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Drug Safety Issues in Pregnancy Following Transplantation and Immunosuppression

Effects and Outcomes

Drug Safety volume 19, pages 219–232 (1998)Cite this article

Abstract

Successful pregnancy outcomes are possible after solid organ transplantation. While there are risks to mother and fetus, there has not been an increased incidence of malformations noted in the newborn of the transplant recipient. It is essential that there is closely coordinated care that involves the transplant team and an obstetrician in order to obtain a favourable outcome.

Current data from the literature, as well as from reports from the National Transplantation Pregnancy Registry (NTPR), support the concept that immuno suppression be maintained at appropriate levels during pregnancy. At present, most immunosuppressive maintenance regimens include combination therapy, usually cyclosporin or tacrolimus based. Most female transplant recipients will be receiving maintenance therapy prior to and during pregnancy. For some agents, including monoclonal antibodies and mycophenolate mofetil, there is either no animal reproductive information or there are concerns about reproductive safety.

The optimal (lowest risk) transplant recipient can be defined by pre-conception criteria which include good transplant graft function, no evidence of rejection, minimum 1 to 2 years post-transplant and no or well controlled hypertension. For these women pregnancy generally proceeds without significant adverse effects on mother and child.

It is of note that the epidemiological data available to date on azathioprine-based regimens are favourable in the setting of a category D agent (i.e. one that can cause fetal harm). Thus, there is still much to learn regarding potential toxicities of immunosuppressive agents. The effect of improved immunosuppressive regimens which use newer or more potent (and potentially more toxic) agents will require further study.

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References

  1. Murray JE, Reid DE, Harrison JH, et al. Successful pregnancies after human renal transplantation. N Engl J Med 1963; 269: 341–3

    PubMed  Article  CAS  Google Scholar 

  2. Friedman JM, Polifka JE. The effects of drugs on the fetus and nursing infant: a handbook for health care professionals. Baltimore: John Hopkins University Press, 1996

    Google Scholar 

  3. Fraser FC, Fainstat TD. The production of congenital defects in the offspring of pregnant mice treated with cortisone: a progress report. Pediatrics 1951; 8: 527–33

    PubMed  CAS  Google Scholar 

  4. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51: 45–6

    PubMed  Article  CAS  Google Scholar 

  5. Reinisch JM, Simon NG, Karow WG, et al. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978; 202: 436–8

    PubMed  Article  CAS  Google Scholar 

  6. Yeast JD. Immunosuppressives in pregnant transplant patients — what risks? Pharmacology 1987; 30: 117–24

    Google Scholar 

  7. Saarikoski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from mother to the fetus. Am J Obstet Gynecol 1973; 115: 1100–6

    PubMed  CAS  Google Scholar 

  8. Reimers TJ, Sluss PM. 6-Mercaptopurine treatment of pregnant mice: effect of second and third generation. Science 1978; 201: 65–7

    PubMed  Article  CAS  Google Scholar 

  9. Voogd CE. Azathioprine, a genotoxic agent to be considered non-genotoxic in man. Mutat Res 1989; 221: 133–52

    PubMed  Article  CAS  Google Scholar 

  10. Registration Committee of the European Dialysis and Transplant Association. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980; 87: 839–45

    Article  Google Scholar 

  11. Penn I, Makowski EL, Harris P. Parenthood following renal and hepatic transplantation. Transplantation 1980; 30: 397–400

    PubMed  Article  CAS  Google Scholar 

  12. Rudolph J, Schweizer RT, Bartus SA. Pregnancy in renal transplant patients. Transplantation 1979; 27: 26–9

    PubMed  Article  CAS  Google Scholar 

  13. Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis 1991; 17: 127–32

    PubMed  CAS  Google Scholar 

  14. Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 1985; 92: 233–9

    PubMed  Article  CAS  Google Scholar 

  15. Leb DE, Weisskopf B, Kanovitz BS. Chromosome aberrations in the child of a kidney transplant recipient. Arch Intern Med 1971; 128: 441–4

    PubMed  Article  CAS  Google Scholar 

  16. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol 1981; 58: 247–50

    PubMed  CAS  Google Scholar 

  17. Mason RJ, Thomson AW, Whiting PH, et al. Cyclosporine-induced feto-toxicity in the rat. Transplantation 1985; 39: 9–12

    PubMed  CAS  Google Scholar 

  18. Fein A, Vechoropoulos M, Nebel L. Cyclosporin-induced embryotoxicity in mice. Biol Neonate 1989; 56: 165–73

    PubMed  Article  CAS  Google Scholar 

  19. Kovarik JM, Mueller EA, Richard F, et al. Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation. Transplantation 1996; 62: 759–63

    PubMed  Article  CAS  Google Scholar 

  20. Kahan BD, Welsh M, Schoenberg L, et al. Variable oral absorption of cyclosporine: a biopharmaceutical risk factor for chronic renal allograft rejection. Transplantation 1996; 62: 599–606

    PubMed  Article  CAS  Google Scholar 

  21. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977–83

    PubMed  Article  CAS  Google Scholar 

  22. Farley DE, Shelby J, Alexander D, et al. The effect of two new immunosuppressive agents FK506 and Didemnin B, in murine pregnancy. Transplantation 1991; 52: 106–10

    PubMed  Article  CAS  Google Scholar 

  23. Newstead CG. Tacrolimus in renal transplantation. Nephrol Dial Transplant 1997; 12: 1312–5

    PubMed  Article  CAS  Google Scholar 

  24. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64: 559–65

    PubMed  Article  CAS  Google Scholar 

  25. Sollinger HW, Cho S, Danovitch G. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–32

    PubMed  Article  CAS  Google Scholar 

  26. The Mycophenolate Mofetil Renal Refractory Rejection Study Group. Mycophenolate mofetil for the treatment of refractory, acute, cellular renal transplant rejection. Transplantation 1996; 61: 722–9

    Article  Google Scholar 

  27. Pickrell MD, Sawers R, Michael J. Pregnancy after renal transplantation: severe intra-uterine growth retardation during treatment with cyclosporin A. BMJ 1988; 296: 825

    PubMed  Article  CAS  Google Scholar 

  28. Ahslwede KM, Armenti VT, Moritz MJ, et al. Premature births in female renal transplant recipients: degree and effect of immunosuppressive regimen. Surg Forum 1992; 43: 524–25

    Google Scholar 

  29. Lindheimer MD. Hypertension in pregnancy [clinical conference]. Hypertension 1993; 22: 127–37

    PubMed  Article  CAS  Google Scholar 

  30. Martikainen AM, Heinonen KM, Saarikoski SV. The effect of hypertension in pregnancy on fetal and neonatal condition. Int J Gynaecol Obstet 1989; 30: 213–20

    PubMed  Article  CAS  Google Scholar 

  31. Armenti VT, Ahlswede KM, Ahlswede BA, et al. National Transplantation Pregnancy Registry: outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994; 54: 502–6

    Google Scholar 

  32. Venkataramanan R, Koneru B, Wang C-CP, et al. Cyclosporine and it metabolites in mother and baby. Transplantation 1988; 468-9

  33. Bourget P, Fernandez H, Bismuth H, et al. Transplacental passage of cyclosporine after liver transplantation. Transplantation 1990; 49: 663–4

    PubMed  Article  CAS  Google Scholar 

  34. Bourget P, Fernandez H, DeLouis C. Accumulation of cyclosporine in the conceptus during the first trimester of pregnancy after liver transplantation. Transplantation 1991; 51: 1306–7

    PubMed  Article  CAS  Google Scholar 

  35. Klintmalm G, Althoff P, Appleby G, et al. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984; 38: 198–9

    PubMed  Article  CAS  Google Scholar 

  36. Shaheen FA, Al-Sulaiman M, Al-Khader AA. Long-term nephrotoxicity after exposure to cyclosporine in utero. Transplantation 1993; 56: 224–5

    PubMed  Article  CAS  Google Scholar 

  37. Pilarski LM, Yacyshyn BR, Lazarovits AL Analysis of peripheral blood lymphocyte populations and immune function from children exposed to cyclosporine or to azathioprine in utero. Transplantation 1994; 57: 133–44

    PubMed  Article  CAS  Google Scholar 

  38. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93: 137–50

    Google Scholar 

  39. Coolam CB, Moyer TP, Jiang N-S, et al. Breastfeeding after renal transplantation. Transplant Proc 1982; 14: 605–9

    Google Scholar 

  40. Flechner SM, Katz AR, Rogers AJ, et al. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis 1985; 5: 60

    PubMed  CAS  Google Scholar 

  41. Thiru Y, Bateman DN, Coulthard MG. Successful breast feeding while mother was taking cyclosporine. BMJ 1997; 345: 463

    Article  Google Scholar 

  42. Nyberg G, Haljamäe U, Frisenette-Fich C, et al. Breast-feeding during treatment with cyclosporine. Transplantation 1998; 65: 253

    PubMed  Article  CAS  Google Scholar 

  43. Anonymous. A warm chain for breastfeeding [editorial]. Lancet 1994; 344: 1239-41

  44. Grekas DM, Vasiliou SS, Lazarides AN. Immunosuppressive therapy and breast feeding after renal transplantation. Nephron 1984; 37: 68

    PubMed  Article  CAS  Google Scholar 

  45. Sturgiss SN, Davison JM. Effect of pregnancy on long-term function of renal allografts. Am J Kidney Dis 1992; 19: 167–72

    PubMed  CAS  Google Scholar 

  46. First MR, Combs CA, Weiskittel P, et al. Lack of effect of pregnancy on renal allograft survival or function. Transplantation 1995; 59: 472–6

    PubMed  CAS  Google Scholar 

  47. Sturgiss SN, Davison JM. Effect of pregnancy on the long-term function of renal allografts: an update. Am J Kidney Dis 1995; 26: 54–6

    PubMed  Article  CAS  Google Scholar 

  48. Kozlowska-Boszko B, Lao M, Gaciong Z, et al. Chronic rejection as a risk factor for deterioration of renal allograft function following pregnancy. Transplant Proc 1997; 29: 1522–3

    Article  Google Scholar 

  49. Biesenbach G, Zazgornik J, Kaiser W, et al. Cyclosporin requirement during pregnancy in renal transplant recipients. Nephrol Dial Transplant 1989; 4: 667–9

    PubMed  CAS  Google Scholar 

  50. Muirhead N, Sabharwal AR, Rieder MJ, et al. The outcome of pregnancy following renal transplantation — the experience of a single center. Transplantation 1992; 54: 429–32

    PubMed  Article  CAS  Google Scholar 

  51. Wagoner L, Taylor DO, Olsen SL, et al. Immunosuppressive therapy, management and outcome of heart transplant recipients during pregnancy. J Heart Lung Transplant 1993; 13: 993–1000

    Google Scholar 

  52. Roberts M, Brown A, James OFW, et al. Interpretation of cyclosporin A levels in pregnancy following orthotopic liver transplantation: a case report. Br J Obstet Gynecol 1995; 102: 570–2

    Article  CAS  Google Scholar 

  53. Armenti VT, Radomski JS, Moritz MJ. Parenthood after liver transplantation. Liver Transplant Surg 1995; 1: 84–8

    CAS  Google Scholar 

  54. Armenti VT, Ahlswede KM, Ahlswede BA, et al. Variables affecting birthweight and graft survival in 197 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1995; 59: 476–9

    PubMed  CAS  Google Scholar 

  55. Armenti VT, Jarrell BE, Radomski JS, et al. National Transplantation Pregnancy Registry (NTPR): cyclosporine dosing and pregnancy outcome in female renal transplant recipients. Transplant Proc 1996; 28: 2111–2

    PubMed  CAS  Google Scholar 

  56. Branch KR, Wagoner LE, McGrory CH, et al. Risks of subsequent pregnancies on mother and newborn in female cardiac transplant recipients. J Heart Lung Transplant. In press

  57. Donaldson S, Novotny D, Paradowski L, et al. Acute and chronic lung allograft rejection during pregnancy. Chest 1996; 110: 293–6

    PubMed  Article  CAS  Google Scholar 

  58. Parry D, Hextall A, Banner N, et al. Pregnancy following lung transplantation. Transplant Proc 1997; 29: 629

    PubMed  Article  CAS  Google Scholar 

  59. Scantlebury V, Gordon R, Tzakis A, et al. Childbearing after liver transplantation. Transplantation 1990; 49: 317–21

    PubMed  Article  CAS  Google Scholar 

  60. Radomski JS, Moritz MJ, Munoz SJ, et al. National Transplantation Pregnancy Registry: analysis of pregnancy outcomes in female liver transplant recipients. Liver Transplant Surg 1995; 1: 281–4

    Article  CAS  Google Scholar 

  61. McGrory CH, Radomski JS, Moritz MJ, et al. Pregnancy outcomes in 10 female pancreas/kidney (P/K) recipients. J Transplant Coord 1998; 8: 55–9

    CAS  Google Scholar 

  62. Armenti VT, Herrine SK, Moritz MJ. Reproductive function after liver transplantation. Clin Liver Dis 1997; 1: 471–85

    PubMed  Article  CAS  Google Scholar 

  63. Armenti VT, McGrory CH, Cater J. The National Transplantation Pregnancy Registry: comparison between pregnancy outcomes in diabetic cyclosporine-treated female kidney recipients and CyA treated female pancreas-kidney recipients. Transplant Proc 1997; 29: 669–70

    PubMed  Article  CAS  Google Scholar 

  64. Catnach SM, McCarthy M, Jauniaux E, et al. Liver transplantation during pregnancy complicated by cytomegalovirus infection. Transplantation 1995; 60: 510–1

    PubMed  Article  CAS  Google Scholar 

  65. Fair J, Klein AS, Feng T, et al. Intrapartum orthotopic liver transplantation with successful outcome of pregnancy. Transplantation 1990; 50: 534–35

    PubMed  Article  CAS  Google Scholar 

  66. Finlay DE, Foshager MC, Longley DG, et al. Ischemic injury to the fetus after maternal liver transplantation. Am Inst Ultrasound Med 1994; 13: 145–8

    CAS  Google Scholar 

  67. Laifer SA, Darby MJ, Scantlebury VP, et al. Pregnancy and liver transplantation. Obstet Gynecol 1990; 76: 1083–8

    PubMed  CAS  Google Scholar 

  68. Moreno EG, Garcia GI, Gomez SR, et al. Fulminant hepatic failure during pregnancy successfully treated by orthotopic liver transplantation. Transplantation 1991; 52: 923–6

    PubMed  Article  CAS  Google Scholar 

  69. Lindheimer MD, Katz AL Pregnancy in the renal transplant patient. Am J Kidney Dis 1992; 19: 173–6

    PubMed  CAS  Google Scholar 

  70. Davison JM, Lind T, Uldall PR. Planned pregnancy in a renal transplant recipient. Br J Obstet Gynaecol 1976; 83: 518–27

    PubMed  Article  CAS  Google Scholar 

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Affiliations

  1. Division of Transplantation, Department of Surgery, Thomas Jefferson University, 605 College Building, 1025 Walnut Street, Philadelphia, Pennsylvania, 19107, USA

    Vincent T. Armenti & Michael J. Moritz

  2. Department of Obstetrics and Gynaecology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, England

    John M. Davison

Authors
  1. Vincent T. Armenti
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  2. Michael J. Moritz
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  3. John M. Davison
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Armenti, V.T., Moritz, M.J. & Davison, J.M. Drug Safety Issues in Pregnancy Following Transplantation and Immunosuppression. Drug-Safety 19, 219–232 (1998). https://doi.org/10.2165/00002018-199819030-00005

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  • DOI: https://doi.org/10.2165/00002018-199819030-00005

Keywords

  • Adis International Limited
  • Tacrolimus
  • Transplant Recipient
  • Acute Rejection
  • Mycophenolate Mofetil