Because of the effect of end-stage renal disease on the hypothalamic pituitary gonadal axis, a significant proportion of patients with end-stage renal disease develop anovulation, irregular cycles and low chances of conception 1. Pregnancy in addition to chronic renal disease carries a higher risk of complications and morbidity, particularly when serum creatinine level is more than 2.5 mg/dl, with chances of premature birth exceeding 70% and a 40% risk of preeclampsia 2. Renal transplantation is associated with return of menstruation and potential fertility; however, these patients require a multidisciplinary approach with transplant nephrologists and maternal foetal medicine experts to optimize the outcome, which is usually favourable, but careful counselling on morbidity is essential 3. Renal transplant patients who are on constant immunosuppressive medications have a 35-fold higher risk of developing malignancies with loss of immune surveillance; of these, 9% are gynaecologic carcinomas and the risk of development of squamous cell carcinoma of the cervix is increased by a factor of 13, necessitating close cytological surveillance every 4–6 months 4. The sexual dysfunction that is common in patients with end-stage renal disease is improved following transplantation, necessitating careful contraception in these patients 4.
Pregnancy following renal transplantation does not seem to increase the risk of graft rejection, with rejection rates similar to those of other transplant populations, particularly with good renal functions evidenced by creatinine levels less than 1.5 mg/dl 5. The mortality in transplant patients following pregnancy was reported to be 10% after 7 years and reaching up to 50% within 15 years because of immune suppression and their underlying disease state, which highlights the importance of careful counselling of these patients 6. Two prognostic factors were shown to mostly affect the outcome of these patients, namely, the interval from transplantation to pregnancy of around 2 years and stable renal functions as shown by serum creatinine levels of less than 2 mg/dl 7. In contrast, the presence of arterial hypertension, suboptimal renal functions, high doses of immunosuppressants and the higher incidence of viral infections would lead the patients to further delay pregnancy for 1 year following transplantation 8. Also, it would seem more reasonable to delay pregnancy for at least 6 months following the start of immunosuppression despite the lack of consensus on its impact on early foetal development 9. Most specialized centres for renal transplantation use a combination of corticosteroid such as prednisone with an antimetabolite such as azathioprine or mycophenolate and/or a calcineurin inhibitor such as tacrolimus or cyclosporine 3.
A calcium supplement is needed to improve the bone mineral density loss that occurs secondary to the use of corticosteroids, but the use of bisphosphonates or calcitriol did not show additional benefit to the use of calcium alone 10. The use of cyclosporine in renal transplant patients is associated with intrauterine growth retardation; a clear distinction of whether this is because of the drug or the underlying medical condition of the patient is difficult to ascertain. Its use is not associated with an increased risk for foetal malformations, but it causes mild renal dysfunction and is associated with a higher incidence of preeclampsia than tacrolimus 11. The doses of cyclosporine required were increased by about a quarter particularly during the second and third trimester, necessitating close surveillance of the drug serum levels 12. Part of the maternal complications of cyclosporine is the increased risk of developing obstetric cholestasis secondary to inhibition of bile salt excretion pump function by the drug, necessitating close monitoring from the second trimester onwards 13. In terms of its effect on the foetus secondary to exposure during pregnancy, cyclosporine inhibits T cell, B cell, and natural killer cell function in the infant. These implications are still evident until 1 year following birth, suggesting delay in conventional vaccination 14. In a cohort of 175 children born to renal transplant patients who received cyclosporine during pregnancy and were followed beyond 4 years postnatally, under 2% of those children were found to have major disabilities and 16% had developmental delay 15. There are some sporadic reports on the impact of azathioprine on the foetus including hypospadias, preaxial polydactyly, isolated foetal immune deficiency and structural malformation. Despite this and being labelled as a category D drug, it is still frequently used as part of immunosuppressive regimens 16.
The impact of pregnancy on graft loss was shown in the results of the US National Transplantation Registry, which reported an incidence of 2% biopsy-proven acute graft rejection for patients on cyclosporine and 5% for patients on tacrolimus. There was also a high prevalence of 2-year postpregnancy graft loss of up to 17% 17. Preterm delivery is common in renal transplant patients, occurring both spontaneously and because of higher incidences of complications resulting in iatrogenic delivery. Vaginal delivery can be attempted in these patients and elective caesarean section is performed only for obstetric indications. Care should be exercised to avoid injury to the graft at the time of surgery as it is in the pelvic cavity 3. Breast feeding was abandoned in all these patients as the drugs cross the mother’s milk causing marked depression of the immune system in the neonates 18.
The study aimed to understand the impact of renal transplantation and immunosuppressive medications both on the mother and on the foetus to determine the complications in these patients by comparing them with healthy pregnant controls.
Patients and methods
The study compared two groups of patients; each group included 20 cases. The patients in the study group became pregnant following renal transplantation and the control group included 20 normal healthy cases; this study aimed to determine the outcome of pregnancy, including maternal and foetal complications. In the study group, we assessed the history sheets including maternal age, transplant to conception interval, gestational age and mode of delivery and birth weight. Types and levels of immunosuppressant drugs were noted. In addition, we determined the complications encountered in pregnancy such as miscarriage, premature birth, hypertension, preeclampsia, anaemia and urinary tract infection. The cases were recruited from the following units: the Maternity and Nephrology Department at Cairo University, the El Matarya National Institute for Renal Disease, the Renal Center El-Mansoura University, the Medical Insurance Hospital and the Arab Contractor Medical Center. The cases were recruited from August 2008 until November 2009.
Local ethical committee approval was obtained before the study.
Data management and analysis were carried out using the SigmaStat Program (version 3.5; Systat Software, Inc., San Jose, California, USA). Graphs were drawn using Microsoft Excel (Microsoft, Remington, Washington, USA). Data were statistically described as range, mean±SD and median. Categorical data were summarized as percentages. Comparisons between categorical variables were made using the χ2-test. All P-values were considered significant when P-values were less than 0.05.
The descriptive data of the study and the control group are shown in Table 1.
The mean age of the patients was not statistically different between the two groups, but there was a significant difference in the birth weight and gestational age at delivery.
The causes of renal failure in the study group are shown in Table 2.
As noted from the above results in Table 2, the most common cause was previous preeclampsia, followed by hypertension and glomerulonephritis.
In the study group, 70% of patients were nulliparous compared with 45% in the control group.
In terms of the type of immunosuppressants used, 95% of the study cases (19 cases) used a combination of three medications, namely, cyclosporine+steroids+azathioprine, and 5% (one case) used azathioprine and steroids alone.
The dose and blood levels of cyclosporine in the study group are shown in Table 3.
The results comparing the complications occurring in pregnancy between the study and the control group are summarized in the Table 4.
In the study group, 80% of the patients delivered by caesarean section compared with 20% in the control group. In addition, there was one case of still birth in the study group and none in the control group. In both groups, there was one case of spontaneous miscarriage in the first trimester.
The haemoglobin concentration throughout pregnancy was not statistically different before pregnancy, but a significant difference was found, with greater incidence of anaemia noted during pregnancy in the study group as shown in Table 5.
The serum creatinine levels were not significantly different before pregnancy between the study and the control group, but showed a significant difference particularly in the first and second trimesters; these results are summarized in Table 6.
In our study, the mean interval between transplantation and conception was 42.8±31.95 months and 45% of the study group became pregnant 2–5 years after transplantation following the guidelines of Chu et al. 7, who reported that the most important factor affecting the outcome was an adequate interval of about 2 years between transplantation and conception. In our study, only three (15%) patients conceived in the first year following transplantation; these patients had good outcomes, which may be because of the fact that they had good and stable renal functions with no hypertension or rejection episodes. This is in agreement with the data of Armenti et al. 19, who showed that transplantation to conception intervals of less than 1 year were not associated with adverse outcome compared with longer intervals. In our study, five (25%) patients conceived more than 5 years following transplantation, which is not usually recommended as too long an interval may lead to an unfavourable outcome because of increased maternal age and affection of transplant graft function over time 19.
In our study, all patients had a mean serum creatinine before pregnancy of 0.82±0.13 mg/dl, with a good postnatal value of 1.09±0.23 mg/dl, associated with a good outcome; this is in agreement with the results of Thompson et al. 20, which showed that pregnancy does not have a significant effect on long-term graft function in patients with serum creatinine level less than 1.5 mg/dl.
The data of our study are consistent with previous studies reporting that pregnancy does not have an adverse effect on graft survival and function as reported by the majority of authors such as Yildirim and Uslu 21, who found no significant modifications in blood creatinine levels during pregnancy.
In our study, most (95%) of our patients were placed on a combination of immunosuppressants that included (cyclosporine+steroids+azathioprine), which is in conformity with other centres that use a combination of corticosteroid such as prednisone with an antimetabolite such as azathioprine or mycophenolate and/or a calcineurin inhibitor such as tacrolimus or cyclosporine 3. The cyclosporine levels were monitored closely during pregnancy in our patients as there is an increase in the requirements particularly during the second and third trimesters 12.
In our study, 65% of transplant patients developed anaemia versus 36% in the control patients, which is in agreement with the results of Yassaee and Moshiri 22, who reported similar results; however, the reason why anaemia developed was not clear and it seemed to be more complicated than simple iron deficiency.
In our study, the mean gestational age at birth was 35.89±2.45 weeks, whereas in the control group, it was 38.21±1.72 weeks; this is in agreement with the reports from Sibanda et al. 23. They reported that most US and UK transplant registries reported a mean gestational age at delivery of ∼36 weeks, with more than 50% delivering at less than 37 weeks 23. In our study, 20% of our study group developed premature rupture of membranes versus 5.3% in the control group. This was shown previously by Davidson 24, who reported that researchers have reported an increased incidence of premature rupture of membranes in transplant women because of the long-term use of steroids, which is postulated to weaken amniotic membrane integrity.
In our work, the mean birth weight in the transplant group was 2657±417 g compared with a birth weight of 3394±327 g in the control group; this is usually a result of delivery of more preterm infants, and it was also reported that these patients are at a higher risk of delivering small for gestational age babies. In addition, there was a 5% incidence of intrauterine foetal death, which is in agreement with other reports of around a 3% risk of intrauterine foetal death in transplant patients 6.
We did not encounter cases of major congenital anomalies in our study group, which is in agreement with other studies reporting a 2% risk of foetal anomalies in transplant patients on a combination of immunosuppressive therapy, which is more or less similar to the background population 15.
In our study group, 80% of patients underwent caesarean delivery; all were lower segment, with no reported complications. This is slightly higher, but still similar to the results of the reports of Ducarme et al. 25, who reported a 64% rate of caesarean delivery in transplant patients, indicating the high degree of clinical caution exercised in these patients and higher rate of maternal complications.
Breast feeding was abandoned in all patients of the study group because of the potential impact of immunosuppressive drugs on neonates until further research confirms its safety.
Renal transplantation has provided women of childbearing age with return of fertility and the possibility of a successful pregnancy outcome. Several prognostic factors should be considered to help counsel the patients carefully on the impact of pregnancy and the use of medications on the mother and foetus. Those patients should receive careful monitoring with a multidisciplinary team of maternal, foetal medicine specialists in addition to a transplant physician.
Conflicts of interest
There are no conflicts of interest.
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