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Reproduction and Transplantation: Report on the AST Consensus Conference on Reproductive Issues and Transplantation

2005; Elsevier BV; Volume: 5; Issue: 7 Linguagem: Inglês

10.1111/j.1600-6143.2005.00969.x

1600-6143

Dianne B. McKay, Michelle A. Josephson,

Assisted Reproductive Technology and Twin Pregnancy

Vincent T. Armenti, MD, PhD, Professor of Surgery, Temple University School of Medicine, Abdominal Transplant Program, Philadelphia, Pennsylvania Phyllis August, MD, MPH, Professor of Medicine, Division of Hypertension, Weill Medical College of Cornell University, New York, New York Lisa A. Coscia, RN, BSN, CCTC, Research Coordinator, National Transplantation Pregnancy Registry, Temple University School of Medicine, Philadelphia, Pennsylvania Connie L. Davis, MD, Professor of Medicine, Div. of Nephrology, Univ. of Washington, Box 356174, 1959 NE Pacific St., Seattle, WA 98195 John M Davison MD, Professor of Obstetric Medicine, Consultant Obstetrician, University of Newcastle upon Tyne, School of Surgical and Reproductive Sciences, Faculty of Medical Sciences, William Leech Building, Newcastle upon Tyne NE2 4HH, UK Thomas Easterling, MD, Professor, Maternal Fetal Medicine, University of Washington, Box 356460, 1959 ND Pacific Street, Seattle, WA 98195 Jan M. Friedman, MD, PhD, Professor of Medical Genetics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3 Susan Hou, MD, Professor of Medicine, Department of Medicine, Loyola University Medical Center, Maywood, IL Janet Karlix, Pharm, D, FCCP, Associate Professor, College of Pharmacy, University of Florida, Gainesville, FL Kathleen D, Lake, Pharm.D., BCPS, FCCP, Adjunct Professor, University of Michigan Medical School and College of Pharmacy, Ann Arbor, MI, Medical Transplant Liaison, Roche Laboratories, Nutley, NJ Marshall Lindheimer, MD, Professor Emeritus, Departments of Obstetrics & Gynecology, and Medicine,, University of Chicago, Chicago, Ill Arthur J. Matas, MD, Professor of Surgery, University of Minnesota, Department of Surgery, University of Minnesota Hospital, Minneapolis, MN Michael J. Moritz, MD, Professor of Surgery, Drexel University College of Medicine, Director, Abdominal Transplantation, Hahnemann University Hospital, Philadelphia, Pennsylvania Caroline A. Riely, MD, Professor, Medicine and Pediatrics, Chief of Hepatology Section, Gastroenterology Division, University of Tennessee Science Center Lainie Friedman Ross, MD, PhD, Associate Director, MacLean Center for Clinical Medical Ethics, Associate Professor, University of Chicago, Department of Pediatrics, Chicago, Illinois James R. Scott, MD, Professor and Chair Emeritus, Department of Obstetrics and Gynecology, University of Utah Medical Center, Salt Lake City, Utah Lynne E. Wagoner, MD, Director, Heart Failure and Transplantation, Associate Professor, Division of Cardiology, University of Cincinnati, Cincinnati, Ohio Lucile Wrenshall, MD, PhD, Associate Professor, Department of Surgery, Division of Transplantation, University of Nebraska Medical Center, Omaha, NE And the consensus committee organizers of the Women's Health Committee of the American Society of Transplantation: Patricia L. Adams, MD, Professor of Medicine, Associate Dean for Student Services, Wake Forest University School of Medicine, Med Center Blvd, Winston Salem, NC 27157 Ginny L. Bumgardner MD, PhD, Associate Professor of Surgery, Division of Transplantation, The Ohio State University Med. Center, Columbus, Ohio Richard N. Fine, MD, Professor and Chairman, State U. of NY, Health Science Centre T-11 020, Stony Brook, NY 11794–8111 Simin Goral, MD, Associate Professor of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania Health System, Philadelphia, Pennsylvania Sheri M. Krams, PhD, Associate Professor, Department of Surgery/Transplant, Stanford University School of Medicine, 1201 Welch Road, MSLS P313, Stanford, CA 94305–5492 Olivia M. Martinez, PhD, Associate Professor, Stanford University School of Medicine, Dept of Surgery, 1201 Welch Road, MSLS P312, Stanford, CA 94305–5492 Nina Tolkoff-Rubin, MD, Director of Hemodialysis and CAPD Units, Medical Director for Renal Transplantation, Massachusetts General Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts Martha Pavlakis, MD, Assistant Professor of Medicine, Harvard Medical School, Medical Director, Kidney and Pancreas Transplantation, Beth Israel Deaconess Medical Center, The Transplant Center LMOB 7th floor, 110 Francis Street, Boston, MA 02215 Velma Scantlebury, MD, Professor of Surgery, Chief, Division of Transplantation, Assistant Dean for Community Education, University of South Alabama, 2451 Fillingim Street, 10th Flr, Suite F, Mobile, Alabama 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. To better understand how to advise and manage pregnant transplant recipients, a Consensus Conference was organized by the Women's Health Committee of the American Society of Transplantation, and held March 1–2, 2003, in Bethesda, Md. Primary goals included developing clinical practice guidelines for both transplant physicians and obstetrical caregivers, identification of areas most needing study, encouraging universal use of established registries, and advocating for prospective observational studies. Table 1 highlights the Consensus reached at this conference. The Consensus Conference attendees were experts in the fields of transplantation medicine and surgery, maternal-fetal medicine, obstetrics and gynecology, pharmacology, clinical teratology, and ethics. Also in attendance were members of the Women's Health Committee of the American Society of Transplantation, members of the National Institutes of Health (NIDDK, NIAID, NICHD) and members of the Maternal Fetal Trials Network. Each invited expert was assigned to a topic and asked to review the published literature, via Medline search. Independently Women's Health Committee members reviewed the published literature within each topic. Each expert presented the topic in lecture format. After the presentations, experts and conference attendees assembled in small groups for further discussion and development of consensus opinions. Following small discussion sessions the whole group reconvened and each topic and consensus opinion was presented. As each topic was discussed a written record of the agreed upon consensus opinion was generated. After the conference was dismissed, all conference participants were sent the consensus summary and asked to make final comments. While there are several good reviews on the subject of pregnancy and transplantation and previous guidelines have been suggested (1-7), the conferees highlighted important gaps in our knowledge. They identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish firm and universal guidelines. A summary of these questions and deliberations follows. The consensus opinion is presented in Table 1. Patients with end-organ failure experience hypothalamic-pituitary-gonadal dysfunction and decreased ovulation and sperm maturation (8-10). Gonadal dysfunction usually resolves by 6 months after successful renal transplantation followed by normalization of fertility (11), but we do not know if recovery of fertility is complete. There are no data to determine if similar improvements in gonadal function follow transplantation of other organs. Post-transplant medications have been reported to influence germ cell function in animal models (12) but do not significantly influence human germ cell function (13). Case reports suggest unimpaired fertility in patients with autoimmune diseases ingesting corticosteroids and/or azathioprine (14, 15). Normal fertility has been inferred from low utilization of assisted reproduction technology by transplant recipients, but this may reflect diminished access to assisted reproduction services. The consensus opinion was that there is a need for a collaborative survey of post-transplant women to verify the current impressions that are based on limited information. Such a survey should also investigate whether transplant recipients have appropriate access to assisted reproduction or adoption services. Fertility is clearly restored to such a degree that careful contraceptive counseling is required before transplantation. There are limited data on appropriate contraception following transplantation. The literature cites many theoretical complications to the hormonal approaches, and generally the transplant community has favored barrier methods, among the least effective of modern contraceptive approaches (16). In addition, immunosuppressive agents decrease the effectiveness of intrauterine devices, and immunocompromised subjects using such devices have increased risk for infection (17). The conference attendees discussed risks and benefits of oral contraceptives. Progestin only oral contraceptives while less effective and subject to irregular bleeding are not associated with adverse medical consequences. While data are limited there is no information to suggest that estrogen/progestin is associated with adverse consequences in transplant patients when hypertension is well controlled. All conference attendees agreed that a discussion of post-transplant contraception should occur prior to transplantation in all transplant recipients of reproductive age. The optimal contraceptive agent/s to use after transplantation depends not only on balancing risks and benefits of each of possible contraceptive method, but also on consideration of costs of contraceptive and patient's ultimate desire to conceive. Renal transplant recipients have traditionally been counseled to wait two years after transplantation before conceiving (1). The waiting period to receive cadaver organs has steadily increased potentially leaving women desirous of pregnancy with fewer childbearing years. Our conferees noted that the initial recommendation to wait two years was based on rejection risk, and more recent and potent immunosuppressive strategies have greatly decreased rejection rates in the first post-transplant year. Therefore the advice to wait for two years after a successful transplant may be more restrictive than necessary and may place undue burden on the transplant patient and her partner. The consensus conference addressed timing of pregnancy and felt several individual factors should be considered when offering advice for timing of pregnancy. These considerations include risk of acute rejection, risk of infection with harmful microbes (e.g. CMV), concomitant therapy with dangerous medications, and adequacy of graft function. If the patient has adequate and stable graft function, is at low risk for opportunistic infections, is not taking teratogenic medications, it may be that pregnancy can be attempted only one year after transplantation without concern of increased risks. One is less optimistic if there have been recent episodes of acute graft rejection or if the serum creatinine is >1.5 mg/dl (1). Information regarding timing of pregnancy for women with other solid organ allografts is limited, and the consensus group warned that one cannot extrapolate results and guidelines prescribed for renal transplant recipients to those receiving other organs, however patients with nonrenal solid organ grafts often have renal dysfunction and this must be taken into consideration. Over 14,000 pregnancies in renal allograft recipients have been documented since 1958, permitting the following guidelines (1). These gestations should all be considered high risk, and preferably managed by both transplant physicians and specialists in high-risk pregnancies. The goals are to assure that patients maintain allograft function using appropriate immunosuppressive dosing during gestation and immediately after delivery. Concerning the pregnancy, the major goals are to optimize maternal health including graft function, to maintain a normal metabolic environment (i.e. maintaining normoglycemia), minimize complications associated with preterm birth, detect and manage hypertensive complications especially preeclampsia (which occurs in as much as 20% of transplant recipients) and to ensure adequate fetal growth (1). These patients require close scrutiny including more frequent prenatal visits. Cesarean deliveries are not required despite the transplanted kidney in the pelvis, such surgical deliveries reserved for obstetric indications. All pregnant renal transplant recipients have renal insufficiency, whether or not creatinine levels are in the “normal range”, and one should apply the same management guidelines as those for pregnant subjects whose native kidneys have various degrees of kidney disease. Ironically, despite years of experience and thousands of recorded gestations specific risk factors for adverse graft outcomes have yet to be defined and/or quantified. Registries have helped determine risks, but the voluntary nature of such data acquisition as well as lack of uniform protocols limits the potential of the data collected. Large prospectively designed observational studies are needed, and the conferees noted that a NIH funded trials networks that comprise tens of thousands of deliveries yearly would be a potential source of these studies. In this latter respect representatives from the National Institute of Child Health and Development's Maternal-Fetal Medicine Trial Network, participated in this conference. Such government-funded networks are a potentially powerful resource for studying both risks and outcomes. Hypertension is common and should be managed aggressively during the pregnancy. There is little consensus on ideal anti-hypertensive agents and best management strategies but early use of antihypertensive medications when mild or moderate levels of hypertension appear will prevent maternal hypertensive crisis (18). The consensus opinion was that blood pressure should be maintained close to normal, a view different than the current guidelines for pregnant women with chronic hypertension (18). Successful pregnancies have occurred after pancreas-kidney transplantation (19). The pancreas graft appears to be able to tolerate pregnancy as normoglycemia has been reported (19). Mean newborn birth weights and gestational ages are less when compared to kidney only recipients (19). Liver recipients are also at high-risk for hypertension, preeclampsia and preterm labor (6, 20, 21). Preeclampsia marked by HELLP syndrome is difficult to distinguish from rejection or progression of underlying liver disease, especially hepatitis associated with Hepatitis C (22). It is not known whether immunosuppressant medication requirements change during pregnancy in liver transplant patients or whether immunosuppressant medications increase the risk for an exaggerated response to certain infections such as hepatitis E or HSV during pregnancy (22). Of particular concern is Hepatitis C, the most common indication for liver transplantation. Hepatitis C patients that receive a liver transplant have a high viral load post-transplant (23). Pregnant women without a transplant who are HCV RNA positive have a low rate of HCV maternal-fetal transmission (4–6%) (24, 25). The rate of maternal-fetal Hepatitis C transmission is unknown in liver transplant recipients and requires additional prospective analysis. Clearly additional registry reporting and prospective studies are needed to better identify the risks associated with pregnancy in liver transplant recipients. Pregnancy following heart or heart-lung transplantation has often been discouraged but successful gestations have been recorded (19). Like with renal transplant recipients, there is risk of rejection, fetal growth restriction, preterm delivery, increased hypertension, preeclampsia, and psychological stress. The heart or heart-lung recipient has unique risks as well. The cardiac allograft must respond to hemodynamic changes including increased blood volume of up to 40%, decreased systemic vascular resistance, and increased circulating catecholamines (26). Even further demands for increased cardiac output occur during delivery (26, 27). Monitoring patients with cardiac allografts for rejection requires regular right ventricular biopsies that may even increase in frequency during pregnancy (27). However, because the procedure may expose the fetus to radiation, alternative approaches such as echocardiographically guided right ventricular biopsies may be employed. Like the renal transplant patient, close-follow-up is advised. Some have suggested that pregnancy is an immunosuppressed state (28), but a great deal of evidence shows pregnant women do not have diminished systemic immunity and that the uterus may in fact be an ‘immunopriviledged site” (29). While paternal cells have been found in maternal tissue, maternal regulatory T cells appear to specifically suppress responses to these antigens (30) and maternal responses to the allogeneic fetus are also suppressed locally, at the maternal-fetal interface (31). This is an important concept to emphasize because inappropriate reduction in immunosuppression during pregnancy will lead to rejection of the transplanted organ. Rejection may be difficult to detect during pregnancy, particularly in renal and liver transplant patients (6, 7). Lung-transplant recipients may experience a higher incidence of rejection during pregnancy than recipients of other solid organs, for reasons that are not yet known (32). The consensus opinion was that steroids are safe for anti-rejection therapy, but the safety of antilymphocyte globulins and rituximab in pregnancy are unknown. IVIG has been used fairly extensively without adverse effects. Immunosuppressants cross the placenta and appear in breast milk to varying degrees (33-36). The extent to which individual immunosuppressants cross the placenta or appear in breast milk depends on several factors: including maternal serum drug concentration; concentration gradient between maternal plasma and breast milk, molecular weight, lipid solubility, protein binding and ionization (37). Cyclosporine levels in breast milk may vary drastically and 24-hour collections are required for accurate information (33). Whether or not to breast-feed is still controversial and further study is required before definitive recommendations can be made. The consensus opinion was that breast feeding need not be viewed as absolutely contraindicated. There are several immediate and long-term risks to discuss with prospective parents prior to transplantation and certainly prior to conception. The risk of prematurity and intrauterine growth restriction is very high – up to 50% of infants born to transplant recipients are premature and up to 20% have intrauterine growth restriction (1, 19). The consequences of decreased gestational age at delivery, particularly < 34 weeks gestation, include neonatal death and long-term morbidities such as cerebral palsy, blindness, deafness and learning disabilities and low intelligence quotients. In addition, low birth weight may be associated with increased hypertension, diabetes and coronary artery disease in adulthood (38). These potential risks need to be discussed frankly with the prospective parents and hard ethical discussions entertained. For the patient that presents pregnant, she needs to be aware of these risks in order to make appropriate decisions about who will care for the potentially disabled child in the event that she or her partner are not available. The US registry data have failed to demonstrate any pattern of congenital anomalies associated with the use of calcineurin inhibitors, azathioprine or steroids. While this is encouraging one must be aware that registry numbers are still too small to permit firm conclusions regarding the use of these therapies, especially, several newer immunosuppressive agents such as TOR inhibitors, therapeutic antibodies, or antimetabolites such as mycophenolate mofetil. Recently a case report of major congential malformations associated with in utero exposure to mycophenolate mofetil has raised concern for the use of mycophenolate mofetil during pregnancy (39). It is important to realize that the registry collects voluntary reports of congenital anomalies. Learning disabilities may not be obvious until a child enters school and even then may be missed for several years. Therefore there is a need to follow the children exposed in utero to immunosuppressive agents and to report on outcomes. Enhanced reporting to registries as well as prospective trials need to be designed to follow these children in order to have a clearer idea of the long-term consequences of immunosuppressive agents. Exposure of infants to immunosuppressive medications in utero might increase the child's risk for autoimmune disease later in life (40). Presumably immunosuppressives given to the mother may interfere with fetal thymic development and there is ample animal data to support this possibility (41). Although there appear to be no obvious congenital abnormalities associated with in utero exposure to conventional immunosuppressive agents, long-term follow-up of exposed children is needed. Data on pregnancy outcomes are collected through a voluntary registry, the National Transplantation Pregnancy Registry (NTPR) in the United States, and through the UK Transplant Pregnancy Registry in the United Kingdom. Both registries point to several trends: spontaneous abortion rate about 14%, a high prevalence of hypertension, and an increased occurrence of preeclampsia (19). Over 50% of babies born to kidney transplant recipients are delivered at less than 37 weeks gestation (1, 19). Because of the high rate of prematurity, developmental delays have been noted in some of the offspring (42, 43). These general trends hold up for liver, heart, and lung transplant recipients too though the specific rates vary between organ recipients (19). The benefits of a voluntary registry are clear and important data have been collected. Although we have learned a great deal about pregnancy and transplantation from these registries, enhanced reporting is needed to better understand the risks of pregnancy to transplant recipients and their offspring. Since the risks of in utero exposure to some immunosuppressive agents are not known, what should transplant physicians say to potential parents? The ethical issues surrounding pregnancy in transplant patients are difficult, but must be considered. While there is ample data showing good outcomes, there may be valid reasons to counsel against pregnancy including the potential risks to the graft, to the mother and to the child. The transplant patient though may have no other option for parenthood due to restricted access to adoption services. Although difficult to discuss, the transplant physician needs to make the potential parents aware of the possibility of having a premature infant who survives with disability. The potential parents also need to be aware of the demands that a disabled, or even a healthy, child make on parents and they need to have a plan for alternative care giving in case of parental disability or death. Once all the information is given the ultimate decision for pregnancy though should be made by the patient and her partner. One final area the conferees considered, was the female patient who has been a kidney donor or who is considering donation. An unresolved question is whether pregnancy adversely affects long-term renal function in patients with a single kidney. There was a concern for potential consequences of hyperfiltration by the single remaining kidney and a recognition that there is a need for long-term studies in donor populations (44). The conferees agreed that current evidence is that the kidney donor does not suffer decreased fertility, or have increased complications when pregnant (45) but that potential donors should be made aware that little published data are available. A consensus conference was convened in March 2003 to better understand the risks of pregnancy in transplant recipients. The conference focused on contraception, timing of pregnancy, optimal medical and obstetrical management, treatment of rejection during pregnancy, breast feeding and short and long-term effects on offspring of transplant recipients. Data were presented from published literature and from both national and European Pregnancy Transplantation Registries. Despite limitations on what is known, consensus was achieved in several areas. The consensus opinions are listed in Table 1. Future research goals were defined during the conference. These included defining the optimal prepregnancy graft function for kidney, pancreas–kidney, liver, heart and lung transplant recipients. Defining how pregnancy impacts on short and long-term graft function was felt to be of utmost importance. Other areas that were considered high priority included the targets for blood pressure control, the best anti-hypertensive agents to use during pregnancy, the optimal immunosuppressive regimen to use during pregnancy, and the long-term effects on the offspring. Furthermore we need to know which immunosuppressives can be used safely during pregnancy and during breast-feeding. The conference attendees agreed that collaborative prospective observational studies could help to answer the remaining questions and that transplant societies should advocate for prospective studies at several levels. These levels include the large NICHD trial networks (Maternal Fetal Trials Network, Neonatal Trials Network) and collaborative initiatives within other institutes (NIDDK, NHLBI, NCI, NIAID, etc.), Office of Women's Health, FDA, and industry. It was also the opinion of the conference attendees that there is a vital need for enhanced reporting to the National Transplantation Pregnancy Registry and institution of international registries to help guide the care of the pregnant transplant recipient and her offspring in the modern immunosuppressive era. We need – Collaborative prospective observational studies and registries using such resources as the large NICHD trial networks (Maternal Fetal Trials Network, Neonatal Trials Network). Also collaborative initiatives within other institutes (NIDDK, NHLBI, NCI, NIAID, etc.), Office of Women's Health, FDA, and industry. We would like to acknowledge assistance from the American Society of Transplantation especially the support and guidance of its executive board, and thank Susan Nelson, Nikki Zuecca, and Tina Squillante, for their extraordinary efforts. We thank William E. Harmon MD for his support of the project. We appreciate the wise advice and encouragement provided by Francis L. Delmonico, MD. In addition we thank the conference participants (Sharon M Bartosh, MD; Nancy C. Chescheir, MD; David F. Colombo, MD; John P. Hayslett, MD; Steven Laifer MD; Mariana S. Markell, MD; Judith Massicot-Fisher PhD; Thomas R. McCune, MD; Margaret A. Miller MD; Kathleen Uhl, MD; Jason Umans MD, PhD; Hilary A. Sanfey, MD) for their insightful comments and contributions.