Michael J. Moritz

Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus

Background. Animal and limited human studies have raised concerns as to the safety of in utero exposure to mycophenolate mofetil (MMF) and sirolimus (SRL) in transplant recipients. This study examined the outcomes of pregnancies with exposure to MMF or SRL from 30 female transplant recipients (39 pregnancies) who have reported pregnancies to the National Transplantation Pregnancy Registry. Methods. Data were collected via questionnaires, phone interviews and medical records. Results. There were 18 kidney recipients reporting 26 pregnancies with exposure to MMF: 15 livebirths (LB), 11 spontaneous abortions (SA). Structural malformations were reported in four of the 15 children (26.7%) including: hypoplastic nails and shortened fifth fingers (one), microtia with cleft lip and palate (one), microtia alone (one), and neonatal death with multiple malformations (one). One kidney/pancreas (K/P) recipient reported one SA. Three liver recipients reported three pregnancies; two LB (no malformations), and one second trimester SA. Two heart recipients reported one LB (no malformations) and two SA. SRL exposures included seven recipients (four kidney, one K/P and two liver) reporting four LB (one infant whose mother was switched from MMF to SRL during late pregnancy had cleft lip and palate and microtia) and three SA. Conclusions. A higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring, while no structural defects have as yet been reported with early pregnancy sirolimus exposures. Centers are encouraged to report all pregnancy exposures in transplant recipients.

National transplantation Pregnancy Registry--outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients.

Outcomes of pregnancies from 115 female kidney transplant recipients maintained on cyclosporine before and during pregnancy were obtained from questionnaires, hospital records, and telephone interviews. The mean age of conception was 29 years with a mean transplant interval of 2.2 years. There were 156 outcomes (2 sets of twins): ectopic 1%, therapeutic abortion 12%, miscarriage 16%, stillborn 2.6%, live birth 68.6%. The incidence of prematurity (< 37 weeks) was 56%, and that of low birthweight (< 2500 g) 49.5%. Complications occurred in 21.7% of newborns, but with only 1 neonatal death. Liveborn infants had a mean gestational age of 35.6 weeks (term 37-42 weeks) and a mean birthweight of 2407 g. The incidence of drug-treated hypertension prior to pregnancy was 51.7%; of diabetes prior to pregnancy, 11.7%; of preeclampsia, 24.8%; and of rejection during pregnancy or within 3 months postdelivery 14.5%. When infants born to women with or without a given risk factor were compared, mothers with pregnancy drug-treated hypertension had significantly lower-birth-weight infants (2250 vs. 2603 g, P = 0.028 by Wilcoxon). Similarly, mothers with prepregnancy creatinine > or = 1.5 mg/dl had smaller infants (2090 vs. 2505 g, P = 0.031 by Wilcoxon). There was a trend toward lower birth-weight in infants of diabetic recipients. Of 107 recipients interviewed, 12(11%) experienced graft loss, 8 associated with graft dysfunction or rejection during pregnancy. There was 1 graft loss during pregnancy due to rejection and 8 grafts were lost within 2 years of the pregnancy. There was one maternal death 4.3 years postpregnancy. For the 8 recipients who lost their graft within 2 years of pregnancy, outcomes included 1 miscarriage and 7 live births. The 7 live births had a mean gestational age of 35.7 weeks and a mean birth-weight of 2194 g. Five of 8 recipients who had graft loss within 2 years of pregnancy were in the drug-treated hypertensive group. Prepregnancy factors that appear to increase the risk to the newborn of a female kidney transplant recipient include maternal drug-treated hypertension, diabetes, and serum creatinine > or = 1.5 mg/dl. More data are needed before specific prepregnancy predictors for maternal graft loss can be determined in this population.

Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes.

Successful pregnancy outcomes are possible after solid organ transplantation. While there are risks to mother and fetus, there has not been an increased incidence of malformations noted in the newborn of the transplant recipient. It is essential that there is closely coordinated care that involves the transplant team and an obstetrician in order to obtain a favourable outcome.Current data from the literature, as well as from reports from the National Transplantation Pregnancy Registry (NTPR), support the concept that immuno suppression be maintained at appropriate levels during pregnancy. At present, most immunosuppressive maintenance regimens include combination therapy, usually cyclosporin or tacrolimus based. Most female transplant recipients will be receiving maintenance therapy prior to and during pregnancy. For some agents, including monoclonal antibodies and mycophenolate mofetil, there is either no animal reproductive information or there are concerns about reproductive safety.The optimal (lowest risk) transplant recipient can be defined by pre-conception criteria which include good transplant graft function, no evidence of rejection, minimum 1 to 2 years post-transplant and no or well controlled hypertension. For these women pregnancy generally proceeds without significant adverse effects on mother and child.It is of note that the epidemiological data available to date on azathioprine-based regimens are favourable in the setting of a category D agent (i.e. one that can cause fetal harm). Thus, there is still much to learn regarding potential toxicities of immunosuppressive agents. The effect of improved immunosuppressive regimens which use newer or more potent (and potentially more toxic) agents will require further study.

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.

Complications encountered with the use of the Greenfield filter

The Greenfield filter can be used with a low complication rate provided one adheres to certain principles. First, preoperative venography to define the inferior vena caval anatomy will help avoid difficulties associated with anatomic variations. At the time the study is carried out, it would be extremely useful if the radiologist places a radiopaque marker at the level of the renal veins. This will ensure that filters will be placed in the infrarenal position when appropriate, thus preventing occasional inadvertent discharge, particularly into the right renal vein. Second, use of a guide wire greatly facilitates passage of the introducer and accurate intracaval positioning. Third, intraoperative technical errors must be recognized and promptly corrected. Finally, meticulous postoperative follow-up is essential, and recurrent embolism or any change in filter position requires repeat roentgenography of the vena cava to guide appropriate corrective treatment.

Variables affecting birthweight and graft survival in 197 pregnancies in cyclosporine-treated female kidney transplant recipients.

Outcomes from 197 pregnancies in 141 female kidney transplant recipients were analyzed from data collected via questionnaires, hospital records, and phone interviews. All recipients were maintained on cyclosporine (CsA) before and during pregnancy. Of the livebirths, 54% were premature (< 37 wk) and 50% were low-birthweight (LBW) (< 2500 g). The incidence of recipient drug-treated hypertension (HTN) was 56%; preeclampsia, 29%; infections and complications 22%; and rejection during pregnancy and up to 3 mo. post delivery (rej.), 11%. Graft loss within 2 years of delivery occurred in 9% of recipients (GrL < 2). No recipients reported a pregnancy after a postpregnancy graft loss. Mean serum creatinine was reported before, during, and after pregnancy. Mean cyclosporine doses were similar in recipients during and after pregnancy. Data were analyzed by logistic regression using SAS. Outcomes included prematurity, LBW, rej., and GrL < 2. In a case-controlled study comparing a recipient group with graft dysfunction during pregnancy vs. a group with good graft function, there was a trend toward lower mean prepregnancy CsA doses (in mg/kg) in the graft dysfunction group. A decline in recipient graft function during pregnancy is associated with lower newborn birthweights and lower maternal graft survival in cyclosporine treated female kidney recipients. Pregnancy-related infections and complications are associated with rejection and graft loss in this population. Close monitoring of CsA dosing and serum creatinine levels during pregnancy and immediately postpartum is recommended as CsA dosage adjustment may be required.

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/ sirolimus combination in kidney transplantation monitored by surveillance biopsy

Background. Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. Methods. In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. Results. Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P=0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P=0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. Conclusions. Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Pregnancy outcomes in female renal transplant recipients

IN THE PRESENCE of adequate, stable graft function, pregnancies in female renal transplant recipients, although high risk, are generally well tolerated. Although pregnancy may occasionally and unpredictably cause an irreversible decline in renal graft function, the consensus is that pregnancy has no adverse effect on graft function or graft survival. The National Transplantation Pregnancy Registry (NTPR) maintains an ongoing database to study the outcomes of pregnancy in female transplant recipients and pregnancies fathered by male transplant recipients. Previously, we reported that deterioration in recipient graft function during pregnancy is associated with lower newborn birthweights and lower maternal graft survival in cyclosporine (CsA, Sandimmune)-treated renal recipients. The purpose of this study was to identify variables affecting postpartum graft loss in female renal recipients.

Factors associated with severe intracranial hypertension in candidates for emergency liver transplantation

Cerebral edema is the leading cause of death in patients with fulminant hepatic failure (FHF). Emergency OLT is often a life-saving therapy for FHF but severe cerebral edema is a contraindication to transplantation. We attempted to identify clinical and biochemical factors associated with the development of severe intracranial hypertension in FHF. Fever, psychomotor agitation, and arterial hypertension were more frequently observed preceding episodes of severe intracranial hypertension, and more than 50% of FHF patients with uncontrolled intracranial hypertension sustained severe brain injury in our series. These observations suggest that vigorous treatment of fever, arterial hypertension, and agitation are important aspects of the intensive care management of FHF patients to maintain their OLT candidacy.

Heterotopic liver transplantation for fulminant Wilson's disease

Wilsons disease may present with severe acute hepatocellular failure. The only effective treatment for fulminant Wilsons disease is liver transplantation, which may lead to reversal of the underlying disease. Some patients with cirrhosis who are too ill to undergo orthotopic liver transplantation have been treated with heterotopic liver transplantation. However, use of heterotopic liver transplantation for fulminant hepatocellular failure has not been successful. This case study involves a patient in whom a heterotopic liver transplant was successfully used for treatment of Wilsons disease presenting with fulminant hepatocellular failure.