Updated Manufacturer and European Medicines Agency Recommendations on the Use of Mycophenolate Acid

Abstract

In female solid organ recipients, the characteristic malformations caused when pregnancy occurs during mycophenolate mofetil (MMF) therapy are termed “mycophenolate mofetil embryopathy” and consists of microtia (underdevelopment of the external ear), atresia of external auditory canal, cleft lip, and/or palate and congenital heart defects.1,2 These have been extensively documented in females exposed to MMF in the first trimester and caused a category D designation by the food and drug administration for MMF and pregnancy.3 Therefore, it is common practice in female recipients who wish to become pregnant to either withdraw MMF or to switch to azathioprine if this is deemed more appropriate for rejection prevention. Recently, the manufacturers of MMF (Cellcept; Roche, Basel) and mycophenolate sodium (Myfortic; Novartis, Basel) and the European Medicines Agency recommended additional measures to prevent use of mycophenolic acid in pregnancy. The warning states: “sexually active (including vasectomized) men taking mycophenolate are recommended to use condoms for sex during treatment and for 90 days thereafter; partners of childbearing potential are also recommended to use highly effective contraception for the same period.”4 We believe that this recommendation is based on very limited data and that it seems premature to formulate a warrant advocating the use of condoms (and contraception in partners) for all men actively taking MPA and the discontinuation of MPA in men who plan to have children. In contrast to mammalian target of rapamycin inhibitors that reversibly affect sperm quality by disrupting spermatogenesis, reduce testosterone levels, and impair male fertility, no evidence could be retrieved concerning effects of MPA on sperm quality, male hormonal status, or fertility.5 One small study showed better overall sperm quality in recipients treated with MMF in combination with tacrolimus compared with patients treated with cyclosporine and azathioprine.6 In addition, when we searched PubMed (1966 to present), we could retrieve only 1 observational study in male recipients that specifically compared the incidence of congenital abnormalities in children fathered while taking MMF to the general population.7 The National Transplantation Pregnancy Registry reports on 152 men (predominantly kidney) transplant recipients with exposure to mycophenolic acids who fathered 205 pregnancies (208 outcomes). There were 194 live births with a prematurity rate of 10.8%, 14 spontaneous abortions (no therapeutic abortions/stillbirths). Among the live births, 6 malformations (3.1%) were reported, none of which were specific for MMF embryopathy. This incidence is not higher than what is expected in the general US and European population.7,8 On the flip side, the withdrawal of MPA after kidney transplantation is associated with an increased risk for acute allograft rejection and graft loss.9-11 And azathioprine use in male recipients has been associated with more elective pregnancy terminations.12 Moreover, when couples decide to store sperm samples before transplantation to resort to in vitro fertilization at a later stage, one has to balance the intrinsic risk of congenital abnormalities. Assisted reproductive technology conceived infants are at a higher risk of congenital malformations (Relative risk = 1.33 to 1.37).13,14 Last but certainly not least, the psychological burden caused by fear of triggering an acute rejection episode by discontinuing MMF or guilt when confronted with a congenital abnormality in case MMF is continued, even when no causality is proven, has to be taken into account when communicating statements to the public. Because absence of proof is not proof of absence, we encourage the transplant community to actively report live births from male recipients taking immunosuppressive drugs. In addition, the effects of MMF on sperm/ovum quality, hormone concentrations, fertility in both male and female recipients, and potential excretion in the seminal liquid should be more intensively studied. We believe that couples who wish to start a family should be informed about the scarcity of evidence for the current warning of potential adverse effects of MMF in male recipients. Also, couples should be made aware of the risk of acute rejection in case MMF is discontinued in young male recipients and the intrinsic risk for congenital malformations when opting for in vitro fertilization methods.