EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Chronic kidney disease (CKD) negatively affects fertility, leading to decreased libido, ovarian dysfunction, anovulatory vaginal bleeding, amenorrhea, and hyperprolactinemia.¹ Chronic kidney disease results in a low incidence of spontaneous conception during dialysis, ranging from 0.9% to 7%.² Fertility generally improves after kidney transplant, leading to an increase in pregnancy rates.³ Pregnancy after kidney transplant presents several challenges because of the risk of maternal and fetal complications, such as increased rate of preeclampsia, gestational diabetes, pregnancy-induced hypertension, cesarean section rates, miscarriages, prematurity, intrauterine growth restriction, and low birth weight.^4-6

According to data from the Brazilian Society of Nephrology, the estimated number of patients with CKD on kidney replacement therapy in 2024 was 172 585, with 19.4% aged 20 to 44 years.⁷ The overall proportion of women on dialysis during this period was 41%. In 2024, Brazil performed 6261 kidney transplants.⁸ In this context, many women of repro-ductive age in Brazil receive transplants, since the need for multiple dialysis sessions is no longer needed, and their fertility is reestablished.

This study aimed to evaluate the maternal and fetal outcomes of women who became pregnant after kidney transplant in Brazil through an integrative review of the literature.

Materials and Methods

Data sources and searches
This integrative review was conducted following
the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁹ The eligibility criteria were structured around the PICOS framework.¹⁰ The population consisted of kidney transplant recipients in Brazil with posttransplant pregnancies. Interventions and comparisons were not conducted in this study. The outcomes evaluated included immunosuppressive therapy during pregnancy, preeclampsia, preterm birth, miscarriage, therapeutic abortion, stillbirth, graft rejection, and graft failure within 2 years after pregnancy. Clinical trials, case reports, case series, case-control, and cohort studies were considered for inclusion. The search strategy involved searching articles in the PubMed/Medline database on July 2, 2025, with the following search syntax: “kidney transplantation” or “renal transplantation” and “Brazil” and “vaginal delivery” or “cesarean” or “abortion” or “miscarriage” or “birth.” Database search results were imported into the Rayyan web app for systematic reviews.¹¹ After removing duplicates, we screened articles based on title and abstracts. The selection of included articles was made after we read the full texts.

Study selection
Two independent reviewers (L.M.C.C. and M.V.S.) screened titles and abstracts to determine eligibility for full-text review. A third author (J.P.S.G.) resolved any discrepancies. Three independent researchers conducted the selection process. We excluded duplicated studies and articles that did not evaluate maternal and/or fetal outcomes in women with posttransplant pregnancies.

Data extraction and main outcomes
Two reviewers (L.M.C.C. and M.V.S.) independently extracted the following data, when available: period of study; study design; number of kidney transplant recipients, pregnancies, and children; immunosup-pressive maintenance therapy during pregnancy; number of cases and prevalence of preeclampsia and/or eclampsia; number of cases and prevalence of preterm births; number of cases and prevalence of pregnancy loss, including miscarriage, therapeutic abortion, and stillbirths; number of cases and prevalence of graft rejection following pregnancies; and number of cases and prevalence of recipients presenting graft failure within 2 years after pregnancy.

The database search returned 33 articles, with 1 duplicate article. After the duplicate was excluded, 32 publications were screened; a further 22 articles were excluded because they did not address maternal and fetal outcomes. Ten articles were eligible for full-text reading, with exclusion of 1 article because the article also did not assess the maternal and fetal outcomes, resulting in inclusion of 9 articles^3,12-19 (Figure 1).

All included articles underwent peer review and were published in Portuguese or English. The period of the included studies was from 1968 to 2019. Most included articles were retrospective cohort studies (n = 5; 55.6%), followed by 3 retrospective case-control design studies (33.3%) and 1 case report (11.1%). In general, studies analyzed 290 transplanted women and 365 pregnancies (Table 1).

Immunosuppression
All included studies reported the use of a calcineurin inhibitor (CNI) in the maintenance immunosup-pressive therapy regimen during pregnancy. Among studies that provided absolute numbers, the most prevalent CNI was cyclosporine (n = 170; 62.0%), followed by tacrolimus in 104 patients (38.0%). Most recipients received azathioprine as an antipro-liferative drug. A study by Radaelli and colleagues¹² reported that 22 women used mycophenolate and 1 woman received a mammalian target of rapamycin inhibitor, which was replaced with azathioprine when pregnancy was desired or unplanned concep-tion was acknowledged. The use of prednisone was reported in 249 pregnancies.

Maternal outcomes
Data on the prevalence of preeclampsia or eclampsia were available in 8 articles (n = 96 cases), rep-resenting an overall incidence of 26.3%. A higher prevalence of preeclampsia and eclampsia was observed in a retrospective cohort by Dinelli and colleagues,¹³ which identified 16 cases among 26 pregnancies evaluated. In that study, 64% of women received a kidney from a living donor and 30.8% had known systemic arterial hypertension before pregnancy, increasing to 61.5% of women with known systemic arterial hypertension during pregnancy. All patients included in the study received azathioprine and prednisone, with tacrolimus used in 72% of cases, whereas cyclosporine was used in the others. A lower preeclampsia rate was reported in a retrospective case-control study by Miranda and colleagues,¹⁴ with 3 cases among 47 pregnancies.

Data on mode of delivery or other clinical or obstetric conditions were not available for most of the included studies.

Fetal outcomes
Two studies showed the absence of miscarriage, therapeutic abortion, or stillbirth. Among the remaining studies, this outcome rate varied from 1.9% to 43.3%, with the higher rate reported in the study by Radaelli and colleagues.¹² High rates were linked to 2 or more risk factors for poor pregnancy outcomes, defined as serum creatinine >1.5 mg/dL or estimated glomerular filtration rate <60 mL/min, urine protein-to-creatinine ratio >0.5, preexisting hypertension, and conception within the first year posttransplant. Rate of prematurity ranged from 17% to 60%, with most rates higher than 50% in most of the included studies.

Graft rejection and graft failure
The effects of pregnancy on graft rejection incidence were discussed in 5 articles. Two articles reported no graft rejection after pregnancy. Most rejection cases were reported by Radaelli and colleagues,¹² with an incidence of 12.4%. In that study, most patients were transplanted before 2000 and received cyclosporine and azathioprine as their maintenance immunosup-pressive therapy. Graft survival over 5 years of follow-up was lower in recipients transplanted before 2000 than in those transplanted after 2000. In a later retrospective cohort study by Candido and colleagues¹⁵ of 36 kidney transplant recipients, most of whom were on tacrolimus, rejection rate after pregnancy was 6.0%. Seven studies analyzed 2-year postgestation graft failure, with 2 studies^16,17 not reporting this outcome. The remaining studies reported a graft failure rate between 1.9% and 21.7%.

Pregnancy after kidney transplant involves potential risks for both mother and fetus, requiring careful planning to reduce those risks. Current guidelines recommend that all women of reproductive age be counseled about contraception after transplant and the optimal timing for pregnancy. Women with a transplant should avoid pregnancy during the first year posttransplant. Assessments before pregnancy should include a comprehensive review of clinical conditions, such as identifying the cause of CKD, discussing genetic testing if appropriate, evaluating potential maternal and fetal effects of pregnancy, managing comorbidities effectively, providing vac-cinations, adjusting immunosuppressive therapy as necessary, and assessing immunological risk and graft function.²⁰ Women who are considered the best candidates for pregnancy after transplant are those who have at least 1 year posttransplant, renal function >60 mL/min, little or no proteinuria (<300-500 mg/day), no hypertension or well-controlled hypertension, no recent rejection episodes, and are on low-dose, properly adjusted immunosuppression with discontinuation of potentially teratogenic agents for at least 6 weeks. Adjustment of the im-munosuppressive regimen is crucial to improve maternal and fetal outcomes in posttransplant pregnancies. Tacrolimus, cyclosporine, azathioprine, and steroids are generally considered safe during pregnancy. Among studies in our review, cyclosporine was used in 46.6% of pregnancies and tacrolimus in 28.5%. These drugs had similar side effects and had not been associated with increased teratogenicity. Mycophenolate should be avoided during pregnancy because of its link to serious cranial and cardio-vascular fetal malformations. Azathioprine and steroids are the most commonly used in this study, as well as in other research. Azathioprine is a teratogen in animal models but not in humans.⁶ Steroids are associated with a high risk of premature rupture of membranes, infectious disease, and gestational diabetes.⁶ Few studies have explored use of mammalian target of rapamycin inhibitors during pregnancy, but discontinuation of its use in anti-cipation of pregnancy is recommended.⁶

Hypertensive disorders in pregnancy are defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure >90 mm Hg, including chronic hypertension when it occurs before 20 weeks of gestation, de novo hypertension, and preeclampsia. Preeclampsia is defined as hypertension associated with end-organ damage, including proteinuria, acute kidney injury, elevated liver enzymes, neurologic manifestations, pulmonary edema, hemolysis, or thrombocytopenia. Preeclampsia can progress to eclampsia, characterized by new-onset tonic-clonic seizures, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.²⁰ Pregnancies after transplant have higher rates of hypertension, with a greater incidence of preeclampsia at 14% to 37%, compared with 3% to 5% in the general population.^6,20 Incidence of preeclampsia in most studies included in our systematic review was higher than the incidence reported by other studies. We hypothesized that this may result from inadequate control of comorbidities presented by women transplanted in Brazil or perhaps because of more accurate antenatal care, leading to a higher frequency of adequate blood pressure assessment. Preeclampsia is an independent risk factor for adverse pregnancy outcomes, and its early identification and proper treatment can lower the risk of severe complications associated with preeclampsia.²¹ For women with pregnancy after kidney transplant, we recommend aggressive blood pressure control, aiming for a blood pressure of <130/80 mm Hg.²⁰ For high-risk nontransplant pregnant women, antiplatelet agents such as low-dose aspirin have proven effective in reducing preeclampsia risk. Although no direct evidence for this approach has been shown in female transplant recipients, women are advised that they begin low-dose aspirin (100 mg/day) therapy between 12 and 16 weeks of pregnancy.²⁰ Calcium supplementation (1 g/day) is also recommended for populations with low dietary intake.

The miscarriage and stillbirth rate among solid-organ transplant recipients was shown to range between 8% and 27%, although the true miscarriage rate may be higher because of episodes not noticed by women. Our study showed a combined rate of miscarriage, therapeutic abortion, and stillbirth of 23.8%, similar to rates reported in the literature. Considering the livebirths, a higher prevalence of preterm birth was reported; we showed a rate above 40% in most of the included studies. In a previous study by Al Duraihimh and colleagues²² that analyzed 234 pregnancies in 140 renal transplant recipients across 5 Middle Eastern countries, prevalence of preterm birth was 40.8%, similar to the rates reported in our review. Postnatal growth in such mothers is usually comparable to growth shown in nontransplant mothers.²⁰

Our review showed an overall graft rejection rate of 4.7%, similar to the range of 4.2% to 9.4% reported in previous studies.^4,23 A healthy pregnancy is characterized by an immune-tolerant state, indicated by reduced expression of major histocompatibility complex (HLA) molecules on trophoblast cells, the presence of complement regulatory proteins, acti-vation of regulatory T cells, and elevated immune response checkpoints.²⁴ However, changes in the distribution and metabolism of immunosuppressive drugs can increase the risk of rejection in female transplant recipients, making it essential to monitor blood levels of these drugs regularly in pregnant transplant recipients.²⁵ Accurate diagnosis of graft rejection requires a biopsy, and the need for biopsy during pregnancy should be carefully assessed because biopsy is associated with some adverse events. Once diagnosed, treatment of graft rejection during pregnancy is difficult because of limited therapeutic options. Besides rejection, other adverse events can lead to graft failure during pregnancy, such as recurrence of the underlying kidney disease, hypertensive and metabolic disorders, and infectious conditions. In a previous study from Basaran and colleagues,²⁶ which included 8 posttransplant preg-nancies in kidney transplant recipients, no episodes of graft rejection were reported during or after pregnancy, with 1 case of chronic transplant nephropathy that worsened during gestation. The causes of graft loss in the articles included in our review were not detailed.

Contraception is a fundamental aspect of care after solid-organ transplant and should be addressed jointly by the clinical and gynecological teams through the appropriate sharing of relevant clinical information. After transplant, patients should be aware of the possibility of fertility returning and can be supported in making decisions about their reproductive future, receiving appropriate contra-ception if there is no desire for pregnancy.²⁶

Our study had some limitations, the main one being that it was based on previously conducted studies without access to the original databases. In addition, the lack of uniformity in the systema-tization and presentation of results greatly hindered the consistency of interpretations. On the other hand, this study has the potential to provide an overview of pregnancies after kidney transplant in Brazil.

In our study of maternal and fetal outcomes among Brazilian women with kidney transplants, higher rates of preeclampsia were shown, highlighting the need for careful management of comorbidities in this population. The fetal outcomes were consistent with other studies. Graft rejection rates were low in the studies, and most women maintained a functioning graft 2 years after pregnancy.

Volume: 24 Issue: 1 January 2026

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