Introduction

The transplanted kidney of renal transplant recipients, which is located in the iliac fossa, requires the long-term use of immunosuppressants after surgery. This has a significant impact on the health and general physiological functioning of the patient, and may result in latent medical problems. As a result, women who have undergone a renal transplant have an increased risk of complications of pregnancy. Understanding these risks and identifying the optimal timing and conditions of conception and pregnancy will enable us to provide guidelines for these patients that may reduce the incidence of neonatal and infant disorders and chronic transplant rejection. To explore this issue, we randomly selected a cohort of 25 female renal transplant recipients who had given birth between August 1989 and August 2008. In this cohort from eight organ transplantation centers in China, there were 38 conceptions and 25 live births.

Patients and Methods

Patient Characteristics

Patients were selected from the following eight centers of organ transplantation in China: Hangzhou Jiulisong Hospital, The Second Affiliated Hospital of Shandong University, The First Affiliated Hospital of Wenzhou Medical College, Shanghai Changzheng Hospital, The First Affiliated People’s Hospital of Shanghai Jiaotong University, The Affiliated Renji Hospital of Medical College of Shanghai Jiaotong University, Zhengzhou 153 Central Hospital, and Wuhan General Hospital. Between July 1977 and December 2007, a total of 10,648 patients with uremia received renal transplantation. Of these patients, we randomly selected a cohort of 25 female renal transplant recipients who had given birth post transplant between August 1989 and August 2008. All the 25 patients had undergone renal transplantation for the first time. The primary disease in all the 25 patients was chronic glomerulonephritis; the duration of the disease ranged from 1 to 84 (27.45 ± 22.95) months. All the patients had received therapeutic maintenance hemodialysis, with a duration of 3–68 (15.76 ± 11.85) months before undergoing renal transplantation.

Use of Immunosuppressants

During the period from conception to childbirth, the immunosuppressants administered to the renal transplant recipients and their doses were as follows: cyclosporin A (CsA), 1.2–3.0 mg/kg/d; tacrolimus (FK506), 0.03–0.1 mg/kg/d; azathioprine (Aza), 50–75 mg/d; prednisone (Pred), 5–10 mg/d; and mycophenolate mofetil (MMF), 1.0–1.5 g/d. Of the 25 female recipients, 20 used CsA + Aza + Pred, three used CsA + MMF + Pred, and two used FK506 + MMF + Pred. (From 2–6 months before conception to 3 months after gestation, MMF was replaced with Aza.)

Methods

A unified standard was employed to acquire and classify the correlated data of recipients and their children conceived and born after renal transplantation. This included the following items: age, pathogenesis, renal transplant time, post-operative conception status, timing of conception, spontaneous abortion, fetal development, rate of premature delivery, infant feeding pattern, effect of pregnancy on transplanted renal function, and immunosuppressants used. This study was approved by the ethics committee of our hospital.

Statistical Analysis

All the data were confirmed for accuracy before they were entered into a computer database. Statistical analyses were performed with the Statistical Package for Social Sciences (SPSS) 11.0 software (SPSS Inc., Chicago, USA). All results are expressed as mean ± standard error of mean (SEM).

Results

A total of 38 conceptions occurring 5–72 months after transplantation were detected in the 25 renal transplant recipients. Of these 38 conceptions, there were six artificial abortions, including two abortions due to patients’ desire, one abortion due to recent transplant surgery, one abortion due to pulmonary infection, and one abortion due to hypertension. Four of these abortions were subsequent to conceptions less than 24 months after transplantation (Table 1). Vacuum aspiration was performed at days 53–68 (59.00 ± 5.18 [means ± SD]) of pregnancy. The artificial abortion recipients were 22–32 (27.00 ± 4.00) years old. There were seven spontaneous abortions, four of which occurred in patients who conceived less than 24 months post-transplantation (Table 1). For the 25 successful pregnancies, which all lead to single births, the duration from the time of renal transplantation to conception ranged from 23 to 72 (35.16 ± 12.34) months, and the mother’s age at conception was from 23 to 33 (27.40 ± 2.86) years. Of the 25 infants born, 10 were male and 15 were female. Of these 25 births, 23 were by cesarean delivery. The primary reasons for cesarean delivery were as follows: six cases of gestational hypertension consisting of three cases of moderate gestational hypertension (Grade II, systolic pressure of 160–179 mm Hg, diastolic pressure of 100–109 mm Hg), and three cases of severe gestational hypertension (Grade III, systolic pressure ≥180 mm Hg; diastolic pressure ≥110 mm Hg), six cases of recipients with compression or functional lesion of the transplanted kidney, and six cases due to other factors (Table 2). The other two births were by spontaneous vaginal delivery. No developmental delay of neonates was found, and the birth weight of the neonates was from 1,920 to 3,840 g (2,940 ± 590). Seven infants were born prematurely (28%), because of the following: three cases with compression or functional lesion of the transplanted kidney, two cases with gestational hypertension, one case with pregnancy complicating heart failure, and one case with fetal distress in utero. The other 18 were term births. All infants received artificial (formula) feedings; none was breast fed. The growth and development of all the infants were normal, with no abnormalities noted. The renal function and urine output of all the 25 female renal transplant recipients were normal before conception. Four patients developed slight hypertension, which was managed by medication. However, during pregnancy, six patients developed impairment of renal function (Blood Cr 183–358 μmol/l), six had urinary tract infections, five developed proteinuria, nine cases displayed moderate or severe hypertension, four cases displayed pulmonary infection, and four cases displayed heart failure. At 1–41 months after giving birth, six patients had to return to hemodialysis therapy due to chronic renal transplant rejection.

Table 1 Rates of spontaneous and artificial abortion following post-transplant conceptions
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Table 2 Factors leading to cesarean deliveries in 23 patients
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Discussion

Effect of Renal Transplantation on Conception

Endocrine function, ovulation, and menstruation gradually normalized subsequent to renal transplantation, along with the recovery of transplanted renal function. Most of the recipients recovered reproductive function soon after renal transplantation [1]. However, many female renal transplant recipients were unaware of the potential fertility effects of renal transplantation and did not use any contraception. The 25 female renal transplant recipients had 38 conceptions after transplantation. We surveyed 647 cases of female renal transplant recipients of reproductive age and found 133 unplanned pregnancies in 98 cases following renal transplantation (reported elsewhere). This suggests that the patients had little difficulty conceiving after renal transplantation. Unexpected conception following transplantation might convey unintended risks to both mother and infants [1]. These risks include preeclampsia, premature delivery, and probability of low-birth weight as well as augmentation of risk of cesarean delivery. It is suggested that these women be provided with contraceptive consultation [2], so that organ transplant recipients not intending pregnancy adopt effective contraceptive measures [3].

Effect of Post-operative Pregnancy on Delivery

Transplanted kidneys were located in the iliac fossa, preventing the obstruction and mechanical injury of the birth canal. However, long-term renal failure, long-term dialysis before renal transplantation, pelvic osteodystrophy induced by long-term corticosteroid use, or uterine changes induced by pregnancy might produce compression leading to impaired renal function. Some female recipients displayed severe pregnancy-induced hypertension syndrome and fetal dystrophy in utero during pregnancy, increasing the proportion of cesarean deliveries. Ghafari et al. [4] reported 24 cesarean deliveries (45.2%) in 61 pregnancies from 53 renal transplant patients. Areia et al. [5] retrospectively studied 34 pregnancies in 28 renal transplant patients between January 1989 and January 2007 and found that 65.5% of deliveries were by cesarean. Likewise, in the current study, 23 of 25 deliveries were by cesarean, which accounts for 92.0% of all patients. The primary cause of the high ratio of cesarean delivery were as follows: six cases of gestational hypertension, six cases of compression or functional lesion of the transplanted kidney, five cases where vaginal birth was considered to pose too high a risk to the fetus, two cases of maternal age being greater than 30, and two cases where cesarean was required to reduce risk to the mother. Cesarean deliveries were primarily due to obstetric conditions. If no obstetric cesarean delivery indications existed, then vaginal delivery was suggested.

Effect of Post-operative Pregnancy on Prematurity

The rate of premature births in the normal population is from 5 to 7% in China, which is comparable to the US single birth prematurity rate of 5.4% [6]. However, the rate of premature births is significantly higher in renal transplant recipients. Oliveira et al. [7] reported a rate of premature births of 38.4% (20/52 cases) in a total of 52 cases. Romero Arauz et al. [8] and Sibanda et al. [9] also reported that half of the renal transplant recipients had premature labor. Areia [5] reported that the prematurity rate was as high as 59.3%. In this study, the rate of premature births in female kidney transplant recipients was 28%. Such a high rate of premature birth may be associated with the long-term post-operative use of immunosuppressants. Previous studies reported that corticosteroids can weaken the membranes of connective tissue, and premature rupture of membranes is prone to occur during mid- and late gestational period, which induces abortion or premature delivery [10]. In addition, it may also correlate with severe PIH syndrome appearing in late pregnancy in renal transplant recipients, fetal distress, and post-operative impairment of kidney function. Such complications may be indications for pre-term delivery by cesarean.

Effect of Post-operative Pregnancy on Transplanted Renal Function

Currently, it is still unclear whether there are adverse effects on the transplanted kidney during pregnancy in renal transplant recipients. Kashanizadeh et al. [11] reviewed reports between 1996 and 2002, dividing the female transplant recipients of child-bearing age into two groups (conception or non-conception) with a follow-up between 45.4 ± 22.0 months and 46.3 ± 19.8 months. Their results indicated that there was no significant difference in the 5-year survival rate between the two groups. First et al. [12] studied the data of 25 total conceptions among 18 female renal transplant recipients, and their results indicated that post-operative pregnancy showed no significant effect on transplanted renal function. Gorgulu et al. [13] analyzed the data of 22 conceptions among 19 female renal transplant recipients, and argued that function and survival of the transplant would not be affected by reproduction. Nevertheless, it has been shown that the increased size of the uterus during pregnancy might cause compression on the transplanted kidney; the hemodynamics of female renal transplant recipients changed after conception; the glomerular filtration rate (GFR) was increased; and the augmentation was correlated with the baseline level of GFR [14]. Salmela et al. [15] reported that among 22 renal transplant recipients (29 conceptions), the 10-year survival of the transplanted kidney was only 69%, while the control group kidney survival was 100%, suggesting that conception and pregnancy had an adverse effect on the transplanted kidney. Some risk factors during the gestational period could induce rejection and subsequent impaired renal function, significantly increasing the risk of incapacitating the transplanted kidney [9]. In our study, we found that the renal function of the 25 female renal transplant recipients was normal before conception, but six had to return to hemodialysis therapy from 1 to 41 months after conception because of the impaired function of the transplanted kidney during the gestational period. Our data suggested that post-operative pregnancy in female renal transplant recipients might sometimes affect transplanted renal function.

Effect of Post-operative Pregnancy on Maternal Health

The incidence of hypertension, preeclampsia, infection, and cesarean delivery significantly increased upon long-term use of immunosuppressants. Oliveira et al. [7] reported 52 pregnancies (2 cases were twin pregnancy), and found hypertension complications in 33 patients (63.5%), anemia in 31 patients (59.6%), urinary tract infection in 22 patients (42.3%), diabetes in four patients (7.7%), and apparent premature rupture of membranes in four patients (7.7%). Many of the complications of pregnancy appeared to occur in the antepartum and perinatal periods. In this case where 25 cases of patients were reported, nine patients (36.0%) had moderate or severe hypertension, six patients (24.0%) had urinary tract infections, five patients (20.0%) had proteinuria, and four patients (16.0%) had pulmonary infection and heart failure complications. The results of this study suggested that post-operative pregnancy of female renal transplant recipients sometimes affected maternal health.

Effect of Post-operative Pregnancy on Breast Feeding for Infants

Breast milk is the best natural food for infants, and it has been shown that infants who received breast feeding instead of artificial feeding had increased body weight, body length, and development of motor skills and language. Renal transplant recipients need to undergo long-term immunosuppressive therapy, and it is currently presumed that immunosuppressants can affect infants through breast milk. However, the reports on the concentration of immunosuppressants in breast milk are not all in agreement. Some reported that the concentration was undetectable, and others reported that the concentration was similar to that in the mother. The American Academy of Pediatrics (AAP) supports breast feeding by mothers who have taken Prednisone, but not by those who have taken CsA [16]. Further investigation is needed to compare the possible negative effects of immunosuppressants on offspring with the advantages of breast feeding, to determine whether breast feeding or formula feeding is more beneficial for these children [17]. In this study, we have reported on a total of 25 infants who received artificial feeding without any breast feeding, and no significant effects on the growth and development of the children were shown.

Timing and Conditions of Post-operative Conception and Pregnancy

Currently, there is no definite conclusion on when female renal transplant recipients can safely go through pregnancy after renal transplantation. However, previous studies have reported that recipients generally conceived from the third to the fourth year of normal renal function after renal transplantation [18, 19]. Early pregnancy could lead to impairment of the kidney, transplant rejection, unsuccessful pregnancy, and other maternal risks. In this study, one of the 25 patients studied conceived in the fifth month postoperatively and had a spontaneous abortion, conceived a second time, and had an artificial abortion due to pulmonary infection in the 13th month postoperatively, but conceived again at 33 months postoperatively and had a successful pregnancy with a female baby. The duration from the time of renal transplantation to conception of successful pregnancies ranged from 23 to 72 (35.16 ± 12.34) months in this study, and the growth and development of all the children were normal. It is important to note that a reasonable immunosuppressive therapy be formulated, which will not only protect transplanted renal function and allow for the good health and survival of recipients, but will also ensure the successful conception and normal growth of the fetus. From the references and data from the centers of organ transplantation, we consider the suitable timing and conditions for the post-transplant conception and pregnancy by female renal transplant recipients to be as follows:

  1. (1)

    Patients’ health is generally adequate for the requirements of pregnancy 2 years after successful renal transplantation.

  2. (2)

    Immunosuppression should be maintained with the following medications: Pred 10 mg/d, Aza 50 mg/d and CsA at a dose less than 3.0 mg/kg/d, with a contraindication for the use of mycophenolate mofetil and sirolimus (Discontinue mycophenolate mofetil and sirolimus 6 weeks before conception.)

  3. (3)

    Maternal age should be less than 30 years.

  4. (4)

    The patient should be in excellent general health, with no renal rejection.

  5. (5)

    Hepatic and renal function should be basically normal, with concentration of serum creatinine less than 133 μmol/l (1.5 mg/dl).

  6. (6)

    Patients should not be hypertensive. Slight hypertension (blood pressure ≤140/90 mm Hg) that can be managed by medication is acceptable.

  7. (7)

    Patients should not have hematuria or proteinuria.

  8. (8)

    Prenatal check-ups should receive special attention after conception to ensure a healthy pregnancy and medical follow-up.

In conclusion, this study found that female renal transplant recipients were able to conceive and to have successful pregnancies after their renal transplantation, but occasionally with some adverse effect on the transplanted kidney. We found no evident negative effect on the growth and development of their infants. There is always a possibility that pregnancy could lead to failure of the transplanted kidney or even threaten the patient’s life. Therefore, post-operative conception and pregnancy should be approached cautiously for female renal transplant recipients, with a comprehensive evaluation being undertaken for each patient. Moreover, obstetricians, transplant physicians, and cardiologists need to coordinate care and co-monitor these patients to assure the health of the transplanted kidney, the patients themselves, and their infants.