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A Pharmacological Approach to Managing Inflammatory Bowel Disease During Conception, Pregnancy and Breastfeeding: Biologic and Oral Small Molecule Therapy

  • Sherman Picardo
  • Cynthia H. SeowEmail author
Review Article
  • 100 Downloads

Abstract

The inflammatory bowel diseases commonly affect individuals during their peak reproductive years. Patients are often concerned about the impact of medical therapies on their ability to conceive, effect on the fetus, as well as the ability to breastfeed, which has led to poor medical adherence during pregnancy. However, most medications are safe, and discontinuation may lead to active disease, which is associated with adverse materno-fetal outcomes. The anti-TNF biologic therapies, infliximab and adalimumab have been extensively studied in the context of pregnancy. They are actively transferred to the placenta during the second and third trimesters; these have not been associated with an increased rate of congenital abnormalities or fetal death. The minimal amounts of drug that are transferred to breast milk are proteolyzed by the infant’s digestive system with no reported short- or long-term adverse effects. There is a paucity of clinical data for the other approved anti-TNF agents or newer anti-integrin (vedolizumab) and anti-interleukin (ustekinumab) therapies used in the management of inflammatory bowel disease; however, no significant safety signals have been documented thus far. The new oral small molecule therapy, tofacitinib is teratogenic in animal models and is contra-indicated in patients attempting pregnancy. It is important that patients, as well as physicians managing patients with these conditions, be aware of the impact of these medical therapies during pregnancy.

Notes

Compliance with Ethical Standards

Funding

No sources of funding were used to support the writing of this manuscript.

Conflict of interest

Cynthia Seow has received funds from Janssen, AbbVie, Takeda, Ferring, Shire and Pfizer for participating in speakers’ bureaus, advisory boards, educational events, grants and for travel to associated meetings. No company had direct input into this manuscript. Sherman Picardo has no conflicts of interest to declare.

References

  1. 1.
    Langholz E. Current trends in inflammatory bowel disease: the natural history. Ther Adv Gastroenterol. 2010;3:77–86.CrossRefGoogle Scholar
  2. 2.
    Heetun ZS, Byrnes C, Neary P, O’Morain C. Review article: reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther. 2007;26:513–33.CrossRefPubMedGoogle Scholar
  3. 3.
    Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut. 2007;56:830–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Bröms G, Granath F, Linder M, Stephansson O, Elmberg M, Kieler H. Birth outcomes in women with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:1.CrossRefGoogle Scholar
  5. 5.
    Ujihara M, Ando T, Ishiguro K, Maeda O, Watanabe O, Hirayama Y, et al. Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis. BMC Res Notes. 2013;6:210.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    de Lima-Karagiannis A, Zelinkova-Detkova Z, van der Woude CJ. The effects of active IBD during pregnancy in the era of novel IBD therapies. Am J Gastroenterol. 2016;111(9):1305–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Kammerlander H, Nielsen J, Kjeldsen J, Knudsen T, Friedman S, Nørgård B. The effect of disease activity on birth outcomes in a nationwide cohort of women with moderate to severe inflammatory bowel disease. Inflamm Bowel Dis. 2017;23:1011–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Gallinger ZR, Rumman A, Nguyen GC. Perceptions and attitudes towards medication adherence during pregnancy in inflammatory bowel disease. J Crohns Colitis. 2016;10:892–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Huang VW-M, Chang H-J, Kroeker KI, Goodman KJ, Hegadoren KM, Dieleman LA, et al. Management of inflammatory bowel disease during pregnancy and breastfeeding varies widely: a need for further education. Can J Gastroenterol Hepatol. 2016;2016:6193275.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lever E, Sheer D. The role of nuclear organization in cancer. J Pathol. 2010;220:114–25.PubMedGoogle Scholar
  11. 11.
    Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet (London, England). 1992;339:89–91.CrossRefGoogle Scholar
  12. 12.
    MacDonald TT, Hutchings P, Choy M-Y, Murch S, Cooke A. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol. 1990;81(2):301–5.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chaparro M, Verreth A, Lobaton T, Gravito-Soares E, Julsgaard M, Savarino E, et al. Long-term safety of in utero exposure to anti-TNFα drugs for the treatment of inflammatory bowel disease: results from the Multicenter European TEDDY Study. Am J Gastroenterol. 2018;113:396–403.CrossRefPubMedGoogle Scholar
  14. 14.
    Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol. 1993;30:1443–53.CrossRefPubMedGoogle Scholar
  15. 15.
    Targan SR, Hanauer SB, van Deventer SJH, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med. 1997;337(15):1029–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet (London, England). 2002;359:1541–9.CrossRefGoogle Scholar
  17. 17.
    Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMedGoogle Scholar
  18. 18.
    Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646.  https://doi.org/10.1155/2012/985646.CrossRefPubMedGoogle Scholar
  19. 19.
    Malek A, Sager R, Schneider H. Transport of proteins across the human placenta. Am J Reprod Immunol. 1998;40:347–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286–92.  https://doi.org/10.1016/j.cgh.2012.11.011 (quiz e24).CrossRefPubMedGoogle Scholar
  21. 21.
    Julsgaard M, Christensen LA, Gibson PR, Gearry RB, Fallingborg J, Hvas CL, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology. 2016;151:110–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Seow CH, Leung Y, Vande Casteele N, Ehteshami Afshar E, Tanyingoh D, Bindra G, et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1329–38.CrossRefPubMedGoogle Scholar
  23. 23.
    de Lima A, Zelinkova Z, van der Ent C, Steegers EAP, van der Woude CJ. Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety. Gut. 2016;65:1261–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol. 2004;99:2385–92.CrossRefPubMedGoogle Scholar
  25. 25.
    Mahadevan U, Martin CFSR. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142:149.CrossRefGoogle Scholar
  26. 26.
    Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107(9):1409–22.  https://doi.org/10.1038/ajg.2012.218.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Deepak P, Stobaugh DJ. Maternal and foetal adverse events with tumour necrosis factor-alpha inhibitors in inflammatory bowel disease. Aliment Pharmacol Ther. 2014;40:1035–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Schnitzler F, Fidder H, Ferrante M, Ballet V, Noman M, Van Assche G, et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy. Inflamm Bowel Dis. 2011;17:1846–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Seirafi M, de Vroey B, Amiot A, Seksik P, Roblin X, Allez M, et al. Factors associated with pregnancy outcome in anti-TNF treated women with inflammatory bowel disease. Aliment Pharmacol Ther. 2014;40:363–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Shihab Z, Yeomans ND, De Cruz P. Anti-tumour necrosis factor α therapies and inflammatory bowel disease pregnancy outcomes: a meta-analysis. J Crohns Colitis. 2016;10:979–88.CrossRefPubMedGoogle Scholar
  31. 31.
    Narula N, Al-Dabbagh R, Dhillon A, Sands BE, Marshall JK. Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:1862–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Truta B, Canner J, Efron J, Safar B. The effect of intrauterine exposure to biologics: two years follow up. Gastroenterology. 2016;150:S773.CrossRefGoogle Scholar
  33. 33.
    Mahadevan U, Martin CF, Chambers C, Kane SV, Dubinsky M, Sandborn W, et al. Achievement of developmental milestones among offspring of women with inflammatory bowel disease: the PIANO Registry. Gastroenterology. 2014;146:S-1.CrossRefGoogle Scholar
  34. 34.
    Chaparro M, Verreth A, Lobaton T, Gravito-Soares E, Julsgaard M, Savarino E, et al. Long-term safety of in utero exposure to anti-TNFα drugs for the treatment of inflammatory bowel disease: results from the multicenter European TEDDY study. Am J Gastroenterol. 2018;113(3):396–403.  https://doi.org/10.1038/ajg.2017.501.CrossRefPubMedGoogle Scholar
  35. 35.
    Luu M, Benzenine E, Doret M, Michiels C, Barkun A, Degand T, et al. Continuous anti-TNFα use throughout pregnancy: possible complications for the mother but not for the fetus. A retrospective cohort on the French national health insurance database (EVASION). Am J Gastroenterol. 2018;113:1669–77.CrossRefPubMedGoogle Scholar
  36. 36.
    van der Woude CJ, Ardizzone S, Bengtson MB, Fiorino G, Fraser G, Katsanos K, et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015;9:107–24.CrossRefPubMedGoogle Scholar
  37. 37.
    Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Nguyen GC, Seow CH, Maxwell C, Huang V, Leung Y, Jones J, et al. The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology. 2016;150:734–757e1.CrossRefPubMedGoogle Scholar
  39. 39.
    Mahadevan U, Terdiman JP, Aron J, Jacobsohn S, Turek P. Infliximab and semen quality in men with inflammatory bowel disease. Inflamm Bowel Dis. 2005;11(4):395–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Ramonda R, Foresta C, Ortolan A, Bertoldo A, Oliviero F, Lorenzin M, et al. Influence of tumor necrosis factor α inhibitors on testicular function and semen in spondyloarthritis patients. Fertil Steril. 2014;101(2):359–65.  https://doi.org/10.1016/j.fertnstert.2013.10.048.CrossRefPubMedGoogle Scholar
  41. 41.
    Villiger PM, Caliezi G, Cottin V, Forger F, Senn A, Ostensen M. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis. 2010;69:1842–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Paschou S, Voulgari PV, Vrabie IG, Saougou IG, Drosos AA. Fertility and reproduction in male patients with ankylosing spondylitis treated with infliximab. J Rheumatol. 2009;36:351–4.CrossRefPubMedGoogle Scholar
  43. 43.
    Gisbert JP, Chaparro M. Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease. Am J Gastroenterol. 2013;108:1426–38.CrossRefPubMedGoogle Scholar
  44. 44.
    Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure concentrations of infants breastfed by women receiving biologic therapies for inflammatory bowel diseases and effects of breastfeeding on infections and development. Gastroenterology. 2018;155:696–704.CrossRefPubMedGoogle Scholar
  45. 45.
    Mahadevan U, Martin CF, Sandler RS, Kane SV, Dubinsky M, Lewis JD, et al. 865 PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142:S-149.CrossRefGoogle Scholar
  46. 46.
    Kane S, Lemieux N. The role of breastfeeding in postpartum disease activity in women with inflammatory bowel disease. Am J Gastroenterol. 2005;100:102–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Guidi L, Pugliese D, Armuzzi A. Update on the management of inflammatory bowel disease: specific role of adalimumab. Clin Exp Gastroenterol. 2011;4:163–72.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323–33 (quiz 591).CrossRefPubMedGoogle Scholar
  49. 49.
    Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Colombel J-F, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.CrossRefPubMedGoogle Scholar
  51. 51.
    Sandborn WJ, van Assche G, Reinisch W, Colombel J, D’Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–265.e1-3.CrossRefPubMedGoogle Scholar
  52. 52.
    Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti–tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:286–92.CrossRefPubMedGoogle Scholar
  53. 53.
    Kanis SL, De Lima-Karagiannis A, Van Der Ent C, Rizopoulos D, Van Der Woude CJ. Anti-TNF levels in cord blood at birth are associated with anti-TNF type. J Crohn’s Colitis. 2018;12(8):939–47.  https://doi.org/10.1093/ecco-jcc/jjy058.CrossRefGoogle Scholar
  54. 54.
    Johnson D, Jones K, Chambers C. Pregnancy outcomes in women exposed to adalimumab: the OTIS autoimmune diseases in pregnancy project. Gastroenterology. 2009;136(5) Supplement 1. Abstract 142.Google Scholar
  55. 55.
    Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the food and drug administration database. J Rheumatol. 2009;36:635–41.CrossRefPubMedGoogle Scholar
  56. 56.
    van den Broek L, van der Werff-Ten Bosch J, Cortoos P-J, van Steijn S, van den Akker M. Severe neutropenia in a breastfed infant: a case report and discussion of the differential diagnosis. Int Med Case Rep J. 2018;11:333–7.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ben-Horin S, Yavzori M, Katz L, Picard O, Fudim E, Chowers Y, et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol. 2010;8:475–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85–95.  https://doi.org/10.1053/j.gastro.2013.05.048 (quiz e14-5).CrossRefPubMedGoogle Scholar
  59. 59.
    Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(96–109):e1.Google Scholar
  60. 60.
    Dragoni G, Le Grazie M, Orlandini B, Rogai F. Golimumab in inflammatory bowel diseases: present and future scenarios. Clin J Gastroenterol. 2019;12(1):1–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Greener T, Boland K, Steinhart AH, Silverberg MS. The unfinished symphony: golimumab therapy for anti-tumour necrosis factor refractory Crohn’s disease. J Crohn’s Colitis. 2018;12:458–64.CrossRefGoogle Scholar
  62. 62.
    Benoit L, Mir O, Berveiller P. Treating ulcerative colitis during pregnancy: evidence of materno–fetal transfer of golimumab. J Crohn’s Colitis. 2018.  https://doi.org/10.1093/ecco-jcc/jjy192.CrossRefGoogle Scholar
  63. 63.
    Lau A, Clark M, Harrison D, Geldhof A, Nissinen R, Sanders M. 2013 Annual meeting abstract supplement. Arthritis Rheum. 2013;65:S1–1331.CrossRefGoogle Scholar
  64. 64.
    Nesbitt A, Fossati G, Bergin M, Stephens P, Stephens S, Foulkes R, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor α agents. Inflamm Bowel Dis. 2007;13:1323–32.CrossRefPubMedGoogle Scholar
  65. 65.
    Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38.CrossRefPubMedGoogle Scholar
  66. 66.
    Porter C, Armstrong-Fisher S, Kopotsha T, Smith B, Baker T, Kevorkian L, et al. Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer. J Reprod Immunol. 2016;116:7–12.CrossRefPubMedGoogle Scholar
  67. 67.
    Mariette X, Förger F, Abraham B, Flynn AD, Moltó A, Flipo RM, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2):228–33.  https://doi.org/10.1136/annrheumdis-2017-212196.CrossRefPubMedGoogle Scholar
  68. 68.
    Clowse MEB, Scheuerle AE, Chambers C, Afzali A, Kimball AB, Cush JJ, et al. Pregnancy outcomes after exposure to certolizumab pegol: updated results from a pharmacovigilance safety database. Arthritis Rheumatol (Hoboken, NJ). 2018;70:1399–407.CrossRefGoogle Scholar
  69. 69.
    Clowse MEB, Wolf DC, Förger F, Cush JJ, Golembesky A, Shaughnessy L, et al. Pregnancy outcomes in subjects exposed to certolizumab pegol. J Rheumatol. 2015;42:2270–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Clowse ME, Förger F, Hwang C, Thorp J, Dolhain RJ, van Tubergen A, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017;76:1890–6.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89.CrossRefPubMedGoogle Scholar
  72. 72.
    Ghosh S, Panaccione R. Anti-adhesion molecule therapy for inflammatory bowel disease. Gastroenterol: Ther Adv; 2010.CrossRefGoogle Scholar
  73. 73.
    Binion DG, West GA, Ina K, Ziats NP, Emancipator SN, Fiocchi C. Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology. 1997;112(6):1895–907.CrossRefPubMedGoogle Scholar
  74. 74.
    Park SC, Jeen YT. Anti-integrin therapy for inflammatory bowel disease. World J Gastroenterol. 2018;24:1868–80.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.CrossRefPubMedGoogle Scholar
  76. 76.
    Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology. 2007;132(5):1672–83.CrossRefPubMedGoogle Scholar
  77. 77.
    Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9(4):438–46.  https://doi.org/10.1016/S1474-4422(10)70028-4.CrossRefPubMedGoogle Scholar
  78. 78.
    Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, Elias-Hamp B, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71:891–5.CrossRefPubMedGoogle Scholar
  79. 79.
    Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J. Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86:144–56.CrossRefPubMedGoogle Scholar
  80. 80.
    Ebrahimi N, Herbstritt S, Gold R, Amezcua L, Koren G, Hellwig K. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler. 2015;21:198–205.CrossRefPubMedGoogle Scholar
  81. 81.
    Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol. 2016;16:150.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Mahadevan U, Martin CF, Dubinsky M, Kane SV, Sands BE, Sandborn W. Exposure to anti-TNFα therapy in the third trimester of pregnancy is not associated with increased adverse outcomes: results from the PIANO registry. Gastroenterology. 2014;146(5, S1):S-170.  https://doi.org/10.1016/S0016-5085(14)60602-8 (abstr no A960).CrossRefGoogle Scholar
  83. 83.
    Natalizumab: PRESCRIBING INFORMATION [Internet] [cited 2019 Jan 15]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s106lbl.pdf.
  84. 84.
    Baker TE, Cooper SD, Kessler L, Hale TW. Transfer of natalizumab into breast milk in a mother with multiple sclerosis. J Hum Lact. 2015;31:233–6.CrossRefPubMedGoogle Scholar
  85. 85.
    Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.  https://doi.org/10.1056/NEJMoa1215734.CrossRefPubMedGoogle Scholar
  86. 86.
    Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.CrossRefPubMedGoogle Scholar
  87. 87.
    Sands BE, Feagan BG, Rutgeerts P, Colombel J-F, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(618–627):e3.Google Scholar
  88. 88.
    Crawford D, Friedman M. Safety analysis of vedolizumab during pregnancy: findings from a reproductive study in monkeys. J Crohn’s Colitis. 2018;12:S129.CrossRefGoogle Scholar
  89. 89.
    Mahadevan U, Martin C, Kane SV, Dubinsky M, Sands BE, Sandborn W. Do infant serum levels of biologic agents at birth correlate with risk of adverse outcomes? Results from the PIANO registry. Gastroenterology. 2016;150(4, S1):S91–S92.  https://doi.org/10.1016/S0016-5085(16)30422-X (abstr no A437).CrossRefGoogle Scholar
  90. 90.
    Mahadevan U, Vermeire S, Lasch K, Abhyankar B, Bhayat F, Blake A, et al. Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45(7):941–50.  https://doi.org/10.1111/apt.13960.CrossRefPubMedGoogle Scholar
  91. 91.
    Moens A, van Hoeve K, Humblet E, Rahier J-F, Bossuyt P, Dewit S, et al. Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab. J Crohns Colitis. 2019;13:12–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Julsgaard M, Kjeldsen J, Bibby BM, Brock B, Baumgart DC. Vedolizumab concentrations in the breast milk of nursing mothers with inflammatory bowel disease. Gastroenterology. 2018;154(752–754):e1.Google Scholar
  93. 93.
    Lahat A, Shitrit AB-G, Naftali T, Milgrom Y, Elyakim R, Goldin E, et al. Vedolizumab levels in breast milk of nursing mothers with inflammatory bowel disease. J Crohns Colitis. 2018;12:120–3.CrossRefPubMedGoogle Scholar
  94. 94.
    Jump RL, Levine AD. Mechanisms of natural tolerance in the intestine. Inflamm Bowel Dis. 2004;10:462–78.CrossRefPubMedGoogle Scholar
  95. 95.
    Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.CrossRefPubMedGoogle Scholar
  96. 96.
    Langrish CL, McKenzie BS, Wilson NJ, De Waal Malefyt R, Kastelein RA, Cua DJ. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev. 2004;202:96–105.CrossRefPubMedGoogle Scholar
  97. 97.
    Nielsen OH, Kirman I, Rüdiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol. 2003;38:180–5.CrossRefPubMedGoogle Scholar
  98. 98.
    Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–41.CrossRefPubMedGoogle Scholar
  99. 99.
    Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet (London, England). 2008;371:1675–84.CrossRefGoogle Scholar
  100. 100.
    Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.CrossRefPubMedGoogle Scholar
  101. 101.
    Scherl E, Jacobstein D, Murphy C, Ott E, Gasink C, Baumgart DC, et al. Pregnancy outcomes in women exposed to ustekinumab in the Crohn’s disease clinical development program. J Can Assoc Gastroenterol. 2018;1(S2):166.  https://doi.org/10.1093/jcag/gwy009.109 (abstr no A109).CrossRefGoogle Scholar
  102. 102.
    Huang VW. From conception to delivery: managing the pregnant inflammatory bowel disease patient. World J Gastroenterol. 2014;20:3495.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Götestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795–810.CrossRefPubMedGoogle Scholar
  104. 104.
    Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–87.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8.CrossRefPubMedGoogle Scholar
  106. 106.
    Rawlings JS. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281–3.CrossRefPubMedGoogle Scholar
  107. 107.
    Flamant M, Rigaill J, Paul S, Roblin X. Advances in the development of janus kinase inhibitors in inflammatory bowel disease: future prospects. Drugs. 2017;77:1057–68.CrossRefPubMedGoogle Scholar
  108. 108.
    Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285:1–24.CrossRefPubMedGoogle Scholar
  109. 109.
    Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60:1895–905.CrossRefPubMedGoogle Scholar
  110. 110.
    Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015;173:949–61.CrossRefPubMedGoogle Scholar
  111. 111.
    Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723–36.CrossRefPubMedGoogle Scholar
  112. 112.
    Dowty ME, Lin J, Ryder TF, Wang W, Walker GS, Vaz A, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab Dispos. 2014;42:759–73.CrossRefPubMedGoogle Scholar
  113. 113.
    Mahadevan U, Dubinsky MC, Su C, Lawendy N, Jones TV, Marren A, et al. Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerative colitis. Inflamm Bowel Dis. 2018;24:2494–500.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Tofacitinib: prescribing information [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s018lbl.pdf.
  115. 115.
    Clowse MEB, Feldman SR, Isaacs JD, Kimball AB, Strand V, Warren RB, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39:755–62.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane SV, Mahadevan U. Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines. Clin Gastroenterol Hepatol. 2018;16:99–105.CrossRefPubMedGoogle Scholar
  117. 117.
    Heller MM, Wu JJ, Murase JE. Fatal case of disseminated BCG infection after vaccination of an infant with in utero exposure to infliximab. J Am Acad Dermatol. 2011;65:870.CrossRefPubMedGoogle Scholar
  118. 118.
    van der Woude CJ, Ardizzone S, Bengtson MB, Fiorino G, Fraser G, Katsanos K, et al. The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohn’s Colitis. 2015;9:107–24.CrossRefGoogle Scholar
  119. 119.
    Mahadevan U, Cucchiara S, Hyams JS, Steinwurz F, Nuti F, Travis SPL, et al. The London position statement of the world congress of gastroenterology on biological therapy for IBD with the European Crohn’s and colitis organisation: pregnancy and pediatrics. Am J Gastroenterol. 2011;106:214–23.CrossRefPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Inflammatory Bowel Disease Centre, Division of Gastroenterology and Hepatology, Department of MedicineUniversity of CalgaryCalgaryCanada

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