Pregnancy in Renal Transplant Recipients

Pregnancy in Renal Transplant Recipients

Pregnancy in Renal Transplant Recipients Karin M. Fuchs, MD,* Danny Wu, MD,* and Zeynep Ebcioglu, MD† Women with renal disease face increasing inferti...

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Pregnancy in Renal Transplant Recipients Karin M. Fuchs, MD,* Danny Wu, MD,* and Zeynep Ebcioglu, MD† Women with renal disease face increasing infertility and high-risk pregnancy as they approach end-stage renal disease due to uremia. Renal transplantation has provided these patients the ability to return to a better quality of life, and for a number of women who are of child bearing age with renal disease, it has restored their fertility and provided the opportunity to have children. But, although fertility is restored, pregnancy in these women still harbors risk to the mother, graft, and fetus. Selected patients who have stable graft function can have successful pregnancies under the supervision of a multidisciplinary team involving maternal fetal medicine specialists and transplant nephrologists. Careful observation and management are required to optimize outcome for mother and fetus. Semin Perinatol 31:339-347 © 2007 Elsevier Inc. All rights reserved. KEYWORDS pregnancy, renal transplant, pancreas transplant, immunosuppression

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omen with renal disease often experience infertility due to hypogonadotropic hypogonadism with only 25% of women on dialysis reporting menstruation.1,2 The origin of this hypothalamic pituitary suppression is likely multifactorial in etiology. The typical preovulatory peak of the pituitary gonadotropin lutenizing hormone (LH) has been found to be absent and thought to result from the loss of positive feedback from estradiol.3,4 In addition, prolactin levels are also commonly elevated in these patients due to autonomous hypersecretion. Although prolactinemia is a common cause of anovulation, bromocriptine therapy to normalize prolactin concentration has not been shown to restore ovulation in anovulatory patients with renal disease.3,4 Despite the decreased fertility noted in women with renal disease, spontaneous pregnancies do occur in 1/200 premenopausal women on dialysis.5 These pregnancies, however, are at significantly increased risk for both maternal and fetal complications. Pregnant women with renal disease are at increased risk of worsening proteinuria and development of hypertension and/or preeclampsia.6 For those patients not yet on dialysis, there may also be increasing loss of renal function during and after their pregnancy.5,6 These maternal complications lead to a higher incidence of intrauterine growth restriction and preterm birth.6,7 Historically, fetal sur-

*Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY. †Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY. Address reprint requests to Zeynep Ebcioglu, MD, 622 West 168th Street, PH 4-124, New York, NY 10032. E-mail: [email protected]

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2007.09.003

vival in these pregnancies has been low with less than 20% live births reported in the 1980s.8 Renal transplantation can offer these women with endstage renal disease not only an improved quality of life but also the possibility of increased fertility and improved pregnancy outcomes. After a successful kidney transplant, uremia resolves and the pituitary hypothalamic hormonal function returns to normal.9,10 Although approximately 16% of patients may have persistent amenorrhea, the majority of women become ovulatory and resume menstruation by 12 months after renal transplantation.9,10 Unplanned pregnancies in transplant recipients, however, may compromise graft function and survival, and may also risk unnecessary fetal exposure to immunosuppressive medications. Accordingly, the restoration of fertility after transplant necessitates the use of contraception in transplant recipients to allow for conception once stable graft function has been achieved. With an increasing number of successful renal transplants being performed in women of childbearing age and a sizeable cohort of pediatric kidney transplant recipients approaching adulthood, significant data have been accumulated regarding pregnancy outcome in renal transplant recipients. There have been over 10,000 pregnancies reported in renal transplant recipients.11-13 The National Transplantation Pregnancy Registry (NTPR) was established in the United States in 1991 and has since recorded pregnancy outcomes in thousands of female renal transplant recipients as well as growing numbers of other solid organ recipients. Similar registries exist in Europe14 and in the United Kingdom,15,16 and additional data have been published in large retrospective cases series from numerous transplant centers.17 These data suggest that welltimed pregnancies in selected renal transplant recipients can 339

340 result in live births with good outcomes for both mother and fetus. In this chapter, we will highlight the risks of pregnancy in renal transplant recipients and the steps that can be taken to achieve favorable pregnancy outcomes.

Maternal Complications Hypertension and Preeclampsia The incidence of hypertension among renal transplant patients ranges between 60% and 80%.18,19 In pregnancy, the rate of hypertension is similar, with both the UK Registry and the NTPR reporting an approximately 70% incidence of hypertension.11,16 There are multiple factors that may lead to secondary hypertension in renal transplant recipients, including renal artery stenosis and renal insufficiency.18-20 Immunosuppressive therapy with calcineurin inhibitors and steroids have also been shown to cause hypertension in organ transplant recipients.21,22 Although both cyclosporine and tacrolimus have been shown to cause hypertension, patients on tacrolimus have been found to require fewer antihypertensives than patients on cyclosporine.18,19 Deceased donor transplants, delayed graft function, obesity, smoking, and alcohol consumption are also associated with hypertension in transplant recipients.18-20 The continued presence of native kidneys after transplantation is also thought to contribute to the development of post transplant hypertension through increased renin production.18,19,23 Hypertension is associated with increased rates of pregnancy complications in women with isolated hypertension, women with concomitant renal disease, and those with hypertension after a prior renal transplant. These women with prepregnancy hypertension experience a higher incidence of preeclampsia, approximately 30% in comparison to only 8% of the general population.12 In addition, women with preexisting hypertension are at increased risk of intrauterine growth restriction (IUGR) and preterm delivery. Women with nephrotic range proteinuria have also been shown to have an increased risk of spontaneous abortion, preterm delivery, and IUGR.24 Conversely, the absence of hypertension and presence of mild proteinuria (less than 500 mg/24 hours) before conception has been associated with improved pregnancy outcomes and fewer complications.25-27 Although mild to moderate hypertension is not necessarily controlled in the general population, hypertension in renal transplant recipients should be treated expeditiously and aggressively to prevent complications before and during pregnancy.28 Preeclampsia is defined as new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman, with hypertension defined as blood pressure above 140/90 and proteinuria defined as ⬎300 mg of protein in a 24-hour urine collection.29 This diagnosis, however, can be difficult to make in renal transplant recipients, many of whom have hypertension and proteinuria in excess of 300 mg/24 hours at baseline.26,27 Although uric acid has been shown to be elevated in women with preeclampsia, uric acid has not been a useful marker in transplant recipients because these patients also tend to have increased serum

K.M. Fuchs, D. Wu, and Z. Ebcioglu levels at baseline.30 Research is ongoing to identify additional serologic markers of preeclampsia which may assist with diagnosis of this disorder, but no one analyte to date has been shown to be sufficiently sensitive and specific to reliably diagnose preeclampsia in this, or any, population.31 At present, diagnosis of preeclampsia in renal transplant recipients requires a low threshold to evaluate patients for evidence of worsening hypertension, end organ dysfunction, or worsening proteinuria which may indicate preeclampsia.

Risk of Allograft Loss Most studies have shown that graft survival is equivalent for pregnant and nonpregnant renal transplant recipients.32-34 NTRP data estimate graft loss in pregnant transplant patients to be between 4% and 14% two years postpregnancy, rates which are similar to those seen in nonpregnant recipients.12,27 Although one study demonstrated worse graft survival at 10 years in renal transplant recipients who had been pregnant (69%) than in those never pregnant (100%), the controls had a unusually high graft survival, making the results difficult to apply to other populations.35 Data suggest that pregnancy does not have significant effect on long-term graft function in women with serum creatinine less than 1.5 mg/dL, whereas a serum creatinine greater than 1.5 mg/dL has been associated with increased risk of graft loss, obstetric complications, and low birth weight infants.36 In an attempt to further define the parameters which may predict graft survival, the European Best Practice Guidelines (EBPG) advise that renal transplant recipients should have stable graft function for at least 2 years before conception.28 Other studies have demonstrated improved pregnancy outcomes for both mother and fetus when there was a 2-year interval between transplantation and conception.5,25,37 Some argue, however, that it may be reasonable to allow patients to conceive 1 year post transplant if there has been no history of complications, including rejection or infections.12 Although there have been successful pregnancies reported in the first year after transplantation, this is generally not recommended due to the higher incidence of graft rejection, higher frequency of potentially teratogenic infections, and higher doses of immunosuppressants used in the first year after transplantation. Even with optimal timing, rejection may occur during and after pregnancy. Graft rejection during pregnancy is more common in women who have had episodes of rejection in the recent past and in women who have had recent adjustments in their immunosuppression regimen. Although severe allograft rejection may present with fevers, tenderness over the allograft, decreased urine output, and hematuria, mild rejection typically has a subtle presentation and may only be indicated by a slight rise in the serum creatinine in an otherwise asymptomatic patient. Accordingly, careful monitoring of renal function is essential during pregnancy in renal transplant recipients. Furthermore, because renal blood flow and the glomerular filtration rate (GFR) can increase up to 60% in the vasodilated state of pregnancy and serum creatinine concentrations normally decrease in pregnancy,27 any rise in serum

Pregnancy in renal transplant recipients creatinine should raise suspicion for rejection in pregnant transplant recipients. If rejection is suspected clinically or confirmed based on the results of ultrasound-guided needle biopsy, it is prudent to start initial treatment with methylprednisolone. Mild rejection usually responds to methylprednisolone,38 although steroid-resistant cases or moderate to severe rejection may necessitate the use of additional immunosuppressants. Data for the use of anti-T-lymphocyte agents, such as muromonoab-CD3 and antithymocyte globulin, in pregnancy are limited,39 but IVIG has been used during pregnancy and appears to be safe.40

Maternal Infections Pregnant women are at increased risk for bacterial urinary tract infections, and this is compounded by immunosuppression in renal transplant patients. During their pregnancy, 40% of transplant patients have a urinary tract infection.41 In addition, pregnancy is associated with a physiologic hydronephrosis caused by compression of the ureter by the gravid uterus. This increases the risk of urine refluxing into the kidney leading to an increased risk of pyelonephritis, which may be of special concern in transplant recipients.5,41 Furthermore, if there is documented hydronephrosis at the time of conception, the rate of urinary tract infection appears to be even higher. Treatment of urinary tract infections in pregnancy is essential as pylelonephritis has been associated with serious complications, including pneumonia with respiratory compromise and preterm labor.36 An additional concern for transplant patients is the potential transplacental passage of viral infections leading to congenital infection. Of particular concern is cytomegalovirus (CMV) infection and toxoplasmosis. Those at highest risk for CMV disease are those patients who are serologically negative pretransplant and have a CMV-positive donor.42,43 Because of the risk of reactivated CMV infection, transplant recipients are maintained on CMV-prophylaxis for 3 to 6 months after transplant when the risk of CMV is greatest. By 2 years post transplant, the incidence of CMV infection is very low. Delaying pregnancy until 2 years post transplant can reduce the risk of fetal exposure, and measuring maternal CMV IgG/IgM titer and CMV PCR may improve detection of CMV infection and reduce fetal complications. Toxoplasmosis also can be transmitted transplacentally and result in congenital infection. It is recommended that toxoplasmosis titers be checked every 3 months in renal transplant recipients and patients with increasing titers be considered for treatment.28,44

Obstetric/Fetal Outcomes Data accumulated in the various registries and large case series offer sufficient information from which pregnant female transplant recipients can be counseled regarding expected pregnancy outcomes. In general, pregnant renal transplant recipients experience a slightly increased rate of spontaneous miscarriage in the first trimester as well as an increased incidence of preeclampsia, IUGR, and preterm de-

341 livery.45 Because transplant recipients are maintained on at least a maintenance regimen of immunosuppressant therapy in pregnancy, however, it is difficult to determine whether the adverse pregnancy outcomes seen in this population may stem from exposure to the immunosuppressive medications or from the underlying maternal disease itself. It is important that physicians and patients recognize the confounders within these data and interpret these retrospective outcome data with caution.

Pregnancy Loss Despite the relative frequency with which renal transplant recipients have favorable pregnancy outcomes, the women experience a first trimester loss rate higher than the general population. Specifically, Davison reported a spontaneous miscarriage rate of 14%, and both the Toronto and the UK Transplant registry noted a similar rate of early pregnancy loss, with approximately 11% to 13% of women suffering a miscarriage in the first trimester.16,17 According to the United States’ NTPR, the rate of spontaneous miscarriage among renal transplant recipients on cyclosporine was 12% to 19%, whereas almost 25% of women maintained on tacrolimus experience a first trimester pregnancy loss. Although most studies suggest that the vast majority of women who successfully complete the first trimester are likely to deliver live born infants, renal transplant recipients appear to be at higher risk of second and third trimester fetal loss than the general population. In both the US and UK registries, 2% to 3% of renal transplant recipients suffered an intrauterine fetal demise,16,46 whereas the largest series out of Canada demonstrated an almost 10% risk of stillbirth.17

Preterm Delivery In 2004 the premature birth rate in the US was 12.5%, representing an all time high and a more than 30% increase since 1981.47 Among renal transplant recipients, however, the preterm birth rate is substantially higher. According to both the US and the UK transplant registries, the mean gestational age at delivery among renal transplant recipients was approximately 36 weeks, with more than 50% delivering at less than 37 weeks.16,46 Similarly, among the largest Canadian series of pregnancies among renal transplant recipients, the mean gestational age at delivery was 36.5 weeks with 44% delivering before 37 weeks gestation.17 Despite the markedly elevated rate of preterm birth demonstrated in the large series, it is difficult to determine the etiology of this increased rate of preterm birth from the existing data. Although there is biologic plausibility as to how long-term glucocorticoid therapy may contribute to an increased incidence of spontaneous preterm labor in this population, renal transplant recipients are also at risk for a number of obstetric complications that may warrant iatrogenic preterm delivery for either maternal or fetal benefit. Registry data and national birth data unfortunately do not reliably allow for the differentiation of those preterm births that result from spontaneous labor from those which result from iatrogenic delivery due to maternal or fetal complications or due

K.M. Fuchs, D. Wu, and Z. Ebcioglu

342 to electively scheduled deliveries near term. Although the UK Transplant Registry reported the percentage of patients who were delivered as a result of spontaneous labor and the percentage of patients who were electively delivered, the gestational ages were not reported for either group, making it impossible to determine the relative contributions spontaneous preterm labor and iatrogenic delivery have on the increased rate of preterm delivery.16 Unfortunately, few studies report even this much information regarding the etiology of preterm births in renal transplant recipients. Future efforts should aim to improve the reporting and collection of data pertaining to these preterm deliveries so that we can better understand the etiology of the high rate of preterm birth seen in this population and develop prevention strategies when possible.

IUGR Female renal transplant recipients are not only at increased risk of preterm delivery, but are also at risk of delivering small for gestational age infants. According to the NTPR, the mean birth weight among renal transplant recipients was 2493 g with almost 50% of these women delivering infants weighing ⬍2500 g.46 The UK Transplant Registry reported similar numbers with a mean birth weight of 2316 g and 54% of infants weighing ⬍2500 g.16 The Canadian series reported a mean birth weight of 2540 g, which was significantly lower than that seen among controls (P 0.0001).17 It is unclear, however, whether these infants weighing ⬍2500 g were appropriately grown preterm infants, or whether there is an increased incidence of pathologic IUGR among pregnant renal transplant recipients. Again, future efforts should be aimed at improving the reporting of pregnancy complications in these women and to determine the true incidence of growth restriction in these offspring.

Recommendations for Pregnancy Management Preconceptional Counseling Data collected from numerous case series and transplant registries indicate that pregnancies in renal transplant recipients can result in favorable outcomes for both mother and fetus. Nevertheless, recipients of solid organ transplants are at significantly increased risk of graft rejection and adverse pregnancy outcome immediately following transplantation, and patients are usually advised to delay pregnancy for 1 to 2 years to minimize the risk of rejection and to avoid fetal exposure to high-dose immunosuppression. Accordingly, effective contraception is essential for 1 to 2 years after kidney or other solid organ transplantation. Once stable graft function has been achieved and a maintenance regimen of immunosuppressants has been initiated, it is reasonable for women of childbearing age to consider pregnancy. It is recommended that a multidisciplinary approach be taken in managing these pregnancies with a team of transplant nephrologists and maternal fetal medicine experts working together to optimize the outcome for both

mother and fetus. A preconceptional consult with a maternal fetal medicine specialist should be arranged to assess risk and to optimize the immunosuppressant regimen to avoid unnecessary fetal risk from medication exposure. Although pregnancy outcomes after renal transplantation are frequently favorable, patients should be counseled regarding the possibility of maternal and fetal morbidity in these pregnancies. In addition, patients should be counseled regarding the possibility of adoption as a means to avoid the maternal and graftrelated complications a pregnancy may pose.

Genetics Given the necessity that all transplant recipients continue immunosuppressive medications throughout their pregnancy, preconceptional genetic counseling is warranted in these cases to discuss the effects of medication exposure on fetal development and pregnancy outcome. Consideration should be given to the etiology of the maternal renal failure that necessitated renal transplantation. Although most renal transplants in adults occur due to end-stage renal disease resulting from chronic acquired medical conditions, a number of renal transplants occur for inherited conditions such as polycystic kidney disease. In pregnant patients receiving renal transplants as children, however, inherited disorders are a much more common etiology of renal transplant and have been estimated to lead to almost 25% of the renal transplants in childhood. Although genetic mutations have not been identified for many of the inherited disorders known to progress to end-stage renal disease, specific genetic mutations have been identified for some and prenatal genetic diagnosis may become available. For example, direct sequencing is now commercially available to test for the genetic mutations most commonly associated with autosomal dominant polycystic kidney, making preimplantation genetic diagnosis and prenatal diagnosis possible.48

Prenatal Care Renal transplant recipients should be comanaged by a team of maternal fetal medicine specialists and transplant nephrologists. Communication and cooperation between these services is essential to provide patients with the close surveillance and coordinated care they require. With regard to the frequency of prenatal visits, low-risk patients are usually seen by an obstetric provider monthly until 28 weeks, every 2 weeks from 28 to 36 weeks, and then weekly until delivery. Because pregnant renal transplant recipients are at significantly increased risk for maternal and fetal complications, prenatal visits should occur more frequently in this population. Although there is no official recommendation regarding the optimal frequency of prenatal visits in this and other high-risk populations, we see our transplant recipients every 2 weeks until approximately 28 to 32 weeks, and then weekly for the remainder of the pregnancy. At the first visit, the patient’s initial weight and blood pressure should be recorded. Baseline labs (24-hour quantitative protein excretion, urinalysis, urine culture, serum creatinine, blood urea nitrogen, electrolytes, hepatic function panel, and

Pregnancy in renal transplant recipients complete blood count) should be sent at this time to assess end organ function and to establish a baseline for comparison if the values become abnormal later in pregnancy. Although mild proteinuria is common in renal transplant recipients, current guidelines suggest that proteinuria should be less than 500 mg/d before pregnancy is considered.26-28 At each subsequent visit, a patient’s weight and blood pressure should be measured and we also repeat screening labs (24hour quantitative protein excretion, urinalysis, urine culture, serum creatinine, hepatic function panel, and complete blood count) on a monthly basis. Patients with worsening proteinuria on routine urine dip should perform a repeat 24-hour urine collection to quantitatively assess the degree of worsening proteinuria. The patient should be carefully assessed for clinical or laboratory evidence of preeclampsia or evolving renal dysfunction which may reflect graft rejection. Although there is little literature on the incidence of diabetes among pregnant transplant recipients, the immunosuppressants prednisone and tacrolimus are known to be diabetogenic.37,49 Careful screening for gestational diabetes is warranted, and at-risk patients should be given an early glucose challenge test in addition to the diabetic screen performed routinely at 24 to 28 weeks.50 Asymptomatic bacteruria should be treated in all pregnant women because of the associated risk of pyelonephritis and preterm delivery.51 In addition, some experts recommend that renal transplant recipients with a urinary tract infection in pregnancy be treated for a full 2 weeks and then remain on prophylactic antibiotics for the remainder of the pregnancy.27 Given the high likelihood of preterm delivery in this population, special consideration should be given to the administration of antenatal corticosteroids to hasten fetal lung development if and when preterm delivery appears likely for either maternal or fetal indication.

Antihypertensive Therapy As outlined above, patients with hypertension are at increased risk of not only worsening renal function, but also maternal and fetal pregnancy complications.52 Accordingly, hypertension should be treated in patients with elevated blood pressures at baseline, and these patients should be aggressively screened for worsening hypertension during their pregnancy, which may be evidence of either worsening disease or superimposed preeclampsia. Similarly, women who are normotensive in the first trimester should also be closely monitored during the pregnancy for the development of new onset hypertension, which may be evidence of preeclampsia. Although a number of medications have been used to treat hypertension in pregnancy, there are no clear guidelines to support the use of one antihypertensive over another. Methyldopa and labetolol are the antihypertensives most widely used to treat hypertension in pregnancy, and both have relatively long track records to demonstrate their safety and efficacy.53-55 Although labetolol is relatively widely used in pregnancy, there is some concern regarding the safety of other beta-adrenergic blockers in pregnancy due to the risk

343 of decreasing uterine perfusion and the possibility of fetal growth restriction.56-58 Atenolol, specifically, has been found to induce increased vascular resistance in the umbilical artery and fetal aorta when administered together with a calcineurin inhibitor.56 The cumulative effect may result in the delivery of lower birth weight infants in transplant patients maintained on both of these medications.36 Labetolol, however, appears to have less adverse effect on fetal growth possibly due to its combined alpha- and beta-blocking activity, which helps to maintain uterine blood flow. In addition to methyldopa and labetolol, there has been increasing experience with calcium channel blockers such as nifedipine. Existing data suggest that these medications are both safe and effective alternatives for the treatment of maternal hypertension in pregnancy.59-62 Although diuretics are not commonly used as a primary treatment of hypertension in pregnancy, current recommendations allow for the continued use of thiazide diuretics in the treatment of chronic hypertension in selected patients.55,63 Care should be taken to avoid maternal volume depletion, which could have a deleterious effect on placental perfusion. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are known to be teratogenic and should not be used in pregnancy.13,64 Transplant recipients treated with ACE inhibitors or angiotensin receptor antagonists should be advised to discontinue these medications before considering pregnancy and should be switched to an alternative regimen for blood pressure control. With regard to hypertensive therapy, there are no specific guidelines in the obstetric literature regarding the threshold at which antihypertensive therapy should be started, nor for target blood pressures once medications have been initiated. Our practice is to begin treatment when systolic blood pressures are sustained above 150 mm Hg or with diastolic blood pressures above 10, and to titrate medications to achieve systolic blood pressures between 130 and 150 and diastolics between 80 and 100. Because of the physiologic lowering of blood pressures to a nadir in the second trimester, many women can have their antihypertensive medications tapered (or even stopped altogether) in the early part of pregnancy. These women, however, still require close monitoring of the maternal blood pressure as the pregnancy advances and will likely require antihypertensive therapy as the pregnancy advances. Given the morbidity associated with severe hypertension, consideration should be given to inpatient evaluation of women with worsening hypertension or evidence of possible superimposed PEC. In all of our pregnant renal transplant recipients, whether hypertensive or normotensive at baseline, our practice is to record maternal blood pressure at each prenatal visit, which should occur at least every 2 weeks. In addition, we recommend that our hypertensive patients have a blood pressure cuff at home, and that they report elevations above 160/110. All patient are also encouraged to call with any signs or symptoms of preeclampsia, including headache, epigastric or right upper quadrant pain, or scotomata. To have baseline labs available for comparison, we obtain a number of laboratory studies on all of our renal transplant recipients in the first

K.M. Fuchs, D. Wu, and Z. Ebcioglu

344 trimester. As mentioned above, urine should be dipped at each prenatal visit, and women with a change in the degree of proteinuria should perform a repeat 24-hour urine collection. In addition, we also perform an EKG on all of our patients with underlying chronic hypertension and recommend an echocardiogram for those patients with electrical evidence of ventricular hypertrophy or atrial enlargement.

Fetal Monitoring Sonographic confirmation of gestational age should also be obtained early in the first trimester to provide accurate interpretation of fetal growth scans in the second and third trimesters. Although fundal heights may be a reliable assessment of fetal growth in some patients, we have a low threshold to perform serial ultrasounds to assess fetal growth given the increased incidence of IUGR in this population. Furthermore, in the setting of hypertension, fetal growth restriction, or other conditions that may compromise fetal well being, fetal surveillance with ultrasound and fetal heart rate monitoring should also be performed to assess both fetal growth and well-being. Although there are no proven methods of fetal testing that have been shown to universally prevent stillbirth, fetal testing should be performed women identified as having hypertension, IUGR, and/or preeclampsia to prevent adverse pregnancy outcomes.

Timing and Mode of Delivery Spontaneous preterm delivery is common among pregnant renal transplant recipients, and these women are also at risk for maternal and fetal complications which may prompt iatrogenic preterm delivery. In those women reaching term, however, elective delivery is justified at 39 weeks given the risk of additional maternal and fetal morbidity with continuing gestation. With regard to mode of delivery, prior renal transplantation is not a contraindication to vaginal delivery, and caesarean section should be performed for obstetric indications only. Because the renal allograft, however, is within the pelvic cavity, the obstetrician should make every effort to review the operative note of the transplant and to know the locations of the transplanted organ to avoid damage to the graft at the time of cesarean section. The maintenance glucocorticoids on which most renal transplant patients are maintained can pose additional complications at the time of delivery. Although daily doses of prednisone of less than 5 mg per day have not been shown to cause suppression of the hypothalamic-pituitary axis, other data suggest that there is significant variability in the degrees of adrenal suppression in patients maintained on 5 mg or more per day.65,66 Chronic glucocorticoids therapy has also been shown to lead to immunosuppression and impaired wound healing with an increased incidence of hematomas and skin breakdown.67 Accordingly, we recommend administration of stress dose steroids at the time of delivery (both vaginal and cesarean section) for our renal transplant recipients maintained on a daily dose of prednisone.

Pregnancy After Pancreatic Transplantation Introduction In most cases, pancreas transplant is performed as part of a combined pancreas– kidney transplantation (PKT) in the setting of type I diabetes in patients with end-stage renal failure. The first pancreatic transplantation was described in 1967,68 and more than 23,000 pancreas transplants have since been reported to the International Pancreas Transplant Registry (IPTR).69 Although pregnancies have been reported in patients with PKT since the late 1980s,69-77 information on this topic remains limited. Most of the evidence comes from case reports or small case series, as well as registry databases. The United States’ National Transplantation Pregnancy Registry (NTPR) has published pregnancy outcome data on 56 pregnancies in 38 pancreas– kidney recipients,46 and the IPTR has reported 19 pregnancies in 17 combined pancreas– kidney recipients.78

Pregnancy/OB Outcomes Women with a history of PKT are at risk of pregnancy complications similar to those seen in women with isolated renal transplant (Table 1). The incidence of spontaneous abortion in this population is 14%, and no stillbirths have been reported to date.46 The mean gestational age at birth was 34 weeks with more than three-quarters of pregnancies delivering at ⬍37 weeks, and the mean birth weight was 2069 g with 63% of infants weighing ⬍2500 g.46 The IPTR reported similar findings with a mean gestational age at delivery of 35.2 weeks (range 32-40 weeks) and a mean birth weight of 2150 g.78 These are lower than the mean birth weight and mean gestational ages reported among recipients of isolated kidney transplants. As with renal transplant recipients, the cesarean section rate reported in the literature is high among patients with combined PKT. The cesarean section rate in the United States’ NTPR was 57%, whereas all 17 patients in the IPTR underwent elective cesarean section.46,78 Interestingly, 6 of Table 1 Pregnancy Outcomes After Pancreatic Transplantation

Pregnancy outcomes Therapeutic abortion Spontaneous abortion Ectopic pregnancy Stillbirth Livebirth Livebirth outcomes Mean gestational age Premature (<37 weeks) Mean birthweight Low birthweight (<2500 g) Cesarean section

IPTR Data78

NTPR Data46

Not reported Not reported Not reported Not reported 19 cases

5% 14% 2% 0% 79%

35 weeks 72% 2150 g Not reported

34 weeks 78% 2096 g 63%

100%

57%

Pregnancy in renal transplant recipients

345

Table 2 Maternal Outcomes After Pancreatic Transplantation Maternal Outcomes No. of pregnancies Transplant to conception interval Diabetes during pregnancy Infection during pregnancy Rejection episode during pregnancy Preeclampsia Graft loss with 2 years Cesarean section

IPTR

Data78

NTPR

Data46

19 2.7 years

56 3.7 years

0% Not reported 0%

2% 55% 6%

Not reported 11% 100%

34% 16% 57%

the 17 cesarean sections reported in the IPTR were performed via vertical hysterotomy in an attempt to avoid contact with the pancreatic graft in the pelvis.78

Maternal Outcomes According to the NTPR database, the rates of hypertension and preeclampsia are similar in PKT recipients as in renal transplant recipients, with approximately 75% carrying a diagnosis of hypertension and 34% developing preeclampsia60 (Table 2). In comparison to renal transplant recipients, women with combined PKT experienced significantly more infections during pregnancy (55% versus 23%).46 The rate of rejection during pregnancy among PKT recipients in the NTPR was 6%, whereas none of the women in the ITPR had an episode of rejection during pregnancy.46,78 Although there is not enough information to determine impact of pregnancy on pancreatic graft survival, the NTPR has reported the loss of 6 grafts within 2 years postpartum.46 In addition to the general concerns shared with other solid organ transplant recipients, women with combined PKT face the additional concerns regarding the endocrine function of the transplanted pancreas. Although a successful pancreas transplant usually results in normal glucose levels without additional insulin therapy,79 there is theoretical concern regarding the ability of the pancreatic graft to meet the increased insulin demand during pregnancy and to maintain glycemic control. In the series from the IPTR, all 17 pancreas grafts were able to produce enough insulin to overcome the increased insulin resistance caused by pregnancy in the second and third trimesters.78 Similarly, Armenti and coworkers reported only 1 case of gestational diabetes among 56 pregnancies. Insulin therapy was started for that patient at 24 weeks but was discontinued postpartum.46 These findings are encouraging as it appears that, in majority of the cases, the transplanted pancreas can produce enough insulin to meet the increased insulin demand of pregnancy.

Preconceptional Counseling As with pregnancies in renal transplant recipients, pregnancies in patients with a combined PKT should be comanaged by a multidisciplinary team comprised of specialists in maternal fetal medicine, nephrology, and transplant medicine. Preconception counseling should take place during the pre-

transplantation period, and contraception should be given to those who do not desire pregnancy. For those patients who desire future pregnancy, most centers have advised that conception be delayed until the second posttransplantation year.45 Interestingly, patients with combined pancreas– kidney transplants have been reported to have false-negative urinary pregnancy tests both early in pregnancy and later in gestation.75,80 This phenomenon can be explained by the fact that the exocrine secretion of the pancreas being diverted to the urinary bladder where it subsequently degrades hCG thereby preventing the excretion of hCG which would normally result in a positive urine pregnancy test. Patients should be warned of this phenomenon and should be encouraged to seek serum testing when pregnancy is suspected. As outlined above, genetic counseling is recommend for all solid organ transplant recipients to discuss not only the possible effects of fetal exposure to immunosuppressant medications, but also the possible inheritance of the maternal condition that necessitated organ transplantation. Epidemiological studies suggest that the children of women with type I diabetes are at high risk of developing type I diabetes themselves.81 Even in the short-term follow-up data available through existing registries, the incidence of type 1 diabetes in the offspring of previously diabetic PKT recipients was 5%. Accordingly, PKT recipients should be informed of this increased risk of type 1 diabetes in their offspring and should be referred for genetic counseling.

Pregnancy Management Pregnancy management of patients with combined PKT is similar to that outlined above for patients with isolated renal transplants. In addition to the baseline laboratory studies that are recommended in women with isolated renal transplants, combined PKT patients should be screened for underlying thyroid disease with a TSH and free T4 in the first trimester given the high incidence of thyroid dysfunction in women with type I diabetes.82 In addition, women with a history of pregestational diabetes should have a comprehensive eye examination in the first trimester (or every 12 months) and be counseled on the risk of development and/or progression of diabetic retinopathy. Women with a history of diabetes who have achieved normal serum glucose levels after PKT should still be screened for gestational diabetes during pregnancy. Because of the relatively high incidence of infection during pregnancy, patients with PKT should also be screened for asymptomatic bacteruria, and providers should be vigilant in treating any potential infection. As with other immunosuppressed patients, prophylactic antibiotics are recommended at the time of cesarean section.

Conclusion Renal transplantation has provided women of childbearing age with increased fertility and the possibility of successful pregnancy outcomes. Pregnancy registries have been established to track the outcomes of pregnancies in transplant

346 recipients and to monitor the potential effects of immunosuppressant exposure on fetal and neonatal development. From the available literature, we know that these pregnancies are at significant risk for maternal and fetal complications ranging from hypertension, preeclampsia, graft rejection, and infection to preterm delivery and fetal growth restriction. Selected patients who have stable graft function can, however, have successful pregnancies under the careful supervision and cooperative efforts of a maternal fetal medicine specialist and transplant physician. Preconceptional counseling is imperative to assess maternal health and to optimally time pregnancy to minimize maternal risk of complications and to avoid fetal exposure to potentially teratogenic medications. During pregnancy, graft function and proteinuria should be closely monitored, hypertension should be aggressively treated, and patients should be screened for subclinical infections. Pancreas– kidney transplant recipients can similarly have successful pregnancies and can maintain glycemic control without the use of insulin. Patients and providers should be encouraged to continue to report pregnancy outcomes to the existing registries, and future research should continue to focus on optimizing the outcomes of this growing population of women.

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