Risks of Pregnancy to Allograft Function

In the non-transplant CKD population, those with mild kidney disease (creatinine <1.3 mg/dL) do not typically experience progression of renal disease during pregnancy [16]. Data from the Australia and New Zealand Dialysis and Transplant Registry echo these findings in transplant recipients. Sixty-four paired preconception and 3-month postpartum serum creatinine were compared. Median pre- and postpartum creatinine levels did not differ significantly [17]. Not surprisingly, those with moderate to severe allograft dysfunction (creatinine greater than 1.3 and 1.9, respectively) are at a higher risk for progressive CKD and allograft loss during pregnancy. General consensus is that those with a serum creatinine greater than 1.5 mg/dL and a 24-h urine protein greater than 500 mg are at a significantly increased risk for irreversible graft loss as a result of pregnancy [13, 18].

Pregnancy and Risk, Diagnosis, and Treatment of Allograft Rejection

With the change in volume of distribution that comes with pregnancy, calcineurin inhibitor (CNI) serum levels typically decrease, and the CNI dosage usually needs to be increased to achieve the same serum blood level. Frequent monitoring of serum drug levels during pregnancy is therefore required. It has been well studied that the uterus exists as an immunoprivileged site and that the fetus is protected from rejection by local immunoregulatory mechanisms at the maternal-fetal interface [19, 20]. Some have made the argument that pregnancy is an immunosuppressed state that, therefore, patients may require lower levels of immunosuppression to prevent allograft rejection. In a small study in which tacrolimus doses were not changed during pregnancy despite lower troughs, there were no rejections [21]. Despite the success reported in the study, this tactic is not recommended. While during pregnancy there is some degree of systemic immune tolerance that has been shown to occur, this effect has only been shown with respect to the fetus and to autoimmune targets. It should not be assumed that this tolerance extends to the transplanted kidney. And in fact allograft rejection has been reported to occur at similar rates in gravid and non-gravid patients [22]. Expert opinion is that pregnancy does not ensure safety of lower immunosuppression levels and that similar prepregnancy and pregnancy troughs should be maintained to prevent rejection [13].

The diagnosis of rejection by serum creatinine monitoring may be difficult because of pregnancy-induced renal hyperfiltration. Rejection can occur with only a small rise in serum creatinine. Biopsies can typically be safely performed under ultrasound in gravid transplant patients. Treatment with methylprednisolone is considered safe, but treatment with anti-thymocyte globulin, basiliximab, and rituximab has limited safety data. IVIG has been used without observed adverse effects²².

Hypertension and Preeclampsia in Gravid Renal Transplant Recipients

The NTPR reports hypertension rates as high as 49% in pregnant kidney transplant recipients. Consensus guidelines recommend a normotensive state in kidney transplant recipients during pregnancy. Acceptable antihypertensive medications include methyldopa, nifedipine, and labetalol. Under certain circumstances, diuretics can be used with caution and close monitoring. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in pregnancy because of adverse fetal effects. There are concerns regarding fetal growth with atenolol, and it should be avoided. Preeclampsia has been reported in approximately 30% of gravid renal transplant recipients in databases both from the United States and from Australia and New Zealand [17]. Preexisting proteinuria, elevated uric acid levels, hypertension, and edema can make the diagnosis of preeclampsia more challenging in transplant recipients.

Spontaneous Abortion, Preterm Growth, and IUGR

Spontaneous abortion rates of 14–18% have been reported by both the NTPR and the UK Transplant Pregnancy Registry. Registry reports and many case series consistently cite rates of small birth weight and preterm births, at 20% and 50%, respectively. Registry data from the United Kingdom reported that the median gestational age at delivery was 36 weeks. The most common indications for either induction of labor or cesarean section were concern for renal compromise (39%) and preeclampsia or worsening hypertension (23%) [23]. A meta-analysis that included studies published between 2000 and 2010 found a live birthrate of 73.5% (higher than in the US general population). It is unclear why the live birthrate was higher in the transplant population, and this finding could be due to reporting bias. The rate of preeclampsia was 27%. Cesarean section and preterm delivery rates were 56.9% and 45.6%, respectively. Reasons for preterm birth were not reported [24].

In this same meta-analysis, hypertension, elevated serum creatinine, and proteinuria prepartum were associated with poorer outcomes, while younger maternal age was associated with improved pregnancy outcomes. In addition, studies with a mean interval between transplant and pregnancy of more than 2 years had more favorable pregnancy outcomes.

In a study of the UK pregnancy database, the majority of pregnancies in posttransplant recipients were categorized as having good outcomes. A good outcome was defined as live birth greater than 32 weeks gestation. Poor outcomes, defined as first or second trimester loss, stillbirth, neonatal death, birth less than 32 weeks, or congenital anomaly, were reported in 23% of pregnancies of transplant recipients. Adverse risk factors included a history of two or more kidney transplants and women with a higher median creatinine. There were no significant differences in pregnancy outcomes between women whose creatinine displayed the expected fall in the second trimester and with those whose creatinine remained stable or even rose in the second trimester. Almost one third of patients developed proteinuria that was not associated with preeclampsia²³.

Immunosuppressive Agents and the Fetus

A typical immunosuppressive regimen of a nonpregnant renal transplant recipient consists of a calcineurin inhibitor (tacrolimus or less commonly cyclosporine) and an antimetabolite (mycophenolate mofetil, enteric-coated mycophenolic acid, or less commonly azathioprine). Many, but not all, patients are maintained on low-dose prednisone. None of these agents are designated as category A medications in terms of safety during pregnancy.

Both tacrolimus and cyclosporine are classified by the FDA as category C drugs. But from the US registry data, there is nothing to support an association between calcineurin inhibitors and congenital anomalies. Several isolated birth defects have been reported, but the numbers are so low, and malformations inconsistent such that either the incidence is exceedingly low or perhaps a definable relationship may not exist. Several small studies in human neonates have found some immune irregularities. One study found that infants who were exposed to tacrolimus in utero had low numbers of T and B cells at birth but normalized within a few months [25]. The clinical implications of these findings are unclear; however, other studies have shown no immunologic defects in those exposed in utero. Calcineurin inhibitors are routinely used during pregnancy in transplant recipients.

NTPR analyses found exposure to mycophenolic acid products to be associated with a high incidence of spontaneous abortions and structural birth defects. Due to these findings, in 2007, the FDA changed the pregnancy category of mycophenolate mofetil and enteric-coated mycophenolic acid from C to D. It is recommended that female patients discontinue mycophenolate mofetil 6 weeks prior to conception or longer. Azathioprine is generally used in place of mycophenolate mofetil.

Azathioprine does pass into the fetal circulation. One report found only inactive metabolites in the fetal circulation, suggesting that the fetus may lack the enzyme required to convert azathioprine into its active metabolite [26]. Azathioprine is designated as category D because of abnormalities observed in rodent fetuses and rare reports (2) of structural abnormalities in fetuses born to a parent taking azathioprine. Dose-related and transient fetal immunosuppression has been reported in those born to mothers on azathioprine. Because of the extreme rarity of reports of birth defects in humans, azathioprine is routinely used in pregnancy and remains to be the preferred antimetabolite in gravid transplant recipients.

Prednisone does cross the placenta, but most of the maternal dose is metabolized within the placenta prior to reaching the fetus. Birth defects have been reported in only rare instances in fetuses of patients taking greater than 20 mg of prednisone a day. Prednisone, especially at low doses, is generally considered safe in pregnancy and is in widespread use in gravid transplant recipients. Although methylprednisolone (used in treatment of rejection) crosses the placenta, it is metabolized relatively quickly and is detected only at low levels in the fetal circulation [27, 28].

There is very little data regarding in utero exposure to sirolimus in NPTR reports. The small amount of data does not indicate that there is increased risk of birth defects with exposure, but due to the small numbers, this must be interpreted with caution. There are extremely limited data on belatacept, a newer drug that suppresses the immune system via co-stimulation blockade, use during pregnancy.

Follow-up of children of transplant recipients has been conducted by the NPTR. Over 1000 children have been followed for an average of almost 15 years. Information from this follow-up supports that most children are healthy and developing well. The authors of the report state that preliminary data suggest that children exposed to calcineurin inhibitors in utero show cognitive and physical development that is comparable to that of the general population. However, the authors do not describe the exact method and depth of data collection.

Rhesus Immunization After Renal Transplant

There are very little data on the incidence of rhesus immunization and renal transplant, and most of the data and case reports were based on older data. A retrospective review of Rh-negative recipients of allografts from Rh-positive donors that ultimately included 42 subjects was published in 1996. Out of the 42 Rh-negative allograft recipients, 2 were found to have developed new anti-RhD-positive antibodies after transplant. Both patients developed antibodies after their second RhD-positive allograft. It was not noted if the patients received antilymphocyte induction therapy. The group was unable to find any reports of hemolytic disease of newborn in pregnancies following transplantation [29]. There are no official recommendations regarding administration of anti-D immunoglobulin in Rh-negative transplant recipients receiving allografts from RhD-positive donors. However, it seems reasonable to administer a single dose of Rhogam 300 μg at the time of the transplant in Rh-negative female recipients of childbearing or potential childbearing age (i.e., children) who receive a kidney from an Rh-positive donor.