- Email: [email protected]
Pregnancy and Kidney Transplantation
Pregnancy and Kidney Transplantation Michelle A. Josephson, MD,* and Dianne B. McKay, MD†,,‡ Summary: Despite decades of experience with child bearing in women with kidney transplants, these pregnancies remain high risk with an increased prevalence of hypertension and pre-eclampsia. Infertility, common in women with end-stage renal disease, is rapidly restored after transplant although pregnancy rates appear lower in transplant recipients than the general public. Many unanswered questions exist, some old questions such as what is the optimal timing of pregnancy after transplant, whether breast feeding is safe, the long-term impact if any on the offspring, and whether pregnancy negatively affects the kidney graft; and some new questions such as whether to modify immunosuppression in a patient taking a mycophenolic acid– containing drug, whether kidney donation has a deleterious impact on future pregnancies, whether to use erythropoietin-stimulating agents, and the role of BK virus. Counseling about contraception and pregnancy after transplant should be initiated during the pretransplant evaluation process. It is important because of the rapid restoration of fertility that occurs after transplant as well as the many risks and unanswered questions that remain. Semin Nephrol 31:100-110 © 2011 Published by Elsevier Inc. Keywords: Kidney transplantation, pregnancy, immunosuppression, contraception
n 1979 Rudolph et al,1 surveying both North American transplant centers and the existing literature, concluded, “if the patient very much desires pregnancy, it may be permitted providing that good renal function has been present and stable on low-dose maintenance immunosuppression for 1 year, or preferably 2,” and the bulk of these investigator descriptions from 30 years ago ring true today. Several years later Davison,2 noting that patient survival at 5 years was best if kidney function was normal 2 years posttransplant, advised waiting 2 years before considering pregnancy and this remained the standard recommendation until a more recent examination of this issue was undertaken at a consensus conference convened by the American Society of Transplantation, whose recommendations were published in 2005.3 By then, progress with immunosuppres-
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*Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL †The Scripps Research Institute, La Jolla, CA ‡Balboa Institute of Transplantation, San Diego, CA Address reprint requests to Michelle A. Josephson, MD, University of Chicago Hospitals, 5841 South Maryland Ave, MC 5100, Chicago, IL 60637. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2010.10.009
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sive strategies had decreased rejection rates, and this plus a concern that a longer wait time for deceased donor transplants could place some women near the end of their reproductive years led to a conclusion that a single year of waiting was sufficient as long as certain specific conditions were met. The results of the consensus conference and subsequent progress form the basis of this review. OPTIMAL TIMING The American Society of Transplantation consensus opinion suggested that conception would not jeopardize graft survival 1 year posttransplantation under the following conditions: the patient should have had no rejection in the past year; allograft function was adequate (similar to other recommendations arbitrarily defined for kidney allografts as a serum creatinine level ⬍ 1.5 mg/dL and with no or minimal proteinuria); there were no infections that could impact the fetus (eg, cytomegalovirus); the patient was not receiving teratogenic medications; and the immunosuppressive medication dosing was stable at maintenance levels.3 The consensus recommendations cautioned,
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however, that pregnancy after 1 year might be too risky if the creatinine level was 1.5 mg/dL or greater, if there were any recent acute rejection episodes, if the patient had hypertension or other comorbid factors, or if there was evidence of noncompliance with immunosuppressive medications.3 It also was noted that recommendations for the optimal timing of pregnancy might need to be individualized. The 1-year waiting time recommendation recently was challenged. In 2008, Kim et al4 described 74 pregnancies in 48 women in which 11 pregnancies conceived within the first year of transplant had comparable obstetric and graft outcomes with those conceived after a longer posttransplant interval. The investigators proposed that transplanted women could safely conceive within the first year of transplant. However, despite the observations of Kim at 4 al, early conception posttransplant has not been proven to be optimal. Gill et al5 analyzed data from the United States Renal Data System on females 15 to 45 years of age who received a kidney transplant between January 1, 1990, and December 31, 2003, and evaluated those insured only by Medicare at the time of transplant. The data revealed a borderline increase in the risk of fetal loss for pregnancies during the first transplant year compared with subsequent years.5 Given these findings, the recommendation to wait at least a year after transplantation remains reasonable. COUNSELING THE TRANSPLANT RECIPIENT ABOUT THE RISKS OF PREGNANCY An important duty of the caregiver is to counsel transplant recipients of childbearing age about the risks of pregnancy, and given that fertility improves rapidly posttransplantation, such advice should be given rapidly (ie, at the first pretransplant evaluation appointment and at intervals thereafter) to avoid unplanned conception. To permit truly informed consent among couples the partner should attend the counseling session and must understand his duty to ensure a caretaker for the offspring will always be provided because of the limited life expectancy for the mother and her propensity to be ill as a result of her chronic kidney disease.
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Despite registry reports showing successful pregnancies in transplant recipients, registry reports are flawed by voluntary reporting and limited data. There are real risks to both the expectant mother and her offspring. The risks of pregnancy for the mother include rejection and/or allograft loss, and risks of hypertension/ preeclampsia. The risks of acute rejection and graft loss are probably not higher than in the nongravid patient, as long as the immunosuppressive doses are maintained at an adequate level, and the patient has good graft function (creatinine level, ⬍1.5 mg/dL, with ⬍500 mg protein/24 h) and her graft function has been stable during the 6 months before pregnancy.3 The risks for worsening hypertension and preeclampsia, however, are substantial (as discussed later); more than 30% of pregnant transplant recipients experience preeclampsia.6 Potential short- and long-term risks to the offspring also need to be discussed with the expectant parents. Fetal risks include those that occur as a result of preterm delivery and intrauterine growth retardation; these include hypertension, diabetes mellitus, neurologic abnormalities, and developmental delays.6 There also may be independent risks for structural abnormalities (especially owing to in utero mycophenolate exposure) as well as for immunologic and neurocognitive deficits. The risks for the offspring are poorly quantitated because there have been few if any prospective studies that have followed up offspring who were exposed in utero to immunosuppressive medications. An important concept to explain to the patient is that all immunosuppressive medications cross the maternal-fetal barrier and the fetus will be exposed to these medications throughout its developmental phases.6 The long-term outcomes of in utero exposure to immunosuppressive medications are not yet known. FERTILITY AND CONTRACEPTION IN TRANSPLANT RECIPIENTS End-stage renal disease (ESRD) is marked by alterations in the normal hypothalamic-pituitary-ovarian axis and those alterations manifest as menstrual irregularities, anovulation, and infertility. Commonly, women with ESRD have increased prolactin levels, as well as increased
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follicle-stimulating and luteinizing hormone levels.7 These hormonal abnormalities are accompanied by sexual dysfunction— 65% of female ESRD patients report problems with sexual function and 40% no longer engage in sexual activity.7,8 Menstrual irregularities are very common in ESRD patients. Matuszkiewicz-Rowinska et al9 showed in 2004 that 73% of patients experienced menstrual problems, ranging from amenorrhea to oligomenorrhea, whereas 27% had no irregularities. Of the women receiving hemodialysis treatment who underwent endometrial biopsies, pathologic changes in the endometrium were observed in 80% of the patients.9 Infertility is so common in women with ESRD that complacency can occur with contraception. After transplantation the hypothalamic-pituitary-ovarian axis function rapidly improves, and in many cases fertility is restored.10 Because fertility returns rapidly after successful transplantation, effective contraception should be instituted before transplantation in all women of childbearing age. The patient and her gynecologist should determine the best contraceptive method, but it is cautioned that barrier methods alone are inadvisable because nonadherence can have adverse outcomes. There are reports of patients who experience premature ovarian failure or persistence of infertility. A study by Gill et al5 analyzed Medicare claims reports between 1990 and 2000 and found the pregnancy rate in women with kidney transplants was lower than that in the general public5 (Fig. 1). In general, women with CKD experience menopause 4.5 years sooner than women without kidney disease.11 The optimal contraceptive approach is use of the method that provides the greatest efficacy and least risk. If the patient does not wish to ever become pregnant, sterilization of either the transplant recipient or her male partner can be considered. If the patient wishes to have reversible contraception, her choices include intrauterine devices that are either copper- or progestin-based, progesterone-containing systemic contraceptives (such as depot medroxyprogesterone acetate), progestin implant, progestinonly pills, estrogen-containing contraceptives such as birth control pills, contraceptive patches,
M.A. Josephson and D.B. McKay
Figure 1. Pregnancy rate in transplant recipients and the general population. Pregnancy rates in transplant recipients were determined by the year of transplantation and included pregnancies in the first three posttransplant years while patients retained transplant function. Pregnancy rates were determined in the 12,690 women transplanted before December 31, 2000, who had the potential for 3 years of posttransplant follow-up evaluation for ascertainment of pregnancy-related events. Pregnancy rates in the general population are for women in the same age range (15-45 y) as transplant recipients, but are determined by the calendar year. Reprinted with permission.5
and a vaginal ring.12,13 Earlier concerns of infection and lack of efficacy with intrauterine devices have been replaced by newer reports suggesting that intrauterine devices might be safe in transplant recipients.12,14,15 Depot medroxyprogesterone acetate (depot medroxyprogesterone acetate or Depo-Provera; Pfizer, New York, NY) and subcutaneous progestin implants are reasonable options for transplant recipient, but depot medroxyprogesterone acetate increases the risk for osteoporosis.12 Combining oral contraceptive use and barrier methods (to limit sexually transmitted disease risk) is also a safe and effective contraceptive method.12 Men with ESRD also experience infertility, impotence, and spermatogenic abnormalities, some of these problems are related to low testosterone levels. Also, the testes of men with ESRD show signs of histologic injury, including germinal aplasia and seminiferous tubule destruction that may or may not be reversible. After transplantation, the hypothalamic-pituitary function is restored, with improved sperm motility. Sperm counts and morphology, however, are not completely restored and therefore fertility also may not be completely restored.16,17
Pregnancy and kidney transplantation
Infertility in men after transplantation also has been linked to immunosuppressive medications. There have been several reports of infertility associated with sirolimus owing to low free testosterone and increased luteinizing hormone and follicle-stimulating hormone, which appears to be caused by a block in testosterone synthesis.18 Because sirolimus has been shown to decrease testosterone, this should be avoided in men wishing to father children. HYPERTENSION AND ITS MANAGEMENT DURING PREGNANCY Chronic hypertension is a common problem in all transplant recipients19 and thus not surprisingly it often is present in pregnant transplant recipients. Twenty-one percent to 73% of transplant recipients have hypertension during the pregnancy, depending on whether or not they are taking calcineurin inhibitors.20-22 By comparison, 1% to 5% of pregnant women in the general population have been reported to have chronic hypertension.23 Although treatment recommendations vary for nontransplanted pregnant patients with chronic hypertension, treatment of systolic blood pressure greater than 160 mm Hg and diastolic readings more than 110 or even 100 is endorsed.24-26 However, should patients have evidence of end-organ damage, they are treated as aggressively as nonpregnant hypertensive patients are. The approach toward hypertension in pregnant transplant recipients is different. As with other pregnancies in the setting of kidney dysfunction, or hypertensive gravidas with any evidence of end-organ damage, blood pressure should be controlled to the same levels suggested for nonpregnant populations. The American Society of Transplantation consensus opinion was that blood pressure should be maintained close to normal.3 Current recommendations are that blood pressure in the pregnant transplant patient should be maintained at levels recommended for nonpregnant patients with kidney dysfunction.27 The current Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the National Kidney Foundation Kidney Disease Outcomes
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Quality Initiative (NKF KDOQI™) guidelines suggest a goal of less than 130/80 mm Hg.28,29 Chronic hypertension in pregnancy is associated with abruptio placentae, acute renal failure, cardiac decompensation, and cerebral accidents in the mother.23 There is also an increased incidence of growth restriction and death of the fetus.27 These adverse events usually occur in the setting of superimposed preeclampsia (approximately 20% incidence in chronic hypertensive patients without kidney transplants and 30% incidence in kidney transplant recipients). These negative outcomes may occur even more frequently in female transplant recipients older than the age of 30, and in those with end-organ damage.23 Because all kidney transplant recipients have some degree of chronic kidney disease, all are at increased risk for the complications associated with pregnancy and CKD (eg, increased incidence of preeclampsia) and are best managed in a highrisk setting. Pregnancy management with a maternal medicine subspecialist in consultation with the patient’s transplant nephrologist is suggested. The need to control hypertension is certainly another reason that pregnancies are best planned prospectively in this patient population, for instance, to allow for discontinuation of potentially fetotoxic antihypertensive agents (eg, angiotensin converting enzyme inhibitors) before pregnancy.27,30 Atenolol used early in pregnancy has been associated with fetal growth restriction.31 Acceptable oral agents often used in pregnancy include methyldopa (often considered first-line), labetalol, and nifedipine. Hydralazine and thiazide diuretics have been used safely as adjunctive agents.25,26,32 Antihypertensive use during pregnancy is detailed further in a separate article in this issue. Because chronic hypertension accounts for the majority of hypertension observed in pregnant transplant patients, antihypertensive agents are likely to be needed after delivery. For those women who plan to breastfeed, many antihypertensive agents, even angiotensin converting enzyme inhibitors, are safe to use.26 This, too, is discussed in the article by Podymow and August in this issue, p. 70.
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PREECLAMPSIA Any article in an issue edited by Drs. Karmachi and Lindheimer cannot ignore the issue of preeclampsia, particularly because it occurs relatively frequently in women with kidney and kidney-pancreas transplants. Preeclampsia is reported to develop in approximately one third of pregnant women with a kidney or kidney-pancreas transplant.33 However, the accuracy of this estimate is questionable because establishing preeclampsia in the transplant setting is challenging given that blood pressure often increases after the 20th week of gestation and many transplant patients have preexisting proteinuria.34 Transplant patients without proteinuria will in general be excreting amounts nearer the upper limits of normal, and will be close to their maximum tubular reabsorptive capacity. Because proteinuria increases in all pregnant women in late pregnancy,35,36 abnormal values may be first noted then, especially in those with the highest normal excretion who, as noted, will quickly reach and surpass their maximum tubular reabsorptive capacity. Another confounding variable is that calcineurin inhibitors increase uric acid levels, rendering uric acid a less helpful marker for preeclampsia.37 In the general population the diagnosis of preeclampsia is based on clinical criteria. In this respect, clinical-pathologic (ie, biopsy) correlation studies published 30 years ago showed that the diagnosis could be wrong in up to 15% of nulliparas and far more multiparas.38 Given the ambiguity of potential clinical signs, and/or the meaning of laboratory abnormalities in transplant recipients, the diagnosis of preeclampsia may be even less reliable than in the general population. Although potential biomarkers for preeclampsia, such as s-flt and soluble endoglin, have been identified and could be particularly helpful in establishing a diagnosis in pregnant transplant recipients, their use in the clinical setting has yet to be established.39 Observations that women with a history of preeclampsia are at increased risk of developing cardiovascular disease and metabolic diseases later in life is of particular concern in transplant recipients who carry other risks for cardiovascular disease.40-43 This is compounded by further observations that remote cardiovas-
M.A. Josephson and D.B. McKay
cular disease is greatest in preeclamptic patients who have had preterm births or small for gestational age offspring, the latter describing a frequent outcome of gestation in transplant recipients.42 Similarly, findings that preeclampsia is a marker for increased risk of subsequent ESRD is noteworthy.44 An increased incidence of stroke in offspring of women with preeclampsia also has been suggested.45 Unfortunately, thus far, large-scale trials have failed to identify prophylactic interventions that will significantly reduce the incidence of preeclampsia.46-49 Whether preeclampsia is a marker for preexisting increased cardiovascular risk or causes the increased risk is also a hot topic of debate. But what is not contested is that kidney transplant recipients have a much higher incidence of preeclampsia than the general public. For transplant recipients the question then becomes whether the high rate of preeclampsia simply reflects their known increased risk of cardiovascular disease or more ominously portends an even higher risk for the future. DONORS Until recently, there were few concerns regarding pregnancy in live kidney donors, their prognosis was considered similar to the live donor population as a whole. However, two recent publications have evoked some concerns. One is based on registry data, the other on survey information, and together they indicate that kidney donors may be at increased risk for preeclampsia. This concern arises when pregnancies in live kidney donors completed before donation are compared with gestations that took place afterward. Reisaeter et al50 correlated data obtained from the Medical Birth Registry of Norway and Norwegian Renal Registry. The investigators identified 326 donors with 620 pregnancies as well as 21,511 pregnancies from nondonors. A significantly higher incidence of preeclampsia was noted in postdonation compared with predonation pregnancies (Table 1). Although the preeclampsia risk was comparable with the general public, their individual risk after donation appeared greater. Ibrahim et al51 reported on two surveys mailed to 1,769 female donors at the University of Minnesota between November 1963 and De-
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Table 1. Preeclampsia in Births Randomly Selected From the Medial Birth Registry of Norway and
Births in Kidney Donors in Norway (1967–2002) Donors
Preeclampsia, N (%)
Birth Registry ⬇ 1% of Births
Pregnancy Before
Pregnancy After
P*
P†
666 (3.1)
16 (2.6)
6 (5.7)
.22
.026
*By Fisher exact text, calculated between all three groups. †Generalized linear mixed models calculated between before and after donation groups. The method adjusts for some mother’s contributing with more than one birth causing dependence within the data. Adjusted for the mother’s age, birth order, and year of birth. P ⫽ .037, .017, and .047, respectively. Reprinted with permission.50
cember 2007. The responses indicated that postdonation pregnancies were statistically less likely to have gone to term and more likely to result in fetal loss compared with predonation pregnancies. As well, postdonation pregnancies were associated more often with the development of gestational diabetes, gestational hypertension, preeclampsia, and proteinuria. These study results need confirmation. In the interim, potential kidney donors of childbearing age should be informed that pregnancies after donation may have more risks compared with predonation, but that the risk has not been firmly established. INFECTION
Polyomaviruses and Pregnancy Polyomaviruses are a family of DNA viruses that include BK, JC, and SV40 strains. BK, the initials of the inflicted patient, was first described as afflicting a kidney transplant recipient in 1971, but after that report was rarely described until the 1990s. Since that time BK viruria has been noted in 20% to 60%52 and viremia in approximately 15%53 of transplant recipients. Nephropathy is noted in 1% to 10%52 of patients. Because the type of nephropathy causing polyomavirus rarely is ascertained, the entity is referred to as polyomavirus nephropathy (PVAN), rather than BK nephropathy. BK virus reactivation occurs among pregnant women in the general population. For women with kidney transplants, a group that is already at risk for polyomavirus, the propensity toward polyomavirus reactivation raises several issues: should
BK be monitored in pregnant women with transplants, how does one treat a pregnant transplanted women if the BK levels are increasing, should women with BK viremia be advised against pregnancy, can transplacental transmission occur, and how should women with a history of previous BK be advised regarding pregnancy? There are few data to answer most of these questions, but the authors feel that monitoring for BK in pregnant women with kidney transplants who have a known history of BK seems sensible. Whether to do so in women without a history of BK, even viruria, is unclear. The issue of mother-to-child transmission has been examined in nontransplanted patients. Although several investigators found no evidence of transmission54,55 at least one group56 noted evidence that BK virus may be transmitted vertically. Also, there is one case report whose investigators described a successful pregnancy in a woman who lost her first kidney transplant to PVAN and was retransplanted.57 During the pregnancy BK viruria reappeared although viremia was not documented. How to manage an active BK infection during pregnancy is unclear. For those with PVAN, use of either leflunomide (Food and Drug Administration [FDA] pregnancy category X) and cidofovir (FDA pregnancy category C) is problematic. In the case of the former it appears contraindicated, whereas in the case of the latter therapy, human data are not available and rat and rabbit studies have revealed that cidofovir is embryotoxic in animal studies.58 Immunosuppression
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reduction in the setting of PVAN or viremia seems reasonable. Whether or not to lower immunosuppression if viruria occurs is unknown.
M.A. Josephson and D.B. McKay
Table 2. Maintenance Therapy: Used on a
Daily Basis to Prevent Rejection of the Graft Medication
ANEMIA The authors of a European study published in 2003 that included more than 4,000 kidney transplant recipients observed the prevalence of anemia as 39%, whereas data published in 2004 revealed that 25% of European transplant recipients were receiving erythropoietin-stimulating agents.59,60 Given the high prevalence of anemia in transplant recipients, it is not surprising that anemia frequently complicates pregnancies in kidney transplant patients, even in the absence of functional deterioration of the allograft. Also, compared with normal pregnancies, transplant recipients may have inappropriately low erythropoietin levels.61 The safe use of erythropoietin-stimulating agents has been reported during pregnancy in transplant recipients, although concern over the possibility of it playing a role in maternal hypertension has been raised.62 In essence, we could find no evidence that might contraindicate the use of erythropoietin-stimulating agents during pregnancy. Management of anemia in women with kidney transplants is similar to that for women with pre-existing kidney disease. IMMUNOSUPPRESSANT MEDICATIONS AND FETAL DEVELOPMENT All immunosuppressive medications cross the maternal fetal barrier to some degree,63-67 but the distribution of the medications in the fetal circulation are difficult to quantify. There have been many reports showing that corticosteroids pass the maternal-fetal interface, although in general they have been detected at low levels in the fetus.63,64 Possibly this is because the placenta efficiently metabolizes corticosteroids. Although maternal azathioprine and 6-mercaptopurine are teratogenic in animals there are few data supporting teratogenicity in human beings.68 There is a large anecdotal clinical experience of transplant recipients ingesting the drug during pregnancy without structural defects. Azathioprine, 6-mercaptopurine, and
Calcineurin inhibitors Cyclosporine Tacrolimus, FK506 Antiproliferative agents Mycophenolate mofetil Azathioprine Rapamycin, sirolimus Leflunomide Corticosteroids Prednisone
FDA Category C C D D C X B
the inactive metabolite thiouric acid can pass though the human placenta. The suggestion has been made that the fetal liver may lack active inosinate pyrophosphorylase, and, consequently, 6-mercaptopurine is not converted to its active metabolite.69 Therefore, it is believed to be relatively safe by practitioners to use in pregnancy. Calcineurin inhibitors also are able to cross the maternal-fetal interface and they have been detected in the amniotic fluid, placenta, and fetal tissue, and have been shown to have immunosuppressive properties in fetal blood.70 More recently, mycophenolate mofetil has been linked to congenital abnormalities in the fetus, although its FDA classification is D, we consider it contraindicated.71 Little is known about sirolimus in pregnancy and therefore caution remains for its use. The FDA has categorized immunosuppressive agents according to safety recommendations (Table 2). Unfortunately, the FDA categories are somewhat confusing. For instance, azathioprine is listed as category D (evidence of fetal risk) and calcineurin inhibitors are listed as category C (fetal risk cannot be ruled out). The recent change of mycophenolate mofetil to category D was stimulated by evidence showing a pattern of malformations in in utero– exposed human fetuses.71 BREASTFEEDING The pharmacokinetics and pharmacodynamics of immunosuppressant secretion in breast milk
Pregnancy and kidney transplantation
have not been defined and varied reports of immunosuppressive levels in breast milk exist.72-74 It is therefore almost impossible to make firm recommendations at this time for or against breastfeeding. Limited case reports are available suggesting that tacrolimus levels in breast milk are approximately half that in maternal serum,75 although large controlled studies that evaluate breast milk concentrations of immunosuppressant medications have not been performed. The American Society of Transplantation consensus report suggested that breastfeeding is not necessarily contraindicated,3 but the mother should be informed of the fact that it is unknown whether the risks of further exposure of her infant to immunosuppression outweigh the benefits of breastfeeding. OUTCOMES Whether pregnancy adversely affects a kidney transplant recipient remains a long-standing and unresolved question. Davison76 showed that renal allografts frequently show the physiological adaptations to pregnancy such as an increase in GFR (although the magnitude may be blunted). Most studies have indicated that serum creatinine level may increase slightly after pregnancy, but an adverse effect on longterm outcome could not be shown.77-79 At least one study, however, indicated that pregnancy has a negative effect on transplant function.80 Of interest is an analysis of 40 years of pregnancyrelated outcomes for transplant recipients published in 2009. In this analysis the investigators matched 120 parous and 120 nulliparous women by year of transplantation, duration of transplant, age, and predelivery creatinine level for parous women and creatinine for nonparous women. This analysis failed to show that pregnancy negatively influenced graft or patient survival.81 Individuals with pancreas/kidney transplants may be at higher risk for worse long-term outcomes than diabetic patients who received kidney transplants only. In 2008, the National Transplant Pregnancy Registry (Philadelphia, PA) reported a comparison of outcomes for 43 pancreas/kidney recipients and 34 kidney only recipients.82 Women with pancreas/kidney al-
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lografts had a significantly higher incidence of infection reported as well as a significantly higher risk of graft loss (23.3% versus 2.9%). The reason for these differences is unclear. LONG-TERM FOLLOW-UP EVALUATION OF THE OFFSPRING Human data on which to base information about the long-term effects of in utero exposure to immunosuppressive agents are extremely limited. Abundant animal data suggest a real risk exists for neurocognitive and immunologic defects. Neurocognitive and immunologic testing are not generally prescribed for children of transplant recipients and therefore little if any objective information is available. Registry data that are based on telephone conversations with parents suggest that the offspring of transplant recipients experienced no greater risk than the normal population for attention-deficit hyperactivity disorder,82 despite an overall 24% risk of learning disabilities reported in an earlier study.83 There were also no immunologic abnormalities reported by the parents. Because no objective neurocognitive or immunologic testing was reported for these children, or statistical validation reported for telephone findings, it is impossible to analyze this information. It also is important that opinion-based information does not discourage investigations in this important area, and that long-term follow-up evaluation of the offspring of transplant recipients is promoted. REFERENCES 1. Rudolph JE, Schweizer RT, Bartus SA. Pregnancy in renal transplant patients: a review. Transplantation. 1979;27:26-9. 2. Davison JM. Pregnancy in renal allograft recipients: prognosis and management. Baillieres Clin Obstet Gynaecol. 1987;1:1027-45. 3. McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant. 2005;5:1592-9. 4. Kim HW, Seok HJ, Kim TH, Han DJ, Yang WS, Park SK. The experience of pregnancy after renal transplantation: pregnancies even within postoperative 1 year may be tolerable. Transplantation. 2008;85: 1412-9. 5. Gill JS, Zalunardo N, Rose C, Tonelli M. The preg-
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nancy rate and live birth rate in kidney transplant recipients. Am J Transplant. 2009;9:1541-9. McKay DB, Josephson MA. Pregnancy after kidney transplantation. Clin J Am Soc Nephrol. 2008;3 Suppl 2:S117-25. Anantharaman P, Schmidt RJ. Sexual function in chronic kidney disease. Adv Chronic Kidney Dis. 2007;14:119-25. Schover LR, Novick AC, Steinmuller DR, Goormastic M. Sexuality, fertility, and renal transplantation: a survey of survivors. J Sex Marital Ther. 1990;16:3-13. Matuszkiewicz-Rowinska J, Skorzewska K, Radowicki S, et al. Endometrial morphology and pituitary-gonadal axis dysfunction in women of reproductive age undergoing chronic haemodialysis—a multicentre study. Nephrol Dial Transplant. 2004;19:2074-7. Guazzelli CA, Torloni MR, Sanches TF, Barbieri M, Pestana JO. Contraceptive counseling and use among 197 female kidney transplant recipients. Transplantation. 2008;86:669-72. Pietrzak B, Cyganek A, Jabiry-Zieniewicz Z, et al. Function of the ovaries in female kidney transplant recipients. Transplant Proc. 2006;38:180-3. Gomez-Lobo V. Gynecologic care of the transplant recipient. Postgrad Obstet Gynecol. 2009;29:1-6. Pietrzak B, Bobrowska K, Jabiry-Zieniewicz Z, et al. Oral and transdermal hormonal contraception in women after kidney transplantation. Transplant Proc. 2007;39:2759-62. Estes CM, Westhoff C. Contraception for the transplant patient. Semin Perinatol. 2007;31:372-7. Stringer EM, Kaseba C, Levy J, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol. 2007;197:144-8. Xu LG, Xu HM, Zhu XF, et al. Examination of the semen quality of patients with uraemia and renal transplant recipients in comparison with a control group. Andrologia. 2009;41:235-40. Zeyneloglu HB, Oktem M, Durak T. Male infertility after renal transplantation: achievement of pregnancy after intracytoplasmic sperm injection. Transplant Proc. 2005;37:3081-4. Zuber J, Anglicheau D, Elie C, et al. Sirolimus may reduce fertility in male renal transplant recipients. Am J Transplant. 2008;8:1471-9. Hillebrand U, Suwelack BM, Loley K, et al. Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients. Transpl Int. 2009; 22:1073-80. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. National transplantation Pregnancy Registry— outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation. 1994;57:502-6. McKay DB, Josephson MA. Pregnancy in recipients of solid organs— effects on mother and child. N Engl J Med. 2006;354:1281-93.
22. Radomski JS, Ahlswede BA, Jarrell BE, et al. Outcomes of 500 pregnancies in 335 female kidney, liver, and heart transplant recipients. Transplant Proc. 1995;27: 1089-90. 23. Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;339:667-71. 24. Lindheimer MD, Taler SJ, Cunningham FG. ASH position paper: hypertension in pregnancy. J Clin Hypertens (Greenwich). 2009;11:214-25. 25. Magee LA, Abalos E, von DP, Sibai B, Walkinshaw SA. Control of hypertension in pregnancy. Curr Hypertens Rep. 2009;11:429-36. 26. Yoder SR, Thornburg LL, Bisognano JD. Hypertension in pregnancy and women of childbearing age. Am J Med. 2009;122:890-5. 27. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 1990;163:1691-712. 28. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1-290. 29. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289:2560-72. 30. Pryde PG, Sedman AB, Nugent CE, Barr M Jr. Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol. 1993;3:1575-82. 31. Podymow T, August P. Hypertension in pregnancy. Adv Chronic Kidney Dis. 2007;14:178-90. 32. Umans JG. Medications during pregnancy: antihypertensives and immunosuppressives. Adv Chronic Kidney Dis. 2007;14:191-8. 33. Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2003; 131-141. 34. Stratta P, Canavese C, Giacchino F, Mesiano P, Quaglia M, Rossetti M. Pregnancy in kidney transplantation: satisfactory outcomes and harsh realities. J Nephrol. 2003;16:792-806. 35. Holt JL, Mangos GJ, Brown MA. Measuring protein excretion in pregnancy. Nephrology (Carlton). 2007; 12:425-30. 36. Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach. Obstet Gynecol. 2010;115:365-75. 37. Morales JM, Hernandez PG, Andres A, Prieto C, Hernandez E, Rodicio JL. Uric acid handling, pregnancy and cyclosporin in renal transplant women. Nephron. 1990;56:97-8. 38. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in pregnancy: clinical-pathological corre-
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lations and remote prognosis. Medicine (Baltimore). 1981;60:267-76. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672-83. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335:974. Funai EF, Friedlander Y, Paltiel O, et al. Long-term mortality after preeclampsia. Epidemiology. 2005;16: 206-15. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001;323: 1213-7. Wolf M, Hubel CA, Lam C, et al. Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab. 2004;89:6239-43. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008;359:800-9. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009;40:1176-80. Lindheimer MD, Sibai BM. Antioxidant supplementation in pre-eclampsia. Lancet. 2006;367:1119-20. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebocontrolled trial. Lancet. 2006;367:1145-54. Villar J, Abalos E, Nardin JM, Merialdi M, Carroli G. Strategies to prevent and treat preeclampsia: evidence from randomized controlled trials. Semin Nephrol. 2004;24:607-15. Villar J, bdel-Aleem H, Merialdi M, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006;194:639-49. Reisaeter AV, Roislien J, Henriksen T, Irgens LM, Hartmann A. Pregnancy and birth after kidney donation: the Norwegian experience. Am J Transplant. 2009;9:820-4. Ibrahim HN, Akkina SK, Leister E, et al. Pregnancy outcomes after kidney donation. Am J Transplant. 2009;9:825-34. Ramos E, Drachenberg CB, Wali R, Hirsch HH. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation. 2009;87:621-30. Koukoulaki M, Grispou E, Pistolas D, et al. Prospective monitoring of BK virus replication in renal transplant recipients. Transpl Infect Dis. 2009;11:1-10. Boldorini R, Veggiani C, Amoruso E, et al. Latent human polyomavirus infection in pregnancy: investigation of possible transplacental transmission. Pathology. 2008;40:72-7. Kalvatchev Z, Slavov S, Shtereva M, Savova S. Reacti-
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vation of Polyomavirus hominis 1 (BKV) during pregnancy and the risk of mother-to-child transmission. J Clin Virol. 2008;43:328-9. Pietropaolo V, Di TC, Degener AM, et al. Transplacental transmission of human polyomavirus BK. J Med Virol. 1998;56:372-6. Midtvedt K, Bjorang O, Letting AS. Successful pregnancy in renal transplant recipient with previous known polyomavirus nephropathy. Clin Transplant. 2007;21:571-3. Gilead Sciences I. VISTIDE prescribing information. 1996. Heinze G, Kainz A, Horl WH, Oberbauer R. Mortality in renal transplant recipients given erythropoietins to increase haemoglobin concentration: cohort study. BMJ. 2009;339:b4018. Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence and management of anemia in renal transplant recipients: a European survey. Am J Transplant. 2003;3:835-45. Magee LA, von DP, Darley J, Beguin Y. Erythropoiesis and renal transplant pregnancy. Clin Transplant. 2000;14:127-35. Goshorn J, Youell TD. Darbepoetin alfa treatment for post-renal transplantation anemia during pregnancy. Am J Kidney Dis. 2005;46:e81-6. Anderson GG, Rotchell Y, Kaiser DG. Placental transfer of methylprednisolone following maternal intravenous administration. Am J Obstet Gynecol. 1981;140: 699-701. Blanford AT, Murphy BE. In vitro metabolism of prednisolone, dexamethasone, betamethasone, and cortisol by the human placenta. Am J Obstet Gynecol. 1977;127:264-7. Ceckova-Novotna M, Pavek P, Staud F. P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol. 2006;22:400-10. Ostensen M. Disease specific problems related to drug therapy in pregnancy. Lupus. 2004;13:746-50. Sangalli L, Bortolotti A, Passerini F, Bonati M. Placental transfer, tissue distribution, and pharmacokinetics of cyclosporine in the pregnant rabbit. Drug Metab Dispos. 1990;18:102-6. Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology. 2002;65: 240-61. Saarikoski S, Seppla M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973;115:1100-6. Flechner SM, Katz AR, Rogers AJ, Van BC, Kahan BD. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis. 1985;5: 60-3. Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006;82:1698-702.
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72. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 1994;93:137-50. 73. Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation. 2003;75: 2144-6. 74. Ost L, Wettrell G, Bjorkhem I, Rane A. Prednisolone excretion in human milk. J Pediatr. 1985;106:1008-11. 75. Gardiner SJ, Begg EJ. Breastfeeding during tacrolimus therapy. Obstet Gynecol. 2006;107:453-5. 76. Davison JM. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int. 1985;27: 74-9. 77. First MR, Combs CA, Weiskittel P, Miodovnik M. Lack of effect of pregnancy on renal allograft survival or function. Transplantation. 1995;59:472-6. 78. Sturgiss SN, Davison JM. Effect of pregnancy on the long-term function of renal allografts: an update. Am J Kidney Dis. 1995;26:54-6.
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79. Tanabe K, Kobayashi C, Takahashi K, et al. Long-term renal function after pregnancy in renal transplant recipients. Transplant Proc. 1997;29:1567-8. 80. Salmela KT, Kyllonen LE, Holmberg C, GronhagenRiska C. Impaired renal function after pregnancy in renal transplant recipients. Transplantation. 1993;56: 1372-5. 81. Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc Nephrol. 2009;20:2433-40. 82. Coscia LA, Constantinescu S, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2008;89-105. 83. Stanley CW, Gottlieb R, Zager R, et al. Developmental well-being in offspring of women receiving cyclosporine post-renal transplant. Transplant Proc. 1999; 31:241-2.
n 1979 Rudolph et al,1 surveying both North American transplant centers and the existing literature, concluded, “if the patient very much desires pregnancy, it may be permitted providing that good renal function has been present and stable on low-dose maintenance immunosuppression for 1 year, or preferably 2,” and the bulk of these investigator descriptions from 30 years ago ring true today. Several years later Davison,2 noting that patient survival at 5 years was best if kidney function was normal 2 years posttransplant, advised waiting 2 years before considering pregnancy and this remained the standard recommendation until a more recent examination of this issue was undertaken at a consensus conference convened by the American Society of Transplantation, whose recommendations were published in 2005.3 By then, progress with immunosuppres-
I
*Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL †The Scripps Research Institute, La Jolla, CA ‡Balboa Institute of Transplantation, San Diego, CA Address reprint requests to Michelle A. Josephson, MD, University of Chicago Hospitals, 5841 South Maryland Ave, MC 5100, Chicago, IL 60637. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2010.10.009
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sive strategies had decreased rejection rates, and this plus a concern that a longer wait time for deceased donor transplants could place some women near the end of their reproductive years led to a conclusion that a single year of waiting was sufficient as long as certain specific conditions were met. The results of the consensus conference and subsequent progress form the basis of this review. OPTIMAL TIMING The American Society of Transplantation consensus opinion suggested that conception would not jeopardize graft survival 1 year posttransplantation under the following conditions: the patient should have had no rejection in the past year; allograft function was adequate (similar to other recommendations arbitrarily defined for kidney allografts as a serum creatinine level ⬍ 1.5 mg/dL and with no or minimal proteinuria); there were no infections that could impact the fetus (eg, cytomegalovirus); the patient was not receiving teratogenic medications; and the immunosuppressive medication dosing was stable at maintenance levels.3 The consensus recommendations cautioned,
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however, that pregnancy after 1 year might be too risky if the creatinine level was 1.5 mg/dL or greater, if there were any recent acute rejection episodes, if the patient had hypertension or other comorbid factors, or if there was evidence of noncompliance with immunosuppressive medications.3 It also was noted that recommendations for the optimal timing of pregnancy might need to be individualized. The 1-year waiting time recommendation recently was challenged. In 2008, Kim et al4 described 74 pregnancies in 48 women in which 11 pregnancies conceived within the first year of transplant had comparable obstetric and graft outcomes with those conceived after a longer posttransplant interval. The investigators proposed that transplanted women could safely conceive within the first year of transplant. However, despite the observations of Kim at 4 al, early conception posttransplant has not been proven to be optimal. Gill et al5 analyzed data from the United States Renal Data System on females 15 to 45 years of age who received a kidney transplant between January 1, 1990, and December 31, 2003, and evaluated those insured only by Medicare at the time of transplant. The data revealed a borderline increase in the risk of fetal loss for pregnancies during the first transplant year compared with subsequent years.5 Given these findings, the recommendation to wait at least a year after transplantation remains reasonable. COUNSELING THE TRANSPLANT RECIPIENT ABOUT THE RISKS OF PREGNANCY An important duty of the caregiver is to counsel transplant recipients of childbearing age about the risks of pregnancy, and given that fertility improves rapidly posttransplantation, such advice should be given rapidly (ie, at the first pretransplant evaluation appointment and at intervals thereafter) to avoid unplanned conception. To permit truly informed consent among couples the partner should attend the counseling session and must understand his duty to ensure a caretaker for the offspring will always be provided because of the limited life expectancy for the mother and her propensity to be ill as a result of her chronic kidney disease.
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Despite registry reports showing successful pregnancies in transplant recipients, registry reports are flawed by voluntary reporting and limited data. There are real risks to both the expectant mother and her offspring. The risks of pregnancy for the mother include rejection and/or allograft loss, and risks of hypertension/ preeclampsia. The risks of acute rejection and graft loss are probably not higher than in the nongravid patient, as long as the immunosuppressive doses are maintained at an adequate level, and the patient has good graft function (creatinine level, ⬍1.5 mg/dL, with ⬍500 mg protein/24 h) and her graft function has been stable during the 6 months before pregnancy.3 The risks for worsening hypertension and preeclampsia, however, are substantial (as discussed later); more than 30% of pregnant transplant recipients experience preeclampsia.6 Potential short- and long-term risks to the offspring also need to be discussed with the expectant parents. Fetal risks include those that occur as a result of preterm delivery and intrauterine growth retardation; these include hypertension, diabetes mellitus, neurologic abnormalities, and developmental delays.6 There also may be independent risks for structural abnormalities (especially owing to in utero mycophenolate exposure) as well as for immunologic and neurocognitive deficits. The risks for the offspring are poorly quantitated because there have been few if any prospective studies that have followed up offspring who were exposed in utero to immunosuppressive medications. An important concept to explain to the patient is that all immunosuppressive medications cross the maternal-fetal barrier and the fetus will be exposed to these medications throughout its developmental phases.6 The long-term outcomes of in utero exposure to immunosuppressive medications are not yet known. FERTILITY AND CONTRACEPTION IN TRANSPLANT RECIPIENTS End-stage renal disease (ESRD) is marked by alterations in the normal hypothalamic-pituitary-ovarian axis and those alterations manifest as menstrual irregularities, anovulation, and infertility. Commonly, women with ESRD have increased prolactin levels, as well as increased
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follicle-stimulating and luteinizing hormone levels.7 These hormonal abnormalities are accompanied by sexual dysfunction— 65% of female ESRD patients report problems with sexual function and 40% no longer engage in sexual activity.7,8 Menstrual irregularities are very common in ESRD patients. Matuszkiewicz-Rowinska et al9 showed in 2004 that 73% of patients experienced menstrual problems, ranging from amenorrhea to oligomenorrhea, whereas 27% had no irregularities. Of the women receiving hemodialysis treatment who underwent endometrial biopsies, pathologic changes in the endometrium were observed in 80% of the patients.9 Infertility is so common in women with ESRD that complacency can occur with contraception. After transplantation the hypothalamic-pituitary-ovarian axis function rapidly improves, and in many cases fertility is restored.10 Because fertility returns rapidly after successful transplantation, effective contraception should be instituted before transplantation in all women of childbearing age. The patient and her gynecologist should determine the best contraceptive method, but it is cautioned that barrier methods alone are inadvisable because nonadherence can have adverse outcomes. There are reports of patients who experience premature ovarian failure or persistence of infertility. A study by Gill et al5 analyzed Medicare claims reports between 1990 and 2000 and found the pregnancy rate in women with kidney transplants was lower than that in the general public5 (Fig. 1). In general, women with CKD experience menopause 4.5 years sooner than women without kidney disease.11 The optimal contraceptive approach is use of the method that provides the greatest efficacy and least risk. If the patient does not wish to ever become pregnant, sterilization of either the transplant recipient or her male partner can be considered. If the patient wishes to have reversible contraception, her choices include intrauterine devices that are either copper- or progestin-based, progesterone-containing systemic contraceptives (such as depot medroxyprogesterone acetate), progestin implant, progestinonly pills, estrogen-containing contraceptives such as birth control pills, contraceptive patches,
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Figure 1. Pregnancy rate in transplant recipients and the general population. Pregnancy rates in transplant recipients were determined by the year of transplantation and included pregnancies in the first three posttransplant years while patients retained transplant function. Pregnancy rates were determined in the 12,690 women transplanted before December 31, 2000, who had the potential for 3 years of posttransplant follow-up evaluation for ascertainment of pregnancy-related events. Pregnancy rates in the general population are for women in the same age range (15-45 y) as transplant recipients, but are determined by the calendar year. Reprinted with permission.5
and a vaginal ring.12,13 Earlier concerns of infection and lack of efficacy with intrauterine devices have been replaced by newer reports suggesting that intrauterine devices might be safe in transplant recipients.12,14,15 Depot medroxyprogesterone acetate (depot medroxyprogesterone acetate or Depo-Provera; Pfizer, New York, NY) and subcutaneous progestin implants are reasonable options for transplant recipient, but depot medroxyprogesterone acetate increases the risk for osteoporosis.12 Combining oral contraceptive use and barrier methods (to limit sexually transmitted disease risk) is also a safe and effective contraceptive method.12 Men with ESRD also experience infertility, impotence, and spermatogenic abnormalities, some of these problems are related to low testosterone levels. Also, the testes of men with ESRD show signs of histologic injury, including germinal aplasia and seminiferous tubule destruction that may or may not be reversible. After transplantation, the hypothalamic-pituitary function is restored, with improved sperm motility. Sperm counts and morphology, however, are not completely restored and therefore fertility also may not be completely restored.16,17
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Infertility in men after transplantation also has been linked to immunosuppressive medications. There have been several reports of infertility associated with sirolimus owing to low free testosterone and increased luteinizing hormone and follicle-stimulating hormone, which appears to be caused by a block in testosterone synthesis.18 Because sirolimus has been shown to decrease testosterone, this should be avoided in men wishing to father children. HYPERTENSION AND ITS MANAGEMENT DURING PREGNANCY Chronic hypertension is a common problem in all transplant recipients19 and thus not surprisingly it often is present in pregnant transplant recipients. Twenty-one percent to 73% of transplant recipients have hypertension during the pregnancy, depending on whether or not they are taking calcineurin inhibitors.20-22 By comparison, 1% to 5% of pregnant women in the general population have been reported to have chronic hypertension.23 Although treatment recommendations vary for nontransplanted pregnant patients with chronic hypertension, treatment of systolic blood pressure greater than 160 mm Hg and diastolic readings more than 110 or even 100 is endorsed.24-26 However, should patients have evidence of end-organ damage, they are treated as aggressively as nonpregnant hypertensive patients are. The approach toward hypertension in pregnant transplant recipients is different. As with other pregnancies in the setting of kidney dysfunction, or hypertensive gravidas with any evidence of end-organ damage, blood pressure should be controlled to the same levels suggested for nonpregnant populations. The American Society of Transplantation consensus opinion was that blood pressure should be maintained close to normal.3 Current recommendations are that blood pressure in the pregnant transplant patient should be maintained at levels recommended for nonpregnant patients with kidney dysfunction.27 The current Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the National Kidney Foundation Kidney Disease Outcomes
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Quality Initiative (NKF KDOQI™) guidelines suggest a goal of less than 130/80 mm Hg.28,29 Chronic hypertension in pregnancy is associated with abruptio placentae, acute renal failure, cardiac decompensation, and cerebral accidents in the mother.23 There is also an increased incidence of growth restriction and death of the fetus.27 These adverse events usually occur in the setting of superimposed preeclampsia (approximately 20% incidence in chronic hypertensive patients without kidney transplants and 30% incidence in kidney transplant recipients). These negative outcomes may occur even more frequently in female transplant recipients older than the age of 30, and in those with end-organ damage.23 Because all kidney transplant recipients have some degree of chronic kidney disease, all are at increased risk for the complications associated with pregnancy and CKD (eg, increased incidence of preeclampsia) and are best managed in a highrisk setting. Pregnancy management with a maternal medicine subspecialist in consultation with the patient’s transplant nephrologist is suggested. The need to control hypertension is certainly another reason that pregnancies are best planned prospectively in this patient population, for instance, to allow for discontinuation of potentially fetotoxic antihypertensive agents (eg, angiotensin converting enzyme inhibitors) before pregnancy.27,30 Atenolol used early in pregnancy has been associated with fetal growth restriction.31 Acceptable oral agents often used in pregnancy include methyldopa (often considered first-line), labetalol, and nifedipine. Hydralazine and thiazide diuretics have been used safely as adjunctive agents.25,26,32 Antihypertensive use during pregnancy is detailed further in a separate article in this issue. Because chronic hypertension accounts for the majority of hypertension observed in pregnant transplant patients, antihypertensive agents are likely to be needed after delivery. For those women who plan to breastfeed, many antihypertensive agents, even angiotensin converting enzyme inhibitors, are safe to use.26 This, too, is discussed in the article by Podymow and August in this issue, p. 70.
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PREECLAMPSIA Any article in an issue edited by Drs. Karmachi and Lindheimer cannot ignore the issue of preeclampsia, particularly because it occurs relatively frequently in women with kidney and kidney-pancreas transplants. Preeclampsia is reported to develop in approximately one third of pregnant women with a kidney or kidney-pancreas transplant.33 However, the accuracy of this estimate is questionable because establishing preeclampsia in the transplant setting is challenging given that blood pressure often increases after the 20th week of gestation and many transplant patients have preexisting proteinuria.34 Transplant patients without proteinuria will in general be excreting amounts nearer the upper limits of normal, and will be close to their maximum tubular reabsorptive capacity. Because proteinuria increases in all pregnant women in late pregnancy,35,36 abnormal values may be first noted then, especially in those with the highest normal excretion who, as noted, will quickly reach and surpass their maximum tubular reabsorptive capacity. Another confounding variable is that calcineurin inhibitors increase uric acid levels, rendering uric acid a less helpful marker for preeclampsia.37 In the general population the diagnosis of preeclampsia is based on clinical criteria. In this respect, clinical-pathologic (ie, biopsy) correlation studies published 30 years ago showed that the diagnosis could be wrong in up to 15% of nulliparas and far more multiparas.38 Given the ambiguity of potential clinical signs, and/or the meaning of laboratory abnormalities in transplant recipients, the diagnosis of preeclampsia may be even less reliable than in the general population. Although potential biomarkers for preeclampsia, such as s-flt and soluble endoglin, have been identified and could be particularly helpful in establishing a diagnosis in pregnant transplant recipients, their use in the clinical setting has yet to be established.39 Observations that women with a history of preeclampsia are at increased risk of developing cardiovascular disease and metabolic diseases later in life is of particular concern in transplant recipients who carry other risks for cardiovascular disease.40-43 This is compounded by further observations that remote cardiovas-
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cular disease is greatest in preeclamptic patients who have had preterm births or small for gestational age offspring, the latter describing a frequent outcome of gestation in transplant recipients.42 Similarly, findings that preeclampsia is a marker for increased risk of subsequent ESRD is noteworthy.44 An increased incidence of stroke in offspring of women with preeclampsia also has been suggested.45 Unfortunately, thus far, large-scale trials have failed to identify prophylactic interventions that will significantly reduce the incidence of preeclampsia.46-49 Whether preeclampsia is a marker for preexisting increased cardiovascular risk or causes the increased risk is also a hot topic of debate. But what is not contested is that kidney transplant recipients have a much higher incidence of preeclampsia than the general public. For transplant recipients the question then becomes whether the high rate of preeclampsia simply reflects their known increased risk of cardiovascular disease or more ominously portends an even higher risk for the future. DONORS Until recently, there were few concerns regarding pregnancy in live kidney donors, their prognosis was considered similar to the live donor population as a whole. However, two recent publications have evoked some concerns. One is based on registry data, the other on survey information, and together they indicate that kidney donors may be at increased risk for preeclampsia. This concern arises when pregnancies in live kidney donors completed before donation are compared with gestations that took place afterward. Reisaeter et al50 correlated data obtained from the Medical Birth Registry of Norway and Norwegian Renal Registry. The investigators identified 326 donors with 620 pregnancies as well as 21,511 pregnancies from nondonors. A significantly higher incidence of preeclampsia was noted in postdonation compared with predonation pregnancies (Table 1). Although the preeclampsia risk was comparable with the general public, their individual risk after donation appeared greater. Ibrahim et al51 reported on two surveys mailed to 1,769 female donors at the University of Minnesota between November 1963 and De-
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Table 1. Preeclampsia in Births Randomly Selected From the Medial Birth Registry of Norway and
Births in Kidney Donors in Norway (1967–2002) Donors
Preeclampsia, N (%)
Birth Registry ⬇ 1% of Births
Pregnancy Before
Pregnancy After
P*
P†
666 (3.1)
16 (2.6)
6 (5.7)
.22
.026
*By Fisher exact text, calculated between all three groups. †Generalized linear mixed models calculated between before and after donation groups. The method adjusts for some mother’s contributing with more than one birth causing dependence within the data. Adjusted for the mother’s age, birth order, and year of birth. P ⫽ .037, .017, and .047, respectively. Reprinted with permission.50
cember 2007. The responses indicated that postdonation pregnancies were statistically less likely to have gone to term and more likely to result in fetal loss compared with predonation pregnancies. As well, postdonation pregnancies were associated more often with the development of gestational diabetes, gestational hypertension, preeclampsia, and proteinuria. These study results need confirmation. In the interim, potential kidney donors of childbearing age should be informed that pregnancies after donation may have more risks compared with predonation, but that the risk has not been firmly established. INFECTION
Polyomaviruses and Pregnancy Polyomaviruses are a family of DNA viruses that include BK, JC, and SV40 strains. BK, the initials of the inflicted patient, was first described as afflicting a kidney transplant recipient in 1971, but after that report was rarely described until the 1990s. Since that time BK viruria has been noted in 20% to 60%52 and viremia in approximately 15%53 of transplant recipients. Nephropathy is noted in 1% to 10%52 of patients. Because the type of nephropathy causing polyomavirus rarely is ascertained, the entity is referred to as polyomavirus nephropathy (PVAN), rather than BK nephropathy. BK virus reactivation occurs among pregnant women in the general population. For women with kidney transplants, a group that is already at risk for polyomavirus, the propensity toward polyomavirus reactivation raises several issues: should
BK be monitored in pregnant women with transplants, how does one treat a pregnant transplanted women if the BK levels are increasing, should women with BK viremia be advised against pregnancy, can transplacental transmission occur, and how should women with a history of previous BK be advised regarding pregnancy? There are few data to answer most of these questions, but the authors feel that monitoring for BK in pregnant women with kidney transplants who have a known history of BK seems sensible. Whether to do so in women without a history of BK, even viruria, is unclear. The issue of mother-to-child transmission has been examined in nontransplanted patients. Although several investigators found no evidence of transmission54,55 at least one group56 noted evidence that BK virus may be transmitted vertically. Also, there is one case report whose investigators described a successful pregnancy in a woman who lost her first kidney transplant to PVAN and was retransplanted.57 During the pregnancy BK viruria reappeared although viremia was not documented. How to manage an active BK infection during pregnancy is unclear. For those with PVAN, use of either leflunomide (Food and Drug Administration [FDA] pregnancy category X) and cidofovir (FDA pregnancy category C) is problematic. In the case of the former it appears contraindicated, whereas in the case of the latter therapy, human data are not available and rat and rabbit studies have revealed that cidofovir is embryotoxic in animal studies.58 Immunosuppression
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reduction in the setting of PVAN or viremia seems reasonable. Whether or not to lower immunosuppression if viruria occurs is unknown.
M.A. Josephson and D.B. McKay
Table 2. Maintenance Therapy: Used on a
Daily Basis to Prevent Rejection of the Graft Medication
ANEMIA The authors of a European study published in 2003 that included more than 4,000 kidney transplant recipients observed the prevalence of anemia as 39%, whereas data published in 2004 revealed that 25% of European transplant recipients were receiving erythropoietin-stimulating agents.59,60 Given the high prevalence of anemia in transplant recipients, it is not surprising that anemia frequently complicates pregnancies in kidney transplant patients, even in the absence of functional deterioration of the allograft. Also, compared with normal pregnancies, transplant recipients may have inappropriately low erythropoietin levels.61 The safe use of erythropoietin-stimulating agents has been reported during pregnancy in transplant recipients, although concern over the possibility of it playing a role in maternal hypertension has been raised.62 In essence, we could find no evidence that might contraindicate the use of erythropoietin-stimulating agents during pregnancy. Management of anemia in women with kidney transplants is similar to that for women with pre-existing kidney disease. IMMUNOSUPPRESSANT MEDICATIONS AND FETAL DEVELOPMENT All immunosuppressive medications cross the maternal fetal barrier to some degree,63-67 but the distribution of the medications in the fetal circulation are difficult to quantify. There have been many reports showing that corticosteroids pass the maternal-fetal interface, although in general they have been detected at low levels in the fetus.63,64 Possibly this is because the placenta efficiently metabolizes corticosteroids. Although maternal azathioprine and 6-mercaptopurine are teratogenic in animals there are few data supporting teratogenicity in human beings.68 There is a large anecdotal clinical experience of transplant recipients ingesting the drug during pregnancy without structural defects. Azathioprine, 6-mercaptopurine, and
Calcineurin inhibitors Cyclosporine Tacrolimus, FK506 Antiproliferative agents Mycophenolate mofetil Azathioprine Rapamycin, sirolimus Leflunomide Corticosteroids Prednisone
FDA Category C C D D C X B
the inactive metabolite thiouric acid can pass though the human placenta. The suggestion has been made that the fetal liver may lack active inosinate pyrophosphorylase, and, consequently, 6-mercaptopurine is not converted to its active metabolite.69 Therefore, it is believed to be relatively safe by practitioners to use in pregnancy. Calcineurin inhibitors also are able to cross the maternal-fetal interface and they have been detected in the amniotic fluid, placenta, and fetal tissue, and have been shown to have immunosuppressive properties in fetal blood.70 More recently, mycophenolate mofetil has been linked to congenital abnormalities in the fetus, although its FDA classification is D, we consider it contraindicated.71 Little is known about sirolimus in pregnancy and therefore caution remains for its use. The FDA has categorized immunosuppressive agents according to safety recommendations (Table 2). Unfortunately, the FDA categories are somewhat confusing. For instance, azathioprine is listed as category D (evidence of fetal risk) and calcineurin inhibitors are listed as category C (fetal risk cannot be ruled out). The recent change of mycophenolate mofetil to category D was stimulated by evidence showing a pattern of malformations in in utero– exposed human fetuses.71 BREASTFEEDING The pharmacokinetics and pharmacodynamics of immunosuppressant secretion in breast milk
Pregnancy and kidney transplantation
have not been defined and varied reports of immunosuppressive levels in breast milk exist.72-74 It is therefore almost impossible to make firm recommendations at this time for or against breastfeeding. Limited case reports are available suggesting that tacrolimus levels in breast milk are approximately half that in maternal serum,75 although large controlled studies that evaluate breast milk concentrations of immunosuppressant medications have not been performed. The American Society of Transplantation consensus report suggested that breastfeeding is not necessarily contraindicated,3 but the mother should be informed of the fact that it is unknown whether the risks of further exposure of her infant to immunosuppression outweigh the benefits of breastfeeding. OUTCOMES Whether pregnancy adversely affects a kidney transplant recipient remains a long-standing and unresolved question. Davison76 showed that renal allografts frequently show the physiological adaptations to pregnancy such as an increase in GFR (although the magnitude may be blunted). Most studies have indicated that serum creatinine level may increase slightly after pregnancy, but an adverse effect on longterm outcome could not be shown.77-79 At least one study, however, indicated that pregnancy has a negative effect on transplant function.80 Of interest is an analysis of 40 years of pregnancyrelated outcomes for transplant recipients published in 2009. In this analysis the investigators matched 120 parous and 120 nulliparous women by year of transplantation, duration of transplant, age, and predelivery creatinine level for parous women and creatinine for nonparous women. This analysis failed to show that pregnancy negatively influenced graft or patient survival.81 Individuals with pancreas/kidney transplants may be at higher risk for worse long-term outcomes than diabetic patients who received kidney transplants only. In 2008, the National Transplant Pregnancy Registry (Philadelphia, PA) reported a comparison of outcomes for 43 pancreas/kidney recipients and 34 kidney only recipients.82 Women with pancreas/kidney al-
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lografts had a significantly higher incidence of infection reported as well as a significantly higher risk of graft loss (23.3% versus 2.9%). The reason for these differences is unclear. LONG-TERM FOLLOW-UP EVALUATION OF THE OFFSPRING Human data on which to base information about the long-term effects of in utero exposure to immunosuppressive agents are extremely limited. Abundant animal data suggest a real risk exists for neurocognitive and immunologic defects. Neurocognitive and immunologic testing are not generally prescribed for children of transplant recipients and therefore little if any objective information is available. Registry data that are based on telephone conversations with parents suggest that the offspring of transplant recipients experienced no greater risk than the normal population for attention-deficit hyperactivity disorder,82 despite an overall 24% risk of learning disabilities reported in an earlier study.83 There were also no immunologic abnormalities reported by the parents. Because no objective neurocognitive or immunologic testing was reported for these children, or statistical validation reported for telephone findings, it is impossible to analyze this information. It also is important that opinion-based information does not discourage investigations in this important area, and that long-term follow-up evaluation of the offspring of transplant recipients is promoted. REFERENCES 1. Rudolph JE, Schweizer RT, Bartus SA. Pregnancy in renal transplant patients: a review. Transplantation. 1979;27:26-9. 2. Davison JM. Pregnancy in renal allograft recipients: prognosis and management. Baillieres Clin Obstet Gynaecol. 1987;1:1027-45. 3. McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant. 2005;5:1592-9. 4. Kim HW, Seok HJ, Kim TH, Han DJ, Yang WS, Park SK. The experience of pregnancy after renal transplantation: pregnancies even within postoperative 1 year may be tolerable. Transplantation. 2008;85: 1412-9. 5. Gill JS, Zalunardo N, Rose C, Tonelli M. The preg-
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