Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Saito S, Nakashima A, Shima T, Ito M (2010) Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 63:601–610

    Article  CAS  PubMed  Google Scholar 

  2. Knippen MA (2011) Michroquimerism: sharing genes in illness and in health. Intern Scholar Res Net. doi:10.5402/2011/893819

    Google Scholar 

  3. Trussell J, Lalla A, Doan Q, Reyes E, Pinto L, Gricar J (2009) Cost effectiveness of contraceptives in the United States. Contraception 79:5–14

    Article  PubMed  Google Scholar 

  4. Skorpen CG, Hoelzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C et al (2016) The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 75:795–810

    Article  CAS  Google Scholar 

  5. Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K et al (2016) BSR and BHPR guidelines on prescribing drugs in pregnancy and breastfeeding—part I: standart and buiologic disease –modifying anti-rheumatic drugs and corticosteroids. Rheumatology. doi:10.1093/rheumatology/kev404

    Google Scholar 

  6. Majetschak M, Obertacke U, Schade FU, Bardenheuer M, Voggenreiter G, Bloemeke B et al (2002) Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin Diagn Lab Immunol 9:1205–1211

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65

    Article  CAS  PubMed  Google Scholar 

  8. Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635

    Article  CAS  PubMed  Google Scholar 

  9. Brogin Moreli J, Cirino Ruocco AM, Vernini JM, Rudge MV, Calderon IM (2012) Interleukin 10 and tumor necrosis factor-alpha in pregnancy: aspects of interest in clinical obstetrics. Obstet Gynecol 2012:230742

    Google Scholar 

  10. Alijotas-Reig J (2009) Immunological puzzle related to recurrent miscarriage: overview. Curr Immunol Rev 5:175–186

    Article  CAS  Google Scholar 

  11. Alijotas-Reig J, Llurba E, Gris JM (2014) Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta 35:241–248

    Article  CAS  PubMed  Google Scholar 

  12. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M et al (2010) Programmed death-1-induced interleukin-10 production by monocytes impairs CD4 + T cell activation during HIV infection. Nature Med 16:452–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM et al (1999) Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod 14:2386–2391

    Article  CAS  PubMed  Google Scholar 

  14. Banerjee P, Jana SK, Pasricha P, Ghosh S, Chakravarty B, Chaudhury K (2013) Proinflammatory cytokines induced altered expression of cylcooxigenase 2 gene results in unreceptive endometrium in women with idiopathic spontaneous miscarriage. Fertil Steril 99:179–187

    Article  CAS  PubMed  Google Scholar 

  15. Wedekind L, Belkacemi L (2016) Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development. J Diabetes Complicat. doi:10.1016/j.jdiacomp.2016.05.011

    PubMed  Google Scholar 

  16. Coughlan MT, Oliva K, Georgion HM, Permezel JMH, Rice GE (2001) Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabet Med 18:921–927

    Article  CAS  PubMed  Google Scholar 

  17. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-Presley L (2002) Friedman JE. Diabetes 51:2207–2213

    Article  CAS  PubMed  Google Scholar 

  18. Moreli JB, Corrêa-Silva S, Damasceno DC, Sinzato YK, Lorenzon-Ojea AR, Borbely AU (2015) Changes in the TNF-alpha/IL-10 ratio in hyperglycemia-associated pregnancies. Diabetes Res Clin Pract 107:362–369

    Article  CAS  PubMed  Google Scholar 

  19. Berman J, Girardi G, Salmon JE (2005) TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 174:1222–1226

    Article  Google Scholar 

  20. Yuan J, Li J, Huang SY, Sun X (2015) Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol 110:81–88

    Article  CAS  PubMed  Google Scholar 

  21. Peraçoli JC, Rudge MVC, Perçoli MTS (2007) Tumor necrosis factor-alpha in gestation and puerperium of women with gestational hypertension and pre-eclampsia. Am J Reprod Immunol 57:177–185

    Article  PubMed  CAS  Google Scholar 

  22. James DG, Williams WJ (1985) Sarcoidosis and other granulomatous disorders. In: Smith LLH (ed) Major problems in internal medicine, vol 24. W.B. Saunders Co, Philadelphia, pp 1–254

    Google Scholar 

  23. Rynes RI (1993) Antimalarial drugs. In: Kelley WN, Harris ED, Ruddyn S, Sledge CB (eds) Textbook of rheumatology [4th edition]. W.B. Saunders, Philadelphia, pp 731–742

    Google Scholar 

  24. Alijotas-Reig J (2013) Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 22:6–17

    Article  CAS  PubMed  Google Scholar 

  25. Alijotas-Reig J, Ferrer-Oliveras R, Ruffatti A, Tincani A, Lefkou E, Bertero MT et al (2015) The European registry on obstetric antiphospholipid syndrome (EUROAPS): a survey of 247 consecutive cases. Autoimmun Rev 14:387–395

    Article  PubMed  Google Scholar 

  26. Mekinian A, Costedoat-Chalumeau N, Masseau A, Tincani A, De Caroli S, Alijotas-Reig J et al (2015) Obstetrical APS: is there a place for hydroxychloroquine to improve the pregnancy outcome? Autoimmun Rev 14:23–29

    Article  CAS  PubMed  Google Scholar 

  27. Ruffatti A, Salvan E, Del Ross T, Gerosa M, Andreoli L, Alijotas-Reig J et al (2014) Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicentre retrospective study. Thromb Haemost 112:727–735 Erratum in: Thromb Haemost. 2014 Dec;112

    Article  PubMed  Google Scholar 

  28. Espinola RG, Pierangeli SS, Gharavi AE, Harris EN (2002) Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholid antibodies. Thromb Haemost 87:518–522

    CAS  PubMed  Google Scholar 

  29. Edwards MH, Pierangeli SS, Liu X, Barker JH, Anderson G, Harris EN (1997) Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 96:4380–4384

    Article  CAS  PubMed  Google Scholar 

  30. Ruiz-Irastorza G, Khamashta MA (2011) Lupus and pregnancy: integrating clues from the bench and bedside. Eur J Clin Investig 41:672–678

    Article  Google Scholar 

  31. Wozniacka A, Lesiak A, Narbutt JM, McCauliffe DP, Sysa-Jedrzejowska A (2006) Chloroquine treatment influences proinflammatory cytokine level in systemic lupus erythematosus patients. Lupus 15:268–275

    Article  CAS  PubMed  Google Scholar 

  32. Mangubat CP, Thaker PP, Cavalcante M (2001) Etanercept and immune treatment in multiple IVF failures. Am J Reprod Immunol 45:24

    Google Scholar 

  33. Chaouat G, Assal-Meliani A, Martal J, Raghupathy R, Elliott JF, Mosmann T et al (1995) IL-10 prevents naturally occurring fetal loss in the CBAxDBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau. J Immunol 154:426–428

    Google Scholar 

  34. Zhong XH, Shi WY, Ma AT, Gong XC, Zhai XH, Zhang T et al (2008) Efects of Radix scutellariae and Rhizoma atractylodis on LPS-induced abortion and the uterine IL-10 contents in mice. Am J Chin Med 36:141–148

    Article  CAS  PubMed  Google Scholar 

  35. Shaw SM, Shah MKH, Williams SG, Fildes JE (2009) Immunological mechanisms of pentoxifylline in chronic heart failure. Eur J Heart Fail 11:113–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu D, Song H, Li Y, Shi G (2012) Pentoxifylline for endometriosis. Cochrane Database Syst Rev 1:CD007677

    PubMed  Google Scholar 

  37. Creus M, Fabregues F, Carmona F, del Pino M, Manau D, Balasch J (2008) Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial. Hum Reprod 23:1910–1916

    Article  CAS  PubMed  Google Scholar 

  38. Bick RL (2001) Antiphospholipid thrombosis syndromes. Clin Appl Thromb Hemost 7:241–258

    Article  CAS  PubMed  Google Scholar 

  39. Letur-Konirsch H, Delanian S (2003) Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with prematureovarian failure who are resistant to hormobe replacement therapy. Fertil Steril 79:439–441

    Article  PubMed  Google Scholar 

  40. Nurmohamed MT, Dijkmans BA (2005) Efficacy, tolerability and cost effectiveness of diseases-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis. Drugs 65:661–694

    Article  CAS  PubMed  Google Scholar 

  41. Ramos-Casals M, Brito-Zeron P, Muñoz S, Soria N, Galiana D, Bertolaccini L et al (2007) Autoimmune diseases induced by TNF-targeted therapies. Medicine (Baltimore) 86:242–251

    Article  Google Scholar 

  42. Idriss HT, Naismith JH (2000) TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50:184–195

    Article  CAS  PubMed  Google Scholar 

  43. Mukai Y, Shibata H, Nakamura T, Yoshioka Y, Abe Y, Nomura T et al (2009) Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant. J Mol Biol 385:1221–1229

    Article  CAS  PubMed  Google Scholar 

  44. Conti F, Ceccarelli L, Massaro E, Cipriano M, Di Franco C, Alessandri FR et al (2013) Biological therapies in rheumatic diseases. Clin Ter 164:e413–e428

    CAS  PubMed  Google Scholar 

  45. Alijotas-Reig J, Vilardell-Tarrés M (2010) Is obstetric antiphospholipid syndrome a primary non-thrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies? Obstet Gynecol Surv 65:39–45

    Article  PubMed  Google Scholar 

  46. Meroni PL, Borghi MO, Raschi E et al (2011) Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 7:330–339

    Article  CAS  PubMed  Google Scholar 

  47. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R (2016) Treating pregnant women with systemic rheumatic or autoimmune disease with immunosuppressive and biologic drugs. Med Clin (Barc). doi:10.1016/j.medcli.2016.05.020

    Google Scholar 

  48. Papagoras C, Voulgari PV, Drosos AA (2015) Golimumab, the newest TNF-α blocker, comes of age. Clin Exp Rheumatol 33:570–577

    PubMed  Google Scholar 

  49. Cetrone M, Parisi G, Tricarico D, Pierri CL, Bossis F, Punzi G, De Grassi A (2016) Molecular modeling of antibodies for the treatment of TNF α -related immunological diseases. Pharmacol Res Perspect 4:e00197. doi:10.1002/prp2.197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. de Fidelix TS, Vieira LA, de Freitas D, Trevisani VF (2015) Biologic therapy for refractory scleritis: a new treatment perspective. Int Ophthalmol 35:903–912

    Article  PubMed  Google Scholar 

  51. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285 Erratum in: JAMA. 2006 Jun 7;295(21):2482

    Article  CAS  PubMed  Google Scholar 

  52. Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, Lioté F, Goeb V et al (2009) Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 76:28–34

    Article  CAS  PubMed  Google Scholar 

  53. Salmon JE, Alpert D (2006) Are we coming to terms with tumor necrosis factor inhibition in pregnancy? Arthritis Rheum 54:2353–2355

    Article  CAS  PubMed  Google Scholar 

  54. Rosner I, Haddad A, Boulman N, Feld J, Avshovich N, Slobodin G et al (2007) Pregnancy in rheumatology patients exposed to anti-tumor [TNF]-alpha therapy. Rheumatology 46:1508–1509

    Article  CAS  PubMed  Google Scholar 

  55. Mozaffari S, Abdolghaffari AH, Nikfar S, Abdollahi M (2015) Pregnancy outcomes in women with inflammatory bowel disease following exposure to thiopurines and antitumor necrosis factor drugs: a systematic review with meta-analysis. Hum Exp Toxicol 34:445–459

    Article  CAS  PubMed  Google Scholar 

  56. Bank LHB (2002) Unexpected dramatic clinical response of psoriasis lesions and unexpected pregnancy in an infertile patient in response to treatment with anti-tumor necrosis factor monoclonal antibody for Crohn’s disease. Am J Gastroenterol 97:S260

    Article  Google Scholar 

  57. Ostensen M, Lockshin M, Doria A, Valesini G, Meroni PL, Gordon C et al (2008) Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology 47:iii28–iii31

    Article  PubMed  Google Scholar 

  58. Clowse ME, Wolf DC, Förger F, Cush FJ, Go A, Shaughnessy L (2015) Pregnancy outcomes in subjects exposed to certolizumab pegol. J Rheumatol. doi:10.3899/jrheum.140189

    PubMed  Google Scholar 

  59. Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA (2008) Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol 22:847–861

    Article  CAS  PubMed  Google Scholar 

  60. Kolarz B, Madjan M, Darmochwal-Kolarz DA, Dryglewska M (2014) Antihpospholipid antibodies during 6-months treatment with infliximab: a preliminary report. Med Sci Mionit 20:1227–1231

    Article  CAS  Google Scholar 

  61. Winger EE, Reed JL, Ashoush S, Ahuja El-Toukhy T, Taranisi M (2009) Treatment with adalimumab [HumiraR] and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol 61:113–120

    Article  CAS  PubMed  Google Scholar 

  62. Winger EE, Reed JL (2008) Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves live birth rates in women with recurent spontaneous abortion. Am J Reprod Immunol 60:8–16

    Article  CAS  PubMed  Google Scholar 

  63. Deeks ED (2013) Certolizumab pegol. Review of its use in the rheumatoid arthritis treatment. Drugs 73:75–97

    Article  CAS  PubMed  Google Scholar 

  64. Simister NE, Story CM (1997) Human placental Fc receptors and the transmission of antibodies from mother to fetus. J Reprod Immunol 37:1–23

    Article  CAS  PubMed  Google Scholar 

  65. Leroy C, Rigot JM, Leroy M, Decanter C, Le Mapihan K, Parent AS et al (2015) Immunosuppressive drugs and fertility. Orphan J Rare Dis 10:136. doi:10.1186/s13023-015-0332-8

    Article  Google Scholar 

  66. Micu M, Micu R, Surd S, Girlovanu M, Bolboaca S, Ostensen M (2014) TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology 53:1250–1255

    Article  CAS  PubMed  Google Scholar 

  67. Wallenius M, Lie E, Daltveit AK, Salvesen KA, Skomsvoll JF, Kasltad S et al (2015) No excess risks in offspring with paternal preconception exposure to disease-modifying antirheumatic drugs. Arthritis Rheum 67:296–301

    Article  CAS  Google Scholar 

  68. McConell RA, Mahadevan U (2016) Use of immunomodulators and biologics before, during and after pregnancy. Inflamm Bowel Dis 22:213–223

    Article  Google Scholar 

  69. Kavanaugh A, Cush J, Ahmed M, Bermas BL, Chakravarty E, Chambers C et al (2015) Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and systemic inflammatory diseases. Arthritis Care Res 67:313–325

    Article  Google Scholar 

  70. Østensen M, Andreoli L, Brucato A, Cetin I, Chambers C, Clowse ME et al (2015) State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev 14:376–386

    Article  PubMed  Google Scholar 

  71. Alijotas-Reig J, Garrido-Gimenez C (2013) Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv 68:445–466

    Article  PubMed  Google Scholar 

  72. Practice Committee of the American Society for Reproductive Medicine (2013) Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 99:63–68

    Article  Google Scholar 

  73. Rai R, Regan L (2006) Recurrent miscarriage. Lancet 368:601–611

    Article  PubMed  Google Scholar 

  74. Greer IA, Brenner B, Gris JC (2014) Antithrombotic treatment for pregnancy complications: which path for the journey to precision medicine? Br J Haematol 165(5):585–599

    Article  PubMed  Google Scholar 

  75. Simcox LE, Ormesher L, Tower C, Greer IA (2015) Thrombophilia and pregnancy complications. Int J Mol Sci 16:28418–28428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Toth B, Jeschke U, Rogenhofer N, Scholz C, Würfel W, Thaler CJ (2010) Makrigiannakis a recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Imunol 85:25–32

    Article  CAS  Google Scholar 

  77. Rand JH (2007) The antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 136-4

  78. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 4:295–306

    Article  CAS  PubMed  Google Scholar 

  79. Levy RA, Dos Santos FC, de Jesús GR, de Jesús NR (2015) Antiphospholipid antibodies and antiphospholipid syndrome during pregnancy: diagnostic concepts. Front Immunol 6:205. doi:10.3389/fimmu.2015.00205. eCollection

  80. Esteve-Valverde E, Ferrer-Oliveras R, Alijotas-Reig J (2016) Obstetric antiphospholipid syndrome. Rev Clin Esp 216:135–145

    Article  CAS  PubMed  Google Scholar 

  81. Chighizola CB, Raschi E, Borghi MO, Meroni PL (2015) Update on the pathogenesis and treatment of the antiphospholipid syndrome. Curr Opin Rheumatol 27:476–482

    Article  CAS  PubMed  Google Scholar 

  82. Alijotas-Reig J, Ferrer-Oliveras R, EUROAPS Study Group (2012) The European registry on obstetric antiphospholipid syndrome (EUROAPS): a preliminary first year report. Lupus 21:766–768

    Article  CAS  PubMed  Google Scholar 

  83. Azizieh FY, Raghupathy RG (2015) Tumor necrosis factor-α and pregnancy complications: a prospective study. Med Princ Pract 24:165–170

    Article  PubMed  Google Scholar 

  84. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranisi M (2011a) Degree of THF-α/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with adalimumab (Humira) and IVIG. Am J Reprod Immunol 65:610–618

    Article  CAS  PubMed  Google Scholar 

  85. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taraanisi M (2011b) Birth defect rates in women using adalimumab (Humira) to treat immunologic-based infertility in IVF patients. Am J Repord Immunol 66:214–223

    Google Scholar 

  86. Alijotas-Reig J, Steve-Valverde E, Ferrer-Oliveras R, Llurba E, Mekinian A (in press) Treatment of refractory poor aPL-related obstetric outcomes with anti-TNF blockers: maternal-foetal outcomes in a series of 11 cases. J Autoimmun

  87. Llurba E, Crispi F, Verlohren S (2015) Update on the pathophysiological implications and clinical role of angiogenic factors in pregnancy. Fetal Diagn Ther 37:81–92

    Article  PubMed  Google Scholar 

  88. Harmon A, Cornelius D, Maral L, Paige A, Herse F, Ibrahim T et al (2015) IL-10 supplementation increase Tregs and decreases hypertension in the RUPP rat model of preeclampsia. Hypertens Pregnancy 34:291–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Udenze I, Amadi C, Awolola N, Makwe C (2015) The role of cytokines as inflammatory mediators in preeclampsia. Pan Afr Med J 20:219. doi:10.11604/pamj.205.20.219.5317 eCollection 2015

    PubMed  PubMed Central  Google Scholar 

  90. Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y (2007) The role of the immune system in pre-eclampsia. Mol Asp Med 28:192–209

    Article  CAS  Google Scholar 

  91. Robertson SA, Bromfield JJ, Tremellen KP (2003) Seminal ‘priming’ for protection from pre-eclampsia-a unifying hypothesis. J Reprod Immunol 59:253–265

    Article  PubMed  Google Scholar 

  92. Lai Z, Kalkunte S, Sharma S (2011) A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. Hypertension 57:505–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Reslan OM, Khalil RA (2010) Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia. Cardiovasc Hematol Agents Med Chem 8:204–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Olusi SO, Diejomaoh M, Omu A, Abdulaziz A, Prabha K, George S (2000) Interleukins in preeclampsia. Annals of Saudi Medicine 20:4–8

    Article  CAS  PubMed  Google Scholar 

  95. Afshar JT, Ghomian N, Shameli A, Shakeri M, Fahmidehkar MA, Mahajer E (2005) Determination of interleukin-6 and tumor necrosis factor-alpha concentrations in Iranian-Khorasanian patients with preeclampsia. BMC Pregnancy and Childbirth 5:14

    Article  CAS  Google Scholar 

  96. Greer IA, Lyall F, Perera T, Boswell F, Macara LM (1994) Increased concentrations of cytokines interleukin-6 and interleukin-1 receptor antagonist in plasma of women with preeclampsia: a mechanism for endothelial dysfunction? Obstet Gynaecol 84:937–940

    CAS  Google Scholar 

  97. Weel IC, Baergen RN, Romão-Veiga M, Borges VT, Ribeiro VR, Witkin SS et al (2016) Association between placental lesions, cytokines and angiogenic factors in pregnant women with preeclampsia. PLoS One 11:e0157584. doi:10.1371/journal.pone.0157584 eCollection 2016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Gomaa MF, Naguib AH, Swedan KH, Abdellatif SS (2015) Serum tumor necrosis factor-α level and uterine artery Doppler indices at 11-13 weeks’ gestation for preeclampsia screening in low-risk pregnancies: a prospective observational study. J Reprod Immunol 109:31–34

    Article  CAS  PubMed  Google Scholar 

  99. E Holanda-Moura SB, Park F, Murthi P, Martins WP, Kane SC, Williams P et al (2016) TNF-R1 as a first trimester marker for prediction of pre-eclampsia. J Matern Fetal Neonatal Med 29:897–903

    Article  PubMed  CAS  Google Scholar 

  100. Xu B, Nakhla S, Makris A, Hennessy A (2011) TNF-α inhibits trophoblast integration into endothelial cellular networks. Placenta 32:241–246

    Article  CAS  PubMed  Google Scholar 

  101. Vargas-Rojas MI, Solleiro-Villavicencio H, Soto-Vega E (2016) Th1, Th2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med 29:1642–1645

    Article  CAS  PubMed  Google Scholar 

  102. Savaj S, Vaziri D (2012) An overview of recent advances in pathogenesis and diagnosis of preeclampsia. Kidney Dis 6:334–338

    Google Scholar 

  103. Karumanchi SA (2016) Angiogenic factors in preeclampsia from diagnosis to therapy. Hypertension 67

  104. Sasser JM, Murphy SR, Granger JP (2015) Emerging drugs for preeclampsia—the endothelium as a target. Exp Opin Emerg Drugs 20:527–530

    Article  CAS  Google Scholar 

  105. Mekinian A, Cohen J, Alijotas-Reig J, Carbillon L, Nicaise-Roland P, Kayem G et al (2016) Unexplained recurrent miscarriage and recurrent implantation failure: is there a place for immunomodulation? Am J Reprod Immunol 76:8–28

    Article  CAS  PubMed  Google Scholar 

  106. Hu B, Yang J, Huang Q, Bao J, Brennecke SP, Liu H (2016) Cyclosporin a significantly improves preeclampsia signs and suppresses inflammation in a rat model. Cytokine 81:77–81

    Article  CAS  PubMed  Google Scholar 

  107. Qian L, Wang H, Wu F, Li M, Chen W, Lianzheng LV (2015) Vitamin D3 alters Toll-like receptor 4 signaling in monocytes of pregnant women at risk for preeclampsia. Int J Clin Exp Med 8:1888041–1888049

    Google Scholar 

  108. Murphy SR, LaMarca BB, Parrish M, Cockrell K, Granger JP (2013) Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-α. Am J Physiol Regul Integr Comp Physiol 304:R130–R135

    Article  CAS  PubMed  Google Scholar 

  109. Gutkowska J, Granger JP, Lamarca BB, Danalache BA, Wang D, Jankowski M (2011) Changes in cardiac structure in hypertension produced by placental ischemia in pregnant rats: effect of tumor necrosis factor blockade. J Hypertens 29:1203–1212

    Article  CAS  PubMed  Google Scholar 

  110. Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich K, BSRBR control centre consortium, BSR biologics Register (2011) Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 70:823–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nielsen OH, Loftus EV, Jess T (2013) Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Med 11:174–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cooper WO, Cheetham TC, De-Kun L, Stein M, Callahan ST, Morgan TM et al (2014) Adverse foetal outcomes associated with immunosuppressive medications for chronic immune mediated diseases in pregnancy. Arthritis Rheumatol 66:444–450

    Article  PubMed  PubMed Central  Google Scholar 

  113. Diav-Citrin O, Otcheretianski-Volodarsky A, Shechtman S, Ornoy A (2014) Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study. Reprod Toxicol 43:78–84

    Article  CAS  PubMed  Google Scholar 

  114. Mahadevan U, Martin CF, Sandler RS, Kane SV, Dubinsky M, Lewis JD (2012) PIANO: a 1,000-patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterol Hepatol 8(suppl 5):14–15

    Google Scholar 

  115. Hyrich KL, Verstappen SM (2014) Biologic therapies and pregnancy: the story so far. Rheumatology 53:1377–1385

    Article  CAS  PubMed  Google Scholar 

  116. Förger F, Villiger PM (2016) Treatment of rheumatoid arthritis during pregnancy: present and future. Expert Rev Clin Immunol 12:937–944

    Article  PubMed  CAS  Google Scholar 

  117. Cimaz R, Meregalli E, Biggioggero M, Borghi A, Tincani M, Motta M et al (2004) Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy. Toxicil Lett 149:155–162

    Article  CAS  Google Scholar 

  118. Sands K, Jansen R, Zaslau S, Greenwald D (2015) The safety of therapeutic drugs in male inflammatory bowel disease patients wishing to conceive. Aliment Pharmacol Ther. doi:10.1111/apt.13142

    Google Scholar 

  119. European Medicines Agencie (2015) CIMZIA (certulizumab pegol) EMA summary of product characteristics. Available from :www.emea.europa.eu/docs/en_GB/docuement_library/EPAR__Product_Information/human/001037/WC500069763.pdf. (Accesed 22 Sep 2015).

  120. Villiger PM, Caliezi G, Cottin V, Senn A, Østensen M (2010) Effects of TNF antagonists on sperm characteristics in patients with spondiloarthritis. Ann Rheum Dis 69:1842–1844

    Article  CAS  PubMed  Google Scholar 

  121. Begg EJ, Atkitson HC, Duffull SB (1992) Prospective evaluation of a model for the prediction of milk: plasma drug concentration from physicochemical characteristics. Br J Pharmacol 33:501–505

    Article  CAS  Google Scholar 

  122. Kane S, Ford J, Cohen R, Wagner C (2009) Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn’s disease before and after delivery. J Clin Gastroenterol 43:613–616

    Article  CAS  PubMed  Google Scholar 

  123. Ben-Horin S, Yavzori M, Kopylov U, Picard O, Fudim E, Eliakin R et al (2011) Detection of infliximab in Brest milk or nursing mothers with inflammatory bowel disease. J Crohns Cloitis 5:555–558

    Article  Google Scholar 

  124. Keeling S, Wolbink GJ (2010) Measuring multiple etanercept levels in the breast milk of a nursing mother with rheumatoid arthritis [letter]. J Rheumatol 37:1551

    Article  PubMed  Google Scholar 

  125. Berthelsen BG, Fjeldsoe-Nielsen H, Nielsen CT, Hellmuth E (2010) Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology 49:2225–2227

    Article  CAS  PubMed  Google Scholar 

  126. Ben-Horin S, Yavzori M, Katz L, Picard O, Fudim E, Chowers Y et al (2010) Adalimumab levels in breast milk of a nursing mother. Clin Gastroenterol Hepatol 8:475–476

    Article  PubMed  Google Scholar 

  127. Broussard CS, Frey MT, Hernandez-Diaz S, Green MF, Chambers CD, Sahin L et al (2014) Developing a systematic approach to safer medication use during pregnancy: summary of a centers for disease control and prevention-convened meeting. Am J Obstet Gynecol 211:208–214

    Article  PubMed  PubMed Central  Google Scholar 

  128. O’Shea JJ, Plenge R (2012) JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36:542–550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. O’Shea JJ, Husa M, Li D, Hofmann SR, Watford W, Roberts JL et al (2004) Jak3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol 41:727–737

    Article  PubMed  CAS  Google Scholar 

  130. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ et al (1995) Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797–800

    Article  CAS  PubMed  Google Scholar 

  131. Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ (2012) Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 12:464–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Markopoulou A, Kyttaris VC (2013) Small molecules in the treatment of systemic lupus erythematosus. Clin Immunol 148:359–368

    Article  CAS  PubMed  Google Scholar 

  133. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG et al (2016) Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. doi:10.1002/art.39818

    Google Scholar 

  134. Yokoyama S, Perera PY, Terawaki S, Watanabe N, Kaminuma O, Waldmann TA et al (2015) Janus kinase inhibitor tofacitinib shows potent efficacy in a mouse model of autoimmune lymphoproliferative syndrome (ALPS). J Clin Immunol 35:661–667

    Article  CAS  PubMed  Google Scholar 

  135. Miscia S, Marchisio M, Grilli A, Di Valerio V, Centurione L, Sabatino G (2002) Tumor necrosis factor alpha (TNF-alpha) activates Jak1/Stat3-Stat5B signaling through TNFR-1 in human B cells. Cell Growth Differ 13:13–18

    CAS  PubMed  Google Scholar 

  136. Taylor DD, Bohler HC, Gercel-Taylor C (2006) Pregnancy-linked suppression of TcR signaling pathways by a circulating factor absent in recurrent spontaneous pregnancy loss. Mol Immunol 43:1872–1880

    Article  CAS  PubMed  Google Scholar 

  137. von Versen-Höynck FI, Rajakumar A, Parrott MS, Powera RW (2009) Leptin affects system A amino acid transport activity in the human placenta: evidence for STAT3 dependent mechanisms. Placenta 30:361–367

  138. Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O’Shea JJ (2008) Therapeutic targeting of Janus kinases. Immunolo Rev 223:132–142

    Article  CAS  Google Scholar 

  139. Henriques C (2016) AbbVie launches phase 3 trial for rheumatoid arthritis. Rheumatoid Arthritis News. BioNews Services, LLC. Retrieved 16 July 2016

  140. Cai J, Li M, Huang Q, Fu X, Wu H (2016) Differences in cytokine expression and STAT3 activation between healthy controls and patients of unexplained recurrent spontaneous abortion (URSA) during early pregnancy. PLoS One 11:e0163252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Gathiram P, Moodley J (2016) Pre-eclampsia: its pathogenesis and pathophysiology. Cardiovasc J Afr 27:71–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Liang Z, Zhu J, Wang Y, Wang Y, Zhang Y, Lin J, Di W (2014) Three transcription factors and the way immune cells affected by different plasma change in opposite ways in the development of the syndrome of pre-eclampsia. Chin Med J 127:2252–2258

    CAS  PubMed  Google Scholar 

  143. Ferreira DG, Cavalhieri LT, Ventura AC, Aires FT, Garcia JM, Mesquita MR et al (2012l) The role of the JAK-STAT pathways and SOCS in preeclampsia. Pregnancy Hypertens 2:338–339

    CAS  PubMed  Google Scholar 

  144. Cheng SB, Sharma S (2015) Interleukin-10: a pleiotropic regulator in pregnancy. Am J Reoprod Immunol 73:487–500

    Article  CAS  Google Scholar 

  145. Yin N, Zhang H, Luo X, Ding Y, Xiao X, Liu X et al (2014) IL-27 activates human trophoblasts to express IP-10 and IL-6: implications in the immunopathophysiology of preeclampsia. Mediat Inflamm 2014:926875

    Article  CAS  Google Scholar 

  146. Eastabrook GD, Hu Y, Tan R, Dutz JP, Maccalman CD, von Dadelszen P (2012) Decidual NK cell-derived conditioned medium (dNK-CM) mediates VEGF-C secretion in extravillous cytotrophoblasts. Am J Reprod Immunol 67:101–111

    Article  CAS  PubMed  Google Scholar 

  147. Ernst M, Inglese M, Waring P, Campbell IK, Bao S, Caly FJ (2001) Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med 194:189–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nakamura H, Kimura T, Koyama S, Ogita K, Tsutsui T, Shimoya T et al (2006) Mouse model of human infertility: transient and local inhibition of endometrial STAT-3 activation results in implantation failure. FEBS Lett 580:2717–2722

    Article  CAS  PubMed  Google Scholar 

  149. Albaghdadi AJH, Kan FWK (2012) Endometrial receptivity defects and impaired implantation in diabetic NOD mice. Biol Reprod 87:30. doi:10.1095/biolprepod.112.100016

    Article  PubMed  PubMed Central  Google Scholar 

  150. Sun X, Bartos A, Whitsett JA, Dey SK (2013) Uterine deletion of gp130 or STAST3 shows implantation failure with increased estrogenic responses. Mol Endocrinol 27:1492–1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Choi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS et al (2016) Integrative analyses of uterine transcriptome and MicroRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent/repeated implantation failure (RIF). PLoS One 11:e0157696

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. D’Ippolito S, Marana R, Di Nicuolo F, Castellani R, Veglia M, Stinson J et al (2012) Effect of low molecular weight heparins (LMWHs) on antiphospholipid antibodies (aPL)-mediated inhibition of endometrial angiogenesis. PLoS One 7:e29660

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Jaume Alijotas-Reig

  2. Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Jaume Alijotas-Reig

  3. Department of Internal Medicine, Althaia Network Health, Manresa, Barcelona, Spain

    Enrique Esteve-Valverde

  4. Obstetric High Risk Unit, Obstetric Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

    Raquel Ferrer-Oliveras

  5. Obstetric High Risk Unit, Obstetric Department, Vall d’Hebron University Hospital, Barcelona, Spain

    Elisa Llurba

  6. Pediatric, Obstetric and Gynecology Department, Universitat Autònoma de Barcelona, Barcelona, Spain

    Elisa Llurba

  7. Reproductive Medicine Unit, Obstetric Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

    Josep Maria Gris

Authors
  1. Jaume Alijotas-Reig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Enrique Esteve-Valverde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raquel Ferrer-Oliveras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elisa Llurba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josep Maria Gris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaume Alijotas-Reig.

Ethics declarations

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.

Funding

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alijotas-Reig, J., Esteve-Valverde, E., Ferrer-Oliveras, R. et al. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clinic Rev Allerg Immunol 53, 40–53 (2017). https://doi.org/10.1007/s12016-016-8596-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-016-8596-x

Keywords

Search

Navigation