title: 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.
authors.affiliation: Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. jalijotas@vhebron.net.|Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. jalijotas@vhebron.net.
authors.forename: Jaume
authors.initials: J
authors.lastname: Alijotas-Reig
authors.affiliation: Department of Internal Medicine, Althaia Network Health, Manresa, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Esteve-Valverde
authors.affiliation: Obstetric High Risk Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ferrer-Oliveras
authors.affiliation: Obstetric High Risk Unit, Obstetric Department, Vall d'Hebron University Hospital, Barcelona, Spain.|Pediatric, Obstetric and Gynecology Department, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Llurba
authors.affiliation: Reproductive Medicine Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Gris
mesh_terms: D000026:Abortion, Habitual / Q000276:immunology / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D001688:Biological Products; D016207:Cytokines / Q000378:metabolism; D010064:Embryo Implantation; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D018812:Paternal Exposure; D010431:Pentoxifylline / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000276:immunology / Q000378:metabolism; D011247:Pregnancy; D050791:STAT Transcription Factors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D001688:Biological Products; D016207:Cytokines; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D053612:Janus Kinases; D010431:Pentoxifylline
keywords: Antiphospholipid syndrome; Implantation failure; JAK-STAT; Pre-eclampsia; Recurrent abortion; TNF-α blockers; Th1-cytokines