Clinical Reviews in Allergy & Immunology

, Volume 53, Issue 1, pp 40–53 | Cite as

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

  • Jaume Alijotas-ReigEmail author
  • Enrique Esteve-Valverde
  • Raquel Ferrer-Oliveras
  • Elisa Llurba
  • Josep Maria Gris


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.


Antiphospholipid syndrome Implantation failure JAK-STAT Pre-eclampsia Recurrent abortion Th1-cytokines TNF-α blockers 



The authors thank Ms. Christine O’Hara for reviewing and correcting the style and grammar of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The author also state that they do not have any commercial or any other type of interest that may have influenced the drawing up and the results of this paper.


There is no funding source.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human participants or animals performed by any of the authors.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Jaume Alijotas-Reig
    • 1
    • 2
    Email author
  • Enrique Esteve-Valverde
    • 3
  • Raquel Ferrer-Oliveras
    • 4
  • Elisa Llurba
    • 5
    • 6
  • Josep Maria Gris
    • 7
  1. 1.Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1Vall d’Hebron University HospitalBarcelonaSpain
  2. 2.Department of Medicine, Faculty of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Department of Internal MedicineAlthaia Network HealthManresaSpain
  4. 4.Obstetric High Risk Unit, Obstetric DepartmentVall d’Hebron University Hospital, Universitat Autònoma de BarcelonaBarcelonaSpain
  5. 5.Obstetric High Risk Unit, Obstetric DepartmentVall d’Hebron University HospitalBarcelonaSpain
  6. 6.Pediatric, Obstetric and Gynecology DepartmentUniversitat Autònoma de BarcelonaBarcelonaSpain
  7. 7.Reproductive Medicine Unit, Obstetric DepartmentVall d’Hebron University Hospital, Universitat Autònoma de BarcelonaBarcelonaSpain

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