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Biologika in Schwangerschaft und Stillzeit

Biologics during pregnancy and breast-feeding

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Zusammenfassung

Der Einsatz von Biologika-Therapien, insbesondere von TNF-α-Inhibitoren als therapeutisches Konzept bei Patienten mit unzureichendem Ansprechen auf traditionelle Basistherapien, nimmt zu. Frauen mit entzündlich-rheumatischen Erkrankungen benötigen nicht selten eine medikamentöse Therapie in der Schwangerschaft und Stillzeit, hier stellt sich die Frage nach deren Sicherheit. TNF-α-Inhibitoren werden von der FDA in die Kategorie B eingestuft, da keine ausreichenden Daten zur Schwangerschaft beim Menschen vorliegen. Im letzten Jahrzehnt gab es eine wachsende Anzahl von Publikationen mit exponierten Schwangerschaften, insbesondere Fallserien und Registerdaten. Legt man diese zugrunde, haben die bisher vorliegenden Daten keine belastbaren Hinweise auf ein erhöhtes Risiko von Fehlbildungen ergeben. Da nur wenige Fallberichte über eine Exposition während der gesamten Schwangerschaft vorliegen, sollte sicherheitshalber nach der Konzeption abgesetzt werden.

Allerdings kann es in Einzelfällen nach sorgfältiger Abwägung der klinischen Situation begründet sein, die Therapie auch in der Schwangerschaft fortzusetzen. Stillen unter TNF-α-Inhibitoren ist wahrscheinlich sicher. Das fetale Risiko zur Exposition mit anderen Biologika-Therapien wie z. B. Rituximab ist nicht geklärt.

Abstract

Over the past years, biological therapies, especially anti-TNF-α antibody therapy has emerged as a treatment approach in patients who have failed to achieve or maintain remission with tradional DMARDs. Women suffering from inflammatory arthritis may need to continue therapy throughout pregnancy and/or in the lactation period, hence the increased concern over the safety of antirheumatic drugs during pregnancy. Anti-TNF agents fall within the US FDA category B concerning fetal risk, indicating that no adequate and well-controlled studies have been conducted in pregnant or lactating women. However, in the last decade, numerous case series and registry data of pregnancies exposed to anti-TNF therapy have accumulated in the literature. According to these data, TNF inhibitor therapies appear to be safe in pregnancy, since no increased risk of malformations has been demonstrated. Ceasing therapy after conception should be considered, but treatment may be continued during pregnancy when indicated.

The use of these agents is likely compatible with breast-feeding. The extent of fetal risk is not clarified for exposure to other biologics, such as Rituximab.

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Literatur

  1. Hunt JS, Chen HL, Miller L (1996) Tumor necrosis factors: pivotal components of pregnancy? Biol Reprod 54:554–562

    Article  CAS  PubMed  Google Scholar 

  2. Toder V, Fein A, Carp H, Torchinsky A (2003) TNF-alpha in pregnancy loss and embryo maldevelopment: a mediator of detrimental stimuli or a protector of the fetoplacental unit? J Assist Reprod Genet 20:73–81

    Article  CAS  PubMed  Google Scholar 

  3. 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 174:485–490

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Winger EE, Reed JL, Ashoush S et al (2009) Treatment with adalimumab (Humira) and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol 61:113–120

    Article  CAS  PubMed  Google Scholar 

  6. Treacy G (2000) Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 19:226–228

    Article  CAS  PubMed  Google Scholar 

  7. Briggs GG (2005) Drugs in pregnancy and lactation. 7.Aufl. Williams & Wilkins, Baltimore

  8. Martin PL, Cornacoff JB, Treacy G et al (2008) Effects of administration of a monoclonal antibody against mouse tumor necrosis factor alpha during pregnancy and lactation on the pre- and postnatal development of the mouse immune system. Int J Toxicol 27:341–347

    Article  CAS  PubMed  Google Scholar 

  9. Vasiliauskas EA, Church JA, Silverman N et al (2006) Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 4:1255–1258

    Article  PubMed  Google Scholar 

  10. Mahadevan U, Terdiman JP, Church J et al (2007) Infliximab levels in infants born to women with inflammatory bowel disease. Dig Dis Week, abstract 959

  11. Murashima A, Watanabe N, Ozawa N et al (2009) Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann Rheum Dis 68:1793–1794

    Article  CAS  PubMed  Google Scholar 

  12. Porter C, Kopotsha T, Smith B et al (2010) No significant transfer of certolizumab pegol compared with IgG in the perfused human placenta in vitro. Ann Rheum Dis 69 (Suppl3):210

    Article  Google Scholar 

  13. Nesbitt ABD, Stephens S, Foulkes R (2006) Placental transfer and accumulation in milk of the anti TNF-antibody TN3 in rats: immunoglobulin G1 versus PEGylated FAB. Am J Gastroenterol, abstract 119

  14. Oussalah A, Bigard MA, Peyrin-Biroulet L (2009) Certolizumab in pregnancy. Gut 58:608

    Article  CAS  PubMed  Google Scholar 

  15. Cush JJ (2005) Biological drug use: US perspectives on indications and monitoring. Ann Rheum Dis 64:iv18–23

    Article  CAS  PubMed  Google Scholar 

  16. Ostensen M, Lockshin M, Doria A et al (2008) Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology (Oxford) 47:iii28

    Google Scholar 

  17. Vinet E, Pineau C, Gordon C et al (2009) Biologic therapy and pregnancy outcomes in women with rheumatic diseases. Arthritis Rheum 61:587–592

    Article  CAS  PubMed  Google Scholar 

  18. Ali YM, Kuriya B, Orozco C et al (2010) Can tumor necrosis factor inhibitors be safely used in pregnancy? J Rheumatol 37:9–17

    Article  CAS  PubMed  Google Scholar 

  19. Katz JA, Antoni C, Keenan GF et al (2004) Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol 99:2385–2392

    Article  PubMed  Google Scholar 

  20. Snoeckx Y, Keenan G, Sanders M, Gardiner M (2009) Update on pregnancy outcomes in women taking Infliximab: the Infliximab safety database. Ann Rheum Dis 68 (Suppl 3):122

    Google Scholar 

  21. Hyrich K, Watson K, Dixon W et al (2006) Pregnancy experience in women with rheumatic diseases exposed to biologic agents: results from the BSR biologic register. Arthritis Rheum 54:2701–2702

    Article  PubMed  Google Scholar 

  22. King Y, Watson KD, Symmons DPM et al (2008) Pregnancy outcome in women exposed to Anti-TNF Agents: An update from the British Society for Rheumatoogy Biologics Register. Arthritis Rheum (Suppl 58):S542 (abstract)

    Google Scholar 

  23. Garcia-Gonzalez A, Joven B, Ruiz T et al (2006) Pregnancy in women receiving anti TNF-alpha therapy: experience in Spain. Ann Rheum Dis 65:317 (abstract)

    Google Scholar 

  24. Strangfeld A, Listing J, Rau R et al (2007) Pregnancy outcome after exposure to biologics: Results from the German Biologics Register RABBIT. ACR 2007 No. 730 (abstract)

  25. Johnson DL, Jones KL, Jimenez J et al (2009) Pregnancy outcomes in women exposed to adalimumab: An update on the autoimmune diseases in pregnancy uroject. http://www.otispregnancy.org/hm/download.php?id=12&client_id

  26. Johnson DL, Jones KL, Chambers CD (2008) Pregnancy outcomes in women exposed to etanercept. The OTIS autoimmune disease in pregnancy project. http://www.otispregnancy.org/hm/download.php?id=12&client_id)

  27. Mahadevan U, Kane S, Sandborn WJ et al (2005) Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther 21:733–738

    Article  CAS  PubMed  Google Scholar 

  28. Tursi A (2006) Effect of intentional infliximab use throughout pregnancy in inducing and maintaining remission in Crohn’s disease. Dig Liver Dis 8:439–440

    Article  Google Scholar 

  29. Schnitzler F, Fidder HH, Ferrante M et al (2007) Intentional treatment with infliximab during pregnancy in women with inflammatory bowel disease. Dig Dis Week, abstract 958

  30. Rosner I, Haddad A, Boulman N et al (2007) Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology (Oxford) 46:1508

    Google Scholar 

  31. Vesga L, Terdiman JP, Mahadevan U (2005) Adalimumab use in pregnancy. Gut 54:890

    Article  CAS  PubMed  Google Scholar 

  32. Coburn LA, Wise PE, Schwartz DA (2006) The successful use of adalimumab to treat active Crohn’s disease of an ileoanal pouch during pregnancy. Dig Dis Sci 51:2045–2047

    Article  PubMed  Google Scholar 

  33. Mishkin DS, Van Deinse W, Becker JM, Farraye FA (2006) Successful use of adalimumab (Humira) for Crohn’s disease in pregnancy. Inflamm Bowel Dis 12:827–828

    Article  PubMed  Google Scholar 

  34. Berthelot JM, De Bandt M, Goupille P 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 

  35. Rump JA, Schönborn H (2010) Conception and course of eight pregnancies in five women on TNF blocker etanercept treatment. Z Rheumatol [Epub ahead of print Jun 9]

  36. Carter JD, Valeriano J, Vasey FB (2006) Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 33:1014–1017

    PubMed  Google Scholar 

  37. Carter JD, Ladhani A, Ricca LR et al (2009) A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 36:635–641

    Article  PubMed  Google Scholar 

  38. Amato RJ de, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085

    Article  PubMed  Google Scholar 

  39. Østensen M, Förger F, Nelson JL et al (2005) Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis 64:839–844

    Article  PubMed  Google Scholar 

  40. Förger F, Matthias T, Oppermann M et al (2004) Infliximab in breast milk. Lupus 13:753

    Google Scholar 

  41. 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 

  42. Ostensen M, Eigenmann GO (2004) Etanercept in breast milk. J Rheumatol 31:1017–1018

    PubMed  Google Scholar 

  43. Berthelsen B, Nielsen HF, Nielsen CT, Hellmuth E (2010) Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology (Oxford) [Epub ahead of print]

  44. Ben-Horin S, Yavzori M, Katz L et al (2010) Adalimumab Level in Breast Milk of a Nursing Mother. Clin Gastroenterol Hepatol 8:475–476

    Article  PubMed  Google Scholar 

  45. Paschou S, Voulgari PV, Vrabie IG et al (2009) Fertility and reproduction in male patients with ankylosing spondylitis treated with infliximab. J Rheumatol 36:351–354

    PubMed  Google Scholar 

  46. Barcelo M, Sellas A, Rodríguez-Diez B et al (2009) Paternity in patients treated with Anti-TNF therapy. ACR 2009 [SAT0279]

  47. Suominen JS, Wang Y, Kaipia A, Toppari J (2004) Tumor necrosis factor-alpha (TNF-alpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist. Eur J Endocrinol 151:629–640

    Article  CAS  PubMed  Google Scholar 

  48. Said TM, Agarwal A, Falcone T et al (2005) Infliximab may reverse the toxic effects induced by tumor necrosis factor alpha in human spermatozoa: an in vitro model. Fertil Steril 83:1665–1673

    Article  CAS  PubMed  Google Scholar 

  49. La Montagna GL, Malesci D, Buono R, Valentini G (2005) Asthenoazoospermia in patients receiving anti-tumour necrosis factor {alpha} agents. Ann Rheum Dis 64:1667

    Article  Google Scholar 

  50. Villiger PM, Caliezi G, Cottin V et al (2010) Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis 69:1842–1844

    Article  CAS  PubMed  Google Scholar 

  51. Murtha AP, Nieves A, Hauser ER et al (2006) Association of maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth. Am J Obstet Gynecol 195:1249–1253

    Article  CAS  PubMed  Google Scholar 

  52. Sadowsky DW, Adams KM, Gravett MG et al (2006) Preterm labor is induced by intraamniotic infusions or interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhumate primate model. Am J Obstet Gynecol 195:1578–1589

    Article  CAS  PubMed  Google Scholar 

  53. Berger CT, Recher M, Steiner U, Hauser TM (2009) A patients wish: anakinra in pregnancy. Ann Rheum Dis 68:1794–1795

    Article  CAS  PubMed  Google Scholar 

  54. Bazzani C, Ramoni V, Scrivo R et al (2010) Pregnancy outcomes in women exposed to biologic treatment and affected by chronic arthritis. Ann Rheum Dis 69 (Suppl 3):678

    Google Scholar 

  55. (o A) (2007) Fachinformation Orencia Bristol-Myers Squibb

  56. Østensen M, Lockshin M, Doria A et al (2008) Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology (Oxford) 47(Suppl 3):iii28–31

    Google Scholar 

  57. Ishikawa H, Kanamono T, Kojima T et al (2010) Treatment of young female patients with rheumatoid arthritis using biological agents- results from 6 years of clinical practice in Japanese TBC registry for the patients with rheumatoid arthritis using biologics. Ann Rheum Dis 69 (Suppl):679

    Article  Google Scholar 

  58. Kimby E, Sverrisdottir A, Elinder G (2004) Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol 72:292–295

    Article  PubMed  Google Scholar 

  59. Decker M, Rothermundt C, Holländer G et al (2006) Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy. Lancet Oncol 7:693–694

    Article  PubMed  Google Scholar 

  60. Friedrichs B, Tiemann M, Salwender H et al (2006) The effects of rituximab treatment during pregnancy on a neonate, Haematologica 91:1426–1427

    Google Scholar 

  61. Scully M, Starke R, Lee R et al (2006) Successful management of pregnancy in women with a history of thrombotic thrombocytopaenic purpura. Blood Coagul Fibrinolysis 17:459–463

    Article  PubMed  Google Scholar 

  62. Ojeda-Uribe M, Gilliot C, Jung G et al (2006) Administration of rituximab during the first trimester of pregnancy without consequences for the newborn. J Perinatol 26:252–255

    Article  CAS  PubMed  Google Scholar 

  63. Klink DT, Elburg RM van, Schreurs MW, Well GT van (2008) Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol 27:1363

    Google Scholar 

  64. Diaz MC, Gutierrez JJM, Buitrago VV (2008) Rituximab and pregnancy: Case report. EULAR 0448

  65. Pellkofer HL, Suessmair C, Schulze A et al (2009) Course of neuromyelitis optica during inadvertent pregnancy in a patient treated with rituximab. Mult Scler 15:1006–1008

    Article  CAS  PubMed  Google Scholar 

  66. Rey J, Coso D, Roger V et al (2009) Rituximab combined with chemotherapy for lymphoma during pregnancy. Leuk Res 33:e8–e9

    Article  CAS  PubMed  Google Scholar 

  67. Ponte P, Lopes MJ (2010) Apparent safe use of single dose rituximab for recalcitrant atopic dermatitis in the first trimester of a twin pregnancy. J Am Acad Dermatol 63:355–356

    Article  PubMed  Google Scholar 

  68. Herold M, Schnohr S, Bittrich H (2001) Efficacy and safety of a combined rituximab chemotherapy during pregnancy. J Clin Oncol 19:3439

    CAS  PubMed  Google Scholar 

  69. Magloire LK, Pettker CM, Buhimschi CS, Funai EF (2006) Burkitt’s lymphoma of the ovary in pregnancy. Obstet Gynecol 108:743–745

    PubMed  Google Scholar 

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Die korrespondierende Autorin weist auf folgende Beziehungen hin: Vorträge und Beratungstätigkeit für Abbott, Wyeth, Essex, Roche, Chugai.

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Correspondence to R.E. Fischer-Betz MD.

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Fischer-Betz, R., Schneider, M. Biologika in Schwangerschaft und Stillzeit. Z. Rheumatol. 69, 780–787 (2010). https://doi.org/10.1007/s00393-010-0640-2

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