INTRODUCTION — Abnormalities in both sexual and reproductive function are common among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In women, CKD leads to hypogonadism, which manifests clinically as menstrual irregularities, anovulation, reduced libido, and infertility [1]. Many of these disturbances typically persist after these patients have initiated chronic dialysis. Pregnancy occurs rarely among women with advanced kidney failure, and, even when conception is successful, it is associated with adverse maternal and fetal outcomes. In addition, women with CKD have an earlier onset of menopause compared with the general population. Abnormalities also occur in a significant proportion of men with moderate to severe CKD, who may complain of decreased libido, erectile dysfunction (ED), gynecomastia, and impaired fertility. Although some of these problems may improve with maintenance dialysis, they rarely normalize and frequently contribute to a decreased quality of life. (See "Epidemiology and etiologies of male sexual dysfunction".)
Kidney transplantation helps to restore sexual and reproductive function in both females and males, although certain features of reproductive function may remain impaired. This topic will review issues relevant to the sexual and reproductive health of patients who have undergone kidney transplantation. A discussion of pregnancy in kidney donors and in nontransplant patients with underlying kidney disease is presented separately:
●(See "Pregnancy in women with nondialysis chronic kidney disease".)
SEXUAL FUNCTION AFTER TRANSPLANTATION
In females — Disturbances in menstruation, fertility, and sexual function are common in women with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) due to abnormalities in the hypothalamic-pituitary-gonadal axis that result in varying degrees of hypogonadism. Women with ESKD frequently report oligomenorrhea or amenorrhea, anovulation, decreased libido, problems with vaginal lubrication, and the inability to achieve orgasm [2]. Such women commonly have elevated circulating levels of prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and reduced levels of estradiol and progesterone. In addition, the preovulatory LH surge is typically absent in these patients.
After kidney transplantation, many of these hormonal disturbances improve rapidly (as early as a few weeks posttransplant), and, in many patients, the hypothalamic-pituitary-gonadal axis can normalize as early as six months posttransplant [3]. As restoration of fertility can occur rapidly, contraception should be planned before transplantation. Initiation of estrogen-containing contraceptives should be delayed until six weeks after transplantation to avoid the increased risk of thrombotic event during the perioperative period. (See 'Contraception' below.)
In addition, libido and sexual function frequently improve after transplantation. In one study of 33 female kidney transplant recipients, loss of libido went from 70 percent pretransplant to 10 percent posttransplant [4]. The degree of improvement of sexual health may also be impacted by the health of the allograft, the presence of other comorbidities (such as diabetes and hypertension), certain medications, and psychological factors.
In males — A significant proportion of men with advanced CKD experience disturbances in sexual function, including erectile dysfunction (ED), decreased libido, and a decline in the frequency of intercourse. These abnormalities may improve but rarely normalize with the institution of maintenance dialysis. (See "Epidemiology and etiologies of male sexual dysfunction".)
However, sexual and reproductive health generally improve in most men after kidney transplantation. An improvement in reproductive function occurs in association with normalization of the serum testosterone concentration and, in many patients, an increase in sperm count [5,6]. In addition, serum levels of FSH, LH, and prolactin, which are usually increased in uremic men, begin to improve as early as a few weeks after a successful kidney transplant and approach normal levels within a few months posttransplant [3,7,8]. The degree of improvement in sexual and reproductive health is also impacted by other factors, including the health of the allograft, other comorbidities (such as diabetes, hypertension, dyslipidemia, and smoking history), certain medications, recipient age, as well as psychological factors.
As with female transplant recipients, male recipients should be counseled about the potential for improvements in sexual and reproductive health posttransplant. For men who wish to conceive, routine semen analysis is not advised, unless additional risk factors for infertility are present (see "Causes of male infertility"). Sexually active men should be reminded of the importance of preventing sexually transmitted infections (STIs) with condoms when not in a long-term, monogamous relationship. However, some men, especially those with multiple comorbidities, may continue to experience some degree of impairment, particularly with reduced libido and ED.
Immunosuppressive agents used in kidney transplantation may affect male fertility. Although numerous reports have indicated that male transplant recipients can successfully father healthy offspring [9], some studies suggest that mammalian (mechanistic) target of rapamycin (mTOR) inhibitors such as sirolimus may cause impaired spermatogenesis and reduce male fertility [10-13]. This is discussed in more detail elsewhere. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Teratogenicity/effects on pregnancy and fertility'.)
CONTRACEPTION
Female contraception — We advise that women of childbearing age receive counseling regarding contraception before undergoing transplantation and again at posttransplant clinic visits. Since sexual function in women improves within a few weeks posttransplant, we recommend that clinicians and patients discuss a contraceptive plan prior to transplant and that women initiate contraception before they resume sexual activity. Such discussion is particularly important because the immunosuppressant mycophenolate appears to decrease serum estrogen concentrations, which could theoretically reduce efficacy of estrogen-progestin contraceptives (pill, ring, or patch) [14]. We also review data indicating that female transplant recipients should avoid pregnancy during the first posttransplant year. (See 'Timing of conception' below.)
The optimal form of contraception for transplant recipients is not known and is individualized based upon the side-effect profile [15,16]. Thus, we educate women who desire to avoid pregnancy about all contraceptive methods that are reasonable choices given their medical issues and encourage the use of the most effective types (figure 1). The approach to contraceptive selection is presented in detail elsewhere. (See "Contraception: Counseling and selection".)
For women who desire reversible contraception, we first discuss long-acting reversible contraception because these methods have the highest efficacy rates (figure 1). Long-acting reversible contraception methods include the intrauterine devices (IUDs) and the progestin-releasing implant. For women who elect contraceptive pills, patch, or ring, we discuss that antibiotic use, with the exception of rifampin, does not decrease efficacy [17-20]. We prefer to delay the start of estrogen-containing contraceptives (pills, ring, or patch) until six weeks posttransplant because of the increased risk of thromboembolic events with estrogen use. The United States Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria for Contraceptive Use 2016 help guide the counseling of women with solid organ transplants based on the type of transplant, other comorbid issues, and concomitant medication use [21]:
●Uncomplicated transplant – Women with uncomplicated kidney transplants can use any method compatible with their other medical issues as the benefits are believed to outweigh any theoretical or proven risks. Specifically, although supporting data are limited, women with kidney transplants can use either the copper or levonorgestrel-releasing IUDs (eg, new start or continuation of existing device), the progestin-only methods (implant, injection, or pills), or estrogen-containing methods (pill, patch, or ring). Women with risk factors for thromboembolic disease should generally avoid estrogen-containing contraceptives regardless of transplant status. In our practice, we also prefer to avoid the progestin injection because long-term use is associated with reduced bone density independent of that associated with kidney transplantation. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects' and "Kidney transplantation in adults: Bone disease after kidney transplantation".)
●Complicated transplant – Women with complicated solid organ transplants (eg, those with acute or chronic graft failure, rejection, or cardiac allograft vasculopathy) can continue existing IUDs but are not advised to initiate new ones, although supporting data are sparse. These women can use any of the progestin-only methods. Use of estrogen-containing contraceptives is not advised for women with complicated transplants, although this guidance is mainly based on one study that reported serious adverse events in 8 percent (2/26) of women using estrogen-progestin contraceptive pills and a case report of a woman who developed cholestasis while taking high-dose estrogen-progestin contraceptive pills.
Women who desire permanent contraception are offered female tubal ligation or placement of a long-acting reversible contraceptive as the efficacy is the same between these methods (figure 1). Use of long-acting reversible contraceptives eliminates the need for surgery and the resultant risk of surgical complications.
Male contraception — We advise that men receive counseling regarding fathering and contraception before transplantation and again at the posttransplant clinic visits. Since sexual function in men tends to improve within a few weeks posttransplant, and fathering a pregnancy becomes a distinct possibility, we recommend that men use contraception after transplant as soon as they become sexually active.
For men who desire permanent contraception, we offer vasectomy. For men who desire reversible contraception, male condoms are the main option. However, for some men with erectile dysfunction (ED), condoms can worsen the sexual experience, which leaves these patients without a reliable contraceptive method [22]. While some men practice withdrawal, the pregnancy rate is over 20 percent per 100 women per years with this method, and, therefore, this approach is not advised (figure 1).
Emergency contraception — Women with kidney transplants can use emergency contraception (EC) [21]. As with regular contraception, the suggested methods vary based on the patient's transplant status, and the CDC Medical Eligibility Criteria for Contraceptive Use 2016 guide patient counseling [21]:
●Uncomplicated transplant – There are no restrictions to using ulipristal acetate, levonorgestrel, or combined estrogen-progestin contraceptive pills in women with uncomplicated kidney transplants. The copper IUD is also an option as the benefits are believed to outweigh any theoretical or established risks. Of note, the copper IUD is the most effective EC, is not affected by patient body weight, has no systemic hormonal effects, and provides ongoing contraception. Thus, the multiple benefits of the copper IUD make it our preferred EC for women who desire EC and are accepting of an IUD. (See "Emergency contraception", section on 'What are the emergency contraception methods?'.)
●Complicated transplant – The CDC defines complicated transplants as those with acute or chronic graft failure, graft rejection, or vasculopathy (cardiac allografts). In women with these issues, the copper IUD is believed to have more risks than benefits and, thus, is avoided. Medical therapy with ulipristal acetate, levonorgestrel, or combined estrogen-progestin contraceptive pills is offered to these women who desire EC. (See "Emergency contraception", section on 'What are the emergency contraception methods?'.)
Details regarding the methods of EC, efficacy, and risks and benefits are presented separately. (See "Emergency contraception".)
STI PREVENTION — Options for prevention of sexually transmitted infections (STIs) mainly include male and, to a lesser degree, female condoms. Any patient at risk of STI acquisition is advised on condom use regardless of contraceptive needs. Human papillomavirus (HPV) vaccination is discussed with both female and male patients as part of assessing immunization status during the routine pretransplant evaluation. (See "Immunizations in solid organ transplant candidates and recipients".)
The prevention of STIs is discussed in greater detail in the following topics:
●(See "Prevention of sexually transmitted infections".)
●(See "External (formerly male) condoms", section on 'Protection from STIs'.)
●(See "Internal (formerly female) condoms", section on 'Sexually transmitted infections'.)
PREGNANCY — Since the first successful pregnancy in a kidney transplant recipient was described in 1958 [23], many other successful pregnancies have been reported among the kidney transplant population. However, despite the return of fertility after kidney transplantation, the rates of both pregnancy and successful pregnancy remain far lower than in the general population. Pregnancy in the transplant recipient is considered high risk given the multiple risk factors for both the mother and the developing fetus, and kidney transplant recipients who are considering pregnancy should be managed by a high-risk obstetrician in conjunction with a transplant nephrologist.
Obstetric outcomes
Maternal outcomes — Available data on pregnancy outcomes in posttransplant pregnancy are primarily derived from case reports, single-center studies, and four voluntary registries including the Transplant Pregnancy Registry International (TPR; previously known as the United States National Transplantation Pregnancy Registry [NTPR]), the Transplant Pregnancy Registry of the United Kingdom, the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) registry, and the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). Limitations of most of these studies include retrospective study design, relatively small patient numbers, and reporting bias.
●Pregnancy rate – Fertility generally returns after kidney transplantation [24-28]. However, pregnancy rates remain far lower than in the general population [27-31]. The best data come from a longitudinal cohort of 30,078 female transplant recipients aged 15 to 45 years [27]. During the first three posttransplant years, the unadjusted pregnancy rate was 33 per 1000 women compared with more than 100 per 1000 women in the general population. There was also a temporal trend toward reduced pregnancy rates over time, ranging from 59 per 1000 women in 1990 to 19 per 1000 women in 2003.
The reason for such a marked reduction in the fertility rate in women of childbearing potential is unclear. While the difference could be explained, to some extent, by the degree of chronic kidney disease (CKD) observed in the transplant population, other potential explanations include the deliberate avoidance of pregnancy secondary to more education and overall knowledge about the high-risk nature of posttransplant pregnancies, the uncertainties regarding immunosuppression during pregnancy and its impact on the fetus, fear of allograft loss, changing views on women's health, and better education regarding the use of different contraceptive methods.
●Live birth rate – Among kidney transplant recipients who do conceive, the live birth rate appears to be comparable with that of the general population. As an example, a systematic review and meta-analysis of 50 studies (4706 pregnancies in 3570 kidney transplant recipients) reported a live birth rate among transplant recipients of 73.5 percent, compared with 66.7 percent in the general population [29]. Other retrospective studies have found similar live birth rates ranging from 71 to 79 percent [28,32-34]. One study, however, has reported a lower live birth rate in transplant recipients. In the large, longitudinal cohort study mentioned above, 55 percent of pregnancies resulted in a live birth compared with nearly 70 percent in the general population [27]. Although the proportion of successful pregnancies remained relatively constant between 1990 and 2003, the reasons for fetal loss changed over time. The unadjusted rate of therapeutic abortions declined from 19 to 6 percent, while fetal loss due to other causes increased from 25 to 37 percent.
●Cesarean delivery – Although a trial of vaginal labor is advised, kidney transplant recipients have a higher risk of cesarean delivery compared with the general population, with a reported frequency of 43 to 72 percent [29,32,33,35]. In a study of the UK Obstetric Surveillance System (UKOSS), the risk of cesarean section in kidney transplant recipients was nearly fivefold higher than in the general population [33]. The most common indications for cesarean delivery before the onset of labor included concern for fetal well-being (23 percent), previous cesarean section (19 percent), and deteriorating kidney function (16 percent), whereas the most common indication for in-labor cesarean section was fetal distress (67 percent). Three percent of cesarean deliveries were performed only because the patient had a kidney transplant, in the absence of a clinical indication. (See 'Mode of delivery' below.)
●Maternal mortality – Although studies have shown that long-term survival of pregnant transplant recipients appears to be comparable with that of nonpregnant recipients [28,36], there are little data regarding rates of maternal death (defined as death of a woman while pregnant or within 42 days of termination of pregnancy) among pregnant transplant recipients. In the UKOSS study cited above, among 105 pregnancies in 101 recipients, there were no maternal deaths [33]. Studies in nontransplant patients with CKD suggest that the risk of maternal death is limited to women with immunologic disorders such as systemic lupus erythematosus or vasculitis [37]. (See "Overview of maternal mortality".)
Fetal outcomes — Although the majority of pregnancies after kidney transplantation result in a live birth, the risk of fetal complications, such as preterm birth, low birth weight, and fetal growth restriction (FGR), remains high.
●Preterm birth – Preterm birth (delivery at <37 weeks of gestation) occurs more commonly among transplant recipients [27-29,31-33,38]. As examples:
•In a meta-analysis that included 4706 pregnancies in 3570 kidney transplant recipients, preterm delivery occurred in 46 percent of patients, compared with approximately 13 percent in the general United States population [29].
•Of 105 pregnancies in 101 transplant recipients who were identified through UKOSS, 52 percent delivered at <37 weeks compared with the national rate in the United Kingdom of 8 percent [33]. The risk of preterm delivery among kidney transplant recipients was nearly 13-fold greater than the general population (adjusted odds ratio 12.7, 95% CI 8.0-20.1).
In one study, predictors of preterm delivery among kidney transplant recipients included the presence of maternal hypertension and a serum creatinine of >1.7 mg/dL before pregnancy [32].
●Low birth weight – The frequency of low birth weight (defined as a birth weight of <2500 g) is also higher among kidney transplant patients and ranges from 20 to 50 percent versus 8.1 percent in the general United States population [32,34]. In the analysis of the UKOSS cohort mentioned above, transplant recipients had a 12-fold higher risk of delivering a low birth weight baby compared with the general population [33]. The burden of preterm birth and low birth weight can involve significant neonatal morbidity and long-term complications, including neurodevelopmental deficits and an increased risk of chronic disease in adulthood such as diabetes mellitus, hypertension, and coronary heart disease [39].
●Fetal growth restriction – Pregnancy among kidney transplant recipients is associated with a higher incidence of FGR (defined as estimated fetal weight below the 10th percentile for gestational age), ranging from 20 to 50 percent compared with approximately 3 to 10 percent in the general population [40-43]. Risk factors associated with the development of FGR in the kidney transplant population include prepregnancy hypertension, proteinuria, and calcineurin inhibitor (CNI) use [40,42].
●Spontaneous abortion – Rates of spontaneous abortion (or miscarriage), defined as the spontaneous loss of a pregnancy before the 20th week of gestation, are generally comparable between transplant and nontransplant patients. As an example, one meta-analysis found a miscarriage rate of 14 compared with 17.1 percent in the general population [29]. Similar rates of spontaneous abortion have been reported in two other observational studies [32,33]. However, in one analysis of over 16,000 kidney transplant recipients transplanted between 1990 and 2003, the rate of spontaneous abortion was 23.7, 20.7, and 18.8 percent for pregnancies occurring in the first, second, and third posttransplant years, respectively [27]. (See 'Timing of conception' below.)
Mycophenolate mofetil/sodium has been associated with an increased incidence of spontaneous abortions. According to data from the 2016 TPR, the spontaneous abortion rate after kidney transplantation was 18 percent; most of these pregnancies (83 percent) were documented to have had first trimester mycophenolate exposure [44]. The use of mycophenolate is contraindicated among pregnant transplant recipients. (See 'Management of immunosuppression' below and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)
●Stillbirth – Rates of stillbirth among transplant recipients range from 1.5 to 3 percent [27,29,32,44], compared with less than 1 percent in the United States general population. In one meta-analysis, the rate of stillbirth was higher among women of more advanced maternal age (>30 years old) versus those with a younger maternal age (<30 years old; 3.6 versus 2.2 percent, respectively). (See "Stillbirth: Incidence, risk factors, etiology, and prevention", section on 'Strategies for prevention of recurrent stillbirth'.)
Predictors of pregnancy outcomes — A number of factors have been associated with poor pregnancy outcomes in kidney transplant recipients. As examples:
●In a systematic review and meta-analysis of 50 studies (4706 pregnancies in 3570 recipients), hypertension, a serum creatinine >1.5 mg/dL (133 micromol/L), and proteinuria were identified as prepregnancy predictors of adverse pregnancy outcomes [29]. The presence of hypertension before pregnancy was associated with FGR, low birth weight, miscarriage, and preterm delivery. A prepregnancy serum creatinine >1.5 mg/dL (133 micromol/L) was associated with preterm delivery, low birth weight, and miscarriage.
●In the analysis of the UKOSS cohort cited above, a poor pregnancy outcome (first or second trimester loss, stillbirth, neonatal death, very preterm birth <32 weeks, or a congenital anomaly) was predicted by first trimester serum creatinine >1.4 mg/dL (125 micromol/L), diastolic blood pressure >90 mmHg in the second and third trimesters, and more than one previous kidney transplant [33].
Conversely, several studies have shown that patients with a serum creatinine of ≤1.5 mg/dL (133 micromol/L), controlled blood pressure, and no significant proteinuria have improved maternal, fetal, and graft outcomes [1,26,27,29,33,45-50].
The timing of pregnancy after transplant also appears to impact both maternal and fetal outcomes. A pregnancy during the first posttransplant year is considered to be higher risk and is generally discouraged as the risk for acute rejection and infection is highest during this time period. In one observational study, for example, the rate of fetal loss was 55.3 percent among pregnancies during the first posttransplant year, compared with 40.2 and 37.6 percent of those during the second and third posttransplant years, respectively [27]. Most data have suggested improved outcomes in patients who wait a minimum of one year after transplantation [51]; however, some studies have found no association between time from transplant to conception and pregnancy outcomes [33]. The optimal timing of pregnancy has not been clearly defined [27,28,52,53]. (See 'Timing of conception' below.)
Additional factors that have been associated with a higher risk of fetal loss include diabetes as the cause of end-stage kidney disease (ESKD), advanced maternal age, and low median household income; Black females also have a higher risk [27-29,52,53].
Effect of pregnancy on graft function and outcomes — During normal pregnancy, glomerular filtration rate (GFR) increases by approximately 50 percent, and there is a reduction in serum creatinine levels. In pregnant transplant recipients, the decrease in creatinine may be more subtle. In one study of 105 pregnancies in 101 recipients, the median serum creatinine decreased from 1.33 mg/dL (118 micromol/L) before pregnancy to 1.18 mg/dL (104 micromol/L) in the first and second trimesters, then rose to 1.39 (123 micromol/L) in the third trimester [33]. However, 49 percent of patients did not experience a reduction in serum creatinine during the second trimester, and a reduction in graft function (defined as an increase in serum creatinine of ≥20 percent from the lowest level in pregnancy) occurred in 38 percent. Among those with a reported cause for the increased creatinine, 63 percent were attributed to preeclampsia and 11 percent to acute rejection. In another study, the increase in 24-hour creatinine clearance measured at 10 weeks of gestation was comparable between transplant recipients and healthy nontransplant women (34 versus 38 percent) [54].
Urine protein excretion also increases during pregnancy due to hyperfiltration, and this increase has been shown to be greater in pregnant kidney transplant recipients compared with healthy pregnant women. One study found that mean 24-hour urine protein excretion increased threefold by the third trimester to 500 mg in transplant recipients, compared with 200 mg among healthy women [54]. Proteinuria returned to nonpregnant levels by 8 to 12 weeks postpartum.
Kidney allograft outcomes in pregnant transplant recipients with a well-functioning allograft appear to be comparable with that of nonpregnant transplant recipients [28,36,51,55-59]. The following studies illustrate the range of findings:
●In an analysis of the ANZDATA that matched 120 pregnant with 120 nonpregnant kidney transplant recipients, delivery of a first live birth was not associated with poorer 20-year graft or patient survival [28].
●In another study, the long-term outcomes of 39 women who became pregnant with a functioning allograft were each compared with three matched control patients [36]. Prepregnancy serum creatinine levels were <1.4 mg/dL (124 micromol/L) in most (85 percent) of the pregnant recipients. At 15 years posttransplant, allograft and patient survival were similar in both groups (72 and 85 percent in pregnant women versus 69 and 79 percent in the control group, respectively). In addition, kidney function was similar at 1, 5, and 10 years posttransplant.
●In the 2016 TPR annual report, which reported data for 1031 transplant recipients who became pregnant between 1967 and 2016, the rate of graft loss within two years of pregnancy outcome was 5.9 percent [44]. Rejection during or after pregnancy occurred in 0.9 and 1.4 percent, respectively.
Important factors that appear to influence graft stability during and after pregnancy include graft function and proteinuria before pregnancy [29,54,60,61], the presence of hypertension before or during pregnancy [32,62], and the stability of immunosuppression levels during pregnancy [54,62,63]. In addition, the timing of pregnancy after transplantation has also been shown to impact graft outcomes. In a study of 729 pregnancies among 21,814 female kidney transplant recipients between 1990 and 2010, pregnancy in the first or second, but not the third, posttransplant year was associated with an increased risk of death-censored graft loss [52].
Preconception care
Preconception counseling — Preconception counseling should be initiated during the pretransplant evaluation. Patients should be informed that pregnancy after transplantation is considered high risk [33] and will require a multidisciplinary effort that involves both a high-risk obstetrician and nephrologist working closely together. The following issues should be discussed with the patient prior to, as well as soon after, transplantation:
●Pregnancy outcomes (both maternal and fetal) after transplant (see 'Maternal outcomes' above and 'Fetal outcomes' above)
●Maternal risks, including both potential obstetric complications and risks to the allograft (see 'Maternal complications' below and 'Effect of pregnancy on graft function and outcomes' above)
●Contraceptive methods (see 'Female contraception' above)
●Recommended timing of conception after transplant (see 'Timing of conception' below)
●Management of maintenance immunosuppression before, during, and after pregnancy (see 'Management of immunosuppression' below)
Patients with complex disease processes such as systemic lupus erythematosus and diabetes should not be entirely discouraged from pursuing pregnancy but rather evaluated on a case-by-case basis [64]. These women should also be educated as to alternate family building options such as adoption and surrogacy, where legal.
A discussion of preconception care for the general population is presented in detail separately. (See "The preconception office visit".)
Timing of conception — The optimal time for conception after kidney transplantation is uncertain. We agree with the 2005 American Society of Transplantation (AST) report on the Consensus Conference on Reproductive Issues and Transplantation, which states that the kidney transplant recipient can safely proceed with pregnancy, provided that the following conditions are met [31]:
●It has been more than one year since kidney transplantation.
●Graft function is optimal, defined as a serum creatinine of <1.5 mg/dL (133 micromol/L), with no or minimal proteinuria.
●There have been no episodes of rejection in the previous year.
●There are no concurrent fetotoxic infections, such as cytomegalovirus (CMV).
●The patient is not on known teratogenic or fetotoxic medications.
●The immunosuppressive regimen is stable at maintenance levels.
In addition, patients who have a history of recent (but not currently active) CMV disease should be advised to wait at least six months and preferably one year from the resolution of disease before trying to conceive. There are no high-quality data to guide the optimal timing of pregnancy after CMV infection. At our center, we advocate waiting one year following complete resolution of infection.
While we, and most experts, recommend avoiding pregnancy during the first posttransplant year (when the risk of rejection and infection is highest), the timing of pregnancy may need to be individualized in certain patients, such as those who are older and have a limited number of reproductive years. Successful pregnancies within the first posttransplant year have been reported, with no difference in pregnancy outcomes, maternal and fetal complications, or graft survival compared with pregnancies that occurred after one year [51,65].
Even when the above conditions are met, pregnancy presents some risk to the patient, allograft, and fetus. The major risks to the patient include the risk of rejection and allograft failure due to changes in the metabolism of immunosuppressive medications and increased filtration that occurs during pregnancy. (See 'Effect of pregnancy on graft function and outcomes' above and 'Rejection' below.)
Baseline evaluation — In all kidney transplant recipients who are considering becoming pregnant, we advise a multidisciplinary evaluation that includes a transplant nephrologist, a transplant surgeon, and a maternal-fetal medicine specialist (high-risk obstetrician). We perform the following baseline evaluation prior to planned conception:
●Assessment of the patient's medical history to identify any important clinical events (eg, episodes of rejection, potentially fetotoxic infections such as CMV) in the preceding year
●Assessment of the patient's medication history for potential teratogenic or fetotoxic medications (discontinue and/or substitute medications that have been identified to be potentially teratogenic or fetotoxic [eg, angiotensin-converting enzyme (ACE) inhibitors])
●Assessment of the patient's maintenance immunosuppression regimen (see 'Management of immunosuppression' below)
●Assessment of vaccination status (see 'Vaccination' below)
●Assessment of blood pressure (see 'Hypertension' below)
●Measurement of serum creatinine, bicarbonate, and electrolytes
●Measurement of fasting plasma glucose and hemoglobin glycated hemoglobin (A1C) (see 'Gestational diabetes' below)
●Liver function tests (see 'Preeclampsia' below)
●Complete blood count (see 'Anemia' below)
●Plasma polymerase chain reaction (PCR) testing for CMV and BK virus (see "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Kidney transplantation in adults: BK polyomavirus-associated nephropathy")
●Urinalysis and spot urine protein-to-creatinine ratio from a first or second morning void (and, if proteinuria is present, a 24-hour urine collection for protein)
●Ultrasound with Doppler of the kidney allograft
Management of immunosuppression — Modification of the maintenance immunosuppression regimen is frequently necessary prior to conception. The immunosuppressive medications used in transplantation pass through the maternal-fetal barrier to varying degrees, and all carry some risk in pregnancy [66]. The recommended maintenance immunosuppression regimen in pregnant transplant recipients is the combination of a CNI (either tacrolimus or cyclosporine), azathioprine, and low-dose prednisone. This regimen is considered safe in pregnancy. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients who become pregnant'.)
The use of mycophenolate mofetil/sodium and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) is contraindicated in pregnancy. Mycophenolate mofetil/sodium should be discontinued at least six weeks prior to conception because of reports of severe structural malformations associated with these agents [67]. Patients taking sirolimus should be advised to continue contraception for at least 12 weeks after sirolimus therapy has been stopped, while those taking everolimus should continue contraception for at least eight weeks after everolimus has been stopped. We typically switch all patients taking mycophenolate mofetil/sodium or an mTOR inhibitor to azathioprine. All patients undergoing adjustment of immunosuppression should have close monitoring of allograft function for a few months to ensure stability of the allograft. In addition, patients should be informed of the increased risk of rejection following changes in immunosuppression.
The safety of belatacept use during pregnancy is still unknown [68].
The true impact of the immunosuppressive regimen on the developing fetus is not well defined, and the long-term risks are unknown. There are possible concerns about neurocognitive disorders and immunologic disturbances in addition to structural congenital anomalies. Evidence on the effects of these agents on pregnancy outcomes are discussed elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)
Vaccination — Patients should ideally be vaccinated pretransplant against influenza, Pneumococcus, hepatitis B, human papillomavirus (HPV), and tetanus. If not, the patient should receive these vaccines before pregnancy. Live vaccines should not be administered posttransplant. (See "Immunizations during pregnancy" and "Immunizations in solid organ transplant candidates and recipients".)
Management during pregnancy
Antenatal testing for fetal aneuploidy — Antenatal testing for aneuploidy does not differ for kidney transplant recipients. (See "Down syndrome: Overview of prenatal screening".)
Monitoring during pregnancy — Kidney transplant recipients should be under the care of both a high-risk obstetrician and a transplant nephrologist and monitored closely throughout the pregnancy [31]. There are no consensus guidelines for monitoring this patient population.
Maternal monitoring — In the absence of data, we advise that patients be seen every two to four weeks throughout pregnancy and followed closely by both the transplant nephrologist and high-risk obstetrician. Monitoring should include ongoing surveillance for hypertension, preeclampsia, gestational diabetes, kidney allograft dysfunction, and infection.
The following assessments should be performed regularly at each visit:
●Blood pressure (in addition to daily monitoring at home) (see 'Hypertension' below and 'Preeclampsia' below)
●Serum creatinine, bicarbonate, and electrolytes (see 'Graft dysfunction' below and 'Rejection' below)
●Fasting blood glucose (see 'Gestational diabetes' below)
●Whole blood trough tacrolimus (or cyclosporine) levels
●Complete blood count and differential (see 'Anemia' below)
●Liver function tests
●Urinalysis (and a urine culture if the dipstick reveals white blood cells or nitrates) and spot urine protein-to-creatinine ratio (see 'Preeclampsia' below and 'Graft dysfunction' below and 'Gestational diabetes' below and 'Infections' below)
In addition, we perform the following tests at intervals as described below:
●Oral glucose tolerance testing to screen for gestational diabetes, performed every trimester (see 'Gestational diabetes' below)
●CMV PCR testing, performed every trimester (see 'Infections' below)
CNI (tacrolimus or cyclosporine) levels are monitored more closely during pregnancy since wide fluctuations are expected with pregnancy-related changes in the distribution and clearance of these drugs. CNI levels should generally be maintained at the same levels as they were prior to pregnancy.
Fetal assessment — Women with kidney transplant undergo similar antenatal testing to women without transplants, but the frequency is often increased because of the increased risk of fetal complications such as growth restriction.
In the first trimester, all women are offered screening for fetal aneuploidy, which is typically done with the full integrated test (first-trimester ultrasound measurement of nuchal translucency and serum pregnancy-associated plasma protein-A [PAPP-A] level, followed by second-trimester serum measurements of alpha-fetoprotein, unconjugated estriol, beta human chorionic gonadotropin [beta-hCG], and inhibin A), as this screening test offers the highest efficiency (balance of high detection rate and low false-positive rate). Cell-free fetal DNA testing to assess fetal aneuploidy is not advised in women with kidney transplants; cell-free DNA technology that measures donor DNA is being evaluated to identify graft rejection [69]. The components of fetal aneuploidy screening are presented in detail separately:
●(See "Down syndrome: Overview of prenatal screening".)
●(See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)
●(See "Prenatal screening for common aneuploidies using cell-free DNA".)
●(See "Sonographic findings associated with fetal aneuploidy".)
Separate from aneuploidy screening, all women are offered an ultrasound (sonogram) evaluation of the fetus at approximately 18 to 20 weeks gestation to assess fetal growth, placentation, and cervical length as well as evaluate for sonographically diagnosed congenital malformations. Based upon expert opinion, most women with kidney transplants then undergo repeat ultrasound measurement of fetal growth every three to four weeks. Additional testing consisting of weekly (or more frequent) nonstress tests begins at 32 to 34 weeks gestation or at the time FGR or oligohydramnios is diagnosed.
While women with kidney transplants are at increased risk for preterm birth, this risk is generally related to medical complications of pregnancy (eg, FGR, preeclampsia) that result in early delivery rather than cervical insufficiency or preterm labor. If a woman is diagnosed with a short cervix on second-trimester ultrasound, she is given the same counseling and offered the same interventions as her nontransplant pregnant peers. These issues are presented in detail in the following discussions:
●(See "Preterm birth: Risk factors, interventions for risk reduction, and maternal prognosis".)
●(See "Cervical insufficiency".)
●(See "Short cervix before 24 weeks: Screening and management in singleton pregnancies".)
●(See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth".)
Mode of delivery — Vaginal birth is the preferred mode of delivery if there are no obstetric contraindications. Although most transplant patients (over 50 percent) will undergo a cesarean delivery, there is no clear evidence to support its routine use, and it should be reserved for obstetric indications only.
●Vaginal birth – Vaginal birth should not be impaired, as the pelvic allograft does not obstruct the birth canal in most patients. The obstetrician should review operative notes from the transplant procedure to confirm location of the allograft and ureter. As the need for cesarean delivery for obstetric reasons is unpredictable, clinicians can perform an ultrasound in the third trimester to confirm the anatomic location of the graft in the setting of the gravid uterus. This information should be placed in the prenatal record to guide the surgeon if a cesarean delivery is required. Prophylactic antibiotics are warranted to avoid complications in these immunocompromised patients.
●Planned cesarean delivery – If a cesarean delivery is planned, obtaining preoperative input from a transplant surgeon is recommended to discuss potential surgical challenges and anatomic alternations relating to the transplant. In addition, surgical support from the transplant team should be available in case of complication. A keen awareness, both before and during surgery, of the anatomy and position of the transplanted kidney, the donor ureter, and the recipient's bladder in relationship to the gravid uterus is critical to avoid unintentional injury to these organs. Injury to the allograft is uncommon with cesarean delivery but has been reported following a Pfannenstiel (ie, horizontal) incision [70]. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Indications'.)
●Supporting data – Data to guide the safest mode of delivery for pregnancies after kidney transplant are limited. A registry study of 1435 female kidney transplant recipients with live births reported 68 percent underwent a trial of labor and 32 percent underwent scheduled cesarean delivery [71]. Among those who had a trial of labor, most (71 percent) had a vaginal delivery. Compared with scheduled cesarean delivery, a trial of labor was not associated with an increase in severe maternal morbidity and was associated with decreased odds of neonatal composite morbidity (adjusted odds ratio [OR] 0.52 and 0.36 for those resulting in cesarean and vaginal delivery, respectively). There was no difference in short-term graft loss based on mode of delivery.
●Stress-dose steroids – In uncomplicated pregnancies, the use of stress-dose glucocorticoids is not routinely recommended for kidney transplant recipients who are taking chronic glucocorticoids with prednisone doses of 5 mg/day or less for maintenance immunosuppression. Each pregnancy, however, should be individualized. We do administer stress-dose glucocorticoids in patients who are considered to be at high risk for adrenal insufficiency. Such patients include those who are experiencing a complicated pregnancy, are acutely ill, are hemodynamically unstable, and/or are likely to undergo surgery. (See "The management of the surgical patient taking glucocorticoids".)
Maternal complications — Significant potential complications in pregnant kidney transplant recipients include hypertension, preeclampsia, rejection, and infection. These and other obstetrical complications are discussed below.
Hypertension — Chronic (preexisting) hypertension is common in the pregnant kidney transplant population, with reported rates of 20 to 70 percent compared with approximately 1 to 5 percent of pregnant women in the general population [29,34]. Similar to pregnant nontransplant patients with chronic hypertension, hypertensive transplant recipients are at a higher risk for a variety of obstetrical complications including preeclampsia and eclampsia. In addition, the presence of prepregnancy hypertension in transplant patients has been associated with IUGR, low birth weight, miscarriage, and preterm delivery [29,32]. Thus, blood pressure should be closely monitored in kidney transplant recipients throughout pregnancy, both during clinic visits as well as by patients daily at home.
There are no definitive recommendations to guide the optimal blood pressure goal in pregnant kidney transplant recipients. The 2005 AST report on the Consensus Conference on Reproductive Issues and Transplantation states that blood pressure should be maintained close to normal [31], although it was noted that this target differs from higher blood pressure goals of existing guidelines for pregnant women with chronic hypertension without end-organ damage. In pregnant kidney transplant recipients with preexisting hypertension, our treatment target is a systolic pressure of 120 to 140 mmHg and diastolic pressure of 80 to 90 mmHg. In those who do not have preexisting hypertension, we initiate antihypertensive therapy when the blood pressure is consistently >140/90 mmHg. (See "Treatment of hypertension in pregnant and postpartum patients".)
The treatment of hypertension in pregnant transplant recipients is similar to that in pregnant nontransplant patients (see "Treatment of hypertension in pregnant and postpartum patients" and "Gestational hypertension"). Methyldopa, beta blockers (particularly labetalol), hydralazine, and dihydropyridine calcium channel blockers can all be safely used in hypertensive pregnant transplant patients. Nondihydropyridine calcium channel blockers (such as diltiazem and verapamil) can increase CNI levels and should be avoided if possible. ACE inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are associated with significant fetal risk and are contraindicated during pregnancy. Women who are taking any of these agents should discontinue them as soon as they are contemplating pregnancy and should be discouraged from conceiving for at least six weeks after discontinuation.
Preeclampsia — Kidney transplant recipients have an increased risk of preeclampsia compared with the general population [29,32,33,35,72]. The incidence of preeclampsia among kidney transplant recipients varies from 24 to 38 percent compared with 3 to 4 percent among the general population [29,33]. Preeclampsia is associated with significant maternal complications, including maternal death, increased risk of acute kidney injury, placental abruption, cerebral hemorrhage, hepatic failure, pulmonary edema, progression to eclampsia, and future risk of cardiovascular disease [73,74]. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Antepartum management and timing of delivery".)
Differentiating between preeclampsia and chronic hypertension in kidney transplant recipients can be challenging [74]. Clinicians should be aware that the natural decrease in blood pressure during pregnancy seen in the nontransplant population can be blunted in pregnant transplant patients. As mentioned above, urine protein excretion increases (up to threefold by the third trimester) during pregnancy due to hyperfiltration, making it difficult to distinguish this physiologic change from the proteinuria of preeclampsia, rejection, or other allograft injury, particularly in patients with preexisting proteinuria prior to pregnancy. (See 'Effect of pregnancy on graft function and outcomes' above.)
In addition, the typical rise in serum uric acid seen in nonpregnant transplant patients on CNIs may also make it more difficult to accurately establish the diagnosis of preeclampsia. Patients with preeclampsia, however, may have other suggestive laboratory findings such as evidence of hemolysis (eg, schistocytes on peripheral blood smear, elevated serum indirect bilirubin level), thrombocytopenia, and/or abnormal liver chemistries.
Low-dose aspirin, if not already prescribed, should be initiated to help prevent preeclampsia if there are no contraindications to its use [74,75]. The management of preeclampsia in pregnant kidney transplant recipients is similar to that in nontransplant patients and is discussed separately:
●(See "Preeclampsia: Prevention".)
●(See "Preeclampsia: Antepartum management and timing of delivery".)
Graft dysfunction — Patients who are found on routine testing to have an increase in serum creatinine or proteinuria should be promptly evaluated for allograft dysfunction. Common causes of allograft dysfunction among pregnant recipients include rejection, preeclampsia, volume depletion, and CNI toxicity; although less common, obstruction should also be considered. The evaluation and diagnosis of kidney allograft dysfunction in pregnant transplant recipients are similar to that in nonpregnant recipients. In some cases, a kidney allograft biopsy may be necessary to determine the cause of graft dysfunction. Although data are limited, ultrasound-guided kidney allograft biopsies are generally safe and well tolerated during pregnancy [76-78]. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Evaluation of acute allograft dysfunction'.)
Rejection — Reported rates of kidney allograft rejection are generally comparable between pregnant and nonpregnant kidney transplant recipients [28,29,35,57] (see "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Acute rejection'), although the risk of rejection may be higher in sensitized recipients (ie, panel reactive antibody [PRA] levels >0 percent) [79]. Risk factors for the development of rejection during pregnancy include an elevated prepregnancy serum creatinine level and fluctuating immunosuppressive drug levels caused by pregnancy-related changes in the distribution and clearance of these agents. As discussed above, we recommend closely monitoring CNI levels every two to four weeks and maintaining them at the same levels as they were prior to pregnancy. (See 'Monitoring during pregnancy' above.)
The clinical presentation of acute rejection in pregnant recipients is similar to that in nonpregnant recipients (see "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Clinical manifestations'). While most patients are asymptomatic, presenting only with an elevation in serum creatinine and/or proteinuria, those with more serious rejection may present with fever, oliguria, and graft pain or tenderness. Occasionally, the diagnosis may be missed in patients with subtle increases in serum creatinine and/or proteinuria, which can be masked by the normal pregnancy-related changes in GFR and proteinuria. Rejection must also be distinguished from preeclampsia (see 'Preeclampsia' above), which can also present with an increase in serum creatinine and proteinuria, and acute pyelonephritis, which can present with fever and graft tenderness. In patients who are suspected of having acute rejection, an ultrasound-guided kidney allograft biopsy should be performed to establish the diagnosis and guide treatment. This procedure is generally safe and well tolerated in pregnancy, although data regarding kidney allograft biopsies in pregnancy are limited [76-78].
Treatment options are limited because of the potential fetotoxicity of many of the agents normally used to treat acute rejection. Augmentation of baseline immunosuppression and glucocorticoids are generally safe and are considered first-line therapy for both acute T cell-mediated (TCMR) and antibody-mediated rejection (ABMR) in pregnant recipients. In patients who are suspected of having rejection but cannot undergo a kidney allograft biopsy, glucocorticoids can be given as empiric treatment for rejection. Rabbit antithymocyte globulin (rATG), which is used to treat more severe forms of acute TCMR, is not recommended during pregnancy, as there are insufficient data regarding risk to the fetus. Patients with acute ABMR can receive intravenous immune globulin (IVIG), rituximab, and plasmapheresis, which have been used to treat pregnant patients with idiopathic thrombocytopenic purpura and acquired thrombotic thrombocytopenic purpura, respectively. However, there are limited data on fetal risk when these drugs are used in kidney transplantation patients. (See "Thrombocytopenia in pregnancy", section on 'ITP therapies' and "Thrombocytopenia in pregnancy", section on 'Need for therapeutic plasma exchange or anti-complement therapy'.)
In patients with rejection who are treated with high-dose glucocorticoids, we do not routinely give antibiotic prophylaxis against Pneumocystis pneumonia (PCP), since the risk of PCP in this setting is low and trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, and inhaled pentamidine should all be avoided in pregnancy.
A more detailed discussion of the diagnosis and treatment of acute rejection is presented elsewhere:
●(See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)
●(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
Gestational diabetes — Some, but not all, studies have suggested higher rates of gestational diabetes in the pregnant transplant population. According to the TPR 2016 annual report, gestational diabetes can be seen in 8 percent of pregnant kidney transplant recipients taking a CNI, compared with approximately 2 to 5 percent of the general pregnant population [44]. Another study from the United Kingdom, however, reported rates of gestational diabetes in the transplant population that were comparable with that of the general population (approximately 3 percent) [33]. Factors that contribute to the development of gestational diabetes in transplant recipients include CNI use, glucocorticoids, obesity, and insulin resistance that can be seen after transplantation [29,34,46]. Uncontrolled blood glucose levels during the first trimester have been associated with a higher incidence of congenital anomalies. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Fetal and neonatal risks'.)
The management of gestational diabetes is discussed elsewhere. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention" and "Gestational diabetes mellitus: Glucose management and maternal prognosis" and "Gestational diabetes mellitus: Obstetric issues and management".)
Infections — The risk of infections is increased in pregnant kidney transplant recipients, primarily due to the use of immunosuppressive agents:
●Urinary tract infections – Bacterial urinary tract infections, which are not uncommon in normal pregnancy, occur more frequently in pregnant transplant recipients [80,81]. Because of the anatomy of the transplanted urinary tract, bladder infections are also more likely to progress to pyelonephritis during pregnancy. Pyelonephritis has been associated with adverse pregnancy outcomes, including preterm delivery and low birth weight. We recommend routinely screening all pregnant transplant recipients for asymptomatic bacteriuria every two to four weeks with a urinalysis, and, if evidence for infection is found, we obtain a urine culture [82]. We treat asymptomatic bacteriuria with antibiotics tailored to culture results. These issues are discussed in more detail elsewhere. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy" and "Urinary tract infection in kidney transplant recipients".)
●Cytomegalovirus – CMV infection has the potential for maternal-fetal transmission and must be closely monitored during pregnancy. In transplant recipients, documented CMV infection should not have occurred within the year prior to becoming pregnant (see 'Timing of conception' above). However, it is possible for the patient to acquire primary CMV infection or develop CMV reactivation during pregnancy. Patients at highest risk for reactivation are those who were seronegative at the time of transplant and who received a seropositive allograft. In all pregnant transplant recipients, we perform surveillance CMV PCR testing of the mother every trimester and as clinically indicated (eg, in the setting of new-onset leukopenia). Women with documented CMV infection during pregnancy are offered ultrasound surveillance for evidence of congenital CMV. (See "Cytomegalovirus infection in pregnancy".)
While nonpregnant women with CMV are treated with antiviral medications, data on CMV treatment in pregnancy are limited, and there are no therapies proven to prevent or treat congenital CMV infection. As a result, the Society for Maternal-Fetal Medicine advises treatment of pregnant women with antivirals or CMV hyperimmune globulin only as part of a research protocol [83]. If antiviral treatment is chosen, valganciclovir should not be used during pregnancy and/or prior to conception, because it is fetotoxic [66]. It is also recommended that ganciclovir and foscarnet be avoided during pregnancy. Further, treatment with hyperimmune globulin does not appear to be helpful [84]. The approach to treatment of pregnant and nonpregnant patients with CMV and kidney transplant is presented in detail separately:
•(See "Cytomegalovirus infection in pregnancy".)
●Other – While it is reasonable to assume that pregnant transplant recipients may be at greater risk of pregnancy-related infections such as chorioamnionitis and endometritis, supporting data are lacking. However, clinicians caring for pregnant kidney transplant patients should have a high index of suspicion if the patient presents with symptoms suggestive of infection.
Anemia — The Centers for Disease Control and Prevention (CDC) has defined anemia of pregnancy as hemoglobin levels of less than 11 g/dL in the first and third trimesters and less than 10.5 g/dL in the second trimester [85]. Although both plasma volume and red blood cell (RBC) mass increase during pregnancy as a result of increasing erythropoietin levels, the expansion in plasma volume is disproportionately greater than the increase in RBC mass, and, therefore, a dilutional anemia can occur. Transplant-specific factors such as iron deficiency, kidney function impairment, and immunosuppressive medications can also contribute to anemia in pregnant recipients. The diagnosis and management of anemia in pregnant transplant patients are similar to that in nonpregnant transplant patients. These issues are discussed separately. (See "Kidney transplantation in adults: Anemia and the kidney transplant recipient".)
Other obstetric complications — Patients with nausea and vomiting of pregnancy, and in particular those who develop hyperemesis gravidarum, may have decreased absorption of their immunosuppressive medications, possibly resulting in inadequate immunosuppression. Such patients should have more frequent monitoring of CNI levels while symptomatic. If symptoms are severe enough, inpatient admission for intravenous medications and hydration may be warranted. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation" and "Nausea and vomiting of pregnancy: Treatment and outcome".)
Postpartum care — After giving birth, most of the physiologic changes discussed above will normalize, although at indeterminate time intervals, and, therefore, CNI levels must be closely monitored and adjusted for several weeks postpartum. Other aspects of postpartum care do not differ among women with or without kidney transplants and are presented in detail elsewhere. (See "Overview of the postpartum period: Normal physiology and routine maternal care".)
Breastfeeding — Although available data are limited, we encourage breastfeeding in transplant recipients taking prednisone, azathioprine, and tacrolimus (or cyclosporine). Women should be fully informed about the potential and unknown risks of breastfeeding while on immunosuppressive medication. According to the TPR 2016 annual report, there has been a trend toward increasing breastfeeding practices between 1994 and 2016 [44]. (See "Infant benefits of breastfeeding" and "Safety of rheumatic disease medication use during pregnancy and lactation".)
There are reassuring data in transplant recipients taking prednisone, azathioprine, and either tacrolimus or cyclosporine for maintenance immunosuppression [44,86]. Exposure to these agents via breast milk is less than in utero and has not been associated with any reported adverse effects. The amount of drug ingested by breastfed infants is significantly less than the maternal dose, and levels detected in infants are minimal [33,86]. As an example, at maintenance doses of 5 to 10 mg daily, exposure to prednisone via breast milk is less than the endogenous glucocorticoid produced by an infant [86]. Similarly, levels of the active metabolites of azathioprine were undetectable among infants breastfed by mothers taking 1.2 to 2.1 mg/kg/day of azathioprine [87,88]. Similar findings have been noted in infants exposed to tacrolimus or cyclosporine during breastfeeding [89-91]. However, long-term follow-up of infants exposed to these immunosuppressive agents is not well documented. There are insufficient data for mycophenolic acid products (eg, mycophenolate mofetil), mTOR inhibitors, and belatacept; thus, breastfeeding should be avoided in patients taking these medications.
Postpartum contraception — It is critical to discuss the importance of birth spacing and postpartum contraception with all new mothers. (See "Postpartum contraception: Counseling and methods" and 'Female contraception' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of pregnancy" and "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●General principles – Abnormalities in both sexual and reproductive function are common among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Kidney transplantation helps to restore sexual and reproductive function in both females and males, although certain features of reproductive function may remain impaired. (See 'Introduction' above and 'Sexual function after transplantation' above.)
●Contraception – Sexual function typically improves in both females and males within a few weeks posttransplant. Women of childbearing age and men should receive counseling regarding contraception before undergoing transplantation and again at posttransplant clinic visits. We advise female transplant recipients to start contraception before they become sexually active since it is highly recommended that women avoid pregnancy during the first posttransplant year. Similarly, we advise that male recipients use contraception as soon as they become sexually active if they do not wish to father a pregnancy. (See 'Contraception' above.)
●Pregnancy
•Preconception care – In all kidney transplant candidates who desire to become pregnant, preconception counseling should be initiated during the pretransplant evaluation. Patients should be informed that pregnancy after transplantation is considered high risk and will require a multidisciplinary effort that involves both a high-risk obstetrician and nephrologist working closely together. (See 'Preconception care' above.)
•Timing of conception – The optimal time for conception after kidney transplantation is uncertain. We agree with the 2005 American Society of Transplantation (AST) guidelines discussing the medical criteria for proceeding with pregnancy. We advise women to wait a minimum of one year after transplantation to conceive. In addition, patients who have a history of recent (but not currently active) cytomegalovirus (CMV) disease are advised to wait at least six months and preferably one year from the resolution of disease before trying to conceive. (See 'Timing of conception' above.)
•Baseline evaluation – In all kidney transplant recipients who are considering becoming pregnant, we advise a multidisciplinary evaluation that includes a transplant nephrologist, a transplant surgeon, and a maternal-fetal medicine specialist (high-risk obstetrician). (See 'Baseline evaluation' above.)
•Management of immunosuppression – Modification of the maintenance immunosuppression regimen is frequently necessary prior to conception. The immunosuppressive medications used in transplantation pass through the maternal-fetal barrier to varying degrees, and all carry some risk in pregnancy. The recommended maintenance immunosuppression regimen in pregnant transplant recipients is the combination of a calcineurin inhibitor (CNI; either tacrolimus or cyclosporine), azathioprine, and low-dose prednisone. This regimen is considered safe in pregnancy. The use of mycophenolate mofetil/sodium and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) is contraindicated in pregnancy. All patients undergoing adjustment of immunosuppression should have close monitoring of allograft function for a few months to ensure stability of the allograft. In addition, patients should be informed of the increased risk of rejection following changes in immunosuppression. (See 'Management of immunosuppression' above.)
•Monitoring during pregnancy – We advise that patients be seen every two to four weeks throughout pregnancy and followed closely by both the transplant nephrologist and high-risk obstetrician. Monitoring should include ongoing surveillance for hypertension, preeclampsia, gestational diabetes, kidney allograft dysfunction, and infection. (See 'Monitoring during pregnancy' above.)
•Mode of delivery – Vaginal delivery is the preferred mode of delivery if there are no obstetric contraindications. Although most transplant patients (over 50 percent) will undergo a cesarean delivery, there is no clear evidence to support its routine use, and it should be reserved for obstetric indications only. If a cesarean delivery is planned, obtaining preoperative input from a transplant surgeon is recommended to discuss potential surgical challenges and anatomic alternations relating to the transplant. (See 'Mode of delivery' above.)
•Maternal complications – Significant potential complications in pregnant kidney transplant recipients include hypertension, preeclampsia, graft dysfunction, rejection, gestational diabetes, infection (particularly bacterial urinary tract infections and CMV infection), and anemia. (See 'Maternal complications' above.)
•Postpartum care – After giving birth, most of the pregnancy-related physiologic changes will normalize, although at indeterminate time intervals, and, therefore, CNI levels must be closely monitored and adjusted for several weeks postpartum. Other aspects of postpartum care do not differ among women with or without kidney transplants. Although available data are limited, we encourage breastfeeding in patients taking prednisone, azathioprine, and either tacrolimus or cyclosporine for maintenance immunosuppression. Women should be fully informed about the potential and unknown risks of breastfeeding while on immunosuppressive medication. (See 'Postpartum care' above.)
