- Email: [email protected]
Pregnancy in Kidney Transplant Recipients
Pregnancy in Kidney Transplant Recipients F. Pour-Reza-Gholi, M. Nafar, F. Farrokhi, A. Entezari, N. Taha, A. Firouzan, and B. Einollahi ABSTRACT Purpose. Our aim was to investigate kidney allograft, obstetric, and maternal outcomes in pregnant women undergoing kidney transplantation in our center. Methods. Retrospective data on 74 pregnancies in 60 patients were reviewed and completed through phone interviews were compared with information on a control group of female kidney recipients. Results. Mean age of patients at transplantation was 26.55 ⫾ 4.72 years and the median interval between transplantation and pregnancy was 27.5 months. Gestational period was 8 months. Live birth was the outcome in 43.2% of pregnancies; 9.5% led to still birth, 24.3% were aborted, and obstetrical data of the remaining were unavailable. Among the 11 patients who became pregnant within 12 months after transplantation, we observed seven live births and four abortions. None of pregnancies that were accompanied by acute rejection episodes (ARE) were successful. Twenty-six patients experienced at least one ARE versus 23 patients of the control group (P ⫽ NS). However, the first ARE occurred later in the pregnant group (P ⫽ .028). Chronic rejection and graft loss were seen in 24 and 18 study group cases and 17 and 17 control cases, respectively (P ⫽ NS). One-, 3-, 5-, and 10-year graft survivals were 100%, 96.5%, 94.5%, and 77.1% in the pregnant group versus 93.2%, 85.7%, 81%, and 64.7% in the control group, respectively (P ⫽ .07). Conclusion. Pregnancy in kidney recipients seems to be safe for kidney allograft recipients even within the first year posttransplant. Nonetheless, the outcomes of pregnancy in this group of patients is not always favorable, especially when rejection occurs simultaneously.
K
IDNEY TRANSPLANTATION offers a chance to bear children; normal menstrual function is restored within 1 to 20 months.1–3 However, interactions of pregnancy on kidney allograft function may impact on the outcome.4 Studies have shown an association of poorer prognosis with poorer renal function,5 but more information is needed to understand pregnancy in kidney recipients. Accordingly, we reviewed pregnancy cases among our kidney transplant patients compared them with a group of female recipients without pregnancy after transplantation. MATERIALS AND METHODS Between 1984 and 2004, 512 among more than 2150 kidney transplants were performed in female recipients of reproductive age (15 to 45 years) including 74 pregnancies in 60 women (11.7%). Nine women experienced two pregnancies; one patient, three pregnancies; and four in one case. All patients received a kidney transplant from a living donor. Up to 81% of donors in this center are living unrelated. Thus, 40
(66.7%) pregnant women had received a kidney from a living unrelated donor. Collected data included immunosuppressant regimen, serum creatinine levels, rejection episodes, long-term graft outcome, and pregnancy outcome. Sixty female recipients with no conception during the posttransplant period were selected in a randomly stratified fashion, matched for age at transplantation, date of transplant, and immunosuppressive regimen. Acute rejection episodes and graft survival were compared in pregnant versus nonpregnant groups. Student t, Mann-Whitney, and chi-square tests were used for comparisons between groups; survival analyses were performed by KaplanMeier and log-rank tests.
From the Urology and Nephrology Research Center, Shaheed Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. Address reprint requests to Farhat Farrokhi, Urology/Nephrology Research Center (UNRC), No. 44, 9th Boustan, Pasdaran, Tehran, Iran 1666679951. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.08.033
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3090
Transplantation Proceedings, 37, 3090 –3092 (2005)
PREGNANCY AFTER KIDNEY TRANSPLANTATION
3091 Table 2. Serum Creatinine Levels at the End of Follow-up of the Pregnant and Control Groups
RESULTS Patient and Graft Data
Mean age of patients at transplantation and pregnancy were 26.55 ⫾ 4.72 and 29.78 ⫾ 4.67 years, respectively. Median interval between transplantation and pregnancy was 27.5 months (range 1 to 144). Mean gestational age was 7.22 ⫾ 2.30 (range 1 to 9) months (median 8 months). Immunosuppressive regimen comprised prednisolone plus azathioprine in 1.5%, prednisolone plus cyclosporine in 40.8% and combined with azathioprine in 57.7% (6.9% on Cellcept, discontinued when pregnancy was confirmed). Creatinine levels were classified as ⬍1.5 mg/dL, 1.5 to ⬍3 mg/dL, 3 to ⬍4.5 mg/dL, ⱖ4.5 mg/dL, or dialysis dependent. At the time of conception, creatinine levels were less than 1.5 mg/dL in 64 cases, of whom 51 (68.9%) had no increase at delivery (Table 1). Four patients had a creatinine of 1.5 to 3 mg/dL at pregnancy; no one had an higher creatinine level. Four patients had creatinine increase up to more than 3 mg/dL, of whom one underwent dialysis. Pregnancy period was complicated by ARE in 5 (6.7%) patients, none of whom had successful labor. Twenty-six (43.4%) patients experienced at least one ARE, 23 (39%) of which were after pregnancy. Median interval between pregnancy and the following acute rejection was 19 months. In the control group 23 (39%) cases had at least one acute rejection episode (P ⫽ NS). Chronic rejection was seen in 24 (40%) and 17 (28.3%) of pregnant and control groups, respectively (P ⫽ .12). Thirteen pregnancies (17.5%) were conceived within the first posttransplant year; their graft survival was 100% up to year 2. In four patients pregnancy occurred within the first 3 months with graft survival of 100% up to year 2. Also 13 (17.5%) patients were pregnant 5 years after transplantation; their graft function was stable at 1 year postpartum. Chronic graft dysfunction and graft loss was seen in 24 and 18 cases of the pregnant group and in 17 and 17 cases of the control group, respectively (P ⫽ .125; P ⫽ NS). The median interval from the first pregnancy episode to graft loss was 66 months (range 17 to 126). Mean follow-up of the pregnant group was 100.83 ⫾ 48.49 months and it was 74.78 ⫾ 55.87 months for the control group. Last creatinine level was not significantly different in the pregnant versus control group (Mann-Whitney, P ⫽ .156) (Table 2). One-, 3-, 5-, and
Last Creatinine Level (mg/dL)
⬍1.5 1.5 to ⬍3 3 to ⬍4.5 ⱖ4.5 Dialysis dependent
Pregnant Group (%)
Control Group (%)
24 (40) 10 (16.7) 2 (3.4) 5 (8.3) 18 (30)
35 (58.3) 4 (6.9) 1 (1.7) 2 (3.4) 17 (28.3)
10-year graft survivals were 100%, 96.5%, 94.5%, and 77.1% in the pregnant group versus 93.2%, 85.7%, 81%, and 64.7% in the control group, respectively (P ⫽ .07) (Fig 1). Obstetric Data
Live birth was the outcome in 43.2% of pregnancies; 9.5% led to still birth, 24.3% were aborted, and the obstetrical data of the remaining were not available (23%). Among the 11 patients pregnant within 12 months after transplantation, we observed 7 live births and 4 abortions. Also, of four pregnancies within 3 months, three were successful. None of the pregnancies accompanied by ARE were successful. Unfortunately, detailed data of pregnancies and obstetric results were not complete; the outcomes of 23% were not known. However, it is noteworthy that one patient had four pregnancies, all of which ended in abortion. But another patient had three consecutive successful pregnancies, resulting in three full-term, healthy children. DISCUSSION
The patients in our study had a relatively short interval between their transplantation and pregnancy. Many previous reports include longer intervals. Thompson et al7 for instance, reported a mean time of 6.5 years in 48 cases. They also showed that early pregnancies had a poorer prognosis.7 But we found that pregnancy in the first year
Table 1. Serum Creatinine Level Changes at the Beginning and End of Pregnancy Pregnancy
No increase ⬍1.5 1.5 to ⬍3 1.5 to ⬍3 Increase ⬍1.5 ⬍1.5 ⬍1.5 1.5 to ⬍3
End of pregnancy
Number of Patients (%)
⬍1.5 1.5 to ⬍3 ⬍1.5
51 (75) 2 (2.9) 1 (1.5)
1.5 to ⬍3 3 to ⬍4.5 ⱖ4.5 Dialysis
10 (14.7) 2 (2.9) 1 (1.5) 1 (1.5)
Fig 1. Graft survival curves of pregnant and control groups (Kaplan-meier).
3092
had no significant impact on child or graft outcome. Thus, it seems that recommending to delay pregnancy may be controversial. Almost all the studies on this matter have reported high incidences of abortions and stillbirths. Among 33 pregnancies in a study by Crowe et al,8 28 healthy births were seen, but other studies report 63% to 69% successful pregnancies.9,10 In our study, graft outcome was desirable in pregnant women, corresponding to relatively higher graft survivals and comparable rates of graft dysfunction and graft loss to a control group. However, the 1-year graft survival of 100% may be due to an inevitable bias that these patients were the ones who had a favorable health situation in the first year posttransplant to get pregnant. Overall, the high 5-year survival is in favor of the long-term safety of pregnancy in transplanted women. Many studies concur with our findings. Crowe observed 90% graft survival at 2 years postpartum.8 Sturgiss et al4 compared 17 pregnant cases with 17 transplanted controls. They reported a graft loss in one woman with a pregnancy history versus four controls. Plasma creatinine at the end of the follow-up period (1.40 ⫾ 0.52 mg/dL and 1.54 ⫾ 0.95 mg/dL, respectively) increased from 3 years earlier by 11% and 7%, respectively, which was not statistically significant.4 Accordingly, most authors believe that pregnancy does not adversely affect renal transplant function. However, a few studies have shown the opposite results: Thompson et al7 reported a permanent, significant decline in graft function in 20% of the cases by 6 months postdelivery.
POUR-REZA-GHOLI, NAFAR, FARROKHI ET AL
In summary, our findings indicate no long-term adverse effects of pregnancy on transplant recipients even when it occurs in the early posttransplant period. But, a simultaneous ARE leads to an unsuccessful pregnancy. Saving the infant and providing a healthy delivery requires an intense level of attention.6 REFERENCES 1. Murray JE, Reid DE, Harrison JH, et al: Successful pregnancies after human renal transplantation. N Engl J Med 269:341, 1963 2. Rudolph JE, Schweitzer RT, Bartus SA: Pregnancy in renal transplant patients. Transplantation 27:26, 1979 3. Mattix Kramer HJ, Tolkoff-Rubin NE, Williams WW, et al: Reproductive and contraceptive characteristics of premenopausal kidney transplant recipients. Prog Transplant 13:193, 2003 4. Sturgiss SN, Davison JM: Effect of pregnancy on the longterm function of renal allografts: an update. Am J Kidney Dis 26:54, 1995 5. Davison JM, Bailey DJ: Pregnancy following renal transplantation. J Obstet Gynaecol Res 29:227, 2003 6. Pezeshki M, Taherian AA, Gharavy M, et al: Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet 85:119, 2004 7. Thompson BC, Kingdon EJ, Tuck SM, et al: Pregnancy in renal transplant recipients: the Royal Free Hospital experience. QJM 96:837, 2003 8. Crowe AV, Rustom R, Gradden C, et al: Pregnancy does not adversely affect renal transplant function. QJM 92:631, 1999 9. Hooi LS, Rozina G, Shaariah MY, et al: Pregnancy in patients with renal transplants in Malaysia. Med J Malaysia 58:27, 2003 10. Tan PK, Tan AS, Tan HK, et al: Pregnancy after renal transplantation: experience in Singapore General Hospital. Ann Acad Med Singapore 31:285, 2002
K
IDNEY TRANSPLANTATION offers a chance to bear children; normal menstrual function is restored within 1 to 20 months.1–3 However, interactions of pregnancy on kidney allograft function may impact on the outcome.4 Studies have shown an association of poorer prognosis with poorer renal function,5 but more information is needed to understand pregnancy in kidney recipients. Accordingly, we reviewed pregnancy cases among our kidney transplant patients compared them with a group of female recipients without pregnancy after transplantation. MATERIALS AND METHODS Between 1984 and 2004, 512 among more than 2150 kidney transplants were performed in female recipients of reproductive age (15 to 45 years) including 74 pregnancies in 60 women (11.7%). Nine women experienced two pregnancies; one patient, three pregnancies; and four in one case. All patients received a kidney transplant from a living donor. Up to 81% of donors in this center are living unrelated. Thus, 40
(66.7%) pregnant women had received a kidney from a living unrelated donor. Collected data included immunosuppressant regimen, serum creatinine levels, rejection episodes, long-term graft outcome, and pregnancy outcome. Sixty female recipients with no conception during the posttransplant period were selected in a randomly stratified fashion, matched for age at transplantation, date of transplant, and immunosuppressive regimen. Acute rejection episodes and graft survival were compared in pregnant versus nonpregnant groups. Student t, Mann-Whitney, and chi-square tests were used for comparisons between groups; survival analyses were performed by KaplanMeier and log-rank tests.
From the Urology and Nephrology Research Center, Shaheed Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. Address reprint requests to Farhat Farrokhi, Urology/Nephrology Research Center (UNRC), No. 44, 9th Boustan, Pasdaran, Tehran, Iran 1666679951. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.08.033
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3090
Transplantation Proceedings, 37, 3090 –3092 (2005)
PREGNANCY AFTER KIDNEY TRANSPLANTATION
3091 Table 2. Serum Creatinine Levels at the End of Follow-up of the Pregnant and Control Groups
RESULTS Patient and Graft Data
Mean age of patients at transplantation and pregnancy were 26.55 ⫾ 4.72 and 29.78 ⫾ 4.67 years, respectively. Median interval between transplantation and pregnancy was 27.5 months (range 1 to 144). Mean gestational age was 7.22 ⫾ 2.30 (range 1 to 9) months (median 8 months). Immunosuppressive regimen comprised prednisolone plus azathioprine in 1.5%, prednisolone plus cyclosporine in 40.8% and combined with azathioprine in 57.7% (6.9% on Cellcept, discontinued when pregnancy was confirmed). Creatinine levels were classified as ⬍1.5 mg/dL, 1.5 to ⬍3 mg/dL, 3 to ⬍4.5 mg/dL, ⱖ4.5 mg/dL, or dialysis dependent. At the time of conception, creatinine levels were less than 1.5 mg/dL in 64 cases, of whom 51 (68.9%) had no increase at delivery (Table 1). Four patients had a creatinine of 1.5 to 3 mg/dL at pregnancy; no one had an higher creatinine level. Four patients had creatinine increase up to more than 3 mg/dL, of whom one underwent dialysis. Pregnancy period was complicated by ARE in 5 (6.7%) patients, none of whom had successful labor. Twenty-six (43.4%) patients experienced at least one ARE, 23 (39%) of which were after pregnancy. Median interval between pregnancy and the following acute rejection was 19 months. In the control group 23 (39%) cases had at least one acute rejection episode (P ⫽ NS). Chronic rejection was seen in 24 (40%) and 17 (28.3%) of pregnant and control groups, respectively (P ⫽ .12). Thirteen pregnancies (17.5%) were conceived within the first posttransplant year; their graft survival was 100% up to year 2. In four patients pregnancy occurred within the first 3 months with graft survival of 100% up to year 2. Also 13 (17.5%) patients were pregnant 5 years after transplantation; their graft function was stable at 1 year postpartum. Chronic graft dysfunction and graft loss was seen in 24 and 18 cases of the pregnant group and in 17 and 17 cases of the control group, respectively (P ⫽ .125; P ⫽ NS). The median interval from the first pregnancy episode to graft loss was 66 months (range 17 to 126). Mean follow-up of the pregnant group was 100.83 ⫾ 48.49 months and it was 74.78 ⫾ 55.87 months for the control group. Last creatinine level was not significantly different in the pregnant versus control group (Mann-Whitney, P ⫽ .156) (Table 2). One-, 3-, 5-, and
Last Creatinine Level (mg/dL)
⬍1.5 1.5 to ⬍3 3 to ⬍4.5 ⱖ4.5 Dialysis dependent
Pregnant Group (%)
Control Group (%)
24 (40) 10 (16.7) 2 (3.4) 5 (8.3) 18 (30)
35 (58.3) 4 (6.9) 1 (1.7) 2 (3.4) 17 (28.3)
10-year graft survivals were 100%, 96.5%, 94.5%, and 77.1% in the pregnant group versus 93.2%, 85.7%, 81%, and 64.7% in the control group, respectively (P ⫽ .07) (Fig 1). Obstetric Data
Live birth was the outcome in 43.2% of pregnancies; 9.5% led to still birth, 24.3% were aborted, and the obstetrical data of the remaining were not available (23%). Among the 11 patients pregnant within 12 months after transplantation, we observed 7 live births and 4 abortions. Also, of four pregnancies within 3 months, three were successful. None of the pregnancies accompanied by ARE were successful. Unfortunately, detailed data of pregnancies and obstetric results were not complete; the outcomes of 23% were not known. However, it is noteworthy that one patient had four pregnancies, all of which ended in abortion. But another patient had three consecutive successful pregnancies, resulting in three full-term, healthy children. DISCUSSION
The patients in our study had a relatively short interval between their transplantation and pregnancy. Many previous reports include longer intervals. Thompson et al7 for instance, reported a mean time of 6.5 years in 48 cases. They also showed that early pregnancies had a poorer prognosis.7 But we found that pregnancy in the first year
Table 1. Serum Creatinine Level Changes at the Beginning and End of Pregnancy Pregnancy
No increase ⬍1.5 1.5 to ⬍3 1.5 to ⬍3 Increase ⬍1.5 ⬍1.5 ⬍1.5 1.5 to ⬍3
End of pregnancy
Number of Patients (%)
⬍1.5 1.5 to ⬍3 ⬍1.5
51 (75) 2 (2.9) 1 (1.5)
1.5 to ⬍3 3 to ⬍4.5 ⱖ4.5 Dialysis
10 (14.7) 2 (2.9) 1 (1.5) 1 (1.5)
Fig 1. Graft survival curves of pregnant and control groups (Kaplan-meier).
3092
had no significant impact on child or graft outcome. Thus, it seems that recommending to delay pregnancy may be controversial. Almost all the studies on this matter have reported high incidences of abortions and stillbirths. Among 33 pregnancies in a study by Crowe et al,8 28 healthy births were seen, but other studies report 63% to 69% successful pregnancies.9,10 In our study, graft outcome was desirable in pregnant women, corresponding to relatively higher graft survivals and comparable rates of graft dysfunction and graft loss to a control group. However, the 1-year graft survival of 100% may be due to an inevitable bias that these patients were the ones who had a favorable health situation in the first year posttransplant to get pregnant. Overall, the high 5-year survival is in favor of the long-term safety of pregnancy in transplanted women. Many studies concur with our findings. Crowe observed 90% graft survival at 2 years postpartum.8 Sturgiss et al4 compared 17 pregnant cases with 17 transplanted controls. They reported a graft loss in one woman with a pregnancy history versus four controls. Plasma creatinine at the end of the follow-up period (1.40 ⫾ 0.52 mg/dL and 1.54 ⫾ 0.95 mg/dL, respectively) increased from 3 years earlier by 11% and 7%, respectively, which was not statistically significant.4 Accordingly, most authors believe that pregnancy does not adversely affect renal transplant function. However, a few studies have shown the opposite results: Thompson et al7 reported a permanent, significant decline in graft function in 20% of the cases by 6 months postdelivery.
POUR-REZA-GHOLI, NAFAR, FARROKHI ET AL
In summary, our findings indicate no long-term adverse effects of pregnancy on transplant recipients even when it occurs in the early posttransplant period. But, a simultaneous ARE leads to an unsuccessful pregnancy. Saving the infant and providing a healthy delivery requires an intense level of attention.6 REFERENCES 1. Murray JE, Reid DE, Harrison JH, et al: Successful pregnancies after human renal transplantation. N Engl J Med 269:341, 1963 2. Rudolph JE, Schweitzer RT, Bartus SA: Pregnancy in renal transplant patients. Transplantation 27:26, 1979 3. Mattix Kramer HJ, Tolkoff-Rubin NE, Williams WW, et al: Reproductive and contraceptive characteristics of premenopausal kidney transplant recipients. Prog Transplant 13:193, 2003 4. Sturgiss SN, Davison JM: Effect of pregnancy on the longterm function of renal allografts: an update. Am J Kidney Dis 26:54, 1995 5. Davison JM, Bailey DJ: Pregnancy following renal transplantation. J Obstet Gynaecol Res 29:227, 2003 6. Pezeshki M, Taherian AA, Gharavy M, et al: Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet 85:119, 2004 7. Thompson BC, Kingdon EJ, Tuck SM, et al: Pregnancy in renal transplant recipients: the Royal Free Hospital experience. QJM 96:837, 2003 8. Crowe AV, Rustom R, Gradden C, et al: Pregnancy does not adversely affect renal transplant function. QJM 92:631, 1999 9. Hooi LS, Rozina G, Shaariah MY, et al: Pregnancy in patients with renal transplants in Malaysia. Med J Malaysia 58:27, 2003 10. Tan PK, Tan AS, Tan HK, et al: Pregnancy after renal transplantation: experience in Singapore General Hospital. Ann Acad Med Singapore 31:285, 2002