INTRODUCTION
In the first ages of renal transplantation pregnancy was contraindicated, however the first offspring of a renal transplanted woman was born 48 years ago1 and since then the concepts have progressively changed, so that nowadays it is considered that pregnancy is just another positive aspect of kidney transplant; there are still several concerns about its effects on the mother and the fetus.2 The patients with advanced chronic renal disease present hypothalamic-gonadal dysfunction leading to infertility in virtually all cases; however, 6 months after the transplant this gonadal dysfunction disappears giving rise to the possibility of conception.
The most accurate data have been obtained from three specific registers on pregnancy and transplantation (the European, the American, and the British)3-5 reporting on the peculiarities that pregnancy entails for kidney-transplanted patients. The most relevant data show that 24%-34% of them present a therapeutic or spontaneous miscarriage, the prevalence of AHT is high, preeclampsia is increased, and in more than 50% of the cases prematurity and low birth weight will occur.
MATERIAL AND METHODS
An observational prospective study was carried out analyzing 10 kidney-transplanted patients that got pregnant, with a mean age of 28.9 years (18-36). The average post-transplantation time was 44 months (12-113). The mean glomerular filtration rate estimated by the MDRD equation was 64 mL/min (49-82), and the immunosuppressive therapy that was given to all patients was prednisone 5 mg/day and tacrolimus (variable dosing to achieve plasma levels of 6-8 ng/mL).
We assessed different variables related with the renal graft, during both the pregnancy months and after the delivery (renal function, proteinuria, blood pressure, tacrolimus doses and levels), as well as other variables related with the delivery and the neonate.
The results are expressed as means, with the minimal and maximal values between brackets.
RESULTS
After revising the course during gestation and the months after, we observed that pregnancy was completed in nine patients and there was one spontaneous miscarriage during the first trimester. The delivery was through natural way in 6 cases and a cesarean section was needed in 3 patients.
The analysis of the blood pressure revealed an increase towards the end of the pregnancy, of both the systolic BP and diastolic BP (table I). Only one patient was on hypotensive therapy before the pregnancy (amlodipine), which was maintained through it, adding alpha-metildopa during the third trimester. The remaining patients were not on anti-hypertensive therapy before the pregnancy and it was necessary to prescribe alpha-metildopa in one patient during the third trimester, requiring an emergency cesarean section due to preeclampsia.
Table I shows the renal function monitoring, which remained stable during the pregnancy, and proteinuria, which slightly increased during the third trimester. This table also shows that the dose of tacrolimus had to be increased to achieve the target plasma levels. There was no case of acute rejection and there was only one case of preeclampsia that was resolved with the cesarean section.
The delivery occurred at 37.2 (34-40) weeks, and the newborns weighed 2,809 (2,040-3,760) grams, with two newborns affected of prematurity-low birth weight. However, none of these neonates had remarkable complications.
DISCUSSION
Our experience on the follow-up of post-transplantation pregnancy using prednisone and tacrolimus is satisfactory since there have not been any complications, either in the mother or the fetus. This is likely due to the fact that the patients met the recommendations set forth by both the «Report on the AST Consensus Conference on Reproductive Issues and Transplantation»6 and the European Guidelines7 for considering a pregnancy after renal transplantation (table II).
When analyzing the different published reviews of kidneytransplanted patients, we observed that high blood pressure is prevalent among patients on calcineurin antagonists, varying 47%-73% according to the different registers.8-11 In our study, we observed an increase in both systolic and diastolic blood pressure. Preeclampsia occurs in 30% of pregnant transplanted patients,11, 12 being a difficult diagnosis since blood pressure tends to increase after week 20, and many patients already have mild proteinuria before the pregnancy, in addition to increased uric acid levels. Arterial hypertension may explain, at least in part, the fact that more than half of the pregnancies end up before the due date. The management of AHT has to be aggressive13 and metildopa, labetalol, and calcium-hannel blockers may be safely used.14 Angiotensin-renin system inhibitors are formally contraindicated after the first trimester of pregnancy and, id possible, they should be discontinued before conception. Since the effective plasma volume is decreased during the pregnancy, diuretics are not recommended either, with the exception of thiazides if the patient was taking them before.
When analyzing the renal function, we may highlight that in those patients with pre-existent renal dysfunction (creatinine > 1.5 mg% - > 133 μmol/L) the risk for graft loss is increased, during both the pregnancy and after it, so that pregnancy is not recommended in patients with values higher than these. Although a study15 published in 1993 reported that the graft survival at 10 years was lower in patients that had got pregnant, as compared with those that had not, recent publications16,17 show that the survival rates for the graft and the patient after 15 years of follow-up are the same in transplanted patients that got pregnant after the transplant and in those that did not. Graft dysfunction may be difficult to detect during the pregnancy given that usually creatinine levels go down during gestation, particularly during the first and second trimesters, as is observed in our sample; sometimes rejection only manifests as mild increases of plasma creatinine levels. If rejection presents, it usually responds to methylprednisolone. The safety of anti-lymphocytic globulins and rituximab is unknown.
Adequate immunosuppression levels are necessary during the pregnancy. As observed in our analysis, the plasma levels of calcineurin antagonists may vary since during gestation there are changes in the distribution volume and the extracellular volume.7, 18 However, most of the studies published have not recorded these levels. In our study, after analyzing the levels of tacrolimus, we observed that the doses must be increased in order to reach the target range, which is in agreement with those works monitoring this treatment.19 On the other hand, in a study carried out in 21 patients without modifying the dose of tacrolimus, no episodes of acute rejection were observed.20
According to the published guidelines, although gestation in a kidney-transplanted patient should be considered a highrisk pregnancy, the cesarean section would only be indicated for obstetric reasons; however, although in our series this occurred in 33% of the patients, other series have reported to occur in 50% of the deliveries.
The final outcome of only 10% of miscarriages in our series differs from the data obtained when reviewing the European, American, and British registers,3-5 in which spontaneous or therapeutic abortion occurs in 24-34% of pregnant women.
In our experience, only two patients had non-complicated urinary tract infection. The pregnancy in the kidney-transplanted patient increases the risk for infection, especially bacterial infections. About 40% of pregnant women have urinary infection, particularly in patients with chronic pyelonephritis or vesicouretheral reflux as the primary cause of renal disease (a criterion that was met by our two patients). For this reason, it is recommended to perform a sediment analysis and urine culture monthly, and if asymptomatic bacteriuria is present to treat with antibiotics for two weeks and then administering them prophylactically until delivery.7
When analyzing the fetal complications, we may highlight that the risk for prematurity and low birth weight is higher than 50%, and that for delayed intrauterine growth higher than 20% according to the different series,4, 21 the percentage in our modest sample being of 22%.
All immunosuppressants go through the placental barrier, so that the fetus is exposed to the toxicity of the different drugs. With prednisone, 90% of the dose administered is metabolized at the placenta before reaching the fetus; however, there have been cases reported of adrenal suppression in the fetus. With calcineurin-antagonists, plasma levels have been detected in the fetus, although at a concentration lower than in the mother.22 The potential adverse effects may vary from major malformations to neurocognitive defects that may be only detected after birth. According to the European Guidelines, if the immunosuppressive therapy is based on calcineurin antagonists, with or without steroids or azathioprine, the patient may continue with the same treatment throughout the pregnancy. Other drugs, such as mycofenolate mofetil or mTOR inhibitors are not recommended.7
We did not observe any malformation in the newborns. According to the American Register, the prevalence of structural malformations is 4-5%, very similar to the figure of 3% in the series of pregnancies in the general population.4, 23 However, although a particular pattern of malformation has not been shown to be associated with prednisone, azathioprine or calcineurin antagonists, some malformations have been related with the administration of mycofenolate mofetil, so that it is recommended to discontinue this drug before conception. 24 The long-term effects from the exposure to immunosuppressants during the pregnancy are unknown. In a study carried out on 48 children followed for an average time of 5.2 years,25 no structural or developmental abnormalities were observed, although in this series the prematurity rate was 56%. In the American Register,4 four percent of the newborns from a cohort of 164 patients transplanted with different solid organs had some structural abnormality, although long-term followup of these children is not available. In another study on 175 children exposed to cyclosporin during gestation,26 71 attended the primary school (5-12 years) and 24% of them had delayed mental development. Although not conclusive, these data do indicate that it seems necessary that these children have a long-term neurocognitive follow-up. It is likely that the data from the registers underestimate complications such as delayed fetal development, preeclampsia, and premature births, all of them risk factors for neurocognitive impairment.
Although our experience with only 10 cases has been satisfactory, we may comment on two final issues. In the first place, many kidney-transplanted patients are not receiving the same immunosuppressive regimen as ours, either because of early withdrawal of steroids, or because of the combination with mycofenolate mofetil or switch from calcineurin antagonists to an mTOR inhibitor. Since there are no safety data with these regimens, they should be modified before the pregnancy, taking into account the risks that this modification may represent. On the other hand, the information should be exact and individualized to each patient, explaining in detail the potential risks, although preserving the mother¿s right to choose.
Although there are not definitive data in the literature, and given that immunosuppressants have been detected in the breast milk at variable concentrations, it seems wise to advise against breastfeeding, which was done in our patients.
To conclude, post-renal transplantation pregnancy is quite safe with an immunosuppressive regimen based on steroids and tacrolimus, with good outcomes when renal function is adequate before the pregnancy, there is no proteinuria, and the blood pressure is under control. However, post-renal transplantation pregnancy should still be considered as a high-risk gestation due to the complications that may occur in both the mother (infection, proteinuria, anemia, AHT, and acute rejection) and the fetus (prematurity and low birth weight),7 so that it should be approached in a multidisciplinary way, and both the follow-up visits and immunosuppressants monitoring should be carried out more often.
