Serban Constantinescu

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.

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.

Outcomes of Pregnancies Fathered by Solid-Organ Transplant Recipients Exposed to Mycophenolic Acid Products:

Context In women, exposure to mycophenolic acid products during pregnancy results in an increase in both miscarriages and birth defects in the live born. Objective To describe the outcomes of pregnancies fathered by transplant recipients who were being maintained on mycophenolic acid products at the estimated time of conception and compare these pregnancies with pregnancies in the general population. Methods Data were collected by the National Transplantation Pregnancy Registry via questionnaires, telephone interviews, and medical records. Results One hundred fifty-two male transplant recipients with exposure to mycophenolic acid products fathered 205 pregnancies (208 outcomes, including 3 pairs of twins). Pregnancy outcomes included 194 live births with a prematurity rate of 10.8%, 14 spontaneous abortions, and no therapeutic abortions or stillbirths. Among the live births, 6 malformations were reported, for an incidence of 3.1%. No pattern of malformations was identified. Conclusion The outcomes of pregnancies fathered by transplant recipients treated with mycophenolic acid products appear similar to outcomes in the general population.

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.

Update on the Teratogenicity of Maternal Mycophenolate Mofetil

Mycophenolic acid (MPA) products, namely mycophenolate mofetil and mycophenolate sodium, are immunosuppressive medications used to prevent rejection in solid organ transplant recipients and to treat various autoimmune disorders. Mycophenolate therapy is considered to be teratogenic based on observational studies of pregnancies exposed to MPA, which demonstrated an increased incidence of miscarriages in pregnancies exposed to MPA during their first trimester and a pattern of birth defects in the offspring of some pregnancies exposed to MPA. Herein, we have detailed case and series reports in a comprehensive literature review summarizing what is known to date regarding fetal exposure to MPA. Based on evidence from the literature, results of postmarketing surveillance, and information from registries such as the National Transplantation Pregnancy Registry in the United States, it is advised that pregnancy be avoided by women taking MPA. Preconception planning offers the opportunity to explore the alternatives to protect the mother, her transplanted organ, and minimize fetal risk. How to proceed in cases of unplanned pregnancies exposed to MPA in transplant recipients is a complex issue. Research involving large epidemiological studies is expected to be sparse as women heed the warnings about becoming pregnant on MPA. Published recommendations for managing MPA in women of childbearing potential include discontinuing the medication prior to conception, switching the MPA to another medication, or discontinuing the MPA when the pregnancy is discovered.

Pregnancy after lung transplant.

The purpose of this study was to analyze pregnancy outcomes in female lung transplant recipients. Data were collected from the National Transplantation Pregnancy Registry via questionnaires, interviews, and hospital records. Twenty-one female lung recipients reported 30 pregnancies with 32 outcomes (1 triplet pregnancy). Outcomes included 18 live births, 5 therapeutic abortions, and 9 spontaneous abortions. No stillbirths or ectopic pregnancies were reported. Mean (SD) interval from transplant to conception was 3.6 (3.3) years (range, 0.1–11.3 years). Comorbid conditions during pregnancy included hypertension in 16, infections in 7, diabetes in 7, preeclampsia in 1, and rejection in 5 women. Ten of the 21 recipients received a transplant because of cystic fibrosis and accounted for 12 pregnancy outcomes (7 live births, 3 spontaneous abortions, and 2 therapeutic abortions). At last recipient contact, 13 had adequate function, 2 had reduced function, 5 recipients had died (2 with cystic fibrosis), and 1 recipient had a nonfunctioning transplant. Mean gestational age of the newborn was 33.9 (SD, 5.2) weeks, and 11 were born preterm (<37 weeks). Mean birthweight was 2206 (SD, 936) g and 11 were low birthweight (<2500 g). Two neonatal deaths were associated with a triplet pregnancy; one fetus spontaneously aborted at 14 weeks and 2 died after preterm birth at 22 weeks. At last follow-up, all 16 surviving children were reported healthy and developing well. Successful pregnancy is possible after lung transplant, even among recipients with a diagnosis of cystic fibrosis.

Long-Term Functional Recovery, Quality of Life, and Pregnancy After Solid Organ Transplantation

This article reviews the salient features of functional recovery, health-related quality of life (HR-QOL), and reproductive health, with special emphasis on pregnancy outcomes in kidney and liver recipients. Transplantation results in improved functional status and HR-QOL. Addressing factors that limit the optimal rehabilitation of transplant recipients can improve transplant outcomes. After successful transplantation, there is a rapid return of fertility, warranting counseling regarding contraception. Practitioners should be aware of the teratogenic potential of mycophenolic acid products. Posttransplant pregnancies are high risk, with increased incidences of hypertension, preeclampsia, and prematurity. Most pregnancies in kidney and liver recipients have successful maternal and newborn outcomes.

Mycophenolate and Pregnancy: Teratology Principles and National Transplantation Pregnancy Registry Experience.

We, the investigators of the National Transplantation Pregnancy Registry (NTPR), read with concern King and colleagues’ Pregnancy Outcomes Related to Mycophenolate Exposure in Female Kidney Transplant Recipients [1], based on a limited subset of our data, which concludes that first trimester exposure to mycophenolate (MPA) may not be associated with increased fetal risks. We disagree with their interpretation of the data and feel strongly that their conclusions convey false information regarding MPA safety during pregnancy. In contrast, our analysis of this data finds: (1) the significant risks to pregnancies exposed to MPA any time in the first trimester are miscarriage and phenotypic birth defects, and (2) no association between discontinuing MPA products <6 weeks preconception and the risk of graft loss at 5 years. We attribute the authors’ invalid conclusions to systematic errors in assigning recipients to their comparison groups and missing information. This article is protected by copyright. All rights reserved.

Nutrition, Pregnancy, and Transplantation:

One benefit of transplantation, along with the restoration of health, is the opportunity for successful pregnancies. A growing number of pregnancies have been reported among all types of solid-organ recipients. There is an increasing need for practice guidelines that include nutrition information in order to assist practitioners caring for and counseling these high-risk patients. In the transplant community, guidelines for managing pregnancies in transplant recipients have been evolving but lack specific nutrition recommendations. As for all pregnancies, there is a need to optimize nutrition for the mother and her infant, with additional consideration given to the transplant recipients graft. This article reviews outcomes of posttransplant pregnancies and management guidelines, with special emphasis on nutrition in this unique population.