Update on the Teratogenicity of Maternal Mycophenolate Mofetil

In Memoriam

This article is dedicated to Vincent T. Armenti, MD, PhD (1952–2014), the founder and principal investigator of the NTPR. His guidance and leadership allowed the NTPR to flourish and provide countless transplant recipients with scientific information on which to base their family planning decisions.

Abstract

Mycophenolic acid (MPA) products, namely mycophenolate mofetil and mycophenolate sodium, are immunosuppressive medications used to prevent rejection in solid organ transplant recipients and to treat various autoimmune disorders. Mycophenolate therapy is considered to be teratogenic based on observational studies of pregnancies exposed to MPA, which demonstrated an increased incidence of miscarriages in pregnancies exposed to MPA during their first trimester and a pattern of birth defects in the offspring of some pregnancies exposed to MPA. Herein, we have detailed case and series reports in a comprehensive literature review summarizing what is known to date regarding fetal exposure to MPA. Based on evidence from the literature, results of postmarketing surveillance, and information from registries such as the National Transplantation Pregnancy Registry in the United States, it is advised that pregnancy be avoided by women taking MPA. Preconception planning offers the opportunity to explore the alternatives to protect the mother, her transplanted organ, and minimize fetal risk. How to proceed in cases of unplanned pregnancies exposed to MPA in transplant recipients is a complex issue. Research involving large epidemiological studies is expected to be sparse as women heed the warnings about becoming pregnant on MPA. Published recommendations for managing MPA in women of childbearing potential include discontinuing the medication prior to conception, switching the MPA to another medication, or discontinuing the MPA when the pregnancy is discovered.

Keywords

mycophenolate mofetil - mycophenolic acid - mycophenolate sodium - fetus - immunosuppression - teratogen - birth defect - transplantation - pregnancy

• References

• 1 Sollinger HW. A few memories from the beginning. Transplantation 2005; 80 (2, Suppl): S178-S180
• 2 Mitsui A, Suzuki S. Immunosuppressive effect of mycophenolic acid. J Antibiot (Tokyo) 1969; 22 (8) 358-363
• 3 Sabbatini M, Capone D, Gallo R , et al. EC-MPS permits lower gastrointestinal symptom burden despite higher MPA exposure in patients with severe MMF-related gastrointestinal side-effects. Fundam Clin Pharmacol 2009; 23 (5) 617-624
• 4 Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 data report. Am J Transplant 2012; 12 (Suppl. 01) 1-156
• 5 Dooley MA, Jayne D, Ginzler EM , et al; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365 (20) 1886-1895
• 6 Hu W, Liu C, Xie H, Chen H, Liu Z, Li L. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant 2008; 23 (4) 1307-1312
• 7 Callen JP, Krueger GG, Lebwohl M , et al; AAD. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49 (5) 897-899
• 8 Ang GS, Simpson SA, Reddy AR. Mycophenolate mofetil embryopathy may be dose and timing dependent. Am J Med Genet A 2008; 146A (15) 1963-1966
• 9 Goldblum R. Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin Exp Rheumatol 1993; 11 (Suppl. 08) S117-S119
• 10 Czaja AJ. Current and prospective pharmacotherapy for autoimmune hepatitis. Expert Opin Pharmacother 2014; 15 (12) 1715-1736
• 11 Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis 2014; 15 (4) 167-178
• 12 Hoeltzenbein M, Elefant E, Vial T , et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012; 158A (3) 588-596
• 13 Fujiyama N, Miura M, Kato S, Sone T, Isobe M, Satoh S. Involvement of carboxylesterase 1 and 2 in the hydrolysis of mycophenolate mofetil. Drug Metab Dispos 2010; 38 (12) 2210-2217
• 14 Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000; 47 (2-3) 85-118
• 15 Sollinger HW ; U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60 (3) 225-232
• 16 Mathew TH ; Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Transplantation 1998; 65 (11) 1450-1454
• 17 European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345 (8961) 1321-1325
• 18 Kobashigawa J, Miller L, Renlund D , et al; Mycophenolate Mofetil Investigators. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66 (4) 507-515
• 19 The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61 (7) 1029-1037
• 20 Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34 (6) 429-455
• 21 Tjeertes IF, Bastiaans DE, van Ganzewinkel CJ, Zegers SH. Neonatal anemia and hydrops fetalis after maternal mycophenolate mofetil use. J Perinatol 2007; 27 (1) 62-64
• 22 Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol 2014; 88 (7) 1351-1389
• 23 Le Meur Y, Büchler M, Thierry A , et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007; 7 (11) 2496-2503
• 24 Wang X, Qin X, Wang Y , et al. Controlled-dose versus fixed-dose mycophenolate mofetil for kidney transplant recipients: a systematic review and meta-analysis of randomized controlled trials. Transplantation 2013; 96 (4) 361-367
• 25 Mycophenolate mofetil [Package insert]. South San Francisco, CA: Genentech USA Inc; 2013
• 26 Mycophenolic acid [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2013
• 27 Eckardt K, Stahlmann R. Use of two validated in vitro tests to assess the embryotoxic potential of mycophenolic acid. Arch Toxicol 2010; 84 (1) 37-43
• 28 Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82 (12) 1698-1702
• 29 Perez-Aytes A, Ledo A, Boso V , et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype?. Am J Med Genet A 2008; 146A (1) 1-7
• 30 Anderka MT, Lin AE, Abuelo DN, Mitchell AA, Rasmussen SA. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 2009; 149A (6) 1241-1248
• 31 Lin AE, Singh KE, Strauss A, Nguyen S, Rawson K, Kimonis VE. An additional patient with mycophenolate mofetil embryopathy: cardiac and facial analyses. Am J Med Genet A 2011; 155A (4) 748-756
• 32 Parisi MA, Zayed H, Slavotinek AM, Rutledge JC. Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?. Am J Med Genet A 2009; 149A (6) 1237-1240
• 33 Finnell RH. Teratology: general considerations and principles. J Allergy Clin Immunol 1999; 103 (2, Pt 2): S337-S342
• 34 Fawcett LB, Brent RL. Developmental toxicology, drugs, and fetal teratogenesis. In: Reece EA, Hobbins JC, , eds. Clinical Obstetrics: The Fetus and Mother. 3rd ed. Malden, MA: Blackwell Publishing Inc; 2007: 217-235
• 35 Wilson JG. Embryological considerations in teratology. Ann N Y Acad Sci 1965; 123: 219-227
• 36 Pérgola PE, Kancharla A, Riley DJ. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 2001; 71 (7) 994-997
• 37 Le Ray C, Coulomb A, Elefant E, Frydman R, Audibert F. Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal malformations. Obstet Gynecol 2004; 103 (5, Pt 2): 1091-1094
• 38 Källén B, Westgren M, Aberg A, Olausson PO. Pregnancy outcome after maternal organ transplantation in Sweden. BJOG 2005; 112 (7) 904-909
• 39 El Sebaaly Z, Charpentier B, Snanoudj R. Fetal malformations associated with mycophenolate mofetil for lupus nephritis. Nephrol Dial Transplant 2007; 22 (9) 2722
• 40 Velinov M, Zellers N. The fetal mycophenolate mofetil syndrome. Clin Dysmorphol 2008; 17 (1) 77-78
• 41 Schoner K, Steinhard J, Figiel J, Rehder H. Severe facial clefts in acrofacial dysostosis: a consequence of prenatal exposure to mycophenolate mofetil?. Obstet Gynecol 2008; 111 (2, Pt 2) 483-486
• 42 Huang SY, Chueh HY, Shaw SW, Shih JC, Cheng PJ. Sonographic diagnosis of fetal malformations associated with mycophenolate mofetil exposure in utero. Am J Obstet Gynecol 2008; 199 (2) e6-e8
• 43 Vento M, Perez Aytes A, Ledo A, Boso V, Carey JC. Mycophenolate mofetil during pregnancy: some words of caution. Pediatrics 2008; 122 (1) 184-185
• 44 Carey JC. “Where observation is concerned, chance favors only the prepared mind”. Obstet Gynecol 2008; 111 (2, Pt 2): 479-480
• 45 Andrade Vila JH, da Silva JP, Guilhen CJ, Baumgratz JF, da Fonseca L. Even low dose of mycophenolate mofetil in a mother recipient of heart transplant can seriously damage the fetus. Transplantation 2008; 86 (2) 369-370
• 46 Pisoni CN, D'Cruz DP. The safety of mycophenolate mofetil in pregnancy. Expert Opin Drug Saf 2008; 7 (3) 219-222
• 47 Dei Malatesta MF, Rocca B, Gentile T , et al. A case of coloboma in a newborn to a woman taking mycophenolate mofetil in pregnancy after kidney transplantation. Transplant Proc 2009; 41 (4) 1407-1409
• 48 Jackson P, Paquette L, Watiker V, Randolph L, Ramanathan R, Seri I. Intrauterine exposure to mycophenolate mofetil and multiple congenital anomalies in a newborn: possible teratogenic effect. Am J Med Genet A 2009; 149A (6) 1231-1236
• 49 Perales-Puchalt A, Vila Vives JM, López Montes J, Diago Almela VJ, Perales A. Pregnancy outcomes after kidney transplantation-immunosuppressive therapy comparison. J Matern Fetal Neonatal Med 2012; 25 (8) 1363-1366
• 50 Klieger-Grossmann C, Chitayat D, Lavign S , et al. Prenatal exposure to mycophenolate mofetil: an updated estimate. J Obstet Gynaecol Can 2010; 32 (8) 794-797
• 51 Coscia LA, McGrory CH, Ohler L, Moritz MJ, Armenti VT. Pregnancy outcomes in heart transplant recipients with exposure to mycophenolic acid products. [Abstract] J Heart Lung Transplant 2013; 32 (4) 39A
• 52 National Transplantation Pregnancy Registry (NTPR). 2013 Annual report: Gift of Life Institute: Philadelphia, PA: NTPR; 2014
• 53 Mohamed-Ahmed O, Nelson-Piercy C, Bramham K , et al. Pregnancy outcomes in liver and cardiothoracic transplant recipients: a UK national cohort study. PLoS ONE 2014; 9 (2) e89151
• 54 Coscia LA, Constantinescu S, Moritz MJ , et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Terasaki PI, Cecka JM, , eds, Clincial Transplants 2010. Los Angeles, CA: Terasaki Foundation Laboratory; 2011: 65-85
• 55 Constantinescu S, Axelrod P, Coscia L, Moritz MJ, Armenti VT. Pregnancy outcomes in kidney recipients who discontinued mycophenolic acid products prior to conception. [Abstract] J Am Soc Nephrol 2013; 24S: 861A
• 56 Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 2009; 85 (1) 63-68
• 57 Ruiz-Campillo C, Castillo F, Perapoch J, Salcedo S. Mycophenolate mofetil use for lupus nephritis during pregnancy: report of a case of fetal malformations and literature update. The Internet J Gynecology Obstetrics 2008; 11 (2)
• 58 Zahra T, Seyyed Alireza T, Shirin S. Successful pregnancies in two orthotopic liver transplant (OLT) recipients in Iran; two case reports. J Reprod Infertil 2009; 10 (3) 225-229
• 59 Koshy AN, Strong D, Earles G, Fassett RG. Congenital malformations with low-dose mycophenolate mofetil after kidney transplantation. Nephrology (Carlton) 2010; 15 (1) 133-135
• 60 Ortiz EC, Torralba KD, Evelyn CM, Jr Q, Francisco P. Fetal and maternal outcomes with mycophenolate mofetil (MMF) exposure during first trimester of pregnancy in patients with systemic lupus erythematosus. [Abstract] Arthritis Rheum 2009; 60 (S10): 1587
• 61 March of Dimes. Pregnancy Loss. Available at: http://www.marchofdimes.org/loss/miscarriage.aspx# . Accessed December 11, 2014.
• 62 Armenti VT, Radomski JS, Moritz MJ, Branch KR, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, , eds, Clinical Transplants 1997. Los Angeles, CA: UCLA Tissue Typing Laboratory; 1998: 101-112
• 63 Clowse ME, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 2005; 52 (2) 514-521
• 64 Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010; 5 (11) 2060-2068
• 65 EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002; 17 (Suppl. 04) 50-55
• 66 European Medicines Agency European Public Assessment Report. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000082/WC500021859.pdf . Accessed December 19, 2014
• 67 Medsafe New Zealand Medicines and Medical Devices Safety Authority. Available at: http://www.medsafe.govt.nz/profs/datasheet/c/Cellceptcapsuspinf.pdf . Accessed December 19, 2014
• 68 Kim M, Rostas S, Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation strategies. Am J Transplant 2013; 13 (6) 1383-1389
• 69 Sifontis NM, Constantinescu S, Coscia LA , et al. Pregnancy outcomes with exposure to mycophenolic acid products: is there a dose relationship?. [Abstract] Am J Transplant 2011; 11 (S2) 206
• 70 Ghafari A, Sanadgol H. Pregnancy after renal transplantation: ten-year single-center experience. Transplant Proc 2008; 40 (1) 251-252
• 71 Fischer-Betz R, Specker C, Brinks R, Aringer M, Schneider M. Low risk of renal flares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology (Oxford) 2013; 52 (6) 1070-1076
• 72 Al Maimouni H, Gladman DD, Ibañez D, Urowitz MB. Switching treatment between mycophenolate mofetil and azathioprine in lupus patients: indications and outcomes. Arthritis Care Res (Hoboken) 2014; 66 (12) 1905-1909
• 73 Jordan N, D'Cruz D. Lupus nephritis flares precipitated by switching from mycophenolate mofetil to azathioprine in pre-pregnancy planning. Arthritis Rheum 2013; 65 (S10): 580
• 74 Bertsias GK, Tektonidou M, Amoura Z , et al; European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012; 71 (11) 1771-1782
• 75 Kasiske BL, Zeier MG, Chapman JR , et al; Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010; 77 (4) 299-311
• 76 Goldstein LH, Dolinsky G, Greenberg R , et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007; 79 (10) 696-701
• 77 Cleary BJ, Källén B. Early pregnancy azathioprine use and pregnancy outcomes. Birth Defects Res A Clin Mol Teratol 2009; 85 (7) 647-654
• 78 Langagergaard V, Pedersen L, Gislum M, Nørgard B, Sørensen HT. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy: A Danish nationwide cohort study. Aliment Pharmacol Ther 2007; 25 (1) 73-81
• 79 Sifontis NM, Coscia LA, Lundgren MP , et al. Pregnancy outcomes in solid organ transplant recipients with a switch from a mycophenolic acid product to azathioprine prior to conception. [Abstract] Am J Transplant 2013; 13 (S5) 161
• 80 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) 153-157
• 81 Ward RA, Brier ME. Retrospective analyses of large medical databases: what do they tell us?. J Am Soc Nephrol 1999; 10 (2) 429-432
• 82 Kennedy DL, Uhl K, Kweder SL. Pregnancy exposure registries. Drug Saf 2004; 27 (4) 215-228
• 83 Cox E, Martin BC, Van Staa T, Garbe E, Siebert U, Johnson ML. Good research practices for comparative effectiveness research: approaches to mitigate bias and confounding in the design of nonrandomized studies of treatment effects using secondary data sources: the International Society for Pharmacoeconomics and Outcomes Research Good Research Practices for Retrospective Database Analysis Task Force Report—Part II. Value Health 2009; 12 (8) 1053-1061
• 84 Merlob P, Stahl B, Klinger G. Tetrada of the possible mycophenolate mofetil embryopathy: a review. Reprod Toxicol 2009; 28 (1) 105-108
• 85 Coscia LA, Constantinescu S, Davison JM, Moritz MJ, Armenti VT. Immunosuppressive drugs and fetal outcome. Best Pract Res Clin Obstet Gynaecol 2014; 28 (8) 1174-1187
• 86 Hou S. Pregnancy in renal transplant recipients. Adv Chronic Kidney Dis 2013; 20 (3) 253-259
• 87 Hahn BH, McMahon MA, Wilkinson A , et al; American College of Rheumatology. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64 (6) 797-808
• 88 Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012; 129 (3) e827-e841
• 89 Constantinescu S, Pai A, Coscia LA, Davison JM, Moritz MJ, Armenti VT. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol 2014; 28 (8) 1163-1173