Mycophenolat Mofetil och spermieöverföring

Fråga: Tid frisk ung man. Oklar orsak till njursvikt-ev ngt medfött. Njurtransplanterad. Bra njurfunktion. Fick primär EBV-infektion post-op och immunsuppressionen har minskats. Behandlas med Prednisolon, Tacrolimus och Mycophenolat Mofetil (MMF). Önskar nu bli far. Hustru är frisk. Tidigare brydde vi oss inte om mannens MMF-behandling. I FASS har paret läst att det kanske finns risk med MMF-beh hos mannen och att man skall överväga utsättning av MMF 90 dagar före spermieöverföring. I hans fall innebär nog det övergång från MMF till Azathioprin då vi pga hans EBV-infektion vill hålla tacrolimuskonc låg. Vad säger litteraturen om handfasta råd?

Svar: It is well known that exposure to mycophenolic acid or mycophenolate mofetil (MPA/MMF) in early pregnancy of female transplant recipients has been associated with increased rate of miscarriages and birth defects (1, 2). Accordingly, a common practice in female patients who wish to become pregnant is either to withdraw MPA or switch to azathioprine before conception.

In October 2015 the European Medicines Agency (3) and the manufacturers of MPA/MMF preparations recommended additional measures to prevent MPA/MMF exposure in pregnancy. The EMA recommends the use of effective contraception during MPA treatment in males (even vasectomized), and up to 90 days after stopping therapy due to the potential risk of mutagenic effect in sperm cells and/or the possibility of transfer of MPA/MMF into semen and subsequent exposure to the fetus.

However, there is very limited published data on the possible effect of MPA/MMF on human sperms and/or fertility and the possible effects of children whose fathers used MPA/MMF at time of conception (2, 4). In an animal study, MMF had no effect on the fertility of male rats at a dose that would be equivalent to 200?mg/day in humans, while fetal malformations were noted in female rats at less than a quarter of this dose. Of note, no ill effects on the subsequent generation were observed (2).

We found one small controlled clinical study on sperm cell parameters (5), and two retrospective studies (6, 7) comparing outcomes in pregnancies fathered by organ transplant men either exposed to MPA or not at time of conception and/or pregnancy, as follows:

The study by Cao ZG (5) evaluated the effects of different immunosuppressants on sperm cell parameters of kidney transplant recipients. The study involved 15 healthy fertile men and 37 kidney transplant recipients. Twenty patients were treated with Prograf (tacrolimus) in combination with MMF and prednisone; 17 patients were treated with cyclosporine (CsA) in combination with azathioprine and prednisone. There was no significant difference in sperm viability rate, curve line velocity and velocity of average path between the groups. The rate of anomaly and straight-line velocity in tacrolimus in combination with MMF were significantly lower and higher, respectively, than those in the group of CsA in combination with azathioprine. The authors concluded that tacrolimus combined with MMF could help recover mobility and morphology of sperm cells in kidney transplantation recipients.

The study by Jones A et al (6) described the outcomes of pregnancies fathered by transplant recipients who were being maintained on MPA products at the estimated time of conception and compared these pregnancies with pregnancies in the general population. Data were collected by the National Transplantation Pregnancy Registry (Philadelphia, PA, USA). The outcomes of pregnancies fathered by transplant recipients treated with MPA products appeared similar to outcomes in the general population. A total of 152 male transplant recipients with exposure to MPA products fathered 205 pregnancies (208 outcomes, including 3 pairs of twins). Pregnancy outcomes included 194 live births with a prematurity rate of 10.8%, 14 spontaneous abortions, and no therapeutic abortions or stillbirths. Among the live births, 6 malformations (3 from children to kidney transplant recipients) for an incidence of 3.1%, were reported and no pattern of malformations was identified.

The second, nationwide population-based retrospective cohort, study by a Norwegian group (7) compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway. The authors concluded that paternal exposure to MPA did not increase the risk of adverse birth outcomes in children fathered by male kidney transplanted patients. During the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significantly increased risk of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts. The authors (7) further declared that their results are reassuring and support the continuation of paternal MPA treatment before, during, and after conception. The authors questioned whether EMA recommendation was solely due to precautionary measures. The authors argued that the study result supports the previous findings published by Jones et al (6) and questions the validity of the EMA recommendations and even urged the EMA to reconsider their current recommendations regarding MPA.

1. Deshpande NA, Coscia LA, Gomez-Lobo V, Moritz MJ, Armenti VT. Pregnancy after solid organ transplantation: a guide for obstetric management. Rev Obstet Gynecol. 2013; 6(3-4):116-25.
2. Kim M, Rostas S, Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation strategies. Am J Transplant. 2013 Jun; 13(6):1383-9.
3. European Medicines Agency. EMA recommends additional measures to prevent use of mycophenolate in pregnancy. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/10/news_detail_002418.jsp&;mid=WC0b01ac058004d5c1. Published October 23 2015.
4. Produktresume. www.FASS.se
5. Cao ZG, Liu JH, Zhu YP, Zhou SW, Qi L, Dong XC, Wu B, Lin ZB. Effects of different immunodepressants on the sperm parameters of kidney transplant recipients. Zhonghua Nan Ke Xue. 2006 May;12(5):405-7.
6. Jones A, Clary MJ, McDermott E, Coscia LA, Constantinescu S, Moritz MJ, Armenti VT. Outcomes of pregnancies fathered by solid-organ transplant recipients exposed to mycophenolic acid products. Prog Transplant. 2013 Jun; 23(2):153-7.
7. Midtvedt K, Bergan S, Reisæter AV, Vikse BE, Åsberg A. Exposure to Mycophenolate and Fatherhood. Transplantation. 2017 Jul; 101(7): e214–e217.