Female renal transplant recipients experience benefits and require consideration of health issues specific to gender, including fertility, contraception, pregnancy, breast-feeding and malignancy surveillance.

While on renal replacement therapy, only 25% of premenopausal women reportedly menstruate, while after renal transplantation most experience menstrual cycle resumption, with regular cycles returning in 47% to 54% (1,2). Cycles may be irregular in 29% to 33% and amenorrhea persists in 0% to 16%. Among women who menstruate after transplant, resumption occurs within 1 to 12 months with an average of 5 months post. On average, it takes 7 months to recover regular cycles. Return of ovulatory cycles occurs with correction of uremia associated abnormal pituitary-hypothalamic hormonal function (3,4). Transplantation is also associated with a return of normal libido in 85% of women, compared to a pretransplant complete loss of libido in 70% (5).

As fertility is potentially restored as soon as 1 month after transplantation, patients of childbearing age require contraceptive counseling to prevent a mistimed pregnancy. Family planning clinics may not be comfortable providing contraception to medically complicated patients without input from the transplant team. Barrier contraception is most commonly used postrenal transplantation (1) and may be thought of as the safest option; however, unintended pregnancies occur in 3% to 14% of couples using only male condoms (6). Intrauterine devices are considered relatively contraindicated for use by transplant patients due to the risk of infection and a decrease in contraceptive effectiveness associated with immunosuppressive therapy (7). Oral contraception containing synthetic progestin and estrogen may be used in renal transplant recipients; however, it is not recommended in women over 35 years, smokers, or those with risk factors for cardiovascular disease (such as hypertension not normalized by antihypertensive medication), stroke or coronary artery disease, hypercoagulability risk factors, or a personal or strong family history of thromboembolic disease. In those without contraindications, oral contraception and related methods may be considered, as reviewed by Sucato and Murray (6). Hormonal contraception may increase levels of cyclosporine, tacrolimus and sirolimus; therefore, blood levels require monitoring. Similarly, plasma levels of corticosteroids may increase by up to 30% and require surveillance for steroid side effects such as hypertension, diabetes and weight gain (8). Antibiotic use may variably decrease the effectiveness of hormonal contraception, and while rifampin consistently impairs the effectiveness of oral contraception, other antibiotics do not have predictable interactions, and sulfamethoxazole-trimethoprim may actually increase plasma estrogens. A small risk of contraceptive failure does exist, and patients should be counseled toward
additional use of nonhormonal contraceptive methods during a course of antibiotic use (9). When required, emergency oral contraception can be provided to a renal transplant patient up to 5 days after unprotected intercourse and has no known contraindication, even in those who have contraindications to long-term hormonal contraceptive use (6). This should be followed with a pregnancy test within 2 weeks to confirm effectiveness.

As of 2003, there have been over 14,000 pregnancies in recipients of renal transplants, with registries in the United States and United Kingdom contributing significantly to current knowledge of pregnancy outcomes in this population (10,11). It is estimated that 2% of transplanted women of childbearing age become pregnant. Best practice guidelines have outlined criteria for considering pregnancy in renal transplant recipients (12). Patients are advised to wait at least 1 and preferably 2 years posttransplant prior to conceiving. This allows sufficient time to establish good general health, stable renal function, lower maintenance levels of immunosuppressant therapy and lower risk of cytomegalovirus infection. Intervals of shorter duration have less favorable outcomes for the newborn, recipient and graft, while intervals longer than 5 years result in similar outcomes to a 2-year interval (13). Other criteria to consider prior to conception include good graft function with creatinine <2 mg/dL (<177 μmol/L) preferably <1.5 g/dL (<133 μmol/L), no recent acute or ongoing rejection, normal blood pressure on minimal antihypertensive therapy, proteinuria <0.5 g/day and normal graft ultrasound. Further, the data regarding teratogenic effects of mycophenolate mofetil (MMF) and sirolimus are limited and these medications should be stopped 6 weeks prior to conception; other medications such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during the period of fetal organogenesis and must be stopped or substituted prior to the second trimester (12,14,15). Of pregnancies in transplant recipients, 20% miscarry or are terminated, and of the remainder, over 95% result in a live-born infant (13). Successful pregnancy outcome using in vitro fertilization in a renal transplant recipient has been described, using a modified hormonal protocol and with a lower number of embryos transferred to minimize the risks of hyperstimulation syndrome (16). In all cases, pregnancy should be diagnosed as early as possible, be considered high risk, and should be monitored by both an obstetrician and the transplant physician with delivery in a specialized center.

Normal pregnancy is characterized by dramatic physiologic alterations in blood pressure and renal hemodynamics. Vasodilatation, detectable by the first trimester, results in lower blood pressure, increased renal blood flow and an increased glomerular filtration rate (GFR) (17). In healthy women, GFR may increase by as much as 50%, resulting in decreases in serum creatinine of about 20% (18). Increased protein excretion is also observed in normal pregnancy, due in part to increased renal hemodynamics and possible alterations in glomerular permeability. This pregnancy-related increase in renal hemodynamics has also been observed in renal allografts. Women with good graft function prior to pregnancy experience an increase in 24-hour creatinine clearance of 10% to 60% from baseline by the tenth gestational week and larger increases are seen in those with better prepregnancy renal function. In late pregnancy, the 24- hour creatinine clearance goes on to decrease by approximately 30% in the pregnant transplant patient; this alone does not represent graft deterioration or lead to permanent impairment (19). Protein excretion may increase to three times nonpregnant levels in transplant patients (19); in one study the increase was to a mean of 1.1 g/24 h at delivery with resolution to baseline by 3 months postpartum (20).

Pregnancy is not thought to have a harmful effect on long-term graft function if it was acceptable prior to conception. When patients who lost their graft postpartum were compared with those with no graft loss, the graft loss group had higher mean serum creatinine levels prepregnancy (1.6 vs 1.3 mg/dL), during pregnancy (1.9 vs 1.2 mg/dL) and postpartum (2.3 vs 1.4 mg/dL) (21). Patients with a higher prepregnancy serum creatinine must be informed of an increased risk of postpartum graft loss.

Immunosuppression during pregnancy is a concern from the perspective of both maternal and fetal safety issues. Blood volume and volume of distribution increase during pregnancy, thus blood levels of immunosuppressive drugs are often lower, though there is no evidence that effective immunosuppression is inadequate if prepregnancy doses are used. Thus, it is probably not necessary to increase immunosuppression in response to lower drugs levels, although this question has never been tested in clinical trials.

Immunosuppressants are variably toxic to the fetus. Azathioprine crosses the placenta, but is not converted to its active metabolite 6-mercaptopurine by the immature fetal liver. This medication has been associated with intrauterine growth restriction (IUGR), and in women receiving only azathioprine and prednisone, the frequency of low birth weight (<2,500 g) was 39% and very low birth weight (<1,500 g) was 7.7% (22). Dose-related myelosuppression in the fetus may be prevented by maintaining a maternal leukocyte count greater than 7.5 cells/mL (23). The desired drug dose of azathioprine is 2 mg/day or less (14). Cyclosporine (Sandimmune) and cyclosporine emulsion (Neoral) are not associated with fetal malformations but are associated with IUGR; low birth weight is noted in 49.5% and very low birth weight in 17.8%. Although some recommend
dosing cyclosporine based on blood levels, with 4-5 gm/kg/day or less cited as the ideal (12,24), others argue that in stable patients remote from transplantation, increasing the dose of drug in response to lower levels during pregnancy is not necessary and may be associated with increased blood pressure and adverse renal effects. Prednisone crosses the placenta but has a low maternal to cord blood ratio, and adrenal insufficiency and thymic hypoplasia are unlikely if the prednisone dose is 15 mg/day or less (14,24). Doses of greater than 20 mg/day have been associated with maternal infection and placental abruption (25). Experience with tacrolimus in pregnancy is limited; it crosses the placenta but dose adjustment does not appear to be required (24). It has been associated with neonatal hyperkalemia and one case of anuria, but fetal malformations are rare. A case series of 39 mothers and 49 babies reported that 32% were delivered preterm (prior to 36 weeks), and 22% weighed less than 2,000 g (26). A separate case series of tacrolimus in 100 pregnancies noted preterm delivery in 57% (27). MMF has been reported to cause head and eye malformations in the offspring of rats. Reported experience in human pregnancies with MMF is limited to less than 15 patients. There have been birth defects in a few cases (28,29), but current data are insufficient to determine incidence of specific malformations, and its use is not recommended. Sirolimus causes delayed ossification in animal reproductive studies, and its use is contraindicated in humans until more data are available (12).