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Immunosuppression and Reproductive Health After Kidney Transplantation

Chandra, Anupam MD1; Midtvedt, Karsten MD, PhD2; Åsberg, Anders PhD2,3; Eide, Ivar Anders MD, PhD1

doi: 10.1097/TP.0000000000002903
Review
Open

Following successful kidney transplantation, recipients usually regain fertility. Post-engraftment pregnancies should be planned and the teratogenic mycophenolic acid should be replaced with azathioprine before conception. To avoid unintentional pregnancies, pre-conception counseling is mandatory in women of reproductive age who are scheduled for a kidney transplant. Counseling should be repeated after transplantation. Female recipients should receive advice to use long-acting reversible contraception and avoid pregnancy for a minimum of 1 year following transplantation. Conception should be deferred even longer in female recipients with moderate to severe proteinuria, uncontrolled hypertension or reduced graft function and be very carefully discussed in highly HLA-sensitized patients. The recipient wishes, values and acceptance of pregnancy-related risk should receive attention. Assisted fertilization increases the risk of pre-eclampsia, but still result in live births. Pregnancy management in kidney transplant recipients should be provided by a multidisciplinary team consisting of a nephrologist, a midwife and an obstetrician with expertise in high-risk pregnancies. Until measurement of unbound fraction of calcineurin inhibitors becomes clinically available, we recommend to adjust calcineurin inhibitor dose according to whole blood trough level, even though it overestimates the effective drug concentration during pregnancy. If nephrotoxicity is suspected, the calcineurin inhibitor dose should be reduced. Breastfeeding should be accepted after kidney transplantation since infant immunosuppressive drug exposure via breastmilk is extremely low. The prevalence of congenital malformations in children fathered by male recipients, including patients on mycophenolic acid therapy at the time of conception, is at level with the general population.

1 Department of Renal Medicine, Akershus University Hospital, Lorenskog, Norway.

2 Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Norway.

3 Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.

Received 1 February 2019. Revision received 29 June 2019.

Accepted 1 July 2019.

All authors jointly agreed upon the outline of the article. A.C. wrote the draft, and all authors contributed in the revision and finalization of the manuscript.

The authors declare no funding or conflicts of interest.

Correspondence: Anupam Chandra, MD, Department of Renal Medicine, Akershus University Hospital, Pb 1000, 1478 Lorenskog, Norway. (Anupam.Chandra@ahus.no).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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INTRODUCTION

Kidney transplantation reduces morbidity and mortality, improves quality of life and restores sexual function and fertility in most patients with end-stage renal disease.1 Historically, female kidney transplant recipients (KTRs) were advised not to become pregnant, due to concern for maternal, graft, and fetal health.2 Since pregnant women are excluded from immunosuppressive drug trials, safety data in KTR pregnancies are limited to animal studies and slowly accumulating epidemiological data, mainly from voluntary registries, plus case series and retrospective single-center cohort studies. Thus, recommendations for use of immunosuppressive drugs in pregnant KTRs are established with a rather low level of proof.3 Epidemiological data suggest a high likelihood of successful KTR pregnancy outcomes, especially for women on mycophenolic acid (MPA) free regimens who conceive beyond the first year post-transplant.4-6 In this review, we will address some unresolved issues and uncertainties concerning immunosuppressive therapy and reproductive health in KTRs.

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FERTILITY

Renal insufficiency inhibits gonadal function, thus most men and women with end-stage renal disease are infertile.7 During the first few months after kidney transplantation, sex hormone levels tend to normalize, sexual function improve, menstruation returns in female KTRs, motile sperms are produced in male KTRs and fertility is restored in the majority of patients.7 Therefore, we strongly recommend that pre-conception counseling becomes mandatory in female recipients of reproductive age.3,8 We also recommend physicians to provide pre-conception counseling for all young- and middle-aged female and male patients scheduled for a kidney transplant, to repeat counseling in the early post-transplant phase and thereafter provide annual counseling for women of reproductive age. Some frequent questions during pre-conception counseling are given in Table 1. The counseling should also address the fact that some recipients remain infertile due to antiviral or immunosuppressive drugs side-effects9-17 and non-pharmacological causes,7,18,19 as presented in Table 2.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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FATHERHOOD

MPA is teratogenic.20 Paternal MPA exposure at the time of conception could theoretically pose a threat to the unborn child; thus the European Medicines Agency recommend that sexually active men on MPA should use a barrier contraceptive method and advice their female partners to use highly effective contraception.21 This is, however, not supported by epidemiological data or theoretic pharmacological calculations.

Jones et al (n = 152 pregnancies, United States) reported a 94% live birth rate fathered by male solid organ transplant recipients on MPA therapy at the time of conception. There were 11% preterm deliveries, which is more frequent than in the general population, but only 3% congenital malformations, similar to the general population.22 Morken et al (n = 474 pregnancies, Norway) reported that pre-eclampsia was more frequent in pregnancies fathered by transplant recipients (odds ratio 1.5), while preterm delivery, small for gestation age and congenital malformation prevalence was similar in post-transplant deliveries and the general population.23 A major strength of this study was that the cohort included all consecutively transplanted males nationwide in Norway, as opposed to voluntary registry cohort studies subject to reporting bias. Unfortunately, the proportion of patients on MPA treatment was not given in this article. In a recent cohort study of children fathered by KTRs (n = 350, deliveries on MPA n = 155 and not on MPA treatment n = 195, Norway), Midtvedt et al24 found no differences in congenital malformation prevalence or birth weight between the groups. A strength of this publication was the fact that the authors provided MPA trough-values close to the time of conception. Congenital malformations after maternal MPA exposure during pregnancy typically form a pattern of orofacial defects.20 No such pattern was shown after paternal MPA exposure.24 A recent small cohort study by Lopez-Lopez et al found a trend towards more miscarriages in pregnancies fathered by KTRs on MPA therapy (n = 20) compared with recipients not on MPA (n = 13, of whom 8 received azathioprine [AZA]) at the time of conception (18% versus 9%), but no difference in congenital malformations.25

Data accumulated from voluntary registries suggest that paternal exposure to corticosteroids (CS), calcineurin inhibitors (CNIs), cyclosporine A (CsA), tacrolimus (Tac), and AZA do not increase risk of obstetric complications or congenital malformations.9 Data on pregnancies fathered by KTRs on mammalian target of rapamycin inhibitor (mTORi) or belatacept therapy are very limited. Antithymocyte globulin (ATG) or basiliximab are frequently used as induction therapy, and to the best of our knowledge, there are no data addressing the specific impact on male fertility or pregnancies fathered by KTRs receiving these drugs. Induction with rituximab can be used in ABO blood group incompatibility and in highly human leukocyte antigen (HLA)-sensitized patients.26 A small meta-analysis of case reports by Mouyis et al27 (n = 16) focused on pregnancy outcomes after paternal exposure to rituximab. From 9 pregnancies with reliable outcome data, there were 7 uncomplicated live births and 2 miscarriages, suggesting that paternal rituximab exposure is compatible with successful pregnancies, although paucity of data infer caution.27

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PRE-CONCEPTION COUNSELLING IN FEMALE RECIPIENTS

Pregnancy and Graft Outcomes

Pregnancy is advisable beyond 1 year post-engraftment (Figure 1), when there has been no history of rejection during the last year, no current or recent fetotoxic infections, no or well-controlled hypertension, no or minimal proteinuria, stable graft function (serum creatinine <1.5 mg/dL, <133 µmol/L) and maintenance immunosuppression at stable dosing.3 However, even then, pre-eclampsia, preterm delivery, low birth weight, and small for gestation age are prevalent in KTR pregnancies.4-6 A 2-fold higher prevalence of gestational diabetes likely contributes to a higher risk of infections, some of which may be transmitted to the fetus. A 10-fold higher prevalence of hypertension in KTR pregnancies partly explains the high pre-eclampsia rate.4 Nonetheless, KTR pregnancies on MPA-free regimens are not associated with a higher risk of miscarriage.4-6 An increased risk of graft loss during pregnancy is shown for pregnancies during the first 3 years following transplantation, which in most cases were women with impaired renal graft function (serum creatinine >1.5 mg/dL/>133 µmol/L) at the time of conception.4,28

FIGURE 1

FIGURE 1

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Adverse Maternal and Fetal Effects of Immunosuppressive Drugs

All immunosuppressive drugs commonly used after kidney transplantation cross the placenta to some degree, where they pass into the fetal circulation via the fetal intestine system and carry some risk of teratogenic and fetotoxic effects, and some also increase the risk of obstetric complications and maternal disease,1,20,29-48 presented in Table 3. MPA stand out with frequent birth defects with a typical pattern and a high miscarriage rate.20 Other obstetric complications like preterm birth and intra-uterine growth retardation are also common after MPA exposure.20 CS and CNIs put the pregnant recipient at increased risk of diabetes and hypertension.1 Due to paucity of pregnancy outcome data on mTORi and belatacept, they are not considered the drug of choice in women who want to conceive and should be discontinued in case of pregnancy.33,48 There is also very limited data on the impact of recent rituximab, basiliximab, and ATG exposure in pregnant women.33,48 Some other drugs commonly used after kidney transplantation like statins, antiviral drugs, and angiotensin-converting enzyme inhibitors should also be discontinued in pregnancy.3 In contrast, large amount of voluntary registry data accumulated over the last 6 decades suggest that CS, CNIs, and AZA can be used in pregnant KTRs with little risk of adverse effects on the fetus or graft.3,48 Detailed discussions on this topic can be found elsewhere.33,48

TABLE 3

TABLE 3

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Timing of Conception

The American Society of Transplantation recommends to avoid pregnancy during the first year after kidney transplantation and defer conception further in recipients at increased risk of fetal or maternal adverse events, including patients with diabetes, obesity, uncontrolled hypertension, moderate or severe proteinuria, advanced maternal age, multiple pregnancies, recurrent urinary tract infections, recurrent viral infections and/or use of antiviral agents, assisted fertilization, high-dose maintenance immunosuppressive therapy or immunosuppressive drug non-adherence.3 Delaying conception implies that the recipient will miss valuable childbearing years and more patients will conceive at an advanced maternal age (≥35 y), which increases the risk of miscarriage,4 or they may even miss their chance of conceiving. On the other hand, the prevalence of pre-eclampsia and preterm delivery was slightly higher in pregnancies conceived during the first 2 years after transplantation.4 Some physicians have questioned whether the recommendation to defer conception beyond 1-year post-transplant could be further liberalized in selected recipients.49 However, Gill et al50 (n = 530 pregnancies, United States) reported a borderline increased risk of miscarriage in pregnancies during the first year after transplantation (odds ratio 1.7), suggesting caution. A recent study by Rose et al (n = 729 pregnancies, United States) showed an increased graft failure risk for pregnancies during the first 3 years post-engraftment,28 suggesting that conception should be deferred in younger recipients.

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Contraceptive Use and Interactions With Immunosuppressive Drugs

Typical use failure rates for available contraceptive methods and interactions between immunosuppressive and contraceptive drugs are presented in Table 4.51–55 Long-acting reversible contraceptive methods like intra-uterine devices or progestin subdermal implants offer highly efficient contraception at level with sterilization, while failure rates are relatively high for contraceptive pills and barrier methods like condoms.51 MPA and CS might interact with combined hormonal contraceptive drugs, reducing their efficacy.56 An excellent review provides an in-depth discussion of safety and efficacy of available contraceptive methods in organ transplantation.52

TABLE 4

TABLE 4

Recent reports from Guazzelli et al (n = 197, Brazil) and Eide et al (n = 118, Norway) indicate that <10% of female KTRs of reproductive age use a long-acting reversible contraceptive methods,57,58 even in the modern era where efficient contraception has received more focus.8 It is disturbing that 51% of the Brazilian recipients and 37% of the Norwegian recipients could not recall having received any advice on contraceptive use from healthcare personnel.57,58 Surprisingly, KTRs who received such advice used a barrier method more often than women who did not receive any contraception counseling.57 Condom was the most frequent contraceptive method followed by contraceptive pills, and could partly explain the high rate of unintentional pregnancies.57,58

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Shared Decision-making

Women of reproductive age who are scheduled for or have received a kidney transplant are faced with many dilemmas concerning reproductive health; hence, they need counseling. The treating physician must ensure that information about maternal, graft and fetal risks related to post-transplant pregnancy is comprehended by the patient. Recipients report a need for more information about reproductive health issues, and many feel that their physician does not support their wish to become pregnant.59 Post-engraftment pregnancy rates have dropped after the introduction of MPA.50 Some physicians might be reluctant to replace MPA with AZA due to a higher risk of rejection and therefore avoid pre-conception counseling or advice the recipient to avoid pregnancy.60 To the best of our knowledge, physicians’ attitudes toward pre-conception counseling in KTRs have not been studied.

Recipient autonomy may be lost, as their medical conditions complicate pregnancy decision-making. There are many aspects of reproductive and mental health that needs to be considered: Anxiety for congenital malformations and obstetric complications, pregnancy leading to impaired graft function and return to dialysis, guilt for disappointing their partner if they choose not to become pregnant or for becoming a mother with a somewhat reduced life-expectancy.61 In addition to medical advice, physicians should offer the recipient psychological support and build their advice on the wishes, values, and acceptance of pregnancy-related risk to enhance patient autonomy and ensure shared decision making.61 A recent Italian position statement on KTR pregnancies have incorporated shared decision-making in their recommendations to set a new standard in preconception counseling.8

Recipients with advanced maternal age and recipients who receive advice to delay conception for a minimum of 2 years after kidney transplantation may consider adoption. However, some transplant recipients experience restricted access to adoption services due to morbidity or shorter life-expectancy, leaving them no other chance for parenthood than pregnancy. It is critical that patients at particular high risk of adverse maternal or graft outcomes receive repeated personalized counseling on contraceptive use and timing of conception.3,8

Pregnancy management should be provided by a multidisciplinary team (nephrologist, a midwife and an obstetrician),3 but there is at present little data to confirm that this service is actually provided.

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Highly Human Leukocyte Antigen-Sensitized Patients

Highly HLA-sensitized KTRs have an increased risk of antibody-mediated rejection.62 Pregnancy data on highly HLA-sensitized KTR pregnancies are very limited. Ajaimy et al63 compared pregnancy and graft outcomes in sensitized (n = 8) and non-sensitized recipients. They found a higher cumulative incidence of pre-eclampsia, preterm delivery and low birth weight in sensitized patients, as well as a marked increase in antibody-mediated rejections leading to graft loss (n = 3 out of 8 sensitized recipients). These findings make clear that highly HLA-sensitized KTRs need to be explained the potential risk a pregnancy may pose for them, and physicians should ensure that they have understood this information. For the treating practitioner, it may seem clear that pregnancy is too risky and that they should consider not to proceed pregnancy due to a high risk for both the recipient and for the fetus. Nevertheless, some individuals may prioritize pregnancy so highly that they may be willing to take on this risk even after receiving balanced information from the medical team.

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Assisted Fertilization

Successful pregnancy after assisted fertilization is possible after kidney transplantation, but data are limited to case-reports.64 All studies reported healthy deliveries and no deterioration of graft function. However, 4 out of 5 cases were complicated by gestational hypertension, pre-eclampsia, premature rupture of membranes, and premature delivery.64 In addition, assisted fertilization is associated with multiple pregnancies, which further increases the risk of obstetric complications.65 These case reports do not include data specifically on the follicle-stimulating hormone pre-treatment. Moreover, since only a few cases have been reported, there could be a publication bias underestimating adverse events after assisted fertilization in KTRs.8

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MANAGEMENT OF PREGNANT AND LACTATING RECIPIENTS

Therapeutic Drug Monitoring

During pregnancy, cytochrome P450 3A4 is upregulated which increase CNI metabolism and reduce whole blood CNI concentrations.31 In addition, plasma volume is increased and drug-binding red blood cell and albumin levels are lower, leading to a further decline in whole blood drug concentrations.31 By the end of the first trimester, a 25%–50% increase in CNI dose could be necessary to maintain whole blood through levels. Adjusting the dose to reach target trough levels may, however, induce over-immunosuppression.30

Tac binds to red blood cell (85%–95%) and albumin (5%–15%), with only a minor unbound fraction. In line with Tac being a medium/low extraction drug, Zheng et al31 showed that the unbound Tac concentration remained virtually unchanged, since the unbound clearance is only minorly increased, despite a 39% decline on average in whole blood trough levels during pregnancy. Moreover, no acute rejection episode was observed in 21 pregnancies in single kidney or simultaneous kidney-pancreas recipients, where Tac dosage was not adjusted despite lower whole blood trough levels.66 The ideal Tac monitoring of pregnant KTRs would be measurement of the unbound Tac concentration. This is possible, but the technique is challenging and expensive and not commonly available.

Two Tac dosing strategies have been suggested: (1) maintain Tac dose unchanged from conception and throughout pregnancy, and only increase dose if whole blood through levels drop >50% or (2) adjust Tac dose to stay in the trough target range and decrease dose only if nephrotoxicity is suspected.30 Until more robust data are available, we recommend to use strategy 2.

Most of circulating CsA is bound to red blood cell and plasma lipoproteins and the free fraction range between 4% and 12%.67 Similar to Tac, CsA trough levels are based on whole blood measurements, but it is the free concentration that is active.68 In a study on pregnant KTRs, CsA trough levels decreased on average by 23% in first trimester, 39% in second trimester, and 29% in third trimester compared with pre-conception levels.68 The Transplant Pregnancy Registry International report that CsA dose was increased in 44% of KTR pregnancies, although dose adjustment is in theory not necessary.69

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Acute Rejection Therapy

Pregnancy induce hyperfiltration and increased creatinine clearance, accompanied by a small reduction in serum creatinine level.70 Thus, a small increase in serum creatinine is suggestive of an acute rejection episode, pre-eclampsia, CNI nephrotoxicity or in rare cases caused by the growing uterus obstructing flow through the transplant ureter.2 To rule out ectopic pregnancies we recommend to perform a baseline ultrasound examination early after conception. In case of decreasing graft function during pregnancy, an indication ultrasound examination should be performed. If pre-eclampsia, urinary tract infection, and ureter obstruction are ruled out, an ultrasound-guided renal allograft biopsy can help establish the acute rejection diagnosis. With verified rejection, high-dose methylprednisolone therapy is considered safe in pregnant KTRs (Table 3), while there is insufficient safety data on ATG and rituximab to recommend their use in pregnant recipients.3,48

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Unintentional Pregnancies

Data on the prevalence of unintentional KTR pregnancies are surprisingly scarce.3 Some studies report that most KTR pregnancies were not planned,58 in which use of contraceptive methods with high failure rates was reported in most cases. Maternal and fetal risks related to unintentional pregnancies in KTRs greatly exceed that of contraceptive use.2 A major concern is MPA exposure during pregnancy, causing congenital malformations.20 KTRs who have become unintentionally pregnant and express no clear intention to terminate the pregnancy, should without further delay, immediately replace MPA with AZA. There are no data on unintentional pregnancies on mTORi therapy; thus it should be discontinued and the immunosuppressive regimen changed to a combination of CS, CNI, and AZA. Repeated ultrasound examinations to look for signs of congenital malformations should be performed, but even severe structural malformations may not be visible in the early phase of pregnancy.

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Breastfeeding

Recipients have traditionally been advised to refrain from breastfeeding to avoid transfer of immunosuppressive drugs to the infant via breastmilk.71 In recent years, recommendations have been liberalized, since neonatal exposure to immunosuppressive drugs via breastmilk is extremely low71-77 (Table 3). The recommended combination of CS, CNI, and AZA in pregnancy can be safely continued in lactating women.71 Due to paucity of data, patients on MPA, mTORi or belatacept therapy, as well as patients recently exposed to rituximab are however recommended to avoid breastfeeding. When KTRs stop breastfeeding, patients who were switched from MPA to AZA before conception and have no plan for becoming pregnant again in the near future, should be converted back to MPA therapy to lower the risk of rejection. An excellent review provides an in-depth discussion of this topic.71

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CONCLUSIONS

This review mainly focuses on unresolved issues regarding immunosuppression and reproductive health in KTRs and point out some related key points (Table 5). There is a need for more knowledge on, for example, the impact of in utero exposure to mTORi and belatacept, CNI dosing strategies during pregnancy and possible effects of commonly used induction therapies like ATG or basiliximab. Additional studies on the impact of paternal MPA exposure on the fetus are also warranted. Pre-conception counseling is mandatory and should acknowledge the importance of recipient autonomy and shared decision-making.

TABLE 5

TABLE 5

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