Pregnancy outcomes in female renal transplant recipients

Pregnancy Outcomes in Female Renal Transplant Recipients V.T. Armenti, C.H. McGrory, J.R. Cater, J.S. Radomski, and M.J. Moritz

I

N THE PRESENCE of adequate, stable graft function, pregnancies in female renal transplant recipients, although high risk, are generally well tolerated. Although pregnancy may occasionally and unpredictably cause an irreversible decline in renal graft function, the consensus is that pregnancy has no adverse effect on graft function or graft survival.1,2 The National Transplantation Pregnancy Registry (NTPR) maintains an ongoing database to study the outcomes of pregnancy in female transplant recipients and pregnancies fathered by male transplant recipients. Previously, we reported that deterioration in recipient graft function during pregnancy is associated with lower newborn birthweights and lower maternal graft survival in cyclosporine (CsA, Sandimmune)-treated renal recipients.3,4 The purpose of this study was to identify variables affecting postpartum graft loss in female renal recipients. MATERIALS AND METHODS Data were collected via questionnaires submitted by transplant recipients identified by their transplant coordinators or physicians or by self report to the NTPR. Additional data were obtained via phone interviews and hospital records. Statistical analysis was by a Cox proportional hazards model and by logistic regression. Forty CsA recipients whose renal transplant failed anytime after pregnancy were compared to 81 randomly selected CsA renal recipients who reported a pregnancy without a graft loss.5 For multiple posttransplant pregnancies, data for analysis were taken from the last pregnancy. Not all episodes of rejection were confirmed by biopsy, and many appeared to be progression of chronic rejection. It could not be determined if there was a change in immunosuppressive regimen in all cases.

RESULTS

Outcomes of 412 pregnancies in 285 renal recipients reported to the NTPR were analyzed. Immunosuppressive regimens during pregnancy included CsA (Sandimmune) (265 recipients, 392 pregnancies), cyclosporine microemulsion (Neoral), (13 pregnancies, 5 of whom were switched from Sandimmune to Neoral during pregnancy), and tacrolimus (Prograf) based regimens (7 pregnancies). Outcomes of these pregnancies are shown in Table 1. The Neoral- or tacrolimus-based recipients are relatively few in number and their pregnancies occurred more recently (shorter follow-up), but there have been no graft losses or structural malformations reported in their newborn. From a

Table 1. Pregnancy Outcomes in Female Renal Recipients Regimen

n

Liveborn Incidence

BW*

GA†

CsA CsA 3 Neoral Neoral Tacrolimus (Prograf)

392 5 8 7

75% 80% 75% 71%

2465 2335 2481 2211

35.9 37.0 36.3 32.8

*BW 5 birthweight (g), †GA 5 gestational age (wks).

group of 230 CsA renal recipients, postpartum graft loss was reported in 40 (17%) recipients (Tables 2 and 3). From the no graft loss group (n 5 190), 81 were randomly selected for comparison to the graft loss group. Recipients in the graft loss group had higher mean serum creatinine levels prepregnancy, during pregnancy, and postpartum when compared to the no graft loss group (Table 4). A high serum creatinine at any time (before, during, and after pregnancy) was associated with an increased risk of postpartum graft loss (Table 5). Other variables associated with graft loss included low birthweight newborn (P 5 .02, risk ratio 2.94; 95% confidence interval (CI) 1.2 to 6.97), rejection during (P 5 .0001, risk ratio 6.22, 95% CI, 2.7 to 14.5), and after pregnancy (P 5 .0001, risk ratio 6.11, 95% CI 3.1 to 12.1). Variables not associated with graft loss are shown in Table 6. Recipients with serum creatinine before pregnancy $2.5 mg/dL were approximately three times more likely to experience postpartum graft loss than those recipients with serum creatinine before pregnancy of ,1.5 mg/dL (risk ratio 2.95, P 5 .03 95% CI 1.10 to 7.96). By logistic regression, variables associated with rejection during pregnancy included rejection before pregnancy (P 5 .012, odds ratio 14.6; high creatinine before P 5 .0003, odds ratio 5.13; and during pregnancy P 5 .003, odds ratio 2.46). There were no predominant malformations noted among the CsA renal recipient offspring (n 5 175; mean age of 4.4 yrs).

From the Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. Supported by grants from Sandoz Transplant, a Division of Novartis Pharmaceuticals Corp, Fujisawa USA, Inc, and Roche Laboratories Inc. Address reprint requests to Vincent T. Armenti, MD, PhD, Department of Surgery, 1025 Walnut Street, 605 College Building, Philadelphia, PA 19107.

0041-1345/98/$19.00 PII S0041-1345(98)00408-4

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Transplantation Proceedings, 30, 1732–1734 (1998)

PREGNANCY RESULTS IN FEMALE TRANSPLANT RECIPIENTS

1733 Table 4. Female CsA Renal Recipients

Table 2. Female CsA Renal Recipients Maternal Conditions

Mean age first transplant Mean estimated age at conception Mean transplant to conception interval Rejection before pregnancy Hypertension Diabetes Preeclampsia Rejection during pregnancy Cesarean section Rejection postpartum (within 3 months of delivery)

No Graft Loss After Pregnancy (n 5 190)

Graft Loss After Pregnancy (n 5 40)

24.5 y 28.4 y

23.7 y 26.2 y

3.1 y

2.6 y

33% 65% 11% 33% 2% 50% 5%

54% 57% 11% 29% 13% 68% 28%

DISCUSSION

Data analyzed by the NTPR regarding safety of pregnancy has to date been largely derived from the experience with CsA-based regimens. For these recipients there have been good maternal outcomes without specific or predominant malformation patterns in the offspring. The concept that graft function in renal recipients is not adversely affected by pregnancy has been supported by case-controlled studies in which the long-term graft survival of renal recipients who became pregnant was compared to age-matched nonpregnant controls.6 – 8 Davison and colleagues did suggest that a minor deleterious effect of pregnancy on long-term graft function could not be excluded.8 A single-center study showed impaired renal function after pregnancy, however, the control group had a graft survival of 100% at 10 years.9 In a recent center report of 21 pregnancies in 16 recipients (one of whom received a pancreas/kidney), graft survival was compared with two control groups, including 10 recipients with early pregnancy terminations and 31 recipients who did not have pregnancies.10 There were no significant differences noted in survival among the three groups. Four Table 3. Female CsA Renal Recipients Pregnancy Outcomes

No Graft loss

Graft Loss

Ectopic Stillborn Miscarriage Therapeutic abortion Livebirth Premature (,37 wks) Low birthweight (,2500 g) Very low birthweight (,1500 g)

0.7% 2.5% 12.6% 8.7% 76% 36% 44% 11%

0% 5.3% 19.3% 15.8% 60% 59% 65% 29%

Liveborn Outcomes Mean gestational age Mean birthweight

36 wks 2485 g

35 wks 2138 g

No graft loss Graft loss

Before Pregnancy

Mean Serum Creatinine (mg/dL) During Pregnancy

After Pregnancy

1.3 1.6

1.2 1.9

1.4 2.3

grafts were lost after pregnancy within 2 years of delivery related to chronic rejection (n 5 2), disease recurrence (n 5 1), and poor compliance (n 5 1). In a prior report from the NTPR, a case-controlled study compared CsA renal recipients with stable graft function to those CsA renal recipients who developed graft dysfunction during pregnancy. Prepregnancy serum creatinine was higher among the graft dysfunction group. Of note, prepregnancy serum creatinine alone was not shown to be a predictor of graft loss (within 2 years of delivery).3 Among the published preconception guidelines for renal recipients is a recommendation that there be no or minimal proteinuria before pregnancy.1 In a recent study of 33 renal recipients, all of whom were on CsA based regimens, 6 of the 33 recipients had a significant rise in serum creatinine following delivery.11 When these recipients were compared to the group without a creatinine rise, there was significantly greater proteinuria before, during, and after delivery in the graft dysfunction group. Additionally, chronic rejection was diagnosed in all six of these recipients, on clinical grounds in two and by renal biopsy in four, adding support to the concern that prepregnancy proteinuria or chronic rejection is a risk factor for postpartum graft loss. The present study demonstrates that for female CsA renal recipients, there are now sufficient data to show a direct relationship between high creatinine levels before and during pregnancy and an increased risk of postpartum graft loss. Of note, a number of variables are not associated with increased risk of graft loss including hypertension and multiple pregnancies. A recent report described successful successive pregnancies in female renal recipients,12 and this has also been noted in NTPR data. In summary, pregnancy in the renal transplant recipient must be considered high risk. In addition to being apprised of the risk of low birthweight and prematurity, those recipients with a high prepregnancy serum creatinine must be advised that they have an increased risk of postpartum graft loss, and that their pregnancy outcomes are somewhat less favorable when compared to recipients with lower mean prepregnancy serum creatinine. No predominant malformations have been noted in CsA recipient offspring. Continuing registry efforts with folTable 5. Relative Risk of Graft Loss of Higher Creatinine

Cr (before pregnancy) Cr (during) Cr (after)

P Value

Hazard Ratio (95% CI)

.03 .0001 .0001

1.62 (1.04, 2.52) 2.02 (1.52, 2.70) 1.79 (1.39, 2.31)

Abbreviations: CI, confidence interval; Cr, creatinine.

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ARMENTI, MCGRORY, CATER ET AL Table 6. Female CsA Renal Recipients

Variables Not Associated With Risk of Graft Loss

Maternal age at conception Transplant number Donor source Rejection before pregnancy Azathioprine Transplant to conception interval Hypertension before pregnancy Hypertension during pregnancy Diabetes before pregnancy Diabetes during pregnancy Preeclampsia Pregnancy number

P Value

0.16 0.64 0.34 0.08 0.90 0.70 0.76 0.89 0.91 0.89 0.65 0.73

low-up of parent and offspring will allow for further recommendations, especially in light of new regimens. ACKNOWLEDGMENTS The authors gratefully acknowledge the transplant physicians, coordinators, and recipients who have contributed their time and

information to the Registry. The authors acknowledge Jennifer Ann Smith for the preparation of the manuscript.

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