Matthew R. Weir and Edgar V. Lerma (eds.)Kidney Transplantation2014Practical Guide to Management10.1007/978-1-4939-0342-9_17
© Springer Science+Business Media New York 2014
17. Risks of Pregnancy in Renal Transplant Recipients
(1)
Department of Medicine-Nephrology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
(2)
Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL, USA
Abstract
Renal transplant recipients have received the gift of life; with that gift comes the expectation that a normal life can be resumed. An aspect of normal life for many patients is the opportunity to reproduce. While reproduction is considered safe for women without chronic medical conditions, there are many concerns regarding the safety of pregnancy in women with kidney transplants. The safety concerns involve both the mother and her developing fetus. This chapter will review what we know about the risks of pregnancy after transplantation for both the mother and her offspring and provide information from registry data, center studies, and case reports.
History of Pregnancy in Transplant Recipients
Dr. Joseph Murray, who later received the Nobel Prize for performing the first successful kidney transplant, published the first report of pregnancy in transplant recipients in the NEJM [1]. Physicians at that time were worried about the safety of pregnancy in women with kidney transplants and cautioned physicians that there might be significant risks associated with pregnancy in maternal transplant recipients [2, 3]. Despite these early warnings, pregnancy in women with kidney transplants became commonplace. As pregnancy became more common though the care of the pregnant transplant recipient became guided by opinion-based practice, rather than established guidelines [4, 5]. To date we still do not have established guidelines for the care of pregnant transplant recipients or their offspring exposed to immunosuppressive medications in utero.
Sources of Data About Outcomes of Pregnancy in Transplant Recipients
Despite the lack of established guidelines, several registries have evolved to collect outcome data about reproductive issues in renal transplant recipients. These registries have developed both within the United States and throughout the world and provide important information about outcomes for both female and male transplant recipients. The way we manage pregnancy is based on information derived from reports from these voluntary registry data as well as from multi- and single-center reports, many of which rely on retrospective data.
In the United States, the National Transplantation Pregnancy Registry (NTPR) is the predominant source of information on pregnancy outcomes. The registry publishes outcomes on an annual basis and over 2,000 recipients reporting over 3,300 pregnancies have participated in the registry (www.ntpr.giftoflifeinstitute.org). The NTPR relies on voluntary reporting by either the patient or the physician caring for the patient.
Another registry that had previously provided a great deal of information on pregnancy outcomes was the United Kingdom Transplant Pregnancy Registry. This registry directly sought voluntary information from obstetrical units and aggressively collected data from 1992 to 2001. Another voluntary registry that provided important information was the European Dialysis and Transplant Association (EDTA) Registry. The EDTA Registry collected pregnancy data from 1960 to 1992, and recently began to collect data on pregnancies that occurred between 2007 and 2011 through the DIAlysis and Pregnancies in EuRope (DIAPER) study (www.era-edta-reg.org).
Other registries have evolved since these early ones, including registries that continue to provide information about pregnancy collected through the Australia and New Zealand Dialysis and Transplant Registry (www.anzdata.org.au) and several reports have come from centers participating in the Saudi Center for Organ Transplantation (www.scot.org.sa). At this time numerous other registries have developed to study outcomes in maternal transplant recipients and their offspring that are funded by pharmaceutical companies interested in evaluating the short- and long-term risks of their medications during pregnancy.
Fertility in Patients with ESRD
Fertility is decreased for both women and men on dialysis [6–8]. Women are often anovulatory, although it is reversed soon after transplantation [9, 10]. Women have been reported to become pregnant soon after transplantation and there are reports of early pregnancy occurring, due to rapid resumption of ovulation in the successfully transplanted patient [11–15]. Men are often infertile as well, due to defects in gonadal function, and their fertility is improved by transplantation [16]. Whether fertility is resumed to normal after transplantation is not known and data on the use of assisted reproduction in transplant recipients is evolving.
As our patients are waiting longer for deceased donor transplants, we are faced with women aging through their ideal reproductive years. In fact women with ESRD reach menopause at an earlier age than women with normal renal function [8]. Since patients are generally waiting longer to receive a deceased donor transplant, women are usually older when they undergo transplantation, and therefore conception can be challenging for the older female transplant recipient. This should be considered in counseling the female transplant recipient considering pregnancy. Men wishing to father children should not be prescribed sirolimus as there are several reports of infertility associated with sirolimus [17–19].
Contraception in Renal Transplant Recipients
Contraception is mandatory in all women of reproductive age and the American Society of Transplantation has recommended that contraception begin before the transplant procedure in women of reproductive age [5]. A report from a single center in Brazil demonstrated that although most female kidney transplant recipients were sexually active before and after transplantation, many were not counseled about the need for contraception and did not use any form of birth control [20]. It is strongly recommended that contraceptive methods be discussed with potential maternal transplant recipients during their pretransplant evaluation [5]. Contraception has not been recommended for male transplant recipients, as data to date suggest that male transplant recipients are not at significant risk of germ cell mutations associated with the use of immunosuppressive medications. There are no recommendations to delay reproduction assigned to male transplant recipients.
Effective contraception requires reliable suppression of fertility. Recommendations do not include the use of single barrier methods—such as condoms or diaphragms, due to the potential unreliability of their use. Reversible contraception methods include intrauterine devices (IUDs), hormonal methods, and barrier methods. The optimal method of contraception depends on several factors, including comorbid diseases that might be impacted by contraceptive hormones (such as liver and bone disease) and interactions with other medications. Although older reports suggested that IUDs were contraindicated in transplant recipients, newer types of IUD formulations appear to be effective without risk of pelvic inflammatory disease [21, 22]. Hormonal agents such as Depo-Provera or Depot medroxyprogesterone acetate are metabolized in the liver and have been associated with bone loss [22]. A recent report suggested efficacy and safety of the contraceptive vaginal ring (NuvaRing) in renal and liver transplant recipients [23]. Recent recommendations of the mycophenolate risk evaluation and mitigation strategies (REMS) program are that transplant recipients at risk of pregnancy either use effective reversible contraception (defined as IUD, combination of one hormone and one barrier method, or simultaneous use of two barrier methods) or consider irreversible contraception (tubal ligation or male vasectomy).
Timing of Pregnancy
The female transplant recipient should become pregnant in a planned manner. The recommendations are that pregnancy is delayed for a year after successful transplantation [5]. This recommendation replaces an earlier one that advised women to wait for 2 years after their transplant to become pregnant. It has now been recognized that newer immunosuppressive medications have decreased the risk of rejection and that allograft function is usually stable by 1 year in the uncomplicated renal transplant recipient. The American Society of Transplantation recommends that pregnancy could be safe in the first year as long as the following caveats were considered: graft function was stable, with no evidence of rejection; allograft function was good (defined as a serum creatinine <1.5 and less than 500 mg protein excreted per 24 h); that the patient was not currently taking teratogenic medications (such as valganciclovir); there were no active infections with agents that could adversely impact the fetus (such as CMV); and that the allograft function was stable. Since the reproductive phase is shortened for women with ESRD, and patients are waiting longer for deceased donor organs, the risk of waiting for 2 years after transplantation to become pregnant is that the patient may no longer be fertile. There are several recent reports that suggest that the rate of spontaneous abortion might be higher in pregnancies planned before 2 years, although this is an area of controversy [24–26].
Risks Associated with Pregnancy for the Mother
There are several risks to consider for pregnancy in the maternal transplant recipient, including the risks of short- and long-term graft function, allograft rejection, acceleration of hypertension, and preeclampsia. Each of these will be discussed under the subheadings below.
Short- and Long-Term Graft Function
The risks of graft loss appear to correlate with allograft function at the time of conception. Hou et al. reported in 1999 that women with graft dysfunction before pregnancy (defined as a serum creatinine >1.5 mg/dL (133 mol/L)) were at increased risk for graft dysfunction during and after pregnancy [27]. The American Society of Transplantation echoed these concerns in their 2008 consensus conference report and stated that maternal transplant recipients with a creatinine <1.5 mg/dL and with minimal proteinuria were at low risk for short- and long-term graft loss, as long as adequate immunosuppression was maintained during the pregnancy (discussed below) [5]. Registry data have subsequently confirmed that women with good graft function at the time of pregnancy did not appear to have an accelerated loss of graft function [28–30]. It is important to realize that assessments of renal function in this population have generally depended on measurements of serum creatinine and protein excretion, and that prospective monitoring of glomerular filtration rates has not been reported in large numbers of patients during and after pregnancy.
Allograft Rejection
Rejection during pregnancy should be prevented if possible, as its detection is more difficult than in the nonpregnant transplant recipient. Creatinine levels normally decrease with the expanding intravascular volume and increased glomerular filtration rate that normally accompanies pregnancy [31]. In fact, two maternal deaths have occurred after discontinuation of immunosuppressive medications during gestation [32]. To avoid rejection, immunosuppressive drug dosing should be watched closely and frequent monitoring of serum drug levels is a must. It is important to monitor calcineurin levels frequently because marked alterations in the volume of drug distribution occur during gestation that affect levels [10]. A recent report though suggests that interpretation of whole blood tacrolimus levels during pregnancy might be challenging, due to variable factors that can increase the unbound fraction of tacrolimus [33].
It is important to realize that the mother is not “naturally” immunosuppressed during her pregnancy and therefore therapeutic immunosuppressive dosing must be maintained [10]. In fact rejection rates in women with solid organ transplants are equivalent to rejection rates in nonpregnant transplant recipients [34]. If rejection does occur, it usually responds to methylprednisolone [35], although antithymocyte globulin and basiliximab have been used successfully based on a registry report [36].
Hypertension
Most transplant recipients have chronic hypertension and maternal transplant recipients are at risk for worsening hypertension during their pregnancy. The NTPR reported hypertension during pregnancy to be at extremely high rates (reported incidence of near 75 %) [37, 38]. The blood pressure varies throughout normal gestation, with the lowest levels during the first trimester, followed by resumption of pre-pregnancy blood pressures late in gestation. A similar, but blunted, pattern is seen in maternal transplant recipients [39]. It is important to try to maintain the blood pressure near normal levels in pregnant recipients to avoid preterm delivery [40]. The preferred agent for blood pressure control during pregnancy is methyldopa, although alpha- and beta-blockers, calcium-channel blockers, alpha-adrenergic blockers, and thiazide diuretics have also been prescribed [41]. Angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers are associated with fetal death and are therefore contraindicated after the first trimester; and atenolol has been associated with poor fetal growth [41].
Preeclampsia
Preeclampsia occurs commonly in maternal transplant recipients, for reasons that have not yet been clarified. The NTPR reports that up to one third of pregnant transplant recipients develop preeclampsia [42]. The incidence of preeclampsia in patients without hypertension or chronic disease is 5 % [40]. The diagnosis of preeclampsia is challenging because there is often preexisting proteinuria, the blood pressure typically rises in the last trimester in transplant recipients, and uric acid levels are commonly elevated in patients taking calcineurin inhibitors [3, 43]. Whether circulating angiogenic factors will ultimately be used as biomarkers for early detection is too early to tell, but intriguing reports suggest there may be a future role [44]. Close monitoring of the patient by her high-risk obstetrician is mandatory to increase the detection and proper treatment of preeclampsia.
Risks Associated with Pregnancy for the Infant
The developing infant is at risk for several serious complications and these risks have been consistently reported in registry and center publications. The complications reported include preterm birth, low birth weight, intrauterine growth retardation, as well as short-term and long-term defects in immunologic and neurocognitive function.
Preterm Birth
Several recent reports have shown that preterm birth is very common, with an average infant gestational age of 36 weeks [28, 29, 45]. The gestational birth ages seem to be consistent among recipients of other solid organs as well [10]. The reason for early birth rates in maternal transplant recipients is not known, but preterm birth has frequently been seen in maternal patients with chronic kidney disease [46]. The overall risk of preterm delivery is 50 % among all published studies [10]. Data from the NTPR shows a mean gestational age of 36 weeks for maternal transplant recipients taking cyclosporine versus 35 weeks for those prescribed tacrolimus [28]. Whether there are significant differences between preterm birth rates based on immunosuppressive drug regimen is not known at this time.
Low Birth Weight
Approximately 50 % of infants born to transplanted mothers have a birth weight less than 2,500 g (5.5 lbs) [28, 29, 45]. Normal birth weight is approximately 3,400 g (7 lbs, 8 oz). The reason for this low birth is not clear, but may be associated with the high rates of preterm birth. Other reasons for low birth rate in the general population include a young (maternal age under 17) or older (maternal age over 35) mother, a previous history of preterm birth, smoking, high body mass index, uterine infections, and placental growth restriction. The long-term consequences of low birth weight have been reported widely and include a higher likelihood for development of neurocognitive defects and cardiovascular and renal disease later in life, probably related to alterations in organ development during vulnerable times in fetal growth [47]. Pregnancy in women with chronic kidney disease is also highly associated with low birth weight and small gestational age for infants, implying a primary pathological process associated with diminished maternal kidney function [46].
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