- Email: [email protected]
Pregnancy in Renal Transplant Recipients and Donors
Pregnancy in Renal Transplant Recipients and Donors Kate Bramham, PhD
Summary: Women with renal transplants have restoration of fertility with improved kidney function; however, pregnancy rates in renal transplant recipients appear to be lower than the general population, which might be influenced by patient choice. Women with renal transplants need to evaluate potential neonatal outcomes, graft outcomes, and risks to their own health to make informed decisions about conception. Pregnancy should be carefully planned in renal transplant recipients to reduce risk for graft loss, optimize pregnancy outcomes, and ensure immunosuppression regimes are nonteratogenic. Neonatal outcomes remain significantly worse for women with renal transplants than healthy controls, particularly for those with reduced graft function, hence prepregnancy, antenatal, and postpartum care of women with renal transplants should be guided by a multidisciplinary team of nephrologists and specialist obstetricians. Semin Nephrol 37:370-377 C 2017 Published by Elsevier Inc. Keywords: Pregnancy, renal transplant, kidney donor
W
omen with severe chronic kidney disease are frequently recommended to delay conception until after transplantation to enable restoration of fertility and improve pregnancy outcomes. However, further complexity to pregnancy planning is introduced after renal transplantation, including optimal timing of conception, teratogenicity of immunosuppression, risk of graft loss, and concerns regarding mode of delivery. In addition, both maternal and neonatal pregnancy complications remain higher than they are for the general population, despite near normal glomerular filtration rates in many women with kidney transplants.
PREGNANCY RATES AND FERTILITY IN RENAL TRANSPLANT RECIPIENTS The incidence of pregnancy was reported, in an assessment of Medicare data, to be considerably lower in women with renal transplants compared with the general population. A significant reduction in the pregnancy rate was seen between 1990 and 2000, which decreased from 59 to 20 pregnancies/1,000 transplant recipients.1 Similarly, a lower rate of pregnancy compared with the Australian general population (0.19 [95% confidence interval 0.17 to 0.21]) was reported by the Australian and New Zealand Dialysis and Transplant Registry with a further decline during the same time period, particularly for women in their twenties.2 Estimates of the proportion of women with renal transplants who become pregnant range from 2% Division of Transplantation and Mucosal Biology, King’s College London, London, UK. Financial disclosure and conflicts of interest: none. Address reprint requests to Kate Bramham, PhD, 10 Cutcombe Rd, London, SE5 9RJ, UK. E-mail: [email protected] 0270-9295/ - see front matter & 2017 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.semnephrol.2017.05.009
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to 5%,3,4 despite over half of patients with renal transplants being of child-bearing age. The low pregnancy rate in women with renal transplants is unexplained, but it is possible that women choose not to conceive to preserve graft function. The decline in pregnancy rate with time might also be related to the introduction of mycophenolate mofetil in 1995, which is teratogenic, or it might be a consequence of improved prepregnancy counseling, but further qualitative analysis of decision-making regarding pregnancy in this population is needed. There is limited understanding of fertility in women with renal transplants, but one Iranian study described infertility problems in 13 out of 126 (10.4%) women with renal transplants,5 which is comparable with general population rates. A small prospective study reported that prolactin, luteinising hormone, and follicle stimulations hormone in seven women returned to normal within 14-21 days of restoration of renal function,6 and numerous case reports describe ovulation7 and even pregnancy within weeks after transplantation.8 Nonetheless, the global trend to delay pregnancy is likely to contribute to lower pregnancy rates in women with renal transplants due to reduced fertility compounded by long waiting lists, which indirectly contribute to increased maternal age in this group.
TRANSPLANTATION-TO-CONCEPTION INTERVAL Evidence for optimal timing for conception is limited to single center and retrospective studies, of which some report adverse pregnancy outcomes to be inversely related to the interval between transplantation and conception,3,9–11 while others report no influence.12–14 However, a meta-analysis of outcomes of 4,706 pregnancies in renal transplant recipients was suggestive that live-birth rates are higher in studies with a mean interval between transplantation and pregnancy of o2 years (80.1%) compared with studies with an interval Seminars in Nephrology, Vol 37, No 4, July 2017, pp 370–377
Renal Transplant Recipient and Donor Pregnancies
of 2-3 years (64.2%), 3-4 years (76.1%), and 44 years (75.4%).15 However, it is important to recognize that individual patients’ data were not analyzed in this study, and only three studies had a mean interval of o2 years compared with 14 studies that had longer time intervals.15 Furthermore, comparisons of intervals between transplantation and conception were made for other pregnancy outcomes, and the rates of preeclampsia, gestational diabetes, cesarean section, and preterm birth were more common in studies with a mean interval of o2 years between transplantation and conception than in studies with longer intervals.15 A recent retrospective study of renal transplant outcomes obtained from the US Renal Data System occurring in 1990-2010 in 21,814 women of child-bearing age with (N ¼ 729) and without pregnancies (N ¼ 21,085) demonstrated a significantly higher rate of graft failure in those who conceived within two years of transplantation.16 Only women who conceived after three years had comparable rates of graft loss to those women who did not have pregnancies.16 Cessation of mycophenolate mofetil at least three months prior to pregnancy is desired to avoid teratogenicity, but the effect of switching to azathioprine on long-term graft function in those wishing to conceive within two years of transplantation requires further study because there is likely a complex interplay between pregnancy timing, maternal age, and existing comorbidities. The American Society of Transplantation guidelines for timing of conception17 are outlined in Figure 1.
CONTRACEPTION Contraception counseling is an essential part of pregnancy planning; however, a Brazilian study of female transplant recipients reported that contraception recommendations were made more commonly before transplantation than after, with only 49% of women having discussed contraception with their physician despite 80% being sexually active.17 There frequently is uncertainty regarding contraceptive safety and efficacy in women with renal transplants in relation to immunosuppression and vascular risk. Estrogen can increase
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blood levels of immunosuppressants and should be avoided in those with hypertension, vascular disease, in smokers, and persons with diabetes because of the increased risk for thrombotic stroke and myocardial infarction.19 Depot medroxyprogesterone acetate is not recommended in women with low bone mineral density.20 There is no evidence that intrauterine devices are less effective due to immunosuppression21 or are associated with increased risk for pelvic inflammatory disease. Nonetheless, assessment for gonorrhea and chlamydia is suggested before insertion.22
MEDICATION BEFORE, DURING, AND AFTER PREGNANCY An overview of medication safety during pregnancy and lactation is outlined in Table 1.23,24 Frequently conflict arises regarding manufacturers recommendations for pregnancy and breast-feeding, which invariably suggest that medications should be avoided because of the lack of robust safety data. However, the danger of ceasing immunosuppression and other medications during pregnancy usually far outweighs any potential risk of fetotoxicity and needs to be carefully explained to women with renal transplants. Important principles of prescribing immunosuppression in women with renal transplants during pregnancy include the following:
Tacrolimus, cyclosporine, azathioprine, and pre
dnisolone are all considered to be safe during pregnancy and breast-feeding. Mycophenolate mofetil is teratogenic and should be stopped at least three months before pregnancy to ensure graft stability on alternative agents. Azathioprine is a preferred alternative to mycophenolate mofetil and has an excellent safety profile in pregnancy and breast-feeding, despite being classified as Food and Drug Administration category D because of its teratogenicity in animals. However, only two cases of congenital abnormalities have been reported after several decades of use in pregnancy. The pharmacokinetics of calcineurin inhibitors are altered during pregnancy; lower blood concentrations often occur.25 Dose adjustments (by 20%25% or more) are frequently necessary to achieve the target concentrations, but caution should be used because preliminary data suggest that free tacrolimus concentrations might be higher in pregnant than in nonpregnant women.26
PREGNANCY OUTCOMES Figure 1. Recommendations of the American Society of Transplantations to follow before Conception.18
In general, pregnancy outcomes in women with renal transplants are better than those on dialysis, although a
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Table 1. Commonly Used Drugs in Pregnant Women with Chronic Kidney Disease23,24 Drug
Teratogenicity
Fetal/Neonatal Effects
Commonly used immunosuppression during pregnancy Rare except at large doses Prednisolone Possible (cataract, adrenal increase in insufficiency, and infection) oral clefts Azathioprine None Sporadic congenital abnormalities, transient immune alterations in neonates Tacrolimus None Rare, hyperkalemia and renal impairment Cyclosporine
None
Rare, hyperkalemia and renal impairment
Recommendations in Pregnancy
Recommendations in Breast-Feeding
Yes
Yes, but not encouraged if 460 mg prednisolone daily Yes
Yes
Yes, usually increased required to achieve prepregnancy target Yes, usually increased required to achieve prepregnancy target
doses
Yes
levels doses
Yes
levels
Immunosuppression recommended to be stopped before pregnancy No, stop 3 months Yes Congenital abnormalities in Mycophenolate preconception 22.9%: cleft mofetil/ lip and palate, absent mycophenolic auditory canal, acid hypertelorism, microtia, brachydactyly of the fifth finger, limb abnormalities, and hypoplastic toenails Sirolimus Unknown Toxicity in animal studies, but No, stop 3 months not teratogenicity preconception Everolimus Unknown Toxicity in animal studies, but No, stop 3 months not teratogenicity preconception Treatment for acute rejection and induction Methylprednisolone None Rare, cataract, adrenal insufficiency, and infection Intravenous None None reported immunoglobulin Alemtuzumab Unknown Unknown
Unknown Unknown
Yes
Yes
Yes
Yes Unknown, but possible transfer into milk, neonate gastrointestinal digestion
Basiliximab
Unknown
No toxicity or teratogenicity in monkeys
Belatacept
Unknown
Unknown
Manufacturer recommends avoiding pregnancy for at least 6 months after exposure Manufacturer recommends avoiding pregnancy for at least 4 months after exposure Do not administer in pregnancy
Antithymocyte globulin
Unknown
Unknown
Do not administer in pregnancy
*
No
Unknown, but possible transfer into milk, neonate gastrointestinal digestion Unknown, but transfer into breast milk unlikely as Fc fragment of IgG1 Unknown, but possible transfer into milk, neonate gastrointestinal digestion
Adapted from references.23,24
formal comparison with women on intensive hemodialysis is yet to be reported. Despite restoration of renal function, rates of preeclampsia, preterm delivery, low birth weight, and admission to maternal and neonatal care remain higher for women with renal
transplants compared with the general population.15 An overview of pregnancy outcomes from national registry data is presented in Table 2.14,15,27,28 In addition to the interval from transplantation to conception, predictors of adverse pregnancy outcome
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Table 2. Registry Data Reporting Pregnancy Outcomes in Women with Renal Transplants14,27,28 Category
Data Source Sibanda et al, 2007
Number of pregnancies (number of women) 193 (176) Years of study 1994-2001 Study design Renal unit questionnaire Country
United Kingdom
Median time to conception after transplant
6 years (range 3 months to 19 years) Median maternal age, years 30 (range 20-43) Preeclampsia/superimposed preeclampsia, — % Spontaneous delivery, % 12 Induced, % 24 Cesarean section, % 72 Gestational diabetes, % Live birth, % 79 Miscarriage, % 11 Therapeutic termination, % 6 Intrauterine death, % 2 Stillbirth, % 2 Gestational age at delivery, mean ⫾ SE, 35.6 ⫾ 0.3 weeks Preterm delivery, o37 weeks, % 50 Birth weight, mean ⫾ SE, g 2,316 ⫾ 80 Birth weight, o2,500 g, % 54
Coscia et al, 2014
Wyld et al, 2013
1,742 (986) 1991-2014 Self- or clinicianreported United States
200 2000-2010 Renal unit reporting
—
Australia and New Zealand 5 years (IQR 3-9 years)
— 30
31 (IQR 27-34) 29
— — 53 8 76 17 4 — 2 —
— — — 3 76 9 11 Perinatal mortality 5.8 3 35.5 ⫾ 4.6
51 41
450 2,485 ⫾ 783 -
Abbreviations: IQR, Interquartile range; SE, standard error.
include prepregnancy glomerular filtration rates and preexisting hypertension.13,14,15,27,28 A prospective cohort study also indicated that women with two or more transplants were more likely to have severe neonatal outcomes.13
MATERNAL COMPLICATIONS Preeclampsia Preeclampsia might be difficult to diagnose in women with renal transplants because many of them have preexisting hypertension,3,29–31 and several develop gestational proteinuria without preeclampsia.13 The high incidence of preeclampsia in these women compared with the general US population (27% versus 3.8%, respectively)15 indicates the need for serial monitoring of fetal growth and Doppler studies together with assessment of other maternal organ involvement (eg, liver enzymes) for all women with renal transplants to guide timing of delivery. Gestational Diabetes Women with renal transplants are at higher risk of developing gestational diabetes than the general
population. A meta-analysis of 52 studies reporting pregnancy outcomes in women with renal transplants showed a pooled incidence rate of 8.0% compared with 3.6% in the US general population.15 The incidence of gestational diabetes in individual studies is variable and is likely to be dependent on thresholds used for diagnosis, as well as other influences including maternal age, obesity, and dose of prednisolone and tacrolimus. Screening with oral glucose tolerance testing should be offered to all women with renal transplants earlier in gestation. Graft Injury During Delivery Women might be concerned about damage to the graft during delivery; however, this complication is extremely rare and is restricted only to those with surgical deliveries. Vaginal delivery is not affected by the anatomic location of the graft. Nonetheless, most women with renal transplants are delivered by cesarean section (Table 2).14,15,27,28 Mode of delivery is likely to be related to high rates of maternal and fetal complications; however, one UK prospective cohort study found that women were also delivering by cesarean section with no additional indications other than the presence of the transplant.13
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Infections Urinary tract infection is the most common infection encountered by women with renal transplants during pregnancy, with incidence rates ranging from 14.6% to 42%.33-35 Regular surveillance with monthly midstream urine tests is recommended with prompt treatment if infection is identified.36 There is no robust evidence to support this practice, but many experts recommend long-term prophylactic antibiotics after one infection or in patients with a history of urinary tract infections to prevent recurrence.37 If pregnancy is delayed until at least 1 year after transplantation, the risk for opportunistic infections is likely to be lower. However, there are cases of cytomegalovirus in pregnant transplant recipents that were successfully treated with ganciclovir.38,39 Cytomegalovirus can cause fetotoxicity, sensorineural deafness, impaired psychomotor development, choroidoretinitis, dental problems, fetal growth restriction, respiratory distress, and seizures.40 Reactivation rather than de novo infection is associated with a lower risk for complications, but prophylaxis is not recommended due to teratogenicity of ganciclovir. Graft Dysfunction Gestational adaptation occurs in renal grafts, regardless of age or sex of the donor,41 although one small study suggests that augmentation in creatinine clearance might be impaired in later pregnancy compared with healthy controls.42 Loss of graft function due to pregnancy is one of the greatest concerns for women with renal transplants. However, the majority can be reassured that long-term graft function is unaffected by gestation. Researchers using data from the Australian and New Zealand Dialysis and Transplant Registry did not detect a difference in rates of graft loss at 20 years between 120 women with renal transplants with pregnancies and nulliparous controls matched for graft vintage, age, and graft function.2 Numerous single center studies also support that gestation does not have a detrimental effect on renal function.43,44 Data from the US National Transplant Pregnancy Registry (NTPR) indicated that women with graft loss during or after pregnancy were more likely to have higher prepregnancy creatinine than those with stable graft function (1.5 ⫾ -0.6 mg/dL versus 1.3 ⫾ 0.4 mg/dL),29 and African-American women have an increased risk for graft loss within 2 years of delivery (13%) in comparison with whites (5%).14 Although the overall risk for adverse graft outcomes during pregnancy for most women is not significant, acute graft dysfunction during pregnancy or postpartum is common.13 Acute rejection is rare, with only 4.2% (102/2,412) of women reporting graft rejection in
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a recent meta-analysis on pregnancy outcomes in women with renal transplants.15 If rejection is suspected, biopsy should be performed before the fetus becomes viable, and if at a late gestation period, empirical treatment with intravenous methylprednisolone with planned delivery should be considered. The most common cause of a rise in serum creatinine concentrations during pregnancy in women with renal transplants is preeclampsia,13 but other causes of graft dysfunction, including urinary tract infection, tacrolimus toxicity, and obstruction, need to be investigated and promptly treated. Maternal Death Women with renal transplants have a higher mortality rate during pregnancy compared with the general population, but pregnancy was not demonstrated to be associated with an additional increase in mortality by Australian and New Zealand Dialysis and Transplant Registry data when comparing postpartum survival in 120 women with renal transplants with nulliparous controls.2 However, it is important to reflect on the overall survival rates reported; approximately one in ten renal transplant recipients would not be alive by the 10th birthday of their child, and one in four would have died before their child’s 20th birthday. Influence of Preexisting Disease Women with genetic renal disorders should be counseled about the risk for inheritance, and for those with known single gene mutations (eg, Alport syndrome and autosomal dominant polycystic kidney disease), prenatal diagnosis can be discussed. For others with more complex inheritance patterns, eg, reflux nephropathy, recommendations for screening of offspring should be given. Women with lupus nephritis should be assessed for the presence of the Ro and La antibody, which could lead to fetal heart block or neonatal cutaneous lupus, respectively. There is a theoretical risk for reactivation of atypical hemolytic-uremic syndrome, and those who have previously been affected should be assessed for hemolysis given the increased risk for relapse during pregnancy.
PREGNANCY AND GRAFT OUTCOMES IN WOMEN WITH KIDNEY PANCREAS TRANSPLANTS There is increasing experience of pregnancy in kidneypancreas transplant recipients. The US NTPR now report 104 pregnancies from 58 recipients.14 Although overall outcomes of women with kidney and pancreas transplants are likely to be superior to those of women with moderate-to-severe diabetic nephropathy, both maternal and fetal complication rates are high.
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Table 3. Pregnancy Outcomes for Women with Tacrolimus-Based Immunosuppression Having Either Kidney Transplants Alone or Kidney-Pancreas Transplants14 Outcomes
Kidney Transplant
Kidney-Pancreas Transplant
Number of recipients (number of pregnancies) Transplant-to-conception interval, mean ⫾ SE, years Hypertension during pregnancy, % Diabetes during pregnancy, % Infection during pregnancy, % Preeclampsia, % Rejection episode during pregnancy, % Graft loss within 2 yrs of delivery, % Live births, % (n) Gestation, mean ⫾ SE, weeks Premature, o37 weeks, % Low birthweight, o2,500 g, % Cesarean section, % Neonatal deaths within 30 days of birth, n (%)
254 (427) 4.8 ⫾ 3.3 53 9 20 35 2 9 71.5 (315) 35.4 ⫾ 3.6 52 42 58 5 (1.6)
30 (57) 4.4 ⫾ 3 35 4 21 30 4 7 66.1 (41) 34.1 ⫾ 3.4 73 59 76 0 (0)
Abbreviation: SE, Standard error.
Table 3 presents pregnancy outcomes in women with kidney-pancreas transplants and kidney-only transplants using NTPR-sourced data.14 The mechanisms underlying worse outcomes are poorly understood, but are likely to be related to preexisting microvascular disease impairing maternal hemodynamic adaptation. In addition, placental function appears to be impaired, and most infants are delivered early and of low birth weight. The intraperitoneal position of kidney-pancreas grafts might lead to obstruction from uterine expansion, and regular surveillance in late pregnancy is warranted. Furthermore, graft loss postpartum is high; as indicated by NTPR, 8 (19%) of 43 women lose one or more grafts within two years after delivery.45 In this cohort, acute rejection or a rise in serum creatinine during pregnancy, but not prepregnancy creatinine, were the strongest predictors of subsequent graft failure.46
PREGNANCY COMPLICATIONS IN KIDNEY DONORS The exponential global rise in living donor kidney transplants has led to an increasing number of pregnant women who have donated a kidney. The understanding of possible complications in this unique group is important, not only for management in a current pregnancy, but also to enable those contemplating donation to make informed choices about timing of conception in relation to donating their kidney. In view of the rigorous screening before donation for risk factors for future renal disease, which also are associated with adverse pregnancy outcomes (eg, hypertension, obesity, and diabetes), it might be expected that women who have donated a kidney should have minimal complications. Current literature
is limited, but suggests that pregnancy complications appear to be more common in postdonation pregnancies than in predonation pregnancies and pregnancies in the general population. In a US survey of 1,589 women who donated their kidney between 1963-2007, only 490 out of 3,213 pregnancies (15%) occurred after transplantation.48 Rates of preeclampsia were higher in pregnancies after donation (5.5%) than pregnancies before (0.8%). Similarly, Norwegian registry data from 326 female kidney donors indicated higher rates of preeclampsia in pregnancies after donation (5.7%) than before (2.6%).49 More recently, a Canadian population study assessed pregnancy complications in 85 kidney donors with 131 pregnancies and reported that the rate of preeclampsia was higher (6%) in comparison to the 510 controls (3%) matched for age, parity, year of pregnancy, and socioeconomic status.49 Rates of gestational hypertension also were higher in kidney donors than in controls (5% versus 2%, respectively), similar to the preeclampsia rates reported in pregnancies after donation (5.7%) in the US survey study described above. However, in the Norwegian survey study, gestational hypertension was not more frequent after donation, although only small numbers of women were affected. All of the studies reporting pregnancy outcomes in kidney donors are limited by patient reporting and coding data for diagnosis of preeclampsia. These findings are supportive in confirming a role for the kidney in the pathophysiology of preeclampsia, which might be independent of preexisting endothelial dysfunction. Differences in other pregnancy outcomes are less consistent. The US survey study reported higher rates of fetal loss in pregnancies after donation (19.2%)
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compared with those before donation (11.3%),47 but no differences were reported from the Norwegian registry data.48 In the Canadian population study, only pregnancies carried beyond 20 weeks’ gestation were included, so, this analysis in the Canadian population was not possible. In the US study, gestational diabetes and preterm delivery also were reported to be higher in pregnancies after donation than pregnancies before (diabetes, 2.7% versus 0.7%; preterm delivery, 26.3% versus 15.4%, respectively), but not by other studies.47,49 Importantly, there have been no differences in birth weight described by Norwegian and Canadian studies, suggestive that placental function remains intact. Long-term maternal health for kidney donors affected by preeclampsia should also be considered. The US survey reported that there were no differences in rates of future development of hypertension or proteinuria between women who had pregnancies before or after kidney donation.47 However, 36% of kidney donors who had preeclampsia either before or after donation developed proteinuria within 3.1 years after donation, and 58% became hypertensive within 9.4 years after donation, ie, a higher rate than women with a history of preeclampsia without kidney donation, but numbers are small and formal comparison between donors and controls is required.
CONCLUSIONS Transplantation offers women with severe renal disease an opportunity to conceive, and many women have excellent pregnancy outcomes after transplantation surgery. Counseling regarding contraception use, timing of conception, and modification of immunosuppression regimes are important aspects of prepregnancy planning. Despite improved renal function, many women who are kidney transplant recipients have worse neonatal complications than pregnant women in the general population. The increased severity of complications during pregnancy in transplant recipients is likely caused by their higher rates of preeclampsia. Hence, heightened fetal surveillance is warranted. Most women can be reassured that long-term graft function is unlikely to be affected by pregnancy, but graft dysfunction is relatively common in later pregnancy and might lead to recommendations for early delivery. Pregnancy rates in women with renal transplants are lower than the general population; therefore, a better understanding of which women are at risk for graft dysfunction and fetal complications is needed to provide more reassurance for women who currently might be avoiding pregnancy because of their uncertainties regarding outcomes.32
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REFERENCES 1. Gill JS, Zalunardo N, Rose C, Tonelli M. The pregnancy rate and live birth rate in kidney transplant recipients. Am J Transplant. 2009;9:1541-9. 2. Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc Nephrol. 2009;20:2433-40. 3. McKay DB, Josephson MA. Pregnancy in recipients of solid organs-effects on mother and child. N Engl J Med. 2006; 354:1281-93. 4. Sturgiss SN, Davison JM. Perinatal outcome in renal allograft recipients: prognostic significance of hypertension and renal function before and during pregnancy. Obstet Gynecol. 1991;78: 573-577. 5. Lessan-Pezeshki M, Ghazizadeh S, Khatami MR, Mahdavi M, Razeghi E, Seifi S, et al. Fertility and contraceptive issues after kidney transplantation in women. Transplant Proc. 2004;36: 1405-1406. 6. Saha MT, Saha HH, Niskanen LK, Salmela KT, Pasternack AI. Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron. 2002;92:735-7. 7. Watnick S, Rueda J. Reproduction and contraception after kidney transplantation. Curr Opin Obstet Gynecol. 2008;20: 308-312. 8. 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. 9. Armenti VT, Radomski JS, Moritz MJ, Philips LZ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2000:123-34. 10. 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. 11. Pezeshki M, Taherian AA, Gharavy M, Ledger WL. Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet. 2004;85:119-25. 12. 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. 13. Bramham K, Nelson-Piercy C, Gao H, Pierce M, Bush N, Spark P, et al. Pregnancy in renal transplant recipients: a UK national cohort study. Clin J Am Soc Nephrol. 2013;8: 290-8. 14. Coscia LA, Constantinescu S, Moritz MJ, Carlin FR, McGrory CH, Armenti D Annual report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. 2014 [cited 2016 May]. Available from www. NTPRegistry.org 15. Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, Garonzik-Wang JM, Montgomery RA, et al. Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis. Am J Transplant. 2011;11:2388-404. 16. Rose C, Gill J, Zalunardo N, Johnston O, Mehrotra A, Gill JS. Timing of pregnancy after kidney transplantation and risk of allograft failure. Am J Transplant. 2016;16:2360-7. 17. Guazzelli CA, Torloni MR, Sanches TF, Barbieri M, Pestana JO. Contraceptive counseling and use among 197 female kidney transplant recipients. Transplantation. 2008 Sep 15;86: (5): 669-72. http://dx.doi.org/10.1097/TP.0b013e3181817e7d.PMID: 18791448 18. McKay DB, Josephson MA, Armenti VT, August P, Coscia LA, Davis CL, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant. 2005;5:1592-9.
Renal Transplant Recipient and Donor Pregnancies 19. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366:2257-66. 20. Harel Z, Wolter K, Gold MA, Cromer B, Stager M, Johnson CC, et al. Biopsychosocial variables associated with substantial bone mineral density loss during the use of depot medroxyprogesterone acetate in adolescents. Contraception. 2010;82:503-12. 21. Ramhendar T, Byrne P. Use of the levonorgestrel-releasing intrauterine system in renal transplant recipients: a retrospective case review. Contraception. 2012;86:288-9. 22. Estes CM, Westhoff C. Contraception for the transplant patient. Semin Perinatol. 2007;31:372-7. 23. Bramham K, Lightstone L. Pre-pregnancy counseling for women with chronic kidney disease. J Nephrol. 2012;25:450-9. 24. Briggs GG, Freeman RK, Yaffe SK. Drugs in pregnancy and lactation, A reference guide to fetal and neonatal risk. Philadelphia: Lippincott, Williams and Wilkins, 2011 25. Kim H, Jeong JC, Yang J, Yang WS, Ahn C, Han DJ, et al. The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation. Clin Transplant. 2015;29:142-8. 26. Zheng S, Easterling TR, Umans JG, Miodovnik M, Calamia JC, Thummel KE, et al. Pharmacokinetics of tacrolimus during pregnancy. Ther Drug Monit. 2012;34:660-70. 27. Wyld ML, Clayton PA, Jesudason S, Chadban SJ, Alexander SI. Pregnancy outcomes for kidney transplant recipients. Am J Transplant. 2013;13:3173-82. 28. Sibanda N, Briggs JD, Davison JM, Johnson RJ, Rudge CJ. Pregnancy after organ transplantation: a report from the UK Transplant Pregnancy Registry. Transplantation. 2007;83: 1301-7. 29. Coscia LA, Constantinescu S, Moritz MJ, Frank A, Ramirez CB, Maley WL, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2009;103-22. 30. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. National Transplantation Pregnancy Registryoutcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation. 1994;57:502-6. 31. Radomski JS, Ahlswede BA, Jarrell BE, Mannion J, Cater J, Moritz MJ, et al. Outcomes of 500 pregnancies in 335 female kidney, liver, and heart transplant recipients. Transplant Proc. 1995;27:1089-90. 32. Thompson BC, Kingdon EJ, Tuck SM, Fernando ON, Sweny P. Pregnancy in renal transplant recipients: the Royal Free Hospital experience. QJM. 2003;96:837-44. 33. Galdo T, Gonzalez F, Espinoza M, Quintero N, Espinoza O, Herrera S, et al. Impact of pregnancy on the function of transplanted kidneys. Transplant Proc. 2005;37:1577-9. 34. Oliveira LG, Sass N, Sato JL, Ozaki KS, Medina Pestana JO. Pregnancy after renal transplantation-a five-yr single-center experience. Clin Transplant. 2007;21:301-4.
377 35. Hooi LS, Rozina G, Shaariah MY, Teo SM, Tan CH, Bavanandan S, et al. Pregnancy in patients with renal transplants in Malaysia. Med J Malaysia. 2003;58:27-36. 36. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Longterm management of the transplant patient. IV.10. Pregnancy in renal transplant patients. Nephrol Dial Transplant. 2002;17:50-5. 37. Davison JM, Nelson-Piercy C, Kehoe S, Baker P (eds.), Consensus views: renal disease in pregnancy. London: Royal College of Obstetrics and Gynecology Press; 2008. p. 250. 38. Miller BW, Howard TK, Goss JA, Mostello DJ, Holcomb WL Jr, Brennan DC. Renal transplantation one week after conception. Transplantation. 1995;60:1353-4. 39. Puliyanda DP, Silverman NS, Lehman D, Vo A, Bunnapradist S, Radha RK, et al. Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient. Transpl Infect Dis. 2005;7:71-4. 40. American College of Obstetricians and Gynecologists. Clinical management guidelines for obstetricians-gynecologists. Perinatal and parasitic viral infections. ACOG Practice Bulletin No 20. Int J Gynaecol Obstet. 2002;76:95-107. 41. Smith MC, Ward MK, Sturgiss SN, Milne JE, Davison JM. Sex and the pregnant kidney: does renal allograft gender influence gestational renal adaptation in renal transplant recipients? Transplant Proc. 2004;36:2639-42. 42. Davison JM. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int. 1985;27:74-9. 43. Gutierrez MJ, Acebedo-Ribo M, Garcia-Donaire JA, Manzanera MJ, Molina A, Gonzalez E, et al. Pregnancy in renal transplant recipients. Transplant Proc. 2005;37:3721-2. 44. Gutierrez MJ, Gonzalez P, Delgado I, Gutierrez E, Gonzalez E, Siqueira RC, et al. Renal allograft function and cardiovascular risk in recipients of kidney transplantation after successful pregnancy. Transplant Proc. 2009;41:2399-402. 45. Armenti VT, Daller JA, Constantinescu S, Silva P, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation. Clin Transpl. 2006:57-70. 46. Wilson GA, Coscia LA, McGrory CH, Dunn SR, Radomski JS, Moritz MJ, et al. National transplantation pregnancy registry: postpregnancy graft loss among female pancreas-kidney recipients. Transplant Proc. 2001;33:1667-9. 47. Ibrahim HN, Akkina SK, Leister E, Gillingham K, Cordner G, Guo H, et al. Pregnancy outcomes after kidney donation. Am J Transplant. 2009;9:825-34. 48. 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. 49. Garg AX, Nevis IF, McArthur E, Sontrop JM, Koval JJ, Lam NN, et al, and for the DONOR Network. Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med. 2015;372:124-33.
Summary: Women with renal transplants have restoration of fertility with improved kidney function; however, pregnancy rates in renal transplant recipients appear to be lower than the general population, which might be influenced by patient choice. Women with renal transplants need to evaluate potential neonatal outcomes, graft outcomes, and risks to their own health to make informed decisions about conception. Pregnancy should be carefully planned in renal transplant recipients to reduce risk for graft loss, optimize pregnancy outcomes, and ensure immunosuppression regimes are nonteratogenic. Neonatal outcomes remain significantly worse for women with renal transplants than healthy controls, particularly for those with reduced graft function, hence prepregnancy, antenatal, and postpartum care of women with renal transplants should be guided by a multidisciplinary team of nephrologists and specialist obstetricians. Semin Nephrol 37:370-377 C 2017 Published by Elsevier Inc. Keywords: Pregnancy, renal transplant, kidney donor
W
omen with severe chronic kidney disease are frequently recommended to delay conception until after transplantation to enable restoration of fertility and improve pregnancy outcomes. However, further complexity to pregnancy planning is introduced after renal transplantation, including optimal timing of conception, teratogenicity of immunosuppression, risk of graft loss, and concerns regarding mode of delivery. In addition, both maternal and neonatal pregnancy complications remain higher than they are for the general population, despite near normal glomerular filtration rates in many women with kidney transplants.
PREGNANCY RATES AND FERTILITY IN RENAL TRANSPLANT RECIPIENTS The incidence of pregnancy was reported, in an assessment of Medicare data, to be considerably lower in women with renal transplants compared with the general population. A significant reduction in the pregnancy rate was seen between 1990 and 2000, which decreased from 59 to 20 pregnancies/1,000 transplant recipients.1 Similarly, a lower rate of pregnancy compared with the Australian general population (0.19 [95% confidence interval 0.17 to 0.21]) was reported by the Australian and New Zealand Dialysis and Transplant Registry with a further decline during the same time period, particularly for women in their twenties.2 Estimates of the proportion of women with renal transplants who become pregnant range from 2% Division of Transplantation and Mucosal Biology, King’s College London, London, UK. Financial disclosure and conflicts of interest: none. Address reprint requests to Kate Bramham, PhD, 10 Cutcombe Rd, London, SE5 9RJ, UK. E-mail: [email protected] 0270-9295/ - see front matter & 2017 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.semnephrol.2017.05.009
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to 5%,3,4 despite over half of patients with renal transplants being of child-bearing age. The low pregnancy rate in women with renal transplants is unexplained, but it is possible that women choose not to conceive to preserve graft function. The decline in pregnancy rate with time might also be related to the introduction of mycophenolate mofetil in 1995, which is teratogenic, or it might be a consequence of improved prepregnancy counseling, but further qualitative analysis of decision-making regarding pregnancy in this population is needed. There is limited understanding of fertility in women with renal transplants, but one Iranian study described infertility problems in 13 out of 126 (10.4%) women with renal transplants,5 which is comparable with general population rates. A small prospective study reported that prolactin, luteinising hormone, and follicle stimulations hormone in seven women returned to normal within 14-21 days of restoration of renal function,6 and numerous case reports describe ovulation7 and even pregnancy within weeks after transplantation.8 Nonetheless, the global trend to delay pregnancy is likely to contribute to lower pregnancy rates in women with renal transplants due to reduced fertility compounded by long waiting lists, which indirectly contribute to increased maternal age in this group.
TRANSPLANTATION-TO-CONCEPTION INTERVAL Evidence for optimal timing for conception is limited to single center and retrospective studies, of which some report adverse pregnancy outcomes to be inversely related to the interval between transplantation and conception,3,9–11 while others report no influence.12–14 However, a meta-analysis of outcomes of 4,706 pregnancies in renal transplant recipients was suggestive that live-birth rates are higher in studies with a mean interval between transplantation and pregnancy of o2 years (80.1%) compared with studies with an interval Seminars in Nephrology, Vol 37, No 4, July 2017, pp 370–377
Renal Transplant Recipient and Donor Pregnancies
of 2-3 years (64.2%), 3-4 years (76.1%), and 44 years (75.4%).15 However, it is important to recognize that individual patients’ data were not analyzed in this study, and only three studies had a mean interval of o2 years compared with 14 studies that had longer time intervals.15 Furthermore, comparisons of intervals between transplantation and conception were made for other pregnancy outcomes, and the rates of preeclampsia, gestational diabetes, cesarean section, and preterm birth were more common in studies with a mean interval of o2 years between transplantation and conception than in studies with longer intervals.15 A recent retrospective study of renal transplant outcomes obtained from the US Renal Data System occurring in 1990-2010 in 21,814 women of child-bearing age with (N ¼ 729) and without pregnancies (N ¼ 21,085) demonstrated a significantly higher rate of graft failure in those who conceived within two years of transplantation.16 Only women who conceived after three years had comparable rates of graft loss to those women who did not have pregnancies.16 Cessation of mycophenolate mofetil at least three months prior to pregnancy is desired to avoid teratogenicity, but the effect of switching to azathioprine on long-term graft function in those wishing to conceive within two years of transplantation requires further study because there is likely a complex interplay between pregnancy timing, maternal age, and existing comorbidities. The American Society of Transplantation guidelines for timing of conception17 are outlined in Figure 1.
CONTRACEPTION Contraception counseling is an essential part of pregnancy planning; however, a Brazilian study of female transplant recipients reported that contraception recommendations were made more commonly before transplantation than after, with only 49% of women having discussed contraception with their physician despite 80% being sexually active.17 There frequently is uncertainty regarding contraceptive safety and efficacy in women with renal transplants in relation to immunosuppression and vascular risk. Estrogen can increase
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blood levels of immunosuppressants and should be avoided in those with hypertension, vascular disease, in smokers, and persons with diabetes because of the increased risk for thrombotic stroke and myocardial infarction.19 Depot medroxyprogesterone acetate is not recommended in women with low bone mineral density.20 There is no evidence that intrauterine devices are less effective due to immunosuppression21 or are associated with increased risk for pelvic inflammatory disease. Nonetheless, assessment for gonorrhea and chlamydia is suggested before insertion.22
MEDICATION BEFORE, DURING, AND AFTER PREGNANCY An overview of medication safety during pregnancy and lactation is outlined in Table 1.23,24 Frequently conflict arises regarding manufacturers recommendations for pregnancy and breast-feeding, which invariably suggest that medications should be avoided because of the lack of robust safety data. However, the danger of ceasing immunosuppression and other medications during pregnancy usually far outweighs any potential risk of fetotoxicity and needs to be carefully explained to women with renal transplants. Important principles of prescribing immunosuppression in women with renal transplants during pregnancy include the following:
Tacrolimus, cyclosporine, azathioprine, and pre
dnisolone are all considered to be safe during pregnancy and breast-feeding. Mycophenolate mofetil is teratogenic and should be stopped at least three months before pregnancy to ensure graft stability on alternative agents. Azathioprine is a preferred alternative to mycophenolate mofetil and has an excellent safety profile in pregnancy and breast-feeding, despite being classified as Food and Drug Administration category D because of its teratogenicity in animals. However, only two cases of congenital abnormalities have been reported after several decades of use in pregnancy. The pharmacokinetics of calcineurin inhibitors are altered during pregnancy; lower blood concentrations often occur.25 Dose adjustments (by 20%25% or more) are frequently necessary to achieve the target concentrations, but caution should be used because preliminary data suggest that free tacrolimus concentrations might be higher in pregnant than in nonpregnant women.26
PREGNANCY OUTCOMES Figure 1. Recommendations of the American Society of Transplantations to follow before Conception.18
In general, pregnancy outcomes in women with renal transplants are better than those on dialysis, although a
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K. Bramham
Table 1. Commonly Used Drugs in Pregnant Women with Chronic Kidney Disease23,24 Drug
Teratogenicity
Fetal/Neonatal Effects
Commonly used immunosuppression during pregnancy Rare except at large doses Prednisolone Possible (cataract, adrenal increase in insufficiency, and infection) oral clefts Azathioprine None Sporadic congenital abnormalities, transient immune alterations in neonates Tacrolimus None Rare, hyperkalemia and renal impairment Cyclosporine
None
Rare, hyperkalemia and renal impairment
Recommendations in Pregnancy
Recommendations in Breast-Feeding
Yes
Yes, but not encouraged if 460 mg prednisolone daily Yes
Yes
Yes, usually increased required to achieve prepregnancy target Yes, usually increased required to achieve prepregnancy target
doses
Yes
levels doses
Yes
levels
Immunosuppression recommended to be stopped before pregnancy No, stop 3 months Yes Congenital abnormalities in Mycophenolate preconception 22.9%: cleft mofetil/ lip and palate, absent mycophenolic auditory canal, acid hypertelorism, microtia, brachydactyly of the fifth finger, limb abnormalities, and hypoplastic toenails Sirolimus Unknown Toxicity in animal studies, but No, stop 3 months not teratogenicity preconception Everolimus Unknown Toxicity in animal studies, but No, stop 3 months not teratogenicity preconception Treatment for acute rejection and induction Methylprednisolone None Rare, cataract, adrenal insufficiency, and infection Intravenous None None reported immunoglobulin Alemtuzumab Unknown Unknown
Unknown Unknown
Yes
Yes
Yes
Yes Unknown, but possible transfer into milk, neonate gastrointestinal digestion
Basiliximab
Unknown
No toxicity or teratogenicity in monkeys
Belatacept
Unknown
Unknown
Manufacturer recommends avoiding pregnancy for at least 6 months after exposure Manufacturer recommends avoiding pregnancy for at least 4 months after exposure Do not administer in pregnancy
Antithymocyte globulin
Unknown
Unknown
Do not administer in pregnancy
*
No
Unknown, but possible transfer into milk, neonate gastrointestinal digestion Unknown, but transfer into breast milk unlikely as Fc fragment of IgG1 Unknown, but possible transfer into milk, neonate gastrointestinal digestion
Adapted from references.23,24
formal comparison with women on intensive hemodialysis is yet to be reported. Despite restoration of renal function, rates of preeclampsia, preterm delivery, low birth weight, and admission to maternal and neonatal care remain higher for women with renal
transplants compared with the general population.15 An overview of pregnancy outcomes from national registry data is presented in Table 2.14,15,27,28 In addition to the interval from transplantation to conception, predictors of adverse pregnancy outcome
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Table 2. Registry Data Reporting Pregnancy Outcomes in Women with Renal Transplants14,27,28 Category
Data Source Sibanda et al, 2007
Number of pregnancies (number of women) 193 (176) Years of study 1994-2001 Study design Renal unit questionnaire Country
United Kingdom
Median time to conception after transplant
6 years (range 3 months to 19 years) Median maternal age, years 30 (range 20-43) Preeclampsia/superimposed preeclampsia, — % Spontaneous delivery, % 12 Induced, % 24 Cesarean section, % 72 Gestational diabetes, % Live birth, % 79 Miscarriage, % 11 Therapeutic termination, % 6 Intrauterine death, % 2 Stillbirth, % 2 Gestational age at delivery, mean ⫾ SE, 35.6 ⫾ 0.3 weeks Preterm delivery, o37 weeks, % 50 Birth weight, mean ⫾ SE, g 2,316 ⫾ 80 Birth weight, o2,500 g, % 54
Coscia et al, 2014
Wyld et al, 2013
1,742 (986) 1991-2014 Self- or clinicianreported United States
200 2000-2010 Renal unit reporting
—
Australia and New Zealand 5 years (IQR 3-9 years)
— 30
31 (IQR 27-34) 29
— — 53 8 76 17 4 — 2 —
— — — 3 76 9 11 Perinatal mortality 5.8 3 35.5 ⫾ 4.6
51 41
450 2,485 ⫾ 783 -
Abbreviations: IQR, Interquartile range; SE, standard error.
include prepregnancy glomerular filtration rates and preexisting hypertension.13,14,15,27,28 A prospective cohort study also indicated that women with two or more transplants were more likely to have severe neonatal outcomes.13
MATERNAL COMPLICATIONS Preeclampsia Preeclampsia might be difficult to diagnose in women with renal transplants because many of them have preexisting hypertension,3,29–31 and several develop gestational proteinuria without preeclampsia.13 The high incidence of preeclampsia in these women compared with the general US population (27% versus 3.8%, respectively)15 indicates the need for serial monitoring of fetal growth and Doppler studies together with assessment of other maternal organ involvement (eg, liver enzymes) for all women with renal transplants to guide timing of delivery. Gestational Diabetes Women with renal transplants are at higher risk of developing gestational diabetes than the general
population. A meta-analysis of 52 studies reporting pregnancy outcomes in women with renal transplants showed a pooled incidence rate of 8.0% compared with 3.6% in the US general population.15 The incidence of gestational diabetes in individual studies is variable and is likely to be dependent on thresholds used for diagnosis, as well as other influences including maternal age, obesity, and dose of prednisolone and tacrolimus. Screening with oral glucose tolerance testing should be offered to all women with renal transplants earlier in gestation. Graft Injury During Delivery Women might be concerned about damage to the graft during delivery; however, this complication is extremely rare and is restricted only to those with surgical deliveries. Vaginal delivery is not affected by the anatomic location of the graft. Nonetheless, most women with renal transplants are delivered by cesarean section (Table 2).14,15,27,28 Mode of delivery is likely to be related to high rates of maternal and fetal complications; however, one UK prospective cohort study found that women were also delivering by cesarean section with no additional indications other than the presence of the transplant.13
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Infections Urinary tract infection is the most common infection encountered by women with renal transplants during pregnancy, with incidence rates ranging from 14.6% to 42%.33-35 Regular surveillance with monthly midstream urine tests is recommended with prompt treatment if infection is identified.36 There is no robust evidence to support this practice, but many experts recommend long-term prophylactic antibiotics after one infection or in patients with a history of urinary tract infections to prevent recurrence.37 If pregnancy is delayed until at least 1 year after transplantation, the risk for opportunistic infections is likely to be lower. However, there are cases of cytomegalovirus in pregnant transplant recipents that were successfully treated with ganciclovir.38,39 Cytomegalovirus can cause fetotoxicity, sensorineural deafness, impaired psychomotor development, choroidoretinitis, dental problems, fetal growth restriction, respiratory distress, and seizures.40 Reactivation rather than de novo infection is associated with a lower risk for complications, but prophylaxis is not recommended due to teratogenicity of ganciclovir. Graft Dysfunction Gestational adaptation occurs in renal grafts, regardless of age or sex of the donor,41 although one small study suggests that augmentation in creatinine clearance might be impaired in later pregnancy compared with healthy controls.42 Loss of graft function due to pregnancy is one of the greatest concerns for women with renal transplants. However, the majority can be reassured that long-term graft function is unaffected by gestation. Researchers using data from the Australian and New Zealand Dialysis and Transplant Registry did not detect a difference in rates of graft loss at 20 years between 120 women with renal transplants with pregnancies and nulliparous controls matched for graft vintage, age, and graft function.2 Numerous single center studies also support that gestation does not have a detrimental effect on renal function.43,44 Data from the US National Transplant Pregnancy Registry (NTPR) indicated that women with graft loss during or after pregnancy were more likely to have higher prepregnancy creatinine than those with stable graft function (1.5 ⫾ -0.6 mg/dL versus 1.3 ⫾ 0.4 mg/dL),29 and African-American women have an increased risk for graft loss within 2 years of delivery (13%) in comparison with whites (5%).14 Although the overall risk for adverse graft outcomes during pregnancy for most women is not significant, acute graft dysfunction during pregnancy or postpartum is common.13 Acute rejection is rare, with only 4.2% (102/2,412) of women reporting graft rejection in
K. Bramham
a recent meta-analysis on pregnancy outcomes in women with renal transplants.15 If rejection is suspected, biopsy should be performed before the fetus becomes viable, and if at a late gestation period, empirical treatment with intravenous methylprednisolone with planned delivery should be considered. The most common cause of a rise in serum creatinine concentrations during pregnancy in women with renal transplants is preeclampsia,13 but other causes of graft dysfunction, including urinary tract infection, tacrolimus toxicity, and obstruction, need to be investigated and promptly treated. Maternal Death Women with renal transplants have a higher mortality rate during pregnancy compared with the general population, but pregnancy was not demonstrated to be associated with an additional increase in mortality by Australian and New Zealand Dialysis and Transplant Registry data when comparing postpartum survival in 120 women with renal transplants with nulliparous controls.2 However, it is important to reflect on the overall survival rates reported; approximately one in ten renal transplant recipients would not be alive by the 10th birthday of their child, and one in four would have died before their child’s 20th birthday. Influence of Preexisting Disease Women with genetic renal disorders should be counseled about the risk for inheritance, and for those with known single gene mutations (eg, Alport syndrome and autosomal dominant polycystic kidney disease), prenatal diagnosis can be discussed. For others with more complex inheritance patterns, eg, reflux nephropathy, recommendations for screening of offspring should be given. Women with lupus nephritis should be assessed for the presence of the Ro and La antibody, which could lead to fetal heart block or neonatal cutaneous lupus, respectively. There is a theoretical risk for reactivation of atypical hemolytic-uremic syndrome, and those who have previously been affected should be assessed for hemolysis given the increased risk for relapse during pregnancy.
PREGNANCY AND GRAFT OUTCOMES IN WOMEN WITH KIDNEY PANCREAS TRANSPLANTS There is increasing experience of pregnancy in kidneypancreas transplant recipients. The US NTPR now report 104 pregnancies from 58 recipients.14 Although overall outcomes of women with kidney and pancreas transplants are likely to be superior to those of women with moderate-to-severe diabetic nephropathy, both maternal and fetal complication rates are high.
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Table 3. Pregnancy Outcomes for Women with Tacrolimus-Based Immunosuppression Having Either Kidney Transplants Alone or Kidney-Pancreas Transplants14 Outcomes
Kidney Transplant
Kidney-Pancreas Transplant
Number of recipients (number of pregnancies) Transplant-to-conception interval, mean ⫾ SE, years Hypertension during pregnancy, % Diabetes during pregnancy, % Infection during pregnancy, % Preeclampsia, % Rejection episode during pregnancy, % Graft loss within 2 yrs of delivery, % Live births, % (n) Gestation, mean ⫾ SE, weeks Premature, o37 weeks, % Low birthweight, o2,500 g, % Cesarean section, % Neonatal deaths within 30 days of birth, n (%)
254 (427) 4.8 ⫾ 3.3 53 9 20 35 2 9 71.5 (315) 35.4 ⫾ 3.6 52 42 58 5 (1.6)
30 (57) 4.4 ⫾ 3 35 4 21 30 4 7 66.1 (41) 34.1 ⫾ 3.4 73 59 76 0 (0)
Abbreviation: SE, Standard error.
Table 3 presents pregnancy outcomes in women with kidney-pancreas transplants and kidney-only transplants using NTPR-sourced data.14 The mechanisms underlying worse outcomes are poorly understood, but are likely to be related to preexisting microvascular disease impairing maternal hemodynamic adaptation. In addition, placental function appears to be impaired, and most infants are delivered early and of low birth weight. The intraperitoneal position of kidney-pancreas grafts might lead to obstruction from uterine expansion, and regular surveillance in late pregnancy is warranted. Furthermore, graft loss postpartum is high; as indicated by NTPR, 8 (19%) of 43 women lose one or more grafts within two years after delivery.45 In this cohort, acute rejection or a rise in serum creatinine during pregnancy, but not prepregnancy creatinine, were the strongest predictors of subsequent graft failure.46
PREGNANCY COMPLICATIONS IN KIDNEY DONORS The exponential global rise in living donor kidney transplants has led to an increasing number of pregnant women who have donated a kidney. The understanding of possible complications in this unique group is important, not only for management in a current pregnancy, but also to enable those contemplating donation to make informed choices about timing of conception in relation to donating their kidney. In view of the rigorous screening before donation for risk factors for future renal disease, which also are associated with adverse pregnancy outcomes (eg, hypertension, obesity, and diabetes), it might be expected that women who have donated a kidney should have minimal complications. Current literature
is limited, but suggests that pregnancy complications appear to be more common in postdonation pregnancies than in predonation pregnancies and pregnancies in the general population. In a US survey of 1,589 women who donated their kidney between 1963-2007, only 490 out of 3,213 pregnancies (15%) occurred after transplantation.48 Rates of preeclampsia were higher in pregnancies after donation (5.5%) than pregnancies before (0.8%). Similarly, Norwegian registry data from 326 female kidney donors indicated higher rates of preeclampsia in pregnancies after donation (5.7%) than before (2.6%).49 More recently, a Canadian population study assessed pregnancy complications in 85 kidney donors with 131 pregnancies and reported that the rate of preeclampsia was higher (6%) in comparison to the 510 controls (3%) matched for age, parity, year of pregnancy, and socioeconomic status.49 Rates of gestational hypertension also were higher in kidney donors than in controls (5% versus 2%, respectively), similar to the preeclampsia rates reported in pregnancies after donation (5.7%) in the US survey study described above. However, in the Norwegian survey study, gestational hypertension was not more frequent after donation, although only small numbers of women were affected. All of the studies reporting pregnancy outcomes in kidney donors are limited by patient reporting and coding data for diagnosis of preeclampsia. These findings are supportive in confirming a role for the kidney in the pathophysiology of preeclampsia, which might be independent of preexisting endothelial dysfunction. Differences in other pregnancy outcomes are less consistent. The US survey study reported higher rates of fetal loss in pregnancies after donation (19.2%)
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compared with those before donation (11.3%),47 but no differences were reported from the Norwegian registry data.48 In the Canadian population study, only pregnancies carried beyond 20 weeks’ gestation were included, so, this analysis in the Canadian population was not possible. In the US study, gestational diabetes and preterm delivery also were reported to be higher in pregnancies after donation than pregnancies before (diabetes, 2.7% versus 0.7%; preterm delivery, 26.3% versus 15.4%, respectively), but not by other studies.47,49 Importantly, there have been no differences in birth weight described by Norwegian and Canadian studies, suggestive that placental function remains intact. Long-term maternal health for kidney donors affected by preeclampsia should also be considered. The US survey reported that there were no differences in rates of future development of hypertension or proteinuria between women who had pregnancies before or after kidney donation.47 However, 36% of kidney donors who had preeclampsia either before or after donation developed proteinuria within 3.1 years after donation, and 58% became hypertensive within 9.4 years after donation, ie, a higher rate than women with a history of preeclampsia without kidney donation, but numbers are small and formal comparison between donors and controls is required.
CONCLUSIONS Transplantation offers women with severe renal disease an opportunity to conceive, and many women have excellent pregnancy outcomes after transplantation surgery. Counseling regarding contraception use, timing of conception, and modification of immunosuppression regimes are important aspects of prepregnancy planning. Despite improved renal function, many women who are kidney transplant recipients have worse neonatal complications than pregnant women in the general population. The increased severity of complications during pregnancy in transplant recipients is likely caused by their higher rates of preeclampsia. Hence, heightened fetal surveillance is warranted. Most women can be reassured that long-term graft function is unlikely to be affected by pregnancy, but graft dysfunction is relatively common in later pregnancy and might lead to recommendations for early delivery. Pregnancy rates in women with renal transplants are lower than the general population; therefore, a better understanding of which women are at risk for graft dysfunction and fetal complications is needed to provide more reassurance for women who currently might be avoiding pregnancy because of their uncertainties regarding outcomes.32
K. Bramham
REFERENCES 1. Gill JS, Zalunardo N, Rose C, Tonelli M. The pregnancy rate and live birth rate in kidney transplant recipients. Am J Transplant. 2009;9:1541-9. 2. Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc Nephrol. 2009;20:2433-40. 3. McKay DB, Josephson MA. Pregnancy in recipients of solid organs-effects on mother and child. N Engl J Med. 2006; 354:1281-93. 4. Sturgiss SN, Davison JM. Perinatal outcome in renal allograft recipients: prognostic significance of hypertension and renal function before and during pregnancy. Obstet Gynecol. 1991;78: 573-577. 5. Lessan-Pezeshki M, Ghazizadeh S, Khatami MR, Mahdavi M, Razeghi E, Seifi S, et al. Fertility and contraceptive issues after kidney transplantation in women. Transplant Proc. 2004;36: 1405-1406. 6. Saha MT, Saha HH, Niskanen LK, Salmela KT, Pasternack AI. Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron. 2002;92:735-7. 7. Watnick S, Rueda J. Reproduction and contraception after kidney transplantation. Curr Opin Obstet Gynecol. 2008;20: 308-312. 8. 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. 9. Armenti VT, Radomski JS, Moritz MJ, Philips LZ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2000:123-34. 10. 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. 11. Pezeshki M, Taherian AA, Gharavy M, Ledger WL. Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet. 2004;85:119-25. 12. 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. 13. Bramham K, Nelson-Piercy C, Gao H, Pierce M, Bush N, Spark P, et al. Pregnancy in renal transplant recipients: a UK national cohort study. Clin J Am Soc Nephrol. 2013;8: 290-8. 14. Coscia LA, Constantinescu S, Moritz MJ, Carlin FR, McGrory CH, Armenti D Annual report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. 2014 [cited 2016 May]. Available from www. NTPRegistry.org 15. Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, Garonzik-Wang JM, Montgomery RA, et al. Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis. Am J Transplant. 2011;11:2388-404. 16. Rose C, Gill J, Zalunardo N, Johnston O, Mehrotra A, Gill JS. Timing of pregnancy after kidney transplantation and risk of allograft failure. Am J Transplant. 2016;16:2360-7. 17. Guazzelli CA, Torloni MR, Sanches TF, Barbieri M, Pestana JO. Contraceptive counseling and use among 197 female kidney transplant recipients. Transplantation. 2008 Sep 15;86: (5): 669-72. http://dx.doi.org/10.1097/TP.0b013e3181817e7d.PMID: 18791448 18. McKay DB, Josephson MA, Armenti VT, August P, Coscia LA, Davis CL, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant. 2005;5:1592-9.
Renal Transplant Recipient and Donor Pregnancies 19. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366:2257-66. 20. Harel Z, Wolter K, Gold MA, Cromer B, Stager M, Johnson CC, et al. Biopsychosocial variables associated with substantial bone mineral density loss during the use of depot medroxyprogesterone acetate in adolescents. Contraception. 2010;82:503-12. 21. Ramhendar T, Byrne P. Use of the levonorgestrel-releasing intrauterine system in renal transplant recipients: a retrospective case review. Contraception. 2012;86:288-9. 22. Estes CM, Westhoff C. Contraception for the transplant patient. Semin Perinatol. 2007;31:372-7. 23. Bramham K, Lightstone L. Pre-pregnancy counseling for women with chronic kidney disease. J Nephrol. 2012;25:450-9. 24. Briggs GG, Freeman RK, Yaffe SK. Drugs in pregnancy and lactation, A reference guide to fetal and neonatal risk. Philadelphia: Lippincott, Williams and Wilkins, 2011 25. Kim H, Jeong JC, Yang J, Yang WS, Ahn C, Han DJ, et al. The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation. Clin Transplant. 2015;29:142-8. 26. Zheng S, Easterling TR, Umans JG, Miodovnik M, Calamia JC, Thummel KE, et al. Pharmacokinetics of tacrolimus during pregnancy. Ther Drug Monit. 2012;34:660-70. 27. Wyld ML, Clayton PA, Jesudason S, Chadban SJ, Alexander SI. Pregnancy outcomes for kidney transplant recipients. Am J Transplant. 2013;13:3173-82. 28. Sibanda N, Briggs JD, Davison JM, Johnson RJ, Rudge CJ. Pregnancy after organ transplantation: a report from the UK Transplant Pregnancy Registry. Transplantation. 2007;83: 1301-7. 29. Coscia LA, Constantinescu S, Moritz MJ, Frank A, Ramirez CB, Maley WL, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2009;103-22. 30. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. National Transplantation Pregnancy Registryoutcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation. 1994;57:502-6. 31. Radomski JS, Ahlswede BA, Jarrell BE, Mannion J, Cater J, Moritz MJ, et al. Outcomes of 500 pregnancies in 335 female kidney, liver, and heart transplant recipients. Transplant Proc. 1995;27:1089-90. 32. Thompson BC, Kingdon EJ, Tuck SM, Fernando ON, Sweny P. Pregnancy in renal transplant recipients: the Royal Free Hospital experience. QJM. 2003;96:837-44. 33. Galdo T, Gonzalez F, Espinoza M, Quintero N, Espinoza O, Herrera S, et al. Impact of pregnancy on the function of transplanted kidneys. Transplant Proc. 2005;37:1577-9. 34. Oliveira LG, Sass N, Sato JL, Ozaki KS, Medina Pestana JO. Pregnancy after renal transplantation-a five-yr single-center experience. Clin Transplant. 2007;21:301-4.
377 35. Hooi LS, Rozina G, Shaariah MY, Teo SM, Tan CH, Bavanandan S, et al. Pregnancy in patients with renal transplants in Malaysia. Med J Malaysia. 2003;58:27-36. 36. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Longterm management of the transplant patient. IV.10. Pregnancy in renal transplant patients. Nephrol Dial Transplant. 2002;17:50-5. 37. Davison JM, Nelson-Piercy C, Kehoe S, Baker P (eds.), Consensus views: renal disease in pregnancy. London: Royal College of Obstetrics and Gynecology Press; 2008. p. 250. 38. Miller BW, Howard TK, Goss JA, Mostello DJ, Holcomb WL Jr, Brennan DC. Renal transplantation one week after conception. Transplantation. 1995;60:1353-4. 39. Puliyanda DP, Silverman NS, Lehman D, Vo A, Bunnapradist S, Radha RK, et al. Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient. Transpl Infect Dis. 2005;7:71-4. 40. American College of Obstetricians and Gynecologists. Clinical management guidelines for obstetricians-gynecologists. Perinatal and parasitic viral infections. ACOG Practice Bulletin No 20. Int J Gynaecol Obstet. 2002;76:95-107. 41. Smith MC, Ward MK, Sturgiss SN, Milne JE, Davison JM. Sex and the pregnant kidney: does renal allograft gender influence gestational renal adaptation in renal transplant recipients? Transplant Proc. 2004;36:2639-42. 42. Davison JM. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int. 1985;27:74-9. 43. Gutierrez MJ, Acebedo-Ribo M, Garcia-Donaire JA, Manzanera MJ, Molina A, Gonzalez E, et al. Pregnancy in renal transplant recipients. Transplant Proc. 2005;37:3721-2. 44. Gutierrez MJ, Gonzalez P, Delgado I, Gutierrez E, Gonzalez E, Siqueira RC, et al. Renal allograft function and cardiovascular risk in recipients of kidney transplantation after successful pregnancy. Transplant Proc. 2009;41:2399-402. 45. Armenti VT, Daller JA, Constantinescu S, Silva P, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation. Clin Transpl. 2006:57-70. 46. Wilson GA, Coscia LA, McGrory CH, Dunn SR, Radomski JS, Moritz MJ, et al. National transplantation pregnancy registry: postpregnancy graft loss among female pancreas-kidney recipients. Transplant Proc. 2001;33:1667-9. 47. Ibrahim HN, Akkina SK, Leister E, Gillingham K, Cordner G, Guo H, et al. Pregnancy outcomes after kidney donation. Am J Transplant. 2009;9:825-34. 48. 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. 49. Garg AX, Nevis IF, McArthur E, Sontrop JM, Koval JJ, Lam NN, et al, and for the DONOR Network. Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med. 2015;372:124-33.