Successful transplantation improves reproductive function, permitting male KT recipients to father children [22,39,40]. The impact of immunosuppressive medication on the fertility of male KT recipients and their offspring is however unknown, since data related to paternal exposure at the time of conception are sparse. We hereby provide an estimation, based on a survey, of the proportion of male KT recipients having fathered children, and the outcome of the pregnancies.
We report a paternity rate in our population of 17%, a majority of the participants did not have children after renal transplantation.
Infertility issues
The reported infertility rate in our childless population has been estimated at 17% mainly because of spermatogenesis disorders, higher than that in the general population (Table 1). In France, among 10–15% of couples who suffer from infertility, approximately 20–30% have a male origin [42]. It is generally assumed that approximately 6–7% of men face fertility problems [43-45]. Immunosuppressive agents, notably sirolimus, have been associated with impaired fertility after transplant [25,27-29]. In a study from Zuber et al. [29], the proportion of patients who had fathered after KT was significantly lower in patients treated with sirolimus, with abnormalities in sperm analysis. Our results highlight that 27% of patients who had fathered a child after KT needed medically assisted reproduction, with an equal proportion in each group of immunosuppressive agents. The issue of male fertility in kidney transplant recipients requires additional studies.
Outcome of pregnancies fathered by male kidney transplant recipients under immunosuppressive therapy at the time of conception
This is to date one of the largest cohorts, apart from the NTPR reports, regarding paternity in transplanted patients [4,5,22]. In our population, 86%, 9%, 3% and 0.5% of respectively livebirths, spontaneous abortions, therapeutic abortions and stillbirths, occurred. The higher occurrence of unwanted outcomes observed in pregnancies fathered by patients treated with everolimus, sirolimus and belatacept should be interpreted with caution as only a few patients were exposed to these agents. Of note, the occurrence of spontaneous abortion in the general population varies between 12–15% of pregnancies [46]. In France, authorizations for therapeutic abortion are delivered in approximately 0.93% of pregnancies [47], a lower rate than the one observed in our population. The general population stillbirth rate varies from 0.9% to 0.4% [48], which is similar to our results.
In our study, among the 349 livebirths, only 9% were pre-term delivered, 6% had low birth-weights <2.5 Kg, and 4% had malformations. It should be noted that there was a higher rate of pre-term delivery in pregnancies fathered by patients treated with everolimus, and a higher rate of low birth-weight in pregnancies fathered by patients treated with sirolimus. These results should be interpreted very cautiously as only 5 and 7 patients were treated with everolimus and sirolimus, respectively. In the general population, the pre-term delivery and low birth-weight rates are 7.5%, and birth defects occur in approximately 2–3% of newborns [49,50].
Our study shows that there was no difference in the proportion of congenital malformations whether the father was exposed or not to immunosuppressive agents. Reports and analyses from the NTPR concluded that the outcomes of pregnancies fathered by male transplant recipients were similar to those of the general population. In 2010, Coscia et al. [5] reported 902 pregnancies fathered by 591 male KT recipients, with 93% livebirths but birth defects were not described. A Norwegian study reported 474 children born after transplantation, and no increased risk was found for any pregnancy outcomes compared with the general population, with a malformation rate of 1.9% [23]. Of the 13 congenital malformations in our population, 3 (one congenital phimosis, one pyloric stenosis and one Wolf Parkinson White syndrome) are well known malformations that have never been associated with any medication [51-53].
Paternal exposure to MMF/MPA at the time of conception
There has been increasing concern since the EMA recommendations on the precautions male KT recipients should take while being treated with MMF/MPA [32,33,35-37]. These recommendations rely on the theoretical potential of chromosomal damage due to the transfer of MMF/MPA through seminal fluid [30,35]. In our study, pregnancies were mostly conceived under the following medications: CTC, MMF/MPA and tacrolimus, which is currently the most common post-transplant combination worldwide [24]. The malformation rates were 4%, 3% and 5% respectively, without highlighting any over-representation of malformations under MMF. The highest malformation rate (10%) was observed with azathioprine exposure. Jones et al. [22] identified 205 pregnancies fathered by male KT recipients exposed to MMF/MPA at the time of conception, and among 194 livebirths, the rate of malformations and prematurity were 3.1% and 11%, respectively. No specific pattern of malformation was identified [22]. Recently, Midtvedt et al. [24] retrospectively compared outcomes in pregnancies fathered by male KT recipients either exposed to MMF/MPA or not at the time of conception. There were 112 patients who fathered 155 children under MMF/MPA, and 133 patients who fathered 195 children without MMF/MPA exposure. They found no difference in malformations nor pre-term deliveries in children fathered by MMF/MPA exposed compared to KT recipients not exposed [24]. The outcomes of pregnancies fathered by male transplant recipients appear similar to those of the general population and MPA embryopathies have not been noted in pregnancies fathered by those patients [21,54]. Our results add to the available data in the literature, that pregnancies fathered by patients under MMF/MPA at the time of conception do not seem to have more complications than pregnancies in the general population
Anxiety issues
To our knowledge, patient anxiety about the impact of immunosuppressive drugs on pregnancies and children has never been previously studied. Our survey reveals a signal of increased anxiety in this population, which is important to take into account to improve patient’s quality of life. Among participants who never had children, one-third did not have a desire to father children, without any differences across the centres. It remained a common feeling among men who wanted children after transplantation, as the childless patients reported feeling anxious about exposure to immunosuppressive drugs (Table 5). The design of the survey did not inquire about the reasons of this anxiety, nor its care. Our findings will require further qualitative studies, to better describe the sources of anxiety. A multidisciplinary transplant team, to help KT patients medically as well as psychologically, seems necessary in the light of our findings.
Limitation of the survey
This study has several limitations, most notably the limited response rate which was less than 50% despite several relaunches to improve participation. Our population may not be representative of the experiences of all male KT recipients. Participation was voluntary and was thus subject to reporting and selection biases. Although the response rate may limit the generalizability of our results, this survey represents to our knowledge one of the largest sampling of pregnancies fathered by male KT recipients. It should also be noted that surveys may accentuate the concerns of a minority of responders, further limiting generalizability.
The use of a questionnaire to collect past events could introduce memory bias. Participants needed to recall events that could have happened over 10-15 years back in time, which could question the validity of the collected data.
Additionally, in addition to immunosuppressive agents, KT recipients are treated with multiple other medications, and thus exposures to various other agents cannot be excluded. As previously discussed, our spontaneous abortion rate is probably under-estimated due to a misunderstanding of the questionnaire by some patients. Information about immunosuppressive drugs of patients who did not father children after KT was not collected, which limits the interpretation of our infertility rate. Moreover, our study lacks information on the graft function, which also influences male KT recipients’ ability to conceive. Finally, because of the design of the study, medical information about the mother as well as her potential treatments were not available, even though the mothers’ exposure can have a major impact when studying pregnancy outcomes.