embryo implantation rate (59%) of Regimen 1 were significantly higher than those of other regimens, with a live birth rate of 73%; Regimen 3 had the next highest clinical pregnancy rate (50%) and live birth rate (50%); Regimen 2 had a clinical pregnancy rate of 57% and a live birth rate of 54%; while Regimen 4 had a clinical pregnancy rate and embryo implantation rate of 0. These results suggest that TNF-α antagonists combined with immunomodulatory therapy can effectively improve the outcomes of recurrent pregnancy failure related to immune abnormalities, and the combination with IVIG may have a synergistic effect.
For pregnant patients with autoimmune inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis, TNF-α antagonists can effectively control disease activity and reduce the damage of inflammation to the mother and fetus. Studies have shown that pregnant patients using TNF-α antagonists have a significantly lower disease recurrence rate than those in the drug withdrawal group, and the incidence of pregnancy complications (such as preeclampsia and fetal growth restriction) is reduced. In patients with inflammatory bowel disease, drugs such as adalimumab can maintain disease remission, reduce the risk of pregnancy flares, thereby reducing the incidence of premature delivery and low birth weight infants.
Animal experiments provide preliminary support for the safety of TNF-α antagonists: in a cynomolgus monkey embryo-fetal toxicity study, intervention with TNF-α antagonists at doses exceeding 100 times the conventional human dose did not observe teratogenic effects or abnormal embryonic development, suggesting that they still have high safety at high doses.
In terms of clinical data, several observational studies have evaluated the maternal and infant outcomes of exposure to TNF-α antagonists during pregnancy:
A study involving 50 pregnant women with rheumatism showed that only 2 cases of congenital malformations occurred in 36 patients using etanercept, and the incidence was not significantly different from that of the general population;
Follow-up of 37 pregnant women treated with adalimumab for enteritis found that neither the mother nor the fetus had adverse events related to the drug;
Summary data as of 2015 showed that the live birth rate of 472 pregnant women exposed to TNF-α antagonists reached 85.8%, and the risk of congenital abnormalities did not increase significantly.
However, a prospective cohort study covering 9 countries compared 495 exposed patients with 1532 non-exposed patients and found that the rate of major birth defects in the exposed group was 5%, higher than 1.5% in the non-exposed group. Further analysis showed that this difference may be related to the mother's underlying diseases (such as inflammatory bowel disease, rheumatoid arthritis) and other combined drugs, rather than directly caused by TNF-α antagonists.
The placental transfer characteristics of TNF-α antagonists are core issues to be concerned about during pregnancy. Due to differences in molecular structure, different drugs have different times and concentrations of placental passage: infliximab and adalimumab are IgG1 antibodies that can be actively transported to the fetus through the placenta in the second and third trimesters of pregnancy; etanercept and fusion protein drugs have relatively low placental transfer rates, but fetal serum drug concentrations may still be detected in the third trimester.
If medication is continued in the third trimester, TNF-α antagonists may remain in the neonatal serum, which may affect the neonatal immune function, especially restricting live vaccine 接种. Since TNF-α plays an important role in neonatal anti-infective immunity, drug residues may inhibit the body's immune response to live vaccines (such as BCG, measles-mumps-rubella vaccine), increasing the risk of infection. Therefore, the 2016 British Society for Rheumatology (BSR) guidelines recommend that pregnant patients with immune-related diseases using TNF-α antagonists should stop using them by the 30th week of pregnancy to reduce drug residues in neonatal serum and avoid interference with postnatal vaccination.
In addition, drug selection can also optimize safety: TNF-α antagonists with extremely low placental transfer rates, such as golimumab and certolizumab, may be better choices for continuous treatment during pregnancy, but their data in pregnant populations still need to be accumulated.
TNF-α antagonists, by specifically blocking the pathological role of TNF-α, have shown clear clinical value in pregnancy complicated with immune-related diseases, effectively improving pregnancy outcomes and controlling maternal disease activity. Their mechanism of action is rooted in the regulation of immune balance at the maternal-fetal interface, and their clinical efficacy has been initially verified in recurrent pregnancy failure and inflammatory diseases.
In terms of safety, existing evidence does not clearly show that TNF-α antagonists increase the risk of fetal malformations, but attention should be paid to the impact of placental transfer on neonatal vaccination during pregnancy, and the recommended drug withdrawal time in the guidelines (before 30 weeks of pregnancy) should be followed. Future studies should further explore the differences in placental transfer of different TNF-α antagonists, optimize individualized medication regimens, and accumulate long-term maternal and infant follow-up data to provide more solid evidence for rational drug use in pregnancy-related scenarios.
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