Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review

Abstract

Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic interventions in this setting should be discouraged. Finally, adverse effects on sperm quality, or causing embryo-fetal anomalies, in men treated with TNF inhibitors have not been described.

Anti‐TNF treatment during pregnancy and birth outcomes: A population‐based study from Denmark, Finland, and Sweden

“…One concern is the potent immunosuppression of anti‐TNF treatment, which may increase infections prior to delivery, linking anti‐TNF with preterm birth and intrauterine growth restriction . TNF is also involved in implantation, placentation, and delivery . Blocking this pathway with anti‐TNF could have complex consequences, both beneficial and detrimental to birth outcomes in that the increased risk of infection may lead to adverse birth outcomes, but the control of the inflammatory disease by treatment may lower the risk of adverse birth outcomes.…”

Associations of maternal immune response with MeHg exposure at 28 weeks’ gestation in the Seychelles Child Development Study

“…The balance of TNFα and IL-10 is proposed to be critical for pregnancy outcome with an increase in the TNFα:IL-10 ratio related to early and late pregnancy complications. 52 We found MeHg was negatively associated with both TNFα and IL-10 in this cohort, and this may affect this ratio and warrants further investigation. IL-1β is involved in implantation and preimplantation embryo development 53 with elevated first trimester IL-1β associated with preterm preeclampsia.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…TNF-α является плейотропным цитокином, ко-торый оказывает влияние почти на каждую диффе-ренцированную клетку, индуцируя широкий спектр различных клеточных реакций, в том числе актива-цию, пролиферацию, дифференцировку, выжива-ние и гибель клетки [2].…”