- Email: [email protected]
Pregnancy in Renal Transplant Recipients
Pregnancy in Renal Transplant Recipients Susan Hou Fertility in women with kidney failure is restored by transplantation. It requires careful planning and is only advisable in women with good kidney function, controlled blood pressure, and general good health. Immunosuppressive drugs carry risks for the fetus, but the risks of prednisone, azathioprine, cyclosporine, and tacrolimus are surprisingly low. Mycophenolate is teratogenic. The success rate for pregnancy in kidney transplant recipients is lower than in the general population with 70% to 80% of pregnancies resulting in surviving infants. Prematurity, intrauterine growth restriction, and preeclampsia are all increased. Complications are higher and outcomes are worse for women with serum creatinine levels over 1.3 mg/dL. Ten to 15% of women have a temporary or permanent decline in kidney function, particularly if prepregnancy creatinine is high. Transplant-related infections can be serious for the mother and fetus. A multidisciplinary team should coordinate care. Q 2013 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Pregnancy, Kidney transplant, Immunosuppressive drugs, Opportunistic infection
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n March 10, 1958, the first woman to receive a kidney transplant gave birth to the first baby born to a kidney transplant recipient.1 She was transplanted from an identical twin sister, thereby avoiding the problems of immunosuppressive drugs and associated infections in pregnancy. However, this event led to a few important new observations. Transplantation restored fertility in women with kidney failure. The function of a solitary kidney was sufficient to sustain pregnancy. The proximity of the uterus to the transplanted kidney did not cause mechanical problems. The potential for pregnancy raised a multitude of questions about the effect of pregnancy on the transplanted kidney and the effect of kidney disease on the fetus and on pregnancy-related complications. The kidney transplant recipients whose pregnancies followed this first woman were treated with immunosuppressive drugs, with each new generation of drugs requiring evaluation for teratogenicity. All immunosuppressive drugs put the women at risk for opportunistic infections that can be devastating for the developing fetus.
Fertility in Transplant Recipients Women treated with dialysis have markedly decreased fertility (see ‘‘Changes in Fertility and Hormone Replacement Therapy in Kidney Disease’’ in this issue); however, kidney transplantation is usually accompanied by a return of fertility. Even women who have follicle stimulating hormone and luteinizing hormone levels in the postmenopausal range may have normalization of levels and restoration of fertility. The return of fertility is not universal. Pietrzak and colleagues2 noted that only 68.1% of 63 kidney transplant recipients had regular menstrual cycles whereas the rest had irregular cycles. Ovulation was documented by rising progesterone and ultrasound visualization of follicle growth in 59.5% of women with regular menstrual cycles. In vitro fertilization was used in 17 of 1134 pregnancies reported to the National Transplant Pregnancy Registry
(NTPR), 11 in recipients of kidney transplants.3 It is not clear whether infertility is more common in kidney transplant recipients than in the general population. Sirolimus is known to decrease sperm counts and fertility in men,4 but its effect in women is unknown.
Counseling The discussion about pregnancy and childbearing should begin when a woman of childbearing age is seen for her first pretransplant evaluation and continued after transplantation. For those who are too young to be considering pregnancy, the matter should still be mentioned and discussed again as the patient gets older. Part of counseling includes emphasis on the need to continue immunosuppressive therapy. Without the explicit knowledge that loss of graft function carries a higher risk for the baby than the medications, some women have elected to stop drugs on their own for fear of an adverse effect on the baby. Counseling should also emphasize the need to plan pregnancies because medications often need to be changed before conception. Every woman treated with mycophenolate products should be advised of and reminded of their teratogenic potential. Fully 26% of 440 pregnancies reported in an early survey in 1979 ended in elective abortion, often because pregnancy was unexpected and viewed as dangerous.5 It is usually advised that a woman wait at least 1 year before attempting conception. Many would prefer a wait of 2 years but recognize that after a long wait for transplant, the window of fertility may be narrow. The From the Department of Medicine, Loyola University Medical Center, Maywood, IL. Conflict of Interest: S.H. owns stock in Amgen and talks about using erythropoietin in pregnancy. Address correspondence to Susan Hou, MD, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.01.011
Advances in Chronic Kidney Disease, Vol 20, No 3 (May), 2013: pp 253-259
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guidelines that are used for advising transplant recipients about pregnancy are listed in Table 1.
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follow-up, graft survival was 77.8% in women who had become pregnant, 69.2% in the female controls, and 69.8% in the male controls (not significant). TwentyOutcome of Pregnancy in Kidney Transplant eight percent of pregnant women and 31% and 22% of Recipients the 2 control groups used cyclosporine A (CsA). A casecontrol report from the European Dialysis and Transplant The NTPR is the largest body of information on pregAssociation including 53 women who became pregnant nancy outcomes in transplant recipients. Over its matched with controls for year of transplant, type of 20-year history, the registry has collected data on 1490 transplant, and serum creatinine found kidney function pregnancies (1525 outcomes) in 922 kidney transplant reunchanged in case and controls in 67% and worse in cipients. Among the 666 women treated with calcineurin both in 9%.12 In 15% of pairs, the control had a deteriorainhibitors (CNIs), 73.8% of the 1026 pregnancies (1066 tion of kidney function and in 9% the patient who became outcomes) resulted in live births.3 There were 12 neonatal pregnant had a worsening of kidney function. Sturgiss deaths (1.1%). Other outcomes included 17.3% spontaneand Davison compared a group of 18 high-risk women ous abortions, 4.5% therapeutic abortions, 2.5% were who had 34 pregnancies to a control group matched for stillborn, and 0.6% were ectopic pregnancies.3 Other sefactors that affected kidney transplant longevity and ries report similar results.6-9 In one recent report, only found no effect of pregnancy on graft survival.13 All of 32 of 53 (60%) pregnancies in kidney transplant these series are limited by the inclusion of only a few recipients resulted in surviving infants, 69.5% if elective 7 women with impaired kidney function and either a small terminations are excluded. or unspecified number of women treated with CsA. Pregnancy in transplant recipients is also associated There is a single controlled study that suggests that graft with a high rate of prematurity and intrauterine growth function is adversely afrestriction. Of the NTPR fected by pregnancy. Salpregnancies discussed CLINICAL SUMMARY mela and colleagues above, 52% resulted in delivreported long-term graft ery before 37 weeks gesta3 Fertility is restored in kidney transplant recipients. function in 22 female kidney tion. The frequency of transplant recipients with prematurity has remained Successful pregnancy is likely in a woman with good 29 pregnancies compared kidney function and controlled blood pressure when fairly constant over time. undertaken more than a year after transplant. with 38 female controls The severe prematurity that matched for cause of kidney we see in pregnant dialysis Immunosuppressive drugs need to be modified for failure, kidney source, pregnancy. patients is less common. immunosuppression, time Patients need close monitoring for changes in kidney from transplant, and serum function and infection. Effect of Pregnancy on creatinine.14 CsA was used Graft Function during 9 pregnancies and 4 In 1985, Davison published had a prepregnancy serum a report on prospectively studied kidney graft function creatinine of greater than 1.48 mg/dL. During the during 10 pregnancies in 8 kidney transplant recipients.10 follow-up period, 8 of the women who became pregnant All had creatinine clearances of greater than 50 cc/min, lost their grafts, 1 at 1 month postpartum. The other grafts less than 250 mg/24 hours of protein, and well controlled were lost between 1 and 11 years postpartum, but in 3 the deterioration of graft function began during pregnancy. blood pressure. There was a mean increase in creatinine At the 10-year follow-up, transplant survival was 100% clearance of 30% by weeks 9 to 12 (range 10%-60%) defor the control group and 69% for the group who had spite compensatory hypertrophy and increased function of the solitary kidney at the time of transplant. In 2 papregnancies (P , .005). Graft loss could not be correlated tients kidney function was lower than prepregnancy with elevated serum creatinine at the time of conception. levels postpartum. Less is known about changes in gloThe difficulty generalizing from this study lies in the rarmerular filtration rate in women with impaired kidney ity of centers with a 10-year kidney transplant survival of function and in women who conceived in the era of CNIs. 100% such as was seen in the control group. The bulk of the evidence suggests that graft function is usually not There are several studies with case controls looking at adversely affected by pregnancy in women with serum the outcome of pregnancy on kidney graft function. First creatinine less than 1.5 mg/dL treated with prednisone and colleagues reported graft function in 18 women who underwent 25 pregnancies compared with 26 female conand azathioprine. trols and 23 male controls.11 Mean follow-up for the The long-term effect of pregnancy on kidney transgroup who became pregnant was 11.8 years after transplant function is most influenced by prepregnancy kidplantation and 6.9 years after pregnancy with similar ney function. A woman who becomes pregnant with periods of follow-up for the control groups. At last a serum creatinine of 1.4 mg/dL or less is unlikely to
Pregnancy in Renal Transplant Patients
Table 1. Guidelines for Pregnancy After Transplant 1 y after transplant Creatinine ,2 mg/dL (better #1.3 mg/dL) No hypertension No proteinuria No recent rejection No pelvicalyceal distension Prednisone dose #15 mg/d Azathioprine dose #2 mg/kg/d CsA dose , 4 mg/kg/d
have long-term damage to the kidney. However, with the use of CNIs, many women destined to have a functioning graft for many years have serum creatinine levels above 1.4 mg/dL, and many have rephrased guidelines to allow for prepregnancy serum creatinine levels as high as 1.9 mg/dL. The data on the effects of prepregnancy kidney function on pregnancy complications come from a review by John Davison of 3382 pregnancies in 2409 patients. Pregnancy was successful in 96% of women with prepregnancy serum creatinine levels of less than 1.4 mg/ dL and 75% in those with prepregnancy creatinine levels of 1.4 mg/dL or greater.15
Management (see Table 2) Deterioration of Kidney Function During Pregnancy Changes in kidney function during pregnancy are common, with 10% to 18% of women having transient or permanent worsening of kidney function. ‘‘Acute Kidney Injury in Pregnancy—Current Status’’ is discussed separately in this issue. Pregnant kidney transplant recipients are at risk for the causes of kidney failure in other pregnant and nonpregnant patients. A few causes of deterioration are specific for transplant. Rarely there is obstruction of the transplant by the growing uterus, a problem that can often be identified by ultrasound if a first-trimester ultrasound is done for a baseline. If there is a question, then antegrade nephrostogram may be necessary. There are multiple possibilities for elevated CNI levels causing kidney injury because of the need for changing doses and the frequent introduction of other drugs. Acute rejection should be rare 1 year after kidney transplant, but Armenti and colleagues noted rejection in 14.5% of 154 pregnancies in CsA-treated women in an early NTPR report.16 Rejection should be verified by biopsy before treatment. Preeclampsia may be difficult to differentiate from other causes of elevated creatinine, but it may become easier as measurements of antiangiogenic factors are better understood. Hemolytic uremic syndrome can occur from pregnancy or CNI and is discussed separately in ‘‘Acute Kidney Injury in Pregnancy—Current Status’’
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Table 2. Approach to Pregnancy in Kidney Transplant Recipients: Counseling Before and After Transplant About the Return of Fertility and the Need to Plan Pregnancy Before pregnancy Stop mycophenolate 6 weeks before conception. Stop sirolimus and everolimus. May substitute azathioprine. Stop statins and ACE inhibitors. Consultation with high-risk obstetrician. 24-h urine for protein and creatinine clearance. Tests for antibodies to CMV, toxoplasmosis if negative in the past. PCR for CMV and toxoplasmosis. Urine culture. During pregnancy Start low-dose aspirin. The patient should start measuring blood pressure twice daily. Kidney ultrasound during the first trimester. Measurement of CNI levels and complete metabolic profile and CBC every week. Decrease measurement of CNI to every 2 wk if levels are stable. Urine culture and urine protein-to-creatinine ratio monthly. 24-h urine for protein and creatinine clearance; CMV and toxoplasmosis PCR every trimester. Assessment of fetal well being from 26 wk gestation. Peripartum and postpartum C-section only for obstetric indications. Continue twice-daily blood pressure monitoring for 6 wk postpartum. 24-h urine for protein and creatinine clearance 1 mo and 6 mo postpartum. Abbreviations: ACE, angiotensin converting enzyme; CBC, complete blood count.
published in this issue. Rarely, recurrent disease causes acute kidney injury.
Hypertension Hypertension is very common in pregnant transplant recipients. The use of antihypertensive medication and the difficulty making the diagnosis of preeclampsia are discussed in ‘‘Management of Hypertension in Pregnancy’’ and ‘‘Emerging Biomarkers of Preeclampsia’’. There is debate about the level of hypertension that should be treated in normal pregnant women, but with the availability of many antihypertensive drugs that are safe in pregnancy, there is no reason not to treat any blood pressure of 140/ 90 mmHg or more in a woman with a kidney transplant.
Anemia Anemia is common in pregnant kidney transplant recipients. Magee and colleagues found that 74% of a group of pregnant transplant recipients had hemoglobin levels below 10 g/dL compared with 13.5% of controls.17 For the transplant recipient, anemia is likely to be multifactorial. Even with mild chronic kidney disease, erythrocyte production may not increase by the 30% to 40% seen in normal pregnancy. Drugs may cause bone marrow suppression or hemolysis, and transplant recipients are
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also at risk for iron deficiency and for the hemolytic syndromes associated with pregnancy (see ‘‘Acute Kidney Injury in Pregnancy—Current Status’’ in this issue). Normal pregnancy requires 700 to 1000 mg of iron. If oral iron supplementation is not sufficient, then ferric gluconate has been labeled category B for pregnancy by the U.S. Food and Drug Administration (FDA). Because of the high rate of transfer to the fetus, especially after 30 weeks gestation, we limit individual doses to 62.5 mg. Erythropoietin does not appear to be teratogenic. Most pregnant dialysis patients have been exposed to it during the first trimester. Radiolabeled erythropoietin has been shown not to cross the placenta in sheep.18 In all patients with kidney disease, there is an increased risk of stroke with higher doses of erythropoietin. It seems reasonable to start erythropoietin when the hemoglobin level is below 10 g/dL and after other factors have been corrected.
Immunosuppressive Drugs The potential effects of immunosuppressive drugs on the developing fetus have always been a concern for physicians taking care of transplant recipients. New drugs have come into use just as the risks of older drugs have been assessed. Prednisone Prednisone has been widely used in various settings other than kidney transplant, including asthma, idiopathic thrombocytopenia, and systemic lupus erythematosus. It poorly crosses the placenta. The ratio of maternal to cord blood levels of prednisolone in late pregnancy is 8:1 to 10:1.19 Passage of the drug across the placenta early in pregnancy may be higher. In the fully developed placenta placental 11-beta-hydroxylase partially inactivates the drug. Even with the poor passage of prednisone across the placenta, high doses such as those used to treat rejection will result in substantial fetal exposure. However, an infant who appears healthy at birth still needs to be monitored for adrenal insufficiency. Prednisone increases the risk of hypertension and gestational diabetes in the mother. In doses over 20 mg a day, it has been associated with increased risk for opportunistic infection and of premature labor. Azathioprine Azathioprine has been used by thousands of pregnant women but has been labeled as a category D drug by the FDA. The designation is based largely on malformations seen in animals given azathioprine parenterally in higher doses than usually given to humans. Azathioprine and the inactive metabolite 6-mercaptopurine poorly cross the placenta. Maternal and fetal blood levels of the active metabolite 6-thioguaninenucleotide are similar. A prospective study by Goldstein and colleagues compared the rate of birth defects in the infants of 189 women
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receiving azathioprine with the infants of 230 healthy controls.20 Rates were 3.5% in the azathioprine group and 3% in the control group (not significant). There were more preterm infants in the azathioprine group, which was most likely the result of the underlying maternal illness. CsA When CsA was introduced, it was already recognized that prednisone and azathioprine presented acceptable risks during pregnancy but that CsA was essential to preventing rejection in many patients. It was established early on that CsA crossed the placenta and resulted in fetal exposure to CsA levels comparable to maternal levels.21 The frequency of birth defects was comparable to the general population (3%). Kidney function was tested in a group of 22 children exposed to CsA in utero between the ages of 6 and 72 months and was found to be normal.22 Higher rates of prematurity and small-forgestational-age babies have been described with CsA compared with azathioprine, but this finding is hard to attribute to CsA alone.16 Drug levels may change with forces acting to raise and lower levels. The changing space of distribution may decrease the level whereas the high levels of sex steroids may slow hepatic elimination of the drug. Tacrolimus There is not a clear advantage between tacrolimus and CsA in terms of pregnancy risk. In a group of 21 women (27 pregnancies) taking tacrolimus for liver transplants, in 11 of 12 cases in which both maternal and cord blood tacrolimus levels were measured, cord blood levels were on average 36% of maternal levels.23 The placenta appears to provide a barrier to tacrolimus with placental levels being 2 to 56 times higher than cord blood and 4 times higher than maternal blood. Thirty-six percent of infants had transient hyperkalemia and mild kidney impairment. Mycophenolate Mofetil and Mycophenolic Acid Mycophenolate mofetil (MMF) was found to be associated with increased spontaneous abortions and congenital malformations soon after it came into use. In contrast to other medications, MMF was found to embryotoxic in animals in doses lower than those used in human. Malformations described include microtia, cleft lip and palate, auditory canal atresia, hypertelorism, micrognathia, ocular colombona, short fingers, and hypoplastic nails.24 A short 5th finger and hypoplastic nails were described in the first case report of MMF use in pregnancy.25 The NTPR’s 2011 report notes outcomes in 61 pregnancies with exposure to mycophenolate products. There were 30 spontaneous abortions (49%) and 7 of 27 live-born infants had characteristic congenital anomalies.3 The
Pregnancy in Renal Transplant Patients
European Network of Teratology Information Service prospectively followed 57 pregnancies. There were 16 spontaneous abortions and 12 elective abortions, including 2 for congenital anomalies. Six of 29 live-born infants had congenital anomalies.26 Enteric-coated mycophenolic acid carries the same risk. The risk of congenital anomalies with mycophenolate products is serious enough that the FDA has placed a black box warning alerting physicians to the risk of first-trimester use and the company has instituted a Mycophenolate Risk Evaluation and Mitigation Strategy that requires providers to be educated about the teratogenicity of MMF and mycophenolic acid and to document that patients have been educated about the pregnancy risks of the drug. Sirolimus/Everolimus Experience with mammalian target of rapamycin inhibitors in pregnancy is very limited and there is reluctance to use this category of drugs during pregnancy. Other effective immunosuppressive drugs have a track record of relative safety during pregnancy. There are several case reports of the use of sirolimus and one case report of the use of everolimus during organogenesis without resulting congenital anomalies.27-29 The NTPR 2011 Annual Report included 23 pregnancies with sirolimus exposure; in the 3 instances in which congenital anomalies were noted, the mother was also taking MMF.3 Belatacept There is little experience with belatacept use during pregnancy, but its use will be a focus of data collection by the NTPR in the next year.3
Antibodies There is limited information on the use of monoclonal and polyclonal antibodies during pregnancy. Waiting 1 year before conception has as 1 of its goals reducing the risk of acute rejection and the need for antibody therapy. All types of immunoglobulin G (IgG) cross the placenta with increasing efficiency as pregnancy progresses with the greatest chance of crossing being in the last 4 weeks of pregnancy. Although not usually used for treatment of rejection, there are some data on the effect of rituximab, a human/murine chimeric monoclonal IgG directed against the CD 20 protein, on B lymphocytes, which causes B cell depletion. The timing of transfer of IgG would imply a lower risk of congenital anomalies in women who received rituximab in the first trimester, but the drug may persist in the maternal circulation and has been reported to cause hematologic abnormalities and predisposes to infections, including cytomegalovirus (CMV). Women are advised not to conceive for 1 year after receiving rituximab.30
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Plasmapheresis Plasmapheresis has been used in several pregnancyassociated conditions unrelated to transplant with acceptable risk.
Infections Immunosuppression puts the pregnant woman at risk for opportunistic infections that can have severe effects on the newborn. Foremost among these is CMV. In the general population, primary CMV infections are associated with 3% to 40% transmission to the fetus and recurrent infections are associated with 1% transmission. Transmission is less likely to occur early in pregnancy than late in pregnancy, but the effects of the virus are more severe when it is acquired early in pregnancy. If the mother is seriously ill with CMV, she should be treated with the best antiviral drug available. The question remains of when to treat for the benefit of the fetus when the mother is asymptomatic. The diagnosis of intrauterine CMV infection is achieved by measuring CMV via polymerase chain reaction (PCR) of the amniotic fluid, although there are false negatives. One study reports a 13% incidence of long-term sequelae of intrauterine CMV infection in infants of women treated with CMV hyperimmunoglobulin compared with 43% in infants of untreated women.31 The dilemma of deciding about treating asymptomatic CMV becomes more common when surveillance PCRs for CMV are done during pregnancy. Herpes Simplex Herpes simplex is usually spread from mother to child during birth rather than through intrauterine infection.32 Primary infection with herpes simplex virus-1 or herpes simplex virus-2 during pregnancy in normal women carries the risk of neonatal herpes only if infection occurs close to the onset of labor.33 The risk of neonatal herpes can be minimized by Caesarian delivery in women who have a primary infection or reactivation of herpes. Reactivation is associated with neonatal herpes only if the infection occurs near term, but not if there is asymptomatic cervical shedding of the virus. Acyclovir can be safely used in pregnancy.32 Toxoplasmosis Primary toxoplasmosis infection during pregnancy results in neonatal infection in 25% to 65% of infants.34,35 The frequency of neonatal infection increases with increasing number of weeks gestation at the time of infection, but the likelihood of severe manifestations of the infection decreases with increasing length of gestation. Infection in the fetus can be detected in 93% of cases by a combination of testing amniotic fluid and fetal blood and of visualization of ventricular enlargement by ultrasound at 20 to 24 weeks.36 Treatment with
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sulfadiazine and pyrimethamine or spiramycin reduces the likelihood of congenital infection by 60%, and a primary infection should be treated even if the mother is not seriously ill.37 Congenital infection occasionally occurs after reactivation of toxoplasmosis in immunosuppressed patients, and consideration should be given to treating seropositive women with rising antibody titers. Pregnant kidney transplant recipients should be screened for toxoplasmosis each trimester. There are large bodies of literature on vertical infections that may be pertinent to transplant recipients, including HIV, hepatitis B and C, and Trypanosoma cruzii, and their management is beyond the scope of this paper. Urinary Tract Infections Urinary tract infections are by far the most common infections affecting pregnant kidney transplant recipients, up to 40% in some series. In normal pregnancy, it is rare to see pyelonephritis in a woman with a negative screening urine culture, but transplant recipients should be screened monthly. Treatment of pyelonephritis is discussed in the article ‘‘Kidney Stones and Pregnancy’’ in this issue.
Breast Feeding Women with solid organ transplants are usually advised not to breast feed after successful pregnancy. Moretti and colleagues calculated daily CsA intake and measured serum CsA levels in 5 infants who were breastfed. The calculated CsA exposure was low, and in most infants the CsA level in the infant was low or undetectable. However, one infant had near-therapeutic blood levels of CsA.34 The NTPR Annual Report for 2011 reported breast feeding of 126 infants (for a few days to 10 years) without adverse effects.3 At this point, breast feeding has not caused visible problems in the newborns, but more detailed studies, particularly of immunologic development, are needed. With the information available to date, we do not strongly discourage breast feeding.
Conclusions Kidney transplantation remains the best hope for successful pregnancy in women with end-stage kidney disease, although results in dialysis patients discussed in ‘‘Dialysis and Pregnancy’’ in this issue are encouraging. It is important to start counseling early and to have planned pregnancies. The pregnant transplant patient should be cared for by a multidisciplinary team, which includes obstetricians, transplant nephrologists and surgeons, neonatologists, and pharmacists. The team should also include the transplant nurses who have worked with the patients and a social worker because pregnancy is stressful even when the outcome is good. A level 3 nursery should be available for the care of the newborn be-
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cause it may be required. The patients should be seen once every 2 weeks throughout pregnancy and should monitor blood pressures at home. Despite being the best option for women with end-stage kidney disease, the success rate is still only approximately 75%. With wide application of what we already know, the outcome can be improved. There are still elective terminations, most of which can be avoided by counseling and planned pregnancies. Many neonatal deaths are from prematurity, which may be avoided with better diagnosis and treatment of preeclampsia. Ironically, some questions such as the toxicity of new drugs and the outcomes of breast feeding will be known only when pregnancies are accidental or when women elect not to follow our advice.
References 1. Murray JE, Reid DE, Harrison JH, Merrill JP. Successful pregnancies after human renal transplantation. N Engl J Med. 1963;269(2): 341-343. 2. Pietrzak B, Cyganek A, Jabiry-Zieniewic Z, Bobrowska MD, Paczek L, Kami nski P. Function of the ovaries in female transplant recipients. Transplant Proc. 2006;38(1):180-183. 3. National Transplant Pregnancy Registry. 2011 Annual Report. Philadelphia, PA: Thomas Jefferson University; 2012, www.jefferson. edu/ntpr. 4. Zuber Z, Anglicheau D, Elie C, et al. Sirolimus may reduce fertility in male transplant recipients. Am J Transplant. 2008;8(7):1471-1479. 5. Rudolph JE, Schweizer RT, Bartus SA. Pregnancy in renal transplantation: a review. Transplantation. 1979;27(1):26-29. 6. Thompson BC, Kingdon EJ, Tuck SM, Sweny P, Fernando ON. Pregnancy in renal transplant recipients: the Royal Free Hospital experience. QJM. 2003;96(11):837-844. 7. Blume C, Sensoy A, Gross MM, et al. A comparison of outcome of pregnancies after liver and kidney transplant. Transplantation. 2013;95(1):222-227. 8. Al-Durraihimh H, Ghamdi G, Moussa D, et al. Outcome of 234 pregnancies in 140 transplant recipients from five Middle Eastern Countries. Transplantation. 2008;85(6):840-843. 9. Cararach V, Carmona F, Monleon FJ, Andreu J. Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol. 1993;100(2):122-125. 10. Davison JM. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int. 1985;27(1):74-79. 11. First MR, Combs CA, Weislttel P, Miodovnik M. Lack of effect of pregnancy on renal allograft survival or function. Transplantation. 1995;59(4):472-476. 12. Rizzoni G, Ehrich JHH, Broyer M, et al. Successful pregnancies in women on renal replacement therapy: report from the EDTA Registry. Nephrol Dial Transplant. 1992;7(4):279-287. 13. Sturgiss SN, Davison JM. Effect of pregnancy on long term function of renal allografts. Am J Kidney Dis. 1992;19(2):167-172. 14. Salmela KT, Kyll€ onen LEJ, Holmberg C, Gr€ onhagen-Riska C. Impaired renal function after pregnancy in renal transplant recipients. Transplantation. 1993;56(6):1372-1375. 15. Davison JM. Pregnancy in renal allograft recipients: problems, prognosis and practicalities. Baillieres Clin Obstet Gynaecol. 1994;8(2):501-525. 16. 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(4):502-506. 17. Magee LA, von Dadelszen P, Darley J, Beguin Y. Erythropoiesis and renal transplant pregnancy. Clin Transplant. 2000;14(2):127-135.
Pregnancy in Renal Transplant Patients
18. Widness JA, Sawyer ST, Schmidt RL, Chestnut DH. Lack of maternal to fetal transfer of 125I-labeled erythropoietin in sheep. J Dev Physiol. 1991;15(3):139-143. 19. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr. 1972;81(5):936-945. 20. Goldstein LH, Dolinsky G, Greenberg R, et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol. 2007;79(10):696-701. 21. Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis. 1985;5(1):60-63. 22. Shaheen FAM, al-Sulaiman MH, al-Khader AA. Long term nephrotoxicity after exposure to cyclosporine in utero. Transplantation. 1993;56(1):224-225. 23. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplant under tacrolimus. Transplantation. 1997;64(4): 559-565. 24. Merlob P, Stahl B, Klinger G. Tetrada of possible mycophenolate mofetil embryopathy: a review. Reprod Toxicol. 2009;28(1): 105-108. 25. Pergola PE, Kancharla A, Riley D. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus and prednisone. Transplantation. 2001;71(7):994-997. 26. Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of European Network of Teratology Information Services. Am J Med Genet. 2012;158(A)(3): 588-596.
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27. Chu SH, Liu KL, Chiang YJ, Wang HH, Lai PC. Sirolimus used during pregnancy in a living related renal transplant: a case report. Transplant Proc. 2008;40(7):2446-2448. 28. Jankowska I, Oldakowska-Jedynak U, Jabiry-Zieniewicz Z, et al. Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient. Transplant Proc. 2004;36(10):3232-3233. 29. Carta P, Caroti L, Zanazzi M. Pregnancy in a transplant patient treated with everolimus. Am J Kidney Dis. 2012;60(2):329. 30. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011;117(5):1499-1506. 31. Visentin S, Manara R, Milanese L, et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis. 2012;55(4):497-503. 32. Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infections. J Pediatr. 1987;110(1):97-101. 33. Brown ZA, Selke S, Zeh J, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med. 1997;377(8):509-515. 34. Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation. 2003;75(1):2144-2146. 35. MacLeod CL, Lee RV. Parasitic infections. In: Burrow GN, Ferris TF, eds. Medical Complications during Pregnancy. Philadelphia, PA: WB Saunders; 1988. 36. Desmonts G, Forester F, Thulliez Ph, Daffos F, CapellaPavlovsky M, Chartier M. Prenatal diagnosis of congenital toxoplasmosis. Lancet. 1985;1(8247):500-504. 37. Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med. 1988;318(5):271-275.
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n March 10, 1958, the first woman to receive a kidney transplant gave birth to the first baby born to a kidney transplant recipient.1 She was transplanted from an identical twin sister, thereby avoiding the problems of immunosuppressive drugs and associated infections in pregnancy. However, this event led to a few important new observations. Transplantation restored fertility in women with kidney failure. The function of a solitary kidney was sufficient to sustain pregnancy. The proximity of the uterus to the transplanted kidney did not cause mechanical problems. The potential for pregnancy raised a multitude of questions about the effect of pregnancy on the transplanted kidney and the effect of kidney disease on the fetus and on pregnancy-related complications. The kidney transplant recipients whose pregnancies followed this first woman were treated with immunosuppressive drugs, with each new generation of drugs requiring evaluation for teratogenicity. All immunosuppressive drugs put the women at risk for opportunistic infections that can be devastating for the developing fetus.
Fertility in Transplant Recipients Women treated with dialysis have markedly decreased fertility (see ‘‘Changes in Fertility and Hormone Replacement Therapy in Kidney Disease’’ in this issue); however, kidney transplantation is usually accompanied by a return of fertility. Even women who have follicle stimulating hormone and luteinizing hormone levels in the postmenopausal range may have normalization of levels and restoration of fertility. The return of fertility is not universal. Pietrzak and colleagues2 noted that only 68.1% of 63 kidney transplant recipients had regular menstrual cycles whereas the rest had irregular cycles. Ovulation was documented by rising progesterone and ultrasound visualization of follicle growth in 59.5% of women with regular menstrual cycles. In vitro fertilization was used in 17 of 1134 pregnancies reported to the National Transplant Pregnancy Registry
(NTPR), 11 in recipients of kidney transplants.3 It is not clear whether infertility is more common in kidney transplant recipients than in the general population. Sirolimus is known to decrease sperm counts and fertility in men,4 but its effect in women is unknown.
Counseling The discussion about pregnancy and childbearing should begin when a woman of childbearing age is seen for her first pretransplant evaluation and continued after transplantation. For those who are too young to be considering pregnancy, the matter should still be mentioned and discussed again as the patient gets older. Part of counseling includes emphasis on the need to continue immunosuppressive therapy. Without the explicit knowledge that loss of graft function carries a higher risk for the baby than the medications, some women have elected to stop drugs on their own for fear of an adverse effect on the baby. Counseling should also emphasize the need to plan pregnancies because medications often need to be changed before conception. Every woman treated with mycophenolate products should be advised of and reminded of their teratogenic potential. Fully 26% of 440 pregnancies reported in an early survey in 1979 ended in elective abortion, often because pregnancy was unexpected and viewed as dangerous.5 It is usually advised that a woman wait at least 1 year before attempting conception. Many would prefer a wait of 2 years but recognize that after a long wait for transplant, the window of fertility may be narrow. The From the Department of Medicine, Loyola University Medical Center, Maywood, IL. Conflict of Interest: S.H. owns stock in Amgen and talks about using erythropoietin in pregnancy. Address correspondence to Susan Hou, MD, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.01.011
Advances in Chronic Kidney Disease, Vol 20, No 3 (May), 2013: pp 253-259
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guidelines that are used for advising transplant recipients about pregnancy are listed in Table 1.
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follow-up, graft survival was 77.8% in women who had become pregnant, 69.2% in the female controls, and 69.8% in the male controls (not significant). TwentyOutcome of Pregnancy in Kidney Transplant eight percent of pregnant women and 31% and 22% of Recipients the 2 control groups used cyclosporine A (CsA). A casecontrol report from the European Dialysis and Transplant The NTPR is the largest body of information on pregAssociation including 53 women who became pregnant nancy outcomes in transplant recipients. Over its matched with controls for year of transplant, type of 20-year history, the registry has collected data on 1490 transplant, and serum creatinine found kidney function pregnancies (1525 outcomes) in 922 kidney transplant reunchanged in case and controls in 67% and worse in cipients. Among the 666 women treated with calcineurin both in 9%.12 In 15% of pairs, the control had a deteriorainhibitors (CNIs), 73.8% of the 1026 pregnancies (1066 tion of kidney function and in 9% the patient who became outcomes) resulted in live births.3 There were 12 neonatal pregnant had a worsening of kidney function. Sturgiss deaths (1.1%). Other outcomes included 17.3% spontaneand Davison compared a group of 18 high-risk women ous abortions, 4.5% therapeutic abortions, 2.5% were who had 34 pregnancies to a control group matched for stillborn, and 0.6% were ectopic pregnancies.3 Other sefactors that affected kidney transplant longevity and ries report similar results.6-9 In one recent report, only found no effect of pregnancy on graft survival.13 All of 32 of 53 (60%) pregnancies in kidney transplant these series are limited by the inclusion of only a few recipients resulted in surviving infants, 69.5% if elective 7 women with impaired kidney function and either a small terminations are excluded. or unspecified number of women treated with CsA. Pregnancy in transplant recipients is also associated There is a single controlled study that suggests that graft with a high rate of prematurity and intrauterine growth function is adversely afrestriction. Of the NTPR fected by pregnancy. Salpregnancies discussed CLINICAL SUMMARY mela and colleagues above, 52% resulted in delivreported long-term graft ery before 37 weeks gesta3 Fertility is restored in kidney transplant recipients. function in 22 female kidney tion. The frequency of transplant recipients with prematurity has remained Successful pregnancy is likely in a woman with good 29 pregnancies compared kidney function and controlled blood pressure when fairly constant over time. undertaken more than a year after transplant. with 38 female controls The severe prematurity that matched for cause of kidney we see in pregnant dialysis Immunosuppressive drugs need to be modified for failure, kidney source, pregnancy. patients is less common. immunosuppression, time Patients need close monitoring for changes in kidney from transplant, and serum function and infection. Effect of Pregnancy on creatinine.14 CsA was used Graft Function during 9 pregnancies and 4 In 1985, Davison published had a prepregnancy serum a report on prospectively studied kidney graft function creatinine of greater than 1.48 mg/dL. During the during 10 pregnancies in 8 kidney transplant recipients.10 follow-up period, 8 of the women who became pregnant All had creatinine clearances of greater than 50 cc/min, lost their grafts, 1 at 1 month postpartum. The other grafts less than 250 mg/24 hours of protein, and well controlled were lost between 1 and 11 years postpartum, but in 3 the deterioration of graft function began during pregnancy. blood pressure. There was a mean increase in creatinine At the 10-year follow-up, transplant survival was 100% clearance of 30% by weeks 9 to 12 (range 10%-60%) defor the control group and 69% for the group who had spite compensatory hypertrophy and increased function of the solitary kidney at the time of transplant. In 2 papregnancies (P , .005). Graft loss could not be correlated tients kidney function was lower than prepregnancy with elevated serum creatinine at the time of conception. levels postpartum. Less is known about changes in gloThe difficulty generalizing from this study lies in the rarmerular filtration rate in women with impaired kidney ity of centers with a 10-year kidney transplant survival of function and in women who conceived in the era of CNIs. 100% such as was seen in the control group. The bulk of the evidence suggests that graft function is usually not There are several studies with case controls looking at adversely affected by pregnancy in women with serum the outcome of pregnancy on kidney graft function. First creatinine less than 1.5 mg/dL treated with prednisone and colleagues reported graft function in 18 women who underwent 25 pregnancies compared with 26 female conand azathioprine. trols and 23 male controls.11 Mean follow-up for the The long-term effect of pregnancy on kidney transgroup who became pregnant was 11.8 years after transplant function is most influenced by prepregnancy kidplantation and 6.9 years after pregnancy with similar ney function. A woman who becomes pregnant with periods of follow-up for the control groups. At last a serum creatinine of 1.4 mg/dL or less is unlikely to
Pregnancy in Renal Transplant Patients
Table 1. Guidelines for Pregnancy After Transplant 1 y after transplant Creatinine ,2 mg/dL (better #1.3 mg/dL) No hypertension No proteinuria No recent rejection No pelvicalyceal distension Prednisone dose #15 mg/d Azathioprine dose #2 mg/kg/d CsA dose , 4 mg/kg/d
have long-term damage to the kidney. However, with the use of CNIs, many women destined to have a functioning graft for many years have serum creatinine levels above 1.4 mg/dL, and many have rephrased guidelines to allow for prepregnancy serum creatinine levels as high as 1.9 mg/dL. The data on the effects of prepregnancy kidney function on pregnancy complications come from a review by John Davison of 3382 pregnancies in 2409 patients. Pregnancy was successful in 96% of women with prepregnancy serum creatinine levels of less than 1.4 mg/ dL and 75% in those with prepregnancy creatinine levels of 1.4 mg/dL or greater.15
Management (see Table 2) Deterioration of Kidney Function During Pregnancy Changes in kidney function during pregnancy are common, with 10% to 18% of women having transient or permanent worsening of kidney function. ‘‘Acute Kidney Injury in Pregnancy—Current Status’’ is discussed separately in this issue. Pregnant kidney transplant recipients are at risk for the causes of kidney failure in other pregnant and nonpregnant patients. A few causes of deterioration are specific for transplant. Rarely there is obstruction of the transplant by the growing uterus, a problem that can often be identified by ultrasound if a first-trimester ultrasound is done for a baseline. If there is a question, then antegrade nephrostogram may be necessary. There are multiple possibilities for elevated CNI levels causing kidney injury because of the need for changing doses and the frequent introduction of other drugs. Acute rejection should be rare 1 year after kidney transplant, but Armenti and colleagues noted rejection in 14.5% of 154 pregnancies in CsA-treated women in an early NTPR report.16 Rejection should be verified by biopsy before treatment. Preeclampsia may be difficult to differentiate from other causes of elevated creatinine, but it may become easier as measurements of antiangiogenic factors are better understood. Hemolytic uremic syndrome can occur from pregnancy or CNI and is discussed separately in ‘‘Acute Kidney Injury in Pregnancy—Current Status’’
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Table 2. Approach to Pregnancy in Kidney Transplant Recipients: Counseling Before and After Transplant About the Return of Fertility and the Need to Plan Pregnancy Before pregnancy Stop mycophenolate 6 weeks before conception. Stop sirolimus and everolimus. May substitute azathioprine. Stop statins and ACE inhibitors. Consultation with high-risk obstetrician. 24-h urine for protein and creatinine clearance. Tests for antibodies to CMV, toxoplasmosis if negative in the past. PCR for CMV and toxoplasmosis. Urine culture. During pregnancy Start low-dose aspirin. The patient should start measuring blood pressure twice daily. Kidney ultrasound during the first trimester. Measurement of CNI levels and complete metabolic profile and CBC every week. Decrease measurement of CNI to every 2 wk if levels are stable. Urine culture and urine protein-to-creatinine ratio monthly. 24-h urine for protein and creatinine clearance; CMV and toxoplasmosis PCR every trimester. Assessment of fetal well being from 26 wk gestation. Peripartum and postpartum C-section only for obstetric indications. Continue twice-daily blood pressure monitoring for 6 wk postpartum. 24-h urine for protein and creatinine clearance 1 mo and 6 mo postpartum. Abbreviations: ACE, angiotensin converting enzyme; CBC, complete blood count.
published in this issue. Rarely, recurrent disease causes acute kidney injury.
Hypertension Hypertension is very common in pregnant transplant recipients. The use of antihypertensive medication and the difficulty making the diagnosis of preeclampsia are discussed in ‘‘Management of Hypertension in Pregnancy’’ and ‘‘Emerging Biomarkers of Preeclampsia’’. There is debate about the level of hypertension that should be treated in normal pregnant women, but with the availability of many antihypertensive drugs that are safe in pregnancy, there is no reason not to treat any blood pressure of 140/ 90 mmHg or more in a woman with a kidney transplant.
Anemia Anemia is common in pregnant kidney transplant recipients. Magee and colleagues found that 74% of a group of pregnant transplant recipients had hemoglobin levels below 10 g/dL compared with 13.5% of controls.17 For the transplant recipient, anemia is likely to be multifactorial. Even with mild chronic kidney disease, erythrocyte production may not increase by the 30% to 40% seen in normal pregnancy. Drugs may cause bone marrow suppression or hemolysis, and transplant recipients are
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also at risk for iron deficiency and for the hemolytic syndromes associated with pregnancy (see ‘‘Acute Kidney Injury in Pregnancy—Current Status’’ in this issue). Normal pregnancy requires 700 to 1000 mg of iron. If oral iron supplementation is not sufficient, then ferric gluconate has been labeled category B for pregnancy by the U.S. Food and Drug Administration (FDA). Because of the high rate of transfer to the fetus, especially after 30 weeks gestation, we limit individual doses to 62.5 mg. Erythropoietin does not appear to be teratogenic. Most pregnant dialysis patients have been exposed to it during the first trimester. Radiolabeled erythropoietin has been shown not to cross the placenta in sheep.18 In all patients with kidney disease, there is an increased risk of stroke with higher doses of erythropoietin. It seems reasonable to start erythropoietin when the hemoglobin level is below 10 g/dL and after other factors have been corrected.
Immunosuppressive Drugs The potential effects of immunosuppressive drugs on the developing fetus have always been a concern for physicians taking care of transplant recipients. New drugs have come into use just as the risks of older drugs have been assessed. Prednisone Prednisone has been widely used in various settings other than kidney transplant, including asthma, idiopathic thrombocytopenia, and systemic lupus erythematosus. It poorly crosses the placenta. The ratio of maternal to cord blood levels of prednisolone in late pregnancy is 8:1 to 10:1.19 Passage of the drug across the placenta early in pregnancy may be higher. In the fully developed placenta placental 11-beta-hydroxylase partially inactivates the drug. Even with the poor passage of prednisone across the placenta, high doses such as those used to treat rejection will result in substantial fetal exposure. However, an infant who appears healthy at birth still needs to be monitored for adrenal insufficiency. Prednisone increases the risk of hypertension and gestational diabetes in the mother. In doses over 20 mg a day, it has been associated with increased risk for opportunistic infection and of premature labor. Azathioprine Azathioprine has been used by thousands of pregnant women but has been labeled as a category D drug by the FDA. The designation is based largely on malformations seen in animals given azathioprine parenterally in higher doses than usually given to humans. Azathioprine and the inactive metabolite 6-mercaptopurine poorly cross the placenta. Maternal and fetal blood levels of the active metabolite 6-thioguaninenucleotide are similar. A prospective study by Goldstein and colleagues compared the rate of birth defects in the infants of 189 women
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receiving azathioprine with the infants of 230 healthy controls.20 Rates were 3.5% in the azathioprine group and 3% in the control group (not significant). There were more preterm infants in the azathioprine group, which was most likely the result of the underlying maternal illness. CsA When CsA was introduced, it was already recognized that prednisone and azathioprine presented acceptable risks during pregnancy but that CsA was essential to preventing rejection in many patients. It was established early on that CsA crossed the placenta and resulted in fetal exposure to CsA levels comparable to maternal levels.21 The frequency of birth defects was comparable to the general population (3%). Kidney function was tested in a group of 22 children exposed to CsA in utero between the ages of 6 and 72 months and was found to be normal.22 Higher rates of prematurity and small-forgestational-age babies have been described with CsA compared with azathioprine, but this finding is hard to attribute to CsA alone.16 Drug levels may change with forces acting to raise and lower levels. The changing space of distribution may decrease the level whereas the high levels of sex steroids may slow hepatic elimination of the drug. Tacrolimus There is not a clear advantage between tacrolimus and CsA in terms of pregnancy risk. In a group of 21 women (27 pregnancies) taking tacrolimus for liver transplants, in 11 of 12 cases in which both maternal and cord blood tacrolimus levels were measured, cord blood levels were on average 36% of maternal levels.23 The placenta appears to provide a barrier to tacrolimus with placental levels being 2 to 56 times higher than cord blood and 4 times higher than maternal blood. Thirty-six percent of infants had transient hyperkalemia and mild kidney impairment. Mycophenolate Mofetil and Mycophenolic Acid Mycophenolate mofetil (MMF) was found to be associated with increased spontaneous abortions and congenital malformations soon after it came into use. In contrast to other medications, MMF was found to embryotoxic in animals in doses lower than those used in human. Malformations described include microtia, cleft lip and palate, auditory canal atresia, hypertelorism, micrognathia, ocular colombona, short fingers, and hypoplastic nails.24 A short 5th finger and hypoplastic nails were described in the first case report of MMF use in pregnancy.25 The NTPR’s 2011 report notes outcomes in 61 pregnancies with exposure to mycophenolate products. There were 30 spontaneous abortions (49%) and 7 of 27 live-born infants had characteristic congenital anomalies.3 The
Pregnancy in Renal Transplant Patients
European Network of Teratology Information Service prospectively followed 57 pregnancies. There were 16 spontaneous abortions and 12 elective abortions, including 2 for congenital anomalies. Six of 29 live-born infants had congenital anomalies.26 Enteric-coated mycophenolic acid carries the same risk. The risk of congenital anomalies with mycophenolate products is serious enough that the FDA has placed a black box warning alerting physicians to the risk of first-trimester use and the company has instituted a Mycophenolate Risk Evaluation and Mitigation Strategy that requires providers to be educated about the teratogenicity of MMF and mycophenolic acid and to document that patients have been educated about the pregnancy risks of the drug. Sirolimus/Everolimus Experience with mammalian target of rapamycin inhibitors in pregnancy is very limited and there is reluctance to use this category of drugs during pregnancy. Other effective immunosuppressive drugs have a track record of relative safety during pregnancy. There are several case reports of the use of sirolimus and one case report of the use of everolimus during organogenesis without resulting congenital anomalies.27-29 The NTPR 2011 Annual Report included 23 pregnancies with sirolimus exposure; in the 3 instances in which congenital anomalies were noted, the mother was also taking MMF.3 Belatacept There is little experience with belatacept use during pregnancy, but its use will be a focus of data collection by the NTPR in the next year.3
Antibodies There is limited information on the use of monoclonal and polyclonal antibodies during pregnancy. Waiting 1 year before conception has as 1 of its goals reducing the risk of acute rejection and the need for antibody therapy. All types of immunoglobulin G (IgG) cross the placenta with increasing efficiency as pregnancy progresses with the greatest chance of crossing being in the last 4 weeks of pregnancy. Although not usually used for treatment of rejection, there are some data on the effect of rituximab, a human/murine chimeric monoclonal IgG directed against the CD 20 protein, on B lymphocytes, which causes B cell depletion. The timing of transfer of IgG would imply a lower risk of congenital anomalies in women who received rituximab in the first trimester, but the drug may persist in the maternal circulation and has been reported to cause hematologic abnormalities and predisposes to infections, including cytomegalovirus (CMV). Women are advised not to conceive for 1 year after receiving rituximab.30
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Plasmapheresis Plasmapheresis has been used in several pregnancyassociated conditions unrelated to transplant with acceptable risk.
Infections Immunosuppression puts the pregnant woman at risk for opportunistic infections that can have severe effects on the newborn. Foremost among these is CMV. In the general population, primary CMV infections are associated with 3% to 40% transmission to the fetus and recurrent infections are associated with 1% transmission. Transmission is less likely to occur early in pregnancy than late in pregnancy, but the effects of the virus are more severe when it is acquired early in pregnancy. If the mother is seriously ill with CMV, she should be treated with the best antiviral drug available. The question remains of when to treat for the benefit of the fetus when the mother is asymptomatic. The diagnosis of intrauterine CMV infection is achieved by measuring CMV via polymerase chain reaction (PCR) of the amniotic fluid, although there are false negatives. One study reports a 13% incidence of long-term sequelae of intrauterine CMV infection in infants of women treated with CMV hyperimmunoglobulin compared with 43% in infants of untreated women.31 The dilemma of deciding about treating asymptomatic CMV becomes more common when surveillance PCRs for CMV are done during pregnancy. Herpes Simplex Herpes simplex is usually spread from mother to child during birth rather than through intrauterine infection.32 Primary infection with herpes simplex virus-1 or herpes simplex virus-2 during pregnancy in normal women carries the risk of neonatal herpes only if infection occurs close to the onset of labor.33 The risk of neonatal herpes can be minimized by Caesarian delivery in women who have a primary infection or reactivation of herpes. Reactivation is associated with neonatal herpes only if the infection occurs near term, but not if there is asymptomatic cervical shedding of the virus. Acyclovir can be safely used in pregnancy.32 Toxoplasmosis Primary toxoplasmosis infection during pregnancy results in neonatal infection in 25% to 65% of infants.34,35 The frequency of neonatal infection increases with increasing number of weeks gestation at the time of infection, but the likelihood of severe manifestations of the infection decreases with increasing length of gestation. Infection in the fetus can be detected in 93% of cases by a combination of testing amniotic fluid and fetal blood and of visualization of ventricular enlargement by ultrasound at 20 to 24 weeks.36 Treatment with
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sulfadiazine and pyrimethamine or spiramycin reduces the likelihood of congenital infection by 60%, and a primary infection should be treated even if the mother is not seriously ill.37 Congenital infection occasionally occurs after reactivation of toxoplasmosis in immunosuppressed patients, and consideration should be given to treating seropositive women with rising antibody titers. Pregnant kidney transplant recipients should be screened for toxoplasmosis each trimester. There are large bodies of literature on vertical infections that may be pertinent to transplant recipients, including HIV, hepatitis B and C, and Trypanosoma cruzii, and their management is beyond the scope of this paper. Urinary Tract Infections Urinary tract infections are by far the most common infections affecting pregnant kidney transplant recipients, up to 40% in some series. In normal pregnancy, it is rare to see pyelonephritis in a woman with a negative screening urine culture, but transplant recipients should be screened monthly. Treatment of pyelonephritis is discussed in the article ‘‘Kidney Stones and Pregnancy’’ in this issue.
Breast Feeding Women with solid organ transplants are usually advised not to breast feed after successful pregnancy. Moretti and colleagues calculated daily CsA intake and measured serum CsA levels in 5 infants who were breastfed. The calculated CsA exposure was low, and in most infants the CsA level in the infant was low or undetectable. However, one infant had near-therapeutic blood levels of CsA.34 The NTPR Annual Report for 2011 reported breast feeding of 126 infants (for a few days to 10 years) without adverse effects.3 At this point, breast feeding has not caused visible problems in the newborns, but more detailed studies, particularly of immunologic development, are needed. With the information available to date, we do not strongly discourage breast feeding.
Conclusions Kidney transplantation remains the best hope for successful pregnancy in women with end-stage kidney disease, although results in dialysis patients discussed in ‘‘Dialysis and Pregnancy’’ in this issue are encouraging. It is important to start counseling early and to have planned pregnancies. The pregnant transplant patient should be cared for by a multidisciplinary team, which includes obstetricians, transplant nephrologists and surgeons, neonatologists, and pharmacists. The team should also include the transplant nurses who have worked with the patients and a social worker because pregnancy is stressful even when the outcome is good. A level 3 nursery should be available for the care of the newborn be-
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cause it may be required. The patients should be seen once every 2 weeks throughout pregnancy and should monitor blood pressures at home. Despite being the best option for women with end-stage kidney disease, the success rate is still only approximately 75%. With wide application of what we already know, the outcome can be improved. There are still elective terminations, most of which can be avoided by counseling and planned pregnancies. Many neonatal deaths are from prematurity, which may be avoided with better diagnosis and treatment of preeclampsia. Ironically, some questions such as the toxicity of new drugs and the outcomes of breast feeding will be known only when pregnancies are accidental or when women elect not to follow our advice.
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18. Widness JA, Sawyer ST, Schmidt RL, Chestnut DH. Lack of maternal to fetal transfer of 125I-labeled erythropoietin in sheep. J Dev Physiol. 1991;15(3):139-143. 19. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr. 1972;81(5):936-945. 20. Goldstein LH, Dolinsky G, Greenberg R, et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol. 2007;79(10):696-701. 21. Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis. 1985;5(1):60-63. 22. Shaheen FAM, al-Sulaiman MH, al-Khader AA. Long term nephrotoxicity after exposure to cyclosporine in utero. Transplantation. 1993;56(1):224-225. 23. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplant under tacrolimus. Transplantation. 1997;64(4): 559-565. 24. Merlob P, Stahl B, Klinger G. Tetrada of possible mycophenolate mofetil embryopathy: a review. Reprod Toxicol. 2009;28(1): 105-108. 25. Pergola PE, Kancharla A, Riley D. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus and prednisone. Transplantation. 2001;71(7):994-997. 26. Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of European Network of Teratology Information Services. Am J Med Genet. 2012;158(A)(3): 588-596.
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27. Chu SH, Liu KL, Chiang YJ, Wang HH, Lai PC. Sirolimus used during pregnancy in a living related renal transplant: a case report. Transplant Proc. 2008;40(7):2446-2448. 28. Jankowska I, Oldakowska-Jedynak U, Jabiry-Zieniewicz Z, et al. Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient. Transplant Proc. 2004;36(10):3232-3233. 29. Carta P, Caroti L, Zanazzi M. Pregnancy in a transplant patient treated with everolimus. Am J Kidney Dis. 2012;60(2):329. 30. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011;117(5):1499-1506. 31. Visentin S, Manara R, Milanese L, et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis. 2012;55(4):497-503. 32. Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infections. J Pediatr. 1987;110(1):97-101. 33. Brown ZA, Selke S, Zeh J, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med. 1997;377(8):509-515. 34. Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation. 2003;75(1):2144-2146. 35. MacLeod CL, Lee RV. Parasitic infections. In: Burrow GN, Ferris TF, eds. Medical Complications during Pregnancy. Philadelphia, PA: WB Saunders; 1988. 36. Desmonts G, Forester F, Thulliez Ph, Daffos F, CapellaPavlovsky M, Chartier M. Prenatal diagnosis of congenital toxoplasmosis. Lancet. 1985;1(8247):500-504. 37. Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med. 1988;318(5):271-275.