Maternal Use of Immunostimulating or Immunosuppressive Drugs and Infant Congenital Malformations

  • Bengt Källén


Available information on the use of immunostimulating and immunosuppressive drugs during pregnancy is limited. It is generally argued that with the exception of mycophenylate mofetil no certain teratogenic effect is seen of these drugs. The data presented here indicate that use of azathioprine or its active metabolite 6-mercaptopurine is associated with an increased risk of cardiac septum defects and perhaps of hypospadias. Similarly, tacrolimus is generally regarded as without risk for congenital malformations but in a rather small material an increased risk seemed to exist but it was based on few exposed cases and needs confirmation.


  1. Ban L, Tata LJ, Fiaschi L, Card T. Limited risks of major congenital malformations in children of mothers with IBD and effects of medication. Gastroenterology. 2014;146:76–84.CrossRefGoogle Scholar
  2. Bar-Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation. 2001;71:1051–5.CrossRefGoogle Scholar
  3. Bazzani C, Scrivo R, Andreoli L, Baldissera E, Biggioggero M, Canti V, Gerosa M, Pontikaki I, Ramon V, Trespidi L, Zatti S, Caporali T, Gloria R, Iannone F, Lojacono A, Meroni P, Montecucco C, Motta M, Sabbadini MG, Valesini G, Tincani A. Prospectively followed pregnancies in patients with inflammatory arthritis taking biological drugs: an Italian multicenter study. Clin Exp Rheumatol. 2015;33:688–93.PubMedGoogle Scholar
  4. Boskovic R, Wilde R, Wolpin J, Bauer D, Koren G. The reproductive effect of beta interferon in pregnancy: a longitudinal cohort. Neurology. 2005;65:807–11.CrossRefGoogle Scholar
  5. Bröms G, Granath F, Ekbom A, Hellgren K, Pedersen L, Sørensen HT, Stephansson O, Kieler H. Low risk of birth defects for infants whose mothers are treated with anti-tumor necrosis factor agents during pregnancy. Clin Gastroenterol Hepatol. 2016;14:234–41.CrossRefGoogle Scholar
  6. Carman WJ, Accortt NA, Anthony MS, Iles J, Enger C. Pregnancy and infant outcome including major congenital malformations among women with chronic inflammatory arthritis and psoriasis, with and without etanercept use. Pharmacoepidemiol Drug Saf. 2017;26:1109–15.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-α inhibition and VATER association: a causal relationship? J Rheumatol. 2006;33:1014–7.PubMedGoogle Scholar
  9. Cassina M, Johnson DL, Robinsom LK, Braddock SR, Jimenez JL, Mirrasoul N, Salas E, Luo YJ, Jones KL, Chambers CD. Pregnancy outcome in women exposed to lefluonomide before or during pregnancy. Arthritis Rheum. 2012;64:2085–94.CrossRefGoogle Scholar
  10. Chambers CD, Johnson DL, Robinson LK, Braddock SR, Xu R, Lopez-Jimenez J, Mirrasoul N, Salas E, Luo YJ, Jin S, Jones KL. Birth outcomes in pregnant women taking leflunomide. Arthritis Rheum. 2010;62:1494–53.CrossRefGoogle Scholar
  11. Cleary BJ, Källén B. Early pregnancy azathioprine use and pregnancy outcome. Birth Defects Res A Clin Mol Teratol. 2009;85:647–54.CrossRefGoogle Scholar
  12. Clowse MEB. The use of anti-TNFα medications for rheumatologic disease in pregnancy. Int J Womens Health. 2010;2:199–209.CrossRefGoogle Scholar
  13. Clowse MEB, Scheuerie AE, Chambers C, Afzan A, Kimball AB, Cush JJ, Cooney M, Shaughnessy L, Vanderkelen M, Förger F. Pregnancy outcomes after exposure to certolizumab pegol: updated results from a pharmacovigilance safety database. Arthritis Rheumatol. 2018;70(9):1399–407. Scholar
  14. Coffin CS, Shaheen AA, Burak KW, Myers RP. Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl. 2010;16:56–63.CrossRefGoogle Scholar
  15. Cooper WO, Cheethham TC, Li D-K, Stein M, Callahan T, Morgan TM, Shintani AK, Chen N, Griffin MR, Ray WA. Risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immune mediated diseases. Arthritis Rheumatol. 2014;66:444–50.CrossRefGoogle Scholar
  16. Coyle PK, Sinclair SM, Scheuerle AE, Thorpt JM, Albano JD, Rametta MJ. Final results of the Betaseron (interferon β-1b) pregnancy registry: s prospective observational study of birth defects and pregnancy-related adverse events. BMJ Open. 2014;4:e004536. Scholar
  17. Ghazali S, Cruzoi-Shulman N, Spence AR, Mishkin DS, Abenhaim HA. Pregnancy outcome in liver transplant patients, a population-based study. J Matern Fetal Neonatal Med. 2017;30:261–6.CrossRefGoogle Scholar
  18. Hellwig K, Gold R. Glatiramer acetate and interferon-beta throughout gestation and postpartum in women with multiple sclerosis. J Neurol. 2011;258:502–3.CrossRefGoogle Scholar
  19. Hoeltzenbein M, Elefant E, Vial T, Finkel-Pekarsky V, Stephens S, Clementi M, Allignol A, Weber-Schoendorfer C, Schaefer C. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A. 2012;158A:588–96.CrossRefGoogle Scholar
  20. Kainz A, Harabacz I, Cowlrick IS, Gadoil SD, Hagiwara D. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation. 2000;70:1718–21.CrossRefGoogle Scholar
  21. Källén B, Westgren M, Åberg A, Otterblad Olausson P. Pregnancy outcome after maternal organ transplantation in Sweden. BJOG. 2005;112:904–9.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. Langagergaard V, Pedersen L, Gislum M, Nørgård B, Sørensen HT. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy: a Danish nationwide cohort study. Aliment Pharmacol Ther. 2007;25:73–81.CrossRefGoogle Scholar
  24. Marchioni RM, Lichtenstein GR. Tumor necrosis factor-α inhibitor therapy and fetal risk: a systematic literature review. World J Gastroenterol. 2013;19:2591–602.CrossRefGoogle Scholar
  25. Nørgård B, Pedersen L, Christensen LA, Sørensen HT. Therapeutic drug use in women with Crohn’s disease and birth outcomes: a Danish nationwide cohort study. Am J Gastroenterol. 2007;102:1406–13.CrossRefGoogle Scholar
  26. Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT. Azathioprine, mercaptopurine and birth outcome: a population-based cohort study. Aliment Pharmacol Ther. 2003;17:827–34.CrossRefGoogle Scholar
  27. Perez-Aytes A, Ledo A, Boso V, Săenz P, Roma E, Poveda JL, Vento M. In utero exposure to mycophenolate mofetil: a characteristic phenotype. Am J Med Genet A. 2008;146A:1–7.CrossRefGoogle Scholar
  28. Perez-Aytes A, Marin-Reina P, Boso V, Ledo A, Carey JC, Vento M. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet. 2017;60:16–21.CrossRefGoogle Scholar
  29. Pergola PE, Kancharia A, Riley DJ. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation. 2001;71:994–7.CrossRefGoogle Scholar
  30. Saavedra MA, Sánchez A, Morales S, Ángeles U, Jara LJ. Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor outcome. Clin Rheumatol. 2015;34:1211–6.CrossRefGoogle Scholar
  31. Salminen HJ, Leggett H, Boggild M. Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. J Neurol. 2010;257:2020–3.CrossRefGoogle Scholar
  32. Sandberg-Wolheim M, Alteri E, Moraga MS, Kommann G. Pregnancy outcome in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17:423. Scholar
  33. Sandberg-Wolheim M, Frank D, Goodwin TM, Giesser B, Lopez-Bresnahan M, Stam-Moraga M, Chang P. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology. 2005;65:802–6.CrossRefGoogle Scholar
  34. Sebaaly Z, Charpentier B, Snanoudj R. Fetal malformations associated with mycophenolate mofetil for lupus nephritis. Nephrol Dial Transplant. 2007;22:2722–32.CrossRefGoogle Scholar
  35. Seirafi M, de Vroey B, Amiot A, Seksik P, Roblin X, Allez M, Peyrin-Biroulet L, Marteau P, Cadiot G, Laharie D, Boureille A, De Vos M, Savoye G, Rahier J-F, Carbonnel F, Bonaz B. Factors associated with pregnancy outcome in anti-TNF treated women with inflammatory bowel disease. Aliment Pharmacol Ther. 2014;40:363–73.CrossRefGoogle Scholar
  36. 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. Scholar
  37. Sifontis NM, Coscia LA, Constatinescu S, Lavelanet AF, Mortiz MJ, Armenti VT. Pregnancy outcomes in solid organ transplanted recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006;82:1698–702.CrossRefGoogle Scholar
  38. Thiel S, Langer-Gould A, Rockhoff M, Haghikia A, Queisser-Wahrendorf A, Gold R, Hellwig K. Interferon-beta exposure during first trimester is safe in women with multiple sclerosis—a prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry. Mult Scler. 2016;22:801–9.CrossRefGoogle Scholar
  39. Van den Berg SA, de Boer M, van der Meulen-de Jong AE, Jansen JM, Hoentjen E, Russel MG. Safety of tioguanine during pregnancy in inflammatory bowel disease. J Chrons Colitis. 2016;10:159–65.CrossRefGoogle Scholar
  40. Weber-Schoendorfer C, Opperman M, Wacker E, Bernard N. Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective cohort study. Br J Clin Pharmacol. 2015;80:727–39.CrossRefGoogle Scholar
  41. Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler. 2009;15:1037–42.CrossRefGoogle Scholar
  42. Vento M, Perez Aytes A, Ledo A, Boso V, Carey JC. Mycophenolate mofatil during pregnancy: some words of caution. Pediatrics. 2008;122:184. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Bengt Källén
    • 1
  1. 1.Tornblad Institute for Comparative EmbryologyLund UniversityLundSweden

Personalised recommendations