Breast-feeding after transplantation.

Transplantation affords recipients the potential for a full life and, for some, parenthood. Female transplant recipients must continue to take immunosuppression during pregnancy and breast-feeding. This article reviews case and series reports regarding breast-feeding in those taking transplant medications. Avoidance of breast-feeding has been the customary advice because of the potential adverse effects of immunosuppressive exposure on the infant. Subsequent studies have demonstrated that not all medication exposure translates to risk for the infant, that the exposure in utero is greater than via breast milk and that no lingering effects due to breast-feeding have been found to date in infants who were breast-fed while their mothers were taking prednisone, azathioprine, cyclosporine, and/or tacrolimus. Thus, except for those medications where clinical information is inadequate (mycophenolic acid products, sirolimus, everolimus, and belatacept), the recommendation for transplant recipients regarding breast-feeding has evolved into one that is cautiously optimistic.

Immunosuppressive drugs and fetal outcome.

Successful pregnancies have been reported in all types of solid-organ transplant recipients on a variety of immunosuppressive regimens. Immunosuppression is essential to maintain the transplanted organ and maternal health, thus the safety of these medications continues to be studied. This article reviews information in the literature and data from the National Transplantation Pregnancy Registry (NTPR) in the United States related to immunosuppressive medication and pregnancy. Although most maintenance immunosuppressive regimens have not been shown to affect the outcome of posttransplant pregnancies, mycophenolic acid products are associated with an increased incidence of spontaneous abortion and an increase in the incidence and a specific pattern of birth defects. When counseling transplant recipients about the prospect and safety of pregnancy, the health of the mother, her graft, and the developing fetus must all be taken into account.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced Kf and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure.

Breastfeeding and tacrolimus: is it a reasonable approach?

Successful pregnancy after transplantation has become more common and more recipients are choosing to breastfeed their infants, despite the controversy surrounding the safety of breastfeeding while the mother is taking immunosuppressive medications, such as tacrolimus. Data collected to date by the National Transplantation Pregnancy Registry have not revealed specific problems related to breastfeeding; however, individual circumstances must be considered when counseling transplant recipients regarding breastfeeding. Bramham et al. reported on a series of transplant recipients who were maintained on tacrolimus during pregnancy and lactation and concluded that women should not be discouraged from breastfeeding while on tacrolimus. Recently, other authors have also supported the option of breastfeeding while recipients are maintained on tacrolimus. Herein, we review the Bramham article and discuss the key issues to be considered regarding the compatibility of breastfeeding and immunosuppression.

Safety considerations: breastfeeding after transplant.

Organ transplant is an effective treatment for end-stage organ failure. For women, restoration of organ function can restore fertility and the ability to successfully carry a pregnancy. Posttransplant pregnancies have been reported among recipients of all types of solid organ transplants via case and center reports plus registry data. Stable graft function is dependent on prevention of rejection, currently accomplished by using maintenance immunosuppressant medications, to which the fetus is exposed in utero. Common among neonatal outcomes in transplant recipients are preterm and low-birth-weight infants. Emotional, nutritional, and immunologic benefits of breastfeeding have been well-documented and could be valuable for these newborns. Concern must be directed at the effects of the child's exposure to immunosuppressive agents excreted into the breast milk. Breastfeeding could be considered in transplant recipients if it can be shown that the level of exposure does not result in risks to the newborn, immediately and throughout childhood. Despite concerns of health care professionals, some recipients have chosen to breastfeed. Breastfeeding after transplant must be approached with consideration of many issues, and the potential risks require further study. This review focuses on benefits of breastfeeding, common immunosuppressive agents used in organ transplant recipients, a summary of the reports of women who have breastfed their infants while on immunosuppressive therapy and the published studies on breastfeeding and immunosuppressive agents. Recommendations are provided to guide health care professionals to help mothers receiving immunosuppressive agents to make informed choices about breastfeeding their infants.

Pregnancy after cardiac transplantation.

More women are reporting pregnancy following heart transplantation. Although successful outcomes have been reported for the mother, transplanted heart, and newborn, such pregnancies should be considered high risk. Hypertension, preeclampsia, and infection should be treated. Vaginal delivery is recommended unless cesarean section is obstetrically necessary. Most outcomes are live births, and long-term follow-up of children show most are healthy and developing well. Maternal survival, independent of pregnancy-related events, should be part of prepregnancy counseling.

Pregnancy and chronic kidney disease.

This article reviews the association of chronic renal disease and pregnancy. Included are discussions of guidelines for counseling pregnant women with underlying chronic renal disease who are considering conceiving as well as management of those already pregnant. Specifically highlighted are recent studies that question the validity of using estimated glomerular filtration rate and other formulae and questions of whether we should strive to replace the classic counseling approaches based primarily on serum creatinine levels with guidelines based on chronic kidney disease classification. The article concludes with a review as well as a critique of recent research on the prevalence of preeclampsia in women with underlying chronic renal disease, as well as if women with preeclampsia and underlying kidney disease have accelerated courses toward end-stage renal disease.

Pregnancy after transplantation.

The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the outcomes of pregnancies in female transplant recipients and pregnancies fathered by male transplant recipients. Data from the NTPR have helped to endorse the reassurances from publications of smaller experiences that successful pregnancies are possible in the transplant population. In our last review for this journal (2000), we noted that important future issues would include the reassessment of prepregnancy guidelines, gestational and organ-specific problems, the role of new immunosuppressive drugs, and the long-term effects of pregnancy on both graft and child. Data collected by the NTPR over the last 7 years have addressed these issues, thus providing additional information for health care providers of transplant recipients of childbearing age. There has been some refinement of prepregnancy guidelines, but there is a need for additional data collection so that organ-specific outcomes and risks can further be identified. To date, the outcomes of the children followed have been encouraging, and specific remote effects have not been identified, but continued surveillance is still vital. Of special concern are the new immunosuppressive drugs, specifically for mycophenolate mofetil (CellCept, Roche Laboratories Inc., Nutley, New Jersey), where data reported to the NTPR and through postmarketing surveillance have shown an increased incidence of nonviable outcomes and a specific pattern and increased incidence of malformation in the newborn, which has resulted in a pregnancy category change. Newer information points to an increased need for vigilance among centers and continued monitoring of pregnancy outcomes in this population. As the first reported pregnancy after transplantation occurred in a kidney recipient 50 years ago, in March 1958, this review also highlights the first reported pregnancies in other solid organ recipients.

Transplante renal e gravidez / Renal transplantation and pregnancy

Pacientes com insuficiência renal crônica são frequentemente inférteis e a taxa (tasa) de gravidez gira em torno de 1:200. Perda da libido, disfunção ovariana, amenorréia e elevados níveis de prolactina contribuem para a infertilidade. Após (luego) o transplante, entretanto,a fertilidade pode retornar rapidamente e a as taxas de gravidez passam (alcanzan) para 1:50. Não há dúvidas de que essas mulheres constituem um grupo de alto risco e de elevadas taxas de problemas tanto maternos quanto perinatais. Desde a primeira gravidez de sucesso em uma portadora de transplante renal relatada em 1963, diversas publicações têm focado maiores incidências de síndromes hipertensivas, anemia, perda da função renal, pré-eclâmpsia, prematuridade, ruptura prematura de membranas, restrição de crescimento fetal e óbito perinatal. Nosso grupo, na Universidade Federal de SãoPaulo - Brasil tem acumulado experiência nesses casos en este trabalho relatamos nossa experiência comparando com os dados obtidos na literatura. Nós enfatizamos que somente o acompanhamento multiprofissional levará aos melhores resultados. Por fim, gostaríamos de manifestar o nosso desejo (deseo) de entrar em contato com outros grupos para discussão desses (de estos) casos e então aprendermos juntos.

Patients with chronic renal insufficiency are frequentlyinfertile and the incidence of pregnancy is 1:200. Loss oflibido, ovarian dysfunction, anovulatory vaginal bleeding, amenorrhea and high prolactin levels, all contribute to thisinfertility. However, after renal transplantation fertility canreturn rapidly with the chances of pregnancy increasingto about 1:50. There is no doubt that these women are aspecial high risk group with the potential for both maternaland perinatal problems. Since the first successfulpregnancy was reported in 1963 many other publication shave emphasized the increased incidence of hypertension,anaemia, renal function deterioration, pre-eclampsia,preterm delivery, preterm rupture of membranes, fetal growth restriction and stillbirths. At the Federal University of Sao Paulo - Brazil, we have emphasized that a multidisciplinary team approach is essential for their careand in this article we document and analyze the lessonslearnt from our significant single centre experience. We would be happy in contacting other groups of specialists interested in this special group of patients to exchangepoints of view and learn together.

Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry.

BACKGROUND: Maternal and fetal complications in pregnancies after renal transplantation have been highlighted in several reports, but information on their main predisposing factors is limited. The U.K. Transplant Pregnancy Registry was established in 1997 to obtain detailed information on pregnancies in female organ transplant recipients across the U.K. METHODS: For each female kidney, liver, or cardiothoracic organ transplant recipient who had had a recent pregnancy, data on maternal and fetal factors and pregnancy outcomes were collected using forms completed by their transplant follow-up and obstetric units. For kidney transplant recipients, the factors that influence pregnancy outcome were studied using logistic regression, and the effect of pregnancy on graft function was analyzed. RESULTS: There were live births in 83%, 69%, and 79% of pregnancies in cardiothoracic organ, liver, and kidney recipients, respectively. In 50% of live births from renal patients, delivery was preterm (<37 weeks), with 83% of the preterm infants delivered via caesarean. Preterm delivery was associated with maternal drug-treated hypertension and impaired renal function. A matched case-control study showed no evidence of increased renal allograft loss after pregnancy. A univariate survival analysis, however, suggested an association between drug-treated hypertension during pregnancy and poorer postpregnancy graft survival. In patients with prepregnancy serum creatinine (SCr) >150 micromol/L, a trend toward increased postpregnancy SCr was identified. CONCLUSIONS: Pregnancy is likely to end in a live birth in a majority of organ transplant recipients. In patients with greater prepregnancy SCr and/or drug-treated hypertension during pregnancy, however, subsequent renal function may be adversely affected.

Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers.

Maternal renal hemodynamic adaptation to human pregnancy is one of the most dramatic of all physiologic changes, but the factors that are responsible have remained elusive. In rat pregnancy, there are comparable renal hemodynamic changes, and in this species there is comprehensive evidence that the ovarian hormone relaxin (RLX) is responsible. This study investigated the renal effects of recombinant human RLX (rhRLX) in humans. Eleven volunteers (six male, five female) received intravenous infusions of rhRLX over 5 h at an infusion rate that was chosen to sustain serum concentrations that are comparable to early pregnancy. The renal clearances of inulin and para-aminohippurate were used to measure GFR and renal plasma flow, respectively. Irrespective of gender, renal plasma flow was increased by 47% compared with baseline levels (P < 0.0001), but no significant change was observed in GFR. There were no side effects or adverse reactions of rhRLX given as an intravenous infusion, and the data suggest that RLX indeed may be one of the elusive renal vasodilatory factors in human pregnancy. Further work is necessary to elucidate the complimentary factors that permit the concomitant increase in GFR during pregnancy.

Relaxin has a role in establishing a renal response in pregnancy.

Women with normal ovarian function (n = 9) and women who conceived with ovum donation (no circulating relaxin; n = 9) had serial measurements of renal function made during the first trimester of pregnancy by using 24-hour creatinine clearance (CrCl) and plasma osmolality (P(osm)). All pregnancies were associated with increasing CrCl and reduced P(osm), but the change from baseline was significantly greater in the women with normal ovarian function, indicating that in contrast to the rodent model, other factors in addition to circulating relaxin contribute to gestational renal adaptation to human pregnancy.

Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.

It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series and data from voluntary registries to guide the care of their patients. Many uncertainties exist including the risks that pregnancy presents to the graft, the patient herself, and the long-term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established. To begin to address uncertainties and define clinical practice guidelines for the transplant physician and obstetrical caregivers, a consensus conference was held in Bethesda, Md. The conferees summarized both what is known and important gaps in our knowledge. They also identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish evidence-based guidelines. The manuscript summarizes the deliberations and conclusions of the conference as well as specific recommendations based on current knowledge in the field.

The renal response to preeclampsia.

Proteinuria and decreased renal function are classic hallmarks of preeclampsia. The kidney, with its reliance on glomerular blood flow and glomerular barrier integrity, provides a unique window to view the preeclamptic disease process. This review briefly details the characteristic renal structural changes seen in preeclampsia and then focuses on the disordered renal hemodynamics and other determinants of ultrafiltration. Both renal blood flow and glomerular filtration rate (GFR) decrease in preeclampsia, although absolute values may remain above the nonpregnant range. A decrease in the ultrafiltration coefficient (K f ), in the order of 50%, either alone or in combination with reduced renal blood flow, is presented as the most likely mechanism for the decrease in GFR. Proteinuria develops, at least in part, secondary to impaired glomerular barrier integrity with a loss of size selectivity revealed by fractional dextran clearance studies and it is proposed, although yet to be proven, that this is accompanied by a loss of glomerular barrier charge selectivity.

New aspects in the pathophysiology of preeclampsia.

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.

Pregnancy following renal transplantation.

Pregnancy is not contraindicated in renal transplant recipients with stable renal function, and a successful and healthy obstetric outcome can be expected in 95% of such cases. The incidence of both maternal and fetal complications is related to the degree of graft dysfunction and/or hypertension prior to pregnancy. Poorer prognosis is associated with poorer renal function. If complications (usually hypertension, renal deterioration, and/or rejection) occur before 28 weeks, then successful obstetric outcome is reduced by 20%. More information is needed about the intrauterine effects and neonatal consequences of maternal immunosuppression, which appears harmless at maintenance levels. From the data available it seems that pregnancy does not compromise long-term transplant prognosis. In the absence of prospective controlled studies transplant pregnancy registries are the only viable means of providing clinicians with timely and relevant information on pregnancy outcomes on which to base management guidelines.