The newer immunosuppressive agents such as mycophenolate mofetil (MMF) and sirolimus (SRL) have been proven effective in reducing the incidence of acute cellular rejection in renal transplant recipients when compared to traditional agents such as azathioprine (1–3). While the majority of pregnancies reported in the literature after transplantation have occurred in patients treated with combinations of prednisone, calcineurin inhibitors (CNI) and azathioprine, data are accruing on pregnancy outcomes with the use of the newer agents.
The United States Food and Drug Administration (FDA) categorizes drugs for pregnancy safety as: A=adequate and well-controlled studies have failed to demonstrate a risk to the fetus in any trimester of pregnancy; B=animal reproductive studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; C=animal reproductive studies have shown an adverse effect on the fetus or are lacking, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks; D=there is positive evidence of human fetal risk, but potential benefits may warrant use of the drug in pregnant women despite potential risk; X=contraindicated: studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. While most immunosuppressive agents are classified as Pregnancy Category C, there is a broad range of experience and safety among the agents in this category.
Mycophenolate mofetil, an ester prodrug of mycophenolic acid, is a reversible inhibitor of inosine monophosphate dehydrogenase which blocks de novo purine synthesis in T and B lymphocytes. This agent is classified as Pregnancy Category C (4). Reproductive toxicity studies in animals raise the concern that there may be teratogenic risks associated with MMF use. Pregnant rats and rabbits treated with MMF exhibited developmental toxicity, intrauterine death and malformations such as anophthalmia, agnathia, hydroencephaly and diaphragmatic hernia at doses which appear to be within recommended clinical doses based on body surface area (4–7). The manufacturer strongly recommends effective contraception before beginning MMF therapy, during therapy and for six weeks after MMF has been discontinued (4).
Sirolimus is a macrolide immunosuppressant whose primary mechanism of action is inhibition of cytokine driven T-cell proliferation, thereby preventing cell cycle progression from the G1 to S-phase. Like mycophenolate mofetil, sirolimus is classified as a Pregnancy Category C agent (8). In animal studies, decreased fetal weights and delayed ossification of skeletal structures have been reported, however, no evidence of teratogenicity was noted (5–8). Nevertheless, teratogenic risk associated with the use of SRL cannot be ruled out in humans. The manufacturer strongly recommends effective contraception before beginning SRL therapy, during therapy and for 12 weeks after SRL therapy has been discontinued (8).
The purpose of this study was to analyze the outcomes of pregnancies in female solid organ transplant recipients with exposure to MMF or SRL reported to the National Transplantation Pregnancy Registry (NTPR).
The study method included a single page questionnaire with a consent form. The questionnaires were completed and signed by transplant recipients who were identified by their coordinators, physicians, or who self-reported to the NTPR. Consent allowed for contact with the recipients via phone interviews, and for the request of medical records for both parent and child. Periodic follow-up included telephone interviews with the recipient and transplant centers and review of medical records when available.
Mycophenolate Mofetil Exposure in Female Transplant Recipients Reported to the NTPR
There were 18 kidney recipients with 26 pregnancies with exposure to MMF reported to the registry (Table 1). Exposures were varied since, in 14 of these pregnancies, upon discovery of the pregnancy, MMF was decreased or stopped and some women were switched to azathioprine. In general, these pregnancies were premature (mean gestational age <37 weeks). Of the 26 pregnancies, 15 were live births with four (26.7%) of these reporting structural malformations (Table 1 and 2). The structural malformations are discussed in more detail below and concomitant medications are listed in Table 2. The eleven spontaneous abortions occurred in the first trimester.
This recipient was transplanted with her second kidney at three weeks gestation. Her posttransplant immunosuppressive regimen included MMF 1000 mg bid, tacrolimus and prednisone (9). At 26 weeks the pregnancy was discovered and MMF was decreased to 500 mg bid. At 34 weeks gestation the patient delivered a preterm infant with a birth weight of 2440 grams. The child was noted to have hypoplastic nails and shortened fifth fingers. Based on follow-up telephone interviews with the mother, the child was reported to be healthy and developing well at last follow-up at six years of age.
This recipient conceived while maintained on MMF 500 mg bid, tacrolimus and prednisone. At 24 weeks, a biopsy- proven moderate acute rejection (Banff grade II A) occurred which was treated with corticosteroids and Thymoglobulin® and MMF was switched to SRL at that time. Dialysis was also required. The patient delivered a preterm (31 weeks), low birth weight (1531 grams) infant. The newborn was reported to have a cleft lip and palate which was surgically repaired at one year, and microtia, which is a congenital ear malformation. At last follow up, at four years of age, the mother reported that the child currently wears bone conduction hearing aides; but is otherwise healthy and developing well. Further evaluation of the ear deformity is anticipated.
This recipient conceived while on MMF 250 mg bid, tacrolimus and prednisone. MMF was continued throughout the pregnancy. At 35 weeks gestation, the patient delivered a preterm infant weighing 2155 grams. The infant died one day after delivery. Multiple malformations were reported, including cleft lip and palate, microtia, congenital diaphragmatic hernia and congenital heart defects. Medical records suggest a possible association of these observed structural malformations with Fryn’s syndrome, which is an autosomal recessive congenital anomaly characterized by diaphragmatic hernia as well as craniofacial abnormalities and is associated with a high mortality rate.
This recipient conceived while maintained on MMF 1000 mg bid, tacrolimus and prednisone. MMF was discontinued in the second trimester. The patient delivered a full term (39 weeks), normal birth weight (2886 grams) infant. This newborn was also reported to have microtia.
There were six non-renal recipients with seven pregnancies who reported exposure to MMF to the registry (Table 3). These include one kidney/pancreas recipient (one pregnancy), three liver recipients (three pregnancies) and two heart recipients (three pregnancies). MMF exposure was varied in this series as well. Of the seven pregnancies, three were live births and four were spontaneous abortions. No structural malformations were reported in the live births.
Sirolimus Exposure in Female Transplant Recipients Reported to the NTPR
There were seven recipients with seven pregnancies with exposure to SRL (Table 4). This included four kidney recipients, one kidney/pancreas recipient and two liver recipients. SRL was discontinued (n=2) or switched to azathioprine in the first trimester (n=2) in four of the pregnancies. This alteration in therapy occurred within the first six weeks of gestation, upon discovery of pregnancy. Similar to the outcomes in female transplant recipients exposed to MMF reported to the NTPR, the offspring of patients exposed to SRL were generally premature (mean gestational age <37 weeks). Of the seven pregnancies, four were live births. Of the three spontaneous abortions, all occurred in the first trimester. There were structural malformations noted in one pregnancy, (see Case 2 with exposure to MMF). It is important to note that sirolimus exposure in Case 2 was a late pregnancy exposure (24 wks gestation) and therefore the structural malformations are unrelated to sirolimus in this case. There were no live births reported to the NTPR in female recipients exposed to sirolimus throughout gestation.
Negative biases regarding pregnancy after solid organ transplantation are particularly three-fold, relating to 1) the mother- risks to her long-term health and ability to parent, 2) the allograft- any risk of the pregnant state itself and potential changes in drug metabolism increasing the susceptibility to rejection, and 3) the fetus- potential teratogenic risks associated with immunosuppressants. Despite these concerns, more than 14,000 pregnancies have been reported worldwide in solid organ transplant recipients on chronic immunosuppressive therapy, many of them being live births, and without an increase in the incidence of structural defects to date (10–11).
The most recent European Best Practice Guidelines recommends that immunosuppressive therapy based on cyclosporine or tacrolimus with or without corticosteroids and azathioprine may be continued in renal transplant recipients during pregnancy (12). Other drugs, such as MMF or SRL are not recommended based on the current information available (12). The guidelines suggest that women taking MMF should transition to another agent and then wait six weeks before they attempt to conceive. Parenthetically, while six weeks may be the appropriate MMF washout period, the potentially increased risk in rejection associated with a switch to a less efficacious agent such as azathioprine would manifest over a much longer period of time (1–2).
Registry data have failed to demonstrate any pattern of congenital abnormality associated with the use of calcineurin inhibitors, azathioprine or corticosteroids (10). The overall incidence of structural malformations in a recent analysis of the NTPR was 4–5% (10). The etiology of such birth defects may be multifactorial with 2–3% of these defects being classified as teratogen-induced malformations resulting from environmental or drug exposures during pregnancy (5). This series reports a higher incidence of structural malformations in the liveborn reported to the NTPR in recipients with MMF exposure (four cases in 15 liveborn with exposure, 26.7%) which has not been seen in previous NTPR analyses. Further, three of the four (75%) of the structural malformations included microtia, which is defined as a small, abnormally shaped, incompletely formed or absent external and middle ear and may be bilateral or unilateral. Microtia encompasses a broad range of ear defects and can be associated with other congenital malformations. The cause of microtia is thought to be heterogenous, including genetic abnormalities, vascular aberrations and/or teratogens (13–14). Therefore, additional investigation as to the etiology of microtia in the cases reported to the NTPR is warranted.
In addition to these reports to the NTPR, there were similar findings noted in a recent case report from France of major congenital malformations including microtia associated with in utero exposure to MMF (15). Le Ray et al. reported a female renal transplant recipient who was maintained on MMF 250 mg bid, tacrolimus and prednisone before conception and during the first trimester (15). The pregnancy was terminated at 22 weeks because of prenatal diagnosis of multiple fetal malformations which proved to include: cleft lip and palate, microtia and external auditory duct atresia (15). This case report, along with the data from our series documenting an increased risk of structural malformations, particularly microtia, raises concern for the use of MMF during pregnancy.
Whether therapeutic drug monitoring or other immune monitoring techniques for MMF can mitigate pregnancy exposure risk will require further investigation. In contrast to the calcineurin inhibitors and sirolimus, therapeutic drug monitoring of MMF has not been the standard approach in adjusting doses to maintain efficacy and prevent toxicity. Another means to address the concerns of MMF exposures during pregnancy would be to evaluate pregnancy exposures to MMF in the non-transplant population, many of whom would not likely be taking the multiplicity of agents similar to transplant recipients.
Regarding sirolimus, in addition to the results from our series, Jankowska et al. published a recent case report of a female liver recipient maintained on tacrolimus, sirolimus and prednisone before conception and during the first trimester (16). The recipient delivered a healthy term infant at 39 weeks with no structural malformations (16). More recently, in a letter to the editor, Guardia et al. reported on a successful pregnancy under sirolimus based immunosuppression (17). To date, there are limited data on the incidence of structural malformations associated with the use of sirolimus during pregnancy.
The pregnancy issues that face recipients and caretakers regarding the current adjunctive therapies and differing combinations of immunosuppressive regimens continue to require further study. Of most concern is the risk of fetal exposure to MMF or SRL relative to the potential improvement in maternal graft function/survival conferred by these agents. Pregnancy outcomes with exposure to the newer adjunctive agents, however, remain limited. These preliminary data report on the structural malformations noted in the offspring of female kidney transplant recipients exposed to MMF. These data highlight the potential complexities of immunosuppressive choices and management decisions in female transplant recipients of childbearing age.
There are inherent limitations to this study noteworthy of mention. In particular, the fact that reporting to the registry is voluntary could lead to negative bias or underestimation of pregnancy outcomes and/or structural malformations reported. In addition, since patients are treated with multiple medications posttransplantation, exposures and timing of various other agents cannot be ruled out as potential confounders. Given the multiplicity of immunosuppressive regimens and comorbidities, only broad-based registry participation can provide the data needed to answer these questions.
Of the liveborn reported to the NTPR, a higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring. Three of the four defects included microtia (ear deformity), suggesting a pattern of malformations. However, liveborn outcomes without structural malformations have also been noted in the MMF cohort. No structural defects have as yet been reported with early pregnancy sirolimus exposures in a limited number of recipients evaluated.
The structural malformations seen in the MMF exposure group have not been previously reported to the NTPR. While these data appear to support the package insert recommendations of prospectively discontinuing MMF at least six weeks prior to conception, the reality of a significant number of unplanned pregnancies as well as the need for long-term immunouppression in these patients make this approach overly simplistic. Additionally, the reported adverse pregnancy events may be related to other susceptibilities in this population.
Given the ongoing concerns of the newer immunosuppressive agents, clinicians are responsible for providing pregnancy counseling in all pre- and post-transplant recipients of childbearing age. Moreover, centers are encouraged to report all pregnancy exposures in transplant recipients to the NTPR.
The National Transplantation Pregnancy Registry (NTPR) acknowledges the cooperation of transplant recipients and over 200 centers in North America who have contributed their time and information to the registry. The NTPR is supported by grants from Novartis Pharmaceuticals Corp., Astellas Pharma US, Inc., Roche Laboratories Inc. and Wyeth Pharmaceuticals. To contact the NTPR:
Phone (215) 707-8535; Fax (215) 707-8894.
E-mail: [email protected]
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