Chronic renal failure can often lead to amenorrhea, and successful pregnancy is rare. After successful kidney transplantation (KTx), pregnancy is possible. There are several reports of pregnancies after KTx under cyclosporine, azathioprine, and steroids (1, 2). Although there are reports suggesting that tacrolimus is safer in pregnancy compared with cyclosporine after liver transplantation, in terms of less hypertension and toxemia of pregnancy (3, 4), very little data are available on pregnancy after KTx under tacrolimus-based immunosuppression (5, 6).
PATIENTS AND METHODS
All pregnancies between January 1993 to April 2002 under tacrolimus-based immunosuppression after KTx or simultaneous kidney-pancreas transplantation (SPKTx) were examined retrospectively. The course of pregnancy in the mother, changes in renal/pancreatic function and immunosuppression, gestational period, type of delivery, reason for caesarean section, birth weight, and presence of congenital anomalies were recorded. The birth-weight percentile for the gestational period was calculated using the Lubchenco et al. (7) chart. The survival of mothers and their allograft function were followed until December 2002.
Fifteen mothers (13 KTx and 2 SPKTx) delivered 22 babies (13 girls and 9 boys). One mother delivered three babies, and five mothers delivered twice. One mother (case 6) had an uneventful pregnancy course but delivered a stillborn baby at 32 weeks gestational period. This was thought to be related to an unrecognized amniotic fluid leak with a small ischemic placenta from renal impairment; however, 19 months later, she delivered a viable baby. Their primary diagnosis, interval to pregnancy from transplantation, gestational period, birth weight, birth-weight percentile for gestational period, along with the route of delivery, the reason for caesarean section, and the course of pregnancy are shown in Table 1. Two mothers received a living-related KTx, whereas the remaining 11 underwent cadaveric KTx. All mothers were on tacrolimus from the time of the KTx. Two patients (cases 4, 13) had more than one KTx before pregnancy. Two mothers (cases 7, 14) underwent SPKTx, and another mother (case 15) underwent combined retransplantation of the liver and kidney. Six mothers (cases 1, 4, 8, 9b, 11, 12) were on antihypertensive medications before pregnancy.
Allograft and Mother Survival
All 15 mothers survived the pregnancy and retained renal-allograft function during the pregnancy without requiring dialysis (all cases n=15). One mother (case 4), born with spina bifida, received her first KTx at the age of 14 years and her second KTx at 19 years of age. She delivered 50 months after the second KTx; 25 months after delivery (75 months after the second KTx), she lost the kidney to chronic rejection and returned to hemodialysis. She died 33 months later, after starting hemodialysis (58 months postdelivery and 97 months after the second KTx), of a cerebrovascular accident.
Course of Pregnancy after KTx
Three mothers (cases 3, 4, 14) developed toxemia of pregnancy. They presented with proteinuria and pedal edema in their third trimester. They all were managed medically. One of the mothers (case 11) also developed worsening hypertension with prolonged labor. She underwent caesarian section, whereas the other two delivered vaginally at 37, 27, and 37 weeks, respectively. One mother (case 5) was diagnosed with incontinence of the cervix during the first pregnancy. When she conceived a second time, at 19 weeks, she was managed by a cervical stitch with complete bed rest for 6 weeks, and labor was induced at the 25th week. Five more babies were delivered by caesarean section in 4 mothers (Table 1).
Course of Pregnancy after SPKTx
Two mothers (cases 7a, 7b, 14) delivered three babies. Mother 7 delivered twice. She developed pre-eclampsia during both pregnancies and presented with edema of the feet and proteinuria. She was managed medically, labor was induced, and the babies were delivered vaginally. Pancreatic function and renal function were well maintained during the entire pregnancy, and at last follow-up 62, 37, and 42 months postdelivery and 91 and 94 months postSPKTx.
Renal Function for All Mothers
Renal function in all 22 pregnancies during the entire period of pregnancy remained stable. There was an overall decrease in the serum creatinine from 1.38±0.47 prepregnancy to 1.19±0.47 in the first trimester, 1.13±0.44 in the second trimester, and 1.26±0.46 in the third trimester. Individual patients’ serum creatinine in each trimester and at last follow-up are shown in Table 2. Five mothers (cases 2, 6, 8, 10, 13) lost renal function 26, 60, 98, 71, and 20 months (mean 55.6±−32.4) postdelivery and 56, 132, 107, 112, and 90 (mean 99.4±28.5) months posttransplantation, respectively. The mean serum creatinine in these five mothers before pregnancy was 1.6±0.7 (median 1.6, range 0.9–2.8) mg/dL, whereas the mean serum creatinine in mothers who retained renal function was 1.25±0.3 (median 1.3 range 0.9–1.7) mg/dL.
The mean gestational period for all 22 deliveries was 34.4±5.1 (median 36.5, range 24–40) weeks. Nine (40.9%) babies were born with less than 36 weeks of gestational period, and five (23.8%) with less than 30 weeks (Table 1).
The mean birth weight for the 21 viable babies was 2,373±1,011 (median 2,386, range 540–4,261) g. Six (28.6%) babies were less than 2,000 g, and two (9.5%) were less than 1,000 g (Table 1).
Birth-Weight Percentile for the Gestational Period
The mean birth-weight percentile for the 21 viable newborns was 40±28 (median 34, range <10 to >90). Thirteen (61.9%) were below the 50th percentile for the given gestational period, six (28.6%) were below the 25th percentile, and five (23.8%) were below the 10th percentile. All 21 babies are alive and well at last follow-up.
Although there was a considerable decrease in tacrolimus trough levels, with the increase in body volume during the pregnancy, the dosage of tacrolimus was not increased. Acute rejection was not seen during pregnancy, and patients did not require any additional treatment.
Four mothers were on a small dose of prednisone at 2.5 to 7.5 mg per day. In most cases, it was reduced during the pregnancy. Three mothers (cases 7a, 7b, 14, 15), were on azathioprine, 75 to 100 mg per day, and it was continued during all three pregnancies.
Patient 12 was on mycophenolate mofetil before pregnancy; it was discontinued when the pregnancy was confirmed. Details of immunosuppression are shown in Table 3.
All viable babies were normal, and no congenital anomaly was detected in any of the babies. An autopsy was not performed on the stillborn baby; however, no external anomaly was observed.
In the past, we reported the largest single-center experience of pregnancy after liver transplantation under tacrolimus, with satisfactory outcomes, which has been confirmed by others (8, 9). Either small case studies or review articles are available on pregnancy after SPKTx (10, 11).
Excluding our brief citation on pregnancies in renal transplantation under tacrolimus (12), this is the first report on a large series of pregnancies under tacrolimus after KTx from a single center. Although all mothers survived and maintained allograft function, one baby was stillborn at 32 weeks gestation. She delivered a viable baby 19 months later.
There are several reports of successful pregnancies after KTx under azathioprine and cyclosporine (1, 2). Preterm delivery and premature delivery with low birth weight and intrauterine growth retardation have been the common problems in immunosuppressed mothers. A pre-eclampsia rate of approximately 30% has been reported under cyclosporine for KTx patients. In the present series, the pre-eclampsia rate was 13.6% for the KTx patients. In the three SPKTx pregnancies, one mother experienced pre-eclampsia during both pregnancies, whereas the other mother did not. Rejection during pregnancy is a rare phenomenon under cyclosporine, but postpartum rejection and deterioration in renal function has been observed. In this series with tacrolimus, we did not observe any episode of rejection during pregnancy, although there was a reduction in prednisone dosage and a decrease in the tacrolimus concentration by nearly 32%.
There was no increase in serum creatinine during the pregnancy. However, five (38%) mothers lost renal-allograft function 20 to 98 months postdelivery and 56 to 132 months posttransplantation. The impact of pregnancy on graft loss is difficult to evaluate, but the high rate of graft loss is clearly of concern. This observation is also different than what is observed in pregnancies after liver transplantation under tacrolimus (10, 11).
Pregnancy after SPKTx has been previously reported. In this series, there were three deliveries in two mothers; one mother delivered twice and experienced pre-eclampsia on both occasions. She was managed medically and delivered successfully. Both mothers maintained pancreatic and renal function 42 to 62 months after the first delivery.
Pregnancy after KTx and SPKTx under tacrolimus-based immunosuppression has the same problems of prematurity, preterm delivery with low birth weight, and intrauterine growth retardation that have been observed with pregnancy after transplantation with other immunosuppressive agents. Although impaired renal function at the time of pregnancy should be considered an important risk factor, toxemia of pregnancy, deterioration of allograft function, or rejection were relatively rare during pregnancy.
The authors thank Judy Canelos, MA, for her help with typing and editing.
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