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.

The anion gap and routine serum protein measurements in monoclonal gammopathies.

BACKGROUND AND OBJECTIVES: An abnormal anion gap and an increased total protein and globulin are clues to the diagnosis of monoclonal gammopathy. We explored the utility of these markers in IgG, IgA, IgM, and free light chain monoclonal gammopathies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The anion gap, Na(+) - (Cl(-) + HCO(3)(-)), corrected for hypoalbuminemia, was calculated in patients with monoclonal gammopathies. Exclusion criteria were serum calcium >10.5 mg/dl and/or creatinine >2 mg/dl. RESULTS: Among 287 patients, 242 remained after applying exclusion criteria (109 IgG, 64 IgA, 21 IgM, and 48 light chain); 36% of 242 patients required correction for hypoalbuminemia. The anion gap was decreased (<10) in 22% of IgG and increased (>15) in 31% of IgA monoclonal gammopathies. IgM did not affect the gap. In light chain gammopathies, the anion gap showed no consistent trend (15% increased, 17% decreased). Mean clonal IgG, IgA, and IgM concentrations were 10-fold higher than mean clonal free light chain concentrations in the respective monoclonal gammopathies (P < 0.001). These paraprotein level disparities were reflected in significantly increased mean serum total protein and globulin concentrations in IgG, IgA, and IgM versus free light chain monoclonal gammopathies, where mean total protein and globulin levels were within normal limits (P < 0.001). CONCLUSIONS: The anion gap was significantly altered in IgG and IgA monoclonal gammopathies, but it was not a sensitive tool for suspecting the diagnosis. In light chain monoclonal gammopathies, the anion gap, total protein, and globulin did not provide reliable diagnostic clues.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

From the first reports of pregnancy in each of the organ groups to the present, concerns varied and were specific to the type of transplant. Organ-specific issues still require additional attention and analyses. Lung recipients appear at greatest risk for poorer pregnancy outcomes. Given these ongoing concerns and the constant advent of new developments, clinicians are responsible for providing pregnancy counseling in all pre- and posttransplant recipients of childbearing age. As individual physicians and centers accrue experience with these major therapeutic decisions, it is critical that both positive and negative outcomes be reported in appropriate settings-symposia, meetings, publications, and registries. Future analyses from the NTPR are directed at potential effects of newer immunosuppressive regimens, not only from immediate exposure, but also from continued exposures such as may occur from breastfeeding. As the registry study design allows for contact between registry staff and recipients and their health care providers, efforts are ongoing to analyze long-term outcomes of parent and child. Continued close collaboration among specialists will help to identify potential pregnancy risks in these populations, particularly as new immunosuppressive agents are developed. Therefore, centers are encouraged to report all pregnancy exposures in transplant recipients to the NTPR. The 50th anniversary of the first posttransplant pregnancy (reported by Joseph Murray, et al. (11)) was in March 2008. With this important landmark event and with ongoing pregnancy issues concerning posttransplant pregnancy safety, this is an ideal time to raise the awareness of the need for continued worldwide cooperation for data collection. Enhanced assessment of pregnancy safety is essential to the development of guidelines for counseling and management of pregnancy in the transplant population.

Report from the National Transplantation Pregnancy Registry: outcomes of pregnancy after transplantation.

Experience in the field of pregnancy posttransplantation has been gained through continued case reports, center reports, and registry data. The NTPR maintains an ongoing active database to study the safety of pregnancy and includes the outcomes of female transplant recipients as well as male recipients who father pregnancies. Analyses are ongoing and include long-term followup of recipients' graft status and of their offspring. For the most part, guidelines proposed in 1976 for counseling recipients remain applicable (30). While these counseling guidelines were formulated for kidney recipients, they may be extrapolated to other organ recipients as well. Organ-specific issues should also be considered in managing and counseling female transplant recipients. Recipients should be in general good health, and graft function should be stable and, ideally, rejection-free. There should be optimal control of comorbid conditions such as hypertension and diabetes prior to conception. While the shortest safe interval from transplant to conception has not been established, 1 year is a reasonable milestone, given the prerequisites of stable, adequate graft function and maintenance-level immunosuppression. During pregnancy, maintenance-medication regimens should be continued with vigilant monitoring for effective drug levels and drug side effects with appropriate dose adjustment. These pregnancies are high-risk and require close maternal and fetal surveillance through coordinated care among maternal-fetal medicine specialists and transplant personnel. Of the live born reported to the NTPR, a higher incidence of structural malformations has been seen with MMF exposures during pregnancy when compared with the overall kidney transplant recipient offspring group. Three of the four defects included microtia (ear deformity), suggesting a pattern of malformations. However, live-born outcomes without structural malformations have also been noted in the MMF cohort. No structural defects have yet been reported with early pregnancy sirolimus exposures in a limited number of recipients evaluated. Limitations in assessing congenital malformation risk and MMF exposure include methodology and potential reporting bias, small sample size, and our inability to exclude other comorbid factors such as non-immunosuppressive drug effects or other susceptibilities in this population. It is incumbent upon transplant professionals to be aware of any additional risk to the fetus from immunosuppressive medications relative to the potential improvement in maternal graft function/survival conferred by each of these agents. Given the ongoing concerns with the newer immunosuppressive agents, clinicians are responsible for providing pregnancy counseling in all pre- and post-transplant recipients of childbearing age. Centers are encouraged to report all pregnancy exposures in transplant recipients to the NTPR. Future analyses from the NTPR are directed at potential effects of these newer immunosuppressive regimens, not only from immediate exposure but also from continued exposure that may occur from breastfeeding. As the registry study design allows for contact between registry staff and recipients and their health care providers, efforts are ongoing to analyze the long-term outcomes of parents and children. Continued close collaboration among specialists will help to better identify potential pregnancy risks in these populations, particularly as new immunosuppressive agents are developed. The fiftieth anniversary of the first post-transplant pregnancy (reported by Joseph Murray et al.) (31) will be in March 2008. With this important date approaching and with ongoing pregnancy issues concerning post-transplant pregnancy safety, this is an ideal time to raise awareness of the need for continued worldwide cooperation for data collection. Enhanced assessment of pregnancy safety is essential to the development of guidelines for counseling and management of pregnancy in the transplant population.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Experience in the field of pregnancy after transplantation has been gained through continued case reports, center reports, and registry data. The NTPR maintains an ongoing active database to study the safety of pregnancy and includes the outcomes of female transplant recipients as well as male recipients who father pregnancies. Analyses are ongoing and include long-term follow-up of recipients' graft status and of their offspring. For the most part, guidelines proposed in 1976 for counseling recipients remain applicable. While these counseling guidelines were formulated for kidney recipients, they may be extrapolated for other organ recipients as well. Organ-specific issues should also be considered in managing and counseling female transplant recipients. Recipients should be in general good health and graft function should be stable and ideally rejection free. They should have optimal control of comorbid conditions such as hypertension and diabetes prior to conception. While the shortest safe interval from transplant to conception has not been established, one year is a reasonable milestone, given the prerequisites of stable, adequate graft function and maintenance level immunosupression. During pregnancy, stable medication regimens should be changed as little as possible, and close maternal and fetal surveillance are required. These pregnancies are high-risk and require coordinated care among maternal fetal medicine specialists and transplant personnel. The pregnancy issues that face recipients and caretakers with the current adjunctive therapies and differing combinations of immunosuppressive regimens continue to require further study. The most pressing issue is the question of whether fetal exposure to mycophenolate mofetil or sirolimus confers additional risk, relative to the potential improvement in maternal survival and maternal graft function/survival conferred by these drugs. Given the multiplicity of immunosuppressive regimens, only broad-based registry participation can provide the data needed to analyze such complex questions. Future analyses are directed at potential effects of these newer immunosuppressive regimens, not only from immediate exposure, but also from potential long-term exposures such as may occur from breastfeeding. As the registry study design allows for continuing contact between registry staff and recipients and their health care providers, efforts are in progress to analyze long-term outcomes of parent and child. Continued close collaboration among specialists will help to better identify potential pregnancy risks in these populations, especially as new immunosuppressive agents are developed.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR maintains an ongoing active database to study the safety of pregnancy in transplant recipients and currently includes the outcomes of more than 900 female recipients who became pregnant after their transplant and just over 700 male recipients who fathered one or more pregnancies after receiving a transplant. Analyses include the long-term follow-up of the recipient's graft status and their offspring. Successful pregnancy outcomes have been noted for each solid organ recipient group. The Registry includes information on 1,097 pregnancies in 716 kidney recipients, 187 pregnancies in 111 liver recipients, 56 pregnancies in 38 P/K recipients and smaller numbers for other organs and combinations of organs. There are periodic reports of recipients with graft dysfunction, rejection, or graft loss that may be related to pregnancy events, though the majority of outcomes reported to the NTPR appear favorable for parent and newborn. Organ-specific issues and comorbidities must also be considered in analyzing outcomes. The pregnancy issues that face recipients and caretakers with the current newer adjunctive therapies and newer immunosuppressive regimens require ongoing study. The potential risk of teratogenicity must be weighed against the potential risk of rejection when altering drug regimens before planned conceptions or in making dosage adjustments during pregnancy. Unplanned pregnancies present obvious concerns. Pregnancy safety has not been established for either MMF or sirolimus and all centers are encouraged to report pregnancies with exposures to these agents to the NTPR. Continuing analyses are directed at potential effects of the newer immunosuppressive regimens, not only to identify any risks to the pregnancy from immediate exposure, but also for potential postpartum exposures such as from breastfeeding. As the registry study design allows for continued contact, efforts continue to accrue long-term follow-up of both parent and child.

Crescentic glomerulonephritis and subepidermal blisters with autoantibodies to alpha5 and alpha6 chains of type IV collagen.

We describe a novel autoimmune disease characterized by severe subepidermal bullous eruption and crescentic glomerulonephritis with autoantibodies directed against the noncollagenous domain of the alpha5 and alpha6 chains of type IV collagen. Biopsy of perilesional skin revealed a subepidermal blister with marked polymorphonuclear infiltrate with linear deposits of IgA and C3. Light microscopy of a kidney biopsy specimen revealed a crescentic glomerulonephritis, and immunofluorescence microscopy showed linear basement membrane staining for IgA (3+), C3 (1+), and IgG (1+). No electron-dense deposits were observed by transmission electron microscopy. The patient's autoantibodies reacted with normal human skin and kidney: IgA (3+) and IgG (1+) antibodies stained the basement membrane zones of skin, renal glomerulus, and some tubules. The identity of the target antigen was determined by immunochemical analyses of candidate antigens using the patient's autoantibodies. The patient's IgA and IgG autoantibodies reacted with a 185- to 190-kDa antigen from a human dermal extract that was distinguished from the other dermal or epidermal antigens, including the 145- to 290-kDa (type VII collagen) epidermolysis bullosa acquisita antigen, the 165- to 200-kDa alpha3 laminin mucous membrane cicatricial pemphigoid antigen, and the 230-kDa and the 180-kDa bullous pemphigoid antigens. Patient's IgA and IgG autoantibodies further reacted with the alpha5(IV) and weakly with the alpha6(IV) chains of type IV collagen by Western blot and ELISA. This report expands the repertoire of bullous skin disorders and provides an explanation for the association of anti-type IV collagen autoantibodies and glomerulonephritis with subepidermal blisters.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR continues to maintain an ongoing active database as a resource for health professionals counseling recipients regarding pregnancy and for recipients themselves to contact the registry and request information. This includes female transplant recipients as well as male recipients who father pregnancies. Recipients who consent are entered into a database; analyses are ongoing, including long-term follow-up of the recipient, the graft and the offspring. The safety of pregnancy for parent and child remains the goal of the registry. Guidelines for counseling recipients proposed in 1976 remain applicable. Recipients should be in general good health and graft function should be stable and ideally rejection free. Comorbid conditions should be well controlled, especially hypertension and diabetes. While these counseling guidelines were formulated for kidney recipients, they may be extrapolated for other organ recipients. Analyses this year included pregnancy outcomes of recipients on newer agents, MMF and sirolimus. It remains unclear whether these adjunctive therapies should be altered for pregnancy. The balance of immunosuppression and the prevention of rejection need to be weighed against the potential for teratogenicity when counseling these recipients inquiring about pregnancy. Although there are periodic reports of recipients with graft dysfunction, rejection or graft loss possibly related to pregnancy events throughout all the organ groups, whether transplanted as adults or as pediatric patients, the majority of pregnancy outcomes reported to the NTPR appear favorable for parent and newborn. Whether recipients should breastfeed remains controversial. Recent reports in the literature as well as NTPR data appear favorable. This represents the last report from our initial established location at Thomas Jefferson University. In January of this year, the registry moved to Temple University School of Medicine, Department of Surgery, Philadelphia, PA. The NTPR remains committed to investigating outcomes of pregnancies reported by centers or self-referrals nationwide. Some of the active issues for the upcoming year include the potential for teratogenicity with combinations of newer agents, incidence of viral hepatitis, risk assessment for pregnancy in female lung recipients, and long-term maternal and pediatric follow-up.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR maintains an ongoing database to study the outcomes of pregnancies in female transplant recipients as well as those pregnancies fathered by male transplant recipients. Recipients are entered into the database by completing. a single page questionnaire. There is steady follow-up of recipients and their offspring. While the majority of pregnancy outcomes have occurred in kidney recipients, data continue to accrue in the other types of organ recipients. KIDNEY: A small percentage of pregnancies in female kidney recipients are complicated by rejection with poorer outcomes with respect to both maternal graft function and their newborn. Other analyses this year focused on outcomes of recipients with systemic lupus erythematosus and those with multiple gestations. It was observed that recipients with systemic lupus erythematosus were able to maintain a pregnancy with outcomes that appear to be similar to other diagnoses. In an analysis of multiple gestations in female kidney recipients maintained on calcineurin inhibitors, no multiple gestations higher than triplets have been reported to the NTPR. Successful outcomes have been noted among these recipients. This does require continued surveillance, as there has been an increase in the number of multiple gestations in the general population with the use of adjunctive technologies. OTHER ORGANS: In analyzing outcomes in female liver recipients, no specific graft or newborn outcome differences have been noted when a comparison has been made between different caicineurin inhibitor regimens. Pregnancies in female pancreas-kidney recipients appear to be tolerated with respect to pancreas graft function with no diagnoses of gestational diabetes reported to the NTPR. Data continue to accrue among thoracic recipients. Poorer maternal survival postpartum in lung recipients may be related to higher risks inherent in this population and requires further experience and investigation. OTHER ISSUES: With the recent proliferation of newer immunosuppressive agents, a question that is raised is whether a regimen can be specifically designed with recipients of childbearing age in mind. Extensive data published on azathioprine and cyclosporine treated recipients suggests that while there is a pattern of prematurity among the newborn there has not been an increase in the incidence or pattern of specific malformations noted among the newborn. Less assurance can be given with newer agents such as sirolimus and MMF. Calcineurin inhibitor minimization or steroid withdrawal would require that other agents with less reproductive information be implemented. The unknown risk of teratogenicity must be balanced against the potential risk of rejection or graft dysfunction when deciding which agent to use during pregnancy. Through each of the organ recipient groups, there are sporadic cases of rejection, graft dysfunction, and graft deterioration. Birth defect patterns have not appeared to be specific to any specific regimen as yet. Two newborns with malformations have been noted among a limited series with MMF exposure, but other factors may also be at play. The use of MMF during pregnancy continues to be an unresolved issue in the transplant community. As yet, no one regimen has been identified as superior to another for use during pregnancy. Continued surveillance with the newer agents is necessary. Investigators have taken differing views regarding the safety of breastfeeding in the transplant recipient population, especially with regard to drug exposure to the infant. This issue remains unresolved and some transplant recipient mothers have chosen to breastfeed. Other factors for consideration are the potential long-term effects on offspring of transplant recipients. While there may not be specific structural defects noted at birth, more subtle effects on either immunologic or reproductive function may not manifest until later in life. Scott and his group in Utah have raised this issue with a case report and have initiated a study to focus on the next generation. The safety of pregnancy for parent and child remain the goals of the NTPR. Continued entries to the registry, especially in light of newer combinations of immunosuppressive agents, should assist in developing guidelines needed for management in this era of expanding immunosuppressive agents. All centers are encouraged to participate.