Lisa A. Coscia

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.

Ciclosporin Use During Pregnancy

Ciclosporin (cyclosporine) is an immunosuppressive drug first approved for use in organ transplantation to prevent rejection. Ciclosporin is also known to be used for the treatment of psoriasis, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease, among other indications. While it is recommended that all medications that are not absolutely necessary should be avoided during pregnancy, this may not be an option for many women whose quality of life is significantly impacted without treatment, or for those who must continue immunosuppressive therapy to avoid organ rejection. The purpose of this review is to provide a comprehensive report from the literature of ciclosporin exposure during pregnancy. PubMed, MEDLINE and the Cochrane Database of Systematic Reviews were searched for English-language articles published from 1970 to 2012 that included reports of pregnant women treated at any time during pregnancy with ciclosporin. On an initial search, it was evident that much of the available information is limited to pregnancy after transplant, which suggests that ciclosporin use during pregnancy appears to be associated with premature delivery and low birthweight infants. Comorbidities such as hypertension, pre-eclampsia and gestational diabetes mellitus are also reported at higher incidences than the general population. Medical literature concerning women with autoimmune disorders exposed to ciclosporin during pregnancy are currently limited to case reports and registry data, and, as such, it is difficult to determine if any risks associated with ciclosporin therapy during pregnancy are due to exposure to the drug alone or to pre-existing maternal comorbidities. The literature suggests that ciclosporin therapy during pregnancy should be carefully considered by the treating physician, but may be a safe alternative for patients with autoimmune disease refractory to conventional treatment. Continued monitoring of this patient population remains a key component to understanding the risk factors associated with ciclosporin exposure during pregnancy.

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.

Complex chimerism: Pregnancy after solid organ transplantation

Thousands of women with organ transplantation have undergone successful pregnancies, however little is known about how the profound immunologic changes associated with pregnancy might influence tolerance or rejection of the allograft. Pregnant women with a solid organ transplant are complex chimeras with multiple foreign cell populations from the donor organ, fetus, and mother of the pregnant woman. We consider the impact of complex chimerism and pregnancy-associated immunologic changes on tolerance of the allograft both during pregnancy and the postpartum period. Mechanisms of allograft tolerance are likely dynamic during pregnancy and affected by the influx of fetal microchimeric cells, HLA relationships (between the fetus, pregnant woman and/or donor), peripheral T cell tolerance to fetal cells, and fetal minor histocompatibility antigens. Further research is necessary to understand the complex immunology during pregnancy and the postpartum period of women with a solid organ transplant.

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.

Reproductive health in women following abdominal organ transplant

Fertility is commonly impaired in women with end‐stage kidney and liver disease, although most women will have restoration of fertility within 1 year of transplant. Family planning is therefore critical to discuss with reproductive‐aged transplant recipients in the early posttransplant period, in order to ensure timely initiation of contraception, and optimal timing for conception. For women seeking pregnancy, the risks to the mother, graft, and baby should be discussed, including evaluation of immunosuppression safety and potential for adjusting medications prior to conception. With an increasing number of transplant patients now breastfeeding, immunosuppression safety in lactation continues to carry great importance.