Rekommendationer avseende anti-inflammatorisk och immun-modulerande behandling i samband med graviditet och amning

Data talar för att hög sjukdomsaktivitet under graviditeten innebär ökad risk för negativa graviditets- och förlossningsutfall såsom förtidig födsel och tillväxthämning hos fostret. Uppmuntra därför patienten att planera graviditeten till en period då sjukdomen är lågaktiv, helst sedan minst 6 månader tillbaka. Då detta inte alltid är möjligt, och då graviditet i sig kan ge upphov till ökad sjukdomsaktivitet, kommer många patienter att vara i behov av behandling med läkemedel under graviditeten.

En viktig läkemedelsaspekt är förstås risk för teratogena effekter. Den mest vulnerabla perioden för detta är från 4 fullgångna graviditetsveckor fram till vecka 10 med en glidande övergång till vecka 12, det vill säga ofta före tidpunkten för inskrivning på Mödravårdscentralen. Det är därför av stor vikt att patienter (män och kvinnor) med aktuell eller framtida barnönskan noggrant informeras om att graviditet bör planeras så att den medicinska behandlingen i god tid kan justeras. Det är också viktigt att behandlade läkare efterhör att patienten använder sig av en effektiv preventivmetod inför start, och under behandling, med teratogena läkemedel. Om
graviditet uppstår hos en kvinna som är exponerad för teratogena läkemedel tiden runt konception och/eller i tidig graviditet är det viktigt med snabbt samråd mellan kvinnan, hennes partner, specialistmödravården samt behandlade reumatolog för att ge kvinnan så mycket information som möjligt för att kunna fatta beslut om att fortsätta eller avbryta graviditeten.

Risken att framkalla fosterpåverkan med läkemedel måste alltid vägas mot risken av att inte förebygga eller behandla en kronisk sjukdom. I varje enskilt patientfall bör därför behandlande läkare överväga om indikation föreligger för fortsatt behandling. Lägsta möjliga dos av samtliga preparat skall alltid eftersträvas.

Vaccination av barn

Beträffande rekommendation kring vaccination av barn, som har exponerats för immunmodulerande läkemedel under graviditet eller amning, hänvisas till individuell
läkarbedömning med utgångspunkt från det nationella dokumentet ”Vägledning för vaccination med levande försvagade vaccin, av barn som under graviditeten eller vid amning exponerats för immunmodulerande läkemedel”, vilket återfinns på hemsidan för ”Rikshandboken Barnhälsovård för professionen”. Se även avsnittet om TNF-hämmare.

Texten om hydroxiklorokin, kortikosteroider, TNF-hämmare och biologiska läkemedel, icke TNF-hämmare har omformulerats. Behandling med abatacept, tocilizumab, belimumab, ustekinumab samt sekukinumab kan fortsätta fram till konstaterad graviditet. Avsnittet om män är uppdaterat och omformulerat. Män kan fortsätta med metotrexat inför graviditet. Filgotinib kan övervägas till män i samband med planerad graviditet, vid stark medicinsk indikation för behandling med JAK-hämmare. Tabeller och referenser har uppdaterats. Tillägg av nya läkemedel: anifrolumab, voklosporin, kanakinumab och risankizumab.

1. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis & rheumatology (Hoboken, NJ) 2020 doi: 10.1002/art.41191 [published Online First: 2020/02/25]

2. Black E, Khor KE, Kennedy D, et al. Medication Use and Pain Management in Pregnancy: A Critical Review. Pain Pract 2019;19(8):875-99. doi: 10.1111/papr.12814 [published Online First: 2019/06/27]

3. Daniel S, Matok I, Gorodischer R, et al. Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy. The Journal of rheumatology 2012;39(11):2163-9. doi: 10.3899/jrheum.120453 [published Online First: 2012/09/18]

4. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62(6):385-92. doi:10.1002/1096-9926(200012)62:6<385::Aid-tera5>3.0.Co;2-z [published Online First: 2000/11/25]

5. Carmichael SL, Shaw GM, Ma C, et al. Maternal corticosteroid use and orofacial clefts. American journal of obstetrics and gynecology 2007;197(6):585.e1-7; discussion 683-4, e1-7. doi: 10.1016/j.ajog.2007.05.046 [published Online First: 2007/12/07]

6. Skuladottir H, Wilcox AJ, Ma C, et al. Corticosteroid use and risk of orofacial clefts. Birth defects research Part A, Clinical and molecular teratology 2014;100(6):499 506. doi: 10.1002/bdra.23248 [published Online First: 2014/04/30]

7. Bay Bjorn AM, Ehrenstein V, Hundborg HH, et al. Use of corticosteroids in early pregnancy is not associated with risk of oral clefts and other congenital malformations in offspring. American journal of therapeutics 2014;21(2):73-80. doi: 10.1097/MJT.0b013e3182491e02 [published Online First: 2012/09/27]

8. Gur C, Diav-Citrin O, Shechtman S, et al. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reproductive toxicology (Elmsford, NY) 2004;18(1):93-101. doi: 10.1016/j.reprotox.2003.10.007 [published Online First: 2004/03/12]

9. Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne 2011;183(7):796-804. doi: 10.1503/cmaj.101063 [published Online First: 2011/04/13]

10. Bandoli G, Palmsten K, Forbess Smith CJ, et al. A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. Rheumatic diseases clinics of North America 2017;43(3):489-502. doi: 10.1016/j.rdc.2017.04.013 [published Online First: 2017/07/18]

11. Xiao WL, Liu XY, Liu YS, et al. The relationship between maternal corticosteroid use and orofacial clefts-a meta-analysis. Reproductive toxicology (Elmsford, NY) 2017;69:99-105. doi: 10.1016/j.reprotox.2017.02.006 [published Online First: 2017/02/22]

12. Ost L, Wettrell G, Bjorkhem I, et al. Prednisolone excretion in human milk. The Journal of pediatrics 1985;106(6):1008-11. doi: 10.1016/s0022-3476(85)80259-6 [published Online First: 1985/06/01]

13. Greenberger PA, Odeh YK, Frederiksen MC, et al. Pharmacokinetics of prednisolone transfer to breast milk. Clinical pharmacology and therapeutics 1993;53(3):324-8. doi: 10.1038/clpt.1993.28 [published Online First: 1993/03/01]

14. Armenti VT, Constantinescu S, Moritz MJ, et al. Pregnancy after transplantation. Transplantation reviews (Orlando, Fla) 2008;22(4):223-40. doi: 10.1016/j.trre.2008.05.001 [published Online First: 2008/08/12]

15. Akbari M, Shah S, Velayos FS, et al. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflammatory bowel diseases 2013;19(1):15-22. doi: 10.1002/ibd.22948 [published Online First: 2012/03/22]

16. Shim L, Eslick GD, Simring AA, et al. The effects of azathioprine on birth outcomes in women with inflammatory bowel disease (IBD). Journal of Crohn’s & colitis 2011;5(3):234-8. doi: 10.1016/j.crohns.2011.01.009 [published Online First: 2011/05/18]

17. Goldstein LH, Dolinsky G, Greenberg R, et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth defects research Part A, Clinical and molecular teratology 2007;79(10):696-701. doi: 10.1002/bdra.20399 [published Online First: 2007/09/12]

18. Teruel C, Lopez-San Roman A, Bermejo F, et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines. The American journal of gastroenterology 2010;105(9):2003-8. doi: 10.1038/ajg.2010.138 [published Online First: 2010/08/12]

19. Ban L, Tata LJ, Fiaschi L, et al. Limited risks of major congenital anomalies in children of mothers with IBD and effects of medications. Gastroenterology 2014;146(1):76-84. doi: 10.1053/j.gastro.2013.09.061 [published Online First: 2013/10/16]

20. Moretti ME, Verjee Z, Ito S, et al. Breast-feeding during maternal use of azathioprine. The Annals of pharmacotherapy 2006;40(12):2269-72. doi: 10.1345/aph.1H152 [published Online First: 2006/11/30]

21. Christensen LA, Dahlerup JF, Nielsen MJ, et al. Azathioprine treatment during lactation. Alimentary pharmacology & therapeutics 2008;28(10):1209-13. doi: 10.1111/j.1365-2036.2008.03843.x [published Online First: 2008/09/03]

22. http//toxnet.nlm.nih.gov.

23. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Annals of the rheumatic diseases 2016;75(5):795-810. doi: 10.1136/annrheumdis-2015-208840

24. Sau A, Clarke S, Bass J, et al. Azathioprine and breastfeeding: is it safe? BJOG : an international journal of obstetrics and gynaecology 2007;114(4):498-501. doi: 10.1111/j.1471-0528.2006.01232.x [published Online First: 2007/01/31]

25. Ben-Chetrit E, Ben-Chetrit A, Berkun Y, et al. Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arthritis care & research 2010;62(2):143-8. doi: 10.1002/acr.20061 [published Online First: 2010/03/02]

26. Diav-Citrin O, Shechtman S, Schwartz V, et al. Pregnancy outcome after in utero exposure to colchicine. American journal of obstetrics and gynecology 2010;203(2):144.e1-6. doi: 10.1016/j.ajog.2010.02.063 [published Online First: 2010/06/29]

27. Rabinovitch O, Zemer D, Kukia E, et al. Colchicine treatment in conception and pregnancy: two hundred thirtyone pregnancies in patients with familial Mediterranean fever. American journal of reproductive immunology (New York, NY : 1989) 1992;28(3-4):245-6. doi: 10.1111/j.1600-0897.1992.tb00805.x [published Online First: 1992/10/01]

28. Berkenstadt M, Weisz B, Cuckle H, et al. Chromosomal abnormalities and birth defects among couples with colchicine treated familial Mediterranean fever. American journal of obstetrics and gynecology 2005;193(4):1513-6. doi: 10.1016/j.ajog.2005.03.043 [published Online First: 2005/10/06]

29. Noel N, Wechsler B, Nizard J, et al. Behcet’s disease and pregnancy. Arthritis and rheumatism 2013;65(9):2450-6. doi: 10.1002/art.38052

30. Nabil H, Zayed A, State O, et al. Pregnancy outcome in women with familial Mediterranean fever. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 2012;32(8):756-9. doi: 10.3109/01443615.2012.698667 [published Online First: 2012/10/19]

31. Indraratna PL, Virk S, Gurram D, et al. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford, England) 2018;57(2):382-87. doi: 10.1093/rheumatology/kex353 [published Online First: 2017/10/14]

32. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-89. doi: 10.1542/peds.108.3.776 [published Online First: 2001/09/05]

33. Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis research & therapy 2006;8(3):209. doi: 10.1186/ar1957

34. Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. The New England journal of medicine 2000;343(22):1608-14. doi: 10.1056/nejm200011303432204 [published Online First: 2000/11/30]

35. Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Annals of the rheumatic diseases 2017;76(3):476-85. doi: 10.1136/annrheumdis-2016-209770 [published Online First: 2016/07/28]

36. Huybrechts KF, Bateman BT, Zhu Y, et al. Hydroxychloroquine early in pregnancy and risk of birth defects. American journal of obstetrics and gynecology 2020 doi: 10.1016/j.ajog.2020.09.007 [published Online First: 2020/09/23]

37. Ostensen M, Andreoli L, Brucato A, et al. State of the art: Reproduction and pregnancy in rheumatic diseases. Autoimmunity reviews 2015;14(5):376-86. doi: 10.1016/j.autrev.2014.12.011

38. Makol A, Wright K, Amin S. Rheumatoid arthritis and pregnancy: safety considerations in pharmacological management. Drugs 2011;71(15):1973-87. doi: 10.2165/11596240-000000000-00000 [published Online First: 2011/10/12]

39. Motta M, Tincani A, Faden D, et al. Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. Journal of perinatology : official journal of the California Perinatal Association 2005;25(2):86-9. doi: 10.1038/sj.jp.7211208 [published Online First: 2004/10/22]

40. Ostensen M, Forger F. How safe are anti-rheumatic drugs during pregnancy? Current opinion in pharmacology 2013;13(3):470-5. doi: 10.1016/j.coph.2013.03.004

41. Biverkningsnytt; Fetal hemolytisk anemi vid sulfasalazinbehandling under graviditet. Information från Läkemedelsverket 1; 2004: 59-60.

42. Ostensen M, Motta M. Therapy insight: the use of antirheumatic drugs during nursing. Nature clinical practice Rheumatology 2007;3(7):400-6. doi: 10.1038/ncprheum0532 [published Online First: 2007/06/30]

43. Gisbert JP. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding. Inflammatory bowel diseases 2010;16(5):881-95. doi: 10.1002/ibd.21154 [published Online First: 2009/11/04]

44. Saha S, Wald A. Safety and efficacy of immunomodulators and biologics during pregnancy and lactation for the treatment of inflammatory bowel disease. Expert opinion on drug safety 2012;11(6):947-57. doi: 10.1517/14740338.2012.720970 [published Online First: 2012/09/08]

45. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Seminars in arthritis and rheumatism 2005;35(2):112-21. doi: 10.1016/j.semarthrit.2005.05.002

46. Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation 2003;75(12):2144-6. doi: 10.1097/01.Tp.0000066352.86763.D0 [published Online First: 2003/06/28]

47. Hebert MF, Zheng S, Hays K, et al. Interpreting tacrolimus concentrations during pregnancy and postpartum. Transplantation 2013;95(7):908-15. doi: 10.1097/TP.0b013e318278d367 [published Online First: 2013/01/01]

48. Gouraud A, Bernard N, Millaret A, et al. Follow-up of tacrolimus breastfed babies. Transplantation 2012;94(6):e38-40. doi: 10.1097/TP.0b013e3182654d36 [published Online First: 2012/09/22]

49. Bramham K, Chusney G, Lee J, et al. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottlefed infants. Clin J Am Soc Nephrol 2013;8(4):563-7. doi: 10.2215/CJN.06400612 [published Online First: 2013/01/26]

50. Roux CH, Brocq O, Breuil V, et al. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology (Oxford, England) 2007;46(4):695-8. doi: 10.1093/rheumatology/kel400 [published Online First: 2006/12/13]

51. Vinet E, Pineau C, Gordon C, et al. Biologic therapy and pregnancy outcomes in women with rheumatic diseases. Arthritis and rheumatism 2009;61(5):587-92. doi: 10.1002/art.24462

52. Mahadevan U, Cucchiara S, Hyams JS, 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. The American journal of gastroenterology 2011;106(2):214-23; quiz 24. doi: 10.1038/ajg.2010.464 [published Online First: 2010/12/16]

53. Mariette X, Forger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Annals of the rheumatic diseases 2017 doi: 10.1136/annrheumdis-2017-212196

54. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology 2016 doi: 10.1053/j.gastro.2016.04.002

55. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford, England) 2016;55(9):1693-7. doi: 10.1093/rheumatology/kev404 [published Online First: 2016/01/12]

56. Clowse ME, Wolf DC, Forger F, et al. Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol. The Journal of rheumatology 2015;42(12):2270-8. doi: 10.3899/jrheum.140189

57. Ostensen M, Lockshin M, Doria A, et al. Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology (Oxford, England) 2008;47 Suppl 3:iii28-31. doi: 10.1093/rheumatology/ken168

58. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. The American journal of gastroenterology 2009;104(1):228-33. doi: 10.1038/ajg.2008.71 [published Online First:
2008/12/23]

59. Das G, Damotte V, Gelfand JM, et al. Rituximab before and during pregnancy: A systematic review, and a case series in MS and NMOSD. Neurology(R) neuroimmunology & neuroinflammation 2018;5(3):e453. doi: 10.1212/nxi.0000000000000453 [published Online First: 2018/03/23]

60. Kumar M, Ray L, Vemuri S, et al. Pregnancy outcomes following exposure to abatacept during pregnancy. Seminars in arthritis and rheumatism 2015;45(3):351-6. doi: 10.1016/j.semarthrit.2015.06.016 [published Online First: 2015/07/27]

61. Produktresumé Tocilizumab Roche

62. Gerosa M, Argolini LM, Artusi C, et al. The use of biologics and small molecules in pregnant patients with rheumatic diseases. Expert review of clinical pharmacology 2018;11(10):987-98. doi: 10.1080/17512433.2018.1525293 [published Online First: 2018/09/20]

63. Chang Z, Spong CY, Jesus AA, et al. Anakinra use during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis & rheumatology (Hoboken, NJ) 2014;66(11):3227-32. doi: 10.1002/art.38811 [published Online First: 2014/09/17]

64. Fischer-Betz R, Specker C, Schneider M. Successful outcome of two pregnancies in patients with adult-onset Still’s disease treated with IL-1 receptor antagonist (anakinra). Clinical and experimental rheumatology 2011;29(6):1021-3. [published Online First: 2011/12/14]

65. Venhoff N, Voll RE, Glaser C, et al. [IL-1-blockade with Anakinra during pregnancy : Retrospective analysis of efficacy and safety in female patients with familial Mediterranean fever]. Z Rheumatol 2018;77(2):127-34. doi: 10.1007/s00393-017-0354-9 [published Online First: 2017/07/29]

66. Produktresumé Belimumab GlaxoSmithKline.

67. Produktresumé Ustekinumab Janssen.

68. Produktresumé Sekukinumab Novartis.

69. Produktresumé Sarilumab Sanofi AB.

70. Produktresumé Ixekizumab Lilly.

71. Produktresumé Apremilast och personlig kommunikation Celgene 2017.

72. Produktresumé Baricitinib Lilly.

73. Produktresumé Tofacitinib Pfizer Innovations.

74. Produktresumé Upadacitinib.

75. Joyce CL, Nuzzo NA, Wilson L, Jr., et al. Evidence for a role of cyclooxygenase (prostaglandin synthetase) and prostaglandins in the sperm acrosome reaction and fertilization. Journal of andrology 1987;8(2):74-82. doi: 10.1002/j.1939-4640.1987.tb00953.x [published Online First: 1987/03/01]

76. Martini AC, Molina RI, Tissera AD, et al. Analysis of semen from patients chronically treated with low or moderate doses of aspirin-like drugs. Fertility and sterility 2003;80(1):221-2. doi: 10.1016/s0015-0282(03)00550-8 [published Online First: 2003/07/10]

77. Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001;63(2):106-12. doi: 10.1002/1096-9926(200102)63:2<106::Aid-tera1017>3.0.Co;2-r [published Online First: 2001/03/10]

78. De Santis M, Cesari E, Cavaliere A, et al. Paternal exposure and counselling: experience of a Teratology Information Service. Reproductive toxicology (Elmsford, NY) 2008;26(1):42-6. doi: 10.1016/j.reprotox.2008.06.003 [published Online First: 2008/07/05]

79. De Santis M, Straface G, Cavaliere A, et al. Paternal and maternal exposure to leflunomide: pregnancy and neonatal outcome. Annals of the rheumatic diseases 2005;64(7):1096-7. doi: 10.1136/ard.2004.030254 [published Online First: 2005/06/17]

80. Mouyis M, Flint JD, Giles IP. Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence. Seminars in arthritis and rheumatism 2019;48(5):911-20. doi: 10.1016/j.semarthrit.2018.07.011 [published Online First: 2018/09/18]

81. Midtvedt K, Bergan S, Reisaeter AV, et al. Exposure to Mycophenolate and Fatherhood. Transplantation 2017;101(7):e214-e17. doi: 10.1097/TP.0000000000001747 [published Online First: 2017/03/28]

82. Jones A, Clary MJ, McDermott E, et al. Outcomes of pregnancies fathered by solid-organ transplant recipients exposed to mycophenolic acid products. Prog Transplant 2013;23(2):153-7. doi: 10.7182/pit2013636 [published Online First: 2013/06/21]

83. Bermas BL. Paternal safety of anti-rheumatic medications. Best Pract Res Clin Obstet Gynaecol 2020;64:77-84. doi: 10.1016/j.bpobgyn.2019.09.004 [published Online First: 2019/11/16]

84. Beghin D, Cournot MP, Vauzelle C, et al. Paternal exposure to methotrexate and pregnancy outcomes. The Journal of rheumatology 2011;38(4):628-32. doi: 10.3899/jrheum.100600 [published Online First: 2011/01/18]

85. Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers. Scandinavian journal of rheumatology 2012;41(3):196-201. doi: 10.3109/03009742.2011.626442 [published Online First: 2012/03/10]

86. Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, et al. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology (Oxford, England) 2014;53(4):757-63. doi: 10.1093/rheumatology/ket390 [published Online First:
2013/12/27]

87. Eck LK, Jensen TB, Mastrogiannis D, et al. Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy. Obstetrics and gynecology 2017;129(4):707-14. doi: 10.1097/AOG.0000000000001936 [published Online First: 2017/03/10]

88. Winter RW, Larsen MD, Magnussen B, et al. Birth outcomes after preconception paternal exposure to methotrexate: A nationwide cohort study. Reproductive toxicology (Elmsford, NY) 2017;74:219-23. doi: 10.1016/j.reprotox.2017.10.004 [published Online First: 2017/10/31]

89. Ben-Chetrit E, Berkun Y, Ben-Chetrit E, et al. The outcome of pregnancy in the wives of men with familial mediterranean fever treated with colchicine. Seminars in arthritis and rheumatism 2004;34(2):549-52. doi: 10.1016/j.semarthrit.2004.07.004 [published Online First: 2004/10/27]

90. Haimov-Kochman R, Ben-Chetrit E. The effect of colchicine treatment on sperm production and function: a review. Human reproduction (Oxford, England) 1998;13(2):360-2. doi: 10.1093/humrep/13.2.360 [published Online First: 1998/04/29]

91. Both T, van Laar JA, Bonte-Mineur F, et al. [Colchicine has no negative effect on fertility and pregnancy]. Nederlands tijdschrift voor geneeskunde 2012;156(12):A4196. [published Online First: 2012/03/23]

92. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003;21(4):716-21. doi: 10.1200/jco.2003.04.085 [published Online
First: 2003/02/15]

93. Heetun ZS, Byrnes C, Neary P, et al. Review article: Reproduction in the patient with inflammatory bowel disease. Alimentary pharmacology & therapeutics 2007;26(4):513-33. doi: 10.1111/j.1365- 2036.2007.03397.x [published Online First: 2007/07/31]

94. Mahadevan U, Terdiman JP, Aron J, et al. Infliximab and semen quality in men with inflammatory bowel disease. Inflammatory bowel diseases 2005;11(4):395-9. doi: 10.1097/01.mib.0000164023.10848.c4 [published Online First: 2005/04/02]

95. Puchner R, Danninger K, Puchner A, et al. Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clinical and experimental rheumatology 2012;30(5):765-7. [published Online First: 2012/09/01]

96. Micu MC, Micu R, Surd S, et al. TNF-alpha inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology (Oxford, England) 2014;53(7):1250-5. doi: 10.1093/rheumatology/keu007 [published Online First: 2014/03/07]

97. Villiger PM, Caliezi G, Cottin V, et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Annals of the rheumatic diseases 2010;69(10):1842-4. doi: 10.1136/ard.2009.127423 [published Online First: 2010/07/09]

115. www.fass.se

116. Produktresumé Filgotinib

117. Marhofer D, Jaksch W, Aigmüller T, Jochberger S, Urlesberger B, Pils K, Maier B, Likar R, Kayer B, Wallner R, Fink P, Grögl G. Schmerztherapie in der Schwangerschaft : Eine expertInnenbasierte interdisziplinäre Konsensus-Empfehlung [Pain management during pregnancy : An expert-based interdisciplinary consensus recommendation]. Schmerz. 2021 Dec;35(6):382-390. German. doi: 10.1007/s00482-021-00571-4. Epub 2021 Jul 29. PMID: 34324048; PMCID: PMC8613155.

118. Levy RA, de Jesús GR, de Jesús NR, Klumb EM. Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation. Autoimmun Rev 2016; 15(10):995-63. https://doi.org/10.1016/j. autrev.2016.07.014

119. Cassina M, Johnson DL, Robinson LK, Braddock SR, Xu R, Jimenez JL, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum 2012; 64(7):2085-94. https://doi.org/10.1002/art.34419

120. Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 2019; 86(3):301-7. https://doi.org/10.1016/j. jbspin.2018.07.004

121. Grosen A, Kelsen J, Hvas CL, Bellaguarda E, Hanauer SB. The influence of methotrexate treatment on male fertility and pregnancy outcome after paternal exposure. Inflam Bowel Dis 2017; 23(4):561-9. https://doi.org/10.1097/ MIB.0000000000001064

122. Bérard A, Sheehy O, Zhao JP, Vinet E, Quach C, Bernatsky S. Chloroquine and hydroxychloroquine use during pregnancy and the risk of adverse pregnancy outcomes using realworld evidence. Front Pharmacol 2021; 12:722511. https://doi.org/10.3389/fphar.2021.722511

123. Andersson NW, Skov L, Andersen JT. Fetal safety of chloroquine and hydroxychloroquine use during pregnancy: a nationwide cohort study. Rheumatology (Oxford) 2021; 60(5):2317-26. https://doi.org/10.1093/ rheumatology/keaa592

124. Izmirly P, Kim M, Friedman DM, et al. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers. J Am Coll Cardiol 2020;76:292-302.

125. Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76:476-85.

126. Smith J.B., Hellwig K., Fink K., et al. Rituximab, MS, and pregnancy. Neurology(R) neuroimmunology & neuroinflammation 2020 7:4. doi: 10.1212/NXI.0000000000000734 [published Online First: 2020/07/01]

127. Juliao P., Wurst K., Pimenta JM., et al. Belimumab use during prednancy: interim results of the belimumab pregnangy registry. Birth defects Res. 2022 sept 30. doi: 10.1002/Bdr2.2091

128. The Role of TNF-a and Anti-TNF-a Agents during Preconception, Pregnancy and Breastfeeding Int J Mol Sci 2021 Mar 13;22(6):2922

129. Mirdamadi,K.;Salinas,T.;Vali,R.;Papadimitropoulos,M.;Piquette-Miller,M.MetaAnalysisofPregnancyOutcomesafter Exposure to TNF-α Inhibitors during Pregnancy for the Treatment of Arthritic Diseases. J. Popul. Ther. Clin. Pharmacol. 2018, 25, e53–e56.

130. Bröms,G.;Kieler,H.;Ekbom,A.;Gissler,M.;Hellgren,K.;Lahesmaa-Korpinen,A.M.;Pedersen,L.;SchmittEgenolf,M.;Sørensen, H.T.; Granath, F. Anti-TNF treatment during pregnancy and birth outcomes: A population-based study from Denmark, Finland, and Sweden. Pharmacoepidemiol. Drug Saf. 2020, 29, 316–327.

131. Egeberg, A; Feldman, SR, et al. Pregnancy outcomes in patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis receiving ixekizumab. J Dermatolog Treat. 2022 Aug;33(5):2503-2509. doi: 10.1080/09546634.2021.1976375. Epub 2021 Sep 21

132. Ghalandari, N; Crijns, HJMJ; Bergman, J et al. Reported congenital malformations after exposure to non-tumor necrosis factor inhibitor biologics: A retrospecitive comparative study in EudraVigilance. Br J Clin Pharmacol. 2022 Dec;88(12):5378-5388. doi: 10.1111/bcp.15471. Epub 2022 Aug 5

133. Mitrova, K; Pipek, B et al. Safety of ustekinumab and vedolizumab during pregnancy – pregnancy, neonatal and infant outcome: a prospective multicenter study. J Crohns Colitis. 2022 Jun 16;jjac086. doi: 10.1093/ecco-jcc/jjac086.

134. Produktresumé Guselkumab

135. Reinisch W, Hellstrom W, Dolhain R, et al. Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebocontrolled MANTA and MANTA-RAy studies. Annals of the rheumatic diseases 2023;82(8):1049-58. doi:
10.1136/ard-2023-224017 [published Online First: 2023/05/04]

136. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013 May;116(5):1063-1075. doi: 10.1213/ANE.0b013e31828a4b54. Epub 2013 Apr 4. PMID: 23558845.136

137. Palmsten K, Bandoli G, Vazquez-Benitez G, Xi M, Johnson DL, Xu R, Chambers CD. Oral corticosteroid use during pregnancy and risk of preterm birth. Rheumatology (Oxford). 2020 Jun 1;59(6):1262-1271. doi: 10.1093/rheumatology/kez405. PMID: 31566229; PMCID: PMC7244781.

138. Shimada et al, low-dose glucocorticoids could affect adverse pregnancy outcomes, especially in preterm birth, light-for-date newborns, preterm premature rupture of membrane in connective tissue disease patients. Ann Rheum Dis 2019; 78 (Suppl2):783-4

139. Skorpen CG, Lydersen S, Gilboe IM, Skomsvoll JF, Salvesen KÅ, Palm Ø, Svean Koksvik HS, Jakobsen B, Wallenius M. Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study. Ann Rheum Dis. 2018 Feb;77(2):264-269. doi: 10.1136/annrheumdis-2017-211641. Epub 2017 Nov 1. PMID: 29092851.

140. Russell MD, Dey M, Flint J, Davie P, Allen A, Crossley A, Frishman M, Gayed M, Hodson K, Khamashta M, Moore L, Panchal S, Piper M, Reid C, Saxby K, Schreiber K, Senvar N, Tosounidou S, van de Venne M, Warburton L, Williams D, Yee CS, Gordon C, Giles I; BSR Standards, Audit and Guidelines Working Group. British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2023 Apr 3;62(4):e48-e88. doi: 10.1093/rheumatology/keac551. Erratum in: Rheumatology (Oxford). 2022 Dec 13;: PMID: 36318966; PMCID: PMC10070073.

141. Gayed M, Khamashta M, Culliford D et al. O58. Longterm outcomes of children born to mothers with SLE exposed to hydroxychloroquine in pregnancy. Rheumatology 2014;53:i55–i.

142. Peng W, Liu R, Zhang L et al. Breast milk concentration of hydroxychloroquine in Chinese lactating women with connective tissue diseases. Eur J Clin Pharmacol 2019;75:1547–53. 70.

143. Liu R, Zhang L, Mei D, Du X. Excretion of hydroxychloroquine in milk of lactating patients. Pharmacotherapy 2016;36: e261.

144. Chambers CD, Johnson DL, Xu R et al. Birth outcomes in women who have taken hydroxycholoroquine in
pregnancy: a prospective cohort study. Arthritis Rheumatol 2022;74:711–24.

145. Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort
study among 150,000 pregnant women and expectant fathers. Scand J Rheumatol 2012;41:196–201.

146. Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and Reproductive Health After Kidney Transplantation. Transplantation 2019;103:e325–33

147. Produktresumé Voklosporin

148 -150. se pdf

151. Weber-Schoendorfer C, Schaefer C. Pregnancy outcome after tocilizumab therapy in early pregnancy-a case series from the German Embryotox Pharmacovigilance Center. Reprod Toxicol. 2016 Apr;60:29-32. doi: 10.1016/j.reprotox.2016.01.002. Epub 2016 Jan 21. PMID: 26806369.

152. Hoeltzenbein M, Beck E, Rajwanshi R, Gøtestam Skorpen C, Berber E, Schaefer C, Østensen M. Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data. Semin Arthritis Rheum. 2016 Oct;46(2):238-245. doi: 10.1016/j.semarthrit.2016.05.004. Epub 2016 May 25. PMID: 27346577.

153. Youngstein T, Hoffmann P, Gül A, Lane T, Williams R, Rowczenio DM, Ozdogan H, Ugurlu S, Ryan J, Harty L, Riminton S, Headley AP, Roesler J, Blank N, Kuemmerle-Deschner JB, Simon A, Woolf AS, Hawkins PN, Lachmann HJ. International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors. Rheumatology (Oxford). 2017 Dec 1;56(12):2102-2108. doi: 10.1093/rheumatology/kex305. PMID: 28968868; PMCID: PMC6251516.

154. Smith CJF, Chambers CD. Five successful pregnancies with antenatal anakinra exposure. Rheumatology (Oxford). 2018 Jul 1;57(7):1271-1275. doi: 10.1093/rheumatology/key093. PMID: 29660063; PMCID: PMC7191889.

155. Powell et al, pregnancy outcomes for SLE subjects with conception during belimumab intravenous and subcutaneous placebo-controlled clinical trials and lon term Extension trials. Annals of the rheumatis Diseses 2014.

156. Danve A, Perry L, Deodhar A. Use of belimumab throughout pregnancy to treat active systemic lupus erythematosus: a case report. Semin Arthritis Rheum. 2014 Oct;44(2):195-7. doi: 10.1016/j.semarthrit.2014.05.006. Epub 2014 Jun 6. PMID: 25005336.

157. Saito J, Yakuwa N, Ishizuka T, Goto M, Yamatani A, Murashima A. Belimumab Concentrations in Maternal Serum and Breast Milk During Breastfeeding and the Safety Assessment of the Infant: A Case Study. Breastfeed Med. 2020 Jul;15(7):475-477. doi: 10.1089/bfm.2020.0068. Epub 2020 Apr 23. PMID: 32326740; PMCID: PMC7374635.

158. Crisafulli et at, Pregnany in SLE patients treated with belimumab: experience from 3 italian centers. Ann Rheum Dis 2021

159. Kao JH, Lan TY, Lu CH, Cheng CF, Huang YM, Shen CY, Hsieh SC. Pregnancy outcomes in patients treated with belimumab: Report from real-world experience. Semin Arthritis Rheum. 2021 Oct;51(5):963-968. doi: 10.1016/j.semarthrit.2021.06.005. Epub 2021 Jun 24. PMID: 34403811.

160. Produktresumé Risankizumab

161. Produktresumé Anifrolumab

162. Produktresumé Kanakinumab

163. Perez-Garcia LF, Dolhain RJEM, Vorstenbosch S, Bramer W, van Puijenbroek E, Hazes JMW, Te Winkel B.
The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: a systematic review. Hum Reprod Update. 2020 Nov 1;26(6):961-1001. doi: 10.1093/humupd/dmaa022. PMID: 32743663; PMCID: PMC7600290.

164. Perez-Garcia LF, Röder E, Krijthe BP, Kranenburg-van Koppen LJ, van Adrichem R, Zirkzee E, Griffioen PH,
Peeters K, Lin M, Struys EA, Jansen G, van Doorn MB, de Jonge R, Dohle GR, Dolhain RJ. Is methotrexate
safe for men with an immune-mediated inflammatory disease and an active desire to become a father?
Results of a prospective cohort study (iFAME-MTX). Ann Rheum Dis. 2023 Aug;82(8):1068-1075. doi:
10.1136/ard-2023-224032. Epub 2023 Jun 1. PMID: 37263756; PMCID: PMC10359513.

165. Zarén P, Turesson C, Giwercman A. Methotrexate use among men-association with fertility and the perinatal
health of their children: a Swedish nationwide register study. Fertil Steril. 2023 Sep;120(3 Pt 2):661-669.
doi: 10.1016/j.fertnstert.2023.05.005. Epub 2023 Jul 1. PMID: 37395690.